Effects of infant care posture and weight on static postural balance.

BACKGROUND: Studies investigating postural balance during various infant care postures have not been reported yet. OBJECTIVE: The aim of this study was to measure static postural balance when holding an infant dummy in-arms and carrying an infant dummy on back according to different infant dummy weights. METHODS: Sixteen healthy young subjects participated in a balance test. Infant dummies with weights of 4.6 kg (1-month) and 9.8 kg (12-month) were used in this study. All subjects were asked to naturally stand on a force platform in two infant care postures (holding an infant in-arms and carrying an infant on one's back). Center of pressure (COP) was measured from the force platform. Quantitative variables were derived from the COP. Two-way repeated measure analysis of variance (ANOVA) was performed to determine main effects of infant care postures, infant weight, and their interactions on COP variables. RESULTS: Back carrying a 12-month infant dummy had the greatest amplitude in all COP variables. Back carrying posture showed significantly greater mean distance and peak power, faster mean velocity, and wider COP area compared to holding posture (P< 0.05). There were significant weight effects of most COP variables mainly in AP direction (P< 0.01). CONCLUSIONS: Our results could contribute to the prevention of musculoskeletal diseases or prevention of fall due to various infant care activities by developing an assisting device to improve postural balance.

In Vitro and In Vivo Bone-Forming Effect of a Low-Molecular-Weight Collagen Peptide.

This study reveals that low-molecular-weight collagen peptide (LMWCP) can stimulate the differentiation and the mineralization of MC3T3-E1 cells in vitro and attenuate the bone remodeling process in ovariectomized (OVX) Sprague-Dawley rats in vivo. Moreover, the assessed LMWCP increased the activity of alkaline phosphatase (ALP), synthesis of collagen, and mineralization in MC3T3-E1 cells. Additionally, mRNA levels of bone metabolism-related factors such as the collagen type I alpha 1 chain, osteocalcin (OCN), osterix, bone sialoprotein, and the Runt family-associated transcription factor 2 were increased in cells treated with 1,000 µg/ml of LMWCP. Furthermore, we demonstrated that critical bone morphometric parameters exhibited significant differences between the LMWCP (400 mg/kg)-receiving and vehicle-treated rat groups. Moreover, the expression of type I collagen and the activity of ALP were found to be higher in both the femur and lumbar vertebrae of OVX rats treated with LMWCP. Finally, the administration of LMWCP managed to alleviate osteogenic parameters such as the ALP activity and the levels of the bone alkaline phosphatase, the OCN, and the procollagen type 1 N-terminal propeptide in OVX rats. Thus, our findings suggest that LMWCP is a promising candidate for the development of food-based prevention strategies against osteoporosis.

Quantitative Analysis of Postural Balance in Faller and Nonfaller Patients with Parkinson's Disease.

Background: Postural instability has been identified as a fall risk factor with a significant impact on the quality of life of patients with Parkinson's disease (PD). The aim of this study was to compare the center of pressure (COP) between faller and nonfaller patients with PD during static standing. Methods: Thirty-two faller patients and 32 nonfaller patients with PD participated in this study. All patients performed the static balance test on a force plate. COP data were recorded during quiet standing. Mean distance, sway area, mean velocity, mean frequency, and peak power were derived from the COP data. Statistical analysis was performed using independent t-tests to compare faller and nonfaller patients. Results: Fallers presented a greater average distance, wider sway area, faster average speed, and greater peak power than nonfallers (p < 0.05). In contrast, no significant group differences were observed in peak frequency and mean frequency (p > 0.05). Conclusions: Although falls occur during dynamic activities, our study demonstrated that even a safe and simple static postural balance test could significantly differentiate between faller and nonfaller patients. Thus, these results suggest that quantitatively assessed static postural sway variables would be useful for distinguishing prospective fallers among PD patients.

Comparison of resting tremor at the upper limb joints between patients with Parkinson's disease and scans without evidence of dopaminergic deficit.

BACKGROUND: A representative symptom of Parkinson's disease (PD) is resting tremor. The clinical manifestation of scans without evidence of dopaminergic deficit (SWEDD) is similar to it of PD, though the phenomenology of SWEDD is not well known. OBJECTIVE: In the present study, the resting tremor of 9 SWEDD patients was quantitatively compared with that of 11 PD patients. METHODS: Four 3-axis gyro sensors were attached on the index finger, thumb, dorsum of the hand, and arm of the more tremulous side. Root mean square (RMS) angular speed and angular displacement as well as irregularity of angular speed and displacement were derived from the sensor data. RESULTS: Although disease duration and Hoehn and Yahr stages were comparable, SWEDD patients exhibited different tremor features from PD patients. Significantly faster RMS angular speed and greater RMS angular displacement (p< 0.05) were observed in PD patients than in SWEDD patients. The irregularity of angular displacement of pitch direction at the dorsum of the hand was greater in SWEDD patients than in PD patients (p< 0.05). CONCLUSION: These results indicate that quantitative indices obtained from resting tremor task could be important biomarkers for identifying potential patients with SWEDD among patients diagnosed with PD.

Threonine functionalized colloidal cadmium sulfide (CdS) quantum dots: The role of solvent and counterion in ligand induced chiroptical properties.

The functionalization of semiconductor nanocrystals, quantum dots (QDs), with small organic molecules has been studied extensively to gain better knowledge on how to tune the electronic, optical and chiroptical properties of QDs. Chiral QDs have progressively emerged as key materials in a vast range of applications including biosensing and biorecognition, imaging, asymmetric catalysis, optoelectronic devices, and spintronics. To engage the full potential of the unique properties of chiral nanomaterials and be able to prepare them with tailorable chiroptical characteristics, it is essential to understand how chirality is rendered from chiral molecular ligands at the surface of nanocrystals to the electronic states of QDs. Using a series of polar protic and aprotic solvents together with ammonium (NH4+), tetramethylammonium (TMA+), and tetrabutylammonium (TBA+) countercations in the preparation of threonine-functionalized cadmium sulfide (Thr-CdS) QDs by phase transfer ligand exchange approach, we demonstrated the significance of the role both the solvent and the countercations play in the transfer of chirality from chiral molecular ligand to achiral semiconductor QDs as apparent by the modulations of the signatures and anisotropy of the circular dichroism (CD) spectra. Moreover, we have utilized tetrabutylammonium countercation to successfully synthesize chiral QDs in nonpolar cyclohexane solvent for the first time. This study provides further insights into the origin of the ligand induced chirality of colloidal nanomaterials and facilitates the synthesis of tailormade chiral QDs.

Age-related differences in the quantitative analysis of the finger tapping task.

BACKGROUND: Quantitative measures of the finger tapping task is important for objective assessment of bradykinesia. However, age-related changes in quantitative measures are still unclear. OBJECTIVE: The aim of this study was to quantitatively investigate age-related group differences in finger tapping performance. METHODS: Eighty-three healthy normal subjects with age ranging from aged 20 to 89 years participated in this study. All subjects were instructed to tap their index finger and thumbs as rapidly as possible and with as large amplitude as possible. Angular velocity of the finger tapping movement was measured using a gyrosensor. Quantitative variables include root mean squared (RMS) angular velocity, RMS angular displacement, peak power and peak frequency derived from angular velocity signals. RESULTS: Significant age-related differences were observed in RMS angular velocity, peak power and peak frequency (P< 0.001). Specifically, the oldest age group had the slowest average speed, the lowest peak power and peak frequency. These results indicate deterioration in finger speed, intensity of the main movement component and tapping frequency due to aging. CONCLUSIONS: The results suggest that the quantitative variables should be adjusted for age when clinicians assess Parkinsonian bradykinesia. The results contribute to the development of an accurate and quantitative assessment tool for bradykinesia.

Analysis of maximum joint moment during infant lifting-up motion.

BACKGROUND: Infant care activities can induce musculoskeletal disease. However, little is known about the biomechanical joint load during lifting-up of an infant. OBJECTIVE: The aim of this study was to investigate normalized maximum moment during lifting-up of infant dummies weighing 4.6 kg, 7.6 kg, and 9.8 kg. METHODS: Six healthy young subjects participated in our study. All subjects performed lifting-up activities of dummies to shoulder height with their feet apart and natural postures in their comfortable speed. Three-dimensional reflective marker trajectories and ground reaction forces were used as input to calculate joint moments using a full body musculoskeletal model. Joint moments were normalized by each subject's body mass. Friedman's test was performed to compare mean differences of normalized joint moments for lifting up three dummy weights. RESULTS: Lumbar joint had the greatest normalized joint moment. Lumbar and hip extension moments were significantly increased with dummy weight (P< 0.05). In contrast, knee extension and ankle plantarflexion moment were not significantly affected by dummy weight (P> 0.05). CONCLUSIONS: These results indicate that the lumbar joint plays the most important role in infant lifting-up motion and that the load of lumbar and hip joint should be reduced when lifting a heavier infant. These results could contribute to the development of an effective lifting strategy and an assisting device for lifting an infant.

Apple juice and red wine induced mirror-image circular dichroism in quantum dots.

Juices, wines, and extracts from plants contain high concentrations of various chiral compounds such as carboxylic acids or sugars. Several prior studies reported the synthesis of metallic and semiconducting nanoparticles relying on components of complex biological solutions. Herein, we present preparation of chiral CdS and CdSe quantum dots (QDs) using apple juice and red wine via phase transfer ligand exchange. Although both apple juice and red wine contain a complex mixture of chiral and achiral compounds, we have successfully used them for selective induction of predicted chiroptical properties and confirmed L-malic acid from the apple juice and L-tartaric acid from the red wine as the chiral inducers. This work illustrates the capability of using complex mixtures to construct chiral QDs with desired chiroptical properties as well as potential of QDs to selectively report a chiral molecule in a complex chiral mixture without the need for elaborate chiral recognition system.

Kinetic stability modulation of polymeric nanoparticles for enhanced detection of influenza virus via penetration of viral fusion peptides.

Specific interactions between viruses and host cells provide essential insights into material science-based strategies to combat emerging viral diseases. pH-triggered viral fusion is ubiquitous to multiple viral families and is important for understanding the viral infection cycle. Inspired by this process, virus detection has been achieved using nanomaterials with host-mimetic membranes, enabling interactions with amphiphilic hemagglutinin fusion peptides of viruses. Most research has been on designing functional nanoparticles with fusogenic capability for virus detection, and there has been little exploitation of the kinetic stability to alter the ability of nanoparticles to interact with viral membranes and improve their sensing performance. In this study, a homogeneous fluorescent assay using self-assembled polymeric nanoparticles (PNPs) with tunable responsiveness to external stimuli is developed for rapid and straightforward detection of an activated influenza A virus. Dissociation of PNPs induced by virus insertion can be readily controlled by varying the fraction of hydrophilic segments in copolymers constituting PNPs, giving rise to fluorescence signals within 30 min and detection of various influenza viruses, including H9N2, CA04(H1N1), H4N6, and H6N8. Therefore, the designs demonstrated in this study propose underlying approaches for utilizing engineered PNPs through modulation of their kinetic stability for direct and sensitive identification of infectious viruses.

The pathogenic role of c-Kit+ mast cells in the spinal motor neuron-vascular niche in ALS.

Degeneration of motor neurons, glial cell reactivity, and vascular alterations in the CNS are important neuropathological features of amyotrophic lateral sclerosis (ALS). Immune cells trafficking from the blood also infiltrate the affected CNS parenchyma and contribute to neuroinflammation. Mast cells (MCs) are hematopoietic-derived immune cells whose precursors differentiate upon migration into tissues. Upon activation, MCs undergo degranulation with the ability to increase vascular permeability, orchestrate neuroinflammation and modulate the neuroimmune response. However, the prevalence, pathological significance, and pharmacology of MCs in the CNS of ALS patients remain largely unknown. In autopsy ALS spinal cords, we identified for the first time that MCs express c-Kit together with chymase, tryptase, and Cox-2 and display granular or degranulating morphology, as compared with scarce MCs in control cords. In ALS, MCs were mainly found in the niche between spinal motor neuron somas and nearby microvascular elements, and they displayed remarkable pathological abnormalities. Similarly, MCs accumulated in the motor neuron-vascular niche of ALS murine models, in the vicinity of astrocytes and motor neurons expressing the c-Kit ligand stem cell factor (SCF), suggesting an SCF/c-Kit-dependent mechanism of MC differentiation from precursors. Mechanistically, we provide evidence that fully differentiated MCs in cell cultures can be generated from the murine ALS spinal cord tissue, further supporting the presence of c-Kit+ MC precursors. Moreover, intravenous administration of bone marrow-derived c-Kit+ MC precursors infiltrated the spinal cord in ALS mice but not in controls, consistent with aberrant trafficking through a defective microvasculature. Pharmacological inhibition of c-Kit with masitinib in ALS mice reduced the MC number and the influx of MC precursors from the periphery. Our results suggest a previously unknown pathogenic mechanism triggered by MCs in the ALS motor neuron-vascular niche that might be targeted pharmacologically.

FGF23, a novel muscle biomarker detected in the early stages of ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle weakness. Skeletal muscle is a prime source for biomarker discovery since it is one of the earliest sites to manifest disease pathology. From a prior RNA sequencing project, we identified FGF23 as a potential muscle biomarker in ALS. Here, we validate this finding with a large collection of ALS muscle samples and found a 13-fold increase over normal controls. FGF23 was also increased in the SOD1G93A mouse, beginning at a very early stage and well before the onset of clinical symptoms. FGF23 levels progressively increased through end-stage in the mouse. Immunohistochemistry of ALS muscle showed prominent FGF23 immunoreactivity in the endomysial connective tissue and along the muscle membrane and was significantly higher around grouped atrophic fibers compared to non-atrophic fibers. ELISA of plasma samples from the SOD1G93A mouse showed an increase in FGF23 at end-stage whereas no increase was detected in a large cohort of ALS patients. In conclusion, FGF23 is a novel muscle biomarker in ALS and joins a molecular signature that emerges in very early preclinical stages. The early appearance of FGF23 and its progressive increase with disease progression offers a new direction for exploring the molecular basis and response to the underlying pathology of ALS.

A Nitroalkene Benzoic Acid Derivative Targets Reactive Microglia and Prolongs Survival in an Inherited Model of ALS via NF-κB Inhibition.

Motor neuron degeneration and neuroinflammation are the most striking pathological features of amyotrophic lateral sclerosis (ALS). ALS currently has no cure and approved drugs have only a modest clinically therapeutic effect in patients. Drugs targeting different deleterious inflammatory pathways in ALS appear as promising therapeutic alternatives. Here, we have assessed the potential therapeutic effect of an electrophilic nitroalkene benzoic acid derivative, (E)-4-(2-nitrovinyl) benzoic acid (BANA), to slow down paralysis progression when administered after overt disease onset in SOD1G93A rats. BANA exerted a significant inhibition of NF-κB activation in NF-κB reporter transgenic mice and microglial cell cultures. Systemic daily oral administration of BANA to SOD1G93A rats after paralysis onset significantly decreased microgliosis and astrocytosis, and significantly reduced the number of NF-κB-p65-positive microglial nuclei surrounding spinal motor neurons. Numerous microglia bearing nuclear NF-κB-p65 were observed in the surrounding of motor neurons in autopsy spinal cords from ALS patients but not in controls, suggesting ALS-associated microglia could be targeted by BANA. In addition, BANA-treated SOD1G93A rats after paralysis onset showed significantly ameliorated spinal motor neuron pathology as well as conserved neuromuscular junction innervation in the skeletal muscle, as compared to controls. Notably, BANA prolonged post-paralysis survival by ~30%, compared to vehicle-treated littermates. These data provide a rationale to therapeutically slow paralysis progression in ALS using small electrophilic compounds such as BANA, through a mechanism involving microglial NF-κB inhibition.

Psychological well-being and gene expression in Korean adults: The role of age.

BACKGROUND: Happiness has traditionally been thought to comprise two parts - pleasure (hedonia) and meaning (eudaimonia). Even though the two types of happiness are correlated, genomics studies have found distinct transcriptional correlates of hedonia and eudaimonia, particularly in the Conserved Transcriptional Response to Adversity (CTRA) marked by up-regulation of proinflammatory genes and down-regulation of interferon-related genes. Eudaimonia has been associated with reduced CTRA gene expression in several studies, whereas hedonia shows no consistent association with the CTRA. However, most of these social genomics studies have been conducted in Western cultures with Caucasian samples, so it is unclear if these findings extended to non-Western cultures with other ethnic groups. Moreover, it is unknown whether age might modify the association between CTRA gene expression and eudaimonia. To this end, we examined in a sample of Koreans the relationship between CTRA profiles and measures of hedonia and eudaimonia, as well as the role of age in modulating the strength of those relationships. METHODS: Blood samples were collected from 152 healthy Korean adults (mean age = 44.64; 50 % female). Well-being was measured using the Mental Health Continuum short form (MHC-SF), Ryff Scales of Psychological Well-being (PWB), and subjective well-being (SWB) scales. RNA transcriptome profiles were obtained by RNA sequencing. Mixed effect linear model analyses examined the association between CTRA gene expression and measures of MHC-SF, SWB, PWB (total scores and six subscales) and additional analyses examined a possible moderating role of age. RESULTS: CTRA gene expression was significantly downregulated in association with the MHC-SF eudaimonic scores as well as the PWB total scores. Among the six domains of PWB, autonomy showed the strongest inverse correlation with CTRA profiles. Moreover, the inverse association between CTRA and PWB was stronger for older participants. CONCLUSION: Eudaimonia is associated with reduced CTRA gene expression in a Korean population, with particularly marked relationships for autonomy. Findings also suggest that aging with meaning may bring biological advantage in later life.

Low selenium levels are associated with decreased bone mineral densities.

PURPOSE: Osteoporosis has a high worldwide prevalence and detrimental consequences (e.g., increased fracture risk). The amount of bone mineral in bone tissue (i.e., bone mineral density [BMD]) is most widely used indicator of osteoporosis in clinical medicine. Selenium is an essential micronutrient for animals and humans. It is a cofactor for antioxidant enzyme reduction (e.g., glutathione peroxidase). It also enhances immune surveillance and modulates cell proliferation. Study findings on the associations between BMD and selenium levels are inadequate and contradictory. The purpose of this study was to examine the associations between hair selenium levels and lumbar spine and femur BMD values. METHODS: Using a cross-sectional study design, we assessed the associations between hair selenium levels and BMD values in 1,167 Korean adults who underwent a health check-up. Each subject was assigned to one of two groups based on BMD (normal group [T-score ≥ -1.0] or low BMD group [T-score < -1.0]). The associations between hair selenium levels and the risk for low BMD were estimated using multivariate logistic regression models. RESULTS: Study participants with lower hair selenium levels were older and had higher phosphorous, alkaline phosphatase, and osteocalcin levels. They also had lower BMDs, corrected serum calcium levels, uric acid levels, and creatinine clearance. Participants with low BMDs had significantly lower hair selenium levels (P < 0.001). After adjusting for osteoporosis-related risk factors, the risk of a low BMD was significantly greater for the lower hair selenium quartile groups (P = 0.045). CONCLUSION: In conclusion, this study found that lower hair selenium levels were associated with low BMD values, independent of the other osteoporosis risk factors examined. Further prospective studies are warranted to determine the role of selenium in the development of osteoporosis.

Quantitative measures of postural tremor at the upper limb joints in patients with essential tremor.

BACKGROUND: It is important to quantitatively assess tremor for accurate diagnosis and evaluation of the response to interventions in patients with essential tremor (ET). OBJECTIVE: The purpose of this study was to investigate the relationship between quantitative measures of postural tremor and clinical rating scale in patients with ET. METHODS: 18 ET patients performed a postural tremor task that required them to hold their arms outstretched parallel to the floor while wearing a gyro sensor based measurement system. The time domain variables were derived from the sensor signals. Additionally, the frequency domain variables were derived from the power spectrum of the angular velocity signal. Spearman correlation analysis was employed in the relationship between the variables and clinical score. RESULTS: The RMS angular velocity of roll and yaw directions at the hand joint were strongly correlated with the clinical rating scale (r= 0.7, p< 0.01). Similarly, the peak power of roll and yaw directions at the hand joint were moderately correlated with the clinical rating scale (r= 0.61 and r= 0.67, p< 0.01). In contrast, no significant correlation coefficients were observed in the peak frequency (p> 0.05). CONCLUSION: These results indicate that hand tremor of roll and yaw directions are more associated with assessment of severity of ET compared to other joints. This study suggests that quantitative measurements of postural tremor should be considered as tremor directionality as well as attachment location.

The vitamin D activator CYP27B1 is upregulated in muscle fibers in denervating disease and can track progression in amyotrophic lateral sclerosis.

Extra-renal expression of Cytochrome P450 Family 27 Subfamily B Member 1 (CYP27B1) has been well recognized and reflects the importance of intracrine/paracrine vitamin D signaling in different tissues under physiological and pathological conditions. In a prior RNA sequencing project, we identified CYP27B1 mRNA as upregulated in muscle samples from patients with amyotrophic lateral sclerosis (ALS) compared to normal controls. Our aims here were: (1) to validate this finding in a larger sample set including disease controls, (2) to determine which cell type is expressing CYP27B1 protein in muscle tissue, (3) to correlate CYP27B1 mRNA expression with disease progression in the SOD1G93A ALS mouse and in ALS patients. We assessed CYP27B1 expression by qPCR, western blot, and immunohistochemistry in a repository of muscle samples from ALS, disease controls (myopathy and non-ALS neuropathic disease), normal subjects, and muscle samples from the SOD1G93A mouse. Eight ALS patients were studied prospectively over 6-12 months with serial muscle biopsies. We found that CYP27B1 mRNA and protein levels were significantly increased in ALS versus normal and myopathy muscle samples. Neuropathy samples had increased CYP27B1 mRNA and protein expression but at a lower level than the ALS group. Immunohistochemistry showed that CYP27B1 localized to myofibers, especially those with features of denervation. In the SOD1G93A mouse, CYP27B1 mRNA and protein were detected in skeletal muscle in early pre-symptomatic stages and increased through end-stage. In the human study, increases in CYP27B1 mRNA in muscle biopsies correlated with disease progression rates over the same time period. In summary, we show for the first time that CYP27B1 mRNA and protein expression are elevated in muscle fibers in denervating disease, especially ALS, where mRNA levels can potentially serve as a surrogate marker for tracking disease progression. Its upregulation may reflect a local perturbation of vitamin D signaling, and further characterization of this pathway may provide insight into underlying molecular processes linked to muscle denervation.

Schwann cells orchestrate peripheral nerve inflammation through the expression of CSF1, IL-34, and SCF in amyotrophic lateral sclerosis.

Distal axonopathy is a recognized pathological feature of amyotrophic lateral sclerosis (ALS). In the peripheral nerves of ALS patients, motor axon loss elicits a Wallerian-like degeneration characterized by denervated Schwann cells (SCs) together with immune cell infiltration. However, the pathogenic significance of denervated SCs accumulating following impaired axonal growth in ALS remains unclear. Here, we analyze SC phenotypes in sciatic nerves of ALS patients and paralytic SOD1G93A rats, and identify remarkably similar and specific reactive SC phenotypes based on the pattern of S100ß, GFAP, isolectin and/or p75NTR immunoreactivity. Different subsets of reactive SCs expressed colony-stimulating factor-1 (CSF1) and Interleukin-34 (IL-34) and closely interacted with numerous endoneurial CSF-1R-expressing monocyte/macrophages, suggesting a paracrine mechanism of myeloid cell expansion and activation. SCs bearing phagocytic phenotypes as well as endoneurial macrophages expressed stem cell factor (SCF), a trophic factor that attracts and activates mast cells through the c-Kit receptor. Notably, a subpopulation of Ki67+ SCs expressed c-Kit in the sciatic nerves of SOD1G93A rats, suggesting a signaling pathway that fuels SC proliferation in ALS. c-Kit+ mast cells were also abundant in the sciatic nerve from ALS donors but not in controls. Pharmacological inhibition of CSF-1R and c-Kit with masitinib in SOD1G93A rats potently reduced SC reactivity and immune cell infiltration in the sciatic nerve and ventral roots, suggesting a mechanism by which the drug ameliorates peripheral nerve pathology. These findings provide strong evidence for a previously unknown inflammatory mechanism triggered by SCs in ALS peripheral nerves that has broad application in developing novel therapies.

CD34 Identifies a Subset of Proliferating Microglial Cells Associated with Degenerating Motor Neurons in ALS.

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons accompanied by proliferation of reactive microglia in affected regions. However, it is unknown whether the hematopoietic marker CD34 can identify a subpopulation of proliferating microglial cells in the ALS degenerating spinal cord. Immunohistochemistry for CD34 and microglia markers was performed in lumbar spinal cords of ALS rats bearing the SOD1G93A mutation and autopsied ALS and control human subjects. Characterization of CD34-positive cells was also performed in primary cell cultures of the rat spinal cords. CD34 was expressed in a large number of cells that closely interacted with degenerating lumbar spinal cord motor neurons in symptomatic SOD1G93A rats, but not in controls. Most CD34+ cells co-expressed the myeloid marker CD11b, while only a subpopulation was stained for Iba1 or CD68. Notably, CD34+ cells actively proliferated and formed clusters adjacent to damaged motor neurons bearing misfolded SOD1. CD34+ cells were identified in the proximity of motor neurons in autopsied spinal cord from sporadic ALS subjects but not in controls. Cell culture of symptomatic SOD1G93A rat spinal cords yielded a large number of CD34+ cells exclusively in the non-adherent phase, which generated microglia after successive passaging. A yet unrecognized CD34+ cells, expressing or not the microglial marker Iba1, proliferate and accumulate adjacent to degenerating spinal motor neurons, representing an intriguing cell target for approaching ALS pathogenesis and therapeutics.

Mast cells and neutrophils mediate peripheral motor pathway degeneration in ALS.

Neuroinflammation is a recognized pathogenic mechanism underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS), but the inflammatory mechanisms influencing peripheral motor axon degeneration remain largely unknown. A recent report showed a pathogenic role for c-Kit-expressing mast cells mediating inflammation and neuromuscular junction denervation in muscles from SOD1G93A rats. Here, we have explored whether mast cells infiltrate skeletal muscles in autopsied muscles from ALS patients. We report that degranulating mast cells were abundant in the quadriceps muscles from ALS subjects but not in controls. Mast cells were associated with myofibers and motor endplates and, remarkably, interacted with neutrophils forming large extracellular traps. Mast cells and neutrophils were also abundant around motor axons in the extensor digitorum longus muscle, sciatic nerve, and ventral roots of symptomatic SOD1G93A rats, indicating that immune cell infiltration extends along the entire peripheral motor pathway. Postparalysis treatment of SOD1G93A rats with the tyrosine kinase inhibitor drug masitinib prevented mast cell and neutrophil infiltration, axonal pathology, secondary demyelination, and the loss of type 2B myofibers, compared with vehicle-treated rats. These findings provide further evidence for a yet unrecognized contribution of immune cells in peripheral motor pathway degeneration that can be therapeutically targeted by tyrosine kinase inhibitors.

Quantitative analysis of finger and forearm movements in patients with off state early stage Parkinson's disease and scans without evidence of dopaminergic deficit (SWEDD).

BACKGROUND: Scans without evidence of dopaminergic deficit (SWEDD) is a radiological nomenclature which refers to patients with a normal dopamine transporter scan presumed to have parkinsonism. The motor features of SWEDD patients should be understood in order to avoid costly and inappropriate treatments. Therefore, it is important to effectively differentiate SWEDD from Parkinson's disease (PD) in the early stage of disease. As bradykinesia is a cardinal clinical feature of parkinsonism, we quantitatively investigated detailed presentations of hand movement using an angular measurement system in SWEDD and PD patients as well as normal controls. METHODS: Twenty-three patients with SWEDD, 23 patients with off state early stage PD, and 23 age-matched healthy controls participated in this study. Angular velocity was measured during finger-tapping and forearm-rotation movement for the assessment of bradykinesia. RMS (root mean square) velocity and amplitude as well as movement irregularity were derived from the gyro sensor signal. RESULTS: SWEDD patients presented a greater average speed, a larger average amplitude, and more regular speed and amplitude only during forearm rotation than PD patients (p < 0.05). SWEDD patients also exhibited a smaller average speed and average amplitude, and a more irregular speed on average during finger tapping than controls (p < 0.05). CONCLUSIONS: Quantitative variables of forearm rotation movement showed significant differences between SWEDD and PD patients, and quantitative variables of finger tapping movement showed a significant difference between SWEDD patients and the control group. These results suggest that quantitatively-assessed variables using biomedical engineering devices could aid clinicians in the identification of potential SWEDD.