BackgroundMutations in the valosin-containing protein (VCP) gene were first found to cause inclusion- body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD). Mutations in the VCP gene were later reported to occur in familial amyotrophic lateral sclerosis (ALS). But the role of VCP in the neurodegenerative processes that occur in ALS remains unknown. The purpose of the present study was to elucidate the role of VCP in the neurodegeneration seen in sporadic and VCP mutant ALS.ResultsImmunohistochemistry demonstrated that the frequency of distinct VCP-positive nuclei of spinal motor neurons of patients with sporadic ALS (SALS) and the ALS with VCP novel mutation (ALS-VCP, M158V) was increased, compared with that of the control cases. No VCP-positive inclusion bodies were observed in SALS patients, a ALS-VCP patient or in control subjects. Neuropathologic examination of the ALS-VCP case showed loss of motor neurons, the presence of Bunina bodies, and degeneration of the corticospinal tracts. Bunina bodies detected in this case were confirmed to show immunohistochemical and ultrastructural features similar to those previously described. Furthermore, neuronal intracytoplasmic inclusions immunopositive for TAR DNA-binding protein 43 kDa (TDP-43), phosphorylated TDP-43, ubiquitin (Ub), p62, and optineurin were identified in the spinal and medullary motoneurons, but not in the neocortex. Gene analysis of this ALS-VCP patient confirmed the de novo mutation of M158V, which was not found in control cases; and bioinformatics using several in silico analyses showed possible damage to the structure of VCP. Immunocytochemical study of cultured cells showed increased cytoplasmic translocation of TDP-43 in cells transfected with several mutant VCP including our patient’s compared with wild-type VCP.ConclusionThese findings support the idea that VCP is associated with the pathomechanism of SALS and familial ALS with a VCP mutation, presumably acting through a dominant-negative mechanism.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0172-0) contains supplementary material, which is available to authorized users.

Background: The pathological role of obesity in the progression of glomerular lesions has rarely been studied in primary glomerular diseases. The purpose of this study is to investigate the influence of non-diabetic obesity on clinicopathological findings in IgA nephropathy. Methods: 74 patients with biopsy-proven IgA nephropathy were retrospectively divided into two groups according to the criteria for obesity in Japan: non-obese group (group N: n = 50) with BMI <25 kg/m², and obese group (group O: n = 24) with BMI ≥25 kg/m². Clinical and pathological data at the time of renal biopsy were analyzed. Moreover, the outcome of proteinuria in patients treated with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin II receptor blockers (ARB) was evaluated in different groups after a 1-year follow-up. Results: Urinary protein excretion was significantly greater in the obese group compared to normal-weight patients (p < 0.05). There was no significant difference in the prevalence of hypertension and hyperlipidemia. By light microscopy, the obese group showed significantly larger glomerular size (p < 0.0001). On the other hand, the severity of mesangial matrix expansion and crescent formation revealed no difference between the two groups. By electron microscopy, glomerular basement membrane (GBM) thickness was significantly increased in obese patients (p < 0.001). Among 61 patients who were followed up for 1 year in our institute, 15 patients were treated with ACE-I or ARB without steroids. ACE-I or ARB treatment without steroids tended to reduce proteinuria in the obese patients, but this change did not achieve statistical significance. Conclusions: In IgA nephropathy, obesity induces not only glomerular enlargement but also ultrastructural modification of GBM, which would contribute to increase proteinuria.

The pathological role of obesity has rarely been studied in primary glomerular diseases. The purpose of this study is to examine the clinicopathological influence of obesity in IgA nephropathy (IgAN). 74 patients with IgA nephropathy in our institution from October 2000 to January 2004 were retrospectively divided into two groups according to body mass index (BMI): the non-obese group (group N) with BMI < 25 kg/m(2), and the obese group (group O) with BMI > or = 25 kg/m(2). There were 50 patients in group N and 24 patients in group O. Clinical analysis showed no significant difference between these two groups in blood pressure, serum cholesterol, creatinine clearances or grade of hematuria. However, urinary protein excretion and serum creatinine were significantly greater in group O than in group N. Although semiquantitative analysis of light-microscopical findings showed no significant differences in the severity of mesangial proliferation, matrix expansion, glomerulosclerosis or crescent formation, image analysis showed that total glomerular area and tuft area were significantly larger in group O. In addition, ultrastructural study revealed significantly higher glomerular basement membrane thickness in group O. 62 patients (46 patients, group N; 16 patients, group O) were followed in our institution for one year. Urinary protein was significantly decreased only in patients who received steroid in both groups. Although administration of ACE inhibitor or ARB tended to decrease urinary protein in group O, the change was not statistically significant. Our findings indicate that obesity may accelerate the increase of proteinuria in IgAN through ultrastructural modification of the glomerular basement membrane.

While the Surviving Sepsis Campaign guidelines recommend an initial target value of 65 mmHg as the mean arterial pressure (MAP) in patients with septic shock, the optimal MAP target for improving outcomes remains controversial. We performed a meta-analysis to evaluate the optimal MAP for patients with vasodilatory shock, which included three randomized controlled trials that recruited 3,357 patients. Between the lower (60–70 mmHg) and higher (&gt;70 mmHg) MAP target groups, there was no significant difference in all-cause mortality (risk ratio [RR], 1.06; 95% confidence intervals [CI], 0.98–1.16) which was similar in patients with chronic hypertension (RR, 1.10; 95% CI, 0.98–1.24) and patients aged ≥65 years (RR, 1.10; 95% CI, 0.99–1.21). No significant difference in adverse events was observed between the different MAP groups (RR, 1.04; 95% CI, 0.87–1.24); however, supraventricular arrhythmia was significantly higher in the higher MAP group (RR, 1.73; 95% CI, 1.15–2.60). Renal replacement therapy was reduced in the higher MAP group of patients with chronic hypertension (RR, 0.83; 95% CI, 0.71–0.98). Though the higher MAP control did not improve the mortality rate, it may be beneficial in reducing renal replacement therapy in patients with chronic hypertension.Systematic review registration: UMIN Clinical Trials Registry, identifier UMIN000042624

IntroductionThe optimal target of mean arterial pressure (MAP) for better outcomes in patients with vasodilatory shock remains a matter of debate. Although catecholamines are generally used to maintain target blood pressure in hypotensive patients with vasodilatory shock, the adverse effects of catecholamines must also be considered. We will perform a systematic review and meta-analysis of randomised controlled trials (RCTs) to assess the certainty of evidence determining the optimal target of MAP control for patients with vasodilatory shock in critically ill settings.Methods and analysisThis study protocol was registered in the University Hospital Medical Information Network Clinical Trials Registry. We will include only RCTs that evaluated the two different comparators for target MAP to be maintained for clinical outcomes of all-cause mortality: organ dysfunction and adverse events in critically ill adult patients with vasodilatory shock. We will search the electronic bibliographic databases of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials in November 2020. Two reviewers will independently screen titles and abstracts, perform full article reviews and extract study data. We will report study characteristics and assess methodological quality using the Cochrane Risk-of-Bias 2 tool. If pooling is appropriate, we will calculate relative risks with 95% CIs for all outcome measures. Clinical and methodological subgroup and sensitivity analyses will be performed to explore heterogeneity. Overall certainty of evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach.Ethics and disseminationThis study will not involve primary data collection, and formal ethics approval will therefore not be required. We aim to publish this systematic review in a peer-reviewed journal.Trial registration numberUMIN000042624.