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Biomedical subjects

S McWilliams

Publications and source records attributed to S McWilliams.

10 recordsLinked to original sources
PubMed2002

Novel skeletal muscle ryanodine receptor mutation in a large Brazilian family with malignant hyperthermia.

Malignant hyperthermia (MH) is an autosomal dominant disorder that predisposes susceptible individuals to a potentially life-threatening crisis when exposed to commonly used anesthetics. Mutations in the skeletal muscle calcium release channel, ryanodine receptor (RYR1) are associated with MH in over 50% of affected families. Linkage analysis of the RYR1 gene region at 19q13 was performed in a large Brazilian family and a distinct disease co-segregating haplotype was revealed in the majority of members with diagnosis of MH. Subsequent sequencing of RYR1 mutational hot spots revealed a nucleotide substitution of C to T at position 7062, causing a novel amino acid change from Arg2355 to Cys associated with MH in the family. Haplotype analysis of the RYR1 gene area at 19q13 in the family with multiple MH members is an important tool in identification of genetic cause underlying this disease.

Amino Acid Substitution↗
PubMed2001

BRCA1 and GADD45 mediated G2/M cell cycle arrest in response to antimicrotubule agents.

BRCA1 is a tumour suppressor gene implicated in the predisposition to early onset breast and ovarian cancer. We have generated cell lines with inducible expression of BRCA1 to evaluate its role in mediating the cellular response to various chemotherapeutic drugs commonly used in the treatment of breast and ovarian cancer. Induction of BRCA1 in the presence of Taxol and Vincristine resulted in a dramatic increase in cell death; an effect that was preceded by an acute arrest at the G2/M phase of the cell cycle and which correlated with BRCA1 mediated induction of GADD45. A proportion of the arrested cells were blocked in mitosis suggesting activation of both a G2 and a mitotic spindle checkpoint. In contrast, no specific interaction was observed between BRCA1 induction and treatment of cells with a range of DNA damaging agents including Cisplatin and Adriamycin. Inducible expression of GADD45 in the presence of Taxol induced both G2 and mitotic arrest in these cells consistent with a role for GADD45 in contributing to these effects. Our results support a role for both BRCA1 and GADD45 in selectively regulating a G2/M checkpoint in response to antimicrotubule agents and raise the possibility that their expression levels in cells may contribute to the toxicity observed with these compounds.

Antineoplastic Agents↗
PubMed2001

Single-amino-acid deletion in the RYR1 gene, associated with malignant hyperthermia susceptibility and unusual contraction phenotype.

Malignant hyperthermia (MH) is an anesthetic-drug-induced, life-threatening hypermetabolic syndrome caused by abnormal calcium regulation in skeletal muscle. Often inherited as an autosomal dominant trait, MH has linkage to 30 different mutations in the RYR1 gene, which encodes a calcium-release-channel protein found in the sarcoplasmic reticulum membrane in skeletal muscle. All published RYR1 mutations exclusively represent single-nucleotide changes. The present report documents, in exon 44 of RYR1 in two unrelated, MH-susceptible families, a 3-bp deletion that results in deletion of a conserved glutamic acid at position 2347. This is the first deletion, in RYR1, found to be associated with MH susceptibility. MH susceptibility was confirmed among some family members by in vitro diagnostic pharmacological contracture testing of biopsied skeletal muscle. Although a single-amino-acid deletion appears to be a subtle change in the protein, the deletion of Glu2347 from RYR1 produces an unusually large electrically evoked contraction tension in MH-positive individuals, suggesting that this deletion produces an alteration in skeletal-muscle calcium regulation, even in the absence of pharmacological agents.

Adolescent↗
PubMed2001

Uncovering BRCA1-regulated signalling pathways by microarray-based expression profiling.

The introduction of microarray technology to the scientific and medical communities has dramatically changed the way in which we now address basic biomedical questions. Expression profiling using microarrays facilitates an experimental approach where alterations in the transcript level of entire transcriptomes can be simultaneously assayed in response to defined stimuli. We have used microarray analysis to identify downstream transcriptional targets of the BRCA1 (Breast Cancer 1) tumour-suppressor gene as a means of defining its function. BRCA1 has been implicated in the predisposition to early onset breast and ovarian cancer and while its exact function remains to be defined, roles in DNA repair, cell-cycle control and transcriptional regulation have been implied. In the current study we have generated cell lines with tetracycline-regulated, inducible expression of BRCA1 as a tool to identify genes, which might represent important effectors of BRCA1 function. Oligonucleotide array-based expression profiling identified a number of genes that were upregulated at various times following inducible expression of BRCA1 including the DNA damage-responsive gene GADD45 (Growth Arrest after DNA Damage). Identified targets were confirmed by Northern blot analysis and their functional significance as BRCA1 targets examined.

BRCA1 Protein↗
PubMed2000

Posturographic performance in patients with the potential for secondary gain.

OBJECTIVES: To determine the incidence of nonorganic sway patterns on computerized dynamic posturography (CDP) among patients with potential secondary gain compared with patients without any obvious secondary gain. METHODS: A retrospective chart review of 100 patients who underwent clinical evaluation, audiometry, electronystagmography, and CDP was undertaken. Group 1 consisted of 50 patients who were randomly selected from a group who had pending lawsuits, worker's compensation claims, or disability claims. Group 2 consisted of 50 randomly selected patients who had no pending legal status, worker's compensation claims, or disability claims. Previously published criteria for nonorganic sway patterns were then applied to each group. Statistical analysis was performed. RESULTS: The average age of group 1 patients was 43.8 years compared with 63.2 years for group 2 patients (P < 0.0001). Among group 1 patients 50% had normal audiovestibular evaluations compared with only 4% of group 2 patients (P < 0.0001). Nonorganic sway patterns were found in 76% of group 1 patients, but only in 8% of group 2 patients (P < 0.0001). CONCLUSION: Patients who have the potential for secondary gain are generally younger and have a much higher prevalence of normal audiovestibular evaluations and a much higher prevalence of nonorganic sway patterns on CDP. A high degree of clinical suspicion should be maintained when evaluating the dizzy patient who has a pending lawsuit, worker's compensation claim, or disability claim.

Adult↗
PubMed1992

Histological and electron microprobe studies of mineralisation in aluminium-related osteomalacia.

AIMS: To determine a possible mechanism to explain the presence of aluminium lines within fully calcified bone in aluminium-related osteomalacia. METHODS: Fifty five bone cases shown by bone biopsy to be aluminium-related osteomalacia were studied. In 38 specimens aluminium lines were identified within calcified bone by means of the Aluminon stain and a characteristic form of patchy mineralisation was seen within thickened osteoid seams. Five representative examples were analysed quantitatively by histomorphometry and electronprobe X-ray microanalysis and compared with five cases of vitamin D deficiency-related osteomalacia which also had patchy mineralisation. RESULTS: The patchy calcification occupied 40 +/- 8% (mean +/- SEM) of the osteoid and consisted of small focal deposits (less than 40 microns diameter), often (52%) around osteoid osteocytes (probably an underestimate of the association), and larger areas that extended to the aluminium lines at the underlying mineralisation front. Small and large mineralisation nuclei were seen ultrastructurally in the patchy calcification. Quantitative electronprobe X-ray microanalysis showed that calcium concentrations and calcium:phosphorus ratios in the mineralisation nuclei and in the superficial layer of the fully calcified bone of the aluminium-related osteomalacia cases were significantly less than values measured at similar sites in the vitamin D deficiency-related osteomalacia cases. Furthermore, aluminium could not be detected by means of this technique at the mineralisation front or along cement lines in these specimens. CONCLUSIONS: Calcification can occur in thickened osteoid seams in osteomalacia. It can begin around osteoid osteocytes as small deposits that enlarge within the osteoid and extend to the underlying mineralisation front or cement line where aluminium lines may become trapped. Complete calcification of osteoid could account for the presence of aluminium lines within fully calcified bone. The Aluminon stain appears to be a more sensitive method for the detection of aluminium in bone than electronprobe X-ray microanalysis.

Adult↗
PubMed1978

Clients' treatment expectations at a community mental health center.

Clients' expectations about mental health care, particularly differences in these expectations as a function of social class, and the relationship of discrepancies between expectations and perceptions to treatment outcome, is examined in this study with 317 Caucasian clients. In contrast to the majority of studies, no differences in treatment expectations relating to clients' social class, sex, or marital status were found. Nor were discrepancies related to course or outcome of therapy. Discussion focuses around explanation and interpretation of these findings. Particularly relevant is the need to determine the extent to which nonusers in the community share the attitudes and expectations of clients.

Adolescent↗
PubMedDate not supplied

Ondansetron usage in HIV positive patients: a pilot study on the control of nausea and vomiting in patients on high dose co-trimoxazole for Pneumocystis carinii pneumonia.

This was an open, single centre study, to evaluate the safety and efficacy of ondansetron in the treatment of co-trimoxazole associated nausea and vomiting in AIDS patients. Sixteen patients presenting with their first episode of HIV-associated Pneumocystis carinii pneumonia (PCP) on high dose co-trimoxazole were given ondansetron 8 mg orally, every 8 h. Measurements were made from data recorded by each patient on diary cards. In this study 11 out of 16 (69%) patients on ondansetron experienced good control of emesis (2 or less emetic episodes) on their 'worst day' of therapy and 8 out of 16 (50%) of patients demonstrated good control of emesis throughout their treatment with co-trimoxazole. Good control of nausea (mild or none) was achieved in 7 out of 16 (47%) patients. A total of 7 patients were able to complete the full course of co-trimoxazole whilst on ondansetron. One serious adverse event (Stevens-Johnson syndrome) was reported and felt to be unrelated to ondansetron. If conventional anti-emetics fail to achieve control of symptoms or have unacceptable side effects, ondansetron may represent a possible alternative.

AIDS-Related Opportunistic Infections↗