Dietary supplementation of cystinotic mice by lysine inhibits the megalin pathway and decreases kidney cystine content.

Megalin/LRP2 is a major receptor supporting apical endocytosis in kidney proximal tubular cells. We have previously reported that kidney-specific perinatal ablation of the megalin gene in cystinotic mice, a model of nephropathic cystinosis, essentially blocks renal cystine accumulation and partially preserves kidney tissue integrity. Here, we examined whether inhibition of the megalin pathway in adult cystinotic mice by dietary supplementation (5x-fold vs control regular diet) with the dibasic amino-acids (dAAs), lysine or arginine, both of which are used to treat patients with other rare metabolic disorders, could also decrease renal cystine accumulation and protect cystinotic kidneys. Using surface plasmon resonance, we first showed that both dAAs compete for protein ligand binding to immobilized megalin in a concentration-dependent manner, with identical inhibition curves by L- and D-stereoisomers. In cystinotic mice, 2-month diets with 5x-L-lysine and 5x-L-arginine were overall well tolerated, while 5x-D-lysine induced strong polyuria but no weight loss. All diets induced a marked increase of dAA urinary excretion, most prominent under 5x-D-lysine, without sign of kidney insufficiency. Renal cystine accumulation was slowed down approx. twofold by L-dAAs, and totally suppressed by D-lysine. We conclude that prolonged dietary manipulation of the megalin pathway in kidneys is feasible, tolerable and can be effective in vivo.

Liver failure complicating segmental hepatic ischaemia induced by a PTFE-coated TIPS stent.

The use of polytetrafluoroethylene (PTFE)-covered prostheses improves trans-jugular intrahepatic porto-systemic shunt (TIPS) patency and decreases the incidence of clinical relapses and re-interventions. Therefore, the improvement provided by covered stents might expand the currently accepted recommendations for TIPS use. Stent-related occlusion of the hepatic vein with consequent ischaemia of the corresponding liver parenchyma emerges as a novel complication reported in at least 5% of patients implanted with coated stents. However, this complication was reported to be mild, without signs or symptoms of liver failure, and self-limiting. We report a case of segmental liver ischaemia following PTFE-covered stent placement resulting in a marked impairment in liver function in a patient with hepatitis C virus cirrhosis implanted because of refractory oesophageal bleeding, thus expanding the severity range of this new procedural complication. Moreover, we discuss the possible involvement of additional pathogenetic mechanisms other than out-flow obstruction in the onset of coated-stent induced congestive liver ischaemia.

Non invasive diagnosis of portal hypertension in cirrhotic patients.

The measure of disease progression in chronic liver disease represents a key challenge in any of the different stages of evolution. Indeed, a correct and reliable measure of the stage of the disease has relevant implications for assessing the effectiveness of the current therapeutic regimens and for predicting the occurrence of complication. Accordingly, a current major effort is directed at evaluating methodologies characterized by no or low invasiveness to be employed as clinical discriminators in patients populations potentially requiring invasive assessment. This appears particularly relevant in patients with compensated cirrhosis, where the only reference standard is the measurement of portal pressure by hepatic venous pressure gradient (HVPG). In this particular context, transient elastography (TE) appears to be promising and needs to be further investigated, possibly in combination with other non-invasive methodologies such as serum markers algorithms and/or imaging techniques. On the other hand, the application of non-invasive methods for monitoring the response to vasoactive treatment for the reduction of portal pressure and the prevention of related complications seems at the moment not realistic.

ADMA correlates with portal pressure in patients with compensated cirrhosis.

BACKGROUND: Chronic liver diseases are frequently complicated by portal hypertension, an important component of which is the increased intrahepatic vascular resistance, in part related to endothelial dysfunction. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, is an established mediator and marker of endothelial dysfunction. We therefore investigated the possible implication of ADMA in chronic liver diseases-induced portal hypertension. MATERIALS AND METHODS: We studied 39 consecutive patients with compensated hepatitis C virus (HCV) related chronic liver diseases. All patients underwent hepatic venous pressure gradient (HVPG) measurement, and simultaneous blood sampling from the hepatic vein and the pulmonary artery, for ADMA and nitrite/nitrate (NOx) plasma level determinations. RESULTS: A positive correlation between HVPG and ADMA concentrations in hepatic veins (ADMA-h) was found (r = 0.77, P < 0.0001). Moreover, a negative correlation between HVPG and NOx concentrations in the hepatic veins (NO-h) (r = -0.50, P = 0.005), and between ADMA-h and NO-h was observed (r = -0.40, P = 0.02). ADMA concentrations in pulmonary artery (ADMA-p) (0.55 +/- 0.13 micromol L(-1)) were significantly higher than in hepatic veins (0.47 +/- 0.09 micromol L(-1)) (P < 0.0001). CONCLUSIONS: These results suggest that ADMA may play a pathophysiological role in portal hypertension by contributing to the relative intrahepatic NO deficiency typical of endothelial dysfunction.

Cyclic GMP phosphodiesterase activity role in normal and inflamed human dental pulp.

Cyclic GMP phosphodiesterase (cGMP PDE) plays an important role in pulp tissues. High levels of cGMP PDE are found in dental pulp cells. In the present study cGMP PDE activity was analyzed in normal healthy human dental pulps, in reversible pulpitis and in irreversible pulpitis. Enzymatic cGMP PDE control values for normal healthy pulps were 4.74+/-0.32 nmol/mg of proteins. In reversible pulpitis the cGMP PDE activity increased almost 3 times. In irreversible pulpitis specimens the values increased 4.5 times compared with the normal healthy pulps activity. The differences between the groups (control vs. reversible pulpitis and vs. irreversible pulpitis) were statistically significant. These results point to a role of cGMP PDE in the initial pulp response after injury.

Anomalous origin of the circumflex artery and patent foramen ovale: a rare cause of myocardial ischaemia after percutaneous closure of the defect.

A 35 year old man with a history of transient ischaemic attack and atrial septal aneurysm underwent percutaneous closure of a patent foramen ovale (PFO) with a transcatheter device. After the procedure the patient developed effort angina not present previously. Transoesophageal echocardiography confirmed the absence of residual shunt but showed an abnormal linear image running behind the aortic root. Magnetic resonance imaging detected an anomalous origin of the circumflex coronary artery from the right coronary sinus. The anomalous artery was located between the aortic root and the PFO closing device, causing coronary insufficiency. This report describes a rare complication of transcatheter PFO closure.

Value of hepatic arterial phase CT versus lipiodol ultrafluid CT in the detection of hepatocellular carcinoma.

OBJECTIVE: To evaluate the role of hepatic arterial phase (HAP) spiral computed tomography (CT), as compared with iodized oil (Lipiodol ultrafluid [LUF]) CT for revealing nodular hepatocellular carcinomas (HCC). METHODS: Twenty-four cirrhotic patients underwent two-phase HCT examination: HAP 25 seconds and portal phase 70 seconds after injection of 1.5 mL/Kg contrast medium. All patients also underwent hepatic angiography and intraarterial infusion of iodized oil; LUF CT was performed 3-4 weeks after infusion. HCT images were compared with LUF CT images for detection of hepatic nodules. RESULTS: We found no significant difference between the sensitivity of HAP CT and LUF CT for nodules >10 mm, while HAP CT was more sensitive than LUF CT in revealing nodules <10 mm (47 vs. 27, p < 0.001). CONCLUSIONS: HCT should be considered as the first method for the detection of HCC, whereas LUF CT should be used only for therapy.

Endothelin-1 urinary excretion, but not endothelin-1 plasma concentration, is increased in renovascular hypertension.

Animal experiments have shown an increase in prepro-endothelin-1 (prepro-ET-1) mRNA expression in the clipped kidney but none in the aortic and mesenteric arteries in 2-kidney, 1-clip Goldblatt hypertensive rats. The present study was aimed at investigating whether plasma and renal endothelin-1 (ET-1) systems are differently activated in patients with renovascular hypertension (RH). The plasma concentration and urinary excretion of ET-1 were measured in 5 patients with RH (before and after successful renal angioplasty), in 7 patients with essential hypertension (EH), and in 8 normotensive control subjects. Immediately before renal angioplasty, plasma samples for ET-1 and plasma renin activity (PRA) measurements were withdrawn from the aorta and both renal veins. Unlike the PRA, the plasma ET-1 concentration did not significantly differ between the involved and the uninvolved sides. The urinary ET-1 excretion level (Fig 1) was markedly increased in patients with RH (30+/-4 ng/g urinary creatinine (UC) vs. 2.5+/-0.2 ng/g UC and 2.6+/-0.5 ng/g UC in control subjects and patients with EH, respectively; P<.001), whereas the plasma ET-1 concentration was normal (0.8+/-0.2 pg/mL vs. 0.65+/-0.3 pg/mL and 0.8+/-0.2 pg/mL in control subjects and EH, respectively, not significant). Renal angioplasty was followed in all patients by normalization of blood pressure and PRA. One week after angioplasty, urinary ET-1 decreased to one fourth of baseline (8.04+/-5.23 ng/g UC, P<.001 vs. values before angioplasty and P<.04 vs. control subjects) and normalized 1 month thereafter (3.13+/-1.62 ng/g UC, not significant vs. control subjects), whereas plasma ET-1 remained steady. The present findings clearly indicate that in patients with RH, urinary ET-1 excretion is increased, whereas plasma ET-1 concentration remains normal. Successful percutaneous transluminal renal angioplasty induced a notable reduction in ET-1 urinary excretion, whereas it did not affect ET-1 plasma concentration.

Partial anomalous venous return associated with intact atrial septum and persistent left superior vena cava: a case report and literature review.

Left-sided partial anomalous pulmonary venous return (PAPVR) with an intact atrial septum is a rare cardiovascular anomaly. This report deals with the case of a 22-year-old woman who was referred to our Institution because of resting palpitation and exertional dyspnea. Two-dimensional echocardiography revealed right heart volume overload and a dilated coronary sinus. A left-sided PAPVR draining into a persistent left superior vena cava which, in turn, entered a dilated coronary sinus, was correctly detected by magnetic resonance imaging. Diagnosis was confirmed by cardiac catheterization. The literature on this subject is reviewed.

Hypertensive vascular crisis secondary to chronic total renal artery occlusion.

We have reviewed thirty-three cases of accelerated hypertension associated with chronic total renal artery occlusion. During the process of progressive narrowing of the arterial lumen until complete occlusion, an exceptionally elevated blood pressure occurs when a critical reduction of renal blood flow is attained. Then the patient presents one or more of the following clinical manifestations: III-IV grade KWB retinal changes, hypertensive encephalopathy including convulsive attacks, stroke, heart failure, renal insufficiency. We have called this clinical event 'hypertensive vascular crisis'. Mostly in older patients an actual or anamnestic vascular crisis makes a diagnosis of chronic total renal artery occlusion highly probable.

Transthoracic three-dimensional echocardiographic reconstruction of left and right ventricles: in vitro validation and comparison with magnetic resonance imaging.

Two-dimensional (2D) echocardiographic and angiographic measurements of ventricular volumes are limited by geometric assumptions concerning cavity shape. We compared in vitro the accuracy of a three-dimensional (3D) echocardiographic system suitable for transthoracic imaging to magnetic resonance imaging (MRI) in the measurement of left and right ventricular volumes. Ventricular cast volumes from 14 excised formalin-fixed sheep hearts filled with an agarose solution were compared with data derived from 3D echocardiography and MRI. Left and right ventricular volumes from 3D echocardiographic reconstructions agreed well with actual volumes without significant underestimation or overestimation. MRI progressively underestimated left ventricular volumes as these increased and systematically underestimated right ventricular volumes. Our echocardiographic system designed for 3D transthoracic imaging combines excellent measurements of left and right ventricular volumes and the computed reconstruction of tomographic slices with the full spatial resolution of the original 2D images. Thus in this in vitro model, 3D echocardiography exhibited greater accuracy than MRI.

Evaluation of mitral stenosis by cine magnetic resonance imaging.

To evaluate the ability of cine magnetic resonance imaging (cine MRI) in the assessment of mitral stenosis (MS), we studied 20 patients (14 women and 6 men, mean age 60.6 +/- 8.5 years) with rheumatic mitral valve stenosis by using an 0.5 T magnet. Cine MRI showed several signs of MS. Mitral leaflet thickening, reduced diastolic opening, and abnormal valve motion toward the left ventricular outflow tract were all common features. MS was also characterized by an abnormal diastolic transmitral signal from blood. Both left atrial and left ventricular dimensions were similar to those obtained at two-dimensional echocardiography (2-DE) (r = 0.89 and r = 0.86, respectively; p less than 0.001). A significant relationship was also found between the maximum mitral leaflet separation measured by cine MRI in diastole and the mitral valve area as calculated using the pressure half-time method and continuous wave Doppler (r = 0.81; p less than 0.001). These data indicate the improved ability of MRI to detect and assess MS and also suggest that this technique may contribute to the noninvasive assessment of MS.

[Role of local and regional thrombolysis in late thromboses of the branches of prostheses]. / Le rôle de la thrombolyse loco-régionale dans les thromboses tardives des branches de prothèses.

Results of treatment of a personal series of 12 patients developing a thrombus in branches of prostheses after aorto-iliac surgery are presented. A therapeutic procedure used over the last two years consists of initial local and regional thrombolysis to remove the acute obstruction, followed by surgery at the level chosen, and if necessary to correct a faulty technique or progression of the atherosclerosis. Good results were obtained even for thrombosis originating after the conventional 8-10 day postoperative period, insofar as the thrombus that develops in a graft may differ from one forming in an artery. This aspect requires further studies, which will also provide greater clarification of the etiopathogenicity.