bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural Variation in the Human Genome and its Role in Disease
Authors: Stankiewicz Paweł , Lupski James R.
Published: January 2010

During the last quarter of the twentieth century, our knowledge about human genetic variation was limited mainly to the heterochromatin polymorphisms, large enough to be visible in the light microscope, and the single nucleotide polymorphisms (SNPs) identified by traditional PCR-based DNA sequencing. In the past five years, the rapid development and expanded use of microarray technologies, including oligonucleotide array comparative genomic hybridization and SNP genotyping arrays, as well as next-generation sequencing with “paired-end” methods, has enabled a whole-genome analysis with essentially unlimited resolution. The discovery of submicroscopic copy-number variations (CNVs) present in our genomes has changed dramatically our perspective on DNA structural variation and disease. It is now thought that CNVs encompass more total nucleotides and arise more frequently than SNPs. CNVs, to a larger extent than SNPs, have been shown to be responsible for human evolution, genetic diversity between individuals, and a rapidly increasing number of traits or susceptibility to traits; such conditions have been referred to as genomic disorders. In addition to well-known sporadic chromosomal microdeletion syndromes and Mendelian diseases, many common complex traits including autism and schizophrenia can result from CNVs. Both recombination- and replication-based mechanisms for CNV formation have been described.
Molecular Diagnosis and Therapy of Kidney Cancer
Authors: Linehan W. Marston , Bratslavsky Gennady , Pinto Peter A. , Schmidt Laura S. , Neckers Len , Bottaro Donald P. , Srinivasan Ramaprasad
Published: January 2010

Kidney cancer is not a single disease; it is made up of a number of cancers that occur in the kidney, each having a different histology, following a different clinical course, responding differently to therapy, and caused by a different gene. Study of the genes underlying kidney cancer has revealed that it is fundamentally a metabolic disorder. Understanding the genetic basis of cancer of the kidney has significant implications for diagnosis and management of this disease. VHL is the gene for clear cell kidney cancer. The VHL protein forms a complex that targets the hypoxia-inducible factors for ubiquitin-mediated degradation. Knowledge of this pathway provided the foundation for the development of novel therapeutic approaches now approved for treatment of this disease. MET is the gene for the hereditary form of type 1 papillary renal carcinoma and is mutated in a subset of sporadic type 1 papillary kidney cancers. Clinical trials are currently ongoing with agents targeting the tyrosine kinase domain of MET in sporadic and hereditary forms of papillary kidney cancer. BHD is the gene for the hereditary type of chromophobe kidney cancer. It is thought to be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways. Hereditary leiomyomatosis renal cell carcinoma, a hereditary form of type 2 papillary renal carcinoma, is caused by inactivation of a Krebs cycle enzyme due to mutation. Knowledge of these kidney cancer gene pathways has enabled new approaches in the management of this disease and has provided the foundation for the development of targeted therapeutics.
H5N1 Avian Influenza: Preventive and Therapeutic Strategies Against a Pandemic
Authors: Sambhara Suryaprakash , Poland Gregory A.
Published: January 2010

Avian influenza H5N1 viruses that have spread to a number of countries in Asia, the Middle East, and Africa have the potential to cause a pandemic. The most effective public health intervention strategy is to combine preventive vaccination with nonpharmaceutical intervention strategies and enhanced surveillance activities. H5N1 vaccines are poorly immunogenic even at high doses; an adjuvant is needed for enhancement of immunogenicity and for dose-sparing. Lack of effective, yet safe, adjuvants is the limiting factor for candidate vaccines that utilize egg-dependent or egg-independent manufacturing technologies. Hence, developing novel adjuvants is crucial for pandemic influenza vaccine development. Although the use of antiviral drugs is also an important public health countermeasure for preventing and treating influenza, the emergence of drug-resistant strains of avian H5N1 viruses underscores the need to develop not only new drugs but other novel preventive and therapeutic strategies such as vaccines.
Metabolic Surgery to Treat Type 2 Diabetes: Clinical Outcomes and Mechanisms of Action
Authors: Rubino Francesco , Schauer Philip R. , Kaplan Lee M. , Cummings David E.
Published: January 2010

Several gastrointestinal (GI) operations that were designed to promote weight loss can powerfully ameliorate type 2 diabetes mellitus (T2DM). Although T2DM is traditionally viewed as a chronic, relentless disease in which delay of end-organ complications is the major treatment goal, GI surgery offers a novel endpoint: complete disease remission. Ample data confirm the excellent safety and efficacy of conventional bariatric operations—especially Roux-en-Y gastric bypass and laparoscopic adjustable gastric banding—to treat T2DM in severely obese patients. Use of experimental procedures as well as conventional bariatric operations is increasingly being explored in less obese diabetic patients, with generally favorable results, although further assessment of risk:benefit profiles is needed. Mounting evidence indicates that certain operations involving intestinal diversions improve glucose homeostasis through varied mechanisms beyond reduced food intake and body weight, for example by modulating gut hormones. Research to elucidate such mechanisms should facilitate the design of novel pharmacotherapeutics and dedicated antidiabetes GI manipulations. Here we review evidence regarding the use and study of GI surgery to treat T2DM, focusing on available published reports as well as results from the Diabetes Surgery Summit (DSS) in Rome and the World Congress on Interventional Therapies for T2DM in New York City.
Regulation of Phosphate Homeostasis by PTH, Vitamin D, and FGF23
Authors: Bergwitz Clemens , Jüppner Harald
Published: January 2010

In contrast to the regulation of calcium homeostasis, which has been extensively studied over the past several decades, relatively little is known about the regulation of phosphate homeostasis. Fibroblast growth factor 23 (FGF23) is part of a previously unrecognized hormonal bone-parathyroid-kidney axis, which is modulated by PTH, 1,25(OH)2-vitamin D (1,25(OH)2D), dietary and serum phosphorus levels. Synthesis and secretion of FGF23 by osteocytes are positively regulated by 1,25(OH)2D and serum phosphorus and negatively regulated, through yet unknown mechanisms, by the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and by dentin matrix protein 1 (DMP1). In turn, FGF23 inhibits the synthesis of 1,25(OH)2D, and it may negatively regulate the secretion of parathyroid hormone (PTH) from the parathyroid glands. However, FGF23 synergizes with PTH to increase renal phosphate excretion by reducing expression of the renal sodium-phosphate cotransporters NaPi-IIa and NaPi-IIc in the proximal tubules. Most insights gained into the regulation of phosphate homeostasis by these factors are derived from human genetic disorders and genetically engineered mice, which are reviewed in this paper.
Controversies in the Use of Drug-Eluting Stents for Acute Myocardial Infarction: A Critical Appraisal of the Data
Authors: Sakhuja Rahul , Mauri Laura
Published: January 2010

Acute myocardial infarction is a common and life-threatening presentation of coronary artery disease in adults. In the settings of ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction, significant mortality benefit has been observed in randomized trials of coronary stent procedures compared with medical therapy alone. However, data regarding procedural choices, and particularly stent choices, are limited, and significant controversy exists. Drug-eluting stents were introduced in the United States in 2003 and have been widely adopted based on profound reduction in restenosis. Yet recent years have witnessed a decline in use of drug-eluting stents in the setting of myocardial infarction due to long-term safety concerns. We review the current data regarding drug-eluting stent performance relative to bare metal stents in the setting of acute myocardial infarction with regard to effectiveness, safety, and the need for adjunctive long-term pharmacologic therapy.
Arrhythmogenic Cardiomyopathy: Etiology, Diagnosis, and Treatment
Authors: Sen-Chowdhry Srijita , Morgan Robert D. , Chambers John C. , McKenna William J.
Published: January 2010

Arrhythmogenic right ventricular cardiomyopathy (ARVC) has a prevalence of at least 1 in 1000, is a leading cause of sudden cardiac death in people aged ≤35 years, and accounts for up to 10% of deaths from undiagnosed cardiac disease in the <65 age group. The classic form of the disease has an early predilection for the right ventricle, but recognition of left-dominant and biventricular subtypes has prompted proposal of the broader term arrhythmogenic cardiomyopathy. The clinical profile of the disease bridges the gap between the cardiomyopathies and inherited arrhythmia syndromes. The early “concealed” phase is characterized by propensity toward ventricular tachyarrhythmia in the setting of well-preserved morphology, histology, and ventricular function. As the disease progresses, however, myocyte loss, inflammation, and fibroadiposis become evident. Up to 40% of cases harbor rare variants in genes encoding components of the desmosome, specialized intercellular junctions that confer mechanical strength to cardiac and epithelial tissue, and may also participate in signaling networks. Phenotypic heterogeneity and the nonspecific nature of associated features complicate clinical diagnosis, which requires multipronged cardiovascular investigation rather than a single test. Development of a prospectively validated risk-stratification algorithm for the full disease spectrum remains the foremost clinical challenge.
Alveolar Surfactant Homeostasis and the Pathogenesis of Pulmonary Disease
Authors: Whitsett Jeffrey A. , Wert Susan E. , Weaver Timothy E.
Published: January 2010

The alveolar region of the lung creates an extensive epithelial surface that mediates the transfer of oxygen and carbon dioxide required for respiration after birth. Maintenance of pulmonary function depends on the function of type II epithelial cells that synthesize and secrete pulmonary surfactant lipids and proteins, reducing the collapsing forces created at the air-liquid interface in the alveoli. Genetic and acquired disorders associated with the surfactant system cause both acute and chronic lung disease. Mutations in the ABCA3, SFTPA, SFTPB, SFTPC, SCL34A2, and TERT genes disrupt type II cell function and/or surfactant homeostasis, causing neonatal respiratory failure and chronic interstitial lung disease. Defects in GM-CSF receptor function disrupt surfactant clearance, causing pulmonary alveolar proteinosis. Abnormalities in the surfactant system and disruption of type II cell homeostasis underlie the pathogenesis of pulmonary disorders previously considered idiopathic, providing the basis for improved diagnosis and therapies of these rare lung diseases.
Surgical Innovations Arising from the Iraq and Afghanistan Wars
Authors: Ling Geoffrey S.F. , Rhee Peter , Ecklund James M.
Published: January 2010

The delivery of combat casualty care poses numerous challenges including austere conditions, limited supplies and medical personnel, and multiple simultaneous patients. However, the exigent circumstances of the battlefield compel the development of research and the advancement of adaptive, practical medical technologies to support and sustain military health. In Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF), modern changes in medical management, coupled with improved protective gear and evacuation capabilities, have facilitated the highest survival rate in combat history.
Discovery and Development of Therapeutic Aptamers
Authors: Bouchard P.R. , Hutabarat R.M. , Thompson K.M.
Published: January 2010

Therapeutic aptamers are single-stranded structured oligonucleotides that bind to protein targets with high affinity and specificity and modulate protein function. Aptamers are discovered by iterative rounds of selection for binding to the target protein, partitioning, and amplification of binding clones from a diverse starting library (SELEX). Postselection optimization of clones using chemical modification is directed at improving affinity, potency, and metabolic stability. A key attribute of therapeutic aptamers is the ability to tailor the pharmacokinetic profile by modulating the degree of metabolic stability and modulating renal clearance and rate of distribution by conjugation to various sizes of polyethylene glycol (PEG). In toxicology studies, therapeutic aptamers have been largely devoid of the previously reported oligonucleotide class effects of immune stimulation, complement activation, and anticoagulation; and the principal finding is the histologically visible accumulation of drug-related material in mononuclear phagocytes, a finding generally not considered an adverse effect. Good safety margins between the pharmacologically effective dose and toxicologically established no-adverse-effect levels have been observed consistently. There are presently seven aptamers either on the market or in clinical trials, but there is still much to be demonstrated in terms of chronic systemic use to fully realize the potential of this promising new class of drugs.
Tissue Renin-Angiotensin-Aldosterone Systems: Targets for Pharmacological Therapy
Authors: Bader Michael
Published: January 2010

The renin-angiotensin-aldosterone system is one of the most important systems in cardiovascular control and in the pathogenesis of cardiovascular diseases. Therefore, it is already a very successful drug target for the therapy of these diseases. However, angiotensins are generated not only in the plasma but also locally in tissues from precursors and substrates either locally expressed or imported from the circulation. In most areas of the brain, only locally generated angiotensins can exert effects on their receptors owing to the blood-brain barrier. Other tissue renin-angiotensin-aldosterone systems are found in cardiovascular organs such as kidney, heart, and vessels and play important roles in the function of these organs and in the deleterious actions of hypertension and diabetes on these tissues. Novel components with mostly opposite actions to the classical renin-angiotensin-aldosterone systems have been described and need functional characterization to evaluate their suitability as novel drug targets.
Pharmacogenetics of Drug Dependence: Role of Gene Variations in Susceptibility and Treatment
Authors: Khokhar Jibran Y. , Ferguson Charmaine S. , Zhu Andy Z.X. , Tyndale Rachel F.
Published: January 2010

Drug dependency is a highly prevalent mental health disorder that imposes a significant burden on those directly affected, health care systems, and society in general. There is substantial heritability in the susceptibility to drug addiction, which indicates that there are genetic risk factors. Variation in the human genome is abundant and can directly affect drug dependency phenotypes, for example, by altering the function of a gene product or by altering gene expression. Pharmacogenetic studies can assess the effects of genetic variation on the risk for a particular phenotype (e.g., being an alcoholic). In addition, pharmacogenetic variability in treatment efficacy and adverse reactions can be investigated to identify particular genetic variants associated with altered responses. This review highlights examples of genetic variations that are important in the development and maintenance of specific drug dependencies as well as those that affect the response to treatment.
Metabotropic Glutamate Receptors: Physiology, Pharmacology, and Disease
Authors: Niswender Colleen M. , Conn P. Jeffrey
Published: January 2010

The metabotropic glutamate receptors (mGluRs) are family C G-protein-coupled receptors that participate in the modulation of synaptic transmission and neuronal excitability throughout the central nervous system. The mGluRs bind glutamate within a large extracellular domain and transmit signals through the receptor protein to intracellular signaling partners. A great deal of progress has been made in determining the mechanisms by which mGluRs are activated, proteins with which they interact, and orthosteric and allosteric ligands that can modulate receptor activity. The widespread expression of mGluRs makes these receptors particularly attractive drug targets, and recent studies continue to validate the therapeutic utility of mGluR ligands in neurological and psychiatric disorders such as Alzheimer's disease, Parkinson's disease, anxiety, depression, and schizophrenia.
Green tea catechin EGCG inhibits ileal apical sodium bile acid transporter ASBT
Authors: Annaba Fadi , Kumar Pradeep , Dudeja Amish K. , Saksena Seema , Gill Ravinder K. , Alrefai Waddah A.
Published: January 2010

Green tea catechins exhibit hypocholesterolemic effects probably via their inhibitory effects on intestinal bile acid absorption. Ileal apical sodium-dependent bile acid transporter (ASBT) is responsible for reabsorption of bile acids. The present studies were, therefore, designed to investigate the modulation of ASBT function and membrane expression by green tea catechins in human embryonic kidney HEK-293 cells stably transfected with ASBT-V5 fusion protein and intestinal Caco-2 monolayers. Our data showed that ASBT activity was significantly decreased by (−)-epigallocatechin-3-gallate (EGCG) but not other green tea catechins. Inhibition of PKC, phosphatidylinositol 3-kinase, and MAPK-dependent pathways failed to block the reduction in ASBT activity by EGCG. Kinetics studies showed a significant decrease in the Vmax of the transporter, whereas total ASBT content on the plasma membrane was unaltered by EGCG. Concomitant with the decrease in ASBT function, EGCG significantly reduced ASBT pool in the detergent-insoluble fraction, while increasing its presence in the detergent-soluble fraction of plasma membrane. Furthermore, EGCG decreased the association of ASBT with floating lipid raft fractions of cellular membrane on Optiprep density gradient. In conclusion, our data demonstrate a novel role of lipid rafts in the modulation of ASBT function by the dietary component EGCG, which may underlie the hypocholesterolemic effects of green tea.
Attenuation of myocardial injury in mice with functional deletion of the circadian rhythm gene mPer2
Authors: Virag Jitka A. I. , Dries Jessica L. , Easton Peter R. , Friesland Amy M. , DeAntonio Jon H. , Chintalgattu Vishnu , Cozzi Emily , Lehmann Brian D. , Ding Jian M. , Lust Robert M.
Published: January 2010

Variations in circadian rhythms are evident in the incidence of cardiovascular disease, and the risk of cardiovascular events increases when rhythms are disrupted. The suprachiasmatic nucleus is the central circadian pacemaker that regulates the daily rhythm of peripheral organs. Diurnal rhythms have more recently been shown to exist in myocardial tissue and are involved in metabolism and contractile function. Thus we sought to determine whether the functional deletion of the circadian rhythm mouse periodic gene 2 (mPer2) would protect the heart against ischemic injury. Nonreperfused myocardial infarction was induced in anesthetized, ventilated C57 ( n = 17) and mPer2 mutant (mPer2-M; n = 15) mice via permanent ligation of the left anterior descending coronary artery. At 4 days post-myocardial infarction, we observed a 43% reduction of infarct area in mPer2-M mice compared with wild-type mice. This is coincident with 25% less macrophage infiltration, 43% higher capillary density, 17% increase in hypertrophy, and 15% less cardiomyocyte apoptosis in the infarct zone. Also, matrix metalloproteinase-9 was expressed in inflammatory cells in both groups, but total protein was 40% higher in wild-type mice, whereas it was not elevated in mPer2-M mice in response to injury. The functional deletion of the mPer2 gene reduces the severity of myocardial infarct injury by limiting the inflammatory response, reducing apoptosis, and inducing cardiomyocyte hypertrophy, thus preserving cardiac function. These findings collectively imply that the disruption of the circadian clock gene mPer2 is protective. Understanding the interactions between circadian rhythm genes and cardiovascular disease may provide insights into potential preventative and therapeutic strategies for susceptible populations.
Curcumin inhibits fibrosis-related effects in IPF fibroblasts and in mice following bleomycin-induced lung injury
Authors: Smith Monica R. , Gangireddy Srinivasa R. , Narala Venkata R. , Hogaboam Cory M. , Standiford Theodore J. , Christensen Paul J. , Kondapi Anand K. , Reddy Raju C.
Published: January 2010

Idiopathic pulmonary fibrosis (IPF) is a progressive and typically fatal lung disease for which no effective therapy has been identified. The disease is characterized by excessive collagen deposition, possibly in response to dysregulated wound healing. Mediators normally involved in would healing induce proliferation of fibroblasts and their differentiation to myofibroblasts that actively secrete collagen. Curcumin, a polyphenolic compound from turmeric, has been shown to exert a variety of biological effects. Effects on IPF and associated cell types remain unclear, however. We accordingly tested the ability of curcumin to inhibit proliferation and differentiation to myofibroblasts by human lung fibroblasts, including those from IPF patients. To further examine the potential usefulness of curcumin in IPF, we examined its ability to reduce fibrosis in bleomycin-treated mice. We show that curcumin effectively reduces profibrotic effects in both normal and IPF fibroblasts in vitro and that this reduction is accompanied by inhibition of key steps in the transforming growth factor-β (TGF-β) signaling pathway. In vivo, oral curcumin treatment showed no effect on important measures of bleomycin-induced injury in mice, whereas intraperitoneal curcumin administration effectively inhibited inflammation and collagen deposition along with a trend toward improved survival. Intraperitoneal curcumin reduced fibrotic progression even when administered after the acute bleomycin-induced inflammation had subsided. These results encourage further research on alternative formulations and routes of administration for this potentially attractive IPF therapy.
Simultaneous Resection of Colorectal Cancer and Synchronous Liver Metastases: Initial Experience of Laparoscopy for Colorectal Cancer Resection
Authors: Akiyoshi Takashi , Kuroyanagi Hiroya , Saiura Akio , Fujimoto Yoshiya , Koga Rintaro , Konishi Tsuyoshi , Ueno Masashi , Oya Masatoshi , Seki Makoto , Yamaguchi Toshiharu
Published: January 2010

Background/Aims:Although laparoscopy is accepted for treatment of colorectal cancer, there is no established consensus for its use when resection of synchronous liver metastases is performed simultaneously. The purpose of this study was to evaluate whether laparoscopic colorectal resection with simultaneous resection of synchronous liver metastases was technically feasible and whether it may be a therapeutic option. Methods: Ten patients underwent laparoscopic resection for primary colorectal cancer, combined with synchronous resection of liver metastases. Results: The primary tumor location was in the sigmoid colon in 3 patients and the rectum in 7. All laparoscopic colorectal resections were successful, with no conversion to open surgery. Simultaneously, there were 7 conventional open and 3 laparoscopy-assisted liver resections. The median total operating time was 446 (range 300–745) min, including 222 (range 152–313) min for colorectal resection. The median total estimated blood loss was 175 (range 30–1,200) ml, including 10 (range 0–550) ml for colorectal resection. There was no major morbidity, except 1 patient who developed decubitus. Conclusion: This preliminary report suggests that laparoscopic resection for sigmoid colon and rectal cancer, combined with synchronous resection of liver metastases, is a safe and feasible procedure in selected patients.
Behavioral Treatment of Voice Disorders in Teachers
Authors: Ziegler Aaron , Gillespie Amanda I. , Verdolini Abbott Katherine
Published: January 2010

Introduction: The purpose of this paper is to review the literature on the behavioral treatment of voice disorders in teachers. The focus is on phonogenic disorders, that is voice disorders thought to be caused by voice use. Methods: Review of the literature and commentary. Results: The review exposes distinct holes in the literature on the treatment of voice problems in teachers. However, emerging trends in treatment are noted. For example, most studies identified for review implemented a multiple-therapy approach in a group setting, in contrast to only a few studies that assessed a single-therapy approach with individual patients. Although the review reveals that the evidence around behavioral treatment of voice disorders in teachers is mixed, a growing body of data provides some indicators on how effectively rehabilitation of teachers with phonogenic voice problems might be approached. Specifically, voice amplification demonstrates promise as a beneficial type of indirect therapy and vocal function exercises as well as resonant voice therapy show possible benefits as direct therapies. Finally, only a few studies identified even remotely begin to meet guidelines of the Consolidated Standards of Reporting Trials statement, a finding that emphasizes the need to increase the number of investigations that adhere to strict research standards. Conclusions: Although data on the treatment of voice problems in teachers are still limited in the literature, emerging trends are noted. The accumulation of sufficient studies will ultimately provide useful evidence about this societally important issue.
Trainee Experience in Relation to Voice Handicap, General Coping and Psychosomatic Well-Being in Female Student Teachers: A Descriptive Study
Authors: Meulenbroek L.F.P. , de Jong F.I.C.R.S.
Published: January 2010

Objective: The aim of this study was to investigate the relation between trainee experience and voice handicap, general coping and psychosomatic well-being in student teachers. Methods: A longitudinal survey was performed among 43 starting female student teachers, becoming a professional teacher in primary education. The subjective biopsychosocial consequences of voice problems was assessed by the Voice Handicap Index inventory, the general coping style by the Utrecht Coping List and psychosomatic well-being by the Symptom Checklist. Results: Student teachers in general and especially with a higher impact of the voice after two trainee periods showed a more reactive-defensive coping style. Student teachers with a higher impact of the voice after two trainee periods had less psychosomatic well-being. Conclusion: These findings may call for a different attitude of the (university) speech therapist. They should take into account that together with changing the voice handicap, factors of psychosomatic well-being can play an important role in coaching student teachers. Speech therapists should also be encouraged to change the student’s passive coping behaviour into a more active method and to stimulate the student to implement a new coping attitude into new trainee activities.
The Potential Role of Plasma Gelsolin in Dialysis-Related Protein-Energy Wasting
Authors: Lee Po Shun , Bhan Ishir , Thadhani Ravi
Published: January 2010

Protein-energy wasting (PEW) is increasingly recognized to be a prevalent and significant contributor to the clinical deterioration of patients with chronic kidney disease (CKD). While factors reflecting various aspects of PEW correlate with outcomes in CKD, the mechanism linking PEW and CKD outcomes is not completely understood. Plasma gelsolin (pGSN) is a highly abundant circulating protein that is depleted by inflammatory mediators and mainly produced by muscles. Recent data documenting the prognostic ability of low pGSN levels in hemodialysis patients suggests that circulating pGSN levels incorporate the degree of systemic inflammation and muscle wasting. Therefore, pGSN deficiency appears to be a powerful biomarker and a potential therapeutic target in CKD patients.
Aldosterone in Uremia – Beyond Blood Pressure
Authors: Ritz Eberhard , Koleganova Nadezda
Published: January 2010

Aldosterone was in the past considered only as a prohypertensinogenic agent. It has recently become clear that apart from the classical endocrine action, i.e. causing blood pressure elevation as a result of salt retention, aldosterone has numerous blood-pressure-independent actions on nonepithelial tissue. Under conditions of high salt concentration, aldosterone is injurious to the kidney, heart and vasculature. Of particular interest are recent observations that aldosterone is a permissive factor for the effect of minor increases in plasma sodium concentration on endothelial cell dysfunction. Despite surprising effects of aldosterone blockade on blood pressure of anuric dialysis patients, the potential role of mineralocorticoid receptor blockade in dialysis patients is currently unclear and requires controlled investigation to define the risk of potential hazards, specifically hyperkalemia.
Peritonitis – Does Peritoneal Dialysis Modality Make a Difference?
Authors: Piraino Beth , Sheth Heena
Published: January 2010

Background/Aims: Peritonitis remains a significant problem for patients on peritoneal dialysis (PD). There is a certain amount of controversy as to whether peritoneal modality is itself a risk factor for peritonitis, with one modality higher than another. Methods: A literature review was done (August 2009) searching under ‘peritoneal dialysis’, ‘peritonitis’ and ‘modality’ to find all articles related to the topic. The highest-quality articles were extracted for review. Results: Two randomized controlled trials (RCTs) done with disconnect systems for continuous ambulatory PD (CAPD) and Luer lock connections for automated PD (APD) showed important decrements in peritonitis rate on APD compared to CAPD. The variation of peritonitis rates in studies comparing peritonitis on continuous cycling PD (CCPD) and CAPD may relate to the difference in connection type for APD in Europe (Luer lock) and North America (spike) and to differing prescriptions, including in some cases midday exchanges on APD and in other cases a dry abdomen on APD. The variation in peritonitis rates from center to center is marked. In many studies sufficient details regarding the connectology and the prescription, both of which may impact on peritonitis risk, are absent. Conclusion: At the present time, the best data suggest that use of APD with Luer lock connections versus CAPD with a disconnect system results in a reduction in peritonitis risk. More studies are needed on this important topic, particularly the possible advantage of initiating PD with a dry day in those with residual kidney function. This question would be best studied with an RCT comparing peritonitis rates in three groups of patients, i.e. those initiating dialysis on CCPD, CAPD and APD with a dry day.
Reverse Epidemiology, Obesity and Mortality in Chronic Kidney Disease: Modelling Mortality Expectations Using Energetics
Authors: Speakman John R. , Westerterp Klaas R.
Published: January 2010

Background/Aims: Obesity is a predisposing factor for chronic illnesses such as type 2 diabetes, heart disease and cancer. In chronic kidney disease (CKD), the effect of obesity on mortality is reversed. Obese patients appear protected. Two ideas have been advanced to explain this ‘reverse epidemiology’. First, obesity may buffer patients from wasting. Second, fat may sequester uraemic toxins leading to a systematic error in the prescription of dialysis. Our aim was to use data on the scaling of daily energy expenditure, fat and lean tissue mass to predict the pattern of variation in mortality with obesity under the contrasting hypotheses. Methods: We used data on daily energy demands measured using the doubly labelled water technique and body composition collected on a cohort of 503 individuals to model the expected impacts of wasting and fat sequestration/underdialysis on mortality. Results: A model predicting mortality due to wasting replicated the mortality pattern of the obesity paradox. However, quantitatively the beneficial effect of being fat was predicted to be much larger than that observed in the actual CKD population. Similar results were found for the fat sequestration/underdialysis hypothesis, but in this case the discrepancy was smaller. Discussion: These models tend to support the fat sequestration and underdialysis idea more than the wasting hypothesis. In part (or in whole) this may be because of inadequacies in the model construction which are currently based on rather crude assumptions. Refinement of the models may enable better tests between alternative ideas for the obesity paradox.
The Role of Peripheral Ultrafiltration in the Management of Acute Decompensated Heart Failure
Authors: Andrade Jason G. , Stadnick Ellamae , Virani Sean A.
Published: January 2010

Heart failure is a common and highly morbid condition associated with recurrent hospitalizations for disease decompensation. As such, heart failure is a growing public health concern from both a utilization and cost perspective. The current standard of care for the management of volume overload symptoms is underpinned by a diuretic-based treatment regimen. There is now increasing data to suggest that this approach may be counterproductive and result in progression of cardiac and renal disease with resultant higher mortality rates. Peripheral ultrafiltration is emerging as a viable, and in some cases preferred, option for sodium and fluid removal. Initial research trials have shown that this treatment modality results in improved clinical, biochemical and quality of life parameters. Moreover, these benefits are durable over the long term with decreased recidivism and health care utilization at 1 year. It remains unclear whether these benefits will translate into hard cardiovascular endpoints; greater adoption of this technology coupled with newer clinical trials will help researchers and clinicians identify the optimal strategy for treating symptoms of volume overload among heart failure patients.
Automated Regional Citrate Anticoagulation: Technological Barriers and Possible Solutions
Authors: Szamosfalvi Balazs , Frinak Stanley , Yee Jerry
Published: January 2010

Background: Large-scale adoption of regional citrate anticoagulation (RCA) is prevented by risks of the technique as practiced traditionally. Safe RCA protocols with automated delivery on customized dialysis systems are needed. Methods: We applied kinetic analysis of solute fluxes during RCA to design a protocol for sustained low-efficiency dialysis (SLED) for critically ill patients. We used a high-flux hemodialyzer, a zero-calcium (Ca) dialysate, a dialysis machine with online clearance and access recirculation monitoring, and a separate optical hematocrit (Hct) sensor. Flow rates were QB = 200 ml/min for blood; QD = 400 ml/min for dialysate, with Na = 140 mmol/l and HCO3 = 32 mmol/l; Qcitrate = 400 ml/h of acid citrate dextrose A; ultrafiltration as indicated. The QCa was infused into the return blood line, adjusted hourly based on online Hct and a <24-hour-old albumin level. Results: Using the SLED-RCA protocol in an anhepatic, ex vivo dialysis system, ionized Ca (iCa) was >1 mmol/l in the blood reservoir and <0.3 mmol/l in the blood circuit after citrate but before Ca infusion (QCa) with normal electrolyte composition of the blood returning to the reservoir. Clinically, SLED-RCA completely abrogated clotting, without adverse electrolyte effects. The QCa prediction algorithm maintained normal systemic iCa (0.95–1.4 mmol/l) in all patients. The high citrate extraction on the dialyzer prevented systemic citrate accumulation even in shock liver patients. Safety analysis shows that building a dialysis system for automated SLED-RCA is feasible. Conclusion: Using predictive QCa dosing and integrating control of the infusion pumps with the dialysis machine, SLED-RCA can be near-automated today to provide a user-friendly and safe system.
Positive Lymphocytotoxic Crossmatch Does Not Adversely Affect Survival in Living Donor Liver Transplantation
Authors: Sugawara Yasuhiko , Tamura Sumihito , Kaneko Junichi , Togashi Junichi , Makuuchi Masatoshi , Kokudo Norihiro
Published: January 2010

Background/Aims: The influence of lymphocytotoxic crossmatch on survival or acute rejection in liver transplantation remains controversial. Data regarding graft survival and acute rejection of living donor liver transplantation (LDLT) are limited. Methods: We retrospectively examined the influence of a positive T or B lymphocytotoxic crossmatch on survival and acute rejection in patients using a database of 414 consecutive LDLT cases. Results: The rejection-free rate at 90 days after LDLT was lower in patients that were T crossmatch-positive compared to patients that were both T and B crossmatch-negative (52 vs. 74%, p = 0.03). No patients with a positive lymphocytotoxic crossmatch died due to immunologic causes. The crossmatch results had no effect on graft survival. Conclusion: In the positive crossmatch groups, there was no acute rejection that was untreatable or that caused graft loss. These findings indicate that a positive crossmatch graft should not be considered a contraindication for LDLT.
Thrombophilia in Women with Pregnancy-Associated Complications: Fetal Loss and Pregnancy-Related Venous Thromboembolism
Authors: Kovac M. , Mitic G. , Mikovic Z. , Djordjevic V. , Savic O. , Mandic V. , Rakicevic L.J. , Antonijevic N. , Radojkovic D.
Published: January 2010

Backgound/Aims: Existing data regarding the prevalence of thrombophilia in women with pregnancy complications are conflicting. Methods: To investigate the relationship between pregnancy-associated complications and the presence of thrombophilia, we studied the records of 453 women with pregnancy-associated complications. In 55 women, intrauterine fetal death (fetus mortus in utero, FMU) after 20 weeks of gestation was recorded, in 231 two or more consecutive recurrent fetal losses (RFL) were recorded, while 167 had a venous thromboembolism (VTE) during one of their pregnancies. The control group consisted of 128 healthy women, with no previous history of thrombotic events or miscarriages. Results: In the FMU group we found 54.5% of women had thrombophilia, in the RFL group 38%, and in the VTE group 52.7%. The most frequent thrombophilia in the VTE group was the FV Leiden (OR 17.9, 95% CI 4.2–75.9). The most frequent thrombophilia in the FMU group was the FII G20210A (OR 7.09, 95% CI 1.8–27.9). Statistical difference between RFL and the control group was observed only for FV Leiden (OR 6.8, 95% CI 1.6–29.7). Conclusion: Thrombophilia was found to be considerably more common in women with pregnancy-associated complications in comparison with the women with normal pregnancies, most frequently in patients with VTE or FMU.
Increased Risk of Chronic Kidney Disease in Elderly with Metabolic Syndrome and High Levels of C-Reactive Protein: Kahrizak Elderly Study
Authors: Fakhrzadeh Hossein , Ghaderpanahi Maryam , Sharifi Farshad , Badamchizade Zohre , Mirarefin Mojde , Larijani Bagher
Published: January 2010

Background: To explore the interrelationship between metabolic syndrome (MS), chronic kidney disease (CKD) and C-reactive protein (CRP) in an elderly Iranian cohort. Methods: 122 residents of Kahrizak Charity Foundation aged ≧60 years were enrolled in this survey. MS was defined according to the NCEP-ATPIII criteria. CKD was defined as an estimated glomerular filtration rate <60 ml/min/1.73 m2. CRP levels ≧3 mg/dl were determined as a high CRP. Results: The multivariate-adjusted odds ratio (OR) for CKD in MS was 5.81 (95% confidence interval (CI) 1.72–19.58) compared to those without MS. High blood pressure and high triglyceride levels were significantly associated with an increased risk of CKD (OR 4.01, 95% CI 1.55–10.37 and OR 3.27, 95% CI 1.25–8.53, respectively). Subjects with MS and high CRP levels had a 1.71-fold greater risk of having CKD compared to those without MS and low CRP levels (95% CI 1.02–2.84). Conclusion: There was a strong and independent relation between MS and risk of CKD in these elderly people. High blood pressure and hypertriglyceridemia increased the risk of CKD. Combination of high CRP and MS was strongly associated with an increased risk of CKD.
Distal Renal Tubular Acidosis in Filipino Children, Caused by Mutations of the Anion-Exchanger SLC4A1 (AE1, Band 3) Gene
Authors: Anacleto Francisco E. , Bruce Lesley J. , Clayton Peter , Hegde Shivram , Resontoc Lourdes P. , Wrong Oliver
Published: January 2010

Aim: To describe the clinical features and genetic basis of distal renal tubular acidosis (dRTA) in Filipino children. Methods: Clinical description and gene analysis of affected members of 7 families. Results: In all affected children, the disease was associated with mutations of the SLC4A1 gene that codes for the bicarbonate/chloride anion-exchanger 1 (AE1, band 3) protein situated in the red cell membrane and the α-intercalated (proton-secreting) cell of the renal collecting duct. In 2 families, affected children were homozygous for a substitution of aspartic acid for glycine in residue 701 of the AE1 protein (G701D); in the other 5 families, affected children were compound heterozygotes of this mutation with the AE1 mutation (Δ400–408) that causes Southeast Asian ovalocytosis (SAO). All affected children had morphological red cell changes that closely resembled SAO, including the children who were homozygous for G701D and did not have the SAO mutation. Homozygous G701D thus produces morphological red cell changes that are not readily distinguishable from SAO. The parents of all 7 families were originally domiciled in the islands of the Visayas group in the central part of the Philippine archipelago. Conclusion: Recessive renal tubular acidosis in Filipinos is usually caused by SLC4A1 mutations, commonly G701D.
Metallothionein Enhances Angiogenesis and Arteriogenesis by Modulating Smooth Muscle Cell and Macrophage Function
Authors: Zbinden Stephan , Wang Jinsong , Adenika Remi , Schmidt Marcel , Tilan Justin U. , Najafi Amir H. , Peng XinZhi , Lassance-Soares Roberta M. , Iantorno Micaela , Morsli Hakim , Gercenshtein Leonid , Jang Gil Jin , Epstein Stephen E. , Burnett Mary Susan
Published: January 2010

Objective—In a previous study we identified metallothionein (MT) as a candidate gene potentially influencing collaterogenesis. In this investigation, we determined the effect of MT on collaterogenesis and examined the mechanisms contributing to the effects we found.

Methods and Results—Collateral blood flow recovery was assessed using laser Doppler perfusion imaging, and angiogenesis was measured using a Matrigel plug assay. Smooth muscle cells were isolated from MT knockout (KO) mice for functional assays. Gene expression of matrix metalloproteinase-9, platelet-derived growth factor, vascular endothelial growth factor, and Fat cadherin in smooth muscle cells was measured by real-time polymerase chain reaction, and protein levels of vascular endothelial growth factor and matrix metalloproteinase-9 were determined using enzyme-linked immunosorbent assay and Western blot. CD11b+macrophages were tested for invasiveness using a real-time impedance assay. Both flow recovery and angiogenesis were impaired in MT KO mice. Proliferation, migration, and invasion were decreased in MT KO smooth muscle cells, and matrix metalloproteinase-9, platelet-derived growth factor, and vascular endothelial growth factor expression were also decreased, whereas FAT-1 cadherin expression was elevated. MT KO CD11b+cells were more invasive than wild-type cells.

Conclusion—MT plays an important role in collateral flow recovery and angiogenesis, an activity that appears to be mediated, in part, by the effects of MT on the functionality of 3 cell types essential for these processes: endothelial cells, smooth muscle cells, and macrophages.
Uncoupling Protein-2 Modulates Myocardial Excitation-Contraction Coupling
Authors: Turner Jay D. , Gaspers Lawrence D. , Wang Guoqiang , Thomas Andrew P.
Published: January 2010

Rationale
:

Uncoupling protein (UCP)2 is a mitochondrial inner membrane protein that is expressed in mammalian myocardium under normal conditions and upregulated in pathological states such as heart failure. UCP2 is thought to protect cardiomyocytes against oxidative stress by dissipating the mitochondrial proton gradient and mitochondrial membrane potential (ΔΨ
m
), thereby reducing mitochondrial reactive oxygen species generation. However, in apparent conflict with its uncoupling role, UCP2 has also been proposed to be essential for mitochondrial Ca
2+
uptake, which could have a protective action by stimulating mitochondrial ATP production.

Objective
:

The goal of this study was to better understand the role of myocardial UCP2 by examining the effects of UCP2 on bioenergetics, Ca
2+
homeostasis, and excitation-contraction coupling in neonatal cardiomyocytes.

Methods and Results
:

Adenoviral-mediated expression of UCP2 caused a mild depression of ΔΨ
m
and increased the basal rate of oxygen consumption but did not affect total cellular ATP levels. Mitochondrial Ca
2+
uptake was examined in permeabilized cells loaded with the mitochondria-selective Ca
2+
probe, rhod-2. UCP2 overexpression markedly inhibited mitochondrial Ca
2+
uptake. Pretreatment with the UCP2-specific inhibitor genipin largely reversed the effects UCP2 expression on mitochondrial Ca
2+
handling, bioenergetics, and oxygen utilization. Electrically evoked cytosolic Ca
2+
transients and spontaneous cytosolic Ca
2+
sparks were examined using fluo-based probes and confocal microscopy in line scan mode. UCP2 overexpression significantly prolonged the decay phase of [Ca
2+
]
c
transients in electrically paced cells, increased [Ca
2+
]
c
spark activity and increased the probability that Ca
2+
sparks propagated into Ca
2+
waves. This dysregulation results from a loss of the ability of mitochondria to suppress local Ca
2+
-induced Ca
2+
release activity of the sarcoplasmic reticulum.

Conclusion
:

Increases in UCP2 expression that lower ΔΨ
m
and contribute to protection against oxidative stress, also have deleterious effects on beat-to-beat [Ca
2+
]
c
handling and excitation-contraction coupling, which may contribute to the progression of heart disease.