Randomized, controlled, open-label, non-inferiority study of the CONSORT algorithm for individualized dosing of follitropin alfa.

In this randomized, controlled, open-label, phase IV study, ovarian response after a follitropin alfa starting dose determined by the CONSORT calculator was compared with a standard dose (150 IU). Normo-ovulatory women (aged 18-34 years) eligible for assisted reproductive techniques were recruited (23 centres: nine European countries and Chile); 200 women were randomized (CONSORT [n = 96]; standard dosing [n = 104]). Significantly lower mean daily (121.5 versus 167.4 IU; P < 0.001) and total (1288.5 versus 1810.0 IU; P < 0.001) doses of follitropin alfa were administered in the CONSORT group. Clinical pregnancy rates were CONSORT (36.0%) and standard dosing (35.5%); estimated difference (confidence interval 0.6%; -13.5 to 14.6). Ovarian hyperstimulation syndrome occurred in 6.3% and 12.5% of patients in the CONSORT and standard-dosing groups, respectively. The primary efficacy analysis found a significantly lower mean [SD] number of oocytes retrieved in the CONSORT (10.0 [5.6]; P = 0.037) versus standard-dosing group (11.8 [5.3]). Although the CONSORT calculator was statistically inferior to standard dosing in the number of oocytes retrieved, clinical pregnancy rates (fresh embryo transfers) were similar in both groups, and incidence of ovarian hyperstimulation syndrome was lower in the CONSORT group.

Factors related to successful ovulation induction in patients with WHO group II anovulatory infertility.

To identify baseline characteristics related to successful ovulation induction, data were analysed from oligo- or anovulatory patients undergoing their first cycle of human recombinant FSH (r-hFSH; follitropin alfa) in a chronic low-dose (75 IU starting dose), step-up protocol in two clinical trials (n=446). Patients were grouped according to response: group A, ovulated within 14 days (75 IU follitropin alfa); group B, ovulated after 14 days (>75 IU follitropin alfa); group C, not administered human chorionic gonadotrophin (HCG) because of poor response; group D, cycle cancelled due to over-response (HCG not administered); group E, spontaneous ovulation prior to obtaining criteria for administration of HCG. Mean body mass index (BMI) of group A (25.0 kg/m(2)) was significantly lower than groups B (27.1 kg/m(2), P<0.001) or C (28.2 kg/m(2), P<0.0001), but similar to group D (24.3 kg/m(2)). Mean antral follicle count (AFC) of group A was also significantly lower than group C (18.3 versus 22.7; P=0.018), but not significantly different from groups B (21.5) or D (19.5); group E had the highest mean AFC (35.7). Comparatively low BMI, low AFC and higher (although still within the normal range) FSH concentration at baseline were associated with successful ovulation induction in infertile women undergoing a chronic low-dose, step-up stimulation protocol.

Isolation and mapping of three new polymorphic markers to chromosomes 3, 20 and 21.

Screening of single human chromosome plasmid libraries using a digoxygenin labelled (AAAT)15 oligonucleotide probe led to the identification of several positive clones. DNA sequence analysis of these was carried out and showed the presence of a number of simple DNA repeats. Oligonucleotide primers were designed from the sequences flanking these repeats and tested in PCR amplification reactions of human genomic DNA. Three of the markers tested were shown to be polymorphic with heterozygosities ranging from 40% to 69%. The markers were assigned to chromosomes using a panel of monochromosomal somatic cell hybrids combined with linkage analysis using DNA from the CEPH panel of families. The markers designated (AAAT)11, (AAAT)12 and (CA)19 were thus assigned to chromosomes 3, 21 and 20 respectively.

Chromosomal assignment of 79 cDNAs from a range of human tissues.

Single-pass DNA sequencing of cDNAs selected at random from a human mixed tissue cDNA library have generated a series of more than 2000 expressed sequence tags. One hundred twenty-eight unique cDNA fragments with little or no known protein or nucleic acid homologies have been selected for further analysis. Oligonucleotide primer pairs have been designed from the cDNAs and used in PCR amplification in combination with genomic DNA from a panel of monochromosomal somatic cell hybrids. This has allowed us to assign 70 of these transcribed genes to a single chromosome, and a further 9 have been located on two or three chromosomes. Additionally, 3 cDNAs contain short tandem repeats that may allow them to be further localized by linkage analysis.

The Lutheran blood group glycoprotein, another member of the immunoglobulin superfamily, is widely expressed in human tissues and is developmentally regulated in human liver.

Glycoproteins expressing the Lutheran blood group antigens were isolated from human erythrocyte membranes and from human fetal liver. Amino acid sequence analyses allowed the design of redundant oligonucleotides that were used to generate a 459-bp, sequence-specific probe by PCR. A cDNA clone of 2400 bp was isolated from a human placental lambda gt 11 library and sequenced, and the deduced amino acid sequence was studied. The predicted mature protein is a type I membrane protein of 597 amino acids with five potential N-glycosylation sites. There are five disulfide-bonded, extracellular, immunoglobulin superfamily domains (two variable-region set and three constant-region set), a single hydrophobic, membrane-spanning domain, and a cytoplasmic domain of 59 residues. The overall structure is similar to that of the human tumor marker MUC 18 and the chicken neural adhesion molecule SC1. The extracellular domains and cytoplasmic domain contain consensus motifs for the binding of integrin and Src homology 3 domains, respectively, suggesting possible receptor and signal-transduction function. Immunostaining of human tissues demonstrated a wide distribution and provided evidence that the glycoprotein is under developmental control in liver and may also be regulated during differentiation in other tissues.

Development of a panel of monochromosomal somatic cell hybrids for rapid gene mapping.

We have assembled a panel of monochromosomal somatic cell hybrids for use in gene mapping. DNA from each individual hybrid was used as a probe on normal human metaphases to identify the human chromosome and any fragments by reverse painting. To test the efficiency of the panel PCR amplification of DNA from the monochromosomal somatic cell hybrid panel was used in combination with human specific oligonucleotide primers to assign alpha-catenin (CTNNA1) and p21/WAF1 to chromosomes 5 and 6 respectively. These genes were localized further using hybrids containing specific translocations to 5q11-qter and 6p21 respectively. We also developed primers to enable us to assign 17 ESTs sequenced by the HGMP Resource Centre. The hybrid panel was developed with support of the UK HGMP and the DNA is available to all registered users.

Comparison of body size measurements as predictors of NIDDM in Pima Indians.

OBJECTIVE--To determine and compare the abilities of various anthropometric measurements to predict the development of non-insulin-dependent diabetes mellitus (NIDDM) in Pima Indian men and women. RESEARCH DESIGN AND METHODS--A total of 290 male and 443 female Pima Indians were followed for up to 6 years for the development of NIDDM. A proportional hazards analysis was used to assess the ability of anthropometric measurements evaluated at baseline to predict NIDDM. Receiver operating characteristic (ROC) curves were used to compare individual variables in predicting NIDDM. RESULTS--In separate models controlled for age and sex, body mass index (BMI), waist circumference, thigh circumference, waist-to-thigh ratio (WTR), weight, and percentage body fat (PBF) estimated by bioelectric resistance each predicted NIDDM, which developed in 30 men and 52 women. The highest incidence rate ratios (IRRs; for 1 SD of a variable) were for WTR in men and for PBF in women, although the confidence interval (CI) for PBF was wide. In stepwise analyses, WTR was the most significant predictor in men (IRR for 1 SD = 1.58, 95% CI = 1.20-2.07), and BMI was the most significant predictor in women (IRR for 1 SD = 1.65, 95% CI = 1.29-2.11). However, by ROC analyses, thigh circumference was the only variable significantly worse than WTR in men or BMI in women at predicting NIDDM. CONCLUSIONS-- Measurements such as waist circumference, WTR, weight, and BMI may be useful as more complicated measurements, such as PBF by bioelectrical resistance, for identifying groups of individuals whose body habitus places them at high risk of developing NIDDM.

Neuroendocrine and behavioural responses to hyperosmolality in rats with lesions of the lateral hypothalamus made by N-methyl-D-aspartate.

Excitotoxic lesions of rat lateral hypothalamus produce impairments in eating and drinking, but not motor deficits. However, it has not been established what causes these eating and drinking impairments. In the present experiments, drinking, plasma osmolality and arginine-vasopressin concentration were measured in lateral hypothalamic-lesioned and control rats following systemic injection of hypertonic saline. In response to hyperosmolality, N-methyl-D-aspartate-lesioned rats drank significantly less than controls but showed normal increases in plasma osmolality and arginine-vasopressin concentration. This dissociation of neuroendocrine and behavioural responses suggests that the impairment of rats with excitotoxic lesions of the lateral hypothalamus is unrelated to physiological (as opposed to behavioural) mechanisms of homeostasis.