The production of JAK2 wild‐type platelets is not downregulated in patients with JAK2 V617F mutant‐positive essential thrombocythaemia

To clarify the relationship between the levels of JAK2 wild‐type (WT) and V617F mutant‐positive platelets in patients with essential thrombocythaemia (ET), we quantified mutant levels in purified cells from 10 V617F‐positive patients prior to receiving cytoreductive therapy. Mutant levels were significantly higher in platelet than neutrophil RNA (P = 0·002), but the mutation was still only present in a sub‐population of platelets (median 54%). When the absolute number of WT platelets was calculated, it was always within or above the normal platelet range, indicating that there is an aberration in the negative feedback to JAK2 WT platelets in ET.     

Response rates for providing a blood specimen for HIV testing in a population-based survey of young adults in Zimbabwe

Background  

To determine differences among persons who provided blood specimens for HIV testing compared with those who did not among those interviewed for the population-based Zimbabwe Young Adult Survey (YAS).     

Safety of high-dose nicotinamide: a review

Nicotinamide, the amide derivative of nicotinic acid, has over the past forty years been given at high doses for a variety of therapeutic applications. It is currently in trial as a potential means of preventing the onset of Type I (insulin-dependent) diabetes mellitus in high-risk, first-degree relatives. Nicotinamide is for regulatory purposes classed as a food additive rather than a drug and has not therefore required the formal safety evaluation normally expected of a new therapy. Because the safety of treatment with megadoses of vitamins cannot be assumed, a full literature review has been undertaken. The therapeutic index of nicotinamide is wide but at very high doses reversible hepatotoxicity has been reported in animals and humans. Minor abnormalities of liver enzymes can infrequently occur at the doses used for diabetes prevention. There is no evidence of teratogenicity from animal studies and nicotinamide is not in itself oncogenic; at very high doses it does however potentiate islet tumour formation in rats treated with streptozotocin or alloxan. There is no evidence of oncogenicity in man. Growth inhibition can occur in rats but growth in children is unaffected. Studies of its effects on glucose kinetics and insulin sensitivity are inconsistent but minor degrees of insulin resistance have been reported. The drug is well tolerated, especially in recent studies which have used relatively pure preparations of the vitamin. Experience to date therefore suggests that the ratio of risk to benefit of long-term nicotinamide treatment would be highly favourable, should the drug prove efficacious in diabetes prevention. High-dose nicotinamide should still, however, be considered as a drug with toxic potential at adult doses in excess of 3 gm/day and unsupervised use should be discouraged. [Diabetologia (2000) 43: 1337–1345]     

The effects of high parity and socioeconomic status on obstetric and neonatal outcome

Summary We studied the interaction of social status and high partiy in 15,102 consecutive births in one inner-city hospital, of which 1874 (12.4%) occurred in mothers who had given birth to seven or more infants (Grand multiparae). Group 1 consisted of 1258 grand multiparae from a socioeconomically stable and homogeneous ultra-orthodox Jewish community in Jerusalem, and group 2, included all other grand multiparae of relatively greater age and lower socioeconomic status. A significantly higher rate of small for gestational age, low birth weight and preterm infants was found in group 2 compared with group 1. The results suggest that grand multiparity is not of itself a risk factor, but reflects the confounding effect of environmental conditions.     

Sinusoidal heart rate pattern and an normal biophysical profile in a severely compromised fetus

A case is described in which a woman complained of weakened fetal movements, and a persistent sinusoidal heart rate pattern was demonstrated in the presence of normal fetal breathing movements, normal fetal tone, and normal amount of amniotic fluid. In view of the subjective complaints and disregarding the normal biophysical profile, termination of pregnancy was performed. A compromised, severely anemic fetus was delivered by cesarean section. The role of sinusoidal heart rate pattern and the limitations of biophysical scores as a single determinant of fetal well being are discussed.     

Grand multiparity: an obstetric or neonatal risk factor?

Grand multiparity has been considered to be a factor in maternal and neonatal morbidity. In addition, families with seven or more children have been associated with low socioeconomic status. To minimize the confounding effect of the socioeconomic status, the outcome of grand multiparity has been investigated in a mostly homogeneous, ultraorthodox Jewish community in Jerusalem, Israel. A total of 5916 deliveries in one community hospital (Bikur Cholim) were studied, of which 893 (13%) occurred in mothers who had given birth to seven or more infants. There was a significant decrease in the incidence of small for gestational age infants among the grand multiparous women (3.6% as opposed to 5.8% in the control population). This difference was independent of maternal age. Moreover, grand multiparous women gave birth to significantly more large for gestational age infants. No increase in obstetric complications or neonatal morbidity and mortality was found among the offspring of the grand multiparous mothers. Having taken socioeconomic status into account, we conclude that grand multiparity does not carry an increased risk of perinatal morbidity or mortality.     

Angiogenic, mitogenic, and chemotactic activity of human follicular fluid

Human follicular fluid was found to induce the formation of new blood vessels on the chick chorioallantoic membrane 3 to 5 days after implantation. To characterize this response more fully, the effects of human follicular fluid on a continuous line of bovine aortic arch endothelial cells were studied. Human follicular fluid showed strong mitogenic activity toward endothelial cells, ranging from a threefold increase in thymidine incorporation at a dilution of 1:10 to a 1.4-fold increase at a dilution of 1:3200. Endothelial cells also exhibited a directional migration (chemotaxis) toward human follicular fluid. A 1:10 dilution of human follicular fluid induced a 6.8-fold increase in directional cellular migration through membranes with 8 microns pores, and a 1:800 dilution induced a 1.8-fold increase in migration. Endothelial cells responding to gradients of human follicular fluid also demonstrated a marked change in morphologic structure when compared with control cells. Human plasma and fibrinogen were angiogenic and chemotactic (but not mitogenic) toward endothelial cells, which suggested that fibrinogen may account for at least part of the angiogenic activity of human follicular fluid. These results indicate that human follicular fluid is strongly angiogenic and that this biologic activity can be associated with effects directly on endothelial cells in vitro.     

Comparative pharmacokinetics of lovastatin extended-release tablets and lovastatin immediate-release tablets in humans

The pharmacokinetics of lovastatin and its active metabolite lovastatin acid was evaluated in 9 healthy subjects in a three-period crossover study following a single oral dose of lovastatin extended-release (ER) tablets and lovastatin immediate-release (IR) tablets. Participants were dosed with lovastatin IR 40 mg tablets following a standard breakfast, lovastatin ER 40 mg tablets following a standard breakfast, and lovastatin ER 40 mg tablets underfasting conditions. Serial plasma samples were collected for up to 48 hours postdose and assayed for lovastatin and lovastatin acid using a liquid chromatography/mass spectroscopy/mass spectroscopy method. Lovastatin ER tablets, unlike lovastatin IR tablets, exhibited delayed- and extended-release characteristics. The relative bioavailability, in terms of area under the curve values, of lovastatin (156%) and lovastatin acid (124%) was greater from lovastatin ER tablets as compared with lovastatin IR tablets when given with breakfast. An even greater increase in the bioavailability of lovastatin (261%) and lovastatin acid (231%) was observed when the lovastatin ER tablets were administered under fasting conditions. Thus, greater gastrointestinal tract drug absorption of lovastatin from lovastatin ER tablets was demonstrated. Ingestion of a standard breakfast prior to administration of lovastatin ER tablets decreased absorption of lovastatin by approximately 40%, relative to lovastatin ER tablets under fasting conditions.     

Pharmacokinetics of lovastatin extended-release dosage form (Lovastatin XL) in healthy volunteers

The purpose of this study was to evaluate pharmacokinetics and dose proportionality of lovastatin extended-release dosage form (ER-lovastatin) in the dosage levels of 10, 20 and 40 mg in 9 healthy male subjects. Each subject was randomized to receive a single oral dose of ER-lovastatin either 10, 20 or 40 mg in a three-way crossover design with a washout period of 7 days between the treatments. Subjects were served dinner at approximately 5:30 PM followed by dosing at approximately 10:00 PM in each study period. Serial plasma samples were collected up to 48 h after dosing and assayed for lovastatin and its active metabolite lovastatin acid using an LC/MS/MS method. The plasma concentration-time profiles of lovastatin and its active metabolite lovastatin acid exhibited delayed- and extended-release characteristics at each dose. Mean (+/-) values for the C(max) of lovastatin were 1.04+/-0.43, 2.03+/-0.65 and 4.03+/-3.02 ng/ml for the 10, 20 and 40 mg dosage, respectively. The corresponding values for the AUC(0-48 h) of lovastatin were 14.6+/-7.8, 34.1 +/-13.7, and 53.9+/-35.6 ng h/ml. The same tendency was also found for C(max) and AUC(0-48 h) values of lovastatin acid. Results from this study demonstrated as the dose of ER-lovastatin increased from 10 to 40 mg, the C(max) and AUC(0-48 h) values of lovastatin as well as lovastatin acid appeared to increase linearly.