energy balance in obese and non-obese humans
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Publication
Journal: Gastroenterology
March/31/2010
Abstract
OBJECTIVE
The outcome of patients with hepatocellular carcinoma (HCC) remains poor because of late diagnosis. The aim of this study was to compare the accuracy of alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) in the early diagnosis of HCC.
METHODS
Among 1031 patients randomized in the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) Trial, a nested case-control study of 39 HCC cases (24 early stage) and 77 matched controls was conducted to compare the performance of AFP and DCP. Testing was performed on sera from 12 months prior (month -12) to the time of HCC diagnosis (month 0).
RESULTS
The sensitivity and specificity of DCP at month 0 was 74% and 86%, respectively, at a cutoff of 40 mAU/mL and 43% and 100%, respectively, at a cutoff of 150 mAU/mL. The sensitivity and specificity of AFP at month 0 was 61% and 81% at a cutoff of 20 ng/mL and 22% and 100% at a cutoff of 200 ng/mL. At month -12, the sensitivity and specificity at the low cutoff was 43% and 94%, respectively, for DCP and 47% and 75%, respectively, for AFP. Combining both markers increased the sensitivity to 91% at month 0 and 73% at month 12, but the specificity decreased to 74% and 71%, respectively. Diagnosis of early HCC was triggered by surveillance ultrasound in 14, doubling of AFP in 5, and combination of tests in 5 patients.
CONCLUSIONS
Biomarkers are needed to complement ultrasound in the detection of early HCC, but neither DCP nor AFP is optimal.
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Publication
Journal: AIDS
January/27/2010
Abstract
BACKGROUND
Cardiovascular disease (CVD) is an increasing cause of morbidity and mortality in HIV-infected patients. However, it is controversial whether HIV infection contributes to accelerated atherosclerosis independent of traditional CVD risk factors.
METHODS
Cross-sectional study of HIV-infected participants and controls without pre-existing CVD from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) and the Multi-Ethnic Study of Atherosclerosis (MESA). Preclinical atherosclerosis was assessed by carotid intima-medial thickness (cIMT) measurements in the internal/bulb and common regions in HIV-infected participants and controls after adjusting for traditional CVD risk factors.
RESULTS
For internal carotid, mean IMT was 1.17 +/- 0.50 mm for HIV-infected participants and 1.06 +/- 0.58 mm for controls (P < 0.0001). After multivariable adjustment for demographic characteristics, the mean difference of HIV-infected participants vs. controls was 0.188 mm [95% confidence interval (CI) 0.113-0.263, P < 0.0001]. Further adjustment for traditional CVD risk factors modestly attenuated the HIV association (0.148 mm, 95% CI 0.072-0.224, P = 0.0001). For the common carotid, HIV infection was independently associated with greater IMT (0.033 mm, 95% CI 0.010-0.056, P = 0.005). The association of HIV infection with IMT was similar to that of smoking, which was also associated with greater IMT (internal 0.173 mm, common 0.020 mm).
CONCLUSIONS
Even after adjustment for traditional CVD risk factors, HIV infection was accompanied by more extensive atherosclerosis measured by IMT. The stronger association of HIV infection with IMT in the internal/bulb region compared with the common carotid may explain previous discrepancies in the literature. The association of HIV infection with IMT was similar to that of traditional CVD risk factors, such as smoking.
Publication
Journal: Alcoholism: Clinical and Experimental Research
March/21/2005
Abstract
BACKGROUND
Recent research has implicated the endogenous opioid system in the development of alcohol use disorders. The A118G polymorphism of the OPRM1 gene has been shown to confer functional differences to mu-opioid receptors, such that the G variant binds beta-endorphin three times more strongly than the A variant. The goal of this study was to test whether the A118G polymorphism is associated with sensitivity to the effects of alcohol.
METHODS
Participants who were either homozygous for the A allele (n = 23) or heterozygous (n = 15) received intravenous doses of alcohol designed to reach three target levels of breath alcohol concentration: 0.02, 0.04, and 0.06. The testing procedure consisted of measures of subjective intoxication, stimulation, sedation, and mood states at baseline and at each of the three target breath alcohol concentrations.
RESULTS
The results suggested that individuals with the G allele reported higher subjective feelings of intoxication, stimulation, sedation, and happiness across trials as compared with participants with the A allele. Furthermore, participants with the G allele were almost three times more likely to report a positive family history of alcohol use disorders than participants with the A allele.
CONCLUSIONS
These findings may help to explain previous research suggesting that naltrexone is more effective among individuals with the G allele. A medication that reduces feelings of euphoria after alcohol consumption may be more successful among individuals with a genetic predisposition to greater feelings of euphoria after consuming alcohol.
Publication
Journal: Surgery, gynecology & obstetrics
August/24/1980
Abstract
Eighteen patients were treated with primary cadaveric renal transplantation using cyclosporin A therapy, and four more patients undersent cadaveric retransplantation. Eleven of the 22 recipients were conditioned with lymphoid depletion before transplantation, using thoracic duct drainage or lymphapheresis for two to eight and one-half weeks. Cyclosporin A was begun a few hours before grafting. The other 11 patients were pretreated with cyclosporin A for from one day to 18 days. After transplantation, the majority of patients in both subgroups of 11 had rejection develop, but in most, the immunologic process was readily controlled with relatively small dosages of prednisone. After follow-up periods of two to four and one-half months, one patient has died of the complications of a coronary artery reconstruction that was not related to the transplantation. Another graft was lost from rejection, and a third organ was removed because of ureteral necrosis. Nineteen of the original 22 cadaveric kidneys are functioning, including 17 of the 18 kidneys given to patients who were undergoing transplantation for the first time. The only loss in the latter group of 18 patients was in the patient who died after an open heart operation. Results of these studies have shown that cyclosporin A is a superior and safe immunosuppressive drug but that, for optimal use in cadaveric transplantation, it usually should not be given alone. Steroid therapy greatly amplified the value of cyclosporin A. Unless major delayed morbidity develops which is not obvious so far, this drug combination should permit revolutionary advances in the transplantation of all organs. Other adjuncts to the cyclosporin A-steroid combination, including lymphoid depletion techniques, will require further investigation.
Publication
Journal: Journal of Clinical Endocrinology and Metabolism
July/25/2010
Abstract
BACKGROUND
Autoantibodies to islet antigen-2 (IA-2A) and glutamic acid decarboxylase (GADA) are markers for diagnosis, screening, and measuring outcomes in National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) consortia studies. A harmonization program was established to increase comparability of results within and among these studies.
METHODS
Large volumes of six working calibrators were prepared from pooled sera with GADA 4.8-493 World Health Organization (WHO) units/ml and IA-2A 2-235 WHO units/ml. Harmonized assay protocols for IA-2A and GADA using (35)S-methionine-labelled in vitro transcribed and translated antigens were developed based on methods in use in three NIDDK laboratories. Antibody thresholds were defined using sera from patients with recent onset type 1 diabetes and healthy controls. To evaluate the impact of the harmonized assay protocol on concordance of IA-2A and GADA results, two laboratories retested stored TEDDY study sera using the harmonized assays.
RESULTS
The harmonized assays gave comparable but not identical results in the three laboratories. For IA-2A, using a common threshold of 5 DK units/ml, 549 of 550 control and patient samples were concordantly scored as positive or negative, specificity was greater than 99% with sensitivity 64% in all laboratories. For GADA, using thresholds equivalent to the 97th percentile of 974 control samples in each laboratory, 1051 (97.9%) of 1074 samples were concordant. On the retested TEDDY samples, discordance decreased from 4 to 1.8% for IA-2A (n = 604 samples; P = 0.02) and from 15.4 to 2.7% for GADA (n = 515 samples; P < 0.0001).
CONCLUSIONS
Harmonization of GADA and IA-2A is feasible using large volume working calibrators and common protocols and is an effective approach to ensure consistency in autoantibody measurements.
Publication
Journal: European Respiratory Journal
September/25/2002
Abstract
Idiopathic pulmonary fibrosis (IPF) has a high mortality rate, and current therapies are only marginally effective. A serum biomarker that predicts clinical outcome would be useful to stage disease, indicate prognosis and the need for aggressive therapy, and help stratify patients for clinical trials. The goals of this study were to determine whether serum levels of surfactant protein-A (SP-A) or surfactant protein-D (SP-D) would distinguish between IPF and other types of interstitial lung disease and whether serum SP-A or SP-D levels predict outcome in patients with IPF. The authors found that serum SP-A and SP-D levels were significantly elevated in patients with IPF and systemic sclerosis compared to sarcoidosis, beryllium disease and normal controls, and that SP-D correlated with radiographic abnormalities in patients with IPF. In addition, the authors found that both serum SP-A and SP-D levels were highly predictive of survival in patients with IPF. This is the largest North American data set of surfactant protein measurements in idiopathic pulmonary fibrosis and the first report using multivariate analysis comparing serum surfactant proteins-A and -D to other commonly measured predictors of survival in idiopathic pulmonary fibrosis. Based on these results, the authors propose that serum surfactant proteins may prove to be useful biomarkers in patients with idiopathic pulmonary fibrosis.
Publication
Journal: Archives of general psychiatry
June/28/1984
Abstract
A deficit in inhibitory gating of auditory evoked responses was examined in 15 schizophrenic patients, their first-degree relatives, and normal subjects, using a conditioning-testing paradigm with the P50 wave of the auditory evoked response. This paradigm demonstrates inhibition by presenting paired stimuli to the subject; the P50 wave evoked by the second stimulus is reduced because of inhibitory mechanisms activated during the response to the first stimulus. In normal subjects, the mean amplitude of the second P50 response was reduced to less than 20%. In the schizophrenics, the mean amplitude of the second response was more than 85% of the first, a result that replicates our previous finding of a deficit in inhibition in schizophrenia. Approximately half the first-degree relatives, generally including at least one parent, had a similar deficit. Presence of this deficit in the parents was associated with a family history of schizophrenia. Family members with this deficit also had significantly higher scores on several scales of the Minnesota Multiphasic Personality Inventory than did family members without the deficit. Despite the deficit in inhibition, other characteristics of the P50 wave were normal in the relatives, in contrast to unmedicated schizophrenics, who showed additional abnormalities in wave latency and amplitude.
Publication
Journal: AIDS
July/2/2007
Abstract
OBJECTIVE
Microalbuminuria is associated with increased risk of cardiovascular disease and mortality. The objective of the study was to evaluate if HIV infection was an independent risk factor for microalbuminuria.
METHODS
Cross sectional.
METHODS
The relationship between HIV infection and microalbuminuria was assessed using subjects enrolled in the study of Fat Redistribution and Metabolic Change in HIV Infection, which consists of HIV-positive and control men and women. Participants with proteinuria (dipstick>>or= 1+) were excluded.
RESULTS
Microalbuminuria (urinary albumin/creatinine ratio, ACR>> 30 mg/g) was present in 11% of HIV infected, and 2% of control participants (P < 0.001); a fivefold odds after multivariate adjustment (odds ratio, 5.11; 95% confidence interval, 1.97-13.31; P=0.0008). Several cardiovascular risk factors were associated with higher ACR in HIV participants: insulin resistance (HOMA>> 4; 32%, P < 0.0001), systolic blood pressure (21%, P = 0.01 for 120-140 versus < 120 mmHg, and 43%, P = 0.06 for>> 140 versus < 120 mmHg), and family history of hypertension (17%, P = 0.03). Higher CD4 cell count was associated with lower albumin/creatinine ratio (-24%, P = 0.009 for 200-400 versus < 200 cells/ml and -26%, P = 0.005 for>> 400 versus < 200 cells/ml).
CONCLUSIONS
HIV infection had a strong and independent association with microalbuminuria, the severity of which was predicted by markers of insulin resistance, hypertension, and advanced HIV infection. These associations warrant further investigation, as the increased prevalence of microalbuminuria in HIV infection may be a harbinger of future risk of cardiovascular and kidney diseases.
Publication
Journal: Gastroenterology
May/20/1982
Abstract
We have previously shown that in pregnancy fasting gallbladder volume is increased and emptying after a small volume liquid meal is incomplete. In this study we measured gallbladder volume throughout day and night in healthy women ingesting regular meals. Pregnant women, postpartum women, contraceptive-steroid users, and controls in both phases of the ovulatory cycle were studied. After an overnight fast gallbladder volume was measured by realtime ultrasonography in the fasting state and every 5-10 min for 90 min after breakfast. Residual volume was the lowest volume achieved and the rate constant of gallbladder emptying was calculated from the ln/linear regression of gallbladder volume vs. time. Gallbladder volume was also measured hourly from 11 AM to midnight while subjects ate regular, standard meals, allowing the determination of an average hourly volume. There was no effect of phase of the ovulatory cycle on any measure of gallbladder function. Fasting, residual, and average hourly volume were increased in all trimesters of pregnancy, but tended to return to normal in the postpartum period. Women taking contraceptive steroids had an increased fasting volume. Two distinct rates of emptying after breakfast, an early and a late one, were identified. The early rate was the same in all groups. Pregnant women had a slower late rate of emptying, but women taking contraceptive steroids had emptying rates similar to controls. Retention of bile in the gallbladder may be one reason for the increased risk of cholesterol cholelithiasis in pregnant women and in those taking contraceptive steroids.
Publication
Journal: Journal of Allergy and Clinical Immunology
May/12/2004
Abstract
BACKGROUND
Atopic dermatitis (AD) is a chronic inflammatory skin disease involving colonization by superantigen (SAg)-secreting Staphylococcus aureus. CD4+CD25+ T regulatory (Treg) cells are thought to play an important role in controlling inflammatory responses.
OBJECTIVE
In this study we examined whether Treg cells might be deficient in patients with AD.
METHODS
CD4+CD25+ and CD4+CD25- T cells were isolated from PBMCs by using immunomagnetic beads. Cells were cultured with anti-CD3 or SAg, staphylococcal enterotoxin B (SEB), for 72 hours. Proliferation was measured by means of tritiated thymidine incorporation. CD4, CD8, CD25, and cutaneous lymphocyte-associated antigen expression on PBMCs was assessed by means of flow cytometry. RNA was extracted from isolated subsets of T cells, and the results of real-time PCR for FoxP3 mRNA were determined.
RESULTS
Surprisingly, CD4+CD25+ T cells were significantly (P <.01) increased in patients with AD (6.68%+/-0.99%, n=15) compared with in asthmatic patients (3.42%+/-0.58%, n=12) or nonatopic healthy control subjects (3.34%+/-0.43%, n=14). Patients with AD also had a higher expression of CD25+ in skin-homing, CD4+, cutaneous lymphocyte-associated antigen-positive T cells than asthmatic and nonatopic subjects, with values of 35.95% versus 22.44% versus 23.03%, respectively (P <.006). Only CD4+CD25+ cells expressed FoxP3, whereas CD4+CD25- T cells and CD4- cells did not. Consistent with known properties of Treg cells, CD4+CD25+ cells were anergic to anti-CD3 stimulation. When CD4+CD25+ cells from each study group were mixed with CD4+CD25- cells, proliferative responses were equally suppressed after anti-CD3 stimulation. In contrast, after SEB stimulation, CD4+CD25+ cells were no longer anergic. Furthermore, when CD4+CD25+ cells were mixed with CD4+CD25- cells and stimulated with SEB, the suppressive function of Treg cells was reversed.
CONCLUSIONS
Patients with AD have significantly increased numbers of peripheral blood Treg cells with normal immunosuppressive activity. However, after SAg stimulation, Treg cells lose their immunosuppressive activity. These data suggest a novel mechanism by which SAgs could augment T-cell activation in patients with AD.
Publication
Journal: The Journal of investigative dermatology
September/7/2008
Abstract
Atopic dermatitis (AD) is an inflammatory skin disease associated with frequent skin infection and impaired skin barrier function. Recent studies indicate that increased Th2 cytokine expression contributes to reduction in antimicrobial peptides and reduced filaggrin (FLG) expression, however, the mechanisms leading to this effect is unknown. Using proteomics, we found the S100 calcium-binding protein A11 (S100/A11) to be significantly downregulated in the presence of IL-4 and IL-13. Culturing keratinocytes with increased calcium concentrations significantly induced S100/A11 expression. This corresponded with an increase in human beta-defensin (HBD)-3 and FLG expression. Interference of S100/A11 expression, by siRNA, inhibited induction of HBD-3 and FLG. Furthermore p21, a cyclin-dependent kinase inhibitor downstream of S100/A11, was required for calcium-mediated induction of HBD-3 and FLG. Importantly, transduction of p21-recombinant protein into keratinocytes prevented IL-4/IL-13-mediated inhibition of FLG and HBD-3 expression. S100/A11 and p21 gene expression was also found to be significantly lower in acute and chronic AD skin. This study demonstrates an important role for S100/A11 and p21 in regulating skin barrier integrity and the innate immune response.
Publication
Journal: Journal of Physiology
September/12/2001
Abstract
1. In experimental animals chronic elevations in arterial blood flow increase the lumen diameter and reduce the intima-media thickness (IMT) of the arterial segment involved. We determined whether intermittent elevations in active muscle blood flow associated with regular aerobic leg exercise induced such expansive arterial remodelling in the common femoral artery of humans. 2. In the cross-sectional study 53 sedentary (47 +/- 2 years) and 55 endurance exercise-trained (47 +/- 2 years) men were studied. Common femoral artery lumen diameter (B-mode ultrasound) was 7 % greater (9.62 +/- 0.12 vs. 9.03 +/- 0.13 mm), and femoral IMT (0.46 +/- 0.02 vs. 0.55 +/- 0.02 mm) and IMT/lumen ratio were 16-21 % smaller in the endurance-trained men (all P < 0.001). Basal femoral artery blood flow (duplex ultrasound) was not different, shear stress tended to be lower (P = 0.08), and mean femoral tangential wall stress was 30 % higher in the endurance-trained men (P < 0.001). 3. In the intervention study 22 men (51 +/- 2 years) were studied before and after 3 months of regular aerobic leg exercise (primarily walking). After training, the femoral diameter increased by 9 % (8.82 +/- 0.18 vs. 9.60 +/- 0.20 mm), and IMT (0.65 +/- 0.05 vs. 0.56 +/- 0.05 mm) and the IMT/lumen ratio were approximately 15-20 % smaller (all P < 0.001). Basal femoral blood flow and shear stress were not different after training, whereas the mean femoral tangential wall stress increased by 31 %. The changes in arterial structure were not related to changes in risk factors for atherosclerosis. 4. Our results are consistent with the concept that regular aerobic leg exercise induces expansive arterial remodelling in the femoral artery of healthy men. This adaptive process is produced by even a moderate training stimulus, is not obviously dependent on corresponding improvements in risk factors for atherosclerosis, and is robust, occurring in healthy men of different ages.
Publication
Journal: Hypertension
August/7/2007
Abstract
Increased endothelin-1-mediated vasoconstrictor tone has been linked to the etiology of a number of pathologies associated with human aging, including hypertension, congestive heart failure, and coronary artery disease. However, it is currently unclear whether aging, per se, is associated with enhanced endothelin-1 system activity. We hypothesized that endothelin-1 vasoconstrictor activity is greater in healthy older compared with young men and that regular aerobic exercise is an effective intervention for reducing endothelin-1 vasoconstrictor tone in older previously sedentary men. Forearm blood flow (plethysmography) responses to intra-arterial infusion of endothelin-1 (5 pmol/min; for 20 minutes) and selective (BQ-123; 100 nmol/min; for 60 minutes) and nonselective (BQ-123+BQ-788; 100 nmol/min; for 60 minutes) endothelin-1 receptor blockade were determined in 28 healthy, sedentary men: 13 younger (age: 27+/-1 years) and 15 older (age: 62+/-2 years). The vasoconstrictor response to endothelin-1 was significantly blunted ( approximately 65%) in the older versus younger men. In response to BQ-123, resting forearm blood flow increased ( approximately 20%; P<0.05) in the older but not in the younger men. The addition of BQ-788 to BQ-123 did not significantly affect the blood flow responses to BQ-123 in either group. Eight of the 15 older sedentary men completed a 3-month aerobic exercise intervention. After the intervention, the vasoconstrictor response to endothelin-1 was markedly increased (225%; P<0.05), whereas BQ-123 resulted in modest vasoconstriction in the previously sedentary older men. These results demonstrate that endothelin-1-mediated vasoconstrictor tone increases with age in healthy men but can be alleviated with regular aerobic exercise.
Publication
Journal: Journal of Physiology
May/1/2006
Abstract
Vascular oxidative stress is the key mechanism involved in the age-related decline in endothelium-dependent dilatation (EDD). We tested the hypothesis that xanthine oxidase (XO), a major vascular source of reactive oxygen species, contributes to the impairment in EDD with ageing. At baseline, brachial artery flow-mediated dilatation (FMD) was 55% lower in older (n = 9, 64 +/- 2 years, 8M/1F, mean +/- S.E.M.) versus young (n = 9, 26 +/- 1 years, 8M/1F) healthy adults (3.41 +/- 0.44 versus 7.53 +/- 0.67%, P < 0.001), whereas endothelium-independent dilatation (EID; sublingual nitroglycerin) did not differ between groups. Plasma oxidized low-density lipoprotein (oxi-LDL), a measure of systemic oxidative stress, was greater at baseline in the older subjects (58.3 +/- 5.9 versus 46.8 +/- 2.4 U l(-1), P < 0.05) and inversely correlated with baseline FMD (r = - 0.54; P < 0.05). Acute administration of allopurinol, a competitive inhibitor of XO, reduced plasma uric acid concentrations similarly in both groups (P < 0.001), but did not affect FMD, EID, or oxi-LDL in either group. Vascular endothelial protein expression of XO (immunofluorescence) was not different in antecubital venous cells from the young and older subjects (0.56 +/- 0.12 versus 0.68 +/- 0.19 XO intensity/human umbilical vein endothelial cell intensity, P = 0.49). We conclude that XO does not contribute to oxidative stress-associated reductions in peripheral conduit artery EDD with ageing in humans, possibly due to an absence of age-associated up-regulation of endothelial XO.
Publication
Journal: Journal of Investigative Dermatology
November/2/2005
Abstract
Recurrent skin infections in extrinsic atopic dermatitis (EAD) may be because of the suppression of anti-microbial peptide (AMP) expression by interleukin (IL)-4 and IL-13. Twenty to thirty percent of AD, however, are classified as intrinsic atopic dermatitis (IAD). They exhibit normal serum IgE levels, no allergen-specific sensitization, and lower levels of IL-4 and IL-13 than EAD. Both forms of AD have increased propensity to skin infection, suggesting a novel mechanism for infection in IAD. In this study, we observed significantly decreased human beta-defensin (HBD)-2 gene expression in the skin of both IAD (p = 0.010) and EAD (p = 0.004), as compared with psoriasis patients. Conversely, IAD (p = 0.019) and EAD (p = 0.002) skin lesions exhibited elevated IL-10 gene expression when compared with psoriasis. Using primary keratinocytes, we found that the deficiency in AMP expression is an acquired rather than a constitutive defect. Interestingly, neutralizing antibodies to IL-10 augmented the production of tumor necrosis factor-alpha and interferon-gamma by peripheral blood mononuclear cell from AD patients. Additionally, treatment of AD skin explants with anti-IL-10 augmented the expression of both HBD-2 and LL-37. Thus, increased levels of IL-10 may contribute to the AMP deficiency in both IAD and EAD by reducing cytokines that induce AMP.
Publication
Journal: Diabetes Care
July/27/2005
Abstract
OBJECTIVE
Autoimmune thyroid disease (AIT), celiac disease, and Addison's disease are characterized by the presence of autoantibodies: thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TGAb) in AIT, tissue transglutaminase antibody (TTGAb) in celiac disease, and 21-hydroxylase antibody (21-OHAb) in Addison's disease. The objective of this study was to define the prevalence of these autoantibodies and clinical disease in a population with type 1 diabetes.
METHODS
We screened 814 individuals with type 1 diabetes for TPOAb, TGAb, TTGAb, and 21-OHAb. Clinical disease was defined by chart review. Factors related to the presence of autoimmunity and clinical disease including age at onset of type 1 diabetes, duration of diabetes, age at screening, sex, and the presence of autoantibodies were reviewed.
RESULTS
The most common autoantibodies expressed were TPOAb and/or TGAb (29%), followed by TTGAb (10.1%) and 21-OHAb (1.6%). Specific HLA DR/DQ genotypes were associated with the highest risk for expression of 21-OHAb (DRB1*0404-DQ8, DR3-DQ2) and TTGAb (DR3-DQ2- DR3-DQ2). The expression of thyroid autoantibodies was related to 21-OHAb but not to TTGAb. The presence of autoantibodies was associated with and predictive of disease.
CONCLUSIONS
In this large cohort of individuals with type 1 diabetes, the expression of organ-specific autoantibodies was very high. The grouping of autoantibody expression suggests common factors contributing to the clustering.
Publication
Journal: Journal of Clinical Investigation
January/30/2003
Abstract
Chronic beryllium disease (CBD) is caused by exposure to beryllium in the workplace, and it remains an important public health concern. Evidence suggests that CD4(+) T cells play a critical role in the development of this disease. Using intracellular cytokine staining, we found that the frequency of beryllium-specific CD4(+) T cells in the lungs (bronchoalveolar lavage) of 12 CBD patients ranged from 1.4% to 29% (mean 17.8%), and these T cells expressed a Th1-type phenotype in response to beryllium sulfate (BeSO(4)). Few, if any, beryllium-specific CD8(+) T cells were identified. In contrast, the frequency of beryllium-responsive CD4(+) T cells in the blood of these subjects ranged from undetectable to 1 in 500. No correlation was observed between the frequency of beryllium-responsive bronchoalveolar lavage (BAL) CD4(+) T cells as detected by intracellular staining and lymphocyte proliferation in culture after BeSO(4) exposure. Staining for surface marker expression showed that nearly all BAL T cells exhibit an effector memory cell phenotype. These results demonstrate a dramatically high frequency and compartmentalization of antigen-specific effector memory CD4(+) cells in the lungs of CBD patients. These studies provide insight into the phenotypic and functional characteristics of antigen-specific T cells invading other inaccessible target organs in human disease.
Publication
Journal: American Journal of Clinical Nutrition
May/27/2010
Abstract
Zinc has earned recognition recently as a micronutrient of outstanding and diverse biological, clinical, and global public health importance. Regulation of absorption by zinc transporters in the enterocyte, together with saturation kinetics of the absorption process into and across the enterocyte, are the principal means by which whole-body zinc homeostasis is maintained. Several physiologic factors, most notably the quantity of zinc ingested, determine the quantity of zinc absorbed and the efficiency of absorption. Other factors are age and the time over which zinc is ingested. Zinc from supplements has not been shown to be absorbed differently from that taken with meals that lack inhibitors of zinc absorption. The principal dietary factor known to impair zinc bioavailability is inositol hexa- (and penta-) phosphate or phytate. Modeling of zinc absorption as a function of dietary zinc and phytate accounts for >80% of the variability in the quantity of zinc absorbed. Fitting the model to new data has resulted in continual improvement in parameter estimates, which currently indicate a maximal absorption in adults of approximately 6 mg Zn/d and that the average estimated dietary requirement doubles with 1000 mg dietary phytate/d. Intestinal excretion of endogenous zinc is regulated in response to recent absorption and to zinc status. The quantitative relation of intestinal excretion of endogenous zinc to zinc absorption is currently considered to be of major importance in the determination of zinc requirements. The effects of phytate on intestinal losses of endogenous zinc merit further investigation but are probably not of the same magnitude as its inhibitory effects on absorption of exogenous zinc.
Publication
Journal: Medicine and Science in Sports and Exercise
March/24/2010
Abstract
Most mechanical forces acting on the skeleton are generated either through impact with the ground (i.e., gravitational loading) or through muscle contractions (i.e., muscle loading). If one of these conduits for activating mechanotransduction in bone is more effective than the other with respect to developing or maintaining bone strength, this would have important clinical implications for prescribing physical activity for the prevention or treatment of osteoporosis. This section of the symposium considered whether there is evidence from studies of humans that the effectiveness of physical activity to preserve bone health is dependent on whether the activities stimulate the skeleton primarily through gravitational or muscle loading. Conclusive evidence is lacking, but several lines of research suggest that physical activities that involve impact forces, and therefore generate both gravitation and muscle loading, are most likely to have beneficial effects on bone metabolism and reduce fracture risk.
Publication
Journal: Journal of Hepatology
April/26/2007
Abstract
OBJECTIVE
Although the antiviral and histological benefits of peginterferon/ribavirin therapy are well established, the effects on health-related quality of life (HRQOL) and sexual health are less certain. This study assessed HRQOL and sexual health in patients with advanced fibrosis or cirrhosis in the HALT-C Trial.
METHODS
Subjects completed SF-36 and sexual health questionnaires prior to and after 24 weeks of peginterferon/ribavirin therapy (n=1144). Three hundred and seventy-three (33%) subjects were HCV RNA negative at week 20 and continued therapy through week 48; 258 were seen at week 72. One hundred and eighty achieved sustained virological responses (SVR) and 78 relapsed.
RESULTS
At baseline, patients had poorer scores for all eight SF-36 domains compared to healthy controls. Patients with cirrhosis had lower HRQOL scores than those with bridging fibrosis, as did patients with higher depression scores. SVR patients had significant improvements in seven domains, whereas relapsers had significant worsening in one domain. Sexual scores improved in SVR patients and decreased in relapsers (p=0.03). In multivariate analyses, improvements in HRQOL and sexual scores were significantly associated with SVR but were less striking in patients with lower depression scores.
CONCLUSIONS
Achievement of SVR after peginterferon/ribavirin therapy improves HRQOL and sexual health in chronic hepatitis C patients with advanced fibrosis or cirrhosis.
Publication
Journal: Annals of Internal Medicine
February/10/1985
Abstract
Dermal collagen deposition is the hallmark of the early indurative phase of progressive systemic sclerosis (scleroderma). This process, however, tends to remit in late stages of the disease. Because mast cells are believed to participate in the development of fibrotic processes, we measured the density of the cutaneous mast cell population in clinically involved and uninvolved skin of a group of patients with scleroderma. Mast cell counts in clinically involved skin of patients with early stages of scleroderma (111 +/- 28 [SD] cells/mm2) were significantly greater than those in clinically uninvolved skin of the same patients (58 +/- 26 cells/mm2) and also greater than those of normal controls (50 +/- 14 cells/mm2). Mast cell counts in clinically involved and uninvolved skin of patients with late scleroderma were normal. When mast cell density was analyzed by depth of dermis, an 85% increase was noted in involved papillary dermis and a 152% increase in involved reticular dermis in patients with early scleroderma when compared with densities in controls. These results suggest that mast cells may be important in the pathogenesis of the early cutaneous lesions of progressive systemic sclerosis, perhaps by promoting fibrosis.
Publication
Journal: Diabetes Care
July/28/2009
Abstract
OBJECTIVE
Depression is associated with poor glycemic control and complications in people with type 1 diabetes. We assessed the prevalence of depression and antidepressant medication use among adults with and without type 1 diabetes and the association between depression and diabetes complications.
METHODS
In 2006-2008, the Coronary Artery Calcification in Type 1 Diabetes Study applied the Beck Depression Inventory II (BDI-II) to 458 participants with type 1 diabetes (47% male, aged 44 +/- 9 years, type 1 diabetes duration 29 +/- 9 years) and 546 participants without diabetes (nondiabetic group) (51% male, aged 47 +/- 9 years). Use of antidepressant medication was self-reported. Depression was defined as a BDI-II score >14 and/or use of antidepressant medication. Occurrence of diabetes complications (retinopathy, blindness, neuropathy, diabetes-related amputation, and kidney or pancreas transplantation) was self-reported.
RESULTS
Mean BDI-II score, adjusted for age and sex, was significantly higher in participants with type 1 diabetes than in nondiabetic participants (least-squares mean +/- SE: 7.4 +/- 0.3 vs. 5.0 +/- 0.3; P < 0.0001). Type 1 diabetic participants reported using more antidepressant medications (20.7 vs. 12.1%, P = 0.0003). More type 1 diabetic than nondiabetic participants were classified as depressed by BDI-II cut score (17.5 vs. 5.7%, P < 0.0001) or by either BDI-II cut score or antidepressant use (32.1 vs. 16.0%, P < 0.0001). Participants reporting diabetes complications (n = 209) had higher mean BDI-II scores than those without complications (10.7 +/- 9.3 vs. 6.4 +/- 6.3, P < 0.0001).
CONCLUSIONS
Compared with nondiabetic participants, adults with type 1 diabetes report more symptoms of depression and more antidepressant medication usage. Depression is highly prevalent in type 1 diabetes and requires further study on assessment and treatment.
Publication
Journal: Diabetes Technology and Therapeutics
September/27/2012
Abstract
Cardiovascular disease (CVD) remains the leading cause of death in people with diabetes, and the risk of CVD for adults with diabetes is at least two to four times the risk in adults without diabetes. Complications of diabetes, including not only CVD but also microvascular diseases such as retinopathy and nephropathy, are a major health and financial burden. Diabetes is a disease of glucose intolerance, and so much of the research on complications has focused on the role of hyperglycemia. Clinical trials have clearly demonstrated the role of hyperglycemia in microvascular complications of diabetes, but there appears to be less evidence for as strong of a relationship between hyperglycemia and CVD in people with diabetes. Hypoglycemia has become a more pressing health concern as intensive glycemic control has become the standard of care in diabetes. Clinical trials of intensive glucose lowering in both type 1 and type 2 diabetes populations has resulted in significantly increased hypoglycemia, with no decrease in CVD during the trial period, although several studies have shown a reduction in CVD with extended follow-up. There is evidence that hypoglycemia may adversely affect cardiovascular risk in patients with diabetes, and this is one potential explanation for the lack of CVD prevention in trials of intensive glycemic control. Hypoglycemia causes a cascade of physiologic effects and may induce oxidative stress and cardiac arrhythmias, contribute to sudden cardiac death, and cause ischemic cerebral damage, presenting several potential mechanisms through which acute and chronic episodes of hypoglycemia may increase CVD risk. In this review, we examine the risk factors and prevalence of hypoglycemia in diabetes, review the evidence for an association of both acute and chronic hypoglycemia with CVD in adults with diabetes, and discuss potential mechanisms through which hypoglycemia may adversely affect cardiovascular risk.
Publication
Journal: Diabetes Care
December/15/2014
Abstract
OBJECTIVE
We examined the effects of an intensive lifestyle intervention (ILI), compared with a diabetes support and education (DSE) control intervention, on long-term changes in depression symptoms, antidepressant medication (ADM) use, and health-related quality of life (HRQoL) in overweight/obese individuals with type 2 diabetes.
METHODS
Look AHEAD was a multisite randomized controlled trial of 5,145 overweight/obese participants assigned to ILI (designed to produce weight loss) or DSE and followed for a median of 9.6 years. The Beck Depression Inventory (BDI) was administered at baseline, annually at years 1-4, and again at year 8. Mean BDI scores and incidence of BDI scores ≥10, indicative of likely mild or greater depression, were examined. Annually through year 10, participants reported their ADM use and completed the Medical Outcomes Study Short Form 36 (SF-36) questionnaire, which yields physical component summary (PCS) and mental component summary (MCS) scores.
RESULTS
ILI significantly reduced the incidence of mild or greater depression symptoms (BDI scores ≥10) compared with DSE (hazard ratio [HR] = 0.85; 95% CI 0.75-0.97; P = 0.0145). Although SF-36 PCS scores worsened over time in both groups, ILI participants reported better physical function than DSE throughout the first 8 years (all P values <0.01). There were no significant differences between treatment arms in the proportion of participants who used ADMs or in SF-36 MCS scores.
CONCLUSIONS
ILI for overweight/obese patients with type 2 diabetes may reduce the risk of developing clinically significant symptoms of depression and preserve physical HRQoL. These findings should be considered when evaluating the potential benefits of ILIs.
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