Ventilation-perfusion inequality in the human lung is not increased following no-decompression-stop hyperbaric exposure

Venous gas bubbles occur in recreational SCUBA divers in the absence of decompression sickness, forming venous gas emboli (VGE) which are trapped within pulmonary circulation and cleared by the lung without overt pathology. We hypothesized that asymptomatic VGE would transiently increase ventilation-perfusion mismatch due to their occlusive effects within the pulmonary circulation. Two sets of healthy volunteers (n = 11, n = 12) were recruited to test this hypothesis with a single recreational ocean dive or a baro-equivalent dry hyperbaric dive. Pulmonary studies (intrabreath VA/Q (iV/Q), alveolar dead space, and FVC) were conducted at baseline and repeat 1- and 24-h after the exposure. Contrary to our hypothesis VA/Q mismatch was decreased 1-h post-SCUBA dive (iV/Q slope 0.023 ± 0.008 ml−1 at baseline vs. 0.010 ± 0.005 NS), and was significantly reduced 24-h post-SCUBA dive (0.000 ± 0.005, p < 0.05), with improved VA/Q homogeneity inversely correlated to dive severity. No changes in VA/Q mismatch were observed after the chamber dive. Alveolar dead space decreased 24-h post-SCUBA dive (78 ± 10 ml at baseline vs. 56 ± 5, p < 0.05), but not 1-h post dive. FVC rose 1-h post-SCUBA dive (5.01 ± 0.18 l vs. 5.21 ± 0.26, p < 0.05), remained elevated 24-h post SCUBA dive (5.06 ± 0.2, p < 0.05), but was decreased 1-hr after the chamber dive (4.96 ± 0.31 L to 4.87 ± 0.32, p < 0.05). The degree of VA/Q mismatch in the lung was decreased following recreational ocean dives, and was unchanged following an equivalent air chamber dive, arguing against an impact of VGE on the pulmonary circulation

A Fokker-Planck formalism for diffusion with finite increments and absorbing boundaries

Gaussian white noise is frequently used to model fluctuations in physical systems. In Fokker-Planck theory, this leads to a vanishing probability density near the absorbing boundary of threshold models. Here we derive the boundary condition for the stationary density of a first-order stochastic differential equation for additive finite-grained Poisson noise and show that the response properties of threshold units are qualitatively altered. Applied to the integrate-and-fire neuron model, the response turns out to be instantaneous rather than exhibiting low-pass characteristics, highly non-linear, and asymmetric for excitation and inhibition. The novel mechanism is exhibited on the network level and is a generic property of pulse-coupled systems of threshold units.Comment: Consists of two parts: main article (3 figures) plus supplementary text (3 extra figures

PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews

The methods and results of systematic reviews should be reported in sufficient detail to allow users to assess the trustworthiness and applicability of the review findings. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement was developed to facilitate transparent and complete reporting of systematic reviews and has been updated (to PRISMA 2020) to reflect recent advances in systematic review methodology and terminology. Here, we present the explanation and elaboration paper for PRISMA 2020, where we explain why reporting of each item is recommended, present bullet points that detail the reporting recommendations, and present examples from published reviews. We hope that changes to the content and structure of PRISMA 2020 will facilitate uptake of the guideline and lead to more transparent, complete, and accurate reporting of systematic reviews

The HSP70 Molecular Chaperone Is Not Beneficial in a Mouse Model of α-synucleinopathy

BACKGROUND: Aggregation and misfolded alpha-synuclein is thought to be central in the pathogenesis of Parkinson's disease (PD). Heat-shock proteins (HSPs) that are involved in refolding and degradation processes could lower the aggregate load of alpha-synuclein and thus be beneficial in alpha-synucleinopathies. METHODOLOGY/PRINCIPAL FINDINGS: We co-overexpressed human A53T point-mutated alpha-synuclein and human HSP70 in mice, both under the control of Thy1 regulatory sequences. Behavior read-outs showed no beneficial effect of HSP70 expression in mice. In contrast, motor coordination, grip strength and weight were even worse in the alpha-synucleinopathy model in the presence of HSP70 overexpression. Biochemical analyses revealed no differences in alpha-synuclein oligomers/aggregates, truncations and phosphorylation levels and alpha-synuclein localization was unchanged in immunostainings. CONCLUSION/SIGNIFICANCE: Overexpressing HSP70 in a mouse model of alpha-synucleinopathy did not lower the toxic load of alpha-synuclein species and had no beneficial effect on alpha-synuclein-related motor deficits

Dopamine-Induced Conformational Changes in Alpha-Synuclein

Background: Oligomerization and aggregation of α-synuclein molecules play a major role in neuronal dysfunction and loss in Parkinson's disease [1]. However, α-synuclein oligomerization and aggregation have mostly been detected indirectly in cells using detergent extraction methods [2], [3], [4]. A number of in vitro studies showed that dopamine can modulate the aggregation of α-synuclein by inhibiting the formation of or by disaggregating amyloid fibrils [5], [6], [7]. Methodology/Principal Findings: Here, we show that α-synuclein adopts a variety of conformations in primary neuronal cultures using fluorescence lifetime imaging microscopy (FLIM). Importantly, we found that dopamine, but not dopamine agonists, induced conformational changes in α-synuclein which could be prevented by blocking dopamine transport into the cell. Dopamine also induced conformational changes in α-synuclein expressed in neuronal cell lines, and these changes were also associated with alterations in oligomeric/aggregated species. Conclusion/Significance: Our results show, for the first time, a direct effect of dopamine on the conformation of α-synuclein in neurons, which may help explain the increased vulnerability of dopaminergic neurons in Parkinson's disease

Effects of body position on autonomic regulation of cardiovascular function in young, healthy adults

Background: Analysis of rhythmic patterns embedded within beat-to-beat variations in heart rate (heart rate variability) is a tool used to assess the balance of cardiac autonomic nervous activity and may be predictive for prognosis of some medical conditions, such as myocardial infarction. It has also been used to evaluate the impact of manipulative therapeutics and body position on autonomic regulation of the cardiovascular system. However, few have compared cardiac autonomic activity in supine and prone positions, postures commonly assumed by patients in manual therapy. We intend to redress this deficiency. Methods: Heart rate, heart rate variability, and beat-to-beat blood pressure were measured in young, healthy non-smokers, during prone, supine, and sitting postures and with breathing paced at 0.25 Hz. Data were recorded for 5 minutes in each posture: Day 1 - prone and supine; Day 2 - prone and sitting. Paired t-tests or Wilcoxon signed-rank tests were used to evaluate posture-related differences in blood pressure, heart rate, and heart rate variability. Results: Prone versus supine: blood pressure and heart rate were significantly higher in the prone posture (p &lt; 0.001). Prone versus sitting: blood pressure was higher and heart rate was lower in the prone posture (p &lt; 0.05) and significant differences were found in some components of heart rate variability. Conclusion: Cardiac autonomic activity was not measurably different in prone and supine postures, but heart rate and blood pressure were. Although heart rate variability parameters indicated sympathetic dominance during sitting (supporting work of others), blood pressure was higher in the prone posture. These differences should be considered when autonomic regulation of cardiovascular function is studied in different postures

Pitfalls and complications in the treatment of cervical spine fractures in patients with ankylosing spondylitis

Patients with ankylosing spondylitis are at significant risk for sustaining cervical spine injuries following trauma predisposed by kyphosis, stiffness and osteoporotic bone quality of the spine. The risk of sustaining neurological deficits in this patient population is higher than average. The present review article provides an outline on the specific injury patterns in the cervical spine, diagnostic algorithms and specific treatment modalities dictated by the underlying disease in patients with ankylosing spondylitis. An emphasis is placed on the risks and complication patterns in the treatment of these rare, but challenging injuries

Short Term Synaptic Depression Imposes a Frequency Dependent Filter on Synaptic Information Transfer

Depletion of synaptic neurotransmitter vesicles induces a form of short term depression in synapses throughout the nervous system. This plasticity affects how synapses filter presynaptic spike trains. The filtering properties of short term depression are often studied using a deterministic synapse model that predicts the mean synaptic response to a presynaptic spike train, but ignores variability introduced by the probabilistic nature of vesicle release and stochasticity in synaptic recovery time. We show that this additional variability has important consequences for the synaptic filtering of presynaptic information. In particular, a synapse model with stochastic vesicle dynamics suppresses information encoded at lower frequencies more than information encoded at higher frequencies, while a model that ignores this stochasticity transfers information encoded at any frequency equally well. This distinction between the two models persists even when large numbers of synaptic contacts are considered. Our study provides strong evidence that the stochastic nature neurotransmitter vesicle dynamics must be considered when analyzing the information flow across a synapse

Treatment Efficacy, Clinical Utility, and Cost-Effectiveness of Multidisciplinary Biopsychosocial Rehabilitation Treatments for Persistent Low Back Pain: A Systematic Review

Study Design: Systematic review. Objectives: To review the current literature on the treatment efficacy, clinical utility, and cost-effectiveness of multidisciplinary biopsychosocial rehabilitation (MBR) for patients suffering from persistent (nonspecific) lower back pain (LBP) in relation to pain intensity, disability, health-related quality of life, and work ability/sick leave. Methods: We carried out a systematic search of Web of Science, Cochrane Library, PubMed Central, EMBASE, and PsycINFO for English- and German-language literature published between January 2010 and July 2017. Study selection consisted of exclusion and inclusion phases. After screening for duplication, studies were excluded on the basis of criteria covering study design, number of participants, language of publication, and provision of information about the intervention. All the remaining articles dealing with the efficacy, utility, or cost-effectiveness of intensive (more than 25 hours per week) MBR encompassing at least 3 health domains and cognitive behavioral therapy–based psychological education were included. Results: The search retrieved 1199 publications of which 1116 were duplicates or met the exclusion criteria. Seventy of the remaining 83 articles did not meet the inclusion criteria; thus 13 studies were reviewed. All studies reporting changes in pain intensity or disability over 12 months after MBR reported moderate effect sizes and/or p-values for both outcomes. The effects on health-related quality of life were mixed, but MBR substantially reduced costs. Overall MBR produced an enduring improvement in work ability despite controversy and variable results. Conclusions: MBR is an effective treatment for nonspecific LBP, but there is room for improvement in cost-effectiveness and impact on sick leave, where the evidence was less compelling

Pathologic and Phenotypic Alterations in a Mouse Expressing a Connexin47 Missense Mutation That Causes Pelizaeus-Merzbacher–Like Disease in Humans

Gap junction channels are intercellular conduits that allow diffusional exchange of ions, second messengers, and metabolites. Human oligodendrocytes express the gap junction protein connexin47 (Cx47), which is encoded by the GJC2 gene. The autosomal recessive mutation hCx47M283T causes Pelizaeus-Merzbacher–like disease 1 (PMLD1), a progressive leukodystrophy characterized by hypomyelination, retarded motor development, nystagmus, and spasticity. We introduced the human missense mutation into the orthologous position of the mouse Gjc2 gene and inserted the mCx47M282T coding sequence into the mouse genome via homologous recombination in embryonic stem cells. Three-week-old homozygous Cx47M282T mice displayed impaired rotarod performance but unchanged open-field behavior. 10-15-day-old homozygous Cx47M282T and Cx47 null mice revealed a more than 80% reduction in the number of cells participating in glial networks after biocytin injections into oligodendrocytes in sections of corpus callosum. Homozygous expression of mCx47M282T resulted in reduced MBP expression and astrogliosis in the cerebellum of ten-day-old mice which could also be detected in Cx47 null mice of the same age. Three-month-old homozygous Cx47M282T mice exhibited neither altered open-field behavior nor impaired rotarod performance anymore. Adult mCx47M282T expressing mice did not show substantial myelin alterations, but homozygous Cx47M282T mice, additionally deprived of connexin32, which is also expressed in oligodendrocytes, died within six weeks after birth and displayed severe myelin defects accompanied by astrogliosis and activated microglia. These results strongly suggest that PMLD1 is caused by the loss of Cx47 channel function that results in impaired panglial coupling in white matter tissue