Analysis of gene expression in wild‐type and Notch1 mutant retinal cells by single cell profiling

Results: To examine the molecular underpinnings of this observation, microarray analysis of single retinal cells from wild‐type or Notch1 conditional knockout retinas was performed. In situ hybridization was carried out to validate some of the findings. 相似文献   

Comparative efficacy and safety of aliskiren, an oral direct renin inhibitor, and ramipril in hypertension: a 6-month, randomized, double-blind trial

OBJECTIVES: This double-blind study compared long-term efficacy, safety and tolerability of the oral direct renin inhibitor aliskiren and the angiotensin-converting enzyme inhibitor ramipril alone and combined with hydrochlorothiazide in patients with hypertension. METHODS: After a 2-4-week placebo run-in, 842 patients [mean sitting diastolic blood pressure (msDBP) 95-109 mmHg] were randomized to aliskiren 150 mg (n = 420) or ramipril 5 mg (n = 422). Dose titration (to aliskiren 300 mg/ramipril 10 mg) and subsequent hydrochlorothiazide addition (12.5 mg, titrated to 25 mg if required) were permitted at weeks 6, 12, 18 and 21 for inadequate blood pressure control. Patients completing the 26-week active-controlled treatment period were re-randomized to their existing regimen or placebo for a 4-week double-blind withdrawal phase. RESULTS: Six hundred and eighty-seven patients (81.6%) completed the active treatment period. At week 26, aliskiren-based therapy produced greater mean reductions in mean sitting systolic blood pressure (17.9 versus 15.2 mmHg, P = 0.0036) and msDBP (13.2 versus 12.0 mmHg, P = 0.025), and higher rates of systolic blood pressure control (< 140 mmHg; 72.5 versus 64.1%, P = 0.0075) compared with ramipril-based therapy. During withdrawal, blood pressure increased more rapidly after stopping ramipril than aliskiren-based therapy; median blood pressure reached 140/90 mmHg after 1 and 4 weeks, respectively. Blood pressure reductions were maintained with continued active treatment. Aliskiren therapy was well tolerated. Overall adverse event rates were similar with aliskiren (61.3%) and ramipril (60.4%); cough was more frequent with ramipril (9.5%) than aliskiren (4.1%). CONCLUSIONS: Aliskiren-based therapy was well tolerated and produced sustained blood pressure reductions in patients with hypertension over 6 months, greater than those with ramipril-based therapy.     

The effects of household wealth on HIV prevalence in Manicaland,Zimbabwe – a prospective household census and population-based open cohort study

Introduction

Intensified poverty arising from economic decline and crisis may have contributed to reductions in HIV prevalence in Zimbabwe.

Objectives

To assess the impact of the economic decline on household wealth and prevalent HIV infection using data from a population-based open cohort.

Methods

Household wealth was estimated using data from a prospective household census in Manicaland Province (1998 to 2011). Temporal trends in summed asset ownership indices for sellable, non-sellable and all assets combined were compared for households in four socio-economic strata (small towns, agricultural estates, roadside settlements and subsistence farming areas). Multivariate logistic random-effects models were used to measure differences in individual-level associations between prevalent HIV infection and place of residence, absolute wealth group and occupation.

Results

Household mean asset scores remained similar at around 0.37 (on a scale of 0 to 1) up to 2007 but decreased to below 0.35 thereafter. Sellable assets fell substantially from 2004 while non-sellable assets continued increasing until 2008. Small-town households had the highest wealth scores but the gap to other locations decreased over time, especially for sellable assets. Concurrently, adult HIV prevalence fell from 22.3 to 14.3%. HIV prevalence was highest in better-off locations (small towns) but differed little by household wealth or occupation. Initially, HIV prevalence was elevated in women from poorer households and lower in men in professional occupations. However, most recently (2009 to 2011), men and women in the poorest households had lower HIV prevalence and men in professional occupations had similar prevalence to unemployed men.

Conclusions

The economic crisis drove more households into extreme poverty. However, HIV prevalence fell in all socio-economic locations and sub-groups, and there was limited evidence that increased poverty contributed to HIV prevalence decline.     

Benefit of treatment interruption in HIV-infected patients with multiple therapeutic failures: a randomized controlled trial (ANRS 097)

BACKGROUND: Both highly potent antiretroviral drug rescue therapy and treatment interruption have been suggested to be effective in patients with multiple treatment failure. OBJECTIVE: To assess both the benefits and risks of an 8-week treatment interruption associated with a six to nine-drug rescue regimen in patients with multiple treatment failures. DESIGN: A randomized comparative controlled trial in 19 university hospitals in France. PATIENTS: Sixty-eight HIV-infected patients with multiple previous treatment failures and CD4 cell counts less than 200 x 10(6) cells/l and plasma HIV-1-RNA levels of 50,000 copies/ml or greater. MEASUREMENTS: The primary efficacy outcome was the proportion of patients with at least a 1 log10 decrease (copies/ml) in the plasma HIV-1-RNA level after 12 weeks of therapy. RESULTS: Treatment interruption followed by multidrug salvage therapy led to a greater proportion of patients achieving virological success (i.e. 1 log10 decrease) at 12 weeks compared with patients receiving multidrug therapy alone (62 versus 26%, intent-to-treat analysis; P = 0.007). The median decrease in the HIV-1-RNA level was -1.91 and -0.37 log10 copies/ml (P = 0.008), respectively. Treatment interruption led to an increase in the number of sensitive drugs of the multidrug regimen (71 versus 35% of regimen with at least two sensitive drugs; P = 0.004). Factors associated with virological success were treatment interruption, the reversion of at least one mutation to wild type, adequate plasma drug concentration, and the use of lopinavir. CONCLUSION: Treatment interruption was beneficial for treatment-experienced HIV-infected patients with advanced HIV disease and multidrug-resistant virus.     

Mandibular flexure and its significance on implant fixed prostheses: a review

Purpose: The aims of this review are to determine the effect of mandibular flexure on the “implant‐framework system,” and analyze the existing literature on the topic. Materials and Methods: A MEDLINE and PubMed search was conducted to identify any articles in English related to the topic published up to May 2010 using the search words “mandible,”“dental implants,”“dental impression technique,”“jaw movement,”“dental stress analysis,” and “mechanical stress.” Results: The search identified 40 and 36 articles from MEDLINE and PubMed, respectively. Twenty articles met the inclusion criteria. Conclusions: Mandibular flexure is a multifactorial phenomenon, and the effect of the implant‐framework system in this is unclear. Studies have focused mainly on the fully edentulous mandible. These have found that mandibular flexure should be taken into consideration when designing a prosthesis and have suggested that dividing the prosthesis at the symphysis region, or into multiple implant fixed dental prostheses, may minimize the effect of mandibular flexure on the implant prosthesis. At this time, no studies have investigated the effect of mandibular flexure on long‐span, unilateral, implant fixed prostheses. The clinical significance of mandibular flexure on the success of dental implant treatment is at this time unclear, and further research is needed.     

A clinically relevant population of leukemic CD34(+)CD38(-) cells in acute myeloid leukemia

Relapse of acute myeloid leukemia (AML) is thought to reflect the failure of current therapies to adequately target leukemia stem cells (LSCs), the rare, resistant cells presumed responsible for maintenance of the leukemia and typically enriched in the CD34(+)CD38(-) cell population. Despite the considerable research on LSCs over the past 2 decades, the clinical significance of these cells remains uncertain. However, if clinically relevant, it is expected that LSCs would be enriched in minimal residual disease and predictive of relapse. CD34(+) subpopulations from AML patients were analyzed by flow cytometry throughout treatment. Sorted cell populations were analyzed by fluorescence in situ hybridization for leukemia-specific cytogenetic abnormalities (when present) and by transplantation into immunodeficient mice to determine self-renewal capacity. Intermediate (int) levels of aldehyde dehydrogenase (ALDH) activity reliably distinguished leukemic CD34(+)CD38(-) cells capable of engrafting immunodeficient mice from residual normal hematopoietic stem cells that exhibited relatively higher ALDH activity. Minimal residual disease detected during complete remission was enriched for the CD34(+)CD38(-)ALDH(int) leukemic cells, and the presence of these cells after therapy highly correlated with subsequent clinical relapse. ALDH activity appears to distinguish normal from leukemic CD34(+)CD38(-) cells and identifies those AML cells associated with relapse.