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In Vivo Fiber Optic Raman Spectroscopy of Muscle in Preclinical Models of Amyotrophic Lateral Sclerosis and Duchenne Muscular Dystrophy
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Research Article

In Vivo Fiber Optic Raman Spectroscopy of Muscle in Preclinical Models of Amyotrophic Lateral Sclerosis and Duchenne Muscular Dystrophy
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  • Maria Plesia
    Maria Plesia
    Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK
    More by Maria Plesia
  • Oliver A. Stevens
    Oliver A. Stevens
    Interface Analysis Centre, School of Physics, University of Bristol, Bristol BS8 1TL, UK
    More by Oliver A. Stevens
  • Gavin R. Lloyd
    Gavin R. Lloyd
    Phenome Centre Birmingham, University of Birmingham, Birmingham B15 2TT, UK
    Biophotonics Research Unit, Gloucestershire Hospitals NHS Foundation Trust, Gloucester GL1 3NN, UK
    More by Gavin R. Lloyd
  • Catherine A. Kendall
    Catherine A. Kendall
    Biophotonics Research Unit, Gloucestershire Hospitals NHS Foundation Trust, Gloucester GL1 3NN, UK
    More by Catherine A. Kendall
  • Ian Coldicott
    Ian Coldicott
    Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK
    More by Ian Coldicott
  • Aneurin J. Kennerley
    Aneurin J. Kennerley
    Department of Chemistry, University of York, York YO10 5DD, UK
    More by Aneurin J. Kennerley
  • Gaynor Miller
    Gaynor Miller
    Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2RX, UK
    More by Gaynor Miller
  • Pamela J. Shaw
    Pamela J. Shaw
    Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK
    Cross-Faculty Neuroscience Institute, University of Sheffield, Sheffield S10 2HQ, UK
    More by Pamela J. Shaw
  • Richard J. Mead
    Richard J. Mead
    Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK
    Cross-Faculty Neuroscience Institute, University of Sheffield, Sheffield S10 2HQ, UK
    More by Richard J. Mead
  • John C. C. Day
    John C. C. Day
    Interface Analysis Centre, School of Physics, University of Bristol, Bristol BS8 1TL, UK
    More by John C. C. Day
  • James J. P. Alix*
    James J. P. Alix
    Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK
    Cross-Faculty Neuroscience Institute, University of Sheffield, Sheffield S10 2HQ, UK
    *Email: [email protected]. Phone: 0114 215 9100.
    More by James J. P. Alix
    Orcidhttp://orcid.org/0000-0001-8391-9749
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ACS Chemical Neuroscience

Cite this: ACS Chem. Neurosci. 2021, 12, 10, 1768–1776
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https://doi.org/10.1021/acschemneuro.0c00794
Published May 5, 2021

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Abstract

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Neuromuscular diseases result in muscle weakness, disability, and, in many instances, death. Preclinical models form the bedrock of research into these disorders, and the development of in vivo and potentially translational biomarkers for the accurate identification of disease is crucial. Spontaneous Raman spectroscopy can provide a rapid, label-free, and highly specific molecular fingerprint of tissue, making it an attractive potential biomarker. In this study, we have developed and tested an in vivo intramuscular fiber optic Raman technique in two mouse models of devastating human neuromuscular diseases, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy (SOD1G93A and mdx, respectively). The method identified diseased and healthy muscle with high classification accuracies (area under the receiver operating characteristic curves (AUROC): 0.76–0.92). In addition, changes in diseased muscle over time were also identified (AUROCs 0.89–0.97). Key spectral changes related to proteins and the loss of α-helix protein structure. Importantly, in vivo recording did not cause functional motor impairment and only a limited, resolving tissue injury was seen on high-resolution magnetic resonance imaging. Lastly, we demonstrate that ex vivo muscle from human patients with these conditions produced similar spectra to those observed in mice. We conclude that spontaneous Raman spectroscopy of muscle shows promise as a translational research tool.

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Introduction

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The development of biomarkers to identify and track pathology in disorders of nerves and muscles (termed collectively, neuromuscular disorders) is central to efforts aimed at improving the lives of patients with these disorders. For example, better determination of disease state would allow clinicians to intervene earlier in disease course, while also improving clinical trial design. Neuromuscular diseases cause considerable mortality and morbidity with annual per patient costs typically in excess of $50 000; (1) as a result, these conditions are intensively researched in both preclinical and clinical settings. Two examples are amyotrophic lateral sclerosis (ALS) and Duchenne muscular dystrophy (DMD).
ALS is an incurable neurodegenerative disorder characterized by dysfunction and death of motor neurones in the brain and spinal cord, resulting in muscle weakness and death. (2) Interestingly, there is evidence that muscle pathology can occur independently of neurone loss and starts early in disease, (3,4) making muscle an attractive target for biomarker development. Preclinical models of the disease, usually mouse models, are crucial for understanding the pathobiology of the condition. Of those available, mice overexpressing the human mutant superoxide dismutase-1 (SOD1) gene are the best studied. (5) However, it is now recognized that a lack of sensitive biomarkers of disease has hampered ALS preclinical studies. (6)In vivo biomarkers presently in use include time-consuming gait analysis systems and phenotype scores, (7) expensive imaging tools, such as magnetic resonance imaging (MRI), (8) and challenging electrophysiological measures. (9)
While ALS is typically encountered in the second half of life, DMD is the most common, fatal muscle wasting disease of childhood with a birth prevalence of up to 19.5 per 100 000 live births. (10) It is an X-chromosome linked recessive disease caused by mutations (most commonly deletions) in the dystrophin gene. The ensuing absence/reduction in the cytoskeletal protein dystrophin results in muscle damage caused by repeated contractions. The mdx mouse is the most studied model of DMD. (11) The mdx phenotype is relatively mild, and as a result, there are few in vivo methods for studying disease onset and progression. Techniques such as wire hanging and grip strength struggle to identify the mild symptoms and are confounded by animal weight and behavior; (12) furthermore, some papers report using groups of up to 100 mice. (13) As a result, muscle force studies and histological studies are done after sacrificing the animals in order to definitively study muscle pathology. Sensitive in vivo detection of the disease state therefore remains an area of unmet need.
Spontaneous Raman spectroscopy uses laser light of a single frequency to stimulate the vibrational modes of molecules within a sample. When assessing tissue samples, the resulting Raman spectrum provides a “biochemical fingerprint”. (14) Biomedical applications of the technology are achieving sensitive, real-time tissue analysis across different tissues in cancer. (15−19) Pertinent to the present study, a recent report used stimulated Raman scattering microscopy in vivo to study nerve pathology in several mouse models of ALS. (20) In addition, spontaneous Raman has been used to study the spinal cord in the SOD1G93A model (21) and to examine fly models of human muscle diseases (myopathies). (22) While these studies require either technically challenging in vivo methods or rely on ex vivo analysis, they demonstrate the potential of the technique for the study of neuromuscular disorders. Indeed, there are few in vivo techniques capable of providing the molecular information obtained through Raman spectroscopy.
Our aim in this study was to develop and test a methodology for identifying muscle pathology invivo in different mouse models of fatal neuromuscular diseases. Detecting the weak Raman signal within living tissue poses technical challenges relating to miniaturization, targeting the light to the organ of interest, photoluminescence, and spectral artifacts from probe components (e.g., silica). We have overcome these challenges and developed a simple, minimally invasive fiber-optic-based method for the label-free study of living muscle in preclinical models of devastating human diseases. Together with data from ex vivo human patient samples, the results highlight the growing potential of Raman spectroscopy as a translational biomedical research tool.

Results and Discussion

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Using the SOD1G93A model of ALS and mdx model of DMD, we were able to record spectra from living muscles, which were clearly different from those of neighboring tissues such as blood and bone (Figure 1, Supporting Information Figure 1). Tentative peak assignments for all tissues can be found in Supporting Information Table 1. Mean muscle spectra, both with (Figures 1 and 2) and without (Supporting Information Figure 2) baseline subtraction, comprised peaks relating to the key constituents of muscle such as myosin, tropomyosin, and actin (Supporting Information Table 2). As expected, these prominent peaks were common to muscle from both murine models. Muscle histology demonstrated both the underlying similarity of the muscle and the pathological features of each model (Figure 2).

Figure 1

Figure 1. Intramuscular, in vivo, fiber optic Raman spectroscopy assessment. (a) A flowchart of the experiments. (b) A schematic of the fiber optic Raman system. (c) A mouse undergoing the procedure; the laser light can be appreciated within the hindleg as the camera used does not filter out the light. (d) Raman spectra obtained from muscle, blood, and bone. See Supporting Information Table 1 for tentative peak assignments and references.

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Figure 2

Figure 2. Intramuscular, in vivo Raman spectra and muscle histology. (a, b) Average spectra are shown for mdx and SOD1G93A, together with the relevant WT/NTg control for 30 and 90 days of age. Prominent peaks across the different groups are labeled (a and b). (c) Prominent Raman peaks in baseline subtracted spectra (present also in non-baseline subtracted spectra; Supporting Information Figure 2) and tentative peak assignments. See Supporting Information Table 1 for peak references. (d) Histological assessment at 30 days in mdx reveals necrotic fibers with inflammatory cells (arrow) and evidence of early regeneration (small myofibers with central nuclei, arrow heads). (e) The 90 day mdx muscle is characterized by regenerated myofibers, larger cells with central nuclei (arrow heads). (f) The 30 day SOD1G93A muscle appears normal. The myofibers have peripheral nuclei and a regular shape. (g, h) The 90 day SOD1G93A muscle displays evidence of denervation in the form of grouped atrophy (g, double arrow), small angular fibers (g, chevrons), and hypertrophic fibers (h, arrows) and centrally placed nuclei (g, h, arrowhead). (i) Normal myofibers from a 90 day WT mouse. Magnification for all images = x40, all scale bars = 100 μm. WT = wild type, NTg = nontransgenic.

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In order to test the ability of the in vivo intramuscular method to detect muscle disease and visualize more subtle differences in the spectra, we employed a range of multivariate techniques. Results for two-group PCA-LDA are shown in the main text (Table 1); data from PCA-QDA and PLS-DA are presented in Supporting Information Tables 3–5.
Table 1. Classification of Different Neuromuscular Disease Modelsa
 sensitivity (±SD)specificity (±SD)AUROC (±SD)
30 day SOD1G93A/ vs WT   
90 day SOD1G93A/ WT82.5 (±2.0)78.0 (±3.1)0.86 (±0.01)
30 day/90 day SOD1G93A85.5 (±3.8)86.6 (±2.5)0.92 (±0.01)
30 day female mdx/ WT71.3 (±3.1)65.7 (±2.6)0.76 (±0.02)
90 day female mdx/ WT91.6 (±2.2)76.4 (±3.0)0.91 (±0.01)
30 day/90 day mdx (female)95.6 (±1.8)71.6 (±3.4)0.92 (±0.01)
30 day female mdx/ SOD1G93A89.9 (±1.8)97.1 (±2.0)0.97 (±0.01)
90 day female mdx/ SOD1G93A93.5 (±2.6)73.3 (±1.7)0.89 (± 0.02)
a

The different comparisons are shown along with the classification performance parameters from PCA-LDA. In the 30 day SOD1 vs WT analysis, there were no significant PCs identified; thus, no model was generated.

In the SOD1G93A model, the 30 day time-point is prior to disease onset; by 90 days, the mice have established disease. (7,23,24) This was apparent in the classification performance. At 30 days, discrimination between transgenic (Tg) and non-transgenic (NTg) mice was not possible; however, at 90 days (Tg vs NTg) and between 30 and 90 day Tg mice, high classification performances (AUROC ≥ 0.86) were observed (Table 1, Supporting Information Figure 3). Examination of muscle histology is in keeping with these results, with no pathology evidence at 30 days but marked evidence of denervation at 90 days (Figure 2). The linear discriminant (LD) score plots for these comparisons are shown as histograms, together with the associated loading plots and tentative peak assignments (Figure 3 and Supporting Information Figure 4). Average and difference spectra demonstrated reduced concentrations of phenylalanine (ring breathing mode, 1000 cm–1), proteins (935, 1044, and 1444 cm–1), and the C═O stretching of amide I (1654 cm–1) in disease states (Supporting Information Figures 2 and 5).

Figure 3

Figure 3. Linear discriminant function histograms and loadings plots. (a) Linear discriminant function (LDF) histogram and associated loadings plot for the comparison between 90 day SOD1G93A and NTg mice. (b) Tentative peak assignments for the 90 day SOD1G93A vs NTg comparison. (c) LDF histogram and associated loadings plot for the comparison between 30-day mdx and WT mice. (d) LDF histogram and associated loadings plot for the comparison between 90 day mdx and WT mice. (e) Tentative peak assignments for the mdx vs WT comparisons. Peak references can be found in Supporting Information Table 1. Wn = wavenumber.

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The mdx mouse undergoes an acute onset of disease at approximately 30 days of age characterized by inflammation and necrosis, followed by highly effective regeneration (25) (Figure 2). We observed a high classification performance at both 30 and 90 days of age (Table 1, Supporting Information Figure 3). Comparison of the mdx and SOD1G93A models at both 30 and 90 days of age demonstrated accurate identification (AUROC > 0.89) of each disease model (Table 1).
Examination of the LD loadings for the different analyses revealed a key spectral fingerprint for muscle health across both mouse models, comprising similar peaks to those identified in the difference spectra (Figure 3, Supporting Information Figures 2 and 4). Tentative assignments are given in Figure 3. When comparing SOD1G93A and mdx with each other at 30 days, a similar picture emerges, with key muscle health peaks attributed to the presymptomatic SOD1G93A muscle (Supporting Information Figures 2 and 6). At 90 days, when muscle pathology in both models is established, mdx mice manifest greater losses in protein-related peaks, and a more complex picture emerges in the multivariate analysis, with shifts in proteins and lipids across both groups seen (Supporting Information Figure 6). Lastly, four group models, comprising 30- and 90-day-old disease-only mice (i.e., SOD1G93A and mdx mice), also demonstrated a high classification performance (Supporting Information Figures 7 and 8).
If invivo Raman spectroscopy of muscle is to be used in studies with models such as SOD1G93A and mdx, then it is important that motor function is not compromised by the procedure. Motor function testing utilizing the rotarod demonstrated no significant change in performance at 1 day after either a Raman or a sham procedure, for any of the disease groups tested (Figure 4; Supporting Information Figure 9). In the subset of mice undergoing a further recording at 2 weeks postprocedure, no change in performance was seen in mdx (Figure 4). A significant decline in performance was seen for the 90 day SOD1G93A group (Figure 4c). Our previous work has demonstrated a prominent decline in disease-related motor performance between 90 and 114 days, (7) and so we also tested a cohort of mice that did not undergo either the Raman or sham procedure (Figure 4d). No significant difference in rotarod performance was seen across Raman, sham, and no procedure groups, indicating a disease-related performance decline. In addition, a comprehensive assessment of gait using the catwalk gait analysis system did not demonstrate any systematic effect (Supporting Information Figure 10).

Figure 4

Figure 4. Post-in vivo Raman spectroscopy motor performance. Rotarod performance for 30 day SOD1G93A mice for both Raman (a) and sham (b) experiments. At 90 days of age, a significant decline in performance was seen two weeks postprocedure (c). However, there was no difference in rotarod performance at this final age (104 days) between mice undergoing Raman, sham, and no procedure (d), suggesting a disease-related decline. No change in rotarod performance was seen at either 30 days (e, f) or 90 days (g, h) in the mdx mice. ** = P < 0.01. d = day; wks = weeks.

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Assessment for subclinical muscle injury was performed using high-resolution MRI. WT mice were used to avoid pathological changes relating to disease complicating image interpretation. In mice undergoing MRI at 6 h post-Raman (n = 3), we observed subtle T2 hyperintensities in the gastrocnemius muscles around the site of needle placement (Figure 5). In one mouse, similar changes were apparent at 2 days; no changes were seen in any mice at 2 weeks postprocedure. No signal changes were apparent in mice undergoing the sham procedure (Figure 5). These results may suggest that laser exposure induces a degree of thermal injury, although we were only able to scan a small number of mice in both the Raman and sham groups.

Figure 5

Figure 5. 7T MRI evaluation of muscle that has undergone in vivo Raman spectroscopy. (a) Axial MRI (ex vivo) from NTg (healthy) mice. Muscles were studied at three different time points post-Raman measurement. Each panel represents a different mouse. The yellow arrows denote high T2 signal which may be due to postprocedure edema. (b) Axial MRI (ex vivo) from two time points following a sham procedure. Each panel represents a different mouse.

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Finally, to explore the translation potential of fiber optic Raman spectroscopy we undertook ex vivo recordings from human muscle samples obtained from patients with ALS (n = 3) and DMD (n = 3) (Figure 6). The ex vivo human spectra appeared similar to the in vivo mouse spectra. The limited availability of muscle tissue from children with muscle diseases means that a robust assessment of the classification performance between ALS and DMD human samples is not possible with these data. However, differences in the spectra were apparent, even without chemometric analysis (see also Supporting Information Figure 11).

Figure 6

Figure 6. Human muscle spectra (ex vivo) and corresponding in vivo mouse model spectra. (a) Average ex vivo muscle spectra from patients with MND (orange) and in vivo spectra from 90 day-old SOD1G93A mice (blue). (b) Average ex vivo muscle spectra from patients with DMD (orange) and in vivo spectra from 90 day-old mdx mice (blue).

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Our results demonstrate that in vivo fiber optic Raman spectroscopy can identify muscle pathology in murine models of human neuromuscular disease. The simplicity of Raman spectroscopy offers potential as a translational biomarker in both preclinical and clinical studies.
In analyses based on spectral differences (both simple subtraction and multivariate statistics), a key fingerprint for muscle health emerged. Peaks associated with phenylalanine (1000 cm–1) and α-helical protein content (e.g., 935, 1300-5, 1654 cm–1) were seen to reduce in disease states, including with progression of the disease. These protein changes may represent the relative loss of the long α-helical structures within muscle proteins, (26) as well as membrane phospholipids and proline, which act to enhance protein synthesis in muscle. (27) When comparing fly models of different human muscle diseases, Gautam et al. also observed a reduction in α-helix content in the disease models. (22) Of note, transcriptome studies in SOD1 mouse models of both ALS and DMD indicate upregulation of genes associated with protein degradation. (28−30) As α-helices are the most abundant structures in proteins, our results would be in keeping protein breakdown. In addition, oxidative stress, known to occur in the muscles of both mouse models, (31,32) has been shown to cause similar structural changes in different tissues/cells. (33−35)
Our methodology did not appear to result in any functional impairment using two standard methods of monitoring skeletal muscle function (rotarod and catwalk). In the catwalk analyses, a small number of postprocedure changes were observed, but these were not consistent. While catwalk is commonly used in studies concerning muscle injury and neuromuscular function, there are concerns regarding the reliability of the tests. (36) Some authors suggest only using a certain set of parameters, none of which manifested changes in our analyses. Similarly, we did not observe changes in gait parameters documented by others after muscle injury. (37,38) Overall, the lack of effect on motor function suggests that our approach can be incorporated into preclinical studies.
MRI studies demonstrated a transient change in T2 muscle signal postprocedure, which likely reflects edema cause by a resolving inflammatory response. In murine models of muscle injury and human subjects after intramuscular injection, similar time-limited changes in T2 signal intensity have been reported. (39−41) We did attempt to undertake in vivo imaging with a view to complete serial scans in the same mouse, which would have allowed more mice to be imaged; however, long scan times failed to produce the desired resolution (data not shown).
Our approach has several strengths that make it appealing for use in future preclinical studies. The procedure can be performed under a standard anesthetic protocol and is quick to perform. The collection of Raman spectra took no more than 3 min; this contrasts to recording times of around 1 h required for in vivo MRI. (8) Unlike new in vivo confocal imaging approaches, (42) our Raman spectroscopy method requires no tissue preparation or prelabeling.
In the present study, we made several compromises in the in vivo recording protocol to reduce the potential for tissue damage. Probe diameter was limited to 0.5 mm to reduce the trauma of the insertion. A larger probe with a higher etendue for light collection may facilitate a better signal-to-noise ratio, as might longer acquisition times and/or increased laser power. However, the latter two would increase thermal energy exposure and possibly exacerbate any tissue injury. In this regard it is encouraging that in vivo human studies across a range of tissues and using a variety of laser powers/probe sizes have not reported any significant tissue damage. (43,19,44) The fiber optic probe, operating at 60 mW laser power, has a maximum power density of 7.6 Wmm–2 at the distal tip, which is orders of magnitude below that typically used in conventional microscope-based systems. Furthermore, we only observed a transient tissue damage known to occur with procedures involving needle penetration of muscle. (40,45) The relative size of the needle to the muscle being studied is also much larger in mice than would be the case in most human muscles. Thus, in vivo human recordings should be technically and practically feasible, although as with any new application of biophotonics, widespread uptake of the technique is likely to take time to realize.
In summary, our results demonstrate the use of minimally invasive fiber-optic spontaneous Raman spectroscopy for the in vivo assessment of muscle in preclinical models of neuromuscular diseases. The technique accurately distinguished between different types and stages of muscle disease. No impairment of motor function was seen, making it amenable for incorporation into preclinical drug studies. Analysis of ex vivo human muscle specimens demonstrated the translational potential of the technique. Spontaneous Raman spectroscopy of muscle is a promising biomarker for devastating human neuromuscular diseases.

Methods

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Details on the animal models used, human muscle samples, MRI methodology, histology, and motor function assessments can be found in the Supporting Information. Further details on data analysis can also be found in the Supporting Information.

In Vivo Fiber Optic Raman Spectroscopy

Mice were anaesthetised using 2% isoflurane and positioned on a heat pad to maintain body temperature. The hindlimbs were shaved, and the fiber optic needle probe was inserted into the medial and lateral heads of both gastrocnemius muscles (Figure 1). The total time under anesthesia was 4 min.
The novel miniature (0.5 mm) fiber optic Raman probe was housed inside a standard 21 guage hypodermic needle. The design was based on that presented by Day and Stone (46) and is shown schematically in Figure 1. A 830 nm semiconductor laser (Innovative Photonics Solutions) was used to provide a superior signal/noise ratio due to lower background fluorescence than shorter wavelength excitation. (19,47) In line filters were placed approximately 15 cm from the probe tip to reduce the effect of Raman and fluorescence generated in the delivery fibers. These comprised a bandpass filter on the excitation delivery fiber and a long-pass filter on the collection fiber (Semrock Inc.). All fibers were low OH, with a 105 μm silica core of NA 0.22. The probe was optically matched to the spectrometer (Raman Explorer Spectrograph, Headwall Photonics, Inc. and iDus 420BR-DD CCD camera, Andor Technology, Ltd.) for optimum efficiency. A robust Raman signal of interest was recorded through a 40 s exposure consisting of 10 × 4 s epochs which were averaged. Beam divergence, with a 60 mW laser power at the probe tip and a near-infrared laser, reduces the potential for tissue damage through a lower energy density. (14) Spectra from PTFE were acquired for wavenumber calibration. Following PTFE offset correction, an air background signal was recorded to check consistency across measurements. Spectra were acquired over a 2 year period with multiple groups of mice (i.e., both SOD1G93A/mdx and different ages) tested at each sitting to avoid any unknown factors confounding the results of a single group. All comparisons between disease and WT/NTg used n = 16 mice in each group. For assessment of muscle injury, a sham procedure was also used in which mice underwent the same procedure as above, with the exception that the laser was not switched on.

Data Analysis

Over 6000 spectra were available for analysis, which was done using MATLAB (MATLAB R2019b The MathWorks, Inc., Natick, MA). Raw spectra were interpolated between 900 and 1800 cm–1, normalized using standard normal variate normalization (SNV) (48) and mean-centered. Spectra were windowed between 900 and 1800 cm–1, as outside this region, the spectra were dominated by peaks and background related to the silica in the optical fibers (before 900 cm–1) or consisted of uninformative noise (after 1800 cm–1). Human tissue spectra (but not mouse spectra) were smoothed using a fifth order Savitzky–Golay filter (49) (window width = 15 data points).
Principal component analysis-fed linear discriminant analysis (PCA-LDA), principal component analysis-fed quadratic discriminant analysis (PCA-QDA), and partial least-squares discriminant analysis (PLS-DA) classification models were generated for all the data sets. The first 10 principal components (PCs) were interrogated for significant between group differences using student’s t test or analysis of variance (ANOVA), followed by false discovery rate (fdr) correction (Q = 0.05). Those PCs demonstrating significant differences between the groups under assessment were used as inputs to LDA. Linear discriminant functions (LDFs) using PCs identified as statistically significant were plotted in order to illustrate the important peaks for spectral classification. For PLS-DA (Supporting Information), selection of the optimal number of latent variables was done by increasing their number until prediction accuracy no longer increased. The classification performance of the different models was validated using repeated leave-some-mice-out-cross-validation (RLSMOCV). The analysis was repeated 100 times using randomly selected combinations of left-out-mice. Area under the receiver operating characteristic curve (AUROC) was calculated. These curves plot the true positive rate (sensitivity) against the false positive rate (1-sensitivity) and illustrate the ability of a classifier to separate classes. As performance across the different classification algorithms was similar, PCA-LDA results are shown in the main text using linear discriminant loadings plots. (14) These combine the information from relevant PCs, thus providing a more comprehensive exploration of the spectral features underlying class differentiation than single PC or latent variable loadings plots.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschemneuro.0c00794.

  • Additional methods; tabulation of tentative peak assignments and references; prominent Raman peaks; two-group classification for SOD1G93A mice; two-group classification for mdx mice; two-group classification between SOD1G93A and mdx mice; PC1 scores and loadings plots; average and difference spectra; ROC curves; linear discriminant function histograms and loadings plots; phenylalanine and α-helical protein content in disease comparisons; linear discriminant function histograms and loadings plots; supervised four group classification model results; unsupervised four group hierarchical clustering; additional rotarod data following Raman or sham procedures; catwalk gait analysis following the Raman procedure; and human ALS and DMD Raman spectra and tentative peak assignments. (PDF)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

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  • Corresponding Author
    • James J. P. Alix - Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK;  Cross-Faculty Neuroscience Institute, University of Sheffield, Sheffield S10 2HQ, UK;  Orcidhttp://orcid.org/0000-0001-8391-9749;  Email: [email protected]
  • Authors
    • Maria Plesia - Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK
    • Oliver A. Stevens - Interface Analysis Centre, School of Physics, University of Bristol, Bristol BS8 1TL, UK
    • Gavin R. Lloyd - Phenome Centre Birmingham, University of Birmingham, Birmingham B15 2TT, UK;  Biophotonics Research Unit, Gloucestershire Hospitals NHS Foundation Trust, Gloucester GL1 3NN, UK
    • Catherine A. Kendall - Biophotonics Research Unit, Gloucestershire Hospitals NHS Foundation Trust, Gloucester GL1 3NN, UK
    • Ian Coldicott - Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK
    • Aneurin J. Kennerley - Department of Chemistry, University of York, York YO10 5DD, UK
    • Gaynor Miller - Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2RX, UK
    • Pamela J. Shaw - Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK;  Cross-Faculty Neuroscience Institute, University of Sheffield, Sheffield S10 2HQ, UK
    • Richard J. Mead - Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK;  Cross-Faculty Neuroscience Institute, University of Sheffield, Sheffield S10 2HQ, UK
    • John C. C. Day - Interface Analysis Centre, School of Physics, University of Bristol, Bristol BS8 1TL, UK
  • Funding

    The work was support by an Academy of Medical Sciences Starter grant (JJPA, SGL015\1001) and a Medical Research Council Confidence in Concept award (J.J.P.A., J.C.D., R.J.M., P.J.S., MC_PC_15034). P.J.S. is supported as a National Institute for Health Research (NIHR) Senior Investigator (NF-SI-0617-10077) and by the NIHR Sheffield Biomedical Research Centre (IS-BRC-1215-20017).

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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We thank the staff of the Biological Services Unit, University of Sheffield, for their dedicated support. We acknowledge the Oxford Brain Bank, supported by the Medical Research Council (MRC), Brains for Dementia Research (BDR) (Alzheimer Society and Alzheimer Research UK), Autistica, UK, and the NIHR Oxford Biomedical Research Centre.

Abbreviations

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ALS

amyotrophic lateral sclerosis

AUROC

area under the receiver operating characteristic curve

DMD

Duchenne muscular dystrophy

FDR

false discovery rate

LD

linear discriminant

LDF

linear discriminant function

MRI

magnetic resonance imaging

NTg

nontransgenic

PC

principal component

PCA

principal component analysis

PCA-LDA

principal component analysis fed linear discriminant analysis

PCA-QDA

principal component analysis fed quadratic discriminant analysis

PLS-DA

partial least-squares-discriminant analysis

SNV

standard normal variate

SOD1

superoxide dismutase-1

Tg

transgenic

Wn

wavenumber

References

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This article references 49 other publications.

  1. 1
    Larkindale, J., Yang, W., Hogan, P. F., Simon, C. J., Zhang, Y., Jain, A., Habeeb-Louks, E. M., Kennedy, A., and Cwik, V. A. (2014) Cost of illness for neuromuscular diseases in the United States. Muscle Nerve 49 (3), 431– 438,  DOI: 10.1002/mus.23942
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    Cost of illness for neuromuscular diseases in the United States
    Larkindale Jane; Yang Wenya; Hogan Paul F; Simon Carol J; Zhang Yiduo; Jain Anjali; Habeeb-Louks Elizabeth M; Kennedy Annie; Cwik Valerie A
    Muscle & nerve (2014), 49 (3), 431-8 ISSN:.
    INTRODUCTION: We conducted a comprehensive study of the costs associated with amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD). and myotonic dystrophy (DM) in the U.S. METHODS: We determined the total impact on the U.S. economy, including direct medical costs, nonmedical costs, and loss of income. Medical costs were calculated using a commercial insurance database and Medicare claims data. Nonmedical and indirect costs were determined through a survey of families registered with the Muscular Dystrophy Association. RESULTS: Medical costs were driven by outpatient care. Nonmedical costs were driven by the necessity to move or adapt housing for the patient and paid caregiving. Loss of income correlated significantly with the amount of care needed by the patient. CONCLUSIONS: We calculated the annual per-patient costs to be $63,693 for ALS, $50,952 for DMD, and $32,236 for DM. Population-wide national costs were $1,023 million (ALS), $787 million (DMD), and $448 million (DM).
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    Hardiman, O., Al-Chalabi, A., Chio, A., Corr, E. M., Logroscino, G., Robberecht, W., Shaw, P. J., Simmons, Z., and van den Berg, L. H. (2017) Amyotrophic lateral sclerosis. Nat. Rev. Dis Primers 3, 17071,  DOI: 10.1038/nrdp.2017.71
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    Nature reviews. Disease primers (2017), 3 (), 17071 ISSN:.
    Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is characterized by the degeneration of both upper and lower motor neurons, which leads to muscle weakness and eventual paralysis. Until recently, ALS was classified primarily within the neuromuscular domain, although new imaging and neuropathological data have indicated the involvement of the non-motor neuraxis in disease pathology. In most patients, the mechanisms underlying the development of ALS are poorly understood, although a subset of patients have familial disease and harbour mutations in genes that have various roles in neuronal function. Two possible disease-modifying therapies that can slow disease progression are available for ALS, but patient management is largely mediated by symptomatic therapies, such as the use of muscle relaxants for spasticity and speech therapy for dysarthria.
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    Kostic, V., Jackson-Lewis, V., de Bilbao, F., Dubois-Dauphin, M., and Przedborski, S. (1997) Bcl-2: prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis. Science 277 (5325), 559– 562,  DOI: 10.1126/science.277.5325.559
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    Bcl-2: prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis
    Kostic, Vladimir; Jackson-Lewis, Vernice; de Bilbao, Fabienne; Dubois-Dauphin, Michel; Przedborski, Serge
    Science (Washington, D. C.) (1997), 277 (5325), 559-562CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Mutations in the gene encoding copper/zinc superoxide dismutase enzyme produce an animal model of familial amyotrophic lateral sclerosis (FALS), a fatal disorder characterized by paralysis. Overexpression of the proto-oncogene bcl-2 delayed onset of motor neuron disease and prolonged survival in transgenic mice expressing the FALS-linked mutation in which glycine is substituted by alanine at position 93. It did not, however, alter the duration of the disease. Overexpression of bcl-2 also attenuated the magnitude of spinal cord motor neuron degeneration in the FALS-transgenic mice.
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    Jenkins, T. M., Alix, J. J. P., David, C., Pearson, E., Rao, D. G., Hoggard, N., O’Brien, E., Baster, K., Bradburn, M., Bigley, J. (2018) Imaging muscle as a potential biomarker of denervation in motor neuron disease. J. Neurol., Neurosurg. Psychiatry 89 (3), 248– 255,  DOI: 10.1136/jnnp-2017-316744
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    Imaging muscle as a potential biomarker of denervation in motor neuron disease
    Jenkins Thomas M; Alix James J P; David Charlotte; Pearson Eilish; McDermott Christopher J; Shaw Pamela J; Jenkins Thomas M; McDermott Christopher J; Shaw Pamela J; Alix James J P; Rao D Ganesh; Hoggard Nigel; Bigley Julia; Wilkinson Iain D; O'Brien Eoghan; Baster Kathleen; Bradburn Michael
    Journal of neurology, neurosurgery, and psychiatry (2018), 89 (3), 248-255 ISSN:.
    OBJECTIVE: To assess clinical, electrophysiological and whole-body muscle MRI measurements of progression in patients with motor neuron disease (MND), as tools for future clinical trials, and to probe pathophysiological mechanisms in vivo. METHODS: A prospective, longitudinal, observational, clinicoelectrophysiological and radiological cohort study was performed. Twenty-nine patients with MND and 22 age-matched and gender-matched healthy controls were assessed with clinical measures, electrophysiological motor unit number index (MUNIX) and T2-weighted whole-body muscle MRI, at first clinical presentation and 4 months later. Between-group differences and associations were assessed using age-adjusted and gender-adjusted multivariable regression models. Within-subject longitudinal changes were assessed using paired t-tests. Patterns of disease spread were modelled using mixed-effects multivariable regression, assessing associations between muscle relative T2 signal and anatomical adjacency to site of clinical onset. RESULTS: Patients with MND had 30% higher relative T2 muscle signal than controls at baseline (all regions mean, 95% CI 15% to 45%, p<0.001). Higher T2 signal was associated with greater overall disability (coefficient -0.009, 95% CI -0.017 to -0.001, p=0.023) and with clinical weakness and lower MUNIX in multiple individual muscles. Relative T2 signal in bilateral tibialis anterior increased over 4 months in patients with MND (right: 10.2%, 95% CI 2.0% to 18.4%, p=0.017; left: 14.1%, 95% CI 3.4% to 24.9%, p=0.013). Anatomically, contiguous disease spread on MRI was not apparent in this model. CONCLUSIONS: Whole-body muscle MRI offers a new approach to objective assessment of denervation over short timescales in MND and enables investigation of patterns of disease spread in vivo. Muscles inaccessible to conventional clinical and electrophysiological assessment may be investigated using this methodology.
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    Van Damme, P., Robberecht, W., and Van Den Bosch, L. (2017) Modelling amyotrophic lateral sclerosis: progress and possibilities. Dis. Models &amp; Mech. 10 (5), 537– 549,  DOI: 10.1242/dmm.029058
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    Scott, S., Kranz, J. E., Cole, J., Lincecum, J. M., Thompson, K., Kelly, N., Bostrom, A., Theodoss, J., Al-Nakhala, B. M., Vieira, F. G. (2008) Design, power, and interpretation of studies in the standard murine model of ALS. Amyotrophic Lateral Scler. 9 (1), 4– 15,  DOI: 10.1080/17482960701856300
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    Design, power, and interpretation of studies in the standard murine model of ALS
    Scott, Sean; Kranz, Janice E.; Cole, Jeff; Lincecum, John M.; Thompson, Kenneth; Kelly, Nancy; Bostrom, Alan; Theodoss, Jill; Al-Nakhala, Bashar M.; Vieira, Fernando G.; Ramasubbu, Jeyanthi; Heywood, James A.
    Amyotrophic Lateral Sclerosis (2008), 9 (1), 4-15CODEN: ALSMC3; ISSN:1748-2968. (Informa Healthcare)
    Identification of SOD1 as the mutated protein in a significant subset of familial amyotrophic lateral sclerosis (FALS) cases has led to the generation of transgenic rodent models of autosomal dominant SOD1 FALS. Mice carrying 23 copies of the human SOD1G93A transgene are considered the std. model for FALS and ALS therapeutic studies. To date, there have been at least 50 publications describing therapeutic agents that extend the lifespan of this mouse. However, no therapeutic agent besides riluzole has shown corresponding clin. efficacy. We used computer modeling and statistical anal. of 5429 SOD1G93A mice from our efficacy studies to quantify the impact of several crit. confounding biol. variables that must be appreciated and should be controlled for when designing and interpreting efficacy studies. Having identified the most crit. of these biol. variables, we subsequently instituted parameters for optimal study design in the SOD1G93A mouse model. We retested several compds. reported in major animal studies (minocycline, creatine, celecoxib, sodium phenylbutyrate, ceftriaxone, WHI-P131, thalidomide, and riluzole) using this optimal study design and found no survival benefit in the SOD1G93A mouse for any compds. (including riluzole) administered by their previously reported routes and doses. The presence of these uncontrolled confounding variables in the screening system, and the failure of these several drugs to demonstrate efficacy in adequately designed and powered repeat studies, leads us to conclude that the majority of published effects are most likely measurements of noise in the distribution of survival means as opposed to actual drug effect. We recommend a min. study design for this mouse model to best address and manage this inherent noise and to facilitate more significant and reproducible results among all labs. employing the SOD1G93A mouse.
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    Mead, R. J., Bennett, E. J., Kennerley, A. J., Sharp, P., Sunyach, C., Kasher, P., Berwick, J., Pettmann, B., Battaglia, G., Azzouz, M. (2011) Optimised and rapid pre-clinical screening in the SOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis (ALS). PLoS One 6 (8), e23244  DOI: 10.1371/journal.pone.0023244
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    Optimised and rapid pre-clinical screening in the SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis (ALS)
    Mead, Richard J.; Bennett, Ellen J.; Kennerley, Aneurin J.; Sharp, Paul; Sunyach, Claire; Kasher, Paul; Berwick, Jason; Pettmann, Brigitte; Battaglia, Guiseppe; Azzouz, Mimoun; Grierson, Andrew; Shaw, Pamela J.
    PLoS One (2011), 6 (8), e23244CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    The human SOD1G93A transgenic mouse has been used extensively since its development in 1994 as a model for amyotrophic lateral sclerosis (ALS). In that time, a great many insights into the toxicity of mutant SOD1 have been gained using this and other mutant SOD transgenic mouse models. They all demonstrate a selective toxicity towards motor neurons and in some cases features of the pathol. seen in the human disease. These models have two major drawbacks. Firstly the generation of robust preclin. data in these models has been highlighted as an area for concern. Secondly, the amt. of time required for a single preclin. expt. in these models (3-4 mo) is a hurdle to the development of new therapies. We have developed an inbred C57BL/6 mouse line from the original mixed background (SJL×C57BL/6) SOD1G93A transgenic line and show here that the disease course is remarkably consistent and much less prone to background noise, enabling reduced nos. of mice for testing of therapeutics. Secondly we have identified very early readouts showing a large decline in motor function compared to normal mice. This loss of motor function has allowed us to develop an early, sensitive and rapid screening protocol for the initial phases of denervation of muscle fibers, obsd. in this model. We describe multiple, quant. readouts of motor function that can be used to interrogate this early mechanism. Such an approach will increase throughput for reduced costs, while reducing the severity of the exptl. procedures involved.
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    Caron, I., Micotti, E., Paladini, A., Merlino, G., Plebani, L., Forloni, G., Modo, M., and Bendotti, C. (2015) Comparative Magnetic Resonance Imaging and Histopathological Correlates in Two SOD1 Transgenic Mouse Models of Amyotrophic Lateral Sclerosis. PLoS One 10 (7), e0132159  DOI: 10.1371/journal.pone.0132159
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    Mancuso, R., Santos-Nogueira, E., Osta, R., and Navarro, X. (2011) Electrophysiological analysis of a murine model of motoneuron disease. Clin. Neurophysiol. 122 (8), 1660– 1670,  DOI: 10.1016/j.clinph.2011.01.045
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    Electrophysiological analysis of a murine model of motoneuron disease
    Mancuso Renzo; Santos-Nogueira Eva; Osta Rosario; Navarro Xavier
    Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology (2011), 122 (8), 1660-70 ISSN:.
    OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motoneurons of the primary motor cortex, the brainstem and the spinal cord, for which there are not effective treatments. Several transgenic mice that mimic motoneuron disease have been used to investigate potential treatments. The objective of this work is to characterize electrophysiologically the SOD1(G93A) transgenic mouse model of ALS, and to provide useful markers to improve early detection and monitoring of progression of the disease. METHODS: We performed nerve conduction tests, motor unit number estimation (MUNE), H reflex tests and motor evoked potentials (MEPs) in a cohort of transgenic and wild type mice from 4 to 16 weeks of age. RESULTS: The results revealed dysfunction of spinal motoneurons evidenced by deficits in motor nerve conduction tests starting at 8 weeks of age, earlier in proximal than in distal muscles of the hindlimb. MUNE demonstrated that spinal motoneurons loss muscle innervation and have a deficit in their sprouting capacity. Motor evoked potentials revealed that, coexisting with peripheral deficits, there was a dysfunction of central motor tracts that started also at 8 weeks, indicating progressive dysfunction of upper motoneurons. CONCLUSIONS: These electrophysiological results provide important information about the SOD1(G93A) mouse model, as they demonstrate by the first time alterations of central motor pathways simultaneously to lower motoneuron dysfunction, well before functional abnormalities appear (by 12 weeks of age). SIGNIFICANCE: The finding of concomitant dysfunction of upper and lower motoneurons contributes to the validation of the SOD1(G93A) mouse as model of ALS, because this parallel involvement is a diagnostic condition for ALS. Electrophysiological tests can be used as early markers of the disease and to evaluate the potential benefits of new treatments on both upper and lower motoneurons.
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    Ryder, S., Leadley, R. M., Armstrong, N., Westwood, M., de Kock, S., Butt, T., Jain, M., and Kleijnen, J. (2017) The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: an evidence review. Orphanet J. Rare Dis 12 (1), 79,  DOI: 10.1186/s13023-017-0631-3
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    The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: an evidence review
    Ryder S; Leadley R M; Armstrong N; Westwood M; de Kock S; Butt T; Jain M; Kleijnen J
    Orphanet journal of rare diseases (2017), 12 (1), 79 ISSN:.
    BACKGROUND: Duchenne Muscular Dystrophy (DMD) is a rapidly progressive, lethal neuromuscular disorder, present from birth, which occurs almost exclusively in males. We have reviewed contemporary evidence of burden, epidemiology, illness costs and treatment patterns of DMD. This systematic review adhered to published methods with information also sought from the web and contacting registries. Searches were carried out from 2005 to June 2015. The population of interest was individuals with clearly defined DMD or their carers. RESULTS: Nine thousand eight hundred fifty titles were retrieved from searches. Fifty-eight studies were reviewed with three assessed as high, 33 as medium and 22 as low quality. We found two studies reporting birth and four reporting point prevalence, three reporting mortality, 41 reporting severity and/or progression, 18 reporting treatment patterns, 12 reporting quality of life, two reporting utility measures, three reporting costs of illness and three treatment guidelines. Birth prevalence ranged from 15.9 to 19.5 per 100,000 live births. Point prevalence per 100,000 males was for France, USA, UK and Canada, 10.9, 1.9, 2.2 and 6.1 respectively. A study of adult DMD patients at a centre in France found median survival for those born between 1970 and 1994 was 40.95 years compared to 25.77 years for those born between 1955 and 1969. Loss of ambulation occurred at a median age of 12 and ventilation starts at about 20 years. There was international variation in use of corticosteroids, scoliosis surgery, ventilation and physiotherapy. The economic cost of DMD climbs dramatically with disease progression - rising as much as 5.7 fold from the early ambulatory phase to the non-ambulatory phase in Germany. CONCLUSIONS: This is the first systematic review of treatment, progression, severity and quality of life in DMD. It also provides the most recent description of the burden, epidemiology, illness costs and treatment patterns in DMD. There are evidence gaps, particularly in prevalence and mortality. People with DMD seem to be living longer, possibly due to corticosteroid use, cardiac medical management and ventilation. Future research should incorporate registry data to improve comparability across time and between countries and to investigate the quality of life impact as the condition progresses.
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    Yucel, N., Chang, A. C., Day, J. W., Rosenthal, N., and Blau, H. M. (2018) Humanizing the mdx mouse model of DMD: the long and the short of it. NPJ. Regen Med. 3, 4
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    Humanizing the mdx mouse model of DMD: the long and the short of it
    Yucel Nora; Chang Alex C; Blau Helen M; Day John W; Rosenthal Nadia
    NPJ Regenerative medicine (2018), 3 (), 4 ISSN:.
    Duchenne muscular dystrophy (DMD) is a common fatal heritable myopathy, with cardiorespiratory failure occurring by the third decade of life. There is no specific treatment for DMD cardiomyopathy, in large part due to a lack of understanding of the mechanisms underlying the cardiac failure. Mdx mice, which have the same dystrophin mutation as human patients, are of limited use, as they do not develop early dilated cardiomyopathy as seen in patients. Here we summarize the usefulness of the various commonly used DMD mouse models, highlight a model with shortened telomeres like humans, and identify directions that warrant further investigation.
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    Grounds, M. D., Radley, H. G., Lynch, G. S., Nagaraju, K., and De Luca, A. (2008) Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy. Neurobiol. Dis. 31 (1), 1– 19,  DOI: 10.1016/j.nbd.2008.03.008
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    Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy
    Grounds, Miranda D.; Radley, Hannah G.; Lynch, Gordon S.; Nagaraju, Kanneboyina; De Luca, Annamaria
    Neurobiology of Disease (2008), 31 (1), 1-19CODEN: NUDIEM; ISSN:0969-9961. (Elsevier Inc.)
    This review discusses various issues to consider when developing std. operating procedures for pre-clin. studies in the mdx mouse model of Duchenne muscular dystrophy (DMD). The review describes and evaluates a wide range of techniques used to measure parameters of muscle pathol. in mdx mice and identifies some basic techniques that might comprise standardized approaches for evaluation. While the central aim is to provide a basis for the development of standardized procedures to evaluate efficacy of a drug or a therapeutic strategy, a further aim is to gain insight into pathophysiol. mechanisms in order to identify other therapeutic targets. The desired outcome is to enable easier and more rigorous comparison of pre-clin. data from different labs. around the world, in order to accelerate identification of the best pre-clin. therapies in the mdx mouse that will fast-track translation into effective clin. treatments for DMD.
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    Carlson, C. G., Rutter, J., Bledsoe, C., Singh, R., Hoff, H., Bruemmer, K., Sesti, J., Gatti, F., Berge, J., and McCarthy, L. (2010) A simple protocol for assessing inter-trial and inter-examiner reliability for two noninvasive measures of limb muscle strength. J. Neurosci. Methods 186 (2), 226– 230,  DOI: 10.1016/j.jneumeth.2009.11.006
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    A simple protocol for assessing inter-trial and inter-examiner reliability for two noninvasive measures of limb muscle strength
    Carlson C George; Rutter John; Bledsoe Cathy; Singh Rajvir; Hoff Helena; Bruemmer Kay; Sesti Jenna; Gatti Francesca; Berge Jonas; McCarthy Laura
    Journal of neuroscience methods (2010), 186 (2), 226-30 ISSN:.
    Noninvasive measures of limb muscle strength are quite useful in preclinical translational studies that use mouse models of muscle disease, peripheral nerve disease, and movement disorders. The present study uses a simple protocol for assessing both inter-trial and inter-examiner reliability for two noninvasive methods of assessing limb strength in dystrophic (mdx) and wild type mice. One method, termed the whole body tension (WBT) method or escape test, measures the total phasic pulling tension exerted by the fore- and hindlimbs while a mouse attempts to escape into a darkened tube. Another procedure, termed the four limb wire grid holding test, measures the minimal amount of sustained tension (physical impulse) exerted by the fore- and hindlimbs while the mouse hangs suspended in an upside-down position. A comparison of the two methods revealed significant inter-trial and inter-examiner correlations in each procedure, although the WBT procedure consistently produced higher correlations than the four limb wire grid holding test. Inter-trial reliability for each test was higher than inter-examiner reliability, indicating that each longitudinal series of tests is best performed by a single investigator. The holding test also did not consistently detect differences between wild type and mdx populations at ages greater than 4 months. These results demonstrate the utility of a simple protocol for assessing the reliability of noninvasive tests that measure limb strength, and should be useful in comparing different functional measures in a broad range of translational studies.
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    Butler, H. J., Ashton, L., Bird, B., Cinque, G., Curtis, K., Dorney, J., Esmonde-White, K., Fullwood, N. J., Gardner, B., Martin-Hirsch, P. L. (2016) Using Raman spectroscopy to characterize biological materials. Nat. Protoc. 11 (4), 664– 687,  DOI: 10.1038/nprot.2016.036
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    Using Raman spectroscopy to characterize biological materials
    Butler, Holly J.; Ashton, Lorna; Bird, Benjamin; Cinque, Gianfelice; Curtis, Kelly; Dorney, Jennifer; Esmonde-White, Karen; Fullwood, Nigel J.; Gardner, Benjamin; Martin-Hirsch, Pierre L.; Walsh, Michael J.; McAinsh, Martin R.; Stone, Nicholas; Martin, Francis L.
    Nature Protocols (2016), 11 (4), 664-687CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)
    Raman spectroscopy can be used to measure the chem. compn. of a sample, which can in turn be used to ext. biol. information. Many materials have characteristic Raman spectra, which means that Raman spectroscopy has proven to be an effective anal. approach in geol., semiconductor, materials and polymer science fields. The application of Raman spectroscopy and microscopy within biol. is rapidly increasing because it can provide chem. and compositional information, but it does not typically suffer from interference from water mols. Anal. does not conventionally require extensive sample prepn.; biochem. and structural information can usually be obtained without labeling. In this protocol, we aim to standardize and bring together multiple exptl. approaches from key leaders in the field for obtaining Raman spectra using a microspectrometer. As examples of the range of biol. samples that can be analyzed, we provide instructions for acquiring Raman spectra, maps and images for fresh plant tissue, formalin-fixed and fresh frozen mammalian tissue, fixed cells and biofluids. We explore a robust approach for sample prepn., instrumentation, acquisition parameters and data processing. By using this approach, we expect that a typical Raman expt. can be performed by a nonspecialist user to generate high-quality data for biol. materials anal.
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    Khristoforova, Y. A., Bratchenko, I. A., Myakinin, O. O., Artemyev, D. N., Moryatov, A. A., Orlov, A. E., Kozlov, S. V., and Zakharov, V. P. (2019) Portable spectroscopic system for in vivo skin neoplasms diagnostics by Raman and autofluorescence analysis. J. Biophotonics 12, 1,  DOI: 10.1002/jbio.201800400
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    McGregor, H. C., Short, M. A., McWilliams, A., Shaipanich, T., Ionescu, D. N., Zhao, J., Wang, W., Chen, G., Lam, S., and Zeng, H. (2017) Real-time endoscopic Raman spectroscopy for in vivo early lung cancer detection. J. Biophotonics 10 (1), 98– 110,  DOI: 10.1002/jbio.201500204
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    Real-time endoscopic Raman spectroscopy for in vivo early lung cancer detection
    McGregor, Hanna C.; Short, Michael A.; McWilliams, Annette; Shaipanich, Tawimas; Ionescu, Diana N.; Zhao, Jianhua; Wang, Wenbo; Chen, Guannan; Lam, Stephen; Zeng, Haishan
    Journal of Biophotonics (2017), 10 (1), 98-110CODEN: JBOIBX; ISSN:1864-0648. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Currently the most sensitive method for localizing lung cancers in central airways is autofluorescence bronchoscopy (AFB) in combination with white light bronchoscopy (WLB). The diagnostic accuracy of WLB + AFB for high grade dysplasia (HGD) and carcinoma in situ is variable depending on physician's experience. When WLB + AFB are operated at high diagnostic sensitivity, the assocd. diagnostic specificity is low. Raman spectroscopy probes mol. vibrations and gives highly specific, fingerprint-like spectral features and has high accuracy for tissue pathol. classification. In this study we present the use of a real-time endoscopy Raman spectroscopy system to improve the specificity. A spectrum is acquired within 1 s and clin. data are obtained from 280 tissue sites (72 HGDs/malignant lesions, 208 benign lesions/normal sites) in 80 patients. Using multivariate analyses and waveband selection methods on the Raman spectra, we have demonstrated that HGD and malignant lung lesions can be detected with high sensitivity (90%) and good specificity (65%).
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    Discrimination between benign, primary and secondary malignancies in lymph nodes from the head and neck utilising Raman spectroscopy and multivariate analysis
    Lloyd, Gavin Rhys; Orr, Linda E.; Christie-Brown, Jonathan; McCarthy, Keith; Rose, Simon; Thomas, Michael; Stone, Nicholas
    Analyst (Cambridge, United Kingdom) (2013), 138 (14), 3900-3908CODEN: ANALAO; ISSN:0003-2654. (Royal Society of Chemistry)
    Background: The potential use of Raman spectroscopy (RS) for the detection of malignancy within lymph nodes of the head and neck was evaluated. RS measures the presence of biomols. by the inelastic scattering of light within cells and tissues. This can be performed in vivo in real-time. Methods: 103 lymph nodes were collected from 23 patients undergoing surgery for suspicious lymph nodes. Five pathologies, defined by consensus histopathol., were collected including reactive nodes (benign), Hodgkin's and non-Hodgkin's lymphomas, metastases from both squamous cell carcinomas and adenocarcinomas. Raman spectra were measured with 830 nm excitation from numerous positions on each biopsy. Spectral diagnostic models were constructed using principal component anal. followed by linear discriminant anal. (PCA-LDA), and by partial least squares discriminant anal. (PLS-DA) for comparison. Two-group models were constructed to distinguish between reactive and malignant nodes, and three-group models to distinguish between the benign, primary and secondary conditions. Results: Results were validated using a repeated subsampling procedure. Sensitivities and specificities of 90% and 86% were obtained using PCA-LDA, and 89% and 88% using PLS-DA, for the two-group models. Both PCA-LDA and PLS-DA models were also found to be very successful at discriminating between pathologies in the three-group models achieving sensitivities and specificities of over 78% and 89% for PCA-LDA, and over 81% and 89% for PLS-DA for all three pathol. groups. Conclusion: Raman spectroscopy and chemometric techniques can be successfully utilized in combination for discriminating between different cancerous conditions of lymph nodes from the head and neck.
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    Nicolson, F., Jamieson, L. E., Mabbott, S., Plakas, K., Shand, N. C., Detty, M. R., Graham, D., and Faulds, K. (2018) Multiplex imaging of live breast cancer tumour models through tissue using handheld surface enhanced spatially offset resonance Raman spectroscopy (SESORRS). Chem. Commun. (Cambridge, U. K.) 54 (61), 8530– 8533,  DOI: 10.1039/C8CC04267E
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    Multiplex imaging of live breast cancer tumour models through tissue using handheld surface enhanced spatially offset resonance Raman spectroscopy (SESORRS)
    Nicolson, Fay; Jamieson, Lauren E.; Mabbott, Samuel; Plakas, Konstantinos; Shand, Neil C.; Detty, Michael R.; Graham, Duncan; Faulds, Karen
    Chemical Communications (Cambridge, United Kingdom) (2018), 54 (61), 8530-8533CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    Through using the depth penetration capabilities of SESORS, multiplexed imaging and classification of three singleplex nanotags and a triplex of nanotags within breast cancer tumor models is reported for the first time through depths of 10 mm using a handheld SORS instrument.
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    Jermyn, M., Mok, K., Mercier, J., Desroches, J., Pichette, J., Saint-Arnaud, K., Bernstein, L., Guiot, M. C., Petrecca, K., and Leblond, F. (2015) Intraoperative brain cancer detection with Raman spectroscopy in humans. Sci. Transl Med. 7 (274), 274ra219,  DOI: 10.1126/scitranslmed.aaa2384
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    Tian, F., Yang, W., Mordes, D. A., Wang, J. Y., Salameh, J. S., Mok, J., Chew, J., Sharma, A., Leno-Duran, E., Suzuki-Uematsu, S. (2016) Monitoring peripheral nerve degeneration in ALS by label-free stimulated Raman scattering imaging. Nat. Commun. 7, 13283,  DOI: 10.1038/ncomms13283
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    Monitoring peripheral nerve degeneration in ALS by label-free stimulated Raman scattering imaging
    Tian, Feng; Yang, Wenlong; Mordes, Daniel A.; Wang, Jin-Yuan; Salameh, Johnny S.; Mok, Joanie; Chew, Jeannie; Sharma, Aarti; Leno-Duran, Ester; Suzuki-Uematsu, Satomi; Suzuki, Naoki; Han, Steve S.; Lu, Fa-Ke; Ji, Minbiao; Zhang, Rosanna; Liu, Yue; Strominger, Jack; Shneider, Neil A.; Petrucelli, Leonard; Xie, X. Sunney; Eggan, Kevin
    Nature Communications (2016), 7 (), 13283CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
    The study of amyotrophic lateral sclerosis (ALS) and potential interventions would be facilitated if motor axon degeneration could be more readily visualized. Here we demonstrate that stimulated Raman scattering (SRS) microscopy could be used to sensitively monitor peripheral nerve degeneration in ALS mouse models and ALS autopsy materials. Three-dimensional imaging of pre-symptomatic SOD1 mouse models and data processing by a correlation-based algorithm revealed that significant degeneration of peripheral nerves could be detected coincidentally with the earliest detectable signs of muscle denervation and preceded physiol. measurable motor function decline. We also found that peripheral degeneration was an early event in FUS as well as C9ORF72 repeat expansion models of ALS, and that serial imaging allowed long-term observation of disease progression and drug effects in living animals. Our study demonstrates that SRS imaging is a sensitive and quant. means of measuring disease progression, greatly facilitating future studies of disease mechanisms and candidate therapeutics.
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    Picardi, G., Spalloni, A., Generosi, A., Paci, B., Mercuri, N. B., Luce, M., Longone, P., and Cricenti, A. (2018) Tissue degeneration in ALS affected spinal cord evaluated by Raman spectroscopy. Sci. Rep 8 (1), 13110
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    Tissue degeneration in ALS affected spinal cord evaluated by Raman spectroscopy
    Picardi Gennaro; Generosi Amanda; Paci Barbara; Luce Marco; Cricenti Antonio; Spalloni Alida; Longone Patrizia; Mercuri Nicola Biagio; Mercuri Nicola Biagio
    Scientific reports (2018), 8 (1), 13110 ISSN:.
    The Raman spectral features from spinal cord tissue sections of transgenic, ALS model mice and non-transgenic mice were compared using 457 nm excitation line, profiting from the favourable signal intensity obtained in the molecular fingerprint region at this wavelength. Transverse sections from four SOD1G93A mice at 75 days and from two at 90 days after birth were analysed and compared with sections of similarly aged control mice. The spectra acquired within the grey matter of tissue sections from the diseased mice is markedly different from the grey matter signature of healthy mice. In particular, we observe an intensity increase in the spectral windows 450-650 cm(-1) and 1050-1200 cm(-1), accompanied by an intensity decrease in the lipid contributions at ~1660 cm(-1), ~1440 cm(-1) and ~1300 cm(-1). Axons demyelination, loss of lipid structural order and the proliferation and aggregation of branched proteoglycans are related to the observed spectral modifications. Furthermore, the grey and white matter components of the spinal cord sections could also be spectrally distinguished, based on the relative intensity of characteristic lipid and protein bands. Raman spectra acquired from the white matter regions of the SOD1G93A mice closely resembles those from control mice.
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    Gautam, R., Vanga, S., Madan, A., Gayathri, N., Nongthomba, U., and Umapathy, S. (2015) Raman spectroscopic studies on screening of myopathies. Anal. Chem. 87 (4), 2187– 2194,  DOI: 10.1021/ac503647x
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    Raman Spectroscopic Studies on Screening of Myopathies
    Gautam, Rekha; Vanga, Sandeep; Madan, Aditi; Gayathri, Narayanappa; Nongthomba, Upendra; Umapathy, Siva
    Analytical Chemistry (Washington, DC, United States) (2015), 87 (4), 2187-2194CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    Myopathies are among the major causes of mortality in the world. There is no complete cure for this heterogeneous group of diseases, but a sensitive, specific, and fast diagnostic tool may improve therapy effectiveness. In this study, Raman spectroscopy is applied to discriminate between muscle mutants in Drosophila on the basis of assocd. changes at the mol. level. Raman spectra were collected from indirect flight muscles of mutants, upheld1 (up1), heldup2 (hdp2), myosin heavy chain7 (Mhc7), actin88FKM88 (Act88FKM88), upheld101 (up101), and Canton-S (CS) control group, for both 2 and 12 days old flies. Difference spectra (mutant minus control) of all the mutants showed an increase in nucleic acid and β-sheet and/or random coil protein content along with a decrease in α-helix protein. Interestingly, the 12th day samples of up1 and Act88FKM88 showed significantly higher levels of glycogen and carotenoids than CS. A principal components based linear discriminant anal. classification model was developed based on multidimensional Raman spectra, which classified the mutants according to their pathophysiol. and yielded an overall accuracy of 97% and 93% for 2 and 12 days old flies, resp. The up1 and Act88FKM88 (nemaline-myopathy) mutants form a group that is clearly sepd. in a linear discriminant plane from up101 and hdp2 (cardiomyopathy) mutants. Notably, Raman spectra from a human sample with nemaline-myopathy formed a cluster with the corresponding Drosophila mutant (up1). In conclusion, this is the first demonstration in which myopathies, despite their heterogeneity, were screened on the basis of biochem. differences using Raman spectroscopy.
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    Chen, X., Sanchez, G. N., Schnitzer, M. J., and Delp, S. L. (2020) Microendoscopy detects altered muscular contractile dynamics in a mouse model of amyotrophic lateral sclerosis. Sci. Rep 10 (1), 457,  DOI: 10.1038/s41598-019-56555-z
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    Microendoscopy detects altered muscular contractile dynamics in a mouse model of amyotrophic lateral sclerosis
    Chen, Xuefeng; Sanchez, Gabriel N.; Schnitzer, Mark J.; Delp, Scott L.
    Scientific Reports (2020), 10 (1), 457CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
    Abstr.: Amyotrophic lateral sclerosis (ALS) is a fatal disease involving motor neuron degeneration. Effective diagnosis of ALS and quant. monitoring of its progression are crucial to the success of clin. trials. Second harmonic generation (SHG) microendoscopy is an emerging technol. for imaging single motor unit contractions. To assess the potential value of microendoscopy for diagnosing and tracking ALS, we monitored motor unit dynamics in a B6. SOD1G93A mouse model of ALS for several weeks. Prior to overt symptoms, muscle twitch rise and relaxation time consts. both increased, consistent with a loss of fast-fatigable motor units. These effects became more pronounced with disease progression, consistent with the death of fast fatigue-resistant motor units and superior survival of slow motor units. From these measurements we constructed a physiol. metric that reflects the changing distributions of measured motor unit time consts. and effectively diagnoses mice before symptomatic onset and tracks disease state. These results indicate that SHG microendoscopy provides a means for developing a quant., physiol. characterization of ALS progression.
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    Hegedus, J., Putman, C. T., and Gordon, T. (2007) Time course of preferential motor unit loss in the SOD1 G93A mouse model of amyotrophic lateral sclerosis. Neurobiol. Dis. 28 (2), 154– 164,  DOI: 10.1016/j.nbd.2007.07.003
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    Time course of preferential motor unit loss in the SOD1G93A mouse model of amyotrophic lateral sclerosis
    Hegedus, J.; Putman, C. T.; Gordon, T.
    Neurobiology of Disease (2007), 28 (2), 154-164CODEN: NUDIEM; ISSN:0969-9961. (Elsevier)
    Electromyog. analyses of pre-symptomatic motor unit loss in the SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis (ALS) have yielded contradictory findings as to the onset and time course. We recorded hindlimb muscle and motor unit isometric forces to det. motor unit no. and size throughout the life span of the mice. Motor unit nos. in fast-twitch tibialis anterior, extensor digitorum longus and medial gastrocnemius muscles declined from 40 days of age, 50 days before reported overt symptoms and motoneuron loss. Motor unit nos. fell after overt symptoms in the slow-twitch soleus muscle. Muscle forces declined in parallel with motor unit nos., indicating little or no functional compensation by sprouting. Early muscle-specific decline was due to selective preferential vulnerability of large, fast motor units, innervated by large motoneurons. Large motoneurons are hence the most vulnerable in ALS with die-back occurring prior to overt symptoms. We conclude that size of motoneurons, their axons, and their motor unit size are important determinants of motoneuron susceptibility in ALS.
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    Manning, J. and O’Malley, D. (2015) What has the mdx mouse model of Duchenne muscular dystrophy contributed to our understanding of this disease?. J. Muscle Res. Cell Motil. 36 (2), 155– 167,  DOI: 10.1007/s10974-015-9406-4
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    25
    What has the mdx mouse model of duchenne muscular dystrophy contributed to our understanding of this disease?
    Manning, Jennifer; O'Malley, Dervla
    Journal of Muscle Research and Cell Motility (2015), 36 (2), 155-167CODEN: JMRMD3; ISSN:0142-4319. (Springer)
    Duchenne muscular dystrophy (DMD) is a fatal X-chromosome linked recessive disorder caused by the truncation or deletion of the dystrophin gene. The most widely used animal model of this disease is the dystrophin-deficient mdx mouse which was first discovered 30 years ago. Despite its extensive use in DMD research, no effective treatment has yet been developed for this devastating disease. This review explores what we have learned from this mouse model regarding the pathophysiol. of DMD and asks if it has a future in providing a better more thorough understanding of this disease or if it will bring us any closer to improving the outlook for DMD patients.
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    Berkemeier, F., Bertz, M., Xiao, S., Pinotsis, N., Wilmanns, M., Grater, F., and Rief, M. (2011) Fast-folding alpha-helices as reversible strain absorbers in the muscle protein myomesin. Proc. Natl. Acad. Sci. U. S. A. 108 (34), 14139– 14144,  DOI: 10.1073/pnas.1105734108
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    26
    Fast-folding α-helices as reversible strain absorbers in the muscle protein myomesin
    Berkemeier, Felix; Bertz, Morten; Xiao, Senbo; Pinotsis, Nikos; Wilmanns, Matthias; Gater, Frauke; Rief, Matthias
    Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (34), 14139-14144, S14139/1-S14139/7CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    The highly oriented filamentous protein network of muscle constantly experiences significant mech. load during muscle operation. The dimeric protein myomesin has been identified as an important M-band component supporting the mech. integrity of the entire sarcomere. Recent structural studies have revealed a long α-helical linker between the C-terminal Ig domains My12 and My13 of myomesin. In this paper, we have used single-mol. force spectroscopy in combination with mol. dynamics simulations to characterize the mechanics of the myomesin dimer comprising Ig domains My12-My13. We find that at forces of approx. 30 pN the α-helical linker reversibly elongates allowing the mol. to extend by more than the folded extension of a full domain. High-resoln. measurements directly reveal the equil. folding/unfolding kinetics of the individual helix. We show that a-helix unfolding mech. protects the mol. homodimerization from dissocn. at physiol. relevant forces. As fast and reversible mol. springs the myomesin α-helical linkers are an essential component for the structural integrity of the M band.
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    Wu, G., Bazer, F. W., Burghardt, R. C., Johnson, G. A., Kim, S. W., Knabe, D. A., Li, P., Li, X., McKnight, J. R., Satterfield, M. C. (2011) Proline and hydroxyproline metabolism: implications for animal and human nutrition. Amino Acids 40 (4), 1053– 1063,  DOI: 10.1007/s00726-010-0715-z
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    Proline and hydroxyproline metabolism: implications for animal and human nutrition
    Wu, Guoyao; Bazer, Fuller W.; Burghardt, Robert C.; Johnson, Gregory A.; Kim, Sung Woo; Knabe, Darrell A.; Li, Peng; Li, Xilong; McKnight, Jason R.; Satterfield, M. Carey; Spencer, Thomas E.
    Amino Acids (2011), 40 (4), 1053-1063CODEN: AACIE6; ISSN:0939-4451. (SpringerWienNewYork)
    A review. Proline plays important roles in protein synthesis and structure, metab. (particularly the synthesis of arginine, polyamines, and glutamate via pyrroline-5-carboxylate), and nutrition, as well as wound healing, antioxidative reactions, and immune responses. On a per-g basis, proline plus hydroxyproline are most abundant in collagen and milk proteins, and requirements of proline for whole-body protein synthesis are the greatest among all amino acids. Therefore, physiol. needs for proline are particularly high during the life cycle. While most mammals (including humans and pigs) can synthesize proline from arginine and glutamine/glutamate, rates of endogenous synthesis are inadequate for neonates, birds, and fish. Thus, work with young pigs (a widely used animal model for studying infant nutrition) has shown that supplementing 0.0%, 0.355, 0.75, 1.05%, 1.4%, and 2.1% proline to a proline-free chem. defined diet contg. 0.48% arginine and 2% glutamate dose dependently improved daily growth rate and feed efficiency while reducing concns. of urea in plasma. Addnl., maximal growth performance of chickens depended on at least 0.8% proline in the diet. Likewise, dietary supplementation with 0.07%, 0.14%, and 0.28% hydroxyproline (a metabolite of proline) to a plant protein-based diet enhanced wt. gains of salmon. Based on its regulatory roles in cellular biochem., proline can be considered as a functional amino acid for mammalian, avian, and aquatic species. Further research is warranted to develop effective strategies of dietary supplementation with proline or hydroxyproline to benefit health, growth, and development of animals and humans.
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    Ferraiuolo, L., De Bono, J. P., Heath, P. R., Holden, H., Kasher, P., Channon, K. M., Kirby, J., and Shaw, P. J. (2009) Transcriptional response of the neuromuscular system to exercise training and potential implications for ALS. J. Neurochem. 109 (6), 1714– 1724,  DOI: 10.1111/j.1471-4159.2009.06080.x
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    Transcriptional response of the neuromuscular system to exercise training and potential implications for ALS
    Ferraiuolo, Laura; De Bono, Joseph P.; Heath, Paul R.; Holden, Hazel; Kasher, Paul; Channon, Keith M.; Kirby, Janine; Shaw, Pamela J.
    Journal of Neurochemistry (2009), 109 (6), 1714-1724CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)
    The transcriptional adaptive response of motoneurons and muscles to voluntary exercise has been investigated by using laser capture microdissection and microarray anal. Our results show that motoneurons respond to phys. activity by activating a complex transcriptional plan, with changes involved in neurotrophic factor signaling, electrophysiol. changes and synaptic reorganization. Gastrocnemius muscle shows increases in transcripts responsible for neovascularization and new myogenesis. Both tissues show transcriptional changes involved in the growth and reinforcement of the neuromuscular junction. This study indicates that the neuromuscular system undergoes significant structural and functional alterations, aiming to optimize the transmission of both chem. and elec. stimuli, thus prompting axonal outgrowth and mechanisms similar to long-term potentiation in hippocampal neurons. Understanding the response of these cells during exercise has potentially important implications for human neuromuscular disease, including amyotrophic lateral sclerosis, by highlighting candidate genes pivotal for the balance between the physiol. and the pathol. of the neuromuscular system in terms of the stress response to phys. exercise.
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    Gonzalez de Aguilar, J. L., Niederhauser-Wiederkehr, C., Halter, B., De Tapia, M., Di Scala, F., Demougin, P., Dupuis, L., Primig, M., Meininger, V., and Loeffler, J. P. (2008) Gene profiling of skeletal muscle in an amyotrophic lateral sclerosis mouse model. Physiol. Genomics 32 (2), 207– 218,  DOI: 10.1152/physiolgenomics.00017.2007
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    29
    Gene profiling of skeletal muscle in an amyotrophic lateral sclerosis mouse model
    Gonzalez de Aguilar, Jose-Luis; Niederhauser-Wiederkehr, Christa; Halter, Benoit; de Tapia, Marc; di Scala, Franck; Demougin, Philippe; Dupuis, Luc; Primig, Michael; Meininger, Vincent; Loeffler, Jean-Philippe
    Physiological Genomics (2008), 32 (2), 207-218CODEN: PHGEFP; ISSN:1094-8341. (American Physiological Society)
    Muscle atrophy is a major hallmark of amyotrophic lateral sclerosis (ALS), the most frequent adult-onset motor neuron disease. To define the full set of alterations in gene expression in skeletal muscle during the course of the disease, the authors used the G86R superoxide dismutase-1 transgenic mouse model of ALS and performed high-d. oligonucleotide microarrays. The authors compared these data to those obtained by axotomy-induced denervation. A major set of gene regulations in G86R muscles resembled those of surgically denervated muscles, but many others appeared specific to the ALS condition. The first significant transcriptional changes appeared in a subpopulation of mice before the onset of overt clin. symptoms and motor neuron death. These early changes affected genes involved in detoxification (e.g., ALDH3, metallothionein-2, and thioredoxin-1) and regeneration (e.g., BTG1, RB1, and RUNX1) but also tissue degrdn. (e.g., C/EBPδ and DDIT4) and cell death (e.g., ankyrin repeat domain-1, CDKN1A, GADD45α, and PEG3). Of particular interest, metallothionein-1 and -2, ATF3, cathepsin-Z, and galectin-3 genes appeared, among others, commonly regulated in both skeletal muscle (our present data) and spinal motor neurons (as previously reported) of paralyzed ALS mice. The importance of these findings is twofold. First, they designate the distal part of the motor unit as a primary site of disease. Second, they identify specific gene regulations to be explored in the search for therapeutic strategies that could alleviate disease before motor neuron death manifests clin.
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    Porter, J. D., Merriam, A. P., Leahy, P., Gong, B., Feuerman, J., Cheng, G., and Khanna, S. (2004) Temporal gene expression profiling of dystrophin-deficient (mdx) mouse diaphragm identifies conserved and muscle group-specific mechanisms in the pathogenesis of muscular dystrophy. Hum. Mol. Genet. 13 (3), 257– 269,  DOI: 10.1093/hmg/ddh033
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    Temporal gene expression profiling of dystrophin-deficient (mdx) mouse diaphragm identifies conserved and muscle group-specific mechanisms in the pathogenesis of muscular dystrophy
    Porter, John D.; Merriam, Anita P.; Leahy, Patrick; Gong, Bendi; Feuerman, Jason; Cheng, Georgiana; Khanna, Sangeeta
    Human Molecular Genetics (2004), 13 (3), 257-269CODEN: HMGEE5; ISSN:0964-6906. (Oxford University Press)
    Mutations in dystrophin are the proximate cause of Duchenne muscular dystrophy (DMD), but pathogenic mechanisms linking the absence of dystrophin from the sarcolemma to myofiber necrosis are not fully known. The muscular dystrophies also have properties not accounted for by current disease models, including the temporal delay to disease onset, broad species differences in severity, and diversity of skeletal muscle responses. To address the mechanisms underlying the differential targeting of muscular dystrophy, we characterized temporal expression profiles of the diaphragm in dystrophin-deficient (mdx) mice between postnatal days 7 and 112 using oligonucleotide microarrays and contrasted these data with published hindlimb muscle data. Although the diaphragm and hindlimb muscle groups differ in severity of response to dystrophin deficiency, and exhibited substantial divergence in some transcript categories including inflammation and muscle-specific genes, our data show that the general mechanisms operative in muscular dystrophy are highly conserved. The two muscle groups principally differed in expression levels of differentially regulated genes, as opposed to the non-conserved induced/repressed transcripts defining fundamentally distinct mechanisms. We also identified a postnatal divergence of the two wild-type muscle group expression profiles that temporally correlated with the onset and progression of the dystrophic process. These findings support the hypothesis that conserved disease mechanisms interacting with baseline differences in muscle group-specific transcriptomes underlie their differential responses to DMD. We further suggest that muscle group-specific transcriptional profiles contribute toward the muscle targeting and sparing patterns obsd. for a variety of metabolic and neuromuscular diseases.
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    Dobrowolny, G., Aucello, M., Rizzuto, E., Beccafico, S., Mammucari, C., Boncompagni, S., Belia, S., Wannenes, F., Nicoletti, C., Del Prete, Z. (2008) Skeletal muscle is a primary target of SOD1G93A-mediated toxicity. Cell Metab 8 (5), 425– 436,  DOI: 10.1016/j.cmet.2008.09.002
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    Skeletal muscle is a primary target of SOD1G93A-mediated toxicity
    Dobrowolny, Gabriella; Aucello, Michela; Rizzuto, Emanuele; Beccafico, Sara; Mammucari, Cristina; Bonconpagni, Simona; Belia, Silvia; Wannenes, Francesca; Nicoletti, Carmine; Del Prete, Zaccaria; Rosenthal, Nadia; Molinaro, Mario; Protasi, Feliciano; Fano, Giorgio; Sandri, Marco; Musaro, Antonio
    Cell Metabolism (2008), 8 (5), 425-436CODEN: CMEEB5; ISSN:1550-4131. (Cell Press)
    The antioxidant enzyme superoxide dismutase 1 (SOD1) is a crit. player of the antioxidative defense whose activity is altered in several chronic diseases, including amyotrophic lateral sclerosis. However, how oxidative insult affects muscle homeostasis remains unclear. This study addresses the role of oxidative stress on muscle homeostasis and function by the generation of a transgenic mouse model expressing a mutant SOD1 gene (SOD1G93A) selectively in skeletal muscle. Transgenic mice developed progressive muscle atrophy, assocd. with a significant redn. in muscle strength, alterations in the contractile app., and mitochondrial dysfunction. The anal. of mol. pathways assocd. with muscle atrophy revealed that accumulation of oxidative stress served as signaling mols. to initiate autophagy, one of the major intracellular degrdn. mechanisms. These data demonstrate that skeletal muscle is a primary target of SOD1G93A-mediated toxicity and disclose the mol. mechanism whereby oxidative stress triggers muscle atrophy.
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  32. 32
    Schill, K. E., Altenberger, A. R., Lowe, J., Periasamy, M., Villamena, F. A., Rafael-Fortney, J. A., and Devor, S. T. (2016) Muscle damage, metabolism, and oxidative stress in mdx mice: Impact of aerobic running. Muscle Nerve 54 (1), 110– 117,  DOI: 10.1002/mus.25015
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    32
    Muscle damage, metabolism, and oxidative stress in mdx mice: Impact of aerobic running
    Schill, Kevin E.; Altenberger, Alex. R.; Lowe, Jeovanna; Periasamy, Muthu; Villamena, Frederick A.; Rafael-Fortney, Jill A.; Devor, Steven T.
    Muscle & Nerve (2016), 54 (1), 110-117CODEN: MUNEDE; ISSN:0148-639X. (John Wiley & Sons, Inc.)
    Introduction: We tested how a treadmill exercise program influences oxygen consumption, oxidative stress, and exercise capacity in the mdx mouse, a model of Duchenne muscular dystrophy. Methods: At age 4 wk mdx mice were subjected to 4 wk of twice-weekly treadmill exercise. Sedentary mdx and wild-type mice served as controls. Oxygen consumption, time to exhaustion, oxidative stress, and myofiber damage were assessed. Results: At age 4 wk, there was a significant difference in exercise capacity between mdx and wild-type mice. After exercise, mdx mice had lower basal oxygen consumption and exercise capacity, but similar maximal oxygen consumption. Skeletal muscle from these mice displayed increased oxidative stress. Collagen deposition was higher in exercised vs. sedentary mice. Conclusions: Exercised mdx mice exhibit increased oxidative stress, as well as deficits in exercise capacity, baseline oxygen consumption, and increased myofiber fibrosis. Muscle Nerve 54: 110-117, 2016.
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  33. 33
    Rivas-Arancibia, S., Rodriguez-Martinez, E., Badillo-Ramirez, I., Lopez-Gonzalez, U., and Saniger, J. M. (2017) Structural Changes of Amyloid Beta in Hippocampus of Rats Exposed to Ozone: A Raman Spectroscopy Study. Front Mol. Neurosci 10, 137,  DOI: 10.3389/fnmol.2017.00137
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    33
    Structural Changes of Amyloid Beta in Hippocampus of Rats Exposed to Ozone: A Raman Spectroscopy Study
    Rivas-Arancibia Selva; Rodriguez-Martinez Erika; Badillo-Ramirez Isidro; Lopez-Gonzalez Ulises; Saniger Jose M
    Frontiers in molecular neuroscience (2017), 10 (), 137 ISSN:1662-5099.
    The aim of this work was to study the effect of oxidative stress on the structural changes of the secondary peptide structure of amyloid beta 1-42 (Aβ 1-42), in the dentate gyrus of hippocampus of rats exposed to low doses of ozone. The animals were exposed to ozone-free air (control group) and 0.25 ppm ozone during 7, 15, 30, 60, and 90 days, respectively. The samples were studied by: (1) Raman spectroscopy to detect the global conformational changes in peptides with α-helix and β-sheet secondary structure, following the deconvolution profile of the amide I band; and (2) immunohistochemistry against Aβ 1-42. The results of the deconvolutions of the amide I band indicate that, ozone exposure causes a progressively decrease in the abundance percentage of α-helix secondary structure. Furthermore, the β-sheet secondary structure increases its abundance percentage. After 60 days of ozone exposure, the β-sheet band is identified in a similar wavenumber of the Aβ 1-42 peptide standard. Immunohistochemistry assays show an increase of Aβ 1-42 immunoreactivity, coinciding with the conformational changes observed in the Raman spectroscopy of Aβ 1-42 at 60 and 90 days. In conclusion, oxidative stress produces changes in the folding process of amyloid beta peptide structure in the dentate gyrus, leading to its conformational change in a final β-sheet structure. This is associated to an increase in Aβ 1-42 expression, similar to the one that happens in the brain of Alzheimer's Disease (AD) patients.
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  34. 34
    Chen, Y., Wang, Z., Huang, Y., Feng, S., Zheng, Z., Liu, X., and Liu, M. (2019) Label-free detection of hydrogen peroxide-induced oxidative stress in human retinal pigment epithelium cells via laser tweezers Raman spectroscopy. Biomed. Opt. Express 10 (2), 500– 513,  DOI: 10.1364/BOE.10.000500
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    Label-free detection of hydrogen peroxide-induced oxidative stress in human retinal pigment epithelium cells via laser tweezers Raman spectroscopy
    Chen, Yang; Wang, Zhiqiang; Huang, Yan; Feng, Shangyuan; Zheng, Zuci; Liu, Xiujie; Liu, Mengmeng
    Biomedical Optics Express (2019), 10 (2), 500-513CODEN: BOEICL; ISSN:2156-7085. (Optical Society of America)
    Human retinal pigment epithelium cells under hydrogen peroxide-induced oxidative stress and a ligustrazine-based protective effect were investigated using laser tweezers Raman spectroscopy. Protein and lipid were significantly affected by oxidative damage, along with increased reactive oxygen species (ROS) level within cells. The effects of ligustrazine against the reaction of ROS with protein seemed to be able to inhibit such damages but were limited during the desamidization of amides, along with addnl. effect on nucleic acid base and DNA phosphoric acid skeleton. This work laid the basis for both understanding the mol. mechanisms of oxidative stress-induced injury and highlighting possible biomarkers in retinal diseases.
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  35. 35
    Bogliolo, L., Murrone, O., Di Emidio, G., Piccinini, M., Ariu, F., Ledda, S., and Tatone, C. (2013) Raman spectroscopy-based approach to detect aging-related oxidative damage in the mouse oocyte. J. Assist Reprod Genet 30 (7), 877– 882,  DOI: 10.1007/s10815-013-0046-6
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    35
    Raman spectroscopy-based approach to detect aging-related oxidative damage in the mouse oocyte
    Bogliolo Luisa; Murrone Ombretta; Di Emidio Giovanna; Piccinini Massimo; Ariu Federica; Ledda Sergio; Tatone Carla
    Journal of assisted reproduction and genetics (2013), 30 (7), 877-82 ISSN:.
    PURPOSE: Detection of chemical modifications induced by aging-related oxidative damage in mouse metaphase II (MII) oocytes by Raman microspectroscopy. METHODS: CD-1 mice at the age of 4-8 weeks (young mice) and 48-52 weeks (old mice), were superovulated and oocytes at metaphase II stage were recovered from oviducts. MII oocytes from young animals were divided into three groups: A) young oocytes, processed immediately after collection; B) in vitro aged oocytes, cultured in vitro for 10 h before processing; C) oxidative-stressed oocytes, exposed to 10 mM hydrogen peroxide for 2 min before processing. Oocytes from reproductively old mice were referred to as old oocytes (D). All the oocytes were analyzed by confocal Raman microspectroscopy. The spectra were statistically analyzed using Principal Component Analysis (PCA). RESULTS: PCA evidenced that spectra from young oocytes (A) were clearly distinguishable from those obtained from in vitro-aged, oxidative-damaged and old oocytes (B, C, D) and presented significant differences in the bands attributable to lipid components (C = C stretching, 1,659 cm-1; CH2 bending, 1,450 cm-1; CH3 deformation,1,345 cm-1; OH bending, C-N stretching, 1,211 cm-1) and protein components (amide I band,1,659 cm-1; CH2 bending modes and CH3 deformation, 1,450 cm-1; C-N and C-C stretching vibrations, 1,132 cm-1; phenylalanine's vibration, 1,035 cm-1) CONCLUSIONS: Raman spectroscopy is a valuable non-invasive tool for the identification of biochemical markers of oxidative damage and could represent a highly informative method of investigation to evaluate the oocyte quality.
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  36. 36
    Kappos, E. A., Sieber, P. K., Engels, P. E., Mariolo, A. V., D’Arpa, S., Schaefer, D. J., and Kalbermatten, D. F. (2017) Validity and reliability of the CatWalk system as a static and dynamic gait analysis tool for the assessment of functional nerve recovery in small animal models. Brain Behav 7 (7), e00723  DOI: 10.1002/brb3.723
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    Vieira, W. F., Kenzo-Kagawa, B., Cogo, J. C., Baranauskas, V., and Cruz-Hofling, M. A. (2016) Low-Level Laser Therapy (904 nm) Counteracts Motor Deficit of Mice Hind Limb following Skeletal Muscle Injury Caused by Snakebite-Mimicking Intramuscular Venom Injection. PLoS One 11 (7), e0158980  DOI: 10.1371/journal.pone.0158980
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    37
    Low-level laser therapy (904 nm) counteracts motor deficit of mice hind limb following skeletal muscle injury caused by snakebite-mimicking intramuscular venom injection
    Vieira, Willians Fernando; Kenzo-Kagawa, Bruno; Cogo, Jose Carlos; Baranauskas, Vitor; da Cruz-Hofling, Maria Alice
    PLoS One (2016), 11 (7), e0158980/1-e0158980/17CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    Myotoxins present in Bothrops venom disrupt the sarcolemma of muscle fibers leading to the release of sarcoplasmic proteins and loss of muscle homeostasis. Myonecrosis and tissue anoxia induced by vascularization impairment can lead to amputation or motor functional deficit. The objective of this study was to investigate the dynamic behavior of motor function in mice subjected to injection of Bothrops jararacussu venom (Bjssu) and exposed to low-level laser therapy (LLLT). Male Swiss mice received Bjssu injection (830 μg/kg) into the medial portion of the right gastrocnemius muscle. Three hours later the injected region was irradiated with diode semiconductor Gallium Arsenide (GaAs- 904 nm, 4 J/cm2) laser following by irradn. at 24, 48 and 72 h. Saline injection (0.9% NaCl) was used as control. Gait anal. was performed 24 h before Bjssu injection and at every period post-Bjssu using CatWalk method. Data from spatiotemporal parameters Stand, Maximum Intensity, Swing, Swing Speed, Stride Length and Step Cycle were considered. The period of 3 h post venom-induced injury was considered crit. for all parameters evaluated in the right hindlimb. Differences (p<0.05) were concd. in venom and venom + placebo laser groups during the 3 h post-injury period, in which the values of stand of most animals were null. After this period, the gait characteristics were re-established for all parameters. The venom + laser group kept the values at 3 h post-Bjssu equal to that at 24 h before Bjssu injection indicating that the GaAs laser therapy improved spatially and temporally gait parameters at the crit. injury period caused by Bjssu. This is the first study to analyze with cutting edge technol. the gait functional deficits caused by snake envenoming and gait gains produced by GaAs laser irradn. In this sense, the study fills a gap on the field of motor function after laser treatment following snake envenoming.
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  38. 38
    Su, W. H., Wang, C. J., Fu, H. C., Sheng, C. M., Tsai, C. C., Cheng, J. H., and Chuang, P. C. (2019) Human Umbilical Cord Mesenchymal Stem Cells Extricate Bupivacaine-Impaired Skeletal Muscle Function via Mitigating Neutrophil-Mediated Acute Inflammation and Protecting against Fibrosis. Int. J. Mol. Sci. 20 (17), 1,  DOI: 10.3390/ijms20174312
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    Pratt, S. J. P., Lawlor, M. W., Shah, S. B., and Lovering, R. M. (2012) An in vivo rodent model of contraction-induced injury in the quadriceps muscle. Injury 43 (6), 788– 793,  DOI: 10.1016/j.injury.2011.09.015
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    An in vivo rodent model of contraction-induced injury in the quadriceps muscle
    Pratt Stephen J P; Lawlor Michael W; Shah Sameer B; Lovering Richard M
    Injury (2012), 43 (6), 788-93 ISSN:.
    Most animal studies of muscle contractile function utilise the anterior or posterior crural muscle (dorsiflexors and plantarflexors, respectively). An advantage to using these muscles is that the common fibular and tibial nerves are readily accessible, while the small size of the crural muscles is a disadvantage. Working with small muscles not only makes some in vivo imaging and the muscle testing techniques more challenging, but also provides limited amounts of tissue to study. The purpose of this study was to describe a new animal muscle injury model in the quadriceps that results in a significant and reproducible loss of force. The thigh of Sprague Dawley rats (N=5) and C57BL/10 mice (N=5) was immobilised and the ankle was attached to a custom-made lever arm. The femoral nerve was stimulated using subcutaneous electrodes and injury was induced using 50 lengthening ("eccentric") contractions through a 70° arc of knee motion. This protocol produces a significant and reproducible injury, with comparable susceptibility to injury in the rats and mice. This novel model shows that the quadriceps muscle provides a means to study whole muscle contractility, injury, and recovery in vivo. In addition to the usual benefits of an in vivo model, the larger size of the quadriceps facilitates in vivo imaging and provides a significant increase in the amount of tissue available for histology and biochemistry studies. A controlled muscle injury in the quadriceps also allows one to study a muscle, with mixed fibre types, which is extremely relevant to gait in humans and quadruped models.
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  40. 40
    Contreras-Munoz, P., Fernandez-Martin, A., Torrella, R., Serres, X., De la Varga, M., Viscor, G., Jarvinen, T. A., Martinez-Ibanez, V., Peiro, J. L., Rodas, G. (2016) A New Surgical Model of Skeletal Muscle Injuries in Rats Reproduces Human Sports Lesions. Int. J. Sports Med. 37 (3), 183– 190,  DOI: 10.1055/s-0035-1555933
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    A New Surgical Model of Skeletal Muscle Injuries in Rats Reproduces Human Sports Lesions
    Contreras-Munoz P; De la Varga M; Rodas G; Marotta M; Fernandez-Martin A; Martinez-Ibanez V; Peiro J L; Torrella R; Viscor G; Serres X; Jarvinen T A H
    International journal of sports medicine (2016), 37 (3), 183-90 ISSN:.
    Skeletal muscle injuries are the most common sports-related injuries in sports medicine. In this work, we have generated a new surgically-induced skeletal muscle injury in rats, by using a biopsy needle, which could be easily reproduced and highly mimics skeletal muscle lesions detected in human athletes. By means of histology, immunofluorescence and MRI imaging, we corroborated that our model reproduced the necrosis, inflammation and regeneration processes observed in dystrophic mdx-mice, a model of spontaneous muscle injury, and realistically mimicked the muscle lesions observed in professional athletes. Surgically-injured rat skeletal muscles demonstrated the longitudinal process of muscle regeneration and fibrogenesis as stated by Myosin Heavy Chain developmental (MHCd) and collagen-I protein expression. MRI imaging analysis demonstrated that our muscle injury model reproduces the grade I-II type lesions detected in professional soccer players, including edema around the central tendon and the typically high signal feather shape along muscle fibers. A significant reduction of 30% in maximum tetanus force was also registered after 2 weeks of muscle injury. This new model represents an excellent approach to the study of the mechanisms of muscle injury and repair, and could open new avenues for developing innovative therapeutic approaches to skeletal muscle regeneration in sports medicine.
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    Paganoni, S. and Amato, A. (2013) Electrodiagnostic evaluation of myopathies. Phys. Med. Rehabil Clin N Am. 24 (1), 193– 207,  DOI: 10.1016/j.pmr.2012.08.017
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    Electrodiagnostic evaluation of myopathies
    Paganoni Sabrina; Amato Anthony
    Physical medicine and rehabilitation clinics of North America (2013), 24 (1), 193-207 ISSN:.
    Electrodiagnostic studies play an important role in the evaluation of patients suspected of having a myopathic disorder. They are used to exclude alternative diagnoses, confirm the presence of muscle disease, narrow down the differential, and identify an appropriate biopsy site. The most informative part of the electrodiagnostic study is needle electromyography. This allows for the analysis of spontaneous activity and motor unit action potential morphology and recruitment patterns. This article proposes a practical electrodiagnostic approach and describes the electrophysiologic patterns of the most commonly encountered myopathies.
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    Brown, R., Dissanayake, K. N., Skehel, P. A., and Ribchester, R. R. (2014) Endomicroscopy and electromyography of neuromuscular junctions in situ. Ann. Clin. Transl. Neurol. 1 (11), 867– 883,  DOI: 10.1002/acn3.124
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    Endomicroscopy and electromyography of neuromuscular junctions in situ
    Brown, Rosalind; Dissanayake, Kosala N.; Skehel, Paul A.; Ribchester, Richard R.
    Annals of Clinical and Translational Neurology (2014), 1 (11), 867-883CODEN: ACTNCG; ISSN:2328-9503. (John Wiley & Sons, Inc.)
    Objective : Electromyog. (EMG) is used routinely to diagnose neuromuscular dysfunction in a wide range of peripheral neuropathies, myopathies, and neuromuscular degenerative diseases including motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Definitive neurol. diagnosis may also be indicated by the anal. of pathol. neuromuscular innervation in motor-point biopsies. Our objective in this study was to preempt motor-point biopsy by combining live imaging with electrophysiol. anal. of slow degeneration of neuromuscular junctions (NMJs) in vivo. Methods : We combined conventional needle electromyog. with fiber-optic confocal endomicroscopy (CEM), using an integrated hand-held, 1.5-mm-diam. probe. We utilized as a test bed, various axotomized muscles in the hind limbs of anesthetized, double-homozygous thy1.2YFP16: WldS mice, which coexpress the Wallerian-degeneration Slow (WldS) protein and yellow fluorescent protein (YFP) in motor neurons. We also tested exogenous vital stains, including Alexa488-α-bungarotoxin; the styryl pyridinium dye 4-Di-2-Asp; and a GFP conjugate of botulinum toxin Type A heavy chain (GFP-HcBoNT/A). Results : We show that an integrated EMG/CEM probe is effective in longitudinal evaluation of functional and morphol. changes that take place over a 7-day period during axotomy-induced, slow neuromuscular synaptic degeneration. EMG amplitude declined in parallel with overt degeneration of motor nerve terminals. EMG/CEM was safe and effective when nerve terminals and motor endplates were selectively stained with vital dyes. Interpretation : Our findings constitute proof-of-concept, based on live imaging in an animal model, that combining EMG/CEM may be useful as a minimally invasive precursor or alternative to motor-point biopsy in neurol. diagnosis and for monitoring local administration of potential therapeutics.
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    McGregor, H. C., Short, M. A., McWilliams, A., Shaipanich, T., Ionescu, D. N., Zhao, J., Wang, W., Chen, G., Lam, S., and Zeng, H. (2016) Real-time endoscopic Raman spectroscopy for in vivo early lung cancer detection. J. Biophotonics 1,  DOI: 10.1002/jbio.201500204
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    Bergholt, M. S., Zheng, W., Lin, K., Ho, K. Y., Teh, M., Yeoh, K. G., So, J. B., and Huang, Z. (2011) In vivo diagnosis of esophageal cancer using image-guided Raman endoscopy and biomolecular modeling. Technol. Cancer Res. Treat. 10 (2), 103– 112,  DOI: 10.7785/tcrt.2012.500185
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    In vivo diagnosis of esophageal using image-guided raman endoscopy and biomolecular modeling
    Bergholt, M. S.; Zheng, W.; Lin, K.; Ho, K. Y.; Teh, M.; Yeoh, K. G.; So, J. B. Y.; Huang, Z.
    Technology in Cancer Research & Treatment (2011), 10 (2), 103-112CODEN: TCRTBS; ISSN:1533-0346. (Adenine Press)
    The aim of this work was to evaluate the biochem. foundation and clin. merit of multimodal image-guided Raman endoscopy technique for real-time in vivo diagnosis of cancer in the esophagus during clin. endoscopic examns. A novel fiber-optic Raman endoscopy system was utilized for in vivo esophageal Raman measurements at 785 nm laser excitation within 0.5 s under the multimodal wide-field endoscopic imaging (white light reflectance (WLR)) imaging, narrow-band imaging (NBI) and autofluorescence imaging (AFI) guidance. A total of 75 esophageal tissue sites from 27 patients were measured, in which 42 in vivo Raman spectra were from normal tissues and 33 in vivo Raman spectra were from malignant tumors as confirmed by histopathol. The biomol. modeling (non-negativity-constrained least-squares minimization (NNCLSM)) utilizing six basis ref. spectra from the representative biochems. (i.e., actin, collagen, DNA, histones, triolein and glycogen) were employed to est. the biochem. compns. of esophageal tissue. The resulting diagnostically significant fit coeffs. were further utilized through linear discriminant anal. (LDA) and leave-one tissue site-out, cross validation method to develop diagnostic algorithms for esophageal cancer diagnosis. High-quality in vivo Raman spectra in the range of 800-1800 cm-1 can be acquired from normal and cancerous esophageal mucosa in real-time under multimodal endoscopic imaging guidance. Esophageal cancer tissue showed distinct Raman signals mainly assocd. with cell proliferation, lipid redn., abnormal nuclear activity and neovasculation. The fit coeffs. for actin, DNA, histones, triolein, and glycogen were found to be most significant for construction of the LDA diagnostic model, giving rise to an accuracy of 96.0% (i.e., sensitivity of 97.0% and specificity of 95.2%) for in vivo diagnosis of esophageal cancer. This study demonstrates that multimodal image-guided Raman endoscopy technique in conjunction with biomol. modeling has promising potential for the real-time, in vivo diagnosis and detection of esophageal cancer during clin. endoscopic examn.
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    Resendes, M., Helms, C. A., Fritz, R. C., and Genant, H. (1992) MR appearance of intramuscular injections. AJR, Am. J. Roentgenol. 158 (6), 1293– 1294,  DOI: 10.2214/ajr.158.6.1590126
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    MR appearance of intramuscular injections
    Resendes M; Helms C A; Fritz R C; Genant H
    AJR. American journal of roentgenology (1992), 158 (6), 1293-4 ISSN:0361-803X.
    There is no expanded citation for this reference.
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    Day, J. C. and Stone, N. (2013) A subcutaneous Raman needle probe. Appl. Spectrosc. 67 (3), 349– 354,  DOI: 10.1366/12-06651
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    A subcutaneous Raman needle probe
    Day, John C. C.; Stone, Nicholas
    Applied Spectroscopy (2013), 67 (3), 349-354CODEN: APSPA4; ISSN:0003-7028. (Society for Applied Spectroscopy)
    Raman spectroscopy is a powerful tool for studying the biochem. compn. of tissues and cells in the human body. We describe the initial results of a feasibility study to design and build a miniature, fiber optic probe incorporated into a std. hypodermic needle. This probe is intended for use in optical biopsies of solid tissues to provide valuable information of disease type, such as in the lymphatic system, breast, or prostate, or of such tissue types as muscle, fat, or spinal, when identifying a crit. injection site. The optical design and fabrication of this probe is described, and example spectra of various ex vivo samples are shown.
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    Li, R., Verreault, D., Payne, A., Hitchcock, C. L., Povoski, S. P., Martin, E. W., and Allen, H. C. (2014) Effects of laser excitation wavelength and optical mode on Raman spectra of human fresh colon, pancreas, and prostate tissues. J. Raman Spectrosc. 45 (9), 773– 780,  DOI: 10.1002/jrs.4540
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    Effects of laser excitation wavelength and optical mode on Raman spectra of human fresh colon, pancreas, and prostate tissues
    Li, Ran; Verreault, Dominique; Payne, Andrea; Hitchcock, Charles L.; Povoski, Stephen P.; Martin, Edward W., Jr.; Allen, Heather C.
    Journal of Raman Spectroscopy (2014), 45 (9), 773-780CODEN: JRSPAF; ISSN:0377-0486. (John Wiley & Sons Ltd.)
    Early cancer detection is the central and most important factor for allowing successful treatment and resultant pos. long-term patient outcomes. Recently, optical techniques have been applied to this purpose, although each has inherent limitations. In particular, Raman spectroscopy applied in the pathol. diagnosis of cancerous tissues has received increasing attention, with the merit of being highly sensitive to the biochem. alterations in tissue compns. and applicable in vivo. Nevertheless, its application has been impeded by the high background intensity, which masks the Raman signal of biol. mols. In this work, the influence of laser excitation wavelength (785 vs. 830 nm) and optical mode (single mode vs. multimode) on the background intensity of fresh human tissues was studied. Based on the results, laser with 830 nm excitation demonstrated better background redn. than that with 785 nm excitation for the same optical mode, but the Raman signal intensity was conversely reduced, and the signal-to-noise ratio (SNR) not improved. In contrast, by comparing single-mode and multimode 785 nm excitations, it was shown that the single-mode laser with its smaller beam waist and beam propagation factor had better background redn. ability and an improvement of the SNRs. It is speculated that this decrease in background intensity comes from the effect of the optical mode on the Mie scattering from the biol. tissue. High-quality spectra based on a careful selection of both laser excitation wavelength and optical mode will benefit Raman measurements in further research focusing on spectral interpretation and histopathol. correlation ultimately aimed toward intraoperative applications. Copyright © 2014 John Wiley & Sons, Ltd.
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    Barnes, R. J., Dhanoa, M. S., and Lister, S. J. (1989) Standard Normal Variate Transformation and De-trending of Near-Infrared Diffuse Reflectance Spectra. Appl. Spectrosc. 43 (5), 772– 777,  DOI: 10.1366/0003702894202201
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    Standard normal variate transformation and de-trending of near-infrared diffuse reflectance spectra
    Barnes, R. J.; Dhanoa, M. S.; Lister, Susan J.
    Applied Spectroscopy (1989), 43 (5), 772-7CODEN: APSPA4; ISSN:0003-7028.
    Particle size, scatter, and multicollinearity are long-standing problems encountered in diffuse reflectance spectrometry. Multiplicative combinations of these effects are the major factor inhibiting the interpretation of near-IR diffuse reflectance spectra. Sample particle size accounts for the majority of the variance, while variance due to chem. compn. is small. Procedures are presented whereby phys. and chem. variance can be sepd. Math. transformations std. normal variate (SNV) and de-trending (DT) applicable to individual NIR diffuse reflectance spectra are presented. The std. normal variate approach effectively removes the multiplicative interferences of scatter and particle size. De-trending accounts for the variation in base-line shift and curvilinearity, generally found in the reflectance spectra of powd. or densely packed samples, with the use of a 2nd-degree polynomial regression. NIR diffuse reflectance spectra transposed by these methods are free from multicollinearity and are not confused by the complexity of shape encountered with the use of deriv. spectroscopy.
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  • Abstract

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    Figure 1

    Figure 1. Intramuscular, in vivo, fiber optic Raman spectroscopy assessment. (a) A flowchart of the experiments. (b) A schematic of the fiber optic Raman system. (c) A mouse undergoing the procedure; the laser light can be appreciated within the hindleg as the camera used does not filter out the light. (d) Raman spectra obtained from muscle, blood, and bone. See Supporting Information Table 1 for tentative peak assignments and references.

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    Figure 2

    Figure 2. Intramuscular, in vivo Raman spectra and muscle histology. (a, b) Average spectra are shown for mdx and SOD1G93A, together with the relevant WT/NTg control for 30 and 90 days of age. Prominent peaks across the different groups are labeled (a and b). (c) Prominent Raman peaks in baseline subtracted spectra (present also in non-baseline subtracted spectra; Supporting Information Figure 2) and tentative peak assignments. See Supporting Information Table 1 for peak references. (d) Histological assessment at 30 days in mdx reveals necrotic fibers with inflammatory cells (arrow) and evidence of early regeneration (small myofibers with central nuclei, arrow heads). (e) The 90 day mdx muscle is characterized by regenerated myofibers, larger cells with central nuclei (arrow heads). (f) The 30 day SOD1G93A muscle appears normal. The myofibers have peripheral nuclei and a regular shape. (g, h) The 90 day SOD1G93A muscle displays evidence of denervation in the form of grouped atrophy (g, double arrow), small angular fibers (g, chevrons), and hypertrophic fibers (h, arrows) and centrally placed nuclei (g, h, arrowhead). (i) Normal myofibers from a 90 day WT mouse. Magnification for all images = x40, all scale bars = 100 μm. WT = wild type, NTg = nontransgenic.

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    Figure 3

    Figure 3. Linear discriminant function histograms and loadings plots. (a) Linear discriminant function (LDF) histogram and associated loadings plot for the comparison between 90 day SOD1G93A and NTg mice. (b) Tentative peak assignments for the 90 day SOD1G93A vs NTg comparison. (c) LDF histogram and associated loadings plot for the comparison between 30-day mdx and WT mice. (d) LDF histogram and associated loadings plot for the comparison between 90 day mdx and WT mice. (e) Tentative peak assignments for the mdx vs WT comparisons. Peak references can be found in Supporting Information Table 1. Wn = wavenumber.

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    Figure 4

    Figure 4. Post-in vivo Raman spectroscopy motor performance. Rotarod performance for 30 day SOD1G93A mice for both Raman (a) and sham (b) experiments. At 90 days of age, a significant decline in performance was seen two weeks postprocedure (c). However, there was no difference in rotarod performance at this final age (104 days) between mice undergoing Raman, sham, and no procedure (d), suggesting a disease-related decline. No change in rotarod performance was seen at either 30 days (e, f) or 90 days (g, h) in the mdx mice. ** = P < 0.01. d = day; wks = weeks.

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    Figure 5

    Figure 5. 7T MRI evaluation of muscle that has undergone in vivo Raman spectroscopy. (a) Axial MRI (ex vivo) from NTg (healthy) mice. Muscles were studied at three different time points post-Raman measurement. Each panel represents a different mouse. The yellow arrows denote high T2 signal which may be due to postprocedure edema. (b) Axial MRI (ex vivo) from two time points following a sham procedure. Each panel represents a different mouse.

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    Figure 6

    Figure 6. Human muscle spectra (ex vivo) and corresponding in vivo mouse model spectra. (a) Average ex vivo muscle spectra from patients with MND (orange) and in vivo spectra from 90 day-old SOD1G93A mice (blue). (b) Average ex vivo muscle spectra from patients with DMD (orange) and in vivo spectra from 90 day-old mdx mice (blue).

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  • References

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      Electrophysiological analysis of a murine model of motoneuron disease
      Mancuso Renzo; Santos-Nogueira Eva; Osta Rosario; Navarro Xavier
      Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology (2011), 122 (8), 1660-70 ISSN:.
      OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motoneurons of the primary motor cortex, the brainstem and the spinal cord, for which there are not effective treatments. Several transgenic mice that mimic motoneuron disease have been used to investigate potential treatments. The objective of this work is to characterize electrophysiologically the SOD1(G93A) transgenic mouse model of ALS, and to provide useful markers to improve early detection and monitoring of progression of the disease. METHODS: We performed nerve conduction tests, motor unit number estimation (MUNE), H reflex tests and motor evoked potentials (MEPs) in a cohort of transgenic and wild type mice from 4 to 16 weeks of age. RESULTS: The results revealed dysfunction of spinal motoneurons evidenced by deficits in motor nerve conduction tests starting at 8 weeks of age, earlier in proximal than in distal muscles of the hindlimb. MUNE demonstrated that spinal motoneurons loss muscle innervation and have a deficit in their sprouting capacity. Motor evoked potentials revealed that, coexisting with peripheral deficits, there was a dysfunction of central motor tracts that started also at 8 weeks, indicating progressive dysfunction of upper motoneurons. CONCLUSIONS: These electrophysiological results provide important information about the SOD1(G93A) mouse model, as they demonstrate by the first time alterations of central motor pathways simultaneously to lower motoneuron dysfunction, well before functional abnormalities appear (by 12 weeks of age). SIGNIFICANCE: The finding of concomitant dysfunction of upper and lower motoneurons contributes to the validation of the SOD1(G93A) mouse as model of ALS, because this parallel involvement is a diagnostic condition for ALS. Electrophysiological tests can be used as early markers of the disease and to evaluate the potential benefits of new treatments on both upper and lower motoneurons.
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      Ryder, S., Leadley, R. M., Armstrong, N., Westwood, M., de Kock, S., Butt, T., Jain, M., and Kleijnen, J. (2017) The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: an evidence review. Orphanet J. Rare Dis 12 (1), 79,  DOI: 10.1186/s13023-017-0631-3
      10
      The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: an evidence review
      Ryder S; Leadley R M; Armstrong N; Westwood M; de Kock S; Butt T; Jain M; Kleijnen J
      Orphanet journal of rare diseases (2017), 12 (1), 79 ISSN:.
      BACKGROUND: Duchenne Muscular Dystrophy (DMD) is a rapidly progressive, lethal neuromuscular disorder, present from birth, which occurs almost exclusively in males. We have reviewed contemporary evidence of burden, epidemiology, illness costs and treatment patterns of DMD. This systematic review adhered to published methods with information also sought from the web and contacting registries. Searches were carried out from 2005 to June 2015. The population of interest was individuals with clearly defined DMD or their carers. RESULTS: Nine thousand eight hundred fifty titles were retrieved from searches. Fifty-eight studies were reviewed with three assessed as high, 33 as medium and 22 as low quality. We found two studies reporting birth and four reporting point prevalence, three reporting mortality, 41 reporting severity and/or progression, 18 reporting treatment patterns, 12 reporting quality of life, two reporting utility measures, three reporting costs of illness and three treatment guidelines. Birth prevalence ranged from 15.9 to 19.5 per 100,000 live births. Point prevalence per 100,000 males was for France, USA, UK and Canada, 10.9, 1.9, 2.2 and 6.1 respectively. A study of adult DMD patients at a centre in France found median survival for those born between 1970 and 1994 was 40.95 years compared to 25.77 years for those born between 1955 and 1969. Loss of ambulation occurred at a median age of 12 and ventilation starts at about 20 years. There was international variation in use of corticosteroids, scoliosis surgery, ventilation and physiotherapy. The economic cost of DMD climbs dramatically with disease progression - rising as much as 5.7 fold from the early ambulatory phase to the non-ambulatory phase in Germany. CONCLUSIONS: This is the first systematic review of treatment, progression, severity and quality of life in DMD. It also provides the most recent description of the burden, epidemiology, illness costs and treatment patterns in DMD. There are evidence gaps, particularly in prevalence and mortality. People with DMD seem to be living longer, possibly due to corticosteroid use, cardiac medical management and ventilation. Future research should incorporate registry data to improve comparability across time and between countries and to investigate the quality of life impact as the condition progresses.
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    11. 11
      Yucel, N., Chang, A. C., Day, J. W., Rosenthal, N., and Blau, H. M. (2018) Humanizing the mdx mouse model of DMD: the long and the short of it. NPJ. Regen Med. 3, 4
      11
      Humanizing the mdx mouse model of DMD: the long and the short of it
      Yucel Nora; Chang Alex C; Blau Helen M; Day John W; Rosenthal Nadia
      NPJ Regenerative medicine (2018), 3 (), 4 ISSN:.
      Duchenne muscular dystrophy (DMD) is a common fatal heritable myopathy, with cardiorespiratory failure occurring by the third decade of life. There is no specific treatment for DMD cardiomyopathy, in large part due to a lack of understanding of the mechanisms underlying the cardiac failure. Mdx mice, which have the same dystrophin mutation as human patients, are of limited use, as they do not develop early dilated cardiomyopathy as seen in patients. Here we summarize the usefulness of the various commonly used DMD mouse models, highlight a model with shortened telomeres like humans, and identify directions that warrant further investigation.
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    12. 12
      Grounds, M. D., Radley, H. G., Lynch, G. S., Nagaraju, K., and De Luca, A. (2008) Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy. Neurobiol. Dis. 31 (1), 1– 19,  DOI: 10.1016/j.nbd.2008.03.008
      12
      Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy
      Grounds, Miranda D.; Radley, Hannah G.; Lynch, Gordon S.; Nagaraju, Kanneboyina; De Luca, Annamaria
      Neurobiology of Disease (2008), 31 (1), 1-19CODEN: NUDIEM; ISSN:0969-9961. (Elsevier Inc.)
      This review discusses various issues to consider when developing std. operating procedures for pre-clin. studies in the mdx mouse model of Duchenne muscular dystrophy (DMD). The review describes and evaluates a wide range of techniques used to measure parameters of muscle pathol. in mdx mice and identifies some basic techniques that might comprise standardized approaches for evaluation. While the central aim is to provide a basis for the development of standardized procedures to evaluate efficacy of a drug or a therapeutic strategy, a further aim is to gain insight into pathophysiol. mechanisms in order to identify other therapeutic targets. The desired outcome is to enable easier and more rigorous comparison of pre-clin. data from different labs. around the world, in order to accelerate identification of the best pre-clin. therapies in the mdx mouse that will fast-track translation into effective clin. treatments for DMD.
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    13. 13
      Carlson, C. G., Rutter, J., Bledsoe, C., Singh, R., Hoff, H., Bruemmer, K., Sesti, J., Gatti, F., Berge, J., and McCarthy, L. (2010) A simple protocol for assessing inter-trial and inter-examiner reliability for two noninvasive measures of limb muscle strength. J. Neurosci. Methods 186 (2), 226– 230,  DOI: 10.1016/j.jneumeth.2009.11.006
      13
      A simple protocol for assessing inter-trial and inter-examiner reliability for two noninvasive measures of limb muscle strength
      Carlson C George; Rutter John; Bledsoe Cathy; Singh Rajvir; Hoff Helena; Bruemmer Kay; Sesti Jenna; Gatti Francesca; Berge Jonas; McCarthy Laura
      Journal of neuroscience methods (2010), 186 (2), 226-30 ISSN:.
      Noninvasive measures of limb muscle strength are quite useful in preclinical translational studies that use mouse models of muscle disease, peripheral nerve disease, and movement disorders. The present study uses a simple protocol for assessing both inter-trial and inter-examiner reliability for two noninvasive methods of assessing limb strength in dystrophic (mdx) and wild type mice. One method, termed the whole body tension (WBT) method or escape test, measures the total phasic pulling tension exerted by the fore- and hindlimbs while a mouse attempts to escape into a darkened tube. Another procedure, termed the four limb wire grid holding test, measures the minimal amount of sustained tension (physical impulse) exerted by the fore- and hindlimbs while the mouse hangs suspended in an upside-down position. A comparison of the two methods revealed significant inter-trial and inter-examiner correlations in each procedure, although the WBT procedure consistently produced higher correlations than the four limb wire grid holding test. Inter-trial reliability for each test was higher than inter-examiner reliability, indicating that each longitudinal series of tests is best performed by a single investigator. The holding test also did not consistently detect differences between wild type and mdx populations at ages greater than 4 months. These results demonstrate the utility of a simple protocol for assessing the reliability of noninvasive tests that measure limb strength, and should be useful in comparing different functional measures in a broad range of translational studies.
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    14. 14
      Butler, H. J., Ashton, L., Bird, B., Cinque, G., Curtis, K., Dorney, J., Esmonde-White, K., Fullwood, N. J., Gardner, B., Martin-Hirsch, P. L. (2016) Using Raman spectroscopy to characterize biological materials. Nat. Protoc. 11 (4), 664– 687,  DOI: 10.1038/nprot.2016.036
      14
      Using Raman spectroscopy to characterize biological materials
      Butler, Holly J.; Ashton, Lorna; Bird, Benjamin; Cinque, Gianfelice; Curtis, Kelly; Dorney, Jennifer; Esmonde-White, Karen; Fullwood, Nigel J.; Gardner, Benjamin; Martin-Hirsch, Pierre L.; Walsh, Michael J.; McAinsh, Martin R.; Stone, Nicholas; Martin, Francis L.
      Nature Protocols (2016), 11 (4), 664-687CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)
      Raman spectroscopy can be used to measure the chem. compn. of a sample, which can in turn be used to ext. biol. information. Many materials have characteristic Raman spectra, which means that Raman spectroscopy has proven to be an effective anal. approach in geol., semiconductor, materials and polymer science fields. The application of Raman spectroscopy and microscopy within biol. is rapidly increasing because it can provide chem. and compositional information, but it does not typically suffer from interference from water mols. Anal. does not conventionally require extensive sample prepn.; biochem. and structural information can usually be obtained without labeling. In this protocol, we aim to standardize and bring together multiple exptl. approaches from key leaders in the field for obtaining Raman spectra using a microspectrometer. As examples of the range of biol. samples that can be analyzed, we provide instructions for acquiring Raman spectra, maps and images for fresh plant tissue, formalin-fixed and fresh frozen mammalian tissue, fixed cells and biofluids. We explore a robust approach for sample prepn., instrumentation, acquisition parameters and data processing. By using this approach, we expect that a typical Raman expt. can be performed by a nonspecialist user to generate high-quality data for biol. materials anal.
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    15. 15
      Khristoforova, Y. A., Bratchenko, I. A., Myakinin, O. O., Artemyev, D. N., Moryatov, A. A., Orlov, A. E., Kozlov, S. V., and Zakharov, V. P. (2019) Portable spectroscopic system for in vivo skin neoplasms diagnostics by Raman and autofluorescence analysis. J. Biophotonics 12, 1,  DOI: 10.1002/jbio.201800400
      There is no corresponding record for this reference.
    16. 16
      McGregor, H. C., Short, M. A., McWilliams, A., Shaipanich, T., Ionescu, D. N., Zhao, J., Wang, W., Chen, G., Lam, S., and Zeng, H. (2017) Real-time endoscopic Raman spectroscopy for in vivo early lung cancer detection. J. Biophotonics 10 (1), 98– 110,  DOI: 10.1002/jbio.201500204
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      Real-time endoscopic Raman spectroscopy for in vivo early lung cancer detection
      McGregor, Hanna C.; Short, Michael A.; McWilliams, Annette; Shaipanich, Tawimas; Ionescu, Diana N.; Zhao, Jianhua; Wang, Wenbo; Chen, Guannan; Lam, Stephen; Zeng, Haishan
      Journal of Biophotonics (2017), 10 (1), 98-110CODEN: JBOIBX; ISSN:1864-0648. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Currently the most sensitive method for localizing lung cancers in central airways is autofluorescence bronchoscopy (AFB) in combination with white light bronchoscopy (WLB). The diagnostic accuracy of WLB + AFB for high grade dysplasia (HGD) and carcinoma in situ is variable depending on physician's experience. When WLB + AFB are operated at high diagnostic sensitivity, the assocd. diagnostic specificity is low. Raman spectroscopy probes mol. vibrations and gives highly specific, fingerprint-like spectral features and has high accuracy for tissue pathol. classification. In this study we present the use of a real-time endoscopy Raman spectroscopy system to improve the specificity. A spectrum is acquired within 1 s and clin. data are obtained from 280 tissue sites (72 HGDs/malignant lesions, 208 benign lesions/normal sites) in 80 patients. Using multivariate analyses and waveband selection methods on the Raman spectra, we have demonstrated that HGD and malignant lung lesions can be detected with high sensitivity (90%) and good specificity (65%).
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    17. 17
      Lloyd, G. R., Orr, L. E., Christie-Brown, J., McCarthy, K., Rose, S., Thomas, M., and Stone, N. (2013) Discrimination between benign, primary and secondary malignancies in lymph nodes from the head and neck utilising Raman spectroscopy and multivariate analysis. Analyst 138 (14), 3900– 3908,  DOI: 10.1039/c2an36579k
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      Discrimination between benign, primary and secondary malignancies in lymph nodes from the head and neck utilising Raman spectroscopy and multivariate analysis
      Lloyd, Gavin Rhys; Orr, Linda E.; Christie-Brown, Jonathan; McCarthy, Keith; Rose, Simon; Thomas, Michael; Stone, Nicholas
      Analyst (Cambridge, United Kingdom) (2013), 138 (14), 3900-3908CODEN: ANALAO; ISSN:0003-2654. (Royal Society of Chemistry)
      Background: The potential use of Raman spectroscopy (RS) for the detection of malignancy within lymph nodes of the head and neck was evaluated. RS measures the presence of biomols. by the inelastic scattering of light within cells and tissues. This can be performed in vivo in real-time. Methods: 103 lymph nodes were collected from 23 patients undergoing surgery for suspicious lymph nodes. Five pathologies, defined by consensus histopathol., were collected including reactive nodes (benign), Hodgkin's and non-Hodgkin's lymphomas, metastases from both squamous cell carcinomas and adenocarcinomas. Raman spectra were measured with 830 nm excitation from numerous positions on each biopsy. Spectral diagnostic models were constructed using principal component anal. followed by linear discriminant anal. (PCA-LDA), and by partial least squares discriminant anal. (PLS-DA) for comparison. Two-group models were constructed to distinguish between reactive and malignant nodes, and three-group models to distinguish between the benign, primary and secondary conditions. Results: Results were validated using a repeated subsampling procedure. Sensitivities and specificities of 90% and 86% were obtained using PCA-LDA, and 89% and 88% using PLS-DA, for the two-group models. Both PCA-LDA and PLS-DA models were also found to be very successful at discriminating between pathologies in the three-group models achieving sensitivities and specificities of over 78% and 89% for PCA-LDA, and over 81% and 89% for PLS-DA for all three pathol. groups. Conclusion: Raman spectroscopy and chemometric techniques can be successfully utilized in combination for discriminating between different cancerous conditions of lymph nodes from the head and neck.
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    18. 18
      Nicolson, F., Jamieson, L. E., Mabbott, S., Plakas, K., Shand, N. C., Detty, M. R., Graham, D., and Faulds, K. (2018) Multiplex imaging of live breast cancer tumour models through tissue using handheld surface enhanced spatially offset resonance Raman spectroscopy (SESORRS). Chem. Commun. (Cambridge, U. K.) 54 (61), 8530– 8533,  DOI: 10.1039/C8CC04267E
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      Multiplex imaging of live breast cancer tumour models through tissue using handheld surface enhanced spatially offset resonance Raman spectroscopy (SESORRS)
      Nicolson, Fay; Jamieson, Lauren E.; Mabbott, Samuel; Plakas, Konstantinos; Shand, Neil C.; Detty, Michael R.; Graham, Duncan; Faulds, Karen
      Chemical Communications (Cambridge, United Kingdom) (2018), 54 (61), 8530-8533CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      Through using the depth penetration capabilities of SESORS, multiplexed imaging and classification of three singleplex nanotags and a triplex of nanotags within breast cancer tumor models is reported for the first time through depths of 10 mm using a handheld SORS instrument.
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    19. 19
      Jermyn, M., Mok, K., Mercier, J., Desroches, J., Pichette, J., Saint-Arnaud, K., Bernstein, L., Guiot, M. C., Petrecca, K., and Leblond, F. (2015) Intraoperative brain cancer detection with Raman spectroscopy in humans. Sci. Transl Med. 7 (274), 274ra219,  DOI: 10.1126/scitranslmed.aaa2384
      There is no corresponding record for this reference.
    20. 20
      Tian, F., Yang, W., Mordes, D. A., Wang, J. Y., Salameh, J. S., Mok, J., Chew, J., Sharma, A., Leno-Duran, E., Suzuki-Uematsu, S. (2016) Monitoring peripheral nerve degeneration in ALS by label-free stimulated Raman scattering imaging. Nat. Commun. 7, 13283,  DOI: 10.1038/ncomms13283
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      Monitoring peripheral nerve degeneration in ALS by label-free stimulated Raman scattering imaging
      Tian, Feng; Yang, Wenlong; Mordes, Daniel A.; Wang, Jin-Yuan; Salameh, Johnny S.; Mok, Joanie; Chew, Jeannie; Sharma, Aarti; Leno-Duran, Ester; Suzuki-Uematsu, Satomi; Suzuki, Naoki; Han, Steve S.; Lu, Fa-Ke; Ji, Minbiao; Zhang, Rosanna; Liu, Yue; Strominger, Jack; Shneider, Neil A.; Petrucelli, Leonard; Xie, X. Sunney; Eggan, Kevin
      Nature Communications (2016), 7 (), 13283CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
      The study of amyotrophic lateral sclerosis (ALS) and potential interventions would be facilitated if motor axon degeneration could be more readily visualized. Here we demonstrate that stimulated Raman scattering (SRS) microscopy could be used to sensitively monitor peripheral nerve degeneration in ALS mouse models and ALS autopsy materials. Three-dimensional imaging of pre-symptomatic SOD1 mouse models and data processing by a correlation-based algorithm revealed that significant degeneration of peripheral nerves could be detected coincidentally with the earliest detectable signs of muscle denervation and preceded physiol. measurable motor function decline. We also found that peripheral degeneration was an early event in FUS as well as C9ORF72 repeat expansion models of ALS, and that serial imaging allowed long-term observation of disease progression and drug effects in living animals. Our study demonstrates that SRS imaging is a sensitive and quant. means of measuring disease progression, greatly facilitating future studies of disease mechanisms and candidate therapeutics.
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    21. 21
      Picardi, G., Spalloni, A., Generosi, A., Paci, B., Mercuri, N. B., Luce, M., Longone, P., and Cricenti, A. (2018) Tissue degeneration in ALS affected spinal cord evaluated by Raman spectroscopy. Sci. Rep 8 (1), 13110
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      Tissue degeneration in ALS affected spinal cord evaluated by Raman spectroscopy
      Picardi Gennaro; Generosi Amanda; Paci Barbara; Luce Marco; Cricenti Antonio; Spalloni Alida; Longone Patrizia; Mercuri Nicola Biagio; Mercuri Nicola Biagio
      Scientific reports (2018), 8 (1), 13110 ISSN:.
      The Raman spectral features from spinal cord tissue sections of transgenic, ALS model mice and non-transgenic mice were compared using 457 nm excitation line, profiting from the favourable signal intensity obtained in the molecular fingerprint region at this wavelength. Transverse sections from four SOD1G93A mice at 75 days and from two at 90 days after birth were analysed and compared with sections of similarly aged control mice. The spectra acquired within the grey matter of tissue sections from the diseased mice is markedly different from the grey matter signature of healthy mice. In particular, we observe an intensity increase in the spectral windows 450-650 cm(-1) and 1050-1200 cm(-1), accompanied by an intensity decrease in the lipid contributions at ~1660 cm(-1), ~1440 cm(-1) and ~1300 cm(-1). Axons demyelination, loss of lipid structural order and the proliferation and aggregation of branched proteoglycans are related to the observed spectral modifications. Furthermore, the grey and white matter components of the spinal cord sections could also be spectrally distinguished, based on the relative intensity of characteristic lipid and protein bands. Raman spectra acquired from the white matter regions of the SOD1G93A mice closely resembles those from control mice.
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    22. 22
      Gautam, R., Vanga, S., Madan, A., Gayathri, N., Nongthomba, U., and Umapathy, S. (2015) Raman spectroscopic studies on screening of myopathies. Anal. Chem. 87 (4), 2187– 2194,  DOI: 10.1021/ac503647x
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      Raman Spectroscopic Studies on Screening of Myopathies
      Gautam, Rekha; Vanga, Sandeep; Madan, Aditi; Gayathri, Narayanappa; Nongthomba, Upendra; Umapathy, Siva
      Analytical Chemistry (Washington, DC, United States) (2015), 87 (4), 2187-2194CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      Myopathies are among the major causes of mortality in the world. There is no complete cure for this heterogeneous group of diseases, but a sensitive, specific, and fast diagnostic tool may improve therapy effectiveness. In this study, Raman spectroscopy is applied to discriminate between muscle mutants in Drosophila on the basis of assocd. changes at the mol. level. Raman spectra were collected from indirect flight muscles of mutants, upheld1 (up1), heldup2 (hdp2), myosin heavy chain7 (Mhc7), actin88FKM88 (Act88FKM88), upheld101 (up101), and Canton-S (CS) control group, for both 2 and 12 days old flies. Difference spectra (mutant minus control) of all the mutants showed an increase in nucleic acid and β-sheet and/or random coil protein content along with a decrease in α-helix protein. Interestingly, the 12th day samples of up1 and Act88FKM88 showed significantly higher levels of glycogen and carotenoids than CS. A principal components based linear discriminant anal. classification model was developed based on multidimensional Raman spectra, which classified the mutants according to their pathophysiol. and yielded an overall accuracy of 97% and 93% for 2 and 12 days old flies, resp. The up1 and Act88FKM88 (nemaline-myopathy) mutants form a group that is clearly sepd. in a linear discriminant plane from up101 and hdp2 (cardiomyopathy) mutants. Notably, Raman spectra from a human sample with nemaline-myopathy formed a cluster with the corresponding Drosophila mutant (up1). In conclusion, this is the first demonstration in which myopathies, despite their heterogeneity, were screened on the basis of biochem. differences using Raman spectroscopy.
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    23. 23
      Chen, X., Sanchez, G. N., Schnitzer, M. J., and Delp, S. L. (2020) Microendoscopy detects altered muscular contractile dynamics in a mouse model of amyotrophic lateral sclerosis. Sci. Rep 10 (1), 457,  DOI: 10.1038/s41598-019-56555-z
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      Microendoscopy detects altered muscular contractile dynamics in a mouse model of amyotrophic lateral sclerosis
      Chen, Xuefeng; Sanchez, Gabriel N.; Schnitzer, Mark J.; Delp, Scott L.
      Scientific Reports (2020), 10 (1), 457CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
      Abstr.: Amyotrophic lateral sclerosis (ALS) is a fatal disease involving motor neuron degeneration. Effective diagnosis of ALS and quant. monitoring of its progression are crucial to the success of clin. trials. Second harmonic generation (SHG) microendoscopy is an emerging technol. for imaging single motor unit contractions. To assess the potential value of microendoscopy for diagnosing and tracking ALS, we monitored motor unit dynamics in a B6. SOD1G93A mouse model of ALS for several weeks. Prior to overt symptoms, muscle twitch rise and relaxation time consts. both increased, consistent with a loss of fast-fatigable motor units. These effects became more pronounced with disease progression, consistent with the death of fast fatigue-resistant motor units and superior survival of slow motor units. From these measurements we constructed a physiol. metric that reflects the changing distributions of measured motor unit time consts. and effectively diagnoses mice before symptomatic onset and tracks disease state. These results indicate that SHG microendoscopy provides a means for developing a quant., physiol. characterization of ALS progression.
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    24. 24
      Hegedus, J., Putman, C. T., and Gordon, T. (2007) Time course of preferential motor unit loss in the SOD1 G93A mouse model of amyotrophic lateral sclerosis. Neurobiol. Dis. 28 (2), 154– 164,  DOI: 10.1016/j.nbd.2007.07.003
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      Time course of preferential motor unit loss in the SOD1G93A mouse model of amyotrophic lateral sclerosis
      Hegedus, J.; Putman, C. T.; Gordon, T.
      Neurobiology of Disease (2007), 28 (2), 154-164CODEN: NUDIEM; ISSN:0969-9961. (Elsevier)
      Electromyog. analyses of pre-symptomatic motor unit loss in the SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis (ALS) have yielded contradictory findings as to the onset and time course. We recorded hindlimb muscle and motor unit isometric forces to det. motor unit no. and size throughout the life span of the mice. Motor unit nos. in fast-twitch tibialis anterior, extensor digitorum longus and medial gastrocnemius muscles declined from 40 days of age, 50 days before reported overt symptoms and motoneuron loss. Motor unit nos. fell after overt symptoms in the slow-twitch soleus muscle. Muscle forces declined in parallel with motor unit nos., indicating little or no functional compensation by sprouting. Early muscle-specific decline was due to selective preferential vulnerability of large, fast motor units, innervated by large motoneurons. Large motoneurons are hence the most vulnerable in ALS with die-back occurring prior to overt symptoms. We conclude that size of motoneurons, their axons, and their motor unit size are important determinants of motoneuron susceptibility in ALS.
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    25. 25
      Manning, J. and O’Malley, D. (2015) What has the mdx mouse model of Duchenne muscular dystrophy contributed to our understanding of this disease?. J. Muscle Res. Cell Motil. 36 (2), 155– 167,  DOI: 10.1007/s10974-015-9406-4
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      What has the mdx mouse model of duchenne muscular dystrophy contributed to our understanding of this disease?
      Manning, Jennifer; O'Malley, Dervla
      Journal of Muscle Research and Cell Motility (2015), 36 (2), 155-167CODEN: JMRMD3; ISSN:0142-4319. (Springer)
      Duchenne muscular dystrophy (DMD) is a fatal X-chromosome linked recessive disorder caused by the truncation or deletion of the dystrophin gene. The most widely used animal model of this disease is the dystrophin-deficient mdx mouse which was first discovered 30 years ago. Despite its extensive use in DMD research, no effective treatment has yet been developed for this devastating disease. This review explores what we have learned from this mouse model regarding the pathophysiol. of DMD and asks if it has a future in providing a better more thorough understanding of this disease or if it will bring us any closer to improving the outlook for DMD patients.
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    26. 26
      Berkemeier, F., Bertz, M., Xiao, S., Pinotsis, N., Wilmanns, M., Grater, F., and Rief, M. (2011) Fast-folding alpha-helices as reversible strain absorbers in the muscle protein myomesin. Proc. Natl. Acad. Sci. U. S. A. 108 (34), 14139– 14144,  DOI: 10.1073/pnas.1105734108
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      Fast-folding α-helices as reversible strain absorbers in the muscle protein myomesin
      Berkemeier, Felix; Bertz, Morten; Xiao, Senbo; Pinotsis, Nikos; Wilmanns, Matthias; Gater, Frauke; Rief, Matthias
      Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (34), 14139-14144, S14139/1-S14139/7CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      The highly oriented filamentous protein network of muscle constantly experiences significant mech. load during muscle operation. The dimeric protein myomesin has been identified as an important M-band component supporting the mech. integrity of the entire sarcomere. Recent structural studies have revealed a long α-helical linker between the C-terminal Ig domains My12 and My13 of myomesin. In this paper, we have used single-mol. force spectroscopy in combination with mol. dynamics simulations to characterize the mechanics of the myomesin dimer comprising Ig domains My12-My13. We find that at forces of approx. 30 pN the α-helical linker reversibly elongates allowing the mol. to extend by more than the folded extension of a full domain. High-resoln. measurements directly reveal the equil. folding/unfolding kinetics of the individual helix. We show that a-helix unfolding mech. protects the mol. homodimerization from dissocn. at physiol. relevant forces. As fast and reversible mol. springs the myomesin α-helical linkers are an essential component for the structural integrity of the M band.
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    27. 27
      Wu, G., Bazer, F. W., Burghardt, R. C., Johnson, G. A., Kim, S. W., Knabe, D. A., Li, P., Li, X., McKnight, J. R., Satterfield, M. C. (2011) Proline and hydroxyproline metabolism: implications for animal and human nutrition. Amino Acids 40 (4), 1053– 1063,  DOI: 10.1007/s00726-010-0715-z
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      Proline and hydroxyproline metabolism: implications for animal and human nutrition
      Wu, Guoyao; Bazer, Fuller W.; Burghardt, Robert C.; Johnson, Gregory A.; Kim, Sung Woo; Knabe, Darrell A.; Li, Peng; Li, Xilong; McKnight, Jason R.; Satterfield, M. Carey; Spencer, Thomas E.
      Amino Acids (2011), 40 (4), 1053-1063CODEN: AACIE6; ISSN:0939-4451. (SpringerWienNewYork)
      A review. Proline plays important roles in protein synthesis and structure, metab. (particularly the synthesis of arginine, polyamines, and glutamate via pyrroline-5-carboxylate), and nutrition, as well as wound healing, antioxidative reactions, and immune responses. On a per-g basis, proline plus hydroxyproline are most abundant in collagen and milk proteins, and requirements of proline for whole-body protein synthesis are the greatest among all amino acids. Therefore, physiol. needs for proline are particularly high during the life cycle. While most mammals (including humans and pigs) can synthesize proline from arginine and glutamine/glutamate, rates of endogenous synthesis are inadequate for neonates, birds, and fish. Thus, work with young pigs (a widely used animal model for studying infant nutrition) has shown that supplementing 0.0%, 0.355, 0.75, 1.05%, 1.4%, and 2.1% proline to a proline-free chem. defined diet contg. 0.48% arginine and 2% glutamate dose dependently improved daily growth rate and feed efficiency while reducing concns. of urea in plasma. Addnl., maximal growth performance of chickens depended on at least 0.8% proline in the diet. Likewise, dietary supplementation with 0.07%, 0.14%, and 0.28% hydroxyproline (a metabolite of proline) to a plant protein-based diet enhanced wt. gains of salmon. Based on its regulatory roles in cellular biochem., proline can be considered as a functional amino acid for mammalian, avian, and aquatic species. Further research is warranted to develop effective strategies of dietary supplementation with proline or hydroxyproline to benefit health, growth, and development of animals and humans.
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    28. 28
      Ferraiuolo, L., De Bono, J. P., Heath, P. R., Holden, H., Kasher, P., Channon, K. M., Kirby, J., and Shaw, P. J. (2009) Transcriptional response of the neuromuscular system to exercise training and potential implications for ALS. J. Neurochem. 109 (6), 1714– 1724,  DOI: 10.1111/j.1471-4159.2009.06080.x
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      Transcriptional response of the neuromuscular system to exercise training and potential implications for ALS
      Ferraiuolo, Laura; De Bono, Joseph P.; Heath, Paul R.; Holden, Hazel; Kasher, Paul; Channon, Keith M.; Kirby, Janine; Shaw, Pamela J.
      Journal of Neurochemistry (2009), 109 (6), 1714-1724CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)
      The transcriptional adaptive response of motoneurons and muscles to voluntary exercise has been investigated by using laser capture microdissection and microarray anal. Our results show that motoneurons respond to phys. activity by activating a complex transcriptional plan, with changes involved in neurotrophic factor signaling, electrophysiol. changes and synaptic reorganization. Gastrocnemius muscle shows increases in transcripts responsible for neovascularization and new myogenesis. Both tissues show transcriptional changes involved in the growth and reinforcement of the neuromuscular junction. This study indicates that the neuromuscular system undergoes significant structural and functional alterations, aiming to optimize the transmission of both chem. and elec. stimuli, thus prompting axonal outgrowth and mechanisms similar to long-term potentiation in hippocampal neurons. Understanding the response of these cells during exercise has potentially important implications for human neuromuscular disease, including amyotrophic lateral sclerosis, by highlighting candidate genes pivotal for the balance between the physiol. and the pathol. of the neuromuscular system in terms of the stress response to phys. exercise.
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    29. 29
      Gonzalez de Aguilar, J. L., Niederhauser-Wiederkehr, C., Halter, B., De Tapia, M., Di Scala, F., Demougin, P., Dupuis, L., Primig, M., Meininger, V., and Loeffler, J. P. (2008) Gene profiling of skeletal muscle in an amyotrophic lateral sclerosis mouse model. Physiol. Genomics 32 (2), 207– 218,  DOI: 10.1152/physiolgenomics.00017.2007
      29
      Gene profiling of skeletal muscle in an amyotrophic lateral sclerosis mouse model
      Gonzalez de Aguilar, Jose-Luis; Niederhauser-Wiederkehr, Christa; Halter, Benoit; de Tapia, Marc; di Scala, Franck; Demougin, Philippe; Dupuis, Luc; Primig, Michael; Meininger, Vincent; Loeffler, Jean-Philippe
      Physiological Genomics (2008), 32 (2), 207-218CODEN: PHGEFP; ISSN:1094-8341. (American Physiological Society)
      Muscle atrophy is a major hallmark of amyotrophic lateral sclerosis (ALS), the most frequent adult-onset motor neuron disease. To define the full set of alterations in gene expression in skeletal muscle during the course of the disease, the authors used the G86R superoxide dismutase-1 transgenic mouse model of ALS and performed high-d. oligonucleotide microarrays. The authors compared these data to those obtained by axotomy-induced denervation. A major set of gene regulations in G86R muscles resembled those of surgically denervated muscles, but many others appeared specific to the ALS condition. The first significant transcriptional changes appeared in a subpopulation of mice before the onset of overt clin. symptoms and motor neuron death. These early changes affected genes involved in detoxification (e.g., ALDH3, metallothionein-2, and thioredoxin-1) and regeneration (e.g., BTG1, RB1, and RUNX1) but also tissue degrdn. (e.g., C/EBPδ and DDIT4) and cell death (e.g., ankyrin repeat domain-1, CDKN1A, GADD45α, and PEG3). Of particular interest, metallothionein-1 and -2, ATF3, cathepsin-Z, and galectin-3 genes appeared, among others, commonly regulated in both skeletal muscle (our present data) and spinal motor neurons (as previously reported) of paralyzed ALS mice. The importance of these findings is twofold. First, they designate the distal part of the motor unit as a primary site of disease. Second, they identify specific gene regulations to be explored in the search for therapeutic strategies that could alleviate disease before motor neuron death manifests clin.
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    30. 30
      Porter, J. D., Merriam, A. P., Leahy, P., Gong, B., Feuerman, J., Cheng, G., and Khanna, S. (2004) Temporal gene expression profiling of dystrophin-deficient (mdx) mouse diaphragm identifies conserved and muscle group-specific mechanisms in the pathogenesis of muscular dystrophy. Hum. Mol. Genet. 13 (3), 257– 269,  DOI: 10.1093/hmg/ddh033
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      Temporal gene expression profiling of dystrophin-deficient (mdx) mouse diaphragm identifies conserved and muscle group-specific mechanisms in the pathogenesis of muscular dystrophy
      Porter, John D.; Merriam, Anita P.; Leahy, Patrick; Gong, Bendi; Feuerman, Jason; Cheng, Georgiana; Khanna, Sangeeta
      Human Molecular Genetics (2004), 13 (3), 257-269CODEN: HMGEE5; ISSN:0964-6906. (Oxford University Press)
      Mutations in dystrophin are the proximate cause of Duchenne muscular dystrophy (DMD), but pathogenic mechanisms linking the absence of dystrophin from the sarcolemma to myofiber necrosis are not fully known. The muscular dystrophies also have properties not accounted for by current disease models, including the temporal delay to disease onset, broad species differences in severity, and diversity of skeletal muscle responses. To address the mechanisms underlying the differential targeting of muscular dystrophy, we characterized temporal expression profiles of the diaphragm in dystrophin-deficient (mdx) mice between postnatal days 7 and 112 using oligonucleotide microarrays and contrasted these data with published hindlimb muscle data. Although the diaphragm and hindlimb muscle groups differ in severity of response to dystrophin deficiency, and exhibited substantial divergence in some transcript categories including inflammation and muscle-specific genes, our data show that the general mechanisms operative in muscular dystrophy are highly conserved. The two muscle groups principally differed in expression levels of differentially regulated genes, as opposed to the non-conserved induced/repressed transcripts defining fundamentally distinct mechanisms. We also identified a postnatal divergence of the two wild-type muscle group expression profiles that temporally correlated with the onset and progression of the dystrophic process. These findings support the hypothesis that conserved disease mechanisms interacting with baseline differences in muscle group-specific transcriptomes underlie their differential responses to DMD. We further suggest that muscle group-specific transcriptional profiles contribute toward the muscle targeting and sparing patterns obsd. for a variety of metabolic and neuromuscular diseases.
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    31. 31
      Dobrowolny, G., Aucello, M., Rizzuto, E., Beccafico, S., Mammucari, C., Boncompagni, S., Belia, S., Wannenes, F., Nicoletti, C., Del Prete, Z. (2008) Skeletal muscle is a primary target of SOD1G93A-mediated toxicity. Cell Metab 8 (5), 425– 436,  DOI: 10.1016/j.cmet.2008.09.002
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      Skeletal muscle is a primary target of SOD1G93A-mediated toxicity
      Dobrowolny, Gabriella; Aucello, Michela; Rizzuto, Emanuele; Beccafico, Sara; Mammucari, Cristina; Bonconpagni, Simona; Belia, Silvia; Wannenes, Francesca; Nicoletti, Carmine; Del Prete, Zaccaria; Rosenthal, Nadia; Molinaro, Mario; Protasi, Feliciano; Fano, Giorgio; Sandri, Marco; Musaro, Antonio
      Cell Metabolism (2008), 8 (5), 425-436CODEN: CMEEB5; ISSN:1550-4131. (Cell Press)
      The antioxidant enzyme superoxide dismutase 1 (SOD1) is a crit. player of the antioxidative defense whose activity is altered in several chronic diseases, including amyotrophic lateral sclerosis. However, how oxidative insult affects muscle homeostasis remains unclear. This study addresses the role of oxidative stress on muscle homeostasis and function by the generation of a transgenic mouse model expressing a mutant SOD1 gene (SOD1G93A) selectively in skeletal muscle. Transgenic mice developed progressive muscle atrophy, assocd. with a significant redn. in muscle strength, alterations in the contractile app., and mitochondrial dysfunction. The anal. of mol. pathways assocd. with muscle atrophy revealed that accumulation of oxidative stress served as signaling mols. to initiate autophagy, one of the major intracellular degrdn. mechanisms. These data demonstrate that skeletal muscle is a primary target of SOD1G93A-mediated toxicity and disclose the mol. mechanism whereby oxidative stress triggers muscle atrophy.
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    32. 32
      Schill, K. E., Altenberger, A. R., Lowe, J., Periasamy, M., Villamena, F. A., Rafael-Fortney, J. A., and Devor, S. T. (2016) Muscle damage, metabolism, and oxidative stress in mdx mice: Impact of aerobic running. Muscle Nerve 54 (1), 110– 117,  DOI: 10.1002/mus.25015
      32
      Muscle damage, metabolism, and oxidative stress in mdx mice: Impact of aerobic running
      Schill, Kevin E.; Altenberger, Alex. R.; Lowe, Jeovanna; Periasamy, Muthu; Villamena, Frederick A.; Rafael-Fortney, Jill A.; Devor, Steven T.
      Muscle & Nerve (2016), 54 (1), 110-117CODEN: MUNEDE; ISSN:0148-639X. (John Wiley & Sons, Inc.)
      Introduction: We tested how a treadmill exercise program influences oxygen consumption, oxidative stress, and exercise capacity in the mdx mouse, a model of Duchenne muscular dystrophy. Methods: At age 4 wk mdx mice were subjected to 4 wk of twice-weekly treadmill exercise. Sedentary mdx and wild-type mice served as controls. Oxygen consumption, time to exhaustion, oxidative stress, and myofiber damage were assessed. Results: At age 4 wk, there was a significant difference in exercise capacity between mdx and wild-type mice. After exercise, mdx mice had lower basal oxygen consumption and exercise capacity, but similar maximal oxygen consumption. Skeletal muscle from these mice displayed increased oxidative stress. Collagen deposition was higher in exercised vs. sedentary mice. Conclusions: Exercised mdx mice exhibit increased oxidative stress, as well as deficits in exercise capacity, baseline oxygen consumption, and increased myofiber fibrosis. Muscle Nerve 54: 110-117, 2016.
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    33. 33
      Rivas-Arancibia, S., Rodriguez-Martinez, E., Badillo-Ramirez, I., Lopez-Gonzalez, U., and Saniger, J. M. (2017) Structural Changes of Amyloid Beta in Hippocampus of Rats Exposed to Ozone: A Raman Spectroscopy Study. Front Mol. Neurosci 10, 137,  DOI: 10.3389/fnmol.2017.00137
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      Structural Changes of Amyloid Beta in Hippocampus of Rats Exposed to Ozone: A Raman Spectroscopy Study
      Rivas-Arancibia Selva; Rodriguez-Martinez Erika; Badillo-Ramirez Isidro; Lopez-Gonzalez Ulises; Saniger Jose M
      Frontiers in molecular neuroscience (2017), 10 (), 137 ISSN:1662-5099.
      The aim of this work was to study the effect of oxidative stress on the structural changes of the secondary peptide structure of amyloid beta 1-42 (Aβ 1-42), in the dentate gyrus of hippocampus of rats exposed to low doses of ozone. The animals were exposed to ozone-free air (control group) and 0.25 ppm ozone during 7, 15, 30, 60, and 90 days, respectively. The samples were studied by: (1) Raman spectroscopy to detect the global conformational changes in peptides with α-helix and β-sheet secondary structure, following the deconvolution profile of the amide I band; and (2) immunohistochemistry against Aβ 1-42. The results of the deconvolutions of the amide I band indicate that, ozone exposure causes a progressively decrease in the abundance percentage of α-helix secondary structure. Furthermore, the β-sheet secondary structure increases its abundance percentage. After 60 days of ozone exposure, the β-sheet band is identified in a similar wavenumber of the Aβ 1-42 peptide standard. Immunohistochemistry assays show an increase of Aβ 1-42 immunoreactivity, coinciding with the conformational changes observed in the Raman spectroscopy of Aβ 1-42 at 60 and 90 days. In conclusion, oxidative stress produces changes in the folding process of amyloid beta peptide structure in the dentate gyrus, leading to its conformational change in a final β-sheet structure. This is associated to an increase in Aβ 1-42 expression, similar to the one that happens in the brain of Alzheimer's Disease (AD) patients.
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    34. 34
      Chen, Y., Wang, Z., Huang, Y., Feng, S., Zheng, Z., Liu, X., and Liu, M. (2019) Label-free detection of hydrogen peroxide-induced oxidative stress in human retinal pigment epithelium cells via laser tweezers Raman spectroscopy. Biomed. Opt. Express 10 (2), 500– 513,  DOI: 10.1364/BOE.10.000500
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      Label-free detection of hydrogen peroxide-induced oxidative stress in human retinal pigment epithelium cells via laser tweezers Raman spectroscopy
      Chen, Yang; Wang, Zhiqiang; Huang, Yan; Feng, Shangyuan; Zheng, Zuci; Liu, Xiujie; Liu, Mengmeng
      Biomedical Optics Express (2019), 10 (2), 500-513CODEN: BOEICL; ISSN:2156-7085. (Optical Society of America)
      Human retinal pigment epithelium cells under hydrogen peroxide-induced oxidative stress and a ligustrazine-based protective effect were investigated using laser tweezers Raman spectroscopy. Protein and lipid were significantly affected by oxidative damage, along with increased reactive oxygen species (ROS) level within cells. The effects of ligustrazine against the reaction of ROS with protein seemed to be able to inhibit such damages but were limited during the desamidization of amides, along with addnl. effect on nucleic acid base and DNA phosphoric acid skeleton. This work laid the basis for both understanding the mol. mechanisms of oxidative stress-induced injury and highlighting possible biomarkers in retinal diseases.
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    35. 35
      Bogliolo, L., Murrone, O., Di Emidio, G., Piccinini, M., Ariu, F., Ledda, S., and Tatone, C. (2013) Raman spectroscopy-based approach to detect aging-related oxidative damage in the mouse oocyte. J. Assist Reprod Genet 30 (7), 877– 882,  DOI: 10.1007/s10815-013-0046-6
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      Raman spectroscopy-based approach to detect aging-related oxidative damage in the mouse oocyte
      Bogliolo Luisa; Murrone Ombretta; Di Emidio Giovanna; Piccinini Massimo; Ariu Federica; Ledda Sergio; Tatone Carla
      Journal of assisted reproduction and genetics (2013), 30 (7), 877-82 ISSN:.
      PURPOSE: Detection of chemical modifications induced by aging-related oxidative damage in mouse metaphase II (MII) oocytes by Raman microspectroscopy. METHODS: CD-1 mice at the age of 4-8 weeks (young mice) and 48-52 weeks (old mice), were superovulated and oocytes at metaphase II stage were recovered from oviducts. MII oocytes from young animals were divided into three groups: A) young oocytes, processed immediately after collection; B) in vitro aged oocytes, cultured in vitro for 10 h before processing; C) oxidative-stressed oocytes, exposed to 10 mM hydrogen peroxide for 2 min before processing. Oocytes from reproductively old mice were referred to as old oocytes (D). All the oocytes were analyzed by confocal Raman microspectroscopy. The spectra were statistically analyzed using Principal Component Analysis (PCA). RESULTS: PCA evidenced that spectra from young oocytes (A) were clearly distinguishable from those obtained from in vitro-aged, oxidative-damaged and old oocytes (B, C, D) and presented significant differences in the bands attributable to lipid components (C = C stretching, 1,659 cm-1; CH2 bending, 1,450 cm-1; CH3 deformation,1,345 cm-1; OH bending, C-N stretching, 1,211 cm-1) and protein components (amide I band,1,659 cm-1; CH2 bending modes and CH3 deformation, 1,450 cm-1; C-N and C-C stretching vibrations, 1,132 cm-1; phenylalanine's vibration, 1,035 cm-1) CONCLUSIONS: Raman spectroscopy is a valuable non-invasive tool for the identification of biochemical markers of oxidative damage and could represent a highly informative method of investigation to evaluate the oocyte quality.
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    36. 36
      Kappos, E. A., Sieber, P. K., Engels, P. E., Mariolo, A. V., D’Arpa, S., Schaefer, D. J., and Kalbermatten, D. F. (2017) Validity and reliability of the CatWalk system as a static and dynamic gait analysis tool for the assessment of functional nerve recovery in small animal models. Brain Behav 7 (7), e00723  DOI: 10.1002/brb3.723
      There is no corresponding record for this reference.
    37. 37
      Vieira, W. F., Kenzo-Kagawa, B., Cogo, J. C., Baranauskas, V., and Cruz-Hofling, M. A. (2016) Low-Level Laser Therapy (904 nm) Counteracts Motor Deficit of Mice Hind Limb following Skeletal Muscle Injury Caused by Snakebite-Mimicking Intramuscular Venom Injection. PLoS One 11 (7), e0158980  DOI: 10.1371/journal.pone.0158980
      37
      Low-level laser therapy (904 nm) counteracts motor deficit of mice hind limb following skeletal muscle injury caused by snakebite-mimicking intramuscular venom injection
      Vieira, Willians Fernando; Kenzo-Kagawa, Bruno; Cogo, Jose Carlos; Baranauskas, Vitor; da Cruz-Hofling, Maria Alice
      PLoS One (2016), 11 (7), e0158980/1-e0158980/17CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      Myotoxins present in Bothrops venom disrupt the sarcolemma of muscle fibers leading to the release of sarcoplasmic proteins and loss of muscle homeostasis. Myonecrosis and tissue anoxia induced by vascularization impairment can lead to amputation or motor functional deficit. The objective of this study was to investigate the dynamic behavior of motor function in mice subjected to injection of Bothrops jararacussu venom (Bjssu) and exposed to low-level laser therapy (LLLT). Male Swiss mice received Bjssu injection (830 μg/kg) into the medial portion of the right gastrocnemius muscle. Three hours later the injected region was irradiated with diode semiconductor Gallium Arsenide (GaAs- 904 nm, 4 J/cm2) laser following by irradn. at 24, 48 and 72 h. Saline injection (0.9% NaCl) was used as control. Gait anal. was performed 24 h before Bjssu injection and at every period post-Bjssu using CatWalk method. Data from spatiotemporal parameters Stand, Maximum Intensity, Swing, Swing Speed, Stride Length and Step Cycle were considered. The period of 3 h post venom-induced injury was considered crit. for all parameters evaluated in the right hindlimb. Differences (p<0.05) were concd. in venom and venom + placebo laser groups during the 3 h post-injury period, in which the values of stand of most animals were null. After this period, the gait characteristics were re-established for all parameters. The venom + laser group kept the values at 3 h post-Bjssu equal to that at 24 h before Bjssu injection indicating that the GaAs laser therapy improved spatially and temporally gait parameters at the crit. injury period caused by Bjssu. This is the first study to analyze with cutting edge technol. the gait functional deficits caused by snake envenoming and gait gains produced by GaAs laser irradn. In this sense, the study fills a gap on the field of motor function after laser treatment following snake envenoming.
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    38. 38
      Su, W. H., Wang, C. J., Fu, H. C., Sheng, C. M., Tsai, C. C., Cheng, J. H., and Chuang, P. C. (2019) Human Umbilical Cord Mesenchymal Stem Cells Extricate Bupivacaine-Impaired Skeletal Muscle Function via Mitigating Neutrophil-Mediated Acute Inflammation and Protecting against Fibrosis. Int. J. Mol. Sci. 20 (17), 1,  DOI: 10.3390/ijms20174312
      There is no corresponding record for this reference.
    39. 39
      Pratt, S. J. P., Lawlor, M. W., Shah, S. B., and Lovering, R. M. (2012) An in vivo rodent model of contraction-induced injury in the quadriceps muscle. Injury 43 (6), 788– 793,  DOI: 10.1016/j.injury.2011.09.015
      39
      An in vivo rodent model of contraction-induced injury in the quadriceps muscle
      Pratt Stephen J P; Lawlor Michael W; Shah Sameer B; Lovering Richard M
      Injury (2012), 43 (6), 788-93 ISSN:.
      Most animal studies of muscle contractile function utilise the anterior or posterior crural muscle (dorsiflexors and plantarflexors, respectively). An advantage to using these muscles is that the common fibular and tibial nerves are readily accessible, while the small size of the crural muscles is a disadvantage. Working with small muscles not only makes some in vivo imaging and the muscle testing techniques more challenging, but also provides limited amounts of tissue to study. The purpose of this study was to describe a new animal muscle injury model in the quadriceps that results in a significant and reproducible loss of force. The thigh of Sprague Dawley rats (N=5) and C57BL/10 mice (N=5) was immobilised and the ankle was attached to a custom-made lever arm. The femoral nerve was stimulated using subcutaneous electrodes and injury was induced using 50 lengthening ("eccentric") contractions through a 70° arc of knee motion. This protocol produces a significant and reproducible injury, with comparable susceptibility to injury in the rats and mice. This novel model shows that the quadriceps muscle provides a means to study whole muscle contractility, injury, and recovery in vivo. In addition to the usual benefits of an in vivo model, the larger size of the quadriceps facilitates in vivo imaging and provides a significant increase in the amount of tissue available for histology and biochemistry studies. A controlled muscle injury in the quadriceps also allows one to study a muscle, with mixed fibre types, which is extremely relevant to gait in humans and quadruped models.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38zmsFejuw%253D%253D&md5=9c8d2aacfb90667b97a203051fa2aa47
    40. 40
      Contreras-Munoz, P., Fernandez-Martin, A., Torrella, R., Serres, X., De la Varga, M., Viscor, G., Jarvinen, T. A., Martinez-Ibanez, V., Peiro, J. L., Rodas, G. (2016) A New Surgical Model of Skeletal Muscle Injuries in Rats Reproduces Human Sports Lesions. Int. J. Sports Med. 37 (3), 183– 190,  DOI: 10.1055/s-0035-1555933
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      A New Surgical Model of Skeletal Muscle Injuries in Rats Reproduces Human Sports Lesions
      Contreras-Munoz P; De la Varga M; Rodas G; Marotta M; Fernandez-Martin A; Martinez-Ibanez V; Peiro J L; Torrella R; Viscor G; Serres X; Jarvinen T A H
      International journal of sports medicine (2016), 37 (3), 183-90 ISSN:.
      Skeletal muscle injuries are the most common sports-related injuries in sports medicine. In this work, we have generated a new surgically-induced skeletal muscle injury in rats, by using a biopsy needle, which could be easily reproduced and highly mimics skeletal muscle lesions detected in human athletes. By means of histology, immunofluorescence and MRI imaging, we corroborated that our model reproduced the necrosis, inflammation and regeneration processes observed in dystrophic mdx-mice, a model of spontaneous muscle injury, and realistically mimicked the muscle lesions observed in professional athletes. Surgically-injured rat skeletal muscles demonstrated the longitudinal process of muscle regeneration and fibrogenesis as stated by Myosin Heavy Chain developmental (MHCd) and collagen-I protein expression. MRI imaging analysis demonstrated that our muscle injury model reproduces the grade I-II type lesions detected in professional soccer players, including edema around the central tendon and the typically high signal feather shape along muscle fibers. A significant reduction of 30% in maximum tetanus force was also registered after 2 weeks of muscle injury. This new model represents an excellent approach to the study of the mechanisms of muscle injury and repair, and could open new avenues for developing innovative therapeutic approaches to skeletal muscle regeneration in sports medicine.
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    41. 41
      Paganoni, S. and Amato, A. (2013) Electrodiagnostic evaluation of myopathies. Phys. Med. Rehabil Clin N Am. 24 (1), 193– 207,  DOI: 10.1016/j.pmr.2012.08.017
      41
      Electrodiagnostic evaluation of myopathies
      Paganoni Sabrina; Amato Anthony
      Physical medicine and rehabilitation clinics of North America (2013), 24 (1), 193-207 ISSN:.
      Electrodiagnostic studies play an important role in the evaluation of patients suspected of having a myopathic disorder. They are used to exclude alternative diagnoses, confirm the presence of muscle disease, narrow down the differential, and identify an appropriate biopsy site. The most informative part of the electrodiagnostic study is needle electromyography. This allows for the analysis of spontaneous activity and motor unit action potential morphology and recruitment patterns. This article proposes a practical electrodiagnostic approach and describes the electrophysiologic patterns of the most commonly encountered myopathies.
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    42. 42
      Brown, R., Dissanayake, K. N., Skehel, P. A., and Ribchester, R. R. (2014) Endomicroscopy and electromyography of neuromuscular junctions in situ. Ann. Clin. Transl. Neurol. 1 (11), 867– 883,  DOI: 10.1002/acn3.124
      42
      Endomicroscopy and electromyography of neuromuscular junctions in situ
      Brown, Rosalind; Dissanayake, Kosala N.; Skehel, Paul A.; Ribchester, Richard R.
      Annals of Clinical and Translational Neurology (2014), 1 (11), 867-883CODEN: ACTNCG; ISSN:2328-9503. (John Wiley & Sons, Inc.)
      Objective : Electromyog. (EMG) is used routinely to diagnose neuromuscular dysfunction in a wide range of peripheral neuropathies, myopathies, and neuromuscular degenerative diseases including motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Definitive neurol. diagnosis may also be indicated by the anal. of pathol. neuromuscular innervation in motor-point biopsies. Our objective in this study was to preempt motor-point biopsy by combining live imaging with electrophysiol. anal. of slow degeneration of neuromuscular junctions (NMJs) in vivo. Methods : We combined conventional needle electromyog. with fiber-optic confocal endomicroscopy (CEM), using an integrated hand-held, 1.5-mm-diam. probe. We utilized as a test bed, various axotomized muscles in the hind limbs of anesthetized, double-homozygous thy1.2YFP16: WldS mice, which coexpress the Wallerian-degeneration Slow (WldS) protein and yellow fluorescent protein (YFP) in motor neurons. We also tested exogenous vital stains, including Alexa488-α-bungarotoxin; the styryl pyridinium dye 4-Di-2-Asp; and a GFP conjugate of botulinum toxin Type A heavy chain (GFP-HcBoNT/A). Results : We show that an integrated EMG/CEM probe is effective in longitudinal evaluation of functional and morphol. changes that take place over a 7-day period during axotomy-induced, slow neuromuscular synaptic degeneration. EMG amplitude declined in parallel with overt degeneration of motor nerve terminals. EMG/CEM was safe and effective when nerve terminals and motor endplates were selectively stained with vital dyes. Interpretation : Our findings constitute proof-of-concept, based on live imaging in an animal model, that combining EMG/CEM may be useful as a minimally invasive precursor or alternative to motor-point biopsy in neurol. diagnosis and for monitoring local administration of potential therapeutics.
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    43. 43
      McGregor, H. C., Short, M. A., McWilliams, A., Shaipanich, T., Ionescu, D. N., Zhao, J., Wang, W., Chen, G., Lam, S., and Zeng, H. (2016) Real-time endoscopic Raman spectroscopy for in vivo early lung cancer detection. J. Biophotonics 1,  DOI: 10.1002/jbio.201500204
      There is no corresponding record for this reference.
    44. 44
      Bergholt, M. S., Zheng, W., Lin, K., Ho, K. Y., Teh, M., Yeoh, K. G., So, J. B., and Huang, Z. (2011) In vivo diagnosis of esophageal cancer using image-guided Raman endoscopy and biomolecular modeling. Technol. Cancer Res. Treat. 10 (2), 103– 112,  DOI: 10.7785/tcrt.2012.500185
      44
      In vivo diagnosis of esophageal using image-guided raman endoscopy and biomolecular modeling
      Bergholt, M. S.; Zheng, W.; Lin, K.; Ho, K. Y.; Teh, M.; Yeoh, K. G.; So, J. B. Y.; Huang, Z.
      Technology in Cancer Research & Treatment (2011), 10 (2), 103-112CODEN: TCRTBS; ISSN:1533-0346. (Adenine Press)
      The aim of this work was to evaluate the biochem. foundation and clin. merit of multimodal image-guided Raman endoscopy technique for real-time in vivo diagnosis of cancer in the esophagus during clin. endoscopic examns. A novel fiber-optic Raman endoscopy system was utilized for in vivo esophageal Raman measurements at 785 nm laser excitation within 0.5 s under the multimodal wide-field endoscopic imaging (white light reflectance (WLR)) imaging, narrow-band imaging (NBI) and autofluorescence imaging (AFI) guidance. A total of 75 esophageal tissue sites from 27 patients were measured, in which 42 in vivo Raman spectra were from normal tissues and 33 in vivo Raman spectra were from malignant tumors as confirmed by histopathol. The biomol. modeling (non-negativity-constrained least-squares minimization (NNCLSM)) utilizing six basis ref. spectra from the representative biochems. (i.e., actin, collagen, DNA, histones, triolein and glycogen) were employed to est. the biochem. compns. of esophageal tissue. The resulting diagnostically significant fit coeffs. were further utilized through linear discriminant anal. (LDA) and leave-one tissue site-out, cross validation method to develop diagnostic algorithms for esophageal cancer diagnosis. High-quality in vivo Raman spectra in the range of 800-1800 cm-1 can be acquired from normal and cancerous esophageal mucosa in real-time under multimodal endoscopic imaging guidance. Esophageal cancer tissue showed distinct Raman signals mainly assocd. with cell proliferation, lipid redn., abnormal nuclear activity and neovasculation. The fit coeffs. for actin, DNA, histones, triolein, and glycogen were found to be most significant for construction of the LDA diagnostic model, giving rise to an accuracy of 96.0% (i.e., sensitivity of 97.0% and specificity of 95.2%) for in vivo diagnosis of esophageal cancer. This study demonstrates that multimodal image-guided Raman endoscopy technique in conjunction with biomol. modeling has promising potential for the real-time, in vivo diagnosis and detection of esophageal cancer during clin. endoscopic examn.
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    45. 45
      Resendes, M., Helms, C. A., Fritz, R. C., and Genant, H. (1992) MR appearance of intramuscular injections. AJR, Am. J. Roentgenol. 158 (6), 1293– 1294,  DOI: 10.2214/ajr.158.6.1590126
      45
      MR appearance of intramuscular injections
      Resendes M; Helms C A; Fritz R C; Genant H
      AJR. American journal of roentgenology (1992), 158 (6), 1293-4 ISSN:0361-803X.
      There is no expanded citation for this reference.
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    46. 46
      Day, J. C. and Stone, N. (2013) A subcutaneous Raman needle probe. Appl. Spectrosc. 67 (3), 349– 354,  DOI: 10.1366/12-06651
      46
      A subcutaneous Raman needle probe
      Day, John C. C.; Stone, Nicholas
      Applied Spectroscopy (2013), 67 (3), 349-354CODEN: APSPA4; ISSN:0003-7028. (Society for Applied Spectroscopy)
      Raman spectroscopy is a powerful tool for studying the biochem. compn. of tissues and cells in the human body. We describe the initial results of a feasibility study to design and build a miniature, fiber optic probe incorporated into a std. hypodermic needle. This probe is intended for use in optical biopsies of solid tissues to provide valuable information of disease type, such as in the lymphatic system, breast, or prostate, or of such tissue types as muscle, fat, or spinal, when identifying a crit. injection site. The optical design and fabrication of this probe is described, and example spectra of various ex vivo samples are shown.
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    47. 47
      Li, R., Verreault, D., Payne, A., Hitchcock, C. L., Povoski, S. P., Martin, E. W., and Allen, H. C. (2014) Effects of laser excitation wavelength and optical mode on Raman spectra of human fresh colon, pancreas, and prostate tissues. J. Raman Spectrosc. 45 (9), 773– 780,  DOI: 10.1002/jrs.4540
      47
      Effects of laser excitation wavelength and optical mode on Raman spectra of human fresh colon, pancreas, and prostate tissues
      Li, Ran; Verreault, Dominique; Payne, Andrea; Hitchcock, Charles L.; Povoski, Stephen P.; Martin, Edward W., Jr.; Allen, Heather C.
      Journal of Raman Spectroscopy (2014), 45 (9), 773-780CODEN: JRSPAF; ISSN:0377-0486. (John Wiley & Sons Ltd.)
      Early cancer detection is the central and most important factor for allowing successful treatment and resultant pos. long-term patient outcomes. Recently, optical techniques have been applied to this purpose, although each has inherent limitations. In particular, Raman spectroscopy applied in the pathol. diagnosis of cancerous tissues has received increasing attention, with the merit of being highly sensitive to the biochem. alterations in tissue compns. and applicable in vivo. Nevertheless, its application has been impeded by the high background intensity, which masks the Raman signal of biol. mols. In this work, the influence of laser excitation wavelength (785 vs. 830 nm) and optical mode (single mode vs. multimode) on the background intensity of fresh human tissues was studied. Based on the results, laser with 830 nm excitation demonstrated better background redn. than that with 785 nm excitation for the same optical mode, but the Raman signal intensity was conversely reduced, and the signal-to-noise ratio (SNR) not improved. In contrast, by comparing single-mode and multimode 785 nm excitations, it was shown that the single-mode laser with its smaller beam waist and beam propagation factor had better background redn. ability and an improvement of the SNRs. It is speculated that this decrease in background intensity comes from the effect of the optical mode on the Mie scattering from the biol. tissue. High-quality spectra based on a careful selection of both laser excitation wavelength and optical mode will benefit Raman measurements in further research focusing on spectral interpretation and histopathol. correlation ultimately aimed toward intraoperative applications. Copyright © 2014 John Wiley & Sons, Ltd.
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    48. 48
      Barnes, R. J., Dhanoa, M. S., and Lister, S. J. (1989) Standard Normal Variate Transformation and De-trending of Near-Infrared Diffuse Reflectance Spectra. Appl. Spectrosc. 43 (5), 772– 777,  DOI: 10.1366/0003702894202201
      48
      Standard normal variate transformation and de-trending of near-infrared diffuse reflectance spectra
      Barnes, R. J.; Dhanoa, M. S.; Lister, Susan J.
      Applied Spectroscopy (1989), 43 (5), 772-7CODEN: APSPA4; ISSN:0003-7028.
      Particle size, scatter, and multicollinearity are long-standing problems encountered in diffuse reflectance spectrometry. Multiplicative combinations of these effects are the major factor inhibiting the interpretation of near-IR diffuse reflectance spectra. Sample particle size accounts for the majority of the variance, while variance due to chem. compn. is small. Procedures are presented whereby phys. and chem. variance can be sepd. Math. transformations std. normal variate (SNV) and de-trending (DT) applicable to individual NIR diffuse reflectance spectra are presented. The std. normal variate approach effectively removes the multiplicative interferences of scatter and particle size. De-trending accounts for the variation in base-line shift and curvilinearity, generally found in the reflectance spectra of powd. or densely packed samples, with the use of a 2nd-degree polynomial regression. NIR diffuse reflectance spectra transposed by these methods are free from multicollinearity and are not confused by the complexity of shape encountered with the use of deriv. spectroscopy.
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    49. 49
      Savitzky, A. and Golay, M. J. E. (1964) Smoothing and Differentiation of Data by Simplified Least Squares Procedures. Anal. Chem. 36 (8), 1627– 1639,  DOI: 10.1021/ac60214a047
      49
      Smoothing and differentiation of data by simplified least squares procedures
      Savitzky, Abraham; Golay, Marcel J. E.
      (1964), 36 (8), 1627-39CODEN: ANCHAM; ISSN:0003-2700.
      The operation may be carried out on a computer by convolution of the data. Two examples are presented as subroutines in the FORTRAN language.
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  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschemneuro.0c00794.

    • Additional methods; tabulation of tentative peak assignments and references; prominent Raman peaks; two-group classification for SOD1G93A mice; two-group classification for mdx mice; two-group classification between SOD1G93A and mdx mice; PC1 scores and loadings plots; average and difference spectra; ROC curves; linear discriminant function histograms and loadings plots; phenylalanine and α-helical protein content in disease comparisons; linear discriminant function histograms and loadings plots; supervised four group classification model results; unsupervised four group hierarchical clustering; additional rotarod data following Raman or sham procedures; catwalk gait analysis following the Raman procedure; and human ALS and DMD Raman spectra and tentative peak assignments. (PDF)


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