Inhibition of DNA polymerase alpha by gossypol.

Our earlier studies have shown that gossypol is a specific inhibitor of DNA synthesis in cultured cells at low doses. In an attempt to determine the mechanism for the inhibition of DNA synthesis by gossypol we observed that gossypol does not interact with DNA per se but may affect some of the enzymes involved in DNA replication. These studies indicated that gossypol inhibits both in vivo and in vitro the activity of DNA polymerase alpha (EC 2.7.7.7), a major enzyme involved in DNA replication, in a time- and dose-dependent manner. Kinetic analysis revealed that gossypol acts as a noncompetitive inhibitor of DNA polymerase alpha with respect to all four deoxynucleotide triphosphates and to the activated DNA template. Inhibition of DNA polymerase alpha does not appear to be due to either metal chelation or reduction of sulfhydryl groups on the enzyme. Gossypol also inhibited HeLa DNA polymerase beta in a dose-dependent manner, but had no effect on DNA polymerase gamma. These results suggest that inhibition of DNA polymerase alpha may account in part for the inhibition of DNA synthesis and the S-phase block caused by gossypol. The data also raise the possibility that gossypol may interfere with DNA repair processes as well.

Obesity predicts increased overall complications following pancreas transplantation.

PURPOSE: We sought to evaluate the role of recipient body mass index (BMI) on postoperative complications in patients receiving pancreas transplants. METHODS: A single-institution retrospective study of 145 consecutive patients undergoing either simultaneous kidney pancreas (SPK) or pancreas after kidney (PAK) transplantation from January 1997 through December 2003. Variables analyzed included: age, sex, BMI, number of prior transplants, cytomegalovirus status of donor and recipient, postoperative insulin resistance, complications, and overall patient and graft survival. Differences in continuous variables and dichotomous variables were evaluated using two-tailed t test and Fisher exact test, respectively. Univariate and multivariate logistic regression analyses were employed to identify predictors of overall complications following surgery. RESULTS: Obesity was defined by a BMI > or = 30. Of the 145 patients, 33 (23%) had a BMI > or = 30 and 112 (77%) had a BMI < 30. There was no significant difference in age or sex between obese and nonobese patients (P = .98 and P = .56, respectively). The type of transplantation, SPK or PAK, did not affect the complication rate (P = .36). Overall complications (infection, dehiscence, evisceration, ventral hernia, allograft failure, gangrene, necrotizing fasciitis, postoperative bleeding, or death) were significantly higher in the obese group (81% vs 40%, P < .001). Obesity was specifically associated with increased frequency of dehiscence, ventral hernia, intra-abdominal infection, gangrene, necrotizing fasciitis, and repeat laparotomy. Obese patients also had a threefold higher rate of graft pancreatitis/enteric leak. Multivariate logistic regression analysis identified age > or = 50 and BMI > or = 30 as independent predictors of overall complications following surgery (odds ratio 4.0, P = .014 and OR 6.8, P < .001, respectively). There was no difference identified between groups with regards to allograft failure, posttransplant insulin resistance, and death. CONCLUSION: Obese patients are at increased risk of overall complications following pancreas transplantation. Specifically, obese patients experience higher frequency of dehiscence, ventral hernia, intra-abdominal infection, gangrene, and necrotizing fasciitis. This study demonstrates the need for careful postoperative monitoring in the obese patient.

The influence of combined trophic factors on the success of fetal pancreas grafts.

BACKGROUND: Fetal pancreas (FP) has the capacity for abundant proliferation and beta cell differentiation. Insulin-like growth factor-1 (IGF-1) promotes FP engraftment in the i.m. site and reversal of diabetes in a rodent model. However, reversal of diabetes by an FP transplant in rats under the influence of IGF-1 is still an inefficient process requiring multiple FP grafts and a prolonged latent period. Numerous other growth and differentiation factors, which include platelet derived growth factor (PDGF), vascular endothelial growth factor, endothelial cell growth factor-alpha and pancreatic islet neogenesis-associated protein, have been implicated in beta cell neogenesis and proliferation. We have analyzed the in vivo role of these growth factors in FP engraftment and reversal of streptozotocin-induced diabetes in rats. METHODS: IGF-1 alone or in combination with other trophic factors was locally administered to eight FP isografts in the thigh muscle of diabetic rats. RESULTS: Diabetes was reversed in a mean of 60+/-26 days in 11 of 11 animals treated with IGF-1. PDGF alone did not promote reversal of diabetes; however, PDGF + IGF-1 resulted in euglycemia in 6 of 6, with a mean of 36+/-14 days (P<0.05). Islet neogenesis-associated protein +IGF-1 resulted in reversal of diabetes in 6 of 6 rats with a mean interval of 50+/-10 days. Vascular endothelial growth factor or endothelial cell growth factor-alpha + IGF-1 provided no advantage compared with IGF-1 alone. CONCLUSIONS: These results demonstrate that IGF-1 is a potent trophic factor for transplanted FP and that PDGF acts synergistically with IGF-1 to promote reversal of diabetes by transplanting FP.

Intracranial arteriovenous malformation masquerading as a cardiac disorder.

In this report, we describe an adult with a large intracranial arteriovenous malformation which mimicked a cardiac lesion. The patient presented with predominant cardiac symptoms, a prominent continuous murmur and signs of arterial run-off. The diagnosis was confirmed by digital subtraction angiography. We report the case to highlight the rare presentation.

Balloon valvotomy for mitral restenosis after open or closed surgical commissurotomy.

Balloon mitral valvotomy was performed in 48 patients (Group I) with mitral restenosis following prior surgical commissurotomy 3-21 years previously. Their results were compared with those of balloon valvotomy in 302 patients without prior commissurotomy (Group II). The procedure was successful in 91.7% of Group I. The mitral valve area, cardiac output, mitral valve gradient, mean left atrial and pulmonary arterial pressures significantly improved following valvotomy (all P < 0.001) in Group I and similar results were obtained in Group II. A comparison of the absolute and percentage change in the mitral valve area following valvotomy amongst the two groups revealed no significant difference (P = N.S.). The baseline clinical characteristics in both the groups were similar except for a higher echocardiographic score (8.64 +/- 1.5 vs. 7 +/- 1.7; P < 0.005) in Group I. Despite the high echo score, achievement of an 'optimal' result and occurrence of postprocedural mitral regurgitation were similar in both groups. The complications included systemic embolus in one patient and increase in mitral regurgitation to > or = 2+ in 2. There were no deaths. Balloon valvotomy for mitral restenosis following surgical commissurotomy is safe, effective and produces clinical and hemodynamic results comparable to those in unoperated cases.

Mitral and pulmonary balloon valvotomy in pregnant patients.

Two pregnant patients, one each with mitral and pulmonary valvar stenosis, underwent successful balloon valvotomy during their third trimester. Single balloon technique was utilised in both and this resulted in a short procedure and fluoroscopy time (9 minutes in patient with mitral stenosis and 3.5 minutes in pulmonary stenosis). The procedure produced satisfactory hemodynamic and symptomatic benefits in both cases with no complications. The patient remained asymptomatic without medications and delivered healthy full term babies at term. Balloon valvotomy is feasible, effective, and safe during pregnancy and should be considered as an alternative to surgery in symptomatic patients refractory to medical therapy.

Percutaneous mitral valvotomy in 200 patients using Inoue balloon-immediate and early haemodynamic results.

We report our experience with percutaneous balloon valvotomy using the Inoue technique in 200 cases with rheumatic mitral stenosis. The procedure was successful in 195 (97.5%) cases with a fluoroscopy time of 9 +/- 2.7 and procedure time of 60 +/- 19 minutes. Mitral valve area as estimated by Gorlin's equation and pressure half time increased from 0.86 +/- 0.17 to 2.21 +/- 0.41 and from 0.94 +/- 0.14 to 1.90 +/- 0.26 (p < 0.001) respectively. Other hemodynamic variables including mitral valve gradient, cardiac output, left atrial mean and pulmonary artery pressure improved significantly. There were no deaths and the incidence of major complications was small. Increase in mitral regurgitation was observed in 35 (17.9%) with grade 2+ increase in 7 (3.6%). Inoue balloon technique is safe, easy to perform and provides excellent clinical and hemodynamic benefits in majority of cases.

Supravalvar aortic stenosis secondary to familial hypercholesterolaemia. Report of two cases.

Two cases of supravalvar aortic stenosis secondary to familial hypercholesterolaemia (type II A hyperlipoproteinaemia) are reported and the role of echocardiography in the diagnosis of this uncommon condition is discussed. The management of these patients is difficult and in one patient the serum cholesterol decreased substantially after treatment with gemfibrozil.

Value of haemodynamic studies during pericardiocentesis in a cardiac catheterisation laboratory.

Pericardiocentesis was performed in 20 patients using a 7F diagnostic catheter in a cardiac catheterisation laboratory under fluoroscopic control, with haemodynamic and electrocardiographic monitoring. This technique offers several advantages over the bedside technique which utilises a sharp needle. The technique utilised for percutaneous aspiration is safe and simple and allows complete drainage of fluid. The haemodynamic monitoring before and after drainage aids in detecting cases of effusive constriction.

Total anomalous pulmonary venous connection: asymptomatic survival for 50 years without surgical intervention.

Total anomalous pulmonary venous connection (TAPVC) is an uncommon cyanotic heart disease and survival beyond infancy is rare. We report a patient of TAPVC of the supracardiac variety who has survived till the age of 50 years without surgery.

Supply and demand for liver transplant surgery: are we training enough surgeons?

The purpose of our study is to determine whether the current level of transplant fellow training is sufficient to meet the future demand for liver transplantation in the United States. Historical data from the Nationwide Inpatient Samples (NIS) for the years 1998 through 2003 were used to construct an estimate of the annual number of liver transplant procedures currently being performed in the United States, and the number projected for each year through 2020. Estimates for the current and future number of surgeons performing liver transplant procedures were also constructed using the same database. The NIS database was used because current national transplant registries do not include information on the number of surgeons performing liver transplant procedures. Using historical data derived from the NIS database, we project that the estimated number of liver transplant procedures per surgeon will remain relatively stable through 2020, with each surgeon performing an average of 12.9 procedures in 2020 compared to 12.9 currently. We conclude that the relationship between demand for liver transplantation in the United States and the supply of liver transplant surgeons will remain stable over the next 15 years.