Dihydroxyphenylacetaldehyde Lowering Treatment Improves Locomotor and Neurochemical Abnormalities in the Rat Rotenone Model: Relevance to the Catecholaldehyde Hypothesis for the Pathogenesis of Parkinson's Disease.

The catecholaldehyde hypothesis for the pathogenesis of Parkinson's disease centers on accumulation of 3,4-dihydroxyphenylacetaldehyde (DOPAL) in dopaminergic neurons. To test the hypothesis, it is necessary to reduce DOPAL and assess if this improves locomotor abnormalities. Systemic administration of rotenone to rats reproduces the motor and central neurochemical abnormalities characterizing Parkinson's disease. In this study, we used the monoamine oxidase inhibitor (MAOI) deprenyl to decrease DOPAL production, with or without the antioxidant N-acetylcysteine (NAC). Adult rats received subcutaneous vehicle, rotenone (2 mg/kg/day via a minipump), or rotenone with deprenyl (5 mg/kg/day i.p.) with or without oral NAC (1 mg/kg/day) for 28 days. Motor function tests included measures of open field activity and rearing. Striatal tissue was assayed for contents of dopamine, DOPAL, and other catechols. Compared to vehicle, rotenone reduced locomotor activity (distance, velocity and rearing); increased tissue DOPAL; and decreased dopamine concentrations and inhibited vesicular sequestration of cytoplasmic dopamine and enzymatic breakdown of cytoplasmic DOPAL by aldehyde dehydrogenase (ALDH), as indicated by DA/DOPAL and DOPAC/DOPAL ratios. The addition of deprenyl to rotenone improved all the locomotor indices, increased dopamine and decreased DOPAL contents, and corrected the rotenone-induced vesicular uptake and ALDH abnormalities. The beneficial effects were augmented when NAC was added to deprenyl. Rotenone evokes locomotor and striatal neurochemical abnormalities found in Parkinson's disease, including DOPAL buildup. Administration of an MAOI attenuates these abnormalities, and NAC augments the beneficial effects. The results indicate a pathogenic role of DOPAL in the rotenone model and suggest that treatment with MAOI+NAC might be beneficial for Parkinson's disease treatment.

The Use of Brain Natriuretic Peptide as a Decision-supporting Tool in Hospitalized Patients.

BACKGROUND: Most dyspneic patients in internal medicine departments have co-morbidities that interfere with the clinical diagnosis. The role of brain natriuretic peptide (BNP) levels is well-established in the acute setting but not in hospitalized patients. OBJECTIVES: To evaluate the additive value of BNP tests in patients with dyspnea admitted to medical wards who did not respond to initial treatment. METHODS: We searched the records of patients who were hospitalized in the department of internal medicine D at Sheba Medical Center during 2012 and were tested for BNP in the ward. Data collected included co-morbidity, medical treatments, diagnosis at presentation and discharge, lab results including BNP, re-hospitalization, and mortality at one year following hospitalization. RESULTS: BNP results were found for 169 patients. BNP was taken 1.7 ± 2.7 days after hospitalization. According to BNP levels, dividing the patients into tertiles revealed three equally distributed groups with a distinctive character. The higher tertile was associated with higher rates of cardiac co-morbidities, including heart failure, but not chronic obstructive pulmonary disease. Higher BNP levels were related to one-year re-hospitalization and mortality. In addition, higher BNP levels were associated with higher rates of in-admission diagnosis change. CONCLUSIONS: BNP levels during hospitalization in internal medicine wards are significantly related to cardiac illness, the existence of heart failure, and patient prognosis. Thus, BNP can be a useful tool in managing dyspneic patients in this setting.

Normal-range emergency department serum phosphorus levels and all-cause mortality.

PURPOSE OF THE STUDY: Hypophosphataemia and hyperphosphataemia are frequently encountered in hospitalised patients and are associated with significant clinical consequences. However, the prognostic value of normal-range phosphorus levels on all-cause mortality and hospitalisations is not well established. Therefore, we examined the association between normal-range phosphorus levels, all-cause mortality and hospitalisations in patients presenting to the emergency department of a tertiary medical centre in Israel. STUDY DESIGN: A retrospective analysis of patients presenting to the Chaim Sheba Medical Center emergency department between 2012 and 2018. The cohort was divided into quartiles based on emergency department phosphorus levels: 'very-low-normal' (p ≥ 2 mg/dL and p ≤ 2.49 mg/dL), 'low-normal' (p ≥ 2.5 mg/dL and p ≤ 2.99 mg/dL), 'high-normal' (p≥  3 mg/dL and p≤3.49 mg/dL) and 'very-high-normal' (p ≥  3.5 mg/dL and p ≤ 4 mg/dL). We analysed the association between emergency department phosphorus levels, hospitalisation rate and 30-day and 90-day all-cause mortality. RESULTS: Our final analysis included 223 854 patients with normal-range phosphorus levels. Patients with 'very-low-normal' phosphorus levels had the highest mortality rate. Compared with patients with 'high-normal' phosphorus levels, patients with 'very-low-normal' levels had increased 30-day all-cause mortality (OR 1.3, 95% CI 1.1 to 1.4, p<0.001), and increased 90-day all-cause mortality (OR 1.2, 95% CI 1.1 to 1.3, p<0.001). Lower serum phosphorus levels were also associated with a higher hospitalisation rate, both for the internal medicine and general surgery wards (p<0.001). CONCLUSIONS: Lower phosphorus levels, within the normal range, are associated with higher 30-day and 90-day all-cause mortality and hospitalisation rate.

[ROLE OF THE IMMUNE SYSTEM IN THE PATHOGENESIS OF HYPERTENSION].

INTRODUCTION: The understanding that the immune system has a role in the pathogenesis of essential hypertension was established over the last few decades, with many different works showing that manipulating the immune system effects blood pressure. Pro-inflammatory cell activation can cause hypertension while anti-inflammatory cell activation restrains it. These activations involve different cell types, cytokine and chemokine secretions, and affect different target organs. Additionally, there is evidence that hypertension itself may affect the immune system. This article reviews the main findings in this area.

The association between fasting plasma glucose and glycated hemoglobin in the prediabetes range and future development of hypertension.

BACKGROUND: Prediabetes is a well-established risk factor for progression to overt diabetes mellitus (DM), which is in turn associated with development of hypertension (HTN) and vice versa. However, the role of prediabetes and HbA1c in particular as an independent risk factor for the development of hypertension is unclear. AIM: In this current study, we aimed to evaluate the association between both fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) levels in the prediabetes range and development of HTN among a large cohort of normotensive subjects. DESIGN AND METHODS: We investigated 5016 normotensive participants without DM and other cardiovascular risk factors who were annually screened in a tertiary medical center. Subjects were divided into normoglycemic and prediabetic groups. Normoglycemia was defined as HbA1c < 5.7% and FPG < 100 mg/dl. Prediabetes was defined according to the ADA criteria, i.e., 6.5% > HbA1c ≥ 5.7% or impaired fasting glucose (IFG):126 mg/dl > FPG ≥ 100 mg/dl. Subgroup analysis was made by dividing participants into four groups according to FPG and HbA1C levels, i.e., normoglycemia, impaired HbA1c only, IFG only, and both parameters impaired. RESULTS: During a follow-up of 3.7 ± 2.9 years, 318 (6.3%) subjects developed HTN. A cumulative hazard function for the development of hypertension showed a 2.89-fold ([95% CI 2.19-3.83], p < .0001) increased risk for HTN in the prediabetic population. In a multivariable Cox proportional hazard regression model adjusted to common confounding risk factors for HTN, prediabetes was found to be independently associated with a 1.95-fold ([95%, CI 1.43-2.52] p < .0001) increased risk for hypertension. Impaired HbA1C only was not found to be independently associated with HTN, while IFG only showed a 2.13-fold (95%, [CI 1.46-3.11] p < .0001) increased risk for HTN compared to normoglycemic, and a 2.55-fold ([95% CI 1.85-3.51] p < .0001) increased risk for HTN when both parameters impaired. CONCLUSION: Our study demonstrates that FPG in the prediabetes range, albeit not glycated hemoglobin, is independently and significantly associated with future development of HTN. Therefore, our findings further highlight the pivotal predictive role of IFG for HTN development as opposed to the limited independent role of abnormal HbA1c levels.

Effect of tumor necrosis factor-α inhibitors on ambulatory 24-h blood pressure.

Tumor necrosis factor alpha (TNF-α) inhibitors are increasingly being used in inflammatory rheumatic diseases (IRD). The risk of cardiovascular disease is elevated in patients with IRD and TNF-α inhibitors reduce this risk. We assessed whether the beneficial effect of TNF-α inhibitors on cardiovascular risk is mediated by blood pressure reduction. We measured blood pressure levels with 24-h ambulatory blood pressure measurements device in patients with IRD before and 3 months after treatment with TNF-α inhibitors. The study population consisted of 15 subjects (6 men; mean age 45.9 ± 14.1 years). Most patients had either rheumatoid arthritis or psoriatic arthritis and adalimumab was the most common TNF-α inhibitor used. Mean 24-h systolic and diastolic blood pressure levels remained the same after treatment (121 ± 12/66 ± 7 before and 123 ± 11/67 ± 10 mm Hg after; p = 0.88 and 0.66, respectively). The study demonstrates that TNF-α inhibitors have no effect on blood pressure levels.

Melatonin prevents kidney injury in a high salt diet-induced hypertension model by decreasing oxidative stress.

Melatonin, a potent antioxidant molecule, plays a role in blood pressure regulation. We hypothesized that melatonin may generate a protective effect in a high salt diet (HSD) rodent model mediated by decreasing renal oxidative stress. Dahl salt-sensitive rats were divided into three groups according to diet: normal chow (control); HSD; HSD with melatonin [30/mg/kg/day]) placed in their water (HSD + Mel) over an 8-wk period. Blood pressure was measured by the tail cuff method. Kidney injury was evaluated by 24 H urine protein excretion. Glomerular injury index (GII) (fibrotic glomeruli/100 glomeruli) was evaluated from a Masson's trichrome-stained section. Kidney oxidative stress was determined by superoxide production via dihydroethidium staining. Expression of oxidative stress-related genes was measured by reverse transcriptase-qPCR. Melatonin had no effect on blood pressure increase induced by HSD and attenuated proteinuria induced by HSD (HSD--50.7 ± 12, HSD + Mel--22.3 ± 4.3, controls--6.5 ± 1.0 gram protein/gram creatinine, P < 0.001). HSD-induced glomerular damage was significantly diminished by melatonin (GII in HSD--24 ± 6, HSD + Mel--3.6 ± 0.8, controls--0.8 ± 0.5, P < 0.05). Superoxide production was significantly higher in kidneys of HSD fed rats than the controls (99 ± 9 versus 60 ± 7 relative fluorescent units (RFU)/µm(2), respectively, P < 0.05). Melatonin also decreased superoxide production (74 ± 5 RFU/µm(2), P < 0.05). The expression of kidney inducible nitric oxide synthase and p67(phox) mRNA was significantly higher in HSD than in the controls and HSD + Mel rats. Treatment with melatonin eliminated the deleterious effect of HSD in the kidneys of Dahl salt-sensitive rats. The beneficial effect of melatonin is not mediated by lowering blood pressure but by a direct antioxidative effect.

Limited reproducibility of 24-h ambulatory blood pressure monitoring.

Results of 24-h ambulatory blood pressure monitoring (ABPM) including average blood pressure, variability, and nocturnal dipping are considered the gold standard for diagnosis and the best predictor of the future end organ damage in chronic hypertension. Here we report on the reproducibility of ABPM results for these three measures over a period of months. A total of 35 hypertensive patients (43% female, mean age 64 years), underwent two separate ABPM recordings within 14 weeks, with unchanged medical treatment and lifestyle in the interim. The day and night average blood pressure, dipping status of systolic pressure, and the standard deviation of systolic and diastolic blood pressure as a measure of variability were compared between the two recordings. Individual values for average systolic and diastolic pressures showed only a modest correlation between the two measurements (r = 0.56, r = 0.81, p < 0.01). Standard deviations of 24-h pressure were also positively but weakly correlated (r = 0.4, p < 0.001). The occurrence of dipping was reproducible in 71% of the patients. Average blood pressure, pressure variability, and dipping as assessed by ABPM are only moderately reproducible. Clinical decision-making based on single ABPM datasets should be made with caution, and repetition of ABPM seems justified in some cases.

Diabetes mellitus with normal renal function is associated with anaemia.

BACKGROUND: Anaemia is a common complication of diabetes mellitus (DM), usually related to renal failure. There is scarce information as to the levels of haemoglobin (Hb) and the rate of anaemia in diabetic patients with normal renal function. We, therefore, evaluated haemoglobin levels and the rate of anaemia in diabetic subjects with normal renal functions [estimated glomerular filtration rate (eGFR) > 60 mL/min]. METHODS: The charts of 9250 subjects who attended the Institute of Periodic Medical Examinations at the Chaim Sheba Medical Center for a routine yearly check-up were reviewed. Four hundred and forty-five subjects with type 2 DM and normal renal function were indentified and compared with those without DM who were routinely examined at the same time. Subjects' electronic records were used to build a biochemical and clinical database. RESULTS: Mean haemoglobin levels were lower in subjects with DM than in those without (14.2 vs. 14.7 g/dL, respectively; p < 0.001). Anaemia was observed in 48 (10.8%) subjects in the diabetic group and in only 12 (2.7%) in the nondiabetic group (p < 0.001). Multivariate analysis revealed that age, gender, history of gastrointestinal disease, use of beta blockers, renal function and DM were independent determinants of haemoglobin levels. After adjustment for age, gender, history of gastrointestinal tract diseases and renal function, DM remained a significant determinant of anaemia with an odds ratio of 2.15 (confidence interval: 1.07-4.31). CONCLUSIONS: Anaemia is more common in diabetic patients even when eGFR > 60 mL/min.

Trends in antihypertensive treatment--lessons from the National Acute Stroke Israeli (NASIS) registry.

BACKGROUND: Recent guidelines recommended different approaches to hypertension therapy. Our aim was to evaluate trends in blood pressure (BP) management among patients admitted with acute stroke over the past decade. METHODS: The study population comprised 6279 consecutive patients, admitted with an acute stroke, and included in a national registry of three consecutive periods conducted during the years 2004-2010. We compared patients' characteristics and temporal trends of antihypertensive therapy utilization before hospital admission. RESULTS: Among 4727 hypertensive patients, 3940 (83%) patients have taken antihypertensive drug therapy - 1430 (30.2%) a single agent, 1500 (31.7%) two agents and 1010 (21.4%) three or more antihypertensive agents. The most common class used was renin-angiotensin system (RAS) blockers (n = 2575; 54%) followed by beta-blockers (n = 2033; 43%). The same pattern was observed in patients treated with monotherapy. The use of RAS blockers and beta-blockers has increased over the years (p < 0.001 for both), whereas the use of diuretics decreased and the use of calcium antagonists remained stable. Among those who were treated with a single agent, the use of diuretics and calcium antagonists decreased and the use of RAS blockers increased, whereas the use of beta-blockers remained unchanged. CONCLUSIONS: RAS blockers and beta-blockers are the most common antihypertensive agents used in Israel. Over time, the use of RAS blockers and beta-blockers has increased, whereas the use of diuretics decreased.

[The role of the immune system in the pathogenesis of hypertension].

Inflammation plays an important role in the pathogenesis of hypertension. Innate and adaptive immune response may contribute to this process. The mechanisms implicating immune response in hypertension are still elusive. To date, the evidence originates in three major areas of data: cytokine production, central nervous system (CNS) stimulation and kidney damage. The cytokine microenvironment can become proinflammatory and propagate low-grade inflammation, which may contribute to vascular injury and end-organ damage in hypertension. In addition, stimulation of the CNS by some stimuli (e.g. angiotensin II) causes mild hypertension that may modulate peripheral immune responses leading to aggravation of blood pressure elevation. The immune response can induce kidney injury and also interfere with sodium excretion, further contributing to elevation of blood pressure.

Non-Interventional Weight Changes Are Associated with Alterations in Serum Uric Acid Levels.

Background/Objectives: Serum uric acid is an established cardiovascular risk factor. Higher serum uric acid levels are associated with overweight and obesity. We assessed whether non-interventional weight changes affect serum uric acid levels. Methods: We performed a retrospective analysis of 19,193 participants referred to annual medical screening. Body mass index (BMI) and serum uric acid were measured annually. Subjects were divided into five groups according to changes in BMI between visits: large reduction (reduction of more than 5% in BMI), moderate reduction (reduction of more than 2.5% and 5% or less in BMI), unchanged (up to 2.5% change in BMI), moderate increase (increase of more than 2.5% and 5% or less in BMI), and large increase (increase of more than 5% in BMI). The primary outcome was serum uric acid level changes between visits. Results: A decrease in serum uric acid levels was evident as BMI decreased and an increase in serum uric acid levels was associated with an increase in BMI. The proportion of patients whose serum uric acid levels were increased by at least 10% between visits increased with the relative increase in BMI, while the proportion of patients whose serum uric acid levels were reduced by at least 10% decreased with the relative decrease in BMI. Conclusions: Non-interventional weight changes, even modest, are associated with significant alterations in serum uric acid levels. Our findings may aid in better risk stratification and the primary prevention of cardiovascular morbidity and mortality.

A 120-Minute Saline Infusion Test for the Confirmation of Primary Aldosteronism: A Pilot Study.

BACKGROUND: The saline infusion test (SIT) to confirm primary aldosteronism requires infusing 2 L of normal saline over 240 minutes. Previous studies raised concerns regarding increased blood pressure and worsening hypokalemia during SIT. We aimed to evaluate the diagnostic applicability of a SIT that requires 1 L of saline infusion over 120 minutes. METHODS: A cross-sectional study, including all patients in a large medical center who underwent SIT from 1 January 2015 to 30 April 2023. Blood samples were drawn for baseline renin and aldosterone (t = 0) after 2 hours (t = 120 min) and after 4 hours (t = 240 min) of saline infusion. We used ROC analysis to evaluate the sensitivity and specificity of various aldosterone cut-off values at t = 120 to confirm primary aldosteronism. RESULTS: The final analysis included 62 patients. A ROC analysis yielded 97% specificity and 90% sensitivity for a plasma aldosterone concentration (PAC) of 397 pmol/L (14 ng/dL) at t = 120 to confirm primary aldosteronism, and an area under the curve of 0.97 (95% CI [0.93, 1.00], P < 0.001). Almost half (44%) of the patients did not suppress PAC below 397 pmol/L (14 ng/dL) at t = 120. Of them, only one (4%) patient suppressed PAC below 276 pmol/L (10 ng/dL) at t = 240. Mean systolic blood pressure increased from 140.1 ±â€…21.3 mm Hg at t = 0 to 147.6 ±â€…14.5 mm Hg at t = 240 (P = 0.011). CONCLUSIONS: A PAC of 397 pmol/L (14 ng/dL) at t = 120 has high sensitivity and specificity for primary aldosteronism confirmation.

Obesity Is Associated with Fatty Liver and Fat Changes in the Kidneys in Humans as Assessed by MRI.

BACKGROUND: Obesity is associated with metabolic syndrome and fat accumulation in various organs such as the liver and the kidneys. Our goal was to assess, using magnetic resonance imaging (MRI) Dual-Echo phase sequencing, the association between liver and kidney fat deposition and their relation to obesity. METHODS: We analyzed MRI scans of individuals who were referred to the Chaim Sheba Medical Center between December 2017 and May 2020 to perform a study for any indication. For each individual, we retrieved from the computerized charts data on sex, and age, weight, height, body mass index (BMI), systolic and diastolic blood pressure (BP), and comorbidities (diabetes mellitus, hypertension, dyslipidemia). RESULTS: We screened MRI studies of 399 subjects with a median age of 51 years, 52.4% of whom were women, and a median BMI 24.6 kg/m2. We diagnosed 18% of the participants with fatty liver and 18.6% with fat accumulation in the kidneys (fatty kidneys). Out of the 67 patients with fatty livers, 23 (34.3%) also had fatty kidneys, whereas among the 315 patients without fatty livers, only 48 patients (15.2%) had fatty kidneys (p < 0.01). In comparison to the patients who did not have a fatty liver or fatty kidneys (n = 267), those who had both (n = 23) were more obese, had higher systolic BP, and were more likely to have diabetes mellitus. In comparison to the patients without a fatty liver, those with fatty livers had an adjusted odds ratio of 2.91 (97.5% CI; 1.61-5.25) to have fatty kidneys. In total, 19.6% of the individuals were obese (BMI ≥ 30), and 26.1% had overweight (25 < BMI < 30). The obese and overweight individuals were older and more likely to have diabetes mellitus and hypertension and had higher rates of fatty livers and fatty kidneys. Fat deposition in both the liver and the kidneys was observed in 15.9% of the obese patients, in 8.3% of the overweight patients, and in none of those with normal weight. Obesity was the only risk factor for fatty kidneys and fatty livers, with an adjusted OR of 6.3 (97.5% CI 2.1-18.6). CONCLUSIONS: Obesity is a major risk factor for developing a fatty liver and fatty kidneys. Individuals with a fatty liver are more likely to have fatty kidneys. MRI is an accurate modality for diagnosing fatty kidneys. Reviewing MRI scans of any indication should include assessment of fat fractions in the kidneys in addition to that of the liver.

Non-Interventional Weight Changes Are Associated with Alterations in Lipid Profiles and in the Triglyceride-to-HDL Cholesterol Ratio.

BACKGROUND: Obesity is associated with dyslipidemia, and weight loss can improve obese patients' lipid profile. Here, we assessed whether non-interventional weight changes are associated with alterations in lipid profile, particularly the triglyceride (TG)-to-high-density lipoprotein cholesterol (HDL-C) ratio (TG/HDL-C). METHODS: In this retrospective analysis of subjects referred to medical screening, body mass index (BMI), low-density lipoprotein cholesterol (LDL-C), TG, and HDL-C levels were measured annually. Patients were divided according to BMI changes between visits. The primary outcomes were the changes in LDL-C, TG, HDL-C, and the TG/HDL-C ratio between visits. RESULTS: The final analysis included 18,828 subjects. During the year of follow-up, 9.3% of the study population lost more than 5% of their weight and 9.2% gained more than 5% of their weight. The effect of weight changes on TG and on the TG/HDL-C ratio was remarkable. Patients with greater BMI increases showed greater increases in their TG/HDL-C ratio, and conversely, a decreased BMI level had lower TG/HDL-C ratios. This is true even for moderate changes of more than 2.5% in BMI. CONCLUSIONS: Non-interventional weight changes, even modest ones, are associated with significant alterations in the lipid profile. Understanding that modest, non-interventional weight changes are associated with alterations in the TG/HDL-C ratio may aid in better risk stratification and primary prevention of CV morbidity and mortality.

Elevated International Normalized Ratio and Mortality in Hospitalized Patients Treated with Direct Oral Anticoagulants.

BACKGROUND: Direct oral anticoagulants (DOACs) are associated with a prolongation of the prothrombin time and an increased international normalized ratio (INR). The clinical significance of these changes is unclear. This study aimed to examine the association between an elevated INR on admission and in-hospital death and long-term survival in patients treated with DOACs. METHODS: Data were retrospectively retrieved from records of hospitalized patients at the Sheba Medical Center between November 2008 and July 2023. Patients were selected based on DOAC treatment, coagulation profile, and INR test done within 48 hours of hospitalization. The outcomes were in-hospital mortality and mortality in the year following hospitalization. RESULTS: The study included 11,399 hospitalized patients treated with DOACs. Patients with elevated INR had a 180% higher risk of in-hospital mortality (adjusted odds ratio 2.80; 95% confidence interval, 2.30-3.39) and a 57% increased risk of death during the following year (adjusted hazard ratio 1.57; 95% confidence interval, 1.44-1.71). Similar results were observed in subgroup analyses for each DOAC. CONCLUSIONS: An elevated INR on admission is associated with a higher risk for in-hospital death and increased risk for mortality during the first year following hospitalization in hospitalized patients treated with DOACs. This highlights that elevated INR levels in patients on DOACs should not be dismissed as laboratory variations due to DOAC treatment, as they may serve as a prognostic marker.

Preservation of endothelium-dependent relaxation in atherosclerotic mice with endothelium-restricted endothelin-1 overexpression.

In human atherosclerosis, which is associated with elevated plasma and coronary endothelin (ET)-1 levels, ETA receptor antagonists improve coronary endothelial function. Mice overexpressing ET-1 specifically in the endothelium (eET-1) crossed with atherosclerosis-prone apolipoprotein E knockout mice (Apoe(-/-)) exhibit exaggerated high-fat diet (HFD)-induced atherosclerosis. Since endothelial dysfunction often precedes atherosclerosis development, we hypothesized that mice overexpressing endothelial ET-1 on a genetic background deficient in apolipoprotein E (eET-1/Apoe(-/-)) would have severe endothelial dysfunction. To test this hypothesis, we investigated endothelium-dependent relaxation (EDR) to acetylcholine in eET-1/Apoe(-/-) mice. EDR in mesenteric resistance arteries from 8- and 16-week-old mice fed a normal diet or HFD was improved in eET-1/Apoe(-/-) compared with Apoe(-/-) mice. Nitric oxide synthase (NOS) inhibition abolished EDR in Apoe(-/-). EDR in eET-1/Apoe(-/-) mice was resistant to NOS inhibition irrespective of age or diet. Inhibition of cyclooxygenase, the cytochrome P450 pathway, and endothelium-dependent hyperpolarization (EDH) resulted in little or no inhibition of EDR in eET-1/Apoe(-/-) compared with wild-type (WT) mice. In eET-1/Apoe(-/-) mice, blocking of EDH or soluble guanylate cyclase (sGC), in addition to NOS inhibition, decreased EDR by 36 and 30%, respectively. The activation of 4-aminopyridine-sensitive voltage-dependent potassium channels (Kv) during EDR was increased in eET-1/Apoe(-/-) compared with WT mice. We conclude that increasing eET-1 in mice that develop atherosclerosis results in decreased mutual dependence of endothelial signaling pathways responsible for EDR, and that NOS-independent activation of sGC and increased activation of Kv are responsible for enhanced EDR in this model of atherosclerosis associated with elevated endothelial and circulating ET-1.

Normal adiponectin levels in kidney transplant patients with hypertension.

BACKGROUND: Kidney transplant patients are a unique population where despite correction of their kidney function they are still considered to be at high cardiovascular (CV) risk. Adiponectin, an adipokine secreted from adipocytes, has protective CV properties. Patients with essential hypertension (HTN) have low adiponectin levels that are associated with a high CV risk. The aim of this study was to assess adiponectin levels in hypertensive renal transplant recipients. MATERIALS AND METHODS: Fasting blood adiponectin levels were measured in hypertensive kidney transplant patients (n = 18), patients with essential HTN (n = 17) and healthy subjects (n = 14). Patients with diabetes mellitus and renal failure were excluded from the study. Anthropomorphic and metabolic parameters were also measured. RESULTS: Patients with essential HTN had lower adiponectin levels than healthy controls (6 ± 0.7 µg/mL vs. 11 ± 0.9 µg/mL, p < 0.001), whereas hypertensive kidney transplant patients had adiponectin levels that were similar to adiponectin levels found in normal controls (11 ± 1.1 µg/mL). Adiponectin levels in healthy subjects were inversely correlated with plasma triglycerides (r = -0.876, p < 0.001) and with body weight (r = -0.7, p < 0.001). There was no such a correlation in patients with HTN. CONCLUSION: Adiponectin in hypertensive kidney transplant recipients is not an appropriate CV risk marker as it does not adequately distinguish these patients from normal controls.

Rosiglitazone and bezafibrate modulate gene expression in a rat model of non-alcoholic fatty liver disease--a historical prospective.

BACKGROUND: Genetic factors implicated in the pathogenesis of non-alcoholic fatty liver disease are poorly understood. Our aim was to characterize three genes involved in a rat model of non-alcoholic fatty liver disease and investigate the effect of rosiglitazone and bezafibrate. METHOD: Five rats were fed a chow diet (controls) and 18 a fructose-enriched diet (FED) for 5 weeks: 6 were administered rosiglitazone and 6 bezafibrate during the last 2 weeks and 6 were not treated at all. Livers were examined by reverse transcription-PCR for the genes encoding peroxisome proliferator-activated receptors (PPAR), PPAR-α, PPAR-γ, and Mn superoxide dismutase2 (Mn SOD2). Western blot was used for proteins levels. RESULT: The FED rats showed a decrease in mRNA of MnSOD2, PPAR-α, and PPAR-γ (3, 3.5 fold, and 27%, respectively) (p<0.05). The 3 genes normalized in response to rosiglitazone and bezafibrate. The proteins of MnSOD2, PPAR-α and PPAR-γ in the FED rats decreased (2.5, 2, and 2.2, respectively) (p<0.05). Following administration of rosiglitazone, proteins of MnSOD2, PPAR-α and PPAR-γ in the FED rats increased (reaching 1.5-fold, a 20% increase and normalization, respectively), (p<0.05). Administration of bezafibrate to the FED rats restored the proteins of 3 genes to baseline. CONCLUSION: A consistent reduction in hepatic expression of MnSOD2, PPAR-α and PPAR-γ in the FED rats compared with controls was observed. Administration of either rosiglitazone or bezafibrate to the FED rats restored these genes to a pre-morbid state.

Nsaids Linked to IgA-Mediated Hypersensitivity Vasculitis and Purpura Fulminans-Like Eruption.

Background: IgA vasculitis and hypersensitivity reactions following exposure to non-steroidal anti-inflammatory drugs (NSAIDs) are very rarely associated with purpura fulminans (PF). The latter is a coagulation event characterised by decreased levels of protein C and a rapidly progressive purpuric rash, often leading to ischaemia, amputations and death. Case summary: A previously healthy 66-year-old man presented with a vasculitic rash and abdominal pain following exposure to naproxen (NSAID), which quickly deteriorated to purpura fulminans-like eruption and skin necrosis, mainly involving the face and hands. The presence of IgA sediments on skin biopsy and decreased levels of complement as well as protein C pointed to an immune-mediated inflammatory process. Dramatic clinical escalation with immediate risk to organs and life required an aggressive and broad-spectrum therapeutic approach in an intensive care setting. Clinical improvement and complete reconstitution of protein C were achieved following plasma exchange with fresh frozen plasma (FFP) and immunosuppression with glucocorticoids with no persistent organ damage. Conclusions: This rare case illustrates the catastrophic cross links between NSAIDs, IgA-mediated hypersensitivity vasculitis and purpura fulminans-like syndrome. A high index of suspicion is required for the evaluation of environmental exposures such as drugs and infections in patients with vasculitis and/or purpura. A rapid and comprehensive therapeutic approach should be implemented to avoid multi-organ damage, amputations and death. Complete avoidance of the offending agent is key for future prevention of recurrence. LEARNING POINTS: This case illustrates a rare cross link between a commonly used drug (NSAIDs) and severe, life-threatening hypersensitivity reactions (IgA vasculitis and purpura fulminans-like eruption).These events require a high index of suspicion and emphasise the importance of considering environmental exposures such as drugs in the immediate diagnosis of both conditions.In addition to long-term drug avoidance, early and aggressive interventions are required to avoid organ damage, amputations or death.