Low dose recombinant FSH treatment may reduce multiple gestations caused by controlled ovarian hyperstimulation and intrauterine insemination

OBJECTIVE: To evaluate the rate of multiple pregnancies in intrauterine insemination cycles stimulated with a minimal dose of recombinant follicle stimulating hormone (rec-FSH). DESIGN: Retrospective study. SETTING: University Medical Center. POPULATION: A total of 1256 patients underwent 3219 consequent intrauterine insemination cycles with minimal ovarian stimulation. METHODS: Patients received 50 or 75 IU of rec-FSH from day four to day seven. The dose was adjusted according to oestradiol (E(2)) levels in order to achieve a maximum of two follicles on the day of hCG administration. MAIN OUTCOME MEASURES: Peak E(2) levels, the number of follicles >15 mm and pregnancy rates were calculated. The predictive value of E(2) levels for multiple gestations was also estimated. RESULTS: Of 3219 cycles, 334 resulted in pregnancies (10%). Of these, 238 (91%) were singletons, 28 (8%) twins and 1 (0.3%) was a triplet. The cumulative overall pregnancy rate was 43%. Patients over 40 years old had a significantly lower pregnancy rate per cycle and overall live birth rate (P < 0.05). Most pregnancies (83%) occurred during the first three cycles. Pregnancy rates per cycle varied from 8% for tubal factor to 14% for anovulation infertility. CONCLUSIONS: Minimal FSH stimulation in intrauterine insemination cycles may reduce the rates of twins and high order multiple pregnancies without affecting overall pregnancy rates.     

Malaysian siblings with friedreich ataxia and chorea: a novel deletion in the frataxin gene

BACKGROUND: Friedrich ataxia (FRDA1) is most often the result of a homozygous GAA repeat expansion in the first intron of the frataxin gene (FRDA gene). This condition is seen in individuals of European, North African, Middle Eastern and Indian descent and has not been reported in Southeast Asian populations. Approximately 4% of FRDA1 patients are compound heterozygotes. These patients have a GAA expansion on one allele and a point mutation on the other and have been reported to have an atypical phenotype. OBJECTIVE: To describe a novel dinucleotide deletion in the FRDA gene in two Malaysian siblings with FRDA1. SETTING: Tertiary referral university hospital setting. PATIENTS AND METHODS: A previously healthy 10-year-old Malaysian boy, presented with fever, lethargy, headaches, dysarthria, dysphagia, vertigo and ataxia which developed over a one week period. His neurological exam revealed evidence of dysarthria and ataxia, mild generalized weakness and choreoform movements of the tongue and hands. His reflexes were absent and Babinski sign was present bilaterally. A nine-year-old sister was found to have mild ataxia but was otherwise neurologically intact. RESULTS: Molecular genetic studies demonstrated that both siblings were compound heterozygotes with a GAA expansion on one allele and a novel dinucleotide deletion on the other allele. CONCLUSIONS: We describe a novel dinucleotide deletion in the first exon of the FRDA gene in two siblings with FRDA1. Additionally this is the first report of FRDA1 occurring in a family of southeast Asian descent, it demonstrates intrafamilial phenotypic variability, and confirms that atypical phenotypes are associated with compound heterozygosity.     

Huntington's Disease-like 2 (HDL2) in North America and Japan

Huntington's Disease-like 2 (HDL2) is a progressive, autosomal dominant, neurodegenerative disorder with marked clinical and pathological similarities to Huntington's disease (HD). The causal mutation is a CTG/CAG expansion mutation on chromosome 16q24.3, in a variably spliced exon of junctophilin-3. The frequency of HDL2 was determined in nine independent series of patients referred for HD testing or selected for the presence of an HD-like phenotype in North America or Japan. The repeat length, ancestry, and age of onset of all North American HDL2 cases were determined. The results show that HDL2 is very rare, with a frequency of 0 to 15% among patients in the nine case series with an HD-like presentation who do not have the HD mutation. HDL2 is predominantly, and perhaps exclusively, found in individuals of African ancestry. Repeat expansions ranged from 44 to 57 triplets, with length instability in maternal transmission detected in a repeat of r2=0.29, p=0.0098). The results further support the evidence that the repeat expansion at the chromosome 16q24.3 locus is the direct cause of HDL2 and provide preliminary guidelines for the genetic testing of patients with an HD-like phenotype.     

Increased liability of tramadol–warfarin interaction in individuals with mutations in the cytochrome<Emphasis Type="Italic"> P</Emphasis><Subscript>450</Subscript> 2D6 gene

Objective This study aimed to investigate the importance of cytochrome P₄₅₀ enzymes for the reported interaction between tramadol and warfarin.Materials and methods Cases of suspected interaction between tramadol and warfarin resulting in International Normalised Ratios increases that were reported to the Swedish Adverse Drug Reactions Advisory Committee until March 2003 were included. Ten cases had been genotyped for known polymorphisms of CYP2D6, CYP2C9 and CYP2C19.Results Seven of ten patients carried defective CYP2D6 alleles (population prevalence 42.2%) (one-sided binomial test, P=0.07). A further patient received concomitant drug treatments that may have resulted in CYP2D6 enzyme inhibition.Conclusion The liability to an interaction between tramadol and warfarin may be related to the CYP2D6 activity.     

Intra- and interlaboratory calibration of the DR CALUX bioassay for the analysis of dioxins and dioxin-like chemicals in sediments

In the Fourth National Policy Document on Water Management in The Netherlands, it is defined that in 2003, in addition to the assessment of chemical substances, special guidelines for the assessment of dredged material should be recorded. The assessment of dredged material is based on integrated chemical and biological effect measurements. Among others, the DR CALUX (dioxin responsive-chemically activated luciferase expression) bioassay has tentatively been recommended for inclusion in the dredged material assessment. To ensure the reliability of this bioassay, an intra- and interlaboratory validation study, or ring test, was performed, organized by the Dutch National Institute for Coastal and Marine Management (RIKZ) in cooperation with BioDetection Systems BV (BDS). The intralaboratory repeatability and reproducibility and the limit of detection (LOD) and quantification (LOQ) of the DR CALUX bioassay were determined by analyzing sediment extracts and dimethyl sulfoxide (DMSO) blanks. The highest observed repeatability was found to be 24.1%, whereas the highest observed reproducibility was calculated to be 19.9%. Based on the obtained results, the LOD and LOQ to be applied for the bioassay are 0.3 and 1.0 pM, respectively. The interlaboratory calibration study was divided into three phases, starting with analyzing pure chemicals. During the second phase, sediment extracts were analyzed, whereas in the third phase, whole sediments had to be extracted, cleaned, and analyzed. The average interlaboratory repeatability increased from 14.6% for the analysis of pure compound to 26.1% for the analysis of whole matrix. A similar increase in reproducibility with increasing complexity of handlings was observed with the interlaboratory reproducibility of 6.5% for pure compound and 27.9% for whole matrix. The results of this study are intended as a starting point for implementing the integrated chemical-biological assessment strategy and for systematic monitoring of dredged materials and related materials in the coming years.     

Percentile curves of serum estradiol levels during controlled ovarian stimulation in 905 cycles stimulated with recombinant FSH show that high estradiol is not detrimental to IVF outcome

BACKGROUND: High, normal and poor responders are usually defined by reference to subjectively selected estradiol E2 levels at days 4-6 and the day of hCG administration (d-hCG). The purpose of this study was to use E2 percentile curves from day 5 until d-hCG to determine high, normal and poor responders, and to predict IVF outcome. METHODS: In this retrospective study, 762 patients underwent 905 cycles with a GnRH agonist/recombinant FSH short protocol. They were divided into three groups according to their age. Percentile E2 curves according to E2 levels were plotted. High responders were those patients with E2 levels above the 90th percentile, normal responders had E2 between the 10th and 90th percentiles, and poor responders had E2 below the 10th percentile. RESULTS: IVF outcome, expressed as number of oocytes, total embryos obtained and number of high grade embryos, was significantly better for patients with E2 above the 90th percentile at d-hCG for the three age groups and at day 5 for group A (<35 years). Pregnancy rates were higher for high responders, but the difference did not reach statistical significance. CONCLUSIONS: Percentile curves can be useful in controlled ovarian stimulation cycles to define high, normal and poor responders, and also to predict IVF outcome.     

The 2-year costs and effects of a public health nursing case management intervention on mood-disordered single parents on social assistance

Rationale, aims and objectives This randomized controlled trial was designed to evaluate the 2‐year costs and effects of a proactive, public health nursing case management approach compared with a self‐directed approach for 129 single parents (98% were mothers) on social assistance in a Canadian setting. A total of 43% of these parents had a major depressive disorder and 38% had two or three other health conditions at baseline. Methods Study participants were recruited over a 12 month period and randomized into two groups: one receiving proactive public health nursing and one which did not. Results At 2 years, 69 single parents with 123 children receiving proactive public health nursing (compared with 60 parents with 91 children who did not receive public health nursing services) showed a slightly greater reduction in dysthymia and slightly higher social adjustment. There was no difference between the public health and control groups in total per parent annual cost of health and support services. However, costs were averted due to a 12% difference in non‐use of social assistance in the previous 12 months for parents in the public health nursing group. This translates into an annual cost saving of $240 000 (Canadian) of costs averted within 1 year for every 100 parents. Conclusions In the context of a system of national health and social insurance, this study supports the fact that it is no more costly to proactively service this population of parents on social assistance.     

Optimizing a portfolio of health care programs in the presence of uncertainty and constrained resources

Much research has been devoted to handling uncertainty in cost-effectiveness analysis. The current literature suggests summarizing uncertainty in cost-effectiveness analysis using acceptability curves or net health benefits. These approaches, however, focus only on uncertainty associated with costs and effects of the programs under consideration. In the real world, most decision-makers have to fund a portfolio of health care programs. Therefore, a more comprehensive approach would include in the analysis the uncertainty of costs and effects of all programs supported by the fixed budget. This paper extends the decision rule described by Birch and Gafni (J. Health Econ. 11(3) (1992) 279) within the context of a portfolio of programs when costs and effects are uncertain and resources constrained.     

Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes

Type 2 diabetes is characterized by impaired insulin secretion. Some but not all studies suggest that a decrease in beta-cell mass contributes to this. We examined pancreatic tissue from 124 autopsies: 91 obese cases (BMI >27 kg/m(2); 41 with type 2 diabetes, 15 with impaired fasting glucose [IFG], and 35 nondiabetic subjects) and 33 lean cases (BMI <25 kg/m(2); 16 type 2 diabetic and 17 nondiabetic subjects). We measured relative beta-cell volume, frequency of beta-cell apoptosis and replication, and new islet formation from exocrine ducts (neogenesis). Relative beta-cell volume was increased in obese versus lean nondiabetic cases (P = 0.05) through the mechanism of increased neogenesis (P < 0.05). Obese humans with IFG and type 2 diabetes had a 40% (P < 0.05) and 63% (P < 0.01) deficit and lean cases of type 2 diabetes had a 41% deficit (P < 0.05) in relative beta-cell volume compared with nondiabetic obese and lean cases, respectively. The frequency of beta-cell replication was very low in all cases and no different among groups. Neogenesis, while increased with obesity, was comparable in obese type 2 diabetic, IFG, or nondiabetic subjects and in lean type 2 diabetic or nondiabetic subjects. However, the frequency of beta-cell apoptosis was increased 10-fold in lean and 3-fold in obese cases of type 2 diabetes compared with their respective nondiabetic control group (P < 0.05). We conclude that beta-cell mass is decreased in type 2 diabetes and that the mechanism underlying this is increased beta-cell apoptosis. Since the major defect leading to a decrease in beta-cell mass in type 2 diabetes is increased apoptosis, while new islet formation and beta-cell replication are normal, therapeutic approaches designed to arrest apoptosis could be a significant new development in the management of type 2 diabetes, because this approach might actually reverse the disease to a degree rather than just palliate glycemia.