Natural course of Fabry disease and the effectiveness of enzyme replacement therapy: a systematic review and meta-analysis

Objective

Current available evidence on long-term effectiveness of enzyme replacement therapy (ERT) for Fabry disease is limited. More insight is needed whether ERT effectiveness differs in patients with and without baseline end-organ damage.

Design

Through a systematic review, untreated and ERT treated males and females with Fabry disease were compared for main clinical outcomes: renal function, left ventricular mass (LVmass), cerebral white matter lesions (WMLs) and end-organ complications. Through a meta-analysis ERT effectiveness was estimated in different disease stages.

Data extraction

Two reviewers assessed quality of the included studies according to guidelines for prognosis research. Data were synthesized using a random effects meta-analysis.

Results

Thirty-one studies were systematically reviewed while six studies were included in the meta-analysis. In patients with a GFR?>?60 ml/min/1.73 m², decline of renal function was similar for treated and untreated patients. Only ERT treated males with a GFR?<?60 ml/min/1.73 m² had a slower rate of decline in renal function, possibly attributable to anti-proteinuric therapy. Regardless of left ventricular hypertrophy (LVH) at baseline, LVmass remained stable or increased in males despite ERT, however at a slower rate compared to untreated male patients. In ERT treated females with LVH LVmass decreased, and remained stable in females without LVH. WMLs can not be prevented by ERT. Stroke, cardiac and end-stage renal complications develop, though the incidence of new complications seems to be reduced during ERT.

Conclusion

ERT is effective in reducing LVH, but has a limited effect on renal function. Improved treatment options are needed for Fabry disease.     

Cardioprotection by Farnesol: Role of the Mevalonate Pathway

Purpose

Farnesol is a key metabolite of the mevalonate pathway and known as an antioxidant. We examined whether farnesol treatment protects the ischemic heart.

Methods

Male Wistar rats were treated orally with 0.2, 1, 5, and 50 mg/kg/day farnesol/vehicle for 12 days, respectively. On day 13, the effect of farnesol treatment on cardiac ischemic tolerance and biochemical changes was tested. Therefore, hearts were isolated and subjected either to 30 min coronary occlusion followed by 120 min reperfusion to measure infarct size or to 10 min aerobic perfusion to measure cardiac mevalonate pathway end-products (protein prenylation, cholesterol, coenzyme Q9, coenzyme Q10, dolichol), and 3-nitrotyrosine (oxidative/nitrosative stress marker), respectively. The cytoprotective effect of farnesol was also tested in cardiomyocytes subjected to simulated ischemia/reperfusion.

Results

Farnesol pretreatment decreased infarct size in a U-shaped dose–response manner where 1 mg/kg/day dose reached a statistically significant reduction (22.3?±?3.9 % vs. 40.9?±?6.1 % of the area at risk, p?<?0.05). Farnesol showed a similar cytoprotection in cardiomyocytes. The cardioprotective dose of farnesol (1 mg/kg/day) significantly increased the marker of protein geranylgeranylation, but did not influence protein farnesylation, cardiac tissue cholesterol, coenzyme Q9, coenzyme Q10, and dolichol. While the cardioprotective dose of farnesol did not influence 3-nitrotyrosine, the highest dose of farnesol (50 mg/kg/day) tested did not show cardioprotection, however, it significantly decreased cardiac 3-nitrotyrosine.

Conclusions

This is the first demonstration that oral farnesol treatment reduces infarct size. The cardioprotective effect of farnesol likely involves increased protein geranylgeranylation and seems to be independent of the antioxidant effect of farnesol.     

Azilsartan Decreases Renal and Cardiovascular Injury in the Spontaneously Hypertensive Obese Rat

Purpose

Angiotensin II type 1 receptor blockers (ARBs) are widely used in treating hypertension. In the present study, we tested the hypothesis that a novel ARB, azilsartan medoxomil (AZL-M) will prevent renal and cardiovascular injury in the spontaneously hypertensive obese rat (SHROB), a model of cardiometabolic syndrome.

Methods

Male SHROB were treated with vehicle or AZL-M orally for 56 days. Vehicle treated normotensive Wistar-Kyoto (WKY) rats served as controls. The effects of AZL-M on kidney injury, vascular endothelial and heart functions, lipid profile, and glucose tolerance were assessed.

Results

AZL-M demonstrated anti-hypertensive effects along with markedly improved vascular endothelial function in SHROB. In these rats, AZL-M demonstrates strong kidney protective effects with lower albuminuria and nephrinuria along with reduced tubular cast formation and glomerular injury. AZL-M treatment also improved left ventricular heart function, attenuated development of left ventricular hypertrophy, and reduced cardiac fibrosis in SHROB.

Conclusion

Overall, these findings demonstrate kidney and heart protective effects of AZL-M in SHROB, and these effects were associated with its ability to lower blood pressure and improve endothelial function.     

Preclinical Efficacy of Melatonin to Reduce Methotrexate-Induced Oxidative Stress and Small Intestinal Damage in Rats

Background

Methotrexate is widely used as a chemotherapeutic agent for leukemia and other malignancies. The efficacy of this drug is often limited by mucositis and intestinal injury, which are the major causes of morbidity in children and adults.

Aim

The present study investigates whether melatonin, a powerful antioxidant, could have a protective effect.

Method

Rats were pretreated with melatonin (20 and 40 mg/kg body weight) daily 1 h before methotrexate (7 mg/kg body weight) administration for three consecutive days. After the final dose of methotrexate, the rats were sacrificed and the small intestine was used for light microscopy and biochemical assays. Intestinal homogenates were used for assay of oxidative stress parameters malondialdehyde and protein carbonyl content, and myeloperoxidase activity, a marker of neutrophil infiltration as well as for the activities of the antioxidant enzymes.

Result

Pretreatment with melatonin had a dose-dependent protective effect on methotrexate (MTX)-induced alterations in small intestinal morphology. Morphology was saved to some extent with 20 mg melatonin pretreatment and near normal morphology was achieved with 40 mg melatonin pretreatment. Biochemically, pretreatment with melatonin significantly attenuated MTX-induced oxidative stress (P < 0.01 for MDA, P < 0.001 for protein carbonyl content) and restored the activities of the antioxidant enzymes (glutathione reductase P < 0.05, superoxide dismutase P < 0.01).

Conclusion

The results of the present study demonstrate that supplementation by exogenous melatonin significantly reduces MTX-induced small intestinal damage, indicating that it may be beneficial in ameliorating MTX-induced enteritis in humans.     

Probucol Ameliorates the Development of Nonalcoholic Steatohepatitis in Rats Fed High-Fat Diets

Aims

We sought to evaluate the effects of probucol on steatohepatitis and associated molecular mechanisms in a rat model of nonalcoholic steatohepatitis (NASH) induced by high-fat diet (HFD).

Methods

Forty male rats weighing 100–120 g were randomly assigned to the following treatments (n = 10 for each treatment): standard diet + normal saline (NC group), standard diet + 500 mg/kg/day probucol (NP group), HFD + normal saline (HD group), and HFD + 500 mg/kg/day probucol (HP group). All animals received the above treatments for 15 weeks. Lipid metabolism and steatohepatitis were assessed. Systemic insulin resistance, oxidative stress status, serum tumor necrosis factor-alpha (TNF-α) and adiponectin levels, and gene expression were examined.

Results

High-fat feeding resulted in macrovesicular steatosis, lobular inflammation, and hepatocellular ballooning degeneration in the liver, coupled with increased concentrations of serum aspartate aminotransferase and alanine aminotransferase. Probucol exposure attenuated the biochemical and histological changes comparable with NASH. Moreover, probucol treatment significantly prevented the elevations of serum total cholesterol, low-density lipoprotein, and high-density lipoprotein and the increase in the expression of numerous lipid metabolism-related genes in HFD-fed rats. There were increased insulin sensitivity and serum adiponectin levels and enhanced hepatic AMP-activated protein kinase phosphorylation in the HP group. Probucol lessened the HFD-induced elevation of serum TNF-α and hepatic malondialdehyde and reduced antioxidant enzymatic activities.

Conclusions

Probucol shows beneficial effects on HFD-induced steatohepatitis by improving insulin resistance and attenuating oxidative stress and systemic inflammation.     

Is l-Glutathione More Effective Than l-Glutamine in Preventing Enteric Diabetic Neuropathy?

Background

Diabetes and its complications appear to be multifactorial. Substances with antioxidant potential have been used to protect enteric neurons in experimental diabetes.

Aim

This study evaluated the effects of supplementation with l-glutamine and l-glutathione on enteric neurons in the jejunum in diabetic rats.

Methods

Rats at 90 days of age were distributed into six groups: normoglycemic, normoglycemic supplemented with 2 % l-glutamine, normoglycemic supplemented with 1 % l-glutathione, diabetic (D), diabetic supplemented with 2 % l-glutamine (DG), and diabetic supplemented with 1 % l-glutathione (DGT). After 120 days, the jejunums were immunohistochemically stained for HuC/D+ neuronal nitric oxide synthase (nNOS) and vasoactive intestinal polypeptide (VIP). Western blot was performed to evaluate nNOS and VIP. Submucosal and myenteric neurons were quantitatively and morphometrically analyzed.

Results

Diabetic neuropathy was observed in myenteric HuC/D, nNOS, and VIP neurons (p < 0.05). In the submucosal plexus, diabetes did not change nitrergic innervation but increased VIPergic neuronal density and body size (p < 0.05). Supplementation with l-glutathione prevented changes in HuC/D neurons in the enteric plexus (p < 0.05), showing that supplementation with l-glutathione was more effective than with l-glutamine. Myenteric nNOS neurons in the DGT group exhibited a reduced density (34.5 %) and reduced area (p < 0.05). Submucosal neurons did not exhibit changes. The increase in VIP-expressing neurons was prevented in the submucosal plexus in the DG and DGT groups (p < 0.05).

Conclusion

Supplementation with l-glutathione exerted a better neuroprotective effect than l-glutamine and may prevent the development of enteric diabetic neuropathy.     

N-terminal pro-brain natriuretic peptide and risk of cardiovascular events in older patients with type 2 diabetes: the Edinburgh Type 2 Diabetes Study

Aims/hypothesis

The aim of this study was to investigate the association of N-terminal pro-brain natriuretic peptide (NT-proBNP) with traditional cardiovascular risk factors and incident cardiovascular events in older people with type 2 diabetes.

Methods

In the prospective phase of the Edinburgh Type 2 Diabetes Study, 1066 men and women aged 60 to 75 years with type 2 diabetes mellitus were followed for 4 years; 112 participants had an incident cardiovascular event. At baseline, cardiovascular risk factors, pre-existing cardiovascular disease and levels of NT-proBNP were evaluated.

Results

Raised plasma NT-proBNP levels were associated with these classical cardiovascular risk factors: increased duration of diabetes, use of insulin, raised BMI, reduced HDL-cholesterol, reduced renal function and use of lipid-lowering and anti-hypertensive medication (all p?Conclusions/interpretation In older people with type 2 diabetes, NT-proBNP is associated with the development of coronary and cerebrovascular events, independent of a wide range of other vascular and metabolic risk factors, and may prove a useful addition to current vascular risk scores in diabetes populations.     

Frequency and Severity of Cirrhotic Cardiomyopathy and Its Possible Relationship with Bacterial Endotoxemia

Background

The cardiac dysfunction presented in cirrhotic patients is already known as cirrhotic cardiomyopathy. The pathogenesis of this entity is not fully understood.

Aims

The aim of this study was to evaluate the frequency and characteristics of cirrhotic cardiomyopathy and to investigate the possible role of bacterial endotoxemia on its aggravation.

Methods

Forty-five cirrhotics were studied by a tissue Doppler imaging echocardiography at rest and after stress. The diagnosis of left ventricular diastolic dysfunction was based on the latest guidelines of the American Society of Echocardiography, whereas its severity was defined by the E/e’av ratio. Endotoxemia was estimated by measuring the serum levels of lipopolysaccharide-binding protein (LBP) and cytokines.

Results

None of the patients had systolic dysfunction, but 17/45 (37.8 %) had a diastolic one. Patients with grade II diastolic dysfunction had significantly longer QTc (p = 0.049), larger left atrium volume (p = 0.013), higher Brain Natriuretic Peptide levels (p = 0.007) and higher LBP levels (p = 0.02), compared to those with normal cardiac function, without differences in the systemic hemodynamics and the cytokines’ levels. Moreover, the severity of diastolic dysfunction as reflected by the E/e’av. was significantly correlated with the LBP levels (p = 0.002). On the multivariate analysis, the LBP was independently associated with the presence of diastolic dysfunction.

Conclusions

Cirrhosis is commonly complicated by cardiac dysfunction. Patients with severe cirrhotic cardiomyopathy have higher LBP levels, which are significantly correlated with the degree of diastolic dysfunction. Our findings support a potential role of bacterial endotoxemia on the aggravation of cardiomyopathy in cirrhotic patients.     

Reducing Excess Cardiac Biomarker Testing at an Academic Medical Center

BACKGROUND

Elimination of wasteful diagnostic testing will improve value for the United States health care system.

OBJECTIVE

Design and implement a multimodal intervention to improve evidence-based ordering of cardiac biomarkers for the diagnosis of acute coronary syndrome (ACS).

DESIGN

Interrupted times series.

SUBJECTS

A total of 60,494 adult inpatient admissions from January 2009 through July 2011 (pre-intervention) and 24,341 admissions from November 2011 through October 2012 (post-intervention) at an academic medical center in Baltimore, Maryland.

INTERVENTION

Multimodal intervention introduced August through October 2011 that included dissemination of an institutional guideline and changes to the computerized provider order entry system.

MAIN MEASURES

The primary outcome was percentage of patients with guideline-concordant ordering of cardiac biomarkers, defined as three or fewer troponin tests and zero CK-MB tests in patients without a diagnosis of ACS. Secondary outcomes included counts of tests ordered per patient, incidence of diagnosis of ACS, and estimated change in charges for cardiac biomarker tests in the post-intervention period.

KEY RESULTS

Twelve months following the intervention, we estimated that guideline-concordant ordering of cardiac biomarkers increased from 57.1 % to 95.5 %, an absolute increase of 38.4 % (95 % CI, 36.4 % to 40.4 %). We estimated that the intervention led to a 66 % reduction in the number of tests ordered, and a $1.25 million decrease in charges over the first year. At 12 months, there was an estimated absolute increase in incidence of primary diagnosis of ACS of 0.3 % (95 % CI, 0.0 % to 0.5 %) compared with the expected baseline rate.

CONCLUSIONS

We implemented a multimodal intervention that significantly increased guideline-concordant ordering of cardiac biomarker testing, leading to substantial reductions in tests ordered without impacting diagnostic yield. A trial of this approach at other institutions and for other diagnostic tests is warranted and if successful, would represent a framework for eliminating wasteful diagnostic testing.     

Impact of coronary artery disease on in-hospital mortality in patients with aortic valve disease

Objective

Although aortic valve disease (AVD) is frequently associated with coronary artery disease (CAD), little is known about the impact of significant coronary artery disease on mortality after diagnostic cardiac catheterization in patients with AVD.

Methods

We analyzed data of the coronary angiography registry of the “Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte” (ALKK) in Germany. The primary endpoint was in-hospital mortality.

Results

A total of 1427 consecutive patients with AVD (438 patients with CAD versus 989 patients without CAD) underwent diagnostic catheterization in 2006 in 42 hospitals. All cause in-hospital mortality was more than threefold higher in patients with CAD (16/438; 3.7%) as compared to patients without CAD (12/989; 1.2%; p?<?0.01; OR 3.09, 95% CI 1.45–6.58). Even after adjustment for age, sex, presence of diabetes mellitus and renal insufficiency, in-hospital all cause mortality remained statistically significant different between the two groups (OR 2.4; 95% CI 1.09–5.28; p?<?0.01). Several factors, such as transient ischemic attack/stroke, volume of contrast agent, and left heart catheter-associated complications could not be identified as possible causes for the increase in mortality.

Conclusion

This analysis in patients with the leading diagnosis of AVD shows a significantly higher in-hospital mortality after diagnostic cardiac catheterization in case of an accompanying CAD. However, further studies are necessary to identify the driving force for the increase in mortality.     

Mortality and morbidity in relation to changes in albuminuria,glucose status and systolic blood pressure: an analysis of the ONTARGET and TRANSCEND studies

Aims/hypothesis

Urinary albumin excretion is a strong predictor of cardiovascular disease. It is uncertain whether improvement from microalbuminuria or deterioration from normoalbuminuria over time in patients with differing changes in glucose and BP change their cardiovascular risk.

Methods

Data on mortality, cardiovascular and renal outcomes were analysed in 22,984 patients from two large parallel randomised clinical trials followed for 56 months. A central laboratory analysed first morning spot urine samples at baseline and after 24 months, and events were recorded over the subsequent 32 months. Patients were stratified by changes in albuminuria, glucose status and mean systolic BP over 2 years.

Results

There was a strong association between albuminuria status and all-cause and cardiovascular mortality and combined cardiovascular and renal endpoints (all p?p?=?0.0004).

Conclusions/interpretation

Patients who showed improvement to normoalbuminuria over 2 years were at lower risk of all-cause and cardiovascular mortality and of cardiovascular and renal events than those who deteriorated to microalbuminuria over time. Albuminuria over time was significantly better than glucose status and BP control in predicting mortality and both cardiovascular and renal outcomes in patients at a high cardiovascular risk.     

Clinical Effectiveness of Tolvaptan in Patients with Acute Decompensated Heart Failure and Renal Failure: Design and Rationale of the AQUAMARINE Study

Purpose

Over half of all admitted acute decompensated heart failure (ADHF) patients have renal failure. Although diuretics represent the mainstay of treatment strategy even in this population, there are unmet needs for safer and more effective treatment. Tolvaptan is a vasopressin-2 receptor antagonist, and we hypothesized that adding tolvaptan to standard diuretic therapy would be more effective in ADHF patients with renal function impairment.

Methods

The Answering question on tolvaptan’s efficacy for patients with acute decompensated heart failure and renal failure (AQUAMARINE) is a multicenter, randomized controlled clinical trial, which will enroll 220 patients from 17 hospitals in Japan. ADHF patients whose estimated glomerular filtration rate is above 15 and below 60 mL/min/1.72 m² will be randomly assigned within 6 h after admission to usual care with furosemide or tolvaptan add-on therapy. Primary endpoint is achieved urine output within 48 h. Secondary endpoints include dyspnea relief measured by 7-points Likert scale, incidence of worsening renal function, dose of furosemide used within 48 h, and changes of brain natriuretic peptide.

Conclusion

This study is the first multicenter study in Japan to evaluate clinical effectiveness of tolvaptan add-on therapy in ADHF patients with renal failure. The results of this study address the treatment strategy of this high-risk population (UMIN Clinical Trial Registry Number: UMIN000007109).     

Cytokine Combination Therapy with Erythropoietin and Granulocyte Colony Stimulating Factor in a Porcine Model of Acute Myocardial Infarction

Purpose

Erythropoietin (EPO) and granulocyte colony stimulating factor (GCSF) have generated interest as novel therapies after myocardial infarction (MI), but the effect of combination therapy has not been studied in the large animal model. We investigated the impact of prolonged combination therapy with EPO and GCSF on cardiac function, infarct size, and vascular density after MI in a porcine model.

Methods

MI was induced in pigs by a 90 min balloon occlusion of the left anterior descending coronary artery. 16 animals were treated with EPO+GCSF, or saline (control group). Cardiac function was assessed by echocardiography and pressure-volume measurements at baseline, 1 and 6 weeks post-MI. Histopathology was performed 6 weeks post-MI.

Results

At week 6, EPO+GCSF therapy stabilized left ventricular ejection fraction, (41?±?1% vs. 33?±?1%, p?<?0.01) and improved diastolic function compared to the control group. Histopathology revealed increased areas of viable myocardium and vascular density in the EPO+GCSF therapy, compared to the control. Despite these encouraging results, in a historical analysis comparing combination therapy with monotherapy with EPO or GCSF, there were no significant additive benefits in the LVEF and volumes overtime using the combination therapy.

Conclusion

Our findings indicate that EPO+GCSF combination therapy promotes stabilization of cardiac function after acute MI. However, combination therapy does not seem to be superior to monotherapy with either EPO or GCSF.     

Dose-dependent response of tumor vasculature to radiation therapy in combination with Sunitinib depicted by three-dimensional high-frequency power Doppler ultrasound

Purpose

Large doses of radiation (8–20 Gy) preferentially target tumor vasculature. This vascular response is suggested to regulate tumor response to radiotherapy. Here, we investigate the relative contributions of direct cell killing by radiation versus tumor cell death due to radiation effects on the vasculature. We also examine Sunitinib’s mechanism of action as a tumor radiosensitizer.

Experimental Design

MDA-MB-231 xenografts were treated with radiation doses of 2–16 Gy alone, or in combination with bFGF (endothelial radio-protector) or Sunitinib as pharmacological modulators of the vasculature. Sunitinib was orally administered for 2 weeks at 30 mg/kg before radiotherapy; bFGF was intravenously injected 1 h prior to irradiation. Three-dimensional high-frequency power Doppler ultrasound was used to assess relative changes in tumor vasculature. Immunohistochemistry, clonogenic and tumor growth assays were used to quantify tumor response.

Results

Significant reductions in power Doppler signal of up to 50 % were observed for 8 and 16 Gy treatments, along with a dose-dependent increase in cell death. No significant change in power Doppler signal and minimal tumor cell death were noted for tumors treated with radiation and bFGF. Treatments where Sunitinib was combined with radiation demonstrated a significant increase in flow signal at doses equal or greater than 8 Gy. This was accompanied with a significant increase in cell death when compared to radiation or Sunitinib alone.

Conclusion

We confirm that tumor response to high doses of radiation is regulated by its vasculature. We also posit that the response observed when radiation is combined with Sunitinib is linked to a vascular “normalization” effect.     

Heparan sulfate derived disaccharides in plasma and total urinary excretion of glycosaminoglycans correlate with disease severity in Sanfilippo disease

Background

Sanfilippo disease (Mucopolysaccharidosis III) is a neurodegenerative lysosomal disorder characterized by accumulation of the glycosaminoglycan heparan sulfate (HS). MPS III has a large phenotypic variability and early assessment of disease severity is difficult. We investigated the correlation between disease severity and the plasma concentration of HS (pHS, defined by the sum of the heparan sulfate derived disaccharides obtained after enzymatic digestion) and urinary total GAGs level (uGAGs, measured by the dimethylene blue test) in a cross-sectional cohort of 44 MPS III patients.

Methods

Disease severity was established on the basis of the age of complete loss of independent walking and of full loss of speech in all patients. Hazard ratios (HR) were obtained with cox-regression analysis. In order to allow prediction of a severe phenotype based on a cut-off value for pHS, patients were divided in two groups (severely affected and less severely affected) based on predictive mutations or on the age of full loss of speech. Receiver operator characteristics (ROC) were obtained for pHS.

Results

pHS and uGAGs were independently and linearly associated with an increased risk of speech loss with a HR of 1.8 (95 % CI 1.3–2.7) per 500 ng/ml increase of HS in plasma (p?=?0.002), and a HR of 2.7 (95 % CI 1.6–4.4) per 10 mg/mmol creatinine increase of uGAGs (p?<?0.001). pHS and uGAGS were less strongly associated with loss of walking. The area under the ROC curve for pHS was 0.85, indicating good discrimination.

Conclusion

pHS and uGAGs may be useful biomarkers for prediction of severity in MPS III.     

Risk Factors for Nosocomial Gastrointestinal Bleeding and Use of Acid-Suppressive Medication in Non-Critically Ill Patients

BACKGROUND

It is unknown whether there exist certain subsets of patients outside of the intensive care unit in whom the risk of nosocomial gastrointestinal bleeding is high enough that prophylactic use of acid-suppressive medication may be warranted.

OBJECTIVE

To identify risk factors for nosocomial gastrointestinal bleeding in a cohort of non-critically ill hospitalized patients, develop a risk scoring system, and use this system to identify patients most likely to benefit from acid suppression.

DESIGN

Cohort study.

PATIENTS

Adult patients admitted to an academic medical center from 2004 through 2007. Admissions with a principal diagnosis of gastrointestinal bleeding or a principal procedure code for cardiac catheterization were excluded.

MAIN MEASURES

Medication, laboratory, and other clinical data were obtained through electronic data repositories maintained at the medical center. The main outcome measure—nosocomial gastrointestinal bleeding occurring outside of the intensive care unit—was ascertained via ICD-9-CM coding and confirmed by chart review.

KEY RESULTS

Of 75,723 admissions (median age = 56 years; 40 % men), nosocomial gastrointestinal bleeding occurred in 203 (0.27 %). Independent risk factors for bleeding included age > 60 years, male sex, liver disease, acute renal failure, sepsis, being on a medicine service, prophylactic anticoagulants, and coagulopathy. Risk of bleeding increased as clinical risk score derived from these factors increased. Acid-suppressive medication was utilized in > 50 % of patients in each risk stratum. Our risk scoring system identified a high risk group in whom the number-needed-to-treat with acid-suppressive medication to prevent one bleeding event was < 100.

CONCLUSIONS

In this large cohort of non-critically ill hospitalized patients, we identified several independent risk factors for nosocomial gastrointestinal bleeding. With further validation at other medical centers, the risk model derived from these factors may help clinicians to direct acid-suppressive medication to those most likely to benefit..     

Effects of Tolvaptan on Systemic and Renal Hemodynamic Function in Dogs with Congestive Heart Failure

Purpose

We investigated the effects of tolvaptan, a vasopressin V₂-receptor antagonist, on diuretic response and systemic and renal hemodynamic characteristics in conscious dogs with congestive heart failure (CHF). We also compared these effects with those of furosemide, a loop diuretic.

Methods

CHF was induced by rapid right-ventricular pacing at 260 beats/min for at least 3 weeks, and maintained with a pacing rate of 220–240 beats/min. CHF dogs were orally given tolvaptan (10 mg/kg), furosemide (10 mg/kg) and vehicle in random order during the stable CHF state. Urine excretion, systemic and renal hemodynamic parameters, and plasma hormone levels were measured over 6-hour periods after drug administration.

Results

Tolvaptan induced aquaresis with an increase in free water clearance, resulting in a significant increase in serum sodium concentrations and a decrease in cumulative water balance. Tolvaptan also decreased pulmonary capillary wedge pressure without affecting systemic vascular resistance, glomerular filtration rate or renal blood flow. Tolvaptan tended to increase plasma arginine vasopressin concentrations but did not affect plasma renin activity. In contrast, furosemide induced clear saluresis with increased electrolyte excretion, resulting in decreased pulmonary capillary wedge pressure. However, furosemide also decreased serum potassium concentration and increased plasma arginine vasopressin concentrations and plasma renin activity.

Conclusion

Tolvaptan elicited a potent aquaretic response and reduced the cardiac preload without unfavorable effects on systemic or renal hemodynamics, the renin–angiotensin–aldosterone system, or the sympathetic nervous system in CHF dogs. Thus, tolvaptan may offer a novel approach to remove excess water congestion from patients with CHF.

     

Protective Effect of Grape Seed and Skin Extract Against High-Fat Diet-Induced Liver Steatosis and Zinc Depletion in Rat

Background

Obesity is a tremendous public health problem, characterized by ectopic deposition of fat into non-adipose tissues as liver generating an oxidative stress that could lead to steato-hepatitis. Grape seed and skin extract (GSSE) is a complex mixture of polyphenolics exhibiting robust antioxidative properties.

Aim

We hypothesize that GSSE could protect the liver from fat-induced lipotoxicity and have a beneficial effect on liver function.

Methods

Hepatoprotective effect of GSSE was measured by using an experimental model of fat-induced rat liver steatosis. Male rats were fed a standard diet or a high-fat diet (HFD) during 6 weeks and treated or not with 500 mg/kg bw GSSE. Lipid deposition into the liver was assessed by triglyceride, cholesterol and phospholipid measurements. Fat-induced lipoperoxidation, carbonylation, depletion of glutathione and of antioxidant enzyme activities were used as oxidative stress markers with a special emphasis on transition metal distribution.

Results

HFD induced liver hypertrophy and inflammation as assessed by high liver transaminases. HFD also induced an oxidative stress characterized by increased lipid and protein oxidation, a drop in glutathione and antioxidant enzyme activities as glutathione peroxidase and superoxide dismutase and a drastic depletion in liver zinc. Importantly, GSSE prevented all the deleterious effects of HFD treatment.

Conclusions

Data suggest that GSSE could be used as a safe preventive agent against fat-induced liver lipotoxicity which could also have potential applications in other non-alcoholic liver diseases.     

Sulforaphane protects H9c2 cardiomyocytes from angiotensin II-induced hypertrophy

Background

Cardiac hypertrophy is an adaptive process of the heart in response to various stimuli, but sustained cardiac hypertrophy will finally lead to heart failure. Sulforaphane—extracted from cruciferous vegetables of the genus Brassica such as broccoli, brussels sprouts, and cabbage—has been evaluated for its anticarcinogenic and antioxidant effects.

Aims

To investigate the effect of sulforaphane on angiotensin II (Ang II)-induced cardiac hypertrophy in vitro.

Methods

Embryonic rat heart-derived H9c2 cells were co-incubated with sulforaphane and Ang II. The cell surface area and mRNA levels of hypertrophic markers were measured to clarify the effect of sulforaphane on cardiac hypertrophy. The underlying mechanism was further investigated by detecting the activation of Akt and NF-κB signaling pathways.

Results

We found that H9c2 cells pretreated with sulforaphane were protected from Ang II-induced hypertrophy. The increasing mRNA levels of ANP, BNP, and β-MHC in Ang II-stimulated cells were also down-regulated after sulforaphane treatment. Moreover, sulforaphane repressed the Ang II-induced phosphorylation of Akt, GSK3β, mTOR, eIF4e, as well as of IκBα and NF-κB.

Conclusion

Based on our results, sulforaphane attenuates Ang II-induced hypertrophy of H9c2 cardiomyocytes mediated by the inhibition of intracellular signaling pathways including Akt and NF-κB.     

Renal dysfunction and hypophosphatemia during long-term lamivudine plus adefovir dipivoxil therapy in patients with chronic hepatitis B

Background

Renal dysfunction and Fanconi’s syndrome associated with hypophosphatemia caused by long-term administration of low-dose adefovir dipivoxil (ADV) has been reported in recent years. The aim of this retrospective study was to determine the incidence and factors associated with renal dysfunction and hypophosphatemia in patients with hepatitis B infection on long-term treatment with ADV and lamivudine (LAM).

Methods

The study subjects were 292 patients treated with 10 mg/day ADV and 100 mg/day LAM for more than 6 months. We evaluated estimated glomerular filtration rate (eGFR), serum creatinine and serum phosphate level at the start of ADV and every 6 months.

Result

During a median treatment duration of 64 months, 28 (9.6 %) patients developed renal impairment (defined as eGFR < 50 ml/min/1.73 m²), and 73 (27.1 %) developed hypophosphatemia, including 14 with persistent hypophosphatemia. The cumulative incidences of renal impairment at 1, 3, and 5 years were 1.4, 7.5, 10.5 %, respectively, and those of hypophosphatemia were 6.8, 20.6, 26.7 %, respectively. Multivariate analysis identified old age, liver cirrhosis and hypertension as determinants of renal impairment, and male sex, HCC, low baseline serum phosphate as determinants of hypophosphatemia. Three of the 14 patients with persistent hypophosphatemia developed Fanconi’s syndrome; their serum creatinine level remained normal, but eGFR was lower than at baseline.

Conclusion

Long-term treatment of hepatitis B with low-dose (10 mg/day) ADV and LAM can potentially cause renal impairment and hypophosphatemia. We advocate regular monitoring of serum phosphate and evaluation of eGFR, in addition to serum creatinine, in such patients.