Metabotropic Glutamate Receptors Protect Oligodendrocytes from Acute Ischemia in the Mouse Optic Nerve.

Studies by Bruce Ransom and colleagues have made a major contribution to show that white matter is susceptible to ischemia/hypoxia. White matter contains axons and the glia that support them, notably myelinating oligodendrocytes, which are highly vulnerable to ischemic-hypoxic damage. Previous studies have shown that metabotropic GluRs (mGluRs) are cytoprotective for oligodendrocyte precursor cells and immature oligodendrocytes, but their potential role in adult white matter was unresolved. Here, we report that group 1 mGluR1/5 and group 2 mGluR3 subunits are expressed in optic nerves from mice aged postnatal day (P)8-12 and P30-35. We demonstrate that activation of group 1 mGluR protects oligodendrocytes against oxygen-glucose deprivation (OGD) in developing and young adult optic nerves. In contrast, group 2 mGluR are shown to be protective for oligodendrocytes against OGD in postnatal but not young adult optic nerves. The cytoprotective effect of group 1 mGluR requires activation of PKC, whilst group 2 mGluR are dependent on negatively regulating adenylyl cyclase and cAMP. Our results identify a role for mGluR in limiting injury of oligodendrocytes in developing and young adult white matter, which may be useful for protecting oligodendrocytes in neuropathologies involving excitoxicity and ischemia/hypoxia

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

The synaptic blocker botulinum toxin A decreases the density and complexity of oligodendrocyte precursor cells in the adult mouse hippocampus

Oligodendrocyte progenitor cells (OPCs) are responsible for generating oligodendrocytes, the myelinating cells of the CNS. Life-long myelination is promoted by neuronal activity and is essential for neural network plasticity and learning. OPCs are known to contact synapses and it is proposed that neuronal synaptic activity in turn regulates their behavior. To examine this in the adult, we performed unilateral injection of the synaptic blocker botulinum neurotoxin A (BoNT/A) into the hippocampus of adult mice. We confirm BoNT/A cleaves SNAP-25 in the CA1 are of the hippocampus, which has been proven to block neurotransmission. Notably, BoNT/A significantly decreased OPC density and caused their shrinkage, as determined by immunolabeling for the OPC marker NG2. Furthermore, BoNT/A resulted in an overall decrease in the number of OPC processes, as well as a decrease in their lengths and branching frequency. These data indicate that synaptic activity is important for maintaining adult OPC numbers and cellular integrity, which is relevant to pathophysiological scenarios characterized by dysregulation of synaptic activity, such as age-related cognitive decline, Multiple Sclerosis and Alzheimer's disease

Endemic pemphigus in the peruvian Amazon: epidemiology and risk factors for the development of complications during treatment Pênfigo endêmico na Amazônia peruana: epidemiologia e fatores de risco para o desenvolvimento de complicações durante o tratamento

BACKGROUND: Pemphigus is an autoimmune blistering disease. According to a report, in areas of endemic pemphigus foliaceus (EPF) in Peru there are cases of pemphigus vulgaris with epidemiologic, clinical and histopathologic characteristics similar to those of "endemic pemphigus vulgaris" (EPV) in Brazil. OBJECTIVES: To determine the clinical and epidemiologic characteristics of endemic pemphigus and the risk factors of patients for developing complications during treatment. METHODS: A study was carried out from July 2003 to March 2008. The study population was 60 patients with EPF and 7 patients with EPV evaluated in hospitals and clinics in the Peruvian Amazon and Lima. A multivariate analysis was carried out using binary logistic regression. RESULTS: The average age of EPF patients was 31.4 years; 55% were men; 60% presented the generalized clinical variant. Non-compliance with the treatment was seen in 57.1% of the patients. Thirty-five percent presented complications (e.g. pyodermitis and pyelonephritis) during treatment. The risk factors for developing complications during treatment were non-compliance with the treatment and having the generalized clinical form. In the EPV group, the average age was 21.7 years; 71.4% were men. All patients presented with the mucocutaneous clinical variant and the initial presentation consisted of oral mucosa lesions; 71.4% presented complications during treatment, pyodermitis being the most frequent. CONCLUSIONS: Non-compliance with the treatment and the generalized clinical form are risk factors for the development of complications during treatment of patients with EPF. Peru indeed has EPV cases with epidemiologic characteristics similar to EPF. Living in a rural area may represent a risk factor for the development of complications during treatment of patients with EPV.<br>FUNDAMENTOS: O pênfigo é uma doença auto-imune bolhosa. Segundo um relatório, em áreas de pênfigo foliáceo endêmico no Peru há casos de pênfigo vulgar com características epidemiológicas, clínicas e histopatológicas semelhantes às do "pênfigo vulgar endêmico" no Brasil. OBJETIVOS: Determinar as características clínicas e epidemiológicas do pênfigo endêmico e os fatores de risco para o desenvolvimento de complicações durante o tratamento. MÉTODOS: Um estudo foi realizado de julho de 2003 a março de 2008. 60 doentes de pênfigo foliáceo endêmico e 7 de pênfigo vulgar endêmico foram avaliados em hospitais e clínicas na Amazônia peruana e em Lima. Uma análise multivariante foi feita usando regressão logística binária. RESULTADOS: A idade média dos doentes de pênfigo foliáceo endêmico foi 31,4 anos; 55% eram homens, 60% apresentavam a forma clínica generalizada. 57,1% nao cumpriram o tratamento. 35% apresentaram complicações (por exemplo, piodermites e pielonefrite). Os fatores de risco foram não cumprir o tratamento e ter a forma clínica generalizada. No grupo pênfigo vulgar endêmico, a idade média foi 21,7 anos; 71,4% eram homens. Todos os pacientes apresentavam a variante clínica mucocutânea e a apresentação inicial consistia de lesões da mucosa bucal; 71,4% apresentaram complicações durante o tratamento, piodermites sendo a mais freqüente. CONCLUSÕES: Não cumprir o tratamento e ter a forma clínica generalizada são fatores de risco para o desenvolvimento de complicações durante o tratamento de pênfigo foliáceo endêmico. Peru realmente tem casos de pênfigo vulgar endêmico com características epidemiológicas semelhantes às do pênfigo foliáceo endêmico. Viver numa área rural pode ser um fator de risco para o desenvolvimento de complicações

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

Background: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit