Administration Time‐Dependent Effects of Valsartan on Ambulatory Blood Pressure in Elderly Hypertensive Subjects

Previous results have indicated that valsartan administration at bed‐time, as opposed to upon wakening, improves the diurnal/nocturnal ratio of blood pressure (BP) toward a normal dipping pattern, without loss of 24 h efficacy. This ratio is characterized by a progressive decrease with aging. Accordingly, we investigated the administration time‐dependent antihypertensive efficacy of valsartan, an angiotensin blocking agent, in elderly hypertensive patients. We studied 100 elderly patients with grade 1–2 essential hypertension (34 men and 66 women), 68.2±4.9 years of age, randomly assigned to receive valsartan (160 mg/d) as a monotherapy either upon awakening or at bed‐time. BP was measured for 48 h by ambulatory monitoring, at 20 min intervals between 07∶00 to 23∶00 h and at 30 min intervals at night, before and after 3 months of therapy. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately determine the duration of sleep and wake spans to enable the accurate calculation of the diurnal and nocturnal means of BP for each subject. There was a highly significant BP reduction after 3 months of valsartan treatment (p<0.001). The reduction was slightly larger with bed‐time dosing (15.3 and 9.2 mm Hg reduction in the 24 h mean of systolic and diastolic BP, respectively) than with morning dosing (12.3 and 6.3 mm Hg reduction in the 24 h mean of systolic and diastolic BP, respectively). The diurnal/nocturnal ratio, measured as the nocturnal decline of BP relative to the diurnal mean, was unchanged in the group ingesting valsartan upon awakening (?1.0 and ?0.3 for systolic and diastolic BP; p>0.195). This ratio was significantly increased (6.6 and 5.4 for systolic and diastolic BP; p<0.001) when valsartan was ingested at bed‐time. The reduction of the nocturnal mean was doubled in the group ingesting valsartan at bed‐time, as compared to the group ingesting it in the morning (p<0.001). In elderly hypertensive patients, mainly characterized by a diminished nocturnal decline in BP, bed‐time valsartan dosing is better than morning dosing since it improves efficacy during the nighttime sleep span, with the potential reduction in cardiovascular risk that has been associated with a normalized diurnal/nocturnal BP ratio.     

Dose‐ And Administration Time‐Dependent Effects Of Nifedipine Gits On Ambulatory Blood Pressure In Hypertensive Subjects

Previous chronotherapy studies have shown that the circadian pattern of blood pressure (BP) remains unchanged after either morning or evening dosing of several calcium channel blockers (CCB), including amlodipine, isradipine, verapamil, nitrendipine, and cilnidipine. This trial investigated the antihypertensive efficacy and safety profile of the slow‐release, once‐a‐day nifedipine gastrointestinal therapeutic system (GITS) formulation administered at different times with reference to the rest‐activity cycle of each participant. We studied 80 diurnally active subjects (36 men and 44 women), 52.1±10.7 yrs of age, with grade 1–2 essential hypertension, who were randomly assigned to receive nifedipine GITS (30 mg/day) as a monotherapy for eight weeks, either upon awakening in the morning or at bedtime at night. Patients with uncontrolled BP were up‐titrated to a higher dose, 60 mg/day nifedipine GITS, for an additional eight weeks. BP was measured by ambulatory monitoring every 20 min during the day and every 30 min at night for 48 consecutive hours before and after therapy with either dose. The BP reduction after eight weeks of therapy with the lower dose of 30 mg/day was slightly, but not significantly, larger with bedtime dosing. The efficacy of 60 mg/day nifedipine GITS in non‐responders to the initial 30 mg/day dose was twice as great with bedtime as compared to morning dosing. Moreover, bedtime administration of nifedipine GITS reduced the incidence of edema as an adverse event by 91%, and the total number of all adverse events by 74% as compared to morning dosing (p=0.026). Independent of the time of day of administration, a single daily dose of 30 mg/day of nifedipine GITS provides full 24 h therapeutic coverage. The dose‐dependent increased efficacy and the markedly improved safety profile of bedtime as compared to morning administration of nifedipine GITS should be taken into account when prescribing this CCB in the treatment of essential hypertension.     

Cardiovascular Risk of Resistant Hypertension: Dependence on Treatment-Time Regimen of Blood Pressure–Lowering Medications

In resistant hypertension, ingesting one or more blood pressure (BP)-lowering medications at bedtime is associated with significant reduction of sleep-time BP, a sensitive prognostic marker of cardiovascular disease (CVD) risk. This randomized trial investigated if bedtime therapy with at least one hypertension medication exerts better BP control and CVD risk reduction than conventional, morning-time therapy with all medications. We conducted a prospective, open-label, blinded-endpoint trial on 776 patients (387 men/389 women) with resistant hypertension, 61.6?±?11.2 (mean?±?SD) yrs of age. Patients were randomized to ingest all their prescribed hypertension medications upon awakening or ≥1 of them at bedtime. BP was measured by ambulatory monitoring for 48?h at baseline, and again annually or more frequently (quarterly) if treatment adjustment was required. After a median follow-up of 5.4 yrs (range, .5–8.5 yrs), participants ingesting ≥1 hypertension medications at bedtime showed a significantly lower hazard ratio (HR) of total CVD events (adjusted by age, sex, and diabetes) than those ingesting all medications upon awakening (.38 [95% CI: .27–.55]; number of events 102 vs. 41; p?<?.001). The difference between groups in the adjusted HR of major CVD events (a composite of CVD death, myocardial infarction, ischemic stroke, and hemorrhagic stroke) was also statistically significant (.35 [95% CI: .18–.68]; number of events 32 vs. 12; p?=?.002). At the last evaluation, patients treated with the bedtime versus awakening-time-treatment regimen showed significantly lower sleep-time systolic/diastolic BP mean values (121.6/65.4 vs. 113.0/61.1?mm Hg; p?<?.001) and higher prevalence of controlled ambulatory BP (61% vs. 46%; p?<?.001). The progressive decrease in the sleep-time systolic BP mean during follow-up was the most significant predictor of event-free survival (15% risk reduction per 5?mm Hg decreased asleep systolic BP mean). Among patients with resistant hypertension, ingestion of at least one hypertension medication at bedtime, compared with all medications upon waking, resulted in improved ambulatory BP control and fewer hard and soft CVD events. (Author correspondence: rhermida@uvigo.es)     

Dosing Time‐Dependent Effect of Raloxifene on Plasma Fibrinogen Concentration in Ovariectomized Rats

The chronopharmacological effect of raloxifene, a selective estrogen‐receptor modulator, was evaluated by repeated dosing of ovariectomized rats. Bilateral ovariectomy or sham operation was performed at age 12 wks, and animals were kept in rooms with a 12 h light‐12 h dark cycle. Raloxifene (3 mg/kg, once daily for 10 wks) or vehicle was given repeatedly at either 2 h after lights‐on (2 HALO) or 14 h after lights‐on (14 HALO). Plasma fibrinogen concentration at the end of the study was reduced by the drug, and the reduction was significantly prominent in rats in whom the drug was dosed at 2 HALO rather than 14 HALO. Femur bone density decreased, and urinary excretion of deoxypyridinoline, an index of bone resorption capacity of osteoclasts, increased in ovariectomized animals at the end of the study. Treatment with raloxifene ameliorated these changes in a dosing time‐independent manner. Serum calcium, ALT, and total protein concentrations at the end of the study also did not differ acccording to treatment regime, which indicates that protein synthesis and liver function may not contribute to the effects. This is the first study to determine dosing time‐dependent changes in the efficacy of raloxifene in an animal model of osteoporosis. Because fibrinogen concentration is reported to be a marker of cardiovascular events, consideration of dosing time of raloxifene may be important to obtain a better cardioprotective effect of this medication when it is prescribed to postmenopausal women with osteoporosis.     

Circadian Rhythm of Blood Pressure Challenges Office Values as the “Gold Standard” in the Diagnosis of Gestational Hypertension

Despite poor sensitivity and specificity, office blood pressure (BP) determinations are still the “gold standard” for diagnosing gestational hypertension. This prospective blind study evaluates the prognostic value of office values as compared with ambulatory monitoring in pregnancy. We analyzed 2175 BP series systematically sampled from 355 non-preeclamptic pregnant women for 48 h every 4 wks from the first hospital visit until delivery. Women were divided for comparative purposes into three groups: “detected” gestational hypertension, defined on the basis of casual clinical BP>140/90 mm Hg after 20 wks of gestation and hyperbaric index (area of BP excess above the upper limit of a time-specified tolerance interval adjusted for the circadian pattern of the reference population) consistently above the threshold for diagnosing hypertension in pregnancy; “undetected” gestational hypertension, women with office BP<140/90 mm Hg but hyperbaric index consistently above the threshold for diagnosis; and normotension, women with both office values and hyperbaric index below the respective thresholds for diagnosis. Small and insignificant differences in the 24 h mean BP between “detected” and “undetected” gestational hypertension is observed in all trimesters, in contrast with highly significant differences between these two groups and normotensive pregnancies. Normotensive women are characterized by highly significant lesser incidence by 60% in preterm delivery, 70% in intrauterine growth retardation, and 50% in delivery by cesarean section (P<0.001) compared with women with “detected” and “undetected” gestational hypertension (P>0.715). In pregnancy, the hyperbaric index is markedly superior to office BP measurements for diagnosis of what should be truly considered gestational hypertension, and for prediction of the outcome of pregnancy.     

Ambulatory Blood Pressure Monitoring: Importance of Sampling Rate and Duration—48 Versus 24 Hours—on the Accurate Assessment of Cardiovascular Risk

Independent prospective studies have found that ambulatory blood pressure (BP) monitoring (ABPM) is more closely correlated with target organ damage and cardiovascular disease (CVD) risk than clinic BP measurement. This is based on studies in which BP was sampled every 15–30?min for ≤24?h, without taking into account that reproducibility of any estimated parameter from a time series to be potentially used for CVD risk assessment might depend more on monitoring duration than on sampling rate. Herein, we evaluated the influence of duration (48 vs. 24?h) and sampling rate of BP measurements (form every 20–30?min up to every 2?h) on the prognostic value of ABPM-derived parameters. 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 ≥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 the awake and asleep BP means. Identical assessment was scheduled annually and more frequently (quarterly) if treatment adjustment was required. ABPM profiles were modified to generate time series of identical 48-h duration but with data sampled at 1- or 2-h intervals, or shorter, i.e., first 24?h, time series with data sampled at the original rate (daytime 20-min intervals/nighttime 30-min intervals). Bland-Altman plots indicated that the range of individual differences in the estimated awake and asleep systolic (SBP) and diastolic BP (DBP) means between the original and modified ABPM profiles was up to 3-fold smaller for data sampled every 1?h for 48?h than for data sampled every 20–30?min for the first 24?h. Reduction of ABPM duration to just 24?h resulted in error of the estimated asleep SBP mean, the most significant prognostic marker of CVD events, in the range of ?21.4 to +23.9?mm Hg. Cox proportional-hazard analyses adjusted for sex, age, diabetes, anemia, and chronic kidney disease revealed comparable hazard ratios (HRs) for mean BP values and sleep-time relative BP decline derived from the original complete 48-h ABPM profiles and those modified to simulate a sampling rate of one BP measurement every 1 or 2?h. The HRs, however, were markedly overestimated for SBP and underestimated for DBP when the duration of ABPM was reduced from 48 to only 24?h. This study on subjects evaluated prospectively by 48-h ABPM documents that reproducibility in the estimates of prognostic ABPM-derived parameters depends markedly on duration of monitoring, and only to a lesser extent on sampling rate. The HR of CVD events associated with increased ambulatory BP is poorly estimated by relying on 24-h ABPM, indicating ABPM for only 24?h may be insufficient for proper diagnosis of hypertension, identification of dipping status, evaluation of treatment efficacy, and, most important, CVD risk stratification. (Author correspondence: rhermida@uvigo.es)     

Are Retinal Vessels Calibers Influenced by Blood Pressure Measured at the Time of Retinography Acquisition?

Background

Retinal arterial narrowing is associated with higher office blood pressure (BP) and ambulatory blood pressure monitoring, and increased incidence of cardiovascular disease, but it is still unknown if the vessel caliber is associated with BP measured at the time of retinography acquisition.

Methods

Retinal arteriolar and venular calibers were measured by the microdensitometric method in 448 patients with hypertension. Participants underwent 24-hours ambulatory blood pressure (24-h ABP) monitoring simultaneously with the retinography acquisition. Association between arteriolar and venular calibers with increase of 10 mmHg in the mean 24-hours, daily, and nightly BP, and with BP measured at the time of retinography, was evaluated by ANOVA and multivariate analyses.

Results

Mean 24-hours, daytime and nighttime systolic and diastolic BP were inversely associated with the arteriolar caliber, but not with the venular caliber. Arteriolar caliber decreased -0.8 (95% CI -1.4 to -0.2) μm per 10-mmHg increase in 24-hours mean systolic BP, adjusted for age, gender, fellow vessel, and duration of hypertension (P = 0.01). The corresponding decreasing in arteriolar caliber by 10 mmHg of increasing in mean diastolic BP was -1.1 μm (-2.0 to -0.2, P = 0.02). The decrease of arteriolar caliber by the same increasing of BP measured at the time of retinography was lower and not statistically significant, particularly for mean diastolic BP and outer arterioles calibers: -1.0 (-1.8 to -0.2) μm in the daytime BP average versus -0.3 (-0.9 to 0.3) at the moment of retinography acquisition.

Conclusions

These findings suggest that the caliber of arteriolar retinal vessels in patients with uncontrolled hypertension are not significantly influenced by blood pressure measured at the time of retinography acquisition.     

The Effects of Circadian Rhythmicity and Time‐Awake on a Simple Motor Task

The aim of the study was to assess if a simple motor task, one that required muscle contractions well below maximum, showed evidence of circadian changes and time‐awake. The task consisted of using a larger counter to flick a number of smaller counters to land as near as possible to the center of a target. The closer a counter landed next to the center of the target, the higher the score obtained. Two distances from the target were used (long and short), and 20 counters were flicked at each distance. The task was performed by 72 diurnally active healthy participants at six test sessions distributed every 4 h throughout the day (08:00 h, 12:00 h, … , 04:00 h), so covering a circadian cycle. When performing the sessions, subjects had been awake for about 1, 4, … , 20 h. Before each test session, sublingual temperature was measured, and estimates of the individual's fatigue and alertness were made. Clear normally phased circadian rhythms (p<0.0001) in oral temperature and alertness with mean peak time (i.e., acrophases of 17.2 h and 15.9 h, respectively) and fatigue (i.e., mean acrophase of 3.4 h) were detected. The total scores for both the long and short distances also showed circadian rhythms that peaked slightly before the temperature rhythm (by 2.31±0.91 h and 1.77±0.77 h, mean±SE, respectively), and the number of occasions that the target was missed altogether showed rhythms that were in anti‐phase (mean acrophases=3.8 h and 4.1 h for the long and short distances, respectively) to that of total scores (mean acrophases=16.0 h and 15.2 h for the long and short distances, respectively). With the long and, particularly, short distances, there were generally significant correlations (r<0.0005) between both the measures of accuracy (total score and number of misses) and body temperature and time‐awake. The accuracy of performance at this task seems to show circadian and time‐awake effects, and so makes it of potential value in protocols where repetitive measurements during the course of a day are required.     

Time‐of‐Day Effects on Myoelectric and Mechanical Properties of Muscle During Maximal and Prolonged Isokinetic Exercise

The aim of this study was to examine the time‐of‐day (TOD) effects in myoelectric and mechanical properties of muscle during a maximal and prolonged isokinetic exercise. Twelve male subjects were asked to perform 50 maximal voluntary contractions (MVC) of the knee extensor muscles at a constant angular velocity of 2.09 rad · sec^?1, at 06∶00 and 18∶00 h. Torque and electromyographic (EMG) parameters were recorded for each contraction, and the ratio between these values was calculated to evaluate variations of the neuromuscular efficiency (NME) with fatigue and with TOD. The results indicated that maximal torque values (T₄₅Max) was significantly higher (7.73%) in the evening than in the morning (p<0.003). The diurnal variation in torque decrease was used to define two phases. During the first phase (1st to the 26th repetition), torque values decreased fast and values were higher in the evening than in the morning, and during the second phase (27th to the 50th repetition), torque decreased slightly and reached a floor value that appeared constant with TOD. The EMG parameters (Root Mean Square; RMS) were modified with fatigue, but were not TOD dependent. The NME decrease–significantly with fatigue, showing that peripheral factors were mainly involved in the torque decrease. Furthermore, NME decrease was greater at 18∶00 than at 06∶00 h for the vastus medialis (p<0.05) and the vastus lateralis muscles (p<0.002), and this occurred during the first fatigue phase of the exercise. In conclusion, the diurnal variation of the muscle fatigue observed during a maximal and prolonged isokinetic exercise seems to reflect on the muscle, with a greater contractile capacity but a higher fatigability in the evening compared to the morning.     

Gender Dependency of Circadian Blood Pressure and Heart Rate Profiles in Spontaneously Hypertensive Rats: Effects of Beta‐Blockers

This study investigated (i) blood pressure (BP), heart rate (HR), and their relation to urinary NOx and eNOS protein expression in male and female spontaneously hypertensive rats (SHR), as well as (ii) gender‐dependent cardiovascular effects of nebivolol (NEB) in comparison to metoprolol (MET) in SHR. BP and HR were measured telemetrically after a single intraperitoneal application of NEB or MET at 07.00 and 19.00 h in male rats and at 19.00 h in proestrus female rats. The two β‐blockers varied in time of decreasing BP and HR and also in duration. In males, MET decreased BP and HR for few hours exclusively when applied at the onset of the activity phase (i.e., at 19.00 h), while after its application at 07.00 h, BP and HR were unchanged. In females, MET also caused a short‐lasting BP and HR reduction, with the effect being more pronounced than in males. In males, NEB at either dosing time decreased HR and BP to a greater extent than did MET. This effect was evident both during the activity and rest periods and persisted for at least five days. In females, NEB provoked a similar, but more pronounced, effect on BP and HR in comparison to males. These findings demonstrate that significant gender‐dependent differences in the circadian profile of BP and HR exist. BP and urinary NOx as well as eNOS expression are inversely correlated, and the cardiovascular effects of NEB and MET vary, depending on the time of application as well as gender.     

Biological Time‐Dependent Difference in Effect of Peroxynitrite Demonstrated by the Mouse Hot Plate Pain Model

We previously demonstrated the rhythmic pattern of L‐arginine/nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) cascade in nociceptive processes. The coupled production of excess NO and superoxide leads to the formation of an unstable intermediate peroxynitrite, which is primarily responsible for NO‐mediated toxicity. In the present study, we evaluated the biological time‐dependent effects of exogenously administered peroxynitrite on nociceptive processes and peroxynitrite‐induced changes in the analgesic effect of morphine using the mouse hot‐plate pain model. Experiments were performed at four different times of day (1, 7, 13, and 19 hours after lights on, i.e., HALO) in mice of both sexes synchronized to a 12 h:12 h light‐dark cycle. Animals were injected intraperitoneally (i.p.) with saline or 10 mg/kg morphine 30 min before and 0.001 mg/kg peroxynitrite 30 sec before hot‐plate testing, respectively. The analgesic effect of morphine exhibited significant biological time‐dependent differences in the thermally‐induced algesia; whereas, administration of peroxynitrite alone exhibited either significant algesic or analgesic effect, depending on the circadian time of its injection. Concomitant administration of peroxynitrite and morphine reduced morphine‐induced analgesia at three of the four different study time points. In conclusion, peroxynitrite displayed nociceptive and antinociceptive when administered alone according to the circadian time of treatment, while it diminished analgesic activity when administered in combination with morphine at certain biological times.     

Are Free Radicals Involved in the Pathobiology of Human Essential Hypertension?

Possible involvement of reactive oxygen species and nitric oxide in the pathogenesis of human essential hypertension was investigated. It was observed that both superoxide anion and hydrogen peroxide production by polymorphonuclear leukocytes and the plasma levels of lipid peroxides are higher in uncontrolled essential hypertension compared with normal controls. Nitric oxide levels measured as its stable metabolite nitrite, as an index of nitric oxide synthesis, revealed its levels to be low in hypertensive patients. Superoxide anion, hydrogen peroxide, lipid peroxides and nitric oxide levels reverted to normal values after the control of hypertension by drugs. The concentrations of anti-oxidants such as vitamin E and superoxide dismutase were found to be decreased in patients with uncontrolled hypertension. Several anti-hypertensive drugs inhibited lipid peroxidation in vitro. Angiotensin-II, a potent vasoconstrictor, stimulated free radical generation in normal leukocytes which could be blocked by calmodulin antagonists. These results suggest that an increase in free radical generation and a simultaneous decrease in the production of nitric oxide and anti-oxidants such as SOD and vitamin E occurs in essential hypertension. This increase in free radical generation can inactivate prostacyclin and nitric oxide and decrease their half life which can lead to an increase in peripheral vascular resistance and hypertension.     

The Effect of Pedal Rate and Time of Day on the Time to Exhaustion from High‐Intensity Exercise

The aim of this study was to examine the supposed influence of pedal rate on the diurnal fluctuation of the time to exhaustion from high‐intensity exercise. Eleven male cyclists performed three tests at 06:00 h and three at 18:00 h at a free pedal rate (FPR) and two imposed pedal rates (80% and 120% of the FPR). They performed the tests until exhaustion using a power output corresponding to 95% maximal power (P_max). Time to exhaustion, rectal temperature, oxygen consumption (V˙O₂), M. quadriceps, vastus medialis, M. biceps femoris electromyographic Root Mean Square activity rise (RMS slope), and blood lactate concentration were measured. The mean time to exhaustion recorded at 18:00 h (270.6±104.8 sec) was greater than at 06:00 h (233.9±84.9 sec). The time to exhaustion was significantly greater when the pedal rate was imposed at 80% versus 120% FPR. The blood lactate concentration and absolute core temperature at the point of exhaustion were significantly higher during tests done at 18:00 h. There was no diurnal variation in core temperature increase, V˙O₂, and RMS slope. The time‐of‐day effect for every variable did not depend on pedal rate. Diurnal variations in maximal aerobic endurance cannot be explained by a change in aerobic metabolism or in muscular fatigue. The origin of the diurnal variation in the time to exhaustion is likely to lie in greater participation in anaerobic metabolism. Also, the influence of temperature on neuromuscular functioning as an explanation for the diurnal variation in performance cannot be excluded in this study. The hypothesis on the basis of which pedal rate would influence diurnal variations in time to exhaustion in cycling was not validated by this research.     

Could Selenium Administration Alleviate the Disturbances of Blood Parameters Caused by Lithium Administration in Rats?

Lithium is widely used in medicine, but its administration can cause numerous side effects. The present study aimed at the evaluation of the possible application of selenium, an essential and antioxidant element, as a protective agent against lithium toxicity. The experiment was performed on four groups of Wistar rats: I (control)—treated with saline, II (Li)—treated with lithium (Li₂CO₃), III (Se)—treated with selenium (Na₂SeO₃) and IV (Li?+?Se)—treated with lithium and selenium (Li₂CO₃ and Na₂SeO₃) in the form of water solutions by stomach tube for 6 weeks. The following biochemical parameters were measured: concentrations of sodium, potassium, calcium, magnesium, phosphorus, iron, urea, creatinine, cholesterol, glucose, total protein and albumin and activities of alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase in serum as well as whole blood superoxide dismutase and glutathione peroxidase. Morphological parameters such as red blood cells, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets, white blood cells, neutrophils as well as lymphocytes were determined. Lithium significantly increased serum calcium and glucose (2.65?±?0.17 vs. 2.43?±?0.11; 162?±?31 vs. 121?±?14, respectively), whereas magnesium and albumin were decreased (1.05?±?0.08 vs. 1.21?±?0.15; 3.85.?±?0.12 vs. 4.02?±?0.08, respectively). Selenium given with lithium restored these parameters to values similar to those observed in the control (Ca—2.49?±?0.08, glucose—113?±?26, Mg—1.28?±?0.09, albumin—4.07?±?0.11). Se alone or co-administered with Li significantly increased aspartate aminotransferase and glutathione peroxidase. The obtained outcomes let us suggest that the continuation of research on the application of selenium as an adjuvant in lithium therapy seems warranted.     

Alterations of the Characteristics of the Circadian Rest‐Activity Rhythm of Cancer In‐Patients

The aim of the present study was to evaluate the characteristics of the circadian rest‐activity rhythm of cancer patients. Thirty‐one in‐patients, consisting of 19 males and 12 females, were randomly selected from the Regional Cancer Center, Pandit Jawaharlal Nehru Medical College, Raipur, India. The rest‐activity rhythm was studied non‐invasively by wrist actigraphy, and compared with 35 age‐matched apparently healthy subjects (22 males and 13 females). All subjects wore an Actiwatch (AW64, Mini Mitter Co. Inc., USA) for at least 4–7 consecutive days. Fifteen‐second epoch length was selected for gathering actigraphy data. In addition, several sleep parameters, such as time in bed, assumed sleep, actual sleep time, actual wake time, sleep efficiency, sleep latency, sleep bouts, wake bouts, and fragmentation index, were also recorded. Data were analyzed using several statistical techniques, such as cosinor rhythmometry, spectral analysis, ANOVA, Duncan's multiple‐range test, and t‐test. Dichotomy index (I<O) and autocorrelation coefficient (r24) were also computed. The results validated a statistically significant circadian rhythm in rest‐activity with a prominent period of 24 h for most cancer patients and control subjects. Results of this study further revealed that cancer patients do experience a drastic alteration in the circadian rest‐activity rhythm parameters. Both the dichotomy index and r24 declined in the group of cancer patients. The occurrence of the peak (acrophase, Ø) of the rest‐activity rhythm was earlier (p<0.001) in cancer patients than age‐ and gender‐matched control subjects. Results of sleep parameters revealed that cancer patients spent longer time in bed, had longer assumed and actual sleep durations, and a greater number of sleep and wake bouts compared to control subjects. Further, nap frequency, total nap duration, average nap, and total nap duration per 1 h awake span were statistically significantly higher in cancer patients than control subjects. In conclusion, the results of the present study document the disruption of the circadian rhythm in rest‐activity of cancer in‐patients, with a dampening of amplitude, lowering of mean level of activity, and phase advancement. These alterations of the circadian rhythm characteristics could be attributed to disease, irrespective of variability due to gender, sites of cancer, and timings of therapies. These results might help in designing patient‐specific chronotherapeutic protocols.     

Association of E/E′ and NT-proBNP with Renal Function in Patients with Essential Hypertension

Objectives

To evaluate the association of left ventricular (LV) diastolic function and N-terminal pro-brain natriuretic peptide (NT-proBNP) with renal function in essential hypertension.

Methods

LV diastolic function was estimated by the ratio of early diastolic velocities (E) from transmitral inflow to early diastolic velocities (E′) of tissue Doppler at mitral annulus (septal corner); NT-proBNP was measured in 207 hypertensive patients (mean age 56±14 years). The subjects were classified into 3 groups: E/E′≤10 group (n = 48), 10<E/E′≤15 group (n = 109) and E/E′>15 group (n = 50). The renal function was estimated by glomerular filtration rate (GFR) with ^99mTc-DTPA. GFR from 30 to 59 ml/min/1.73 m² was defined as Stage 3 chronic kidney disease (CKD). GFR was also estimated using the modified MDRD equation. Albuminuria was defined by urinary albumin/creatinine ratio (UACR).

Results

GFR was lower and UACR was higher in E/E′ >15 group than in 10< E/E′ ≤15 group or E/E′ ≤10 group (p<0.0001), GFR was significantly negative and UACR was positive correlated with E/E′ and NT-proBNP (p<0.0001). In multivariate stepwise linear analysis, GFR had significant correlation with age (p = 0.001), gender (p = 0.003), E/E′ (p = 0.03), lgNT-proBNP (p = 0.001) and lgUACR (p = 0.01), while eGFR had no significant correlation with E/E′ or lgNT-proBNP. Multivariate logistic regression analysis, adjusted for potential confounding factors, showed that participants in E/E′>15 group were more likely to have Stage 3 CKD compared with those in E/E′≤10 group with an adjusted odds ratio of 8.31 (p = 0.0036).

Conclusions

LV diastolic function, assessed with E/E′ and NT-proBNP is associated with renal function in essential hypertension.     

Effects of 2‐Chloro‐2′‐Deoxyadenosine on the Cell Cycle in the Human Leukemia EHEB Cell Line

To explain why 2‐chloro‐2′‐deoxyadenosine (CdA) is unable to block DNA synthesis and cell cycle progression, and paradoxically enhances progression from G1 into S phase in the CdA‐resistant leukemia EHEB cell line, we studied its metabolism and effects on proteins regulating the transition from G1 to S phase. A low deoxycytidine kinase activity and CdATP accumulation, and a lack of p21 induction despite p53 phosphorylation and accumulation may account for the inability of CdA to block the cell cycle. An alternative pathway involving pRb phosphorylation seems implicated in the CdA‐induced increase in G1 to S phase progression.