Progress in the experimental and computational methods of work function evaluation of materials: A review.

The work function, which determines the behaviour of electrons in a material, remains a crucial factor in surface science to understand the corrosion rates and interfacial engineering in making photosensitive and electron-emitting devices. The present article reviews the various experimental methods and theoretical models employed for work function measurement along with their merits and demerits are discussed. Reports from the existing methods of work function measurements that Kelvin probe force microscopy (KPFM) is the most suitable measurement technique over other experimental methods. It has been observed from the literature that the computational methods that are capable of predicting the work functions of different metals have a higher computational cost. However, the stabilized Jellium model (SJM) has the potential to predict the work function of transition metals, simple metals, rare-earth metals and inner transition metals. The metallic plasma model (MPM) can predict polycrystalline metals, while the density functional theory (DFT) is a versatile tool for predicting the lowest and highest work function of the material with higher computational cost. The high-throughput density functional theory and machine learning (HTDFTML) tools are suitable for predicting the lowest and highest work functions of extreme material surfaces with cheaper computational cost. The combined Bayesian machine learning and first principle (CBMLFP) is suitable for predicting the lowest and highest work functions of the materials with a very low computational cost. Conclusively, HTDFTML and CBMLFP should be used to explore the work functions and surface energy in complex materials.

Ivermectin shows clinical benefits in mild to moderate COVID19: a randomized controlled double-blind, dose-response study in Lagos.

INTRODUCTION: In vitro studies have shown the efficacy of Ivermectin (IV) to inhibit the SARS-CoV-2 viral replication, but questions remained as to in-vivo applications. We set out to explore the efficacy and safety of Ivermectin in persons infected with COVID19. METHODS: We conducted a translational proof of concept randomized, double blind placebo controlled, dose response and parallel group study of IV efficacy in RT-polymerase chain reaction proven COVID 19 positive patients. Sixty-two patients were randomized to three treatment groups. (A) IV 6 mg regime, (B) IV 12 mg regime (given Q84 h for 2 weeks) (C, control) Lopinavir/Ritonavir. All groups plus standard of Care. RESULTS: The Days to COVID negativity (DTN) was significantly and dose dependently reduced by IV (P = 0.0066). The DTN for Control were, = 9.1+/-5.2, for A 6.0 +/- 2.9 and for B 4.6 +/-3.2. Two way repeated measures ANOVA of ranked COVID 19 +/- scores at 0, 84, 168 and252h showed a significant IV treatment effect (P = 0.035) and time effect (P < 0.0001). IV also tended to increase SPO2% compared to controls, P = 0.073, 95% CI-0.39 to 2.59 and increased platelet count compared to C (P = 0.037) 95%CI 5.55-162.55 × 103/ml. The platelet count increase was inversely correlated to DTN (r = -0.52, P = 0.005). No SAE was reported. CONCLUSIONS: 12mg IV regime given twice a week may have superior efficacy over 6mg IV given twice a week, and certainly over the non IV arm of the study. IV should be considered for use in clinical management of SARS-COV2, and may find applications in prophylaxis in high risk areas.

Pathophysiologically based antihypertensive pharmacotherapeutics rationality, efficacy and safety in Sub Saharan African Nations - A review.

BACKGROUND: Hypertension (HT) prevalence, Uncontrolled Blood Pressure (UBP), morbidity and mortality are highest in Sub-Saharan Africa (SSA). Correlating pathophysiology of HT to pharmaco-therapy with antihypertensive drugs (AHD) may bring amelioration. Aims:To review peculiarities of HT in SSA, UBP causes, diagnostic modalities, AHD use, rationality and efficacy. METHODS AND RESULTS: 14 published therapeutic audits in 4 SSA nations on Google Scholar or PUBMED, (total n = 6496 patients) were evaluated. Calcium Channel blockers (CCB) amlodipine, and thiazide diuretics (TD), hydrochlorothiazide (HCTZ) were the commonest AHD. Thiazide Like Diuretics (TLD) were underutilized. The % of patients on AHD were: 1 drug 5.4-55%; 2 drugs 37-82%; >/ = 3 drugs 6-50.3%. 2-drug combinations were: ACEI/ARB + TD (42%); CCB + TD (36.8%); ACEI + CCB (15.8%) of studies. Triple/quadruple therapy included Methyldopa (MTD) with ACEI + CCB or TD. The (%) attaining BP < 140/< 90 mmHg, ranged from 29 to 53.6%, median, 44%. The co-morbidities, range and median were: Diabetes Mellitus (DM): 9.8-64%, 19.2%; Chronic Kidney Disease (CKD): 5.7-7.5%, 6.9%, and Coronary artery Disease (CAD): 0.9-2.6%, 2.3%. ACEI + CCB ± TD were the preferred AHD for comorbidities. CONCLUSIONS: Therapeutic inertia; Non-compliance; co-morbidities; refractory HT; ignorance; substandard AHD; contribute to UBP. Studies relating 24 hour ABPM to complications and mortality in SSA hypertensives; and impact of different AHD classes on ABPM, are needed. Study of ACEI + alpha-1 blockers + TLD on 24 hour ABPM and personalized care, are required.

Phenotypic identification of soil bacterial and fungal communities inhabiting an archaeological monument at Augustine University, Ilara Epe, southwest Nigeria

Background: The Sungbo Eredo Monument is an ancient public work with a system of defensive walls and ditches located in Eredo Local Council Development Area of Epe, Lagos State, southwest Nigeria. A huge section of the monument cuts through the Augustine University campus, forming two-sided vertical walls with a deep ridge in-between. The objective of this investigative study is to determine the microbial profile of soil samples from the monument in the University campus. Methodology: Soil samples were collected from the topsoil at a depth of 7.5cm from four randomly selected points along the edge of the monument. The samples were transported to the microbiology laboratory of the Department of Biological Sciences of Augustine University for analysis. Samples were cultured on Nutrient agar (NA) and incubated aerobically for 24-48 hours for bacteria isolation and on Sabouraud's Dextrose agar (SDA) for 72 hours for fungi isolation. Bacterial colonies on NA were preliminarily identified to genus level by Gram reaction and conventional biochemical test scheme for Gram-positive (catalase, coagulase, starch hydrolysis) and Gram-negative isolates (oxidase, urease test, indole, methyl red, Voges Proskauer and sugar fermentation tests). Fungi colonies on SDA were identified using conventional macroscopic and microscopic characteristics. Antibiotic susceptibility test of the bacterial isolates to selected antibiotics was done using the Kirby Bauer disc diffusion method. Results: A total of twenty-three bacterial isolates in four genera; Bacillus, Staphylococcus, Cellobiococcus and Micrococcus and nine fungal isolates in three genera; Saccharomyces, Aspergillus and Botrytis were identified from the cultures. The bacterial isolates were sensitive (>50% sensitivity) to only gentamicin and ofloxacin, with 65.2% and 78.3% sensitivity rates respectively, while they were largely resistant to all other antibiotics such as ceftriaxone, erythromycin, cefuroxime, cloxacillin, ceftazidime and augmentin, with resistance rates of 65.2%, 65.2%, 73.9%, 82.6%, 86.9%, 91.3% respectively. Conclusion: The results of this investigative study revealed the presence of antibiotic-resistant bacteria (mainly Gram-positive) and fungi on the archaeological monument of Augustine University, adding to the existing data on microbial spectrum of archaeological monuments that could be useful for unraveling human cultural habits and microbe-related human diseases. However, further studies on molecular identification of these microbial spectrum will be required to ascertain their genetic relatedness and ancestral phylogeny, which will be useful for archaeologists in their study of the Sungbo-Eredo ancestral monument.

Characterization of α-Amylase from Soursop (Annona muricata Linn.) Fruits Degraded by Rhizopus stolonifer.

Rhizopus stolonifer is a fungus and one of the most common species of the genus Rhizopus. The organism has been a very important microbe used in the field of industrial microbiology. It has been used in the production of many hydrolytic and extracellular enzymes among which is the α-amylase. This enzyme has found various uses in the industry. Fruit juices are important sources of nutrients and they contain several important therapeutic properties that may reduce the risk of various diseases. An investigation on α-amylase extracted from soursop fruits deteriorated by R. stolonifer and the effect of the enzyme on soursop juice clarification was carried out in this study. The results obtained shows that the soursop juice with low concentration of extracted enzyme and less incubation time was more viscous and cloudy compared with the juice with high concentrations of amylase and higher incubation time which was clearer and less viscous. The results of this research will be very useful in soursop juice producing companies.

Clarification of Tomato Juice with Polygalacturonase Obtained from Tomato Fruits Infected by Aspergillus niger.

Two varieties of tomato fruits commonly available in Nigerian markets are the Roma VF and Ibadan local varieties of tomato fruits. The Roma VF fruits are oval in shape. It is a common type of cultivar in the Northern region of Nigeria and it is not susceptible to cracking. The Ibadan local variety of tomato fruits is a local variety commonly found on farmers fields in South-western region of Nigeria. They are highly susceptible to cracking. The Ibadan local variety was employed for this research. There are lots of benefits derived from the consumption of tomato fruits. The fruits can be made into tomato juice clarified with pectinases. Polygalacturonase is one of the pectinases used commercially in the clarification of fruit juice from different fruits. This study examined the production of polygalacturonase during the deterioration of tomato fruits by Aspergillus niger and the role of the purified polygalacturonase in the clarification of tomato juice. Tomato fruits of the Ibadan local variety were inoculated with mycelia discs containing spores of a 96-h-old culture of Aspergillus niger served as the inoculum. The organism from the stock culture was subcultured onto potato dextrose agar plates. The extraction of polygalacturonase after 10 days of incubation at 27 degrees C was carried out by homogenizing the fruits with liquid extractant using the MSE homogenizer after the deteriorated fruits had been chilled for 30 min inside a freezer. Control fruits were similarly treated except that sterile potato dextrose agar served as the inoculum. The effect of different temperature of incubation and different volume of enzyme on the tomato juice from the tomato fruits was investigated. Extracts from the inoculated fruits exhibited appreciable polygalacturonase activity. The juice with polygalacturonase was visually clearer and more voluminous than the juice treated with water for all parameters studied. The highest volume of juice was obtained after an incubation period of 30 min for the tomato fruits. The increase in juice yield can be attributed to the hydrolysis of pectin which releases the sap inside the cells of the pulp. The occurrence of polygalacturonase in tomato tissues infected by A. niger coupled with the trace amount in the non-infected tissues suggests that the enzyme is of fungal origin. The role of the polygalacturonase in the clarification process was established. This study will be very useful for industrial tomato juice production.

Genetic diversity of Plasmodium falciparum field isolates from south western Nigeria.

BACKGROUND: Plasmodium falciparum the main causative agent of malaria is an important public health vector. With the use of PCR, its genetic diversity has been extensively studied with dearth information from Nigeria. METHODS: In this study, 100 P. falciparum strains merozoite surface protein 1(msp-1), merozoite surface protein 2 (msp-2) and Glutamate rich protein (Glurp) from Ogun State General Hospitals were characterized. The genetic diversity of P. falciparum isolates was analyzed by restriction fragment length polymorphism following gel electrophoresis of DNA products from nested polymerase chain reactions (PCR) of their respective allelic families KI, MAD 20, RO33 (MSP-1);FC27, 3D7 (MSP-2) and Glutamate rich protein respectively. RESULTS: Majority of the patients showed monoclonal infections while multiplicity of the infection for msp-1 and msp-2 were 1.1 and 1.2 respectively. The estimated number of genotypes was 8 msp-1 (4 KI; 3 MAD; 1 RO33) and 6 msp-2 (3 FC27; 3 3D7). 80% of the isolates coded for Glurp with allelic size ranged between 700 and 900 bp. CONCLUSION: The allelic distributions however were similar to those previously reported in other endemic malaria countries. Future studies will be designed to include other malaria endemic regions of Nigeria such as the oil exploration regions.

Genital ulcer diseases among HIV-infected female commercial sex workers in Ibadan, Nigeria.

We evaluated the prevalence and association of Genital Ulcer Diseases (GUDs) among HIV-1 infected female commercial sex workers (FCSWs) in Ibadan, Nigeria. A total of 250 FCSWs from brothels in Ibadan were tested for presence of antibodies to HIV and Syphilis. Pelvic examinations for signs of sexually transmitted infections (STIs) were carried out on the subjects. Endocervical and high vaginal swabs were collected from each of the subjects to establish laboratory diagnosis of STIs. Their age ranged from 15 to 55 years (Mean = 25.8 yrs; SD = 3.74). Majority (246/250) were Nigerians, while 1.6% were from neighboring West African countries. Sixty four (25.6%) of the subjects were positive for HIV-1 while seven (2.8%) had dual HIV-1/2 infection. Analysis of the STIs showed that 49 (19.6%) of the CSWs had GUDs. Herpes genitalis was the commonest GUDs as it occurred in 25 (10%) of the subjects. Other STIs identified were chancroid (5.6%), syphilis (4.0%) and lymphogranuloma venerum (LGV) (4%). Sixteen (64.0%) of the CSWs with herpes genitalis had HIV-1 infection. The risk ratio of herpes genitalis for HIV acquisition was 3.0 (95% CI: 2.0 - 4.4). Syphilis and chancroid were also found tobe significantly associated with increased risk of HIV infection (p < 0.0001). The adjusted odd ratios for Herpes genitalis, chancroid, and syphilis were 3.7 (1-13.0, p < 0.05), 19.8 (2.7-13.0, p < 0.05) and 19.1 (1-231.0, p < 0.05) respectively. There is need to educate FCSWs continually to adopt safer sexual behaviours, seek early diagnosis and treatment of GUDs to reduce their risk of transmitting HIV infection.

Genital ulcer diseases among HIV_infected female commercial sex workers in Ibadan, Nigeria

We evaluated the prevalence and association of Genital Ulcer Diseases (GUDs) among HIV-1 infected female commercial sex workers (FCSWs) in Ibadan; Nigeria. A total of 25O FCSWs from brothels in Ibadan were tested for presence of antibodies to HIV and Syphilis. Pelvic examinations for signs of sexually transmitted infections (STIs) were carried out on the subjects. Endocervical and high vaginal swabs were collected from each of the subjects to establish laboratory diagnosis of STIs. Their age ranged from 15 to 55 years (Mean = 25.8yrs; SD =3.74). Majority (246/250) were Nigerians; while 1.6were from neighboring West African countries. Sixty four (25.6) of the subjects were positive for HIV-1 while seven (2.8) had dual HIV-1/2 infection. Analysis of the STIs showed that 49 (19.6) of the CSWs had GUDs. Herpes genitalis was the commonest GUDs as it occurred in 25 (10) of the subjects. Other STIs identified were chancroid (5.6); syphilis (4.0) and lymphogranuloma venerum (LGV) (4). Sixteen (64.0) of the CSWs with herpes genitalis had HIV-1 infection. The risk ratio of herpes genitalis for HIV acquisition was 3.0 (95CI: 2.0 - 4.4). Syphilis and chancroid were also foundto be significantly associated with increased risk of HIV infection (p0.0001). The adjusted odd ratios for Herpes genitalis; chancroid; and syphilis were 3.7(1-13.0; p0.05); 19.8 (2.7-13 .0; p0.05) and 19.1(1-231.0; p 0.05) respectively. There is need to educate FCSWs continually to adopt safer sexual behaviours; seek early diagnosis and treatment of GUDs to reduce their risk of transmitting HIV infection

Comparison of the effects of unfractionated heparin and the low-molecular-weight heparins dalteparin and enoxaparin on spontaneous platelet aggregation and adenosine diphosphate activity in platelets during the third trimester of pregnancy.

Low-molecular-weight heparins (LMWHs) have demonstrable pharmacokinetic, pharmacodynamic and safety advantages over unfractionated heparin (UH) in routine clinical use and are now the preferred agents in routine anticoagulant therapy. However, the utility and impact of the LMWH compared with that of UH has not been studied extensively in human pregnancy, wherein the prophylaxis against venous thromboembolism is imperative. Human pregnancy is a hypercoagulable state with an increase in spontaneous platelet aggregation (SPA) in vivo. We evaluated and compared the effects of UH and the LMWHs dalteparin and enoxaparin (10 U/ml) on SPA in citrated whole blood with an ultraflow platelet counter in pregnancy and also investigated the role of adenosine diphosphate (ADP) in heparin-induced platelet aggregation in the third trimester of pregnant women (aged 28 +/- 3 years, gestational age 34 +/- 5 weeks) and in healthy, age-matched nonpregnant women. Pregnant women showed a significantly increased SPA of 37% 6 5% compared with 16% 6 3% in nonpregnant women (p < 0.01). UH exerted a significantly greater proaggregatory effect on SPA compared with that of LMWHs or saline (p < 0.0002; ANOVA). The maximum values of SPA were as follows: UH, 69% +/- 5%; dalteparin, 46% +/- 5%; and enoxaparin, 54% +/- 3%. There was no difference between SPA induced by LMWHs and saline or between enoxaparin and dalteparin. At 480 s, there was no difference in SPA induced by LMWH between pregnant and nonpregnant women, but UH substantially and specifically increased SPA in pregnant women compared with that in nonpregnant women (p < 0.01). This heparin-induced platelet activation and thrombocytopenic response was reversed by apyrase grade II (ADP scavenger) that also inhibited SPA in pregnancy to a level similar to that of nonpregnant women (p < 0.0002; ANOVA). These results indicate that the LMWHs dalteparin and enoxaparin cause significantly less platelet aggregation in whole blood in pregnancy and in the nonpregnant state when compared with UH. The proaggregatory platelet effects of UH is substantially enhanced in pregnancy, a property not shared by LMWHs. The reversal of the heparin-induced platelet activation by apyrase grade II suggests that the mechanism is, at least in part, mediated by copious ADP release from platelets or red cells by heparin but not LMWHs.

Castration reduces platelet thromboxane A2 receptor density and aggregability.

BACKGROUND: Exogenously administered testosterone upregulates platelet thromboxane A2 (TXA2) receptors and increases aggregation response to thromboxane mimetics in healthy male volunteers. However, the biological impact of endogenous testosterone on platelet TXA2 receptor expression, especially in older men at risk of coronary artery disease, is unclear. AIM: To investigate the impact of reduction in circulating testosterone on platelet TXA2 receptor expression in older men. DESIGN: Cross-sectional case-control study. METHODS: We studied surgically and/or medically castrated men with prostate cancer (group A, n = 8, aged 71 +/- 8 years) and age-matched, uncastrated urology patients (group B, n = 7, aged 67 +/- 9 years). Plasma testosterone was measured by radioimmunoassay. Platelet TXA2 receptor expression was assessed by radioligand binding studies using radioactive 125I-BOP. Platelet aggregation responses to TXA2-mimetic I-BOP, and to thrombin, were also studied. RESULTS: Group A had significantly lower plasma testosterone than group B (16 +/- 5 ng/dl vs. 308 +/- 47 ng/dl, p<0.001). Platelet TXA2 receptor density (B(max)) but not affinity (K(d)) was lower in group A (0.50 +/- 0.12 vs. 1.01 +/- 0.17 pmol/mg protein, p = 0.03). Maximum platelet aggregation response to I-BOP (E(max)), but not sensitivity (EC50) was lower in group A (53 +/- 2% vs. 63 +/- 2%, p = 0.003 ANOVA). In vitro, high concentrations of hydroxyflutamide (100 microM) competitively inhibited U46619-induced platelet aggregation in washed platelets, without affecting the binding of 125I-BOP to platelet TXA2 receptors. DISCUSSION: Endogenous testosterone regulates platelet TXA2 receptor B(max) and the E(max) aggregation response to thromboxane mimetic I-BOP. Blockade of androgen receptors or inhibition of testosterone production may reduce platelet aggregation responses. Preliminary evidence suggests the presence of functional androgen receptors on human platelets, which may regulate TXA2 receptor expression.

Endogenous opioids, mu-opiate receptors and chloroquine-induced pruritus: a double-blind comparison of naltrexone and promethazine in patients with malaria fever who have an established history of generalized chloroquine-induced itching.

AIMS: Chloroquine induces a severe generalized pruritus, in predisposed Black African patients, during treatment of malaria fever, and also in some Caucasian patients treated for rheumatological diseases. We have previously shown that chloroquine may release endogenous opioids and/or interact with micro-opiate receptors in rats, and that both histamine and malaria parasite blood density, contribute to the itching severity in malaria fever in humans. The aim of our present study was to assess and compare the antipruritic efficacy of the micro-opiate receptor antagonist, naltrexone, and the antihistamine, promethazine, in chloroquine treated patients with malaria fever. METHODS: A double-blind, randomized, parallel group comparison of the chloroquine-induced pruritus intensity and time profile in patients with parasitologically proven malaria fever, who were pretreated with a single dose of either naltrexone 50 mg or promethazine 25 mg orally (six patients each). All patients had an established history of severe pruritus following chloroquine treatment of malaria fever. A self-assessed itching severity score was undertaken at 0, 6, 12, 24, 48 and 72 h after initial chloroquine dosing, and the areas under the pruritus-intensity time curve AUCP0-72 h was determined in each patient and correlated to the malaria parasite density in blood. RESULTS: Both naltrexone and promethazine subjectively reduced itching severity compared with prior historical experience. One patient on naltrexone and two on promethazine never experienced any itching. There was no statistically significant treatment effect, but a significant time effect (P = 0.001, F = 4.77 d.f. 5) by two-way repeated measures ANOVA. The AUCP for naltrexone was 82 +/- 25 units/h, and 57 +/- 34 units/h for promethazine [95% confidence interval for the difference being -73 to 123]. However, the malaria parasite density in the naltrexone group (740 +/- 178 microl(-1)) tended to be higher than in the promethazine group 314 +/- 69 microl(-1) (P = 0.056, 95% confidence interval for the difference being -15 to 866 microl(-1)). Correction of the AUCP for malaria parasite density (parasite pruritogenic index, AUCP. units/h/parasites/microl blood) tended to be lower with naltrexone 9.1 +/- 2.6 than with promethazine 12.2 +/- 7.0 There was a highly significant and positive correlation between the malaria parasite density and the AUCP0-72 h, on naltrexone (r2 = 0.78, P = 0.040) and promethazine (r2 = 0.93, P = 0.008). However, comparison of regressions revealed that the slope of the regression was significantly steeper with promethazine 0.48 than naltrexone 0.12 (P = 0.006, t = 4.2), with the intercepts showing a trend to a difference (P = 0.086). CONCLUSION: Naltrexone exerted an antipruritic action, at least to a similar extent to promethazine in patients with chloroquine-induced itching in malaria fever. However, the relationship between parasite density and resultant pruritus was significantly different between naltrexone and promethazine. Thus, micro-opiate receptors/and or endogenous opioids may contribute to chloroquine itching in malaria fever, in humans, in accord with animal experimental findings. Malaria parasite density in blood is a strong determinant of itching severity in patients predisposed to chloroquine-induced pruritus.

Sickle cell trait and gender influence type 2 diabetic complications in African patients.

BACKGROUND: Black and African patients with type 2 diabetes have a greater frequency and more severe vascular complications of the disease, even after correction for socioeconomic factors. Asymptomatic sickle cell trait (SCT; hemoglobin AS) is also common among black Africans and may independently cause endothelial damage, manifested as isolated target organ complication or infarction. We examined the possibility that patients with concurrent type 2 diabetes and SCT may be predisposed to more frequent or severe diabetic macro- or microvascular complications than those without SCT. METHODS: Fifty-two type 2 diabetic patients were divided into four groups, according to gender and hemoglobin genotype (normal: AA or SCT: AS). The groups were well matched for age and for clinical and demographic parameters. Diabetic complications were assessed in each patient and scored. Hemoglobin genotype was determined by hemoglobin-gel electrophoresis. Statistical comparisons were made between the groups. RESULTS: The composite complication score for vascular disease differed significantly according to gender and genotype (p<0.027 ANOVA). Male diabetics with SCT had a higher risk ratio (RR 1.6, p<0.02) for complications than those with normal hemoglobin; however, this was not the case with female diabetics. Among the male diabetics with SCT, there was a significantly greater proportion with proteinuria (p<0.02) or retinopathy (p<0.05) than among those with a normal hemoglobin genotype. Multiple regression analysis showed that gender and SCT were independent predictors of the vascular complication severity score and that exclusion of hemoglobin genotype weakened the predictability of the regression. A significantly higher proportion of male than female diabetics had at least one detectable complication. Systolic or diastolic blood pressure had no significant impact on the regressions. CONCLUSION: Male gender and SCT may adversely affect the expression of microvascular diabetic complications in Africans. Diabetic patients from populations predisposed to the sickle gene should be screened for the trait as part of their initial risk assessment. Large-scale studies on the impact of hemoglobin genotype on diabetic complications are clearly indicated.

Sex hormone regulation of systemic endothelial and renal microvascular reactivity in type-2 diabetes: studies in gonadectomized and sham-operated Zucker diabetic rats.

BACKGROUND: Male Zucker diabetic rats exhibit a more severe endotheliopathy in comparison with their female diabetic litter mates. The plasma concentrations of both thromboxanes and endothelins are elevated in diabetes, and the receptor cross-talk between TXA(2) and ET-1 receptors may be enhanced in type-2 diabetic Zucker rats. AIMS: To determine the role of the endogenous sex steroid hormones, testosterone and estradiol on the systemic and renal microvascular reactivity to ET-1, thromboxane-mimetic U46619, ET-TXA(2) receptor interaction, and the nitric oxide vasodilator system in Zucker hypertensive-diabetic rats. METHODS: Male and female Zucker rats aged 8-10 weeks were each divided into two groups. The male rats were castrated or underwent a sham operation. The female rats were spayed (bilateral ovariectomy and hysterectomy) or had a sham operation. All rats were studied 4-6 weeks after the gonadectomy or sham operations. Blood glucose and insulin as well as plasma concentrations of testosterone and estradiol were determined. Haemodynamic studies were undertaken with determination of the dose-response curve for mean arterial pressure (MAP), renal cortical flow (RCF) and renal medullary blood flow (MBF) in response to ET-1 and U46619, and the effect of interdiction of the ET-TXA(2) interaction with ET-antagonists BQ610 and BQ788. The role of endogenous NO was assessed by its response to graded acetylcholine doses and to a L-NG-nitro-arginine methyl ester (L-NAME) infusion. RESULTS: Castrated male rats had a significantly lower blood glucose concentration (295 +/- 33 mg dL(-1)) compared with their sham-controls (481 +/- 40 mg dL(-1)), P = 0.008. Mean arterial pressure tended to be lower in the castrated rats. Gonadectomy reduced the plasma testosterone and estradiol concentrations. Castration abolished the hypotensive action of U46619 compared with sham-operated male rats (P < 0.0001, anova). Conversely, the pressor action of U46619 seen in the sham-operated female rats was reversed to a profound hypotensive action in the spayed rats (P < 0.001, anova). The change in MAP after U46619 was inversely correlated to the plasma testosterone concentration (r = -0.73, P = 0.027). The paradoxical hypotensive response elicited by ET-1 in the Zucker diabetic rats of both sexes was abolished by castration only (P < 0.005, anova). Castration caused a significant (P = 0.011) augmentation of the vasodilator response to acetylcholine, while spaying caused a slight attenuation. Castration, but not spaying, resulted in significant increases in MBF after U46619 (P = 0.003, anova), ET-1 (P = 0.005, anova) and acetylcholine (P = 0.053, anova). The ET-(B) antagonist BQ788 augmented the U46619-induced rise in MAP in castrated male rats, and also abolished the U46619-induced increase in MBF (P < 0.01 anova). L-NAME (25 mg kg(-1)) increased MAP and decreased MBF in the gonadectomized and sham-operated rats, except for the castrated male Zucker rats, where it significantly increased MBF (+90 +/- 31 PU) (P = 0.0004, anova) despite the increase in MAP. CONCLUSIONS: Testosterone and estradiol regulate systemic and microvascular reactivity to TXA(2) receptor stimulation in type-2 diabetic Zucker rats. The impact of testosterone on blood glucose concentration, blood pressure, and the systemic and renal microcirculatory response to ET-1 and NO, as well as the endothelin-thromboxane receptor cross talk, is greater, and opposite to that of estradiol. The effects of testosterone withdrawal may at least in part be mediated by the ET-B receptor subtype and NO generation. Androgen blockade should be investigated further for the reversal or delay of hypertensive-diabetic endotheliopathy.

Alteration in endothelin receptor sub-type responsiveness and in the endothelin-TXA(2) mimetic U46619 interaction, in type-2 hypertensive diabetic Zucker rats.

BACKGROUND: Type-2 diabetes is characterized by endotheliopathy, which increases target organ damage and mortality. There is excessive endothelin-1 and TXA(2) production, and abnormal vascular reactivity to endothelin-1, manifested as a paradoxical hypotensive action in Zucker diabetic, but not lean rats. We examined the hypothesis that there is an alteration in the ET-A/ET-B receptor subtype sensitivity, and/or the interaction or cross-talk between ET-1 and TXA(2) in type-2 diabetes, using Zucker diabetic rats and their lean littermates. MATERIALS AND METHODS: Hemodynamic studies were performed in lean and Zucker fatty diabetic rats of both sexes. Laser doppler flowmetry was used to measure renal cortical (RCF) and medullary blood flow (MBF) responses. Dose response curves for mean arterial blood pressure (MAP), MBF and RCF in response to ET-1, U46619, acetylcholine, and L-NAME (25mg/kg) were constructed after pre-treatment of the rats with either BQ610 1mg/kg i.v. or BQ788 0.5mg/kg i.v. The effects of BQ610 and BQ788 on whole blood impedance aggregation were also assessed. RESULTS: BQ788, but not BQ610 abolished both the paradoxical hypotensive action of ET-1 in Zucker diabetic rats (n=7 each, P<0.001 ANOVA) as well as the dose-dependent rise in MBF (P<0.001 ANOVA). BQ788, but not BQ610 abolished the difference in response to ET-1 between lean and diabetic Zucker rats. U46619 caused a hypotensive action in male Zucker rats which was abolished by L-NAME 25mg/kg or indomethacin 10mg/kg i.v. The U46619 interaction with BQ788 on both MAP and MBF was significantly (P<0.03 ANOVA) different between lean and diabetic Zucker rats. BQ788, but not BQ610 attenuated both the MAP and MBF responses to acetylcholine or L-NAME P<0.02 ANOVA). However, BQ610 dose-dependently attenuated the slope of platelet aggregation in both lean and Zucker diabetic rats (P<0.02 ANOVA). CONCLUSION: ET-B receptor antagonism abolished the abnormal vascular reactivity and MBF responses to ET-1, and also normalized the vasoactive responses to the level seen in healthy lean Zucker rats. ET-1 receptor blockade influences the responses to TXA(2) receptor activation. In the systemic and renal circulation, this interaction appears to be mostly ET-B receptor mediated, whilst in platelets, ET-A receptor role may be predominant. The interaction or cross-talk between ET-1 and TXA(2) is altered in the type-2 diabetic state. Collectively, these pathophysiological changes may contribute to the vicious circle of diabetic endotheliopathy.

Shifting trends in the pharmacologic treatment of hypertension in a Nigerian tertiary hospital: a real-world evaluation of the efficacy, safety, rationality and pharmaco-economics of old and newer antihypertensive drugs.

The current prescription patterns for essential hypertension and the efficacy, safety, tolerability and cost-effectiveness of the newer antihypertensive drugs were evaluated in Nigerian patients. The findings were compared with that of a previous study conducted in the same tertiary hospital 10 years earlier. A cross-sectional evaluation of blood pressure (BP) control in a hypertension clinic was undertaken among 150 Nigerian patients aged 61 +/- 12 years (55% females), with a duration of treatment on a particular drug class or combination of 9 +/- 3 months. The initial blood pressure was 176 +/- 20/108 +/- 11 mmHg and 22% of the patient had concurrent diabetes mellitus. Thiazide diuretics (D) alone or in combination remained the most commonly prescribed drugs in 56% of all patients. There were significant increases in the prescriptions of calcium channel blockers (CCBs) (51%), P < 0.0001, and ACE-inhibitors (ACEIs) (24%), P < 0.0001, but a slight reduction in the use of methyldopa, and fixed drug combinations (P < 0.01) compared to the previous study. The fall in systolic blood pressure on D (r = 0.65, P < 0.001) or CCB (r = 0.48, P < 0.02) was significantly correlated with the initial systolic blood pressure, but not age. More patients achieved normotension BP < 140/90 mmHg on CCB monotherapy (71%), than D monotherapy (56%). Combination therapy with ACEIs + D or methyldopa+thiazides normalized BP in 63 and 68%, respectively. Pulse pressure, a surrogate marker for cardiovascular complications and mortality in essential hypertension, was significantly reduced (P < 0.01) equally by all treatments, with 95% confidence intervals ranging from -28 to -1 mmHg. However, hypertensive-diabetic (HT-DM) patients (n = 33) exhibited no significant change in pulse pressure in response to treatment. Adverse drug reactions that occurred in 11% were impotence or postural dizziness with D, headache and pitting oedema with CCB, and dry cough with ACEI. Pharmaco-economic comparison of the drug classes revealed that for every US dollar (dollar) spent per month, the percentage of treated patients attaining normotension was 18.6 for D, 4.73 for CCB, 3.5 for ACEI + D and 13.6 for methyldopa + thiazides. A combination of ACEI + CCB or D was the preferred treatment for hypertensive-diabetic Nigerians, but only 24% attained a BP < 130/85 mmHg. These results demonstrate a shift in trend to a more rational and efficacious treatment of hypertension over a 10 year period. This may be associated, at least in part, with the intensive and continuous education of the prescribers in rational drug use and the introduction of a hospital formulary. Methyldopa is still a highly efficacious and cost-effective drug in this population. Black HT-DM Africans still constitute a subgroup who not only require more and costlier antihypertensive drugs, but whose BP control is suboptimal, and exhibit a poor therapeutic response to other risk factors (pulse pressure) that constitute a continuing risk for cardiovascular mortality.

Gender difference in vascular and platelet reactivity to thromboxane A(2)-mimetic U46619 and to endothelial dependent vasodilation in Zucker fatty (hypertensive, hyperinsulinemic) diabetic rats.

We examined the hypothesis that gender differences exist in platelet and vascular reactivity in type-2 diabetes mellitus, using Zucker fatty diabetic rats of both sexes and their lean littermates. Type-2 diabetes is characterized by excessive platelet production of TXA(2), which is thrombogenic. Testosterone up-regulates platelet TXA(2) receptors and the aggregation response to thromboxane mimetics. Conversely, estrogen increases vascular nitric oxide (NO) production and inhibits platelet aggregation. Hemodynamic studies were undertaken with the determination of dose-response curve for MAP and renal cortical blood flow (RCF) in response to U46619, angiotensin-II, phenylephrine and endothelin-1, as well as the systemic hemodynamic response to acetylcholine and L-NG nitro-arginine methylester (L-NAME). Platelet aggregation response was evaluated using whole blood impedance aggregometry. There were significant gender differences in the systemic blood pressure and RCF response to TXA(2)-mimetic U46619 and angiotensin-II (P<0.02, ANOVA) but not to phenylephrine or endothelin-1. Male rats exhibited a paradoxical hypotensive response to U46619 (-18+/-11 mmHg) compared with a peak pressor response of +6+/-1 mmHg in female rats (P<0.01, ANOVA). The male rats exhibited an attenuated systemic vasodilator response (P<0.001, ANOVA) to acetylcholine (fall in MAP in male diabetic rats being -24+/-8 mmHg, compared with a fall of -50+/-8 mmHg in females), but a greater rise in the renal cortical resistance in response to NO inhibition by L-NAME (P<0.03) compared with the female rats. Both the slope (46+/-2) and the peak magnitude of the U46619-induced whole blood platelet aggregation (13+/-1) ohms were significantly higher (P<0.01, ANOVA) in male (n=10) compared with female diabetic rats (n=8) (29+/-0.8 slope, 10.0+/-0.8 ohms, respectively). Thus, the male diabetic Zucker rats exhibited an impaired response to vasoconstrictors (U46619 and angiotensin-II) and to endothelial (NO)-mediated vasodilation. The male gender may therefore be associated with the greater prothrombotic activity and a worse impairment of endothelial reactivity in the type-2 diabetic state.