bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers
Authors: Louis Mariam , Punjabi Naresh M.
Published: March 2009

Accumulating evidence suggests that obstructive sleep apnea is associated with alterations in glucose metabolism. Although the pathophysiology of metabolic dysfunction in obstructive sleep apnea is not well understood, studies of murine models indicate that intermittent hypoxemia has an important contribution. However, corroborating data on the metabolic effects of intermittent hypoxia on glucose metabolism in humans are not available. Thus the primary aim of this study was to characterize the acute effects of intermittent hypoxia on glucose metabolism. Thirteen healthy volunteers were subjected to 5 h of intermittent hypoxia or normoxia during wakefulness in a randomized order on two separate days. The intravenous glucose tolerance test (IVGTT) was used to assess insulin-dependent and insulin-independent measures of glucose disposal. The IVGTT data were analyzed using the minimal model to determine insulin sensitivity (SI) and glucose effectiveness (SG). Drops in oxyhemoglobin saturation were induced during wakefulness at an average rate of 24.3 events/h. Compared with the normoxia condition, intermittent hypoxia was associated with a decrease in SI [4.1 vs. 3.4 (mU/l)−1·min−1; P = 0.0179] and SG (1.9 vs. 1.3 min−1×10−2, P = 0.0065). Despite worsening insulin sensitivity with intermittent hypoxia, pancreatic insulin secretion was comparable between the two conditions. Heart rate variability analysis showed the intermittent hypoxia was associated with a shift in sympathovagal balance toward an increase in sympathetic nervous system activity. The average R-R interval on the electrocardiogram was 919.0 ms during the normoxia condition and 874.4 ms during the intermittent hypoxia condition ( P < 0.04). Serum cortisol levels after intermittent hypoxia and normoxia were similar. Hypoxic stress in obstructive sleep apnea may increase the predisposition for metabolic dysfunction by impairing insulin sensitivity, glucose effectiveness, and insulin secretion.
Griscelli Syndrome Type 2: Long-Term Follow-Up after Unrelated Donor Bone Marrow Transplantation
Authors: Rossi Alfredo , Borroni Riccardo G. , Carrozzo Anna Maria , de Felice Catia , Menichelli Adriana , Carlesimo Marta , Calvieri Stefano
Published: March 2009

Griscelli syndrome (GS) is a rare autosomal recessive disease characterized by silvery hair (‘partial albinism’). Three forms exist; GS type 2 (GS2), the most common one, is characterized by severe primary immunodeficiency with acute episodes of hemophagocytic lymphohistiocytosis (HLH) which may be fatal in the absence of hematopoietic stem cell transplantation. A 5-year-old boy with HLH was referred to us because of silvery-gray hair present since birth. Abnormal pigment clumps were observed in the medulla of hair shafts on light microscopy. Electron microscopy of a skin biopsy revealed melanosomes in melanocytes, but not in keratinocytes. Leukocytes were devoid of intracytoplasmic granules on blood smear. Neurological signs were absent. Genotyping revealed a homozygous haplotype for polymorphic markers linked to the RAB27A locus, but no RAB27A mutation. A diagnosis of GS2 was established. The patient received bone marrow transplantation (BMT) from an unrelated donor, and after 72 months he did not show relapse of HLH. The long, uneventful follow-up supports the use of BMT from an unrelated donor if transplantation from a relative is not possible.
Increased Plasma Brain-Derived Neurotropic Factor, Not Nerve Growth Factor-Beta, in Schizophrenia Patients with Better Response to Risperidone Treatment
Authors: Lee Bun-Hee , Kim Yong-Ku
Published: March 2009

Background: Some neurotropins, including brain-derived neurotropic factor (BDNF) or nerve growth factor-β (β-NGF), play important roles in neurodevelopment and neuroprotection. We examined the plasma levels of these 2 factors in schizophrenia patients at the time of admission and after 6 weeks of treatment with risperidone. Methods: Plasma BDNF and β-NGF levels were measured in 36 schizophrenia patients and 36 healthy controls. All the patients underwent 6 weeks of treatment with risperidone. The severity of schizophrenia and response to treatment were assessed with the positive and negative syndrome scale (PANSS). We compared plasma BDNF and β-NGF levels among much-improved (n = 13, 36.1%, ≥50% PANSS score reduction), minimal-improved (n = 15, 41.7%, ≥25% and <50% PANSS score reduction) and nonresponse patients (n = 8, 22.2%, <25% PANSS score reduction). Results: At baseline, plasma BDNF had no significant difference between schizophrenia patients and controls, but β-NGF levels were significantly lower in schizophrenia patients than controls (p = 0.037). Plasma BDNF and β-NGF in all schizophrenia patients had no significant changes between pre- and posttreatment. Baseline BDNF levels were significantly lower in nonresponse patients than others (p = 0.038). After treatment, much-improved patients had significantly higher plasma BDNF than nonresponse patients (p = 0.023). However, β-NGF levels had no significant differences between them. Conclusions: Our data suggest that higher plasma BDNF levels might be associated with better response to risperidone treatment, while plasma β-NGF levels might have no effect on the clinical response in schizophrenia patients.
Clinical Evaluation of Local Ocular Toxicity in Candidate Anti-Adenoviral Agents in vivo
Authors: Inoue Hirotoshi , Sonoda Koh-hei , Ishikawa Makoto , Kadonosono Kazuaki , Uchio Eiichi
Published: March 2009

Background: Adenovirus causes ophthalmological nosocomial infections. Although cidofovir may be used systemically for immunocompromised patients in disseminated adenoviral infections, no specific anti-adenoviral agent has been established for the treatment of adenoviral ocular infection. It has been reported that cidofovir may cause lacrimal duct obstruction when used locally. We have reported that zalcitabine and stavudine showed anti-adenoviral activity in vitro. We now evaluate the side effects of these agents in eyes and ocular adnexa in an animal model. Methods: Cidofovir, zalcitabine and stavudine 1% solutions and balanced salt solution were given as eye drops to healthy female Japanese albino rabbits 4 times a day for 14 days. Clinical scores in the conjunctiva and eyelid were recorded, and lacrimal irrigation was carried out. The diameter of the lacrimal canaliculus was scanned with an ultrasonograph. Histopathological analysis was carried out in the cidofovir group. Results: In the cidofovir group, significant narrowing of lacrimal canaliculus, redness of eyelids and conjunctival injection were observed, but no obstruction of the lacrimal duct was found. Histology showed eosinophils, suggesting an allergic inflammation. Although zalcitabine and stavudine induced eyelid redness and conjunctival injection, no change was observed in the lacrimal pathway. Conclusions: These drugs may be possible candidates as eye drops for adenoviral conjunctivitis but further study is required to prove its safety.
Tumor Cell Dissemination in a Human Colon Cancer Animal Model: Orthotopic Implantation or Intraportal Injection?
Authors: Thalheimer A. , Otto C. , Bueter M. , Illert B. , Gattenlohner S. , Gasser M. , Fein M. , Germer C.T. , Waaga-Gasser A.-M.
Published: March 2009

Background: The development of therapeutic strategies for treatment of metastasized colorectal carcinoma requires biologically relevant and adequate animal models generating both metastases and the dissemination of tumor cells. Methods: To prove the efficiency of orthotopic implantation concerning induction of minimal residual disease (MRD) colorectal cancer tissue from 10 patients was transplanted orthotopically into nude mice. In the intraportal injection model 1 × 106 HT-29 human colon cancer cells were injected. We investigated by histological studies and CK-20 RT-PCR the occurrence of hematogenous metastases and the dissemination of human colon cancer cells in bone marrow. Results: Following orthotopic implantation of human colon cancer tissue the lymph node and hepatic metastasis rates were low. MRD as reflected by CK-20 positivity of the bone marrow was present in 22.2%. The intraportal injection of 1 × 106 HT-29 human colon cancer cells produced hepatic metastases in up to 89% of all animals. The intraportal injection of 1 × 106 cells also generated MRD in the bone marrow in 63% of animals. Conclusions: The intraportal injection model represents a biologically relevant and adequate animal model for the induction of both reproducible hepatic metastasis and MRD in the bone marrow. In this regard it seems to be superior to the orthotopic implantation model.
The Effects of Dairy Components on Energy Partitioning and Metabolic Risk in Mice: A Microarray Study
Authors: Bruckbauer Antje , Gouffon Julia , Rekapalli Bhanu , Zemel Michael B.
Published: March 2009

Background/Aim: High-calcium diets modulate energy metabolism and suppress inflammatory stress. These effects are primarily mediated by calcium suppression of calcitriol. We have now investigated the effect of additional components in dairy products [branched-chain amino acids (BCAA) and angiotensin-converting enzyme inhibitors (ACEi)] on adipocyte and muscle metabolism in an animal model of diet-induced obesity. Methods: aP2-agouti mice were fed four different 70% restricted diets for 6 weeks: basal-restricted diet (0.4% Ca), nonfat dry milk (1.2% Ca), calcium-depleted milk (0.4% Ca), or basal-restricted diet (0.4% Ca) with supplemented BCAA/ACEi. A high-density oligonucleotide microarray approach was used to compare the effects on energy metabolism. Results: Lipogenic genes in adipose tissue were downregulated in the milk group while in muscle protein synthetic pathways were stimulated by the Ca-depleted and low Ca/BCAA/ACEi diets. Pathways involved in inflammation were altered in adipose tissue and muscle by all three diet treatment groups. Conclusions: The results support our previous findings that calcium and BCAA contribute to the alteration of energy partitioning between adipose tissue and muscle. They provide further evidence for a calcium-independent effect of BCAA and ACEi in energy metabolism and inflammation.
Disrupted Serotonergic and Sympathoadrenal Systems in Patients with Chronic Heart Failure May Serve as New Therapeutic Targets and Novel Biomarkers to Assess Severity, Progression and Response to Treatment
Authors: Nigmatullina Razina R. , Kirillova Venera V. , Jourjikiya Roen K. , Mukhamedyarov Marat A. , Kudrin Vladimir S. , Klodt Petr M. , Palotás András
Published: March 2009

Background: It is well established that the serotonergic system (SS) plays important roles in the pathogenesis of cardiovascular diseases. However, the impact of serotonin and its inter-relation with the sympathoadrenal system (SAS) in chronic heart failure (CHF) is poorly understood. Methods: Utilizing high-performance liquid chromatography with electrochemical detection, we determined blood plasma levels of serotonin (5-hydroxy-triptamine, [5-HT]p), 5- hydroxy-indole-acetic acid ([5-HIAA]p), epinephrine ([E]p), norepinephrine ([NE]p), 3,4-dihydroxy-L-phenyl-alanine ([DOPA]p), dopamine ([DA]p) and the platelet concentration of serotonin ([5-HT]pt) in CHF patients with different morphofunctional alterations of myocardium. The morphofunctional alterations included diastolic dysfunction (DD), diastolic dysfunction with left ventricular hypertrophy (DD&LVH), and diastolic and systolic dysfunction (D&SD). Results: All CHF groups showed significant rises of [5-HT]p and [5-HT]pt. DD&LVH and D&SD individuals also had increased [5-HIAA]p. Levels of SAS blood biomarkers were also significantly changed. The correlation between SS and SAS was increased in CHF and corresponded with disease severity. Conclusions: These results clearly demonstrate that in CHF patients significant changes in SS and SAS occur, which are thought to relate to the morphofunctional alterations of myocardium. The observed changes in the levels of these biomarkers may serve as potential surrogates to monitor severity of disease, to evaluate response to drug treatment, and as a rational basis for new therapeutic approaches.
Outcomes after Combined Laparoscopic Gastrectomy and Laparoscopic Cholecystectomy in Gastric Cancer Patients
Authors: Jeong I.H. , Choi S.U. , Lee S.R. , Kim J.H. , Park J.M. , Jin S.H. , Choi E.K. , Cho Y.K. , Han S.U.
Published: March 2009

Background/Aims: The purpose of this study was to determine the effect of performing laparoscopic cholecystectomy on patients undergoing laparoscopic-assisted gastrectomy for gastric cancer. Methods: This single center study involved a retrospective review of a database of 400 patients who underwent consecutive laparoscopic-assisted gastrectomy for early gastric cancer from June 2003 to July 2007. Outcomes in 26 patients who underwent both laparoscopic-assisted gastrectomy and laparoscopic cholecystectomy were compared with outcomes from 364 patients who underwent laparoscopic-assisted gastrectomy without laparoscopic cholecystectomy. Results: There were no postoperative 30-day mortalities in the combined cholecystectomy group. The mean surgery duration, time to first flatus and postoperative hospital stay for the laparoscopic gastric resection without combined operation were 181.7 min, 2.7 days and 9.7 days, respectively, and 196.7 min, 2.6 days and 8.8 days, respectively, for the combined cholecystectomy group. None of the postoperative complications was related to combined cholecystectomy. Conclusion: Performing a combined cholecystectomy prolonged the mean surgery duration by approximately 15 min, but had no effect on surgical outcomes. It appears that performing a cholecystectomy at the same time as laparoscopic gastric resection is safe and feasible in patients with both early gastric cancer and gallbladder disease.
Osteopontin and ‘Melanoma Inhibitory Activity’: Comparison of Two Serological Tumor Markers in Metastatic Uveal Melanoma Patients
Authors: Haritoglou Ingrid , Wolf Armin , Maier Tanja , Haritoglou Christos , Hein Rüdiger , Schaller Ulrich Christoph
Published: March 2009

Background: Evaluation of the protein osteopontin (OPN) as a potential new marker in comparison to melanoma inhibitory activity (MIA) for screening and detection of metastatic uveal melanoma. Methods: Plasma levels of 32 patients with uveal melanoma were analyzed for OPN and MIA by enzyme-linked immunosorbent assay (ELISA). Fourteen of these patients had clinically detectable liver metastases. Results: Median plasma concentration of OPN in patients with metastatic disease was 152.01 ng/ml compared to 47.39 ng/ml in patients without clinically detectable metastases (p < 0.001). The difference between the median MIA plasma levels in patients with (13.11 ng/ml) and patients without (5.64 ng/ml) metastatic disease was also statistically significant (p < 0.001). No correlation could be found between MIA or OPN levels and tumor height in patients without clinically detectable metastases. Conclusion: The proteins MIA and OPN seem to be promising tumor markers for the metastasis screening in patients with uveal melanoma.
Long-Term Outcome of Laparoscopic Cystogastrostomy Performed Using a Posterior Approach with a Stapling Device
Authors: Oida Takatsugu , Mimatsu Kenji , Kawasaki Atsushi , Kano Hisao , Kuboi Youichi , Aramaki Osamu , Amano Sadao
Published: March 2009

Background: Internal drainage of an acute pancreatic pseudocyst is indicated 6 weeks after its first detection. Laparoscopic treatment of pancreatic pseudocysts enables definitive drainage with faster recovery. Pseudocysts located adjacent to the posterior gastric wall are best drained by pseudocyst gastrostomy. Although the anterior approach for drainage has frequently been reported, reports on the posterior approach are rare. Methods: Seven patients underwent laparoscopic cystogastrostomy for pancreatic pseudocysts. The posterior approach that enables the direct visualization of the posterior gastric wall and pseudocyst was used, and the cyst was drained with a needle. After creating a sufficient drainage orifice, the cyst was thoroughly debrided. Cystogastrostomy was performed using the posterior approach with a stapling device. The insertion site of the stapling device closed using a hernia stapler. Results: Cystogastrostomy was performed using the posterior approach with a stapling device in all patients, without requiring conversion to the anterior approach or open surgery. There were neither operative complications nor late recurrences during the follow-up period (median 65 months). Conclusion: Laparoscopic cystogastrostomy using the posterior approach, which facilitates adequate internal drainage, is a safe and feasible procedure for pancreatic pseudocyst, and it is not accompanied with a risk of recurrence in the long term.
Right Hepatectomy for Hepatocellular Carcinoma in Patients with an Indocyanine Green Retention Rate at 15 Minutes of 10% or Higher
Authors: Ariizumi Shun-ichi , Yamamoto Masakazu , Takasaki Ken
Published: March 2009

Background/Aims: Liver failure after right hepatectomy for hepatocellular carcinoma (HCC) in patients with an indocyanine green retention rate at 15 min (ICGR15) of 10% or higher remains a controversial issue. Methods: Between 1995 and 2004, 98 patients with an ICGR15 of 10% or higher were scheduled to undergo right hepatectomy or tri-sectionectomy for HCC. The hepatic resection volume (HR) excluding the tumor was measured using computed tomography. The allowable HR (AHR) was determined in each patient with a logarithmic graph based on the ICGR15 and the %HR. Liver failure and mortality were evaluated between 54 patients with HR ≤ AHR (low-risk group) and 44 patients with HR > AHR (high-risk group). Results: The number of patients with liver failure was significantly lower in the low-risk group (2%) than in the high-risk group (23%, p = 0.0021). No mortality was observed in the low-risk group, while mortality was seen in the high-risk group (11%, p = 0.016). Multivariate analysis showed that the high-risk group was identified as a significant predictor of liver failure (p = 0.011). Conclusions: In patients with an ICGR15 of 10% or higher, determination of AHR is useful to predict liver failure prior to right hepatectomy or tri-sectionectomy.
Effect of Irsogladine Maleate on NSAID-Induced Reduction of Gastric Mucosal Blood Flow in Anesthetized Dogs
Authors: Sato Motonori , Manabe Noriaki , Hata Jiro , Ishii Manabu , Kamada Tomoari , Kusunoki Hiroaki , Shiotani Akiko , Haruma Ken
Published: March 2009

Background and Aim: Although mucoprotective agents are commonly used against gastric and duodenal lesions in Japan, their availability as agents for non-steroidal anti-inflammatory drug (NSAID)-induced gastrointestinal damage has not been clarified. To investigate the effect of irsogladine maleate (IM) on gastric mucosal blood flow (GMBF) reduction induced by diclofenac sodium, a NSAID commonly used in Japan, by laser Doppler flowmetry (LDF) and ultrasonography (US) in canine stomach. Methods: GMBF was measured by LDF and contrast-enhanced US in 15 beagles. US was performed employing real-time harmonic imaging under low acoustic power after intravenous contrast injection using Definity™ (60 mg/kg). 60 min after insertion of a diclofenac sodium suppository (1.0 mg/kg) into the rectum, LDF and contrast-enhanced US were repeated. The examination was done in a crossover, single-blinded fashion. Results: The mean extent of the change in GMBF in the IM group and in the placebo group was +29.3 and –38%, respectively. Conclusions: IM alleviates the reduction of GMBF induced by diclofenac sodium.
Developmental Influences on Medically Unexplained Symptoms
Authors: Buffington C.A. Tony
Published: March 2009

Background: Medically unexplained (or ‘functional’) symptoms (MUS) are physical symptoms that prompt the sufferer to seek healthcare but remain unexplained after an appropriate medical evaluation. Examples of MUS also occur in veterinary medicine. For example, domestic cats suffer a syndrome comparable to interstitial cystitis, a chronic pelvic pain syndrome of humans. Method: Review of current evidence suggests the hypothesis that developmental factors may play a role in some cases of MUS. Maternal perception of a threatening environment may be transmitted to the fetus when hormones cross the placenta and affect fetal physiology, effectively ‘programming’ the fetal stress response system and associated behaviors toward enhanced vigilance. After birth, intense stress responses in the individual may result in similar vulnerability, which may be unmasked by subsequent stressors. Results: Epigenetic modulation of gene expression (EMGEX) appears to play a central role in creation of this ‘survival phenotype’. The recent development of techniques to identify the presence of EMGEX provides new tools to investigate these questions, and drugs and other interventions that may reverse EMGEX are also under active investigation. Conclusion: Viewing MUS from the perspective of underlying developmental influences involving EMGEX that affect function of a variety of organs based on familial (genetic and environmental) predispositions rather than from the traditional viewpoint of isolated organ-originating diseases has at least two important implications: it provides a parsimonious explanation for findings heretofore difficult to reconcile, and it opens whole new areas of investigation into causes and treatments for this class of disorders.
The Effects of Dysthymic Disorder on Health-Related Quality of Life and Disability Days in Persons with Comorbid Medical Conditions in the General Population
Authors: Baune Bernhard T. , Caniato Riccardo N. , Arolt Volker , Berger Klaus
Published: March 2009

Background: We aimed to investigate in medical disorders the effects of comorbid dysthymic disorder as compared to major depressive disorder (MDD) on health-related quality of life (HR-QoL) and disability days in the general population. Methods: In a population-based study 4,181 individuals were assessed for the presence of dysthymic disorder and depression, utilizing the Composite International Diagnostic Interview. Each participant received a thorough medical examination to assess the presence of comorbid somatic conditions. HR-QoL was evaluated using the Medical Outcomes Survey Short-Form 36 (SF-36) and disability days were provided by self-report. Descriptive statistics, analysis of variance and multivariable logistic regression were used. Results: Comorbidity with illnesses from a maximum of 6 somatic disease groups was more prevalent in persons with dysthymic disorder (78.7%) than in those with MDD (70.4%). Persons with dysthymic disorder had a significantly lower mental health summary score in the SF-36 and more disability days than those with MDD. The physical health summary scores were not significantly different between participants with dysthymic disorder and MDD (after Bonferroni correction), suggesting that limitations in physical functioning due to comorbid medical conditions were similar in both affective disorder groups. Conclusions: These results show that affective disorders comorbid with medical, somatic illnesses have a major impact on HR-QoL and disability with more pronounced effects in dysthymic disorder than in MDD. Differences in the time course of both conditions might contribute to this finding. Our results support the need for an improved identification and treatment of affective disorders in patients with somatic illnesses.
Expectancy in Double-Blind Placebo-Controlled Trials: An Example from Alcohol Dependence
Authors: Colagiuri Ben , Morley Kirsten , Boakes Robert , Haber Paul
Published: March 2009

Background: Double-blind placebo-controlled trials are intended to control for the impact of expectancy on outcomes. Whether they always achieve this is, however, questionable. Methods: Reanalysis of a clinical trial of naltrexone and acamprosate for alcohol dependence investigated this issue further. In this trial, 169 alcohol-dependent patients received naltrexone, acamprosate or placebo for 12 weeks. In addition to being assessed on various indices of alcohol dependence, they were asked whether they believed they received active medication or placebo. Results: While there were no differences in outcomes between treatment groups, those who believed they had been taking active medication consumed fewer alcoholic drinks and reported less alcohol dependence and cravings. That is, irrespective of actual treatment, perceived medication allocation predicted health outcomes. Conclusions: These results highlight the differences between treatment administration in clinical trials and standard medical practice, a discrepancy that may sometimes decrease the validity of these types of trials.
Organ Cross Talk in the Critically Ill: The Heart and Kidney
Authors: Kociol Robb , Rogers Joseph , Shaw Andrew
Published: March 2009

Heart failure results in significant morbidity and mortality in the United States. Chronic heart failure is often complicated by renal insufficiency. Further, acute decompensated heart failure is often complicated by worsening renal function or the development of diuretic resistance. Heart failure complicated by renal dysfunction has a significantly worse prognosis. The pathophysiology underlying this so-called cardiorenal syndrome (CRS) is unclear. It likely involves a combination of maladaptive neurohormonal activation and renal homeostatic mechanisms. The treatment (including recombinant B-type natriuretic peptide, ultrafiltration, continuous furosemide infusions and vasopressin antagonists) has thus far been marginally successful at best. Further research into the mechanism and treatment of CRS is required.
Characteristics and Molecular Mechanism of Adhesion Proteins on Reused Hemodialysis Membranes
Authors: Xu Xiulin , Yang Yujing , Zhu Naishuo
Published: March 2009

In order to study the mechanism of protein adhesion on the Fresenius F6 polysulfone membrane dialyzer, two-dimensional gel electrophoresis, LC-ESI-MS/MS and bioinformatics methods were used to analyze the protein which adhered to the dialyzer membrane. Six of the adhered proteins account for more than 50% of the total 179 proteins, i.e. ficolin precursor, complement C3 precursor, 3 variants of MASP1 and albumin. The results also showed that easily adhered proteins have a greater percentage of acidic amino acids (p < 0.01). The isoelectric point of the 20 proteins with the most deposits is 6.2 ± 1.08, which is obviously lower than of those with the least deposits (7.56 ± 1.36, p < 0.01). The dipole moment of a polysulfone membrane molecule has a tendency to absorb molecules with a negative charge. These results are of significance in understanding and improving membrane protein interactions.
Assessment of Body Composition in Dialysis Patients by Arm Bioimpedance Compared to MRI and 40K Measurements
Authors: Carter M. , Zhu F. , Kotanko P. , Kuhlmann M. , Ramirez L. , Heymsfield S.B. , Handelman G. , Levin N.W.
Published: March 2009

This study used multi-frequency bioimpedance spectroscopy (BIS) of the arm and whole body to estimate muscle mass (MM) and subcutaneous adipose tissue (SAT) in 31 hemodialysis (HD) patients comparing these results with magnetic resonance imaging (MRI) and body potassium (40K) as gold standards. Total body and arm MM (MMMRI) and SAT (SATMRI) were measured by MRI. All measurements were made before dialysis treatment. Regression models with the arm (aBIS) and whole body (wBIS) resistances were established. Correlations between gold standards and the BIS model were high for the arm SAT (r2 = 0.93, standard error of estimate (SEE) = 3.6 kg), and whole body SAT (r2 = 0.92, SEE = 3.5 kg), and for arm MM (r2 = 0.84, SEE = 2.28 kg) and whole body MM (r2 = 0.86, SEE = 2.28 kg). Total body MM and SAT can be accurately predicted by arm BIS models with advantages of convenience and portability, and it should be useful to assess nutritional status in HD patients.
Nutritional Status in Relation to Balance and Falls in the Elderly
Authors: Shahar Danit , Levi Meital , Kurtz Ilan , Shany Shraga , Zvili Irene , Mualleme Ezra , Shahar Avner , Sarid Orly , Melzer Itzik
Published: March 2009

Background/Aim: In elderly persons, fall-related injury is a serious public health problem. We investigated the impact of essential nutritional elements on falls in the elderly. Methods: Clinical function, balance, gait and disability tests and health and nutritional status assessments were performed. All subjects were interviewed regarding the occurrence of falls in the last year. Blood tests for serum vitamin D, folate and B12 were conducted among a randomly selected subsample of 54 participants in the same month. Results: One hundred 65- to 91-year-old volunteers participated in the study, and 29 of them fell at least once during the past year. The depression score was higher (indicating more depressive symptoms) among fallers compared with non-fallers (4.0 ± 3.2 vs. 2.5 ± 2.3, respectively). The overall function score (indicating better function) was marginally higher in non-fallers. Subsequent comparisons between fallers and non-fallers were adjusted for overall function and depression scores. Serum folate was significantly lower in fallers (9.5 ± 7.1 vs. 16.2 ± 6.7 ng/ml, p = 0.02). Dietary intake was equal in both groups. Correlation analyses indicate a significant association between vitamin D and the functional measurements: timed get up and go (negative), Berg balance test, overall functional score, lower extremity score and limitation score (positive correlation coefficients). Serum folate was highly and negatively associated with the number of falls and with prescribed medications and was the only protective factor against falls in a multivariate analysis. Conclusions: Vitamin D was related to most functional and balance measurements. Serum folate was protective against falls. For every 1 ng/ml increase in serum folate the occurrence of falls decreased by 19%.
Fish Consumption, Allergic Sensitisation and Allergic Diseases in Adults
Authors: Schnappinger Markus , Sausenthaler Stefanie , Linseisen Jakob , Hauner Hans , Heinrich Joachim
Published: March 2009

Background: Previous studies have suggested that fish intake plays a protective role in the development of allergic diseases because of its high content of n-3 very long chain polyunsaturated fatty acid (VLC-PUFA). However, it is not clear whether fish intake also has a beneficial effect in adulthood, when allergic diseases are thought to be predominantly manifested. Methods: Data from 388 adults from German study centres within the European Community Respiratory Health Study II were analysed. These subjects completed an extensive interviewer-administered questionnaire as well as a food frequency questionnaire, lung function measurement and blood drawing for specific IgE testing at the study centre. Results: Allergic sensitisation (RAST ≥2) was negatively associated with high fish consumption (adjusted OR 0.20, 95% CI 0.05–0.83) and high docosahexaenoic acid (DHA) intake (adjusted OR 0.26, 95% CI 0.07–0.95) in females but not in males when comparing the fourth quartile with the first quartile of intake. No other outcome was related to fish or DHA consumption. Conclusions: The findings of this study suggest that adult females with a high fish and DHA intake have a lower rate of allergic sensitisation. It is not understood why this association was only seen in females, but gender-related differences in metabolism of PUFAs could be a possible explanation.
Acenocoumarol and Pregnancy Outcome in a Patient with Mitral Valve Prosthesis: A Case Report
Authors: Stefanidis Konstantinos , Papoutsis Dimitris , Daskalakis George , Loutradis Dimitris , Antsaklis Aris
Published: March 2009

Background: There is considerable controversy concerning the correct management of gravid patients with cardiac valve prostheses. Case Report: We describe the uneventful course of pregnancy and delivery in a pregnant patient with a mechanical heart valve receiving anticoagulation treatment. A 35-year-old primigravida received anticoagulation throughout pregnancy because of mitral valve replacement at the age of 16 due to rheumatic disease. The antithrombotic regimen used was acenocoumarol (coumarin derivative) 2 mg/day throughout the 2nd and 3rd trimesters of pregnancy with replacement of acenocoumarol by enoxaparin sodium 60 mg twice daily (low-molecular-weight heparin – LMWH) in the 1st trimester during weeks 7–12. International normalization ratio (INR) values were kept above 2.5. At 36 weeks of gestation, acenocoumarol was substituted with unfractionated heparin and 2 days later the patient entered spontaneous premature labor and was emergently delivered via cesarean section (INR = 1.4). A healthy male infant was born 2,560 g, Apgar scores 8 and 10 at 1 and 5 min. No coumarin embryopathy was revealed and the postoperative course of the mother was uneventful. Conclusion: Even though the use of acenocoumarol throughout pregnancy replaced by LMWH in the 1st trimester was proven safe and efficacious in this case report, large randomized controlled studies are still needed to make definitive recommendations about optimal antithrombotic therapy in pregnant patients with mechanical heart valves.
Development of Skeletal Muscle Sodium and Potassium Currents in Zebrafish sofa potato Mutants
Authors: Coutts Christopher A. , Cunningham Marcus E. , Ali Declan W.
Published: March 2009

In some cells, the development of voltage-gated channels requires synaptic input, while in others it does not. Here we investigate whether the sodium and potassium currents in the skeletal muscle of zebrafish sofa potato (sop–/–) mutants develop normally. Zebrafish sop–/– mutants do not express nicotinic acetylcholine receptors at neuromuscular junctions, and therefore do not exhibit synaptic activity in muscle. We find that in both red and white muscle fibers, sop–/– mutants are able to support normal potassium current development during early stages of development [1–3 days post fertilization (dpf)], but at 6 dpf the potassium current density is significantly smaller than that in their phenotypically wild-type siblings (sop+/?). In contrast, sodium current density is unaffected. The steady-state properties of potassium currents are unaltered in the sop–/– mutants, but there is a significant difference in the V50 of inactivation of sodium currents. This is the first study in zebrafish to investigate activity-dependent mechanisms of ion channel development and our results indicate that some aspects of ion current development in skeletal muscle require synaptic activity, whereas others do not.
Mitochondrial Telomerase Reverse Transcriptase Binds to and Protects Mitochondrial DNA and Function From Damage
Authors: Haendeler Judith , Dröse Stefan , Büchner Nicole , Jakob Sascha , Altschmied Joachim , Goy Christine , Spyridopoulos Ioakim , Zeiher Andreas M. , Brandt Ulrich , Dimmeler Stefanie
Published: March 2009

Objective—

The enzyme telomerase and its catalytic subunit the telomerase reverse transcriptase (TERT) are important for maintenance of telomere length in the nucleus. Recent studies provided evidence for a mitochondrial localization of TERT. Therefore, we investigated the exact localization of TERT within the mitochondria and its function.

Methods and Results—

Here, we demonstrate that TERT is localized in the matrix of the mitochondria. TERT binds to mitochondrial DNA at the coding regions for ND1 and ND2. Binding of TERT to mitochondrial DNA protects against ethidium bromide–induced damage. TERT increases overall respiratory chain activity, which is most pronounced at complex I and dependent on the reverse transcriptase activity of the enzyme. Moreover, mitochondrial reactive oxygen species are increased after genetic ablation of TERT by shRNA. Mitochondrially targeted TERT and not wild-type TERT revealed the most prominent protective effect on H
2
O
2
-induced apoptosis. Lung fibroblasts from 6-month-old TERT
−/−
mice (F2 generation) showed increased sensitivity toward UVB radiation and heart mitochondria exhibited significantly reduced respiratory chain activity already under basal conditions, demonstrating the protective function of TERT in vivo.

Conclusion—

Mitochondrial TERT exerts a novel protective function by binding to mitochondrial DNA, increasing respiratory chain activity and protecting against oxidative stress–induced damage.
Statin Cost-Effectiveness in the United States for People at Different Vascular Risk Levels
Authors:   Heart Protection Study Collaborative Group
Published: March 2009

Background—

Statins reduce the rates of heart attacks, strokes, and revascularization procedures (ie, major vascular events) in a wide range of circumstances. Randomized controlled trial data from 20 536 adults have been used to estimate the cost-effectiveness of prescribing statin therapy in the United States for people at different levels of vascular disease risk and to explore whether wider use of generic statins beyond the populations currently recommended for treatment in clinical guidelines is indicated.

Methods and Results—

Randomized controlled trial data, an internally validated vascular disease model, and US costs of statin therapy and other medical care were used to project lifetime risks of vascular events and evaluate the cost-effectiveness of 40 mg simvastatin daily. For an average of 5 years, allocation to simvastatin reduced the estimated US costs of hospitalizations for vascular events by ≈20% (95% CI, 15 to 24) in the different subcategories of participants studied. At a daily cost of $1 for 40 mg generic simvastatin, the estimated costs of preventing a vascular death within the 5-year study period ranged from a net saving of $1300 (95% CI, $15 600 saving to $13 200 cost) among participants with a 42% 5-year major vascular event risk to a net cost of $216 500 ($123 700 to $460 000 cost) among those with a 12% 5-year risk. The costs per life year gained with lifetime simvastatin treatment ranged from $2500 (−$40 to $3820) in people aged 40 to 49 years with a 42% 5-year major vascular event risk to $10 990 ($9430 to $14 700) in people aged 70 years and older with a 12% 5-year risk.

Conclusions—

Treatment with generic simvastatin appears to be cost-effective for a much wider population in the United States than that recommended by current guidelines.
TRAIL/Apo2L Mediates the Release of Procoagulant Endothelial Microparticles Induced by Thrombin In Vitro
Authors: Simoncini Stéphanie , Njock Makon-Sébastien , Robert Stéphane , Camoin-Jau Laurence , Sampol José , Harlé Jean-Robert , Nguyen Catherine , Dignat-George Françoise , Anfosso Francine
Published: March 2009

Microparticles are small vesicles playing a crucial role in cell communication by promoting prothrombotic and proinflammatory responses. However, the molecular mechanisms underlying their release are still elusive. We previously established that thrombin promoted the generation of endothelial microparticles (EMPs). In the present study, gene profiling identified
TRAIL/Apo2L
, a cytokine belonging to the tumor necrosis factor-α superfamily, as a target of thrombin. Thrombin increased the expression of cell-associated and soluble forms of TRAIL (sTRAIL) in HMEC-1 cells and human umbilical vein endothelial cells (HUVECs). Blocking TRAIL by specific antibodies or by small interfering RNA reduced both the number and the procoagulant activity of EMPs released by thrombin. Consistent with an involvement of sTRAIL in thrombin-induced EMP release, we showed that (1) exogenously added sTRAIL generated procoagulant EMPs; (2) supernatants from thrombin-stimulated endothelial cells induced EMP release by HMEC-1 cells and HUVECs, whereas those recovered from TRAIL knockdown endothelial cells displayed no effect. TRAIL/TRAIL-R2 complex mediated EMP release by initiating the recruitment of adaptor proteins and the activation of nuclear factor κB. Moreover, sTRAIL modulated intercellular adhesion molecule-1 and interleukin-8 expression induced by thrombin by a downstream pathway involving nuclear factor κB activation. Our data reveal a novel mechanism controlling EMP release and identify TRAIL as a key partner in the pathway linking coagulation and inflammation elicited by thrombin.
Cardiac-Specific Deletion of
Mkk4
Reveals Its Role in Pathological Hypertrophic Remodeling but Not in Physiological Cardiac Growth
Authors: Liu Wei , Zi Min , Jin Jiawei , Prehar Sukhpal , Oceandy Delvac , Kimura Tomomi E. , Lei Ming , Neyses Ludwig , Weston Arthur H. , Cartwright Elizabeth J. , Wang Xin
Published: March 2009

Mitogen-activated protein kinase kinase (MKK)4 is a critical member of the mitogen-activated protein kinase family. It is able to activate the c-Jun NH
2
-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase in response to environmental stresses. JNK and p38 are strongly implicated in pathological cardiac hypertrophy and heart failure; however, the regulatory mechanism whereby the upstream kinase MKK4 activates these signaling cascades in the heart is unknown. To elucidate the biological function of MKK4, we generated mice with a cardiac myocyte-specific deletion of
mkk4
(MKK4
cko
mice). In response to pressure overload or chronic β-adrenergic stimulation, upregulated NFAT (nuclear factor of activated T-cell) transcriptional activity associated with exacerbated cardiac hypertrophy and the appearance of apoptotic cardiomyocytes were observed in MKK4
cko
mice. However, when subjected to swimming exercise, MKK4
cko
mice displayed a similar level of physiological cardiac hypertrophy compared to controls (MKK4
f/f
). In addition, we also discovered that MKK4 expression was significantly reduced in heart failure patients. In conclusion, this study demonstrates for the first time that MKK4 is a key mediator which prevents the transition from an adaptive response to maladaptive cardiac hypertrophy likely involving the regulation of the NFAT signaling pathway.
Downregulation of MiR-199a Derepresses Hypoxia-Inducible Factor-1α and Sirtuin 1 and Recapitulates Hypoxia Preconditioning in Cardiac Myocytes
Authors: Rane Shweta , He Minzhen , Sayed Danish , Vashistha Himanshu , Malhotra Ashwani , Sadoshima Junichi , Vatner Dorothy E. , Vatner Stephen F. , Abdellatif Maha
Published: March 2009

MicroRNAs are posttranscriptional gene regulators that are differentially expressed during various diseases and have been implicated in the underlying pathogenesis. We report here that miR-199a is acutely downregulated in cardiac myocytes on a decline in oxygen tension. This reduction is required for the rapid upregulation of its target, hypoxia-inducible factor (Hif)-1α. Replenishing miR-199a during hypoxia inhibits Hif-1α expression and its stabilization of p53 and, thus, reduces apoptosis. On the other hand, knockdown of miR-199a during normoxia results in the upregulation of Hif-1α and Sirtuin (Sirt)1 and reproduces hypoxia preconditioning. Sirt1 is also a direct target of miR-199a and is responsible for downregulating prolyl hydroxylase 2, required for stabilization of Hif-1α. Thus, we conclude that miR-199a is a master regulator of a hypoxia-triggered pathway and can be exploited for preconditioning cells against hypoxic damage. In addition, the data demonstrate a functional link between 2 key molecules that regulate hypoxia preconditioning and longevity.
Pulse Pressure in Youth and Carotid Intima-Media Thickness in Adulthood
Authors: Raitakari Olli T. , Juonala Markus , Taittonen Leena , Jula Antti , Laitinen Tomi , Kähönen Mika , Viikari Jorma S.A.
Published: March 2009

Background and Purpose—

Large pulse pressure associates with atherosclerosis, but it is unclear if it contributes to the development of atherosclerosis or if atherosclerosis leads to pulse pressure widening. We examined whether exposure to large pulse pressure in childhood predicts carotid artery intima-media thickness in adulthood.

Methods—

Carotid intima-media thickness was measured in 2146 adults in the Cardiovascular Risk in Young Finns Study. These subjects have blood pressure data available dating back to their childhood (baseline in 1980, ages 3 to 18 years).

Results—

Baseline pulse pressure measured in adolescence was significantly related to carotid intima-media thickness measured in adulthood 21 years later (
r
=0.123,
P
<0.0001). The relation remained significant (
P
=0.0029) in models adjusted for age, sex, adolescent mean arterial pressure, adult systolic pressure, adult pulse pressure, body mass index, smoking, physical activity, and carotid artery diameter. Each 10 mm Hg increment in pulse pressure was associated with a 0.008-mm (95% CI, 0.003 to 0.013 mm) increase in carotid intima-media thickness.

Conclusions—

Exposure to wide pulse pressure in adolescence may induce changes that contribute to carotid artery intima-media thickening.
Hemoglobin Concentration and Cerebral Metabolism in Patients With Aneurysmal Subarachnoid Hemorrhage
Authors: Oddo Mauro , Milby Andrew , Chen Isaac , Frangos Suzanne , MacMurtrie Eileen , Maloney-Wilensky Eileen , Stiefel Michael , Kofke W. Andrew , Levine Joshua M. , Le Roux Peter D.
Published: March 2009

Background and Purpose—

The optimal hemoglobin (Hgb) target after aneurysmal subarachnoid hemorrhage is not precisely known. We sought to examine the threshold of Hgb concentration associated with an increased risk of cerebral metabolic dysfunction in patients with poor-grade subarachnoid hemorrhage.

Methods—

Twenty consecutive patients with poor-grade subarachnoid hemorrhage who underwent multimodality neuromonitoring (intracranial pressure, brain tissue oxygen tension, cerebral microdialysis) were studied prospectively. Brain tissue oxygen tension and extracellular lactate/pyruvate ratio were used as markers of cerebral metabolic dysfunction and the relationship between Hgb concentrations and the incidence of brain hypoxia (defined by a brain tissue oxygen tension <20 mm Hg) and cell energy dysfunction (defined by a lactate/pyruvate ratio >40) was analyzed.

Results—

Compared with higher Hgb concentrations, a Hgb concentration <9 g/dL was associated with lower brain tissue oxygen tension (27.2 [interquartile range, 21.2 to 33.1] versus 19.9 [interquartile range, 7.1 to 33.1] mm Hg,
P
=0.02), higher lactate/pyruvate ratio (29 [interquartile range, 25 to 38] versus 36 [interquartile range, 26 to 59],
P
=0.16), and an increased incidence of brain hypoxia (21% versus 52%,
P
<0.01) and cell energy dysfunction (23% versus 43%,
P
=0.03). On multivariable analysis, a Hgb concentration <9 g/dL was associated with a higher risk of brain hypoxia (OR, 7.92; 95% CI, 2.32 to 27.09;
P
<0.01) and cell energy dysfunction (OR, 4.24; 95% CI, 1.33 to 13.55;
P
=0.02) after adjusting for cerebral perfusion pressure, central venous pressure, PaO
2
/FIO
2
ratio, and symptomatic vasospasm.

Conclusions—

A Hgb concentration <9 g/dL is associated with an increased incidence of brain hypoxia and cell energy dysfunction in patients with poor-grade subarachnoid hemorrhage.