Renin messenger RNA localization in congenital mesoblastic nephroma using in situ hybridization

Renin messenger (m) RNA distribution was studied in congenital mesoblastic nephroma, a usually benign renal tumour of early infancy which may be associated with excess renin production and hypertension. Using in situ hybridization with synthetic radiolabelled oligonucleotide probes combined with immunohistochemical studies, renin expression was found in areas of tumours containing recognizable cortical structures including glomeruli and tubules. Renin mRNA was also detected in vessels and larger vascular spaces within the tumour not associated with cortical structures. Cells in the tumour vessel walls and sinusoids which expressed renin also stained positively for vascular smooth muscle-specific alpha actin.     

Exercise testing at 3 weeks, 6 weeks and 18 months after infarction and the outcome at 3 years in young patients (under 55 years).

To examine the prognostic value of routine postinfarction exercise tests in young patients, exercise tests were carried out at 3 and 6 weeks and 18 months after infarction in 149 patients aged under 55 years at the time of the index infarction. The patients also had coronary angiography and left ventriculography a mean of 3 months after infarction. Three years after infarction, only two of the 149 patients have died, reinfarction occurred in only seven (4.7%) patients; unstable angina in four (3%) patients and coronary artery surgery was needed in 31 (20.8%) patients; 16 in the first, 10 in the second, and 5 in the third year of follow-up. Angina on exercise testing at 6 weeks was the only variable with any predictive value. Eighteen (38%) of the 47 patients with, compared to 12 (11.8%) of the 102 patients without, angina on exercise testing at 6 weeks had coronary surgery (less than 0.001). None of the other exercise variables reliably predicted death, or other complications, including coronary surgery. Ten (13.8%) of the 75 patients excluded from the study died during follow-up; six of them within 6 weeks of infarction. Four (67%) of these patients were excluded from the study because of heart failure. Therefore, the 3-year outcome in young survivors of a myocardial infarction is good and is not reliably predicted by exercise testing at 3 and 6 weeks or 18 months.     

The physiological stress response to high-intensity sprint exercise following the ingestion of sodium bicarbonate

The purpose of this study was to investigate the effects of pre-exercise alkalosis on the physiological stress response to high-intensity exercise. Seven physically active males (age 22 ± 3 years, height 1.82 ± 0.06 m, mass 81.3 ± 8.4 kg and peak power output 300 ± 22 W) performed a repeated sprint cycle exercise following a dose of 0.3 g kg^?1 body mass of sodium bicarbonate (NaHCO₃) (BICARB), or a placebo of 0.045 g kg^?1 body mass of sodium chloride (PLAC). Monocyte-expressed heat shock protein 72 (HSP72) and plasma thiobarbituric acid reactive substances (TBARS) were significantly attenuated in BICARB compared to PLAC (p = 0.04 and p = 0.039, respectively), however total anti-oxidant capacity, the ratio of oxidised to total glutathione, cortisol, interleukin 6 and interleukin 8 were not significantly induced by the exercise. In conclusion, monocyte-expressed HSP72 is significantly increased following high-intensity anaerobic exercise, and its attenuation following such exercise with the ingestion of NaHCO₃ is unlikely to be due to a decreased oxidative stress.     

Balloon dilatation of unoperated aortic coarctation: immediate results and one year follow up.

Fifteen patients aged 1-19 years (mean 10.9) with previously unoperated aortic coarctation underwent percutaneous balloon angioplasty between January 1985 and February 1986. Nine (60%) were hypertensive at presentation. Under general anaesthetic the systolic coarctation gradient was 24-50 mm Hg (mean 29) and the coarctation diameter was 4-9 mm (mean 5.5). Meditech balloon catheters 8-18 mm in diameter were inflated 1-4 times at 410-760 kPa. After dilatation the systolic coarctation gradient decreased to 0-20 mm Hg (mean 6) and the coarctation diameter increased to 7-20 mm (mean 12). One patient developed a fusiform aneurysm of the aorta at the coarctation site immediately after the procedure. At reinvestigation 6-16 months (mean 12.5) after dilatation 14 of the 15 patients were normotensive. In 13 patients the residual coarctation gradient was 0-10 mm Hg (mean 3). Two patients had recoarctation with residual gradients of 20 and 24 mm Hg and underwent successful repeat dilatation. One patient had developed a small discrete aneurysm at the coarctation site. Balloon angioplasty is thus a safe and effective method of relieving unoperated aortic coarctation. The frequency of aortic aneurysm and recoarctation is small and probably related to balloon size. This early experience is encouraging, but long term results and further experience are required before this approach is used to treat coarctation generally.     

Recanalisation of an occluded modified Blalock-Taussig shunt by balloon dilatation.

A four year old boy with pulmonary atresia and ventricular septal defect had an acute cyanotic episode three years after undergoing a right-sided, 6 mm diameter, modified Blalock-Taussig shunt. On admission no continuous murmur could be heard from the shunt and the typical high velocity, continuous flow profile of the shunt could not be identified by Doppler echocardiography. At catheterisation a right subclavian artery angiogram confirmed shunt occlusion. From the subclavian artery, an 0.035 inch wire was used to enter the occluded shunt and then the pulmonary artery. Balloon angioplasty of the entire length of the shunt was performed with 6 mm diameter balloon. After angioplasty the arterial oxygen saturation increased from 63% to 83%. The patient was treated with intravenous heparin followed by warfarin. Repeat catheterisation and angiography eight days later confirmed wide patency of the shunt.     

Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain

P-glycoprotein, an ATP-driven drug efflux pump, is a major obstacle to the delivery of small-molecule drugs across the blood-brain barrier and into the CNS. Here we test a unique signaling-based strategy to overcome this obstacle. We used a confocal microscopy-based assay with isolated rat brain capillaries to map a signaling pathway that within minutes abolishes P-glycoprotein transport activity without altering transporter protein expression or tight junction permeability. This pathway encompasses elements of proinflammatory- (TNF-α) and sphingolipid-based signaling. Critical to this pathway was signaling through sphingosine-1-phosphate receptor 1 (S1PR1). In brain capillaries, S1P acted through S1PR1 to rapidly and reversibly reduce P-glycoprotein transport activity. Sphingosine reduced transport by a sphingosine kinase-dependent mechanism. Importantly, fingolimod (FTY720), a S1P analog recently approved for treatment of multiple sclerosis, also rapidly reduced P-glycoprotein activity; similar effects were found with the active, phosphorylated metabolite (FTY720P). We validated these findings in vivo using in situ brain perfusion in rats. Administration of S1P, FTY720, or FTY729P increased brain uptake of three radiolabeled P-glycoprotein substrates, ³H-verapamil (threefold increase), ³H-loperamide (fivefold increase), and ³H-paclitaxel (fivefold increase); blocking S1PR1 abolished this effect. Tight junctional permeability, measured as brain ¹⁴C-sucrose accumulation, was not altered. Therefore, targeting signaling through S1PR1 at the blood-brain barrier with the sphingolipid-based drugs, FTY720 or FTY720P, can rapidly and reversibly reduce basal P-glycoprotein activity and thus improve delivery of small-molecule therapeutics to the brain.     

The role of two-dimensional echocardiology in the diagnosis of infective endocarditis [corrected

Two-dimensional echocardiography has had a significant impact on and is considered the technique of choice for the diagnosis and management of infective endocarditis. Over a thirty-six month period, 106 patients were evaluated by echocardiography for the possibility of endocarditis. The diagnosis of endocarditis was determined by strict clinical and laboratory criteria. All clinical histories, blood cultures, echocardiograms, and autopsy results were reviewed. Five echocardiograms were technically inadequate, resulting in a study population of 101 patients. The age of the patients ranged from forty-five days to eighty-eight years (mean fifty-seven years). The clinical manifestations of endocarditis included fever (83%), chills (60%), congestive heart failure (25%), and splenomegaly (18%). Twelve patients had preexisting valvular or congenital heart disease. Gram-positive cocci were the most common microorganisms. Complications included mitral regurgitation, subarachnoid hemorrhage, renal infarction, stroke, and a pulmonary embolus. The patients were divided into two groups: Group I consisted of 36 patients with definite vegetations by echocardiography, and Group II had 65 patients with no vegetations. In Group I, acute infective endocarditis was present in 35 patients, whereas only 4 patients had endocarditis in Group II. The sensitivity of two-dimensional echocardiography for detecting endocarditis was 90%. The specificity was 98%. The predictive accuracy for a positive test was 97%, and the predictive accuracy for a negative test was 94%. Thus, two-dimensional echocardiography appears to have a high sensitivity, specificity, and predictive value in the evaluation of patients with suspected endocarditis.