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Background Normotensive hypokalaemic tubulopathies (Bartter and Gitelman syndromes (BS/GS)) are genetic diseases that are considered benign. However, QT prolongation, left ventricular dysfunction and reduction of cardiac index upon exercise leading to arrhythmias and sudden cardiac death have been reported in these patients. Hence, we aimed to verifying whether an isometric exercise could represent a useful tool for the identification of patients at risk for future cardiac events. Patients and methods Myocardial function (MF) and perfusion, evaluated as myocardial blood flow (MBF) of 10 BS/GS patients and 10 healthy controls, were investigated at rest and during isometric exercise. MF and MBF were evaluated using quantitative two-dimensional and myocardial contrast echocardiography. Results BS/GS patients had normal baseline MF and MBF. During exercise in BS/GS patients, corrected QT (QTc) was prolonged to peak value of 494 ± 9·1 ms ( P < 0·001). In controls, MF increased from resting to peak exercise (left ventricular ejection fraction: 65 ± 4% to 78 ± 5%, P < 0·003) while in seven BS/GS patients (Group 1) it declined (64 ± 5% to 43 ± 9%, P < 0·001). Myocardial perfusion increased upon exercise in controls as shown by changes of its markers: β (a measure of myocardial flow velocity; 0·89 ± 0·12 vs. 0·99 ± 0·12, P < 0·001) and myocardial blood volume (14·4 ± 2 vs. 20·2 ± 0·25, P < 0·001), while in Group 1 BS/GS it decreased (0·87 ± 0·15 vs. 0·67 ± 0·15, P < 0·001; and 14·5 ± 1·9 vs. 8·3 ± 0·22, P < 0·001, respectively). Conclusions Our results document for the first time that exercise induce coronary microvascular and myocardial defects in BS/GS patients. Therefore, this may challenge the idea that BS/GS are benign diseases. In addition, the diagnostic approach to these syndromes should include an in-depth cardiac assessment in order to identify patients at higher risk. [ABSTRACT FROM AUTHOR]

Studies in patients with Bartter's and Gitelman's syndromes performed in the last 10 years have provided important insights into the mechanistic details of relevant pathways of angiotensin II signaling and vascular tone regulation, therefore making these syndromes a good human model to gain insight into the mechanisms responsible for maintaining/controlling vascular tone. Extensive studies of patients with Bartter's/Gitelman's syndromes have, in fact, shown biochemical abnormalities of angiotensin II short- and long-term cell signaling, which depict a mirror image of those found in hypertension. The information obtained from the study of this human model of altered vascular tone regulation show that it can be used to gather more general data and/or confirm mechanistic details of the cellular and biochemical events involved in the pathophysiology of vascular tone control and to shed light on the multiplicity of the angiotensin II signaling-related mechanisms responsible for the pathophysiology of hypertension and its long-term complication such as cardiovascular remodeling and atherogenesis.Kidney International (2006) 69, 963–966. doi:10.1038/sj.ki.5000253; published online 15 February 2006 [ABSTRACT FROM AUTHOR]

The role of oxidative stress in the pathophysiology of hypertension has stimulated the investigation of strategies to reduce oxidative stress via antioxidant defenses. Using a molecular biology approach, we report, in essential hypertensive patients, the effect of doxazosin treatment on the mononuclear cell gene and protein expression of two major elements in the oxidative stress and vascular remodeling-related pathways: p22 phox and PAI-1. Ten essential hypertensive patients were treated with Doxazosin (4 mg/day) for two weeks (EH + D) and compared with ten untreated hypertensive patients (EH) and ten normotensive subjects (C). In EH p22 phox and PAI-1 mRNA and protein level was increased compared with C. In EH + D, doxazosin reduced p22 phox and PAI-1 gene and protein expression, which was similar to that of C. These results demonstrate for doxazosin an inhibitory effect on oxidative stress related proteins at gene and protein level, which confirms at molecular level a powerful antioxidant potential for this agent that could translate, in the long term, into a powerful antiatherosclerotic effect. [ABSTRACT FROM AUTHOR]

We examined the interaction between ephrins and metabotropic glutamate (mGlu) receptors in the developing brain and cultured neurons. EphrinB2 coimmunoprecipitated with mGlu1a receptors, in all of the brain regions examined, and with mGlu5 receptors in the corpus striatum. In striatal slices, activation of ephrinB2 by a clustered form of its target receptor, EphB1, amplified the mGlu receptor-mediated stimulation of polyphosphoinositide (PI) hydrolysis. This effect was abolished in slices treated with mGlu1 or NMDA receptor antagonists but was not affected by pharmacological blockade of mGlu5 receptors. An interaction among ephrinB2, mGlu1 receptor, and NMDA was supported by the following observations: (1) the NR1 subunit of NMDA receptors coimmunoprecipitated with mGlu1a receptors and ephrinB2 in striatal lysates; (2) clustered EphB1 amplified excitatory amino acid-stimulated PI hydrolysis in cultured granule cells grown under conditions that favored the expression of mGlu1a receptors; and (3) clustered EphB1 amplified the enhancing effect of mGlu receptor agonists on NMDA toxicity in cortical cultures, and its action was sensitive to mGlu1 receptor antagonists. Finally, fluorescence resonance energy transfer and coclustering analysis in human embryonic kidney 293 cells excluded a physical interaction between ephrinB2 and mGlu1a (or mGlu5 receptors). A functional interaction between ephrinB and mGlu1 receptors, which likely involves adaptor or scaffolding proteins, might have an important role in the regulation of developmental plasticity. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The aim of this study was to evaluate the efficacy and the impact on quality of life of a new ablative approach to the right atrium in patients with atrial fibrillation (AF). METHODS AND RESULTS: Seventy-four symptomatic patients with paroxysmal (n = 49) or permanent (n = 25) refractory AF underwent radiofrequency ablation. A nonfluoroscopic electroanatomic mapping system was used to perform the following lesions: (1) an isthmus line between the tricuspid annulus and the inferior vena cava; (2) a posterior intercaval line from the superior vena cava and the inferior vena cava; (3) a septal line from the superior vena cava to the fossa ovalis, proceeding to the coronary sinus ostium where a circumferential line around the ostium was performed, and then on to the inferior vena cava; and (4) a transversal lesion connecting the posterior intercaval and the septal lesions. In addition, electrical disconnection of the superior vena cava was performed. There were no complications. Postablation remapping showed the absence of discrete electrical activity inside and just around the ablation lines. Electrical disconnection of the superior vena cava was obtained in all patients. After 21 +/- 6 months, 49 patients (66%) had stable sinus rhythm with continuation of the previous antiarrhythmic drug therapy, 13 patients (18%) were considered improved, and 12 (16%) received no benefit (unsuccessful procedure). After ablation, quality of life was significantly improved, reaching the levels of the general Italian population. Ejection fraction and the extent of the low-voltage area were found by multivariate analysis to be independent predictors of AF recurrence. CONCLUSION: The results of the present study suggest that this ablative approach in combination with antiarrhythmic drugs is safe and effective in treating AF, leading to a marked increase in quality of life in patients with refractory AF. [ABSTRACT FROM AUTHOR]

Abstract Aims Inappropriate production of nitric oxide (NO) may be responsible for the haemodynamic disturbances of diabetic ketoacidosis. We investigated whether this metabolic condition is associated with increased plasma nitrate (the stable oxidation product of NO) levels and NO synthase gene expression in lymphomonocytes. Research design and methods Plasma nitrate concentrations, lymphomonocyte-inducible nitric oxide synthase (iNOS) gene expression, tumour necrosis factor-alpha (TNF-α) and soluble thrombomodulin were measured in 11 Type 1 diabetic patients at baseline, during mild ketosis and after euglycaemia was re-established. Results During diabetic ketosis plasma nitrate concentrations were higher (18 (16–21) vs. 9 (7–11) µmol/l; (95% lower-upper confidence interval) P < 0.05) than at baseline. At baseline lymphomonocyte iNOS mRNA expression and iNOS protein levels were undetectable, but in ketosis both were increased (both at P < 0.0001). After recovery from ketosis, NO 3 concentration, iNOS mRNA, and iNOS expression (270 ± 36%, mean ± sd) decreased but not significantly. No significant changes were observed in either TNF-α or soluble thrombomodulin levels between the three conditions. Conclusions Diabetic ketosis is associated with increased nitrate levels and the activation of iNOS expression in circulating lymphomonocytes, but it does not affect either the proinflammatory cytokine TNF-α or a marker of endothelial dysfunction such as thrombomodulin. Our data support the hypothesis that, during diabetic ketosis, alterations in NO homeostasis are present in circulating lymphomonocytes. [ABSTRACT FROM AUTHOR]

The article relates a study that assesses the urinary albumin/creatinine ratio (UACR) as a potential marker of endothelial dysfunction in Bartter's/Gitelman's syndromes (BS/GS) patients. It was taken into account that BS/GS have biochemical and hormonal characteristics typical of hypertension yet normotensive. Findings reveals that UACR in BS/GS did not differ from healthy subjects, indicating increased UACR reflects endothelial dysfunction and its associated increased cardiovascular risk.

• A mephedrone-related acute toxicity case. • Chemsex: misuse of mephedrone in a sexual context. • Effects of mephedrone similar to those of cocaine, amphetamines, and metamphetamines. • Mephedrone cross-reacts with methamphetamine screening tests. The chemsex or slamsex phenomenon has attracted attention worldwide, with concerns also expressed by health professionals for the spread of sexually transmitted diseases. Mephedrone or 4-methylmethcathinone, a substituted cathinone homolog of ephedrine, is one of the most popular substances used as a cheaper alternative to other traditional drugs. Fatal cases of chemsex are still rare. We present here the first case-report to the best of our knowledge of a mephedrone-related acute toxicity case in Parma (Italy) detected and quantitated in biological specimens (2.0 mg/L in urine sample, 1.1 mg/L in bile and 1.0 mg/L in central blood while 0.8 mg/L in peripheral blood). None of the other most common drugs of abuse could be detected. Autopsy findings such as facies edematosa, oedema and polyvisceral congestion, interstitial petechiae are compatible elements with a death from acute cardio-respiratory failure, with peri-mortem agony of few minutes in which the cardiac hypertrophy, the moderate aortocoronary sclerosis and mephedrone injection have played a substantial role in the evaluation of the final cause due to an accidental acute intoxication with mephedrone. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about phosphorus posing a nutrient pollution problem in the blood.

McKittrick and Wheelock syndrome (MKW), firstly described in 1954[1] is a diarrhea sustained by a rectal villous adenoma. Learning points for clinicians Nephrologists, endocrinologists and internal medicine physicians should be aware of McKittrick and Wheelock syndrome, which should be considered in the differential diagnosis in presence of electrolyte abnormalities, diarrhea and acute kidney injury. Electrolyte abnormalities and acidosis improved, diarrhea episodes reduced to one per day and oliguria resolved after 2 days with progressive improving of renal function up to normal. [Extracted from the article]

The aim of this case–control study was to analyse the prevalence of gynaecological, obstetrical and other more general bleeding symptoms in 114 women affected by various inherited bleeding disorders, who were compared with 114 apparently healthy women. Retrospective information were collected by means of two specific questionnaires, one on gynaecological and obstetrical bleeding symptoms, with special focus on the presence of menorrhagia as defined by a pictorial blood loss assessment chart (PBAC); and the other on general bleeding symptoms, whose severity was graded by means of the bleeding score (BS). Compared to normal women, the whole group of women with inherited bleeding disorders had a higher prevalence of excessive bleeding at menarche (25% vs. 5%, P < 0.0001) and menorrhagia (59% vs. 46%, P = 0.06). Affected women also had a higher frequency than controls of general bleeding symptoms that scored as severe by a BS ≥ 12 (49% vs. 0%, P < 0.0001). In affected women, the BS increased according to the severity of the haemostasis defect. In conclusions, the BS and the PBAC are simple tools to evaluate the severity of general bleeding symptoms and menorrhagia in women with inherited bleeding disorders. These instruments may help to identify those women for whom a therapeutic intervention is warranted. [ABSTRACT FROM AUTHOR]

Isolated ventricular premature beats (VPBs) are commonly found during pre‐participation screening in athletes. Currently, the debate about the role of detraining in reducing the number of VPBs is still open. This study evaluated the arrhythmic risk in a population of young competitive athletes who showed VPBs during eligibility evaluation and that did not undergo detraining but continued practicing competitive sports. 3746 consecutive subjects underwent pre‐participation screening. Athletes who showed VPBs were selected and underwent second level evaluation (Echocardiogram, 24 hour Holter ECG and Exercise test). Athletes were re‐evaluated after a follow‐up period (6‐48 months) while they continued practicing competitive sports. 5.3% of the whole population showed ventricular arrhythmias. 73% of the subjects showed isolated VPBs. 88% of the subjects showed monomorphic VPBs, and 12% of athletes showed polymorphic VPBs. At echocardiogram, there was not any pathology which contraindicated competitive sport activity. At 24 hour Holter ECG recording, mean number of daily VPBs was 1592±3217 (range 0‐16678). At holter ECG follow‐up (16±12 months), the median number of VPBs decreased from 93 (IQR 20‐3065) to a new value of 72 (IQR 2‐1299). Continuing competitive sport in subjects with ventricular arrhythmias even though frequent but with a low grade of complexity and without structural cardiomyopathy does not increase sudden death risk. [ABSTRACT FROM AUTHOR]

It is unclear whether revascularization of renal artery stenosis (RAS) by means of percutaneous renal angioplasty and stenting (PTRAS) is advantageous over optimal medical therapy. Hence, we designed a randomized clinical trial based on an optimized patient selection strategy and hard experimental endpoints. Primary objective of this study is to determine whether PTRAS is superior or equivalent to optimal medical treatment for preserving glomerular filtration rate (GFR) in the ischemic kidney as assessed by 99mTcDTPA sequential renal scintiscan. Secondary objectives of this study are to establish whether the two treatments are equivalent in lowering blood pressure, preserving overall renal function and regressing target organ damage, preventing cardiovascular events and improving quality of life. The study is designed as a prospective multicentre randomized, un-blinded two-arm study. Eligible patients will have clinical and angio-CT evidence of RAS. Inclusion criteria is RAS affecting the main renal artery or its major branches either >70% or, if <70, with post-stenotic dilatation. Renal function will be assessed with 99mTc-DTPA renal scintigraphy. Patients will be randomized to either arms considering both resistance index value in the ischemic kidney and the presence of unilateral/bilateral stenosis. Primary experimental endpoint will be the GFR of the ischemic kidney, assessed as quantitative variable by 99TcDTPA, and the loss of ischemic kidney defined as a categorical variable. [ABSTRACT FROM AUTHOR]

In type 1 diabetic patients, acute loss of metabolic control is associated with increased blood flow, which is believed to favor the development of long-term complications. The mechanisms for inappropriate vasodilation are partially understood, but a role of endothelium-derived nitric oxide (NO) production can be postulated. We assessed, in type 1 diabetic patients, the effect of the acute loss of metabolic control and its restoration on forearm endothelial function in 13 type 1 diabetic patients who were studied under conditions of mild ketosis on two different occasions. In study 1, after basal determination, a rapid amelioration of the metabolic picture was obtained by insulin infusion. In study 2, seven type 1 diabetic patients underwent the same experimental procedure, except that fasting plasma glucose was maintained constant throughout. Basal plasma venous concentrations of nitrites/nitrates (NO2- + NO3-) were determined both before and after intravenous insulin infusion. Endothelium-dependent and -independent vasodilation of the brachial artery was assessed by an intra-arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA) and sodium nitroprusside (SNP), respectively. The same parameters were determined in 13 control subjects at baseline conditions and during a hyperinsulinemic-euglycemic glucose clamp. Baseline forearm blood flow (4.89 +/- 0.86 vs. 3.65 +/- 0.59 ml x (100 ml tissue)(-1) x min(-1)) and NO2- + NO3- concentration (30 +/- 8 vs. 24 +/- 3 micromol/l) were higher in type 1 diabetic patients than in control subjects (P < 0.05). Insulin infusion was associated with lower forearm blood flow and plasma (NO2- + NO3-) concentration (P < 0.05), irrespective of the prevailing glucose levels, as compared with patients under ketotic conditions. The responses to L-NMMA were significantly lower in type 1 diabetic patients during euglycemia and hyperglycemic hyperinsulinemia (-11 +/- 5 and -10 +/- 4%, respectively, of the ratio of the infused arm to the control arm) than in control subjects at baseline (-18 +/- 6%, P < 0.05) and during hyperinsulinemia (-32 +/- 11%, P < 0.01). We conclude that the acute loss of metabolic control is associated with a functional disturbance of the endothelial function characterized by hyperemia and increased NO release during ketosis and blunted NO-mediated vasodilatory response during restoration of metabolic control by intravenous insulin. This functional alteration is unlikely to be explained by hyperglycemia itself. [ABSTRACT FROM AUTHOR]