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Biomedical subjects

M Brown

Publications and source records attributed to M Brown.

At least 55 records · Page 3Linked to original sources
PubMed2003

Suggestive linkage of 2p22-25 and 11q12-13 with low bone mineral density at the lumbar spine in the Irish population.

Osteoporosis is a disease characterized by low bone mineral density (BMD) and poor bone quality. Peak bone density is achieved by the third decade of life, after which bone is maintained by a balanced cycle of bone resorption and synthesis. Age-related bone loss occurs as the bone resorption phase outweighs the bone synthesis phase of bone metabolism. Heritability accounts for up to 90% of the variability in BMD. Chromosomal loci including 1p36, 2p22-25, 11q12-13, parathyroid hormone receptor type 1 (PTHR1), interleukin-6 (IL-6), interleukin 1 alpha (IL-1alpha) and type II collagen A1/vitamin D receptor (COL11A1/VDR) have been linked or shown suggestive linkage with BMD in other populations. To determine whether these loci predispose to low BMD in the Irish population, we investigated 24 microsatellite markers at 7 chromosomal loci by linkage studies in 175 Irish families of probands with primary low BMD (T-score < or = -1.5). Nonparametric analysis was performed using the maximum likelihood variance estimation and traditional Haseman-Elston tests on the Mapmaker/Sibs program. Suggestive evidence of linkage was observed with lumbar spine BMD at 2p22-25 (maximum LOD score 2.76) and 11q12-13 (MLS 2.55). One region, 1p36, approached suggestive linkage with femoral neck BMD (MLS 2.17). In addition, seven markers achieved LOD scores >1.0, D2S149, D11S1313, D11S987, D11S1314 including those encompassing the PTHR1 (D3S3559, D3S1289) for lumbar spine BMD and D2S149 for femoral neck BMD. Our data suggest that genes within a these chromosomal regions are contributing to a predisposition to low BMD in the Irish population.

Adult↗
PubMed2003

Serious perinatal complications of non-proteinuric hypertension: an international, multicentre, retrospective cohort study.

OBJECTIVE: To determine the proportion of births complicated by either a pre-existing or a gestational non-proteinuric hypertension, presenting at <34 weeks' gestation, and the associated incidence with 1 or more serious perinatal complications or birth weight <3rd centile for gestational age. METHODS: A retrospective chart review was conducted in 5 international centres, from 1998 to 2002, where "tight" control (normalization) of blood pressure (BP) is the norm. International Classification of Diseases (ICD) codes were used to identify women who delivered at > or =20 weeks' gestation, with any hypertensive disorder of pregnancy. Women were included if they had a diastolic blood pressure (dBP) of 90 to 109 mm Hg, due to either a pre-existing or a gestational non-proteinuric hypertension, presenting at <34 weeks' gestation. Women were excluded if they had ongoing severe hypertension, or if at presentation with dBP of 90 to 109 mm Hg, they had 1 or more of the following: proteinuria, an indication for "tight" control of BP or imminent delivery, or a known intrauterine fetal death or lethal fetal anomaly. Data were collected on paper forms, scanned into an electronic database, and summarized descriptively by type of hypertension. RESULTS: There were 305 eligible women (0.7% deliveries, 12.8% hypertensive deliveries) identified with non-proteinuric hypertension that was either pre-existing (133 [43.6%]) or gestational (172 [56.4%]). Regardless of hypertension type, 16.4% (n = 50) of pregnancies were complicated by birth weight <3rd centile or 1 or more serious perinatal complications, 34.3% (n = 100) by preterm birth, 30.8% (n = 94) by preeclampsia, and 2.0% (n = 6) by serious maternal complications. CONCLUSION: Non-proteinuric pre-existing or gestational hypertension, presenting before 34 weeks' gestation, identifies a subpopulation of hypertensive pregnant women at both substantial perinatal risk and maternal risk. The CHIPS (Control of Hypertension In Pregnancy Study) trial is designed to determine how best to manage the hypertension of such women in order to optimize perinatal outcome.

Adult↗
PubMed2003

Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study.

The aim of this study was to assess the antitumour response and time to progression (TTP) of patients treated with imatinib mesylate (Glivec, Gleevec, formerly STI-571) who had advanced and/or metastatic gastrointestinal stroma tumours (GIST) or other soft tissue sarcomas (STS). Patients with measurable lesions and adequate organ function were entered. They were treated with imatinib mesylate at the dose of 400 mg twice daily (bid). All tumours were subject to a stringent pathological review by an expert panel. Immunohistochemical expression of KIT expression was evaluated. A total of 51 patients (27 GIST, 24 other STS), median age 53 years, median World Health Organization (WHO) performance score 1, were entered. 71% of the patients had received prior chemotherapy. The most frequent side-effects were anaemia (92%), periorbital oedema (84%), skin rash (69%), fatigue (76%), nausea (57%), granulocytopenia (47%) and diarrhoea (47%). Most of these side-effects were mild to moderate and no patient was taken off study due to side-effects. Skin rash and periorbital oedema frequently seem to be self limiting, despite continued treatment. In GIST patients, the current response rates (RRs) are 4% complete remission (CR), 67% partial remission (PR), 18% stable disease (SD) and 11% progression (PD). 73% of GIST patients are free from progression at 1 year. In the other STS group, there were no objective responses. The median time to progression in this subgroup was only 58 days. Imatinib mesylate is well tolerated at a dose of 400 mg bid. This dose is active in patients with KIT-positive GIST, but patients with other STS subtypes unselected for a molecular target are unlikely to benefit.

Adult↗
PubMed2002

Lymphoplasmacytoid lymphoma presenting as severe osteoporosis.

We report four cases presenting with severe osteoporosis which on further investigation were found to have an underlying lymphoplasmacytoid lymphoma (LPL). Common secondary causes of osteoporosis were excluded in each case. Three of the cases responded to treatment with a biphosphonate. As these lymphomas share some common pathological and clinical features with multiple myeloma (MM) an association with osteoporosis is likely to represent more than a coincidental finding. The incidence of osteoporosis occurring with LPL will become clearer if routine imaging is carried out in patients at presentation. Issues relating to the treatment of the osteoporosis as well as the lymphoma arise in patients that present in this way. Based on the model of bone disease in MM, correlating serum levels of osteoclast activating cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumour necrosis factor (TNF) with the actual finding of bone disease provides a basis for future research into the pathogenesis and management of bone disease in these rare forms of low grade non-Hodgkin's lymphoma.

Aged↗
PubMed2002

Global analysis of gene expression patterns in developing mouse neocortex using serial analysis of gene expression.

Molecular inventories of the developing mouse neocortex before and after birth were generated using the global gene expression profiling tool serial analysis of gene expression (SAGE). Libraries were generated from embryonic day 15 and postnatal day 1 mouse neocortex and more than 40,000 tags were collected (20,211 and 22,001 tags, representing 11,706 and 12,402 transcripts, respectively). Comparison of the two libraries resulted in the identification of 321 transcripts that were differentially expressed (P < 0.05). Differential expression was independently verified for selected genes by Northern blotting, and in situ hybridization revealed spatial expression patterns in the neocortex. Differentially expressed transcripts included genes known to be important in neocortical development (e.g., brain factor 1, neuroD2, and Id2), genes not previously associated with neocortical development (such as brahma-related gene 1, receptor for activated C-kinase I, hypermethylated in cancer 2, and Evi9), and genes of unknown identity or function.

Animals↗
PubMed2002

Thalidomide, an antiangiogenic agent with clinical activity in cancer.

Despite the teratogenic past of thalidomide, there is recent evidence indicating the drug's efficacy in the management of various diseases from immune disorders to cancers. The history, pharmacodynamic and pharmacokinetic properties of thalidomide in the clinic are discussed in this review article.

Angiogenesis Inhibitors↗
PubMed2002

HLA Class I typing of volunteers for a bone marrow registry: QC analysis by DNA-based methodology identifies serological typing discrepancies in the assignment of HLA-A and B antigens.

Until recently, the majority of newly recruited volunteer donors were typed for HLA-A and -B by serology onto the National Marrow Donor Program Registry. Quality control of this serological typing performed by contracted laboratories was carried out by retesting approximately 1% of each laboratory's test volume utilizing DNA-based techniques (SSOP). The criteria used for selection included samples presumed to be homozygotes, samples with split antigen specificities and samples with antigens considered to be difficult to define. Out of 1983 samples analyzed, 156 HLA-A (3.9%) and 265 HLA-B (6.7%) locus discrepancies were identified. Review of these discrepancies by both the serological and QC laboratory revealed that the majority of discrepancies were due to errors in serological typing. Serological discrepancies were categorized as follows: blank antigens identified (36.8%) and misassignments (63.2%). Misassignments were defined as either the incorrect assignment of antigens within a group ("wrong split"), or a complete misassignment. Antigens reported as blanks most frequently belonged to the A19 and A28 groups and to the B70, 46 and 40 groups. The most frequent misassignments within groups were the A19 and A10 groups, and the B40 and B15 groups. Other HLA-A misassignments included A2 vs A28 or A2 vs A69, while other HLA-B misassignments included B35 and B70. This QC analysis showed that serological typing of class I antigens for the purposes of NMDP registry typing is prone to a significant error rate. Careful evaluation and selection of contracted laboratories by the NMDP suggests methodological limitations rather than poor performance as the main cause of these observations.

Alleles↗
PubMed2002

The potential for efficacy of the modified (ICP 34.5(-)) herpes simplex virus HSV1716 following intratumoural injection into human malignant glioma: a proof of principle study.

We have previously demonstrated the safety of intratumoural administration of the selectively replication-competent herpes simplex virus mutant HSV1716 in patients with high-grade glioma (HGG). Here we show its potential for efficacy by demonstrating that the virus survives and replicates when injected into the tumours of patients. Since HSV replication is a cytolytic process it must result in tumour cell killing. Twelve patients with biopsy-verified HGG received an intratumoural injection of 10(5) plaque-forming units (p.f.u.) of HSV1716. Four to 9 days after inoculation, tumours were removed and assayed for evidence of viral replication. In two patients, HSV1716, in excess of the input dose was recovered from the injection site. HSV DNA was detected by PCR at the sites of inoculation in 10 patients and at distal tumour sites in four. HSV-specific antigen was detected in tumour tissue from two patients. In five patients an immunological response to HSV1716, as detected by changes in levels of IgG and IgM, was demonstrated. This study demonstrates that HSV1716 replicates in HGG without causing toxicity in both HSV-seropositive and -seronegative patients.

Adult↗
PubMed2002

Are we negating the benefits of CABG by forgetting secondary prevention?

UNLABELLED: The objective of the study was to examine medically managed secondary prevention at one year after coronary artery bypass grafting (CABG). In all, 214 consecutive patients undergoing isolated elective CABG seen four weeks preoperatively and one year post-operatively. Preoperative systolic blood pressure averaged 135+/-20 mmHg, which increased to 148+/-25 mmHg (P<0.0001) as did diastolic pressure (81+/-12 to 87+/-13 mmHg; P<0.0001). Anginal symptoms were reported by 45.1% (P<0.0001) although median severity scored lower (4.0 [3.0-5.4] vs 0 [0-2.0]; P<0.0001). Breathlessness decreased from 93% to 64% (P<0.0001) and was scored less severely (4.0 [2.0-5.0] vs 2.0 [0-4.0]; P<0.0001. In all, 88% with postoperative angina reported dyspnoea against 44% of those without (P<0.0001). Calcium antagonist use was more common in patients with angina (27.2% vs 5.1%; P<0.0001), but not nitrates (P=0.8695), diuretics (P=0.4218), digoxin (P=0.2565), beta-blockers (P=0.0820), or ACE inhibitors (P=0.7256). Preoperatively 166 patients (80.2%) took aspirin vs 69.2% afterwards (P=0.0131). Twelve patients (6.5%) received warfarin after operation vs none preoperatively. Two took digoxin (0.97%) preoperatively and 14 (7.7%) postoperatively (P=0.001) for chronic atrial fibrillation. One of these took warfarin. Long-acting nitrate use fell from 63.4% to 15.8% (P <0.0001). Short-acting nitrate use fell similarly (P<0.0001). Preoperatively 37 patients (17.9%) took ACE inhibitors vs 44 postoperatively (24.2%); 39 had not received them before. Preoperatively 48 (23.2%) took diuretics vs 30 (16.5%) postoperatively (P=0.127); 24 had not previously taken diuretics. More patients took HMGCoA inhibitors postoperatively (P=0.0068) and total cholesterol was significantly reduced with a concomitant increase in HDL fraction. Smoking habit was virtually unchanged from 17.8% to 15.1% (P=0.5023). IN CONCLUSION: angina was common. Apart from statin prescribing, postoperative secondary prevention measures were poorly applied, less widespread and less effective than preoperatively. The implications are disturbing.

Angina Pectoris↗
PubMed2002

Prospective study of the incidence and outcome of intra-abdominal hypertension and the abdominal compartment syndrome.

BACKGROUND: Intra-abdominal hypertension has been recognized as a source of morbidity and mortality in the traumatized patient following laparotomy. Multiple organ dysfunction attributable to intra-abdominal hypertension has been called the abdominal compartment syndrome. The epidemiology and characteristics of these processes remain poorly defined. METHODS: Intra-abdominal pressure was measured prospectively in all patients admitted to a trauma intensive care unit over 9 months. Data were gathered on all patients with intra-abdominal hypertension. RESULTS: Some 706 patients were evaluated. Fifteen (2 per cent) of 706 patients had intra-abdominal hypertension. Six of the 15 patients with intra-abdominal hypertension had abdominal compartment syndrome. Half of the patients with abdominal compartment syndrome died, as did two of the remaining nine patients with intra-abdominal hypertension. Patients with abdominal compartment syndrome had a mean intra-abdominal pressure of 42 mmHg compared with 26 mmHg in patients with intra-abdominal hypertension only (P < 0.05). CONCLUSION: The incidence of intra-abdominal hypertension and abdominal compartment syndrome was 2 and 1 per cent respectively. Intra-abdominal hypertension did not necessarily lead to abdominal compartment syndrome, and often resolved without clinical sequelae. Abdominal compartment syndrome did not occur in the absence of earlier laparotomy. Abdominal compartment syndrome was associated with a marked increase in intra-abdominal pressure (above 40 mmHg).

Adolescent↗
PubMed2002

Evaluating the effects of historic bottleneck events: an assessment of microsatellite variability in the endangered, North Atlantic right whale.

Commercial exploitation reduced the North Atlantic right whale (Eubalaena glacialis) population from c. 12,000 in the 11th century to around 300 by the 21st century. We examine the effect of this population decline on levels of genetic variation at 16 microsatellite loci and contrast levels of variability to that in a closely related species (E. australis). Of the 13 loci developed from the E. glacialis genome, 100% were polymorphic in E. australis. In contrast, nine loci were polymorphic in E. glacialis and four were fixed. Both allelic diversity (A) and heterozygosity (H) were significantly lower in E. glacialis than E. australis (A = 3.2 +/- 2.6 vs. A= 6.9 +/- 3.3, P < 0.001; H= 0.31 +/- 0.25 vs. H= 0.72 +/- 0.23, P < 0.001, respectively). Bottleneck anlayses indicate that the population is in mutation-drift equilibrium and that a genetic bottleneck did not occur during the most recent decline (18th-20th centuries). Nevertheless, low frequency alleles are relatively uncommon in E. glacialis, suggesting that genetic variability has been reduced in this population. Possible origins of low genetic variability are discussed, including the slow but continual erosion of alleles during the 800-year period of decline.

Alleles↗
PubMed2002

Regional and urban Victorian diabetic youth: clinical and quality-of-life outcomes.

OBJECTIVES: To compare groups of urban and regional Victorian diabetic children and assess their quality of life, diabetes knowledge, access to services and metabolic control. METHODS: Forty-seven children from three regional Victorian communities (Horsham, Warrnambool and Sale; n = 16, 18 and 13, respectively) were compared with 120 age-, sex- and duration of diabetes-matched children attending the Royal Children's Hospital (RCH) diabetes clinic in Melbourne. Quality of life, diabetes knowledge, use of services, and metabolic control were assessed using the child health questionnaire (CHQ PF-50/CF-80); a diabetes-knowledge questionnaire; access to a diabetes nurse educator (DNE), dietitian and complication screening; and indices of mean HbA1C (values are taken every 3 months in the 'yearly HbA1C'), respectively. RESULTS: Comparisons of CHQ data showed that regional diabetic youth scored significantly lower on most subscales. The greatest deficits were seen in areas of mental health, self-esteem, parent impact (emotional) and family cohesion. Diabetes knowledge and median yearly HbA1C for patients were not significantly different between the regional and urban centres (8.1%, 8.9%, 8.4% and 8.6% at RCH, Horsham, Warrnambool and Sale, respectively). Patients in regional centres had reportedly less access to team-based diabetes care. CONCLUSIONS: Regional youth in Victoria, with similar levels of metabolic control and diabetes knowledge as their urban counterparts, have a markedly lower quality of life, implying a negative synergy between diabetes and the demands of regional lifestyles.

Adolescent↗
PubMed2002

[The mitochondrial genome and human mitochondrial diseases].

To date, more than 100 point mutations and several hundreds of structural rearrangements of mitochondrial DNA (mtDNA) are known too be connected with characteristic neuromuscular and other mitochondrial syndromes varying form those causing death at the neonatal stage to diseases with late ages of onset. The immediate cause of mitochondrial disorders is a defective oxidative phosphorylation. Wide phenotypic variation and the heteroplasmy phenomenon, which some authors include in mutation load, are characteristic of human mitochondrial diseases. As the numbers of cases identified and pedigrees described increase, data on the genotype--phenotype interaction and the structure and frequency of pathogenic and conditionally pathogenic mtDNA mutations in human populations are rapidly accumulated. The data on the genetics and epidemiology of mitochondrial diseases are not only important for differential diagnosis and genetic counseling. Since both neutral and mildly pathogenic mutations of mtDNA are progressively accumulated in maternal phyletic lines, molecular analysis of these mutations permits not only reconstruction of the genealogical tree of modern humans, but also estimation of the role that these mutations play in natural selection.

DNA, Mitochondrial↗
PubMed2001

Collapsin response mediator protein switches RhoA and Rac1 morphology in N1E-115 neuroblastoma cells and is regulated by Rho kinase.

The formation and directional guidance of neurites involves dynamic regulation of Rho family GTPases. Rac and Cdc42 promote neurite outgrowth, whereas Rho activation causes neurite retraction. Here we describe a role for collapsin response mediator protein (Crmp-2), a neuronal protein implicated in axonal outgrowth and a component of the semaphorin 3A pathway, in switching GTPase signaling when expressed in combination with either dominant active Rac or Rho. In neuroblastoma N1E-115 cells, co-expression of Crmp-2 with dominant active RhoA V14 induced Rac morphology, cell spreading and ruffling (and the formation of neurites). Conversely, co-expression of Crmp-2 with dominant active Rac1 V12 inhibited Rac morphology, and in cells already expressing Rac1 V12, Crmp-2 caused localized peripheral collapse, involving Rho (and Cdc42) activation. Rho kinase was a pivotal regulator of Crmp-2; Crmp-2 phosphorylation was required for Crmp-2/Rac1 V12 inhibition, but not Crmp-2/RhoA V14 induction, of Rac morphology. Thus Crmp-2, regulated by Rho kinase, promotes outgrowth and collapse in response to active Rho and Rac, respectively, reversing their usual morphological effects and providing a mechanism for dynamic modulation of growth cone guidance.

3T3 Cells↗