Asthma control and exacerbations: two different sides of the same coin.

Purpose of review: Optimal asthma management includes both the control of asthma symptoms and reducing the risk of future asthma exacerbations. Traditionally, treatment has been adjusted largely on the basis of symptoms and lung function and for many patients, this approach delivers both excellent symptom control and reduced risk. However, the relationship between these two key components of the disease may vary between different asthmatic phenotypes and disease severities and there is increasing recognition of the need for more individualized treatment approaches.

Recent findings: A number of factors which predict exacerbation risk have been identified including demographic and behavioural features and specific inflammatory biomarkers. Type-2 cytokine-driven eosinophilic airways inflammation predisposes to frequent exacerbations and predicts response to corticosteroids, and the usefulness of sputum eosinophilia as both a marker of exacerbation risk and biomarker for adjustment of corticosteroid treatment has been established for some time. However, attempts to develop surrogate markers, which would be more straightforward to deliver in the clinic, have been challenging.

Summary: Some patients with asthma have persistent symptoms in the absence of type-2 cytokine driven-eosinophilic airways inflammation due to noncorticosteroid responsive mechanisms (T2-low disease). Composite biomarker strategies using easily measured surrogate indicators of type-2 inflammation (such as fractional exhaled nitric oxide, blood eosinophil count and serum periostin levels) may predict exacerbation risk better but it is unclear if they can be used to adjust corticosteroid treatment. Biomarkers will be used to target novel biologic treatments but additionally may be used to optimize corticosteroid treatment dose and act as prognostics for exacerbation risk and potentially other important longer term asthma outcomes.

Drug therapies in severe asthma - the era of stratified medicine

Difficult-to-treat asthma affects up to 20% of patients with asthma and is associated with significant healthcare cost. It is an umbrella term that defines a heterogeneous clinical problem including incorrect diagnosis, comorbid conditions and treatment non-adherence; when these are effectively addressed, good symptom control is frequently achieved. However, in 3–5% of adults with difficult-to-treat asthma, the problem is severe disease that is unresponsive to currently available treatments. Current treatment guidelines advise the ‘stepwise’ increase of corticosteroids, but it is now recognised that many aspects of asthma are not corticosteroid responsive, and that this ‘one size fits all’ approach does not deliver clinical benefit in many patients and can also lead to side effects. The future of management of severe asthma will involve optimisation with currently available treatments, particularly corticosteroids, including addressing non-adherence and defining an ‘optimised’ corticosteroid dose, allied with the use of ‘add-on’ target-specific novel treatments. This review examines the current status of novel treatments and research efforts to identify novel targets in the era of stratified medicines in severe asthma.

Anti-Tumor Necrosis Factor Alpha-Induced Drug Eruptions: One Patient, More Than a Pattern

Background: Tumor necrosis factor alpha (TNFα) antagonists are effective in treating several immune-inflammatory diseases, including psoriasis and inflammatory bowel disease. The paradoxical and unpredictable induction of psoriasis and psoriasiform skin lesions is a recognized adverse event, although of unclear aetiology. However, histological analysis of these eruptions remains insufficient, yet suggesting that some might constitute a new pattern of adverse drug reaction, rather than true psoriasis. Case report: The authors report the case of a 43-year-old woman with severe recalcitrant Crohn disease who started treatment with infliximab. There was also a personal history of mild plaque psoriasis without clinical expression for the past eight years. She developed a heterogeneous cutaneous eruption of psoriasiform morphology with pustules and crusts after the third infliximab infusion. The histopathological diagnosis was of a Sweet-like dermatosis. The patient was successfully treated with cyclosporine in association with both topical corticosteroid and vitamin D3 analogue. Three weeks after switching to adalimumab a new psoriasiform eruption was observed, histologically compatible with a psoriasiform drug eruption. Despite this, and considering the beneficial effect on the inflammatory bowel disease, it was decided to maintain treatment with adalimumab and to treat through with topicals, with progressive control of skin disease. Discussion: Not much is known about the pathogenesis of psoriasiform eruptions induced by biological therapies, but genetic predisposition and Koebner phenomenon may contribute to it. Histopathology can add new facets to the comprehension of psoriasiform reactions. In fact, histopathologic patterns of such skin lesions appear to be varied, in a clear asymmetry with clinical findings. Conclusion: The sequential identification in the same patient of two clinical and histopathologic patterns of drug reaction to TNFα antagonists is rare. Additionally, to the authors’ knowledge, there is only one other description in literature of a TNFα antagonist-induced Sweet-like dermatosis, emphasizing the singularity of this case report.

Acute Upper Limb Ischemia, a Rare Presentation of Giant Cell Arteritis

Giant cell arteritis (GCA) is a systemic large vessel vasculitis, with extracranial arterial involvement described in 10-15% of cases, usually affecting the aorta and its branches. Patients with GCA are more likely to develop aortic aneurysms, but these are rarely present at the time of the diagnosis. We report the case of an 80-year-old Caucasian woman, who reported proximal muscle pain in the arms with morning stiffness of the shoulders for eight months. In the previous two months, she had developed worsening bilateral arm claudication, severe pain, cold extremities and digital necrosis. She had no palpable radial pulses and no measurable blood pressure. The patient had normochromic anemia, erythrocyte sedimentation rate of 120 mm/h, and a negative infectious and autoimmune workup. Computed tomography angiography revealed concentric wall thickening of the aorta extending to the aortic arch branches, particularly the subclavian and axillary arteries, which were severely stenotic, with areas of bilateral occlusion and an aneurysm of the ascending aorta (47 mm). Despite corticosteroid therapy there was progression to acute critical ischemia. She accordingly underwent surgical revascularization using a bilateral carotid-humeral bypass. After surgery, corticosteroid therapy was maintained and at six-month follow-up she was clinically stable with reduced inflammatory markers. GCA, usually a chronic benign vasculitis, presented exceptionally in this case as acute critical upper limb ischemia, resulting from a massive inflammatory process of the subclavian and axillary arteries, treated with salvage surgical revascularization.

Remodelage neuronal de la cicatrice cardiaque suite à un infarctus du myocarde

Suite à un infarctus du myocarde, la formation d’une cicatrice, nommée fibrose de réparation, représente un processus adaptatif et essentiel empêchant la rupture du myocarde. La cicatrice est constituée de myofibroblastes, de cellules vasculaires, de fibres sympathiques ainsi que de cellules souches neuronales cardiaques exprimant la nestine. Une perturbation au niveau de ces constituants cellulaires résulte en une formation maladaptative de la cicatrice et éventuellement, une diminution de la fonction cardiaque. La compréhension des événements cellulaires ainsi que les mécanismes sous-jacents participant à cette fibrose est alors d’une importance primordiale. Cette thèse est axée sur l’identification du rôle du système sympathique et des cellules souches neuronales cardiaques exprimant la nestine dans la formation de la cicatrice ainsi que leur interaction potentielle. Nos travaux examinent l’hypothèse que les cellules souches neuronales exprimant la nestine sont endogènes au cœur et que suite à un dommage ischémique, elles contribuent à la réponse angiogénique et à la réinnervation sympathique du tissu lésé. Les cellules souches neuronales exprimant la nestine sont retrouvées dans les cœurs de différentes espèces incluant le cœur infarci humain. Elles sont résidentes dans le cœur, proviennent de la crête neurale lors du développement et sont intercalées entre les cardiomyocytes n’exprimant pas la nestine. Suite à leur isolation de cœurs infarcis de rats, les cellules souches neuronales cardiaques prolifèrent sous forme de neurosphères et, dans des conditions appropriées in vitro, se différencient en neurones exprimant le neurofilament-M. Suite à un infarctus du myocarde, les niveaux de l’ARNm de nestine sont significativement augmentés au niveau de la région infarcie et non-infarcie. Nos résultats suggèrent que cette augmentation de l’expression de nestine dans la cicatrice reflète en partie la migration des cellules souches neuronales cardiaques exprimant la nestine de la région non-infarcie vers la région infarcie. Lors de la fibrose de réparation, ces cellules représentent un substrat cellulaire pour la formation de nouveaux vaisseaux et contribuent aussi à la croissance des fibres sympathiques dans la région infarcie. Finalement, nous démontrons que la formation de la cicatrice est associée à une innervation sympathique de la région infarcie et péri-infarcie. De plus, les fibres sympathiques présentes dans la région infarcie sont observées à proximité de vaisseaux de petits calibres. Ces données suggèrent indirectement que l’innervation de la cicatrice par les fibres sympathiques peut jouer un rôle dans la réponse angiogénique suite à un infarctus du myocarde. Suite à l’administration du corticostéroïde dexaméthasone, nous détectons un amincissement de la cicatrice, associé à une réduction significative des fibres sympathiques exprimant le neurofilament-M dans la région infarcie et péri-infarcie. La diminution de la densité de ces fibres par le dexaméthasone peut être reliée à une diminution de la prolifération des myofibroblastes et de la production de l’ARNm du facteur neurotrophique nerve growth factor.

Caractérisation de l'état hypercoagulable associé à l'hyperadrénocorticisme chez le chien

Cette étude avait comme objectif d’évaluer la coagulation par l’utilisation de la thrombélastographie (TEG®) et de la génération de thrombine (GT) chez des beagles en santé recevant de la prednisone ainsi que chez des chiens atteints d’hyperadrénocorticisme (HAC). Dans un premier temps, six beagles adultes en santé ont été évalués dans une étude prospective longitudinale au courant de laquelle chaque individu recevait 1 mg/kg/jour de prednisone par la voie orale pendant 2 semaines. Après un arrêt de traitement d’une durée de 6 semaines, ils ont finalement reçu 4 mg/kg/jour de prednisone pour encore 2 semaines. Les tracés TEG® et les mesures de la GT ont été obtenus au temps 0, à la fin des 6 semaines d’interruption de traitement, ainsi qu’à la suite des 2 dosages de prednisone. Suite aux 2 traitements avec la prednisone, des résultats significatifs,lorsque comparés aux valeurs de base, ont été obtenus pour la cinétique du caillot (« clot kinetics » ou K), l’angle alpha (α) et l’amplitude maximale (« maximal amplitude » ou MA). La GT avait augmenté de manière significative mais seulement après la dose de 1 mg/kg/jour de prednisone. Dans un deuxième temps, 16 chiens atteints d’HAC ont été évalués avant l’initiation d’un traitement pour leur condition. Quinze chiens ont été évalués par TEG® et 15 par GT. Les données obtenues ont ensuite été comparées aux valeurs normales. L’analyse par TEG® a démontré que 12/15 chiens avaient au moins un paramètre suggérant un état d’hypercoagulabilité. L’analyse par GT a démontré que 4/15 chiens avaient des changements compatibles avec un état d’hypercoagulabilité. Un test t-pairé pour des valeurs de variance inégales a démontré que le groupe de chiens atteints d’HAC avait des tracés hypercoagulables et un potentiel endogène de thrombine (« endogenous thrombin potential » ou ETP) plus élevé, lorsque comparé à la population de référence.

Transforaminal versus intra-articular facet steroid injections for the treatment of cervical radiculopathy : a randomized, double-blinded, controlled study.

Cette étude a été subventionnée par le Fonds de recherche du Québec - Santé (FRQ-S, grant # 21230 – 2)

Desenlaces maternos y fetales en el manejo expectante de la preeclampsia lejos del término

Introducción La preeclampsia hace parte del espectro de los trastornos hipertensivos asociados al embarazo y es causa de alta morbimortalidad materna. La edad gestacional ha sido relacionada con la presentación más severa de esta cuando ocurren lejanas al término. Hoy en día existe la posibilidad de proporcionar manejo expectante en estos casos en unidades de cuidado obstétrico especializadas, con el fin de disminuir el riesgo de morbimortalidad asociada a la prematurez extrema. Metodología Se realizó un estudio de corte transversal que incluyó pacientes con preeclampsia lejos del término entre las 24 y 34 semanas que recibieron manejo expectante entre 2009 y 2012 en la Unidad de Cuidado Intensivo Obstétrico de la Clínica Colsubsidio Orquídeas. Resultados Se incluyeron 121 pacientes con preeclampsia lejos del término, quienes recibieron manejo expectante. La edad promedio fue 29.8, el promedio de días de manejo expectante fue 4 días, con una mediana de tres días. La edad gestacional de ingreso fue 30 1/7 semanas y la edad promedio de terminación 30 5/7 semanas. El 88.4% recibieron esquema de maduración completo. El 81.6% presentaron preeclampsia severa. El desenlace materno más frecuente fue Síndrome Hellp (37%) y el desenlace fetal fue restricción de crecimiento intrauterino (29%). Discusión Se debe considerar el manejo expectante en toda paciente con preeclampsia previa a la semana 34 para manejo antenatal con corticoesteroides, el cual demostró ser un factor protector para muerte perinatal temprana. No se encontraron diferencias significativas entre la aparición de complicaciones y la cantidad de días de manejo expectante.

Evidencia actual sobre características demográficas en mastitis granulomatosa idiopática

Introducción: La mastitis granulomatosa idiopática es una enfermedad crónica benigna, rara y de etiología desconocida; tiende a confundirse con otras enfermedades debido a síntomas similares. Este estudio pretende identificar y cuantificar las características demográficas, los antecedentes ginecoobstétricos relevantes y las manifestaciones clínicas prediagnósticas de esta enfermedad Metodología: Se realizó una revisión sistemática con análisis agrupado de datos tipo meta análisis. Se utilizó una estrategia de búsqueda en PubMed. Todos los estudios relacionados con la definición, manifestaciones clínicas, diagnóstico, tratamiento y pronóstico de la mastitis granulomatosa idiopática fueron elegibles. Las variables de interés fueron edad, país, antecedente de contracepción hormonal, tiempo de evolución, tiempo desde el último embarazo, diagnóstico inicial, y manifestaciones clínicas previas a la consulta. No hubo restricción en fechas de publicación. Resultados: Fueron incluidas 641 mujeres con diagnóstico de MGI reportadas en 68 publicaciones que cumplieron los criterios de selección. La edad media fue 35.9 años, 14.1% de ellas estaba embarazada o lactando, el antecedente de consumo de anticonceptivos hormonales fue 21% y el tiempo promedio desde el último parto fue de 3.9 años. La afectación ocurre principalmente en mama izquierda y en cuadrante superoexterno. El cáncer de mama y el absceso mamario son diagnósticos diferenciales en la consulta. Discusión: El diagnóstico de MGI es un reto para el ginecólogo desde la consulta inicial. Debido a que sus manifestaciones clínicas no son específicas, su diagnóstico parece apuntar a la necesidad de un proceso de descarte de otras patologías más frecuentes e incluso de peor pronóstico. Palabras clave mastitis granulomatosa idiopática

Identification of stimulatory and inhibitory inputs to the hypothalamic-pituitary-adrenal axis during hypoglycaemia or transport in ewes

This study used the novel approach of statistical modelling to investigate the control of hypothalamic-pituitary-adrenal (HPA) axis and quantify temporal relationships between hormones. Two experimental paradigms were chosen, insulin-induced hypoglycaemia and 2 h transport, to assess differences in control between noncognitive and cognitive stimuli. Vasopressin and corticotropin-releasing hormone (CRH) were measured in hypophysial portal plasma, and adrenocorticotropin hormone (ACTH) and cortisol in jugular plasma of conscious sheep, and deconvolution analysis was used to calculate secretory rates, before modelling. During hypoglycaemia, the relationship between plasma glucose and vasopressin or CRH was best described by log(10) transforming variables (i.e. a positive power-curve relationship). A negative-feedback relationship with log(10) cortisol concentration 2 h previously was detected. Analysis of the 'transport' stimulus suggested that the strength of the perceived stimulus decreased over time after accounting for cortisol facilitation and negative-feedback. The time course of vasopressin and CRH responses to each stimulus were different However, at the pituitary level, the data suggested that log(10) ACTH secretion rate was related to log(10) vasopressin and CRH concentrations with very similar regression coefficients and an identical ratio of actions (2.3 : 1) for both stimuli. Similar magnitude negative-feedback effects of log(10) cortisol at -110 min (hypoglycaemia) or -40 min (transport) were detected, and both models contained a stimulatory relationship with cortisol at 0 min (facilitation). At adrenal gland level, cortisol secretory rates were related to simultaneously measured untransformed ACTH concentration but the regression coefficient for the hypoglycaemia model was 2.5-fold greater than for transport. No individual sustained maximum cortisol secretion for longer than 20 min during hypoglycaemia and 40 min during transport. These unique models demonstrate that corticosteroid negative-feedback is a significant control mechanism at both the pituitary and hypothalamus. The amplitude of HPA response may be related to stimulus intensity and corticosteroid negative-feedback, while duration depended on feedback alone.

Estudo do papel da proteína multifuncional APE1/Ref-1 sobre a resposta inflamatória na meningite bacteriana

Despite advances in antibiotic therapy, bacterial meningitis (BM) remains with high mortality and morbidity rates in worldwide. One important mechanism associated to sequels during disease is the intense inflammatory response which promotes an oxidative burst and release of reactive oxygen species, consequently leading to cell death. Activation of DNA repair enzymes during oxidative stress has been demonstrated in several neurological disorders. APE1/Ref-1 is a multifunctional protein involved in DNA repair and plays a redox function on transcription factors such as NFkB and AP-1.The aim of this study was assess the role of APE1/Ref-1 on inflammatory response and the possibility of its modulation to reduce the sequels of the disease. Firstly it was performed an assay to measure cytokine in cerebrospinal fluid of patients with BM due to Streptococcus pneumoniae and Neisseriae meningitides. Further, a cellular model of inflammation was used to observe the effect of the inhibition of the endonuclease and redox activity of APE1/Ref-1 on cytokine levels. Additionally, APE1/Ref-1 expression in cortex and hippocampus of rat with MB after vitamin B6 treatment was evaluated. Altogether, results showed a similar profile of cytokines in the cerebrospinal fluid of patients from both pathogens, although IFNy showed higher expression in patients with BM caused by S. pneumoniae. On the other hand, inhibitors of APE1/Ref-1 reduced cytokine levels, mainly TNF-α. Reduction of oxidative stress markers was also observed after introduction of inhibitors in the LPS-stimulated cell. In the animal model, BM increased the expression of the protein APE1/Ref-1, while vitamin B6 promoted reduction. Thereby, this data rise important factors to be considered in pathogenesis of BM, e.g., IFNy can be used as prognostic factor during corticosteroid therapy, APE1/Ref-1 can be an important target to modulate the level of inflammation and VIII oxidative stress, and vitamin B6 seems modulates several proteins related to cell death. So, this study highlights a new understanding on the role of APE1/Ref-1 on the inflammation and the oxidative stress during inflammation condition

Adult partner preference and sexual behavior of male rats exposed prenatally to betamethasone

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Primary cutaneous cryptococcosis in Brazil: report of 11 cases in immunocompetent and immunosuppressed patients

Background Primary cutaneous cryptococcosis is an uncommon infectious disease caused by Cryptococcus neoformans or Cryptococcus gattii affecting immunosuppressed as well as immunocompetent patients. It is often misdiagnosed as it may mimic other cutaneous diseases. Materials and methods We report a series of cases diagnosed from 2005 to 2010 in two general hospitals. The diagnosis in all patients was made on the basis of histopathology and culture. Phenoloxidase and canavanine-glycine-bromothymol blue tests were used in order to identify the Cryptococcus species. Systematic investigation ruled out the systemic involvement in every case. Results Eleven patients, 81.8% male, were diagnosed during this study. The immunosuppression status was identified in 54.5% of patients, and all of them were under corticosteroid therapy due to a variable set of diseases. All patients presented with circumscribed lesions on their upper limbs. Most lesions showed an infiltrative or tumoral aspect with up to 40 cm diameter. Fluconazole, up to 400 mg/daily, was the main therapeutic regimen and proved to be efficient. Conclusions Primary cutaneous cryptococcosis has been diagnosed in both immunosuppressed and immunocompetent patients. Its peculiar clinical aspect could facilitate early diagnosis. Culture and biochemical tests should be performed in order to define the species involved.

Predictors of first-year survival in patients with advanced COPD treated using long-term oxygen therapy

Little evidence-based guidance is available to aid clinicians in determining short-term prognoses in very severe COPD patients. Therefore, the present study was designed to provide a prospective assessment (1) of the mortality rates and (2) whether the baseline measurements may be determinants of 1-year mortality in hypoxemic COPD patients receiving long-term oxygen therapy (LTOT).Seventy-eight clinically stable patients with advanced COPD treated using LTOT were enrolled in a prospective cohort study. Outcome variable: first-year mortality. Baseline measurements: categorical variables: age (<60 or >= 60 years); gender; body mass index (<20 or >= 20 kg/m(2)); fat-free mass (FFM) index (<16 [men] and <15kg/m(2) [women]; baseline dyspnea index (BDI) (<= 3 or >3); and corticosteroid use. Continuous variables: smoking history; lung function; FFM; fat mass; hemoglobin; hematocrit; arterial blood gases; forearm muscle strength; St. George's Respiratory Questionnaire (SGRQ); and comorbidity score. By the end of 1-year of follow-up, 12 patients (15.4%) had died. Kaplan-Meier curves showed that BDI <= 3 was the only variable associated with higher mortality. Cox proportional hazards analysis revealed that tower PaO2 and SPO2, higher PaCO2 and SGRQ scores were associated with reduced survival. In the multivariate analysis, BDI remained predictive of mortality (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.31-0.81), as did PaO2 (HR, 0.49; 95% CI, 0.26-0.95). These data suggest that readily available parameters as dyspnea intensity and hypoxemia severity may be useful in predicting first-year survival rates in advanced COPD patients receiving LTOT (C) 2007 Elsevier Ltd. All rights reserved.

Fatores de risco associados à mortalidade de recém-nascidos de muito baixo peso na cidade de Botucatu, São Paulo, no período 1995-2000

OBJETIVOS: avaliar as práticas assistenciais, a ocorrência de doenças, a mortalidade durante a hospitalização e os fatores associados em recém-nascidos prematuros de muito baixo peso (PT-MBP). MÉTODOS: estudo transversal comparando dois períodos: 1995-1997 e 1998-2000 e envolvendo todos os PT-MBP nascidos vivos (n= 451), em um centro perinatal, em Botucatu, São Paulo, Brasil. Os fatores de risco pré-natal e pós-natal foram submetidos a análise multivariada. RESULTADOS: a mortalidade diminuiu de 36,2% para 29,5%. A sobrevida melhorou e foi superior a 50% a partir de 28 semanas e de 750 g de peso. O uso de corticosteróide antenatal aumentou de 25% para 42%, o surfactante exógeno de 14% para 28%, com redução na incidência e gravidade da síndrome do desconforto respiratório. A regressão logística mostrou que a síndrome do desconforto respiratório grave, Odds ratio=18, e a sepse precoce, Odds ratio=2,8, foram importantes fatores de risco para morte em 1995-1997. No período de 1998-2000, a sepse precoce e tardia, Odds ratio=10,5 e 12, respectivamente, aumentaram o risco de morte. CONCLUSÕES: a melhora na assistência perinatal diminuiu a mortalidade do PT-MBP. O aumento na exposição antenatal ao corticosteróide diminuiu a gravidade da síndrome do desconforto respiratório. em 1998-2000, a sepse foi o único fator de risco para morte.