DFP Labeling of Platelets During Recovery from Thrombocytopenia

Rat platelets were labeled with tritiated diisopropylfluorophosphate(³H-DFP) during recovery from acute thrombocytopenia. The results indicated that there was significant labeling of megakaryocytes by ³H-DFPwhich, in the presence of an increased rate of platelet production, resulted inmaintenance of relatively constant values for platelet-bound radioactivity during the period of maximum platelet production and reactive thrombocytosis.Significant random loss of platelets was apparent, and, when a cohort ofyoung platelets was transfused to normal recipients, they were destroyed at anormal rate.

     

Effects of growth hormone deficiency and rhGH replacement therapy on the 6β-hydroxycortisol/free cortisol ratio,a marker of CYP3A activity,in growth hormone-deficient children

Objective To determine the effect of both growth hormone deficiency (GHD) and rhGH replacement therapy on CYP3A activity as well as the potential influence of gender.Methods The sample consisted of 35 GHD children (16 males and 19 females), aged 2.9–13.1 years, and a control group of 35 healthy children matched for age and sex. The urinary ratio 6-hydroxycortisol/free cortisol was used as a marker of CYP3A activity. In patients, urine samples were collected at two times, prior to starting rhGH replacement treatment and 30 days after beginning therapy.Results A significantly higher metabolic activity in GHD children was observed in relation to controls (P=0.0001) without sex differences. Paired comparisons demonstrated a sexually dimorphic effect of rhGH therapy on the CYP3A activity. While boys displayed a significant decrease (P=0.003), girls showed no significantly different values of CYP3A marker (P>0.05). Unpaired comparison between controls and GHD children after therapy demonstrated absence of significant differences in boys (P>0.05) and a strikingly higher activity in girls (P=0.0001).Conclusions The data suggests that: (a) GHD in children increases CYP3A activity in a non-sex-dependent manner, (b) rhGH treatment for 30 days to GHD children results in a sexually dimorphic effect on CYP3A activity, with a significant decrease in males toward normalization in relation to controls and non-significant changes in females. The results of this study may have important clinical implications for GHD children, since changes in CYP3A activity importantly affect the metabolism of both steroid hormones and CYP3A substrate drugs.     

A randomized,double-blind,placebo-controlled,phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma

RMP-7, a bradykinin analog, temporarily increases the permeability of the blood-brain tumor barrier to chemotherapy drugs like carboplatin. We conducted a randomized, controlled trial of carboplatin and RMP-7 versus carboplatin and placebo in patients with recurrent malignant glioma. The primary outcome measure was time to tumor progression (TTP). Adults with recurrent glioblastoma multiforme or anaplastic glioma were randomized in a 1:1 ratio to receive carboplatin and either RMP-7 or placebo. Radiation therapy had failed in all patients, and they may have received prior chemotherapy. Carboplatin (dosed to achieve an area under the curve of 5 mg/ml x time for patients who had received prior chemotherapy, or 7 mg/ml x time for those who had not) was given intravenously every 4 weeks, followed by intravenous infusion of either RMP-7 or placebo (300 ng/kg). TTP, tumor response, neuropsychological assessments, functional independence, and quality of life assessments were analyzed every 4 weeks. There were 122 patients enrolled, 62 in the RMP-7 and carboplatin group and 60 in the placebo and carboplatin group. Median TTP was 9.7 weeks (95% CI, 8.3-12.6 weeks) for the RMP-7 and carboplatin group and 8.0 weeks (95% CI, 7.4-12.6 weeks) for the placebo and carboplatin group. Median survival times were 26.9 weeks (95% CI, 21.3-37.6 weeks) for the RMP-7 group and 19.9 weeks (95% CI, 15.0-31.3 weeks) for the placebo group. No differences were noted for time to worsening of neuropsychological assessments, functional independence, or quality of life assessments. The use of RMP-7 had no effect on the pharmacokinetics or toxicity of carboplatin. At the dose and schedule used in this trial, RMP-7 did not improve the efficacy of carboplatin. Recent preclinical pharmacokinetic modeling of RMP-7 suggests that higher doses of RMP-7 may be required to increase carboplatin delivery to tumor.     

Geographical distribution of the male/female ratio of cardiovascular mortality in Spain

Objectives: To describe the geographic distribution of the male/female ratio (MFR) of mortality from ischaemic heart disease (IHD) and cerebrovascular disease (CVD) in 1991-1995 in Spain, and to examine wether the differences between men and women in exposure to cardiovascular risk factors could explain such distribution.Methods: Mortality data come from National Vital Statistics. Age-adjusted mortality rates for the period 1991-1995 were calculated for IHD and CVD using the direct method, in population aged 40 to 79 years. Data on tobacco and alcohol consumption, hypertension, hypercholesterolemia, diabetes, obesity, sedentariness, and health services use come from the 1993 Spanish National Health Survey, and socioeconomic data from the 1991 Population Census. Data were analyzed by correlation and Poisson regression methods.Results: MFR of mortality from IHD and CVD are higher in the provinces of the north of Spain, and are correlated negatively with mortality from IHD and CVD. This negative association is stronger for mortality in women than in men. Among the risk factors examined, only MFR of alcohol consumption showed a significant (p < 0.05) association with MFR of mortality from IHD and CVD. MFR of alcohol consumption explains 23 and 14% of the provincial variation in MFR of mortality from IHD and CVD, respectively, and showed a U shaped relationship with MFR of mortality for both diseases.Conclusions: Provinces in the north of Spain, which register the lowest cardiovascular mortality, show the highest MFR of IHD and CVD mortality, because of the lower mortality in women than in men. As derived from the dose-response relationship between MFR of IHD and CVD mortality and the MFR of alcohol consumption, a higher alcohol consumption in men could contribute to a higher MFR of cardiovascular mortality in some Spanish provinces.     

Prolonged QT interval and cardiac arrhythmias in two neonates: sudden infant death syndrome in one case

Two neonates with arrhythmias and the long QT syndrome are described. The arrhythmias were detected in utero and both infants were apparently well after birth. The first infant, although well, had a bradycardia for the first 9 days of life. A normal heart rate was documented at 10 days but a prolonged QT interval was not appreciated on the ECG. He was discharged from hospital but died suddenly and unexpectedly 3 days later. A post-mortem examination failed to find a cause for his death which therefore fell into the category of the sudden infant death syndrome (SIDS). A retrospective analysis of the perinatal electrocardiogram showed a probable junctional rhythm with 2:1 conduction to the ventricle; the QT interval was prolonged at 0.52 seconds (QTC = 0.63). The second infant had a QT interval of 0.52 seconds (QTC = 0.54) and frequent ventricular premature beats on a 24-hour electrocardiogram. She was treated with propranolol and remains well 2 years later. Sudden infant death has often been described in the siblings of children with the long QT syndrome and one other report described a case of SIDS which was said to have had a prolonged QT interval on the perinatal ECG. This report, however, provides unquestionable evidence, in one case, of an association between the long QT syndrome and SIDS.     

Evaluation of the Sheffield system for identifying children at risk from unexpected death in infancy. Results from Birmingham and Newcastle upon Tyne

The "at birth" system which is used in Sheffield to identify children likely to die unexpectedly in infancy, was tested retrospectively in Birmingham (83 cases) and in Newcastle upon Tyne (56 cases). The discrimination between cases and age-matched controls was poor in both cities. Analysis of the 8 factors used in the system showed that only 2 maintained significant case/control differences in Birmingham and Newcastle. Further investigation showed that other factors from maternity records showed significant case/control differences in these cities. Although the system used in Sheffield would not be of use in a prospective prevention programme in either Newcastle or Birmingham, the possibility of evolving an "at risk" system which might apply more widely is discussed.