Spontaneous loss of a co-twin and the risk of birth defects after assisted conception.

The study of very early pregnancy loss is impractical in the general population, but possible amongst infertility patients receiving carefully monitored treatments. We examined the association between fetal loss and the risk of birth defects in the surviving co-twin in a retrospective cohort study of infertility patients within an infertility clinic in South Australia from January 1986 to December 2002, linked to population registries for births, terminations and birth defects. The study population consisted of a total of 5683 births. Births from singleton pregnancies without loss were compared with survivors from (1) pregnancies with an empty fetal sac at 6-8 weeks after embryo transfer, (2) fetal loss subsequent to 8-week ultrasound and (3) multiple pregnancy continuing to birth. Odds ratios (OR) for birth defects were calculated with adjustment for confounders. Amongst infertility patients, the prevalence of birth defects was 7.9% for all twin pregnancies without fetal loss compared with 14.6% in pregnancies in which there had been an empty sac at ultrasound, and 11.6% for pregnancies with fetal loss after 6-8 weeks. Compared with singleton pregnancies without loss, the presence of an empty sac was associated with an increased risk of any defect (OR=1.90, 95% confidence intervals (CI)=1.09-3.30) and with multiple defects (OR=2.87, 95% CI=1.31-6.28). Twin pregnancies continuing to birth without loss were not associated with an overall increased prevalence of defects. We conclude that the observed loss of a co-twin by 6-8 weeks of pregnancy is related to the risk of major birth defects in the survivor.

UGT2B17 genetic polymorphisms dramatically affect the pharmacokinetics of MK-7246 in healthy subjects in a first-in-human study.

MK-7246, an antagonist of the chemoattractant receptor on T helper type 2 (Th2) cells, is being developed for the treatment of respiratory diseases. In a first-in-human study, we investigated whether genetic polymorphisms contributed to the marked intersubject variability in the pharmacokinetics of MK-7246 and its glucuronide metabolite M3. Results from in vitro enzyme kinetic studies suggested that UGT2B17 is probably the major enzyme responsible for MK-7246 metabolism in both the liver and the intestine. As compared with those with the UGT2B17*1/*1 wild-type genotype, UGT2B17*2/*2 carriers, who possess no UGT2B17 protein, had 25- and 82-fold greater mean dose-normalized values of area under the plasma concentration-time curve (AUC) and peak concentration of MK-7246, respectively, and a 24-fold lower M3-to-MK-7246 AUC ratio. The apparent half-life of MK-7246 was not as variable between these two genotypes. Therefore, the highly variable pharmacokinetics of MK-7246 is attributable primarily to the impact of UGT2B17 genetic polymorphisms and extensive first-pass metabolism of MK-7246.

Birthweight and thinness at birth independently predict symptoms of polycystic ovary syndrome in adulthood.

BACKGROUND: The aetiology of polycystic ovary syndrome (PCOS) is unknown and contested. While it has been suggested that PCOS could have origins in perturbed development, epidemiological findings have been inconclusive. We aimed to examine potential fetal origins of PCOS. METHODS: A retrospective birth cohort of 948 singleton female babies born at one hospital in South Australia in 1973-1975 was assembled. Birth characteristics were obtained from hospital records and PCOS symptoms were identified through interview and clinical examination when women were ~30 years old. Based on the combination of PCOS symptoms, women formed seven outcome groups. A multinomial logistic regression analysis was used to investigate associations between birth characteristics and these outcome groups. RESULTS: After adjusting for gestational age, two distinct birth characteristics were associated with two PCOS symptom groups. Each 100 g increase in birthweight increased the risk of hyperandrogenism (as a single symptom) in adulthood by 5% [relative risk ratio: 1.05, 95% confidence interval (CI): 1.01-1.09]. In contrast, each one unit increase in the ponderal index at birth decreased the risk of all three key PCOS symptoms (hyperandrogenism, menstrual dysfunction and polycystic ovaries) by 21% (0.79, 95% CI: 0.66-0.93). CONCLUSIONS: These results suggest two discrete fetal programming pathways (related to high birthweight and to thinness at birth) are operating. Our findings point to differing aetiologies for symptom clusters, and inform the debate over symptoms that best represent the disorder.

Effects of central administration of insulin or l-NMMA on rat skeletal muscle microvascular perfusion.

AIM: Intracerebroventricular (ICV) administration of a nitric oxide synthase (NOS) inhibitor to rats has been reported to raise blood pressure (BP) and cause insulin resistance, suggestive of a central effect of insulin that is NO dependent. Herein we test whether ICV insulin has peripheral haemodynamic and metabolic effects and whether peripheral effects of systemic insulin are affected by the ICV administration of the NOS inhibitor N(G) -methyl-l-arginine (l-NMMA). METHODS: Anaesthetized rats were fitted with an ICV cannula for insulin, artificial cerebrospinal fluid (aCSF) or l-NMMA infusion. Rats receiving ICV l-NMMA (500 µg) underwent systemic insulin clamp (10 mU/min/kg) or saline treatment for 70 min and were compared with animals receiving an equal amount of l-NMMA infused systemically. RESULTS: ICV aCSF or insulin (135 mU/min/kg brain) for 70 min or systemic l-NMMA (500 µg) had no effect on BP, heart rate (HR), femoral blood flow (FBF), glucose infusion rate, muscle 2-deoxyglucose uptake, microvascular perfusion or plasma insulin. However, ICV l-NMMA reduced systemic insulin-mediated increases in FBF (2.05 ± 0.08 to 1.55 ± 0.15 ml/min), 2-deoxyglucose uptake (17.7 ± 0.15 to 10.0 ± 0.03 µg/g/min) and microvascular perfusion (10.5 ± 0.5 to 6.6 ± 1.1 mol/min) (each mean ± SE, p < 0.05); plasma insulin, HR and BP were unaffected. CONCLUSIONS: Central insulin administration had no effect on skeletal muscle haemodynamics or glucose metabolism. However, systemic insulin-mediated increases in limb blood flow, muscle microvascular perfusion and glucose uptake may be regulated by a central pathway that is NO dependent.

Health effects of daily indoor nitrogen dioxide exposure in people with asthma.

Household gas appliances produce nitrogen dioxide (NO2), which may be associated with an increase in symptoms in asthmatics. The relationship between indoor NO2 exposure, and respiratory symptoms in people with asthma was evaluated. Self-reported asthmatics (n=125) wore lapel badges that measured NO2 daily over 6 weeks at home. Outdoor pollutants, spores and meteorological parameters were measured daily, in addition to smoking status and demographic factors. Seven asthma symptoms were recorded in diaries, for analysis by same day and also with 1 day lag exposures, using a generalized estimating equation. Significant interactions were demonstrated between NO2 at age < or =14 yrs, with respect to the symptoms of chest tightness on the same day (odds ratio (OR): 1.29, 95% confidence interval (CI): 1.16-1.43) and with a 1 day lag (OR: 1.29, 95% CI: 1.14-1.46), breathlessness on exertion with a 1 day lag (OR: 1.13, 95% CI: 1.00-1.28), daytime asthma attacks on the same day (OR: 1.13, 95% CI: 1.02-1.26) night asthma attacks on the same day (OR: 1.16, 95% CI:1.03-1.30) and with a 1 day lag (OR: 1.15, 95% CI; 1.03-1.29) after adjustment for potential confounders. A significant interaction between NO2 and age 35-49 yrs was demonstrated for coughs with a 1 day lag (OR: 1.15, 95% CI: 1.01-1.31). Daily personal exposures to NO2 are associated with asthmatic symptoms in children.

Impact of an information and consent form on patients having chemotherapy.

Of 100 patients having chemotherapy who were given a written information and consent form, only 34 understood the purpose of the form and only one considered it the major source of information; 75 patients could not name any of their drugs, 26 did not know the goal of therapy and only 15 remembered all of four general side effects. Such forms may not satisfy the requirements of informed consent.