Management of the sensitized cardiac recipient: the use of plasmapheresis and intravenous immunoglobulin

Previously, we reported that the combination of plasmapheresis (PP) and intravenous immunoglobulin (IVIg) allow sensitized patients to undergo orthotopic heart transplantation (OHT), even across a positive crossmatch. In the current study, the effect of that combination, PP+IVIg, on survival of a larger group of such recipients is investigated. The latter group (I) consisted of 35 sensitized patients who received PP+IVIG together with standard immunosuppressive drugs. Rejection was seen in 11 patients, findings strongly suggestive of a vascular (humoral) being identified in five of those cases. Four deaths occurred, two of them in the immediate post-operative period, one after almost six months, and one after almost two yr post-OHT. Follow-up range 4.5 months to 7.8 yr post-OHT (average=1.1 yr). Patient survival was analyzed after generation of a Kaplan-Meier plot. Comparison with a control OHT group (II) given standard immunosuppressive drugs only (N=276) showed enhanced survival of group I (p=0.0414 by log-rank test). We conclude that the combination of PP and IVIG (i) is associated with declines in T- and B-percent-reactive antibody and in crossmatch positivity, and (ii) is very useful in the management of the sensitized cardiac patient undergoing OHT, often allowing a successful outcome to transplantation in the face of a positive crossmatch.     

Topical estrogen protects against SIV vaginal transmission without evidence of systemic effect

BACKGROUND: Accumulating data suggest that the state of the vaginal epithelium affects a woman's risk of HIV vaginal transmission and several human and non-human primate studies have shown that the rate of HIV or SIV vaginal transmission is decreased when estrogen is dominant. Systemic estrogen can protect against SIV vaginal transmission. OBJECTIVE: To determine the safety and efficacy of topical estrogen in preventing SIV vaginal transmission. DESIGN: The non-human primate model of HIV vaginal transmission was used to assess vaginal estriol cream in ovariectomized macaques. METHODS: Twelve macaques were treated intravaginally with estriol and eight with placebo cream twice a week. The vaginal and systemic effects of estriol were determined by colposcopy and serum luteinizing hormone, levels of which would decline in the presence of systemic estrogen. After 5 weeks of therapy, the animals were challenged vaginally with pathogenic SIVmac251. RESULTS: Vaginal estriol resulted in minimal serum estriol levels and had no effect on serum luteinizing hormone levels. Vaginal epithelia cornified and thickened significantly in response to estriol therapy. One of the estriol-treated animals became infected after this single challenge, while six of the control animals became infected (P = 0.0044). CONCLUSIONS: These data demonstrate that topical vaginal estriol can strongly protect against SIV vaginal transmission, while having no detectable systemic effect. These results support the study of topical vaginal estriol in preventing HIV vaginal transmission in at-risk women.     

Massive right atrial myxoma presenting with syncope

A 65-year-old man presented to the emergency room following an episode of syncope. His vital signs and physical examination were unremarkable. A chest X-ray and an ECG were also normal. He was admitted to the hospital for further work-up. A computed tomography scan of his brain did not reveal any evidence of stroke, hemorrhage, or mass effect. A transesophageal echocardiogram, however, revealed tricuspid regurgitation and a right atrial mass with finger-like projections, which appeared to originate from the tricuspid valve. Left heart catheterization was performed, showing a 99% proximal right coronary artery stenosis. The patient was scheduled to undergo atrial mass resection, tricuspid valve annuloplasty, and coronary bypass. During the procedure, a large myxoma was found to be adherent to the right side of the atrial septum, adjacent to the fossa ovalis. The mass was friable and was attached to the endocardium by a pedicle. Following resection of the atrial mass and tricuspid valve annuloplasty, a single saphenous vein graft bypass to the right coronary artery was performed. The patient's postoperative course was unremarkable and he was discharged home on postoperative day 6.     

Magnitude of dyslipedemia and its association with micro and macro vascular complications in type 2 diabetes: a hospital based study from Bikaner (Northwest India)

AIM: Type 2 diabetes is not only associated with hyperglycemia but also with disorders of lipid metabolism. The aim of this study was to investigate the association of dyslipedemia with micro and macro vascular complications of diabetes. METHODS: Population based cross sectional study included 4067 diabetic patients who visited hospital during January 2000 to December 2002. Lipid profile was estimated by semi autoanalyser, Retinopathy was assessed by fundoscopy, Nephropathy by microalbuminurea, coronary artery disease (CAD) by electro cardiogram (ECG) changes, peripheral vascular disease (PVD) by doppler study and neuropathy by clinical examinations. The association of dyslipedemia with micro and macro vascular complications was assessed by regression analysis. RESULTS: The prevalence of dyslipedemia is high in diabetic population with high serum cholesterol >240mg/dl was seen in 15%, serum triglycerides >160mg/dl was seen in 42.41%, raised LDL >130mg/dl in 45.26%, VLDL >40mg/dl in 24.09% and low levels of HDL-C <40mg/dl were seen in 52.27%. On regression analysis, CAD had strong correlation with high levels of VLDL (0.76), triglycerides (0.82), LDL (0.23) and low HDL (-0.81). Similar association was seen with PVD. Diabetic retinopathy and nephropathy were found to have significant correlation with low HDL (-0.43) and raised LDL (0.37), respectively. Neuropathy was not found to have any significant correlation with lipid profile abnormalities. CONCLUSION: Lipid profile abnormalities are very common in type 2 diabetes and it has great influence on CAD and PVD. Hence, appropriate preventive and treatment strategies should be considered timely.     

Total pancreatic lipomatosis with malabsorption syndrome

Total fat replacement of the pancreas is rare. Focal fatty replacement is the most common degenerative lesion of pancreas. Focal fatty deposits have no major clinical significance; however, extreme fat replacement is of pathologic significance, as it is associated with marked reduction in exocrine function of pancreas, resulting in malabsorption due to pancreatic enzyme insufficiency.     

Isolation and characterization of process-related impurities in linezolid

Two unknown impurities in linezolid bulk drug at levels below 0.1% (ranging from 0.05 to 0.1%) were detected by a simple isocratic reverse phase high performance liquid chromatography (HPLC). These impurities were isolated from crude sample of linezolid using reverse phase preparative HPLC. Based on the spectroscopic data (IR, NMR and MS) the structures of the impurities were characterized as (S)-N-[[-(3-(3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl] acetate(I) and (S)-N-[[-(3-(3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl] chloride(II). The synthesis from an unambiguous route and the formation of impurities was discussed.     

Right ventricular beneficial effects of beta adrenergic receptor kinase inhibitor (βARKct) gene transfer in a rat model of severe pressure overload

Heart failure is associated with abnormalities in βAR cascade regulation, calcium cycling, expression of inflammatory mediators and apoptosis. Adenoviral mediated gene transfer of βARKct has beneficial indirect effects on these pathologic processes upon the left ventricular myocardium. The concomitant biochemical changes that occur in the right ventricle have not been well characterized. Sprague–Dawley rats underwent aortic banding and were followed by echocardiography. After a decrease in fractional shortening of 25% from baseline, intracoronary injection of adenoviral-βARKct (n = 14) or adenoviral-β-galactosidase (control, n = 13) was performed. Rats were randomly euthanized on post-operative day 7, 14 or 21. Protein analysis including RV myocardial levels of βARKct, βARK1, SERCA_2a, inflammatory tissue mediators (IL-1, IL-6 and TNF-α), apoptotic markers (bax and bak), and MAP kinases (jnk, p38 and erk) was performed. ANOVA was employed for group comparison. Adenoviral-βARKct treated animals showed increased expression of βARKct and decreased levels of βARK1 compared with controls. This treatment group also demonstrated normalization of SERCA_2a expression and decreased levels of the inflammatory markers IL-1, IL-6 and TNF-α. The pro-apoptotic markers bax and bak were similarly improved. Ventricular levels of the MAP kinase jnk were increased. Differences were most significant 7 days after gene transfer, but the majority of these changes persisted at 21 days. These results suggest that attenuation of the pathologic mechanisms of beta adrenergic receptor desensitization, SERCA_2a expression, inflammation and apoptosis, not only occur in the left ventricle but also in the right ventricular myocardium after intracoronary gene transfer of βARKct during heart failure.     

In vitro–in vivo correlation for nevirapine extended release tablets

An in vitro–in vivo correlation (IVIVC) for four nevirapine extended release tablets with varying polymer contents was developed. The pharmacokinetics of extended release formulations were assessed in a parallel group study with healthy volunteers and compared with corresponding in vitro dissolution data obtained using a USP apparatus type 1. In vitro samples were analysed using HPLC with UV detection and in vivo samples were analysed using a HPLC‐MS/MS assay; the IVIVC analyses comparing the two results were performed using WinNonlin^®. A Double Weibull model optimally fits the in vitro data. A unit impulse response (UIR) was assessed using the fastest ER formulation as a reference. The deconvolution of the in vivo concentration time data was performed using the UIR to estimate an in vivo drug release profile. A linear model with a time‐scaling factor clarified the relationship between in vitro and in vivo data. The predictability of the final model was consistent based on internal validation. Average percent prediction errors for pharmacokinetic parameters were <10% and individual values for all formulations were <15%. Therefore, a Level A IVIVC was developed and validated for nevirapine extended release formulations providing robust predictions of in vivo profiles based on in vitro dissolution profiles. Copyright © 2009 John Wiley & Sons, Ltd.