Protease-activated receptor-2 stimulates angiogenesis and accelerates hemodynamic recovery in a mouse model of hindlimb ischemia

Proteinase-activated receptors (PAR-2) are expressed by the cardiovascular system and mediate vasodilation, plasma protein extravasation, and endothelial cell proliferation, all regarded as essential steps for neovascularization. We investigated the angiogenic action of PAR-2 signaling in vivo. The effect of the PAR-2 activating peptide (PAR-2AP, SLIGRL-NH2) was assessed in the absence of ischemia, and the therapeutic potential of PAR-2AP and the PAR-2 agonist trypsin (at 300 and 1.5 nmol IM daily for 21 days, respectively) was also tested in mice subjected to unilateral limb ischemia. PAR-2AP increased capillarity in normoperfused adductor skeletal muscles, whereas neither the vehicle of the PAR2-AP nor the PAR-2 reverse peptide (PAR-2RP, LRGILS-NH2) did produce any effect. In addition, both PAR-2AP and trypsin enhanced reparative angiogenic response to limb ischemia, an effect that was not produced by PAR-2RP or the vehicle of PAR-2 agonists. Potentiation of reparative angiogenesis by PAR-2AP or trypsin resulted in an accelerated hemodynamic recovery and enhanced limb salvage. In conclusions, our study is the first to demonstrate the angiogenic potential of PAR-2 stimulation in vivo. If similar effects occur in humans, PAR-2AP agonists could have some therapeutic potential for the treatment of tissue ischemia.     

Nerve growth factor gene therapy using adeno-associated viral vectors prevents cardiomyopathy in type 1 diabetic mice

Diabetes is a cause of cardiac dysfunction, reduced myocardial perfusion, and ultimately heart failure. Nerve growth factor (NGF) exerts protective effects on the cardiovascular system. This study investigated whether NGF gene transfer can prevent diabetic cardiomyopathy in mice. We worked with mice with streptozotocin-induced type 1 diabetes and with nondiabetic control mice. After having established that diabetes reduces cardiac NGF mRNA expression, we tested NGF gene therapies with adeno-associated viral vectors (AAVs) for the capacity to protect the diabetic mouse heart. To this aim, after 2 weeks of diabetes, cardiac expression of human NGF or β-Gal (control) genes was induced by either intramyocardial injection of AAV serotype 2 (AAV2) or systemic delivery of AAV serotype 9 (AAV9). Nondiabetic mice were given AAV2-β-Gal or AAV9-β-Gal. We found that the diabetic mice receiving NGF gene transfer via either AAV2 or AAV9 were spared the progressive deterioration of cardiac function and left ventricular chamber dilatation observed in β-Gal-injected diabetic mice. Moreover, they were additionally protected from myocardial microvascular rarefaction, hypoperfusion, increased deposition of interstitial fibrosis, and increased apoptosis of endothelial cells and cardiomyocytes, which afflicted the β-Gal-injected diabetic control mice. Our data suggest therapeutic potential of NGF for the prevention of cardiomyopathy in diabetic subjects.     

Moving Mammogram-Reluctant Women to Screening: A Pilot Study

Background  

Effective interventions are needed for women long overdue for screening mammography.     

Adverse relationship between blood transfusions and survival after colectomy for colon cancer

Random-donor blood transfusions are deliberately given before cadaver renal allografting to improve allograft survival. Since host modifications that improve the outcome of an allograft might be associated with a decreased ability of the host to control cancer growth, the relationship between blood transfusions and the outcome of 146 Dukes' stages A, B, and C colon cancers treated by resection during the years 1974 to 1979 was studied. It was found that 65 patients (45%) had been transfused and that at 5 years, overall survival was significantly better in the nontransfused patients compared to the transfused patients (0.68 and 0.51 5-year product limit survival fractions respectively; P = 0.03 for unadjusted log-rank comparison of entire survival curves). Relative risk of death due to cancer in transfused patients versus nontransfused patients was 2.3 (P = 0.05) when controlled for sex, age, stage, histologic differentiation, cancer location, and pre-resection hemoglobin level using Cox regression analysis. Thus, blood transfusion appears to be an additional important prognostic variable. The hypothesis suggested but not proven by these data that the outcome for some malignancies may be related to the immunomodulating effects of blood transfusions needs further study.     

Hypersensitivity reactions to trimetrexate

Summary Trimetrexate is a nonclassical antifol currently being tested for efficacy in cancer patients and as an antiparasitic agent against Pneumocystis carinii pneumonia in AIDS patients. We have now received the first reports of hypersensitivity reactions in Phase II cancer trials. Two types of reactions were noted. The most severe reaction, immediate hypotension with loss of consciousness, occurred in only one patient. Four other patients exhibited an immediate systemic effect with one or more of the following symptoms: facial flushing, fever, shaking, pruritus, bronchospasm, periorbital edema, and difficulty in swallowing. Immediate hypersensitivity should now be considered a known side effect of trimetrexate therapy, occurring in < 2% of patients.     

5-Fluorouracil-associated cardiotoxicity

Cardiotoxicity manifested as myocardial ischemia is not generally recognized as a side effect of 5-fluorouracil. However, there have been at least 35 cases reported since 1975. In only one of these cases was a somewhat detailed evaluation done to rule out underlying coronary disease. The case reported here of 5-FU cardiotoxicity included an extensive cardiac evaluation to rule out underlying coronary disease and to assess spasm. The literature on 5-FU cardiotoxicity is also reviewed, and its possible mechanisms are analyzed.