bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age-Related Changes in Serum Testosterone and Sex Hormone Binding Globulin in Australian Men: Longitudinal Analyses of Two Geographically Separate Regional Cohorts
Authors: Liu Peter Y. , Beilin Jonathan , Meier Christian , Nguyen Tuan V. , Center Jacqueline R. , Leedman Peter J. , Seibel Markus J. , Eisman John A. , Handelsman David J. 
Published: June 2007

Abstract
Background: Cross-sectional studies from different populations show a variable decline in blood testosterone concentrations as men age. Few population representative cohorts have been followed up over time.
Objective: The objective of the study was to quantify longitudinally the change in serum testosterone and SHBG concentrations with age in two well-defined, representative but geographically widely separated regional Australian cohorts.
Subjects and Setting: The Busselton cohort comprises individuals aged 18–90 yr residing in Western Australia assessed prospectively since 1981. Sera were assayed from 910 men, from whom further samples were available 14 yr later in 480. The Dubbo cohort involves individuals aged 61–90 yr living in Eastern Australia. Baseline sera were collected from 610 men and additional sera on a second (n = 370) and third (n = 200) occasion from 1989 to 2004. Men from both cohorts are community dwelling and of predominately European origin.
Results: Longitudinal analyses show the following: 1) total testosterone declines comparably (P &gt; 0.9) by 1.3% (Busselton) and 0.9% (Dubbo) per annum with the same rates of decline when analyses were restricted to men older than 60 yr of age; 2) annual changes in SHBG were also very similar in age-restricted analyses (2.3% vs. 2.5%, P = 0.48); and 3) the annual increase in SHBG was steeper in middle-aged and older men (P &lt; 10−3vs. young men). These longitudinal changes were all up to 4-fold greater in magnitude, compared with cross-sectional analyses of baseline data.
Conclusion: In two separate regional Australian populations, blood testosterone fell and SHBG increased comparably with age. Age-related changes in blood testosterone and SHBG previously described in urban-dwelling men are the same in men who reside in smaller regional cities of another continent.
Insulin-Like Growth Factor Binding Protein-5 Interacts with the Vitamin D Receptor and Modulates the Vitamin D Response in Osteoblasts
Authors: Schedlich Lynette J. , Muthukaruppan Anita , O’Han Michelle K. , Baxter Robert C. 
Published: June 2007

AbstractThe 1,25 dihydroxyvitamin D3 [1,25(OH)2D3]-induced differentiation of osteoblasts comprises the sequential induction of cell cycle arrest at G0/G1 and the expression of bone matrix proteins. Reports differ on the effects of IGF binding protein (IGFBP)-5 on bone cell growth and osteoblastic function. IGFBP-5 can be growth stimulatory or inhibitory and can enhance or impair osteoblast function. In previous studies, we have shown that IGFBP-5 localizes to the nucleus and interacts with the retinoid receptors. We now show that IGFBP-5 interacts with nuclear vitamin D receptor (VDR) and blocks retinoid X receptor (RXR):VDR heterodimerization. VDR and IGFBP-5 were shown to colocalize to the nuclei of MG-63 and U2-OS cells and coimmunoprecipitate in nuclear extracts from these cells. Induction of osteocalcin promoter activity and alkaline phosphatase activity by 1,25(OH)2D3 were significantly enhanced when IGFBP-5 was down-regulated in U2-OS cells. Moreover, we found IGFBP-5 increased basal alkaline phosphatase activity and collagen α1 type 1 expression, and that 1,25(OH)2D3 was unable to further induce the expression of these bone differentiation markers in MG-63 cells. Expression of IGFBP-5 inhibited MG-63 cell growth and caused cell cycle arrest at G0/G1 and G2/M. Furthermore, IGFBP-5 reduced the effects of 1,25(OH)2D3 in blocking cell cycle progression at G0/G1 and decreased the expression of cyclin D1. These results demonstrate that IGFBP-5 can interact with VDR to prevent RXR:VDR heterodimerization and suggest that IGFBP-5 may attenuate the 1,25(OH)2D3-induced expression of bone differentiation markers while having a modest effect on the 1,25(OH)2D3-mediated inhibition of cell cycle progression in bone cells.
Glucocorticoid-Induced Degradation of Glycogen Synthase Kinase-3 Protein Is Triggered by Serum- and Glucocorticoid-Induced Protein Kinase and Akt Signaling and Controls β-Catenin Dynamics and Tight Junction Formation in Mammary Epithelial Tumor Cells
Authors: Failor Kim L. , Desyatnikov Yelena , Finger Lindsay A. , Firestone Gary L. 
Published: June 2007

Abstract
Glucocorticoid hormones stimulate adherens junction and tight junction formation in Con8 mammary epithelial tumor cells and induce the production of a stable nonphosphorylated β-catenin protein localized exclusively to the cell periphery. Glycogen synthase kinase-3 (GSK3) phosphorylation of β-catenin is known to trigger the degradation of this adherens junction protein, suggesting that steroid-activated cascades may be targeting this protein kinase. We now demonstrate that treatment with the synthetic glucocorticoid dexamethasone induces the ubiquitin-26S proteasome-mediated degradation of GSK3 protein with no change in GSK3 transcript levels. In transfected cells, deletion of the N-terminal nine amino acids or mutation of the serine-9 phosphorylation site on GSK3-β prevented its glucocorticoid-induced degradation. Expression of stabilized GSK3 mutant proteins ablated the glucocorticoid-induced tight junction sealing and resulted in production of a nonphosphorylated β-catenin that localizes to both the nucleus and the cell periphery in steroid-treated cells. Serine-9 on GSK3 can be phosphorylated by Sgk (serum- and glucocorticoid-induced protein kinase) and by Akt. Expression of dominant-negative forms of either Sgk- or Akt-inhibited glucocorticoid induced GSK3 ubiquitination and degradation and disrupted the dexamethasone-induced effects on β-catenin dynamics. Furthermore, the steroid-induced tight junction sealing is attenuated in cells expressing dominant-negative forms of either Sgk or Akt, although the effect of blunting Sgk signaling was significantly greater. Taken together, we have uncovered a new cellular cascade in which Sgk and Akt trigger the glucocorticoid-regulated phosphorylation, ubiquitination, and degradation of GSK3, which alters β-catenin dynamics, leading to the formation of adherens junctions and tight junction sealing.
“Insight” into Drug Quality: Comparison of Simvastatin Tablets from the US and Canada Obtained via the Internet
Authors: Veronin Michael A , Lee Eunah , Lewis E Neil 
Published: June 2007

Background: Recently, there has been much debate in the US concerning drug importation from Canadian Internet pharmacies. The Food and Drug Administration and US drug manufacturers assert that drugs obtained from international markets via the Internet present a health risk to consumers from substandard products. The public's perception is that drugs from Canada are as safe as those from the US. Objective: To determine whether simvastatin tablets obtained via the Internet from Canadian generic manufacturers are comparable in blend uniformity, a major attribute of tablet quality, with the US innovator product. Methods: Generic simvastatin tablets from 4 Canadian Internet pharmacy Web sites and the US innovator product were obtained for pharmaceutical analysis, Tablet samples were analyzed using near-infrared spectroscopic imaging techniques, which are designed to detect formulation defects of drug products during the manufacturing process. Digital images were created, revealing the tablets’ internal structures. Results: The blend uniformity of the active pharmaceutical ingredient in the tablet samples from Canada was determined and compared with that of the US innovator product. Results indicated that there is little significant difference in blend uniformity among US innovator and Canadian generic tablets. Conclusions: Results of this study suggest comparable quality assurance manufacturing standards for the US innovator product and the Canadian generic drug products tested. These findings have clinical, legal, and economic implications that should be addressed by policy makers to safeguard consumers who choose to purchase Canadian-manufactured drugs via the Internet.
Probiotics for Clostridium difficile–Associated Diarrhea: Focus on Lactobacillus rhamnosus GG and Saccharomyces boulardii
Authors: Segarra-Newnham Marisel 
Published: June 2007

Objective: To review the literature on the use of probiotics to treat or prevent recurrences of Clostridium difficile-associated diarrhea (CDAD) by replacing normal gastric flora. Data Sources: PubMed (1970–March 2007) was searched using the terms probiotics, Clostridium difficile, colitis, diarrhea, prevention, and treatment. Study Selection and Data Extraction: Case reports, case series, and clinical trials describing the use of probiotics in the treatment or prevention of recurrences of CDAD as primary outcome were included. Data Synthesis: A variety of controlled trials, case series, and case reports have evaluated probiotics to treat first or recurrent episodes of CDAD. In addition, a meta-analysis has been conducted to try to determine the rote of probiotics in CDAD. In general, most case series and case reports have shown favorable results with Lactobacillus rhamnosus GG or Saccharomyces boulardii. However, other reports have shown lack of benefit. The meta-analysis showed that these probiotics may be useful in treating or preventing recurrences of CDAD. Nonetheless, the heterogeneity of the studies makes definite conclusions difficult. In addition, several cases of bacteremia or fungemia associated with probiotic use have been reported, particularly in the last decade. Patients most commonly affected by these complications are immunosuppressed. Unfortunately, these are also the patients more likely to have severe CDAD or are at risk for recurrences. Conclusions: Additional experience with and study of probiotics are warranted due to numerous unanswered questions. Given the potential for complications in debilitated and immunosuppressed patients, the risks may outweigh benefits, and rational antibiotic use may be a better option to prevent a first episode or recurrence of CDAD.
Inappropriate Drug Use in the Elderly: a Nationwide Register-Based Study
Authors: Johnell Kristina , Fastbom Johan , Rosén Måns , Leimanis Andrejs 
Published: June 2007

Background: Potentially inappropriate drug use (IDU) is an important and preventable safety concern in the care of elderly patients and has been associated with adverse drug reactions, hospitalization, and mortality. Objective: To estimate the prevalence of potentially IDU among the elderly in Sweden and investigate whether age. sex, and number of dispensed drugs are associated with IDU. Methods: We analyzed data on age, sex, and dispensed drugs for people aged 75 years and older who were listed in the Swedish Prescribed Drug Register from October–December 2005 (N = 732 226). The main outcome measures of IDU were prescription of anticholinergics, prescription of long-acting benzodiazepines, concurrent use of 3 or more psychotropic drugs, and an indication of potentially serious drug-drug interactions. Results: Prevalence for IDU was 17%; for anticholinergic drugs 6%, long-acting benzodiazepines 5%, 3 or more psychotropic drugs 5%, and potentially serious drug–drug interactions 4%. After adjustment for age and sex, number of dispensed drugs was strongly associated with all 4 measures of IDU. After adjustment for sex and number of dispensed drugs, increasing age was moderately associated with a higher probability of IDU, long-acting benzodiazepines, and 3 or more psychotropic drugs, After adjustment for age and number of dispensed drugs, women had a slightly increased probability of IDU, anticholinergic drugs, long-acting benzodiazepines, and 3 or more psychotropic drugs. Conclusions: IDU was fairly common among the elderly in Sweden in 2005 and was strongly connected to the number of dispensed drugs they were taking. Older age and female sex were related to inappropriate use of psychotropic drugs, whereas the opposite relationship prevailed for potentially serious drug–drug interactions. Future research is needed to determine whether IDU will become more common due to increasing use of drugs among elderly persons. The challenge is to balance the problems related to IDU without denying older people potentially valuable drug therapy.
Awakening and Counterregulatory Response to Hypoglycemia During Early and Late Sleep
Authors: Jauch-Chara Kamila , Hallschmid Manfred , Gais Steffen , Oltmanns Kerstin M. , Peters Achim , Born Jan , Schultes Bernd 
Published: June 2007

OBJECTIVE—Nocturnal hypoglycemia represents an important problem for diabetic patients, which has been primarily attributed to an attenuated hormonal counterregulation during sleep. So far, hypoglycemia counterregulation has been exclusively examined during early nocturnal sleep, although early sleep differs markedly in sleep stage architecture from late sleep. Here, we investigated whether awakening and counterregulatory responses differ between early and late sleep.
RESEARCH DESIGN AND METHODS—Sixteen healthy subjects were tested on three occasions. On two nights, a linear fall in plasma glucose to a nadir of 2.2 mmol/l within 60 min was induced by insulin infusion. On one night, this was done immediately after sleep onset and on the other night after ∼3.5 h of sleep. In a further control night, no hypoglycemia was induced.
RESULTS—During early sleep, 10 subjects awoke in response to hypoglycemia, whereas no subject awoke during the corresponding interval of the control night (P &lt; 0.004). During late sleep, all subjects awoke upon hypoglycemia, and four subjects awoke spontaneously during the corresponding control interval (P &lt; 0.001). The pattern indicates that the frequency of awakenings caused by hypoglycemia is similar for early and late sleep. Increases in epinephrine, norepinephrine, ACTH, cortisol, and growth hormone were distinctly weaker during late than early hypoglycemia (all P &lt; 0.05).
CONCLUSIONS—Diminished hormonal counterregulation during late sleep could be one factor contributing to the clinically observed accumulation of hypoglycemic episodes in the later part of the night in patients with diabetes.
Insulin Resistance and Clustering of Cardiometabolic Risk Factors in Urban Teenagers in Southern India
Authors: Ramachandran Ambady , Snehalatha Chamukuttan , Yamuna Annasami , Murugesan Narayanasamy , Narayan K.M. Venkat 
Published: June 2007

OBJECTIVE— We sought to study the occurrence of cardiometabolic risk variables, their clustering, and their association with insulin resistance among healthy adolescents in urban south India.
RESEARCH DESIGN AND METHODS— School children aged 12–19 years (n = 2,640; 1,323 boys and 1,317 girls) from diverse socioeconomic backgrounds were studied. Demographic, social, and medical details were obtained; anthropometry and blood pressure were measured. Fasting plasma glucose, insulin, and lipid profiles were measured. Clusters of risk variables were identified by factor analysis. Association of insulin resistance (homeostasis model assessment) with individual risk variables and their clusters were assessed.
RESULTS— One or more cardiometabolic abnormalities (i.e., low HDL cholesterol, elevated triglycerides, fasting plasma glucose, or blood pressure) was present in 67.7% of children (in 64.8% of normal weight and 85% of overweight children). Insulin resistance was associated with the above abnormalities except HDL cholesterol. It also showed significant positive association with BMI, waist circumference, body fat percentage, and total cholesterol (P &lt; 0.0001). Factor analysis identified three distinct clusters, with minor differences in the sexes: 1) waist circumference and blood pressure; 2) dyslipidemia, waist circumference, and insulin; and 3) waist circumference, glucose, and plasma insulin, with minor differences in the sexes. Insulin was a component of the lipid and glucometabolic cluster. In girls, it was a component of all three clusters.
CONCLUSIONS— Cardiometabolic abnormalities are present in nearly 68% of young, healthy, Asian-Indian adolescents and even among those with normal weight. Insulin resistance is associated with individual cardiometabolic factors, and plasma insulin showed association with clustering of some variables.
Impact of Oral Antihyperglycemic Therapy on All-Cause Mortality Among Patients With Diabetes in the Veterans Health Administration
Authors: Kahler Kristijan H. , Rajan Mangala , Rhoads George G. , Safford Monika M. , Demissie Kitaw , Lu Shou-En , Pogach Leonard M. 
Published: June 2007

OBJECTIVE— The objective of this analysis was to evaluate the impact of several classes of oral antihyperglycemic therapy relative to sulfonylurea monotherapy on all-cause mortality among a cohort of patients with diabetes from the Veterans Health Administration (VHA).
RESEARCH DESIGN AND METHODS— A retrospective cohort study using data obtained from the VHA Diabetes Epidemiology Cohort was used. Users of oral antihyperglycemic therapy were classified into the following cohorts: sulfonylurea monotherapy, metformin monotherapy, metformin plus sulfonylurea, thiazolidinedione (TZD) use alone or in combination with other oral agents (TZD users), and no drug therapy. All-cause mortality was the outcome of interest. Multivariate mixed models incorporating a propensity score to account for imbalance among cohorts were used to estimate drug effects on mortality with associated 95% CIs.
RESULTS— A total of 39,721 patients with diabetes were included in the study. Adjusted odds ratios and 95% CIs for all-cause mortality were 0.87 (0.68–1.10) for metformin monotherapy users, 0.92 (0.82–1.05) for metformin plus sulfonylurea users, and 1.04 (0.75–1.46) for TZD users, relative to sulfonylurea monotherapy users.
CONCLUSIONS— We did not find any significant drug effect on all-cause mortality for any oral treatment cohorts relative to sulfonylurea oral monotherapy.
AIR Inhaled Insulin in Subjects With Chronic Obstructive Pulmonary Disease
Authors: Rave Klaus , de la Peña Amparo , Tibaldi Fabián S. , Zhang Liping , Silverman Bernard , Hausmann Michaela , Heinemann Lutz , Muchmore Douglas B. 
Published: June 2007

OBJECTIVE— In this open-label, randomized, crossover study, pharmacokinetic and glucodynamic responses were compared in healthy subjects versus subjects with moderate chronic obstructive pulmonary disease (COPD), following administration of 12 units equivalent AIR inhaled insulin versus 12 units subcutaneous insulin lispro.
RESEARCH DESIGN AND METHODS— Three nonsmoking groups (n = 15 each)— healthy subjects (baseline mean ± SD age 38 ± 13 years, forced expiratory volume in 1 s [FEV1] 4.06 ± 1.04 l), subjects with chronic bronchitis (aged 53 ± 9 years, FEV1 2.14 ± 0.60 l), and subjects with pulmonary emphysema (aged 58 ± 6 years, FEV1 1.67 ± 0.61 l)— were randomly assigned to one of three treatment sequences. Three euglycemic glucose clamp procedures were performed.
RESULTS— In subjects with chronic bronchitis and emphysema, AIR inhaled insulin administration resulted in reduced insulin exposure (area under the serum insulin concentration curve from time zero until time of return to baseline [AUC0–t′]) (55.7%, P = 0.13 and 78.5%, P &lt; 0.001, respectively) and reduced total insulin effect (total glucose infusion rate) (60.4%, P &lt; 0.01 and 67.1%, P &lt; 0.01, respectively) relative to healthy subjects. Subcutaneous insulin lispro administration resulted in similar responses across study groups for insulin exposure and metabolic effect. Intrasubject pharmacokinetic and glucodynamic variability ranged from 17 to 52% across groups. No significant differences were shown for pre- and postclamp pulmonary function tests. During clamps, FEV1 and forced vital capacity declined modestly in both COPD groups, with no difference between AIR insulin and subcutaneous insulin lispro.
CONCLUSIONS— Short-term exposure to AIR inhaled insulin was well tolerated by COPD subjects, showing similar time-exposure and time-action profiles, but with reduced insulin absorption and metabolic effect compared with healthy subjects. Further clinical evaluation is warranted in patients with comorbid diabetes and COPD.
Validation of Steady-State Insulin Sensitivity Indices in Chronic Kidney Disease
Authors: Crutchlow Michael F. , Robinson Bruce , Pappachen Binu , Wimmer Neil , Cucchiara Andrew J. , Cohen Debbie , Townsend Raymond 
Published: June 2007

OBJECTIVE— Insulin resistance may contribute to cardiovascular disease and the progression of renal insufficiency in patients with chronic kidney disease (CKD). However, feasible methods for estimating insulin sensitivity in large-population CKD studies have not been validated. The purpose of this study was to attempt to validate several commonly used steady-state insulin sensitivity (SI-SS) indices in a CKD population.
RESEARCH DESIGN AND METHODS— Twenty-seven subjects with estimated glomerular filtration rate (eGFR) ranging from 70 to &lt;10 ml/min per 1.73m2 (median eGFR = 48) underwent a frequently sampled intravenous glucose tolerance test (FSIVGTT) on a single occasion. Correlations were obtained between the minimal model-derived insulin sensitivity parameter from the FSIVGTT (SI-FSIVGTT) and seven SI-SS indices derived from fasting insulin and glucose data obtained just before the FSIVGTT.
RESULTS— Each of the seven steady-state indices was significantly correlated with SI-FSIVGTT. For indices obtained using the mean of four fasting insulin and glucose values over 15 min, Pearson correlation coefficients (|r|) ranged from 0.51 to 0.87 (P &lt; 0.01 for each). For indices using single fasting insulin and glucose values, |r| ranged from 0.51 to 0.72 (P &lt; 0.01 for each). By both the four and one time point approaches, 1/I0 had the highest correlation with SI-FSIVGTT. The correlation with SI-FSIVGTT did not change significantly according to eGFR level for any of the SI-SS indices.
CONCLUSIONS— SI-SS indices are valid surrogates for SI-FSIVGTT in the CKD population. Their use will expand the range of testable hypotheses in CKD cohort studies.
Primary Aldosteronism in Diabetic Subjects With Resistant Hypertension
Authors: Umpierrez Guillermo E. , Cantey Paul , Smiley Dawn , Palacio Andres , Temponi Diana , Luster Karen , Chapman Arlene 
Published: June 2007

OBJECTIVE— Despite the high prevalence of hypertension in patients with type 2 diabetes, the prevalence of primary aldosteronism in this population has not been determined.
RESEARCH DESIGN AND METHODS— One hundred subjects with type 2 diabetes and resistant hypertension, defined as blood pressure &gt;140/90 mmHg despite the use of ≥3 antihypertensive agents, were screened for primary aldosteronism. Screening was performed by measuring the plasma aldosterone (PAC)-to-plasma renin activity (PRA) ratio. Subjects with a PAC-to-PRA ratio &gt;30 ng · ml−1 · h−1 underwent confirmatory salt load testing. Diagnostic criteria included 24-h urine aldosterone ≥12 μg during the 3rd day of the oral salt load or a PAC ≥5 ng/dl after the 4-h intravenous saline load.
RESULTS— Thirty-four subjects had a PAC-to-PRA ratio &gt;30 ng · ml−1 · h−1. Fourteen subjects (14% [95% CI 7.2–20.8]) had a confirmed diagnosis of primary aldosteronism. Ninety-three patients were African Americans. There were no differences in age, glycemic control, and number of antihypertensive drugs between subjects with and without primary aldosteronism. Subjects with primary aldosteronism had lower serum potassium (3.7 ± 0.4 vs. 4.0 ± 0.4 mmol/l, P = 0.012), higher PAC (15.6 ± 8 vs. 9.1 ± 6 ng/dl, P = 0.0016), and higher PAC-to-PRA ratio (98 ± 74 vs. 21 ± 30 · ml−1 · h−1, P &lt; 0.001) than patients without primary aldosteronism.
CONCLUSIONS— Primary aldosteronism is common in diabetic patients with resistant hypertension, with a prevalence of 14%. Our results indicate that diabetic subjects with poorly controlled hypertension who are taking ≥3 antihypertensive drugs should be screened for primary aldosteronism.