Microglial activation arises after aggregation of phosphorylated-tau in a neuron-specific P301S tauopathy mouse model

Alzheimer's disease, progressive supranuclear palsy and frontotemporal dementia are characterized by neuronal expression of aberrant tau protein, tau hyperphosphorylation (pTAU), tau aggregation and neurofibrillary tangle formation sequentially culminating into neuronal cell death, a process termed tauopathy. Our aim was to address at which tauopathy stage neuroinflammation starts and to study the related microglial phenotype. We used Thy1-hTau.P301S (PS) mice expressing human tau with a P301S mutation specifically in neurons. Significant levels of cortical pTAU were present from 2 months onwards. Dystrophic morphological complexity of cortical microglia arose after pTAU accumulation concomitant with increased microglial lysosomal volumes and a significant loss of homeostatic marker Tmem119. Interestingly, we detected increases in neuronal pTAU and postsynaptic structures in the lysosomes of PS microglia. Moreover, the overall cortical postsynaptic density was decreased in 6-month-old PS mice. Together, our results indicate that microglia adopt a pTAU-associated phenotype, and are morphologically and functionally distinct from wild-type microglia after neuronal pTAU accumulation has initiated

Myelination synchronizes cortical oscillations by consolidating parvalbumin-mediated phasic inhibition

Parvalbumin-positive (PV+) γ-aminobutyric acid (GABA) interneurons are critically involved in producing rapid network oscillations and cortical microcircuit computations but the significance of PV+ axon myelination to the temporal features of inhibition remains elusive. Here using toxic and genetic mouse models of demyelination and dysmyelination, respectively, we find that loss of compact myelin reduces PV+ interneuron presynaptic terminals, increases failures and the weak phasic inhibition of pyramidal neurons abolishes optogenetically driven gamma oscillations in vivo. Strikingly, during behaviors of quiet wakefulness selectively theta rhythms are amplified and accompanied by highly synchronized interictal epileptic discharges. In support of a causal role of impaired PV-mediated inhibition, optogenetic activation of myelin-deficient PV+ interneurons attenuated the power of slow theta rhythms and limited interictal spike occurrence. Thus, myelination of PV axons is required to consolidate fast inhibition of pyramidal neurons and enable behavioral state-dependent modulation of local circuit synchronization

Addition of sulphonylurea to metformin does not relevantly change body weight:a prospective observational cohort study (ZODIAC-39)

Aim: To investigate changes in body weight trajectories after the addition of individual sulphonylureas (SUs) to metformin in patients with type 2 diabetes. Materials and methods: We conducted a retrospective observational cohort study, in a primary care setting in the Netherlands. Patients aged >= 18 years with type 2 diabetes who were included in the ZODIAC cohort between 1998 and 2012 and who received metformin monotherapy at inclusion (n = 29 195), and had used metformin as monotherapy for at least 1 year before receiving dual therapy through the addition of an SU for at least 1 year were eligible for inclusion. The primary outcome was within-drug yearly change in body weight after receiving add-on therapy with individual SUs during 5 years of follow-up. The secondary outcome was within-drug yearly change in glycated haemoglobin (HbA1c). Annual changes in weight and HbA1c were estimated with linear mixed models, adjusted for age, gender and diabetes duration. Results: A total of 2958 patients were included. No significant weight changes were observed within and between any of the individual SUs after treatment intensification (p = 0.24). In addition, no significant difference in weight between the add-on therapy combinations was observed (p = 0.26). The average HbA1c the year before intensification was 7.2% (55 mmol/mol) and dropped below 7.0% (53 mmol/mol) the year after. Conclusions: In patients with type 2 diabetes treated in primary care, strict glycaemic control can be maintained with SUs used as add-on therapy to metformin, without the offset of relevant weight changes

Gene expression down-regulation in CD90+ prostate tumor-associated stromal cells involves potential organ-specific genes

<p>Abstract</p> <p>Background</p> <p>The prostate stroma is a key mediator of epithelial differentiation and development, and potentially plays a role in the initiation and progression of prostate cancer. The tumor-associated stroma is marked by increased expression of CD90/THY1. Isolation and characterization of these stromal cells could provide valuable insight into the biology of the tumor microenvironment.</p> <p>Methods</p> <p>Prostate CD90⁺stromal fibromuscular cells from tumor specimens were isolated by cell-sorting and analyzed by DNA microarray. Dataset analysis was used to compare gene expression between histologically normal and tumor-associated stromal cells. For comparison, stromal cells were also isolated and analyzed from the urinary bladder.</p> <p>Results</p> <p>The tumor-associated stromal cells were found to have decreased expression of genes involved in smooth muscle differentiation, and those detected in prostate but not bladder. Other differential expression between the stromal cell types included that of the CXC-chemokine genes.</p> <p>Conclusion</p> <p>CD90⁺prostate tumor-associated stromal cells differed from their normal counterpart in expression of multiple genes, some of which are potentially involved in organ development.</p

Locus for severity implicates CNS resilience in progression of multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults(1,2). Here, to provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF-ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3-PIGC locus and significant heritability enrichment in CNS tissues. Mendelian randomization analyses suggested a potential protective role for higher educational attainment. In contrast to immune-driven susceptibility(3), these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS

Myelination synchronizes cortical oscillations by consolidating parvalbumin-mediated phasic inhibition

Parvalbumin-positive (PV+) γ-aminobutyric acid (GABA) interneurons are critically involved in producing rapid network oscillations and cortical microcircuit computations but the significance of PV+ axon myelination to the temporal features of inhibition remains elusive. Here using toxic and genetic mouse models of demyelination and dysmyelination, respectively, we find that loss of compact myelin reduces PV+ interneuron presynaptic terminals, increases failures and the weak phasic inhibition of pyramidal neurons abolishes optogenetically driven gamma oscillations in vivo. Strikingly, during behaviors of quiet wakefulness selectively theta rhythms are amplified and accompanied by highly synchronized interictal epileptic discharges. In support of a causal role of impaired PV-mediated inhibition, optogenetic activation of myelin-deficient PV+ interneurons attenuated the power of slow theta rhythms and limited interictal spike occurrence. Thus, myelination of PV axons is required to consolidate fast inhibition of pyramidal neurons and enable behavioral state-dependent modulation of local circuit synchronization

Hypotensive hemostatis (permissive hypotension) for ruptured abdominal aortic aneurysm: are we really in control?

Item does not contain fulltextThe purpose of this study was to investigate whether a protocol for permissive hypotension was feasible for patients admitted with a ruptured abdominal aortic aneurysm (RAAA). It was aimed to limit prehospital intravenous fluid administration to 500 mL and to maintain systolic blood pressure at a range of 50 to 100 mm Hg following admission, using nitrates when indicated. The diagnosis of RAAA was confirmed with sonography, and all patients with uncontrolled hypovolemic shock immediately underwent open aneurysm repair (OAR). In all other cases, computed tomographic (CT) angiography was performed to determine the eligibility for endovascular aneurysm repair (EVAR). From January 1, 2004, to December 31, 2006, 95 patients with a suspected RAAA were admitted. In 77 patients, the diagnosis of RAAA was confirmed. Twenty-eight cases (36%) underwent OAR for uncontrolled hemodynamic instability. Following CT-angiographic evaluation, 25 of the remaining 49 cases were considered unsuitable for EVAR and subsequently underwent OAR. In 24 of 77 cases (31%), the RAAA was treated with EVAR. Preoperative systolic blood pressure recordings in EVAR patients showed median values (+/- SD) of 98 (+/- 34.7) mm Hg in the emergency department and 114 (+/- 26.2) mm Hg in the operating theater. The desired systolic blood pressure range of 50 to 100 mm Hg was reached in 11 of 24 cases (46%). In 13 of 24 cases (54%), a systolic blood pressure higher than 100 mm Hg was recorded for a period longer than 60 minutes. The 30-day mortality was 32 of 77 (42%), with 6 of 24 (25%) in the EVAR group and 26 of 53 (49%) in the OAR group. This is the first published series of RAAA in which a protocol of permissive hypotension has been adopted. The concept appeared to be feasible in the majority of cases. Protocol violations were sparse (n = 5). Uncontrolled hypotension occurred in 36% (28 of 77) of all patients, and the desired systolic blood pressure range was achieved in 46% (11 of 24) of the EVAR patients

Microglia transcriptional profiling in major depressive disorder shows inhibition of cortical grey matter microglia

BACKGROUND: Microglia have been implicated in the pathophysiology of major depressive disorder (MDD), but information on biological mechanisms is limited. Therefore, we investigated the gene expression profile of microglial cells in relation to neuronal regulators of microglia activity in well-characterized MDD and control autopsy brains. METHODS: Pure, intact microglia were isolated at brain autopsy from occipital cortex grey matter (GM) and corpus callosum white matter (WM) of 13 MDD and 10 age-matched control donors for RNA sequencing. Top differentially expressed genes were validated using immunohistochemistry (IHC) staining. Since gene expression changes were only detected in GM microglia, neuronal regulators of microglia were investigated in cortical tissue and synaptosomes from the cortex by RT-qPCR and Western blot. RESULTS: Transcriptome analysis revealed 92 genes differentially expressed in microglia isolated from GM, but none in microglia from WM in MDD, compared to controls. Of these, 81 genes were less abundantly expressed in GM MDD, including CD163, MKI67, SPP1, CD14, FCGR1A/C, and C1QA/B/C. Accordingly, pathways related to effector mechanisms, such as the complement system and phagocytosis were differentially regulated in GM microglia in MDD. IHC staining revealed significantly lower expression of CD163 protein in MDD. Whole tissue analysis showed an increase in CD200 (p+0.0009) and CD47 (p=0.068) mRNA, and CD47 protein was significantly elevated (p=0.0396) in synaptic fractions of MDD cases. CONCLUSIONS: Transcriptional profiling indicates an immune-suppressed microglial phenotype in MDD, possibly caused by neuronal regulation

Localizing chronic Q fever: a challenging query

Contains fulltext : 125615.pdf (publisher's version ) (Open Access)BACKGROUND: Chronic Q fever usually presents as endocarditis or endovascular infection. We investigated whether 18F-FDG PET/CT and echocardiography were able to detect the localization of infection. Also, the utility of the modified Duke criteria was assessed. METHODS: Fifty-two patients, who had an IgG titre of >/= 1024 against C. burnetii phase I >/= 3 months after primary infection or a positive PCR >/= 1 month after primary infection, were retrospectively included. Data on serology, the results of all imaging studies, possible risk factors for developing proven chronic Q fever and clinical outcome were recorded. RESULTS: According to the Dutch consensus on Q fever diagnostics, 18 patients had proven chronic Q fever, 14 probable chronic Q fever, and 20 possible chronic Q fever. Of the patients with proven chronic Q fever, 22% were diagnosed with endocarditis, 17% with an infected vascular prosthesis, and 39% with a mycotic aneurysm. 56% of patients with proven chronic Q fever did not recall an episode of acute Q fever. Ten out of 13 18F-FDG PET/CT-scans in patients with proven chronic Q fever localized the infection. TTE and TEE were helpful in only 6% and 50% of patients, respectively. CONCLUSIONS: If chronic Q fever is diagnosed, 18F-FDG PET/CT is a helpful imaging technique for localization of vascular infections due to chronic Q fever. Patients with proven chronic Q fever were diagnosed significantly more often with mycotic aneurysms than in previous case series. Definite endocarditis due to chronic Q fever was less frequently diagnosed in the current study. Chronic Q fever often occurs in patients without a known episode of acute Q fever, so clinical suspicion should remain high, especially in endemic regions