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Background Onychomycosis is a difficult-to-treat fungal nail infection whose treatment can involve systemic or topical antifungal approaches. Objectives To assess the efficacy and safety of terbinafine 10% nail lacquer in distal lateral subungual onychomycosis (DLSO). Patients/methods Patients with mild-to-moderate DLSO were randomised (3:3:1) to receive double-blind topical terbinafine 10% (n = 406) or its vehicle (n = 410) administered once daily for 4 weeks and then once weekly for 44 weeks, or open-label topical amorolfine 5% (n = 137) for 48 weeks, with a 12-week follow-up period. The primary efficacy endpoint, complete cure rate at Week 60, was a composite of negative potassium hydroxide (KOH) microscopy, negative culture for dermatophytes and no residual clinical involvement of the target big toenail. Results Complete cure rates at Week 60 in the terbinafine, vehicle and amorolfine groups were 5.67%, 2.20% and 2.92%, respectively (odds ratio (OR) vs vehicle = 2.68; 95% confidence intervals (CI): 1.22-5.86; p = .0138). Statistically significant differences in responder (negative KOH and negative culture and ≤10% residual clinical involvement) and mycological cure rates (negative KOH and negative culture) at Week 60 were obtained between terbinafine and vehicle. Terbinafine was well-tolerated with no systemic adverse reactions identified; the most common topical adverse reactions were erythema and skin irritation. Conclusions Terbinafine 10% nail lacquer was an effective treatment for mild-to-moderate onychomycosis improving both clinical and mycological criteria compared with vehicle. Furthermore, there may be some benefits compared to the currently available topical agent, amorolfine 5%. Treatment was well-tolerated and safe.

Objective We present the results of a cross‐cultural validation of the Mental Health Global State (MHGS) scale for adults and adolescents (

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the clinical effects and safety of haloperidol compared to olanzapine for people with schizophrenia and schizophrenia‐like illnesses.

Spleen tyrosine kinase (Syk) is essential for signal transduction of immunoreceptors. Inhibition of Syk abrogates mast cell degranulation and B cell responses. We hypothesized that Syk inhibition in the lung by inhaled route could block airway mast cells degranulation and the early asthmatic response without the need of systemic exposure. We discovered LAS189386, a novel Syk inhibitor with suitable properties for inhaled administration. The aim of this study was to characterize the in vitro and in vivo profile of LAS189386. The compound was profiled in Syk enzymatic assay, against a panel of selected kinases and in Syk-dependent cellular assays in mast cells and B cells. Pharmacokinetics and in vivo efficacy was assessed by intratracheal route. Airway resistance and mast cell degranulation after OVA challenge was evaluated in an ovalbumin-sensitized Brown Norway rat model. LAS189386 potently inhibits Syk enzymatic activity (IC50 7.2 nM), Syk phosphorylation (IC50 41 nM), LAD2 cells degranulation (IC50 56 nM), and B cell activation (IC50 22 nM). LAS189386 inhibits early asthmatic response and airway mast cell degranulation without affecting systemic mast cells. The present results support the hypothesis that topical inhibition of Syk in the lung, without systemic exposure, is sufficient to inhibit EAR in rats. Syk inhibition by inhaled route constitutes a promising therapeutic option for asthma.

Long-acting muscarinic antagonists are widely used to treat chronic obstructive pulmonary disease (COPD). In addition to bronchodilation, muscarinic antagonism may affect pulmonary histopathological changes. The effects of long-acting muscarinic antagonists have not been thoroughly evaluated in experimental models of COPD induced by chronic exposure to cigarette smoke (CS). We investigated the effects of aclidinium bromide on pulmonary function, airway remodeling, and lung inflammation in a CS-exposed model of COPD. A total of 36 guinea pigs were exposed to CS and 22 were sham exposed for 24 weeks. Animals were nebulized daily with vehicle, 10 μg/ml, or 30 μg/ml aclidinium, resulting in six experimental groups. Pulmonary function was assessed weekly by whole-body plethysmography, determining the enhanced pause (Penh) at baseline, after treatment, and after CS/sham exposure. Lung changes were evaluated by morphometry and immunohistochemistry. CS exposure increased Penh in all conditions. CS-exposed animals treated with aclidinium showed lower baseline Penh than untreated animals (P = 0.02). CS induced thickening of all bronchial wall layers, airspace enlargement, and inflammatory cell infiltrate in airways and septa. Treatment with aclidinium abrogated the CS-induced smooth muscle enlargement in small airways (P = 0.001), and tended to reduce airspace enlargement (P = 0.054). Aclidinium also attenuated CS-induced neutrophilia in alveolar septa (P = 0.04). We conclude that, in guinea pigs chronically exposed to CS, aclidinium has an antiremodeling effect on small airways, which is associated with improved respiratory function, and attenuates neutrophilic infiltration in alveolar septa. These results indicate that, in COPD, aclidinium may exert beneficial effects on lung structure in addition to its bronchodilator action.

Background and purpose The Janus Kinase (JAK) family mediates the cytokine receptor-induced signalling pathways involved in inflammatory processes. The activation of the signal transducers and activators of transcription (STATs) by JAK kinases is a key point in these pathways. Four JAK proteins, JAK1, JAK2, JAK3 and tyrosine kinase 2 (Tyk2) associate with the intracellular domains of surface cytokine receptors are phosphorylating STATs and modulating gene expression. The aim of this study was to explore the role of JAK inhibition in an acute model of inhaled lipopolysaccharide (LPS)-induced airway inflammation in rats through evaluating the effects of tofacitinib, a marketed pan-JAK inhibitor. Specifically, some pulmonary inflammation parameters were studied and the lung STAT3 phosphorylation was assessed as a target engagement marker of JAK inhibition in the model. Experimental approach Rats were exposed to an aerosol of LPS (0.1 mg/ml) or phosphate-buffered saline (PBS) during 40 min. Bronchoalveolar lavage fluid (BALF) and lung samples were collected 4 h after PBS or LPS exposure. Neutrophils in BALF were counted and a panel of cytokines were measured in BALF. Phosphorylation of STAT3 was studied in lung homogenates by ELISA and localization of phospho-STAT3 (pSTAT3) in lung tissue was also evaluated by immunohistochemistry. In order to assess the effect of JAK inhibition, tofacitinib was administered 1 h before challenge at doses of 3, 10 and 30 mg/kg p.o. Key results Inhaled LPS challenge induced an augment of neutrophils and cytokines in the BALF as well as an increase in pSTAT3 expression in the lungs. Tofacitinib by oral route inhibited the LPS-induced airway neutrophilia, the levels of some cytokines in the BALF and the phosphorylation of STAT3 in the lung tissue. Conclusions and implications In summary, this study shows that JAK inhibition ameliorates inhaled LPS-induced airway inflammation in rats, suggesting that at least JAK/STAT3 signalling is involved in the establishment of the pulmonary neutrophilia induced by LPS. JAKs inhibitors should be further investigated as a potential therapy for respiratory inflammatory diseases.

Data from the Mexican national leprosy control programme 1989-2009 are described and analysed. After initial increases associated with the introduction of MDT and the start of the global elimination initiative in the early 1990 s, both prevalence and incidence declined dramatically throughout most of the country. Reported prevalence fell below 1 per 10000 in 1994 and has remained below that level ever since. There is considerable geographic heterogeneity, with highest case detection rates in western states bordering the Pacific and lowest in the south east. Reasons for these geographic differences are unclear. There is evidence of increases in average age of cases, and in proportions male and MB, as in several other populations with declining leprosy. There is some evidence of increasing leprosy in states bordering on Texas, USA, where M. leprae is known to be harboured in armadillos. The relevance of armadillos for leprosy in Mexico is unclear but a priority question.

Pain is a complex disease that usually remains poorly treated or undertreated, especially the neuropathic pain caused by injury to the peripheral or central nervous system. Antagonists of the NMDA receptor complex have emerged as potential drugs for pain management. A strong case is being raised for non-competitive or uncompetitive antagonists with low-to-moderate affinity and fast on/offset kinetics as drugs with good therapeutic profiles, because of their reduced side effects.

RESUMEN: Objetivo: Observar las relaciones entre estatus socioeco-nómico, estatura y problemas nutricionales de sobrepe-so, obesidad, riesgo de complicaciones metabólicas en hombres y mujeres de Medellín. Métodos: estudio transversal, descriptivo con una mues-tra de 5,556 adultos con edades entre 18 y 69 años. Se evaluaron peso, estatura y perímetro de cintura. Como variables socioeconómicas se evaluaron los ingresos fa-miliares, el estrato socioeconómico y el nivel educativo. Resultados: Se encontró que en hombres y mujeres la estatura alcanzada está asociada con las condiciones so-cioeconómicas medidas por estrato e ingresos familiares. En las mujeres la estatura alcanzada, la edad y el estrato están asociados con la obesidad, el sobrepeso y los ries-gos de complicaciones metabólicas. Conclusión: la obesidad, el sobrepeso y el riesgo de com-plicaciones metabólicas en la adultez son el resultado no solo de hábitos individuales no saludables como patrón alimentario basado en alimentos altamente energéticos, sumado a bajo gasto calórico, sino también a una acumu-lación de privaciones alimentarias a lo largo de la vida y deben ser intervenidas antes del nacimiento y durante la infancia y la adultezÁlvarez LS et al / Colombia Médica - Vol. 44 Nº 3, 2013 (Jul-Sep) ABSTRACT: Objective: to observe the relationship between socioeconomic status, height and nutritional problems related to obesity, overweight and risk of metabolic complications in men and women of Medellin (Colombia). Methods: cross-sectional study with a sample of 5,556 adults between 18 and 69 years of age. We assessed weight, height and waist circumference. Socioeconomic variables were evaluated by family income, socioeconomic stratum and academic level achieved. Results: we found that in men and women the height reached in adulthood is associated with socioeconomic conditions as measured by the socioeconomic strata and family income. In women, height, age, and socioeconomic strata are associated with obesity, overweight and risk of obesity, and risk of metabolic complications. Conclusion: These results are not only from individual unhealthy habits, such as eating patterns based on high density foods combined with low energy expenditure, but also from the cumulative effect of food deprivation throughout life. Therefore, policies intended to prevent them should take a preventive approach that begins before birth and continues during childhood and adulthood COL0065608 COL0003249

Vanilloid receptor subunit 1 (TRPV1) is an integrator of physical and chemical stimuli in the peripheral nervous system. This receptor plays a key role in the pathophysiology of inflammatory pain. Thus, the identification of receptor antagonists with analgesic and anti-inflammatory activity in vivo is an important goal of current neuropharmacology. Here, we report that [L-arginyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl) glycinamide (H-Arg-15-15C) is a channel blocker that abrogates capsaicin and pH-evoked TRPV1 channel activity with submicromolar activity. Compound H-Arg-15-15C preferentially inhibits TRPV1, showing marginal block of other neuronal receptors. Compound H-Arg-15-15C acts as a noncompetitive capsaicin antagonist with modest voltage-dependent blockade activity. The compound inhibited capsaicin-evoked nerve activity in afferent fibers without affecting mechanically activated activity. Notably, administration of compound H-Arg-15-15C prevented the irritant activity of a local administration of capsaicin and formalin and reversed the thermal hyperalgesia evoked by injection of complete Freund’s adjuvant. Furthermore, it attenuated carrageenan-induced paw inflammation. Compound H-Arg-15-15C specifically decreased inflammatory conditions without affecting normal nociception. Taken together, these findings demonstrate that compound H-Arg-15-15C is a channel blocker of TRPV1 with analgesic and anti-inflammatory activity in vivo at clinically useful doses and substantiate the tenet that TRPV1 plays an important role in the etiology of chronic inflammatory pain., Supported by grants from the Ministerio de Educacion Ciencia y Deporte (SAF 2003/0509), La Fundación Ramón Areces (01/08-500), and Generalitat Valenciana (GV04B-0398) to A.F.M., PROFIT-090000-2001-70 and CDTI-03-006 (Ministerio de Industria) to DiverDrugs, SL.

28 pages, 5 figures., Inflammatory pain is a condition caused by tissue injury and requires efficient drug treatment. The identification and cloning of the vanilloid receptor TRPV1 represents a significant step in the clarification of the molecular mechanisms underlying transduction of noxious chemical and thermal stimuli by peripheral nociceptors. Because of its central implication in hyperalgesia, the TRPV1 receptor has emerged as a key therapeutic target for inflammatory pain management. Modulators of the TRPV1 receptor complex are considered to be useful and selective painkillers. The challenge, however, is to develop receptor-selective drugs that preserve the physiological activity of TRPV1 receptors while correcting those contributing to pathology. Thus, normal proprioceptive and nociceptive responses that represent a safety mechanism to prevent tissue injury must be preserved., Financial support from grants from MCYT, Fundació La Caixa, Fundació Marató TV3, and FIS.

IFSCC Magazine, 11 (2008) (4) 311–315 This paper was presented as a keynote lecture at the IFSCC Congress 2008, Barcelona, Spain. Cutaneous neurogenic inflammation is emerging as an underlying mechanism for several skin conditions. The intimate cross-talk between the cutaneous immune system and the peripheral nervous system is fundamental for skin biology. However, an imbalance or dysfunction results in the onset of an inflammatory state that is reinforced by the synergic and complementary action of both systems. Cumulative evidence indicates that the thermoreceptor TRPV1 is a key player of neurogenic inflammation. This receptor is activated by both physical and chemical stimuli, and its activity is potentiated by pro-inflammatory mediators. An increase in TRPV1 activity results in an increment of neuronal excitability that leads to the release of proalgesic agents that stimulate the immune system. Therefore, the TRPV1 receptor is being considered as a cosmeceutical target, and agents that reduce its activity will be useful cosmeceuticals. Keywords: Algogens, epidermis, immune system, nociceptor, sensitization