BCR-ABL and interleukin 3 promote haematopoietic cell proliferation and survival through modulation of cyclin D2 and p27Kip1 expression.

Although it is evident that BCR-ABL can rescue cytokine-deprived hematopoietic progenitor cells from cell cycle arrest and apoptosis, the exact mechanism of action of BCR/ABL and interleukin (IL)-3 to promote proliferation and survival has not been established. Using the pro-B cell line BaF3 and a BaF3 cell line stably overexpressing BCR-ABL (BaF3-p210), we investigated the proliferative signals derived from BCR-ABL and IL-3. The results indicate that both IL-3 and BCR-ABL target the expression of cyclin Ds and down-regulation of p27(Kip1) to mediate pRB-related pocket protein phosphorylation, E2F activation, and thus S phase progression.

Accessing and using hospital activity data.

Hospital activity data can be accessed from a variety of sources ranging from hospitals to the Department of Health. These data provide valuable and widely used information, but care is needed in their use and interpretation. Hospital activity rates reflect not only the underlying prevalence and severity of disease, individual factors and referral practices, but also variations related to provider-specific factors: the 'provider effect'.

Simple detection of point mutations associated with HIV-1 drug resistance.

A novel assay is described for the detection of HIV-1 drug resistance that is simple, cheap and sensitive. HIV-1 drug resistance in B and non-B HIV-1 subtypes was investigated using Mutagenically-Separated PCR (MS--PCR) --- a competitive semi-nested PCR which uses mutagenic primers. The assay was assessed for sensitivity, specificity and its ability to detect mutant virus within a mixed mutant--wild-type population.

Prion diseases of humans and animals: their causes and molecular basis.

Prion diseases are transmissible neurodegenerative conditions that include Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE) and scrapie in animals. Prions appear to be composed principally or entirely of abnormal isoforms of a host-encoded glycoprotein, prion protein. Prion propagation involves recruitment of host cellular prion protein, composed primarily of alpha-helical structure, into a disease specific isoform rich in beta-sheet structure.

African Burkitt's lymphoma: a new perspective.

High titres of antibody to Epstein-Barr virus (EBV) late genes identify individuals at risk of developing endemic Burkitt's lymphoma (eBL). Viral lytic cycle early and intermediate-early gene expression in BL is associated with a favourable tumour response to chemotherapy. Our study investigated whether serological data identifying antibody expression to zta, a viral function that activates lytic-cycle gene expression, correlate with expression of its gene in tumours, and could have prognostic value.

Hepatitis B surface antigen variants in vaccinees, blood donors and an interferon-treated patient.

Variants of hepatitis B virus (HBV), with amino acid substitutions in the major antigenic "a" determinant of hepatitis B surface antigen (HBsAg), have been described mainly in vaccinated children. In the present study in addition to vaccinated children, we have investigated Chinese blood donors positive for anti-HBc alone, and a patient with continuing liver disease after interferon-induced seroconversion to anti-HBs. Variants were detected in two of four children with break-through infections.

Palindromic sequence plays a critical role in human foamy virus dimerization.

The retroviral RNA genome is dimeric, consisting of two identical strands of RNA linked near their 5' ends by a dimer linkage structure. Previously it was shown that human foamy virus (HFV) RNA transcribed in vitro contained three sites, designated SI, SII, and SIII, which contributed to the dimerization process (O. Erlwein, D.

The molecular biology of prion propagation.

Prion diseases such as Creutzfeldt-Jakob disease (CJD) in humans and scrapie and bovine spongiform encephalopathy (BSE) in animals are associated with the accumulation in affected brains of a conformational isomer (PrP(Sc)) of host-derived prion protein (PrP(C)). According to the protein-only hypothesis, PrP(Sc) is the principal or sole component of transmissible prions. The conformational change known to be central to prion propagation, from a predominantly alpha-helical fold to one predominantly comprising beta structure, can now be reproduced in vitro, and the ability of beta-PrP to form fibrillar aggregates provides a plausible molecular mechanism for prion propagation.

Prions and the lymphoreticular system.

Following intracerebral or peripheral inoculation of mice with scrapie prions, infectivity accumulates first in the spleen and only later in the brain. In the spleen of scrapie-infected mice, prions were found in association with T and B lymphocytes and to a somewhat lesser degree with the stroma, which contains the follicular dendritic cells (FDCs) but not with non-B, non-T cells; strikingly, no infectivity was found in lymphocytes from blood of the same mice. Transgenic PrP knockout mice expressing PrP restricted to either B or T lymphocytes show no prion replication in the lymphoreticular system.

A phase I/II study of the safety and activity of a microsphere formulation of KNI-272 in patients with HIV-1 infection.

Eighteen patients with symptomatic HIV disease were enrolled into a phase I/II study of a microsphere formulation of the HIV protease inhibitor KNI-272, with doses escalated up to a maximum dose of 60 mg/kg/day. One patient developed reversible elevation in hepatic transaminase. The plasma half-life of the drug was very short, varying between 0.

Analyzing the influence of PrP primary structure on prion pathogenesis in transgenic mice.

Expression of prion protein (PrP) genes in transgenic (Tg) mice has been an extremely effective means of studying human and animal prion diseases. Indeed, much of what we currently understand about the molecular basis of prion pathogenesis derives from such studies. Despite these advances, the emergence of a new variant of Creutzfeldt-Jakob disease (vCJD), apparently the human manifestation of bovine spongiform encephalopathy (BSE), demonstrates that our understanding of the factors controlling prion transmission is far from complete.

Observations on recurrent syncope and presyncope in 641 patients.

Background: Syncope is a common disorder that is potentially disabling and affects both young and old. Once neurological, cardiological, and metabolic causes have been excluded, there remains a group in which diagnosis is unclear; some may have an autonomic basis. We therefore did a retrospective study on consecutive patients referred to our tertiary referral autonomic centres between 1992 and 1998 with recurrent syncope and presyncope, in whom non-autonomic causes, before referral, had been sought and excluded.

Onset of ataxia and Purkinje cell loss in PrP null mice inversely correlated with Dpl level in brain.

PrP knockout mice in which only the open reading frame was disrupted ('Zürich I') remained healthy. However, more extensive deletions resulted in ataxia, Purkinje cell loss and ectopic expression in brain of Doppel (Dpl), encoded by the downstream gene, PRND: A new PrP knockout line, 'Zürich II', with a 2.9 kb PRNP: deletion, developed this phenotype at approximately 10 months (50% morbidity).

HTLV-I infection and the low prevalence of Helicobacter pylori infection in Japan.

HTLV-I retrovirus infection and Helicobacter pylori infection are common in Japan; however a report in this issue shows a significantly low prevalence of H. pylori in patients infected with HTLV-I. The reasons for this may be due to differences in genetic susceptibility of the infections, the gastric milieu in HTLV-I being unable to support H.

mRNA detection by in situ rt-PCR.

In situ polymerase chain reaction (PCR) is a recently developed technique whereby DNA (or cDNA) is enzymically amplified within cells or tissue sections, enabling the localization of specific low copy number sequences within a heterogeneous cell population. In situ reverse transcriptase PCR (RT-PCR) is an adaptation of the technique in which mRNA sequences are reverse transcribed to give a DNA copy (i.e.

Investigation of colonic disease.

Bowel cancer awareness among the general public has heightened in recent years. The promotion of prompt referral and the pressure on early diagnosis will alter our previous strategies on colonic evaluation. This article gives an overview of the colonic investigations currently available.

Prion disease--the propagation of infectious protein topologies.

Prion propagation is associated with accumulation of a conformational isomer of host encoded cellular prion protein, PrP(C). Solution structures of several mammalian PrPs have now been reported and they have stimulated a significant advance in our understanding of the folding dynamics of PrP. Studies on recombinant PrP have shown the polypeptide chain is able to adopt different topologies in different solvent conditions.

In-vitro ovarian steroidogenesis in women with pelvic congestion.

Follicular fluid steroid content and theca and granulosa cell steroidogenesis in pelvic congestion cystic ovaries were compared with steroidogenic function in both normal and polycystic ovaries. Ovaries were obtained at oophorectomy for benign gynaecological conditions, and classified according to gross morphology at dissection. Individual follicles were dissected out, follicular fluid aspirated, and granulosa and theca cells cultured in vitro.

Comparative quantification of diverse serotypes of HIV-1 in plasma from a diverse population of patients.

HIV-1 is characterised by extensive genetic variability encompassing at least 10 different phylogenetically related clades within the major group of HIV-1 subtypes. Most commercially available HIV-1 RNA plasma viral load assays have been optimised with clade B viruses and may yield misleadingly low RNA levels for nonclade B viruses that are increasingly found in Europe. In this study we compare the most recent versions of the Roche Amplicor HIV Monitor and the Chiron Quantiplex for ability to detect viraemia in a population of patients infected with a range of HIV-1 subtypes.

Response to alendronate in osteoporosis after previous treatment with etidronate.

Bisphosphonates such as etidronate and alendronate are widely accepted as effective agents for the treatment of osteoporosis. However, some physicians find the choice of which one to use in different patients, and the comparative magnitude of response, unclear. Fifty postmenopausal women with osteoporosis [group 1: 27 women who had received 3 years of previous cyclical etidronate treatment, mean age 70.

The structure of endometrial microvessels.

Recent studies have provided substantial evidence to highlight abnormalities in the structure of endometrial microvessels in users of progestogen-only contraception. Structural changes alone are unlikely to lead to breakthrough bleeding, but appear to be associated with a reduction in vessel integrity, and may reflect alterations in the control and growth of endometrial microvessels in those exposed to exogenous progestogens. In users of low-dose progestogens, immunohistochemical studies have demonstrated changes in superficial endometrial vascular morphology, density and in endometrial migratory cell populations.

A functional model for progestogen-induced breakthrough bleeding.

During the past 5 years, a number of important advances have been made in our understanding of the mechanisms of sex steroid-induced breakthrough bleeding (BTB). These observations suggest that superficial endometrial vascular fragility may be the mechanism underlying BTB, and molecular changes in the microvasculature as well as hysteroscopic observations have supported this hypothesis. This paper aims to present a unified picture of our current understanding of BTB, particularly that associated with progestogens, to indicate current gaps in our knowledge and possible directions for future research.

Epidemiology and the medical causes of miscarriage.

Human reproduction is extraordinarily wasteful. The reasons for this have taxed all of the contributors to this book. As we move into the 21st century it is sobering to reflect on the fact that we have failed to harness the power of the evolving revolution in molecular medical biology to answer the fundamental question: why is the fate of a fertilized egg so hazardous and so unsuccessful? The following account summarizes our limited knowledge of the epidemiology of miscarriage and then moves on to consider some of the medical causes of miscarriage.