Angiogenesis is indispensable for the growth of solid tumors and angiogenic factors are also involved in the progression of hematological malignancies. Targeting the formation of blood vessels is therefore regarded as a promising strategy in cancer therapy. Interestingly, besides demonstration of some beneficial effects of novel anti-angiogenic compounds, recent data on the activity of already available drugs point to their potential application in anti-angiogenic therapy. Among these are the statins, the inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Statins are very efficient in the treatment of hypercholesterolemia in cardiovascular disorders; however, their effects are pleiotropic and some are not directly related to the inhibition of cholesterol synthesis. Some reports particularly highlight the pro-angiogenic effects of statins, which are caused by low, nanomolar concentrations and are regarded as beneficial for the treatment of cardiovascular diseases. On the other hand, the anti-angiogenic activities, observed at micromolar concentrations of statins, may be of special significance for cancer therapy. Those effects are caused by the inhibition of both proliferation and migration and induction of apoptosis in endothelial cells. Moreover, the statin-mediated inhibition of vascular endothelial growth factor synthesis, the major angiogenic mediator, may contribute to the attenuation of angiogenesis. It has been suggested that the anti-cancer effect of statins can be potentially exploited for the cancer therapy. However, several clinical trials aimed at the inhibition of tumor growth by treatment with very high doses of statins did not provide conclusive data. Herein, the reasons for those outcomes are discussed and the rationale for further studies is presented.

Angiogenesis occurring during reparative or pathological processes is driven by various inflammatory mediators that influence the synthesis of growth factors. It has been recognized recently that reactive oxygen species (ROS) and nitric oxide (NO) are important modulators of the synthesis and activity of vascular endothelial growth factor (VEGF), a major angiogenic molecule. Moreover, heme oxygenase-1 (HO-1), a ubiquitous stress-inducible enzyme that is induced by ROS and NO, was recently discovered to be involved in angiogenesis. Genetic overexpression of HO-1 enhanced VEGF synthesis and augmented formation of vascular capillaries, improving the blood flow in ischemic tissues. In addition, by-products of HO-1 exert numerous effects that can also influence angiogenesis in both positive and negative ways. Therefore, the antiinflammatory effects of HO-1 can attenuate the excess formation of blood vessels in inflammatory angiogenesis. In this review, the recent data on the role of HO-1 in angiogenesis are critically discussed. It is suggested that further studies using potent and specific augmentation of HO-1 gene expression by viral vectors, as well as targeted, specific inhibition of HO-1 expression, are required to elucidate fully the complex role of this enzymatic pathway in angiogenesis.

La presión arterial se caracteriza por presentar variación a lo largo de las 24 horas del día. La cronoterapia de la hipertensión arterial contempla esta variación circadiana, con la elevación matutina y el descenso durante el descanso nocturno de la presión arterial, junto con las posibles modificaciones en las características farmacocinéticas y farmacodinámicas de los fármacos antihipertensivos, en función del momento circadiano de su administración. Las diferencias dependientes de la hora de la administración de los fármacos antihipertensivos, tanto en la cinética (cronocinética) como en la efectividad terapéutica (cronodinámica) son conocidas. Así, el patrón de variación circadiano de la presión arterial alterado en pacientes hipertensos con insuficiencia renal crónica, sólo se normaliza cuando se administra el calcioantagonista Isradipino en la tarde, pero no en la mañana. Por su parte, la curva dosis-respuesta, la eficacia y la duración de la respuesta terapéutica del alfabloqueante Doxazosina GITS dependen del instante circadiano de administración del fármaco. La administración de otro bloqueante de los canales del calcio como Nifedipino GITS, a la hora de acostarse, reduce de forma significativa los efectos secundarios y aumenta la eficacia antihipertensiva en comparación con la administración del fármaco a la hora de levantarse. Además, en pacientes con hipertensión resistente, la Cronoterapia ha demostrado que mejora el control de la presión arterial, al mismo tiempo que revierte el perfil no-dipper, altamente prevalente en este grupo de pacientes. La hipertensión nocturna, caracterizada por la pérdida del descenso del 10-20% en la presión arterial durante las horas de descanso nocturno (patrón no-dipper), aumenta el riesgo de eventos cerebro y cardiovasculares. La Cronoterapia antihipertensiva aporta soluciones en el marco de un tratamiento más individualizado, en función del perfil circadiano de presión arterial de cada paciente, y puede suponer un avance en la optimización del control de la hipertensión arterial y en la reducción del riesgo cardiovascular del paciente hipertenso. Blood pressure displays appreciable predictable-in-time circadian variation. The Chronotherapy of hypertension takes into account the clinically relevant features of the 24h pattern of blood pressure, e.g., the accelerated morning rise and nighttime decline during sleep, plus potential administration circadian time determinants of the pharmacokinetics and dynamics of antihypertensive medications. Significant administration-time differences in the kinetics (i.e., Chronokinetics) plus the beneficial and adverse effects (termed Chronodynamics) of antihypertensive drugs are well known. Thus, evening, but not morning, dosing with isradipine significantly reduced and normalized nocturnal blood pressure in hypertensive patients with chronic renal failure. Too, the dose-response curve, therapeutic coverage, and efficacy of doxazosin GITS are all markedly dependent on the circadian time of drug administration. The administration of nifedipine GITS at bedtime significantly reduces secondary effects well increasing antihypertensive efficacy as compared to the administration of the drug upon awakening. Moreover, in patients with resistant hypertension, Chronotherapy has been shown to improve blood pressure control and to revert the non-dipper profile highly prevalent among these patients. Nocturnal hypertension, which is characterized by the loss or even reversal of the expected 10-20% sleep-time blood pressure decline, increases the risk of cardiac and cerebrovascular events. Chronotherapy provides a mean of individualizing treatment of hypertension according to the circadian profile of blood pressure of each patient. The chronotherapeutic strategy constitutes a new option to optimize blood pressure control and to reduce risk. Arteria-presioa aldatu egiten da egunean zehar. Arteria-hipertentsioaren kronoterapiak kontuan hartzen du aldakuntza zirkadiano hori; alegia, goizeko igoera, eta gaueko atsedenarekin gertatzen den jaitsiera, baita hipertentsioaren kontrako botikak hartzen diren une zirkadianoaren arabera ezaugarri farmakozinetikoetan eta farmakodinamikoetan gerta daitezkeen balizko aldakuntzak ere. Hipertentsioaren kontrako botikak hartzen diren orduaren araberako aldakuntzak ezagunak dira, bai zinetikari (kronozinetika) eragiten diotenak, bai eraginkortasun terapeutikoari eragiten diotenak ere (kronodinamika). Hala, giltzurrinetako gutxiegitasun kronikoa duten gaixoen arteria-presioaren aldakuntza-eredua normalizatzeko, Isradipino kaltzioantagonista arratsaldean eman behar zaie, eta ez goizean. Bestalde, dosia-erantzuna kurba eta Doxazosina GITS alfablokeatzailearen erantzun terapeutikoaren iraupena aldatu egiten dira botika hartzen den une zirkadianoaren arabera. Oheratzerakoan kaltzioaren kanalak blokeatzen dituen beste botikaren bat hartuz gero -adibidez Nifedipino GITS-, nabarmen murrizten dira ondorio sekundarioak eta areagotu egiten da hipertentsioaren kontrako eraginkortasuna, botika ohetik altxatzean hartzearekin alderatuta. Gainera, kronoterapiak erakutsi duenez, hipertentsio sendoa duten gaixoetan arteria-presioaren kontrola hobetu dezake, eta, aldi berean, era horretako gaixoetan nagusi den ez-dipper profila aldatzea dakar. Gaueko hipertentsioak, gaueko atseden orduetako arteria-presioaren % 10-20 jaitsieraren galera ezaugarri duenak (ez-dipper patroia), garuneko eta bihotzeko hodietako gorabeherak izateko arriskua areagotzen du. Hipertentsioaren kontrako kronoterapiak irtenbideak ematen ditu tratamendu indibidualizatuagoetan, gaixo bakoitzaren arteria-presioaren profil zirkadianoaren arabera, eta aurrerapen handiak ekar ditzake arteria-hipertentsioaren kontrola optimizatzeari begira eta hipertentsioa duen gaixoaren arrisku kardiobaskularra murrizteari begira.


 
 
 
 We review arguments for CBDC issuance in India. These include facilitating payments, enhancing financial inclusion, enabling the central bank and government to retain control of the payments system, facilitating cross-border transactions, reducing dependence on the dollar-dominated global payments system, and providing an encompassing platform for digital financial innovation. We then compare progress in India with other countries. In setting an end-2022 target date for issuance, India is in line with the other BRICS, but not with other countries with comparable levels of per capita GDP, which have been more reluctant to commit to a date. Nor is it in line with other countries with comparably independent central banks, which have been more cautious about setting a deadline. Finally, we sketch a roadmap and timeline for India’s CBDC project going forward.
 
 
 

Preeclampsia and gestational hypertension are major contributors to perinatal morbidity and mortality. Several studies aimed to test the effects of low-dose aspirin (ASA) in the prevention of preeclampsia concluded that the beneficial effects of such treatment outweigh adverse ones. Such benefits have not been fully corroborated by larger randomized trials usually carried out in low-risk women, testing a dose of 60 mg/d ASA presumably ingested in the morning, and including women randomized as late as at 26-32 wks of gestation. The authors conducted a prospective, randomized, double-blind, placebo-controlled, chronotherapy trial on 350 high-risk pregnant women (183 nulliparous), 30.7 ± 5.3 (mean ± SD) yrs of age, and 13.5 ± 1.4 wks of gestation at the time of recruitment. Women were randomly assigned to one of six groups, defined according to treatment (placebo or ASA, 100 mg/d) and time of treatment: upon awakening, 8 h after awakening, or at bedtime. Intervention started at 12-16 wks of gestation and continued until delivery. Blood pressure (BP) was measured by ambulatory monitoring (ABPM) for 48-h at baseline, every 4 wks until the 7th month of gestation, every 2 wks thereafter until delivery, and at puerperium. The effects of ASA on ambulatory BP were markedly dependent on administration time: there was no effect on BP, compared with placebo, when ASA was ingested upon awakening, but the BP reduction was highly statistically significant when low-dose ASA was ingested 8 h after awakening and, to a greater extent, at bedtime (p < .001). At puerperium, 6-8 wks after discontinuation of treatment, there was no statistically significant difference in 24-h BP means between the groups of women who ingested ASA at different circadian times. Women ingesting low-dose ASA, compared with placebo, evidenced a significantly lower hazard ratio (HR) of serious adverse outcomes, a composite of preeclampsia, preterm delivery, intrauterine growth retardation (IUGR), and stillbirth (.35, 95% confidence interval [CI]: .22-.56; p < .001). The HR of individual outcome variables, i.e., preeclampsia, preterm delivery, IUGR, and gestational hypertension, were also significantly lower with ASA versus placebo (p always < .041). There were small and nonsignificant differences in outcomes between placebo and low-dose ASA ingested upon awakening. These four groups combined showed highly significant greater event rate of serious adverse outcomes than women ingesting ASA either in the evening or at bedtime (HR: .19, 95% CI: .10-.39; p < .001). There was no increased risk of hemorrhage, either before or after delivery, with low-dose ASA relative to placebo (HR: .57, 95% CI: .25-1.33; p = .194). Results indicate that (i) 100 mg/d ASA should be the recommended minimum dose for prevention of complications in pregnancy; (ii) ingestion of low-dose ASA should start at ≤16 wks of gestation; and (iii) low-dose ASA ingested at bedtime, but not upon awakening, significantly regulates ambulatory BP and reduces the incidence of preeclampsia, gestational hypertension, preterm delivery, and IUGR. ABPM evaluation at the first trimester of pregnancy provides sensitive endpoints for identification of women at high risk for preeclampsia who might benefit most from the cost-effective preventive intervention with timed low-dose ASA.

Valsartan administration at bedtime as opposed to on wakening improves the sleep time–relative blood pressure decline toward a more dipper pattern without loss in 24-hour efficacy. Yet to be determined is whether this administration time-dependent efficacy is a class-related feature, characteristic of all angiotensin receptor blockers or specific only to valsartan. Terminal half-life is a major difference between angiotensin receptor blockers, being largest (≈24 hours) for telmisartan. This trial investigated the administration time-dependent antihypertensive efficacy of telmisartan. We studied 215 patients with hypertension (114 men and 101 women), 46.4±12.0 years of age, randomly assigned to receive telmisartan (80 mg/d) as a monotherapy either on awakening or at bedtime. Blood pressure was measured for 48 hours before and after 12 weeks of treatment. The significant blood pressure reduction after treatment was similar for both groups. Bedtime administration of telmisartan, however, was more efficient than morning dosing in reducing the nocturnal blood pressure mean. The sleep time–relative blood pressure decline was slightly reduced after telmisartan on awakening but significantly increased with bedtime dosing, thus reducing the prevalence of nondipping from baseline by 76%. Telmisartan administered at bedtime, as opposed to morning dosing, improved the sleep time–relative blood pressure decline toward a more dipper pattern without loss in 24-hour efficacy. Nocturnal BP regulation is significantly better achieved with bedtime dosing of telmisartan. Results from this prospective trial suggest that these beneficial features of bedtime dosing may be class related for angiotensin receptor blockers. These results should be taken into account when prescribing this class of antihypertensive medication for treatment of essential hypertension.

Carbon monoxide (CO) is an odorless, tasteless and colorless gas which is generated by heme oxygenase enzymes (HOs). HOs degrade heme releasing equimolar amounts of CO, iron and biliverdin, which is subsequently reduced to bilirubin. CO shares many properties with nitric oxide (NO), an established cellular messenger. Both CO and NO are involved in neural transmission and modulation of blood vessel function, including their relaxation and inhibition of platelet aggregation. CO, like NO, binds to heme proteins, although CO binds only ferrous (FeII) heme, whereas NO binds both ferrous and ferric (FeIII). CO enhances the activity of guanylate cyclase although it is less potent than NO. In contrast, CO inhibits other heme proteins, such as catalase or cytochrome p450. The effects of CO on gene expression can be thus varied, depending on the cellular microenvironment and the metabolic pathway being influenced. In this review the regulation of gene expression by HO/CO in the cardiovascular system is discussed. Recent data, derived also from our studies, indicate that HO/CO are significant modulators of inflammatory reactions, influencing the underlying processes such as cell proliferation and production of cytokines and growth factors.

PVF is subject to a circadian rhythm and postprandial portal hyperemia shows a diurnal variability. Both are highly reproducible.

Abstract Epidemic exposure in an individual's ‘impressionable years’ (ages 18 to 25) has a persistent negative effect on confidence in political institutions and leaders. This loss of trust is associated with epidemic-induced economic difficulties, such as lower income and unemployment later in life. It is observed for political institutions and leaders only and does not carry over to other institutions and individuals. A key exception is a strong negative effect on confidence in public health systems. This suggests that the distrust in political institutions and leaders is associated with the (in)effectiveness of a government's healthcare-related response to epidemics. We show that the loss of political trust is largest for individuals who experienced epidemics under weak governments with low policymaking capacity, and confirm that weak governments in fact took longer to introduce policy interventions in response to COVID-19. We report evidence that the epidemic-induced loss of political trust discourages electoral participation in the long term.

Some specific features of the 24 h blood pressure (BP) pattern are linked to the progressive injury of target tissues and the triggering of cardiac and cerebrovascular events. In particular, many studies show the extent of the nocturnal BP decline relative to the diurnal BP mean (the diurnal/nocturnal ratio, an index of BP dipping) is deterministic of cardiovascular injury and risk. Normalization of the circadian BP pattern is considered to be an important clinical goal of pharmacotherapy because it may slow the advance of renal injury and avert end-stage renal failure. The chronotherapy of hypertension takes into account the epidemiology of the BP pattern, plus potential administration-time determinants of the pharmacokinetics and dynamics of antihypertensive medications, as a means of enhancing beneficial outcomes and/or attenuating or averting adverse effects. Thus, bedtime dosing with nifedipine gastrointestinal therapeutic system (GITS) is more effective than morning dosing, while also reducing significantly secondary effects. The dose-response curve, therapeutic coverage, and efficacy of doxazosin GITS are all markedly dependent on the circadian time of drug administration. Moreover, valsartan administration at bedtime as opposed to upon wakening results in improved diurnal/nocturnal ratio, a significant increase in the percentage of patients with controlled BP after treatment, and significant reductions in urinary albumin excretion and plasma fibrinogen. Chronotherapy provides a means of individualizing treatment of hypertension according to the circadian BP profile of each patient, and constitutes a new option to optimize BP control and reduce risk.

Previous studies have reported sex differences in the pathophysiology of hypertension and responses to blood pressure (BP)-lowering medications. Moreover, men exhibit typically higher BP than women, the differences being greater for systolic (SBP) than diastolic (DBP) BP. These differences become apparent during adolescence and remain significant at least until 55-60 yrs of age. Despite such significant sex-related differences in BP regulation, the current recommended ambulatory BP monitoring (ABPM) thresholds for diagnosis of hypertension do not differentiate between men and women. We aimed to derive separate male and female diagnostic thresholds for the awake and asleep SBP and DBP means based upon cardiovascular disease (CVD) outcome. We prospectively studied 3344 subjects (1718 men/1626 women), 52.6 ± 14.5 yrs of age, during a median follow-up of 5.6 yrs. Those with hypertension at baseline were randomized to ingest all their prescribed hypertension medications upon awakening or the entire daily dose of ≥1 of them at bedtime. At baseline, BP was measured at 20-min intervals from 07:00 to 23:00 h and at 30-min intervals at night for 48 h, and physical activity was simultaneously monitored every minute by wrist actigraphy to accurately derive the awake and asleep BP means. Identical assessment was scheduled annually and more frequently (quarterly) if treatment adjustment was required. Cox regression analysis was used to derive outcome-based reference thresholds for ABPM in men and women. Men exhibited greater event rates than women of CVD death, myocardial infarction, angina pectoris, coronary revascularization, and heart failure; however, event rates of non-CVD death and cerebrovascular events were comparable. The relationship between progressively higher ambulatory BP and CVD risk increased more rapidly in women than men for awake SBP/DBP means ≥125/75 mm Hg and asleep means ≥110/70 mm Hg. The derived outcome-based reference thresholds for men were 135/85 mm Hg for the awake and 120/70 mm Hg for the asleep SBP/DBP means. In terms of CVD outcome, the equivalent cutoff threshold values for women were 125/80 mm Hg for the awake and 110/65 mm Hg for the asleep SBP/DBP means. Outcome-based reference thresholds for the diagnosis of hypertension were 10/5 mm Hg lower for ambulatory SBP/DBP in women than men. This marked sex difference indicates the need for revision of current guidelines that propose diagnostic thresholds for ambulatory BP without differentiation between men and women.

Therapeutic strategies in resistant hypertension include adding another drug or changing drugs in search for a better synergic combination. Most patients, however, receive all of their drugs in a single morning dose. We have evaluated the impact on the circadian pattern of blood pressure on modifying the time of treatment without increasing the number of prescribed drugs. We studied 250 hypertensive patients who were receiving 3 antihypertensive drugs in a single morning dose. Patients were randomly assigned to 1 of 2 groups according to the modification in their treatment strategy: changing 1 of the drugs but keeping all 3 in the morning or the same approach but administering the new drug at bedtime. Blood pressure was measured for 48 hours before and after 12 weeks of treatment. There was no effect on ambulatory blood pressure when all of the drugs were taken on awakening. The baseline prevalence of nondipping (79%) was slightly increased after treatment (86%; P =0.131). The ambulatory blood pressure reduction was statistically significant (9.4/6.0 mm Hg for systolic/diastolic blood pressure; P &lt;0.001) with 1 drug at bedtime. This reduction was larger in the nocturnal than in the diurnal mean of blood pressure. Thus, whereas only 16% of the patients in this group were dippers at baseline, 57% were dippers after therapy ( P &lt;0.001). Results indicate that, in resistant hypertension, time of treatment may be more important for blood pressure control and for the proper modeling of the circadian blood pressure pattern than just changing the drug combination.

Correlation between blood pressure (BP) level and target organ damage, cardiovascular disease (CVD) risk, and long-term prognosis is greater for ambulatory BP monitoring (ABPM) than clinical BP measurements. Nevertheless, the latter continue to be the "gold standard" to diagnose hypertension, assess CVD risk, and evaluate hypertension treatment. Independent ABPM studies have found that elevated sleep-time BP is a better predictor of CVD risk than either the awake or 24-h BP mean. A major limitation of all previous ABPM-based prognostic studies is the reliance only upon a single baseline profile from each participant at the time of inclusion, without accounting for potential changes in the level and pattern of ambulatory BP thereafter during follow-up. Accordingly, impact of the alteration over time, i.e., during long-term follow-up, of specific features of the 24-h BP variation on CVD risk has never been properly investigated. We evaluated the comparative prognostic value of (i) clinic and ambulatory BP; (ii) different ABPM-derived characteristics, e.g., asleep or awake BP mean; and (iii) specific changes in ABPM characteristic during follow-up, mainly whether reduced CVD risk is more related to the progressive decrease of asleep or awake BP. We prospectively studied 3344 subjects (1718 men/1626 women), 52.6 ± 14.5 (mean ± SD) yrs of age, during a median follow-up of 5.6 yrs. Those with hypertension at baseline were randomized to ingest all their prescribed hypertension medications upon awakening or ≥1 of them at bedtime. At baseline, BP was measured at 20-min intervals from 07:00 to 23:00 h and at 30-min intervals at night for 48-h, and physical activity was simultaneously monitored every min by wrist actigraphy to accurately derive awake and asleep BP means. Identical assessment was scheduled annually and more frequently (quarterly) if treatment adjustment was required. Data collected either at baseline or the last ABPM evaluation per participant showed that the asleep systolic BP mean was the most significant predictor of both total CVD events and major CVD events (a composite of CVD death, myocardial infarction, and stroke). Moreover, when the asleep BP mean was adjusted by the awake mean, only the former was a significant independent predictor of outcome in a Cox proportional-hazard model adjusted for sex, age, diabetes, anemia, and chronic kidney disease. Analyses of changes in ambulatory BP during follow-up revealed 17% reduction in CVD risk for each 5 mm Hg decrease in the asleep systolic BP mean (p < .001), independent of changes in any other clinic or ambulatory BP parameter. The increased event-free survival associated with the progressive reduction in the asleep systolic BP mean during follow-up was significant for subjects with either normal or elevated BP at baseline. The ABPM-derived asleep BP mean was the most significant prognostic marker of CVD morbidity and mortality. Most important, the progressive decrease in asleep BP mean, a novel therapeutic target that requires proper patient evaluation by ABPM and best achieved by ingestion of at least one hypertension medication at bedtime, was the most significant predictor of event-free survival.