Effectiveness and toxicity of high-dose cyclophosphamide in obese versus non-obese patients receiving allogeneic hematopoietic stem cell transplant.

PURPOSE: To determine if there is a difference in toxicity and effectiveness between obese and non-obese patients who receive high-dose cyclophosphamide (Cy) prior to allogeneic hematopoietic stem cell transplant (allo-HCT). METHODS: Patients were included in this study if they were at least 18 years of age and received high-dose Cy in combination with total body irradiation (CyTBI) or busulfan (BuCy) prior to allo-HCT between 1 January 2008 and 29 February 2012. The primary endpoint was the difference in overall toxicity between obese and non-obese patients. Secondary objectives examined differences in effectiveness between groups assessed by relapse at day +100, relapse at 1 year, death at 1 year, chimerisms at days +30, +60, and +90, and incidence of acute graft versus host disease (aGVHD). RESULTS: Sixty-one patients met the inclusion criteria, 28 obese and 33 non-obese. Overall toxicity was greater in obese patients compared to non-obese patients (82% vs. 52%, OR 4.3 [95% CI 1.3-14.1]; p = 0.01), which was driven by a greater incidence of renal dysfunction (79% vs. 48%, OR 3.9 [95% CI 1.3-12.1]; p = 0.02). There were no differences in rates of grade 3 or 4 toxicity, hepatic dysfunction, or any measure of effectiveness between groups. CONCLUSION: Obese patients receiving high-dose Cy and allo-HCT are at increased risk for toxicity, although there appears to be no difference in the rate of relapse or survival between obese and non-obese patients.

Phosphoinositide-signaling is one component of a robust plant defense response.

The phosphoinositide pathway and inositol-1,4,5-triphosphate (InsP3) have been implicated in plant responses to many abiotic stresses; however, their role in response to biotic stress is not well characterized. In the current study, we show that both basal defense and systemic acquired resistance responses are affected in transgenic plants constitutively expressing the human type I inositol polyphosphate 5-phosphatase (InsP 5-ptase) which have greatly reduced InsP3 levels. Flagellin induced Ca(2+)-release as well as the expressions of some flg22 responsive genes were attenuated in the InsP 5-ptase plants. Furthermore, the InsP 5-ptase plants were more susceptible to virulent and avirulent strains of Pseudomonas syringae pv. tomato (Pst) DC3000. The InsP 5-ptase plants had lower basal salicylic acid (SA) levels and the induction of SAR in systemic leaves was reduced and delayed. Reciprocal exudate experiments showed that although the InsP 5-ptase plants produced equally effective molecules that could trigger PR-1 gene expression in wild type plants, exudates collected from either wild type or InsP 5-ptase plants triggered less PR-1 gene expression in InsP 5-ptase plants. Additionally, expression profiles indicated that several defense genes including PR-1, PR-2, PR-5, and AIG1 were basally down regulated in the InsP 5-ptase plants compared with wild type. Upon pathogen attack, expression of these genes was either not induced or showed delayed induction in systemic leaves. Our study shows that phosphoinositide signaling is one component of the plant defense network and is involved in both basal and systemic responses. The dampening of InsP3-mediated signaling affects Ca(2+) release, modulates defense gene expression and compromises plant defense responses.

Angiotensin-converting enzyme inhibitors for intermittent claudication associated with peripheral arterial disease.

OBJECTIVE: To review published literature regarding the effectiveness of angiotensin-converting enzyme (ACE) inhibitors for managing intermittent claudication (IC) associated with peripheral arterial disease (PAD). DATA SOURCES: A search of MEDLINE/PubMed (1966-July 2013) using the MeSH terms intermittent claudication and angiotensin-converting enzyme inhibitors was conducted. Limits included articles written in English with human participants. Additional data were identified through bibliographic reviews. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were evaluated. Clinical trials and meta-analyses were included if they evaluated the efficacy of ACE inhibitors for improving functional capacity of patients with PAD with IC. In all, 9 clinical trials and 1 meta-analysis were identified and included for review. ACE inhibitors evaluated in the studies were captopril, lisinopril, perindopril, quinapril, and ramipril. DATA SYNTHESIS: Current medications approved for treating the symptoms and improving function in PAD with IC have limited efficacy. It has been suggested that ACE inhibitors may be effective in PAD with IC. Though data evaluating ACE inhibitors as a class in this patient population are conflicting, results of the largest and longest trial reported that ramipril increases maximum walking time and pain-free walking time and improves quality of life in patients with PAD with IC. CONCLUSIONS: ACE inhibitors may provide some relief of IC symptoms when used in patients with PAD. The greatest functional benefit has been seen with ramipril; it is unknown whether other agents in the class would show similar results. Well-controlled and designed studies with sufficient power and using diverse patient populations are needed.