intravenous immunoglobulin therapy in multiple sclerosis--a pilot study
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Publication
Journal: Gastroenterology
November/27/2011
Abstract
OBJECTIVE
The relative frequency of nonalcoholic steatohepatitis (NASH) as an indication for liver transplantation and comparative outcomes following transplantation are poorly understood.
METHODS
We analyzed the Scientific Registry of Transplant Recipients for primary adult liver transplant recipients from 2001 to 2009.
RESULTS
From 2001 to 2009, 35,781 patients underwent a primary liver transplant, including 1959 for who NASH was the primary or secondary indication. The percentage of patients undergoing a liver transplant for NASH increased from 1.2% in 2001 to 9.7% in 2009. NASH is now the third most common indication for liver transplantation in the United States. No other indication for liver transplantation increased in frequency during the study period. Compared with other indications for liver transplantation, recipients with NASH are older (58.5±8.0 vs 53.0±8.9 years; P<.001), have a larger body mass index (>30 kg/m2) (63% vs 32%; P<.001), are more likely to be female (47% vs 29%; P<.001), and have a lower frequency of hepatocellular carcinoma (12% vs 19%; P<.001). Survival at 1 and 3 years after liver transplantation for NASH was 84% and 78%, respectively, compared with 87% and 78% for other indications (P=.67). Patient and graft survival for liver recipients with NASH were similar to values for other indications after adjusting for level of creatinine, sex, age, and body mass index.
CONCLUSIONS
NASH is the third most common indication for liver transplantation in the United States and is on a trajectory to become the most common. Outcomes for patients undergoing a liver transplant for NASH are similar to those for other indications.
Publication
Journal: American Journal of Physiology - Gastrointestinal and Liver Physiology
December/14/2011
Abstract
Although there are small animal platforms that recapitulate some of the histological features of nonalcoholic fatty liver disease, there are no small animal models of nonalcoholic steatohepatitis (NASH) with consistent hepatocellular ballooning and progressive fibrosis that also exhibit fidelity to the human condition physiologically. We examined the metabolic and histological effects of a diet on the basis of the composition of "fast food" (high saturated fats, cholesterol, and fructose). Mice (n = 8 in each group) were assigned to diets as follows: 1) standard chow (SC), i.e., 13% energy as fat [1% saturated fatty acids (SFA)], 2) high fat (HF), i.e., 60% energy as fat (1% SFA), and 3) fast food (FF), i.e., 40% energy as fat (12% SFA, 2% cholesterol). All three diets were supplemented with high fructose. All diets produced obesity. The HF and FF diets produced insulin resistance. Liver histology was normal in animals fed the SC diet. Steatohepatitis with pronounced ballooning and progressive fibrosis (stage 2) was observed in mice fed the FF diet. Although the HF diet produced obesity, insulin resistance, and some steatosis; inflammation was minimal, and there was no increase in fibrosis. The FF diet produced a gene expression signature of increased fibrosis, inflammation, and endoplasmic reticulum stress and lipoapoptosis. A diet based on high cholesterol, high saturated fat, and high fructose recapitulates features of the metabolic syndrome and NASH with progressive fibrosis. This represents a novel small animal model of fibrosing NASH with high fidelity to the human condition. These results highlight the contribution of dietary composition to the development of nonalcoholic fatty liver disease and NASH.
Publication
Journal: Hypertension
October/26/2005
Abstract
The mechanisms mediating the more striking age related increase in cardiovascular disease in women than in men are poorly understood. We tested the hypothesis that aging has a greater impact on sympathetic traffic in women than in men. Muscle sympathetic nerve activity (MSNA), blood pressure, and heart rate were measured in 120 healthy males and 96 healthy females aged 20 to 72 years. MSNA increased with age in both sexes, but age explained 53% of MSNA variance in female subjects and only 8% of MSNA variance in male subjects. Both the slope and intercept of the regression lines were significantly different between male and female groups (P<0.01 and P<0.001, respectively). For each decade of life, women showed an increase of 6.5 bursts/min in comparison to an increase of 2.6 bursts/min in males. Menopause did not explain the age-related increase in sympathetic traffic. For every 10-burst/min increment in MSNA in subjects older than 40, mean blood pressure increased by 2.7 mm Hg in men and by 6.1 mm Hg in women. Aging is accompanied by a greater increase in sympathetic traffic in women than in men, independent of menopausal status. Sympathetic neural mechanisms may contribute importantly to the more marked influence of age on blood pressure and cardiovascular disease in women.
Publication
Journal: Hepatology
September/16/1998
Abstract
End-stage liver disease secondary to hepatitis C virus (HCV) infection is the leading indication for liver transplantation in the United States. Recurrence of HCV infection is nearly universal. We studied the patients enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database to determine whether pretransplantation patient or donor variables could identify a subset of HCV-infected recipients with poor patient survival. Between April 15, 1990, and June 30, 1994, 166 HCV-infected and 509 HCV-negative patients underwent liver transplantation at the participating institutions. Median follow-up was 5.0 years for HCV-infected and 5.2 years for HCV-negative recipients. Pretransplantation donor and recipient characteristics, and patient and graft survival, were prospectively collected and compared. Cumulative patient survival for HCV-infected recipients was similar to that of recipients transplanted for chronic non-B-C hepatitis, or alcoholic and metabolic liver disease, better than that of patients transplanted for malignancy or hepatitis B (P = .02 and P = .003, respectively), and significantly worse than that of patients transplanted for cholestatic liver disease (P = .001). Recipients who had a pretransplantation HCV-RNA titer of>> or = 1 x 10(6) vEq/mL had a cumulative 5-year survival of 57% versus 84% for those with HCV-RNA titers of < 1 x 10(6) vEq/mL (P = .0001). Patient and graft survival did not vary with recipient gender, HCV genotype, or induction immunosuppression regimen among the HCV-infected recipients. While long-term patient and graft survival following liver transplantation for end-stage liver disease secondary to HCV are generally comparable with that of most other indications, higher pretransplantation HCV-RNA titers are strongly associated with poor survival among HCV-infected recipients.
Publication
Journal: Journal of Clinical Endocrinology and Metabolism
March/14/2007
Abstract
BACKGROUND
Polycystic ovary syndrome (PCOS), the most common cause of anovulatory infertility, is characterized by increased ovarian androgen production and arrested follicle development and is frequently associated with insulin resistance. These PCOS phenotypes are associated with exaggerated ovarian responsiveness to FSH and increased pregnancy loss.
OBJECTIVE
The objective of this study was to examine whether the perturbations in follicle growth and the intrafollicular environment affect gene expression and ultimately development of the PCOS oocyte.
METHODS
Oocyte cDNA was subjected to microarray and PCR analysis.
METHODS
This study was conducted at a university laboratory.
METHODS
The study comprised 10 normal ovulatory women and nine women with PCOS.
METHODS
The intervention was GnRH analog/recombinant human FSH therapy for in vitro fertilization.
METHODS
The main outcome measure was mRNA abundance of oocyte-expressed genes.
RESULTS
Cluster analysis revealed differences in global gene expression profiles between normal and PCOS oocytes. Of the 8123 transcripts expressed in the oocytes, 374 genes showed significant differences in mRNA abundance in PCOS oocytes. Annotation of the data demonstrated that a subset of these genes was associated with chromosome alignment and segregation during mitosis and/or meiosis. Furthermore, 68 of the differentially expressed genes contained putative androgen receptor and/or peroxisome proliferating receptor gamma binding sites.
CONCLUSIONS
These analyses demonstrated that normal and PCOS oocytes that are morphologically indistinguishable and of high quality exhibit different gene expression profiles. Promoter analysis suggests that androgens and other activators of nuclear receptors may play a role in differential gene expression in the PCOS oocyte. Likewise, annotation of the differentially expressed genes suggests that defects in meiosis or early embryonic development may contribute to reduced developmental competency of PCOS oocytes.
Publication
Journal: Journal of Physiology
July/14/2004
Abstract
We tested the hypothesis that nitric oxide (NO) is responsible for blunting sympathetic alpha-adrenergic vasoconstriction in the active muscles of humans (functional sympatholysis). We measured forearm blood flow (Doppler ultrasound) and calculated the reductions in forearm vascular conductance (FVC) in response to alpha-adrenergic receptor stimulation during rhythmic handgrip exercise and during a control non-exercise vasodilator condition (intra-arterial adenosine), before and after local NO synthase (NOS) inhibition in healthy men. The forearm vasoconstrictor responses to endogenous noradrenaline release (intra-arterial tyramine) were significantly blunted during moderate exercise compared with adenosine, and these vasoconstrictor responses were not restored by NOS inhibition with NG-monomethyl-L-arginine (L-NMMA; n = 6) or NG-nitro-L-arginine methyl ester (L-NAME; n = 8). Similarly, L-NAME did not restore the vasoconstrictor responses to tyramine in contracting muscle during heavy rhythmic handgrip exercise (n = 4). In four additional subjects, we also found that the vasoconstrictor responses evoked by tyramine during exercise or adenosine were repeatable in the absence of NOS inhibition (i.e. time control). Finally, in five subjects the forearm vasoconstrictor responses to direct alpha 1-adrenergic (phenylephrine) and alpha 2-adrenergic (clonidine) receptor stimulation were blunted during moderate exercise compared with adenosine; these responses were also unaffected by L-NAME. Taken together, our results demonstrate that NO is not obligatory for functional sympatholysis in contracting skeletal muscles of healthy men.
Publication
Journal: Journal of Physiology
December/8/2002
Abstract
Sympathetic vasoconstriction of muscle vascular beds is important in the regulation of systemic blood pressure. However, vasoconstriction during exercise can also compromise blood flow support of muscle metabolism. This study tested the hypothesis that local factors in exercising muscle blunt vessel responsiveness to sympathetic vasoconstriction. We performed selective infusions of three doses of tyramine into the brachial artery (n = 8) to evoke endogenous release of noradrenaline (norepinephrine) at rest and during moderate and heavy rhythmic handgrip exercise. In separate experiments, tyramine was administered during two doses of adenosine infusion (n = 7) and two doses of sodium nitroprusside (SNP) infusion (n = 8). Vasoconstrictor effectiveness across conditions was assessed as the percentage reduction in forearm vascular conductance (FVC), calculated from invasive blood pressure and non-invasive Doppler ultrasound blood flow measurements at the brachial artery. Tyramine evoked a similar dose-dependent vasoconstriction at rest in all three groups, with the highest dose resulting in a 42-46 % reduction in FVC. This vasoconstriction was blunted with increasing exercise intensity (e.g. tyramine high dose percentage reduction in FVC; rest -43.4 +/- 3.7 %, moderate exercise -27.5 +/- 2.3 %, heavy exercise -16.7 +/- 3.6 %; P < 0.05). In contrast, tyramine infusion resulted in a greater percentage reduction in FVC during both doses of adenosine vs. rest (P < 0.05). Finally, percentage change in FVC was greater during low dose SNP infusion vs. rest (P < 0.05), but not different from rest at the high dose of SNP infusion (P = 0.507). A blunted percentage reduction in FVC during endogenous noradrenaline release in exercise but not vasodilator infusion indicates that sympathetic vasoconstriction is blunted in exercising muscle. This blunting appears to be exercise intensity-dependent.
Publication
Journal: Journal of Applied Physiology
February/18/1997
Abstract
We investigated the separate and combined contributions of nitric oxide (NO) and vasodilating prostaglandins as mediators of reactive hyperemia in the human forearm. Forearm blood flow (FBF) was measured with venous occlusion plethysmography after 5 min of ischemia. In one protocol (n = 12), measurements were made before and after intra-arterial administration of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) to one forearm. In a separate protocol (n = 7), measurements were made before and after systemic administration of the cyclooxygenase inhibitor ibuprofen and again after L-NMMA. L-NMMA reduced baseline FBF at rest (2.7 +/- 0.4 to 1.6 +/- 0.2 ml.100 ml-1.min-1; P < 0.05) and had a modest effect on peak forearm vascular conductance and flow (forearm vascular conductance = 31.1 +/- 3.1 vs. 25.7 +/- 2.5 ml.min-1.100 ml forearm-1.100 mmHg of perfusion pressure-1.min-1, P < 0.05; FBF = 26.6 +/- 2.9 vs. 22.8 +/- 2.6 ml.100 ml-1.min-1, P = 0.055). Total excess flow above baseline during reactive hyperemia was unaffected by L-NMMA (14.3 +/- 3.0 vs. 13.1 +/- 2.4 ml/100 ml; P < 0.05). Ibuprofen did not change FBF at rest, reduced peak FBF from 27.6 +/- 1.9 to 20.3 +/- 2.7 ml.100 ml-1.min-1 (P < 0.05), but had no effect on total excess flow above baseline, Infusion of L-NMMA after ibuprofen reduced FBF at rest by 40%, had no effect on peak flow, but reduced total excess flow above baseline from 12.0 +/- 2.5 to 7.6 +/- 1.3 ml/100 ml (P < 0.05). These date demonstrate that NO synthase inhibition has a modest effect on peak vasodilation during reactive hyperemia but plays a minimal role later. Prostaglandins appear to be important determinants of peak flow. The effects of NO synthase inhibition during reactive hyperemia may also be potentiated by concurrent cyclooxygenase inhibition.
Publication
Journal: Circulation
October/6/2004
Abstract
BACKGROUND
C-reactive protein (CRP) is synthesized from the liver and is regulated by cytokines, especially interleukin-6. Leptin, the adipocyte-derived protein product of the ob gene, is related to amount of body fat. The long form of the leptin receptor resembles cytokine receptors, which include the interleukin-6 receptor. Both leptin and CRP may be increased in women, in obesity, and in inflammation, and both have been linked to cardiovascular pathophysiological processes and increased cardiovascular risk. We tested the hypothesis that leptin is associated with CRP levels independently of the influences of gender, body mass index (BMI), waist-to-hip ratio, and other variables.
RESULTS
We studied 100 healthy volunteers (48 men, and 52 women). For all subjects, leptin was independently associated with CRP after adjustment for age, gender, BMI, waist-to-hip ratio, smoking, and alcohol consumption (F=12.39, P=0.0007). There was a strong and significant positive relationship between leptin and CRP in both women (R=0.61, P<0.0001) and men (R=0.55, P<0.0001) considered separately. The association between leptin and CRP was significant even after adjustment for age, BMI, waist-to-hip ratio, smoking, and alcohol consumption in women (F=7.13, P=0.01) and men (F=5.69, P=0.02). When only subjects with BMI <25 kg/m2 were considered (n=47), CRP was not linked to BMI (R=0.02, P=0.96), but a significant association between leptin and CRP was still evident (R=0.55, P<0.0001).
CONCLUSIONS
Leptin and CRP levels are independently associated in normal humans, providing further evidence linking metabolic and inflammatory cardiovascular disease mechanisms.
Publication
Journal: Acta psychiatrica Scandinavica. Supplementum
May/17/2007
Abstract
OBJECTIVE
The mechanisms mediating hypercortisolemia in depression remain controversial. Adopting the biomarker strategy, we studied adrenocorticotropin (ACTH) and cortisol dynamics in hypercortisolemic and non-hypercortisolemic depressed in-patients, and in normal volunteers.
METHODS
Deconvolution analysis of 24-h pulsatile secretion, approximate entropy (ApEn) estimation of secretory regularity, cross-ApEn quantitation of forward and reverse ACTH-cortisol synchrony, and cosine regression of 24-h rhythmicity.
RESULTS
Hypercortisolemia was strongly associated with melancholic and psychotic depressive subtypes. Hypercortisolemic patients had elevated ACTH and cortisol secretion, mediated chiefly by increased burst masses. Basal ACTH secretion was increased, ACTH half-life was reduced, and mean 24-h ACTH concentration was normal. Cortisol secretion was increased in a highly irregular pattern (high ApEn), with high ACTH ->> cortisol cross-ApEn (impaired feedforward coupling). Cortisol-mediated feedback on the secretory pattern of ACTH was normal. Hypercortisolemic depressed patients had normal programming of the central hypothalamo-pituitary-adrenal (HPA) axis pulse generator: ACTH pulse frequency, cortisol pulse frequency, circadian acrophases, and ApEn of ACTH secretion were normal. Responsiveness of the adrenal cortex to endogenous ACTH was normal. Non-hypercortisolemic patients resembled hypercortisolemic patients on ACTH regulatory parameters but had low total cortisol secretion.
CONCLUSIONS
Increased ACTH secretion occurs in depressed in-patients regardless of cortisolemic status, confirming central HPA axis overdrive in severe depression. Depressive hypercortisolemia results from an additional change in the adrenal cortex that causes ACTH-independent, disorderly basal cortisol release, a sign of physiological stress in melancholic/psychotic depression.
Publication
Journal: Liver Transplantation
September/10/2002
Abstract
Decompensated liver disease associated with chronic hepatitis C virus (HCV) infection is the most common indication for liver transplantation. It was shown previously that greater pretransplantation HCV titers are associated with relatively poor patient and graft survival. The tolerability and efficacy of antiviral therapy in patients with decompensated liver disease are not known. We conducted a pilot study to determine the likely tolerability and efficacy of pretransplantation antiviral therapy with interferon alfa-2b, with or without ribavirin. HCV RNA-positive patients at or near the top of their respective waiting lists were randomly assigned to one of three treatment regimens until the time of liver transplantation: (1) group A, interferon alfa-2b, 1 x 10(6) U/d; (2) group B, interferon alfa-2b, 3 x 10(6) U three times weekly; or (3) group C, interferon alfa-2b, 1 x 10(6) U/d, plus ribavirin, 400 mg twice daily. Less than half the patients screened met entry criteria, with thrombocytopenia and leukopenia the most common reasons for exclusion. Fifteen patients were administered antiviral therapy; three patients in group A and six patients each in groups B and C. Loss of detectable HCV RNA was seen in 33% of patients, whereas 55% had a decrease in viral titers on therapy. Twenty-three adverse events occurred, including 20 serious adverse events. Thrombocytopenia was the most common adverse event. Two infectious complications occurred; one of these had a fatal outcome. We conclude that although pretransplantation antiviral therapy may reduce HCV titers in a minority of patients who meet treatment initiation criteria, adverse events associated with therapy are frequent and often severe in patients with Child's class B and C cirrhosis.
Publication
Journal: American Journal of Human Genetics
April/23/2003
Abstract
Autosomal dominant polycystic liver disease (ADPLD) is a distinct clinical and genetic entity that can occur independently from autosomal dominant polycystic kidney disease (ADPKD). We previously studied two large kindreds and reported localization of a gene for ADPLD to an approximately 8-Mb region, flanked by markers D19S586/D19S583 and D19S593/D19S579, on chromosome 19p13.2-13.1. Expansion of these kindreds and identification of an additional family allowed us to define flanking markers CA267 and CA048 in an approximately 3-Mb region containing >70 candidate genes. We used a combination of denaturing high-performance liquid chromatography (DHPLC) heteroduplex analysis and direct sequencing to screen a panel of 15 unrelated affected individuals for mutations in genes from this interval. We found sequence variations in a known gene, PRKCSH, that were not observed in control individuals, that segregated with the disease haplotype, and that were predicted to be chain-terminating mutations. In contrast to PKD1, PKD2, and PKHD1, PRKCSH encodes a previously described human protein termed "protein kinase C substrate 80K-H" or "noncatalytic beta-subunit of glucosidase II." This protein is highly conserved, is expressed in all tissues tested, and contains a leader sequence, an LDLa domain, two EF-hand domains, and a conserved C-terminal HDEL sequence. Its function may be dependent on calcium binding, and its putative actions include the regulation of N-glycosylation of proteins and signal transduction via fibroblast growth-factor receptor. In light of the focal nature of liver cysts in ADPLD, the apparent loss-of-function mutations in PRKCSH, and the two-hit mechanism operational in dominant polycystic kidney disease, ADPLD may also occur by a two-hit mechanism.
Publication
Journal: Diabetes
August/20/2002
Abstract
Improvement of glycemic status by insulin is associated with profound changes in amino acid metabolism in type 1 diabetes. In contrast, a dissociation of insulin effect on glucose and amino acid metabolism has been reported in type 2 diabetes. Type 2 diabetic patients are reported to have reduced muscle oxidative enzymes and VO(2max). We investigated the effect of 11 days of intensive insulin treatment (T(2)D+) on whole-body amino acid kinetics, muscle protein synthesis rates, and muscle functions in eight type 2 diabetic subjects after withdrawing all treatments for 2 weeks (T(2)D-) and compared the results with those of weight-matched lean control subjects using stable isotopes of the amino acids. Whole-body leucine, phenylalanine and tyrosine fluxes, leucine oxidation, and plasma amino acid levels were similar in all groups, although plasma glucose levels were significantly higher in T(2)D-. Insulin treatment reduced leucine nitrogen flux and transamination rates in subjects with type 2 diabetes. Synthesis rates of muscle mitochondrial, sarcoplasmic, and mixed muscle proteins were not affected by glycemic status or insulin treatment in subjects with type 2 diabetes. Muscle strength was also unaffected by diabetes or glycemic status. In contrast, the diabetic patients showed increased tendency for muscle fatigability. Insulin treatment also failed to stimulate muscle cytochrome C oxidase activity in the diabetic patients, although it modestly elevated citrate synthase. In conclusion, improvement of glycemic status by insulin treatment did not alter whole-body amino acid turnover in type 2 diabetic subjects, but leucine nitrogen flux, transamination rates, and plasma ketoisocaproate level were decreased. Insulin treatments in subjects with type 2 diabetes had no effect on muscle mitochondrial protein synthesis and cytochrome C oxidase, a key enzyme for ATP production.
Publication
Journal: American Journal of Clinical Nutrition
December/22/2010
Abstract
BACKGROUND
Energy intake (EI) during weight loss is difficult and costly to measure accurately.
OBJECTIVE
The objective was to develop and validate a computational energy balance differential equation model to determine individual EI during weight loss.
METHODS
An algorithm was developed to quantify EI during weight loss based on a validated one-dimensional model for weight change. By using data from a 24-wk calorie-restriction study, we tested the validity of the EI model against 2 criterion measures: 1) EI quantified through food provision from weeks 0-4 and 4-12 and 2) EI quantified through changes in body energy stores [measured with dual-energy X-ray absorptiometry (DXA)] and energy expenditure [measured with doubly labeled water (DLW)] from weeks 4-12 and 12-24.
RESULTS
Compared with food provision, the mean (±SD) model errors were 41 ± 118 kcal/d and -22 ± 230 kcal/d from weeks 0-4 and 4-12, respectively. Compared with EI measured with DXA and DLW, the model errors were -71 ± 272 kcal/d and -48 ± 226 kcal/d from weeks 4-12 and 12-24, respectively. In every comparison, the mean error was never significantly different from zero (P values>> 0.10). Furthermore, Bland and Altman analysis indicated that error variance did not differ significantly over amounts of EI (P values>> 0.26). Almost all individual participants' values were within CI limits.
CONCLUSIONS
The validity of the newly developed EI model was supported by experimental observations and can be used to determine an individual participant's EI during weight loss.
Publication
Journal: Cancer
March/9/2009
Abstract
BACKGROUND
Vascular endothelial growth factor (VEGF) plays an important role in the growth and metastatic progression of melanoma. Exposure of melanoma cells to chemotherapy induces VEGF overproduction, which in turn may allow melanoma cells to evade cell death and become chemotherapy resistant. Therefore, in patients with metastatic melanoma, the combination of chemotherapy with an agent that specifically targets VEGF might be able to control tumor growth and progression more effectively than chemotherapy alone.
METHODS
A 2-stage phase 2 clinical trial was conducted in patients with unresectable stage IV (metastatic) melanoma to assess antitumor activity and the toxicity profile of the combination of carboplatin (area under the curve 6 iv on Day 1 of a 28-day cycle), paclitaxel (80 mg/m2 iv on Days 1, 8, and 15), and bevacizumab (10 mg/kg iv on Days 1 and 15). Treatment was continued until progression or intolerable toxicity.
RESULTS
Fifty-three patients (62.3% male) were enrolled. Nine (17%) patients achieved partial remission, and another 30 (57%) achieved stable disease for at least 8 weeks. Median progression-free survival and median overall survival were 6 months and 12 months, respectively. One patient died after 8 treatment cycles from intracranial hemorrhage into undiagnosed brain metastases. The most common severe (grade>or=3) toxicities were neutropenia (53%), thrombocytopenia (11%), hypertension (9%), and anemia (8%).
CONCLUSIONS
This combination of carboplatin, paclitaxel, and bevacizumab appears to be moderately well tolerated and clinically beneficial in patients with metastatic melanoma. Further study of this combination is warranted.
Publication
Journal: The American journal of physiology
June/13/1985
Abstract
To determine the effect of thyroid hormone excess on insulin secretion, metabolism and action in humans, we examined intravenous glucose tolerance, glucose-induced insulin secretion, insulin clearance, monocyte insulin receptor binding, and the dose-response characteristics for the effects of insulin on glucose production, uptake, oxidation, and nonoxidative disposal in 10 normal volunteers for 14 days before and after oral administration of triiodothyronine (T3) in doses that increased plasma T3 to levels observed in spontaneous thyrotoxicosis (P less than 0.001). After T3 postabsorptive plasma glucose (P less than 0.05) and insulin (P less than 0.05) both increased; intravenous glucose tolerance was unaffected, but plasma insulin responses were increased (P less than 0.01); basal glucose production, uptake, and oxidation all increased (all P less than 0.05), whereas nonoxidative glucose disposal was unaffected (P = NS); monocyte insulin receptor binding increased (P less than 0.01) due to increased receptor affinity (P less than 0.05); and receptor number was not significantly altered (P = NS). Insulin clearance was increased. Insulin-induced suppression of glucose production was impaired (Km 22 +/- 3 vs. 37 +/- 7 microU/ml, P less than 0.02); maximal insulin-induced glucose uptake (10.7 +/- 0.6 vs. 13.0 +/- 0.9 mg X kg-1 X min-1, P less than 0.001) and oxidation (3.41 +/- 0.30 vs. 5.34 +/- 0.59 mg X kg-1 X min-1, P less than 0.001) were increased without a significant change in Km. However, submaximal rates of nonoxidative glucose disposal and glucose uptake were inappropriately low for the increased insulin receptor binding.(ABSTRACT TRUNCATED AT 250 WORDS)
Publication
Journal: Gastroenterology
May/12/1991
Abstract
Neurohormonal factors were investigated in 10 patients with functional dyspepsia who had normal or slow upper gut transit and 10 age- and sex-matched healthy controls. Gastric and small bowel motility and transit, jejunal responses to luminal distention and IM neostigmine, gut hormones, and vagal and sympathetic functions were studied. Slow upper gut transit was defined by a gastric emptying slope less than 0.3%/min or 10% small bowel transit time greater than 300 minutes. Four patients with slow transit had reduced postprandial antral motility and gut hormone responses. Two of the four patients had vagal and sympathetic dysfunction. In 6 patients with normal transit, balloon distention in the jejunum was perceived at a lower volume (32.7 +/- 5.9 mL) than in controls (46.6 +/- 3.0 mL). Pressure responses to balloon distention were reduced in 5 and exaggerated in 1 patient; abnormal efferent vagal (2 patients) and sympathetic (1 patient) function were also documented. In view of the normal transit, motility, and jejunal pressure responses to neostigmine in all 6 patients, the abnormal response to distention suggests afferent dysfunction. Functional dyspepsia is a heterogenous disorder. Abnormal transit is sometimes associated with disorders of extrinsic neural control, but the latter are also found in patients with normal transit. Increased perception of intraluminal stimuli in those with normal transit suggests a disturbance in afferent function.
Publication
Journal: Obesity (Silver Spring, Md.)
March/23/2011
Abstract
To elucidate cellular mechanisms of sex-related differences in fat distribution, we determined body fat distribution (dual-energy X-ray absorptiometry and single-slice abdominal computed tomography (CT)), adipocyte size, adipocyte number, and proportion of early-differentiated adipocytes (aP2(+)CD68(-)) in the stromovascular fraction (SVF) in the upper and lower body of normal-weight healthy men (n = 12) and premenopausal women (n = 20) (age: 18-49 years, BMI: 18-26 kg/m(2)). Women had more subcutaneous and less visceral fat than men. The proportion of early differentiated adipocytes in the subcutaneous adipose tissue SVF of women was greater than in men (P = 0.01), especially in the femoral depot, although in vitro adipogenesis, as assessed by peroxisome proliferator activated receptor-γ (PPARγ) expression, was not increased in femoral preadipocytes cultured from women compared with men. In women, differentiation of femoral preadipocytes was less than that of abdominal subcutaneous preadipocytes (P = 0.04), and femoral subcutaneous preadipocytes tended to be more resistant to tumor necrosis factor-α (TNFα)-induced apoptosis (P = 0.06). Thus, turnover and utilization of the preadipocyte pool may be reduced in lower vs. the upper-body fat in women. Collectively, these data indicate that the microenvironment, rather than differences in inherent properties of preadipocytes between genders, may explain the gynoid obesity phenotype and higher percent body fat in women compared to men.
Publication
Journal: Hepatology
September/16/1998
Abstract
A novel DNA virus, TT-virus (TTV), has been reported in patients with non-A-G posttransfusion hepatitis in Japan. We sought to determine whether TTV infection occurs in North American blood donors and to further determine the prevalence of TTV infection in several groups of patients with liver disease, including patients with cryptogenic cirrhosis and idiopathic fulminant hepatic failure. TTV infection was sought by detection of TTV DNA in serum by polymerase chain reaction (PCR) using primers generated from a conserved region of the TTV genome. Blood donors, patients with cryptogenic cirrhosis, idiopathic fulminant hepatic failure, and patients with other forms of advanced liver disease with and without a history of parenteral exposures were studied. TTV infection was present in 1% (1 of 100) of blood donors, 15% (5 of 33) of patients with cryptogenic cirrhosis, 27% (3 of 11) of patients with idiopathic fulminant hepatic failure, 18% (2 of 11) of patients with a history of exposure to blood products, and 4% (1 of 25) of patients without parenteral risk factors. For all patients tested, a history of prior exposure to blood products was associated with an increased risk of TTV infection (relative risk, 4.5; 90% confidence intervals, 0.6-43.9). We conclude that TTV infection is present among North American blood donors and is common in patients with liver disease, including cryptogenic cirrhosis and fulminant hepatic failure. Further studies are required to determine the role of TTV in the pathogenicity of acute and/or chronic liver disease.
Publication
Journal: American Journal of Kidney Diseases
February/2/2006
Abstract
BACKGROUND
The accuracy and precision of ultrasonography (US) in assessing the severity of autosomal dominant polycystic kidney disease (ADPKD) is unknown.
METHODS
US and magnetic resonance imaging (MRI) were performed at baseline and 1 year on 230 subjects with ADPKD. Ellipsoid volume was calculated from US length, width, and depth, and sequential transverse images were used to measure total and cystic volume directly. These were compared with MRI measurements of kidney volume and cystic volume.
RESULTS
Variability between different sonographers ranged from 18% to 42%. Correlations between US and MRI volume were 0.88 and 0.89. The SD of the discrepancy from MRI ranged from 21% to 33% and was unrelated to kidney size or body mass. Kidney length was the most reproducible measurement, and its correlation with MRI volume was 0.84. All patients with an US volume less than 700 cm3 had an MRI volume less than 1,000 cm3, and all patients with an US volume greater than 1,700 cm3 had an MRI volume greater than 1,000 cm3. Increases in volume after 1 year were 12% +/- 36% for the ellipsoid method, 6% +/- 29% for the direct method, and 4.2% +/- 7.2% for MRI. Correlation between US and MRI measurement of fractional cyst volume was 0.80.
CONCLUSIONS
Sonographic measurement of kidney volume in patients with ADPKD is inaccurate and lacks the precision necessary to measure short-term disease progression. However, sonography can provide an estimate of kidney volume that reflects severity and prognosis in individual patients.
Publication
Journal: Diabetes
June/27/2001
Abstract
We have previously reported that splanchnic glucose uptake, hepatic glycogen synthesis, and hepatic glucokinase activity are decreased in people with type 2 diabetes during intravenous glucose infusion. To determine whether these defects are also present during more physiological enteral glucose administration, we studied 11 diabetic and 14 nondiabetic volunteers using a combined organ catheterization-tracer infusion technique. Glucose was infused into the duodenum at a rate of 22 micromol. kg(-1). min(-1) while supplemental glucose was given intravenously to clamp glucose at approximately 10 mmol/l in both groups. Endogenous hormone secretion was inhibited with somatostatin, and insulin was infused to maintain plasma concentrations at approximately 300 pmol/l (i.e., twofold higher than our previous experiments). Total body glucose disappearance, splanchnic, and leg glucose extractions were markedly lower (P < 0.01) in the diabetic subjects than in the nondiabetic subjects. UDP-glucose flux, a measure of glycogen synthesis, was approximately 35% lower (P < 0.02) in the diabetic subjects than in the nondiabetic subjects. This was entirely accounted for by a decrease (P < 0.01) in the contribution of extracellular glucose because the contribution of the indirect pathway to hepatic glycogen synthesis was similar between groups. Neither endogenous and splanchnic glucose productions nor rates of appearance of the intraduodenally infused glucose in the portal vein differed between groups. In summary, both muscle and splanchnic glucose uptake are impaired in type 2 diabetes during enteral glucose administration. The defect in splanchnic glucose uptake appears to be due to decreased uptake of extracellular glucose, implying decreased glucokinase activity. Thus, abnormal hepatic and muscle (but not gut) glucose metabolism are likely to contribute to postprandial hyperglycemia in people with type 2 diabetes.
Publication
Journal: PLoS ONE
September/29/2010
Abstract
BACKGROUND
Cardiovascular disease (CVD) susceptibility differs between men and women and varies with ethnicity. This variability is not entirely explained by conventional CVD risk factors. We examined differences in circulating levels of 47 novel protein markers of CVD in 2561 men and women of African-American (AA) and non-Hispanic White (NHW) ethnicity, enrolled at geographically distinct sites.
RESULTS
Participants (1,324 AAs, mean age 63.5 y, 71% women; 1,237 NHWs, mean age 58.9 y, 57% women) belonged to sibships ascertained on the basis of hypertension. Solid-phase immunoassays and immunoturbidometric, clot-based, chromogenic, and electrophoretic assays were used to measure the 47 protein markers in plasma or serum. Marker levels were log transformed and outliers were adjusted to within 4 SD. To identify markers independently associated with sex or ethnicity, we employed multivariable regression analyses that adjusted for conventional risk factors, prior history of CVD, medication use and lifestyle factors (physical activity, alcohol consumption and education). Generalized estimating equations were used to correct for intrafamilial correlations. After adjustment for the above covariates, female sex was associated with higher levels of 29 markers and lower levels of 6 markers. Female sex was independently associated with higher levels of several inflammatory markers as well as lipoproteins, adipokines, natriuretic peptides, vasoconstrictor peptides and markers of calcification and thrombosis. AA ethnicity was associated with higher levels of 19 markers and lower levels of 6 markers, including higher levels of several inflammatory makers, higher leptin and lower adiponectin levels, lower levels of vasodilator-natriuretic peptides, higher levels of vasoconstrictor-antidiuretic peptides and markers of calcification and thrombosis.
CONCLUSIONS
Plasma levels of several novel protein markers of CVD differ significantly in the context of sex and ethnicity. These results have implications for individualized CVD risk assessment.
Publication
Journal: Journal of Physiology
December/22/1997
Abstract
1. In humans, mental stress elicits vasodilatation in the muscle vascular beds of the forearm that may be neurally mediated. We sought to determine the extent to which this vasodilatation is due to sympathetic withdrawal, active neurogenic vasodilatation, or beta-adrenergically mediated vasodilatation. 2. We simultaneously measured forearm blood flow and muscle sympathetic nerve traffic to the forearm during mental stress in humans. In a second study, we measured forearm blood flow responses to mental stress after selective blockade of alpha-adrenergic neurotransmission in one forearm. In a final study, we measured forearm blood flow responses to mental stress after unilateral anaesthetic blockade of the stellate ganglion, alone or in combination with selective beta-adrenergic receptor blockade of the forearm. 3. During mental stress, muscle sympathetic nerve activity decreased from 5113 +/- 788 to 1509 +/- 494 total integrated activity min-1 (P < 0.05) and forearm vascular resistance decreased from 96 +/- 29 to 33 +/- 7 mmHg (dl of tissue) min ml-1 (P < 0.05). Considerable vasodilation was still elicited by mental stress after selective blockade of alpha-adrenergic neurotransmission. Vasodilatation also occurred during mental stress after stellate ganglion blockade. This dilatation was reduced by selective blockade of beta-adrenergic receptors in the forearm. 4. Our results support a role for both sympathetic withdrawal and beta-adrenergic vasodilatation as the major causes of the forearm vasodilatation during mental stress in humans.
Publication
Journal: Transplantation
December/6/2000
Abstract
BACKGROUND
Poor preoperative nutritional status has been reported to be associated with adverse outcomes after liver transplantation. Published data are, however, conflicting, with methods of preoperative nutritional assessment and postoperative outcomes varying between studies.
METHODS
We prospectively studied the predictive value of preoperative nutritional status for adverse outcomes after liver transplantation. Assessment of preoperative nutritional status included: body cell mass determination, subjective global assessment, anthropometry, handgrip dynamometry, biochemical and amino acid profile, Child's score, and dual-energy x-ray absorptiometry. Death, intensive care unit (ICU) length of stay>> or =4 days, hospital length of stay>> or =15 days, blood usage>> or =36 U of blood products, infection, rejection, and global resource utilization (an index of cost) greater than the median were considered poor outcomes.
RESULTS
Fifty-three patients were studied. Longer ICU stay was associated with lower handgrip strength (P<0.01) and lower aromatic amino acid levels (P<0.01). Longer total hospital stay and the development of infections were associated with lower branched chain amino acid levels (P<0.01 and <0.001, respectively). Acute cellular rejection was associated with lower total body fat (P<0.001) and higher triglyceride levels (P<0.02). Neither death nor higher global resource utilization was associated with any preoperative nutritional parameter.
CONCLUSIONS
Lower preoperative handgrip strength and branched chain amino acid levels are associated with longer ICU stays and increased likelihood of posttransplant infections. In our program, in which nutritional support was provided to potential recipients exhibiting malnourishment, none of the measured nutritional parameters were associated with mortality or greater global resource utilization.
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