bluuebunny/crossref_metadata_2025 huggingface dataset:
“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.
Probiotics for Clostridium difficile Diarrhea: Putting It into Perspective
Authors: Karpa Kelly Dowhower
Published: June 2007

Clostridium difficile diarrhea is an expensive, life-threatening infection associated with serious morbidity and mortality, even among previously healthy individuals. Relapses from the infection are common following standard antibiotic treatments, with 3–5% of patients who contract C. difficile diarrhea unable to discontinue vancomycin due to continual relapses. Such patients may have a focal immunodeficiency in which they tail to mount an immune response against C. difficile. For these individuals, antimicrobial therapies are unable to eradicate the microorganism because no antibiotics are capable of killing C. difficile spores. Although they are considered alternative medicine, probiotics have provided a safe and effective means of restoring gastrointestinal flora and alleviating diarrhea, particularly for individuals experiencing multiple relapses.
Specific determinants of burnout among male and female general practitioners: A cross‐lagged panel analysis
Authors: Houkes Inge , Winants Yvonne H. W. M. , Twellaar Mascha
Published: June 2007

This study aimed to develop and test a specific pattern of relationships between job demands, job resources and person‐related factors on the one hand, and the three burnout dimensions on the other, among Dutch General Practitioners. In addition, we aimed to test whether gender differences exist in this regard. Based on several theoretical models such as the Job Demand‐Control model and the Job Demands‐Resources model of burnout as well as a review of burnout studies among physicians, we formulated a research model of burnout. The research questions were answered by means of self‐report questionnaires using a full panel design with two waves. Cross‐lagged panel analyses indicated that the causal direction of the relationships between demands, resources and person‐related factors on the one hand, and burnout on the other is reciprocal. In addition, multi‐sample analyses revealed that the pattern of relationships between job demands, job resources, person‐related factors and burnout is different for men and women, although results are less clear at the second measurement point. Among other things, we recommend anticipating in a gender sensitive way on risk factors for burnout and motivation loss for young professionals by coaching and empowerment in vocational training.
Apical Junction Complex Protein Expression in the Canine Colon
Authors: Ridyard Alison E. , Brown Jeremy K. , Rhind Susan M. , Else Roderick W. , Simpson James W. , Miller Hugh R.P.
Published: June 2007

Canine idiopathic lymphocytic-plasmacytic colitis (LPC) is a well-recognized clinical and pathological entity in the dog, associated with altered immune cell populations and cytokine expression profiles. Clinical and experimental data indicate that alterations in the permeability of the intestinal epithelium contribute to the pathogenesis of a range of related conditions. The apical junction complex plays a significant role in regulating epithelial paracellular permeability, and we have characterized the distribution of a number of its component tight junction (ZO-1, occludin, claudin-2) and adherens junction (E-cadherin and β-catenin) proteins in normal colon and colon from dogs with idiopathic LPC. ZO-1, occludin, E-cadherin, and β-catenin exhibited a distribution in normal canine colon similar to that described previously in humans and rodents. In contrast to the situation in humans, claudin-2-specific labeling was observed in the normal canine colonic crypt epithelium, decreasing in intensity from the distal to the proximal crypt and becoming barely detectable at the luminal surface of the colon. There was little evidence for significant changes in ZO-1, occludin, E-cadherin, or β-catenin expression in dogs affected by idiopathic LPC. However, claudin-2 expression markedly increased in the proximal crypt and luminal colonic epithelium in affected dogs, suggesting a role in the pathogenesis of canine LPC. (J Histochem Cytochem 55: 1049–1058, 2007)
Fluorescence In Situ Hybridization Using an Old World Monkey Y Chromosome—specific Probe Combined With Immunofluorescence Staining on Rhesus Monkey Tissues
Authors: Xia Xiujin , Rasmussen Terri , Alvarez Xavier , Taguchi Takahiro , Li Marilyn , La Russa Vincent F.
Published: June 2007

To date, there is no commercially available Y chromosome probe that can be used for fluorescence in situ hybridization (FISH) for the male rhesus monkey. We have recently generated a probe for FISH with high specificity to the short arm of the rhesus monkey Y chromosome. In this study, we further describe a method that keeps the integrity of tissue-specific antigenic structures for immunofluorescence staining subsequent to FISH on paraffin-embedded rhesus monkey tissues. We have examined this technique in combination with an epithelial cell—specific marker, cytokeratin 8/18 (CK8/18), on various tissues, including jejunum, liver, kidney, and pancreas. CK8/18 and Y chromosome signals were distinctly seen simultaneously on epithelial cells from the same tissue section from male but not female monkeys. These studies indicate that our FISH immunofluorescence technique can be reliably used to identify and phenotype male cells in paraffin-embedded rhesus monkey tissues.
Diverse perspectives on helping young children build important foundational language and print skills
Authors: GASKINS IRENE W. , LABBO LINDA D.
Published: June 2007

Book reviewed in this article:

Handbook of Early Literacy Research(Vol. 2). Edited by David K. Dickinson and Susan B. Neuman. 2006.
External radial stress changes and axial capacity for suction caissons in soft clay
Authors: Chen W. , Randolph M. F.
Published: June 2007

A series of centrifuge tests was performed on instrumented model caissons in normally consolidated, lightly overconsolidated and sensitive clays, to investigate the external radial stress changes around suction caissons during installation, consolidation and pullout, and axial capacity after consolidation. Total pressure transducers embedded at different elevations of the caisson wall showed external radial total stresses that varied almost linearly with depth during both penetration and extraction of the caisson, with smaller gradients during post-consolidation pullout. Only slight differences were found in the measured external radial total stress when pressure transducers entered the suction-affected zone from the jacking-affected zone. Comparisons are presented between measurements and two theoretical predictions, for both the external radial total stress during caisson installation, and the radial effective stress after consolidation. A simple cavity expansion approach was found to give reasonable predictions of stress changes and post-consolidation external shaft friction for caissons installed by combined self-weight and suction. These findings are consistent with estimates of the amount of internal soil heave during installation, where about 50% of the caisson wall thickness was accommodated by outward flow of soil.
Effect of confining pressure on ballast degradation and deformation under cyclic triaxial loading
Authors: Lackenby J. , Indraratna B. , McDowell G. , Christie D.
Published: June 2007

Traditional railway foundations or substructures have become increasingly overloaded in recent years, owing to the introduction of faster and heavier trains. A lack of substructure re-engineering has resulted in maintenance cycles becoming more frequent and increasingly expensive. Two significant problems arising from increasing axle loads are differential track settlement and ballast degradation. One potential method of enhancing the substructure is to manipulate the level of ballast confinement. To investigate this possibility, a series of high-frequency cyclic triaxial tests has been conducted to examine the effects of confining pressure and deviator stress magnitude on ballast deformation (permanent and resilient) and degradation. Experimental results indicate that, for each deviator stress considered, an 'optimum' range of confining pressures exists such that degradation is minimised. This range was found to vary from 15–65 kPa for a maximum deviator stress of 230 kPa to 50–140 kPa when deviatoric stresses increase to 750 kPa. Ballast specimens tested at low confining pressures indicative of current in situ conditions were characterised by excessive axial deformations, volumetric dilation, and an unacceptable degree of degradation associated mainly with angular corner breakage. The results suggest that in situ lateral pressures should be increased to counteract the axle loads of heavier trains, and practical methods of achieving increased confinement are suggested.
Three-dimensional slope stability analysis by elasto-plastic finite elements
Authors: Griffiths D. V. , Marquez R. M.
Published: June 2007

Slope stability analysis is one of the oldest applications in geotechnical engineering, yet it remains one of the most active areas of study in both research and practice. The vast majority of slope stability analyses are performed in two dimensions under the assumption of plane strain conditions. Even when two-dimensional (2D) conditions are not appropriate, three-dimensional (3D) analysis is rarely performed. There are a number of reasons for this. The majority of work on this subject strongly suggests that the 2D factor of safety is conservative (i.e. lower than the ‘true’ 3D factor of safety). Even when 3D may be justified on geometric grounds, the available methods, being often based on extrapolations of 2D ‘methods of slices’ to 3D ‘methods of columns’, are complex, involve numerous assumptions, and are not readily modified to account for realistic boundary conditions in the third dimension such as sloping abutments. The power and versatility of the elasto-plastic finite element approach to slope stability analysis in 2D are well known, and these advantages are even more attractive in 3D. The paper demonstrates some 3D slope stability analyses by finite elements, placing the results in context with 2D solutions and validating the results where possible against alternative methods.
Effects of Compost and Nitrogen Fertilizer on Wheat Nitrogen Use in Japanese Soils
Authors: Takahashi Shigeru , Anwar Muhuddin R. , de Vera Sharon G.
Published: June 2007

Wheat (Triticum aestivum L.) grain yield (GY) and grain protein concentration (GPr) are influenced by N availability and supply. This study aimed to investigate wheat (cv. Ayahikari) response to compost and N fertilizer. A 3‐yr field experiment was conducted on four Japanese soils varying in N mineralization potential with or without annual compost application (≈220 kg N ha−1 yr−1). Four N fertilizer treatments including a zero‐N control were established each year, and equal amounts of N were applied at preplanting and stem elongation. A significant quadratic relationship of increasing GY with greater N uptake, and increasing GPr with greater N factor (aboveground N uptake, Nup, per unit of GY) occurred for the pooled data. From these relationships, the optimum Nup for appropriate GPr (105 g kg−1) for Japanese ‘Udon’ noodle was estimated to be 139 kg ha−1 and GY could be >5000 kg ha−1. Fertilizer N rate for optimum N uptake in each soil–compost regime was estimated from a significant linear or quadratic relationship between N uptake and fertilizer N rate (Nf). The agronomic efficiency (yield increase per unit of fertilizer N) and apparent fertilizer N recovery at a given rate of fertilizer N tended to be lower in soils with annual compost than without. However, the fertilizer N requirement for an equivalent yield decreased, thus the fertilizer N surplus (Nf − Nup) at optimum N uptake was lower in soils with compost application than without.
Cotton Profitability with Alternative Lime Application Rates, Cover Crops, Nitrogen Rates, and Tillage Methods
Authors: Cochran Rebecca L. , Roberts Roland K. , Larson James A. , Tyler Donald D.
Published: June 2007

Soil acidity and cotton (Gossypium hirsutum L.) yield may be influenced by cover crop, N, and tillage method. Application of half the recommended lime rate may be possible without reducing lint yield and net revenue. The objective was to determine cotton yields and profitability for full and half recommended rates of lime, cover crops, N rates, and tillage methods. Data for 1995 through 2001 from a long‐term experiment on a Memphis silt loam (fine‐silty, mixed, active, thermic Typic Hapludalf) were used to estimate cotton lint yield response functions. The experimental design was a split‐split‐split randomized complete block with four replications. Plots were established in 1981 with four cover crop alternatives, four N rates, and two tillage methods. Soil pH declined until 1995 when plots were split into blocks and assigned a one‐time application of lime at the recommended rate and half the recommended rate. Results for no cover (unplanted winter cover) and winter wheat (Triticum aestivum L.) and hairy vetch (Vicia villosa L.) winter covers suggest that the amount of N fertilizer had a significant effect on lint yields, but was less important for the crimson clover cover (Trifolium incarnatum L.). No‐tillage significantly increased cotton lint yields over time. When either the half or full rates of lime were applied, the plots combined with no‐tillage resulted in the highest net revenues. Cotton lint yields and net revenues for the half rate of lime were comparable or greater than the full rate of lime for both tillage methods and all cover alternatives. In the short‐to‐medium term, cotton farmers may be able to apply half the recommended rate of lime without reducing yield or net revenue.
Use of Anaerobically Digested Swine Manure as a Nitrogen Source in Corn Production
Authors: Loria Esteban R. , Sawyer John E. , Barker Daniel W. , Lundvall John P. , Lorimor Jeffery C.
Published: June 2007

Swine (Sus scrofa) manure is an important source of N for crop production. The processing of manure in an anaerobic digester for biogas production is only a partial manure treatment process and is not designed as a disposal method. However, digestion will alter manure characteristics, and this may affect nutrient availability to crops. The objective of this study was to evaluate the N supply to corn (Zea mays L.) from swine manure before and after anaerobic digestion for biogas production. Raw and digested swine manure were late‐fall applied as main plots, with three manure N rates as subplots, and six fertilizer N rates as sub‐subplots. Response to manure and fertilizer N was determined through soil inorganic N, plant N status and uptake, and grain yield. After 3 yr of study, results indicated no difference between raw and digested swine manure as a source of N for plant use in the year of application or in the residual year. Equivalence to fertilizer N was the same with both raw and digested swine manure, and varied between years with 100 0n 2000, 44 0n 2001, and 60 0n 2002. These differences are attributed to varying growing seasons and N loss potential from time of late fall manure application compared with the spring‐applied fertilizer N. Late fall and early spring soil sampling indicated rapid conversion to NO3 with both sources. Results of this work indicate that digested liquid swine manure can readily supply plant‐available N and management for corn production should be the same as with raw swine manure.
One‐Time Tillage of No‐Till: Effects on Nutrients, Mycorrhizae, and Phosphorus Uptake
Authors: Garcia J. P. , Wortmann C. S. , Mamo M. , Drijber R. , Tarkalson D.
Published: June 2007

Stratification of nutrient availability, especially of P, that develops with continuous no‐till (NT) can affect runoff nutrient concentration and possibly nutrient uptake. The effects of composted manure application and one‐time tillage of NT on the distribution of soil chemical properties, root colonization by arbuscular mycorrhizae (AM), and plant P uptake were determined. Research was conducted on Typic Argiudoll and Mollic Hapludalf soils under rainfed corn (Zea maysL.) or sorghum [Sorghum bicolor(L.) Moench.] rotated with soybean [Glycine max(L.) Merr.] in eastern Nebraska. Tillage treatments included NT, disk, chisel, moldboard plow (MP), and mini‐moldboard plow (MMP). Subplots had either 0 or 87.4 kg P ha−1applied in compost before tillage. Bray‐P1 was five to 21 times as high for the 0‐ to 5‐cm as compared with the 10‐ to 20‐cm soil depth. Greater redistribution of nutrients and incorporation of compost P resulted from MP tillage than from other tillage treatments. One‐time chisel or disk tillage did not effectively redistribute nutrients while MMP tillage had an intermediate effect. Compost application reduced AM colonization of roots at R6 for all crops. Tillage reduced AM colonization with reductions at R6 due to MP tillage of 58 to 87%. The tillage effect on colonization persisted through the second year with no indication of AM recovery. Root P concentration was increased by MP and was negatively correlated to colonization. Decreased colonization did not result in decreased plant P uptake. Infrequent MP tillage can reduce surface soil P and the potential for P loss in runoff, but may reduce AM colonization of the roots, possibly reducing P uptake with some low P soils. The results do not indicate any advantage to one‐time tillage of NT if runoff P loss is not a concern.
One‐Time Tillage of No‐Till Systems: Soil Physical Properties, Phosphorus Runoff, and Crop Yield
Authors: Quincke J. A. , Wortmann C. S. , Mamo M. , Franti T. , Drijber R. A. , García J. P.
Published: June 2007

Continuous no‐till (NT) has numerous benefits, including improved soil aggregate stability in the surface soil and increased rate of water infiltration, but accumulation of soil P at the soil surface with NT can increase P concentration in runoff. We hypothesized that occasional one‐time tillage of NT land, conducted once in 10 or more years, can reduce P runoff and improve crop yields without reducing soil aggregation or increasing runoff. Research was conducted in long‐term NT fields under rainfed corn [Zea mays (L.)] or sorghum [Sorghum bicolor (L.) Moench.] rotated with soybeans [Glycine max (L.) Merr.] at two locations in eastern Nebraska. Tillage treatments were applied in the spring or fall and included continuous NT, tandem disk (disk), chisel with 10‐cm‐wide twisted shanks, moldboard plow (MP), and mini‐moldboard plow (miniMP). Subplots had either 0 or 87.4 kg P ha−1 applied as composted feedlot manure before tillage. Yield and yield components were measured for 2 and 3 yr after the spring and fall one‐time tillage, respectively. In Year 2 or 3 after tillage, soil sorptivity, field‐saturated infiltration rate, runoff volume, runoff P loss, and soil aggregate stability were determined. Yield was not affected by the tillage × compost interaction, but was increased by compost application at one location and sorghum yield was affected by tillage treatments at the second location. Grain yield was never significantly more or less with one‐time tillage as compared with NT. Soil aggregate stability was not affected by tillage treatments. Sorptivity and infiltration were increased with MP tillage compared with NT at one location but reduced at the other. One‐time MP tillage reduced dissolved P loss at both locations and total phosphorus (TP) loss at one location. The benefit of one‐time MP tillage in terms of reduced dissolved reactive P loss in runoff was positive with no negative effect on soil aggregate stability but no gain in yield.
In Celebration of 100 Years of ASA
Authors: Beard James B , Cookingham Peter O.
Published: June 2007

Professor William James Beal (1833–1924) became a leading educator and researcher in applied plant science while serving on the faculty of the new State Agricultural College in Michigan from 1871 to 1910. He was a key leader of the experimental movement of agricultural botany. Beal conducted the (i) first demonstration of hybrid vigor by controlled crossing of corn lines, 1878; (ii) initiation of the oldest ongoing U.S. botanical experiment involving the vitality of buried seeds, 1879; and (iii) first turfgrass experiments, including polystand compatibility, 1880. He initiated early, extensive seed purity/viability testing in 1877, and also organized the oldest, continuously operating U.S. botanical garden in 1877. He was an early advocate for forest conservation and reforestation. These works resulted in more than 1200 papers, plus seven extensive texts. Beal was a key proponent of scholarly communications among the few isolated scientists active in applied botany and in agricultural research. His efforts contributed to the formation of several important early national agricultural science organizations. Beal was a key founder and first President of the (i) Society for the Promotion of Agricultural Science (SPAS), 1880; (ii) Association of Botanists in the United States Agricultural Experiment Stations, 1889; (iii) Botanical Club of the American Association for the Advancement of Science, 1888; and (iv) Michigan Academy of Science, 1884. The visionary outlook in organization of the SPAS was a vital pioneering step leading to formation of the American Society of Agronomy in 1907.
The ATP-Binding Cassette Transporter A1 R230C Variant Affects HDL Cholesterol Levels and BMI in the Mexican Population
Authors: Villarreal-Molina M. Teresa , Aguilar-Salinas Carlos A. , Rodríguez-Cruz Maricela , Riaño Daniela , Villalobos-Comparan Marisela , Coral-Vazquez Ramon , Menjivar Marta , Yescas-Gomez Petra , Königsoerg-Fainstein Mina , Romero-Hidalgo Sandra , Tusie-Luna M. Teresa , Canizales-Quinteros Samuel ,   the Metabolic Study Group
Published: June 2007

Although ATP-binding cassette transporter A1 (ABCA1) is well known for its role in cholesterol efflux and HDL formation, it is expressed in various tissues, where it may have different functions. Because hypoalphalipoproteinemia is highly prevalent in Mexico, we screened the ABCA1 coding sequence in Mexican individuals with low and high HDL cholesterol levels to seek functional variants. A highly frequent nonsynonymous variant (R230C) was identified in low–HDL cholesterol but not in high–HDL cholesterol individuals (P = 0.00006). We thus assessed its frequency in the Mexican-Mestizo general population, seeking possible associations with several metabolic traits. R230C was screened in 429 Mexican Mestizos using Taqman assays, and it was found in 20.1% of these individuals. The variant was significantly associated not only with decreased HDL cholesterol and apolipoprotein A-I levels but also with obesity (odds ratio 2.527, P = 0.005), the metabolic syndrome (1.893, P = 0.0007), and type 2 diabetes (4.527, P = 0.003). All of these associations remained significant after adjusting for admixture (P = 0.011, P = 0.001, and P = 0.006, respectively). This is the first study reporting the association of an ABCA1 variant with obesity and obesity-related comorbidities as being epidemiologically relevant in the Mexican population.
Renal Fibrosis and Glomerulosclerosis in a New Mouse Model of Diabetic Nephropathy and Its Regression by Bone Morphogenic Protein-7 and Advanced Glycation End Product Inhibitors
Authors: Sugimoto Hikaru , Grahovac Gordan , Zeisberg Michael , Kalluri Raghu
Published: June 2007

Diabetic nephropathy is currently the most common cause of end-stage renal disease (ESRD) in the western world. A mouse model for diabetic nephropathy that encompasses the salient features of this disease in the kidney is not available. Here, we report that CD1 mice, in contrast to inbred C57BL/6 and 129Sv strains, develop ESRD associated with prominent tubulointerstitial nephritis and fibrosis within 3 months and die because of diabetic complications by 6–7 months after a single injection of streptozotocin. Histopathologic lesions observed in these mice mimic human diabetic nephropathy, including glomerular hypertrophy, diffuse glomerulosclerosis, tubular atrophy, interstitial fibrosis, and decreased renal excretory function. Next, we tested the therapeutic efficacy of bone morphogenic protein-7 (BMP-7) and inhibitors of advanced glycation end products (AGEs), aminoguanidine and pyridoxamine, to inhibit and regress the progression of renal disease in diabetic CD1 mice. We demonstrate that although aminoguanidine, pyridoxamine, and BMP-7 significantly inhibit glomerular lesions, BMP-7 is most effective in the inhibition of tubular inflammation and tubulointerstitial fibrosis in these mice. Collectively, our results report a new mouse model for diabetic nephropathy with prominent interstitial inflammation and fibrosis and the selective inhibition of diabetic kidney disease by AGE inhibitors and BMP-7.
Metabolic Endotoxemia Initiates Obesity and Insulin Resistance
Authors: Cani Patrice D. , Amar Jacques , Iglesias Miguel Angel , Poggi Marjorie , Knauf Claude , Bastelica Delphine , Neyrinck Audrey M. , Fava Francesca , Tuohy Kieran M. , Chabo Chantal , Waget Aurélie , Delmée Evelyne , Cousin Béatrice , Sulpice Thierry , Chamontin Bernard , Ferrières Jean , Tanti Jean-François , Gibson Glenn R. , Casteilla Louis , Delzenne Nathalie M. , Alessi Marie Christine , Burcelin Rémy
Published: June 2007

Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times, a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPS-containing microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar extent as in high-fat–fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride content, were increased. Furthermore, liver, but not whole-body, insulin resistance was detected in LPS-infused mice. CD14 mutant mice resisted most of the LPS and high-fat diet–induced features of metabolic diseases. This new finding demonstrates that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases.
Triglyceride Uptake and Lipoprotein Lipase–Generated Fatty Acid Spillover in the Splanchnic Bed of Dogs
Authors: Nelson Robert H. , Edgerton Dale S. , Basu Rita , Roesner Justin C. , Cherrington Alan D. , Miles John M.
Published: June 2007

The action of lipoprotein lipase on triglyceride-rich lipoproteins generates fatty acids that are either transported into tissues or mix with circulating free fatty acids (FFAs) via a process known as spillover. In the present study, arterial, portal vein, and hepatic vein sampling catheters were surgically placed in nine mongrel dogs. The animals were subsequently studied after a 42-h fast during infusion of [14C]oleate and a lipid emulsion containing [3H]triolein; the emulsion was used as a surrogate for the study of chylomicron metabolism. More than one-half of splanchnic [3H]triglyceride uptake occurred in the liver, and substantial fractional spillover of [3H]oleate was observed in both liver and nonhepatic tissues (∼50% each). There was a significant correlation between FFA release from nonhepatic tissues (presumably visceral fat) and nonhepatic fractional spillover (R = 0.81, P < 0.01), consistent with a model in which the rate of intracellular lipolysis influences spillover by determining the direction of net fatty acid flow between the cell and the interstitium. There was a significant correlation between “true” and “net” splanchnic spillover (R = 0.84, P < 0.005), the latter representing calculation of spillover between arterial and hepatic venous blood without portal venous data. Metabolism of chylomicron triglycerides in visceral fat may be an important source of portal venous FFAs.
Mutations in ATP-Sensitive K+ Channel Genes Cause Transient Neonatal Diabetes and Permanent Diabetes in Childhood or Adulthood
Authors: Flanagan Sarah E. , Patch Ann-Marie , Mackay Deborah J.G. , Edghill Emma L. , Gloyn Anna L. , Robinson David , Shield Julian P.H. , Temple Karen , Ellard Sian , Hattersley Andrew T.
Published: June 2007

Transient neonatal diabetes mellitus (TNDM) is diagnosed in the first 6 months of life, with remission in infancy or early childhood. For ∼50% of patients, their diabetes will relapse in later life. The majority of cases result from anomalies of the imprinted region on chromosome 6q24, and 14 patients with ATP-sensitive K+ channel (KATP channel) gene mutations have been reported. We determined the 6q24 status in 97 patients with TNDM. In patients in whom no abnormality was identified, the KCNJ11 gene and/or ABCC8 gene, which encode the Kir6.2 and SUR1 subunits of the pancreatic β-cell KATP channel, were sequenced. KATP channel mutations were found in 25 of 97 (26%) TNDM probands (12 KCNJ11 and 13 ABCC8), while 69 of 97 (71%) had chromosome 6q24 abnormalities. The phenotype associated with KCNJ11 and ABCC8 mutations was similar but markedly different from 6q24 patients who had a lower birth weight and who were diagnosed and remitted earlier (all P < 0.001). KATP channel mutations were identified in 26 additional family members, 17 of whom had diabetes. Of 42 diabetic patients, 91% diagnosed before 6 months remitted, but those diagnosed after 6 months had permanent diabetes (P < 0.0001). KATP channel mutations account for 89% of patients with non-6q24 TNDM and result in a discrete clinical subtype that includes biphasic diabetes that can be treated with sulfonylureas. Remitting neonatal diabetes was observed in two of three mutation carriers, and permanent diabetes occurred after 6 months of age in subjects without an initial diagnosis of neonatal diabetes.
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 < 0.004). During late sleep, all subjects awoke upon hypoglycemia, and four subjects awoke spontaneously during the corresponding control interval (P < 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 < 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 < 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 < 0.001, respectively) and reduced total insulin effect (total glucose infusion rate) (60.4%, P < 0.01 and 67.1%, P < 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 <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 < 0.01 for each). For indices using single fasting insulin and glucose values, |r| ranged from 0.51 to 0.72 (P < 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 >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 >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 >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 < 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.