Defects in neurofibromatosis 2 protein function can arise at multiple levels

Neurofibromatosis 2 (NF2) is an inherited cancer syndrome resulting from mutations in the NF2 tumor suppressor gene. Analysis of NF2 mutations has revealed some general genotype-phenotype correlations. Severe disease has been associated with mutations that produce a premature termination while more mild disease has been associated with missense mutations. Here, we provide experimental proof for these genotype-phenotype correlations by demonstrating that nonsense mutations fail to produce stable merlin protein while missense mutations result in the generation of merlin proteins defective in negative growth regulation. This inability to suppress cell growth may result from defects in the function of merlin at several levels, including failure to form an intramolecular complex. Based on these findings, we propose a model for merlin growth suppression that provides a framework for analyzing NF2 patient mutations and merlin function.      

Uterine myomata and outcome of assisted reproduction

The aim of this work was to study the effect of uterine myomata on the implantation rate and outcome in in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Among 406 patients, 51 (12.6%) were found to have uterine corporeal myomata. Twelve patients were excluded from the study as they had large myomata, submucous myomata or intramural myomata encroaching on the cavity. These patients were advised to have myomectomy before being enrolled in the IVF/ICSI programme. The remaining patients (n = 39) were sorted according to the number, site and size of the myomata as assessed by transvaginal sonography. Three patients had more than one myoma. Most of the myomata were subserous (72.7%) and the mean diameter of the myomata was 3.5 +/- 0.9 cm. A control group (n = 367) was chosen with normal uteri and no history of uterine reconstruction surgery. The mean age of myoma patients was 34.7 +/- 3.6 years as compared to 34.0 +/- 4.4 years in the control group. The age, period of infertility, body mass index, duration and number of human menopausal gonadotrophin ampoules needed for stimulation, oestradiol levels, number of oocytes retrieved and the fertilization rate were not significantly different in the myoma patients compared to the control group. Fifteen myoma patients (38.5%) subsequently showed one or more pregnancy sacs on ultrasonography of which three (20%) spontaneously aborted during the first trimester and two (13.3%) had preterm labour, as compared to 123 (33.5%), 19 (15.5%) and nine (7.3%) respectively, among the control group (P = 0.27, 0.33 and 0.21). In conclusion, uterine corporeal myomata, not encroaching on the cavity and <7 cm in mean diameter, do not affect the implantation or miscarriage rates in IVF or ICSI.      

Covariances of Mitogenic Responses in Leukaemic Blood Lymphocytes: a Functional Marker System for the Human B Lymphocyte Differentiation

Various polyclonal activating substances have been shown to stimulate human chronic lymphatic leukaemic (CLL) cells to undergo blast transformation, to divide and to secrete monoclonal immunglobulin. CLL cells from different patients show distinct response patterns to these ligands. We have statistically analysed these response patterns and found that responses to certain ligands demonstrate covariance; that is, a high response to one ligand is statistically associated with a high response to another ligand. A factor analysis of these data on the basis of responses of CLL cells from twenty-one patients and from the use of five different ligands in three different concentrations has shown that as few as two factors can account for as much as 63% of the total variance of these responses. On the assumption that these two factors were T-cell dependency of CLL responses and stage of maturity of the responding CLL cell, we have formulated a theory that explains the basis for this functional marker system for CLL cells. It is possible application to the characterization of individual CLL clones has been discussed.     

Comparative effects on the immune system of methotrexate and trimetrexate

Methotrexate (MTX) is an antimetabolite commonly used in the treatment of neoplastic disease, while trimetrexate (TMQ) is an investigational antifolate which is currently advocated as a potential alternative to MTX. The cytotoxic properties of antifolates to rapidly proliferating cells suggests that the immune system would be a significant and undesirable target for these drugs. We examined the comparative effects of these two chemotherapeutic agents on the murine immune system using in vivo and in vitro methods. Both drugs were potent suppressors of T-dependent antibody formation in vitro as well as in vivo. While TMQ appeared to be more immunosuppressive than MTX following in vitro addition of the drugs, the converse appeared to be true when dosing was performed in vivo. The drug induced suppression of T-dependent antibody formation was dose dependent for both antifolates. Lymphoproliferative studies demonstrated marked suppressive effects on LPS and PHA induced 3H-uridine and 3H-deoxyuridine incorporation following addition of both drugs in vitro suggesting effects on both RNA and thymidylate biosynthesis. Timed addition studies demonstrated a particularly susceptible time period (hours 24-48 after addition of the mitogen LPS) in stimulated lymphocytes with respect to inhibition of 3H-uridine incorporation. Following in vivo administration of either antifolate, natural killer cell activity was significantly decreased with no substantial differences between the two drugs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Identification of the membrane protein of porcine epidemic diarrhea virus

Sequence information on the genome of porcine epidemic diarrhea virus (PEDV) has only recently been determined. In contrast, very little is known about the viral proteins. In the present report we have identified the membrane glycoprotein (M) of PEDV by use of rabbit anti-peptide sera and transient expression of the cloned M gene in Vero cells and by expression in the baculovirus system. The native M protein of PEDV is incorporated into virions, is N-glycosylated, and migrates with a relative mobility (Mr) of 27 k in polyacrylamide gels. In contrast, the M protein synthesized by recombinant baculoviruses migrates with a Mr of 23 k, that is, with identical mobility as the deglycosylated product of PEDV. Thus, it appears that M protein specified by the recombinant baculovirus is poorly, if at all, glycosylated. Using monoclonal antibodies and rabbit antipeptide sera specific for the N and C termini of the M protein, we were able to show that a 19 k band detected in PEDV-infected cells but not in virions represented a fragment of M from which the C terminus had been cleaved off. Finally, by electron microscopy and immunogold labelling, the relative orientation of M within the virion envelope was determined as NexoCcyt. In conclusion, all of these data strongly support the hypothesis that PEDV should be classified with the group I coronaviruses.     

Cerebrospinal fluid virus antibodies. A diagnostic indicator for multiple sclerosis?

Specific antibody activities (antibody per weight unit IgG) of serum and CSF against a broad variety of viruses were compared in multiple sclerosis and certain inflammatory diseases of the central nervous system, e.g. neurosyphilis, as well as herpes simplex and zoster encephalitis. No "unspecific" antiviral activities within the CSF compartment were found in the non-MS diseases. The most frequent antibodies locally produced were directed against measles, rubella and zoster antigens. A diagnostic test with these three viruses would give positive results in about 80% of patients with MS. This finding is not as frequent as the oligoclonal pattern of the CSF gamma-globulins but would have a considerably greater diagnostic significance.     

A case for giving. Stressing its mission to care helps an inner-city hospital attract charitable donations

In the current economic environment, voluntary not-for-profit hospitals must rely increasingly on private philanthropy. At St. Vincent's Hospital and Medical Center, New York City, leaders in the Division of Development and Public Affairs have found that emphasizing the commitment to mission in all the hospital's fund-raising, public-relations, and marketing efforts is an effective way to attract philanthropic support. For more than a century, St. Vincent's has been actively engaged in efforts to raise funds to support its philanthropic projects. However, since the creation of a formal development office in the 1940s, organized fund-raising efforts have flourished. And the inclusion of the hospital's development, public relations, and marketing departments in the same division in the 1980s further enhanced its philanthropic projects. The coordination of these departments' efforts has made it possible for St. Vincent's to highlight its commitment to mission in all of its communications, from letters soliciting funds from potential donors to paid advertisements in the New York Times. And the response to these coordinated efforts has been a significant increase in charitable donations.     

Diazepam metabolism in human foetal and adult liver

Summary Diazepam was metabolized by human foetal liver microsomes to N-desmethyldiazepam and N-methyloxazepam as early as the 13th week of gestation. The metabolic activity was lower than that of microsomes from adult human liver. Diazepam was shown mainly to be hydroxylated to N-methyloxazepam at substrate concentrations higher than 0.1 mM. Diazepam levels above 1.0 mM were inhibitory to the overall metabolic reaction. SKF 525-A inhibited diazepam metabolism by foetal liver microsomes at a concentration of 0.1 mM. The addition of diazepam to foetal and adult human liver microsomes resulted in a type II spectral change. Its inhibition by carbon monoxide indicated that biotransformation of diazepam was performed by the cytochrome P-450-linked mono-oxygenase system.     

Awareness of breast cancer incidence and risk factors among healthy women.

The efficacy of early breast cancer detection programmes seems to be mainly influenced by the awareness of breast cancer in general among healthy women. This study aimed to provide information about women's understanding of breast cancer incidence and risk of disease. Based on a newly developed questionnaire 2108 healthy women were asked about their knowledge and perceptions in relation to breast cancer incidence, risk factors, risk perception and level of concern. Of these women 78.8% were well aware of breast cancer in general terms. However, there were major aspects such as incidence or risk factors that were poorly understood. Only one-third correctly estimated the incidence of breast cancer; 95% understood breast cancer in the familial history as a risk factor, but only 57% understood the age risk; 37.1% of women perceived hormonal contraceptives and 35.9% hormonal replacement therapy as risk factors of breast cancer. The latter estimation was significantly higher in women above 40 years. Recommendations for the improvement of cancer prevention programmes include targeting understanding of lifetime risk of breast cancer, age as a risk factor, survival from breast cancer or hormonal factors. There is a need to separately address the perceptions of women depending on age, social status and educational levels.     

Right-hemisphere dominance for the processing of sound-source lateralization.

Cortical processing of change in direction of a perceived sound source was investigated in 12 human subjects using whole-head magnetoencephalography. The German word "da" was presented either with or without 0.7 msec interaural time delays to create the impression of right- or left-lateralized or midline sources, respectively. Midline stimuli served as standards, and lateralized stimuli served as deviants in a mismatch paradigm. Two symmetrically linked dipoles fitted to the mismatch fields showed stronger moments in the hemisphere contralateral to the side of the deviant. The right dipole displayed equal latencies to both left and right deviants, whereas left dipole latencies were longer for ipsilateral than contralateral deviants. Frequency analysis between 20-70 Hz and statistical probability mapping revealed increased induced gamma-band activity at 53+/-2.5 Hz to both types of deviants. Right deviants elicited spectral amplitude enhancements in this frequency range, peaking at latencies of 160 and 240 msec. These effects were localized bilaterally over the angular gyri and posterior temporal regions. Coherence analysis suggested the existence of two separate interhemispheric networks. For left-lateralized deviants, both spectral amplitude enhancements at 110 and 220 msec and coherence increases were restricted to the right hemisphere. In conclusion, both mismatch dipole latencies at the supratemporal plane and gamma-band activity in posterior parietotemporal areas suggested a right hemisphere engagement in the processing of bidirectional sound-source shifts. In contrast, left-hemisphere regions responded predominantly to contralateral events. These findings may help to elucidate phenomena such as unilateral auditory neglect.