Objectives: Clinical studies have documented morning-evening, administration-time differences in antihypertensive efficacy, duration of action, safety profile and/or effects on the circadian blood pressure (BP) pattern of several different classes of BP-lowering medications. Despite these findings, most hypertensive subjects ingest all their BP-lowering agents in a single morning dose. The MAPEC study investigated if chronotherapy of hypertension has any influence in cardiovascular morbidity and mortality. Methods: This prospective study investigated 3344 subjects (1718 men), 52.6 ± 14.5 years of age. At baseline, BP was measured every 20-min intervals 07:00 to 23:00 h and every 30-min at night for 48 h. Physical activity was simultaneously monitored every minute by wrist actigraphy. The same evaluation procedure was scheduled yearly or more frequently (quarterly) if treatment adjustment was required to improve BP control. The Cox proportional-hazard model was used to estimate relative risks of cardiovascular events associated with use of antihypertensive treatment and circadian time of treatment. Results: At the last evaluation, 625 subjects were normotensive and 606 untreated hypertensives according to ambulatory BP criteria. Among the remaining subjects, 1068 were receiving all antihypertensive medication on awakening, and 1045 were ingesting some antihypertensive agent at bedtime. Compared with normotensive subjects, the relative risk of cardiovascular events was highest for patients ingesting all drugs on awakening (3.84 [2.48–5.95]) and lowest for those receiving all medication at bedtime (0.95 [0.44–2.07]; P = 0.907 compared to normotensive subjects; P < 0.001 compared to all other groups). Compared with untreated subjects, cardiovascular risk was significantly higher with increasing number of drugs on awakening, but consistently lower, independently of the number of drugs, when medication was ingested at bedtime. Non-dipping was significantly lower (28 vs. 61%) among subjects treated at bedtime. Conclusions: In subjects with essential hypertension, pharmacologic therapy should take into account when to treat with respect to the rest-activity pattern of each patient. Treatment at bedtime not only improves BP control and decreases the prevalence of non-dipping, but also significantly reduces cardiovascular risk to the level of normotension.
Barley is one of the most important cereal crops and arranged globally as fourth after wheat, rice, and corn. It is known for its beneficial effects against degenerative diseases including diabetes, obesity, hypertension, and colon inflammation which are associated with eating habits and improper lifestyles. These effects are mainly attributed to its rich dietary fibers, i.e., β-glucan composition. Moreover, barley considered as a good source of starch, minerals, vitamins, and protein pose it as an ideal food supplement. Nevertheless, about 2% of the barley global production is utilized due to unacceptable organoleptic characters. Therefore, continuous modifications are ongoing either to develop new cultivars for different purposes, or novel processing methods to improve its organoleptic characters. In this review, we provide a comprehensive overview of the macroconstituents and microconstituents of barley, its nutritional value and prebiotic effects. Further, different processing procedures performed to improve its organoleptic characters or to decrease its antinutrient levels are outlined with suggestions for further needed cultivars that could preserve the different benefits of barley and maximize its value as a major cereal crop.
The hearsay rule is the most important concepts in the common law of Britain and the United States,occupies a pivotal position.The rules in promoting China's reform of the trial,finding the truth and the facts of the case,has important significance to improve the efficiency of the proceedings.China currently lacks the hearsay rule,resulting in emergence of China's criminal trial court,saying the witnesses very low,low efficiency problem of litigation,our urgent need to establish the rules to promote the trial reform,better find the real case,to improve effectiveness of the proceedings.
Hypertensive patients with high blood pressure (BP) after treatment with 3 or more antihypertensive drugs present elevated cardiovascular risk, and high prevalence of a non-dipper BP pattern (<10% decline in the nocturnal relative to the diurnal BP mean). Recent results indicate that non-dipping in treated patients may be related to the absence of 24-hour therapeutic coverage [J Hypertens. 2002;20:1097-1104]. Accordingly, we studied the impact of the time of treatment on the circadian pattern of BP in patients with resistant hypertension. We studied 444 patients with resistant hypertension (228 men), 58.9±11.0 years of age. Among them, 210 patients received all their medication upon awakening. In the remaining 234 patients, one drug was prescribed to be taken before bedtime. BP was measured at 20-min intervals from 07:00 to 23:00 hours and at 30-min intervals at night for 48 consecutive hours. Physical activity was simultaneously monitored every minute by wrist actigraphy, and the information used to determine diurnal and nocturnal means of BP for each patient according to individual resting time. In comparison with patients who received all their antihypertensive medication upon awakening, subjects with one drug before bedtime were characterized by a significant reduction in the 24-hour mean of systolic BP (4.9 mm Hg, P<0.001). This reduction was much more prominent during nocturnal resting hours (7.5 mm Hg, P<0.001). The reduction in nocturnal mean was also significant in diastolic BP (2.3 mm Hg, P=0.011). Patients receiving one drug before bedtime also showed a significant reduction in the 24-hour mean of pulse pressure (4.3 mm Hg, P<0.001). A very high 82.9% of the patients with all drugs on awakening were non-dippers. This percentage was significantly reduced to just 51.7% in patients who received one antihypertensive drug before bedtime (P<0.001). In patients with resistant hypertension, pharmacological therapy should take into account when to treat with respect to the rest-activity cycle of each patient, as a function of the therapeutic coverage of the drugs and the baseline circadian BP profile of the patient. This chronopharmacology therapeutic approach allows to reduce the prevalence of an altered non-dipper BP profile, associated with an increased cardiovascular risk. Am J Hypertens (2004) 17, 41A–41A; doi: 10.1016/j.amjhyper.2004.03.098
Cancer is a disease driven by both somatic mutations that increase survival and proliferation of cell lineages and the evolution of genes associated with cancer risk in populations. Several genes associated with cancer in humans, hereafter cancer genes, show evidence of germline positive selection among species. Taking advantage of a large collection of mammalian genomes, we systematically looked for signatures of germline positive selection in 430 cancer genes available in COSMIC. We identified 40 cancer genes with a robust signal of positive selection in mammals. We found evidence for fewer selective constraints—higher number of non-synonymous substitutions per non-synonymous site to the number of synonymous substitutions per synonymous site (dN/dS)—and higher incidence of positive selection—more positively selected sites—in cancer genes bearing germline and recessive mutations that predispose to cancer. This finding suggests a potential association between relaxed selection, positive selection, and risk of hereditary cancer. On the other hand, we did not find significant differences in terms of tissue or gene type. Human cancer genes under germline positive selection in mammals are significantly enriched in the processes of DNA repair, with high presence of Fanconi anaemia/Breast Cancer A (FA/BRCA) pathway components and T cell proliferation genes. We also show that the inferred positively selected sites in the two genes with the strongest signal of positive selection, i.e., BRCA2 and PTPRC, are in regions of functional relevance, which could be relevant to cancer susceptibility.
Douglas Theobald recently developed an interesting test putatively capable of quantifying the evidence for a Universal Common Ancestry uniting the three domains of life (Eukarya, Archaea and Bacteria) against hypotheses of Independent Origins for some of these domains. We review here his model, in particular in relation to the treatment of Horizontal Gene Transfer (HGT) and to the quality of sequence alignment.
