Preeclampsia and intrauterine growth restriction (IUGR) are pregnancy-specific disorders that share a common pathophysiology. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that plays an important role in placental development. HIF-1α is elevated in preeclamptic placentas and induces soluble vascular endothelial growth factor receptor-1 (sFLT-1), a central factor in preeclampsia and IUGR pathogenesis. Our objective was to investigate the effects of HIF-1α overexpression on pregnancy in mice. C57BL/6J pregnant mice were systemically administered either adenovirus expressing stabilized HIF-1α (cytomegalovirus [CMV]-HIF), luciferase control (CMV-Luc), or saline on gestational day 8. Pregnant mice overexpressing HIF-1α had significantly elevated blood pressure and proteinuria compared with pregnant controls. HIF-1α mice showed fetal IUGR, decreased placental weights, and histopathological placental abnormalities compared with control mice. Glomerular endotheliosis, the hallmark lesion of preeclampsia, was demonstrated in the kidneys of these mice relative to the normal histology in control mice. Moreover, liver enzyme levels were significantly elevated, whereas complete blood counts revealed significant anemia and thrombocytopenia in CMV-HIF mice compared with controls. Blood smears confirmed microangiopathic hemolytic anemia in CMV-HIF mice, consistent with HELLP (hemolysis, elevated liver enzymes, and low platelets)-like syndrome. CMV-HIF mice showed elevation in serum sFLT-1 and soluble endoglin, providing a mechanistic explanation for the observations. Collectively, our results suggest a possible role for HIF-1α in the pathogenesis of both preeclampsia and IUGR.

Treatment-resistant depression is an important clinical problem presenting a major challenge to clinical psychiatry. While several strategies have been attempted, including medication switch, antidepressant polypharmacy and various augmentative regimens, success remains limited. Amantadine (AMN), an agent traditionally used in the treatment and prophylaxis of influenza, is now known to exhibit prominent effects at the level of dopaminergic, monoamine oxidase and N-methyl-D-aspartate systems. The present reports on the efficacy of AMN as augmentation to standard antidepressant treatment in patients with treatment-resistant depression. Eight patients with treatment-resistant depression consented to receive AMN, titrated up to a dose of 300 mg, over a period of 4 weeks in a non-blinded fashion. Improvement in both depression and anxiety scores were observed from week 1, with patients exhibiting improvement of depressive scores of up to 49% by study completion. Females appeared to exhibit a stronger response, and within a shorter period of time. Side-effects reported included dry mouth and sedation. AMN appears to demonstrate efficacy as a safe and effective augmentative agent in treatment-resistant depression. Further studies are clearly mandated to test these preliminary observations in a double-blinded manner.

Background/Objectives Sarcopenia is defined as the gradual age-associated loss of both muscle quantity and strength in older adults, and is associated with increased mortality, falls, fractures and hospitalisations. Current sarcopenia criteria use dual-energy X-ray absorptiometry (DXA) measures of muscle mass, a test that cannot be performed at the bedside, unlike point-of-care ultrasound (PoCUS). We examined the association between ultrasonic measures of muscle thickness (MT, vastus medialis muscle thickness) and measures of muscle quantity and strength in older adults. Methods A total of 150 older adults (age ≥ 65; mean age 80.0 ± 0.5 years, 66 women, 84 men) were recruited sequentially from geriatric medicine clinics. Each subject had lean body mass (LBM, by bioimpedance assay), grip strength, mid-arm biceps circumference (MABC), gait speed and MT measured. All initial models were adjusted for biological sex. Results In our final parsimonious models, MT showed a strong significant correlation with all measures of muscle mass, including LBM (Standardised β = 0.204 ± 0.058, R2 = 0.577, P < 0.001) and MABC (Standardised β = 0.141 ± 0.067, R2 = 0.417, P = 0.038). With respect to measures of muscle quality, there was a strong significant correlation with grip strength (Standardised β = 0.118 ± 0.115, R2 = 0.511, P < 0.001) but not with subject performance (gait speed). Conclusions MT showed strong correlations with both measures of muscle mass (LBM and MABC) and with muscle strength (grip strength). Although more work needs to be done, PoCUS shows potential as a screening tool for sarcopenia in older adults.

OBJECTIVE Increasing evidence suggests that time spent sedentary predicts increasing cardiometabolic risk independent of other physical activity. We objectively measured activity levels in active older adults and examined the association between sedentary behavior and the continuous metabolic syndrome risk score (cMSy). RESEARCH DESIGN AND METHODS Older adults (age ≥65 years) were recruited from the Whistler Masters ski team, a group of active older adults who undergo organized group training. Daily activity levels were recorded with accelerometers (SenseWear) worn for 7 days. A compositional approach was used to determine proportion of the time spent sedentary as compared with all other nonsedentary behaviors (isometric log-ratio transformation for time spent sedentary [ILR1]). Waist circumference, triglycerides, HDL, systolic blood pressure, and fasting glucose were measured, and cMSy was calculated using principal component analysis (sum of eigenvalues ≥1.0). RESULTS Fifty-four subjects (30 women and 24 men, mean ± SE age 71.4 ± 0.6 years) were recruited. Subjects demonstrated high levels of physical activity (2.6 ± 0.2 h light activity and 3.9 ± 0.2 h moderate/vigorous activity). In our final parsimonious model, ILR1 showed a significant positive association with increasing cMSy (standardized β = 0.368 ± 0.110, R2 = 0.40, P = 0.002), independent of age and biological sex. CONCLUSIONS Despite high levels of activity, ILR1 demonstrated a strong association with cMSy. This suggests that even in active older adults, sedentary behavior is associated with increasing cardiometabolic risk.

Summary In multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), myeloid cells comprise a major part of the inflammatory infiltrate in the central nervous system (CNS). We previously described that motile sperm domain‐containing protein 2 (MOSPD2) is expressed on human myeloid cells and regulates monocyte migration in vitro . The role of MOSPD2 in EAE pathogenesis was studied by generating MOSPD2 knock‐out (KO) mice and monoclonal antibodies directed against MOSPD2. We found that EAE development in MOSPD2 KO mice was significantly suppressed. While frequency representation of leukocyte subsets in lymphoid tissues was comparable, the ratio of inflammatory monocytes in the blood was markedly reduced in MOSPD2 KO mice. In addition, T cells from MOSPD2 KO mice displayed reduced secretion of proinflammatory cytokines and increased production of interleukin (IL)‐4. Prophylactic and post‐onset treatment using monoclonal antibodies (mAbs) generated against MOSPD2 abrogated development and reduced EAE severity. These results suggest that MOSPD2 is key in regulating migration of inflammatory monocytes, and that anti‐MOSPD2 mAbs constitute a potential therapy for the treatment of CNS inflammatory diseases.