Down‐regulation of glutamatergic terminals (VGLUT1) driven by Aβ in Alzheimer's disease

Alzheimer's disease (AD) is characterized phenotypically by memory impairment, histologically by accumulation of pTau and β‐amyloid peptide and morphologically by a loss of nerve terminals in cortical and hippocampal regions. As glutamate is the principle excitatory neurotransmitter of the central nervous system (CNS), the glutamatergic system may play an important role in AD. To date, not many studies have addressed the deleterious effects of Aβ on glutamatergic terminals; therefore the aim of this study was to investigate how Aβ affects glutamatergic terminals and to assess the extent to which alterations in the glutamatergic neurotransmission could impact susceptibility to the illness. The present study shows that Aβ caused a loss of glutamatergic terminals, measured by VGLUT1 protein levels, in Tg2576 primary cell cultures, Tg2576 mice and AD patient brains, and also when Aβ was added exogenously to hippocampal cell cultures. Interestingly, no correlation was found between cognition and decreased VGLUT1 levels. Moreover, when Aβ_1–42 was intracerebroventricularlly administered into VGLUT1+/‐ mice, altered synaptic plasticity and increased neuroinflammation was observed in the hippocampus of those animals. In conclusion, the present study not only revealed susceptibility of glutamatergic nerve terminals to Aβ induced toxicity but also underlined the importance of VGLUT1 in the progression of AD, as the decrease of this protein levels could increase the susceptibility to subsequent deleterious inputs by exacerbating Aβ induced neuroinflammation and synaptic plasticity disruption. © 2016 Wiley Periodicals, Inc.     

Surface topography during neural stem cell differentiation regulates cell migration and cell morphology

We sought to determine the contribution of scaffold topography to the migration and morphology of neural stem cells by mimicking anatomical features of scaffolds found in vivo. We mimicked two types of central nervous system scaffolds encountered by neural stem cells during development in vitro by constructing different diameter electrospun polycaprolactone (PCL) fiber mats, a substrate that we have shown to be topographically similar to brain scaffolds. We compared the effects of large fibers (made to mimic blood vessel topography) with those of small‐diameter fibers (made to mimic radial glial process topography) on the migration and differentiation of neural stem cells. Neural stem cells showed differential migratory and morphological reactions with laminin in different topographical contexts. We demonstrate, for the first time, that neural stem cell biological responses to laminin are dependent on topographical context. Large‐fiber topography without laminin prevented cell migration, which was partially reversed by treatment with rock inhibitor. Cell morphology complexity assayed by fractal dimension was inhibited in nocodazole‐ and cytochalasin‐D–treated neural precursor cells in large‐fiber topography, but was not changed in small‐fiber topography with these inhibitors. These data indicate that cell morphology has different requirements on cytoskeletal proteins dependent on the topographical environment encountered by the cell. We propose that the physical structure of distinct scaffolds induces unique signaling cascades that regulate migration and morphology in embryonic neural precursor cells. J. Comp. Neurol. 524:3485–3502, 2016. © 2016 Wiley Periodicals, Inc.     

Is conservative surgery a good option for patients with “triple negative” breast cancer?

BackgroundTriple negative breast cancers (negative estrogen receptor, progestagen receptor and no overexpression of HER2) seems to be more aggressive than other breast carcinoma subtypes. Therefore, it is necessary to analyze if a more aggressive surgical treatment should be offered to this subgroup of patients.Patients and methodsThe Castellon Cancer Registry Database (C.Valenciana, Spain) was used to identify eligible breast cancer patients. Female patients who were diagnosed and/or treated from January 2000 to December 2008 with primary, invasive, unilateral breast cancer at our hospital were included. A total of 410 patients make up the study population. Kaplan–Meier curves and log-rank tests were used to estimate 5-year local recurrence functions and to compare them across strata. Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals to fit the effect of conservative surgery and other independent variables on local recurrence.ResultsMedian follow-up time was 60 months (1–127 months). A total of 21 patients (5%) presented a local recurrence during follow-up. There was a 9% difference in terms of local recurrence between conservative and non-conservative techniques for triple negative patients, whereas such difference was only 1% for no triple negative patients. On univariate analysis for local recurrence, only tumor size and lymph node metastasis were statistically associated with local recurrence. All other variables (type of surgery, triple negative status, molecular classification, tumor grade, age, adjuvant treatments, and total number of analyzed lymph nodes) were not statistically significant. On multivariate analysis, independent prognostic factors were breast conservative surgery (HR 4.62 95%CI 1.12–16.82), number of positive lymph nodes (HR 1.07 95%CI 1.01–1.17) and millimetre tumor size (HR 1.02 95%CI 1.01–1.06). In contrast, triple negative status trended to be a risk factor but without statistical significance (HR 1.59 95%CI 0.42–8.04).ConclusionsIt was not possible to find statistically significant differences between conservative and non-conservative surgery for triple negative breast cancer. However, a trend was observed for higher recurrence rates after breast conservative surgery for this group of patients. Prospective clinical trials are needed to confirm this observation.     

La disfunción eréctil y su severidad están en relación con el número de factores de riesgo cardiovascular

AimErectile dysfunction (ED) is a very common condition in the general population. ED is closely related to Hypertension (HT), Diabetes Mellitus (DM), Dyslipidemia (DLP) and Metabolic Syndrome (MS). This study has aimed to clarify whether the presence and severity of ED are related to the presence and number of cardiovascular risk factors (CVRF).Material and methodsWe retrospectively analyzed the characteristics of 242 males referred to our center for a prostate biopsy from September 2007 to December 2009. The following variables were collected prospectively: age, height, weight, body mass index (BMI), AHT, DM, DLP and obesity (BMI < 30 kg/m²). The Erection Hardness Score Questionnaire was used to assess erectile function. We analyzed the relation between the presence and severity of ED and the presence of HT, DM, DLP and obesity. We analyzed the clinical variables based on the presence or absence of ED and in relationship to its severity.ResultsThe presence of ED was related to HT (OR: 1.805 [1.128-2.887]; p = 0.013), DM (OR 3.585 [1.613-7.966]; p = 0.001) and Dyslipidemia (OR: 1.928 [1.062-3.500]; p = 0.029). Erectile function was not related to Obesity (OR: 0.929 [0.522-1.632]; p = 0.795). Patients with ED were more likely to have more CVRF (p = 0.009) and the severity of ED was related to the presence of HT (p < 0.001), DM (p < 0.001), DLP (p = 0.001) and the number of CVRF (p < 0.001).ConclusionsThe presence and severity of ED correlate with the presence of HT, DM, Dyslipidemia and the number of DVRF.     

Non-alcoholic Steatohepatitis (NASH) and Hepatocellular Carcinoma

Non-alcoholic fatty liver disease (NAFLD) is characterized by an excessive accumulation of fatty acids and triglycerides within the cytoplasm of the hepatocytes of non-alcohol users. The natural history varies according to the initial histological diagnosis. A current consideration is that cryptogenic cirrhosis may be representative of a late stage of non-alcoholic steatohepatitis (NASH), which has lost its features of necroinflammatory activity and steatosis in up to 80% of patients. Since NASH is able to progress to cirrhosis, hepatocellular carcinoma (HCC) development may be an end-stage of this disease. We report below two clinical cases of patients diagnosed with NASH who developed HCC. The relationship between NAFLD and HCC is reviewed.     

Expression of adhesion molecules and RANTES in kidney transplant from nonheart-beating donors

The main difference between cadaveric kidneys from donors with a heartbeat (HBD) and kidneys from nonheart-beating donors (NHBD) is related to warm ischemia/reperfusion time which constitutes an acute inflammatory process. On the contrary, brain death induces in HBD expression of pro-inflammatory adhesion molecules, making it important to evaluate this kind of molecules in both types of donors. Human renal biopsies from NHBD, HBD and normal kidneys (ischemia time = 0) were taken and frozen just before transplant. A semi-quantitative RT-PCR method was used to determine intracellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), lymphocyte function associated antigen (LFA-1), LFA-3, CD40, CD40 ligand (CD40L) and RANTES (regulated upon activation, normal T-cell expressed and secreted) gene expression. We have detected an elevated relative gene expression of ICAM-1, VCAM-1 and RANTES in NHBD biopsies compared with normal kidneys. In the case of RANTES, the gene expression from NHBD biopsies was higher than observed in HBD biopsies. The rest of genes were not augmented in any group. Preliminary data about early outcome of transplants indicates a correlation between pretransplant RANTES high gene expression levels and early post-transplant acute rejection. The gene expression of pro-inflammatory molecules like adhesion molecules and RANTES is augmented in kidneys from cadaveric NBD just before transplant. The expression is higher probably because of the prolonged warm ischemia period. A larger clinical study is necessary to clarify the effects of these variable expressions on the transplant outcome.     

Intra-articular traumatic disorders of the knee in children and adolescents

Intra-articular knee injuries in children traditionally have been considered rarer than injuries in adults. Few studies establish the prevalence of knee injuries before skeletal maturity, but arthroscopic studies suggest an increased frequency of anterior cruciate ligament ruptures, meniscal tears, and osteochondral fractures. We report our experience with 15 anterior cruciate ligament injuries and 38 meniscus injuries treated between 1996 and 2001. The treatment of anterior cruciate ligament injuries is determined by Tanner's maturity criteria. In the three cases of Stage II injuries, surgery was delayed for up to 24 months in the 12 older patients, an immediate reconstruction was done using hamstring tendons in the three youngest patients, and patellar tendon treatment was done in the remaining cases. We had only one complication caused by the fracturing of the bone plug. The most frequent meniscus injuries were the traumatic tears (23 cases), 80% of which were peripheral and longitudinal. Whenever possible, the entire meniscus (suture in 4 cases) or the greater part of it (economic resection in 19 cases) should be conserved. Despite the satisfactory results, the average followup of the meniscal series (26.1 months) is too short a period to evaluate thoroughly the deterioration of the joint after a meniscectomy.     

Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment

To assess platelet function profiles in diabetic and nondiabetic patients on aspirin and clopidogrel therapy, two patient populations were included to investigate the 1) acute effects of a 300-mg clopidogrel loading dose (group 1, n = 52) and 2) long-term effects of clopidogrel (group 2, n = 120) on platelet function in diabetic compared with nondiabetic patients already on aspirin treatment. Patients were stratified according to the presence of type 2 diabetes. Platelet aggregation was assessed using light transmittance aggregometry (groups 1 and 2). Platelet activation (P-selectin expression and PAC-1 binding) was determined using whole-blood flow cytometry (group 2). Clopidogrel response was also assessed. In group 1, platelet aggregation was significantly increased in diabetic (n = 16) compared with nondiabetic (n = 36) patients at baseline and up to 24 h following a 300-mg loading dose (P = 0.005). In group 2, platelet aggregation and activation were increased in diabetic (n = 60) compared with nondiabetic (n = 60) subjects (P < 0.05 for all platelet function assays). Diabetic subjects had a higher number of clopidogrel nonresponders (P = 0.04). Diabetic patients have increased platelet reactivity compared with nondiabetic subjects on combined aspirin and clopidogrel treatment. Reduced sensitivity to antiplatelet drugs may contribute to the increased atherothombotic risk in diabetic patients.