Reduced-intensity conditioning is effective and safe for transplantation of patients with Shwachman-Diamond syndrome

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potentially curative treatment for the BM dysfunction seen in patients with Shwachman-Diamond syndrome (SDS). Historically, these patients have fared poorly with intensive conditioning regimens with increased regimen-related toxicity especially involving the heart and lungs. We report our institutional experience with a reduced-intensity-conditioning protocol in seven patients with SDS and BM aplasia or myelodysplastic syndrome/AML. The preparative regimen consisted of Campath-1H, fludarabine and melphalan. Four patients received matched related marrow and three received unrelated stem cells (two PBSCs and one marrow). All but one was 8 of 8 allele HLA matched. All patients established 100% donor-derived hematopoiesis. No patient in this cohort developed grades III-IV GVHD. One patient had grade II skin GVHD that responded to systemic corticosteroids and one had grade I skin GVHD, treated with topical corticosteroids. Two out of seven patients developed bacterial infections in the early post transplant period. Viral infections were seen in four out of seven patients and were successfully treated with appropriate antiviral therapy. All patients are currently alive. These data indicate that HSCT with reduced-intensity conditioning is feasible in patients with SDS and associated with excellent donor cell engraftment and modest morbidity.     

Cross-talk between dyslipidemia and renin-angiotensin system and the role of LOX-1 and MAPK in atherogenesis studies with the combined use of rosuvastatin and candesartan

There is increasing evidence of cross-talk between dyslipidemia and renin-angiotensin system (RAS) in atherogenesis. Both dyslipidemia and RAS activation enhance the expression of a newly described receptor for oxidized-low density lipoprotein (ox-LDL), lectin-like ox-LDL receptor-1 (LOX-1). We postulated that the blockade of dyslipidemia with rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor and RAS with candesartan, an angiotensin II type 1 receptor blocker, would have a synergistic inhibitory effect on LOX-1 expression and atherogenesis. Apo-E knockout mice were fed a high-cholesterol diet (1% cholesterol, HC-diet) alone, or HC-diet with rosuvastatin (1mg/(kgd)), candesartan (1mg/(kgd)) or with both. Twelve weeks later the extent of atherosclerosis was determined by Sudan IV staining. Apo-E knockout mice on HC-diet had extensive atherosclerosis. Both rosuvastatin and candesartan decreased the extent of atherosclerosis (by 23 and 26%, respectively), despite the HC-diet; however, the combination of rosuvastatin and candesartan reduced atherosclerosis further (by 67%). Rosuvastatin decreased plasma levels of total cholesterol by over 50%, whereas candesartan had no effect. LOX-1 protein expression was found to be markedly up-regulated in HC-diet-fed apo-E knockout mice. While rosuvastatin and candesartan each had a small inhibitory effect on the expression of LOX-1 in the atherosclerotic tissues, the combination totally blocked the up-regulation of LOX-1. P38 mitogen-activated protein kinase (MAPK) expression and phosphorylation were increased in apo-E knockout mice, attenuated by rosuvastatin or candesartan alone, and completely blocked by the combination of the two agents. P44/42 MAPK expression and phosphorylation were not affected by the HC-diet, rosuvastatin, candesartan, or their combination. This study demonstrates the potent effect of rosuvastatin and candesartan on atherogenesis, as well as on the expression of LOX-1 and on the activation of p38 MAPK, but not p44/42 MAPK.     

Challenges in predicting the need for coronary artery bypass grafting at presentation in patients with non-ST-segment elevation acute coronary syndromes

In the case of non-ST-segment elevation acute coronary syndromes (NSTE-ACSs), the acute use of certain antiplatelet agents is complicated by concerns about perioperative bleeding risks in patients requiring coronary artery bypass grafting (CABG) during the index hospitalization. As a result, clinicians often withhold potentially useful agents, such as clopidogrel, before determining patients' coronary anatomy. An accurate predictive model could allow for a better balance of this safety concern with the demonstrated benefits of agents such as clopidogrel. To create an accurate decision-making tool that would assess, at hospital presentation, the need for CABG in patients with NSTE-ACSs, we studied 61,974 high-risk patients with NSTE-ACS admitted to 311 CABG-capable hospitals participating in Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) from 2001 to 2003. A total of 8,395 patients (14%) underwent CABG during their initial hospital stay. A multivariate model was developed and identified 13 presenting clinical characteristics significantly associated with the likelihood of CABG (previous CABG, male gender, previous heart failure, diabetes, hyperlipidemia, renal insufficiency, ST depression and transient ST elevation, age > or = 75 years, previous percutaneous coronary intervention, family history of coronary artery disease, hypertension, trends in CABG rates, and previous stroke). This model had only modest predictive accuracy and calibration (c-index = 0.67). In conclusion, although certain presenting clinical features are associated with an increased likelihood of CABG in patients with NSTE-ACSs during the index hospitalization, it remains difficult to reliably identify, before diagnostic angiography, those who will subsequently undergo surgical revascularization.     

Prediction of one-year mortality among 30-day survivors after primary percutaneous coronary interventions

Little information exists on the features that influence risk factors for death at 1 year among 30-day survivors of ST-elevation myocardial infarction (STEMI) that is treated with primary percutaneous coronary intervention (PCI). Accordingly, we examined 3,280 patients with STEMI who were enrolled in Stent-PAMI and CADILLAC trials, were treated with primary PCI, and survived >30 days after STEMI. Death at 1 year occurred in 74 patients (2.3%) who survived >30 days after their index STEMI. Patients who died at 1 year were more likely to be older and women and have lower body weight and greater prevalence of previous stroke. Similarly, the sum of ST elevations, 3-vessel or left anterior coronary disease, and final Thrombolysis In Myocardial Infarction grade <3 flow was higher, whereas left ventricular ejection fraction was lower among patients who died versus those who survived. The multivariate logistic regression model identified age >70 years (odds ratio [OR] 3.3 95% confidence interval [CI] 1.9 to 5.7), weight <80 kg (OR 1.9, 95% CI 1.1 to 3.6), any tachyarrhythmia during index hospitalization (defined as ventricular or supraventricular tachycardia that required treatment) (OR 2.4, 95% CI 1.2 to 4.8), number of diseased coronary arteries (OR 1.5, 95% CI 1.1 to 2.1), and left ventricular ejection fraction (each 10% decrease, OR 1.5, 95% CI 1.2 to 1.8) as factors independently associated with risk of death at 1 year among 30-day survivors. In conclusion, our study provides a method for clinicians to advise patients who are treated with primary PCI and survive the acute phase of STEMI with regard to patients' long-term prognosis, thus enhancing planning and setting up of realistic expectations.     

Native aortic valve vegetative endocarditis with Cunninghamella.

Cunninghamella bertholletiae is a rare Mucor species that is seldom the cause for endocarditis of prosthetic heart valves. It is even a more uncommon cause of endocarditis of native heart valves. We present a case of Cunninghamella endocarditis of a native aortic valve in an immuno-compromised patient, diagnosed from tissue culture obtained at the time of surgery. There have only been two other reported cases of native valve endocarditis with a Mucor species, and in those cases, the diagnoses were made post-mortem.     

Research Priorities for Human Immunodeficiency Virus and Sexually Transmitted Infections Surveillance, Screening, and Intervention in Emergency Departments: Consensus-based Recommendations

This article describes the results of the human immunodeficiency virus (HIV) and sexually transmitted infections (STI) prevention in the emergency department (ED) component of the 2009 Academic Emergency Medicine Consensus Conference entitled "Public Health in the ED: Surveillance, Screening, and Intervention." The objectives were to use experts to define knowledge gaps and priority research questions related to the performance of HIV and STI surveillance, screening, and intervention in the ED. A four-step nominal group technique was applied using national and international experts in HIV and STI prevention. Using electronic mail, an in-person meeting, and a Web-based survey, specific knowledge gaps and research questions were identified and prioritized. Through two rounds of nomination and refinement, followed by two rounds of election, consensus was achieved for 11 knowledge gaps and 14 research questions related to HIV and STI prevention in EDs. The overarching themes of the research priority questions were related to effectiveness, sustainability, and integration. While the knowledge gaps appear disparate from one another, they are related to the research priority questions identified. Using a consensus approach, we developed a set of priorities for future research related to HIV and STI prevention in the ED. These priorities have the potential to improve future clinical and health services research and extramural funding in this important public health sector.     

Magnesium metabolism in essential hypertension

Hypertension is a complex, heterogeneous disorder of which the exact etiology is unknown. The difficulty in ascribing an independent role to a single dietary constituent in blood pressure regulation may be due to interactions among nutrients which influence blood pressure. The effect of any one nutrient, particularly magnesium, on hypertension should be considered within the context of overall nutrition in each patient. Clinical, experimental and epidemiologic studies support the role of magnesium in hypertension, whereas a few studies negate this role. Magnesium ions are important in arterial smooth muscle contraction. Since magnesium is found mainly at the inner surface of the cell membranes, it could play a role in cell membrane permeability for sodium and calcium which is important in the etiopathogenesis of hypertension. Magnesium deficiency can predispose to increased contractility of the arteries and its excess can modulate smooth muscle contractility caused by bradykinin, angiotensin II, serotonin, prostaglandins and catecholamines. Magnesium therapy can prevent the development of resistant hypertension and arrhythmias in hypertensives with diuretic-induced hypomagnesemia. It might also reduce blood pressure at least up to 10/5 mm Hg provided adequate magnesium salts are given for an adequate period of time. In view of the still ill defined role of magnesium in hypertension, magnesium supplementation is advised only to those hypertensives who are receiving diuretics and develop resistant hypertension or who have frank magnesium deficiency. A diet rich in magnesium may be used for prevention of hypertension in predisposed communities because of the other advantages of such a diet in prevention.     

Use of vaginal pH in diagnosis of infections and its association with reproductive manifestations

Increase in vaginal secretion pH is an indicator of bacterial vaginosis (BV), but is yet to be in use as a diagnostic tool by clinicians. Similarly, no reports are available on the effect of cervical chlamydia infection and different reproductive manifestations on vaginal secretion pH. This study evaluated the use of vaginal pH for screening of BV, the effect of Chlamydia trachomatis (C. trachomatis) infection, and different reproductive manifestations on vaginal pH of women attending the gynecology outpatient department of a general hospital. Vaginal pH was recorded while diagnosing infections in 358 women, among which 45 were with repeated spontaneous abortion, 79 with infertility, 185 had sign and symptoms of lower genital tract infection, and 49 had no history or symptom of any complications or infections. Normal vaginal pH, BV, and C. trachomatis infection were observed in 72.6, 21.5, and 10.1% of women, respectively. BV and C. trachomatis were observed in 78.6 and 4.1% of women, respectively, with high vaginal pH; 12.3% of women with normal vaginal pH had C. trachomatis infection. C. trachomatis infection or different reproductive manifestations do not lead to change in vaginal pH but high vaginal pH correlated with BV and should be used as a simple tool for its diagnosis.     

Characterization of a CD38-like 78-kilodalton soluble protein released from B cell lines derived from patients with X-linked agammaglobulinemia.

Studies on murine B lymphocytes showed that Bruton's tyrosine kinase mediates signal transduction induced via CD38, a nonlineage-restricted 45-kD ectoenzyme. This signaling is defective in B cells from X-linked immunodeficient mice affected with the analogue of human X-linked agammaglobulinemia (XLA). We performed a structural and functional analysis of CD38 in XLA and other immunodeficiencies, using EBV-immortalized B cells derived from such patients. Membrane CD38 was not significantly different from controls in structure, epitope density, enzymatic activity, and internalization upon binding of agonistic mAbs. Meanwhile, an increased release of soluble CD38 from XLA cells was observed: immunoprecipitation from XLA culture media yielded a protein of approximately 78 kD (p78), reacting also in Western blot and displaying both enzymatic activities and a peptide map similar to membrane CD38. Soluble forms and homotypic aggregations of CD38 were documented in different cell models and by crystallographic analysis of the Aplysia ADP-ribosyl cyclase, the ancestor of human CD38. p78 might represent the product of an altered turn-over of membrane CD38, a starting point for studying its association with Bruton's tyrosine kinase and its role in XLA and other B cell immunodeficiencies.