Axonal Transport, Phase-Separated Compartments, and Neuron Mechanics - A New Approach to Investigate Neurodegenerative Diseases

Many molecular and cellular pathogenic mechanisms of neurodegenerative diseases have been revealed. However, it is unclear what role a putatively impaired neuronal transport with respect to altered mechanical properties of neurons play in the initiation and progression of such diseases. The biochemical aspects of intracellular axonal transport, which is important for molecular movements through the cytoplasm, e.g., mitochondrial movement, has already been studied. Interestingly, transport deficiencies are associated with the emergence of the affliction and potentially linked to disease transmission. Transport along the axon depends on the normal function of the neuronal cytoskeleton, which is also a major contributor to neuronal mechanical properties. By contrast, little attention has been paid to the mechanical properties of neurons and axons impaired by neurodegeneration, and of membraneless, phase-separated organelles such as stress granules (SGs) within neurons. Mechanical changes may indicate cytoskeleton reorganization and function, and thus give information about the transport and other system impairment. Nowadays, several techniques to investigate cellular mechanical properties are available. In this review, we discuss how select biophysical methods to probe material properties could contribute to the general understanding of mechanisms underlying neurodegenerative diseases

Characterisation of the contribution of the GABA-benzodiazepine α1 receptor subtype to [11C]Ro15-4513 PET images

This positron emission tomography (PET) study aimed to further define selectivity of [11C]Ro15-4513 binding to the GABARα5 relative to the GABARα1 benzodiazepine receptor subtype. The impact of zolpidem, a GABARα1-selective agonist, on [11C]Ro15-4513, which shows selectivity for GABARα5, and the nonselective benzodiazepine ligand [11C]flumazenil binding was assessed in humans. Compartmental modelling of the kinetics of [11C]Ro15-4513 time-activity curves was used to describe distribution volume (VT) differences in regions populated by different GABA receptor subtypes. Those with low α5 were best fitted by one-tissue compartment models; and those with high α5 required a more complex model. The heterogeneity between brain regions suggested spectral analysis as a more appropriate method to quantify binding as it does not a priori specify compartments. Spectral analysis revealed that zolpidem caused a significant VT decrease (∼10%) in [11C]flumazenil, but no decrease in [11C]Ro15-4513 binding. Further analysis of [11C]Ro15-4513 kinetics revealed additional frequency components present in regions containing both α1 and α5 subtypes compared with those containing only α1. Zolpidem reduced one component (mean±s.d.: 71%±41%), presumed to reflect α1-subtype binding, but not another (13%±22%), presumed to reflect α5. The proposed method for [11C]Ro15-4513 analysis may allow more accurate selective binding assays and estimation of drug occupancy for other nonselective ligands

Gravidez em cicatriz de cesária: um relato de caso

The term ectopic pregnancy refers to nidations that occur outside the uterine cavity, and may occur in the fallopian tubes, ovaries, abdomen, uterine scar - the latter being the rarest and with the highest risk of morbidity and mortality, due to major complications such as uterine rupture and massive bleeding. Thus, this report describes this rare pregnancy implantation, which has been increasing its incidence due to the increase of elective cesarean sections. A 34-year-old patient, G2C1A1, was admitted to a reference service with an ultrasound report of anembryonic pregnancy. After orientation, the patient opted for expectant management. One month later, the patient returns complaining of vaginal bleeding, and a new ultrasound shows a large amount of ovular debris. Due to the missed abortion, the team performed manual intrauterine aspiration with a small amount of material - incompatible with the ultrasound - which led to a control transvaginal ultrasound. It was identified intrauterine heterogeneous content, with an anechoic image in the central portion - suspicion of ectopic pregnancy in uterine scar or molar pregnancy. A new BHCG and magnetic resonance imaging were requested for diagnostic elucidation, and an ectopic pregnancy implanted in a cesarean section scar was found. After approach, the patient started with fever and laboratory changes, which suggested uterine perforation. With urgency, the patient was reordered and laparotomy was performed, with visualization of uterine serosa bulging and apparent perforation. An abdominal hysterectomy was performed, with no further complications other than increased bleeding, requiring blood transfusion at the end.O termo gravidez ectópica se refere às nidações que ocorrem fora da cavidade uterina, podendo ocorrer nas trompas, ovários, abdome, cicatriz uterina - sendo esta última, a mais rara e com maior risco de morbimortalidade, devido a maiores complicações como rotura uterina e hemorragia volumosa. Dessa forma, este relato descreve esta rara implantação de gestação, a qual vem elevando sua incidência devido ao aumento de cesarianas eletivas. Paciente, 34 anos, G2C1A1, é admitida ao serviço de referência com laudo de gestação anembrionada no ultrassom. Após orientação, optou por conduta expectante. Passado um mês, retorna com queixa de sangramento vaginal e novo ultrassom consta grande quantidade de restos ovulares. Devido ao aborto retido, equipe realiza aspiração manual intrauterina com pequena saída de material - incompatível com ultrassom - o que ocasionou a realização ultrassom trasnvaginal de controle. Foi identificado conteúdo heterogêneo intrauterino, com imagem anecoica na porção central - suspeita de gestação ectópica em cicatriz uterina ou gestação molar. Diante disso, foram solicitados novo BHCG e ressonância magnética para elucidação diagnóstica, constatando gestação ectópica implantada em cicatriz de cesárea. Após abordagem, paciente iniciou com febre e alterações laboratoriais, os quais sugeriam perfuração uterina. Com urgência, paciente foi reabordada e foi realizado laparotomia, com visualização de abaulamento de serosa uterina e aparente perfuração. Realizada histerectomia abdominal, sem mais complicações além de sangramento aumentado, com necessidade de transfusão sanguínea ao final

Vitamin D receptor polymorphisms and survival in patients with cutaneous melanoma: a population-based study

Factors known to affect melanoma survival include age at presentation, sex and tumor characteristics. Polymorphisms also appear to modulate survival following diagnosis. Result from other studies suggest that vitamin D receptor (VDR) polymorphisms (SNPs) impact survival in patients with glioma, renal cell carcinoma, lung, breast, prostate and other cancers; however, a comprehensive study of VDR polymorphisms and melanoma-specific survival is lacking. We aimed to investigate whether VDR genetic variation influences survival in patients with cutaneous melanoma. The analysis involved 3566 incident single and multiple primary melanoma cases enrolled in the international population-based Genes, Environment, and Melanoma Study. Melanoma-specific survival outcomes were calculated for each of 38 VDR SNPs using a competing risk analysis after adjustment for covariates. There were 254 (7.1%) deaths due to melanoma during the median 7.6 years follow-up period. VDR SNPs rs7299460, rs3782905, rs2239182, rs12370156, rs2238140, rs7305032, rs1544410 (BsmI) and rs731236 (TaqI) each had a statistically significant (trend P values < 0.05) association with melanoma-specific survival in multivariate analysis. One functional SNP (rs2239182) remained significant after adjustment for multiple testing using the Monte Carlo method. None of the SNPs associated with survival were significantly associated with Breslow thickness, ulceration or mitosis. These results suggest that the VDR gene may influence survival from melanoma, although the mechanism by which VDR exerts its effect does not seem driven by tumor aggressiveness. Further investigations are needed to confirm our results and to understand the relationship between VDR and survival in the combined context of tumor and host characteristics