The interleukin-1 type I receptor is expressed in human hypothalamus.

Several lines of evidence suggest that interleukin-1 (IL-1) acts directly on the central nervous system, probably within the hypothalamus, causing effects such as fever, activation of the immune response and sickness behaviour. IL-1 has also been shown to be involved in the aetiology of several neuronal diseases, including neurodegeneration, stroke and Alzheimer's disease. However, the question as to whether the full-length type I IL-1 receptor (IL-1RI) is expressed in the human hypothalamus has yet to be addressed. Using the polymerase chain reaction, we cloned a full-length cDNA encoding the human hypothalamic IL-1RI from human hypothalamic cDNA. The DNA sequence of the human hypothalamic receptor was identical to that of the human fibroblast IL-1RI. The IL-1RI receptor protein was detected in astrocytes of normal human hypothalamic brain sections using immunocytochemical techniques. To ascertain that the cloned receptor was functional, Chinese hamster ovary (CHO) cells were transfected with a plasmid vector containing the IL-1RI coding region. IL-1RI-mediated-signal transduction was assessed by microphysiometry and activation of p38 MAP (mitogen-activated protein) kinase. We report the first demonstration that both the type I IL-1 transcript and the protein are expressed in the human hypothalamus. The receptor was expressed in a stable CHO cell line, providing a tool with which to embark on a thorough analysis of the signalling mechanisms mediated by IL-1 via this receptor.

Chorionic villus sampling utilization following reports of a possible association with fetal limb defects.

Prenatal diagnosis choices were reviewed in 473 women who presented for genetic counselling prior to 11 weeks' gestation for the indication of advanced maternal age. Group A consisted of 336 patients who were unaware of a possible association between chorionic villus sampling (CVS) and limb defects. Group B consisted of 137 patients who were provided this information. Fifty-one per cent of patients in group A and 45 per cent of patients in group B chose CVS. This difference was not significant by chi 2 analysis (P = 0.7). Patterns of prenatal diagnosis procedure utilization from 1987 to 1992 revealed a significant reduction in CVS utilization accompanied by a corresponding increase in amniocentesis after the association between CVS and limb defects was publicized. Referrals for CVS counselling also significantly declined. However, acceptance rates did not change for those patients who received genetic counselling. First-trimester genetic counselling, including a discussion regarding a possible association between CVS and limb defects, helps patients make informed decisions concerning prenatal diagnosis options, and, in our population, resulted in no change in CVS acceptance rates.

Knowledge of genetics among residents in obstetrics and gynecology.

A supervised genetics examination was administered to 76 obstetrics and gynecology (ob/gyn) residents from 15 different institutions in the Philadelphia area. The questions were specifically designed to be applicable to obstetrical practice. Overall, the mean score was 69% (range 32%-88%). Using the nonparametric Mann-Whitney rank sum test, we found that the 25 residents from institutions with an obstetrics-gynecology-genetics (OGG) program, coordinated by an obstetrician/gynecologist board certified in clinical genetics, had statistically significant higher scores than the remaining 51 residents from institutions without an OGG program (77% vs. 65%, respectively; P < .001). This study demonstrates that knowledge of genetics among residents in ob/gyn is deficient, especially among residents at institutions without OGG programs. Special efforts should be made to provide genetics education to these individuals. We propose that more obstetricians be encouraged to pursue postgraduate training in genetics in light of the rapid development of medical genetics; its application to prenatal screening, diagnosis, and counseling; the anticipated utilization of genetics services; and the need for educational initiatives geared toward ob/gyn patients.

Prevention of adverse clinical outcome by monitoring of cardiac transplant patients for murine monoclonal CD3 antibody (OKT3) sensitization.

We have previously reported that patients sensitized to murine monoclonal CD3 antibody (OKT3) and maintained on such therapy for induction of immunosuppression have a high mortality and/or allograft loss. In this follow-up study, we retrospectively reviewed all patients routinely and serially monitored by flow cytometry for plasma levels of OKT3 during a 21-month period beginning 1/90. A total of 112 patients were monitored during this period. We retrospectively tabulated the incidence of OKT3 sensitization, rejection pattern and impact on survival of withdrawal of OKT3 at the time of sensitization as compared with the previous study in which withdrawal was not done. Nine patients were excluded from analysis because of withdrawal for reasons other than sensitization: cytokine encephalopathy, infection, postoperative complications, or severe rejection. Twelve patients had OKT3 therapy aborted because of failure to achieve steady-state OKT3 levels or because of decline in levels while on therapy. These patients were thus defined as being sensitized to OKT3. No patient was aborted because of return of CD3 cells in the blood. Only one of the 12 patients sensitized to OKT3 died. Of 91 patients with steady-state OKT3 levels, 6 had high plasma levels (> 1000 ng/ml) and 6 had low plasma levels (< 500 ng/ml). None of these patients had OKT3 therapy aborted and all are alive. Twelve of these 91 patients had successful retreatment with OKT3 for refractory rejection, indicating that absence of sensitization on induction predicts safety of retreatment with OKT3. We also examined the frequency of associated human antimouse antibody (HAMA) production using the blocking assay modified from Jaffers and Mayes. Only the sensitized patients exhibited a significant association with HAMA production (6/7 tested, P = 0.05) Classification of the rejection pattern of the sensitized patients confirmed our previous results: eight of 12 had vascular rejection and 4/12 had mixed rejection. These patterns were prospectively determined. We conclude that serial monitoring of patients for plasma levels of OKT3 is an effective strategy to prevent adverse outcomes of induction with this agent.

cDNA cloning of human and rat brain myo-inositol monophosphatase. Expression and characterization of the human recombinant enzyme.

Inositol monophosphatase (EC 3.1.3.25) is a key enzyme in the phosphoinositide cell-signalling system. Its role is to provide inositol required for the resynthesis of phosphatidylinositol and polyphosphoinositides. It is the probable pharmacological target for lithium action in brain. Using probes derived from the bovine inositol monophosphatase cDNA we have isolated cDNA clones encoding the human and rat brain enzymes. The enzyme is highly conserved in all three species (79% identical). The coding region of the human cDNA was inserted into a bacterial expression vector. The expressed recombinant enzyme was purified and its biochemical properties examined. The human enzyme is very similar to the bovine enzyme.