P-cadherin expression is associated with high-grade ductal carcinoma in situ of the breast

Cadherins are calcium-dependent cell-cell adhesion glycoproteins, separated into several subclasses with distinct adhesive specificities and tissue distribution, which play an important role in many cellular events. We analyse the expression of E-, N- and P-cadherin in a series of ductal carcinoma in situ (DCIS) of the breast, since this disease represents a heterogeneous group, with different risks of progression to invasive breast carcinoma. We also studied the correlation between cadherin expression and DCIS classification systems, namely the Van Nuys and the Holland et al. classification, this latter based on cytonuclear differentiation and cell polarity. Our results showed that, regardless the classification applied, P-cadherin expression is strongly associated with high histological grade of DCIS (P=0.0047) and lack of estrogen receptors (P=0.0008). The use of Holland et al. classification showed a significant correlation between P-cadherin expression and decreased cell polarity (P=0.01). In conclusion, P-cadherin expression seems to be more relevant in DCIS pathogenesis than the altered expression of any other cadherin, including the decrease of E-cadherin expression.     

Development and characterisation of neutralising monoclonal antibody to the SARS-coronavirus

There is a global need to elucidate protective antigens expressed by the SARS-coronavirus (SARS-CoV). Monoclonal antibody reagents that recognise specific antigens on SARS-CoV are needed urgently. In this report, the development and immunochemical characterisation of a panel of murine monoclonal antibodies (mAbs) against the SARS-CoV is presented, based upon their specificity, binding requirements, and biological activity. Initial screening by ELISA, using highly purified virus as the coating antigen, resulted in the selection of 103 mAbs to the SARS virus. Subsequent screening steps reduced this panel to seventeen IgG mAbs. A single mAb, F26G15, is specific for the nucleoprotein as seen in Western immunoblot while five other mAbs react with the Spike protein. Two of these Spike-specific mAbs demonstrate the ability to neutralise SARS-CoV in vitro while another four Western immunoblot-negative mAbs also neutralise the virus. The utility of these mAbs for diagnostic development is demonstrated. Antibody from convalescent SARS patients, but not normal human serum, is also shown to specifically compete off binding of mAbs to whole SARS-CoV. These studies highlight the importance of using standardised assays and reagents. These mAbs will be useful for the development of diagnostic tests, studies of SARS-CoV pathogenesis and vaccine development.     

Drug development strategies for asthma: in search of a new paradigm

The spiraling costs of asthma treatment seem set to continue rising, given the equivocal performance of the latest generation of specific anti-inflammatory drugs in trials in adult asthmatics. We argue that the continuation of this trend is inevitable unless there is a substantial realignment of entrenched drug development policy in the pharmaceutical industry and a parallel shift in licensing policy by regulatory authorities to encourage the development of drugs capable of halting the progression from acute to chronic asthma when the disease first manifests in childhood. The theoretical framework for such an approach, including proof-of-principle data from studies in children with early-stage disease and a range of candidate drugs, already exists. What is needed is informed debate on the risks versus potential benefits of this approach.     

D-penicillamine inhibition of interleukin-1 production: a possible mechanism for its effect on synovial collagen synthesis?

Collagen production was investigated in cultured rabbit synovial fibroblasts exposed in vitro to D-penicillamine (D-Pen). The results show that these cells are rather insensitive to the drug since only a slight increase of the collagen amount secreted was observed for 48-h exposure to concentrations of 200-400 micrograms/ml. However, fibroblasts derived from the synovium of arthritic rabbits proved to be more susceptible to D-Pen, responding by a marked increase of collagen secretion even for concentrations of 50 micrograms/ml. This finding suggests that synovial fibroblasts of arthritic patients, probably stimulated by the inflammation process, could be target cells for the D-Pen action. The activities of 4-prolyl-hydroxylase (4-PH) and galactosylglucosyl-transferase (GGT) were assayed in the same cultures. A correlation has been found between the 4-PH activity and the collagen amount produced. In contrast, no alteration in the level of GGT on exposure to D-Pen was detected. Finally, D-Pen was shown to reduce in vitro the production of collagen-inhibiting factors by phytohaemagglutinin-stimulated mononuclear cells. This effect was associated with an inhibition of the release of monocyte cell factor (MCF/interleukin-1), suggesting that D-Pen could indirectly affect synovial collagen synthesis by interfering with interleukin-1 secretion.     

Seroprevalence of human herpesvirus-8 in blood donors from different geographical regions of Argentina, Brazil, and Chile

Human herpesvirus-8 (HHV-8) causes Kaposi's sarcoma (KS) and lymphoproliferative disorders in both HIV-infected and uninfected patients. HHV-8 has a worldwide occurrence but infection rates vary according to a combination of geographic and behavioral risks. The main transmission route seems to be sexual, nevertheless, nasal secretions, saliva, blood, and organ graft have been proposed. HHV-8 was postulated as a new infectious agent for screening in blood donors. The aim of this study was to evaluate the prevalence of antibodies against HHV-8 antigens in blood donors of South America. Serum samples from 2,470 blood donors from Argentina, Brazil, and Chile corresponding to five geographic regions were studied by indirect immunofluorescence assay (IFA). Seroprevalence rate was 3.7% (92/2,470; 95% CI 2.9-4.5) in the entire blood donor population distributed as follows: Argentina, 4.0% (Buenos Aires city, 4.3%; Bahia Blanca, 2.4%; and Córdoba, 4.0%), Campinas (Brazil), 2.8%; and Santiago de Chile, 3.0%. There was no difference (P>0.05) between men and women or age related, except in Brazil where positive cases were 30-49-year-old males. The present study, which includes different geographical areas of multiple countries from South America, has not been done before. The results show similar prevalence rates among the studied zones corresponding to low-prevalence regions. South America is a large sub-continent with a wide spectrum of population and geographical characteristics, thus, more HHV-8 prevalence studies should be necessary to establish possible regional differences.     

Investigation of Gamma-aminobutyric acid (GABA) A receptors genes and migraine susceptibility

Background  

Migraine is a neurological disorder characterized by recurrent attacks of severe headache, affecting around 12% of Caucasian populations. It is well known that migraine has a strong genetic component, although the number and type of genes involved is still unclear. Prior linkage studies have reported mapping of a migraine gene to chromosome Xq 24–28, a region containing a cluster of genes for GABA A receptors (GABRE, GABRA3, GABRQ), which are potential candidate genes for migraine. The GABA neurotransmitter has been implicated in migraine pathophysiology previously; however its exact role has not yet been established, although GABA receptors agonists have been the target of therapeutic developments. The aim of the present research is to investigate the role of the potential candidate genes reported on chromosome Xq 24–28 region in migraine susceptibility. In this study, we have focused on the subunit GABA A receptors type ε (GABRE) and type θ (GABRQ) genes and their involvement in migraine.     

How do normal subjects learn a simple adaptative task: How and why do paranoid schizophrenic patients fail?

Summary The authors studied the behavior of normal subjects and paranoid schizophrenic patients in a simple problem-solving situation. The schizophrenics were divided into two sample groups, one of individuals under treatment and the other of individuals not under treatment.The learning process involved in this problem-solving situation is very similar to an instrumental conditioning, and can be understood by means of the following assumptions: (1) the subjects use decision functions in reacting to the stimuli, although they may be not fully aware of this; (2) learning is the result of successive transformations of these decisions in the course of time; (3) the changes have specific probabilities and are related to (a) those responses which are made to the latest stimuli, and (b) a differential probability for decision functions which were effective, or only interrupted painful reinforcement, or were completely ineffective.In schizophrenics further factors of importance were (1) an inertia factor and (2) the rigidly continued use of unsuccessful or only partially successful decision criteria.The authors used a systems theory based on Galois field theory and a calculus of operators specifying three groups of subjects. A computer program based on these hypotheses was tested in a simulation experiment.The statistical evaluation of the results showed a congruence between the theoretical approach and the experimental data.This work was carried out with financial support from the Institute de Alta Cultura, Lisbon, between 1970 and 1974