Globular glial tauopathy type II

The globular glial tauopathies (GGTs) are a rare group of neurodegenerative diseases with fewer than 90 autopsy-confirmed cases reported in the literature. Although there has been some uncertainty about whether GGT is entirely distinct from progressive supranuclear palsy, a recent study of tau filament structures supports the definition of GGT as a separate neuropathological entity. We present a sporadic case of GGT type II presenting with a progressive corticobasal-primary lateral sclerosis overlap syndrome in a 74-year-old woman. Neuropathological examination identified neuronal and glial tau inclusions, including globular astrocytic and oligodendroglial inclusions. We also discuss the clinical features and molecular pathophysiology of GGT. Increased awareness of this condition could become more important as patients with GGT may be candidates for anti-tau therapies currently undergoing clinical evaluation in patients with other tauopathies

3D Printed PLA Scaffolds to Promote Healing of Large Bone Defects

One challenge modern medicine faces is the ability to repair large bone defects and stimulate healing. Small defects typically heal naturally, but large bone defects do not and current solutions are to replace the missing tissue with biologically inert materials such as titanium. This limits the amount of bone healing as the defect is not repaired but rather replaced. The focus of our research is to develop a method of using 3D printing to create biodegradable scaffolds which promote bone in-growth and replacement. To accomplish this we used poly lactic acid (PLA) filament and a desktop 3D printer. To promote bone healing and provide mechanical support our team investigated different design methodologies to provide a scaffold of customizable stiffness while allowing cell attachment and in-growth. Our team used CAD modeling to create unique architecture design systems which we analyzed for stiffness using Finite Element Analysis (FEA). We developed a unit cell method of scaffold construction that allowed for customized stiffness of irregular shapes. We 3D printed our designs using a desktop 3D printer and verified our stiffness through mechanical tension and compression testing. We investigated cell viability of the scaffolds by immersing test specimens in culturing media and fibroblast cells. Fibroblast cells are from the same lineage as osteoblast cells but are much faster growing, allowing for more efficient testing. Specimens were left in the media for one week then a total cell count was performed. Scaffold designs were then evaluated based on stiffness and cell viability. We have produced several different viable models with appropriate stiffness for human trabecular bone and good cellular adhesion

Lipodystrophy in HIV infected patients on long term Antiretroviral therapy in western Kenya

Changes in fat distribution has been observed in patients on highly active antiretroviral therapy. The frequently reported drugs that cause fat redistribution are stavudine and protease inhibitors. Stavudine also causes a high incidence of metabolic complications and peripheral neuropathy

A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK.

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2. We found 11 patients (1%) carried more than one pathogenic variant (P = 0.001) consistent with an oligogenic basis of amyotrophic lateral sclerosis. These findings show that the genetic architecture of amyotrophic lateral sclerosis is complex and that variation in the regulatory regions of associated genes may be important in disease pathogenesis

Correcting Mortality for Loss to Follow-Up: A Nomogram Applied to Antiretroviral Treatment Programmes in Sub-Saharan Africa

Matthias Egger and colleagues present a nomogram and a web-based calculator to correct estimates of program-level mortality for loss to follow-up, for use in antiretroviral treatment programs

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10-4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10-7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies

Dry and Humid Periods Reconstructed from Tree Rings in the Former Territory of Sogdiana (Central Asia) and Their Socio-economic Consequences over the Last Millennium

One of the richest societies along the Silk Road developed in Sogdiana, located in present-day Tajikistan, Uzbekistan, and Kyrgyzstan. This urban civilisation reached its greatest prosperity during the golden age of the Silk Road (sixth to ninth century ce). Rapid political and economic changes, accelerated by climatic variations, were observed during last millennium in this region. The newly developed tree-ring-based reconstruction of precipitation for the pastmillennium revealed a series of dry and wet stages. During the Medieval Climate Anomaly (MCA), two dry periods occurred (900–1000 and 1200–1250), interrupted by a phase of wetter conditions. Distinct dry periods occurred around 1510–1650, 1750–1850, and 1920–1970, respectively. The juniper tree-ring record of moisture changes revealed that major dry and pluvial episodes were consistent with those indicated by hydroclimatic proxy data from adjacent areas. These climate fluctuations have had longand short term consequences for human history in the territory of former Sogdiana

Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials

OBJECTIVE: To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was lost in a large cohort of nonresponders. METHODS: Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the UNC13A and C9orf72 genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype. RESULTS: Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7-1.4; p = 0.96). Both the UNC13A and C9orf72 genotype were independent predictors of survival (HR 2.4, 95% CI 1.3-4.3; p = 0.006 and HR 2.5, 95% CI 1.1-5.2; p = 0.032, respectively). The effect of lithium was different for UNC13A carriers (p = 0.027), but not for C9orf72 carriers (p = 0.22). The 12-month survival probability for UNC13A carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2-69.1) to 69.7% (95% CI 50.4-96.3). CONCLUSIONS: This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials