Normal human fibroblasts exposed to high- or low-dose ionizing radiation: differential effects on mitochondrial protein import and membrane potential

How oxidative metabolism modulates effects of ionizing radiation is incompletely understood. Because mitochondria participate in oxidative metabolism, we investigated the modulation of mitochondrial protein import and membrane potential (DeltaPsi) in irradiated cells. Our data show that effects at low dose cannot be predicted from effects at high dose. When density-inhibited normal human fibroblasts were exposed to a toxic dose of 4 Gy, protein import into mitochondria isolated from these cells was decreased. In contrast, protein import into mitochondria isolated from low-dose-irradiated (10 cGy) cells was enhanced, suggesting that mitochondria may play a crucial role in low-dose-induced adaptive responses. At high dose, import defects were not solely due to changes in mitochondrial DeltaPsi, and modulation of import was not tightly linked to the cellular capacity to repair radiation damage. Another striking observation is that in proliferating nonirradiated cells, mitochondrial protein import and DeltaPsi were regulated in a cell cycle-dependent manner, being lower in S phase than in G (1). Interestingly, when quiescent G (0)/G (1) phase cells exposed to high-dose radiation were stimulated to proliferate, events associated with S phase, but not G (1), significantly affected import. The strategy described here may serve as novel end points to study radiation-induced effects.     

Mice lacking epidermal PPARγ exhibit a marked augmentation in photocarcinogenesis associated with increased UVB-induced apoptosis, inflammation and barrier dysfunction

Recent studies suggest that peroxisome proliferator-activated receptor gamma (PPARγ) agonists may have cancer chemopreventive activity. Other studies have shown that loss of epidermal PPARγ results in enhanced chemical carcinogenesis in mice via unknown mechanisms. However, ultraviolet B (UVB) exposure represents the primary etiological agent for skin cancer formation and the role of PPARγ in photobiology and photocarcinogenesis is unknown. In previous studies, we demonstrated that UVB irradiation of cells results in the formation of oxidized glycerophosphocholines that exhibit PPARγ ligand activity. We therefore hypothesized that PPARγ would prove to be a chemopreventive target in photocarcinogenesis. We first showed that UVB irradiation of mouse skin causes generation of PPARγ agonist species in vivo. We then generated SKH-1 hairless, albino mice deficient in epidermal Pparg (Pparg-/-(epi)) using a cytokeratin 14 driven Cre-LoxP strategy. Using a chronic model of UVB photocarcinogenesis, we next showed that Pparg-/-(epi) mice exhibit an earlier onset of tumor formation, increased tumor burden and tumor progression. Increased tumor burden in Pparg-/-(epi) mice was accompanied by a significant increase in epidermal hyperplasia and p53 positive epidermal cells in surrounding skin lacking tumors. After acute UVB irradiation, Pparg-/-(epi) mice exhibited an augmentation of both UVB-induced Caspase 3/7 activity and inflammation. Increased apoptosis and inflammation was also observed after treatment with the PPARγ antagonist GW9662. With chronic UVB irradiation, Pparg-/-(epi) mice exhibited a sustained increase in erythema and transepidermal water loss relative to wildtype littermates. This suggests that PPARγ agonists could have possible chemopreventive activity in non-melanoma skin cancer.     

Cinnamic acid, from the bark of Cinnamomum cassia, regulates glucose transport via activation of GLUT4 on L6 myotubes in a phosphatidylinositol 3-kinase-independent manner

Background: Cinnamomum cassia (Family: Lauraceae) is an Ayurvedic medicinal plant used traditionally for the treatment of a number of diseases, including diabetes. The hypoglycemic effect of this plant has been established in vivo. However, the effects of cinnamic acid, isolated from C. cassia, on the insulin signaling cascade in an in vitro model have not been elucidated. Hence, the aim of the present study was to evaluate the anti‐diabetic effect of cinnamic acid on glucose transport by L6 myotubes. Methods:  The mechanism of action of cinnamic acid was determined using specific targets in the insulin signaling pathway, including protein tyrosine phosphatase (PTP) 1B, phosphatidylinositol 3‐kinase (PI3‐K) and the glucose transporter GLUT4. After differentiation of myoblast to myotubes, the cells were serum deprived for 5 h and then treated with 1 ng/mL cinnamic acid and 50 μmol/L rosiglitazone for 18 h and 100 nmol/L insulin for 20 min for gene expression studies. Results:  Expression of GLUT4 mRNA was increased following treatment of L6 myotubes with 1 ng/mL cinnamic acid. Furthermore, cinnamic acid inhibited PTP1B activity (by 96.5%), but had no significant effect on PI3‐K activity. Conclusion:  On the basis of the results of the present study, we postulate that cinnamic acid isolated from the hydro‐alcoholic extract of Cinnamomum cassia activates glucose transport by a PI3‐K‐independent pathway. However, the detailed mechanism of action requires further analysis.     

Tuberculosis among HIV-infected patients receiving HAART: long term incidence and risk factors in a South African cohort

OBJECTIVES: To determine the long-term incidence of tuberculosis (TB) and associated risk factors among individuals receiving HAART in South Africa. DESIGN: Prospective cohort study. METHODS: Microbiologically or histologically confirmed incident TB was identified in a hospital-based cohort of 346 patients receiving HAART between 1996 and 2005 in Cape Town. RESULTS: The TB incidence density rate was 3.5/100 person-years in the first year and significantly decreased during follow-up, reaching 1.01/100 person-years in the fifth year (P = 0.002 for trend). TB incidence during the study was highest among patients with baseline CD4 cell counts < 100 cells/microl and those with World Health Organization (WHO) clinical stage 3 or 4 disease (5.71 and 3.88/100 person-years, respectively). Risk of TB was independently associated with CD4 cell count < 100 cells/microl (adjusted risk ratio [ARR], 2.38; 95% confidence interval (CI), 1.01-5.60; P = 0.04), WHO stage 3 or 4 disease (ARR, 3.60; 95% CI, 1.32-9.80; P = 0.01) and age < 33 years (ARR, 2.86; 95% CI, 1.29-6.34; P = 0.01). Risk of TB was not independently associated with plasma viral load, previous history of TB, low socioeconomic status or sex. Despite similar virological responses to HAART, blood CD4 cell count increases were much smaller among patients who developed TB than among those who remained free of TB. CONCLUSIONS: Incidence of TB continues to decrease during the first 5 years of HAART and so HAART may contribute more to TB control in low-income countries than was previously estimated from short-term follow-up. Patients with advanced pretreatment immunodeficiency had persistently increased risk of TB during HAART; this may reflect limited capacity for immune restoration among such patients.     

Genital primary herpetic infection in an infant: clinical features, diagnosis and management

Genital herpes is a rare disease in infants and is mainly associated with herpes simplex virus (HSV) type 1. Asymptomatic carriers are frequently implicated as transmitters of the disease. Clinical manifestations are the main criteria for diagnosis, However, type-specific serologies and PCR are the most sensitive techniques for detecting HSV. Genital herpes is treated with local or systemic antiviral therapy depending on the severity of the infection. Reducing transmission relies on counseling patients. The disease prognosis is correlated with the underlying immunological status. We report a case of genital primary herpetic infection in an infant.     

Preferred Models of Integrative Care

Introduction and Objectives

The opinions of healthcare providers play a crucial role in the debate around integrating complementary and alternative medicine (CAM) into the current healthcare system. The aim of this study is to explore the issue of CAM integration from the provider viewpoint by determining (a) what working relationship CAM practitioners and general practitioners (GPs) prefer or find acceptable, (b) whether there is agreement in the responses of CAM practitioners and GPs and (c) whether expressed opinions differ by CAM modalities.

Methods

A cross-sectional random sample of CAM practitioners (acupuncturists, chiropractors, massage therapists, naturopaths, homeopaths and herbalists; n = 1112) and GPs (n = 413) from Alberta and British Columbia, Canada, were mailed a questionnaire at three timepoints in 2003. In total, 457 questionnaires were returned from CAM practitioners (41% response rate) and 85 from GPs (21% response rate). Participants were asked to rate four models of integration (independent model, collaborative model, supervised model, assimilation model) for six CAM therapies (acupuncture, chiropractic, massage therapy, naturopathy, homeopathy and herbology).

Results

The collaborative model was rated as the most acceptable by all CAM practitioners and GPs, across all therapies. The least acceptable model, for both CAM practitioners and GPs, was the assimilation model. CAM practitioners and GPs disagreed on the acceptability of the independent model and the supervised model, and these differences were statistically significant.

Conclusion

A collaborative working relationship is preferred by both CAM practitioners and GPs. An integrative healthcare system would need to faciliate such working relations.