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Biomedical subjects

A Brown

Publications and source records attributed to A Brown.

At least 217 records · Page 12Linked to original sources
PubMed1997

Immunolocalization of the multi-sarco/endoplasmic reticulum Ca2+ ATPase system in human platelets.

We recently identified a multi-SERCA (sarco/endoplasmic reticulum Ca2+ ATPase) system in haemopoietic cells comprising the SERCA 2b, SERCA 3 and a new monoclonal anti-Ca2+ ATPase antibody (PL/IM 430) recognizable SERCA isoforms. We have now investigated the subcellular localization of these enzymes in human platelets by Western blotting of subcellular membrane fractions and by immunoelectron microscopy. We precisely defined the recognition specificity of the polyclonal anti-SERCA 2b, anti-SERCA 3, anti-SERCA 1 antibodies as well as of the monoclonal antibody PL/IM 430 by testing their recognition of the tryptic fragments of the SERCA isoforms. The analysis of fragmented membranes enriched in plasma membrane and intracellular membrane components by Western blotting showed that the SERCA 2b and the SERCA 3 isoforms were found in both the plasma membrane and the intracellular membrane fractions, whereas the PL/IM 430 recognizable SERCA isoform was restricted to membranes associated with the plasma membrane fraction. The immunoelectron microscopical study of the SERCA isoforms in resting platelets showed that: (i) the SERCA 2b isoform was expressed in membranes associated with the plasma membrane and open canalicular system, some alpha-granules and in unidentified membranes; (ii) the SERCA 3 isoform was found associated with plasma and intracellular membranes; and (iii) the PL/IM 430 recognizable SERCA isoform was observed only in structures associated with the cytoplasmic face of the plasma membranes, as confirmed by flow cytometry. Finally, since the PL/IM 430 antibody was raised against intracellular membranes, we looked for a potential membrane redistribution during the isolation procedure used for the preparation of the immunizing membranes. Neuraminidase treatment indeed induced a translocation of the PL/IM 430 recognizable SERCA isoform from plasma to intracellular membranes. Thus, the multi-SERCA system in platelets: (i) is distributed over different platelet membranes, (ii) presents a sub-compartmental organization with some overlapping, and (iii) is partly associated with motile membranes, reflecting an unrecognized level of complexity of Ca2+ stores in these cells.

Antibodies, Monoclonal↗
PubMed1997

Post acute care: can hospitals do better with less?

Judging by reports in medical magazines and journals, 'early discharge schemes', better termed 'post acute care', are not popular with doctors. However, government policy encourages earlier discharge from hospital, so that the choice facing clinicians is to discharge patients early with support, or early without support, or deal with the consequences of length of stay overruns. Fortunately, government funding for post acute care is increasing. There is a strong rationale for post acute care based on better patient outcomes and cost-effectiveness, but these desirable results will only be achieved if scrupulous attention is paid to detail, as embodied in the 10 principles of post acute care. To function optimally, post acute care should be coordinated by the hospital which provided the acute care.

Australia↗
PubMed1997

Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18.

PURPOSE: To determine whether preoperative doxorubicin and cyclophosphamide (AC) permits more lumpectomies to be performed and decreases the incidence of positive nodes in women with primary breast cancer. PATIENTS AND METHODS: Women (n = 1,523) were randomized to National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18; 759 eligible patients received postoperative AC and 747, preoperative AC. The clinical size of breast and axillary tumors was determined before each of four cycles of AC and before surgery. Tumor response to preoperative therapy was clinically complete (cCR), partial (cPR), stable (cSD), or progressive disease (cPD). Tissue from patients with a cCR was evaluated for a pathologic complete response (pCR). RESULTS: Breast tumor size was reduced in 80% of patients after preoperative therapy; 36% had a cCR. Tumor size and clinical nodal status were independent predictors of cCR. Twenty-six percent of women with a cCR had a pCR. Clinical nodal response occurred in 89% of node-positive patients: 73% had a cCR and 44% of those had a pCR. There was a 37% increase in the incidence of pathologically negative nodes. Before randomization, lumpectomy was proposed for 86% of women with tumors < or = 2 cm, 70% with tumors 2.1 to 5.0 cm, and 3% with tumors > or = 5.1 cm. Clinical tumor size and nodal status influenced the physician's decision. Overall, 12% more lumpectomies were performed in the preoperative group; in women with tumors > or = 5.1 cm, there was a 175% increase. CONCLUSION: Preoperative therapy reduced the size of most breast tumors and decreased the incidence of positive nodes. The greatest increase in lumpectomy after preoperative therapy occurred in women with tumors > or = 5 cm, since women with tumors less than 5 cm were already lumpectomy candidates. Preoperative therapy should be considered for the initial management of breast tumors judged too large for lumpectomy.

Antibiotics, Antineoplastic↗
PubMed1997

Antibody response to topical streptokinase.

The aim of this study was to assess anti-streptokinase antibody levels in patients treated with intravenous streptokinase for acute myocardial infarction and in patients treated with topical streptokinase for cutaneous wounds. Sixty-two consecutive patients with acute myocardial infarction (age 65 +/- 12 years), 42 consecutive patients with streptokinase/streptodornase-treated wounds (age 74 +/- 14 years) and a control group of 40 patients with non-streptokinase-treated wounds (age 59 +/- 14 years) were studied over a period of 12 months. Blood was taken prior to commencement of treatment and subsequently at intervals of seven days, one month and six months. Serum was analysed for the presence of anti-streptokinase antibodies, using an ELISA technique. Baseline anti-streptokinase levels were similar in all three groups. Over the subsequent six months, the group treated with intravenous streptokinase developed a significant elevation of antibody levels, whereas antibody levels did not rise significantly in the control group. The group treated with topical streptokinase also developed a significant elevation of antibody levels at one month, but the mean level was significantly lower than that in the intravenous group. By six months, anti-streptokinase levels in the topical group had returned toward baseline values. Topical application of streptokinase causes a significant humoral response by one month, which then declines. The response is significantly lower than that caused by intravenous streptokinase. To ensure clinical thrombolytic efficacy, therefore, it may be preferable to avoid intravenous streptokinase in patients who have been treated with topical streptokinase in the preceding six months.

Administration, Topical↗
PubMed1997

Unilateral brain lesions and performance on Russell's version of the Wechsler Memory Scale in an African American population.

Studies of patients with unilateral lesions report hemisphere-specific and locus-specific impairments on Russell's (1975) Revision of the Wechsler Memory Scale (RWMS). In the current investigation "race-homogeneous" and "race-comparative" paradigms provide the context in which the generalizability of RWMS findings are examined in a population of African Americans with unilateral lesions. The performances of brain-damaged patients were impaired relative to normal controls on five of the six RWMS measures. However, patients with left and right hemisphere damage in our sample did not differ systematically on RWMS subtests. Likewise, among patients with lesions confined to one of the quadrants in the brain, there were no quadrant group differences in performance on RWMS subtests. But, right posteriors were impaired relative to controls on immediate and delayed VR subtests. The relative merits of the race-comparative and race-homogeneous paradigms are considered in the context of these findings.

Adult↗
PubMed1997

Visual organization test performance in an African American population with acute unilateral cerebral lesions.

Controversy abounds as to whether the Hooper Visual Organization Test (VOT) is a measure of hemisphere-specific, region-specific, or non-specific brain damage. The present study examines this issue in a group of African Americans with acute unilateral brain damage and non-brain-injured controls. Consistent with the idea that the VOT is a measure of "organic" cerebral pathology, non-brain damaged controls earned significantly higher VOT scores than brain-damaged patients. While other studies have noted that the VOT is primarily sensitive to damage in the right parietal region of the brain, the present study shows that VOT performance is especially vulnerable to acute lesions in the right anterior quadrant of the brain. This latter finding supports the idea that VOT performance is differentially sensitive to regional cerebral pathology, but challenges the region specific claim of poorer VOT performance among patients with right posterior cerebral damage.

Acute Disease↗
PubMed1997

Potent hypocholesterolemic activity of novel ureido phenoxyisobutyrates correlates with their intrinsic fibrate potency and not with their ACAT inhibitory activity.

The hypocholesterolemic activity for novel ureido fibrate analogues was found to be over 100-fold greater than for any "second-generation" fibrate in cholesterol-fed rats. A comparison of 12 related analogues revealed that the optimal configuration for a urea-bridging region located between two aromatic rings consisted of a trisubstituted nitrogen, optimally substituted with a C7 alkyl chain and linked by dimethylene to a phenoxyisobutyrate moiety found in most fibrate analogues. The hypocholesterolemic potency of these compounds was found to correlate with their increased intrinsic fibrate activity as determined by the ability to induce omega-hydroxylase activity either in rat hepatocyte cultures or in vivo, and not with their 10-fold increased ACAT inhibitory potency when compared to other fibrates. The most active compound, 2-(4-(2-(N'-(2,4- difluorophenyl)-N-heptylureido)ethyl)phenoxy)-2-methylpropionic acid, referred to as (2), was found to induce omega-hydroxylase activity in hepatocytes at concentrations between 5 and 100 nM compared to 1-20 microM concentrations for bezafibrate, and lower serum VLDL+LDL cholesterol in rats at doses between 0.1 and 0.5 mg/kg per day compared to doses of 25-100 mg/kg per day for bezafibrate. Single-dose pharmacokinetic studies with 2 indicated that total drug exposure will be much lower at hypocholesterolemic doses due to the enhanced intrinsic activity, and may result in an improved safety profile for these novel trisubstituted ureido fibrate analogues in rats and humans compared to other fibrates.

Animals↗
PubMed1997

Does pancreatic enzyme supplementation reduce pain in patients with chronic pancreatitis: a meta-analysis.

OBJECTIVE: Pancreatic enzyme therapy is widely used in the treatment of pain in chronic pancreatitis. The aim of our study was to perform a meta-analysis to determine whether pancreatic enzyme supplementation significantly decreases abdominal pain in patients with chronic pancreatitis. METHODS: From a MEDLINE search, we identified, evaluated, and subjected to a meta-analysis, six randomized, double-blind, placebo-controlled trials. Important features of data extraction included the method of subject inclusion, definition of disease, enzyme preparation, response to pancreatic enzyme therapy versus placebo, and modality for measuring response. RESULTS: In the meta-analysis, the pooled estimate of the percentage of patients per study who preferred enzymes relative to placebo was 52% (95% confidence interval, 45-60%). A test of homogeneity indicated that there was no statistically significant heterogeneity across studies in the percentage of patients preferring enzymes. CONCLUSION: Statistical analysis demonstrates no significant benefit of supplemental pancreatic enzyme therapy to relieve pain associated with chronic pancreatitis.

Chronic Disease↗
PubMed1996

Transacylase and phospholipases in the synthesis of bis(monoacylglycero)phosphate.

Bis(monoacylglycero)phosphate (monoacyl-sn-glycero-1-phospho-1'-monoacyl-sn-glycerol) is a unique lipid that represents greater than 15% of the total phospholipid of the resident alveolar macrophage. Bis(monoacylglycero)phosphate is not synthesized de novo but rather is derived from phosphatidylglycerol of the lung surfactant. There are two enantiomers of bis(monoacylglycero)phosphate synthesized, but only the sn-1, and not the sn-3, enantiomer accumulates in vivo. We recently published a scheme in which the sn-3 enantiomer was an intermediate in the synthesis of the final sn-1 bis(monoacylglycero)-phosphate. Here we further expand the understanding of the biosynthesis of bis(monoacylglycero)phosphate by examining the proposed first two steps of the pathway. A phospholipase A and a transacylase activity are partially separated by gel permeation chromatography. Both are optimally active in the acid pH range that supports the concept that they function in the lysosome-endosome compartment of the cell. Independently, these two enzyme systems are incapable of converting phosphatidylglycerol into sn-3 bis(monoacylglycero)phosphate. However, combination of the two partially purified enzymes reestablishes the synthesis of sn-3 bis(monoacylglycero)phosphate from phosphatidylglycerol. The results presented here support our hypothesis that the phospholipase and transacylase are separate enzymes essential to the synthesis of bis(monoacylglycero)phosphate.

Acyltransferases↗
PubMed1996

Effects of postmenopausal hormone replacement therapy on lipoproteins including lipoprotein(a) and LDL subfractions.

The purpose of this study was to examine the effects on lipoprotein risk markers for CHD of oestradiol given alone and in combination with the androgenic progestogen, norethisterone. Eighty postmenopausal women were randomly allocated to receive oestradiol (2 mg/day) alone or with continuous norethisterone (1 mg/day). Serum lipoprotein levels, including lipoprotein(a), were monitored during 12 months on treatment in all the women, and in a sub-set of 32 patients cholesterol was measured in the two major density subfractions of LDL. Oestradiol caused a transient rise in triglycerides, a small decrease in LDL cholesterol (significant only at 3 and 6 months, P < 0.05) and a consistent significant increase in HDL cholesterol (16%, P < 0.01). There was a downward trend in lipoprotein(a) levels which did not achieve statistical significance. The combined preparation caused significant, sustained decreases in triglycerides (31%, P < 0.01), total cholesterol (15%, P < 0.001), VLDL (42%, P < 0.01), LDL (9%, P < 0.05) and HDL (11%, P < 0.001). Lipoprotein(a) was also reduced (39%, P < 0.05). In the sub-set of patients in which LDL subfractions were measured, the reduction in LDL induced by oestradiol monotherapy was significant only at the 3-month visit (6%, P < 0.05). This was due to a decrease in the 'light' (1.025 < d < 1.044 g/ml) subfraction (10%, P < 0.05) and resulted in an apparent shift in subfraction distribution towards the 'heavy' (1.044 < d < 1.060 g/ml) subfraction, although there was no absolute increase in the latter. None of these changes was statistically significant at 12 months. Oestradiol/norethisterone caused sustained decreases in both 'light' (15%, P < 0.05) and 'heavy' (29%, P < 0.05) subfractions, with no significant change in the relative amounts. The changes in 'light' and 'heavy' LDL in this group were highly correlated with changes in triglyceride levels (r = -0.57, P < 0.05 and r = 0.82, P < 0.01 respectively). Therefore, at the end of 1 year's treatment with unopposed oestradiol the only statistically significant change was an increase in HDL cholesterol. Addition of norethisterone to the preparation reversed this potentially beneficial change, but favourably influenced triglycerides, VLDL, LDL subfraction profile and lipoprotein(a), which may counteract the adverse effect on HDL.

Adult↗
PubMed1996

Two patients with duplication of 17p11.2: the reciprocal of the Smith-Magenis syndrome deletion?

J.M. and H.G. are two unrelated male patients with developmental delay. Cytogenetic analysis detected a duplication of 17p11.2 in both patients. The extent of the duplicated region was determined using single copy DNA probes: cen-D17S58-D17S29-D17S258-D17S71-D17S445-+ ++D17S122-tel. Four of the six markers, D17S29, D17S258, D17S71, and D17S445, were duplicated by dosage analysis. Fluorescent in situ hybridization (FISH) analysis of H.G., using cosmids for locus D17S29, confirmed the duplication in 17p11.2. Because the deletion that causes the Smith-Magnesis syndrome involves the same region of 17p11.2 as the duplication in these patients, the mechanism may be similar to that proposed for the reciprocal deletion/duplication event observed in Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) and Charcot-Marie-Tooth Type 1A disease (CMT1A).

Abnormalities, Multiple↗
PubMed1996

Expression of the Tyro4/Mek4/Cek4 gene specifically marks a subset of embryonic motor neurons and their muscle targets.

Tyro4 is a member of the eph family of receptor protein-tyrosine kinases. We present sequence analysis that identifies Tyro4 as the rat homolog of mouse Mek4 and chick Cek4. We also present expression studies that demonstrate an evolutionarily conserved pattern of expression for Tyro4, Mek4, and Cek4. Most strikingly, we find this receptor to be specifically expressed, in all three species, in a subset of motor neurons in the medial motor column and in a subset of axial, but not limb, muscles. Mek4 has previously been ascribed a role in guiding retinal axons to their targets in the optic tectum. Our results extend the purported role of Mek4 in axon guidance to include motor neurons of the medial motor column.

Amino Acid Sequence↗
PubMed1996

Molecular biology of APO E alleles in Alzheimer's and non-Alzheimer's dementias.

Current research into the aetiology of the dementias is focused upon genetic factors which give rise to the disease process. Recently the Apolipoprotein E gene (APO E) and in particular the epsilon 4 allele has been shown to be a risk factor for late onset Alzheimer's disease (AD) where there is an increased frequency of the epsilon 4 allele. The epsilon 4 allele has also been shown to reduce the age at onset of dementia in AD in a dose dependent manner, with the epsilon 2 allele having an opposing effect. We have genotyped a large series of clinically and neuropathologically confirmed cases of AD and found the expected increase in the Apolipoprotein epsilon 4 allele frequency when compared to a control population. Similarly, in Lewy Body Dementia (LBD) an increased epsilon 4 frequency is also found though a normal epsilon 2 frequency exists, unlike in AD where the epsilon 2 frequency is reduced. No changes in APO E allele frequencies were found in presenile AD, Parkinson's disease with or without dementia, or in Down's syndrome. No association was found between any of the APO E alleles and the histopathological indices of AD, cortical senile plaques and neurofibrillary tangles, in any disease category. Neurochemical indicators of AD, loss of choline acetyltransferase activity was also unaffected by APO E genotype. Whilst their appears to be a strong association between the APO E allele and AD and also in LBD, other related neurodegenerative disorders associated with dementia do not show such a linkage. Changes in the epsilon 2 allele frequency may indicate a genetic difference between AD and LBD. The epsilon 4 allele does not appear to influence the burden of AD type pathology and this is particularly relevant given the relative lack of NFT in LBD indicating that factors other than SP or NFT may govern the onset of dementia.

Alleles↗
PubMed1996

Dam-like methylation in legionellae.

The chromosomal DNA of a variety of legionellae, including clinical, environmental, and plasmid-containing strains, was examined for evidence of Dam-like methylation. It was found that Dam-like methylation was present in all the strains examined regardless of their origin or plasmid content.

DNA, Bacterial↗