Blood pressure changes following aerobic exercise in Caucasian and Chinese descendants.

Acute aerobic exercise produces post-exercise hypotension (PEH). Chinese populations have lower prevalence of cardiovascular disease compared to Caucasians. PEH may be associated cardiovascular disease through its influence on hypertension. The purpose of this study was to compare PEH between Caucasian and Chinese subjects following acute aerobic exercise. 62 (30 Caucasian and 32 Chinese, 50% male) subjects underwent measurement of peripheral and central hemodynamics as well as arterial and cardiac evaluations, 30 min and 60 min after 45 min of treadmill exercise. Caucasians exhibited significantly higher baseline BP than the Chinese. While the reduction in brachial artery systolic BP was greater in Caucasian than in the Chinese, there was no difference in changes in carotid systolic BP between the groups. The increase in cardiac output and heart rate was greater in the Chinese than Caucasians, but total peripheral resistance and leg pulse wave velocity decreased by a similar magnitude in the Chinese and Caucasian subjects. We conclude that acute aerobic exercise produces a greater magnitude of PEH in peripheral systolic BP in Caucasian compared to Chinese subjects. The different magnitude in PEH was caused by the greater increase in cardiac output mediated by heart rate, with no change in stroke volume. It is possible that initial BP differences between races influenced the findings.

Sex differences in ventricular-vascular coupling following endurance training.

INTRODUCTION: Ventricular and vascular coupling is defined as the ratio of arterial elastance (Ea) to ventricular elastance (Elv) and describes the interaction between the heart and arterial system. There are sex differences in both arterial and ventricular function in response to both acute exercise and aerobic exercise training. PURPOSE: To examine the effects of aerobic exercise training on elastances and the coupling ratio in young adult men and women. We hypothesized a reduction in the coupling ratio in both sexes due to a decrease in Ea that would be more pronounced in men and an increase in Elv that would be larger in women. METHODS: Fifty-three healthy, young adults completed the study. Central pulse wave velocity and heart volumes were measured before and after an 8-week aerobic training intervention. Elastances were calculated as Ea = end-systolic pressure/stroke volume and Elv = end-systolic pressure/end-systolic volume and indexed to body surface area. RESULTS: After the intervention, women augmented indexed and un-indexed Elv from 2.09 ± 0.61 to 2.52 ± 0.80 mmHg/ml, p < 0.05, and reduced the coupling ratio from 0.72 ± 18 to 0.62 ± 15, p < 0.05, while men maintained their pre-training ratio (from 0.66 ± 0.20 to 0.74 ± 0.21, p > 0.05). Women also reduced end-systolic pressure (from 91 ± 10 to 87 ± 10 mmHg), and both groups reduced central pulse wave velocity (from 6.0 ± 1.0 to 5.6 ± 0.6 m/s, p < 0.05). CONCLUSION: We conclude that after 8 weeks of aerobic training, only women reduced their coupling ratio due to an increase in Elv. This suggests that aerobic exercise training elicits sex-dependent changes in the coupling ratio in young, healthy individuals.

The melanocortin system and insulin resistance in humans: insights from a patient with complete POMC deficiency and type 1 diabetes mellitus.

The central melanocortin system is essential for the regulation of long-term energy homeostasis in humans. Rodent experiments suggest that this system also affects glucose metabolism, in particular by modulating peripheral insulin sensitivity independently of its effect on adiposity. Rare patients with complete genetic defects in the central melanocortin system can provide insight into the role of this system in glucose homeostasis in humans. We here describe the eighth individual with complete proopiomelanocortin (POMC) deficiency and the first with coincidental concomitant type 1 diabetes, which provides a unique opportunity to determine the role of melanocortins in glucose homeostasis in human. Direct sequencing of the POMC gene in this severely obese patient with isolated adrenocorticotropic hormone deficiency identified a homozygous 5' untranslated region mutation -11C>A, which we find to abolish normal POMC protein synthesis, as assessed in vitro. The patient's insulin requirements were as expected for his age and pubertal development. This unique patient suggests that in humans the central melanocortin system does not seem to affect peripheral insulin sensitivity, independently of its effect on adiposity.

Effect of sex on wasted left ventricular effort following maximal exercise.

Wasted left ventricular effort (∆Ew) refers to work required of the left ventricle to eject blood that does not result in increased stroke volume and is related to left ventricular hypertrophy. Literature shows that men and women have differing ventricular and vascular responses to and following exercise. Our purpose was to determine how ∆Ew changes post-exercise in men and women and examine potential mechanisms. We hypothesized a reduction in ∆Ew that would be greater in men and that central pulse wave velocity and wave intensity (WIA) would be related to ∆Ew. Blood pressures, central pulse wave velocity (cPWV), and WIA were obtained at rest, 15 and 30 min after maximal exercise. Both sexes reduced ∆Ew post-maximal exercise (p>0.05 for interaction), but women had higher ∆Ew at each time point (p<0.05). The first peak of WIA increased 15 min post-exercise only in women (p<0.05). cPWV was attenuated (p<0.05) in women at 15 min and men at 30 min (p<0.05) post-exercise with a significant time by sex interaction (p<0.05). WIA (1st peak) was correlated (p<0.05) to ∆Ew in both sexes before and 15 min post-exercise, but cPWV was only associated with ∆Ew in men at 30 min post-exercise. We conclude that both sexes decrease ∆Ew after maximal exercise, but vascular and ventricular changes associated with the attenuation of ∆Ew are not uniform between sexes.

Resting and post exercise arterial-ventricular coupling in endurance-trained men and women.

The relationship between effective arterial elastance (EA) and left ventricular end-systolic elastance (ELV) is a determinant of cardiac performance, known as arterial-ventricular coupling (AVC). The purpose of this study was to examine the acute effects of high-intensity interval (HI) and low-intensity steady state (SS) exercise on AVC. Twenty-three (13 men, 10 women) young (26 years), endurance-trained individuals completed a VO2 peak test followed by an acute SS and HI exercise bout on separate visits. Before (Pre) and 30- and 60-min after each bout, measures of aortic end-systolic pressure (ESP), left ventricular end-systolic volume and stroke volume were obtained. Across both conditions (HI and SS) and both sexes, at 30 and 60 min post exercise, ESP and ELV were reduced from Pre 30 and 60-min exercise (ESP: 86±7, 77±8 and 73±8 mm Hg; ELV: 4.93±1.53, 4.19±1.38 and 4.10±1.53 mm Hg ml(-1) m(-2)). EA was only reduced at 60 min post exercise (1.90±0.36, 1.78±0.50 and 1.57±0.36). Both EA and ELV were reduced following acute SS and HI exercise. This is likely because of similar reductions in total peripheral resistance following both exercise bouts. These results suggest that endurance-trained individuals are able to match peripheral vascular changes with changes in left ventricular function following dynamic exercise of different intensities.

Effect of resistance training on biomarkers of vascular function and oxidative stress in young African-American and Caucasian men.

African Americans (AA) have an earlier onset of hypertension and a different vascular profile than their Caucasian (Cau) peers. Research suggests that biological mediators of vascular inflammation are different among these groups in hypertensive populations. Resistance training (RT) is an important exercise modality that improves the vascular profile of young AA men. We examined the role of RT on biomarkers of vascular function and oxidative stress in body mass index-matched AA and Cau men. RT for 6 weeks elicited significant changes in circulating matrix metalloprotease-9 (MMP-9) and 8-Isoprostane (8-IsoP) in young AA men (n=14, AA; n=18, Cau; 18-35 years). MMP-9 was lower and decreased in AA (pre: P=0.02; post: P<0.001) and a time × group interaction for MMP-9 (F(1, 30)=4.81; P=0.036) and 8-IsoP (F(1, 24)=7.09; P=0.014) was detected. 8-IsoP decreased in AA (P=0.026) but did not change in Cau (P=0.309). Notably, the increase in strength (1-repetition maximum (1-RM)) was correlated with the decrease in MMP-9 (r=-0.398; P=0.022). Furthermore, these adaptations were independent of any improvement in cardiorespiratory fitness. We demonstrate that RT effectively reduces matrix remodeling proteins and oxidative stress in young AA men. Increasing strength may be beneficial for improving vascular health and offsetting novel cardiovascular risk factors of hypertension in young AA men.

Aortic reservoir function, estimated myocardial demand and coronary perfusion pressure following steady-state and interval exercise.

Aortic reservoir function is a measure of the aorta's ability to distribute blood during diastole, attenuating the pulsatility of blood flow, and is important in balancing cardiac flow. Effects of acute high versus moderate exercise intensity on reservoir function and cardiac energetics is unknown. Eighteen athletes completed a interval (INT) and steady-state (SS) cycling bout at 60% of VO(2) peak. Reservoir function was calculated as the ratio of diastolic run-off to stroke volume and expressed as a percentage. Coronary perfusion pressure was derived from tissue Doppler imaging and echocardiography. Systolic tension-time integral (TTI) from the aortic pressure waveform served as a measure of myocardial oxygen consumption. All measures were made at rest, 30-min postexercise and 60-min postexercise. Average reservoir function before SS was 76%, which was reduced to 62% 30-min post-SS and 67% 60-min post-SS (P<0.05). Significantly greater reductions in reservoir function were seen following INT (from 71% pre-INT to 45% 30-min post-INT and 53% 60-min INT, P<0.05). Estimated coronary perfusion pressure was reduced 30 min following INT but not SS; both bouts reduced coronary perfusion pressure at 60-min postexercise (P<0.05). TTI increased following both INT and SS at 30- and 60-min postexercise with greater increases following INT (P<0.05). Following exercise, reservoir function was associated with TTI (P<0.05), but not coronary perfusion pressure (P>0.05). We conclude that reservoir function is attenuated following acute SS and INT, but these reductions were greater post-INT, suggesting that exercise intensity affects reservoir function. Reduction of reservoir function following exercise is related to TTI, a reflection of myocardial oxygen consumption but apparently not associated with coronary perfusion pressure.

Comparison of the acute impact of maximal arm and leg aerobic exercise on arterial stiffness.

Acute aerobic exercise decreases arterial stiffness based on the intensity of the exercise and the arterial segment studied. Arm exercise may differentially affect arterial stiffness compared to leg exercise but this has not been studied. We hypothesized that maximal aerobic exercise would reduce local peripheral pulse wave velocity i.e. femoral-dorsalis pedis (LPWV) following leg exercise and carotid-radial (APWV) following arm exercise without any crossover effect. The main purpose of the study is to compare the effects of maximal arm versus leg aerobic exercise on peripheral and central arterial stiffness. Fifteen healthy participants (9 males and 6 females, 25 ± 5 years) performed maximal arm-ergometer and leg-ergometer exercise in a randomized, crossover design. Peripheral and central pulse wave velocities (PWV) were obtained using applanation tonometry before and 10 min after each maximal exercise bout. 2 × 2 repeated measures analysis of variance was used to detect differences between conditions. There was a significant interaction in the APWV between the two exercise modes. However, there was no condition or interaction effect on LPWV following maximal arm versus leg exercise. There was no significant difference in central PWV between conditions or with time. There was no change in MAP (75 ± 6-77 ± 3) after maximal arm exercise as compared to the maximal leg exercise (73 ± 6-80 ± 2). Arm exercise produced a more generalized effect on arterial stiffness than leg exercise. The prescription of upper limb exercise may be considered for purposes of eliciting post-exercise systemic changes in arterial stiffness.

Bariatric surgery in a patient with complete MC4R deficiency.

Bariatric surgery is often successful for treatment of severe obesity. The mechanisms of weight loss after bariatric surgery and the role of central energy homeostatic pathways in this weight loss process are not well understood. The study of individuals with complete loss of function of genes important in the leptin-melanocortin system may help establish the significance of these pathways for weight loss after bariatric surgery. We describe the outcome of bariatric surgery in an adolescent with compound heterozygosity and complete functional loss of both alleles of the melanocortin 4 receptor (MC4R). The patient underwent laparoscopic adjustable gastric banding and truncal vagotomy at years of age, which resulted in initial, but not long-term weight loss. Our experience with this patient suggests that complete MC4R deficiency impairs response to gastric banding and results in poor weight loss after this surgery.

Selection of solid dosage form composition through drug-excipient compatibility testing.

A drug-excipient compatibility screening model was developed by which potential stability problems due to interactions of drug substances with excipients in solid dosage forms can be predicted. The model involved storing drug-excipient blends with 20% added water in closed glass vials at 50 degrees C and analyzing them after 1 and 3 weeks for chemical and physical stability. The total weight of drug-excipient blend in a vial was usually kept at about 200 mg. The amount of drug substance in a blend was determined on the basis of the expected drug-to-excipient ratio in the final formulation. Potential roles of several key factors, such as the chemical nature of the excipient, drug-to-excipient ratio, moisture, microenvironmental pH of the drug-excipient mixture, temperature, and light, on dosage form stability could be identified by using the model. Certain physical changes, such as polymorphic conversion or change from crystalline to amorphous form, that could occur in drug-excipient mixtures were also studied. Selection of dosage form composition by using this model at the outset of a drug development program would lead to reduction of "surprise" problems during long-term stability testing of drug products.

Putative chikungunya virus-specific receptor proteins on the midgut brush border membrane of Aedes aegypti mosquito.

Two proteins (putative receptors) of 60 and 38 kDa, for chikungunya (CHIK) virus were detected in the brush border membrane fraction (BBMF) of the normal population of Aedes aegypti mosquitoes. Mosquitoes were infected orally with CHIK virus and infectivity checked by testing the head squashes. BBMF was prepared from proved positive and negative mosquitoes. The receptor proteins were found to be present in both the proved genotypes. However, dot-b'ot assays showed that the CHIK virus binding activity of BBMF/mg protein was noticeably low in the proved negative mosquitoes as compared to the positives. BBMF from the larvae of the normal populations also showed the presence of the receptor proteins, binding to CHIK virus. Receptor proteins from larvae as well as the adults were found glycosylated. CHIK virus receptor proteins of 24, 45, 58, 60 and 62 kDa were also seen in the membrane fraction of the C6/36 cells.

Isolation of the new variant influenza A (H3N2) strains during an outbreak in Pune, February, 1996.

During January-February, 1996, an outbreak of influenza-like illness occurred in Pune. The throat and nasal swabs collected from the patients during this outbreak were processed in MDCK and LLC-MK2 cell cultures and influenza A(H3N2) viruses were isolated. They were identified as being similar to the recent circulating global strains A/Johannesburg/33/94 and A/Wuhan/359/95.

Effect of humidity-dependent changes in crystal structure on the solid-state fluorescence properties of a new HMG-CoA reductase inhibitor.

It has been shown previously that the disodium salt of a new HMG-CoA reductase inhibitor (SQ-33600) is capable of existing as a number of hydrate species [1]. Three crystalline solid hydrates and one liquid crystalline phase have been identified, each having a definite stability over a defined range of humidity. These forms have been found to exhibit varying fluorescence properties in their respective solid states, with differences in bandshapes and intensities being noted for each. These spectral variations have been correlated with the known pseudopolymorphism of the compound.

Relative lipophilicities and structural-pharmacological considerations of various angiotensin-converting enzyme (ACE) inhibitors.

Lipophilicities of seven structurally diverse angiotensin-converting enzyme (ACE) inhibitors, viz., captopril, zofenoprilat, enalaprilat, ramiprilat, lisinopril, fosinoprilat, and ceronapril (SQ29852), were compared by determining their octanol-water distribution coefficients (D) under physiological pH conditions. The distribution co-efficients of zofenopril, enalapril, ramipril and fosinopril, which are the prodrug forms of zofenoprilat, enalaprilat, ramiprilat, and fosinoprilat, respectively, were also determined. Attempts were made to correlate lipophilicities with the reported data for oral absorption, protein binding, ACE inhibitory activity, propensity for biliary excretion, and penetration across the blood-brain barrier for these therapeutic entities. Better absorption of prodrugs compared to their respective active forms is in agreement with their greater lipophilicities. Captopril, lisinopril, and ceronapril are orally well absorbed despite their low lipophilicities, suggesting involvement of other factors such as a carrier-mediated transport process. Of all the compounds studied, the two most lipophilic ACE inhibitors, fosinoprilat and zofenoprilat, exhibit a rank-order correlation with respect to biliary excretion. This may explain the dual routes of elimination (renal and hepatic) observed with fosinoprilat in humans. The more lipophilic compounds also exhibit higher protein binding. Both the lipophilicity and a carrier-mediated process may be involved in penetration of some of these drugs into brain. For structurally similar compounds, in vitro ACE inhibitory activity increased with the increase in lipophilicity. However, no clear correlation between lipophilicity and ACE inhibitory activity emerged when different types of inhibitors are compared, possibly because their interactions with enzymes are primarily ionic in nature.

Relative lipophilicities, solubilities, and structure-pharmacological considerations of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors pravastatin, lovastatin, mevastatin, and simvastatin.

The apparent octanol-water partition coefficients (Po/w) and aqueous solubilities for four 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors [pravastatin, lovastatin (mevinolin), mevastatin (compactin), and simvastatin (synvinolin)] were compared. Pravastatin is highly hydrophilic compared with lovastatin, mevastatin, or simvastatin. Pravastatin is clinically used as the active hydroxy acid, while the other three compounds are administered as prodrug lactones which, over a period of time, convert in vivo to their respective active hydroxy acid forms. The order of the Po/w values of the hydroxy acid forms was pravastatin much less than mevastatin less than lovastatin less than simvastatin at each pH evaluated, with approximate ratios of 1:25:75:200, respectively. The relative order and the ratios of partition coefficients for the lactone forms were similar to those for the hydroxy acid forms. In addition, lovastatin, mevastatin, and simvastatin are virtually insoluble in water, with solubility values ranging from 0.0013 to 0.0015 mg/mL at 23 degrees C. In comparison, pravastatin is hydrophilic, as demonstrated by the greater than 100-fold greater solubility of its lactone form (0.18 mg/mL). The greater hydrophilicity of pravastatin may explain its reported lower permeation into nonhepatic cells and the selectivity with respect to inhibition of cholesterol synthesis.

Cloning & expression of chikungunya virus genes coding structural proteins in Escherichia coli.

DNA complementary to the single stranded RNA genome of Chikungunya (CHIK) virus with poly A tract was cloned into the plasmid pGEM-3Zf(-) and 5Zf(+) by blunt end ligation strategy. Clones containing the cDNA inserts were selected by X-gal, IPTG system. They were tested for the expression of structural protein(s) of CHIK virus by in situ enzyme immunoassay and Western blot. The former assay system showed the presence of expressed viral proteins. Analysis of Western blot shows that three structural proteins, E1, E2 and capsid (C) are expressed in Esch. coli. The molecular weights of envelope proteins E1 and E2 were 44-46 Kd and 42-44 Kd respectively, which are lesser than the actual molecular weights of virional proteins (50-52 Kd). This may be due to the absence of glycosylation of these proteins in Esch. coli. In clone no. 382, a high molecular weight protein (56-58 Kd) was observed, which was probably the unglycosylated form of P62 polyprotein coded by the virus during its multiplication. A small protein of MW 6-8 Kd was also expressed in clone nos. 382 and 504, and this appeared to be the unglycosylated form of E3 protein of CHIK virus.

Oligonucleotide fingerprint analysis of a wild strain & its attenuated variant of Japanese encephalitis virus.

A strain of Japanese encephalitis (JE) virus was passaged serially through primary chick kidney cell cultures (45 times) and primary baby hamster kidney cell cultures (21 times). The resultant virus lost its lethal effect to 3 wk old mice by the ic route and 10 day old mice by the ip route. The oligonucleotide fingerprint analysis of the parent and the passaged strains showed 64 spots in common; 17 spots were present in the parent strain which were absent in the passaged virus, while the latter had acquired 9 spots which were not present in the parent virus.

Oligonucleotide fingerprint analysis of Japanese encephalitis virus strains of different geographical origin.

RNA fingerprint analysis was carried out with different strains of Japanese encephalitis virus which were isolated from Japan, China, India and Sri Lanka. From the similarity ratios, a similarity matrix was worked out which yielded a dendrogram. Geographical proximity of the place of isolation did not contribute much to the similarity of the fingerprint of the strains, nor did temporal proximity. The Japanese Nakayama strain had greater similarity with the Asansol strain from West Bengal. However, another strain from West Bengal, the Bankura strain, showed marked difference. Similarly the Bhopal and Beijing (China) strains were relatively close to each other while the Japanese JaGAr15460 strain was nearer to the strain from Gorakhpur. Serial mouse passage of the Asansol strain did not change the fingerprint pattern drastically.

A sensitive and rapid immunochemical method for quantitation of proteins.

A sensitive and rapid ELISA for quantitation of seed globulins is described. This method employs conjugation of pigeon pea (Cajanus cajan) globulin antibodies and the enzyme peroxidase together with dextran. Using this conjugate, proteins as low as 0.1 ng were detected. Dextran conjugate has a ten-fold greater efficiency of quantitating pigeon pea globulins than the commercial goat anti-rabbit IgG conjugate, and is three-fold more efficient than pigeon pea globulin IgG peroxidase conjugate. The method can be conveniently adapted for quantitation of other proteins also.