Biomedical subjects
Publications and source records attributed to B Fowler.
We found increased levels of atherosclerosis-inducing homocysteine in parkinsonian patients with long-term application of levodopa compared with previously untreated parkinsonian patients and controls. We conclude that antiparkinsonian treatment with levodopa promotes occurrence of vascular disease in Parkinson's disease.
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BACKGROUND: American Indian women have among the highest incidence and mortality rates of cervix cancer in the United States. The incidence of cancer of the cervix among American Indians is 19.5/100,000 versus 7.8/100,000 in U.S. whites, and comparison by geographic region/tribe indicates that the rate is four to six times higher in some tribes. Papanicolaou cytological testing (Pap smear) permits the detection of cervical lesions before they become cancerous, effectively reducing the incidence of cervical cancer by 75-90%. The American Cancer Society recommends a Pap smear every year beginning at age 18 years or when sexually active, and more frequent screening in high-risk populations. METHODS: A random household cross-sectional survey was conducted in Phoenix, Arizona, to assess cervical cancer screening rates among 519 adult urban American Indian women. Logistic regression was used to identify predictors of Pap smear use. RESULTS: Three-quarters (76.1%) of urban women American Indian surveyed received a Pap smear within the past 3 years, but only 49.5% received a Pap smear within the last year. Women over age 50 years were significantly less likely to have received a recent Pap smear in comparison to younger women. CONCLUSIONS: The results of this study indicate that limited access to health care and lack of knowledge about the procedure were important barriers to Pap smear use. Improving cervix cancer screening participation rates is an important step in reducing the disease burden in this high-risk population.
PURPOSE: The health issues which have historically faced American Indians are related to infectious disease, but today many chronic diseases play a large role in the health status of this special population. For example, existing data indicate that American Indians have the poorest cancer survival of any group in the U.S. (34% vs. 50% for U.S. Whites). Regular participation in cancer screening and lifestyle factors such as smoking, diet, and alcohol have been found to significantly contribute to cancer risk. However, available information about these behaviors is sparse and suffers from limitations. The purpose of this study was to assess the prevalence of cancer risk behaviors and provider recommendation for cancer screening among urban American Indian women. METHODS: A random household cross-sectional survey was administered to 519 adult American Indian women in Phoenix, Arizona. Smoking and weight status, alcohol consumption, physical activity, and provider referral were assessed by self-report. RESULTS: The results indicate that weight (69.6% were overweight) and excessive alcohol consumption (12.1 reported chronic drinking) were significant health issues in this population. The prevalence of provider referral for smoking cessation (14.9% among ever smokers) and breast as well as cervical cancer screening (30.1% and 55.5%, respectively) were below the 75% level set forth in the Year 2000 Goals. CONCLUSIONS: The results of this study suggest that increased cancer prevention and control efforts are needed in this special population to address the link between diet, weight, and long-term disease prevention.
BACKGROUND: Elevated fasting levels of total homocysteine are now accepted as an independent risk factor for the development of arteriosclerotic vascular diseases. A polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR), caused by the C677T point mutation, leads to increased thermolability of the enzyme, with reduced enzyme activity. We studied the frequency of this mutation in different groups of the Swiss adult population. PATIENTS AND METHODS: DNA from 361 subjects was screened for the thermolabile MTHFR variant with PCR. Included were healthy subjects without vascular disease (n = 118), older healthy subjects (n = 106), patients with coronary artery disease (CAD, n = 75), and patients with peripheral arterial occlusive disease (PAOD, n = 63). RESULTS: In the different groups studied, homozygosity for the mutation ranged from 4.8 to 16.2%, with a frequency of 16.2% in the healthy cohort. The allele frequencies of the thermolabile allele were 38.5 and 27.3 in young and old controls, and 37.3 and 33.3 in CAD and PAOD patients. In the healthy younger subjects the mutant allele was 1.4 times more frequent compared to the older subjects (P = 0.01). No difference in either MTHFR genotype distribution (P = 0.33) or allele frequencies (P = 0.48) between patients and controls was found. Except for the PAOD group with elevated tHcy levels for the +/+ carriers compared to the other genotypes, no statistically significant difference was found comparing homocysteine levels with genotype. CONCLUSION: This study shows no link between the mutation and the occurrence of vascular disease but we found evidence pointing to a correlation between the mutation and longevity in our population.
A meeting on the health effects of arsenic (As), its modes of action, and areas in need of future research was held in Hunt Valley, Maryland, on 22-24 September 1997. Exposure to As in drinking water has been associated with the development of skin and internal cancers and noncarcinogenic effects such as diabetes, peripheral neuropathy, and cardiovascular diseases. There is little data on specific mechanism(s) of action for As, but a great deal of information on possible modes of action. Although arsenite [As(III)] can inhibit more than 200 enzymes, events underlying the induction of the noncarcinogenic effects of As are not understood. With respect to carcinogenicity, As can affect DNA repair, methylation of DNA, and increase radical formation and activation of the protooncogene c-myc, but none of these potential pathways have widespread acceptance as the principal etiologic event. In addition, there are no accepted models for the study of As-induced carcinogenesis. At the final meeting session we considered research needs. Among the most important areas cited were a) As metabolism and its interaction with cellular constituents; b) possible bioaccumulation of As; c) interactions with other metals; d) effects of As on genetic material; e) development of animal models and cell systems to study effects of As; and f) a better characterization of human exposures as related to health risks. Some of the barriers to the advancement of As research included an apparent lack of interest in the United States on As research; lack of relevant animal models; difficulty with adoption of uniform methodologies; lack of accepted biomarkers; and the need for a central storage repository for stored specimens.
BACKGROUND AND AIMS OF THE STUDY: The influence of sizing on the function of a porcine aortic valve after its implantation using the free-hand technique in the subcoronary position was investigated. METHODS: Dynamic function and leaflet configuration of the valve (n = 16) were first analyzed in its natural aortic root in a left heart simulator at 120/80 mmHg pressure and 4 l/min cardiac output. The valve was then implanted in the recipient porcine aortic root and re-studied. Three groups were investigated: group I (n = 4) comprised of 1-2 mm smaller donor aortic valve than the recipient; group II (n = 8) 3-4 mm smaller; and group III (n = 4) 5-7 mm smaller. Orifice area (OA), systolic and diastolic configurations of the leaflets, pattern and timing of leaflet opening and closure, commissural movement, pressure gradient and valvular regurgitation were analyzed. RESULTS: In the intact donor aortic root, average expansion of the aorta at the commissures, for a pressure change from 0 to 80 mmHg, was about 42%. This was reduced significantly in all assemblies. Group I showed a 34% reduction in OA, and excessive leaflet bending; there was no aortic insufficiency (AI) or pressure gradient across the valve. In group III there was a lesser reduction in OA and reduced leaflet bending, but two of four valves had AI. In group II, the reduction in OA was only 13%, there was less leaflet bending, and no AI. CONCLUSIONS: The donor valve 3-4 mm smaller than the recipient seems an optimal match. The current practice of using the same size donor as recipient may be responsible for excessive leaflet bending and may be implicated in early deterioration of the homograft.
In Näätänen's model of early attention, the role of arousal in influencing the permanent feature detection system (indexed by mismatch negativity [MMN]) and the temporary feature-detection system (indexed by processing negativity [PN]) is unclear. To address this question, we investigated the effects of the anesthetic gas nitrous oxide (N2O) on the MMN and PN. Ten subjects performed a dichotic listening task in which discrimination difficulty and breathing mixture (air or 25% N2O) were manipulated factorially. MMN, PN, N1 and P300 at Fz, Cz, and Pz, as well as reaction time (RT), were measured. N2O had no effect on the PN, but decreased MMN amplitude. As expected, N2O decreased the amplitude of the N1 and P300 and increased the latency of the P300 and RT. The dissociation of MMN and PN by N2O suggests that this agent decreases the ability to detect automatic stimulus change without affecting voluntary selective attention. We interpret these results as indicating that arousal has multidimensional effects on early attentional mechanisms. These dimensions can be differentiated chemically by neurotransmitters in the reticular formation of the brain.
BACKGROUND: Stenosis is a major cause of vein graft failure in peripheral arterial surgery. Our goal is to determine whether vein valves play a role in this process by creating a "pressure trap". METHODS: Seventeen patients with femoro-popliteal reversed saphenous vein grafts were studied intraoperatively. Flow and pressure in the grafts were measured, while the graft outflow was gradually occluded and released for 2-4 seconds. In 3 patients the graft flow was reduced by compressing calf muscles. RESULTS: Patients heart rates were 54-84 BPM, blood pressures 170/80-110/55 mm Hg, and normal graft flow was 40-180 ml/min. In 12 patients with competent vein valves, at reduced flow (<30 m/min) the valves opened and closed in each cardiac cycle. At each closure the pressure was "trapped" distal to the valve producing diastolic hypertension. Also the flow was stagnant for a considerable portion of the cardiac cycle. Maximum diastolic pressure gradient across the valve ranged from 35 to 60 mm Hg and the level of pressure trapped was inversely proportional to the graft flow. CONCLUSIONS: In patients in whom reversed vein grafts with competent valves are placed in the femoro-popliteal positions a "pressure-trap" develops in the distal segment. This segmental hypertension combined with the flow stagnation could play an important role in the graft thickening and stenosis.
PGE2 exerts potent diuretic and natriuretic effects on the kidney. This action is mediated in part by direct inhibition of collecting duct Na+ absorption via a Ca++-coupled mechanism. These studies examine the role the Ca++-coupled PGE-E EP1 receptor plays in mediating these effects of PGE2 on Na+ transport. Rabbit EP1 receptor cDNA was amplified from rabbit kidney RNA. Nuclease protection assays demonstrated highest expression of EP1 mRNA in kidney, followed by stomach, adrenal, and ileum. In situ hybridization, demonstrated renal expression of EP1 mRNA was exclusively over the collecting duct. In fura-2-loaded microperfused rabbit cortical collecting duct, EP1 active PGE analogs were 10-1, 000-fold more potent in raising intracellular Ca++ than EP2, EP3, or EP4-selective compounds. Two different EP1 antagonists, AH6809 and SC19220, completely blocked the PGE2-stimulated intracellular calcium increase. AH6809 also completely blocked the inhibitory effect of PGE2 on Na+ absorption in microperfused rabbit cortical collecting ducts. These studies suggest that EP1 receptor activation mediates PGE2-dependent inhibition of Na+ absorption in the collecting duct, thereby contributing to its natriuretic effects.
The LEAFY/FLORICAULA genes from Arabidopsis and Antirrhinum are necessary for normal flower development and play a key role in diverse angiosperm species. A homologue of these flower meristem-identity genes, NEEDLY (NLY), has been identified in Pinus radiata. Although the NLY protein shares extensive sequence similarity with its angiosperm counterparts, it is lacking the proline-rich and acidic motifs thought to function as transcriptional activation domains. NLY already is expressed during vegetative development at least 5 years before the transition to the reproductive phase. Expression of NLY in transgenic Arabidopsis promotes floral fate, demonstrating that, despite its sequence divergence, NLY encodes a functional ortholog of the FLORICAULA/LEAFY genes of angiosperms. Expression of the LFY::NLY transgene can largely complement the defects in flower development caused by a severe lfy allele.
UNLABELLED: The excitotoxic action of homocysteine and related sulphur-containing metabolites was investigated in organotpyic cultures derived from rat brain cortex and hippocampus by inhibition experiments using antagonists selective for different glutamate receptor subtypes. In addition the direct interaction of these metabolites with glutamate receptors expressed in frog oocytes was tested by conventional two electrode voltage clamp techniques. CONCLUSION: Neurodegeneration and epilepsy observed in homocystinuria may be mediated by L-homocysteic and L-homocysteine sulphinic acid. Both metabolites exhibit excitotoxic potency by interaction with different glutamate receptor subtypes.
Deficient activity of an enzyme can result from a defect in the conversion of the vitamin to a co-enzyme as well from an abnormal apo-enzyme or disturbed binding of coenzyme to enzyme. Conversion of dietary vitamin to intracellular active co-enzyme can be complex and require many physiological and biochemical processes including stomach release of bound vitamin, intestinal uptake, carriers/transport, blood transport, cellular uptake, intracellular release and intracellular compartmentalisation. Disorders of malabsorption (food cobalamin malabsorption, intrinsic factor deficiency and abnormal enterocyte cobalamin processing) and transport proteins (transcobalamin II deficiency, R-binder deficiency) mostly lead to disturbed function of the two cobalamin requiring enzymes, methylmalonyl CoA mutase and methionine synthase. Defects of early steps of intracellular cobalamin (cblF, cbl C/D) result in marked deficiencies of both cobalamin co-enzymes and homocystinuria combined with methylmalonic aciduria. Defective synthesis of adenosyl cobalamin in the cbl A/B defects leads to methylmalonyl CoA mutase. Isolated methionine synthase deficiency is also classified as a cobalamin disorder due to its associated deficient formation of methylcobalamin. Folate disorders include methylene-tetrahydrofolate reductase deficiency and glutamate formimino-transferase deficiency. In addition a hereditary disorder of intestinal folate transport has been described. Less well established are disorders of dihydrofolate reductase, methenyl-tetrahydrofolate cyclohydrolase, and defects of cellular folate uptake.
Diagnosis of the homozygous homocystinurias can be performed by investigations at the metabolite, enzyme and DNA level. The existence of variant forms due to the wide range of genetic variation may result in only small differences in various parameters between controls and affected subjects. 1. Sulphur amino acid concentrations in plasma, especially total homocysteine, are useful in first line diagnostic investigations. 2. Cystathionine-beta-synthase (CBS), methylenetetrahydrofolate reductase (MTHFR) and methylfolate homocysteine methyltransferase (MFMT) can be directly assayed in many tissues including fibroblasts (each) and blood cells (except CBS). Indirect whole cell assays which measure pathway activity dependent on a particular enzyme can provide useful diagnostic information. 3. Direct analysis of mutations is available for CBS, MTHFR and recently also for MFMT deficiencies. However the existence of a larger number of very rare, often private, mutations limits the usefulness of this approach in routine diagnosis. The above diagnostic approaches can generally be applied to prenatal diagnosis. Measurement of methylmalonic acid and other metabolites in amniotic fluid by stable isotope dilution / gas chromatography-mass spectrometry is well established for the methylmalonic acidurias. This method has also been applied to combined homocystinuria/methylmalonic aciduria supported by enzyme assays in cultured cells. Total homocysteine measurement in cell free amniotic fluid is also possible, performed so far in 14 cases with two affected fetuses. The indirect assay of methionine formation from [14C] labelled formate in intact cultured amniotic fluid cells has been for prenatal diagnosis of the remethylation defects.
UNLABELLED: The clinical and biochemical findings in a family with late-onset holocarboxylase synthetase (HCS) deficiency are described. The index patient had two life-threatening episodes of metabolic decompensation at the age of 13 and 18 months with ketotic hypoglycaemia, vomiting and progressive loss of consciousness. The child recovered without biotin therapy. Organic aciduria characteristic of multiple carboxylase deficiency (MCD) was found, however, the key metabolites were only slightly elevated in some samples. Biotinidase deficiency was considered but excluded by the finding of normal plasma biotinidase activity. The correct diagnosis was made only at the age of 19 months when severe MCD was found in lymphocytes in the presence of normal plasma biotin concentration. HCS deficiency was confirmed by fibroblast studies. Biotin therapy (20 or 40 mg/day) prevented further episodes and normalized biochemical parameters with so far normal development. During two subsequent pregnancies, 10 mg biotin/day was administered to the mother from the 20th week of gestation. At delivery plasma biotin in cord blood samples was 3 4 times higher than in maternal plasma. The 2nd child was unaffected. In the 3rd pregnancy prenatal diagnosis was performed at 16 weeks of gestation. The concentration of methylcitrate in amniotic fluid was within the normal range and that of 3-hydroxyisovalerate only slightly elevated. However, enzyme assays in cultured amniotic fluid cells were consistent with an affected fetus. At birth, carboxylase activities in lymphocytes of this newborn were only moderately decreased to 37% of mean normal. HCS deficiency was confirmed postnatally in fibroblasts. Development remains normal on biotin therapy (20 mg/day). CONCLUSION: Prenatal diagnosis in families with milder forms of HCS deficiency has to be performed by enzyme assays in cultured amniotic cells since organic acid analysis of amniotic fluid may be inconclusive in affected fetuses. Biotin administered prenatally is effectively taken up by the fetus and prevents functional deficiency of the carboxylases in an affected newborn.
UNLABELLED: Some dietary fibres have been shown to affect the rate of absorption of dietary carbohydrate, protein and fat as well as exocrine pancreatic function. The aim of the study was to examine the effect of partially hydrolysed guar gum (BENEFIBER), on normal absorption of glucose, amino acid (arginine) and fat. In addition hepatic, pancreatic, renal and haematological side effects were evaluated. METHODS: A double blind, randomized and cross-over design was used. Each subject served as its own control. Ten healthy male volunteers participated in the study. Each subject was randomly assigned to two different dietary regimes for a period of 7 days each. The study was repeated with the other diet for another 7-day period after an interval of at least 1 week. In one study period the subjects took liquid formula diet without fibre and during the other study period they took the same diet with fibre. RESULTS: The results of the study demonstrated that BENEFIBER did apparently not interfere with the normal absorption of glucose, amino acid and fat. In keeping with these observations, insulin release and exocrine pancreatic function were not affected. Haematological, renal and hepatic toxicity were not observed in association with BENEFIBER consumption. CONCLUSION: We conclude that BENEFIBER is a safe source of soluble fibre.
BACKGROUND: Elevated homocysteine concentrations have been associated with premature arteriosclerosis and with impairment of key methylation reactions through accumulation of the homocysteine metabolite S-adenosylhomocysteine. In end-stage renal failure high homocysteine concentrations are commonly found but thus far the concentrations of related adenosylated metabolites in plasma have not been assessed. METHODS: In this prospective study we determined plasma homocysteine and related metabolites in 25 patients on regular haemodialysis, and in 40 healthy volunteers. Blood samples from patients were drawn immediately before and in 10 patients additionally after the dialysis session. RESULTS: Folic acid and vitamin B12 in plasma were similar in patients (mean +/- SEM 25+/-2 nmol/l and 400+/-41 pmol/l respectively) and controls (24+/-3 and 324+/-23 respectively). In patients plasma homocysteine, S-adenosylmethionine and S-adenosylhomocysteine were markedly elevated (36.6+/-3.6 micromol/l, 381+/-32nmol/l and 1074+/-55 nmol/l respectively) compared to the control values (6.8+/-0.4 micromol/l, 60+/-3 nmol/l and 24.4+/-1.1 nmol/l respectively) whereas the molar ratio of plasma S-adenosylmethionine and S-adenosylhomocysteine was significantly decreased (0.36+/-0.02 and 2.7+/-0.2 in patients and controls respectively). Haemodialysis failed to normalize the abnormal levels of these metabolites. CONCLUSION: Since the ratio of S-adenosylmethionine : S-adenosylhomocysteine is closely linked to the activity of numerous enzymatic methylation reactions, these results suggest that methylation may be impaired in these patients.
Expression of the acidic dehydrin gene wcor410 was found to be associated with the development of freezing tolerance in several Gramineae species. This gene is part of a family of three homologous members, wcor410, wcor410b, and wcor410c, that have been mapped to the long arms of the homologous group 6 chromosomes of hexaploid wheat. To gain insight into the function of this gene family, antibodies were raised against the WCOR410 protein and affinity purified to eliminate cross-reactivity with the WCS120 dehydrin-like protein of wheat. Protein gel blot analyses showed that the accumulation of WCOR410 proteins correlates well with the capacity of each cultivar to cold acclimate and develop freezing tolerance. Immunoelectron microscope analyses revealed that these proteins accumulate in the vicinity of the plasma membrane of cells in the sensitive vascular transition area where freeze-induced dehydration is likely to be more severe. Biochemical fractionation experiments indicated that WCOR410 is a peripheral protein and not an integral membrane protein. These results provide direct evidence that a subtype of the dehydrin family accumulates near the plasma membrane. The properties, abundance, and localization of these proteins suggest that they are involved in the cryoprotection of the plasma membrane against freezing or dehydration stress. We propose that WCOR410 plays a role in preventing the destabilization of the plasma membrane that occurs during dehydrative conditions.