Phase II trials of rhizoxin in advanced ovarian, colorectal and renal cancer.

Rhizoxin is a tubulin-binding anti-neoplastic agent which is active in a range of murine tumour models. The recommended schedule, of intravenous (i.v.) bolus administration at a dose of 2 mg m-2 every 3 weeks, has been assessed in three phase II trials of ovarian, renal and colorectal cancer. In general terms the drug was fairly well tolerated, but the response rate was disappointing: 0/18, colorectal cancer; 0/18, renal cancer; 1 partial response (PR)/17, ovarian cancer.     

GluR1 and GluR2/3 subunits of the AMPA‐type glutamate receptor are associated with particular types of neurone in laminae I–III of the spinal dorsal horn of the rat

GluR1 and GluR2 subunits of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor are expressed at high levels by neurones in laminae I–III of rat spinal dorsal horn, an area which contains numerous, densely packed small neurones. In order to determine whether these subunits are expressed by inhibitory or excitatory neurones, we combined pre-embedding immunocytochemistry with antibodies that recognize either GluR1, or an epitope common to GluR2 and 3, with postembedding detection of γ-aminobutyric acid (GABA) and glycine. Most (78%) of the neurones with GluR1-immunoreactivity were GABA-immunoreactive, and some of these were also glycine-immunoreactive, whereas nearly all (97%) of the GluR2/3-immunoreactive neurones were not GABA- or glycine-immunoreactive. We carried out double-immunofluorescence and confocal microscopy to provide further information on the neurochemistry of cells that express these subunits. As expected, all neurotensin- and virtually all somatostatin-immunoreactive cells (which are thought to be excitatory interneurones) were GluR2/3- but not GluR1-immunoreactive, whereas parvalbumin-containing cells (most of which are GABAergic) possessed GluR1-, but usually not GluR2/3-immunoreactivity. Neurones that contained nitric oxide synthase (most of which are GABAergic) were more variable, with 57% GluR1-immunoreactive and 41% GluR2/3-immunoreactive. Cholinergic neurones in lamina III (which are also GABAergic) invariably showed each type of GluR-immunoreactivity. These results suggest that neuronal populations in laminae I–III have characteristic patterns of GluR expression: GluR1 is particularly associated with inhibitory neurones, and GluR2 with excitatory neurones. This makes it likely that some of the AMPA receptors present on the inhibitory interneurones lack the GluR2 subunit, and may therefore have significant Ca²⁺-permeability.     

Sexual attitudes and practices of selected groups in Northern Ireland since the emergence of AIDS.

One hundred and seventeen heterosexual males and females attending a sexually transmitted disease clinic and 57 homosexual males from a local "gay" club were asked to complete a questionnaire regarding their attitudes and sexual practices since the emergence of AIDS. The results show a trend towards increasing partner change rate among heterosexual males. There has been an increase in the practice of insertive anal intercourse by homosexual men with Northern Ireland contacts but no corresponding increase with contacts outside Northern Ireland. The practice of receptive anal intercourse has remained constant. Significant differences in attitudes between homosexual and heterosexual males were expressed with regard to testing of 'at risk groups' (p less than 0.001), in the uptake of testing (p less than 0.01), and in attitudes to sexual practices if they themselves became HIV positive. There was a low level of anxiety amongst heterosexuals regarding risk of HIV infection in the future. Less than 50% of the heterosexual patients attending this clinic use condoms, though more claim to intend to use them in future.     

Efficacy of empirical cardiac pacing in syncope of unknown cause.

Cardiac pacing is often considered in patients with recurrent syncope after repeated attempts to document the cause have failed. To assess the results of this tactic we reviewed the records of 104 patients who had received pacemakers for known or suspected bradycardia between September 1973 and March 1985. The patients were classified retrospectively into three groups: group 1 (31 patients with a mean age of 73 years) had unequivocal documentation of bradycardia during syncope, group 2 (42 patients with a mean age of 71 years) had electrocardiographic or electrophysiologic evidence of potential bradycardia but no documentation during spontaneous syncope, and group 3 (31 patients with a mean age of 69 years) had a history "suggestive of" bradycardia-related syncope but no other evidence to support the diagnosis. The rates of recurrence of syncope during follow-up were 6.3%, 7.3% and 32.2% in groups 1, 2 and 3 respectively (p less than 0.01). In group 3 recurrence was more probable in patients with loss of consciousness for more than 2 minutes than in those who were unconscious for 2 minutes or less (p less than 0.05). The results suggest that pacemaker implantation is justified for recurrent syncope after extensive attempts to document a spell have failed if abnormal diagnostic test results suggest bradycardia as a possible cause. Empirical pacing is less satisfactory in patients with normal results of evaluation but may arguably be justified when patients have recurrent syncope with injury.     

Costello syndrome: Clinical phenotype,genotype, and management guidelines

Costello syndrome (CS) is a RASopathy caused by activating germline mutations in HRAS. Due to ubiquitous HRAS gene expression, CS affects multiple organ systems and individuals are predisposed to cancer. Individuals with CS may have distinctive craniofacial features, cardiac anomalies, growth and developmental delays, as well as dermatological, orthopedic, ocular, and neurological issues; however, considerable overlap with other RASopathies exists. Medical evaluation requires an understanding of the multifaceted phenotype. Subspecialists may have limited experience in caring for these individuals because of the rarity of CS. Furthermore, the phenotypic presentation may vary with the underlying genotype. These guidelines were developed by an interdisciplinary team of experts in order to encourage timely health care practices and provide medical management guidelines for the primary and specialty care provider, as well as for the families and affected individuals across their lifespan. These guidelines are based on expert opinion and do not represent evidence‐based guidelines due to the lack of data for this rare condition.     

Large genomic rearrangements in MECP2

In 1999, mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2) were first reported in patients with Rett syndrome (RTT). The MECP2 gene is located at Xq28 and consists of 4 exons. About 80-90 % of the classic RTT patients harbor mutations in the coding region of MECP2, while the molecular cause is unknown in the remaining 10-20%. Several groups have searched for large rearrangements within the MECP2 and the results indicate that a fraction of MECP2-negative RTT cases has large deletions of the MECP2. In this study we have used the Multiplex Ligation-dependent Probe Amplification (MLPA) technique to screen 45 RTT patients, who have previously been tested negative for mutations in the coding region of MECP2. The MECP2-MLPA is a semi-quantitative multiplex PCR approach. It determines the relative number of copies of each MECP2 exon. With this approach we detected seven RTT patients with genomic deletions and further characterized the deletions using real time quantitative PCR (qPCR) and long-range PCR. The seven patients were given a severity score and their X chromosome inactivation profiles were determined in order to identify a possible genotype-phenotype correlation. The results from this study indicate that large deletions in MECP2 cause classic RTT.