bluuebunny/crossref_metadata_2025 huggingface dataset:
Measurements of insulin responses as predictive markers of pancreatic β-cell mass in normal and β-cell-reduced lean and obese Göttingen minipigs in vivo
Authors: Larsen Marianne O. , Rolin Bidda , Sturis Jeppe , Wilken Michael , Carr Richard D. , Pørksen Niels , Gotfredsen Carsten F.
Published: November 2005

At present, the best available estimators of β-cell mass in humans are those based on measurement of insulin levels or appearance rates in the circulation. In several animal models, these estimators have been validated against β-cell mass in lean animals. However, as many diabetic humans are obese, a correlation between in vivo tests and β-cell mass must be evaluated over a range of body weights to include different levels of insulin sensitivity. For this purpose, obese ( n = 10) and lean ( n = 25) Göttingen minipigs were studied. β-Cell mass had been reduced ( n = 16 lean, n = 5 obese) with a combination of nicotinamide (67 mg/kg) and streptozotocin (125 mg/kg), acute insulin response (AIR) to intravenous glucose and/or arginine was tested, pulsatile insulin secretion was evaluated by deconvolution ( n = 30), and β-cell mass was determined histologically. AIR to 0.3 ( r2= 0.4502, P < 0.0001) or 0.6 g/kg glucose ( r2= 0.6806, P < 0.0001), 67 mg/kg arginine ( r2= 0.5730, P < 0.001), and maximum insulin concentration ( r2= 0.7726, P < 0.0001) were all correlated to β-cell mass when evaluated across study groups, and regression lines were not different between lean and obese groups except for AIR to 0.3 g/kg glucose. Baseline pulse mass was not significantly correlated to β-cell mass across the study groups ( r2= 0.1036, NS), whereas entrained pulse mass did show a correlation across groups ( r2= 0.4049, P < 0.001). This study supports the use of in vivo tests of insulin responses to evaluate β-cell mass over a range of body weights in the minipig. Extensive stimulation of insulin secretion by a combination of glucose and arginine seems to give the best correlation to β-cell mass.
Evidence against regulation of AMP-activated protein kinase and LKB1/STRAD/MO25 activity by creatine phosphate
Authors: Taylor Eric B. , Ellingson William J. , Lamb Jeremy D. , Chesser David G. , Compton Cori L. , Winder William W.
Published: November 2005

Muscle contraction results in phosphorylation and activation of the AMP-activated protein kinase (AMPK) by an AMPK kinase (AMPKK). LKB1/STRAD/MO25 (LKB1) is the major AMPKK in skeletal muscle; however, the activity of LKB1 is not increased by muscle contraction. This finding suggests that phosphorylation of AMPK by LKB1 is regulated by allosteric mechanisms. Creatine phosphate is depleted during skeletal muscle contraction to replenish ATP. Thus the concentration of creatine phosphate is an indicator of cellular energy status. A previous report found that creatine phosphate inhibits AMPK activity. The purpose of this study was to determine whether creatine phosphate would inhibit 1) phosphorylation of AMPK by LKB1 and 2) AMPK activity after phosphorylation by LKB1. We found that creatine phosphate did not inhibit phosphorylation of either recombinant or purified rat liver AMPK by LKB1. We also found that creatine phosphate did not inhibit 1) active recombinant α1β1γ1 or α2β2γ2 AMPK, 2) AMPK immunoprecipitated from rat liver extracts by either the α1 or α2 subunit, or 3) AMPK chromatographically purified from rat liver. Inhibition of skeletal muscle AMPK by creatine phosphate was greatly reduced or eliminated with increased AMPK purity. In conclusion, these results suggest that creatine phosphate is not a direct regulator of LKB1 or AMPK activity. Creatine phosphate may indirectly modulate AMPK activity by replenishing ATP at the onset of muscle contraction.
Regulation of cardiac and skeletal muscle protein synthesis by individual branched-chain amino acids in neonatal pigs
Authors: Escobar Jeffery , Frank Jason W. , Suryawan Agus , Nguyen Hanh V. , Kimball Scot R. , Jefferson Leonard S. , Davis Teresa A.
Published: November 2005

Skeletal muscle grows at a very rapid rate in the neonatal pig, due in part to an enhanced sensitivity of protein synthesis to the postprandial rise in amino acids. An increase in leucine alone stimulates protein synthesis in skeletal muscle of the neonatal pig; however, the effect of isoleucine and valine has not been investigated in this experimental model. The left ventricular wall of the heart grows faster than the right ventricular wall during the first 10 days of postnatal life in the pig. Therefore, the effects of individual BCAA on protein synthesis in individual skeletal muscles and in the left and right ventricular walls were examined. Fasted pigs were infused with 0 or 400 μmol·kg−1·h−1 leucine, isoleucine, or valine to raise individual BCAA to fed levels. Fractional rates of protein synthesis and indexes of translation initiation were measured after 60 min. Infusion of leucine increased ( P < 0.05) phosphorylation of eukaryotic initiation factor (eIF)4E-binding protein-1 and increased ( P < 0.05) the amount and phosphorylation of eIF4G associated with eIF4E in longissimus dorsi and masseter muscles and in both ventricular walls. Leucine increased ( P < 0.05) the phosphorylation of ribosomal protein (rp)S6 kinase and rpS6 in longissimus dorsi and masseter but not in either ventricular wall. Leucine stimulated ( P < 0.05) protein synthesis in longissimus dorsi, masseter, and the left ventricular wall. Isoleucine and valine did not increase translation initiation factor activation or protein synthesis rates in skeletal or cardiac muscles. The results suggest that the postprandial rise in leucine, but not isoleucine or valine, acts as a nutrient signal to stimulate protein synthesis in cardiac and skeletal muscles of neonates by increasing eIF4E availability for eIF4F complex assembly.
SMP-534 ameliorates progression of glomerular fibrosis and urinary albumin in diabeticdb/dbmice
Authors: Sugaru Eiji , Nakagawa Tsutomu , Ono-Kishino Michiko , Nagamine Jun , Tokunaga Teruhisa , Kitoh Makoto , Hume W. Ewan , Nagata Ryu , Taiji Mutsuo
Published: November 2005

Diabetic nephropathy is currently the most common cause of end-stage renal disease. Diabetic nephropathy patients, whether insulin dependent or not, develop fibrotic changes in glomeruli that manifest as overt nephropathy. Previously, we demonstrated that 5-chloro-2-{(1E)-3-[2-(4-methoxybenzoyl)-4-methyl-1H-pyrrol-1-yl]prop-1-en-1-yl}- N-(methylsulfonyl)benzamide (SMP-534) reduces extracellular matrix (ECM) production induced by transforming growth factor-β (TGF-β) in vitro and prevents the accumulation of ECM in glomeruli in rat Thy-1 nephritis models. In this study, we examined the long-term effects of SMP-534 on renal insufficiency and glomerulosclerosis in db/db mice, which are models of type 2 diabetes. A diet containing SMP-534 was given to the mice from the age of 9 to 25 wk, and blood and urine analysis were performed at 8, 17, and 25 wk. At the end of study, kidney tissues were analyzed histologically. Treatment with SMP-534 dose dependently suppressed the increase of urinary albumin and type IV collagen excretion in db/db mice. The renal histological analysis showed that SMP-534 dose dependently suppressed the increase of mesangial expansion in the kidney. In the immunohistological analysis, fibronectin and type IV collagen expression were lower in SMP-534-treated db/db mice compared with vehicle-treated db/db mice. This study suggested that SMP-534 ameliorated the increase of ECM production in kidney of db/db mice, possibly through the inhibition of TGF-β action. Hence, antifibrotic agents such as SMP-534 might be a new therapeutic option for the treatment of diabetic nephropathy.
Gene expression profiling of gastrin target genes in parietal cells
Authors: Jain Renu N. , Brunkan Cynthia S. , Chew Catherine S. , Samuelson Linda C.
Published: November 2005

Previous studies demonstrated that mice with a null mutation in the gene encoding the hormone gastrin have impaired gastric acid secretion. Hence, the aim of this study was to evaluate changes in the acid-secreting parietal cell in gastrin-deficient (GAS-KO) mice. Analysis of several transcripts encoding parietal cell proteins involved in gastric acid secretion showed reduced abundance in the GAS-KO stomach, including H+,K+-ATPase α- and β-subunits, KCNQ1 potassium channel, aquaporin-4 water channel, and creatine kinase B, which were reversed by gastrin infusion for 1 wk. Although mRNA and protein levels of LIM and SH3 domain-containing protein-1 (LASP-1) were not greatly changed in the mutant, there was a marked reduction in phosphorylation, consistent with its proposed role as a cAMP signal adaptor protein associated with acid secretion. A more comprehensive analysis of parietal cell gene expression in GAS-KO mice was performed using the Affymetrix U74AV2 chip with RNA from parietal cells purified by flow cytometry to >90%. Comparison of gene expression in GAS-KO and wild-type mice identified 47 transcripts that differed by greater than or equal to twofold, suggesting that gastrin affects parietal cell gene expression in a specific manner. The differentially expressed genes included several genes in signaling pathways, with a substantial number (20%) known to be target genes for Wnt and Myc.
Immunohistochemical and Microarray Analyses of a Mouse Model for the Smith-Lemli-Opitz Syndrome
Authors: Waage-Baudet H. , Dunty Jr. W.C. , Dehart D.B. , Hiller S. , Sulik K.K.
Published: November 2005

The Smith-Lemli-Opitz syndrome is a mental retardation/malformation syndrome with behavioral components of autism. It is caused by a deficiency in 3β-hydroxysteroid-Δ7-reductase (DHCR7), the enzyme required for the terminal enzymatic step of cholesterol biosynthesis. The availability of Smith-Lemli-Opitz syndrome mouse models has made it possible to investigate the genesis of the malformations associated with this syndrome. Dhcr7 gene modification (Dhcr7–/–) results in neonatal lethality and multiple organ system malformations. Pathology includes cleft palate, pulmonary hypoplasia, cyanosis, impaired cortical response to glutamate, and hypermorphic development of hindbrain serotonergic neurons. For the current study, hindbrain regions microdissected from gestational day 14 Dhcr7–/–, Dhcr7+/– and Dhcr7+/+ fetuses were processed for expression profiling analyses using Affymetrix oligonucleotide arrays and filtered using statistical significance (S-score) of change in gene expression. Of the 12,000 genes analyzed, 91 were upregulated and 98 were downregulated in the Dhcr7–/– hindbrains when compared to wild-type animals. Fewer affected genes, representing a reduced affect on these pathways, were identified in heterozygous animals. Hierarchical clustering identified altered expression of genes associated with cholesterol homeostasis, cell cycle control and apoptosis, neurodifferentiation and embryogenesis, transcription and translation, cellular transport, neurodegeneration, and neuronal cytoskeleton. Of particular interest, Dhcr7 gene modification elicited dynamic changes in genes involved in axonal guidance. In support of the microarray findings, immunohistochemical analyses of the netrin/deleted in colorectal cancer axon guidance pathway illustrated midline commissural deficiencies and hippocampal pathfinding errors in Dhcr7–/– mice. The results of these studies aid in providing insight into the genesis of human cholesterol-related birth defects and neurodevelopmental disorders and highlight specific areas for future investigation.
Aging Adversely Affects Postinfarction Inflammatory Response and Early Left Ventricular Remodeling after Reperfused Acute Anterior Myocardial Infarction
Authors: Mahara Keitaro , Anzai Toshihisa , Yoshikawa Tsutomu , Maekawa Yuichiro , Okabe Teruo , Asakura Yasushi , Satoh Toru , Mitamura Hideo , Suzuki Masahiro , Murayama Akira , Ogawa Satoshi
Published: November 2005

Background and Aims: We have demonstrated that an increased peak serum C-reactive protein (CRP) level after acute myocardial infarction (AMI) was a major predictor of left ventricular (LV) remodeling. We sought to clarify the effect of aging on the postinfarction inflammatory response and LV remodeling. Methods: We studied 102 patients who underwent primary angioplasty for a first anterior Q-wave AMI. Serum CRP levels, plasma neurohormones and interleukin-6 (IL-6) levels, and LV volume by left ventriculography were serially measured. Patients were divided into two groups according to their age (≧70 years, n = 33; <70 years, n = 69). Results: There was no difference in use of cardiovascular drugs and coronary angiographic findings. Older patients had a greater increase in LV end-diastolic volume during 2 weeks after AMI (p = 0.0007) and a higher peak CRP level (12.4 ± 7.3 vs. 5.5 ± 4.2 mg/dl, p < 0.0001), although peak CK level was comparable between the two groups. Plasma atrial natriuretic peptide, brain natriuretic peptide and IL-6 levels were higher in older patients at 2 weeks and 6 months after AMI. Conclusions: Augmented and prolonged activation of the inflammatory system after AMI was observed in older patients, in association with exaggerated LV remodeling. Aging may adversely affect LV remodeling through modification of the inflammatory response after AMI.
Nutritional Differences between Elderly Men and Women
Authors: Rurik Imre
Published: November 2005

Background: Many differences exist between the two genders, i.e., biological, sociological, and also behavioral, which often depend on age. Objectives: The aim of this study was to find characteristic differences between nutritional habits of elderly men and women. Methods: 266 elderly people (109 men >65 years, and 157 women >60 years) were consecutively selected from primary care patients, in Budapest, Hungary. A self-managed questionnaire was filled in on lifestyle and eating habits, including a food frequency questionnaire. Medical check-up, registration of anthropometrical parameters, and laboratory tests were also performed. 53 subjects were also involved in a 3-day dietary recall. Results: The meal frequency was increased during aging in both genders, especially in men. Lunch was preferred by most of the women as a principal meal, but one quarter of the men had a filling dinner instead of lunch. Alcoholic beverages were consumed more and frequently by men. The fluid intake was low, especially in women. Milk and diary products, fresh fruit, bread, biscuits, chocolate, coffee and vitamin supplements were consumed more frequently by women. Almost all types of meat, eggs, and vegetables were more preferred by men and their energy intake was also higher (9.75 vs. 8.78 MJ). In both genders, fat represented a higher ratio (39%) of energy intake than recommended. The increase of body weight from youth to elderly was greater in women (14.04 vs. 10.65 kg). Prices had a higher impact on food purchases by women. Conclusion: High energy intake over decades led to overweight in both genders (BMI >27 kg/m2). It seemed that the eating habits and food choices of women were closer to healthy ones and recent recommendations, although due to metabolic reasons and to the lower energy expenditure, they gained more weight. The elderly are the target population on every level of medical care. Further evaluations are needed to determine the differences in nutrition and to promote better administration of drugs and to establish public health suggestions.
Effect of Olive Oil-Fried Sardine Consumption on Cholesterol Content in the Serum, Lipoproteins, Spleen and Adipose Tissue of Hypercholesterolemic Rats
Authors: Bastida Sara , García-Linares M. Carmen , Viejo Jesús , García-Arias M. Trinidad , Sánchez-Muniz Francisco J.
Published: November 2005

Background: The information about the effect of fried-oily fish consumption on cholesterol metabolism is rather scarce. Aim: To test the effect of olive oil-fried sardine consumption on cholesterol content in the serum, lipoproteins, spleen and adipose tissue of hypercholesterolemic rats. Methods: Hypercholesterolemia was induced for 3 weeks by a casein + olive diet containing cholesterol and bovine bile (COC). Rats were later switched for 2 weeks to diets containing casein + olive oil (CO), olive oil-fried sardines (S), and olive oil-fried sardines-cholesterol-bovine bile (SC) while one rat group continued on the COC diet. Cholesterol was determined in serum, lipoproteins, adipose tissue and spleen. Results: The SC diet markedly blocked the hypercholesterolemic induction of the cholesterol-raising agents. Dietary cholesterol withdrawal decreased serum cholesterol levels, with the S diet inducing the highest decrease in serum and VLDL + LDL-cholesterol levels. Cholesterol withdrawal decreased spleen total cholesterol content and weight but the S diet was unable to reduce spleen cholesterol content (µmol/g) more than CO diet. Adipose tissue of S rats displayed the lowest cholesterol values. Cholesterol (mmol/g) of adipose tissue correlated very significantly with total serum cholesterol (r = 0.9225, p < 0.0001) and VLDL + LDL-cholesterol (r = 0.9313, p < 0.0001). Conclusions: Cholesterol in adipose tissue was very sensitive to variations in plasma cholesterol. Consumption of fried sardines interacts with cholesterol withdrawal, accelerating serum cholesterol normalization and reduction of cholesterol levels in adipose tissue.
Pathophysiology of Stroke Rehabilitation: Temporal Aspects of Neurofunctional Recovery
Authors: Kreisel Stefan H. , Bäzner Hansjörg , Hennerici Michael G.
Published: November 2005

Stroke almost always causes an impairment of motor activity and function. Clinical recovery, though usually incomplete, is often highly dynamic and reflects the ability of the neuronal network to adapt. Mechanisms that underlie neurofunctional plasticity are now beginning to be understood. Albeit the enormous efforts undertaken to support the natural course of reconvalescence through rehabilitation, little has been done to relate possible effects of these therapeutic approaches to mechanisms of adaptive pathophysiology. The review presented here focuses on these mechanisms during the course of recovery poststroke. Next to an unmasking of latent network representations, other adaptive processes, such as excitatory metabolic stress, an imbalance in activating and inhibiting transmission, leading to salient hyperexcitability or mechanisms that consolidate novel connections prime the system’s plastic capabilities. These pathophysiological processes potentially interact with rehabilitative interventions. They therefore form the foundation of positive, but possibly also negative recuperation under therapy.
Analysis of Multiple Precipitation Products and Preliminary Assessment of Their Impact on Global Land Data Assimilation System Land Surface States
Authors: Gottschalck Jon , Meng Jesse , Rodell Matt , Houser Paul
Published: November 2005

Precipitation is arguably the most important meteorological forcing variable in land surface modeling. Many types of precipitation datasets exist (with various pros and cons) and include those from atmospheric data assimilation systems, satellites, rain gauges, ground radar, and merged products. These datasets are being evaluated in order to choose the most suitable precipitation forcing for real-time and retrospective simulations of the Global Land Data Assimilation System (GLDAS). This paper first presents results of a comparison for the period from March 2002 to February 2003. Later, GLDAS simulations 14 months in duration are analyzed to diagnose impacts on GLDAS land surface states when using the Mosaic land surface model (LSM).

A comparison of seasonal total precipitation for the continental United States (CONUS) illustrates that the Climate Prediction Center (CPC) Merged Analysis of Precipitation (CMAP) has the closest agreement with a CPC rain gauge dataset for all seasons except winter. The European Centre for Medium-Range Weather Forecasts (ECMWF) model performs the best of the modeling systems. The satellite-only products [the Tropical Rainfall Measuring Mission (TRMM) Real-time Multi-satellite Precipitation Analysis and the Precipitation Estimation from Remotely Sensed Information using Artificial Neural Networks (PERSIANN)] suffer from a few deficiencies—most notably an overestimation of summertime precipitation in the central United States (200–400 mm). CMAP is the most closely correlated with daily rain gauge data for the spring, fall, and winter seasons, while the satellite-only estimates perform best in summer. GLDAS land surface states are sensitive to different precipitation forcing where percent differences in volumetric soil water content (SWC) between simulations ranged from −75% to +100%. The percent differences in SWC are generally 25%–75% less than the percent precipitation differences, indicating that GLDAS and specifically the Mosaic LSM act to generally “damp” precipitation differences. Areas where the percent changes are equivalent to the percent precipitation changes, however, are evident. Soil temperature spread between GLDAS runs was considerable and ranged up to ±3.0 K with the largest impact in the western United States.
Snow Mass over North America: Observations and Results from the Second Phase of the Atmospheric Model Intercomparison Project
Authors: Frei Allan , Brown Ross , Miller James A. , Robinson David A.
Published: November 2005

Eighteen global atmospheric general circulation models (AGCMs) participating in the second phase of the Atmospheric Model Intercomparison Project (AMIP-2) are evaluated for their ability to simulate the observed spatial and temporal variability in snow mass, or water equivalent (SWE), over North America during the AMIP-2 period (1979–95). The evaluation is based on a new gridded SWE dataset developed from objective analysis of daily snow depth observations from Canada and the United States with snow density estimated from a simple snowpack model. Most AMIP-2 models simulate the seasonal timing and the relative spatial patterns of continental-scale SWE fairly well. However, there is a tendency to overestimate the rate of ablation during spring, and significant between-model variability is found in every aspect of the simulations, and at every spatial scale analyzed. For example, on the continental scale, the peak monthly SWE integrated over the North American continent in AMIP-2 models varies between ±50% of the observed value of ∼1500 km3. The volume of water in the snowpack, and the magnitudes of model errors, are significant in comparison to major fluxes in the continental water balance. It also appears that the median result from the suite of models tends to do a better job of estimating climatological mean features than any individual model. Year-to-year variations in large-scale SWE are only weakly correlated to observed variations, indicating that sea surface temperatures (specified from observations as boundary conditions) do not drive interannual variations of SWE in these models. These results have implications for simulations of the large-scale hydrologic cycle and for climate change impact assessments.
The Land Surface Contribution to the Potential Predictability of Boreal Summer Season Climate
Authors: Dirmeyer Paul A.
Published: November 2005

The role of the land surface in contributing to the potential predictability of the boreal summer climate is investigated with a coupled land–atmosphere climate model. Ensemble simulations for 1982–99 have been conducted with specified observed sea surface temperatures (SSTs). Several treatments of the land surface are investigated: climatological land surface initialization, realistic initialization of soil wetness, and a series of experiments where downward surface fluxes over land are replaced with observed proxies of precipitation, shortwave, and longwave radiation. Without flux replacement the model exhibits strong drift in soil wetness and both systematic errors and poor simulation of interannual variations of precipitation and near-surface temperature. With flux replacement there are large improvements in simulation of both spatial patterns and interannual variability of precipitation and surface temperature. The land surface apparently does contribute, through positive feedback with the atmosphere, to regional climate anomalies. However, because of the sizeable noise component in precipitation, the strong land–atmosphere feedback may not translate into reliable enhancements in predictability, particularly in years of weak anomalies in the land surface initial conditions at the start of boreal summer.
Weak Land–Atmosphere Coupling Strength in HadAM3: The Role of Soil Moisture Variability
Authors: Lawrence David M. , Slingo Julia M.
Published: November 2005

A recent model intercomparison, the Global Land–Atmosphere Coupling Experiment (GLACE), showed that there is a wide range of land–atmosphere coupling strengths, or the degree that soil moisture affects the generation of precipitation, amongst current atmospheric general circulation models (AGCMs). Coupling strength in the Hadley Centre atmosphere model (HadAM3) is among the weakest of all AGCMs considered in GLACE. Reasons for the weak HadAM3 coupling strength are sought here. In particular, the impact of pervasive saturated soil conditions and low soil moisture variability on coupling strength is assessed. It is found that when the soil model is modified to reduce the occurrence of soil moisture saturation and to encourage soil moisture variability, the soil moisture–precipitation feedback remains weak, even though the relationship between soil moisture and evaporation is strengthened.

Composites of the diurnal cycle, constructed relative to soil moisture, indicate that the model can simulate key differences in boundary layer development over wet versus dry soils. In particular, the influence of wet or dry soil on the diurnal cycles of Bowen ratio, boundary layer height, and total heat flux are largely consistent with the observed influence of soil moisture on these properties. However, despite what appears to be successful simulation of these key aspects of the indirect soil moisture–precipitation feedback, the model does not capture observed differences for wet and dry soils in the daily accumulation of boundary layer moist static energy, a crucial feature of the feedback mechanism.
Lipids for Psychiatrists - an overview
Authors: Young Ian S.
Published: November 2005

Serum cholesterol is a major risk factor for cardiovascular disease. Total cholesterol, LDL cholesterol and triglycerides are positively related to cardiovascular disease, while HDL cholesterol has an inverse relationship. Measurement of lipids is essential in individuals with established cardiovascular disease or type 2 diabetes, and may also be carried out in healthy individuals as part of cardiovascular risk assessment. Lifestyle measures are important in cardiovascular disease prevention, but the mainstay of lipid lowering therapy is appropriate use of lipid lowering drugs. Total and LDL cholesterol are the primary targets for treatment, but consideration should also be given to raising HDL cholesterol and lowering triglycerides where appropriate. Statins are the most frequently used lipid lowering agents, but there is an important place for other drugs, including ezetimibe, fibrates and nicotinic acid.
Diabetes and schizophrenia 2005: are we any closer to understanding the link?
Authors: Holt Richard I. G. , Bushe Chris , Citrome Leslie
Published: November 2005

The association between schizophrenia and diabetes has been recognized for well over a century, but the underlying reasons for this association are unclear. In October 2003, an international group of diabetologists and psychiatrists met to review the literature relating to the association, and to create pragmatic guidelines for the management of diabetic risk in patients with severe mental illness. Since that meeting, over 100 additional papers have been published on the association between glucose abnormalities and schizophrenia, and this is a clear reflection of the level of interest in this clinically important area. Diabetes is highly prevalent among the schizophrenia population, but most sufferers remain undiagnosed in the community. The reasons why individuals with schizophrenia are more prone to developing diabetes than the general population are poorly defined, but likely to be multifactorial. The role of antipsychotic medications in the development of diabetes and other pre-diabetic states remains controversial, but it appears that the attributable risk is low. Traditional risk factors most probably account for much of the diabetes seen in schizophrenia populations, suggesting that routine screening and aggressive risk factor management are especially important in this patient group.
Clustering of metabolic comorbidity in schizophrenia: a genetic contribution?
Authors: Gough Stephen C. L. , O’Donovan Michael C.
Published: November 2005

People with schizophrenia are more likely to develop type 2 diabetes than the general population. Although an increased risk of diabetes has been attributed to environmental determinants such as diet, lifestyle and antipsychotic drugs, the association between these two disorders was noticed well before the advent of current lifestyles and pharmacological interventions, raising the possibility of a shared genetic basis. Schizophrenia and type 2 diabetes are common diseases with a complex mode of inheritance which includes both genetic factors and environmental determinants. As susceptibility genes for both type 2 diabetes and schizophrenia are beginning to be identified there is increasing interest in the possibility of shared susceptibility loci between the two conditions. This article reviews the genetic basis to schizophrenia and type 2 diabetes and discusses the potential for shared loci between both conditions.
Metabolism, lifestyle and bipolar affective disorder
Authors: Morriss Richard , Mohammed Faizal Amir
Published: November 2005

Lifestyle, illness and treatment factors in people with bipolar disorder (BD) may confer additional risk of morbidity and mortality to the increasing rates of obesity, metabolic syndrome, diabetes mellitus and cardiovascular mortality in the general population.

The aim of this review is to examine whether the risk of obesity and related morbidity and mortality are raised in BD, and possible contributory effects of lifestyle, illness and treatment factors to this risk.

Systematic search of Medline and Cochrane Collaboration for relevant studies followed by a critical review of literature was carried out.

Mortality from cardiovascular causes and pulmonary embolism (standardized mortality ratio approximately 2.0), and morbidity from obesity and type 2 diabetes mellitus may be increased in BD compared to the general population. Reduced exercise and poor diet, frequent depressive episodes, comorbidity with substance misuse and poor quality general medical care contribute to the additional risk of these medical problems in people with BD. There is no evidence that patients with BD are more sensitive than other patients to weight gain and medical problems associated with long-term use of psychotropic medication; in fact long-term treatment with lithium, antipsychotics and tricyclic antidepressants may reduce overall mortality.

Psychiatrists, general practitioners and other health professionals should work together to systematically assess and manage weight gain and related medical problems to reduce the morbidity and mortality associated with obesity in BD. There is insufficient evidence to associate any of these factors with specific drug treatments. More research is required to understand how BD changes the risk for physical health comorbidity.
The potential impact of antipsychotics on lipids in schizophrenia: is there enough evidence to confirm a link?
Authors: Bushe Chris , Paton Carol
Published: November 2005

Lipid abnormalities are common in the general population and early data suggests that they may be more common in people with schizophrenia. Little data exist from treatment-naive patients making it difficult to differentiate any genetic contribution associated with a diagnosis of schizophrenia from the lifestyle risks associated with this diagnosis. Additional potential risks associated with antipsychotic drug treatment have been noted in the literature since 1971. The majority of the existing data on lipids derive from retrospective and cross-sectional analyses of datasets that have been designed for other purposes. Specifically screening bias for lipid testing and treatment selection bias are important potential confounders. Prospective clinical trials are difficult to interpret, as many are short-term, report on non-fasting data and were never designed to evaluate the differential effects of antipsychotic drugs on lipids as a primary endpoint. There is little reported data on lipid fractions such as LDL and HDL. Nevertheless there is some evidence from placebo-controlled studies that antipsychotics may be differentially associated with a small, clinically insignificant increase in cholesterol and a larger, potentially clinically significant increase in triglycerides.

Further prospective randomized trials, using fasting data and controlling for established risk factors such as diet and exercise are essential to determine if there are clinically meaningful differential effects on lipids associated with individual antipsychotic drugs.
Weight gain as a prognostic indicator of therapeutic improvement during acute treatment of schizophrenia with placebo or active antipsychotic
Authors: Ascher-Svanum Haya , Stensland Michael D. , Kinon Bruce J. , Tollefson Gary D.
Published: November 2005

Treatment-emergent weight gain may be a general marker of therapeutic improvement, even when improvements occur in the absence of active antipsychotic treatment.

To investigate the association between treatment-emergent weight gain and therapeutic improvement across placebo and active treatments, and to examine the association between reported treatment-emergent weight changes and the treatments’ reported efficacy.

Data from a randomized, double-blind trial comparing treatment of schizophrenia with placebo and olanzapine were used to correlate weight change and change in psychopathology. Additionally, we correlated effect sizes of the efficacy of clozapine, olanzapine, risperidone, haloperidol and placebo (reported in meta-analytical reviews), with their reported weight changes.

Weight gain significantly correlated with clinical improvements for placebo and olanzapine. The correlation between treatments’ efficacy and corresponding weight changes was high (r 0.88, p 0.05).

Treatment-emergent weight gain appears to be an important marker of symptom reduction, and may not be exclusively attributable to pharmacological perturbations.
Estimation of Markov Chain Transition Probabilities and Rates from Fully and Partially Observed Data: Uncertainty Propagation, Evidence Synthesis, and Model Calibration
Authors: Welton Nicky J. , Ades A. E.
Published: November 2005

Markov transition models are frequently used to model disease progression. The authors show how the solution to Kolmogorov’s forward equations can be exploited to map between transition rates and probabilities from probability data in multistate models. They provide a uniform, Bayesian treatment of estimation and propagation of uncertainty of transition rates and probabilities when 1) observations are available on all transitions and exact time at risk in each state (fully observed data) and 2) observations are on initial state and final state after a fixed interval of time but not on the sequence of transitions (partially observed data). The authors show how underlying transition rates can be recovered from partially observed data using Markov chain Monte Carlo methods in WinBUGS, and they suggest diagnostics to investigate inconsistencies between evidence from different starting states. An illustrative example for a 3-state model is given, which shows how the methods extend to more complex Markov models using the software WBDiff to compute solutions. Finally, the authors illustrate how to statistically combine data from multiple sources, including partially observed data at several follow-up times and also how to calibrate a Markov model to be consistent with data from one specific study.
Willingness to Pay for a Quality-Adjusted Life Year: Implications for Societal Health Care Resource Allocation
Authors: King Joseph T. , Tsevat Joel , Lave Judith R. , Roberts Mark S.
Published: November 2005

Background . Health-state preferences can be combined with willingness-to-pay (WTP) data to calculate WTP per quality-adjusted life year (QALY). The WTP/QALY ratios provide insight into societal valuations of expenditures for medical interventions. Methods . The authors measured preferences for current health in 3 patient populations (N = 391) using standard gamble, time trade-off, visual analog scale, and WTP, then they calculated WTP/QALY ratios. The ratios were compared with several proposed cost/QALY cost-effectiveness ratio thresholds, the value-of-life literature, and with WTP/QALY ratios derived from published preference research. Results . Mean WTP/QALY ratios ranged from $12,500 to $32,200 (2003 $US). All values were below most published cost-effectiveness ratio thresholds, below the ratio from a prototypic medical treatment covered by Medicare (i.e., renal dialysis), and below ratios from the value-of-life literature. The WTP/QALY ratios were similar to those calculated from published preference data for patients with symptomatic meno-pause, dentofacial deformities, asthma, or dermatologic disorders. Conclusions . WTP/QALY ratios calculated using preference data collected from diverse populations are lower than most proposed thresholds for determining what is “cost-effective.” Current proposed cost-effectiveness ratio thresholds may overestimate the willingness of society to pay for medical interventions.
Can Prospect Theory Explain Risk-Seeking Behavior by Terminally Ill Patients?
Authors: Rasiel Emma B. , Weinfurt Kevin P. , Schulman Kevin A.
Published: November 2005

Patients with life-threatening conditions sometimes appear to make risky treatment decisions as their condition declines, contradicting the risk-averse behavior predicted by expected utility theory. Prospect theory accommodates such decisions by describing how individuals evaluate outcomes relative to a reference point and how they exhibit risk-seeking behavior over losses relative to that point. The authors show that a patient’s reference point for his or her health is a key factor in determining which treatment option the patient selects, and they examine under what circumstances the more risky option is selected. The authors argue that patients’ reference points may take time to adjust following a change in diagnosis, with implications for predicting under what circumstances a patient may select experimental or conventional therapies or select no treatment.
The Interpretation of Random-Effects Meta-Analysis in Decision Models
Authors: Ades A. E. , Lu G. , Higgins J. P. T.
Published: November 2005

This article shows that the interpretation of the random-effects models used in meta-analysis to summarize heterogeneous treatment effects can have a marked effect on the results from decision models. Sources of variation in meta-analysis include the following: random variation in outcome definition (amounting to a form of measurement error), variation between the patient groups in different trials, variation between protocols, and variation in the way a given protocol is implemented. Each of these alternatives leads to a different model for how the heterogeneity in the effect sizes previously observed might relate to the effect size(s) in a future implementation. Furthermore, these alternative models require different computations and, when the net benefits are nonlinear in the efficacy parameters, result in different expected net benefits. The authors’ analysis suggests that the mean treatment effect from a random-effects meta-analysis will only seldom be an appropriate representation of the efficacy expected in a future implementation. Instead, modelers should consider either the predictive distribution of a future treatment effect, or they should assume that the future implementation will result in a distribution of treatment effects. A worked example, in a probabilistic, Bayesian posterior framework, is used to illustrate the alternative computations and to show how parameter uncertainty can be combined with variation between individuals and heterogeneity in meta-analysis.
Incorporating Biological Natural History in Simulation Models: Empirical Estimates of the Progression of End-Stage Liver Disease
Authors: Alagoz Oguzhan , Bryce Cindy L. , Shechter Steven , Schaefer Andrew , Chang Chung-Chou H. , Angus Derek C. , Roberts Mark S.
Published: November 2005

Objective. To develop an empiric natural-history model that can predict quantitative changes in the laboratory values and clinical characteristics of patients with end-stage liver disease (ESLD), to be used to calibrate an individual microsimulation model. Methods. The authors report the development of a stochastic model that uses cubic splines to interpolate between observed laboratory values over time in a cohort of 1997 patients with ESLD awaiting liver transplantation at the University of Pittsburgh Medical Center. The splines were recursively sampled to provide a stochastic, quantitative natural history of each candidate’s disease. Results. The model was able to simulate the types of erratic disease trajectories that occur in individual patients and was able to preserve the statistical properties of the natural history of ESLD in cohorts of real patients. Moreover, the model was able to predict pretransplant survival rates (87% at 1 year), which were statistically similar to rates observed in the authors’ local cohort (92%). Conclusions. Cubic splines can be used to generate quantitative natural histories for individual patients with ESLD and may be useful for developing clinically robust microsimulation models of other diseases.
Fulminant Miliary Tuberculosis With Adult Respiratory Distress Syndrome Undiagnosed Until Autopsy: A Report of 2 Cases and Review of the Literature
Authors: Bourbonnais Julie M. , Sirithanakul Kasem , Guzman Jorge A.
Published: November 2005

Despite an overall decline in the incidence of tuberculosis (TB), the percentage of cases representing miliary TB has remained stable. We report 2 cases of fatal miliary TB that remained unrecognized until autopsy, occurring within a 6-month period at 1 Detroit institution. These cases represent the wide range of presentation of miliary TB, from an acute fulminant course to a cryptic prolonged course with subtle clinical findings. Both cases shared a common end point with the development of adult respiratory distress syndrome.
In Acute Organophosphate Poisoning, the Efficacy of Hemoperfusion on Clinical Status and Mortality
Authors: Altintop Levent , Aygun Dursun , Sahin Havva , Doganay Zahide , Guven Hakan , Bek Yüksel , Akpolat Tekin
Published: November 2005

The aims of this study were to report experience in patients with organophosphate poisoning (OPP) and to discuss the potential role for hemoperfusion (HP) in the management of severe OPP. At the emergency service of a university hospital, 52 patients with acute OPP were included in this retrospective study. The patients were divided into 2 groups (Group 1, severe poisoning, n = 25; and Group 2, mild poisoning, n = 27). All patients with mild OPP survived. Seven patients (28%) of the 25 with severe OPP died. This study supports previous data documenting that HP is unnecessary in the management of mild OPP. Although there was not a control group (severe poisoning without HP treatment) in this study, experience suggests that HP can be useful in severe cases. Reports from centers having experience with severe OPP can help clarify this controversial issue. Randomized controlled (prospective) studies investigating the possible beneficial effects of HP on patient survival in patients with severe OPP with control group are needed.
Linezolid-Associated Serotonin Syndrome After Concomitant Treatment With Citalopram and Mirtazepine in a Critically Ill Bone Marrow Transplant Recipient
Authors: Debellis Ronald J. , Schaefer Oren P. , Liquori Michelina , Volturo Gregory A.
Published: November 2005

Linezolid was initially discovered as an antidepressant because of its effect on blocking intracellular metabolism of serotonin, norepinephrine, and other biogenic amines. As time passed, it was realized that linezolid possessed antibacterial activity, and linezolid has been developed and marketed as such. In medicine we are quick to categorize drugs into specific classes as a mechanism to recall indication and use. By classifying linezolid as an antibacterial, it is common to forget about its antidepressant roots. A case report involving linezolid with citalopram and mirtazepine in the precipitation of serotonin syndrome in a critically ill bone marrow transplant patient is described in this article.
Outcome of Critically Ill Human Immunodeficiency Virus-Infected Patients in the Era of Highly Active Antiretroviral Therapy
Authors: Khouli Hassan , Afrasiabi Ardavan , Shibli Muhamad , Hajal Rizan , Barrett C. Redington , Homel Peter
Published: November 2005

The purpose of this study was to determine the effect of prior use of highly active antiretroviral therapy (HAART) on outcome of human immunodeficiency virus (HIV)- patients admitted to intensive care units (ICUs). This study was a retrospective chart review of 242 HIV-infected patients who required 259 consecutive admissions to a university-affiliated hospital ICU during a 3-year period. Patient demographics, CD4 count, admission diagnosis, prior HAART, Pneumocystis jiroveciprophylaxis, length of stay, and ICU and hospital mortality were determined. Overall hospital mortality was 39%. Comparing patients who had received HAART before an ICU admission to those who had not, we found no difference between ICU or hospital mortality, need of mechanical ventilation, ICU and hospital length of stay, and incidence of P jiroveci. Pulmonary diagnosis was the most frequent ICU admission diagnosis (30%). Logistic regression analysis showed HIV-related illness and mechanical ventilation were significant independent predictors of increased hospital mortality.
Indicators of Effective Breastfeeding and Estimates of Breast Milk Intake
Authors: Riordan Jan , Gill-Hopple Kathleen , Angeron Judy
Published: November 2005

The authors tested indicators of effective breastfeeding to identify those that provide reliable estimates of human milk intake. Human milk intake of 82 full-term infants was measured by test weights before and after feeding and compared with commonly used breastfeeding indicators: rooting, length of time before latch-on, latch-on, suckle, observable swallowing, and audible swallowing. Two models were tested: model 1, describing indicators at 96 hours postpartum, and model 2, describing indicators at > 96 hours postpartum. Median (interquartile) milliliters of mother’s milk consumed per feeding was 26 ml (range, 4-47) at 96 hours and 54 ml (range, 26-73) at > 96 hours. Significant predictors of human milk intake in model 1 were rooting and observable swallowing ( R2 = 26%, P < .01). In model 2, audible swallowing alone estimated human milk intake ( R2 = 29%, P < .001). Observed swallowing and rooting during the first 4 days (96 hours) following birth and audible swallowing after that time should be included in the breastfeeding assessment of full-term infants.