A Human Model of Small Fiber Neuropathy to Study Wound Healing

The aim of this study was to develop a human model of acute wound healing that isolated the effects of small fiber neuropathy on the healing process. Twenty-five healthy subjects had the transient receptor vanilloid 1 agonist capsaicin and placebo creams topically applied to contralateral areas on the skin of the thigh for 48 hours. Subjects had shallow (1.2 millimeter) and deep (>3 millimeter) punch skin biopsies from each thigh on days 1 and 14. Biopsy wound healing was monitored photographically until closure. Intra-epidermal and sweat-gland nerve fiber densities were measured for each biopsy. Shallow wounds in capsaicin-treated sites healed more slowly than in placebo treated skin with biopsies taken on day 1 (P<0.001) and day 14 (P<0.001). Deep biopsies in the capsaicin and placebo areas healed at similar rates at both time points. Nerve fiber densities were reduced only in capsaicin treated regions (P<0.01). In conclusion, topical application of capsaicin causes a small fiber neuropathy and is associated with a delay in healing of shallow, but not deep wounds. This novel human model may prove valuable in the study of wound healing in patients with neuropathy

Author response: Effects of orthostatic hypotension on cognition in Parkinson disease

OBJECTIVE: To investigate the relation between orthostatic hypotension (OH) and posture-mediated cognitive impairment in persons with Parkinson's disease (PD) without dementia. METHODS: There were 55 participants: 37 non-demented individuals with idiopathic PD, including 18 with OH (PDOH), and 19 without (PDWOH), and18 control participants (C). All participants completed neuropsychological tests in the supine and in the upright tilted position. Blood pressure was assessed in each posture using a standardized oscillometric cuff at the right brachial artery. RESULTS: The two PD groups performed similarly while supine, with a profile notable for executive dysfunction consisting of deficits in sustained attention, response inhibition, and semantic verbal fluency, as well as reduced verbal memory encoding and retention. When upright, these deficits were exacerbated and broadened to include additional cognitive functions in the PDOH group: deficits in phonemic verbal fluency, psychomotor speed, and both basic and complex aspects of auditory working memory. When group-specific supine scores were used as baseline anchors, both PD groups showed cognitive changes following tilt, though the PDOH group had a wider range of deficits in the executive functioning and memory domains and was the only group to show significant changes in visuospatial skills. CONCLUSIONS: Cognitive deficits in idiopathic PD have been widely reported, though assessments are typically performed in the supine position. While both PD groups had supine deficits that aligned with prior studies and clinical findings, we demonstrated that those with PD and orthostatic hypotension had transient, posture-mediated changes in excess of those found in PD without autonomic failure. These observed changes suggest an acute, reversible effect, and as orthostatic hypotension is a significant comorbid factor in PD, an independent target for clinical intervention. Further understanding of the effects of autonomic failure on cognition in other disorders is desirable, particularly in the context of neuroimaging studies and clinical assessments where data are collected only in the supine or seated positions. Identification of a distinct neuropsychological profile in PD with autonomic failure also has implications for functional activities of daily living and overall quality of life.Accepted manuscrip

Effects of orthostatic hypotension on cognition in Parkinson's disease

OBJECTIVE: To investigate the relation between orthostatic hypotension (OH) and posture-mediated cognitive impairment in Parkinson disease (PD) using a cross-sectional and within-group design. METHODS: Individuals without dementia with idiopathic PD included 18 with OH (PDOH) and 19 without OH; 18 control participants were also included. Neuropsychological tests were conducted in supine and upright-tilted positions. Blood pressure was assessed in each posture. RESULTS: The PD groups performed similarly while supine, demonstrating executive dysfunction in sustained attention and response inhibition, and reduced semantic fluency and verbal memory (encoding and retention). Upright posture exacerbated and broadened these deficits in the PDOH group to include phonemic fluency, psychomotor speed, and auditory working memory. When group-specific supine scores were used as baseline anchors, both PD groups showed cognitive changes following tilt, with the PDOH group exhibiting a wider range of deficits in executive function and memory as well as significant changes in visuospatial function. CONCLUSIONS: Cognitive deficits in PD have been widely reported with assessments performed in the supine position, as seen in both our PD groups. Here we demonstrated that those with PDOH had transient, posture-mediated changes in excess of those found in PD without OH. These observed changes suggest an acute, reversible effect. Understanding the effects of OH due to autonomic failure on cognition is desirable, particularly as neuroimaging and clinical assessments collect data only in the supine or seated positions. Identification of a distinct neuropsychological profile in PD with OH has quality of life implications, and OH presents itself as a possible target for intervention in cognitive disturbance.Accepted manuscriptAccepted manuscrip

Structural and Functional Small Fiber Abnormalities in the Neuropathic Postural Tachycardia Syndrome

Objective: To define the neuropathology, clinical phenotype, autonomic physiology and differentiating features in individuals with neuropathic and non-neuropathic postural tachycardia syndrome (POTS). Methods: Twenty-four subjects with POTS and 10 healthy control subjects had skin biopsy analysis of intra-epidermal nerve fiber density (IENFD), quantitative sensory testing (QST) and autonomic testing. Subjects completed quality of life, fatigue and disability questionnaires. Subjects were divided into neuropathic and non-neuropathic POTS, defined by abnormal IENFD and abnormal small fiber and sudomotor function. Results: Nine of 24 subjects had neuropathic POTS and had significantly lower resting and tilted heart rates; reduced parasympathetic function; and lower phase 4 valsalva maneuver overshoot compared with those with non-neuropathic POTS (P<0.05). Neuropathic POTS subjects also had less anxiety and depression and greater overall self-perceived health-related quality of life scores than non-neuropathic POTS subjects. A sub-group of POTS patients (cholinergic POTS) had abnormal proximal sudomotor function and symptoms that suggest gastrointestinal and genitourinary parasympathetic nervous system dysfunction. Conclusions and Relevance POTS subtypes may be distinguished using small fiber and autonomic structural and functional criteria. Patients with non-neuropathic POTS have greater anxiety, greater depression and lower health-related quality of life scores compared to those with neuropathic POTS. These findings suggest different pathophysiological processes underlie the postural tachycardia in neuropathic and non-neuropathic POTS patients. The findings have implications for the therapeutic interventions to treat this disorder

Cold Exposure Exacerbates the Development of Diabetic Polyneuropathy in the Rat

Diabetic polyneuropathy (DPN) and cold-induced nerve injury share several pathogenic mechanisms. This study explores whether cold exposure contributes to the development of DPN. Streptozotocin-induced diabetic rats and controls were exposed to a room temperature (23°C) or cold environment (10°C). H-reflex, tail and sciatic motor, and sensory nerve conduction studies were performed. Analyses of sural nerve, intraepidermal nerve fibers, and skin and nerve nitrotyrosine ELISAs were performed. Diabetic animals exposed to a cold environment had an increased H-reflex four weeks earlier than diabetic room temperature animals (P = .03). Cold-exposed diabetic animals also had greater reduction in motor conduction velocities at 20 weeks (P = .017), decreased skin nerve fiber density (P = .037), and increased skin nitrotyrosine levels (P = .047). Cold exposure appears to hasten the development of DPN in the rat STZ model of diabetes. These findings support that further study into the relationship between ambient temperature and DPN is warranted

The Periodic Standing-Wave Approximation: Overview and Three Dimensional Scalar Models

The periodic standing-wave method for binary inspiral computes the exact numerical solution for periodic binary motion with standing gravitational waves, and uses it as an approximation to slow binary inspiral with outgoing waves. Important features of this method presented here are: (i) the mathematical nature of the ``mixed'' partial differential equations to be solved, (ii) the meaning of standing waves in the method, (iii) computational difficulties, and (iv) the ``effective linearity'' that ultimately justifies the approximation. The method is applied to three dimensional nonlinear scalar model problems, and the numerical results are used to demonstrate extraction of the outgoing solution from the standing-wave solution, and the role of effective linearity.Comment: 13 pages RevTeX, 5 figures. New version. A revised form of the nonlinearity produces better result

Bubbling AdS Black Holes

We explore the non-BPS analog of `AdS bubbles', which are regular spherically symmetric 1/2 BPS geometries in type IIB supergravity. They have regular horizons and can be thought of as bubbling generalizations of non-extremal AdS black hole solutions in five-dimensional gauged supergravity. Due to the appearance of the Heun equation even at the linearized level, various approximation and numerical methods are needed in order to extract information about this system. We study how the vacuum expectation value and mass of a particular dimension two chiral primary operator depend on the temperature and chemical potential of the thermal Yang-Mills theory. In addition, the mass of the bubbling AdS black holes is computed. As is shown numerically, there are also non-BPS solitonic bubbles which are completely regular and arise from continuous deformations of BPS AdS bubbles.Comment: 37 pages, 2 figure

Genotype-driven identification of a molecular network predictive of advanced coronary calcium in ClinSeq® and Framingham Heart Study cohorts

Background: One goal of personalized medicine is leveraging the emerging tools of data science to guide medical decision-making. Achieving this using disparate data sources is most daunting for polygenic traits. To this end, we employed random forests (RFs) and neural networks (NNs) for predictive modeling of coronary artery calcium (CAC), which is an intermediate endo-phenotype of coronary artery disease (CAD). Methods: Model inputs were derived from advanced cases in the ClinSeq®; discovery cohort (n=16) and the FHS replication cohort (n=36) from 89th-99th CAC score percentile range, and age-matched controls (ClinSeq®; n=16, FHS n=36) with no detectable CAC (all subjects were Caucasian males). These inputs included clinical variables and genotypes of 56 single nucleotide polymorphisms (SNPs) ranked highest in terms of their nominal correlation with the advanced CAC state in the discovery cohort. Predictive performance was assessed by computing the areas under receiver operating characteristic curves (ROC-AUC). Results: RF models trained and tested with clinical variables generated ROC-AUC values of 0.69 and 0.61 in the discovery and replication cohorts, respectively. In contrast, in both cohorts, the set of SNPs derived from the discovery cohort were highly predictive (ROC-AUC ≥0.85) with no significant change in predictive performance upon integration of clinical and genotype variables. Using the 21 SNPs that produced optimal predictive performance in both cohorts, we developed NN models trained with ClinSeq®; data and tested with FHS data and obtained high predictive accuracy (ROC-AUC=0.80-0.85) with several topologies. Several CAD and “vascular aging" related biological processes were enriched in the network of genes constructed from the predictive SNPs. Conclusions: We identified a molecular network predictive of advanced coronary calcium using genotype data from ClinSeq®; and FHS cohorts. Our results illustrate that machine learning tools, which utilize complex interactions between disease predictors intrinsic to the pathogenesis of polygenic disorders, hold promise for deriving predictive disease models and networks. Electronic supplementary material The online version of this article (doi:10.1186/s12918-017-0474-5) contains supplementary material, which is available to authorized users

Corrigendum to "Electrodiagnostic assessment of the autonomic nervous system: A consensus statement endorsed by the American Autonomic Society, American Academy of Neurology, and the International Federation of Clinical Neurophysiology" [Clin. Neurophysiol. 132(2) (2021) 666-682].

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