Increasing Internodal Distance in Myelinated Nerves Accelerates Nerve Conduction to a Flat Maximum

SummaryPredictions that conduction velocities are sensitive to the distance between nodes of Ranvier in myelinated axons have implications for nervous system function during growth and repair [1–3]. Internodal lengths defined by Schwann cells in hindlimb nerves, for example, can undergo a 4-fold increase during mouse development, and regenerated nerves have internodes that are uniformly short [4, 5]. Nevertheless, the influence of internodal length on conduction speed has limited experimental support. Here, we examined this problem in mice expressing a mutant version of periaxin, a protein required for Schwann cell elongation [4]. Importantly, elongation of mutant Schwann cells was retarded without significant derangements to myelination or axon caliber. In young mice with short mutant Schwann cells, nerve conduction velocity was reduced and motor function was impaired. This demonstrates a functional relationship between internodal distance and conduction speed. Moreover, as internodes lengthened during postnatal growth, conduction velocities recovered to normal values and mutant mice exhibited normal motor and sensory behavior. This restoration of function confirms a further prediction by Huxley and Stämpfli that conduction speeds should increase as internodal distances lengthen until a “flat maximum” is reached, beyond which no further gains in conduction velocity accrue [6]

The SH3 domain of postsynaptic density 95 mediates inflammatory pain through phosphatidylinositol-3-kinase recruitment

Sensitization to inflammatory pain is a pathological form of neuronal plasticity that is poorly understood and treated. Here we examine the role of the SH3 domain of postsynaptic density 95 (PSD95) by using mice that carry a single amino-acid substitution in the polyproline-binding site. Testing multiple forms of plasticity we found sensitization to inflammation was specifically attenuated. The inflammatory response required recruitment of phosphatidylinositol-3-kinase-C2α to the SH3-binding site of PSD95. In wild-type mice, wortmannin or peptide competition attenuated the sensitization. These results show that different types of behavioural plasticity are mediated by specific domains of PSD95 and suggest novel therapeutic avenues for reducing inflammatory pain

Involvement of the Melanocortin-1 Receptor in Acute Pain and Pain of Inflammatory but Not Neuropathic Origin

Response to painful stimuli is susceptible to genetic variation. Numerous loci have been identified which contribute to this variation, one of which, MC1R, is better known as a gene involved in mammalian hair colour. MC1R is a G protein-coupled receptor expressed in melanocytes and elsewhere and mice lacking MC1R have yellow hair, whilst humans with variant MC1R protein have red hair. Previous work has found differences in acute pain perception, and response to analgesia in mice and humans with mutations or variants in MC1R.We have tested responses to noxious and non-noxious stimuli in mutant mice which lack MC1R, or which overexpress an endogenous antagonist of the receptor, as well as controls. We have also examined the response of these mice to inflammatory pain, assessing the hyperalgesia and allodynia associated with persistent inflammation, and their response to neuropathic pain. Finally we tested by a paired preference paradigm their aversion to oral administration of capsaicin, which activates the noxious heat receptor TRPV1. Female mice lacking MC1R showed increased tolerance to noxious heat and no alteration in their response to non-noxious mechanical stimuli. MC1R mutant females, and females overexpressing the endogenous MC1R antagonist, agouti signalling protein, had a reduced formalin-induced inflammatory pain response, and a delayed development of inflammation-induced hyperalgesia and allodynia. In addition they had a decreased aversion to capsaicin at moderate concentrations. Male mutant mice showed no difference from their respective controls. Mice of either sex did not show any effect of mutant genotype on neuropathic pain.We demonstrate a sex-specific role for MC1R in acute noxious thermal responses and pain of inflammatory origin

PANC Study (Pancreatitis: A National Cohort Study): national cohort study examining the first 30 days from presentation of acute pancreatitis in the UK

Abstract Background Acute pancreatitis is a common, yet complex, emergency surgical presentation. Multiple guidelines exist and management can vary significantly. The aim of this first UK, multicentre, prospective cohort study was to assess the variation in management of acute pancreatitis to guide resource planning and optimize treatment. Methods All patients aged greater than or equal to 18 years presenting with acute pancreatitis, as per the Atlanta criteria, from March to April 2021 were eligible for inclusion and followed up for 30 days. Anonymized data were uploaded to a secure electronic database in line with local governance approvals. Results A total of 113 hospitals contributed data on 2580 patients, with an equal sex distribution and a mean age of 57 years. The aetiology was gallstones in 50.6 per cent, with idiopathic the next most common (22.4 per cent). In addition to the 7.6 per cent with a diagnosis of chronic pancreatitis, 20.1 per cent of patients had a previous episode of acute pancreatitis. One in 20 patients were classed as having severe pancreatitis, as per the Atlanta criteria. The overall mortality rate was 2.3 per cent at 30 days, but rose to one in three in the severe group. Predictors of death included male sex, increased age, and frailty; previous acute pancreatitis and gallstones as aetiologies were protective. Smoking status and body mass index did not affect death. Conclusion Most patients presenting with acute pancreatitis have a mild, self-limiting disease. Rates of patients with idiopathic pancreatitis are high. Recurrent attacks of pancreatitis are common, but are likely to have reduced risk of death on subsequent admissions. </jats:sec

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Intracellular targets for nitric oxide toxicity to pancreatic beta-cells.

The radical nitric oxide (NO) may be a mediator of pancreatic beta-cell damage in early insulin-dependent diabetes mellitus (IDDM). Under the stimulus of cytokines, invading macrophages and the beta-cell themselves may produce large amounts of NO, leading to beta-cell dysfunction and death. It still remains to be determined which are the intracellular targets for NO-induced damage. Available data from rat islets indicate that the radical inactivates the mitochondrial enzyme aconitase, impairing substrate oxidation and ATP production. Ionic channels and complexes I and II of the mitochondrial electron transport chain are two other possible targets for NO effects which may impair insulin secretion. NO also leads to nuclear DNA damage in both rat and human pancreatic beta-cells, as evaluated by the 'comet assay'. The effects of NO at the DNA level are complex, and involve formation of N-nitrosoamines, deamination of purines and pyrimidines, or damage induced by peroxynitrite. Besides inducing over DNA damage. NO may also inactivate DNA repair/replication enzymes. The outcome of NO-induced beta-cell DNA damage can be cell death by apoptosis or, in some cases, necrosis. Upon cell damage beta-cells trigger cell repair mechanisms. This seems also to be the case following NO exposure, and insulin-producing cells are able to regain their function following treatment with non-lethal concentrations of NO. A better understanding of the mechanisms involved in NO-induced beta-cell damage and repair may be instrumental in developing new strategies for IDDM prevention.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Cytokines induce deoxyribonucleic acid strand breaks and apoptosis in human pancreatic islet cells.

We have previously observed that a 6-day exposure of human pancreatic islets to a combination of cytokines (interleukin-1beta 50 U/ml + tumour necrosis factor-alpha 1000 U/ml + interferon-gamma 1000 U/ml) severely impairs beta-cell functions. In the present study, we examined whether this condition affects DNA integrity and viability of human islet cells. Cells were studied after 3, 6, and 9 days of cytokine treatment by both single cell gel electrophoresis (the "comet assay," a sensitive method for detection of DNA strand breaks) and by a cytotoxicity assay using the DNA binding dyes Hoechst 33342 and propidium iodide as indices for the number of viable, necrotic, and apoptotic cells. Cytokine treatment for 6 and 9 days resulted in a 50% increase in comet length (P < 0.01 vs. controls), indicating DNA strand breaks, as well as in a significant increase in the number of apoptotic cells (P < 0.02 vs. controls), but not in the number of necrotic cells. The arginine analogs N(G)-nitro-L-arginine and N(G)-monomethyl-L-arginine prevented nitric oxide formation by the cytokines but did not interfere with cytokine-induced DNA strand breaks and apoptosis. The present data suggest that prolonged (6-9 days) exposure of human pancreatic islets to a mixture of cytokines induces DNA strand breaks and cell death by apoptosis. These deleterious effects of cytokines appear to be independent of nitric oxide generation.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Sensitivity of human pancreatic islets to peroxynitrite-induced cell dysfunction and death.

Nitric oxide and peroxynitrite (generated by the reaction of nitric oxide with the superoxide anion) may both be mediators of beta-cell damage in early insulin-dependent diabetes mellitus. We observed that acute exposure of primary cultured human pancreatic islets to peroxynitrite results in a significant decrease in glucose oxidation and islet retrieval. DNA strand breaks in single human and rat islet cells are detectable after acute peroxynitrite exposure, followed by a decrease in islet cell survival after 1 h and 24 h. Cell death appeared to occur via a toxic cell death mechanism (necrosis) rather than apoptosis, as suggested by vital staining and ultrastructural evidence of early membrane and organelle degradation, mitochondrial swelling and loss of matrix. This study demonstrates for the first time that cultured human pancreatic islets are susceptible to the noxious effects of peroxynitrite.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe