Assessment of bioequivalence after subcutaneous and intramuscular administration of urinary gonadotrophins

The objective was to demonstrate bioequivalence between s.c. and i.m. administration of Humegon (FSH/LH ratio 1:1) and Normegon (FSH/LH ratio 3:1). In two randomized, single-centre, cross-over studies, 18 healthy volunteers on each formulation were assigned to one of the two administration sequences. Subjects were given single doses of one of the above gonadotrophins after endogenous gonadotrophin production had first been suppressed using high-dose oral contraceptive. Subsequently, rate (Cmax, tmax) and extent (AUC) of absorption of follicle stimulating hormone (FSH) and luteinizing hormone (LH) were determined for 14 days. For Cmax and AUC, analysis of variance (ANOVA) was performed on log-transformed data and for tmax ANOVA was performed on ranks. Intramuscular and s.c. injections of Humegon were bioequivalent with respect to the main pharmacokinetic parameters, being AUC and Cmax of FSH absorption. Intramuscular and s.c. injections of Normegon were bioequivalent with respect to the AUC of FSH and not bioequivalent with respect to the Cmax of FSH. For tmax of FSH as well as for most LH variables of both preparations, bioequivalence could not be proven due to the high intra- and interindividual variability and/or concentrations being close to the detection limit. Thus, the main pharmacokinetic FSH variables after i.m. and s.c. administration of Humegon and Normegon were bioequivalent.      

Audit of admission to medical school: II--Shortlisting and interviews

Analysis of shortlisting of applicants for interview at St Mary's Hospital Medical School showed that factor analysis could reduce the selection criteria to three independent scales--"academic ability," "interests," and "community service"--all of which contributed to the interview decision. Early applicants scored more highly on all three factors but were still at a greater advantage in selection for interview than would have been predicted. The dean's judgment of priority for interview from the UCCA form was found to predict a candidate's chance of acceptance at other medical schools besides St Mary's. Analysis of interviewing showed high correlations among interviewers in their assessments, although there was evidence of influence by the chairmen. Factor analysis showed three major factors--academic suitability, non-academic suitability, and health--of which non academic suitability was the major determinant of interview success. Non academic suitability was related to personality (high extraversion and low psychoticism) and to the choices made on the UCCA form. The system of admission interviews enabled greater emphasis to be put on broader interests and achievements than if selection had been on the basis of UCCA application form alone.     

Enhancing preventive and primary care for children with chronic or disabling conditions served in health maintenance organizations

Health maintenance organizations serve an estimated 20 percent of the child population, approximately 12 million children, many of whom have chronic conditions or disabling conditions. These children consume a disproportionate share of health resources and represent an important challenge in terms of care management. As HMOs increasingly enroll children with private insurance and Medicaid who have various physical, developmental, behavioral, and emotional disorders, they must find new and innovative ways to provide their care. Almost one third of children are affected by chronic conditions, and a smaller percentage (6 percent) suffer from chronic disabling conditions. Seven design elements for enhancing preventive and primary care for children with chronic conditions are presented in this article with illustrative examples from HMOs and state Medicaid programs.     

Cerebral blood flow velocity after mannitol infusion in children

Purpose

There is conflicting evidence as to whether the effect of mannitol on brain bulk arises from haemodynamic, rheologic, or osmotic mechanisms. If mannitol alters cerebral haemodynamics by inducing vasoconstriction, this change should be reflected in cerebral blood flow velocity (CBFV) in the middle cerebral artery (MCA). The purpose of this study was to evaluate the effect of mannitol on CBFV in children.

Methods

Children scheduled for intracranial surgery were enrolled. After a loading dose of 10 μg · kg^?1 of fentanyl, general anaesthesia was maintained with fentanyl (3 μg · kg^?1 · hr^?1), 66% nitrous oxide, and isoflurane (0.2–0.5% inspired). Mean and systolic CBFV (Vm and Vs) and pulsatility index (PI) were recorded with a transcranial Doppler (TCD) directed at the M1 segment of the MCA. Mannitol was administered, 1 gm · kg^?1 iv over 15 min. The osmolality (Osm), haematocrit (Hct), mean arterial pressure (MAP), heart rate (HR), and TCD variables were recorded before and 15, 30, 45, and 60 min after the mannitol infusion.

Results

Mannitol infusion resulted in an increase in Osm and decrease in Hct (P < 0.05). Heart rate, MAP and arterial carbon dioxide tensions did not change (P > 0.05) during the measuring period. The Vm did not vary from baseline. The Vs and P1 both increased briefly (P < 0.01 at 15 min and P < 0.05 at 30 min) after the mannitol, suggesting an increase in resistance distal to the MCA.

Conclusion

The time course of CBFV changes produced by mannitol corresponds with previous animal data concerning cerebrovascular tone. Our results suggest that mannitol briefly increases cerebrovascular resistance and thereby diminishes cerebral blood volume.     

Definition of inseparably fused ventricular myocardium in thoracopagus: Fetal echocardiographic utility and pathologic refinement

Summary Correlative echocardiographic and pathological findings in a thoracopagus with conjoined hearts are reported. One twin had tricuspid atresia with discordant atrioventricular connections and concordant ventriculoarterial connections. The morphologic right ventricle was hypoplastic and there was a large muscular ventricular septal defect. The other twin had hypoplasia of the mitral valve anulus and left ventricle with double-outlet right ventricle and pulmonary valve atresia. The tricuspid valve was severely insufficient in part because of a large orifice and redundant, elongated leaflets with abnormal chordal attachments. The left ventricles of these two twins shared a perforated common free wall with at least two large defects allowing mixing of the circulations at that level. Not all anatomic details were established conclusively by fetal echocardiography; however, sufficient diagnostic information was obtained to support a decision not to aggressively resuscitate these twins after elective cesarean delivery at 31 weeks' gestation.     

Hypospadias trends in two US surveillance systems

OBJECTIVE: Hypospadias is a common congenital anomaly, the cause of which is unknown. Unexplained increases in the rates of hypospadias occurred in five European countries in the 1970s and 1980s. We examined data from two birth defects surveillance systems in the United States for evidence of similar trends. METHODOLOGY: The Metropolitan Atlanta Congenital Defects Program (MACDP) provided birth prevalence rates from 1968 to 1993. The nationwide Birth Defects Monitoring Program (BDMP) provided rates from 1970 to 1993. MACDP data are population-based and could be categorized by the severity of the hypospadias. BDMP data allowed analysis of rate trends for the four census regions of the United States. RESULTS: Data from both surveillance systems showed an approximate doubling of hypospadias rates in the 1970s and 1980s. MACDP data showed that the rate of severe cases increased while the ratio of mild to severe cases decreased. BDMP data showed that hypospadias rates increased markedly in all four regions of the United States. CONCLUSIONS: The observed increases are unlikely to be attributable to increased sensitivity of the surveillance systems or the identification of more mild cases by physicians over time, because either trend would have increased rather than decreased the ratio of mild to severe cases. If real, these trends represent the largest number of cases and the first report of an increase in hypospadias rates outside of Europe. Additional investigation of a possible increase in hypospadias rates is warranted.     

Analyses of mutation and loss of heterozygosity of coding sequences of the entire transforming growth factor beta type II receptor gene in sporadic human gastric cancer

Mutations in the transforming growth factor beta type II receptor (TGFbetaRII) gene have been detected in several human cancer types exhibiting microsatellite instability. Using intron primers previously reported for examination of the entire coding region of the TGFbetaRII gene, 29 sporadic gastric cancers were screened with non-radioactive single strand conformation polymorphism and subsequent DNA sequencing analysis. Mutations of the TGFbetaRII gene were detected in three out of 29 tumors (10%). Two cases showed deletions in a polyadenine tract in both alleles and was positively associated with replication error. One case had an insertion of GA dinucleotide sequence in one allele. Mutations of the TGFbetaRII gene were restricted to exon 3 and other coding regions were not affected. Loss of heterozygosity was detected by analyzing a polymorphic site in intron 2. Three out of nine (33%) informative cases, which were all of intestinal type and advanced cases, showed loss of heterozygosity but neither TGFbetaRII mutation nor replication error was found in these cases. Immunoreactivity of TGFbetaRII in tumor tissues was reduced to a different extent in the gastric cancer with genetically abnormal transforming growth factor. Although the numbers studied are small, homozygous (A)10 deletion or loss of heterozygosity of TGFbetaRII is involved in tumorigenesis and progression of at least some part of sporadic gastric cancer.