The major genetic risk for late onset Alzheimer's disease has been associated with the presence of APOE4 alleles. However, the impact of different APOE alleles on the brain aging trajectory, and how they interact with the brain local environment in a sex specific manner is not entirely clear. We sought to identify vulnerable brain circuits in novel mouse models with homozygous targeted replacement of the mouse ApoE gene with either human APOE3 or APOE4 gene alleles. These genes are expressed in mice that also model the human immune response to age and disease-associated challenges by expressing the human NOS2 gene in place of the mouse mNos2 gene. These mice had impaired learning and memory when assessed with the Morris water maze (MWM) and novel object recognition (NOR) tests. Ex vivo MRI-DTI analyses revealed global and local atrophy, and areas of reduced fractional anisotropy (FA). Using tensor network principal component analyses for structural connectomes, we inferred the pairwise connections which best separate APOE4 from APOE3 carriers. These involved primarily interhemispheric connections among regions of olfactory areas, the hippocampus, and the cerebellum. Our results also suggest that pairwise connections may be subdivided and clustered spatially to reveal local changes on a finer scale. These analyses revealed not just genotype, but also sex specific differences. Identifying vulnerable networks may provide targets for interventions, and a means to stratify patients.
We examined the acute effects of intravenous DL and D sotalol on the energy requirements for internal defibrillation (DF) in 44 dogs anesthetized with pentobarbital (n = 18), enflurane (n = 8), and fentanyl (n = 18). Multiple shocks of varying energies were applied through left and right ventricular epicardial patch electrodes to relate delivered energy to percent success in DF. The energies required for 50% success in DF (E) were estimated by logistic regression. DL or D sotalol was administered in a loading (4 mg/kg over 10 min) and maintenance (1.5 mg/kg/hr) infusion and the energy--success curve was again measured 30 minutes after drug administration. The effect of DL and D sotalol on E50 was compared to controls given saline. Both DL and D sotalol significantly lowered E50 by 16% +/- 14% (P less than 0.05) and 24.5% +/- 8.2% (P less than 0.05), respectively, in fentanyl anesthetized animals; this was accompanied by a 22% +/- 8% (P less than 0.05) and 16% +/- 5% (P less than 0.01) increase in ventricular effective refractory period (VERP), respectively. In pentobarbital anesthetized dogs, DL and D sotalol decreased E50 by 16% +/- 27% (P = ns) and 11% +/- 16% (P less than 0.05), respectively, and were associated with a 23% +/- 5% (P less than 0.01) and 12 +/- 4% (P less than 0.05) prolongation of VERP. DL and D sotalol decrease defibrillation energy requirements, possibly as a result of their Class III antiarrhythmic drug action.
The effect of long-term oral administration of antiarrhythmic drugs on defibrillation energy requirements is not well understood. We examined the effect of clofilium, a drug that prolongs cardiac action potential duration without slowing cardiac conduction, on defibrillation energy requirements and ventricular effective refractory periods in a canine model during a 3-week period. Epicardial patch electrodes were implanted in 12 dogs, and baseline testing was conducted under fentanyl anesthesia on day 7. An oral clofilium (100 mg/day) regimen was started on day 8. Six clofilium-treated and six control dogs underwent repeated testing on days 14, 21, and 28 after surgery. Truncated trapezoidal shocks were given repeatedly at various stored energies in random order; delivered current and impedance were measured; and delivered energy was calculated. The energy and current for 50% success in defibrillation (E50 and I50, respectively) were determined. For control animals, E50 increased by a mean 34 +/- 78%, 60 +/- 83%, and 69 +/- 122% compared with baseline (day 7) on days 14, 21, and 28, respectively. In contrast, E50 in clofilium-treated dogs decreased by 39 +/- 62%, 24 +/- 33%, and 32 +/- 15% on days 14, 21, and 28, respectively. Mean current requirements (I50) remained relatively stable compared with baseline in control animals (-7 +/- 39%, +25 +/- 36%, +40 +/- 75% on days 14, 21, and 28, respectively). After clofilium administration I50 decreased by 36 +/- 22%, 32 +/- 17%, and 33 +/- 17% on days 14, 21, and 28, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
This study seeks to assess the educational value of an international psychiatry elective using a cross section of psychiatric residents. In 2010, a 10-item semi-structured questionnaire was administered to Mount Sinai psychiatric residents who have participated in the Global Health Residency Track of the Mount Sinai School of Medicine. Authors reviewed the qualitative data and arrived at a consensus regarding trends and deviations regarding residents' experiences of their international field work. Six residents participated in this study. Common themes included exposure to sicker, treatment-naïve patients in resource scarce conditions, enhancement of cross-cultural communications skills, renewed appreciation for psychiatry, empowerment as teachers, and greater awareness of health-care systems. Knowing that an international elective existed would be a significant factor in their choice of residency. Respondents had concerns for the sustainability. Participants felt that the elective was a place to consolidate skills already learned during residency and resulted in increased professional confidence although it did not necessarily alter career paths. International electives can enrich psychiatric residency training in terms of understanding of mental health care systems, cross cultural psychiatry, sharpening diagnostic skills, building professional confidence and communication skills, and reaffirming motivation to practice psychiatry.
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