Influence of caloric restriction on the development of atherosclerosis in nonhuman primates: progress to date

Caloric restriction (CR) has been observed to retard aging processes and extend the maximum life span in rodents. In an effort to evaluate the effect of this nutritional intervention on physiologic variables in higher species, several nonhuman primate trials are ongoing. In particular, a study evaluating the independent effect of CR on the extent of atherosclerosis was initiated in 1993 in 32 adult cynomolgus monkeys. Therefore, the trial was designed to achieve identical cholesterol intake after animals were randomized to a control group or a calorie-restricted group (30% reduction from baseline caloric intake). The animals were routinely evaluated for glycated proteins, plasma insulin and glucose levels, insulin sensitivity, and specific measures for abdominal fat distribution by CT scans over a 4-year interval. The results from 4 years of intervention demonstrate that CR improves cardiovascular risk factors (such as visceral fat accumulation) and improves insulin sensitivity. In contrast to other primate studies with normolipidemic animals, CR had no independent effects on plasma lipid levels and composition in the presence of equivalent amounts of dietary cholesterol intake. Preliminary analysis of atherosclerotic lesion extent in the abdominal aorta has failed to demonstrate differences between control animals and CR animals. Follow- up studies are being conducted to determine the effect of CR on atherosclerosis extent in coronary and carotid arteries.      

X-radiation induces 8-hydroxy-2'-deoxyguanosine formation in vivo in rat mammary gland DNA

Ionizing radiation is a carcinogen that induces oxidative DNA damage. 8- Hydroxy-2'-deoxyguanosine (8-OHdG) is a relatively abundant, mutagenic lesion that is widely regarded as a reliable index of oxidative DNA damage. The purpose of this study was to examine the effects of X- radiation on levels of 8-OHdG in the context of an experimental model for breast cancer in which chronic radiation exposure has been shown to be carcinogenic in Sprague-Dawley rats. A secondary objective of this study was to determine if the use of phenol during DNA isolation affected the concentration of 8-OHdG subsequently measured. Our results indicate that a profoundly carcinogenic dose of radiation induced a small but significant increase in 8-OHdG concentration in mammary gland DNA, and that the use of a phenol-based versus a salt-based method of DNA isolation had no significant impact on the levels of 8-OHdG detected in either control or irradiated tissue.      

Bilateral popliteal vein aneurysms

An 82-year-old man was admitted with a left hip fracture sustained in a fall. The fracture was surgically repaired. Ipsilateral leg swelling developed over the following 2 weeks. A lower extremity venous duplex scan demonstrated isolated dilatation of the popliteal veins in both lower extremities. Chronic thrombosis was noted in both popliteal veins at the level of this dilatation. Initial duplex scanning also revealed acute thrombus in the left popliteal, posterior tibial, and peroneal veins. A repeat scan 1 week later identified propagation of thrombus into the superficial femoral vein. Popliteal vein aneurysms, although rare, can cause significant morbidity and mortality. The literature is also reviewed.Presented at the Second Annual Winter Meeting of the Peripheral Vascular Surgery Society, Breckenridge, Colo., January 25–27, 1992.     

ZAK is required for doxorubicin,a novel ribotoxic stressor,to induce SAPK activation and apoptosis in HaCaT cells

Doxorubicin is an anthracycline drug that is one of the most effective and widely used anticancer agents for the treatment of both hematologic and solid tumors. The stress-activated protein kinases (SAPKs) are frequently activated by a number of cancer chemotherapeutics. When phosphorylated, the SAPKs initiate a cascade that leads to the production of proinflammatory cytokines. Some inhibitors of protein synthesis, known as ribotoxic stressors, coordinately activate SAPKs and lead to apoptotic cell death. We demonstrate that doxorubicin effectively inhibits protein synthesis, activates SAPKs, and causes apoptosis. Ribotoxic stressors share a common mechanism in that they require ZAK, an upstream MAP3K, to activate the pro-apoptotic and proinflammatory signaling pathways that lie downstream of SAPKs. By employing siRNA mediated knockdown of ZAK or administration of sorafenib and nilotinib, kinase inhibitors that have a high affinity for ZAK, we provide evidence that ZAK is required for doxorubicin-induced proinflammatory and apoptotic responses in HaCaT cells, a pseudo-normal keratinocyte cell line, but not in HeLa cells, a cancerous cell line. ZAK has two different isoforms, ZAK-α (91 kDa) and ZAK-β (51 kDa). HaCaT or HeLa cells treated with doxorubicin and immunoblotted for ZAK displayed a progressive decrease in the ZAK-α band and the appearance of ZAK-β bands of larger size. Abrogation of these changes after exposure of cells to sorafenib and nilotinib suggests that these alterations occur following stimulation of ZAK. We suggest that ZAK inhibitors such as sorafenib or nilotinib may be effective when combined with doxorubicin to treat cancer patients.Key words: doxorubicin, ZAK, ribotoxic stressor, SAPKs, apoptosis     

The change in capacity and service delivery at public and private hospitals in Turkey: A closer look at regional differences

Background  

Substantial regional health inequalities have been shown to exist in Turkey for major health indicators. Turkish data on hospitals deserves a closer examination with a special emphasis on the regional differences in the context of the rapid privatization of the secondary or tertiary level health services.     

Melanoma/skin cancer screening in a Mediterranean country: results of the Euromelanoma Screening Day Campaign in Greece

Background Since the year 2000 a melanoma/skin cancer screening campaign has been organized annually in Greece in the context of the Euromelanoma Screening Day Campaign. Objectives We aimed to analyse the characteristics of the screened population, to recognize relevant risk factors and to identify the cases of histologically confirmed malignant melanoma (MM) in individuals with suspicious skin lesions. Methods An analysis of the completed screening forms from the years 2000–2004 was performed with respect to relevant demographic, epidemiological and clinical data. Results A total of 9723 individuals were screened, most of whom where below the age of 50 years (71%), female (59%), and of skin phototype II and III (76%). Sunburn during childhood was reported in 47% of participants, while 5% of the screened population had a personal or family history of melanoma. On clinical examination, 14.4% had actinic keratoses, 31.2% had dysplastic nevi, while 6.4% carried a presumptive diagnosis of non‐melanoma skin cancer. In the 2003–2004 screening campaign, 19 out of the 171 clinically suspicious lesions were histologically proven to be MM, the majority of which (58%) were ‘thin’ melanomas (Breslow's thickness of ≤ 1 mm) of the superficial spreading type. Conclusions Our study suggested that, a melanoma/skin cancer screening programme in a Mediterranean country, supported by an intense publicity campaign, attracted many individuals at risk for skin cancer and detected mostly thin melanomas of the superficial spreading type.