High-carotenoid maize: development of plant biotechnology prototypes for human and animal health and nutrition

Carolight (R) is a transgenic maize variety that accumulates extraordinary levels of carotenoids, including those with vitamin A activity. The development of Carolight (R) maize involved the technical implementation of a novel combinatorial transformation method, followed by rigorous testing for transgene expression and the accumulation of different carotenoid molecules. Carolight (R) was envisaged as a way to improve the nutritional health of human populations that cannot access a diverse diet, but this ultimate humanitarian application can only be achieved after extensive testing for safety, agronomic performance and nutritional sufficiency. In this article, we chart the history of Carolight (R) maize focusing on its development, extensive field testing for agronomic performance and resistance to pests and pathogens, and feeding trials to analyze its impact on farm animals (and their meat/dairy products) as well as animal models of human diseases. We also describe more advanced versions of Carolight (R) endowed with pest-resistance traits, and other carotenoid-enhanced maize varieties originating from the same series of initial transformation experiments. Finally we discuss the further steps required before Carolight (R) can fulfil its humanitarian objectives, including the intellectual property and regulatory constraints that lie in its path

Need and importance of health protection training in Nepal

By investing in health protection, the health of the nation can be safeguarded from future threats of uncontrolled infectious disease epidemics and disasters

A meta-analysis of N-acetylcysteine in contrast-induced nephrotoxicity: unsupervised clustering to resolve heterogeneity

<p>Abstract</p> <p>Background</p> <p>Meta-analyses of N-acetylcysteine (NAC) for preventing contrast-induced nephrotoxicity (CIN) have led to disparate conclusions. Here we examine and attempt to resolve the heterogeneity evident among these trials.</p> <p>Methods</p> <p>Two reviewers independently extracted and graded the data. Limiting studies to randomized, controlled trials with adequate outcome data yielded 22 reports with 2746 patients.</p> <p>Results</p> <p>Significant heterogeneity was detected among these trials (<it>I</it>²= 37%; <it>p </it>= 0.04). Meta-regression analysis failed to identify significant sources of heterogeneity. A modified L'Abbé plot that substituted groupwise changes in serum creatinine for nephrotoxicity rates, followed by model-based, unsupervised clustering resolved trials into two distinct, significantly different (<it>p </it>< 0.0001) and homogeneous populations (<it>I</it>²= 0 and <it>p </it>> 0.5, for both). Cluster 1 studies (<it>n </it>= 18; 2445 patients) showed no benefit (relative risk (RR) = 0.87; 95% confidence interval (CI) 0.68–1.12, <it>p </it>= 0.28), while cluster 2 studies (<it>n </it>= 4; 301 patients) indicated that NAC was highly beneficial (RR = 0.15; 95% CI 0.07–0.33, <it>p </it>< 0.0001). Benefit in cluster 2 was unexpectedly associated with NAC-induced decreases in creatinine from baseline (<it>p </it>= 0.07). Cluster 2 studies were relatively early, small and of lower quality compared with cluster 1 studies (<it>p </it>= 0.01 for the three factors combined). Dialysis use across all studies (five control, eight treatment; <it>p </it>= 0.42) did not suggest that NAC is beneficial.</p> <p>Conclusion</p> <p>This meta-analysis does not support the efficacy of NAC to prevent CIN.</p

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Factors affecting the response to the specific treatment of several forms of clinical anestrus in high producing dairy cows

This study was designed to examine estrous response rates to the therapeutic treatment of clinical anestrus in high producing dairy cows and to identify the factors that could affect these rates. Cows with silent ovulation (Subestrus group), cystic ovarian disease (Cyst group) or ovarian hypofunction (OH group) were given specific treatment for their disorder. Data were derived from 1764 treatments in cows producing a mean of 45.4 kg of milk upon treatment including: 889 subestrous cows, 367 cystic cows and 508 cows with ovarian hypofunction. Cows showing estrus following treatment exhibited a similar pregnancy rate to cows attaining natural estrus used as reference: 33% (337/1006) and 35% (626/1796), respectively. No significant ifferences in pregnancy rates were observed among the Subestrus, Cyst and OH groups (34% (196/571), 34% (44/130), 32% (97/305), respectively. Based on the odds ratio, an estrous response for all groups was less likely to occur in cows that had suffered previous anestrus, compared to cows that were anestrous for the first time, whereas the likelihood of an estrous response increased in cows treated after 90 days in milk. Our results indicate that previous anestrus and a late stage of lactation can have a negative and positive effect, respectively, on the estrous response to the specific treatment of clinical anestrus shown by high producing dairy cows. Treatment targeted at each type of clinical anestrus can render similar pregnancy rates to those shown by cows in natural estrus

Relationship between heat stress during peri-implantation period and early fetal loss in cattle.

The aim of the present study was to establish whether temperature-humidity index values, as a measure of heat comfort, from Days 1 to 40 of gestation could be associated with the pregnancy loss rate in high producing dairy cows. Data from 1391 pregnancies were recorded. Pregnancy was diagnosed by transrectal ultrasonography between Days 34 and 45, and again 90 days after insemination. Pregnancy loss was assumed when the second pregnancy diagnosis on Day 90 proved negative and was registered in 7.8% (108/1391) of pregnancies. Mean and maximum temperature-humidity index values were established for each cow for Days 0 (day of insemination), 1, 2 and 3 after insemination, and averages established for Days 0-3, 0-10, 11-20, 21-30 and 31-40 after insemination. Cow and management variables previously found to be significantly correlated with the early fetal loss in the same geographical area were also recorded. The relative contribution of each factor to the probability of pregnancy loss was determined using logistic regression models. Based on the odds ratio, a strong association with pregnancy loss of the factors warm period of pregnancy (warm period-May to September versus cool-October to April), twin pregnancy (as negative factors: odds ratios 3.1 and 3.4, respectively) and an additional corpus luteum (as a positive factor: odds ratio 0.32) was confirmed. The likelihood of pregnancy loss increased by a factor of 1.05 for each additional unit of the mean maximum temperature-humidity index from Days 21 to 30 of gestation. Logistic regression analysis revealed no significant effects of temperature-humidity index values for the remaining gestation periods. Our results indicate that heat stress can compromise the success of gestation during the peri-implantation period, such that high temperature-humidity index values for the period 21-30 days of gestation are a risk factor for subsequent early fetal loss