Constitutive cytoplasmic localization of p21Waf1/Cip1 affects the apoptotic process in monocytic leukaemia

In the present study, we analysed the expression and localization of p21Waf1/Cip1 in normal and malignant haematopoietic cells. We demonstrate that in normal monocytic cells, protein kinase C (PKC)-induced p21 gene activation, which is nuclear factor-κB (NF-κB) independent, results in predominantly cytoplasmic localized p21 protein. In acute monocytic leukaemia (M4, M5), monocytic blasts (N=12) show constitutive cytoplasmic p21 expression in 75% of the cases, while in myeloid leukaemic blasts (N=10), low nuclear and cytoplasmic localization of p21 could be detected, which is also PKC dependent. Constitutive p21 expression in monocytic leukaemia might have important antiapoptotic functions. This is supported by the finding that in U937 cells overexpressing p21, VP16-induced apoptosis is significantly reduced (20.0±0.9 vs 55.8±3.8%, P<0.01, N=5), reflected by a reduced phosphorylation of p38 and JNK. Similarly, AML blasts with high cytoplasmic p21 were less sensitive to VP16-induced apoptosis as compared to AML cases with low or undetectable p21 expression (42.25 vs 12.3%, P<0.01). Moreover, complex formation between p21 and ASK1 could be demonstrated in AML cells, by means of coimmunoprecipitation. In summary, these results indicate that p21 has an antiapoptotic role in monocytic leukaemia, and that p21 expression is regulated in a PKC-dependent and NF-κB independent manner.

Historical changes in the stomatal limitation of photosynthesis: empirical support for an optimality principle

The ratio of leaf‐internal (ci) to ambient (ca) partial pressure of CO2, defined here as χ, is an index of adjustments in both leaf stomatal conductance and photosynthetic rate to environmental conditions. Measurements and proxies of this ratio can be used to constrain vegetation models uncertainties for predicting terrestrial carbon uptake and water use. We test a theory based on the least‐cost optimality hypothesis for modelling historical changes in χ over the 1951‐2014 period, across different tree species and environmental conditions, as reconstructed from stable carbon isotopic measurements across a global network of 103 absolutely‐dated tree‐ring chronologies. The theory predicts optimal χ as a function of air temperature, vapour pressure deficit, ca and atmospheric pressure. The theoretical model predicts 39% of the variance in χ values across sites and years, but underestimates the inter‐site variability in the reconstructed χ trends, resulting in only 8% of the variance in χ trends across years explained by the model. Overall, our results support theoretical predictions that variations in χ are tightly regulated by the four environmental drivers. They also suggest that explicitly accounting for the effects of plant‐available soil water and other site‐specific characteristics might improve the predictions

Identification of a Circadian Clock-Controlled Neural Pathway in the Rabbit Retina

Background: Although the circadian clock in the mammalian retina regulates many physiological processes in the retina, it is not known whether and how the clock controls the neuronal pathways involved in visual processing. Methodology/Principal Findings: By recording the light responses of rabbit axonless (A-type) horizontal cells under darkadapted conditions in both the day and night, we found that rod input to these cells was substantially increased at night under control conditions and following selective blockade of dopamine D2, but not D1, receptors during the day, so that the horizontal cells responded to very dim light at night but not in the day. Using neurobiotin tracer labeling, we also found that the extent of tracer coupling between rabbit rods and cones was more extensive during the night, compared to the day, and more extensive in the day following D 2 receptor blockade. Because A-type horizontal cells make synaptic contact exclusively with cones, these observations indicate that the circadian clock in the mammalian retina substantially increases rod input to A-type horizontal cells at night by enhancing rod-cone coupling. Moreover, the clock-induced increase in D2 receptor activation during the day decreases rod-cone coupling so that rod input to A-type horizontal cells is minimal. Conclusions/Significance: Considered together, these results identify the rod-cone gap junction as a key site in mammals through which the retinal clock, using dopamine activation of D2 receptors, controls signal flow in the day and night fro

A systematic review of primary care models for non-communicable disease interventions in Sub-Saharan Africa

Background Chronic diseases, primarily cardiovascular disease, respiratory disease, diabetes and cancer, are the leading cause of death and disability worldwide. In sub-Saharan Africa (SSA), where communicable disease prevalence still outweighs that of non-communicable disease (NCDs), rates of NCDs are rapidly rising and evidence for primary healthcare approaches for these emerging NCDs is needed. Methods A systematic review and evidence synthesis of primary care approaches for chronic disease in SSA. Quantitative and qualitative primary research studies were included that focused on priority NCDs interventions. The method used was best-fit framework synthesis. Results Three conceptual models of care for NCDs in low- and middle-income countries were identified and used to develop an a priori framework for the synthesis. The literature search for relevant primary research studies generated 3759 unique citations of which 12 satisfied the inclusion criteria. Eleven studies were quantitative and one used mixed methods. Three higher-level themes of screening, prevention and management of disease were derived. This synthesis permitted the development of a new evidence-based conceptual model of care for priority NCDs in SSA. Conclusions For this review there was a near-consensus that passive rather than active case-finding approaches are suitable in resource-poor settings. Modifying risk factors among existing patients through advice on diet and lifestyle was a common element of healthcare approaches. The priorities for disease management in primary care were identified as: availability of essential diagnostic tools and medications at local primary healthcare clinics and the use of standardized protocols for diagnosis, treatment, monitoring and referral to specialist care

Candidate genetic analysis of plasma high-density lipoprotein-cholesterol and severity of coronary atherosclerosis

<p>Abstract</p> <p>Background</p> <p>Plasma level of high-density lipoprotein-cholesterol (HDL-C), a heritable trait, is an important determinant of susceptibility to atherosclerosis. Non-synonymous and regulatory single nucleotide polymorphisms (SNPs) in genes implicated in HDL-C synthesis and metabolism are likely to influence plasma HDL-C, apolipoprotein A-I (apo A-I) levels and severity of coronary atherosclerosis.</p> <p>Methods</p> <p>We genotyped 784 unrelated Caucasian individuals from two sets of populations (Lipoprotein and Coronary Atherosclerosis Study- LCAS, N = 333 and TexGen, N = 451) for 94 SNPs in 42 candidate genes by 5' nuclease assays. We tested the distribution of the phenotypes by the Shapiro-Wilk normality test. We used Box-Cox regression to analyze associations of the non-normally distributed phenotypes (plasma HDL-C and apo A-I levels) with the genotypes. We included sex, age, body mass index (BMI), diabetes mellitus (DM), and cigarette smoking as covariates. We calculated the q values as indicators of the false positive discovery rate (FDR).</p> <p>Results</p> <p>Plasma HDL-C levels were associated with sex (higher in females), BMI (inversely), smoking (lower in smokers), DM (lower in those with DM) and SNPs in <it>APOA5, APOC2</it>, <it>CETP, LPL </it>and <it>LIPC </it>(each q ≤0.01). Likewise, plasma apo A-I levels, available in the LCAS subset, were associated with SNPs in <it>CETP</it>, <it>APOA5</it>, and <it>APOC2 </it>as well as with BMI, sex and age (all q values ≤0.03). The <it>APOA5 </it>variant S19W was also associated with minimal lumen diameter (MLD) of coronary atherosclerotic lesions, a quantitative index of severity of coronary atherosclerosis (q = 0.018); mean number of coronary artery occlusions (p = 0.034) at the baseline and progression of coronary atherosclerosis, as indicated by the loss of MLD.</p> <p>Conclusion</p> <p>Putatively functional variants of <it>APOA2</it>, <it>APOA5, APOC2</it>, <it>CETP, LPL</it>, <it>LIPC </it>and <it>SOAT2 </it>are independent genetic determinants of plasma HDL-C levels. The non-synonymous S19W SNP in <it>APOA5 </it>is also an independent determinant of plasma apo A-I level, severity of coronary atherosclerosis and its progression.</p

Dose dependent effect of statins on postoperative atrial fibrillation after cardiac surgery among patients treated with beta blockers

<p>Abstract</p> <p>Background</p> <p>Previous studies on the effects of Statins in preventing atrial fibrillation (AF) after cardiac surgery have shown conflicting results. Whether statins prevent AF in patients treated with postoperative beta blockers and whether the statin-effect is dose related are unknown.</p> <p>Methods</p> <p>We retrospectively studied 1936 consecutive patients who underwent coronary artery bypass graft (CABG) (n = 1493) or valve surgery (n = 443) at the Minneapolis Veterans Affairs Medical Center. All patients were in sinus rhythm before the surgery. Postoperative beta blockers were administered routinely (92% within 24 hours postoperatively).</p> <p>Results</p> <p>Mean age was 66+10 years and 68% of the patients were taking Statins. Postoperative AF occurred in 588 (30%) patients and led to longer length of stay in the intensive care unit versus those without AF (5.1+7.6 days versus 2.5+2.3 days, p < 0.0001). Patients with a past history of AF had a 5 times higher risk of postoperative AF (odds ratio 5.1; 95% confidence interval 3.4 to 7.7; p < 0.0001). AF occurred in 31% of patients taking statins versus 29% of the others (p = 0.49). In multivariable analysis, statins were not associated with AF (odds ratio (OR) 0.93, 95% confidence interval (CI) 0.7 to 1.2; p = 0.59). However, in a subgroup analysis, the patients treated with Simvastatin >20 mg daily had a 36% reduction in the risk of postoperative AF (OR 0.64, 95% CI 0.43 to 0.6; p = 0.03) in comparison to those taking lower dosages.</p> <p>Conclusion</p> <p>Among cardiac surgery patients treated with postoperative beta blockers Statin treatment reduces the incidence of postoperative AF when used at higher dosages</p

Gender differences in self reported long term outcomes following moderate to severe traumatic brain injury

<p>Abstract</p> <p>Background</p> <p>The majority of research on health outcomes after a traumatic brain injury is focused on male participants. Information examining gender differences in health outcomes post traumatic brain injury is limited. The purpose of this study was to investigate gender differences in symptoms reported after a traumatic brain injury and to examine the degree to which these symptoms are problematic in daily functioning.</p> <p>Methods</p> <p>This is a secondary data analysis of a retrospective cohort study of 306 individuals who sustained a moderate to severe traumatic brain injury 8 to 24 years ago. Data were collected using the Problem Checklist (PCL) from the Head Injury Family Interview (HIFI). Using Bonferroni correction, group differences between women and men were explored using Chi-square and Wilcoxon analysis.</p> <p>Results</p> <p>Chi-square analysis by gender revealed that significantly more men reported difficulty setting realistic goals and restlessness whereas significantly more women reported headaches, dizziness and loss of confidence. Wilcoxon analysis by gender revealed that men reported sensitivity to noise and sleep disturbances as significantly more problematic than women, whereas for women, lack of initiative and needing supervision were significantly more problematic in daily functioning.</p> <p>Conclusion</p> <p>This study provides insight into gender differences on outcomes after traumatic brain injury. There are significant differences between problems reported by men compared to women. This insight may facilitate health service planners and clinicians when developing programs for individuals with brain injury.</p

Intensive consolidation therapy compared with standard consolidation and maintenance therapy for adults with acute myeloid leukaemia aged between 46 and 60 years: final results of the randomized phase III study (AML 8B) of the European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) Leukemia Cooperative Groups

The most effective post-remission treatment to maintain complete remission (CR) in adults aged between 46 and 60 years with acute myeloid leukaemia (AML) is uncertain. Previously untreated patients with AML in CR after induction chemotherapy with daunorubicin and cytarabine were randomized between two intensive courses of consolidation therapy containing high-dose cytarabine, combined with amsacrine or daunorubicin and a standard consolidation and maintenance therapy containing standard dose cytarabine and daunorubicin. One hundred fifty-eight CR patients were assigned to the intensive group and 157 patients to the standard group. After a median follow-up of 7.5 years, the 4-year survival rate was 32 % in the intensive group versus 34 % in the standard group (P = 0.29). In the intensive group, the 4-year relapse incidence was lower than in the standard group: 55 and 75 %, respectively (P = 0.0003), whereas treatment-related mortality incidence was higher: 22 versus 3 % (P < 0.0001). Two intensive consolidation courses containing high-dose cytarabine as post-remission treatment in patients with AML aged between 46 and 60 years old did not translate in better long-term outcome despite a 20 % lower relapse incidence. Better supportive care and prevention of treatment-related complications may improve the overall survival after intensified post-remission therapy in this age group