Maternal stress during pregnancy predicts cognitive ability and fearfulness in infancy

OBJECTIVE: To examine the effects of prenatal stress on cognition and behavioral fearfulness in infants. METHOD: Mothers were recruited at amniocentesis at Queen Charlotte's and Chelsea Hospital, London, between 2001 and 2005, and recalled when their children were 14 to 19 months to assess cognitive development using the Bayley Scales and fearfulness using the Lab-TAB. Measures of prenatal and postnatal life events and current psychological state were collected at the postnatal visit. RESULTS: Prenatal stress predicted both mental development (rs = -0.39, n = 123 p < .0001) and observed fearfulness (rs = 0.33, n = 106, p < .001); the magnitude of effect was essentially unchanged after covarying postnatal stressors, maternal education and psychological state, exposures to medications and substances during pregnancy, and birth outcomes. Prenatal stress accounted for 17% of the variance in cognitive ability and 10% of the variance in observed fearfulness. The correlation between mental development and fearfulness was minimal (r = -0.06, not significant). Prenatal partner relationship strain accounted for 73.5% and 75.0% of the prenatal stress related variance on infant cognitive and fearfulness scores, respectively. CONCLUSIONS: These findings strengthen previous research that suggests that fetal programming can be important for neurodevelopmental and psychiatric outcomes. They imply that the mechanisms by which mental development and fearfulness are affected are different and that prenatal stress due to relationship strain may warrant particular attention.     

Amelioration of intracerebroventricular streptozotocin induced cognitive dysfunction and oxidative stress by vinpocetine — a PDE1 inhibitor

Enhancing cyclic nucleotides signaling by inhibition of phosphodiesterases (PDEs) is known to be beneficial in disorders associated with cognitive decline. The present study was designed to investigate the effect of vinpocetine (PDE1 inhibitor) on intracerebroventricular (i.c.v.) streptozotocin induced experimental sporadic dementia of Alzheimer's type. Infusion of streptozotocin impaired learning and memory, increased oxidative–nitritive stress and induced cholinergic hypofunction in rats. Chronic treatment with vinpocetine (5, 10 and 20 mg/kg i.p.) for 21 days following first i.c.v. streptozotocin infusion significantly improved learning and memory in Morris water maze and passive avoidance paradigms. Further, vinpocetine significantly reduced the oxidative–nitritive stress, as evidenced by decrease in malondialdehyde (MDA) and nitrite levels, and restored the reduced glutathione (GSH) levels. Significant increase in acetylcholinesterase activity and lactate dehydrogenase levels was observed in the present model indicating cholinergic hypofunction and increase in neuronal cell damage. Chronic treatment with vinpocetine also reduced significantly the increase in acetylcholinesterase activity and lactate dehydrogenase levels indicating restorative capacity of vinpocetine with respect to cholinergic functions and preventing the neuronal damage. The observed beneficial effects of vinpocetine on spatial memory may be due to its ability to favorably modulate cholinergic functions, prevent neuronal cell damage and possibly through its antioxidant mechanism also.     

Prolonged Delays for Research Training in Medical School are Associated with Poorer Subsequent Clinical Knowledge

Background Complementary degree programs and research training are important alternative tracks in medical school that typically interrupt the traditional MD curriculum. Objective Examine effects of such a break on clinical knowledge after reentry into the MD curriculum. Design Retrospective cohort study. Participants Three hundred and two graduates of Mayo Medical School. Main Measurements Compared years of delay between the second and third years of medical school with third year clerkship grades, National Board of Medical Examiner’s (NBME) Subject Examinations, and United States Medical License Exam (USMLE) Step 2. Main Results 258, 13, and 31 students spent 0, 1, or ≥3 years pursing research between the second and third year. Baseline measures of knowledge before matriculation and before the third year were similar between groups. Whereas a 1-year delay had no significant effect, a ≥3-year delay was associated with fewer clerkship honors and lower NBME Medicine, Pediatrics, and Psychiatry percentiles compared to no delay (all p < .05). Students with a ≥3-year delay had a 77% reduction in the odds of honors in Medicine. For each year of delay beyond 3, students’ third-year NBME Medicine, Neurology, Obstetrics and Gynecology, and Psychiatry scores decreased as did USMLE Step 2 scores (r = −.38 to −.50, p < .05). Conclusions Delays of ≥3 years between the second and third years of medical school are associated with lower grades and scores on clinical knowledge tests. Further research is needed to determine the optimal timing of research training and develop effective interventions to facilitate reentry into the medical school curriculum.     

Differential Expression of RDC1/CXCR7 in the Human Placenta

Introduction  Chemokine receptor expression by human trophoblast and other placental cells have important implications for understanding the regulation of placental growth, development, and their role in maternofetal HIV transmission. CXCR7, now a deorphanized G protein coupled receptor that has been recently shown to bind to the ligands ITAC and CXCL12 has been proposed to act as a co-receptor for HIV-1, HIV-2, and SIV strains. The differential expression of CXCR7 in the human placenta is not yet reported. Methods  The expression of CXCR7 was studied in 45 different human placental tissues, of which 20 were from early placental tissues (8–10 week old) obtained from medically terminated pregnancies and 25 were placenta from normal term deliveries. Results  Immunohistochemistry and RT-PCR analysis revealed a greater expression of CXCR7 in term human placenta as compared to the early stage. This was further confirmed by real-time PCR. Conclusion  Our study reveals, for the first time, the differential expression of CXCR7 in early (8–10 weeks) and term human placenta. The precise role of CXCR7 in the human placenta needs to be determined. HIV vertical transmission is reported to occur mainly during the end stages of pregnancy. Our finding of increased CXCR7 expression in the term human placenta therefore warrants future studies to assess its role in the vertical transmission of HIV-1.     

Inequalities in maternity care and newborn outcomes: one-year surveillance of births in vulnerable slum communities in Mumbai

Background  

Aggregate urban health statistics mask inequalities. We described maternity care in vulnerable slum communities in Mumbai, and examined differences in care and outcomes between more and less deprived groups.     

Pathogenic mutations in the glycosylphosphatidylinositol signal peptide of PrP modulate its topology in neuroblastoma cells

Point mutations M232R (PrP(232R)), M232T (PrP(232T)), and P238S (PrP(238S)) in the glycosylphosphatidylinositol signal peptide (GPI-SP) of the prion protein (PrP(C)) segregate with familial Creutzfeldt-Jakob disease (CJD). However, the mechanism by which these mutations induce cytotoxicity is unclear since the GPI-SP is replaced by a GPI anchor within 5 min of PrP synthesis and translocation into the endoplasmic reticulum (ER). To examine if mutations in this region interfere with translocation of nascent PrP into the ER or anchor addition, the metabolism of PrP(232R) and PrP(232T) was investigated in transfected human neuroblastoma cells. In this report, we demonstrate that PrP mutations M232R and M232T do not interfere with GPI anchor addition. Instead, these mutations increase the stability and transport of GPI-SP mediated post-translationally translocated PrP to the plasma membrane, where it is linked to the lipid bilayer in a potentially neurotoxic C-transmembrane ((Ctm)PrP) orientation. Furthermore, we demonstrate that the GPI-SP of PrP functions as an efficient co-translational and inefficient post-translational ER translocation signal when tagged to an unrelated protein, underscoring the functional versatility of this peptide. These data uncover an alternate pathway of ER translocation for nascent PrP, and provide information on the possible mechanism(s) of neurotoxicity by mutations in the GPI-SP.     

Characterization of natural antimony resistance in Leishmania donovani isolates

Clinical resistance to pentavalent antimonial compounds has long been recognized as a major problem in the treatment of visceral leishmaniasis in India. However, mechanisms of natural resistance are unclear. In this study, we observed that Leishmania donovani clinical isolates not responsive to sodium stibogluconate showed resistance to antimony treatment in both in vitro and in vivo laboratory conditions. The resistant isolates have increased levels of intracellular thiols. This increase in thiol levels was not mediated by the amplification of gamma-glutamylcysteine synthetase, but was accompanied by amplification of trypanothione reductase and an intracellular ATP-binding cassette transporter gene MRPA. The resistance of parasites to antimony could be reversed by the glutathione biosynthesis-specific inhibitor, buthionine sulfoximine, which resulted in increased drug susceptibility. These results suggest the possible role of thiols and MRPA in antimony resistance in field isolates.     

Lesional T-cell subset in post-kala-azar dermal leishmaniasis

BACKGROUND: The pathogenesis of post-kala-azar dermal leishmaniasis (PKDL) is ill understood. This study was carried out to find the percentage of T-helper and T-suppressor cells in lesional tissue and their probable role in the pathogenesis of PKDL. METHODS: An immunoperoxidase monoclonal antibody technique was used to characterize and quantify the subsets of T lymphocytes in the infiltrate in 25 patients with PKDL. RESULTS: The ratio of T-helper to T-suppressor cells was 0.87 in hypopigmented macules and 0.85 in nodule and/or plaque lesions of PKDL. CONCLUSIONS: In this study, there was a definite preponderance of T-suppressor cells over T-helper cells in both types of skin lesions of PKDL. Further studies should be undertaken on larger numbers of patients to compare T-cell subsets both in skin lesions and the circulation, in order to determine the pathogenesis of PKDL.     

PET in anti-cancer drug development and therapy

Anti-cancer drug development is a major area of research. Monitoring of response to newer anti-cancer drugs has undergone an evolution from structural imaging modalities to targeting functional metabolic activity at cellular level to better define responsive and non-responsive cancerous tissue. This review article highlights the contribution of Positron Emission Tomography (PET) in this field. PET holds a promising role in the future by providing us information pertaining to the drugs effectiveness early in the course of therapy, so that side effects and expenses can be reduced substantially. PET has been used to measure changes in drug induced metabolism, cellular proliferation and tissue perfusion. Also changes induced by immuno-modulating drugs such as apoptosis, telomere activity, growth factor levels and many more can be studied using specific radiolabelled PET tracers whereas conventional imaging modalities which detect changes in tumor size and residual tissue histopathology may not prove useful in such scenario. In future, most PET scanners will be replaced by Hybrid PET-CT scanners, which provide functional and structural information in the same setting. In addition, PET-CT improves characterization of equivocal lesions and decreases interobserver variability. The most important recent patents concerning role of PET in drug development have been presented.