A 3 year retrospective review of intrauterine insemination, using cryopreserved donor spermatozoa and cycle monitoring by urinary or serum luteinizing hormone measurements

Insemination with donor spermatozoa is an integral part of infertility treatment. For the last 3 years in our unit, intrauterine insemination with donor spermatozoa (IUID) has been used in preference to vaginal insemination. In this retrospective study, patients were offered an initial course of five single intrauterine inseminations with cryopreserved donor spermatozoa and treatment was then reviewed. A total of 389 patients received 1465 inseminations. In all, 1119 cycles were monitored using luteinizing hormone serum analyses and 346 cycles using the urine home test kits. The clinical pregnancy rate per insemination for the cycles monitored by the serum assay was 18.0% (202/1119) compared with the urine cycles (13.7%, 46/346) (P <05). The pregnancy loss rate was not significantly different (14.4%, 29/202 and 21.7%, 10/46) (serum and urine cycles respectively). The viable clinical pregnancy rate was significantly higher (P <03) for the serum cycles than for the cycles using the urinary monitoring (15.5%, 173/1119 and 10.4%, 36/346 respectively). The cycles monitored by serum assay had a significantly higher cumulative viable clinical pregnancy rate (P <0001) of 70.2% after nine inseminations compared with the urine monitored cycles of 54.8%. The majority of patients opted for the serum cycles, with a minority self-selecting the urine cycles mainly for travelling convenience. The explanation for the significant differences between the viable clinical pregnancy rates per insemination and the cumulative viable clinical pregnancy rates may be due to the sensitivity of the urine home test kit or the patients' interpretation of the result.      

Population differences in cardiovascular reactivity to the cold pressor test

The interaction of race and climatic adaptation on patterns of cardiovascular reactivity among young adult males was examined. Malay and Chinese subjects living in a tropical climate in the Orient and Caucasians living in a sub-tropical climate in North America were investigated. The cold pressor test with hand immersion in cold water was used as the stressor. Systolic and diastolic blood pressures, cardiac frequency, cardiac output, and stroke volume were measured. The results provided limited evidence for absence of differences in cardiac reactivity among racial groups and for greater vascular reactivity in the Caucasians. Cold immersion also elicited differential responses which could be partially attributed to differences in acclimatizations status. © 1995 Wiley-Liss, Inc.     

Sleep deprivation effects on growth factor expression in neonatal rats: a potential role for BDNF in the mediation of delta power

The sleeping brain differs from the waking brain in its electrophysiological and molecular properties, including the expression of growth factors and immediate early genes (IEG). Sleep architecture and homeostatic regulation of sleep in neonates is distinct from that of adults. Hence, the present study addressed the question whether the unique homeostatic response to sleep deprivation in neonates is reflected in mRNA expression of the IEG cFos, brain-derived nerve growth factor (BDNF), and basic fibroblast growth factor (FGF2) in the cortex. As sleep deprivation is stressful to developing rats, we also investigated whether the increased levels of corticosterone would affect the expression of growth factors in the hippocampus, known to be sensitive to glucocorticoid levels. At postnatal days 16, 20, and 24, rats were subjected to sleep deprivation, maternal separation without sleep deprivation, sleep deprivation with 2 h recovery sleep, or no intervention. mRNA expression was quantified in the cortex and hippocampus. cFos was increased after sleep deprivation and was similar to control level after 2 h recovery sleep irrespective of age or brain region. BDNF was increased by sleep deprivation in the cortex at P20 and P24 and only at P24 in the hippocampus. FGF2 increased during recovery sleep at all ages in both brain regions. We conclude that cortical BDNF expression reflects the onset of adult sleep-homeostatic response, whereas the profile of expression of both growth factors suggests a trophic effect of mild sleep deprivation.     

Effect of subjective perspective taking during simulation of action: a PET investigation of agency

Perspective taking is an essential component in the mechanisms that account for intersubjectivity and agency. Mental simulation of action can be used as a natural protocol to explore the cognitive and neural processing involved in agency. Here we took PET measurements while subjects simulated actions with either a first-person or a third-person perspective. Both conditions were associated with common activation in the SMA, the precentral gyrus, the precuneus and the MT/V5 complex. When compared to the first-person perspective, the third-person perspective recruited right inferior parietal, precuneus, posterior cingulate and frontopolar cortex. The opposite contrast revealed activation in left inferior parietal and somatosensory cortex. We suggest that the right inferior parietal, precuneus and somatosensory cortex are specifically involved in distinguishing self-produced actions from those generated by others.     

Striated intramural gallbladder lucencies on US studies: predictors of acute cholecystitis

Ultrasound scans of 51 consecutive patients with gallbladder wall thickening were reviewed, and specific sonographic features were correlated with surgical and clinical follow-up. Two patterns of thickening were identified as specific indicators of the presence or absence of acute cholecystitis. "Striated" wall thickening, consisting of several alternating, irregular, discontinuous, lucent and echogenic bands, was seen in eight of 13 patients (62%) with acute cholecystitis. This pattern was not encountered in any of the patients who did not have acute cholecystitis. Conversely, "three-layer" thickening, consisting of a single circumferential lucent zone between two relatively uniform echogenic layers, was seen in only one of 13 patients (8%) with acute cholecystitis but in 11 of 38 patients (29%) with other diagnoses. Other abnormalities, including the presence of intramural echogenic foci and wall irregularities, were more frequently seen in patients with acute cholecystitis but were not as helpful. Use of these features may suggest or help exclude a diagnosis of acute cholecystitis in those patients in whom the cause of gallbladder wall thickening is otherwise not apparent.     

A technique for eliminating allele specific amplification failure during DNA amplification of heterozygous cells for preimplantation diagnosis

Advances in techniques of molecular biology have made possible the amplification of specific genes from single cells. This has a major clinical application in preimplantation diagnosis of monogenic disorders. However, the incidence of allele specific amplification failure (allele drop out) in heterozygous single cells can lead to misdiagnosis and the transfer of affected embryos. Few studies have been done to investigate the actual cause of allele drop out, although some investigators have succeeded in reducing but not eliminating it. Here we report the efficiency of amplifying both alleles in heterozygous cells lysed according to two different protocols. A total of 177 heterozygous cells from carriers of cystic fibrosis (CF) and haemoglobin C (HbC) were lysed using two different lysis buffers. Interestingly none of the cells that were lysed with sodium dodecyl sulphate/proteinase K showed any example of allele specific amplification failure whereas in those lysed by KOH/dithiothreitol it was present in 17.6 and 4.7% of the CF and HbC cells respectively. Our results suggest that the phenomenon of allele specific amplification failure is at least in part dependent on the lysis buffer used.      

The economics of orphan drug policy in the US. Can the legislation be improved?

This review of the US Orphan Drug Act (ODA) 1983 outlines how the ODA is intended to stimulate orphan drug research and development of drugs for rare diseases. We also evaluate the effectiveness of the ODA in the past decade and provide recommendations for ODA improvements in the future. The economic incentives embedded in the ODA are presented in a simple economic model, in which a guarantee of market exclusivity plays a central role in encouraging firms to pursue the development of orphan products. Some evidence suggests that this provision has been a major impetus for the rise in orphan drug applications and designations in the last decade. Market exclusivity is the key incentive for orphan drug research, and should be retained. Concerns about a limited number of highly successful 'blockbuster' orphan drugs should be evaluated in terms of the useful economic incentives. In the future, exceptionally high profits could be limited by more precise evaluation of disease prevalence, elasticity of demand, and the other uses of orphan compounds. We further recommend an expansion of the ODA tax credits and research grants programme and targeting of 'priority' diseases. We conclude that the ODA has been a valuable legislative initiative, but it can be strengthened with some simple extensions of the current incentives that it contains.     

Hypotheses: Melatonin/steroid combination contraceptives will prevent breast cancer

Summary The use of the conventional combination oral contraceptives (containing ethinyl-estradiol and a progestin) is associated with reduced risk of ovarian and endometrial cancer. However, prolonged use of these pills before first term pregnancy apparently increases the risk of pre menopausal breast cancer. We propose that the pineal gland hormone melatonin, combined with a progestin, as a new and novel oral contraceptive combination might prevent breast cancer in long term users. This hypothesis is based on the assumption that women have a propensity to develop breast cancer which correlates with number of ovulatory cycles over their lifetime. In evolution, the phylogenetic point at which women became sensitive to breast cancer evolved at a transfer point of the mechanism of ovulation from seasonal ovulation, which is still common in many mammalian species, to the current human pattern of continuous ovulatory cycles. We suggest that melatonin/ovariansteroid contraceptive will restore the lost mechanism of endogenous anovulation, and thus, by preventing continuous epithelial breast cell proliferation, will reduce the risk of breast cancer in long-term users.     

Improved survival in young women with breast cancer

Background: Young age has been hypothesized to be an adverse prognostic factor for women with breast cancer. This association, based on historical data, may not reflect recent advances in breast cancer management. Methods: A retrospective study was conducted of all women age 30 or younger who underwent definitive operation at our institution for primary operable breast carcinoma during one of two consecutive 20-year periods (1950–1969 or 1970–1989). All cancers were restaged according to current staging criteria. Actuarial survival and recurrence-free survival rates from the two patient eras were compared with each other and with published statistics for older breast cancer patients. Results: Eligibility criteria were met by 81 women from the 1950–1969 era and 146 women from the 1970–1989 era. Histologic diagnoses, tumor sizes, incidence of axillary nodal metastases, number of positive nodes, and American Joint Committee on Cancer stage at presentation were similarly distributed in the two eras. Despite these similarities, improved survival (p=0.009) was observed in the later era. Local recurrences were also more common (p<0.05) in the later era in association with less extensive resections. These local recurrences had an adverse impact on recurrence-free survival in the later era, but no concomitant decrease in overall survival was observed. Node-positive patients who received chemotherapy demonstrated a trend toward improved survival (p=0.06) compared with node-positive patients who did not. Survival for patients in the later era was similar to that for older women as reported in other published series. Conclusions: The stage of presentation of breast cancer in women 30 years or younger appears unchanged from prior decades, but survival has improved in association with the use of less extensive surgical resections and the introduction of cytotoxic chemotherapy. With current treatment, primary operable breast cancer in young women appears to have a similar prognosis to breast cancer in older women.Results of this study were presented at the 47th Annual Cancer Symposium of The Society of Surgical Oncology, Houston, Texas, March 17–20, 1994, and was judged Best Clinical Paper in the Resident/Fellow Essay Contest.