��-Synuclein Expression in Rat Substantia Nigra Suppresses Phospholipase D2 Toxicity and Nigral Neurodegeneration

We present genetic evidence that an in vivo role of α-synuclein (α-syn) is to inhibit phospholipase D2 (PLD2), an enzyme that is believed to participate in vesicle trafficking, membrane signaling, and both endo- and exocytosis. Overexpression of PLD2 in rat substantia nigra pars compacta (SNc) caused severe neurodegeneration of dopamine (DA) neurons, loss of striatal DA, and an associated ipsilateral amphetamine-induced rotational asymmetry. Coexpression of human wild type α-syn suppressed PLD2 neurodegeneration, DA loss, and amphetamine-induced rotational asymmetry. However, an α-syn mutant defective for inhibition of PLD2 in vitro also failed to inhibit PLD toxicity in vivo. Further, reduction of PLD2 activity in SNc, either by siRNA knockdown of PLD2 or overexpression of α-syn, both produced an unusual contralateral amphetamine-induced rotational asymmetry, opposite to that seen with overexpression of PLD2, suggesting that PLD2 and α-syn were both involved in DA release or reuptake. Finally, α-syn coimmunoprecipitated with PLD2 from extracts prepared from striatal tissues. Taken together, our data demonstrate that α-syn is an inhibitor of PLD2 in vivo, and confirm earlier reports that α-syn inhibits PLD2 in vitro. Our data also demonstrate that it is possible to use viral-mediated gene transfer to study gene interactions in vivo.     

Differential effects and rates of normal aging in cerebellum and hippocampus

Cognitive functions show many alternative outcomes and great individual variation during normal aging. We examined learning over the adult life span in CBA mice, along with morphological and electrophysiological substrates. Our aim was to compare cerebellum-dependent delay eyeblink classical conditioning and hippocampus-dependent contextual fear conditioning in the same animals using the same conditioned and unconditioned stimuli for eyeblink and fear conditioning. In a subset of the behaviorally tested mice, we used unbiased stereology to estimate the total number of Purkinje neurons in cerebellar cortex and pyramidal neurons in the hippocampus. Several forms of synaptic plasticity were assessed at different ages in CBA mice: long-term depression (LTD) in both cerebellum and hippocampus and NMDA-mediated long-term potentiation (LTP) and voltage-dependent calcium channel LTP in hippocampus. Forty-four CBA mice tested at one of five ages (4, 8, 12, 18, or 24 months) demonstrated statistically significant age differences in cerebellum-dependent delay eyeblink conditioning, with 24-month mice showing impairment in comparison with younger mice. These same CBA mice showed no significant differences in contextual or cued fear conditioning. Stereology indicated significant loss of Purkinje neurons in the 18- and 24-month groups, whereas pyramidal neuron numbers were stable across age. Slice electrophysiology recorded from an additional 48 CBA mice indicated significant deficits in LTD appearing in cerebellum between 4 and 8 months, whereas 4- to 12-month mice demonstrated similar hippocampal LTD and LTP values. Our results demonstrate that processes of aging impact brain structures and associated behaviors differentially, with cerebellum showing earlier senescence than hippocampus.     

Repair of long-gap esophageal atresia: gastric conduits may improve outcome—a 20-year single center experience

Introduction  

Treatment of long-gap esophageal atresia (LEA) is a major challenge. Options for reconstruction include native esophagus, or replacement with stomach, colon, or small intestine. However, debate continues regarding the optimal conduit for esophageal replacement.     

Determination of the venous output function from MR signal phase: Feasibility for quantitative DCE‐MRI in human brain

For dynamic contrast‐enhanced MRI studies in the human brain, it is useful to measure the venous output function (VOF). The purpose of this work was to explore the feasibility of measuring the VOF using the MR signal phase (in absolute units of gadolinium concentration) in the superior sagittal sinus. Phantom experiments were performed to validate the technique for different superior sagittal sinus angles (θ = 0–48° relative to the main magnetic field), different curvatures (straight or radius = 45 mm), and different spatial resolutions (2.2–5.5 mm, to study partial‐volume effects). Additionally, the technique was tested on three patients. The phantom experimental results (echo time = 5.5 ms, θ ≤ 21°) agreed with theoretical predictions to within 10%. For the patient studies, the measured VOFs had reasonable amplitude and shape characteristics and the patients' superior sagittal sinus angles (<15°) and curvatures (radii ≈ 40 mm) were within the range explored with phantoms. Our results suggest that partial‐volume contributions to the VOF will be <5% and that the VOF can be evaluated in vivo to within 10% error. In conclusion, it is highly feasible to use MR signal phase to measure the VOF in the superior sagittal sinus for human dynamic contrast‐enhanced MRI. Magn Reson Med 63:772–781, 2010. © 2010 Wiley‐Liss, Inc.     

Protocol of GLUcose COntrol Safety and Efficacy in type 2 DIabetes,a NETwork meta‐analysis: GLUCOSE DINET protocol—Rational and design

The aim of this study was to propose a ranking of the currently available antidiabetic drugs, regarding vascular clinical outcomes, in patients with type 2 diabetes, through a network meta‐analysis approach. Randomized clinical trials, regardless of the blinding design, testing contemporary antidiabetic drugs, and considering clinically relevant outcomes in patients with type 2 diabetes mellitus will be included. The primary outcomes of this analysis will be overall mortality, cardiovascular mortality, and major cardiovascular events. Diabetic microangiopathy will be a secondary outcome. Adverse events, hypoglycemia, weight evolution, bariatric surgery, and discontinuation of the treatment will also be recorded. Each drug will be analyzed according to its therapeutic class: biguanide, alpha‐glucosidase inhibitors, sulfonylureas, glitazones, glinides, insulin, DPP‐4 inhibitors, GLP‐1 analogs, and gliflozins. The treatment effect of each drug class will be compared using pairwise meta‐analysis and a Bayesian random model network meta‐analysis. Sensitivity analyses will be conducted according to the quality of the studies and the glycemic control. The report will follow the PRISMA checklist for network meta‐analysis. Results of the search strategy and of the study selection will be presented in a PRISMA compliant flowchart. The treatment effects will be summarized with odds ratio (OR) estimates and their 95% credible intervals. A ranking of the drugs will be proposed. Our network meta‐analysis should allow a clinically relevant ranking of the contemporary antidiabetic drugs.