MoMuLV and HIV-1 nucleocapsid proteins have a common role in genomic RNA packaging but different in late reverse transcription

Retroviral nucleocapsid proteins harbor nucleic acid chaperoning activities that mostly rely on the N-terminal basic residues and the CCHC zinc finger motif. Such chaperoning is essential for virus replication, notably for genomic RNA selection and packaging in virions, and for reverse transcription of genomic RNA into DNA. Recent data revealed that HIV-1 nucleocapsid restricts reverse transcription during virus assembly--a process called late reverse transcription--suggesting a regulation between RNA packaging and late reverse transcription. Indeed, mutating the HIV-1 nucleocapsid basic residues or the two zinc fingers caused a reduction in RNA incorporated and an increase in newly made viral DNA in the mutant virions. MoMuLV nucleocapsid has an N-terminal basic region similar to HIV-1 nucleocapsid but a unique zinc finger. This prompted us to investigate whether the N-terminal basic residues and the zinc finger of MoMuLV and HIV-1 nucleocapsids play a similar role in genomic RNA packaging and late reverse transcription. To this end, we analyzed the genomic RNA and viral DNA contents of virions produced by cells transfected with MoMuLV molecular clones where the zinc finger was mutated or completely deleted or with a deletion of the N-terminal basic residues of nucleocapsid. All mutant virions showed a strong defect in genomic RNA content indicating that the basic residues and zinc finger are important for genomic RNA packaging. In contrast to HIV-1 nucleocapsid-mutants, the level of viral DNA in mutant MoMuLV virions was only slightly increased. These results confirm that the N-terminal basic residues and zinc finger of MoMuLV nucleocapsid are critical for genomic RNA packaging but, in contrast to HIV-1 nucleocapsid, they most probably do not play a role in the control of late reverse transcription. In addition, these results suggest that virus formation and late reverse transcription proceed according to distinct mechanisms for MuLV and HIV-1

The availability of snack food displays that may trigger impulse purchases in Melbourne supermarkets

<p>Abstract</p> <p>Background</p> <p>Supermarkets play a major role in influencing the food purchasing behaviours of most households. Snack food exposures within these stores may contribute to higher levels of consumption and ultimately to increasing levels of obesity, particularly within socioeconomically disadvantaged neighbourhoods. We aimed to examine the availability of snack food displays at checkouts, end-of-aisle displays and island displays in major supermarket chains in the least and most socioeconomically disadvantaged neighbourhoods of Melbourne.</p> <p>Methods</p> <p>Within-store audits of 35 Melbourne supermarkets. Supermarkets were sampled from the least and most socioeconomically disadvantaged suburbs within 30 km of the Melbourne CBD. We measured the availability of crisps, chocolate, confectionery, and soft drinks (diet and regular) at the checkouts, in end-of-aisle displays, and in island bin displays.</p> <p>Results</p> <p>Snack food displays were most prominent at checkouts with only five stores not having snack foods at 100% of their checkouts. Snack foods were also present at a number of end-of-aisle displays (at both the front (median 38%) and back (median 33%) of store), and in island bin displays (median number of island displays: 7; median total circumference of island displays: 19.4 metres). Chocolate items were the most common snack food item on display. There was no difference in the availability of these snack food displays by neighbourhood disadvantage.</p> <p>Conclusions</p> <p>As a result of the high availability of snack food displays, exposure to snack foods is almost unavoidable in Melbourne supermarkets, regardless of levels of neighbourhood socioeconomic disadvantage. Results of this study could promote awareness of the prominence of unhealthy food items in chain-brand supermarkets outlets.</p

Performance Scores in General Practice: A Comparison between the Clinical versus Medication-Based Approach to Identify Target Populations

CONTEXT: From one country to another, the pay-for-performance mechanisms differ on one significant point: the identification of target populations, that is, populations which serve as a basis for calculating the indicators. The aim of this study was to compare clinical versus medication-based identification of populations of patients with diabetes and hypertension over the age of 50 (for men) or 60 (for women), and any consequences this may have on the calculation of P4P indicators. METHODS: A comparative, retrospective, observational study was carried out with clinical and prescription data from a panel of general practitioners (GPs), the Observatory of General Medicine (OMG) for the year 2007. Two indicators regarding the prescription for statins and aspirin in these populations were calculated. RESULTS: We analyzed data from 21.690 patients collected by 61 GPs via electronic medical files. Following the clinical-based approach, 2.278 patients were diabetic, 8,271 had hypertension and 1.539 had both against respectively 1.730, 8.511 and 1.304 following the medication-based approach (% agreement = 96%, kappa = 0.69). The main reasons for these differences were: forgetting to code the morbidities in the clinical approach, not taking into account the population of patients who were given life style and diet rules only or taking into account patients for whom morbidities other than hypertension could justify the use of antihypertensive drugs in the medication-based approach. The mean (confidence interval) per doctor was 33.7% (31.5-35.9) for statin indicator and 38.4% (35.4-41.4) for aspirin indicator when the target populations were identified on the basis of clinical criteria whereas they were 37.9% (36.3-39.4) and 43.8% (41.4-46.3) on the basis of treatment criteria. CONCLUSION: The two approaches yield very "similar" scores but these scores cover different realities and offer food for thought on the possible usage of these indicators in the framework of P4P programmes

Determinants of persistence in hypertensive patients treated with irbesartan: results of a postmarketing survey

BACKGROUND: Persistence is a key factor for long-term blood pressure control, which is of high prognostic importance for patients at increased cardiovascular risk. Here we present the results of a post-marketing survey including 4769 hypertensive patients treated with irbesartan in 886 general practices in Switzerland. The goal of this survey was to evaluate the tolerance and the blood pressure lowering effect of irbesartan as well as the factors affecting persistence in a large unselected population. METHODS: Prospective observational survey conducted in general practices in all regions of Switzerland. Previously untreated and uncontrolled pre-treated patients were started with a daily dose of 150 mg irbesartan and followed up to 6 months. RESULTS: After an observation time slightly exceeding 4 months, the average reduction in systolic and diastolic blood pressure was 20 (95% confidence interval (CI) -19.6 to -20.7 mmHg) and 12 mmHg (95% CI -11.4 to -12.1 mmHg), respectively. At this time, 26% of patients had a blood pressure < 140/90 mmHg and 60% had a diastolic blood pressure < 90 mmHg. The drug was well tolerated with an incidence of adverse events (dizziness, headaches,...) of 8.0%. In this survey more than 80% of patients were still on irbesartan at 4 month. The most important factors predictive of persistence were the tolerability profile and the ability to achieve a blood pressure target ≤ 140/90 mmHg before visit 2. Patients who switched from a fixed combination treatment tended to discontinue irbesartan more often whereas those who abandoned the previous treatment because of cough (a class side effect of ACE-Inhibitors) were more persistent with irbesartan. CONCLUSION: The results of this survey confirm that irbesartan is effective, well tolerated and well accepted by patients, as indicated by the good persistence. This post-marketing survey also emphasizes the importance of the tolerability profile and of achieving an early control of blood pressure as positive predictors of persistence

Key Learning Outcomes for Clinical Pharmacology and Therapeutics Education in Europe: A Modified Delphi Study.

Harmonizing clinical pharmacology and therapeutics (CPT) education in Europe is necessary to ensure that the prescribing competency of future doctors is of a uniform high standard. As there are currently no uniform requirements, our aim was to achieve consensus on key learning outcomes for undergraduate CPT education in Europe. We used a modified Delphi method consisting of three questionnaire rounds and a panel meeting. A total of 129 experts from 27 European countries were asked to rate 307 learning outcomes. In all, 92 experts (71%) completed all three questionnaire rounds, and 33 experts (26%) attended the meeting. 232 learning outcomes from the original list, 15 newly suggested and 5 rephrased outcomes were included. These 252 learning outcomes should be included in undergraduate CPT curricula to ensure that European graduates are able to prescribe safely and effectively. We provide a blueprint of a European core curriculum describing when and how the learning outcomes might be acquired

Causes of secondary hypertension in the young population: A monocentric study

Objective: To study the prevalence of different causes of hypertension in young adults referred to a hypertension center in the south west of France. Methods: We conducted a retrospective overview of patients younger than 40years old hospitalized consecutively in the Hypertension department of Toulouse University Hospital between 2012 and 2014. Clinical data about gender, age, anthropomorphic parameters and blood pressure measurement by 24h Ambulatory Blood Pressure Monitoring (ABPM) were recorded. Biological data concerned dosages of kalemia, renin and aldosterone in the supine or after 15min of seating. Recorded radiological examinations were renal artery ultrasound and abdominal CT scan. Results: One hundred and forty-eight detailed medical records were analyzed, 69 women and 79 men. Among the 69 women, the causes of secondary hypertension were primary aldosteronism (n=7), fibromuscular dysplasia (n=5) and renal disease (n=4). Oral contraceptives were involved in 13 women. In addition, essential hypertension concerned 40 women (58%). Among the 79 men, the causes of secondary hypertension were primary aldosteronism (n=10), fibromuscular dysplasia (n=3), left main renal artery entrapment by a diaphragmatic crura (n=2), renal disease (n=1), pheochromocytoma (n=3) and coarctation of the aorta (n=2). In addition, essential hypertension concerned 58 men (73%). Conclusions: In our population, the prevalence of secondary hypertension is close to 33% (42% of females and 27% of males), with the following main causes: primary aldosteronism for 11.5%; fibromuscular dysplasia for 5.4%. Oral contraceptives were involved in the hypertension of 19% of the females

Role of HIV-1 RNA and protein determinants for the selective packaging of spliced and unspliced viral RNA and host U6 and 7SL RNA in virus particles

International audienceHIV-1 particles contain RNA species other than the unspliced viral RNA genome. For instance, viral spliced RNAs and host 7SL and U6 RNAs are natural components that are non-randomly incorporated. To understand the mechanism of packaging select-ivity, we analyzed the content of a large panel of HIV-1 variants mutated either in the 5 0 UTR structures of the viral RNA or in the Gag-nucleocapsid protein (GagNC). In parallel, we determined whether the selection of host 7SL and U6 RNAs is dependent or not on viral RNA and/or GagNC. Our results reveal that the polyA hairpin in the 5 0 UTR is a major packaging determinant for both spliced and un-spliced viral RNAs. In contrast, 5 0 UTR RNA structures have little influence on the U6 and 7SL RNAs, indicating that packaging of these host RNAs is independent of viral RNA packaging. Experiments with GagNC mutants indicated that the two zinc-fingers and N-terminal basic residues restrict the incorporation of the spliced RNAs, while favoring unspliced RNA packaging. GagNC through the zinc-finger motifs also restricts the packaging of 7SL and U6 RNAs. Thus, GagNC is a major contributor to the packaging selectivity. Altogether our results provide new molecular insight on how HIV selects distinct RNA species for incorporation into particles