Long-term exposure to GDNF induces dephosphorylation of Ret, AKT, and ERK1/2, and is ineffective at protecting midbrain dopaminergic neurons in cellular models of Parkinson's disease.

Glial cell line-derived neurotrophic factor (GDNF) promotes differentiation, proliferation, and survival in different cell types, including dopaminergic neurons. Thus, GDNF has been proposed as a promising neuroprotective therapy in Parkinson's disease. Although findings from cellular and animal models of Parkinson's disease were encouraging, results emerging from clinical trials were not as good as expected, probably due to the inappropriate administration protocols. Despite the growing information on GDNF action mechanisms, many aspects of its pharmacological effects are still unclear and data from different studies are still contradictory. Considering that GDNF action mechanisms are mediated by its receptor tyrosine kinase Ret, which activates PI3K/AKT and MAPK/ERK signaling pathways, we aimed to investigate Ret activation and its effect over both signaling pathways in midbrain cell cultures treated with GDNF at different doses (0.3, 1, and 10 ng/ml) and times (15 min, 24 h, 24 h (7 days), and 7 continuous days). The results showed that short-term or acute (15 min, 24 h, and 24 h (7 days)) GDNF treatment in rat midbrain neurons increases Tyrosine hydroxylase (TH) expression and the phosphorylation levels of Ret (Tyr 1062), AKT (Ser 473), ERK1/2 (Thr202/Tyr204), S6 (Ser 235/236), and GSK3-ß (Ser 9). However, the phosphorylation level of these kinases, TH expression, and dopamine uptake, decreased below basal levels after long-term or prolonged treatment with 1 and 10 ng/ml GDNF (7 continuous days). Our data suggest that long-term GDNF treatment inactivates the receptor by an unknown mechanism, affecting its neuroprotective capacity against degeneration caused by 6-OHDA or rotenone, while short-term exposure to GDNF promoted dopaminergic cell survival. These findings highlight the need to find new and more effective long-acting therapeutic approaches for disorders in which GDNF plays a beneficial role, including Parkinson's disease. In this regard, it is necessary to propose new GDNF treatment guidelines to regulate and control its long-term expression levels and optimize the clinical use of this trophic factor in patients with Parkinson's disease.

Recommendations for the prevention and diagnosis of asthma in children: Evidence from international guidelines adapted for Mexico

BACKGROUND: With the availability of high-quality asthma guidelines worldwide, one possible approach of developing a valid guideline, without re-working the evidence, already analysed by major guidelines, is the ADAPTE approach, as was used for the development of National Guidelines on asthma. METHODS: The guidelines development group (GDG) covered a broad range of experts from medical specialities, primary care physicians and methodologists. The core group of the GDG searched the literature for asthma guidelines 2005 onward, and analysed the 11 best guidelines with AGREE-II to select three mother guidelines. Key clinical questions were formulated covering each step of the asthma management. RESULTS: The selected mother guidelines are British Thoracic Society (BTS), GINA and GEMA 2015. Responses to the questions were formulated according to the evidence in the mother guidelines. Recommendations or suggestions were made for asthma treatment in Mexico by the core group, and adjusted during several rounds of a Delphi process, taking into account: 1. Evidence; 2. Safety; 3. Cost; 4. Patient preference - all these set against the background of the local reality. Here the detailed analysis of the evidence present in BTS/GINA/GEMA sections on prevention and diagnosis in paediatric asthma are presented for three age-groups: children with asthma ≤5 years, 6-11 years and ≥12 years. CONCLUSIONS: For the prevention and diagnosis sections, applying the AGREE-II method is useful to develop a scientifically-sustained document, adjusted to the local reality per country, as is the Mexican Guideline on Asthma

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Recommendations for the prevention and diagnosis of asthma in children: Evidence from international guidelines adapted for Mexico.

BACKGROUND: With the availability of high-quality asthma guidelines worldwide, one possible approach of developing a valid guideline, without re-working the evidence, already analysed by major guidelines, is the ADAPTE approach, as was used for the development of National Guidelines on asthma. METHODS: The guidelines development group (GDG) covered a broad range of experts from medical specialities, primary care physicians and methodologists. The core group of the GDG searched the literature for asthma guidelines 2005 onward, and analysed the 11 best guidelines with AGREE-II to select three mother guidelines. Key clinical questions were formulated covering each step of the asthma management. RESULTS: The selected mother guidelines are British Thoracic Society (BTS), GINA and GEMA 2015. Responses to the questions were formulated according to the evidence in the mother guidelines. Recommendations or suggestions were made for asthma treatment in Mexico by the core group, and adjusted during several rounds of a Delphi process, taking into account: 1. Evidence; 2. Safety; 3. Cost; 4. Patient preference - all these set against the background of the local reality. Here the detailed analysis of the evidence present in BTS/GINA/GEMA sections on prevention and diagnosis in paediatric asthma are presented for three age-groups: children with asthma ≤5 years, 6-11 years and ≥12 years. CONCLUSIONS: For the prevention and diagnosis sections, applying the AGREE-II method is useful to develop a scientifically-sustained document, adjusted to the local reality per country, as is the Mexican Guideline on Asthma.

Frequency of adverse events and mortality in patients with pleural empyema in a public referral hospital in Mexico City.

SETTING: Adverse events (AEs) that occur during medical treatment are a public health problem. OBJECTIVE: 1) To measure the prevalence of AEs, 2) to characterize those that occur in patients diagnosed with empyema and 3) to analyze the mortality rate associated with the presence of empyema. DESIGN: Retrospective case series based on a review of files of patient diagnosed with empyema. RESULTS: A total of 347 files were assessed, reporting 96.6% of the total number of patients diagnosed with empyema in that period. There were 176 AEs reported for 150 of the patients. The frequency of at least one AE was 43%, with prolonged hospitalization being the most frequent condition. In these cases, 97% of the AEs were considered preventable. Intrahospital mortality was 4.8%, with age (HR for every 5 years 1.21, 95%CI 1.08-1.35, P < 0.001) and the presence of diabetes mellitus (HR 2.26, 95%CI 1.0-5.0, P = 0.04) being significant associated factors. CONCLUSION: There was a high frequency of AEs in patients with empyema, but most were considered preventable, especially the length of hospitalization, which could be reduced through timely surgery.

[Validation of a visual analog scale to measure dyspnea in patients with diffuse interstitial lung disease]. / Validación de una escala análoga visual para medir disnea en pacientes con enfermedad pulmonar intersticial difusa.

In order to validate a form of measuring dyspnea, a visual analog scale (VAS) was applied to 27 patients with different types of interstitial lung diseases (ILD). The test was done in two days with an interval of one month (dyspnea1 and dyspnea2). Additionally, the forced vital capacity (FVC) was obtained on these occasions (FVC1, FVC2). Nineteen patients with a recent diagnosis of ILD (RD) and eight with a previous diagnosis of ILD (PD) were included. In patients with RD, dyspnea1 correlated with FVC1 (r = -0.66, p < 0.01). A month after the initial treatment with steroids, dyspnea (mean +/- SD) decreased from 38 +/- 25 mm to 17 +/- 19 mm (p < 0.03), while the FVC increased from 1086 +/- 464 mL to 1350 +/- 536 mL (p < 0.05). Likewise, dyspnea2 correlated with FVC2 (r = -0.47, p < 0.05). As expected, patients with PD did not exhibit significant changes in the analysis of dyspnea on the second evaluation. The inter-observer coefficient of variation for the 8 patients with PD was of 5% and 9% for the first and second evaluations respectively, while the intraclass correlation coefficient was 0.92 and 0.91 respectively. The intra-observer coefficient of variation of two different observers was of 15% and 16% respectively, while the intraclass correlation coefficient was 0.69 and 0.62 respectively. These results suggest that the use of a VAS might be useful for the initial evaluation and during the follow-up of patients with ILD.