Ghrelin increases food intake in obese as well as lean subjects

OBJECTIVE: To investigate whether effects on food intake are seen in obese subjects receiving exogenous administration of ghrelin. DESIGN: Randomised, double-blind, placebo-controlled study of intravenous ghrelin at doses 1 pmol/kg/min and 5 pmol/kg/min. SUBJECTS: In all, 12 healthy lean subjects (mean body mass index (BMI) 20.5+/-0.17 kg/m(2)) and 12 healthy overweight and obese subjects (mean BMI 31.9+/-1.02 kg/m(2)). MEASUREMENTS: Food intake, appetite and palatability of food, ghrelin and other obesity-related hormones, growth hormone. RESULTS: Low-dose infusion of ghrelin increased ad libitum energy intake at a buffet meal in the obese group only (mean increase 36.6+/-9.4%, P<0.01.) High-dose ghrelin infusion increased energy intake in both groups (mean increase 20.1+/-10.6% in the lean and 70.1+/-15.5% in the obese, P<0.01 in both cases.) Ghrelin infusion increased palatability of food in the obese group. CONCLUSION: Ghrelin increases food intake in obese as well as lean subjects. Obese people are sensitive to the appetite-stimulating effects of ghrelin and inhibition of circulating ghrelin may be a useful therapeutic target in the treatment of obesity.     

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.     

Immune reconstitution in severe combined immunodeficiency disease after lectin-treated, T-cell-depleted haplocompatible bone marrow transplantation

We describe our 9-year experience with lectin-treated T-cell-depleted haplocompatible parental bone marrow transplantation (BMT) for 24 patients with severe combined immunodeficiency disease (SCID). Nineteen of 21 evaluable patients had T-cell engraftment; 2 of 11 patients tested had B-cell and monocyte engraftment. Fourteen of 24 (58%) patients are alive 7 months to 9.8 years post-BMT. Seventeen of 24 patients received pretransplant conditioning with chemotherapy and/or total body irradiation, and 8 of 24 received more than one transplant. Patients who received conditioning had a survival rate of 61% versus 57% for those who received no conditioning. None received graft-versus- host disease (GVHD) prophylaxis and no patient had acute or chronic GVHD greater than grade I. Kinetics and follow-up of immune recovery were analyzed in 14 patients who are greater than 1 year from transplant. Half of the patients showed evidence of T-cell function by 3 months and normal T-cell function by 4 to 7 months post-BMT. On average, T-cell numbers and subsets became normal 10 to 12 months posttransplant. Recovery of B-cell function was more delayed, although in most patients B-cell numbers and IgM levels were normal by 12 months post-BMT. B-cell function, as determined by isohemagglutinin titers or specific antibodies to pneumococcal polysaccharide, keyhole limpet hemocyanin, or tetanus toxoid, became normal in 10 of 14 patients 2 to 8 years post-BMT. Seven of the 14 are off gammaglobulin therapy. Production of isohemagglutinins tended to predict recovery of antibody response to pneumococcal polysaccharide (P < .064). Based on these results, we believe that haplocompatible BMT is an effective, curative treatment for patients with SCID who lack an HLA-matched related donor.     

Clinical and Pathologic Impact of Select Chromatin-modulating Tumor Suppressors in Clear Cell Renal Cell Carcinoma

Background

Historically, VHL was the only frequently mutated gene in clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent sequencing efforts have identified several novel frequent mutations of histone modifying and chromatin remodeling genes in ccRCC including PBRM1, SETD2, BAP1, and KDM5C. PBRM1, SETD2, and BAP1 are located in close proximity to VHL within a commonly lost (approximately 90%) 3p locus. To date, the clinical and pathologic significance of mutations in these novel candidate tumor suppressors is unknown.

Objective

To determine the frequency of and render the first clinical and pathologic outcome associated with mutations of these novel candidate tumor suppressors in ccRCC.

Design, setting, and participants

Targeted sequencing was performed in 185 ccRCCs and matched normal tissues from a single institution. Pathologic features, baseline patient characteristics, and follow-up data were recorded.

Outcome measurements and statistical analysis

The linkage between mutations and clinical and pathologic outcomes was interrogated with the Fisher exact test (for stage and Fuhrman nuclear grade) and the permutation log-rank test (for cancer-specific survival [CSS]).

Results and limitations

PBRM1, BAP1, SETD2, and KDM5C are mutated at 29%, 6%, 8%, and 8%, respectively. Tumors with mutations in PBRM1 or any of BAP1, SETD2, or KDM5C (19%) are more likely to present with stage III disease or higher (p = 0.01 and p = 0.001, respectively). Small tumors (<4 cm) with PBRM1 mutations are more likely to exhibit stage III pathologic features (odds ratio: 6.4; p = 0.001). BAP1 mutations tend to occur in Fuhrman grade III–IV tumors (p = 0.052) and are associated with worse CSS (p = 0.01). Clinical outcome data are limited by the number of events.

Conclusions

Most mutations of chromatin modulators discovered in ccRCC are loss of function, associated with advanced stage, grade, and possibly worse CSS. Further studies validating the clinical impact of these novel mutations and future development of therapeutics remedying these tumor suppressors are warranted.     

Role of echocardiography in differential diagnosis of broad complex tachycardia

It is not always easy to distinguish between supraventricular tachycardia with aberration and ventricular tachycardia by electrocardiographic analysis alone. M mode echocardiography can often help by providing direct or indirect evidence of the relation between atrial and ventricular contraction. Sixteen consecutive patients with spontaneous sustained broad QRS complex tachycardia with heart rates of 120-225 beats/minute were examined. Echocardiographic evidence of 1:1 conduction was seen in three cases and 2:1 atrioventricular conduction in one (all four had supraventricular tachycardia, confirmed by intracardiac electrocardiography in three). Evidence of retrograde block was seen in 12 (all had ventricular tachycardia, with electrophysiological confirmation in 10). Satisfactory views of the mitral valve were obtained in all patients. Patients with ventricular tachycardia had a variable mitral valve opening time (range 42-110%) compared with those who had supraventricular tachycardia (9-15%). Aortic root and left atrial views gave direct evidence of atrial contraction in three cases, and subcostal right atrial wall views were diagnostic in four of five cases. Seven patients with ventricular tachycardia had been wrongly diagnosed elsewhere as having supraventricular tachycardia. This study confirms that echocardiography is a simple and rapid aid to accurate diagnosis in patients with broad QRS complex tachycardia.