Cost-effectiveness of gamete intrafallopian transfer in comparison with induction of ovulation with gonadotropins in the treatment of female infertility: a clinical trial.

OBJECTIVE: To compare the cost-effectiveness of gamete intrafallopian transfer (GIFT) with that of conventional infertility treatment in couples with female infertility, excluding tubal factors. DESIGN: Patients were randomly divided in two groups: receiving GIFT or conventional infertility treatment. For a period of 2 years, GIFT was compared with conventional infertility treatment in couples with endometriosis, anovulation, idiopathic infertility, cervical mucus factor, female immunologic factor, or multifactorial causes of infertility in a randomized clinical trial. SETTING: The study was performed in the Unit for Human Reproduction, Department of Obstetrics and Gynaecology, Faculty of Medicine, University of the Orange Free State, Bloemfontein, Republic of South Africa. PATIENTS: One hundred seventy-four successive couples with female infertility were selected for the study. All couples were from the higher socioeconomic bracket. INTERVENTIONS: One group received GIFT and the other received conventional infertility treatment consisting of induction of ovulation with gonadotropins followed by intrauterine artificial insemination or normal intercourse. MAIN OUTCOME MEASURES: The results were stratified according to the specific cause of infertility. Outcome was measured by the success rate per treatment cycle, as well as the cost per pregnancy. RESULTS: Overall, GIFT proved to be successful in 26.7% of treatment cycles compared with 9.7% with conventional therapy. CONCLUSIONS: After careful analysis, the authors came to the conclusion that GIFT is more cost-effective than conventional infertility treatment in patients with endometriosis and anovulation. In patients with idiopathic infertility, immunologic infertility, a cervical mucus factor, and multifactorial infertility, induction of ovulation followed by intrauterine artificial insemination or normal intercourse proved to be more cost-effective.     

Hemodynamics is a key epigenetic factor in development of the cardiac conduction system

The His-Purkinje system (HPS) is a network of conduction cells responsible for coordinating the contraction of the ventricles. Earlier studies using bipolar electrodes indicated that the functional maturation of the HPS in the chick embryo is marked by a topological shift in the sequence of activation of the ventricle. Namely, at around the completion of septation, an immature base-to-apex sequence of ventricular activation was reported to convert to the apex-to-base pattern characteristic of the mature heart. Previously, we have proposed that hemodynamics and/or mechanical conditioning may be key epigenetic factors in development of the HPS. We thus hypothesized that the timing of the topological shift marking maturation of the conduction system is sensitive to variation in hemodynamic load. Spatiotemporal patterns of ventricular activation (as revealed by high-speed imaging of fluorescent voltage-sensitive dye) were mapped in chick hearts over normal development, and following procedures previously characterized as causing increased (conotruncal banding, CTB) or reduced (left atrial ligation, LAL) hemodynamic loading of the embryonic heart. The results revealed that the timing of the shift to mature activation displays striking plasticity. CTB led to precocious emergence of mature HPS function relative to controls whereas LAL was associated with delayed conversion to apical initiation. The results from our study indicate a critical role for biophysical factors in differentiation of specialized cardiac tissues and provide the basis of a new model for studies of the molecular mechanisms involved in induction and patterning of the HPS in vivo.     

Distinct spatial and temporal distributions of aggrecan and versican in the embryonic chick heart

Although chondroitin sulfate proteoglycans (CSPGs) are major components of the embryonic extracellular matrix, little attention has been paid to specific CSPGs in early heart development, in part because appropriate antibodies were not available. Therefore we prepared specific polyclonal antibodies against chicken aggrecan, versican, neurocan, and phosphacan. Western blotting and immunohistochemical studies revealed the presence of aggrecan and versican in stages 12-21 chicken embryo hearts in distinctive spatial and temporal patterns. Because this is the first demonstration of aggrecan in heart tissue, we further used RT-PCR to confirm that aggrecan is expressed in the heart and in situ hybridization to confirm the pattern of expression determined using antibodies. Versican is found in the myocardium and the myocardial basement membrane. In contrast, aggrecan is specifically colocalized with several groups of migrating cells including endocardial cushion tissue cells, epicardial cells, a mesenchymal cell population in the outflow tract that may be of neural crest origin, and a mesenchymal cell population in the inflow tract. The combined observations indicate that versican and aggrecan are expressed in unique patterns and suggest that they play very different roles in development.     

The 2000 Burkitt lymphoma trial in Malawi

BACKGROUND: We previously reported 57% 12-month event free survival (EFS) in Malawian children with stage I to III Burkitt lymphoma (BL) with an intermediate dose chemotherapy protocol lasting 77 days. This protocol was shortened to 42 days and evaluated in children with stage I to IV disease for EFS and toxicity. METHODS: All Malawian children admitted to Queen Elizabeth Central Hospital, from 03/08/2000 to 12/03/2002 with confirmed BL were eligible. A fine needle aspirate, bone marrow aspirate, cerebrospinal fluid cytology, haemoglobin (Hb), white cell count (WCC), malaria smear, ELISA for HIV, and abdominal ultrasound were performed routinely. Murphy staging was used. The first dose of chemotherapy (COP1) consisted of 300 mg cyclophosphamide (CPM), 1 mg vincristine, and 60 mg prednisone given on day 1 and followed by COP2 on day 8 (only for patients with larger tumour volumes, stage III or IV disease). The vincristine dose in COP2 was 2 mg. COMP1 and 2 given on days 22 and 36 consisted of 500 mg CPM, 2 mg vincristine, 60 mg prednisone, and 2 g methotrexate. All doses were calculated per body surface area. Intrathecal methotrexate and hydrocortisone were given with COP1 and 2. RESULTS: Forty-two patients, 30 boys and 12 girls median ages 6 and 7.5 years, respectively, had Murphy stage I(n5), II(n8), III(n21), and IV(n8) disease. The face was involved in 74%, abdomen in 55%, bone marrow in 14%, kidneys in 24%, and 12% had paraplegia. Fourteen children died during or shortly after completion of chemotherapy. Three of these were disease related. Twelve patients suffered a local relapse after 57-328 days, and one a CNS relapse at 76 days. The projected EFS at 12 months is 50% in stage I, 50% in stage II, 24% in stage III, 25% in stage IV, and 33% for all patients. The cumulative mean dose of CPM was 62 mg/kg in survivors and 64 mg/kg in children who relapsed. One third of patients experienced significant marrow suppression, and infections after COMP1. CONCLUSIONS: Thirty-three percent of children are in first remission at 12 months. The morbidity and mortality of treatment was high. The high relapse rate in all stages may be due to the low cumulative dose of CPM.     

Cortical amaurosis and status epilepticus with acute porphyria

The most common neurologic manifestations of acute intermittent porphyria (AIP) are autonomic visceral neuropathy, peripheral motor neuropathy, and CNS dysfunctions including seizures and neuropsychiatric disturbances. In rare instances, however, AIP patients have presented with acute cortical blindness. We present a 20-year-old woman who suffered her first attack of AIP. Following 1 week of abdominal pain, she was transferred from a surgical department because of sudden visual loss and deterioration of consciousness. On admission, she developed several generalized seizures. Magnetic resonance imaging showed bilateral DWI lesions occipitally and in the left anterior circulation. Cerebrospinal fluid, MR angiography, and duplex ultrasound were normal. On the following day, sedation and intubation became necessary because of a generalized status epilepticus. Analysis of porphyrinogens in blood, urine and stool showed significantly elevated values. Intravenous therapy with h?m-arginate was initiated and antiepileptic therapy was changed to gagabentine. Under this therapeutical regime she remained stable and extubation was possible 48 h later.     

Partial rescue of neonatal lethality of Dhcr7 null mice by a nestin promoter-driven DHCR7 transgene expression

In humans, genetic disorders affecting post-squalene cholesterol biosynthesis result in a variety of dysmorphology syndromes. One key feature of all of these is the presence of mental retardation and another is the lack of a robust genotype-phenotype correlation. Knockout mice defective in the 3beta hydroxysterol Delta7 reductase (Dhcr7), a model for the most common of such disorders in humans, the Smith-Lemli-Opitz syndrome, all die within 24 h of birth. The cause of this postnatal mortality in these mice has not been fully established. In the present study, we tested the hypothesis that CNS dysfunction was a major cause of this lethality and investigated whether transgenic expression of normal human DHCR7 in neuronal tissues could rescue this neonatal lethality. Transgenic mice, expressing DHCR7 driven by murine nestin promoter, were bred onto Dhcr7 knock-out (Dhcr7(-1-)) background and resulted in a partial rescue of neonatal lethality in 11 of 91 (12%) of transgene-positive Dhcr7(-1-) pups. Despite biochemical analyses that showed continued profound cholesterol deficiency in brain, rescued animals survived between 3 and 17 days. Thus, one important conclusion to be drawn is that defects in CNS in Dhcr7 knockout mice may contribute to the early lethality. Another conclusion is that even small and subtle changes in the brain sterol metabolism were sufficient to enable rescue. These data also provide important clues as to the cause of the variable expressivity seen in SLOS.     

Uterine artery embolisation for symptomatic fibroids: the effect of the large uterus on outcome

Objective   The aim of this study was to evaluate the efficacy of uterine artery embolisation (UAE) in myomatous uteri larger than 24 week's gestation (780 cm³).
Design   Prospective case contro study.
Setting   Universitas Hospital, University of the Free State, Bloemfontein, South Africa.
Population   Sixty-one women, who underwent UAE, were included in the study. The study group comprised of 12 women with uteri ≥780 cm³ and the control group 49 women with uteri <780 cm³.
Methods   UAE was performed and the difference in outcome for the two groups was determined at 12 months.
Main outcome measure   Symptomatic improvement with embolisation of the large uterus.
Results   Reduction of dysmenorrhoea, menorrhagia and pressure effects was similar for both groups. The median reduction in uterine volume (pre- to post-embolisation) was 188 cm³ (range 28–2038 cm³) with a 95% CI for the median difference for paired data of 146.5 and 236. Only 66% of the study group had, however, a reduction in volume to <780 cm³. The complication rates were similar for the two groups with regards to post-embolisation syndrome, fibroid slough, haematoma formation, infection, hysterectomy and failure to embolise. Satisfaction was similar between the two groups, with 91% of women satisfied with the procedure.
Conclusion   The large uterus does not decrease UAE's efficacy. Although 33.3% of the study group still had a uterus of ≥780 cm³, symptom reduction was still similar for both groups. Women may thus still be left with a large uterine volume but without symptoms. This must be taken into consideration when counselling women with an extremely large uterus for UAE.