Hexarelin targets neuroinflammatory pathways to preserve cardiac morphology and function in a mouse model of myocardial ischemia-reperfusion.

Acute myocardial ischemia and reperfusion injury (IRI) underly the detrimental effects of coronary heart disease on the myocardium. Despite the ongoing advances in reperfusion therapies, there remains a lack of effective therapeutic strategies for preventing IRI. Growth hormone secretagogues (GHS) have been demonstrated to improve cardiac function, attenuate inflammation and modulate the autonomic nervous system (ANS) in models of cardiovascular disease. Recently, we demonstrated a reduction in infarct size after administration of hexarelin (HEX), in a murine model of myocardial infarction. In the present study we employed a reperfused ischemic (IR) model, to determine whether HEX would continue to have a cardioprotective influence in a model of higher clinical relevance. Myocardial ischemia was induced by transient ligation of the left descending coronary artery (tLAD) in C57BL/6 J mice followed by HEX (0.3 mg/kg/day; n = 20) or vehicle (VEH) (n = 18) administration for 21 days, first administered immediately prior-to reperfusion. IR-injured and sham mice were subjected to high-field magnetic resonance imaging to assess left ventricular (LV) function, with HEX-treated mice demonstrating a significant improvement in LV function compared with VEH-treated mice. A significant decrease in interstitial collagen, TGF-ß1 expression and myofibroblast differentiation was also seen in the HEX-treated mice after 21 days. HEX treatment shifted the ANS balance towards a parasympathetic predominance; combined with a significant decrease in cardiac troponin-I and TNF-α levels, these findings were suggestive of an anti-inflammatory action on the myocardium mediated via HEX. In this model of IR, HEX appeared to rebalance the deregulated ANS and activate vagal anti-inflammatory pathways to prevent adverse remodelling and LV dysfunction. There are limited interventions focusing on IRI that have been successful in improving clinical outcome in acute myocardial infarction (AMI) patients, this study provides compelling evidence towards the translational potential of HEX where all others have largely failed.

Anti-fibrotic actions of relaxin.

Fibrosis refers to the hardening or scarring of tissues that usually results from aberrant wound healing in response to organ injury, and its manifestations in various organs have collectively been estimated to contribute to around 45-50% of deaths in the Western world. Despite this, there is currently no effective cure for the tissue structural and functional damage induced by fibrosis-related disorders. Relaxin meets several criteria of an effective anti-fibrotic based on its specific ability to inhibit pro-fibrotic cytokine and/or growth factor-mediated, but not normal/unstimulated, fibroblast proliferation, differentiation and matrix production. Furthermore, relaxin augments matrix degradation through its ability to up-regulate the release and activation of various matrix-degrading matrix metalloproteinases and/or being able to down-regulate tissue inhibitor of metalloproteinase activity. Relaxin can also indirectly suppress fibrosis through its other well-known (anti-inflammatory, antioxidant, anti-hypertrophic, anti-apoptotic, angiogenic, wound healing and vasodilator) properties. This review will outline the organ-specific and general anti-fibrotic significance of exogenously administered relaxin and its mechanisms of action that have been documented in various non-reproductive organs such as the cardiovascular system, kidney, lung, liver, skin and tendons. In addition, it will outline the influence of sex on relaxin's anti-fibrotic actions, highlighting its potential as an emerging anti-fibrotic therapeutic. LINKED ARTICLES: This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc.

Allergy tests do not predict food triggers in adult patients with eosinophilic oesophagitis. A comprehensive prospective study using five modalities.

BACKGROUND: The use of allergy tests to guide dietary treatment for eosinophilic oesophagitis (EoE) is controversial and data are limited. Aeroallergen sensitisation patterns and food triggers have been defined in Northern Hemisphere cohorts only. AIMS: To determine if allergy tests that are routinely available can predict food triggers in adult patients with EoE. To define the food triggers and aeroallergen sensitisation patterns in a novel Southern Hemisphere (Australian) cohort of patients. METHODS: Consecutive patients with EoE who elected to undergo dietary therapy were prospectively assessed, demographic details and atopic characteristics recorded, and allergy tests, comprising skin-prick and skin-patch tests, serum allergen-specific IgE, basophil activation test and serum food-specific IgG, were performed. Patients underwent a six-food elimination diet with a structured algorithm that included endoscopic and histological examination of the oesophagus a minimum of 2 weeks after each challenge. Response was defined as <15 eosinophils per HPF. Foods defined as triggers were considered as gold standard and were compared with those identified by allergy testing. RESULTS: No allergy test could accurately predict actual food triggers. Concordance among skin-prick and serum allergen-specific IgE was high for aeroallergens only. Among seasonal aeroallergens, rye-grass sensitisation was predominant. Food triggers were commonly wheat, milk and egg, alone or in combination. CONCLUSIONS: None of the currently-available allergy tests predicts food triggers for EoE. Exclusion-rechallenge methodology with oesophageal histological assessment remains the only effective investigation. The same food triggers were identified in this southern hemisphere cohort as previously described.

Combining an epithelial repair factor and anti-fibrotic with a corticosteroid offers optimal treatment for allergic airways disease.

BACKGROUND AND PURPOSE: We evaluated the extent to which individual versus combination treatments that specifically target airway epithelial damage [trefoil factor-2 (TFF2)], airway fibrosis [serelaxin (RLX)] or airway inflammation [dexamethasone (DEX)] reversed the pathogenesis of chronic allergic airways disease (AAD). EXPERIMENTAL APPROACH: Following induction of ovalbumin (OVA)-induced chronic AAD in 6­8 week female Balb/c mice, animals were i.p. administered naphthalene (NA) on day 64 to induce epithelial damage, then received daily intranasal administration of RLX (0.8 mg·mL(−1)), TFF2 (0.5 mg·mL(−1)), DEX (0.5 mg·mL(−1)), RLX + TFF2 or RLX + TFF2 + DEX from days 67­74. On day 75, lung function was assessed by invasive plethysmography, before lung tissue was isolated for analyses of various measures. The control group was treated with saline + corn oil (vehicle for NA). KEY RESULTS: OVA + NA-injured mice demonstrated significantly increased airway inflammation, airway remodelling (AWR) (epithelial damage/thickness; subepithelial myofibroblast differentiation, extracellular matrix accumulation and fibronectin deposition; total lung collagen concentration), and significantly reduced airway dynamic compliance (cDyn). RLX + TFF2 markedly reversed several measures of OVA + NA-induced AWR and normalized the reduction in cDyn. The combined effects of RLX + TFF2 + DEX significantly reversed peribronchial inflammation score, airway epithelial damage, subepithelial extracellular matrix accumulation/fibronectin deposition and total lung collagen concentration (by 50­90%) and also normalized the reduction of cDyn. CONCLUSIONS AND IMPLICATIONS: Combining an epithelial repair factor and anti-fibrotic provides an effective means of treating the AWR and dysfunction associated with AAD/asthma and may act as an effective adjunct therapy to anti-inflammatory corticosteroids

A prospective open clinical trial of a proton pump inhibitor, elimination diet and/or budesonide for eosinophilic oesophagitis.

BACKGROUND: Elimination diets and high-dose proton pump inhibitors (PPI) are advocated as first-line treatments in patients with eosinophilic oesophagitis (EoE). AIM: To record the treatment outcome for patients with EoE prospectively managed according to a clinical algorithm. METHODS: Patients with oesophageal eosinophilia commenced esomeprazole 40 mg twice daily for 8 weeks. Those in histological remission were re-classified as PPI-responsive oesophageal eosinophilia. Nonresponders were offered the 6-food elimination diet with a PPI, or topical budesonide monotherapy (1 mg orally twice daily as an aqueous gel). Once disease control was achieved remission was reassessed at 3 months (all modalities) and an additional 6 months (diet group). RESULTS: Of 107 patients who completed 8 weeks of PPI, 25 (23%) were PPI-responsive. 56 of 81 (69%) of patients with EoE chose the elimination diet with PPI. 29 (52%) had complete remission, 23 completed dietary reintroduction and food triggers were identified in 20 (36%). 25 chose budesonide with 23/25 (92%) responding. Remission was sustained in >85% of patients at 3 months with all treatment modalities. At 9 months, only 10/18 (55%) of patients who responded to the elimination diet with PPI remained complaint and sustained remission. CONCLUSIONS: Many patients previously diagnosed with EoE will respond to PPI. Initial response >50% is possible with the elimination diet plus PPI, but many will fail to undergo food reintroduction, or will cease the diet and relapse, resulting in only one in four patient sustaining remission at 9 months. Budesonide is very effective short term, but longer term study is needed.

Seasonal recurrence of food bolus obstruction in eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a newly recognised condition that is apparently increasing in prevalence, and the aetiology is poorly understood. The role of aeroallergens in EoE is controversial, given the success of dietary therapy. Massive aeroallergen exposure leading to food bolus obstruction events (FBOE) has been described, and the diagnosis of EoE by esophageal biopsy noted to be more common in the pollen season according to previous case series. AIM: To determine if a seasonal variation and a geographical variation occurred in EoE presenting as FBOE in adults, and to track the prevalence of FBOE and EoE over time. METHOD: A retrospective case-control study analysis was performed from January 2002 to January 2012 to identify all FBOE in adults presenting to five tertiary hospitals in Melbourne, Australia. Endoscopy, histopathological reports, case notes and blood tests were examined, and postcodes recorded. Records of pollen counts were obtained. Cases were defined according to esophageal biopsy and grouped based on month of diagnosis. All other causes of FBOE served as controls. RESULTS: One thousand, one hundred and thirty-two FBOE were identified. Biopsies were only performed in 278 of these cases, and 85 patients were found to have EoE after biopsy. Patients with EoE were younger (mean age 38 years, range 18-72) compared with those with alternative diagnosis (mean age 64.4 range 22-92), more likely to be male (M : F = 4:1 compared with 1.68:1 ) and had a higher eosinophil count in venous blood. Overall no seasonality was demonstrated in FBOE secondary to any diagnosis, although the six cases of recurrent FBOE secondary to EoE mainly occurred in the grass pollen season in subsequent years. FBOE cases were evenly distributed throughout metropolitan Melbourne irrespective of population density. EoE as a percentage of FBOE increased over time. CONCLUSION: Seasonal aeroallergens may be important for a subgroup of patients with EoE presenting as recurrent FBOE. Esophageal biopsies are performed in a minority of patients, representing a significant departure from ideal management and contributing to recurrent unnecessary FBOE. EoE is an increasingly important cause of FBOE.

Identifying multidrug resistance in previously treated tuberculosis patients: a mixed-methods study in Cambodia.

SETTING: Previously treated tuberculosis (TB) patients are a priority for drug susceptibility testing (DST) to identify cases with multidrug-resistant TB (MDR-TB). A Cambodia study found that one third of smear-positive previously treated patients had DST results. OBJECTIVE: To quantify the gaps in the detection of MDR-TB in previously treated TB patients in Cambodia, and describe health workers' perspectives on barriers, facilitators and potential interventions. DESIGN: Analysis of Cambodia's 2004-2012 case notifications and semi-structured interviews with stakeholders. RESULTS: The proportion of previously treated notifications varied significantly across provinces in 2010-2012. If there had been no attrition along the path to detecting MDR-TB among smear-positive notified cases in 2012, an estimated 75 additional MDR-TB cases could have been identified, which would double the number actually detected. Most were lost due to misclassification of previously treated patients as 'new'. Barriers include patients' reluctance to disclose and staff difficulty in eliciting treatment history, partly attributed to the availability of streptomycin (SM) only in hospitals. Facilitators include collection of sputum for DST even if previously treated patients are not receiving SM, streamlining sputum transportation and prompt reporting of results. CONCLUSION: Improved monitoring, supportive staff supervision and training, patient education, and correct classification of previously treated cases are essential for improving the detection of MDR-TB.

Intranasally administered serelaxin abrogates airway remodelling and attenuates airway hyperresponsiveness in allergic airways disease.

BACKGROUND: The peptide hormone relaxin plays a key role in the systemic hemodynamic and renovascular adaptive changes that occur during pregnancy, which is linked to its antiremodelling effects. Serelaxin (a recombinant form of human gene-2 relaxin) has been shown to inhibit lung fibrosis in various disease models and reverse airway remodelling and airway hyperresponsiveness (AHR) in allergic airways disease (AAD). OBJECTIVE: Although continuous systemic delivery of exogenous serelaxin alleviates allergic fibrosis and AHR, more direct routes for administration into the lung have not been investigated. Thus, intranasal administration of serelaxin was evaluated for its ability to reverse airway remodelling and AHR associated with AAD. METHODS: Female Balb/c mice were subjected to a 9-week model of chronic AAD. Subgroups of animals (n = 12/group) were then treated intranasally with serelaxin (0.8 mg/mL) or vehicle once daily for 14 days (from weeks 9-11). Saline-sensitized/challenged mice treated with intranasal saline served as additional controls. Differential bronchoalveolar lavage (BAL) cell counts, ovalbumin (OVA)-specific IgE levels, tissue inflammation, parameters of airway remodelling and AHR were then assessed. RESULTS: Chronic AAD was associated with significant increases in differential BAL cell counts, OVA-specific IgE levels, inflammation, epithelial thickening, goblet cell metaplasia, TGF-ß1 expression, epithelial Smad2 phosphorylation (pSmad2), subepithelial collagen thickness, total lung collagen concentration and AHR (all P < 0.05 vs. respective measurements from saline-treated mice). Daily intranasal delivery of serelaxin significantly diminished AAD-induced epithelial thickening, epithelial pSmad2, subepithelial and total lung collagen content (fibrosis) and AHR (all P < 0.05 vs. vehicle-treated AAD mice). CONCLUSIONS AND CLINICAL RELEVANCE: Intranasal delivery of serelaxin can effectively reduce airway remodelling and AHR, when administered once daily. Respirable preparations of serelaxin may have therapeutic potential for the prevention and/or reversal of established airway remodelling and AHR in asthma.

Risk factors for eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a chronic antigen driven disease, whereby food and/or aeroallergens result in inflammation and luminal narrowing, and the clinical symptoms of dysphagia and food bolus obstruction events (FBOE). Established risk factors are male gender, Caucasian race and atopy. Increased risk amongst family members, and a single nucleotide polymorphism (SNP) in a gene coding thymic stromal lymphopoietin (TSLP) on the pseudoautosomal region of the X and Y chromosomes supports a genetic predisposition. Environmental factors including the timing and nature of food and aeroallergen exposure to the developing immune system may be important, whilst esophageal barrier function integrity and the influence of microbiota are worthy of future research.

Plasminogen-stimulated airway smooth muscle cell proliferation is mediated by urokinase and annexin A2, involving plasmin-activated cell signalling.

BACKGROUND AND PURPOSE: The conversion of plasminogen into plasmin by interstitial urokinase plasminogen activator (uPA) is potentially important in asthma pathophysiology. In this study, the effect of uPA-mediated plasminogen activation on airway smooth muscle (ASM) cell proliferation was investigated. EXPERIMENTAL APPROACH: Human ASM cells were incubated with plasminogen (0.5-50 µg·mL(-1) ) or plasmin (0.5-50 mU·mL(-1) ) in the presence of pharmacological inhibitors, including UK122, an inhibitor of uPA. Proliferation was assessed by increases in cell number or MTT reduction after 48 h incubation with plasmin(ogen), and by earlier increases in [(3) H]-thymidine incorporation and cyclin D1 expression. KEY RESULTS: Plasminogen (5 µg·mL(-1) )-stimulated increases in cell proliferation were attenuated by UK122 (10 µM) or by transfection with uPA gene-specific siRNA. Exogenous plasmin (5 mU·mL(-1) ) also stimulated increases in cell proliferation. Inhibition of plasmin-stimulated ERK1/2 or PI3K/Akt signalling attenuated plasmin-stimulated increases in ASM proliferation. Furthermore, pharmacological inhibition of cell signalling mediated by the EGF receptor, a receptor trans-activated by plasmin, also reduced plasmin(ogen)-stimulated cell proliferation. Knock down of annexin A2, which has dual roles in both plasminogen activation and plasmin-signal transduction, also attenuated ASM cell proliferation following incubation with either plasminogen or plasmin. CONCLUSIONS AND IMPLICATIONS: Plasminogen stimulates ASM cell proliferation in a manner mediated by uPA and involving multiple signalling pathways downstream of plasmin. Targeting mediators of plasminogen-evoked ASM responses, such as uPA or annexin A2, may be useful in the treatment of asthma.

Multidrug resistance in new tuberculosis patients: burden and implications.

In 2010, 30 countries with anti-tuberculosis drug resistance surveillance data were each estimated to have more than 700 multidrug-resistant tuberculosis (MDR-TB) cases among their notified TB cases. New TB patients comprised a median of 54% (interquartile range 45-67) of the MDR-TB cases. The occurrence of MDR-TB in a new TB patient is a warning sign that MDR-TB is spreading in a community. While MDR-TB case-finding efforts should first prioritize previously treated patients, reaching universal access requires rapidly adding other risk groups, and then all new TB patients. Epidemiological data as presented in this paper can help inform country scale-up plans.

Demand valve oxygen: a promising new oxygen delivery system for the acute treatment of cluster headache.

OBJECTIVE: To show that demand valve oxygen is an effective acute treatment for cluster headache and to compare this oxygen delivery technique with standard cluster headache therapy of continuous flow oxygen. METHODS: Single-center, open-label, two-period, two-treatment crossover design, pilot study was used. Subjects treated with one of two sequences: first, headache treated with continuous flow oxygen (100% oxygen at 15 liters per minute), and subsequent with demand valve oxygen, or vice versa. Treatment began when pain was at least moderate. Subjects taught a specific breathing technique for demand valve oxygen that included initial period of hyperventilation. Primary end point was headache response (moderate-to-very-severe pain reduced to mild or none) after 30 minutes of treatment. RESULTS: Three subjects completed the trial, while a fourth completed demand valve oxygen only. All had chronic cluster headache. All subjects treated with demand valve oxygen became pain-free (time in minutes: 15, 19, 6, 8). Three of four had no recurrence within 24 hours. Demand valve oxygen reduced cranial autonomic symptoms in all and resolved them in two subjects. For continuous flow oxygen, two of three subjects became pain-free (20, 10 minutes). Continuous flow oxygen reduced but did not eliminate cranial autonomic symptoms. Continuous flow oxygen had higher recurrence rates. No adverse events noted with either treatment. CONCLUSION: Demand valve oxygen appears to be an effective acute treatment for cluster headache. All subjects became headache-free. Time to pain freedom was fast (average 12 minutes). The small number of study subjects does not allow a direct comparison of efficacy between demand valve oxygen and continuous high flow oxygen.

Female cluster headache in the United States of America: what are the gender differences? Results from the United States Cluster Headache Survey.

OBJECTIVE: To present results from the United States Cluster Headache Survey regarding gender differences in cluster headache demographics, clinical characteristics, diagnostic delay, triggers, treatment response and personal burden. BACKGROUND: Very few studies have looked at the gender differences in cluster headache presentation. The United States Cluster Headache Survey is the largest study of cluster headache sufferers ever completed in the United States and it is also the largest study of female cluster headache patients ever presented. METHODS: The total survey consisted of 187 multiple choice questions which dealt with various issues related to cluster headache including: demographics, clinical characteristics, concomitant medical conditions, family history, triggers, smoking history, diagnosis, treatment response and personal burden. A group of questions were specifically targeted to female cluster headache patients. The survey was placed on a website from October to December 2008. For all survey responders the diagnosis of cluster headache needed to be made by a neurologist but there was no validation of the headache diagnosis by the authors. RESULTS: 1134 individuals completed the survey (816 male, 318 female). Key Points that define the differences between female and male cluster headache include: a. Age of onset: women develop cluster headache at an earlier age than men and are more likely to develop a second peak of cluster headache onset after 50 years of age. b. Family history: woman cluster headache sufferers are more likely to have a family history of both cluster headache and migraine and have an increased familial risk of Parkinson's disease. c. Comorbid conditions: female cluster headaches sufferers are significantly more likely to experience depression and have asthma than males. d. Aura issues: aura with cluster headache is equally common in both sexes, but aura duration is shorter in women. Women are much more likely to experience sensory, language and brainstem auras. e. Pain location: cluster headache pain is typically retro-orbital in location in both sexes but women are significantly more likely to experience cluster headache pain in the jaw, cheek and ear than men. f. Associated symptoms: women with cluster headache develop more "migrainous" associated symptoms than men, especially nausea and they are also more likely to have self-injurious behavior than men. g. Triggers: women with cluster headache are much less likely to have alcohol trigger a headache, but are significantly more likely to have "migrainous" triggers for their cluster headaches than men. h. Smoking issues: women are much less likely to have a smoking history than male cluster headache sufferers, more likely to have never smoked prior to cluster headache onset. i. Cycle issues: spring and fall are the most common time to start a cluster headache cycle in both sexes. Women are statistically significantly less likely to start a cluster headache cycle in the months of October­December than men. Women have more attacks per day and higher pain intensity nighttime attacks than men. j. TREATMENT: in regard to acute treatment women statistically were less response to sumatriptan injectable and nasal spray than men, but statistically more likely to respond to inhaled lidocaine. There was equal efficacy in the sexes to inhaled oxygen but slower response in women. For preventive treatment no significant gender differences were noted, but overall women were less responsive to almost all preventives than men. k. Diagnostic delay: there remains a significant diagnostic delay for cluster headache patients in both sexes but women were more likely to be diagnosed after 10 years of symptom onset than males and significantly fewer women were diagnosed correctly at an initial physician visit than men. l. Female specific issues: cluster headache does not appear to be influenced by menses or menopause but 50% of the survey responders stated their headaches improved with pregnancy. Cluster headache does not appear to alter fertility rates in female cluster headache sufferers. m. Personal burden: cluster headache causes significantly more personal burden in women than men with more loss of employment and/or need of disability, as well as more homebound days. CONCLUSION: Overall women and men with cluster headache have a similar presentation but there are some distinct differences that have been suggested in smaller studies of female cluster headache that we have now verified, while some of our study conclusions have not been shown previously. One major limitation to the study is a lack of validation of diagnosis. A substantial false positive cluster headache diagnosis rate, especially in females, cannot be excluded by the study methods utilized.

Cluster headache in the United States of America: demographics, clinical characteristics, triggers, suicidality, and personal burden.

OBJECTIVE: To present results from the United States (US) Cluster Headache Survey including data on cluster headache demographics, clinical characteristics, suicidality, diagnostic delay, triggers, and personal burden. BACKGROUND: There are few large-scale studies looking at cluster headache patients and none from the USA. This manuscript will present data from The US Cluster Headache Survey, the largest survey ever completed of cluster headache patients living in the USA. METHODS: The total survey was composed of 187 multiple-choice questions that dealt with issues related to cluster headache including demographics, clinical characteristics, comorbid medical conditions, family history, triggers, smoking history, and personal burden. The survey was placed on a Web site from October through December 2008. RESULTS: A total of 1134 individuals completed the survey (816 male, 318 female). Some key highlights from the survey include the following: (1) diagnostic delay: there remains a significant diagnostic delay for cluster headache patients on average 5+ years with only 21% receiving a correct diagnosis at time of initial presentation. (2) Suicidality: suicidal ideations are substantial, occurring in 55%. (3) Eye color: the predominant eye color in cluster headache patients is brown and blue, not hazel as suggested in previous descriptions. (4) Laterality: cluster headache has a right-sided predominance. (5) Attack profile: in US cluster headache sufferers, most attacks occur between early evening and early morning hours with peak time of headache onset between midnight and 3 am; the circadian periodicity for cluster headache is present but is not as predominant in the population as previously thought. (6) Triggers: beer is the most common type of alcohol trigger in US cluster headache patients; noted migraine triggers such as weather changes and smells are also very common cluster headache triggers. (7) Medical comorbidities: peptic ulcer disease does not have a high prevalence in US cluster headache patients as suggested by previous literature; cluster headache is associated with a low prevalence of cardiac disease as well as cerebrovascular disease even though the majority of patients are chronic heavy smokers. In US cluster headache sufferers, there appears to be comorbidity with restless leg syndrome, and this has not been demonstrated in non-US cluster headache populations. (8) Personal burden: cluster headache is disabling to the individual as almost 20% of cluster headache patients have lost a job secondary to cluster headache, while another 8% are out of work or on disability secondary to their headaches. CONCLUSION: Some findings from the US Cluster Headache Survey expound on what is currently known about cluster headache, while some of the results contradict what has been previously written, while other information is completely new about this fascinating headache disorder.

WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update.

The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care. WHO commissioned external reviews to summarise evidence on priority questions regarding case-finding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting ≥ 20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation. Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens.

Inhaled oxygen and cluster headache sufferers in the United States: use, efficacy and economics: results from the United States Cluster Headache Survey.

OBJECTIVE: To present results from the United States Cluster Headache Survey concerning the use of inhaled oxygen as acute treatment for cluster headache (CH). BACKGROUND: Several small clinic and community-based investigations have indicated that more than 50% of CH patients have never used oxygen for the treatment of their headaches. This statistic is alarming and the reasons why they have not tried oxygen have not been determined. METHODS: The United States Cluster Headache Survey is the largest study ever completed looking at CH sufferers living in the United States. The total survey consisted of 187 multiple choice questions, 84 questions dealt with oxygen use, efficacy and economics. The survey was placed on a website from October to December 2008. RESULTS: A total of 1134 individuals completed the survey (816 male, 318 female). Among them 868 patients had episodic CH while 266 had chronic CH. Ninety-three percent of survey responders were aware of oxygen as a CH therapy; however, 34% had never tried oxygen. Forty-four percent of patients had to suggest oxygen to their physicians to get prescribed. Twelve percent of physicians refused to prescribe oxygen. Fifty percent using oxygen never received training on proper use. Forty-five percent had to find their own source for oxygen. On prescriptions only 45% specified flow rate, 50% stated CH as diagnosis and 28% indicated mask type. Seventy percent of the surveyed population felt oxygen was effective but only 25% was presently using oxygen. Potential reasons for this finding include: oxygen is slow to onset; prescribed oxygen flow rates are too low for efficacy and most CH patients need to raise flow rates during attacks to achieve response. The efficacy of oxygen does not vary by the age of the patient, gender, the number of CH attacks per day, and smoking history. Episodic CH responds better and faster to inhaled oxygen than chronic CH. Oxygen plus a triptan may be more efficacious and faster at aborting a CH than a triptan alone. Sixteen percent of CH patients state that oxygen is unaffordable while 12% are getting welder grade oxygen because of costs of medical grade oxygen, and this form of oxygen could be potentially dangerous to the individual user. CONCLUSIONS: Oxygen is underutilized by CH patients living in the United States. Current recommended oxygen treatment regime is not meeting the needs of many CH patients. Prescribed oxygen flow rates are too low for efficacy. Oxygen can be expensive and very difficult to obtain. Physicians need to be better educated on the use of inhaled oxygen for CH.

Predicting outcomes and drug resistance with standardised treatment of active tuberculosis.

New World Health Organization guidelines recommend initial treatment of active tuberculosis (TB) with a 6-month regimen utilising rifampin throughout. We have modelled expected treatment outcomes, including drug resistance, with this regimen, compared to an 8-month regimen with rifampin for the first 2 months only, followed by standardised retreatment. A deterministic model was used to predict treatment outcomes in hypothetical cohorts of 1,000 new smear-positive cases from seven countries with varying prevalence of initial drug resistance. Model inputs were taken from published systematic reviews. Predicted outcomes included number of deaths, failures and relapses, plus the proportion with drug resistance. Sensitivity analyses examined different risks of acquired drug resistance. Compared to use of the standardised 8-month regimen, for every 1,000 new TB cases treated with the 6-month regimen we predict that 48-86 fewer persons will require retreatment, and 3-12 deaths would be avoided. However, the proportion failing or relapsing after retreatment is predicted to be higher, because with the 6-month regimen 50-94% of failures and 3-56% of relapses will have multidrug-resistant TB. We predict substantial public health benefits from changing from the 8-month to the 6-month regimen. However in almost all settings the current standardised retreatment regimen will no longer be adequate.

The role of SMAD4 in early-onset colorectal cancer.

OBJECTIVE: Chromosomal loss within the region of 18q and loss of SMAD4 expression have been reported to be frequent somatic events during colorectal cancer tumour progression; however, their associations with age at onset have not been widely studied. METHOD: We analysed 109 tumours from a population-based case-family study based on colorectal cancers diagnosed before the age of 45 years. These patients with early-onset colorectal cancer had been previously screened for germ-line mismatch repair gene mutations, microsatellite instability (that included the mononucleotide repeat in TGFbetaRII) and somatic k-ras mutations. We measured SMAD4 protein expression using immunohistochemistry and SMAD4 copy number using quantitative real-time PCR. RESULTS: Loss of SMAD4 protein expression was observed in 27/109 (25%) of cancers tested and was more commonly observed in rectal tumours (15/41, 36%) when compared with tumours arising in the colon (11/66, 17%) (P = 0.04). There was no association between SMAD4 protein expression and TGFbetaR11 mutation status, SMAD4 copy number, family history, MSI status, tumour stage or grade. CONCLUSION: Loss of SMAD4 expression is a common feature of early-onset colorectal tumours as it is in colorectal cancers diagnosed in other age-groups. Taken together, the molecular pathways (genetic and epigenetic) now known to be involved in early-onset colorectal cancer only explain a small proportion of the disease and require further exploration.

The effects of current therapies on airway remodeling in asthma and new possibilities for treatment and prevention.

Airway inflammation, airway remodeling and airway hyperresponsiveness are the fundamental components of pathogenesis that lead to symptoms and lung function changes in asthma. Airway remodeling describes the structural changes to the airways in asthma. The remodeling process involves diverse pathological changes including epithelial metaplasia, subepithelial fibrosis, angiogenesis and smooth muscle thickening. Airway remodeling contributes to irreversible loss of lung function and airway hyperresponsiveness. Remodeling is associated with severe and persistent disease but can also occur early in the course of disease pathogenesis and does not resolve spontaneously. Current asthma therapies, for example corticosteroids, are successful in treating allergic inflammation, an important factor contributing to remodeling, but do not specifically target the remodeling process, and remodeling changes progress despite optimal control of inflammation. Moreover, airway remodeling is not eradicated or prevented despite widespread use of anti-inflammatory treatments. There is limited evidence for the effectiveness of leukotriene inhibitors, phosphodiesterase inhibitors, mast cell tryptase inhibitors, and peroxisome proliferator-activated receptor gamma agonists in the treatment or prevention of remodeling changes. The search for novel therapies that can specifically reverse or prevent airway remodeling is an active area of research. Treatments that may be useful in preventing airway remodeling include those that directly or indirectly target single or multiple components of the airway remodeling process. Identification of novel asthma genes may also allow disease targeting. A better understanding of airway remodeling in asthma will facilitate the development of new treatments for asthma beyond control of symptoms and inflammation.