Critical analysis of intravenous immunoglobulin therapy for recurrent miscarriage

Critical analysis of intravenous immunoglobulin therapy for recurrent miscarriage An alloimmune abnormality is believed to be the cause of recurrent miscarriage in couples in whom no other cause can be identified. Because of its immunosuppressive properties, intravenous immunoglobulin (IVIG) is used as a treatment for this disorder. The purpose of this study was to determine whether IVIG improves the chance of successful pregnancy in women with recurrent miscarriage by using individual patient data from efficacy trials. Detailed information on each patient enrolled in these trials was obtained to evaluate the efficacy of IVIG and investigate the effect of clinical variability on pregnancy outcome. Data from 125 patients in the IVIG group and 115 patients in the placebo group were available for analysis. Although the number of previous miscarriages and female age were both negative prognostic factors for successful outcome, there was no significant improvement in successful pregnancy or live birth rate with IVIG. Subgroup analyses indicated that timing of IVIG administration may be important. The results of the present study highlight the importance of stratification for known confounders, so that the role of IVIG can be evaluated in more detail. The collective evidence thus far indicates that IVIG does not have a therapeutic effect that is clinically meaningful.     

Conversion of highly malignant colon cancer from an aggressive to a controlled disease by oral administration of a metalloproteinase inhibitor

In this study, we describe the activity of CT1746, an orally-active synthetic MMP inhibitor that has a greater specificity for gelatinase A, gelatinase B and stromelysin than for interstitial collagenase and matrilysin, in a nude mouse model that better mimics the clinical development of human colon cancer. The model is constructed by surgical orthotopic implantation (SOI) of histologically-intact tissue of the metastatic human colon tumor cell line Co-3. Animals were gavaged with CT1746 twice a day at 100 mg/kg for 5 days after the SOI of Co-3 for 43 days. In this model CT1746 significantly prolonged the median survival time of the tumor-bearing animals from 51 to 78 days. Significant efficacy of CT1746 was observed on primary tumor growth (32% reduction in mean tumor area at day 36), total spread and metastasis (6/20 treated animals had no detectable spread and metastasis at autopsy compared to 100% incidence of secondaries in control groups). Efficacy of CT1746 could also be seen on reducing tumor spread and metastasis to individual organ sites such as the abdominal wall, cecum and lymph nodes compared to vehicle and untreated controls. We conclude that chronic administration of a peptidomimetic MMP inhibitor via the oral route is feasible and results in inhibition of solid tumor growth, spread and metastasis with increase in survival in this model of human cancer, thus converting aggressive cancer to a more controlled indolent disease.     

The faculty work plan and appraisal: its potential for faculty role development

This exploratory study was designed to begin analysis on the "Faculty Work Plan" and its potential for faculty role development in a university setting. The specific goals were: (1) to identify the degree of congruence between faculty work plans and the school goals; and (2) to determine the relationship between faculty work plan/school goal congruence, faculty productivity, potency, and job satisfaction. The sample was composed of 26 respondents, 26 to 50 years old, from a pool of 48 full-time faculty members affiliated with a school of nursing in a university setting. Likert-type rating scores were used to measure Faculty Work Plan-School Goal Congruence (FWP-SG), job satisfaction, productivity, and potency. Data analyses were focused on frequency distribution, group means, and Pearson Correlation Coefficients on selected pairs of variables. Interesting findings were revealed. A strong relationship was found between FWP-SG congruence and faculty productivity (r = .85; p = .000) and potency (r = .84; p = .000). Several recommendations were suggested.     

The detection of early breast cancer: three-year results from a diagnostic breast clinic

The initial results from a diagnostic breast clinic in which clinical examination, x-ray mammography and ultrasound are used to establish a diagnosis during a single patient-visit are described. In 3461 patient-visits, 82 histologically-proven breast cancers were detected. Fifty-two per cent of these cancers were 2 cm or less in diameter and 61% had no axillary lymph-node metastases. Fifteen cancers were impalpable lesions which were detected by mammography alone. The over-all malignant-to-benign biopsy ratio was 1:2.7; for impalpable tumours, this ratio was 1:3.9. The role of such a diagnostic breast clinic is discussed, and attention is drawn to a relatively low attendance of women in the "high-risk" age group of over 50 years of age.     

Catecholamine modulatory effects of nepicastat (RS-25560-197), a novel,potent and selective inhibitor of dopamine-β-hydroxylase

1. Inhibitory modulation of sympathetic nerve function may have a favourable impact on the progression of congestive heart failure. Nepicastat is a novel inhibitor of dopamine-β-hydroxylase, the enzyme which catalyses the conversion of dopamine to noradrenaline in sympathetic nerves. The in vitro pharmacology and in vivo catecholamine modulatory effects of nepicastat were investigated in the present study.
2. Nepicastat produced concentration-dependent inhibition of bovine (IC₅₀=8.5±0.8 nM) and human (IC₅₀=9.0±0.8  nM)dopamine-β-hydroxylase. The corresponding R-enantiomer (RS-25560-198) was approximately 2–3 fold less potent than nepicastat. Nepicastat had negligible affinity (>10 μM) for twelve other enzymes and thirteen neurotransmitter receptors.
3. Administration of nepicastat to spontaneously hypertensive rats (SHRs) (three consecutive doses of either 3, 10, 30 or 100 mg kg⁻¹, p.o.; 12 h apart) or beagle dogs (0.05, 0.5, 1.5 or 5 mg kg⁻¹, p.o.; b.i.d., for 5 days) produced dose-dependent decreases in noradrenaline content, increases in dopamine content and increases in dopamine/noradrenaline ratio in the artery (mesenteric or renal), left ventricle and cerebral cortex. At the highest dose studied, the decreases in tissue noradrenaline were 47%, 35% and 42% (in SHRs) and 88%, 91% and 96% (in dogs) in the artery, left ventricle and cerebral cortex, respectively. When tested at 30 mg kg⁻¹, p.o., in SHRs, nepicastat produced significantly greater changes in noradrenaline and dopamine content, as compared to the R-enantiomer (RS-25560-198), in the mesenteric artery and left ventricle.
4. Administration of nepicastat (2 mg kg⁻¹, b.i.d, p.o.) to beagle dogs for 15 days produced significant decreases in plasma concentrations of noradrenaline and increases in plasma concentrations of dopamine and dopamine/noradrenaline ratio. The peak reduction (52%) in plasma concentration of noradrenaline and the peak increase (646%) in plasma concentration of dopamine were observed on day-6 and day-7 of dosing, respectively.
5. The findings of this study suggest that nepicastat is a potent, selective and orally active inhibitor of dopamine-β-hydroxylase which produces gradual modulation of the sympathetic nervous system by inhibiting the biosynthesis of noradrenaline. This drug may, therefore, be of value in the treatment of cardiovascular disorders associated with over-activation of the sympathetic nervous system, such as congestive heart failure.

     

Lengthening extraocular muscle with autologous muscle transplants

Increasing extraocular muscle length by regenerative growth has been proposed as a potentially useful means of treating patients with paralytic or multiple re-operation strabismus. This study evaluates the viability and pattern of regeneration of fresh, autologous extraocular muscle and temporalis muscle transplants in the canine orbit. Bilateral grafts of either inferior oblique or temporalis muscle were sewn between host lateral rectus muscles and the globe. Grafts were biopsied and examined by light and electron microscopy at survival times to 56 days. Functional responses to abducens nucleus stimulation were examined in one extraocular muscle and one temporalis muscle graft at 15 weeks post-operatively. During the first week, both graft types were characterized by loss of pre-terminal nerve from neuromuscular junctions, muscle fiber necrosis that spared the central fibers, and inflammatory cell infiltrate. Myoblasts migrated into and fused within the existing basal laminae of degenerating fibers. By 14 days, grafts were populated by immature myofibers. Neuromuscular junctions were seen by 56 days, coinciding with muscle fiber differentiation as seen by enzyme histochemistry. Only two grafts failed to show regeneration. At 15 weeks survival, both types of grafts contracted in response to abducens nucleus stimulation. Free skeletal muscle grafts to extraocular muscle survive and mature with clear evidence of contractility by 15 weeks. These data suggest that muscle graft procedures could be useful in the management of certain types of strabismus where greater muscle length is needed.     

Comparison of Chinese and Western rifapentines and improvement of bioavailability by prior taking of various meals

Bioavailability was measured by rifapentine (RPE) serum concentrations and by the urinary ratio between RPE and creatinine, in specimens obtained 4-50 h after 600 mg RPE preceded by food. The bioavailabilities of RPEs manufactured in China and by a Western manufacturer were similar after a standard English breakfast, and serum concentrations were also similar to those obtained in an earlier Italian study following a complex meal. Although absorption of RPE was unsatisfactory after lipid-rich biscuits or shortbread, absorption after egges and toast was excellent and was nearly as good after a fast-food sandwich. The urinary measure of bioavailability at 26 h appeared as efficient as peak serum estimations at 6, 8 and 26 h. Fast-food sandwiches are being taken before RPE in a current clinical trial of Chinese RPE in Hong Kong.     

State mental health agency spending, 1985-1990

Major differences exist among states in the level of spending on mental health care, in the magnitude and direction of changes in those levels, and in the share of resources devoted to state hospital and community-based services. Using data collected by the National Association of State Mental Health Program Directors (NASMHPD) Research Institute, this article describes those differences and examines their relation to a set of state-level fiscal determinants of mental health spending. Levels of spending in 1990 and rates of change in those levels between 1985 and 1990 show virtually no correlation. Changes in spending between 1985 and 1990 are decomposed into several components. States with high growth tend to have high growth in tax capacity and high growth in mental health spending as a share of health and welfare spending.