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Biomedical subjects

C A Brown

Publications and source records attributed to C A Brown.

At least 55 records · Page 3Linked to original sources
PubMed2000

A common polymorphism in methionine synthase reductase increases risk of premature coronary artery disease.

BACKGROUND: Methionine synthase reductase (MTRR) catalyzes the regeneration of methylcobalamin, a cofactor of methionine synthase, an enzyme essential for maintaining adequate intracellular pools of methionine and tetrahydrofolate, as well as for maintaining homocysteine concentrations at nontoxic levels. We recently identified a common A-->G polymorphism at position 66 of the cDNA sequence of MTRR; this variant was associated with a greater than normal risk for spina bifida in the presence of low levels of cobalamin. OBJECTIVE: To investigate whether the polymorphism was associated with alterations in levels of homocysteine, folate, and vitamin B12, and with risk of developing premature coronary artery disease (CAD), in a population of individuals presenting for cardiac catheterization procedures. METHODS: We screened 180 individuals aged < 58 years with angiographically documented coronary-artery occlusions or occlusion-free major arteries for the presence of the 66A-->G MTRR polymorphism using a polymerase-chain-reaction-based assay. RESULTS: We identified a trend in risk of premature CAD across the genotype groups (P = 0.03) with a sex-adjusted relative risk of premature CAD equal to 1.49 (95% confidence interval 1.10-2.03) for the GG versus AA genotype groups. There was no difference in fasting levels of plasma total homocysteine, serum folate, and vitamin B12 among the three MTRR genotypes. CONCLUSIONS: Our findings suggest that the GG genotype of MTRR is a significant risk factor for the development of premature CAD, by a mechanism independent of the detrimental vascular effects of hyperhomocysteinemia. This association needs to be confirmed in other studies.

Age Factors↗
PubMed2000

Effects of diet on rumen proliferation and fecal shedding of Escherichia coil O157:H7 in calves.

Calves inoculated with Escherichia coli O157:H7 and fed either a high-roughage or high-concentrate diet were evaluated for rumen proliferation and fecal shedding of E. coli O157:H7. Calves fed the high-roughage diet had lower mean rumen volatile fatty acid concentrations and higher rumen pH values than did calves fed the high-concentrate diet. Despite these differences in rumen conditions, the calves fed the high-roughage diet did not have greater rumen populations of E. coli O157: H7 and did not exhibit increased or longer fecal shedding compared with the calves fed the high-concentrate diet. Two calves shedding the highest mean concentrations of E. coli O157:H7 were both fed the high-concentrate diet. There was a significant (P < 0.05) positive correlation between fecal shedding and rumen volatile fatty acid concentration in calves fed a high-concentrate diet. The effects of diet on E. coli O157:H7 proliferation and acid resistance were investigated using an in vitro rumen fermentation system. Rumen fluid collected from steers fed a high-roughage diet, but not from steers fed a high-concentrate diet, supported the proliferation of E. coli O157:H7. Rumen fluid from steers fed a high-concentrate diet rapidly induced acid resistance in E. coli O157:H7. The impact of diet on fecal shedding of E. coli O157:H7 is still unclear and may depend on dietary effects on fermentation in the colon and on diet-induced changes in the resident microflora. However, rapid development of acid tolerance by E. coli O157:H7 in the rumens of calves fed high-concentrate diets, allowing larger populations to survive passage through the acidic abomasum to proliferate in the colon, may be one factor that influences fecal shedding in cattle on feed.

Animal Feed↗
PubMed2000

HMO contracting strategies: protecting the provider's interests.

Managers of provider organizations who understand HMOs' motivations and negotiating strategies will be better prepared to negotiate contracts that serve the interests of their organizations. Information that may strengthen a provider's negotiating position with an HMO, such as the HMO's historic and projected general administrative costs, inflation factors, and utilization rates, can be obtained from the proposed premium rates HMOs must file with their state departments of insurance or from HMO annual statements. Providers also should make sure that their contracts give them the right to regularly review the HMO's database of information relating to the provider's costs and revenues. Without this information, the roots of problems may be obscured, leaving providers with no opportunities to turn around a negative situation.

Capitation Fee↗
PubMed1999

Reactivity and assay restriction profiles of monoclonal and polyclonal antibodies to acid phosphatases: a preliminary study.

The development of secure diagnostic immunoassays requires, among others, rigorous characterisation of potential antibody reagents. The reactivity profiles of seven antibodies (six monoclonal [MAb] and one polyclonal [PAb]) with putative specificity for tartrate-resistant acid phosphatase (TRAP) and/or osteoclasts were evaluated in enzyme-linked immunosorbent assay (ELISA) and/or immunocytochemistry. MAbs 2H1, 4E6 and 5Cl demonstrated assay restriction: exhibiting reactivity only in ELISA. The remaining three MAbs (G211D, G312G and V35B) and the PAb 8023 recognised recombinant TRAP (rTRAP) in ELISA and native acid phosphatases in selected tissues and cell lines. The latter were cytochemically assessed for both tartrate-sensitive acid phosphatase (TSAP) and TRAP. V35B showed reactivity against the monocytic leukaemia cell line U937 and guinea pig kidney tissue (both TSAP+ and TRAP+) and ECV304 (TSAP+) cells. Interestingly, the reactivity of MAb G211D co-localised with TRAP activity in the membrane of osteoclasts but also detected cytoplasmic components in U937 cells and human embryonic lung fibroblasts (TRAP+ and TRAP+). G211D exhibited immunoreactivity against placental trophoblasts (positive for total AP). Intriguingly, MAbs 2H1, 4E6, 5Cl and PAb 8023 cross-reacted with potato acid phosphatase in ELISA, suggesting reactivity to conformationally similar epitopes. Thus, some of these reagents could be used in the development of standardised diagnostic immunoassays or as drug-targeting agents for conditions in which the pathological process involves bone resorption, the MAbs G211D, 2H1, 4E6, 5Cl and PAb 8023 being useful in ELISA but not immunocytochemical detection of TRAP.

Acid Phosphatase↗
PubMed1999

An investigational new drug treatment program for patients with gemcitabine: results for over 3000 patients with pancreatic carcinoma.

BACKGROUND: An Investigational New Drug (IND) treatment program allows patients access to a drug that has shown activity against a serious or life-threatening disease prior to full Food and Drug Administration (FDA) review and approval. This treatment IND program, in which patients with locally advanced or metastatic pancreatic carcinoma were treated with gemcitabine, began in 1995. METHODS: Eligibility criteria were < or =1 prior chemotherapy regimen; a Karnofsky performance status (KPS) of > or =50; and adequate bone marrow, liver, and renal function. Gemcitabine was given at a dose of 1000 mg/m2 weekly x 7 followed by a week of rest, then weekly x 3 every 4 weeks thereafter. In this program, disease-related symptom improvement (DRSI) was defined retrospectively as 1) improvement in pain (on a 7-point scale) and/or analgesic class (e.g., morphine improving to codeine) and/or KPS (> or =20 points), or 2) stability of these three parameters with a 7% increase in weight from baseline. RESULTS: A total of 3023 patients enrolled. At baseline, 80% of them had Stage IV disease, and 84% had a baseline KPS > or = 70. The median age was 65 years, and 56% of the patients were male. The cumulative DRSI response rate after the fourth cycle was 18.4%. Of 982 patients with tumor response data, there were 14 with complete response and 104 with partial response, for an overall response rate of 12.0% (95% confidence interval [CI], 10.0-14.0%). For 2380 patients with survival data, the median survival was 4.8 months (95% CI, 4.5-5.1 months) and the 12-month survival was 15%. Gemcitabine was well tolerated; only 4.6% of discontinuations were due to adverse events. CONCLUSIONS: Notable disease-related symptom improvement and survival were seen with gemcitabine in this large, compassionate-use setting, and these findings were in agreement with those of earlier registration trials.

Aged↗
PubMed1999

The C677T methylenetetrahydrofolate reductase polymorphism influences the homocysteine-lowering effect of hormone replacement therapy.

Elevated homocysteine is an independent risk factor for cardiovascular disease and has been associated with a common C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene. Estrogen use has been shown to reduce homocysteine concentrations, suggesting that this might contribute to the cardiovascular benefit of hormone replacement therapy. We examined 90 postmenopausal women to determine if MTHFR genotype affected the response of homocysteine to hormone replacement therapy. Women with the TT genotype did not show decreased homocysteine in response to hormone replacement therapy as demonstrated for women with the CC genotype and may receive decreased cardiovascular benefits from hormone replacement therapy.

Adult↗
PubMed1999

Changes at P183 of emerin weaken its protein-protein interactions resulting in X-linked Emery-Dreifuss muscular dystrophy.

Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked recessive muscular dystrophy characterized by early contractures of the elbows, Achilles tendons and spine, slowly progressive muscle wasting and weakness, and cardiomyopathy associated with cardiac conduction defects. The emerin gene has been mapped to Xq28 and encodes a 34-kDa serine-rich protein, emerin, which has been localized to the nuclear envelope in a wide variety of tissues, including skeletal and cardiac muscle. Mutations spanning the emerin gene have been identified in patients with EDMD. We present here the effect, on emerin protein expression, of two missense mutations identified in unrelated EDMD patients. These alterations predict the replacement of a proline residue at position 183 with either a histidine or a threonine. Biochemical analysis has demonstrated that the mobility and expression levels of the mutant forms of emerin are indistinguishable from that of wild-type emerin, but that they have weakened interactions with nuclear lamina components. In comparison with the usual EDMD phenotype, patients with P183 missense mutations have a later age at onset of first symptoms, elbow contractures, ankle contractures, upper limb weakness and lower limb weakness, but there is no difference for the age at onset of cardiac involvement. This is the first report of protein studies on patients with missense mutations resulting in the clinical features of EDMD. These studies demonstrate the importance of proline 183 for the proper structure/function of emerin.

Adult↗
PubMed1999

Fecal shedding and rumen growth of Escherichia coli O157:H7 in fasted calves.

Nine weaned calves aged from 8 to 12 weeks were fitted with rumen cannulas and were inoculated by cannula with 10(10) CFU of a five-strain mixture of nalidixic acid-resistant Escherichia coli O157:H7. Six calves were fasted for 48 h on days 15 and 16 and days 22 and 23 after inoculation. Samples of rumen contents and feces were obtained daily to enumerate E. coli O157:H7 populations and to determine rumen volatile fatty acid (VFA) concentrations and rumen pH. Fasting resulted in a marked decrease in rumen VFA concentrations from a mean of 135 mmol/liter before the fast to a mean of 35 mmol/liter during the second day of the fast. However, there was no correlation between daily VFA concentration and daily rumen or fecal numbers of E. coli O157:H7 in any of the calves. Fasting generally had no significant effect on the rumen or fecal numbers of E. coli O157:H7. The exception was a single fasted calf that experienced a 3-log(10) CFU/g increase in fecal shedding during and after the first fast. Despite the consistent changes in VFA concentrations in fasted calves, the fluctuations in rumen numbers of E. coli O157:H7 in the rumen of fasted calves were minimal. At the end of the experiment, E. coli O157:H7 was detected in either the rumen or omasum in two of three control calves at necropsy and in either the rumen or reticulum in five of six fasted calves. E. coli O157:H7 was detected in the colon in two of three control calves and in six of six fasted calves at necropsy. These results suggest that in cattle already shedding E. coli O157:H7, feed withdrawal and the associated changes in rumen pH and VFA concentrations have little effect on fecal shedding and rumen proliferation of E. coli O157:H7.

Animals↗
PubMed1998

Complications of pediatric thoracolumbar and lumbar pedicle screws.

STUDY DESIGN: This was a retrospective review of 223 consecutive cases (1986-1996) from one institution where 759 thoracolumbar and lumbar pedicle screws were used in the treatment of various pediatric spinal disorders in patients less than 18 years of age. OBJECTIVES: To determine the incidence of short- and long-term (> 2 years follow-up) complications in this group of patients-specifically, complications related to instrumentation and those directly attributable to pedicle screws in these pediatric patients. SUMMARY OF BACKGROUND DATA: Although much has been written regarding the use of pedicle screws in the adult population, no published study has examined complication rates with regard to thoracolumbar and lumbar pedicle screws placed for pediatric spinal disorders. METHODS: A retrospective review of 223 consecutive cases involving 759 pedicle screws placed for a variety of pediatric spinal disorders was performed. Complications were divided into short term and long term (> 2 years follow-up) and into those relating to instrumentation and those relating to pedicle screws specifically. RESULTS: Short-term complication occurred in 5 patients (2.2%) for a total of 17 screws ultimately removed. Only two of these patients had screws removed for lumbar radicular complaints. No residual sequellae resulted. No long-term (> 2 years postoperative) complications were noted. CONCLUSION: Low short- and long-term complication rates specific for pediatric pedicle screws suggests that for properly trained spinal surgeons, pedicle screws fixation in the pediatric population can be performed safely to treat a variety of spinal disorders.

Adolescent↗
PubMed1998

Impact of carrier status determination for Duchenne/Becker muscular dystrophy by computer-assisted laser densitometry.

Carrier status determination for Duchenne and Becker muscular dystrophies (D/BMD), disorders caused by mutations in the dystrophin gene at Xp21, is complicated by a number of factors. These include a high mutation rate and a 5-10% recombination frequency across the dystrophin gene. For these reasons, linkage analysis frequently gives an inconclusive result, and a direct mutation detection method for females at risk is desirable. Because 65% of the mutations that cause D/BMD are deletions of one or more exons of the dystrophin gene, diagnosis in most affected males is relatively easy using multiplex polymerase chain reaction (PCR) analysis. However, deletion analysis in females is more difficult because of the interference of the normal X chromosome in the deletion assay. We have developed a quantitative PCR-based analysis designated computer-assisted laser densitometry (CALD), which uses the automated fluorescent fragment analysis application of the Applied Biosystems (Foster City, California) automated sequencer. This method has proved to be 100% accurate in retrospective blind studies analysing a total of 351 samples. Subsequent analysis of more than 800 women from more than 400 D/BMD families has shown that a highly accurate carrier risk can be given in more than 90% of cases.

Densitometry↗
PubMed1998

Beneficial effects of chronic administration of dietary omega-3 polyunsaturated fatty acids in dogs with renal insufficiency.

Dietary supplementation with polyunsaturated fatty acids (PUFA) alters the course of experimental renal disease in rats. However, chronic renal disease in other laboratory animals and in human beings frequently responds differently to experimental manipulations. We investigated the effects of variations in dietary PUFA composition on the chronic course of induced renal disease in dogs. Two months after 15/16 nephrectomy, dogs were randomly divided into three groups of seven animals each. For the next 20 months, each group of dogs was fed a low-fat basal diet supplemented with one of three sources of lipid to achieve a final concentration of 15% added fat. Fat sources provided omega-3 PUFA (menhaden fish oil, group FO), omega-6 PUFA (safflower oil, group SO), or saturated fatty acids (beef tallow, group BT). Throughout the dietary trial, the magnitude of proteinuria and the plasma concentrations of creatinine, cholesterol, and triglyceride were lower in group FO. The mean overall glomerular filtration rate was 0.89+/-0.18 ml/min per kilogram of body weight in group SO, a value that was significantly less (p < 0.05) than the corresponding values for groups BT and FO (1.21+/-0.18 and 1.43+/-0.20 ml/min/kg, respectively). Renal interstitial fibrosis also was significantly elevated in group SO. The extents of mesangial matrix expansion, glomerulosclerosis, and renal interstitial cellular infiltrate were similar in groups BT and SO, but lower (p < 0.05) in group FO. We conclude that supplementation with omega-6 PUFA enhanced renal injury; supplementation with omega-3 PUFA was renoprotective.

Animals↗
PubMed1998

Complications in spinal fusion.

Complications in spinal fusion can lead to less than desirable results. The complications of spinal fusion in the cervical and lumbar spine are discussed. Methods of avoiding and correcting complications also are reviewed. Through a better understanding, it is hoped that complications can be prevented.

Bone Plates↗