A divergent transcriptional landscape underpins the development and functional branching of MAIT cells.

MR1-restricted mucosal-associated invariant T (MAIT) cells play a unique role in the immune system. These cells develop intrathymically through a three-stage process, but the events that regulate this are largely unknown. Here, using bulk and single-cell RNA sequencing-based transcriptomic analysis in mice and humans, we studied the changing transcriptional landscape that accompanies transition through each stage. Many transcripts were sharply modulated during MAIT cell development, including SLAM (signaling lymphocytic activation molecule) family members, chemokine receptors, and transcription factors. We also demonstrate that stage 3 "mature" MAIT cells comprise distinct subpopulations including newly arrived transitional stage 3 cells, interferon-γ-producing MAIT1 cells and interleukin-17-producing MAIT17 cells. Moreover, the validity and importance of several transcripts detected in this study are directly demonstrated using specific mutant mice. For example, MAIT cell intrathymic maturation was found to be halted in SLAM-associated protein (SAP)-deficient and CXCR6-deficient mouse models, providing clear evidence for their role in modulating MAIT cell development. These data underpin a model that maps the changing transcriptional landscape and identifies key factors that regulate the process of MAIT cell differentiation, with many parallels between mice and humans.

Innate lymphoid cells: models of plasticity for immune homeostasis and rapid responsiveness in protection.

Innate lymphoid cells (ILCs) have stormed onto the immune landscape as "newly discovered" cell types. These tissue-resident sentinels are enriched at mucosal surfaces and engage in complex cross talk with elements of the adaptive immune system and microenvironment to orchestrate immune homeostasis. Many parallels exist between innate cells and T cells leading to the initial partitioning of ILCs into rather rigid subsets that reflect their "adaptive-like" effector cytokines profiles. ILCs themselves, however, have unique attributes that are only just beginning to be elucidated. These features result in complementarity with, rather than complete duplication of, functions of the adaptive immune system. Key transcription factors determine the pathway of differentiation of progenitors towards an ILC1, ILC2, or ILC3 subset. Once formed, flexibility in the responses of these subsets to stimuli unexpectedly allows transdifferentation between the different subsets and the acquisition of altered phenotypes and function. This provides a mechanism for rapid innate immune responsiveness. Here, we discuss the models of differentiation for maintenance and activation of tissue-resident ILCs in maintaining immune homeostasis and protection.

Granzyme M has a critical role in providing innate immune protection in ulcerative colitis.

Inflammatory bowel disease (IBD) is an immunoregulatory disorder, associated with a chronic and inappropriate mucosal immune response to commensal bacteria, underlying disease states such as ulcerative colitis (UC) and Crohn's disease (CD) in humans. Granzyme M (GrzM) is a serine protease expressed by cytotoxic lymphocytes, in particular natural killer (NK) cells. Granzymes are thought to be involved in triggering cell death in eukaryotic target cells; however, some evidence supports their role in inflammation. The role of GrzM in the innate immune response to mucosal inflammation has never been examined. Here, we discover that patients with UC, unlike patients with CD, display high levels of GrzM mRNA expression in the inflamed colon. By taking advantage of well-established models of experimental UC, we revealed that GrzM-deficient mice have greater levels of inflammatory indicators during dextran sulfate sodium (DSS)-induced IBD, including increased weight loss, greater colon length reduction and more severe intestinal histopathology. The absence of GrzM expression also had effects on gut permeability, tissue cytokine/chemokine dynamics, and neutrophil infiltration during disease. These findings demonstrate, for the first time, that GrzM has a critical role during early stages of inflammation in UC, and that in its absence colonic inflammation is enhanced.

CD3bright signals on γδ T cells identify IL-17A-producing Vγ6Vδ1+ T cells.

Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that has an important role at mucosal sites in a wide range of immune responses including infection, allergy and auto-immunity. γδ T cells are recognized as IL-17 producers, but based on the level of CD3 expression, we now define the remarkable ability of a CD3(bright) γδ T-cell subset with an effector memory phenotype to rapidly produce IL-17A, but not interferon-γ. CD3(bright) γδ T cells uniformly express the canonical germline encoded Vγ6/Vδ1(+) T-cell receptor. They are widely distributed with a preferential representation in the lungs and skin are negatively impacted in the absence of retinoic acid receptor-related orphan receptor gammat expression or endogenous flora. This population responded rapidly to various stimuli in a mechanism involving IL-23 and NOD-like receptor family, pyrin domain containing 3 (NLRP3)-inflammasome-dependent IL-1ß. Finally, we demonstrated that IL-17-producing CD3(bright) γδ T cells responded promptly and strongly to pneumococcal infection and during skin inflammation. Here, we propose a new way to specifically analyze IL-17-producing Vγ6/Vδ1(+) T cells based on the level of CD3 signals. Using this gating strategy, our data reinforce the crucial role of this γδ T-cell subset in respiratory and skin disorders.

IL-17-producing NKT cells depend exclusively on IL-7 for homeostasis and survival.

Natural killer T (NKT) cells are innate-like T cells that rapidly recognize pathogens and produce cytokines that shape the ensuing immune response. IL-17-producing NKT cells are enriched in barrier tissues, such as the lung, skin, and peripheral lymph nodes, and the factors that maintain this population in the periphery have not been elucidated. Here we show that NKT17 cells deviate from other NKT cells in their survival requirements. In contrast to conventional NKT cells that are maintained by IL-15, RORγt(+) NKT cells are IL-15 independent and instead rely completely on IL-7. IL-7 initiates a T-cell receptor-independent (TCR-independent) expansion of NKT17 cells, thus supporting their homeostasis. Without IL-7, survival is dramatically impaired, yet residual cells remain lineage committed with no downregulation of RORγt evident. Their preferential response to IL-7 does not reflect enhanced signaling through STAT proteins, but instead is modulated via the PI3K/AKT/mTOR signaling pathway. The ability to compete for IL-7 is dependent on high-density IL-7 receptor expression, which would promote uptake of low levels of IL-7 produced in the non-lymphoid sites of lung and skin. This dependence on IL-7 is also reported for RORγt(+) innate lymphoid cells and CD4(+) Th17 cells, and suggests common survival requirements for functionally similar cells.

[Moderate wine consumption and prevention of coronary heart disease]. / Moderater Weingenuss und Prävention der koronaren Herzkrankheit.

Moderate alcohol consumption and in particular wine consumption, is associated with a significant reduction in cardiovascular morbidity and mortality in epidemiological studies. Although no randomized placebo-controlled studies with wine intervention exist - and will probably never exist - the observed association can be interpreted as causal due to the existing high biological plausibility. There is more and more evidence that ethanol per se contributes to the most relevant preventive effects. When consumed in moderation the health benefits outweigh the health risks. Whether and to what extend the numerous plant compounds of wine (polyphenolic substances) can provide additional health benefits is still under investigation.

[Vitamin D for prevention of diseases?]. / Vitamin D zur Prävention von Erkrankungen?

Vitamin D3 shows a multitude of possible preventive effects in various diseases. Calcitriol, the biologically active form of vitamin D3, affects not only bone metabolism but also acts on the renal renin secretion, the pancreatic insulin production in the beta cells, growth and proliferation of smooth and cardiac muscle cells and the function of lymphocytes and macrophages. Although the human body can synthesise vitamin D3 itself, vitamin D deficiency is common in the German population. Numerous trials studied the association between vitamin D deficiency and different diseases. It is known that even mild forms of vitamin D deficiency increase the risk for cardiovascular diseases or diabetes mellitus. Furthermore, an association with cancer such as pancreatic or colorectal cancer was observed. This is attributed to the influence of vitamin D on cell differentiation, angiogenesis, DNA repair mechanisms and the transcription of numerous genes. In addition, effects of vitamin D deficiency in diseases such as Parkinson's disease, multiple sclerosis and autoimmune diseases are discussed. However, up to now the level of evidence of all these observations is low. There are missing confirmatory randomized controlled trials. Noting the possible preventive effects of vitamin D, a moderate exposure to sunlight to increase vitamin D synthesis can be recommended. Even a controlled supplementation of vitamin D in patients with vitamin D deficiency is considered as reasonable. However, an uncritical substitution of high-dose vitamin D should be avoided because of the risk of hypercalcaemia.

[Cacoa and dark chocolate in cardiovascular prevention?]. / Kakao und dunkle Schokolade zur kardiovaskulären Prävention?

It has been shown that the consumption of cocoa has a positive influence on a number of cardiovascular surrogate parameters such as arterial vasodilatation and a moderate decrease in blood pressure in humans. In the blood, a decrease in platelet aggregation and an increase in angiogenetic progenitor cells was noted. Furthermore, anti-inflammatory effects, an amelioration of the lipid profile and glucose metabolism was described. An increase of endothelial NO production following the ingestion of the antioxidant cocoa flavanols catechin and epicatechin seems to be the leading mechanism causing these effects. In animal studies of myocardial reperfusion, a decrease in infarct size was noted. In several prospective cohort studies from Europe and the United States, a 50 % reduction of mortality mostly due to a reduction of myocardial infarction was published. Consumption up to about 25 g daily of a flavanol rich dark chocolate (ca. 85 % cocoa content) can be recommended for cardiovascular prevention. In this moderate dosage, the potentially harmful effects due to weight gain and cadmium intake will be minimal. However, controlled randomized trials with well defined clinical endpoints are needed to prove the positive effects described so far. At this point, in time based on the information described in this article, a moderate consumption of flavanol rich cocoa products seems to be effective in the prevention of coronary artery disease and myocardial infarction.

Camphor-Crataegus berry extract combination dose-dependently reduces tilt induced fall in blood pressure in orthostatic hypotension.

In order to test the efficacy of a combination of natural D-camphor and an extract of fresh crataegus berries (Korodin Herz-Kreislauf-Tropfen) on orthostatic hypotension, two similar, controlled, randomized studies were carried out in a balanced crossover design in 24 patients each with orthostatic dysregulation. The camphor-crataegus berry combination (CCC) was orally administered as a single regimen in 3 different dosages of 5 drops, 20 drops and 80 drops; a placebo with 20 drops of a 60% alcoholic solution served as control. Orthostatic hypotension was assessed with the tilt table test before and after medication. Source data of both studies were pooled and meta-analytically evaluated for all 48 patients. CCC drops decreased the orthostatic fall in blood pressure versus placebo, as almost uniformly established at all times by mean arterial pressure and diastolic blood pressure. Mean arterial pressure demonstrated the very fast onset of action by a clearly dose-dependent statistically significant effect even after 1-minute orthostasis. Increase of mean arterial pressure as compared to the orthostasis test before medication was on average 4.5 mmHg. CCC affected diastolic blood pressure after 1 minute of orthostasis in all dosages as compared to placebo. A statistically significant effect of the highest dose of 80 drops on diastolic blood pressure could be demonstrated after 1-, 3-, and 5-minute orthostasis. The hemodynamic findings of a stabilizing effect on arterial pressure in orthostasis corroborate the long-term medical experience with CCC and justify the indication orthostatic hypotension.

The role of antigen in the localization of naive, acutely activated, and memory CD8(+) T cells to the lung during influenza pneumonia.

The role of Ag in the recruitment and localization of naive, acutely activated, and memory CD8(+) T cells to the lung during influenza infection was explored using TCR-transgenic (Tg) mice. Naive, Thy1.2(+)CD8(+) OT-I TCR-Tg cells were primed and recruited to the lung after transfer into congenic Thy1.1(+) recipients challenged with a genetically engineered influenza virus (influenza A/WSN/33 (WSN)-OVA(I)) containing the K(b) restricted OVA(257-264) epitope (siinfekl) in the viral neuraminidase stalk. However, if the transferred animals were infected with a similar influenza virus that expressed an irrelevant K(b) epitope (WSN-PEPII), no TCR-Tg T cells were detectable in the lung, although they were easily visible in the lymphoid organs. Conversely, there were substantial numbers of OT-I cells found in the lungs of WSN-PEPII-infected mice when the animals had been previously, or were concurrently, infected with a recombinant vaccinia virus expressing OVA. Similar results were obtained with nontransgenic populations of memory CD8(+) T cells reactive to a murine gamma-herpesvirus-68 Ag. Interestingly, the primary host response to the immunodominant influenza nucleoprotein epitope was not affected by the presence of memory or recently activated OT-I T cells. Thus, although Ag is required to activate the T cells, the subsequent localization of T cells to the lung during a virus infection is a property of recently activated and memory T cells and is not necessarily driven by Ag in the lung.

Pharmacokinetic and dynamic interactions of the angiotensin-converting enzyme inhibitor imidapril with hydrochlorothiazide, bisoprolol and nilvadipine.

OBJECTIVE: The pharmacokinetic and dynamic interactions of the angiotensin-converting enzyme (ACE) inhibitor imidapril with other therapeutic principles used in hypertension and heart failure were evaluated. METHODS: In three separate, double-blind, placebo-controlled, four-way cross-over studies in healthy volunteers (n = 16 each), single oral doses of imidapril 10 mg (I), hydrochlorothiazide 12.5 mg (H), bisoprolol 5 mg (B) and nilvadipine 8 mg (N) were administered as monotherapies, and in IH, IB and IN combinations. Plasma concentrations of imidaprilat and H were followed up to 48 h, those of B and N up to 24 h and area under the concentration time curve (AUC), maximum plasma concentration (Cmax) and time to Cmax (tmax) were determined. Blood pressure (BP), heart rate (HR) and non-invasive haemodynamics [total peripheral resistance (TPR, N and H), systolic time intervals (STI, N and H), and plasma renin activity (PRA)] were assessed up to 24 h. RESULTS: There were no pharmacokinetic interactions between I plus H, B or N. Bioequivalence between single and combined administrations was verified for all investigational compounds [AUC point estimates (90% confidence interval CI): imidaprilat IH 109% (97.8, 122.8); IB 99.6% (91.2, 109.4); IN 105.7% (92.1, 121.3); H 96.6% (92.5, 100.8); B 103% (100.2, 105.8); N 98% (89, 108)]. The haemodynamic effects were mostly additive and without relevant pharmacodynamic interactions. I significantly reduced the BP by 5-8 mmHg, B by 4-8 mmHg and N by 4-6 mmHg. In addition, H induced a significant reduction of the preload as seen from STI, and B significantly reduced HR (-5 bpm). N induced a significant decrease in TPR (about 15% of baseline values) and showed corresponding changes in STI. PRA increased significantly following I alone (1.5-2.0 ng/ml/h), as well as combined with N (2.5 ng/ ml/h) or H (3.1 ng/ml/h). This increase was clearly blunted by the co-administration of B (0.6 ng/ml/h). CONCLUSIONS: The combination of imidapril with a diuretic, beta-adrenoceptor antagonist or calcium-channel blocker seems a reasonable and safe treatment option when striving for additive pharmacodynamic effects not accompanied by relevant pharmacokinetic interactions.

Treatment of congestive heart failure--current status of use of digitoxin.

Digitalis glycosides exert a positive inotropic effect, i.e. an increase in myocardial contractility associated with a prolongation of relaxation period, and glycosides lower the heart rate (negative chronotropic), impede stimulus conduction (negative dromotropic) and promote myocardial excitability (positive bathmotropic). They seem to influence the activities of both the vagal and the sympathetic systems. Digitalis glycosides that belong to different substance classes are closely comparable concerning pharmacodynamics but differ substantially in regard to pharmacokinetics. Digoxin and its derivatives are less lipophilic, show lower protein binding and shorter half-life, are mainly eliminated via the kidney and accumulate rather rapidly in cases of insufficient kidney function. Digitoxin is highly lipophilic and extensively bound to plasma proteins, has a longer half-life, is mainly eliminated in the metabolized state via urine and faeces and does not accumulate in kidney dysfunction. As a result of a more stable pharmacokinetic profile, the incidence of toxic side effects seems to be lower with digitoxin than with digoxin. Since the beginning of the 1990s, the antagonists of the RAAS qualified as the standard treatment for congestive heart failure, often in combination with diuretics, vasodilators or beta-antagonists. However, the important role of digitalis glycosides as therapeutic comedication or alternative was never denied, especially in atrial fibrillation with tachycardia. The PROVED and RADIANCE trials proved a detrimental effect of the withdrawal of digoxin therapy on exercise capacity, left-ventricular ejection fraction and clinical symptoms. The DIG trial revealed that digoxin comedication in sinus rhythm patients with congestive heart failure was associated with a lower morbidity (as taken from death or hospitalization because of worsening heart failure) and an unchanged overall mortality--being a unique feature among the available inotropic drugs. Comparable studies for digitoxin have not yet been performed but, because of its higher pharmacological stability, it might well be associated with even more advantages in this regard than digoxin.

Pharmacological differences among angiotensin II receptor antagonists.

Angiotensin II AT1 receptor antagonists (AIIRAs) have demonstrated efficacy similar to other classes of antihypertensive agents as well as "placebo-level" tolerability at all doses. Pharmacokinetic and pharmacodynamic studies provide a framework for understanding important intra-class dissimilarities. Disparity in antagonistic effects may be determined by in vivo responses to challenges of exogenous angiotensin II (Ang II) and by ex vivo/in vitro responses to a drug's biological activity by radioligand receptor assay (RRA). Two independent studies have been conducted in which irbesartan exhibited a more pronounced and longer-lasting antagonism to the effects of exogenous Ang II than losartan and valsartan. Comparative trials have indicated that both irbesartan and candesartan show greater clinical efficacy in lowering blood pressure than losartan. Recently, we have compared the Ang II antagonistic properties of irbesartan 150 mg/day and candesartan 8 mg/day. Both drugs block AT1 receptors with "insurmountable" antagonism and demonstrate a long duration of action. While both irbesartan and candesartan showed a similar degree of antagonistic activity in vivo, distinctly higher antagonistic activity in plasma was found for irbesartan by RRA at all time-points. Furthermore, plasma renin activity during periods with high antagonistic activity was significantly higher, and aldosterone levels following Ang II stimulation were blunted to a greater extent, following administration of irbesartan. In summary, in the doses tested, irbesartan exhibits the strongest antagonism when compared with losartan, valsartan and candesartan. This finding may have clinical implications.

Measuring the diaspora for virus-specific CD8+ T cells.

The CD8(+) T cell diaspora has been analyzed after secondary challenge with an influenza A virus that replicates only in the respiratory tract. Numbers of D(b)NP(366)- and D(b)PA(224)-specific CD8(+) T cells were measured by tetramer staining at the end of the recall response, then followed sequentially in the lung, lymph nodes, spleen, blood, and other organs. The extent of clonal expansion did not reflect the sizes of the preexisting memory T cell pools. Although the high-frequency CD8(+) tetramer(+) populations in the pneumonic lung and mediastinal lymph nodes fell rapidly from peak values, the "whole mouse" virus-specific CD8(+) T cell counts decreased only 2-fold over the 4 weeks after infection, then subsided at a fairly steady rate to reach a plateau at about 2 months. The largest numbers were found throughout in the spleen, then the bone marrow. The CD8(+)D(b)NP(366)+ and CD8(+)D(b)PA(224)+ sets remained significantly enlarged for at least 4 months, declining at equivalent rates while retaining the nucleoprotein > acid polymerase immunodominance hierarchy characteristic of the earlier antigen-driven phase. Lowest levels of the CD69 "activation marker" were detected consistently on virus-specific CD8(+) T cells in the blood, then the spleen. Those in the bone marrow and liver were intermediate, and CD69(hi) T cells were very prominent in the regional lymph nodes and the nasal-associated lymphoid tissue. Any population of "resting" CD8(+) memory T cells is thus phenotypically heterogeneous, widely dispersed, and subject to broad homeostatic and local environmental effects irrespective of epitope specificity or magnitude.

Dissecting the host response to a gamma-herpesvirus.

The murine gamma-herpesvirus 68 (MHV-68) provides a unique experimental model for dissecting immunity to large DNA viruses that persist in B lymphocytes. The analysis is greatly facilitated by the availability of genetically disrupted (-/-) mice that lack key host-response elements, and by the fact that MHV-68 is a lytic virus that can readily be manipulated for mutational analysis. The mutant virus strategy is being used, for example, to characterize the part played in vivo by an MHV-68-encoded chemokine-binding protein that may ultimately find an application in human therapeutics. Experiments with various -/- mice and monoclonal antibody depletion protocols have shown very clearly that type I interferons (IFNs) are essential for the early control of MHV-68 replication, while CD4+ T cells producing IFN-gamma function to limit the consequences of viral persistence. Virus-specific CD8+ effectors acting in the absence of the CD4+ subset seem initially to control the lytic phase in the lung following respiratory challenge, but are then unable to prevent the reactivation of replicative infection in epithelia and the eventual death of CD4+ T-cell-deficient mice. This could reflect the fact that the interaction between the CD8+ T cells and the virus-infected targets is partially compromised by the MHV-68 K3 protein, which inhibits antigen presentation by MHC class I glycoproteins. Immunization strategies focusing on the CD8+ T-cell response to epitopes expressed during the lytic phase of MHV-68 infection can limit virus replication, but are unable to prevent the establishment of latency. Other experiments with mutant viruses also suggest that there is a disconnection between lytic MHV-68 infection and latency. The massive nonspecific immunoglobulin response and the dramatic expansion of Vbeta4+ CD8+ T cells, which is apparently MHC independent, could represent some sort of 'smoke screen' used by MHV-68 to subvert immunity. Although MHV-68 is neither Epstein-Barr virus nor human herpesvirus-8, the results generated from this system suggest possibilities that may usefully be addressed with these human pathogens. Perhaps the main lesson learned to date is that all the components of immunity are likely to be important for the control of these complex viruses.

Virus-specific and bystander CD8+ T-cell proliferation in the acute and persistent phases of a gammaherpesvirus infection.

The cycling characteristics of CD8+ T cells specific for two lytic-phase epitopes of murine gammaherpesvirus 68 (gammaHV68) have been analyzed for mice with high or low levels of virus persistence. The extent of cell division is generally reflective of the antigen load and suggests that gammaHV68 may be regularly reactivating from latency for some months after the resolution of the acute phase of the infectious process. Although gammaHV68 infection is also associated with massive proliferation of lymphocytes that are not obviously specific for the virus, the level of "bystander-induced" cycling in a population of influenza virus-specific CD8+ T cells was generally fourfold lower than the extent of cell division seen for the antigen-driven, gammaHV68-specific response. The overall conclusion is that turnover rates substantially in excess of 5 to 10% over 6 days for CD8+ "memory" T-cell populations are likely to be reflective of continued antigenic exposure.

Diversity of epitope and cytokine profiles for primary and secondary influenza a virus-specific CD8+ T cell responses.

Screening with the flow cytometric IFN-gamma assay has led to the identification of a new immunogenic peptide (SSYRRPVGI) [corrected] from the influenza PB1 polymerase (PB1(703--711)) and a mimotope (ISPLMVAYM) from the PB2 polymerase (PB2(198--206)). CD8(+) T cells specific for K(b)PB1(703) make both IFN-gamma and TNF-alpha following stimulation with both peptides. The CD8(+) K(b)PB1(703)(+) population kills PB2(198)-pulsed targets, but cell lines stimulated with PB2(198) neither bind the K(b)PB1(703) tetramer nor become CTL. This CD8(+)K(b)PB1(703)(+) population is prominent in the primary response to an H3N2 virus, although it is much less obvious following secondary challenge of H1N1-primed mice. Even so, we can now account for >40% of the CD8(+) T cells in a primary influenza pneumonia and >85% of those present after H3N2 --> H1N1 challenge. Profiles of IFN-gamma and TNF-alpha staining following in vitro stimulation have been traced for the four most prominent influenza peptides through primary and secondary responses into long-term memory. The D(b)NP(366) epitope that is immunodominant after the H3N2 --> H1N1 challenge shows the lowest frequencies of CD8(+) IFN-gamma(+)TNF-alpha(+) cells for >6 wk, and the intensity of IFN-gamma staining is also low for the first 3 wk. By 11 wk, however, the IFN-gamma/TNF-alpha profiles look to be similar for all four epitopes. At least by the criterion of cytokine production, there is considerable epitope-related functional diversity in the influenza virus-specific CD8(+) T cell response. The results for the K(b)PB1(703) epitope and the PB2(198) mimotope also provide a cautionary tale for those using the cytokine staining approach to identity antigenic peptides.

Prophylaxis of radiogenic sialadenitis and mucositis by coumarin/troxerutine in patients with head and neck cancer--a prospective,randomized, placebo-controlled, double-blind study.

OBJECTIVE: To study the efficacy of coumarin/troxerutine for the protection of salivary glands and mucosa during irradiation. DESIGN: Prospective, randomized, placebo-controlled, double-blind trial. SETTING: University hospital, Germany. PATIENTS: 48 patients who had radiotherapy to the head and neck. MAIN OUTCOME MEASURES: Salivary gland scintigraphy and acute side-effects of radiotherapy (Radiation Therapy Oncology Group (RTOG) score). RESULTS: 23 patients (11 experimental, 12 placebo) completed the study. The global efficacy measure combining scintigraphy and RTOG score favoured the experimental arm (P=0.07). The RTOG score showed significantly fewer acute side-effects of radiation in the experimental arm (P<0.05). CONCLUSION: The results suggest that coumarin/troxerutine have a favourable effect in the treatment of radiogenic sialadenitis and mucositis.

Blocking the tissue renin-angiotensin system: the future cornerstone of therapy.

The development of angiotensin-converting enzyme inhibitors and selective angiotensin type 1 (AT1)-receptor antagonists has provided new insights into understanding the mechanism of the renin-angiotensin system (RAS) in the pathophysiology of cardiovascular disease. There is good evidence from meta-analyses that shows that inhibition of the RAS achieves organ protection features that go beyond blood pressure control. Candesartan cilexetil, a new angiotensin II receptor antagonist, is characterised by its tight binding to and slow dissociation from the AT1 receptor, and high antagonistic potency, resulting in long-lasting antagonistic effects. It is anticipated that these pharmacological characteristics may bring additional benefits to patients, not only for the management of essential hypertension but also for the management of end-organ damage.