Entire 24-hour Period Research Articles

Twenty-four-hour Blood Pressure Monitoring in Central Serous Chorioretinopathy – A Case-control Study

Purpose:A case-control study to explore the diurnal variation of blood pressure (BP) in patients with central serous chorioretinopathy (CSCR).Methods:One-hundred patients (50 cases with central serous chorioretinopathy and 50 age- and sex-matched controls) participated in this study. Twenty-four-hour BP was recorded by auscultatory method using manual standard mercury sphygmomanometer by a single, trained observer. Hypertension was categorised according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VII) classification.Results:Mean systolic BP (SBP) and diastolic BP (DBP) in cases and controls were 123.4 mmHg (range 112.3–134.6), 81.72 mmHg (range 73.0–90.5); 118.33 mmHg (range 108.4–128.2); and 77.50 mmHg (range 71.4–83.6), respectively. The difference in SBP and DBP was statistically significant at p=0.02 for the former and p=0.006 for the latter. The mean difference in maximum and minimum SBP in cases was 18 (±15.81) mmHg versus 9.04 (±3.08) mmHg in controls (p=0.001). Mean difference for DBP in cases was 15.16 (±7.86) mmHg versus 9.16 (±3.68) mmHg in controls (0.001). On the JNC-VII classification scale for hypertension, 66 % of cases were found to be pre-hypertensive (60 %) or hypertensive (6 %). Comparative figures for controls were pre-hypertension (30 %) and hypertension (2 %). The mean SBP and DBP was consistently higher in patients with CSCR compared with controls over the entire 24-hour period. The difference in variation between maximum and minimum SBP and DBP was also found to be statistically significant between the groups.Conclusion:A significant correlation exists between higher values BP and central serous chorioretinopathy. Screening of CSCR patients for pre-hypertension may be useful in decreasing the risk of progression to established hypertension, with its associated risks.

Reactive Oxygen Species and p38 Mitogen-activated Protein Kinase Mediate Exercise-induced Skeletal Muscle-derived Interleukin-6 Expression

Interleukin-6 (IL-6) is a pleiotropic cytokine secreted by many different cell types, and skeletal muscle is an important source of IL-6 during exercise. Here, we studied the effects of glucose deprivation in vitro on skeletal muscle-derived IL-6 expression and release in C2C12 myocytes, as well as its regulation by p38 mitogen-activated protein kinase (p38MAPK) and reactive oxygen species (ROS). C2C12 myotubes were cultured in DMEM medium containing 4.5 g · L−1 glucose (glucose control, GC) or DMEM medium containing no glucose (glucose deprivation, GD) for 0, 6, 12, 18 and 24 hours, and then incubated with 10mM NAC (a ROS scavenger) or 10 μM SB203580 (a p38MAPK inhibitor) under either GC or GD conditions for 24 hours. IL-6 expression levels were subsequently analyzed using RT–PCR, and IL-6 protein levels in the medium were measured using ELISA. Glucose deprivation significantly enhanced IL-6 expression at 18 and 24 hours compared to the glucose control, and caused IL-6 protein levels to increase significantly over the entire 24-hour measurement period. The ROS scavenger NAC inhibited the glucose deprivation-induced release of IL-6 protein almost completely, while the p38MAPK inhibitor SB203580 inhibited glucose deprivation-induced IL-6 protein release to a lesser extent. Our study suggests that glucose deprivation in C2C12 myocytes induces IL-6 expression and release, and that this IL-6 release is mainly mediated via ROS signaling. Skeletal muscle-derived IL-6 may thus play an important role in energy metabolism during exercise.

Vagal activity modulates spontaneous augmentation of J-wave elevation in patients with idiopathic ventricular fibrillation

Although J-wave elevation in the inferolateral leads could be related to idiopathic ventricular fibrillation (IVF), little is known about the pathophysiologic characteristics of J-wave elevation in patients with IVF. This study aimed to determine the relationship between augmentation of J-wave elevation and changes in RR interval or autonomic nervous activities in patients with IVF. Eight patients with IVF and 22 controls with J-wave elevation (≥0.1 mV) in lead V5 were studied. The J-wave amplitude was automatically measured in lead CM5 of a digital Holter electrocardiogram, and the J-RR relationship was determined. Based on the analysis of heart rate variability, the relationship between the J-wave amplitude and the natural logarithm of high-frequency (HF) components (J-ln HF relationship) or the ratio of low frequency (LF) components to HF components (J-LF/HF relationship) was also determined. The J-RR slope (mm/s) was greater in patients with IVF than in controls (3.5 ± 0.7 vs 2.4 ± 0.8; P <.01), as was J-wave amplitude (mm) at an RR interval of 1.2 seconds (2.8 ± 0.9 vs 2.0 ± 0.6; P <.05). The J-wave amplitude was correlated positively with ln HF and negatively with LF/HF, and the slopes of both J-ln HF and J-LF/HF regression lines were greater in patients with IVF than in controls. During an entire 24-hour period, there was no difference between the 2 groups in either HF or LF/HF. Nine of the total 11 episodes (82%) of spontaneous ventricular fibrillation occurred between 18:00 and 6:00. In patients with IVF as compared with control subjects, J-wave elevation was more strongly augmented during bradycardia and was associated with an increase in vagal activity. This could be related to the occurrence of ventricular fibrillation predominantly at night in patients with IVF.

Dietary Induction of Long-Term Hyperoxaluria in the Porcine Model

The purpose of our study was to determine if a hydroxyproline (HP) or gelatin diet could induce long-term hyperoxaluria in the porcine model. A total of 18 gravid crossbred sows (Large White × Landrace) were randomly allotted into three treatment groups: 5% HP, 10% HP, and gelatin diet. All sows were catheterized 1 day before starting treatment diet. Catheters were left in place for 5 days before being removed. Sows were recatheterized for urine collections on days 11 to 12 and days 21 to 22. Urine was collected for each entire 24-hour period, and urinary oxalate was determined by ion chromatography. Urinary oxalate concentrations for all three diets peaked within the first 5 days of the diet. The sows fed the 5% HP, 10% HP, and gelatin diets had an early peak in urinary oxalate concentration (mg/L) at day 2 (158% increase), day 5 (316% increase), and day 5 (830% increase), respectively. The day 21 to 22 time points in all three diets demonstrated markedly increased urinary oxalate concentrations in comparison with baseline, with some concentrations higher than the early time point peaks (day 22: 5% HP=1906% increase, P=0.12; 10% HP=640% increase, P=0.02; gelatin=501% increase, P=0.01). Although both the 10% HP and gelatin diets induce significant short- and long-term hyperoxaluria in the porcine model, the gelatin diet is more cost-effective. The ability to induce long-term hyperoxaluria has important implications in establishing a porcine model for oxalate urolithiasis.

Comparator pH study to evaluate the single-dose pharmacodynamics of dual delayed-release dexlansoprazole 60 mg and delayed-release esomeprazole 40 mg

Background:This paper describes a Phase 1, single-center, randomized, open-label, two-period crossover study which compared the pharmacodynamic effects of single doses of dexlansoprazole modified-release 60 mg and esomeprazole 40 mg on 24-hour intragastric pH in healthy adult subjects.Methods:Forty-four subjects aged 20–54 years were randomized in a 1:1 ratio to two sequence groups defining the order in which they received dexlansoprazole and esomeprazole in periods 1 and 2. Primary pharmacodynamic end points over 24 hours postdose were percentage of time with intragastric pH > 4 and mean pH, and secondary pharmacodynamic end points were percentage of time intragastric pH > 4, and mean pH at 0–12 hours, and at >12–24 hours postdose. Each drug was given after an overnight fast and one hour before breakfast. Continuous pH recording began immediately before dosing through to 24 hours postdose.Results:At 0–24 hours postdose, the mean percentage of time with pH > 4 for dexlansoprazole and esomeprazole was 58% and 48%, respectively; the difference was statistically significant (P = 0.003). The average of mean pH values at 0–24 hours postdose for dexlansoprazole and esomeprazole were 4.3 and 3.7, respectively; the difference was statistically significant (P < 0.001). At >12–24 hours postdose, mean percentage of time with pH > 4 and average of mean pH were greater for dexlansoprazole (60% and 4.5, respectively) compared with esomeprazole (42% and 3.5, respectively); the difference was statistically significant (P < 0.001 for both intervals). At 0–12 hours postdose, the difference in dexlansoprazole and esomeprazole values for the pharmacodynamic end points was not statistically significant.Conclusion:For the entire 24-hour postdose period, predominantly resulting from the >12–24-hour postdose interval, the average intragastric pH following a single dose of dexlansoprazole 60 mg was higher compared with that observed following a single dose of esomeprazole 40 mg, and the difference was statistically significant.

Light at Night Activates IGF-1R/PDK1 Signaling and Accelerates Tumor Growth in Human Breast Cancer Xenografts

Regulation of diurnal and circadian rhythms and cell proliferation are coupled in all mammals, including humans. However, the molecular mechanisms by which diurnal and circadian rhythms regulate cell proliferation are relatively poorly understood. In this study, we report that tumor growth in nude rats bearing human steroid receptor-negative MCF-7 breast tumors can be significantly accelerated by exposing the rats to light at night (LAN). Under normal conditions of an alternating light/dark cycle, proliferating cell nuclear antigen (PCNA) levels in tumors were maximal in the early light phase but remained at very low levels throughout the daily 24-hour cycle period monitored. Surprisingly, PCNA was expressed in tumors continually at a high level throughout the entire 24-hour period in LAN-exposed nude rats. Daily fluctuations of Akt and mitogen activated protein kinase activation in tumors were also disrupted by LAN. These fluctuations did not track with PCNA changes, but we found that activation of the Akt stimulatory kinase phosphoinositide-dependent protein kinase 1 (PDK1) directly correlated with PCNA levels. Expression of insulin-like growth factor 1 receptor (IGF-1R), an upstream signaling molecule for PDK1, also correlated with fluctuations of PDK1/PCNA in the LAN group. In addition, circulating IGF-1 concentrations were elevated in LAN-exposed tumor-bearing nude rats. Finally, RNAi-mediated knockdown of PDK1 led to a reduction in PCNA expression and cell proliferation in vitro and tumor growth in vivo, indicating that PDK1 regulates breast cancer growth in a manner correlated with PCNA expression. Taken together, our findings demonstrate that LAN exposure can accelerate tumor growth in vivo, in part through continuous activation of IGF-1R/PDK1 signaling.

Second Prize: Hydroxyproline-Induced Hyperoxaluria Using Acidified and Traditional Diets in the Porcine Model

Swine models have proven useful for many different disease processes, especially for urologic research. In this study, we sought to create a model of hyperoxaluria in the adult sow by feeding hydroxyproline (HP). The development of an adult porcine model for calcium oxalate stone disease would represent a significant contribution to stone research as previous animal models have been developed only for rats and baby pigs. The experiment included a total of 12 multiparous, gestating sows (Large White x Landrace). Sows were randomly allotted to one of the two treatment groups. Treatments involved basal diets that were either control diet (CD) or acidogenic diet (AD). Urine was collected for 6 consecutive days. On days 1 and 2, each sow was fed 2 kg of the assigned basal diet (CD or AD). On days 3, 4, and 5, 200 g of L-hydroxyproline (Wilshire Technologies, Princeton, NJ) was added to each basal diet for all the 12 sows. The HP was evenly mixed with the basal diets before feeding. On day 6, each sow was fed the basal diet originally assigned without HP ( Fig. 1 ). Urine was collected for each entire 24-hour period to control for differences in the diurnal and postprandial variations in the renal handling of oxalate and glycolate. The addition of HP to the diet increased urinary oxalate excretion. Overall, there was a 192% (CD) and 187% (AD) increase in urinary oxalate between days 1 and 3. The increase peaked on day 3 and gradually returned to baseline by day 6. Student's paired t-test was performed and it confirmed that oxalate on days 3 and 5 was significantly different than baseline (p = 0.009 and p = 0.03, respectively). Urinary glycolate also increased as a result of adding HP to the diet. Overall, there was a 12,340% (CD) and 14,400% (AD) increase in urinary glycolate between days 1 and 3. The increase peaked on day 3 and then declined, although remained more than 10 x greater than baseline at day 6. Student's paired t-test confirmed that glycolate levels on days 3, 5, and 6 were significantly different than baseline (p < 0.001, p = 0.01, and p = 0.03, respectively). The role of oxalate in the formation of kidney stones cannot be understated. Medical prevention and management of calcium oxalate nephrolithiasis will require a comprehensive understanding of oxalate metabolism in humans. A model for human hyperoxaluria can be reliably created in the adult sow. Such a model is necessary to further our understanding of oxalate metabolism and ultimately aid in the prevention of calcium oxalate calculi.

No Higher Dose Requirements with Insulin Detemir than Glargine in Type 2 Diabetes: A Crossover, Double-Blind, and Randomized Study Using Continuous Glucose Monitoring

In a previous publication we reported no difference in the 24-hour glucose response between two basal analog insulins, detemir and glargine, when taken once a day in type 2 diabetes mellitus (T2DM). We now report the dose comparison observed within this randomized, double-blind, crossover study. Of 36 patients on basal insulin and other noninsulin treatments, 29 completed the study. Both insulins were given once a day at 8 pm and no food was taken between 6 pm and the following morning. The dose was titrated daily by continuous glucose monitoring (CGM) until the basal glucose (between 12 and 6 am) was <120 mg/dl but not >5% of CGM readings <70 mg/dl. Subjects were then crossed over to the other insulin and titrated similarly. Glucose goals were achieved in all subjects. The mean dosage was 0.26 U/kg with very few subjects requiring >0.4 U/kg. Only 2 required an absolute dose less than 10 U/day and all others required more, some considerably higher. Of the 29 subjects, 7 required a greater, 6 a smaller, and 16 the same dose of detemir compared to glargine. When given once daily in T2DM and titrated using CGM to the same fasting glucose, there was no difference in the glucose response between basal insulins during the basal titration period (4-10 hours after injection) nor during the entire 24-hour period following the injection. Further, the mean dosage to achieve this glucose goal was the same with both insulins.

Bloqueo iliofascial para analgesia postoperatoria de prótesis stotal de cadera

The objective of this pilot study was to evaluate the effectiveness of the fascia iliaca compartment block to control pain following total hip replacement by assessing pain intensity 24 hours after surgery and recording the use of opiates for rescue analgesia. We performed a prospective observational study of 41 patients undergoing total hip replacement surgery. The patients were divided into 2 groups: a group that received a fascia iliaca compartment block with 0.45% ropivacaine at a dosage of 0.3 mL/kg (maximum dose, 30 mL) and a control group in which no block was performed. Patients were enrolled consecutively as they entered the postanesthetic recovery unit. Postoperative pain was assessed on a visual analog scale (VAS) immediately after surgery and 24 hours later. Other variables recorded were opiate use for rescue analgesia and adverse effects due to the use of opiates. The VAS scores recorded in the postanesthetic recovery unit were significantly different in the 2 groups, with lower scores in the group receiving the fascia iliaca compartment block (P < .001). However, no significant between-group differences were observed in VAS scores recorded on the ward 24 hours after surgery (P = .57). A single-injection fascia iliaca compartment block was effective in controlling initial postoperative pain in a postanesthetic recovery unit. It was effective on the ward in the first few hours after surgery but not for the entire 24-hour period because of the limited duration of the block.

24-hour control of intraocular pressure with 2% dorzolamide/0.5% timolol fixed-combination ophthalmic solution in open-angle glaucoma

ABSTRACTObjective: To evaluate the 24-hour efficacy and tolerability of 2% dorzolamide/0.5% timolol fixed combination (DTFC) solution in open-angle glaucoma and ocular hypertension.Research design and methods: Randomized, parallel, doublemasked, multicenter study. Patients with insufficiently controlled intraocular pressure (IOP≥22 mmHg) were randomized to DTFC (N=117) or timolol (N=115). IOP was measured at baseline, 6 weeks, and 8 weeks, with measurements taken at 6 p.m., 8 p.m., 10 p.m., 2 a.m., 6 a.m., 8 a.m., 10 a.m., and 2 p.m.Main outcome measures: Statistically significant change in IOP from untreated baseline for DTFC at all hours at week 8. Secondary outcome measures included: IOP-lowering at week 6 at all individual time points, change from baseline to 8 weeks in mean daytime IOP (average of 8 a.m., 10 a.m., 2 p.m., 6 p.m., and 8 p.m. IOPs) and night-time IOP (10 p.m., 2 a.m., 6 a.m.), and comparison of DTFC with timolol after 8 weeks.Results: Patients receiving DTFC had a statistically significant and clinically relevant reduction in IOP at week 8 compared with baseline at all eight time points (p<0.001). Significant IOP reductions were also seen at all time points at week 6 (p<0.001). DTFC significantly lowered mean daytime IOP and night-time IOP (p<0.001 for both). Timolol alone also significantly reduced IOP from baseline at 8 weeks for all diurnal time points, and mean daytime and night-time IOP (p<0.001 for all). Compared with timolol alone, there were significantly greater reductions with DTFC at 10 a.m. (p=0.003) and 2 p.m. (p=0.016), and for mean daytime IOP (p=0.025) at 8 weeks. Significant between-treatment differences were not observed at other time points. Both treatments were well-tolerated, with no differences observed in the safety profiles between the treatment groups.Conclusions: Both DTFC and timolol provided significant IOP reduction over the entire 24-hour measurement period. timolol during the daytime, but not at night. Although this study was not designed or powered to compare DTFC and timolol, DTFC exhibited greater IOP-lowering than timolol during the daytime, but not at night.Trial registration: ClinicalTrials.gov identifier: NCT00108017.

Analysis of Recent Papers in Hypertension Jan Basile, MD, Senior Editor

Analysis of Recent Papers in Hypertension Jan Basile, MD, Senior Editor

Comparative Efficacy of Two Different β‐Blockers on 24‐Hour Blood Pressure Control

Atenolol and metoprolol succinate, dosed once daily, have different pharmacokinetic profiles. This study tests the hypothesis that differences that are especially noted in the early morning period, when cardiovascular risk is highest, in 24-hour blood pressure (BP) control exist between these 2 beta-blockers. This was a small, randomized open-label study with blinded end point evaluation in 36 hypertensive patients. All participants received hydrochlorothiazide 12.5 mg for 2 weeks before randomization to either 50 mg atenolol or metoprolol succinate given every morning; both treatments were force-titrated to 100 mg/d at 4 weeks. The primary end point was the change in early morning ambulatory systolic BP. Early morning (12 AM-6 AM) systolic BP differences were 3+/-14 mm Hg with atenolol vs -7+/-8 mm Hg with metoprolol succinate (P=.03). The overall 24-hour changes in systolic BP were 1+/-15 mm Hg with atenolol vs -9+/-11 mm Hg with metoprolol (P=.03). In conclusion, metoprolol succinate was more effective in sustaining 24-hour and early morning BP reductions compared with atenolol in a small group of hypertensive patients also treated with once-daily low-dose hydrochlorothiazide. It is possible that differences in outcome between atenolol-based and other therapies may be the result of inadequate dosing of atenolol, a medication that may not be effective for the entire 24-hour period.

Behavior of Migrant Shorebirds in Saline Lakes of the Southern Great Plains

We recorded and compared diurnal and nocturnal time-activity budgets of American Avocet (Recurvirostra americana), Lesser Yellowlegs (Tringa flavipes), Least Sandpiper (Calidris minutilla), and Wilson’s Phalarope (Phalaropus tricolor) on 21 saline lakes in the Southern Great Plains, USA, during spring and summer/fall 2002 and 2003 to examine importance of saline lakes as migratory stopover sites. All four species spent most of their time feeding (47-70%) and resting (7-37%) by day and at night during spring and fall migrations. Little time was spent in other behaviors. Time budgets differed among species and between seasons, likely due to different energy needs. Time spent foraging varied seasonally between saline lakes and freshwater playas for American Avocets and Least Sandpipers, likely due to differences in vegetation cover and availability of prey between these wetland types. For most species, time spent foraging and resting differed between day and night. Therefore, extrapolating diurnal activity budgets to the entire 24-hour period and from one type of habitat to another within the same region is not recommended. Saline lakes are used by migrant shorebirds as stopover sites where they replenish lipid stores. Conservation efforts should focus on preserving these unique wetlands and the freshwater springs that discharge in them.

Pharmacokinetic and Pharmacodynamic Comparison of Controlled-Release Carvedilol and Immediate-Release Carvedilol at Steady State in Patients with Hypertension

Carvedilol is indicated for the treatment of essential hypertension and mild-to-severe chronic heart failure, as well as the reduction of cardiovascular mortality in clinically stable post-myocardial infarction patients with left ventricular dysfunction. Carvedilol is a racemic mixture of R(+) and S(-) enantiomers that combines beta(1)-, beta(2)-, and alpha(1)-adrenoceptor blockade. For all indications, the immediate-release (IR) formulation of carvedilol is taken twice daily. A controlled-release (CR) formulation of carvedilol that allows once-daily dosing has recently been developed. In this double-blind, parallel-group, crossover study, 122 patients with essential hypertension were randomly allocated to receive low and high doses of carvedilol or placebo. Patients received either a constant low dose (CR 20 mg once daily or IR 6.25 mg twice daily) or were titrated to a high dose (CR 80 mg once daily or IR 25 mg twice daily) before being crossed over to an equivalent dose of the alternative formulation. The pharmacokinetic (PK) and pharmacodynamic (PD) profiles were compared between patients receiving carvedilol CR and carvedilol IR. The PK profiles for R(+)- and S(-)-carvedilol for the 2 formulations were equivalent (based on area under the curve, maximum plasma concentration [C(max)], and trough drug concentration). Consistent with an extended-release formulation, carvedilol CR delayed C(max) by 3.5 hours compared with carvedilol IR. For both carvedilol CR and IR, the attenuation of exercise-induced heart rate in patients with hypertension was maintained over the entire 24-hour period, and the 2 formulations demonstrated equivalent beta(1)-blocking effects at trough (end of the dosing interval [PD(min)]), suggesting that the rate of absorption does not interfere with the PD effect. In this first direct comparison of carvedilol CR and IR in subjects with hypertension, fewer adverse events were reported while subjects were receiving carvedilol CR (59.1% overall) compared with carvedilol IR (77.5% overall). This was true regardless of dose received. Headache was the most commonly reported adverse event for subjects receiving either formulation of carvedilol and placebo. Importantly, dizziness and headache were reported less often when subjects received carvedilol CR. This is the first study to show that both formulations had comparable beta(1)-adrenergic blockade in patients with essential hypertension under steady-state conditions. Notably, carvedilol CR provides consistent beta(1)-adrenergic blockade over 24 hours with a once-daily dose.

Heritability of Indices for Cardiac Contractility in Ambulatory Recordings

Overactivity of the sympathetic nervous system (SNS) plays a pivotal role in the development of cardiovascular disease. This involvement suggests that the genetic susceptibility to adverse cardiovascular events may derive in part from individual differences in SNS activity. To establish a genetic contribution to SNS activity, we measured sympathetic effects on cardiac contractility in 755 healthy adult twins and their singleton siblings. The preejection period (PEP) and the ratio of PEP to the left ventricular ejection time (PEP/LVET ratio) were derived from ambulatory recordings of the ECG and thorax impedance. During this type of prolonged recordings in a real life setting, the extent of cardiac sympathetic activity will vary with the demands of daily activities. Therefore, the genetic architecture of both indices was examined separately across three daytime periods (morning, afternoon, evening), and during nighttime sleep. Results showed significant genetic contribution to PEP (48-62%) over all daily periods. Heritability estimates for PEP/LVET ratio ranged between 35% and 58%. Cardiac sympathetic activity during the waking and sleep periods was largely influenced by genetic factors that were common to the entire 24-hour period. During sleep, additional genetic influences emerged that accounted for 8% of the variance in PEP. Impedance-derived measures of sympathetic effects on cardiac contractility show substantial heritability across all periods of the day and during sleep.

Sustained Restoration of Autonomic Balance With Long- but Not Short-Acting Metoprolol in Patients With Heart Failure

Background The purpose of this study was to compare the effects of immediate-release (IR) metoprolol and extended-release (XL) metoprolol on measures of heart rate variability in chronic systolic heart failure patients. Methods and Results Thirteen metoprolol-treated heart failure patients were randomized to a 2-way crossover study of equal daily doses of metoprolol IR and metoprolol XL, each administered for 3 weeks. After each 3-week interval, patients underwent 24-hour Holter and ambulatory blood pressure monitoring. Over the entire 24-hour period, the ratio of high to total variability (normalized measure of parasympathetic activity) was significantly greater ( P < .05), the ratio of low to total variability (normalized measure of sympathetic activity) was significantly lower ( P < .05), and the ratio of high to low variability (index of parasympathetic to sympathetic balance) was greater ( P < .08) for metoprolol XL compared with metoprolol IR. Over the entire 24-hour period, both systolic and diastolic blood pressure were significantly lower for metoprolol XL compared with metoprolol IR ( P < .0001, and .0005, respectively). Conclusion These data suggest that with twice daily dosing, metoprolol IR is inferior to metoprolol XL in its effects on heart rate variability, autonomic balance, and blood pressure in patients with heart failure.

Relationship Between the Mismatch of 123I-BMIPP and 201Tl Myocardial Single-Photon Emission Computed Tomography and Autonomic Nervous System Activity in Patients With Acute Myocardial Infarction

The purpose of this study was to elucidate the relationship between the mismatch of thallium-201(Tl) and iodine-123-beta-methyl-iodophenyl-pentadecanoic acid (BMIPP) myocardial single-photon emission computed tomography (SPECT) and autonomic nervous system activity in myocardial infarction (MI) patients. The subjects were 40 patients (34 males, 6 females) who underwent examinations by 123I-BMIPP and 201Tl myocardial SPECT imaging and 24-hour Holter monitoring within a 3-day period 3 weeks after the onset of their first MI. R-R intervals were analyzed every hour over a period of 24 hours by fast Fourier transformation (FFT). High frequency (HF) and low frequency (LF) were defined as markers of cardiac vagal activity in the former and the LF/HF ratio as sympathetic activity. Greater or more extensive decreases in the BMIPP image than that in the Tl image were defined as a positive mismatch. Patients were divided into positive and negative mismatch groups of 20 patients each. There were no significant differences between the 2 groups in age, sex, site of infarction, max CK (creatine kinase), max CK-MB, or left ventricular ejection fraction. The incidences of clinical signs suggesting residual myocardial ischemia were significantly greater in the positive than in the negative mismatch group (P < 0.05). The mean values for HF over the entire 24-hour period and over the 5-hour nocturnal period (0-5 AM) in the positive mismatch group were both significantly lower than those in the negative mismatch group (P < 0.001 in both groups). The 24-hour mean HF and mean nighttime HF in patients with signs of residual ischemia were both significantly lower than in those without signs of residual ischemia in the positive mismatch group (P < 0.05 in both groups). The mean LF/HF ratio for both the entire 24-hour and the nocturnal period in the positive mismatch group were significantly higher than those in the negative mismatch group (P < 0.001, P < 0.05, respectively). The daily profile of hourly HF measurements was significantly lower in the positive mismatch group than in the negative mismatch group (P < 0.02). The mean values of HF for 24-hour and 5-hour periods were significantly lower in patients with signs of residual ischemia in the positive mismatch group than in those with signs of residual ischemia in the negative mismatch group (P < 0.01, P < 0.02, respectively). There were no significant differences between the patients with signs of residual ischemia in the negative mismatch group and those without signs of residual ischemia in the positive and negative mismatch group with regard to the mean values of HF and the LF/HF ratio measured every hour for 24 hours and 5 hours. It is concluded from the present study that the findings of a mismatch on 123I-BMIPP and 201Tl myocardial SPECT 3 weeks after a first acute myocardial infarction with uncomplicated moderate or severe heart failure and decreased heart rate variability are related to residual myocardial ischemia. A combined assessment of heart rate variability in 24-hour Holter ECG monitoring and perfusion-metabolism mismatch in 123I-BMIPP and 201Tl myocardial SPECT is useful for determining residual myocardial ischemia in the follow-up of those with acute myocardial infarction.

Triamcinolone Acetonide Destabilizes VEGF mRNA in Müller Cells under Continuous Cobalt Stimulation

To identify the molecular mechanism of steroid-induced downregulation of vascular endothelial growth factor (VEGF) synthesis in Müller cells. Confluent cultures of human Müller cells (MIO-M1) were treated with 100 microM CoCl(2), 1 microg/mL triamcinolone acetonide (TA), or both. VEGF secretion was measured with respect to time by ELISA. VEGF mRNA quantity and stability were analyzed by reverse transcriptase-polymerase chain reaction. The activity of hypoxia-inducible factor (HIF)-1 was measured by the relative binding of HIF-1 protein to the hypoxia response element (HRE), by gel shift and ELISA. The HIF-1alpha protein level was determined with Western blot. TA decreased VEGF secretion by at least 50% in the presence of continuous cobalt stimulus. VEGF mRNA decreased 50- to 100-fold 6 hours after treatment with TA and cobalt compared with cobalt alone. VEGF mRNA stability was decreased in cobalt-stimulated, TA-treated cells compared with cobalt alone in cells synchronized by exposure to actinomycin D. HIF-1alpha protein level was sustained for the entire 24-hour treatment period and partitioned into nuclear, not cytosolic, fractions. HIF-1 activity was decreased by 20% to 30% in the presence of TA and cobalt compared with cobalt alone. TA may decrease VEGF synthesis by nongenomic destabilization of VEGF mRNA in cobalt-stimulated Müller cells. There was little effect on the total HIF-1alpha protein level, HIF-1 partitioning, and HIF-1 activity.

Effect of the renin--angiotensin system on the vessel wall: using ACE inhibition to improve endothelial function.

Plasma renin activity and cardiovascular disease (CVD) incidence correlate closely in people with hypertension. The effects of angiotensin II (Ang II) on blood pressure (BP) are important in hypertensive patients; accumulating data suggest that the growth effects of Ang II in the cardiovascular system play a critical role in the development of atherosclerosis. Atherosclerosis development in hypertensive patients requires fundamental changes in endothelial structure and function. Key among the factors that may affect the endothelium is the renin--angiotensin--bradykinin system. Ang II, independent of other environmental and neurohormonal factors, mediates the vessel wall changes critical for the development of atherosclerotic disease. A strong correlation appears to exist between Ang II and CVD. Blockade of the renin-angiotensin system has a major impact on arterial structure and function independent of BP. Certain angiotensin-converting enzyme (ACE) inhibitors produce significant improvements in arterial compliance, which may yield a reduction in cardiovascular events. Blockade of the neurohormonal system may be a critical first-line approach to management of hypertension in an effort to prevent or reverse endothelial dysfunction. Moreover, the effects of ACE inhibition, in addition to its effect on BP, suggest that this therapeutic approach may be appropriate for managing patients at risk of CVD who do not yet have hypertension. The ideal antihypertensive agent should yield smooth, consistent BP control over the entire 24-hour period, both to avoid BP variability that places patients at increased risk of cardiovascular events and to offer protection during the vulnerable early morning hours when patients are well known to be at high risk.

Effect of baclofen on emesis and 24-hour esophageal pH in neurologically impaired children with gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is difficult to control with medical therapy in neurologically impaired children. The gamma-aminobutyric acid type B receptor agonist baclofen was recently reported to reduce reflux in adult patients with GERD by reducing the incidence of transient lower esophageal sphincter relaxations. The current study was undertaken to investigate the effects of baclofen on GERD in neurologically impaired children. Eight neurologically impaired children with GERD between 2 months and 16 years were studied. Baclofen (0.7 mg/kg/day) was administered orally or via nasogastric tube in three divided doses 30 minutes before meals for 7 days. The frequency of emesis on and off baclofen were recorded as a measure of clinical impact. Twenty-four-hour esophageal pH monitoring was conducted before and on the seventh day of the administration of baclofen. The frequency of emesis was significantly decreased (P = 0.03). The total number of acid refluxes was significantly decreased both during the entire 24-hour period (P = 0.01) and during the postprandial period (P = 0.049). The number of acid refluxes longer than 5 minutes was significantly decreased during the 24-hour period (P = 0.02). The percentage total time of esophageal pH <4.0 and esophageal acid clearance time were not significantly different during the 24-hour period or during the postprandial period. No adverse effects were observed, except for a slight reduction in muscle tone in one subject. In this 1-week trial, repetitive administration of baclofen reduced the frequency of emesis and the total number of acid refluxes in neurologically impaired children with GERD.