PubMed Health⌕ Search

Biomedical subjects

S Welch

Publications and source records attributed to S Welch.

At least 37 records · Page 2Linked to original sources
PubMed1998

Phenylbutyrate-induced glutamine depletion in humans: effect on leucine metabolism.

The present study was designed to determine whether sodium phenylbutyrate (phi B) acutely induces a decrease in plasma glutamine in healthy humans, and, if so, will decrease estimates of whole body protein synthesis. In a first group of three healthy subjects, graded doses (0, 0.18, and 0.36 g.kg-1.day-1) of phi B were administered for 24 h before study: postabsorptive plasma glutamine concentration declined in a dose-dependent manner, achieving an approximately 25% decline for a dose of 0.36 g phi B.kg-1.day-1. A second group of six healthy adults received 5-h infusions of L-[1-14C]leucine and L-[1-13C]glutamine in the postabsorptive state on two separate days: 1) under baseline conditions and 2) after 24 h of oral treatment with phi B (0.36 g.kg-1.day-1) in a randomized order. The 24-h phenylbutyrate treatment was associated with 1) an approximately 26% decline in plasma glutamine concentration from 514 +/- 24 to 380 +/- 15 microM (means +/- SE; P < 0.01 with paired t-test) with no change in glutamine appearance rate or de novo synthesis; 2) no change in leucine appearance rate (Ra), an index of protein breakdown (123 +/- 7 vs. 117 +/- 5 mumol.kg-1.h-1; not significant); 3) an approximately 22% rise in leucine oxidation (Ox) from 23 +/- 2 to 28 +/- 2 mumol.kg-1.h-1 (P < 0.01), resulting in an approximately 11% decline in nonoxidative leucine disposal (NOLD = Ra-Ox), an index of protein synthesis, from 100 +/- 6 to 89 +/- 5 mumol.kg-1.h-1 (P < 0.05). The data suggest that, in healthy adults, 1) large doses of oral phenylbutyrate can be used as a "glutamine trap" to create a model of glutamine depletion; 2) a moderate decline in plasma glutamine does not enhance rates of endogenous glutamine production; and 3) a short-term depletion of plasma glutamine decrease estimates of whole body protein synthesis.

Adult↗
PubMed1998

Ovarian hyperandrogenism is associated with insulin resistance to both peripheral carbohydrate and whole-body protein metabolism in postpubertal young females: a metabolic study.

The role of endogenous androgens in enhancing the body's protein anabolic capacity has been controversial. To examine this question we chose to study whole-body protein and glucose kinetics in a group of 21 young, postpubertal females (16.3 +/- 0.6 yr), 8 of whom had clinical and laboratory evidence of ovarian hyperandrogenism (OH) (BMI = 37.8 +/- 1.3 kg/m2). We used L-[1-13C]leucine and [6,6,2H2]glucose tracer infusions before and after suppression of their endogenous androgens with estrogen/progesterone supplementation in the form of Triphasil for 4 weeks. Their baseline data were also compared with those of similar aged girls, 7 obese (OB) (BMI = 36.4 +/- 1.5) and 6 lean (LN) (BMI = 20.9 +/- 0.7) who were normally menstruating and had no evidence of androgen excess. Despite comparable glucose concentrations, both OH and OB groups had significant hyperinsulinemia (OH > OB), both basally and after iv glucose stimulation, as compared to LN controls (basal insulin: OH, 252 +/- 52 pmol/L; OB, 145 +/- 41; LN, 60 +/- 9, P = 0.009 OH vs. LN; peak insulin: OH, 2052 +/- 417; OB, 1109 +/- 127, LN, 480 +/- 120, P = 0.0009 OH vs. LN). The rate of appearance (Ra) of glucose, a measure of glucose production, was greater in the LN controls than in the OH or OB groups (OH, 2.0 +/- 0.1 mg/kg.fat free mass.min; OB, 1.9 +/- 0.1; LN, 3.3 +/- 0.1, P < 0.004 vs. LN). Calculated total rates of whole-body protein breakdown (leucine Ra), oxidation, and protein synthesis (nonoxidative leucine disposal) were substantially higher in the OH and OB groups as compared with LN controls (P < 0.04 vs. LN); however, when data are expressed on a per kilogram of fat free mass basis, the OH group had higher rates of proteolysis than the OB and LN, with indistinguishable rates between the latter two groups. None of the above-mentioned parameters changed after 1 month of administration of Triphasil, despite marked improvement in circulating testosterone and free testosterone concentrations after treatment (testosterone, -50%, P = 0.003; free testosterone, -70%, P = 0.02). We conclude that obesity in young postpubertal females is associated with insulin resistance for both peripheral carbohydrate and protein metabolism, and that patients with the OH syndrome have even greater insulin resistance as compared with simple obesity, regardless of treatment for the androgen excess. Carefully designed studies targeting interventions to improve both the hyperandrogenic and hyperinsulinemic state may prove useful even in the early juvenile stages of this disease.

Adolescent↗
PubMed1998

Testosterone deficiency in young men: marked alterations in whole body protein kinetics, strength, and adiposity.

To investigate specific effects of androgens on whole body metabolism, we studied six healthy lean men (mean +/- SEM age, 23.2 +/- 0.5 yr) before and after gonadal steroid suppression with a GnRH analog (Lupron), given twice, 3 weeks apart. Primed infusions of [13C]leucine, indirect calorimetry, isokinetic dynamometry, growth factor measurements, and percutaneous muscle biopsies were performed at baseline (D1) and after 10 weeks of treatment (D2); each subject served as his own control. Testosterone concentrations were markedly suppressed after 10 weeks of treatment (D1, 535 +/- 141 ng/dL; D2, 31 +/- 9). Leucine's rate of appearance (index of proteolysis) was markedly suppressed after 10 weeks of hypogonadism (-13%; P = 0.01) as well as the nonoxidative leucine disposal, an index of whole body protein synthesis (-13%; P = 0.01) without any changes in plasma amino acid concentrations. All subjects studied after 10 weeks showed a decrease in fat-free mass, as measured by skinfold calipers and dual emission x-ray absortiometry scans (D1, 56.5 +/- 2.9 kg; D2, 54.4 +/- 2.5; P = 0.005), and an increase in percent fat mass (D1, 19.2 +/- 2.5%; D2, 22.2 +/- 2.5; P = 0.001). Rates of lipid oxidation decreased (-31%; P = 0.05) after treatment, with parallel changes in resting energy expenditure (-9%; P = 0.05). Mean and peak GH concentrations (measured every 10 min for 6 h) and GH production rates did not decrease after testosterone deficiency, with an actual increase in basal secretion (P < 0.02). Plasma insulin-like growth factor I (IGF-I) concentrations did not change significantly after 10 weeks of treatment (D1, 227 +/- 44 micrograms/L; D2, 291 +/- 60; P = 0.08). Isokinetic dynamometry of leg extensors at 60 degrees and 180 degrees/s was also decreased after 10 weeks of hypogonadism. Total ribonucleic acid (RNA) was isolated from muscle biopsy samples, and ribonuclease protection assays were performed using human complementary DNA clones for IGF-I, IGF-binding protein-4, myosin, and actin. Ten weeks after Lupron treatment, messenger RNA (mRNA) concentrations of IGF-I decreased significantly, whereas there was a trend toward higher IGF-binding protein-4 concentrations, with no change in myosin or actin mRNA concentrations. In conclusion, testosterone deficiency in young men is associated with a marked decrease in measures of whole body protein anabolism, decreased strength, decreased fat oxidation, and increased adiposity. These effects of testosterone deficiency are independent of changes in peripheral GH production and IGF-I concentrations, even though im IGF-I mRNA concentrations decrease. These data suggest a direct effect of androgens on whole body lipid and protein metabolism.

Adipose Tissue↗
PubMed1997

Involvement of phosphorylation in doxorubicin-mediated myofibril degeneration. An immunofluorescence microscopy analysis.

Loss of myofilaments has been observed in both adaptive cardiac responses (i.e., hypertrophy) as well as in chemotheraputic use of antineoplastic drugs with cardiotoxic side effects (i.e., doxorubicin). An understanding of the degenerative process is a prerequisite for determining approaches to limit the cardiomyopathic changes associated with chronic heart disease or long-term chemotheraputic treatments. However, little is known about the specific events and molecular changes that initiate the degenerative process. To study this process, neonatal rat cardiomyocytes were treated with doxorubicin, which induced rapid and widespread thin-filament degeneration as observed by fluorescence confocal microscopy. Which demonstrated deterioration of sarcomeric thin-filament structure. Changes in the spontaneous beating of cardiomyocytes corresponding with myofibrillar degeneration were apparent using differential interference contrast video microscopy. After finding induction of kinase activity by doxorubicin in cultured cardiomyocytes, the protective effects of specific inhibitors of kinase activity were assessed for their ability to inhibit doxorubicin-induced myofibrillar break-down. Doxorubicin-induced changes appeared similar to the degeneration observed after treatment with a protein kinase activator (phorbol 12-myristate 13-acetate) or a serine-threonine protein phosphatase inhibitor (okadaic acid). Collectively, these results indicate that activation of protein kinase is an important event in the initiation of myofibrillar degeneration by doxorubicin. Further analyses of myofibrillar proteins with respect to biochemical modifications will be necessary to determine if phosphorylation events transmit signal(s) to initiate degeneration.

Animals↗
PubMed1996

Familial hemiplegic migraine, nystagmus, and cerebellar atrophy.

Familial hemiplegic migraine (FHM) is an autosomal dominant disorder characterized by transient hemiplegia during the aura phase of a migraine attack. Nystagmus has been reported in individuals affected with this disorder, but the origin of the ocular motility findings is unknown. A three-generation family with FHM is described and clinical histories are outlined. Ocular motility evaluations were performed on 7 family members, 5 with a history of hemiplegic migraine and 2 without history of migraine. All affected family members had abnormal eye movements consistent with vestibulocerebellar dysfunction. Magnetic resonance imaging scans in affected family members revealed cerebellar vermian atrophy. DNA linkage analysis revealed a common marker in all the affected family members on chromosome 19. We suggest that the hemiplegic migraine attacks and the cerebellar degeneration are linked genetically and that the eye movements are not the ischemic sequelae of recurrent migraine. Strikingly similar ocular motility findings and cerebellar degeneration are reported in both FHM and a genetically related disorder, hereditary paroxysmal cerebellar ataxia (HPCA). The significance of these similarities is discussed along with a proposed pathophysiology for FHM.

Adolescent↗
PubMed1994

The factor analytic structure of seven physical CHD risk factors: a replication study.

An attempt was made to replicate the results of an earlier confirmatory factor analysis of the seven traditionally employed physical risk factors for CHD. As with the first investigation, a two-factor solution was confirmed; only family history loaded on factor 1; the remaining six risk variables (smoking, serum cholesterol, blood pressure, diet, exercise, and weight control) comprised factor 2. These findings may reflect a broad personality trait, i.e., generalized lack of self-control, which could underlie much CHD risk not associated with a family history of heart disease. Implications are drawn for research and practice in the areas of cardiac rehab and prevention.

Adult↗
PubMed1994

Hepatitis C virus infection detected by antibody tests and the polymerase chain reaction as a cause of liver dysfunction in renal transplant recipients.

Hepatitis C infection (HCV) is more prevalent in patients who have received kidney transplants than in the general population but the morbidity and mortality associated with infection in this group is unclear. Sera taken from 36 renal transplant recipients with chronic liver dysfunction and from 42 with normal liver function were tested for HCV infection by second generation ELISA (Abbott Laboratories) and second generation recombinant immunoblot assay (Chiron Corporation) (RIBA-2). Evidence of HCV replication was sought by reverse transcription polymerase chain reaction (RT PCR) using primers from the 5' nontranslated region (5'NTR). Infection was detected in 20/36 (54%) and in 2/42 (4.8%) controls (P < 0.01). Twelve liver dysfunction patients were positive by all three tests, six were positive by ELISA and RT PCR but had indeterminate RIBA-2, one was positive by ELISA and RIBA but negative by RT PCR, and one was positive only by RT PCR. Of two infected control patients, one was positive by all three tests and one who was later found to have been in the early stage of infection was positive only by RT PCR. Follow-up of infected patients showed persistence of viraemia in 14/15 (93%). Evidence of infection with different types of HCV was shown by the lack of amplification by RT PCR by primers with mismatching bases with HCV types 2 and 3. It is concluded that in our renal transplant patients, chronic HCV infection is usually associated with liver dysfunction and persistent infection is common.

Adult↗
PubMed1994

A radiation hybrid map of human chromosome 18.

A human x Chinese hamster (CH) somatic cell hybrid subclone deficient in HPRT and containing only human chromosome 18 was irradiated with 7000 rad and fused to a thymidine kinase deficient CH cell line. Radiation-rescued hybrid cell lines, selected in HAT medium, were analyzed for human DNA with human interspersed-repeat sequence primers. Size and number of human chromosome fragments retained in a subset of hybrids were determined by FISH. A panel of 98 radiation hybrids (RH) was selected and analyzed for 90 chromosome 18-specific STSs by PCR, and for the D18Z1 centromeric marker by Southern blotting. STSs were developed from previously mapped RFLP loci and from published sequences. In addition, 32 novel STSs were generated from an 18-specific lambda library and from 18-specific YACs previously localized to chromosome bands by FISH. Marker retention frequency varied from 8-65% with an average of 24%. In selected RH the STS typing data were correlated with the chromosome 18 regions retained using 'reverse FISH' of IRS-PCR products from the RH to normal metaphase chromosomes. The order and intermarker distances of loci were determined using two-point and multipoint maximum likelihood methods. The resulting RH map covers most of chromosome 18 with four groups of tightly linked markers and three regions of loosely linked markers, one around the centromere and two on the long arm. More than a third of the markers are polymorphic and allow integration with the linkage map. This RH map provides a framework for establishing a clone contig of the entire chromosome 18.

Animals↗
PubMed1993

Generation of a human chromosome 18-specific YAC clone collection and mapping of 55 unique YACs by FISH and fingerprinting.

A yeast artificial chromosome (YAC) library was constructed from a somatic cell hybrid line in which the human chromosome content had been reduced by repeated subcloning to one or two copies of chromosome 18. Screening of 4700 primary yeast transformants generated 74 clones containing a YAC with a human DNA insert averaging 190 kb in size. The human YACs were localized to subregions of chromosome 18 by in situ hybridization of biotin-labeled Alu-PCR products obtained using total yeast DNA as a template. Comparisons of interspersed repetitive sequence-PCR and restriction fragment fingerprint patterns identified five sets of identical and three sets of overlapping YACs. Dual-label fluorescence in situ hybridization interphase mapping was used to determine the order of some nonoverlapping YACs. STS (sequence-tagged site) content mapping was carried out with PCR primers for 56 chromosome 18-specific markers. The identification of YACs containing four known genes--encoding the pituitary adenylate cyclase activating polypeptide (PA-CAP), the myelin basic protein (MBP), ferrochelatase (FECH), and SSAV1, an endogenous retroviral element related to the SSAV virus--provides a precise cytological map position for the respective loci. Our final collection of 55 randomly isolated, unique, and regionally localized YACs (D18S107-D18S161) is distributed over the entire chromosome and collectively covers approximately 12 Mb, i.e., 16% of the estimated 77 Mb of DNA in euchromatin of chromosome 18. These YACs provide reagents for the isolation of genes in these regions and represent nucleation points for the generation of STS to increase coverage of the chromosome by YAC contigs.

Adenylyl Cyclases↗
PubMed1990

Defective gallium-transferrin binding in Alzheimer disease and Down syndrome: possible mechanism for accumulation of aluminium in brain.

The plasma distribution of gallium (as an analogue of aluminium) was investigated in patients with Alzheimer disease, Down syndrome, or stroke dementia, in subjects on haemodialysis for chronic renal failure, and in healthy controls. Gallium-transferrin binding was significantly lower in the Alzheimer (mean [SEM] 7.9 [1.1]%) and Down syndrome groups (6.9 [0.7]%) than in the controls (17.1 [1.6]%), whereas stroke dementia and haemodialysis patients had normal binding. There were no differences among the groups in plasma citrate concentration. The plasma transferrin concentration was slightly lower in the Alzheimer and Down syndrome groups than in the controls, but even lower in stroke dementia patients (1.74 [0.14] g/l vs 2.98 [0.18] g/l in controls). Transferrin iron saturation was higher in the Alzheimer (58.9%) and Down syndrome groups (81.6%) than in the controls (39.0%) or stroke dementia patients (33.4%). This deficiency of gallium/aluminium binding would leave more unbound aluminium which could move readily into the brain, where it has neurotoxic effects.

Adult↗
PubMed1990

A comparison of the structure and properties of normal human transferrin and a genetic variant of human transferrin.

1. A rare genetic variant of human serum transferrin (TfBSHAW) is reported. 2. The variant and normal transferrins have been purified. 3. The two proteins have been shown to be identical with respect to their molecular weights, heat stability, iron uptake and absorbance spectra. 4. The amino acid substitution is thought to be isoleucine replaced by asparagine at either position 378 or position 381. 5. The ferric iron bound to the C-site of TfBSHAW is unstable in the presence of protons or 6 M urea.

Amino Acids↗
PubMed1990

A comparison of the structure and properties of serum transferrin from 17 animal species.

1. A comparison of the chemical and physical properties of the iron transport protein transferrin, purified from the following seventeen animal sera, is reported; human, rhesus monkey, dog, cat, rabbit, guinea pig, mouse, rat, cow, sheep, goat, horse, pig, turkey, duck, turtle and rattlesnake. 2. Similarities and differences in molecular weight, isoelectric point, antibody specificity, effect of pH on iron release, number of sialic acid residues, amino acid composition and the N-terminal amino acid residue, are discussed. 3. The results are compared with the commonly accepted evolutionary origins of the 17 species.

Amino Acids↗
PubMed1990

Minimal model analysis of intravenous glucose tolerance test-derived insulin sensitivity in diabetic subjects.

Although minimal model analysis of frequently sampled iv glucose tolerance tests (FSIGTs) to measure insulin sensitivity is well recognized, application has been limited by the need for endogenous insulin secretion. In the present study we determined whether use of exogenous insulin could permit minimal model assessment of insulin sensitivity (SI) to be extended to diabetic subjects. Normal volunteers had separate FSIGT assessments supplemented with both tolbutamide and insulin to accelerate glucose disappearance, while diabetics had a FSIGT supplemented only with insulin. There was a strong and highly significant correlation between the two assessments in normal subjects (r = 0.87; P less than 0.001), and the rank order of SI generally was maintained with the two assessments over a 3-fold range of SI; however, insulin-determined SI was 16% lower (3.4 +/- 0.4 vs. 4.1 +/- 0.4 x 10(-4) min/microU.microL; P less than 0.01). Diabetic subjects had markedly lower insulin sensitivity than controls (SI = 0.61 +/- 0.16; P less than 0.0001). Across all subjects, the level of fasting serum glucose was correlated inversely with both insulin sensitivity (r = -0.62; P less than 0.05) and acute insulin responses (r = -0.72; P less than 0.02); however, insulin sensitivity in diabetic subjects with little insulin secretion (0.6 +/- 0.2) was comparable to insulin sensitivity in diabetic subjects with near-normal responses (0.6 +/- 0.3). In subjects with fasting hyperglycemia, there were significant correlations between insulin sensitivity and body mass index, percent fat mass, and waist/hip ratio (all P less than 0.03). Among all female subjects, there was also a strong correlation between insulin sensitivity and upper body obesity, as measured by waist/hip ratio (r = -0.68; P less than 0.02). Model parameters also permitted glucose uptake to be estimated in diabetic vs. normal subjects at comparable hyperglycemia (11.1 mmol/L). Total glucose uptake was decreased in diabetic subjects (5.2 +/- 0.8 vs. 12.7 +/- 1.7 mg/min.kg in normals; P less than 0.001), insulin-dependent glucose uptake was diminished to a greater extent (1.3 +/- 0.4 vs. 6.2 +/- 1.2) than noninsulin-independent glucose uptake (3.9 +/- 0.5 vs. 6.4 +/- 0.9; both P less than 0.02). Administration of insulin permits minimal model FSIGT analysis to be applied to diabetic as well as normal subjects, yielding information about both insulin- and noninsulin-mediated glucose uptake as well as insulin sensitivity and insulin secretion.

Adult↗
PubMed1989

A comparison of the structure and properties of human, rat and rabbit serum transferrin.

1. The chemical and physical properties of human, rat and rabbit serum transferrins were compared. 2. The proteins were found to differ in heat stability, iron release, their behaviour during electrophoresis in SDS polyacrylamide gels, and their sulphur amino acid content. 3. The results are discussed in relation to the possible role of disulphide bridges in maintaining the shape and flexibility of the three transferrins, and in their appearance during the evolution of the transferrin family.

Amino Acids↗