First trimester screening with free beta-hCG,PAPP-A and nuchal translucency in pregnancies conceived with assisted reproduction

OBJECTIVE: To evaluate the effect of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) on free beta-human chorionic gonadotrophin (beta-hCG), pregnancy-associated plasma protein A (PAPP-A) and nuchal translucency (NT). METHODS: First trimester maternal dried whole blood specimens from 74 singleton pregnancies (32 by IVF and 42 by ICSI) and 30 twin pregnancies (16 by IVF and 14 by ICSI) in which conception was achieved with assisted reproduction techniques were matched with five controls resulting in 370 singleton controls and 150 twin controls. NT was measured using the Fetal Medicine Foundation protocol. Free beta-hCG, PAPP-A and NT levels were compared between the IVF and control groups and between the ICSI and control groups using the Mann-Whitney U test. RESULTS: In singleton pregnancies, the only significant difference was a 21% (95% CI: -35%--7%) reduction in PAPP-A in IVF cases. In twin pregnancies, the only significant difference was a 12% (95% CI: -34%--3%) reduction in NT in IVF cases. In singleton pregnancies, the false-positive rate for Down syndrome screening was 1.4% and 1.9% greater for the IVF and ICSI groups, respectively, compared to controls for a general screening population. CONCLUSIONS: Patients undergoing assisted reproduction techniques should be counseled about the possibility of increased false-positive rates. Larger studies are needed to confirm this observation and to develop appropriate adjustment factors to reduce false-positive rates.     

Irradiation induces release of von Willebrand protein from endothelial cells in culture

Human umbilical vein endothelial cells in tissue culture were irradiated with doses between 0 and 40 Gy, and the released von Willebrand (vW) protein and that which remained associated with the cells was quantitated. Doses of 20 Gy and higher produced a statistically significant increase in amount of vW protein secreted. This release was present whether the cells were labeled continuously throughout the experiment or just prelabeled before irradiation. An increase in fibronectin secretion was not observed. The release response to radiation was slow, reaching significance close to 24 hours after irradiation. The release of vW protein was not due to cell lysis, because the secreted vW protein contained very little of the large 260- kilodalton vW precursor subunit present in cell lysates and the cells appeared intact by immunofluorescence staining.     

Modification of nonspecific bronchial reactivity in hypothyroid children under different regimens of substitutive opotherapy

Although it has been experimentally proved that thyroid hormones stimulate beta 2 receptor activity and tissue responsiveness to catecholamines, previous studies have established that asthma and nonspecific bronchial reactivity (NSBR) can worsen if complicated by hyperthyroidism. Our study is an effort toward the analysis of this contradiction. In 20 congenitally hypothyroid children, substitutive opotherapy was completely withdrawn for 1 month, resumed in the original dosage for 2 months, and then increased by 20% from day 91 to day 110. Mean NSBR, expressed in carbachol-related PD20-FEV1 and PD25-V25, was significantly increased by day 30, remained significantly elevated by day 90, and returned to initial values by day 110. These results suggest that thyroid hormones per se in nonasthmatic subjects decrease bronchial reactivity. This observation should be taken into consideration when attempting to explain the worsening condition of asthmatics who became affected with hypothyroidism. Bronchial reactivity appears to be under the control of many factors (including thyroid hormone levels). Once it is altered, a period of time seems necessary to restore the original bronchomotor tone (2 months in our study).     

Maternal CD4+ T cells protect against severe congenital cytomegalovirus disease in a novel nonhuman primate model of placental cytomegalovirus transmission

Elucidation of maternal immune correlates of protection against congenital cytomegalovirus (CMV) is necessary to inform future vaccine design. Here, we present a novel rhesus macaque model of placental rhesus CMV (rhCMV) transmission and use it to dissect determinants of protection against congenital transmission following primary maternal rhCMV infection. In this model, asymptomatic intrauterine infection was observed following i.v. rhCMV inoculation during the early second trimester in two of three rhCMV-seronegative pregnant females. In contrast, fetal loss or infant CMV-associated sequelae occurred in four rhCMV-seronegative pregnant macaques that were CD4⁺ T-cell depleted at the time of inoculation. Animals that received the CD4⁺ T-cell–depleting antibody also exhibited higher plasma and amniotic fluid viral loads, dampened virus-specific CD8⁺ T-cell responses, and delayed production of autologous neutralizing antibodies compared with immunocompetent monkeys. Thus, maternal CD4⁺ T-cell immunity during primary rhCMV infection is important for controlling maternal viremia and inducing protective immune responses that prevent severe CMV-associated fetal disease.Human congenital cytomegalovirus (CMV) infection occurs in 0.7% of all pregnancies (1) and is a major cause of permanent sensorineural and neurocognitive disabilities in infants worldwide. The rate of congenital CMV transmission is as high as 50% among women who acquire primary CMV infection during pregnancy, compared with less than 2% in women with chronic infection (2). Furthermore, congenital CMV transmission following primary maternal infection causes the most severe fetal outcomes including microcephaly, intracranial cyst formation, seizures, and intrauterine growth restriction (3).Although evident, the protective immune correlates of preconceptual immunity have not been determined. Currently, the guinea pig animal model is used to study protective immune responses against congenital CMV infection, as it is the only other species known to be susceptible to placental transmission of its species-specific CMV (4). Despite having limited sequence homology to human CMV (HCMV) (5), guinea pig CMV (GPCMV) crosses the placental barrier at a similar rate following acute maternal infection and establishes fetal infection with comparable CMV-associated sequelae (6). Several vaccine strategies including live-attenuated virus (7, 8), passive immunization of antibodies specific for glycoprotein B (gB) and the gH/gL complex (9, 10), and recombinant gB subunit immunization (11) have proven to be effective at reducing the rate of congenital GPCMV infection and preventing fetal demise. In human clinical trials, gB immunization was only 50% effective in reducing postpartum maternal virus acquisition (12) and passive immunization with CMV hyperimmune globulin of women with primary CMV infection within 6 wk of presumed acquisition did not achieve a significant reduction in the rate of fetal infection compared with placebo controls (13). These findings address the need for a relevant large-animal model with a more closely related CMV genome and wider availability of tools to assess the maternal immune system.Nonhuman primate models are widely used in the preclinical evaluation of vaccine candidates, as they are anatomically, physiologically, and immunologically similar to humans. Furthermore, their widespread use has led to the development of an extensive set of immunological tools that allow rigorous probing and characterization of vaccine-elicited immune responses. Rhesus macaques, a common nonhuman primate animal model, have previously been used to study CMV pathogenesis in the setting of primary and secondary infection (14–16). Rhesus CMV (rhCMV), which has greater sequence and structural homology to HCMV than GPCMV (17–19), results in asymptomatic infection and establishment of a persistent and lifelong infection, similar to that in humans.. Importantly, previous studies have shown that rhCMV inoculated intraperitoneally or intracranially into the developing fetus can induce neurological defects similar to those observed in congenitally infected human infants (20, 21). However, because of the high rate of rhCMV seroprevalence among animals of reproductive age (22) and repeated exposure to rhCMV within breeding colonies where rhCMV is endemic (23), there have been no previous reports of fetal or neonatal macaques exhibiting sequelae consistent with congenital rhCMV infection.Here, to our knowledge, we report the first nonhuman primate model of congenital CMV transmission using rhCMV-seronegative rhesus monkeys. In this model, CD4⁺ T-cell–depleted or immunocompetent rhCMV-seronegative monkeys were inoculated with a defined mixture of rhCMV strains in the early second trimester of pregnancy. Following detection of placental rhCMV transmission, fetuses were observed for signs of rhCMV-associated sequelae, and the maternal immune responses between mothers with severely affected fetuses and asymptomatic or noninfected infants were evaluated to identify potential immune correlates of protection against congenital CMV disease in nonhuman primates.     

Metformin improves performance in high‐intensity exercise,but not anaerobic capacity in healthy male subjects

The aim of this study was to determine the ergogenic effects of metformin in high‐intensity exercise, as well as its effects on anaerobic capacity, in healthy and physically active men. Ten subjects (mean (± standard deviation) maximal oxygen uptake (_2max) 38.6 ± 4.5 mL/kg per min) performed the following tests in a cycle ergometer: (i) an incremental test; (ii) six submaximal constant workload tests at 40%–90% (_2max); and (iii) two supramaximal tests (110% (_2max). Metformin (500 mg) or placebo was ingested 60 min before the supramaximal test. There were no significant differences between the placebo and metformin groups in terms of maximum accumulated oxygen deficit (2.8 ± 0.6 vs 3.0 ± 0.8 L, respectively; P = 0.08), lactate concentrations (7.8 ± 2.6 vs 7.5 ± 3.0 mmol/L, respectively; P = 0.75) or O₂ consumed in either the last 30 s of exercise (40.4 ± 4.4 vs 39.9 ± 4.0 mL/kg per min, respectively; P = 0.35) or the first 110 s of exercise (29.0 ± 2.5 vs 29.5 ± 3.0 mL/kg per min, respectively; P = 0.42). Time to exhaustion was significantly higher after metformin than placebo ingestion (191 ± 33 vs 167 ± 32 s, respectively; P = 0.001). The fast component of recovery was higher in the metformin than placebo group (12.71 vs 12.18 mL/kg per min, respectively; P = 0.025). Metformin improved performance and anaerobic alactic contribution during high‐intensity exercise, but had no effect on overall anaerobic capacity in healthy subjects.