The von Hippel-Lindau tumor suppressor regulates programmed cell death 5-mediated degradation of Mdm2.

Functional loss of the von Hippel-Lindau (VHL) tumor suppressor protein (pVHL), which is part of an E3-ubiquitin ligase complex, initiates most inherited and sporadic clear-cell renal cell carcinomas (ccRCC). Genetic inactivation of the TP53 gene in ccRCC is rare, suggesting that an alternate mechanism alleviates the selective pressure for TP53 mutations in ccRCC. Here we use a zebrafish model to describe the functional consequences of pVHL loss on the p53/Mdm2 pathway. We show that p53 is stabilized in the absence of pVHL and becomes hyperstabilized upon DNA damage, which we propose is because of a novel in vivo interaction revealed between human pVHL and a negative regulator of Mdm2, the programmed cell death 5 (PDCD5) protein. PDCD5 is normally localized at the plasma membrane and in the cytoplasm. However, upon hypoxia or loss of pVHL, PDCD5 relocalizes to the nucleus, an event that is coupled to the degradation of Mdm2. Despite the subsequent hyperstabilization and normal transcriptional activity of p53, we find that zebrafish vhl(-/-) cells are still as highly resistant to DNA damage-induced cell cycle arrest and apoptosis as human ccRCC cells. We suggest this is because of a marked increase in expression of birc5a, the zebrafish homolog of Survivin. Accordingly, when we knock down Survivin in human ccRCC cells we are able to restore caspase activity in response to DNA damage. Taken together, our study describes a new mechanism for p53 stabilization through PDCD5 upon hypoxia or pVHL loss, and reveals new clinical potential for the treatment of pathobiological disorders linked to hypoxic stress.

Are we missing post-thrombotic syndrome syndrome? An orthopaedic perspective in lower limb arthroplasty.

2-5% of patients undergoing hip or knee arthroplasty develop a symptomatic DVT; there is evidence to suggest that without prophylaxis 40-60% of patients have a subclinical DVT. This can be reduced by around half with appropriate thromboprophylaxis; there still remains a significant incidence of subclinical DVT. Therefore, it is important to know, as orthopaedic surgeons, if our patients undergoing large joint arthroplasty are being adversely affected. Post-thrombotic syndrome (PTS) is usually associated with symptomatic DVT, and the purpose of this paper is to address if asymptomatic DVT is also associated with an increased risk of PTS. The majority of evidence gathered does not support a link; therefore, there is no evidence to warrant a change in practice to warn patients of a potential risk or to routinely screen asymptomatic patients.

Maraviroc can improve lipid profiles in dyslipidemic patients with HIV: results from the MERIT trial.

PURPOSE: We investigated the effects of maraviroc, the first approved CC-chemokine receptor 5 (CCR5) antagonist, on blood lipids in a post hoc analysis of the phase 3 MERIT study in treatment-naïve patients. METHODS: Patients received maraviroc 300 mg twice daily (n = 360) or efavirenz 600 mg once daily (n = 361), both in combination with zidovudine/lamivudine, for up to 96 weeks. Baseline and on- treatment lipid profiles were analyzed according to National Cholesterol Education Program (NCEP) thresholds. RESULTS: Baseline characteristics and lipid profiles were comparable between groups. Among patients with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c) below NCEP treatment thresholds at baseline, significantly more efavirenz- than maraviroc-treated patients exceeded those thresholds at 96 weeks (TC: 35% [74/209] vs 11% [20/188], P < .0001; LDL-c: 23% [47/197] vs 8% [15/183], P < .0001). Among patients exceeding NCEP thresholds at baseline, significantly more efavirenz- than maraviroc-treated patients exceeded the thresholds at 96 weeks (TC: 83% [24/29] vs 50% [17/34], P = .0084; LDL-c: 86% [19/22] vs 55% [16/29], P = .0314). Of those with baseline high- density lipoprotein cholesterol (HDL-c) < 40 mg/dL, 43% (56/130) of maravirocand 62% (86/139) of efavirenz-treated patients achieved HDL-c≥40 mg/dL at 96 weeks (P = .0020). CONCLUSIONS: Maraviroc was not associated with elevations in TC, LDL-c, or triglycerides and showed beneficial effects on lipid profiles of dyslipidemic patients.

The stereoselective distribution of halofantrine enantiomers within human, dog, and rat plasma lipoproteins.

PURPOSE: To study the in vitro distribution of the enantiomers of the antimalarial drug halofantrine in human, dog and rat plasma lipoprotein-fractions. METHODS: Plasma was spiked with racemic halofantrine (1,000 ng/ml) and incubated for 1 h at 37 degree C. The fractions (high and low density lipoproteins, triglyceride-rich lipoproteins and lipoprotein deficient plasma) were separated using density gradient ultracentrifugation. Fractions were assayed for halofantrine enantiomer using stereospecific high performance liquid chromatography. RESULTS: The (-) enantiomer of halofantrine displayed higher affinity for the lipoprotein-deficient fraction than the (+) enantiomer in all three species. The (+) enantiomer was predominately located in the lipoprotein rich fractions of dog and human plasma (the (+):(-) ratio ranging from 1.2-9.6). In contrast, the (+):(-) ratio was consistently < 1 in lipoprotein-deficient fractions. Dog displayed a large magnitude of stereoselectivity in halofantrine distribution to the plasma fractions tested. There were substantial interspecies differences in the pattern of distribution of halofantrine enantiomers within the different fractions. A significant positive relationship was observed between halofantrine uptake into lipoprotein-rich fractions and the percent of apolar core lipid in those fractions. There was also a strong negative correlation between total protein concentration and the enantiomeric ratio in the lipoprotein-deficient plasma fraction. CONCLUSION: Distribution of halofantrine enantiomer to plasma lipoprotein-fractions is stereoselective and species specific. This differential binding of halofantrine enantiomers to lipoproteins may need to be considered in viewing pharmacokinetic and pharmacodynamic data involving the drug.

The food consumption patterns and perceptions of dietary advice of older people.

BACKGROUND: Prevention policies do not have an upper age limit, and as the overwhelming majority of older people continue to reside in the community there is a growing role for community dietetics and primary care team members in the promotion of healthy eating. METHOD: The multi-method project ascertained the dietary beliefs and practices of older people residing in high-income, low-income and rural localities of Scotland. One hundred and fifty-two people aged 75 years and over were interviewed using a semistructured interview schedule and 24-h food recall questionnaire. RESULTS: An analysis of the food recall questionnaire demonstrated that the diets of the elderly appear to differ little from the Scottish population as a whole. In all groups there was an under consumption of fruits and vegetables reported. Findings from the interviews demonstrated that dietary beliefs were found to be firmly rooted in childhood and lifetime experiences. Participants defined healthy eating as 'proper meals', 'proper foods', and a variety of foods eaten in moderation. These definitions were based upon the consumption of fresh foods which would be considered healthy. Changing and conflicting advice on health and nutrition was contrasted with personal experiences. Few knew of the role of the dietitian or community dietitian. CONCLUSIONS: This study demonstrates a contrast between stated beliefs and actual consumption patterns. Access to food, and the cost and quality of foods impacted upon food practices. The role of the community dietitian should be promoted. Advice on healthy eating must work with contemporary practices and beliefs building upon positive aspects of diet and eating and involving the food industry, retail sector and health services.

Gallium arsenide transistors: realization through a molecularly designed insulator.

A GaAs-based transistor, analogous to commercial silicon devices, has been fabricated with vapor-deposited cubic GaS as the insulator material. The n-channel, depletion mode, GaAs field-effect transistor shows, in addition to classical transistor characteristics, a channel mobility of 4665.6 square centimeters per volt per second, an interfacial trap density of 10(11) per electron volt per square centimeter, and a transconductance of 7 millisiemens for a 5-micrometer gate length at a gate voltage of 8 volts. Furthermore, the GaAs transistor shows an on-to-off resistance ratio comparable to that of commercial devices.

A survey of Scottish Health Boards and English Health Authorities. The extent of computerisation in health visiting records.

There is a wide variation in how computer technology has been used with regard to child health records and allied services. A survey of health boards in Scotland was extended to English health authorities (HAs) to ascertain if information was collected from health visitor records for computer analysis. The results showed Greater Glasgow Health Board uses a record which is coded for a computer. Fife Health Board also used part of this system. In England, ten of the individually described health authorities have just or are in the process of redesigning their records for health visitors. There is a wide variation of how computer technology has been used with regard to health visiting. For an overall picture of family and child most records either relied on the manual part of the record or did not require this information to be recorded. Developments in health visiting which try to ensure a service to the family as well as the child would therefore remain hidden or, more worryingly, untouched.