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Immune checkpoint inhibitors (ICIs) and Janus kinase inhibitors (JAKis) have raised concerns over serious unexpected cardiovascular adverse events. The widespread pleiotropy in genome-wide association studies offers an opportunity to identify cardiovascular risks from in-development drugs to help inform appropriate trial design and pharmacovigilance strategies. This study uses the Mendelian randomization (MR) approach to study the causal effects of 9 cardiovascular risk factors on ischemic stroke risk both independently and by mediation, followed by an interrogation of the implicated expression quantitative trait loci (eQTLs) to determine if the enriched pathways can explain the adverse stroke events observed with ICI or JAKi treatment. Genetic predisposition to higher systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), waist-to-hip ratio (WHR), low-density lipoprotein cholesterol (LDL), triglycerides (TG), type 2 diabetes (T2DM), and smoking index were associated with higher ischemic stroke risk. The associations of genetically predicted BMI, WHR, and TG on the outcome were attenuated after adjusting for genetically predicted T2DM [BMI: 53.15% mediated, 95% CI 17.21%–89.10%; WHR: 42.92% (4.17%–81.67%); TG: 72.05% (10.63%–133.46%)]. JAKis, programmed cell death protein 1 and programmed death ligand 1 inhibitors were implicated in the pathways enriched by the genes related to the instruments for each of SBP, DBP, WHR, T2DM, and LDL. Overall, MR mediation analyses support the role of T2DM in mediating the effects of BMI, WHR, and TG on ischemic stroke risk and follow-up pathway enrichment analysis highlights the utility of this approach in the early identification of potential harm from drugs.

Supplementary Fig. from Coronarin D, a labdane diterpene, inhibits both constitutive and inducible nuclear factor-κB pathway activation, leading to potentiation of apoptosis, inhibition of invasion, and suppression of osteoclastogenesis

Compounds isolated from members of the Zingiberaceae family are traditionally used as a medicine against inflammatory diseases, but little is known about the mechanism. Here, we report the isolation and structural identification of coronarin D [E-labda-8(17),12-diene-15-ol], a labdane-type diterpene, from Hedychium coronarium and delineate its mechanism of action. Because the transcription factor nuclear factor-κB (NF-κB) is a key mediator of inflammation, apoptosis, invasion, and osteoclastogenesis, we investigated the effect of coronarin D on NF-κB activation pathway, NF-κB-regulated gene products, and NF-κB-regulated cellular responses. The coronarin D inhibited NF-κB activation induced by different inflammatory stimuli and carcinogens. This labdane also suppressed constitutive NF-κB activity in different cell lines and inhibited IκBα kinase activation, thus leading to the suppression of IκBα phosphorylation, degradation, p65 nuclear translocation, and reporter gene transcription. Coronarin D also inhibited the NF-κB-regulated gene products involved in cell survival (inhibitor of apoptosis protein 1, Bcl-2, survivin, and tumor necrosis factor receptor-associated factor-2), proliferation (c-myc, cyclin D1, and cyclooxygenase-2), invasion (matrix metalloproteinase-9), and angiogenesis (vascular endothelial growth factor). Suppression of these gene products by the diterpene enhanced apoptosis induced by TNF and chemotherapeutic agents, suppressed TNF-induced cellular invasion, and abrogated receptor activator of NF-κB ligand-induced osteoclastogenesis. Coronarin D was found to be more potent than its analogue coronarin D acid. Overall, our results show that coronarin D inhibited NF-κB activation pathway, which leads to inhibition of inflammation, invasion, and osteoclastogenesis, as well as potentiation of apoptosis. [Mol Cancer Ther 2008;7(10):3306–17]

Energy and fossil fuel supplies have been threatened by the depletion of fossil fuels on a global scale, as well as by the constant rise in oil prices and the continual increase in environmental degradation. On the other hand, polymer waste has increased due to its usage in a daily lifestyle because of its cheap cost, ease of production, and adaptability. Indirectly, these polymer wastes are causing some major problems for the ecosystem and other living things. By transforming waste polymers into usable energy, can address for both the non-biodegradability of polymers and the need for an alternative fuel. This research paper aims to evaluate the performance of fuel produced by the pyrolysis of polyethylene polymer. Three distinct alcohol additive blends with polymer fuel were investigated in a single-cylinder direct injection diesel engine for their performance and emission characteristics. The results were further analysed using the design of experiment tool, "Full Factorial Design" to determine the most optimal running condition.

Sewer system monitoring is important to keep the city clean. Irregular monitoring of the sewage system leads to obstruction of drainage. Sewer blockages are the main causes of sewer flooding and pollution. Sometimes, out of ignorance, workers may encounter an accident as they may not be aware of the conditions inside the manhole. This document represents an experimentation of the smart sanitation system using IoT. In this model, a water pump motor, transformer, microcontroller and IoT module is used to obtain the desired output from the module.

Background: Enteral nutrition is of paramount importance in management of upper gastrointestinal tract malignancies. Although various access routes for enteral nutrition are available, feeding jejunostomy tube is preferred to other methods. Since minimally invasive techniques have many advantages, we decided to perform it during staging laparoscopy.Methods: The medical records of all patients who underwent laparoscopic feeding jejunostomy between October 2019 and September 2021, in the department of surgical gastroenterology, Madurai medical college were retrospectively reviewed. Patient demographics, ECOG performance status, types of malignancy, indications for feeding jejunostomy, operative time, time to start feeds, length of hospital stay and complications were analysed.Results: 75 patients underwent laparoscopic feeding jejunostomies (51 men and 24 women), with a mean age of 51.6±11.7 years, using this method. ECOG performance status was between 0-2. Mean operating time was 83±8.8 minutes. Mean length of hospital stay was 3.5 days. There was no conversion, however one patient required reoperation for peritubal leak.Conclusions: Feeding jejunostomy can be accomplished by a total laparoscopic technique using intracorporeal suturing. The technique we propose is relatively simple, reproducible, cost effective and can be widely adopted.

Background--Guidelines for hypertension vary in their preference for initial combination therapy or initial monotherapy, stratified by patient profile; therefore, we compared the efficacy and tolerability of these approaches. Methods and Results--We performed a 1-year, double-blind, randomized controlled trial in 605 untreated patients aged 18 to 79 years with systolic blood pressure (BP) ≥150 mm Hg or diastolic BP ≥95 mm Hg. In phase 1 (weeks 0-16), patients were randomly assigned to initial monotherapy (losartan 50-100 mg or hydrochlorothiazide 12.5-25 mg crossing over at 8 weeks), or initial combination (losartan 50-100 mg plus hydrochlorothiazide 12.5-25 mg). In phase 2 (weeks 17-32), all patients received losartan 100 mg and hydrochlorothiazide 12.5 to 25 mg. In phase 3 (weeks 33-52), amlodipine with or without doxazosin could be added to achieve target BP. Hierarchical primary outcomes were the difference from baseline in home systolic BP, averaged over phases 1 and 2 and, if significant, at 32 weeks. Secondary outcomes included adverse events, and difference in home systolic BP responses between tertiles of plasma renin. Home systolic BP after initial monotherapy fell 4.9 mm Hg (range: 3.7-6.0 mm Hg) less over 32 weeks (P < 0.001) than after initial combination but caught up at 32 weeks (difference 1.2 mm Hg [range: -0.4 to 2.8 mm Hg], P=0.13). In phase 1, home systolic BP response to each monotherapy differed substantially between renin tertiles, whereas response to combination therapy was uniform and at least 5 mm Hg more than to monotherapy. There were no differences in withdrawals due to adverse events. Conclusions--Initial combination therapy can be recommended for patients with BP > 150/95 mm Hg.

Microbial community has been a major part in the drug industry. They are known for their effectiveness and do not cause any undesirable effects. Exploitation of bacteria could be fruitful for mankind. Bacteria play a major role in producing useful bioactive compounds. HSV-1 infection causes 80% of oral lesions. A majority of the population is infected by at least one herpes subtype of HSV-1 before adulthood. The infection in some cases does not produce any symptoms. Drugs for HSV-1 are becoming suppressive. In the present study, isolation of endophytic bacteria was carried out from medicinal plant. A grown bacterium was identified and confirmed using molecular 16S rRNA sequencing followed by extraction of bioactive compounds using solvents. Twelve bioactive compounds were then investigated for in vitro cytotoxicity assay and in vitro antiviral assay. Chloroform extract was found to be effective in inhibiting the virus.

In this paper, we study the Schur geometric convexity (concavity) of the ratio of difference of means. Also established some inter related mean inequalities related to the ratio of difference of means.

Compounds isolated from members of the Zingiberaceae family are traditionally used as a medicine against inflammatory diseases, but little is known about the mechanism. Here, we report the isolation and structural identification of coronarin D [E-labda-8(17),12-diene-15-ol], a labdane-type diterpene, from Hedychium coronarium and delineate its mechanism of action. Because the transcription factor nuclear factor-κB (NF-κB) is a key mediator of inflammation, apoptosis, invasion, and osteoclastogenesis, we investigated the effect of coronarin D on NF-κB activation pathway, NF-κB-regulated gene products, and NF-κB-regulated cellular responses. The coronarin D inhibited NF-κB activation induced by different inflammatory stimuli and carcinogens. This labdane also suppressed constitutive NF-κB activity in different cell lines and inhibited IκBα kinase activation, thus leading to the suppression of IκBα phosphorylation, degradation, p65 nuclear translocation, and reporter gene transcription. Coronarin D also inhibited the NF-κB-regulated gene products involved in cell survival (inhibitor of apoptosis protein 1, Bcl-2, survivin, and tumor necrosis factor receptor-associated factor-2), proliferation (c-myc, cyclin D1, and cyclooxygenase-2), invasion (matrix metalloproteinase-9), and angiogenesis (vascular endothelial growth factor). Suppression of these gene products by the diterpene enhanced apoptosis induced by TNF and chemotherapeutic agents, suppressed TNF-induced cellular invasion, and abrogated receptor activator of NF-κB ligand-induced osteoclastogenesis. Coronarin D was found to be more potent than its analogue coronarin D acid. Overall, our results show that coronarin D inhibited NF-κB activation pathway, which leads to inhibition of inflammation, invasion, and osteoclastogenesis, as well as potentiation of apoptosis. [Mol Cancer Ther 2008;7(10):3306–17]

A zero voltage switched pulse width modulated series parallel resonant converter is presented in this paper. The performance of the converter for constant output voltage with the application of constant switching frequency but variable pulse width is analyzed. The converter operation is applied for motor load applications, where the load varies widely but the output voltage is fixed and is well regulated. Hence the speed of the motor is maintained constant.Experi-mental results are obtained to verify the theoretical results.

Concentration of airborne fungal spores inindoor and outdoor environments of a sawmill in Palakkad district of Kerala, India was studied with Burkard Personal Slide Sampler from January to December 1997. Total spore concentration in the indoor and outdoor showed a 3:2 ratio. Higher spore count was observed in indoor in January and in outdoor in October. Thirty three fungal spore types were identified from the indoor and twenty six from the outdoor. Aspergillus/Penicillium, Cladosporium, Nigrospora, Ganoderma, `other basidiospores' and ascospores were the dominant components of the airspora. Aspergillus/Penicillium, the most dominant spore type in the indoor contributed 51.19% and Cladosporium, the most dominant spore type in the outdoor contributed 44.75% of the total spores. The study revealed high prevalence of predominantly allergenic fungal spores in the sawmill environment.

Cognitive impairment is common among individuals diagnosed with autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). It has been suggested that some aspects of intelligence are preserved or even superior in people with ASD compared with controls, but consistent evidence is lacking. Few studies have examined the genetic overlap between cognitive ability and ASD/ADHD. The aim of this study was to examine the polygenic overlap between ASD/ADHD and cognitive ability in individuals from the general population. Polygenic risk for ADHD and ASD was calculated from genome-wide association studies of ASD and ADHD conducted by the Psychiatric Genetics Consortium. Risk scores were created in three independent cohorts: Generation Scotland Scottish Family Health Study (GS:SFHS) (n=9863), the Lothian Birth Cohorts 1936 and 1921 (n=1522), and the Brisbane Adolescent Twin Sample (BATS) (n=921). We report that polygenic risk for ASD is positively correlated with general cognitive ability (beta=0.07, P=6 × 10(-7), r(2)=0.003), logical memory and verbal intelligence in GS:SFHS. This was replicated in BATS as a positive association with full-scale intelligent quotient (IQ) (beta=0.07, P=0.03, r(2)=0.005). We did not find consistent evidence that polygenic risk for ADHD was associated with cognitive function; however, a negative correlation with IQ at age 11 years (beta=-0.08, Z=-3.3, P=0.001) was observed in the Lothian Birth Cohorts. These findings are in individuals from the general population, suggesting that the relationship between genetic risk for ASD and intelligence is partly independent of clinical state. These data suggest that common genetic variation relevant for ASD influences general cognitive ability.Molecular Psychiatry advance online publication, 10 March 2015; doi:10.1038/mp.2015.12.

BACKGROUND: Miscanthus×giganteus (M.×giganteus) is a potential source for bioethanol or other useful products. Pretreatment of lignocellulosic biomass is an essential step prior to enzymatic hydrolysis to sugars and fermentation to bioethanol. RESULTS: In this work, a one-step process uses aqueous ammonia with or without hydrogen peroxide; a proposed two-step process uses aqueous ammonia in the first step and hydrogen peroxide in the second step. In the two-step process, overall 89.5% lignin is removed. The pretreated biomass is followed by using cellulase and β-glucosidase to convert cellulose and hemicellulose from the recovered solid to fermentable sugars. The conversion of cellulose to glucose is 90.2% and to xylose is 73.4%. Characterization data are obtained for the recovered solid using scanning electron microscopy (SEM), attenuated total reflection-infrared spectroscopy (ATR-IR), and X-ray diffraction (XRD) for better understanding of the two-step process. CONCLUSION: Results from the two-step process using aqueous ammonia and hydrogen peroxide separately are much better than those from the one-step process for removing lignin and for enhancing conversion to sugars by enzymatic hydrolysis. © 2013 Society of Chemical Industry.

The primary objective was to evaluate the long-term safety of desvenlafaxine (administered as desvenlafaxine succinate) during open-label treatment in adult outpatients with a primary DSM-IV diagnosis of major depressive disorder (MDD).Depressed adult outpatients (≥ 18 years) who had completed 8-week, double-blind therapy (desvenlafaxine, venlafaxine extended release, or placebo) in a phase 3 study of desvenlafaxine for MDD received up to 10 months of open-label treatment with flexible-dose desvenlafaxine (200 to 400 mg/d). Safety assessments included physical examination, measurement of weight and vital signs, laboratory determinations, and 12-lead electrocardiogram recordings. Adverse events (AEs) and discontinuations due to AEs were monitored throughout the trial. The primary efficacy outcome was mean change from baseline on 17-item Hamilton Depression Rating Scale (HDRS-17) total score. The trial was conducted from August 2003 to March 2006.The safety population included 1,395 patients who took at least 1 dose of open-label desvenlafaxine. Treatment-emergent AEs were reported by 1,238 of 1,395 patients (89%) during the open-label, on-therapy period. Treatment-emergent AEs reported by 10% or more patients were headache, nausea, hyperhidrosis, dizziness, dry mouth, insomnia, upper respiratory infection, nasopharyngitis, and fatigue. Adverse events were the primary reason for study discontinuation in 296 of 1,395 patients (21%). Ten patients (1%) had serious AEs that were considered possibly, probably, or definitely related to the study drug during the on-therapy period. No deaths occurred during the study.Desvenlafaxine can be safely administered for up to 12 months. No new safety findings were observed in this study.clinicaltrials.gov Identifier: NCT01309542.

Spaceborne interferometric synthetic aperture radar (SAR) (InSAR) imaging has been used for over a decade to monitor tectonic movements and landslides, as well as to improve digital elevation models. However, InSAR is affected by variations in round-trip propagation delay due to changes in ionospheric total electron content and in tropospheric humidity and temperature along the signal path. One of the largest sources of uncertainty in estimates of tropospheric path delay is the spatial and temporal variability of water vapor density, which currently limits the quality of InSAR products. This problem can be partially addressed by using a number of SAR interferograms from subsequent satellite overpasses to reduce the degradation in the images or by analyzing a long time series of interferometric phases from permanent scatterers. However, if there is a sudden deformation of the Earth's surface, the detection of which is one of the principal objectives of InSAR measurements over land, the effect of water vapor variations cannot be removed, reducing the quality of the interferometric products. In those cases, high-resolution information on the atmospheric water vapor content and its variation with time can be crucial to mitigate the effect of wet-tropospheric path delay variations. This paper describes the use of a ground-based microwave radiometer network to retrieve 3-D water vapor density with fine spatial and temporal resolution, which can be used to reduce InSAR ambiguities due to changes in wet-tropospheric path delay. Retrieval results and comparisons between the integrated water vapor measured by the radiometer network and satellite data are presented.

TNF-related apoptosis-inducing ligand (TRAIL) shows promise as a cancer treatment, but acquired tumor resistance to TRAIL is a roadblock. Here we investigated whether nimbolide, a limonoid, could sensitize human colon cancer cells to TRAIL. As indicated by assays that measure esterase activity, sub-G(1) fractions, mitochondrial activity, and activation of caspases, nimbolide potentiated the effect of TRAIL. This limonoid also enhanced expression of death receptors (DRs) DR5 and DR4 in cancer cells. Gene silencing of the receptors reduced the effect of limonoid on TRAIL-induced apoptosis. Using pharmacological inhibitors, we found that activation of ERK and p38 MAPK was required for DR up-regulation by nimbolide. Gene silencing of ERK abolished the enhancement of TRAIL-induced apoptosis. Moreover, our studies indicate that the limonoid induced reactive oxygen species production, which was required for ERK activation, up-regulation of DRs, and sensitization to TRAIL; these effects were mimicked by H(2)O(2). In addition, nimbolide down-regulated cell survival proteins, including I-FLICE, cIAP-1, cIAP-2, Bcl-2, Bcl-xL, survivin, and X-linked inhibitor of apoptosis protein, and up-regulated the pro-apoptotic proteins p53 and Bax. Interestingly, p53 and Bax up-regulation by nimbolide was required for sensitization to TRAIL but not for DR up-regulation. Overall, our results indicate that nimbolide can sensitize colon cancer cells to TRAIL-induced apoptosis through three distinct mechanisms: reactive oxygen species- and ERK-mediated up-regulation of DR5 and DR4, down-regulation of cell survival proteins, and up-regulation of p53 and Bax.

Reverse pharmacology, also called the "bedside to bench" approach, that deals with new uses for a well known molecular entity has been used extensively in cancer drug development to identify novel compounds and delineate their mechanisms of action. Here, we show that nimbolide, a triterpenoid isolated from Azadirachta indica, enhanced the apoptosis induced by inflammatory cytokines and chemotherapeutic agents in tumor cells. This limonoid abrogated the expression of proteins associated with cell survival (Bcl-2, Bcl-xL, IAP-1, and IAP-2), proliferation (cyclin D1), invasion (MMP-9), and angiogenesis (VEGF), all regulated by nuclear factor (NF)-κB. Nimbolide inhibited the activation of NF-κB induced by carcinogens and inflammatory stimuli. Constitutively active NF-κB found in most tumor cells was also inhibited. We found that suppression of NF-κB activation by nimbolide was caused by inhibition of IκB kinase (IKK), which led to suppression of IκBα phosphorylation and degradation, nuclear translocation, DNA binding, and gene transcription. Reducing agent reversed the action of the limonoid, suggesting the involvement of a cysteine residue. Replacement of Cys(179) of IKK-β with alanine abolished the effect of nimbolide, suggesting that Cys(179) plays a critical role in inhibiting the NF-κB activation. Overall, our results indicate that nimbolide can sensitize tumor cells to chemotherapeutic agents through interaction with IKK, leading to inhibition of NF-κB-regulated proteins.

This paper presents the results of a pilot study on the marketing strategies followed by Indian exporters of engineering goods to three different foreign markets - American, British and German markets. These were studied within the framework provided by the Interaction model. The nature of the relationships between Indian exporters and their customers in the above country markets was investigated with the focus on the influence of such relationships on the marketing strategies adopted. Some of the unique problems encountered in conducting such research in a developing country environment are also discussed.

When the cartilage damages, sometimes the subchondral bone is involved becoming pathologically altered. An alternative therapeutic approach to surgery for osteochondral defect replacement may consist in the use of innovative scaffolds able to be colonized by cells in vivo. A key role in the scaffold colonization by cells is played by its vasculariza- tion. Aim of the present study is to develop a hydroxyapatite-collagen (HA-Coll) tubular scaffold with a radially oriented porosity in order to enhance the angiogenesis within the scaffold structure. HA crystals in collagen matrix composites 70wt% Coll - 30wt% HA were prepared by direct nucleation of HA using Ca(OH)2 and H3PO4 as calcium and phosphorus precursors; tubular scaffolds were produced by a spin-casting technique followed by a standard freeze-drying and dehydrothermal crosslinking. XRD and EDS spectrum revealed the for- mation of HA crystals on the collagen matrix. SEM analysis of tubular scaffold confirmed the formation of nano-sized apatite crystals on the fibrous collagen with radial oriented pores. FTIR diagram evidenced the chemical interaction between HA crystals and collagen. In vitro/in vivo tests have been used to evaluate the ability of the scaffolds to be colonized by cells, enhance angiogenesis, and sustain the osteo- chondral matrix formation.

This article 'Pathogenic Variability in Xanthomonas oryzae' appeared in the International Rice Research Newsletter series, created by the International Rice Research Institute (IRRI). The primary objective of this publication was to expedite communication among scientists concerned with the development of improved technology for rice and for rice based cropping systems. This publication will report what scientists are doing to increase the production of rice in as much as this crop feeds the most densely populated and land scarce nations in the world.

In the eighth chapter of his Aspects of the Novel, E.M.Forster considers "something which springs mainly out of the plot, and to which the characters and any other element present also contribute." Borrowing his terms from painting and music, Forster calls this aspect "pattern" and "rhythm". Forster's notions on pattern and rhythm are applied to his three major novels, The Longest Journey, Howards End and A Passage to India, in the thesis, to see how far his achievements matched his intentions. The results of the investigation are also seen in relation to the needs of the twentieth-century man, in particular, and, in general, to the needs of men at all times. Master of Arts (MA)

Citrus aurantifolia [C. aurantiifolia] (lime) tree is extensively cultivated in subtropical and tropical areas because of its edible fruits. The lime fruit and its juice are key ingredients in many drinks, confections, pickles and sauces. The flavour and bouquet of limeade and other lime-flavoured drinks are quite different from those prepared from lemons. Lime juice is largely used for citric acid production and is often used extensively for medicinal purposes with lemon juice. The most important quality of lime is its preservation ability. Lime essential oil is utilized for flavouring purposes, particularly in artificial lime juice cordials, which consist of mineral water and a sweetened solution of tartaric acid. This chapter discusses the chemical composition, uses (in food and medicine) and industrial products of lime.

Background: Potassium depletion by thiazide diuretics is associated with a rise in blood glucose. We assessed whether addition or substitution of a potassium-sparing diuretic, amiloride, to treatment with a thiazide can prevent glucose intolerance and improve blood pressure control. Methods: We did a parallel-group, randomised, double-blind trial in 11 secondary and two primary care sites in the UK. Eligible patients were aged 18-80 years; had clinic systolic blood pressure of 140 mm Hg or higher and home systolic blood pressure of 130 mmHg or higher on permitted background drugs of angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, β blockers, calcium-channel blockers, or direct renin inhibitors (previously untreated patients were also eligible in specific circumstances); and had at least one component of the metabolic syndrome in addition to hypertension. Patients with known diabetes were excluded. Patients were randomly assigned (1:1:1) to 24 weeks of daily oral treatment with starting doses of 10 mg amiloride, 25 mg hydrochlorothiazide, or 5 mg amiloride plus 12·5 mg hydrochlorothiazide; all doses were doubled after 12 weeks. Random assignment was done via a central computer system. Both participants and investigators were masked to assignment. Our hierarchical primary endpoints, assessed on a modified intention-to-treat basis at 12 and 24 weeks, were the differences from baseline in blood glucose measured 2 h after a 75 g oral glucose tolerance test (OGTT), compared first between the hydrochlorothiazide and amiloride groups, and then between the hydrochlorothiazide and combination groups. A key secondary endpoint was change in home systolic blood pressure at 12 and 24 weeks. This trial is registered with ClinicalTrials.gov, number NCT00797862, and the MHRA, Eudract number 2009-010068-41, and is now complete. Findings: Between Nov 18, 2009, and Dec 15, 2014, 145 patients were randomly assigned to amiloride, 146 to hydrochlorothiazide, and 150 to the combination group. 132 participants in the amiloride group, 134 in the hydrochlorothiazide group, and 133 in the combination group were included in the modified intention-to-treat analysis. 2 h glucose concentrations after OGTT, averaged at 12 and 24 weeks, were significantly lower in the amiloride group than in the hydrochlorothiazide group (mean difference -0·55 mmol/L [95% CI -0·96 to -0·14]; p=0·0093) and in the combination group than in the hydrochlorothiazide group (-0·42 mmol/L [-0·84 to -0·004]; p=0·048). The mean reduction in home systolic blood pressure during 24 weeks did not differ significantly between the amiloride and hydrochlorothiazide groups, but the fall in blood pressure in the combination group was significantly greater than that in the hydrochlorothiazide group (p=0·0068). Hyperkalaemia was reported in seven (4·8%) patients in the amiloride group and three (2·3%) patients in the combination group; the highest recorded potassium concentration was 5·8 mmol/L in a patient in the amiloride group. 13 serious adverse events occurred but the frequency did not differ significantly between groups. Interpretation: The combination of amiloride with hydrochlorothiazide, at doses equipotent on blood pressure, prevents glucose intolerance and improves control of blood pressure compared with montherapy with either drug. These findings, together with previous data about morbidity and mortality for the combination, support first-line use of amiloride plus hydrochlorothiazide in hypertensive patients who need treatment with a diuretic. Funding: British Heart Foundation and National Institute for Health Research.

In this paper, we give the definition of a Stolarsky type function, and obtain its monotonicity. By using these results, we establish a series of means and their monotonicities in n variables.