New tuberculosis vaccines: advances in clinical development and modelling.

Tuberculosis remains a major source of morbidity and mortality worldwide, with 10 million cases and 1.5 million deaths in 2018. Achieving 'End TB' prevention and care goals by 2035 will likely require a new tuberculosis vaccine. The tuberculosis vaccine development pipeline has seen encouraging progress; however, questions around their population impact and implementation remain. Mathematical modelling investigates these questions to inform vaccine development and deployment strategies. We provide an update on the current vaccine development pipeline, and a systematic literature review of mathematical modelling of the epidemiological impact of new tuberculosis vaccines. Fourteen prophylactic tuberculosis vaccine candidates are currently in clinical trials. Two candidates have shown promise in phase II proof-of-concept efficacy trials: M72/AS01E demonstrated 49.7% (95% CI; 2.1, 74.2) protection against tuberculosis disease, and BCG revaccination demonstrated 45.4% (95% CI; 6.4, 68.1) protection against sustained Mycobacterium tuberculosis infection. Since the last modelling review, new studies have investigated the epidemiological impact of differential vaccine characteristics, age targeting and spatial/risk group targeting. Critical research priorities for M72/AS01E include completing the currently in-design trial, powered to improve the precision of efficacy estimates, include uninfected populations and further assess safety and immunogenicity in HIV-infected people. For BCG revaccination, the priority is completing the ongoing confirmation of efficacy trial. Critical modelling gaps remain on the full value proposition of vaccines, comparisons with other interventions and more realistic implementation strategies. Using carefully designed trials and modelling, we must prepare for success, to ensure that new vaccines will be promptly received by those most in need.

Stress and coping in fourth-year medical and dental students.

UNLABELLED: Medicine and dentistry are stressful professions. Dental and medical students suffer high levels of stress and may experience adverse psychological symptoms and use dysfunctional coping mechanisms. AIM: To investigate levels and sources of stress, anger, anxiety and sadness, and associated coping mechanisms, in fourth-year dental and medical students. METHODS: A link to an online questionnaire was emailed to all fourth-year dental and medical students at the University of Otago, in Dunedin (New Zealand). RESULTS: The response rate was 60.2% (N = 100). The majority of students (58.6%) reported frequently feeling stressed. More dental than medical students reported always feeling stressed, but a greater proportion of medical students reported not coping well with stress, suffering abnormal anxiety, anger and sadness, and having these feelings for prolonged periods. Destructive coping mechanisms were more common among dental students, while positive coping mechanisms were also used by both groups. Few students (13.5%) reported using professional counselling services during their undergraduate years. CONCLUSIONS: Mental stability is indispensable for the compassionate, professional and competent delivery of care by health professionals. The high prevalence of detrimental emotions and adverse mental states reported by students before they enter the health workforce is alarming and needs to be addressed.

Developing Demonstration Test Catchments as a platform for transdisciplinary land management research in England and Wales.

Whilst a large body of plot and field-scale research exists on the sources, behaviour and mitigation of diffuse water pollution from agriculture, putting this evidence into a practical, context at large spatial scales to inform policy remains challenging. Understanding the behaviour of pollutants (nutrients, sediment, microbes and pesticides) and the effectiveness of mitigation strategies over whole catchments and long timeframes requires new, interdisciplinary approaches to organise and undertake research. This paper provides an introduction to the demonstration test catchments (DTC) programme, which was established in 2009 to gather empirical evidence on the cost-effectiveness of combinations of diffuse pollution mitigation measures at catchment scales. DTC firstly provides a physical platform of instrumented study catchments in which approaches for the mitigation of diffuse agricultural water pollution can be experimentally tested and iteratively improved. Secondly, it has established national and local knowledge exchange networks between researchers and stakeholders through which research has been co-designed. These have provided a vehicle to disseminate emerging findings to inform policy and land management practice. The role of DTC is that of an outdoor laboratory to develop knowledge and approaches that can be applied in less well studied locations. The research platform approach developed through DTC has brought together disparate research groups from different disciplines and institutions through nationally coordinated activities. It offers a model that can be adopted to organise research on other complex, interdisciplinary problems to inform policy and operational decision-making.

Determinants of muscle carnosine content.

The main determinant of muscle carnosine (M-Carn) content is undoubtedly species, with, for example, aerobically trained female vegetarian athletes [with circa 13 mmol/kg dry muscle (dm)] having just 1/10th of that found in trained thoroughbred horses. Muscle fibre type is another key determinant, as type II fibres have a higher M-Carn or muscle histidine containing dipeptide (M-HCD) content than type I fibres. In vegetarians, M-Carn is limited by hepatic synthesis of ß-alanine, whereas in omnivores this is augmented by the hydrolysis of dietary supplied HCD's resulting in muscle levels two or more times higher. ß-alanine supplementation will increase M-Carn. The same increase in M-Carn occurs with administration of an equal molar quantity of carnosine as an alternative source of ß-alanine. Following the cessation of supplementation, M-Carn returns to pre-supplementation levels, with an estimated t1/2 of 5-9 weeks. Higher than normal M-Carn contents have been noted in some chronically weight-trained subjects, but it is unclear if this is due to the training per se, or secondary to changes in muscle fibre composition, an increase in ß-alanine intake or even anabolic steroid use. There is no measureable loss of M-Carn with acute exercise, although exercise-induced muscle damage may result in raised plasma concentrations in equines. Animal studies indicate effects of gender and age, but human studies lack sufficient control of the effects of diet and changes in muscle fibre composition.

Effects of ß-alanine supplementation on exercise performance: a meta-analysis.

Due to the well-defined role of ß-alanine as a substrate of carnosine (a major contributor to H+ buffering during high-intensity exercise), ß-alanine is fast becoming a popular ergogenic aid to sports performance. There have been several recent qualitative review articles published on the topic, and here we present a preliminary quantitative review of the literature through a meta-analysis. A comprehensive search of the literature was employed to identify all studies suitable for inclusion in the analysis; strict exclusion criteria were also applied. Fifteen published manuscripts were included in the analysis, which reported the results of 57 measures within 23 exercise tests, using 18 supplementation regimes and a total of 360 participants [174, ß-alanine supplementation group (BA) and 186, placebo supplementation group (Pla)]. BA improved (P=0.002) the outcome of exercise measures to a greater extent than Pla [median effect size (IQR): BA 0.374 (0.140-0.747), Pla 0.108 (-0.019 to 0.487)]. Some of that effect might be explained by the improvement (P=0.013) in exercise capacity with BA compared to Pla; no improvement was seen for exercise performance (P=0.204). In line with the purported mechanisms for an ergogenic effect of ß-alanine supplementation, exercise lasting 60-240 s was improved (P=0.001) in BA compared to Pla, as was exercise of >240 s (P=0.046). In contrast, there was no benefit of ß-alanine on exercise lasting <60 s (P=0.312). The median effect of ß-alanine supplementation is a 2.85% (-0.37 to 10.49%) improvement in the outcome of an exercise measure, when a median total of 179 g of ß-alanine is supplemented.

Claudin-2 expression increases tumorigenicity of colon cancer cells: role of epidermal growth factor receptor activation.

Claudin-2 is a unique member of the claudin family of transmembrane proteins, as its expression is restricted to the leaky epithelium in vivo and correlates with epithelial leakiness in vitro. However, recent evidence suggests potential functions of claudin-2 that are relevant to neoplastic transformation and growth. In accordance, here we report, on the basis of analysis of mRNA and protein expression using a total of 309 patient samples that claudin-2 expression is significantly increased in colorectal cancer and correlates with cancer progression. We also report similar increases in claudin-2 expression in inflammatory bowel disease-associated colorectal cancer. Most importantly, we demonstrate that the increased claudin-2 expression in colorectal cancer is causally associated with tumor growth as forced claudin-2 expression in colon cancer cells that do not express claudin-2 resulted in significant increases in cell proliferation, anchorage-independent growth and tumor growth in vivo. We further show that the colonic microenvironment regulates claudin-2 expression in a manner dependent on signaling through the EGF receptor (EGFR), a key regulator of colon tumorigenesis. In addition, claudin-2 expression is specifically decreased in the colon of waved-2 mice, naturally deficient in EGFR activation. Furthermore, genetic silencing of claudin-2 expression in Caco-2, a colon cancer cell line, prevents the EGF-induced increase in cell proliferation. Taken together, these results uncover a novel role for claudin-2 in promoting colon cancer, potentially via EGFR transactivation.

Control of lipid oxidation during exercise: role of energy state and mitochondrial factors.

Despite considerable progress during recent years our understanding of how lipid oxidation (LOx) is controlled during exercise remains incomplete. This review focuses on the role of mitochondria and energy state in the control of LOx. LOx increases in parallel with increased energy demand up to an exercise intensity of about 50-60% of VO(2max) after which the contribution of lipid decreases. The switch from lipid to carbohydrate (CHO) is of energetic advantage due to the increased ATP/O(2) yield. In the low-intensity domain (<50%VO(2max)) a moderate reduction in energy state will stimulate both LOx and CHO oxidation and relative fuel utilization is mainly controlled by substrate availability and the capacity of the metabolic pathways. In the high-intensity domain (>60%VO(2max)) there is a pronounced decrease in energy state, which will stimulate glycolysis in excess of the substrate requirements of the oxidative processes. This will lead to acidosis, reduced levels of free Coenzyme A (CoASH) and reduced levels of free carnitine. Acidosis and reduced carnitine may limit the carnitine-mediated transfer of long-chain fatty acids (LCFA) into mitochondria and may thus explain the observed reduction in LOx during high-intensity exercise. Another potential mechanism, suggested in this review, is that Acyl-CoA synthetase (ACS), an initial step in LCFA catabolism, functions as a regulator of LOx. ACS activity is suggested to be under control of CoASH and energy state. Furthermore, evidence exists that additional control points exist beyond mitochondrial FA influx. The nature and site of this control remain to be investigated.

Influence of beta-alanine supplementation on skeletal muscle carnosine concentrations and high intensity cycling capacity.

Muscle carnosine synthesis is limited by the availability of beta-alanine. Thirteen male subjects were supplemented with beta-alanine (CarnoSyn) for 4 wks, 8 of these for 10 wks. A biopsy of the vastus lateralis was obtained from 6 of the 8 at 0, 4 and 10 wks. Subjects undertook a cycle capacity test to determine total work done (TWD) at 110% (CCT(110%)) of their maximum power (Wmax). Twelve matched subjects received a placebo. Eleven of these completed the CCT(110%) at 0 and 4 wks, and 8, 10 wks. Muscle biopsies were obtained from 5 of the 8 and one additional subject. Muscle carnosine was significantly increased by +58.8% and +80.1% after 4 and 10 wks beta-alanine supplementation. Carnosine, initially 1.71 times higher in type IIa fibres, increased equally in both type I and IIa fibres. No increase was seen in control subjects. Taurine was unchanged by 10 wks of supplementation. 4 wks beta-alanine supplementation resulted in a significant increase in TWD (+13.0%); with a further +3.2% increase at 10 wks. TWD was unchanged at 4 and 10 wks in the control subjects. The increase in TWD with supplementation followed the increase in muscle carnosine.

Creatine supplementation, sleep deprivation, cortisol, melatonin and behavior.

The effect of creatine supplementation and sleep deprivation, with intermittent moderate-intensity exercise, on cognitive and psychomotor performance, mood state, effort and salivary concentrations of cortisol and melatonin were examined. Subjects were divided into a creatine supplementation group and a placebo group. They took 5 g of creatine monohydrate or a placebo, dependent on their group, four times a day for 7 days immediately prior to the experiment. They undertook tests examining central executive functioning, short-term memory, choice reaction time, balance, mood state and effort at baseline and following 18-, 24- and 36-h sleep deprivation, with moderate intermittent exercise. Saliva samples were taken prior to each set of tests. A group x time analysis of covariance, with baseline performance the covariate, showed that the creatine group performed significantly (p < 0.05) better than the placebo group on the central executive task but only at 36 h. The creatine group demonstrated a significant (p < 0.01) linear improvement in performance of the central executive task throughout the experiment, while the placebo group showed no significant effects. There were no significant differences between the groups for any of the other variables. A significant (p < 0.001) main effect of time was found for the balance test with a linear improvement being registered. Cortisol concentrations on Day 1 were significantly (p < 0.01) higher than on Day 2. Mood significantly (p < 0.001) deteriorated up to 24 h with no change from 24 to 36 h. Effort at baseline was significantly (p < 0.01) lower than in the other conditions. It was concluded that, during sleep deprivation with moderate-intensity exercise, creatine supplementation only affects performance of complex central executive tasks.

Effects of beta-alanine supplementation on the onset of neuromuscular fatigue and ventilatory threshold in women.

This study examined the effects of 28 days of beta-alanine supplementation on the physical working capacity at fatigue threshold (PWCFT), ventilatory threshold (VT), maximal oxygen consumption (VO2-MAX), and time-to-exhaustion (TTE) in women. Twenty-two women (age+/-SD 27.4+/-6.1 yrs) participated and were randomly assigned to either the beta-alanine (CarnoSyn) or Placebo (PL) group. Before (pre) and after (post) the supplementation period, participants performed a continuous, incremental cycle ergometry test to exhaustion to determine the PWCFT, VT, VO2-MAX, and TTE. There was a 13.9, 12.6 and 2.5% increase (p<0.05) in VT, PWCFT, and TTE, respectively, for the beta-alanine group, with no changes in the PL (p>0.05). There were no changes for VO2-MAX (p>0.05) in either group. Results of this study indicate that beta-alanine supplementation delays the onset of neuromuscular fatigue (PWCFT) and the ventilatory threshold (VT) at submaximal workloads, and increase in TTE during maximal cycle ergometry performance. However, beta-alanine supplementation did not affect maximal aerobic power (VO2-MAX). In conclusion, beta-alanine supplementation appears to improve submaximal cycle ergometry performance and TTE in young women, perhaps as a result of an increased buffering capacity due to elevated muscle carnosine concentrations.

The absorption of orally supplied beta-alanine and its effect on muscle carnosine synthesis in human vastus lateralis.

Beta-alanine in blood-plasma when administered as A) histidine dipeptides (equivalent to 40 mg . kg(-1) bwt of beta-alanine) in chicken broth, or B) 10, C) 20 and D) 40 mg . kg(-1) bwt beta-alanine (CarnoSyn, NAI, USA), peaked at 428 +/- SE 66, 47 +/- 13, 374 +/- 68 and 833 +/- 43 microM. Concentrations regained baseline at 2 h. Carnosine was not detected in plasma with A) although traces of this and anserine were found in urine. Loss of beta-alanine in urine with B) to D) was <5%. Plasma taurine was increased by beta-alanine ingestion but this did not result in any increased loss via urine. Pharmacodynamics were further investigated with 3 x B) per day given for 15 d. Dietary supplementation with I) 3.2 and II) 6.4 g . d(-1) beta-alanine (as multiple doses of 400 or 800 mg) or III) L-carnosine (isomolar to II) for 4 w resulted in significant increases in muscle carnosine estimated at 42.1, 64.2 and 65.8%.

Metabolic and physiological effects of ingesting extracts of bitter orange, green tea and guarana at rest and during treadmill walking in overweight males.

OBJECTIVE: This study examined the acute effects of ingesting a widely used commercial formula containing extracts of bitter orange, green tea and guarana (Gx) on the metabolic rate and substrate utilisation in overweight, adult males at rest (study 1) and during treadmill walking (study 2). SUBJECTS: Two different groups of 10 sedentary males with more than 20% body fat participated in studies 1 and 2. DESIGN: In each study, subjects participated in two experimental trials during which they were given two 500 mg capsules containing either Gx or a placebo (P) in a counterbalanced double-blind manner. Doses of the main active ingredients were 6 mg of synephrine, 150 mg caffeine and 150 mg catechin polyphenols. MEASUREMENTS: In study 1, subjects completed 7 h supine rest with baseline measures taken during the first hour, with expired gases, blood pressure, heart rate and venous blood being collected every 30 min for the remaining 6 h following ingestion of Gx or P. In study 2, subjects exercised for 60 min at 60% heart rate reserve following ingestion of Gx or P 1 h previously. Venous blood samples were collected twice at rest and at 5, 10, 15, 20, 30, 40, 50 and 60 min, with expired gas measurements taken at 4, 9, 14, 19, 29, 39, 49 and 59 min. In both studies, venous blood was analysed for NEFA, glycerol, glucose and lactate concentrations, while expired gases were used to calculate ATP production from carbohydrate and NEFA, as well as the total substrate utilised. RESULTS AND CONCLUSION: The results did not show any significant effect of Gx ingestion on total ATP utilisation during 6 h rest or during 60 min treadmill walking. Changes were observed in the relative contributions of CHO and NEFA oxidation to ATP production in both studies, such that there was an increase in ATP production from CHO and a decrease from NEFA. The increase in CHO oxidation was shown to be as high as 30% at rest.

Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol.

RATIONALE: Sleep deprivation has a negative effect on cognitive and psychomotor performance and mood state, partially due to decreases in creatine levels in the brain. Therefore, creatine supplementation should lessen the negative effects of sleep deprivation. OBJECTIVES: The objective of this study was to examine the effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol. METHOD: Subjects were divided into a creatine group (n=10) and a placebo group (n=9). They took 5 g of creatine monohydrate or a placebo, dependent on their group, four times a time a day for 7 days, immediately prior to the experiment. The study was double blind. Subjects undertook tests of random movement generation (RMG), verbal and spatial recall, choice reaction time, static balance and mood state pre-test (0 h), after 6, 12 and 24 h of sleep deprivation, with intermittent exercise. They were tested for plasma concentrations of catecholamines and cortisol at 0 and 24 h. RESULTS: At 24 h, the creatine group demonstrated significantly less change in performance from 0 h (delta) in RMG, choice reaction time, balance and mood state. There were no significant differences between groups in plasma concentrations of catecholamines and cortisol. Norepinephrine and dopamine concentrations were significantly higher at 24 h than 0 h, but cortisol were lower. CONCLUSIONS: Following 24-h sleep deprivation, creatine supplementation had a positive effect on mood state and tasks that place a heavy stress on the prefrontal cortex.

Plasma glutamine concentrations in the horse following feeding and oral glutamine supplementation.

REASONS FOR PERFORMING STUDY: Pharmacological benefits of glutamine supplementation have been shown in athletically and clinically stressed human subjects. In the horse, infection and intense exercise have also been shown to significantly decrease plasma glutamine concentrations, but little is known on how best to supplement. OBJECTIVE: To evaluate whether ingestion of different foodstuffs, with or without L-glutamine (G) or a peptide (Pep) containing 31.5% w/w G in a water-stable form, could affect plasma glutamine concentrations (P-GC). MATERIALS AND METHODS: Nine feeds (molassed sugar beet-pulp (mSB); naked oats (nO); commercial mix (CM); mSB with 30 or 60 mg/kg bwt G or the G-molar equivalent of Pep; and CM with 60 mg/kg bwt G or equivalent Pep) were offered to 6 healthy mature horses on different days following overnight food restriction. The changes in P-GC were monitored for 8 h post feeding. RESULTS: After 1.5 h mean +/- s.d. AP-GC were -0.9 +/- 10.2% (mSB), +12.5 +/- 7.1% (nO) and +44.7 +/- 15.9% (CM; P<0.05). deltaP-GC with mSB supplemented with G was +60.9 +/- 30.0% (30 mg; P<0.05) and +156.8 +/- 34.6% (60 mg; P<0.05) at 1 h; deltaP-GC with Pep was 51.0 +/- 31.0% (30 mg equivalent, P<0.05) and +91.1 +/- 9.5% (60 mg equivalent, P<0.05) at 1 h. After 10 days of supplementation with 60 mg/kg bwt G, AP-GC following a further 60 mg/kg bwt G challenge showed a similar increase at 1 h of +154.3 +/- 37.9%; prevalues were unchanged. G and Pep added to CM, increased P-GC by 246.3 +/- 55.3 (+99.2%) and 252.3 +/- 94.2 micromol/l (96.7%) at 1.5 h with concentrations still above prevalues at 8 h (P<0.05). Apart from the CM (with or without supplement), pre P-GC was always regained by 4 h. Plasma NH3 and plasma protein concentrations were unaffected by supplementation with G or Pep. CONCLUSION: P-GC may be modified by appropriate supplementation with no apparent adverse effects. POTENTIAL RELEVANCE: Increasing P-GC through appropriate supplementation may be of benefit in the athletically or clinically stressed horse with lowered plasma glutamine concentrations.

Renal effects of non-steroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors.

Nonsteroidal antiinflammatory drugs (NSAID) are one of the most commonly used medications worldwide to inhibiting COX activity for the treatment of pain and inflammation. Their nephrotoxicity has been well documented. With the development and clinical implementation of new COX-2 inhibitors, the safety, including the effects on renal function and blood pressure, is attracting increasing attention. In the kidney, COX-2 is constitutively expressed and is highly regulated in response to alterations in intravascular volume. COX-2 metabolites have been implicated in mediation of renin release, regulation of sodium excretion and maintenance of renal blood flow. Similar to conventional NSAIDs, inhibition of COX-2 may cause edema and modest elevations in blood pressure in a minority of subjects. COX-2 inhibitors may also exacerbate preexisting hypertension or interfere with other antihypertensive drugs. Occasional acute renal failure has also been reported. Caution should be taken when COX-2 inhibitors are prescribed, especially in high-risk patients (including elderly and patients with volume depletion). Recently, agents with combined lipooxygenase/COX inhibition and agents that combine NSAIDs with a nitric oxide (NO) donor have been reported to reduce adverse renal effects.

Cyclooxygenase-2 and the renal renin-angiotensin system.

In the kidney, cyclooxygenase-2 (COX-2) is expressed in the macula densa/cTALH and medullary interstitial cells. The macula densa is involved in regulating afferent arteriolar tone and renin release by sensing alterations in luminal chloride via changes in the rate of Na(+)/K(+)/2Cl(-) cotransport, and administration of non-specific cyclooxygenase inhibitors will blunt increases in renin release mediated by macula densa sensing of decreases in luminal NaCl. High renin states [salt deficiency, angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers, diuretic administration or experimental renovascular hypertension] are associated with increased macula densa/cTALH COX-2 expression. Furthermore, there is evidence that angiotensin II and/or aldosterone may inhibit COX-2 expression. In AT1 receptor knockout mice, COX-2 expression is increased similar to increases with ACE inhibitors or AT1 receptor blockers. Direct administration of angiotensin II inhibits macula densa COX-2 expression. Previous studies demonstrated that alterations in intraluminal chloride concentration are the signal for macula densa regulation of tubuloglomerular feedback and renin secretion, with high chloride stimulating tubuloglomerular feedback and low chloride stimulating renin release. When cultured cTALH or macula densa cells were incubated in media with selective substitution of chloride ions, COX-2 expression and prostaglandin production were significantly increased. A variety of studies have indicated a role for COX-2 in the macula densa mediation of renin release. In isolated perfused glomerular preparations, renin release induced by macula densa perfusion with a low chloride solution was inhibited by a COX-2 inhibitor but not a COX-1 inhibitor. In vivo studies in rats indicated that increased renin release in response to low-salt diet, ACE inhibitor, loop diuretics or aortic coarctation could be inhibited by administration of COX-2-selective inhibitors. In mice with genetic deletion of COX-2, ACE inhibitors or low-salt diet failed to increase renal renin expression, although renin significantly increased in wild type mice. In contrast, in COX-1 null mice there were no significant differences in either the basal or ACE inhibitor-stimulated level of renal renin activity from plasma or renal tissue compared with wild type mice. In summary, there is increasing evidence that COX-2 expression in the macula densa and surrounding cortical thick ascending limb cells is regulated by angiotensin II and is a modulator of renal renin production. These interactions of COX-2 derived prostaglandins and the renin-angiotensin system may underlie physiological and pathophysiological regulation of renal function.

Interactions between COX-2 and the renin-angiotensin system in the kidney.

AIM: In adult mammalian kidney, COX-2 expression is found in a restricted subpopulation of cells. The two sites of renal COX-2 localization detected in all species to date are the macula densa (MD) and associated cortical thick ascending limb cells (cTALH) and medullary interstitial cells. Physiological regulation of COX-2 in these cellular compartments suggests functional roles for eicosanoid products of the enzyme. In the MD region, COX-2 expression increases in high renin states [salt restriction, angiotensin converting enzyme (ACE) inhibition, renovascular hypertension], and selective COX-2 inhibitors significantly decrease plasma renin levels and renal renin activity and mRNA expression. An important role for COX-2-derived prostanoids in regulation of renin expression and secretion has also been determined by using mice with selective genetic deletion of either the COX-1 or COX-2 gene. There is evidence for negative regulation of MD/cTALH COX-2 by angiotensin II and by glucocorticoids and mineralocorticoids, suggesting that in the kidney, cortical COX-2 expression is regulated in part by alterations in activity of the renin-angiotensin system.