Prospective predictors of exacerbation status in severe asthma over a 3-year follow-up.

BACKGROUND: A predisposition to exacerbations is being recognized as a distinct phenotype with "previous exacerbations" representing the strongest clinical factor associated with future exacerbation. Thus, to identify additional novel biomarkers associated with asthma exacerbations, "past exacerbation status" must be included as a confounding factor. OBJECTIVE: This study aimed to characterize the clinical and biomarker features associated with asthma exacerbations in severe asthma. METHODS: We evaluated clinical parameters from 105 severe asthmatics yearly for 3 years, as well as their exacerbation status. We classified the subjects into 3 groups: (i) consistent non-exacerbators (CNE, subjects who did not experience any exacerbation over the 3-year period); (ii) consistent frequent exacerbators (CFE, subjects with frequent exacerbation, defined as those who had 2 or more exacerbations within 1 year, throughout the 3-year period); and (iii) intermittent exacerbators (IE). We conducted multivariate analysis for comparisons among the groups for multiple factors, including several Th2-related biomarkers, in addition to the "past exacerbation status." RESULTS: Thirty-nine subjects were classified as CNE, 15 as CFE, and 51 as IE. Frequent exacerbations in the previous year predicted exacerbations for the following year (P < .001). Among the several Th2-related biomarkers, only FeNO was associated with exacerbation status. When we analysed the data after the second visit, the impact of FeNO on predicting future exacerbation remained significant, even after considering the exacerbation status during the first year (P < .05). CONCLUSIONS AND CLINICAL RELEVANCE: Measurement of FeNO has a significant potential to predict future asthma exacerbation, which is independent of the "past exacerbation history."

Life Goals Over Time Among Homeless Adults in Permanent Supportive Housing.

Permanent supportive housing (PSH) is a widely-accepted solution to the challenge of chronic homelessness. While housing support and retention, physical health, and healthcare continue to be important for formerly homeless persons in PSH, "higher-order" and humanistic needs such as thriving have received less attention and as a result are less well understood in this population. One important indicator of thriving is the ability to establish and articulate life goals. This study utilizes longitudinal data from 421 formerly homeless adults prior to their move into PSH, and at 3-, 6- and 12-months after move-in (369 respondents completed all four interviews), to examine what life goals are articulated by this population and how those goals change over time. Prior to housing, most respondents articulated housing attainment as their primary life goal, whereas at follow-up interviews health goals, housing relocation, and financial goals became more prevalent. Aspirational goals (e.g., independence, self-improvement, artistic pursuits) were also common, but demonstrated a decrease over time in housing. Relationship goals remained common and consistent over time. Findings indicate that housing is a necessary, but perhaps not sufficient, step for improving thriving among formerly homeless adults. Implications for practice and future research are discussed.

l-citrulline prevents asymmetric dimethylarginine-mediated reductions in nitric oxide and nitrosative stress in primary human airway epithelial cells.

BACKGROUND: Asthma is associated with reduced systemic levels of l-arginine and increased asymmetric dimethylarginine (ADMA). This imbalance leads to nitric oxide synthase (NOS) uncoupling with reduced nitric oxide (NO) formation and greater oxidative and nitrosative stress. Whether this imbalance also occurs in bronchial epitheliumof asthmatics is unknown. OBJECTIVES: We used primary human bronchial epithelial cells (HBECs) from asthmatics and healthy controls to evaluate: (i) ADMA-mediated NOS uncoupling reduces epithelial production of NO and increases oxygen and nitrogen reactive species, and (ii) l-citrulline can reverse this mechanism by recoupling NOS, restoring NO production and reducing oxidative and nitrosative stress. RESULTS: In HBECsIL-13 and INFγ stimulated NOS2 and increased NOx levels. The addition of ADMA reduced NOx and increased H2 O2 levels (p<0.001). Treatment with l-citrulline (800, 1600 µm) rescued NOx when the l-arginine media concentration was 25 µm but failed to do so with higher concentrations (100 µm). Under reduced l-arginine media conditions, HBECs treated with l-citrulline increased the levels of argininosuccinate, an enzyme that metabolizes l-citrulline to l-arginine. l-citrulline prevented the ADMA-mediated increase in nitrotyrosine in HBECs in cells from asthmatics and controls. CONCLUSIONS AND CLINICAL RELEVANCE: Increasing ADMA reduces NO formation and increases oxidative and nitrosative stress in airway epithelial cells. l-citrulline supplementation restores NO formation, while preventing nitrosative stress. These results, suggest that l-citrulline supplementation may indeed be a powerful approach to restore airway NO production and may have a therapeutic potential in diseases in which there is a defective production of NO.

[Treating nasal obstruction in obstructive sleep apnea patients]. / Behandlung der Nasenatmungsbehinderung bei Patienten mit obstruktiver Schlafapnoe.

The impact of treating nasal obstruction in obstructive sleep apnea (OSA) patients is still intensively discussed at congresses. This is likely due to the highly conflicting results of nasal treatments in regard to restorative sleep on the one hand, and their influence on the severity of OSA on the other. Both conservative and surgical nasal treatments result in a highly significant improvement of sleep quality. Patients' sleep is more restorative, which has a huge impact on several quality of life parameters. In contrast, the impact of conservative and surgical nasal treatments on the severity of OSA measured using the apnea-hypopnea index is very limited, apart from rare exceptions. However, there are preliminary data indicating that successful nasal surgery may facilitate or enable nasal ventilation therapy by lowering the effective pressure.

ENT-specific therapy of obstructive sleep apnoea in adults : A revised version of the previously published German S2e guideline.

The German Society of Otorhinolaryngology, Head and Neck Surgery recently has released the abbreviated version of its scientific guideline "ENT-specific therapy of obstructive sleep apnoea (OSA) in adults", which has been updated in 2015 and can be found online at the Association of the Scientific Medical Societies (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). A summary of the main recommendations is provided in this revised English version. All recommendations are based on a systematic literature research of articles published up until March 2014. Literature research followed the Cochrane Handbook for Systematic Literature Research to create Guidelines published by the German Cochrane Centre. Studies were evaluated with respect to their scientific value according to the recommendations of the Oxford Centre for Evidence-based Medicine, and grades of recommendation are provided regarding each intervention.

[S2e-guideline: "ENT-specific therapy of obstructive sleep apnea in adults" short version : Sleep Medicine Task Force of the German Society for Otorhinolaryngology, Head and Neck Surgery]. / Leitlinie: "HNO-spezifische Therapie der obstruktiven Schlafapnoe bei Erwachsenen" Kurzfassung : ArGe Schlafmedizin der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie.

The present S2e-guideline is an update of the former S2e-guideline "treatment of obstructive sleep apnea in adults". The update was performed on behalf of the German Society for Otorhinolaryngology, Head and Neck Surgery by its Sleep Medicine Task Force. The long version of the guideline is valid from 5.9.2015 to 5.9.2020 and has been available (guideline No. 017-069) since November 2015 on the official AWMF website.The subsequently presented short version of the guideline summarizes the essentials in a legible way. For further information, please refer to the long version.

eQTL of bronchial epithelial cells and bronchial alveolar lavage deciphers GWAS-identified asthma genes.

BACKGROUND: Genome-wide association studies (GWASs) have identified various genes associated with asthma, yet, causal genes or single nucleotide polymorphisms (SNPs) remain elusive. We sought to dissect functional genes/SNPs for asthma by combining expression quantitative trait loci (eQTLs) and GWASs. METHODS: Cis-eQTL analyses of 34 asthma genes were performed in cells from human bronchial epithelial biopsy (BEC, n = 107) and from bronchial alveolar lavage (BAL, n = 94). RESULTS: For TSLP-WDR36 region, rs3806932 (G allele protective against eosinophilic esophagitis) and rs2416257 (A allele associated with lower eosinophil counts and protective against asthma) were correlated with decreased expression of TSLP in BAL (P = 7.9 × 10(-11) and 5.4 × 10(-4) , respectively) and BEC, but not WDR36. Surprisingly, rs1837253 (consistently associated with asthma) showed no correlation with TSLP expression levels. For ORMDL3-GSDMB region, rs8067378 (G allele protective against asthma) was correlated with decreased expression of GSDMB in BEC and BAL (P = 1.3 × 10(-4) and 0.04) but not ORMDL3. rs992969 in the promoter region of IL33 (A allele associated with higher eosinophil counts and risk for asthma) was correlated with increased expression of IL33 in BEC (P = 1.3 × 10(-6) ) but not in BAL. CONCLUSIONS: Our study illustrates cell-type-specific regulation of the expression of asthma-related genes documenting SNPs in TSLP, GSDMB, IL33, HLA-DQB1, C11orf30, DEXI, CDHR3, and ZBTB10 affect asthma risk through cis-regulation of its gene expression. Whenever possible, disease-relevant tissues should be used for transcription analysis. SNPs in TSLP may affect asthma risk through up-regulating TSLP mRNA expression or protein secretion. Further functional studies are warranted.

Correlation of electrochromic properties and oxidation states in nanocrystalline tungsten trioxide.

Although tungsten trioxide (WO3) has been extensively studied since its electrochromic properties were first discovered, the mechanism responsible for the coloration or bleaching effect is still disputed. New insights into the coloration mechanism of electrochromic, nanocrystalline WO3 are provided in this paper by studying thin WO3 films combining the electrochemical and spectroscopic techniques. By employing in situ UV-Vis transmission spectroscopy at a fixed spectral band pass during electrochemical experiments, such as cyclic voltammetry, a two-step insertion process for both protons and lithium ions is identified, of which one step exhibits a significantly higher coloration efficiency than the other. To obtain a better understanding of the insertion process AxWO3 (A = H, Li,…) thin films were studied at different stages of intercalation using UV-Vis and X-ray photoelectron spectroscopy. The results show that the first step of the intercalation process represents the reduction from initial W(6+) to W(5+) and the second step the reduction of W(5+) to W(4+). We found that the blue coloration of this nanocrystalline tungsten trioxide is mainly due to the presence of W(4+) rather than that of W(5+).

Characterisation of an OCS-dependent severe asthma population treated with mepolizumab.

UNLABELLED: A subpopulation of patients with asthma treated with maximal inhaled treatments is unable to maintain asthma control and requires additional therapy with oral corticosteroids (OCS); a subset of this population continues to have frequent exacerbations. Alternate treatment options are needed as daily use of OCS is associated with significant systemic adverse effects that affect many body systems and have a direct association with the dose and duration of OCS use. We compared the population demographics, medical conditions and efficacy responses of the OCS-dependent group from the DREAM study of mepolizumab with the group not managed with daily OCS. TRIAL REGISTRATION NUMBER: NCT01000506.

Formation of protein adducts with Hydroperoxy-PE electrophilic cleavage products during ferroptosis.

Ferroptosis is an iron dependent form of cell death, that is triggered by the discoordination of iron, lipids, and thiols. Its unique signature that distinguishes it from other forms of cell death is the formation and accumulation of lipid hydroperoxides, particularly oxidized forms of polyunsaturated phosphatidylethanolamines (PEs), which drives cell death. These readily undergo iron-catalyzed secondary free radical reactions leading to truncated products which retain the signature PE headgroup and which can readily react with nucleophilic moieties in proteins via their truncated electrophilic acyl chains. Using a redox lipidomics approach, we have identified oxidatively-truncated PE species (trPEox) in enzymatic and non-enzymatic model systems. Further, using a model peptide we demonstrate adduct formation with Cys as the preferred nucleophilic residue and PE(26:2) +2 oxygens, as one of the most reactive truncated PE-electrophiles produced. In cells stimulated to undergo ferroptosis we identified PE-truncated species with sn-2 truncations ranging from 5 to 9 carbons. Taking advantage of the free PE headgroup, we have developed a new technology using the lantibiotic duramycin, to enrich and identify the PE-lipoxidated proteins. Our results indicate that several dozens of proteins for each cell type, are PE-lipoxidated in HT-22, MLE, and H9c2 cells and M2 macrophages after they were induced to undergo ferroptosis. Pretreatment of cells with the strong nucleophile, 2-mercaptoethanol, prevented the formation of PE-lipoxidated proteins and blocked ferroptotic death. Finally, our docking simulations showed that the truncated PE species bound at least as good to several of the lantibiotic-identified proteins, as compared to the non-truncated parent molecule, stearoyl-arachidonoyl PE (SAPE), indicating that these oxidatively-truncated species favor/promote the formation of PEox-protein adducts. The identification of PEox-protein adducts during ferroptosis suggests that they are participants in the ferroptotic process preventable by 2-mercaptoethanol and may contribute to a point of no return in the ferroptotic death process.

U.S. and European severe asthma cohorts: what can they teach us about severe asthma?

Asthma is a global health problem affecting around 300 million patients of all ages and ethnic groups in all countries around the world. In the majority of subjects with persistent, mild-to-moderate asthma (MA), the disease can be relatively well controlled by the use of currently available medications; however, five to ten per cent of patients suffer from a particularly severe disease that is poorly controlled clinically and often refractory to usual treatment. Improved care of severe asthma (SA) is a major unmet medical need and several international consortia aim at improving our understanding of mechanisms in SA. To manage SA better, standardized definitions and concepts of asthma severity, risk and level of control are critical. In the following sections, we present several guidelines approaches and definitions followed by an overview of U.S. (SARP) and European (ENFUMOSA, BIOAIR, U-BIOPRED) SA networks. Key findings regarding SA phenotypes, risk factors and pathophysiology are discussed. International cooperation in the area of respiratory diseases, including SA, across the Atlantic Ocean, will lead to a better understanding of asthma pathology, especially of those severe, not well controlled or difficult-to-treat cases.

Severe asthma: from characteristics to phenotypes to endotypes.

Asthma, and severe asthma, in particular, is increasingly recognized as a heterogeneous disease. While traditional views of asthma have centered around a childhood onset disease with an allergic component, several large scale network studies are now confirming that severe asthma can present in multiple different ways, only 30-50% of which meet traditional childhood onset allergic criteria. To understand the different groups better, initial studies have attempted to define phenotypes of severe asthma. A phenotype is defined as the integration of different characteristics that are the product of the interaction of the patient's genes with the environment. Both clinical and statistical approaches have identified at least 3-5 phenotypes of severe asthma. However, these phenotypes, in isolation, do not identify the immunopathology that makes these clinical phenotypes distinct or identifies a target population for a specific approach to therapy. As biological characteristics are identified, phenotypes should continue to evolve towards asthma endotypes. The identification of these endotypes, either by matching biology, genetics and therapeutic responses to therapy with clinically or statistically defined phenotypes or through unbiased genetic and genomic approaches, remains limited. Moving forward, this integration of genetics, biology and clinical characteristics should substantially enhance our ability to effectively treat complex heterogeneous diseases, such as severe asthma.

Nitric oxide and related enzymes in asthma: relation to severity, enzyme function and inflammation.

BACKGROUND: Exhaled nitric oxide (FeNO) associates with asthma and eosinophilic inflammation. However, relationships between nitric oxide synthases, arginase, FeNO, asthma severity and inflammation remain poorly understood. OBJECTIVES: To determine the relationships of iNOS expression/activation and arginase 2 expression with asthma severity, FeNO, nitrotyrosine (NT) and eosinophilic inflammation. METHODS: Bronchial brushings and sputum were obtained from 25 normal controls, eight mild/no inhaled corticosteroids (ICS), 16 mild-moderate/with ICS and 35 severe asthmatics. The FeNO was measured the same day by ATS/ERS standards. The iNOS, arginase2 mRNA/protein and NT protein were measured in lysates from bronchial brushings by quantitative real-time PCR and Western blot. Induced sputum differentials were obtained. RESULTS: Severe asthma was associated with the highest levels of iNOS protein and mRNA, although the index of iNOS mRNA to arginase2 mRNA most strongly differentiated severe from milder asthma. When evaluating NO-related enzyme functionality, iNOS mRNA/protein expression both strongly predicted FeNO (r = 0.61, P < 0.0001 for both). Only iNOS protein predicted NT levels (r = 0.48, P = 0.003) with the strongest relationship in severe asthma (r = 0.61, P = 0.009). The iNOS protein, FeNO and NT, all correlated with sputum eosinophils, but the relationships were again strongest in severe asthma. Controlling for arginase 2 mRNA/protein did not impact any functional outcome. CONCLUSIONS AND CLINICAL RELEVANCE: These data suggest that while iNOS expression from epithelial brushings is highest in severe asthma, factors controlling arginase2 mRNA expression significantly improve differentiation of severity. In contrast, functionality of the NO pathway as measured by FeNO, NT and eosinophilic inflammation, is strongly associated with iNOS expression alone, particularly in severe asthma.

Toll-like receptors 2, 3 and 4 and thymic stromal lymphopoietin expression in fatal asthma.

BACKGROUND: Airway inflammation in asthma involves innate immune responses. Toll-like receptors (TLRs) and thymic stromal lymphopoietin (TSLP) are thought to be involved in airway inflammation, but their expression in asthmatics' both large and small airways has not been investigated. OBJECTIVE: To analyse the expression of TLR2, TLR3, TLR4 and TSLP in large and small airways of asthmatics and compare their expression in smoking and non-smoking asthmatics; to investigate whether TLR expression is associated with eosinophilic or neutrophilic airway inflammation and with Mycoplasma pneumoniae and Chlamydophila pneumoniae infection. METHODS: Using immunohistochemistry and image analysis, we investigated TLR2, TLR3, TLR4 and TSLP expression in large and small airways of 24 victims of fatal asthma, FA, (13 non-smokers, 11 smokers) and nine deceased control subjects (DCtrl). TLRs were also measured in 18 mild asthmatics (MA) and 12 healthy controls (HCtrl). M. pneumoniae and C. pneumoniae in autopsy lung tissue were analysed using real-time polymerase chain reaction. Airway eosinophils and neutrophils were measured in all subjects. RESULTS: Fatal asthma patients had higher TLR2 in the epithelial and outer layers of large and small airways compared with DCtrls. Smoking asthmatics had lower TLR2 levels in the inner and outer layers of the small airways than non-smoking asthmatics. TSLP was increased in the epithelial and outer layers of the large airways of FA. FA patients had greater TLR3 expression in the outer layer of large airways and greater TLR4 expression in the outer layer of small airways. Eosinophilic airway inflammation was associated with TLR expression in the epithelium of FA. No bacterial DNA was detected in FA or DCtrls. MA and HCtrls had only a small difference in TLR3 expression. CONCLUSIONS AND CLINICAL RELEVANCE: Increased expression of TLR 2, 3 and 4 and TSLP in fatal asthma may contribute to the acute inflammation surrounding asthma deaths.

Relationship between levels of secreted phospholipase A2 groups IIA and X in the airways and asthma severity.

Background Secreted phospholipase A(2) (sPLA(2) ) may be important mediators of asthma, but the specific sPLA(2) s involved in asthma are not known. Objective To evaluate sPLA(2) group IIA, V, and X proteins (sPLA(2) -IIA, sPLA(2) -V, and sPLA(2) -X) in bronchoalveolar lavage (BAL) fluid, BAL cells, and airway epithelial cells of subjects with and without asthma, and examine the relationship between the levels of specific sPLA(2) enzymes and airway inflammation, asthma severity, and lung function. Methods The expression of sPLA(2) -IIA, sPLA(2) -V, and sPLA(2) -X in BAL cells and epithelial brushings was assessed by qPCR. The levels of these sPLA(2) proteins and sPLA(2) activity with and without group II and group X-specific inhibitors were measured in BAL fluid from 18 controls and 39 asthmatics. Results The airway epithelium expressed sPLA(2) -X at higher levels than either sPLA(2) -IIA or sPLA(2) -V, whereas BAL cells expressed sPLA(2) -IIA and sPLA(2) -X at similar levels. The majority of sPLA(2) activity in BAL fluid was attributed to either sPLA(2) -IIA or sPLA(2) -X. After 10-fold concentration of BAL fluid, the levels of sPLA(2) -X normalized to total protein were increased in asthma and were associated with lung function, the concentration of induced sputum neutrophils, and prostaglandin E(2) . The levels of sPLA(2) -IIA were elevated in asthma when normalized to total protein, but were not related to lung function, markers of airway inflammation or eicosanoid formation. Conclusions and Clinical Relevance These data indicate that sPLA(2) -IIA and sPLA(2) -X are the major sPLA(2) s in human airways, and suggest a link between the levels of sPLA(2) -X in the airways and several features of asthma.

Functional analysis of splice site mutations in the human hairless (HR) gene using a minigene assay.

BACKGROUND: Congenital atrichia is a rare autosomal recessive form of isolated alopecia which is caused by mutations in the human hairless (HR) gene. Patients are born with normal hair that is shed almost completely and irreversibly during the first weeks of life. OBJECTIVES: To investigate the molecular genetic basis of congenital atrichia in two patients, and to analyse the functional consequences of one newly identified and all seven previously identified HR splice site mutations using a minigene assay. METHODS: Molecular analysis of the HR gene was performed by direct DNA sequencing. To analyse the functional consequences of the splice site mutations, the respective sequences were cloned into a vector which allows directed splicing. After transfection of COS7 cells, isolation of RNA and cDNA synthesis, sequencing was performed to analyse the products. RESULTS: Two novel mutations were identified: an insertion in exon 2 (c.485insT; p.C162LfsX17), and a splice site mutation (c.2847-1G>A). In vitro analysis revealed aberrant splicing for all eight of the investigated HR splice site mutations. Comparison with the results of two biocomputational programs (neural network splice server and CRYP-SKIP) and calculation of consensus values revealed that the predictions of these two programs were consistent in only five and two of the eight mutations, respectively. CONCLUSIONS: This is the first report to analyse the consequences of HR splice site mutations using a cell-based in vitro assay. The results highlight the importance of performing splicing experiments to clarify the consequences of putative splice site mutations.

Current concepts in laser tattoo removal.

Today, more than 10% of the Western population has at least 1 tattoo, with prevalence of up to one-fourth in the cohort younger than 30 years of age. Many of these individuals come to regret their decision within months due to several reasons, often socially-related, and seek medical treatment. The discovery of selective photothermolysis has enabled the targeted destruction of tattoo pigments with only minimal damage to the surrounding tissue and limited risk of adverse effects, which contrasts previously used nonspecific methods. This treatment modality requires laser pulses of short durations (nanoseconds) and high intensities. However, the inappropriate use of laser parameters, such as inadequate pulse duration, can unnecessarily increase the incidence of permanent adverse effects. This article provides an overview of applicable laser systems and therapeutic strategies for optimized tattoo removal.

Regulation of chick bone growth by leptin and catecholamines.

Leptin and the sympathetic nervous system have a unique role in linking nutritional status to skeletal metabolism in mammals. Such a regulatory mechanism has not been identified in birds but would be beneficial to signal information about energy reserves to an organ system essential for locomotion, reproduction, and survival. To explore this potential role of leptin and the sympathetic nervous system in birds, an ex vivo chick tibiotarsal model was used to test the effects of leptin and sympathetic activity on longitudinal bone growth and the expression of chondrocyte markers. Reverse transcription-PCR analysis revealed the expression of chicken leptin receptor mRNA as well as both alpha-adrenergic (alpha1A, alpha2A, alpha2B, alpha2C) and beta adrenergic (beta1, beta2) receptor subtype mRNA in the whole bone. Incubation with norepinephrine (NE; 0, 10, or 100 microM for 4 d) caused a significant increase in distal condyle length as compared with vehicle-treated, contralateral tibiotarsi. In contrast, no change in condyle length was detected after leptin treatment (0 or 10 nM or 1 microM for 4 d). Analysis of cell proliferation by bromodeoxyuridine incorporation revealed no increase in bromodeoxyuridine-positive cells in the condyles in response to leptin or NE treatments. Real-time PCR analysis showed that NE enhanced type X collagen mRNA expression, a marker of mature hypertrophic chondrocytes, with no effect on type II collagen mRNA, the matrix protein secreted by proliferating chondrocytes. Leptin treatment had no effect on the expression of either matrix protein. Treatment with agonists specific for alpha- or beta-adrenergic receptors indicates that the activation of alpha-adrenergic receptors is most likely responsible for the sympathetic effect on type X collagen gene expression. These results suggest that NE and other sympathetic agonists have positive effects on bone elongation and the changes in critical genes associated with this process. These neurotransmitters may facilitate this by promoting chondrocyte maturation. These studies represent novel evidence suggesting a role of sympathetic tone in the regulation of skeletal growth in avian species.

[Linear IgA disease with ocular involvement associated with ulcerative colitis]. / Lineare IgA-Dermatose mit Augenbeteiligung in Assoziation mit Colitis ulcerosa.

The association of linear IgA disease (LAD), ulcerative colitis and scarring ocular involvement is very rare and represents a considerable therapeutic challenge. We report a 48-year-old male diagnosed with ulcerative colitis in 1995, who received long-term methylprednisolone therapy. Later, he developed ocular inflammation with conjunctival scarring and synechiae formation as well as episodes of vesicles. Although azathioprine was added to his regimen, the disease was not controlled. After the diagnosis of LAD was established, dapsone was added. With this therapy, the ocular inflammation decreased significantly and the methylprednisolone dose could be successfully tapered slowly without reappearance of vesicles.

Angiotensin II: a hormone involved in and contributing to pro-hypertrophic cardiac networks and target of anti-hypertrophic cross-talks.

Angiotensin II (Ang II) plays a major role in the progression of myocardial hypertrophy to heart failure. Inhibiting the angiotensin converting enzyme (ACE) or blockade of the corresponding Ang II receptors is used extensively in clinical practice, but there is scope for refinement of this mode of therapy. This review summarizes the current understanding of the direct effects of Ang II on cardiomyocytes and then focus particularly on interaction of components of the renin-angiotensin system with other hormones and cytokines. New findings described in approximately 400 papers identified in the PubMed database and published during the 2.5 years are discussed in the context of previous relevant literature. The cardiac action of Ang II is influenced by the activity of different isoforms of ACE leading to different amounts of Ang II by comparison with other angiotensinogen-derived peptides. The effect of Ang II is mediated by at least two different AT receptors that are differentially expressed in cardiomyocytes from neonatal, adult and failing hearts. The intracellular effects of Ang II are influenced by nitric oxide (NO)/cGMP-dependent cross talk and are mediated by the release of autocrine factors, such as transforming growth factor (TGF)-beta1 and interleukin (IL)-6. Besides interactions with cytokines, Ang II is involved in systemic networks including aldosterone, parathyroid hormone and adrenomedullin, which have their own effects on cardiomyocytes that modify, amplify or antagonize the primary effect of Ang II. Finally, hyperinsulemia and hyperglycaemia influence Ang II-dependent processes in diabetes and its cardiac sequelae.