A short in-frame deletion in NTRK1 tyrosine kinase domain caused by a novel splice site mutation in a patient with congenital insensitivity to pain with anhidrosis

Background: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive genetic disease characterized by the lack of reaction to noxious stimuli and anhidrosis. It is caused by mutations in the NTRK1 gene, which encodes the high affinity tyrosine kinase receptor I for Neurotrophic Growth Factor (NGF). -- Case Presentation: We present the case of a female patient diagnosed with CIPA at the age of 8 months. The patient is currently 6 years old and her psychomotor development conforms to her age (RMN, SPECT and psychological study are in the range of normality). PCR amplification of DNA, followed by direct sequencing, was used to investigate the presence of NTRK1 gene mutations. Reverse transcriptase (RT)-PCR amplification of RNA, followed by cloning and sequencing of isolated RT-PCR products was used to characterize the effect of the mutations on NTRK1 mRNA splicing. The clinical diagnosis of CIPA was confirmed by the detection of two splice-site mutations in NTRK1, revealing that the patient was a compound heterozygote at this gene. One of these alterations, c.574+1G > A, is located at the splice donor site of intron 5. We also found a second mutation, c.2206-2 A > G, not previously reported in the literature, which is located at the splice acceptor site of intron 16. Each parent was confirmed to be a carrier for one of the mutations by DNA sequencing analysis. It has been proposed that the c.574+1G > A mutation would cause exon 5 skipping during NTRK1 mRNA splicing. We could confirm this prediction and, more importantly, we provide evidence that the novel c.2206-2A > G mutation also disrupts normal NTRK1 splicing, leading to the use of an alternative splice acceptor site within exon 17. As a consequence, this mutation would result in the production of a mutant NTRK1 protein with a seven aminoacid in-frame deletion in its tyrosine kinase domain. --Conclusions: We present the first description of a CIPA-associated NTRK1 mutation causing a short interstitial deletion in the tyrosine kinase domain of the receptor. The possible phenotypical implications of this mutation are discussed.

Monitorización avanzada en el posoperatorio de las cardiopatías congénitas : motorización hemodinámica avanzada en el posoperatorio de cardiopatías congénitas mediante termodilución transpulmonar y espectroscopia cercana al infrarrojo

196 p. : graf.

Randomised, crossover clinical trial, in healthy volunteers, to compare the systemic availability of two topical intranasal budesonide formulations

Background: Budesonide has a long history as intranasal drug, with many marketed products. Efforts should be made to demonstrate the therapeutic equivalence and safety comparability between them. Given that systemic availability significantly varies from formulations, the clinical comparability of diverse products comes to be of clinical interest and a regulatory requirement. The aim of the present study was to compare the systemic availability, pharmacodynamic effect, and safety of two intranasal budesonide formulations for the treatment of rhinitis. Methods: Eighteen healthy volunteers participated in this randomised, controlled, crossover, clinical trial. On two separated days, subjects received a single dose of 512 mu g budesonide (4 puffs per nostril) from each of the assayed devices (Budesonida nasal 64 (R), Aldo-Union, Spain and Rhinocort 64 (R), AstraZeneca, Spain). Budesonide availability was determined by the measurement of budesonide plasma concentration. The pharmacodynamic effect on the hypothalamic-adrenal axis was evaluated as both plasma and urine cortisol levels. Adverse events were tabulated and described. Budesonide availability between formulations was compared by the calculation of 90% CI intervals of the ratios of the main pharmacokinetic parameters describing budesonide bioavailability. Plasma cortisol concentration-time curves were compared by means of a GLM for Repeated Measures. Urine cortisol excretion between formulations was compared through the Wilcoxon's test. Results: All the enroled volunteers successfully completed the study. Pharmacokinetic parameters were comparable in terms of AUC(t) (2.6 +/- 1.5 vs 2.2 +/- 0.7), AUCi (2.9 +/- 1.5 vs 2.4 +/- 0.7), t(max) (0.4 +/- 0.1 vs 0.4 +/- 0.2), C(max)/AUC(i) (0.3 +/- 0.1 vs 0.3 +/- 0.0), and MRT (5.0 +/- 1.4 vs 4.5 +/- 0.6), but not in the case of C(max) (0.9 +/- 0.3 vs 0.7 +/- 0.2) and t(1/2) (3.7 +/- 1.8 vs 2.9 +/- 0.4). The pharmacodynamic effects, measured as the effect over plasma and urine cortisol, were also comparables between both formulations. No severe adverse events were reported and tolerance was comparable between formulations. Conclusion: The systemic availability of intranasal budesonide was comparable for both formulations in terms of most pharmacokinetic parameters. The pharmacodynamic effect on hypothalamic-pituitary-adrenal axis was also similar. Side effects were scarce and equivalent between the two products. This methodology to compare different budesonide-containing devices is reliable and easy to perform, and should be recommended for similar products intented to be marketed or already on the market.

Social, economic, and health impact of the respiratory syncytial virus: a systematic search

Background: Bronchiolitis caused by the respiratory syncytial virus (RSV) and its related complications are common in infants born prematurely, with severe congenital heart disease, or bronchopulmonary dysplasia, as well as in immunosuppressed infants. There is a rich literature on the different aspects of RSV infection with a focus, for the most part, on specific risk populations. However, there is a need for a systematic global analysis of the impact of RSV infection in terms of use of resources and health impact on both children and adults. With this aim, we performed a systematic search of scientific evidence on the social, economic, and health impact of RSV infection. Methods: A systematic search of the following databases was performed: MEDLINE, EMBASE, Spanish Medical Index, MEDES-MEDicina in Spanish, Cochrane Plus Library, and Google without time limits. We selected 421 abstracts based on the 6,598 articles identified. From these abstracts, 4 RSV experts selected the most relevant articles. They selected 65 articles. After reading the full articles, 23 of their references were also selected. Finally, one more article found through a literature information alert system was included. Results: The information collected was summarized and organized into the following topics: 1. Impact on health (infections and respiratory complications, mid-to long-term lung function decline, recurrent wheezing, asthma, other complications such as otitis and rhino-conjunctivitis, and mortality; 2. Impact on resources (visits to primary care and specialists offices, emergency room visits, hospital admissions, ICU admissions, diagnostic tests, and treatments); 3. Impact on costs (direct and indirect costs); 4. Impact on quality of life; and 5. Strategies to reduce the impact (interventions on social and hygienic factors and prophylactic treatments). Conclusions: We concluded that 1. The health impact of RSV infection is relevant and goes beyond the acute episode phase; 2. The health impact of RSV infection on children is much better documented than the impact on adults; 3. Further research is needed on mid-and long-term impact of RSV infection on the adult population, especially those at high-risk; 4. There is a need for interventions aimed at reducing the impact of RSV infection by targeting health education, information, and prophylaxis in high-risk populations.