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In the current economic scenario, tourism management emerges as one of the most dynamic activities of global capitalism. Its importance is appreciated in the contribution to the generation of wealth, according to the World Tourism Organization. In this context, transnational capital has forcefully penetrated with into touristic activity. However, the resulting effects in terms of sustainability have not been favorable. Ecuador has not escaped this dynamic, even though the Ministry of Tourism itself establishes the necessary harmony between this economic activity and sustainable development. Therefore, the work presented in this study, aims to analyze the dynamics of tourism planning and competitiveness in Ecuador. The study was developed under the paradigm of qualitative research, through an interpretive design of a literature review. The data was collected from different sources and checked by the researchers through a data triangulation method. The results show that Ecuador is a country with enormous potential to develop a diverse and attractive tourism market. The literature review made it possible to build a theoretical framework of reference, raising awareness about the importance and need of strategic planning for the development of a tourist destination. It also showed the basic structure of the analysis of the competitiveness of the company and addressing the issue through of an actual Ecuadorian case.

IntroducciónEn los últimos años se ha producido un notable interés por la vitamina D, no sólo por su importancia crucial en el metabolismo mineral óseo, sino también por los efectos extraóseos, cada vez mejor conocidos. Asi mismo, se ha constatado la existencia de valores séricos bajos de vitamina D, por debajo de lo deseable, en diferentes poblaciones, tanto sanas como enfermas, y se discute cuáles serían los niveles óptimos de vitamina D en sangre. Por todo ello, la Sociedad Española de Investigación Ósea y Metabolismo Mineral (SEIOMM), conjuntamente con todas las Sociedades Científicas implicadas en el estudio del metabolismo óseo, han elaborado el presente documento de posición sobre las necesidades y niveles óptimos de vitamina D.

Abstract Background Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, and is the most common single-gene disorder known to be associated with autism. Despite recent advances in functional neuroimaging and our understanding of the molecular pathogenesis, only limited neuropathologic information on FXS is available. Methods Neuropathologic examinations were performed on post-mortem brain tissue from three older men (aged 57, 64 and 78 years) who had received a clinical or genetic diagnosis of FXS. In each case, physical and cognitive features were typical of FXS, and one man was also diagnosed with autism. Guided by reports of clinical and neuroimaging abnormalities of the limbic system and cerebellum of individuals with FXS, the current analysis focused on neuropathologic features present in the hippocampus and the cerebellar vermis. Results Histologic and immunologic staining revealed abnormalities in both the hippocampus and cerebellar vermis. Focal thickening of hippocampal CA1 and irregularities in the appearance of the dentate gyrus were identified. All lobules of the cerebellar vermis and the lateral cortex of the posterior lobe of the cerebellum had decreased numbers of Purkinje cells, which were occasionally misplaced, and often lacked proper orientation. There were mild, albeit excessive, undulations of the internal granular cell layer, with patchy foliar white matter axonal and astrocytic abnormalities. Quantitative analysis documented panfoliar atrophy of both the anterior and posterior lobes of the vermis, with preferential atrophy of the posterior lobule (VI to VII) compared with age-matched normal controls. Conclusions Significant morphologic changes in the hippocampus and cerebellum in three adult men with FXS were identified. This pattern of pathologic features supports the idea that primary defects in neuronal migration, neurogenesis and aging may underlie the neuropathology reported in FXS.

Introduction: Preclinical and clinical evidence has elucidated that cannabis-based medical formulations (CBMFs) may display anxiolytic, antidepressive, and neuroprotective properties. CBMFs are often considered as novel therapeutic anxiolytic agents that can be prescribed as pharmacotherapy for symptomatic domains in anxiety disorders (ADs). Our aim was to explore effectiveness and tolerability of enriched cannabidiol (CBD) oil extract formulations in adults with anxiety symptoms in an outpatient mental health program in Colombia during the COVID-19 pandemic., Methods: We conducted an observational, retrospective, real-world evidence case series from electronic health records at Zerenia Clinic in Bogotá, Colombia between June 2021 and December 2022. Our convenience sample consisted of people searching for CBMFs for the treatment of anxiety symptoms. A cohort of 24 adults was prescribed with enriched CBD in the form of non-sterile oral liquids suspended in sesame seed oil extracts for DSM-5 unspecified anxiety disorder and followed throughout the first year of treatment. CBMFs were prepared by dissolving full-spectrum cannabis extracts in sesame seed oil to a standardized concentration of active ingredients which is CBD-enriched. The oil extract contained 100 mg/mL of CBD and less than 1.9 mg/mL of THC. Primary outcome measures established were the anxiety subscale in the Hospital Anxiety and Depression Scale (HADS-A), and the clinical global impression scale with regard to severity (CGI-S) and improvement (CGI-I) at baseline, 6 months, and 12 months during follow-up. Secondary outcome measures established were HADS depression subscale (HADS-D) and the Epworth Sleepiness Scale (ESS), respectively. Participants also completed the patient-reported outcome measures (PROMs) during each visit throughout the 12-month follow-up. PROMs documented both participant's subjective improvement experience and progressive adverse effects., Results: After 6 months of treatment with sublingually administered enriched CBD oil extracts in a median dosage of 100 mg, more than half (54.17%) of the sample continued to report significant anxiety symptoms. After 12 months, only 37.50% persisted with significant anxiety symptoms with a median dose of 120 mg of enriched CBD oil extracts. Similar subjective improvements were reported with regard to sleep disturbances (SDs) as a secondary outcome. At baseline, less than half (46.83%) of the sample reported significant daytime sleepiness. After 6 months of enriched CBD oil extract treatment, less than one third (29.17%) continued to report SDs. At end point, a high proportion of the sample (87.50%) were considered to have normal daytime sleepiness. The cohort showed no clinically relevant depressive symptoms at baseline based on HADS-D scores; therefore, no improvement could be reported throughout the 12-month follow-up. Minimal gender differences with regard to HADS-D scores may be attributed to modifying effects of menopause-related symptoms. No significant adverse drug reactions or deaths were reported during the 12-month follow-up., Conclusions: Further research should determine the long-term efficacy, safety, and appropriate dosages of enriched CBD oil extracts in treating specific ADs rather than broad and unspecified anxiety symptoms. The state of the art of CBMFs for ADs should be warranted by future randomized controlled trials. The next stage for cannabis research should be focused in performing head-to-head trials comparing enriched CBD extracts or capsules versus first-line treatments proven to be effective in ADs., Competing Interests: J.F.G.-F.: full-time employee for Zerenia Clinic in Bogotá (Colombia). Zerenia is a center focused in cannabis-based medical formulations (CBMFs) treatments owned by Khiron Life Science Corp®. Khiron Life Science Corp® is responsible for the manufacturing processes of oil extracts cannabis-based magistral formulation used in this study. H.F.G.-B. and C.A.F.-P.: the authors declare no conflict of interest. C.E.N.: employee for Zerenia Clinic in Bogotá (Colombia). Zerenia is a center which specializes in medical cannabis treatments owned by Khiron Life Science Corp®. Khiron Life Science Corp® is responsible for the manufacturing processes of oil extracts cannabis-based magistral formulation used in this study. G.M.-S.: full-time employee. Scientific director for Khiron Life Science Corp® is responsible for the manufacturing processes of oil extracts cannabis-based magistral formulation used in this study., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Neuropsychiatric symptoms (NPS) may be disruptive and problematic for patients with Alzheimer's disease (AD) and for their caregivers. Cannabidiol (CBD) may be a safer alternative. The objective was to evaluate whether CBD-rich oil was effective, and safe in adults with NPS secondary to AD., Methods: An open-label, prospective cohort, single-center study in patients with AD onset after the age of 65 with untreated NPS. A CBD-rich oil was administrated 0.1 mL sublingually every 8-12 h, up-titrated weekly. The primary outcome was to establish a reduction in the NPI-Q severity score of >30% at 12 weeks compared with the baseline. A p value of <0.05 was statistically significant., Results: Between July 2020 and July 2023, 59 (93.5%) patients completed ≥3 months of follow-up. The patients were under treatment for a mean of 23.2 months, the median dose of CBD was 111 mg/day. The median NPI-Q severity and caregiver's distress scores at baseline were 24 and 29, respectively. At 3 months, the median NPI-Q severity score shifted to 12 ( p < 0.001) and 14 ( p < 0.001), respectively. The proportion of patients who achieved a reduction in the NPI-Q severity score of >30% was 94.9%, while a reduction of >50% was achieved by 54.2%. The improvement was maintained for up to 24 months., Conclusion: This study shows that CBD-rich oil is an effective and safe therapy for treating NPS in AD patients, while also reducing the caregivers' distress., Competing Interests: Cristian E. Navarro worked at Clínica Zerenia in Bogotá (Colombia) which is a reference center specializing in medical cannabis therapy owned by Khiron Life Science Corp®; Khiron Life Science Corp® manufactures the CBMF used in this study. Juan C. Pérez has nothing to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Central nervous system infections are due to different microorganisms such as viruses, bacteria, mycobacteria, fungi, amoebas, and other parasites. The etiology depends on multiple risk factors, and it defines the infection location because some microorganisms prefer meninges, brain tissue, cerebellum, brain stem or spinal cord. The microorganisms induce diseases in the nervous system through direct invasion, neurotoxin production, and the triggered immune response. To determine the infection etiology, there are several diagnostic tests which may be conducted with cerebrospinal fluid, blood, respiratory and stool samples. These tests include but are not limited to direct microscopic examination of the sample, stains, cultures, antigenic tests, nucleic acid amplification tests, metagenomic next-generation sequencing, immunologic biomarker and neuroimaging, especially contrast-enhanced magnetic resonance imaging. The treatment may consist of specific antimicrobial treatment and supportive standard care. Since viruses have no specific antiviral treatment, antimicrobial treatment is mainly targeted at non-viral infections. This article will focus on diagnosis and treatment of acute acquired infections of the central nervous system beyond the neonatal period. The discussion defines the disease, provides the clinical presentation, explains the etiology and risk factors, and briefly mentions potential complications. This updated review aims to provide the reader with all the elements needed to adequately approach a patient with a central nervous system infection. Mycobacterium tuberculosis infection, Cryptococcus spp. infection and vaccines are not within the scope of this article.

This study reexamines the causal nexus among electricity consumption (EC) and economic growth (EG) for a panel of 31 countries in Latin America and the Caribbean between 1980 and 2021. We find that there are statistically significant feedback impacts among the research variables in the long run. A 1 percent augment in EC raises EG by 0.5 percent and a 1 percent augment in EG produces a 1.54 percent increase in EC which reflects the nature of the latter as a luxury good and implies a tradeoff between economy and environment, since although greater electrical infrastructure drives EG, the latter also increases the EC whose use in a non-responsible manner could lead to environmental degradation through higher CO 2 emissions. Therefore, the main policy implication is that, it is necessary to promote EG based on infrastructure focused on sustainable development, ensuring the well-being of present and future generations., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objectives: To determine the cost-effectiveness of the QuantiFERON-TB Gold Plus (QFT-Plus) test versus the tuberculin skin test in diagnosing latent tuberculosis infection in immunocompetent subjects in the context of the Colombian healthcare system., Methods: A hypothetical cohort of 2000 immunocompetent adults vaccinated with Bacillus Calmette-Guérin at birth who are asymptomatic for tuberculosis disease was simulated and included in a decision tree over a horizon of <1 year. The direct healthcare costs related to tests, antituberculosis treatment, and medical care were considered, and diagnostic performance was used as a measure of effectiveness. The incremental cost-effectiveness ratio (ICER) was estimated, and univariate deterministic and probabilistic sensitivity analyses were carried out using 5000 simulations. The currency was the US dollar for the year 2022, with a cost-effectiveness threshold of $6666 USD (1 gross domestic product per capita for 2022)., Results: QFT-Plus was cost-effective with an ICER of $5687 USD for each correctly diagnosed case relative to a threshold of $6666 USD. In the deterministic analysis, QFT-Plus was cost-effective in half of the proposed scenarios. The variable that most affected the ICER was the prevalence of latent tuberculosis and test sensitivities. In the probabilistic analysis, QFT-Plus was cost-effective in 54.74% of the simulated scenarios, and tuberculin skin test was dominant in 13.84%., Conclusions: The study provides evidence of the cost-effectiveness of QFT-Plus compared with the tuberculin skin test in diagnosing latent tuberculosis infection in immunocompetent adults in the Colombian context., Competing Interests: Author Disclosures Author disclosure forms can be accessed in the Supplemental Material section., (Copyright © 2023 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to determine the cost-utility of ocrelizumab versus rituximab in patients with RRMS, from the perspective of the Colombian healthcare system., Methodology: Cost-utility study based on a Markov model, with a 50-year horizon and payer perspective. The currency was the US dollar for the year 2019, with a cost-effectiveness threshold of $5180 defined for Colombian health system. The model used annual cycles according to the health status determined by the disability scale. Direct costs were considered, and the incremental cost-effectiveness ratio per 1 quality-adjusted life-year (QALY) gained was used as the outcome measure. A discount rate of 5% was applied to costs and outcomes. Multiple one-way deterministic sensitivity analyses and 10 000 Monte Carlo simulation were conducted., Results: For the treatment of patients with RRMS, ocrelizumab versus rituximab had an incremental cost-effectiveness ratio of $73 652 for each QALY gained. After 50 years, 1 subject treated with ocrelizumab earns 4.8 QALYs >1 subject treated with rituximab, but at a higher cost of $521 759 versus $168 752, respectively. Ocrelizumab becomes a cost-effective therapy if its price is discounted > 86% or if there is a high willingness to pay., Conclusions: Ocrelizumab was not a cost-effective drug as compared with rituximab in treating patients with RRMS in Colombia., (Copyright © 2023 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Introduction: The safety and efficacy of a formulation high in cannabidiol (CBD) and low in ∆ 9 -tetrahydrocannabinol (THC) to treat drug-resistant epilepsy have been examined previously in children, but not in adult population. The aim of this study was to evaluate whether CBD-rich oil, as an add-on treatment to conventional antiepileptic drugs, was effective, safe, and well-tolerated in adults with drug-resistant focal epilepsy (DRFE)., Methods: An open-label, prospective cohort, single-center in adult patients with DRFE, were receiving stable doses of antiepileptic drugs (AEDs). A cannabis based-magistral formulation (CBMF) (100 mg/ml CBD and THC <1.9 mg/ml) was administrated 0.1 ml sublingually every 12 hours, up-titrated weekly. The primary outcome was to establish a reduction in seizures frequency >50% at 12 weeks. Adverse-drug reactions monitoring was done. p-value <0.05 was statistically significant., Results: Between August 2020 and July 2022, 44 (38.6%) patients completed >3 months of follow-up. The median daily dose of CBD was 200 mg, that of THC was 4 mg, and that of CBD per kilogram of weight was 3.7 mg. The median number of seizures per month before CBD treatment was 11, and after CBD treatment was 2.5 (p<0.001). A reduction in seizures >50% at 12 week was achieved in 79.5% of the patients. The median percentage change in seizure frequency per month was 84.1% at 12 weeks. Five patients reported any adverse-drug reactions., Conclusion: The CBMF is a highly effective and safety therapy to treat adult patients with DRFE. The reduction in seizures frequency is maintained over time., (© 2022. Fondazione Società Italiana di Neurologia.)

Background: CIRPLAST is a nonprofit volunteer plastic surgery program that has provided free surgery for patients with cleft lip and palate deformities in different parts of Peru since 1995. In 2015, the author reported 6,108 patients that had been successfully operated on by the CIRPLAST team over a 20-year period. A technique, developed by the author, for the straight-line vertical cleft lip closure without skin flaps of the unilateral cleft lip, was mentioned in that publication but it was not described. 1 The purpose of this article is to present the technique, which has been successfully employed in all the CIRPLAST cleft missions in Peru, for the past 25 years., Methods: The straight-line vertical cleft closure does not rely on measurements or skin flaps, and it can be used to close any degree of unilateral cleft lip cleft. The procedure is simple and dependable. After incising the cleft borders on both sides of the cleft, the orbicularis oris muscle is liberated from the surrounding tissues, segmented, and then moved down toward the free border of the lip, so that the cupid's bows can be placed in its normal horizontal position, together with the philtrum on the medial lip, providing normal fullness and pouting of the lower part of the upper lip. Lip length results from the orbicularis oris muscle repair and not from skin flaps. The associated nasal deformity is addressed at the same time as the lip repair, by freeing on the cleft side, the lower lateral cartilage (alar cartilage) from the external nasal skin through a rim incision, and then elevating the cartilage together with its vestibular skin, to place it in its normal position at the tip of the nose, and fixing it there with sutures., Results: The anatomic, functional, and esthetic results of the lip closure together with the correction of the associated nasal deformity have been satisfactory, when comparing the repaired cleft side with the normal side, for symmetry., Conclusions: The straight-line vertical cleft lip closure, based on the orbicularis oris muscle repair, can be used to close any degree of lip clefting, including very wide clefts, without skin flaps. The associated cleft nasal deformity is corrected before the lip closure. The procedure has been used in all the CIRPLAST cleft missions in Peru for the past 25 years, and the outcomes of the repair over time have been satisfactory and stable., Competing Interests: The author reports no conflicts of interest., (Copyright © 2020 by Mutaz B. Habal, MD.)

Health sciences libraries offer core resources and services to expand the knowledge and efficiencies of their communities. Increasingly with the growth of big data, open data, and electronic health records, clinical and translational researchers must be more fluent in finding, manipulating, managing, visualizing, and sharing data. To meet such needs, libraries are increasingly creating roles to educate and collaborate on topics related to health informatics and health data. This column provides examples of the work of the health library informaticist at the Blaisdell Medical Library, University of California, Davis, and how the role facilitates health professions students, faculty and staff to access, manage, and use data assets and software tools for working with data.

Background: Awareness in the community is an important factor across a wide range of diseases and the communication media have an important role in its promotion. However, misinformation and misguide may take place heightening the expectations of people affected by chronic conditions such as multiple sclerosis (MS). This study explores media coverage of MS in a low prevalence country., Methods: We identified the most important written media at national and local levels and performed a search in their digital archives and social media with the words "Multiple Sclerosis". The articles found were categorized as relevant, and non-relevant. We describe the total number, number of relevant and non-relevant articles published every year, since the earliest found until 2018. We identified the topics covered by the relevant articles and described their distribution and performed a quality evaluation of their content., Results: We reviewed the archives of 20 sources. A total of 976 articles where MS was mentioned were reviewed (relevant: 143 [14.6%]; non-relevant: 833 [85.4%]). We observed a steady increase in the annual publication rate, from the first in 1991 up to 107 in 2018. The most frequent covered topic was disease modifying therapies and MS itself, and the least documented topic was rehabilitation. Most of the relevant articles had low quality scores., Conclusion: The media coverage of different topics MS has risen steadily since its first appearance in the early nineties. This should be encouraged, but caution should be held so misinformation is not propagated. We call for the public to discuss misleading information with their healthcare providers., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To identify and describe cost-effectiveness studies that  evaluate disease modifying therapies in the context of relapsing- remitting multiple sclerosis., Method: A systematic review of the literature was carried out by  searching MEDLINE, Embase, the Cochrane Library, LILACS, the Tufts  Medical Center Cost-Effectiveness Analysis Registry, the National Health  Service Economic Evaluation Database and Open Grey. The search was  performed in January 2018 and covered articles published between  January 2010 and December 2017. The studies reviewed were payer- perspective cost-effectiveness analyses for interferon beta-1a, interferon beta-1b, glatiramer acetate, teriflunomide, fingolimod, dimethyl  fumarate, natalizumab, alemtuzumab and rituximab. The Quality of  Health Economic Studies instrument was used to determine the quality  of the studies reviewed. Risk of bias was assessed without a  standardized tool. An analysis was made of direct costs, quality- adjusted life-years and the incremental cost-effectiveness ratio. Data  extraction and evaluation of information were conducted separately by  each author., Results: Four hundred one references were found; nine studies were included. A great degree of variability was identified for several  methodological aspects. Two studies that applied the incremental cost- effectiveness ratio (cost) showed no first-line therapy to be cost- effective. A third study demonstrated dominance of interferon beta-1b  over placebo (USD -315,109.45) and a fourth paper showed dominance  of teriflunomide over interferons and glatiramer acetate (USD - 121,840.37). As regards second-line therapies, dimethyl fumarate was  cost-effective in a study that compared it to glatiramer acetate and  interferon beta-1a and it was dominant in another study that compared  it with glatiramer acetate (USD -158,897.93) and fingolimod (USD - 92,988.97). In the third line of treatment, one study showed  natalizumab to be cost-effective as compared with fingolimod, and  another study showed alemtuzumab to be dominant over fingolimod  (USD -49,221). A third trial demonstrated alemtuzumab to be dominant over natalizumab (USD -1,656,266.07). Many of the trials have  sponsorship bias. Eight of the trials received a high QHES score., Conclusions: The present paper shows that cost-effectiveness studies have high levels of methodological variability, some of them  reaching contradictory results. As a result, it is not possible to  determine which disease- modifying therapy is really cost-effective in  the context of relapsingremitting multiple sclerosis., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

Posterior reversible encephalopathy syndrome is a disorder of reversible subcortical vasogenic brain edema in the context of different diseases or exposure to cytotoxic drugs such as fludarabine. We present the case of a pediatric patient with β-thalassemia who develops a fludarabine-induced posterior reversible encephalopathy while he received an induction regimen to achieve an allogenic hematopoietic cell transplantation. The clinical presentation consists in altered mental state, headache, status epilepticus, visual disturbance, and hypertension. His treatment was carried out with the suspension of the medication and the control of hypertension and status epilepticus; the final outcome was positive without additional complications. There are published reports about fludarabine toxicity in the central nervous system with different doses of the drug in different clinical context. We also made a review of the literature available and conclude that fludarabine is not an extraordinary cause of posterior reversible encephalopathy syndrome.

Objective: The aim of this study was to report the case of a male patient with Parkinson disease who developed brachial plexopathy (BP) due to varicella-zoster virus, which was successfully treated with human immunoglobulin., Method: We report the case of a 75-year-old male subject with a diagnosis of Parkinson disease who came to our hospital complaining of pain, skin lesions, and strength loss in his right arm during the past 2 months. Physical examination revealed vesicular rash compatible with varicella-zoster virus lesions. Nerve conduction studies and magnetic resonance imaging of the brachial plexus showed inflammatory changes at that level. A trial with oral valacyclovir followed by intravenous methylprednisolone bolus was administered without further response. However, human intravenous immunoglobulin resulted in complete recovery of the symptoms., Conclusions: Human immunoglobulin is effective in BP due to zoster infection and must be considered if standard treatment fails. To the best of our knowledge, this is the first report of BP associated to zoster infection successfully treated with intravenous immunoglobulin.

Background: The author presents a 20-year experience leading cleft lip and palate surgical volunteer missions in Peru for CIRPLAST, a nonprofit volunteer plastic surgery goodwill program that has provided free surgery for patients with cleft lip and palate deformities in remote areas of Peru. Surgical procedures were performed by the author, together with a group of experienced plastic surgeons, under the auspices of the Peruvian Plastic Surgery Society, and local health authorities., Methods: CIRPLAST missions are scheduled annually in different locations around Peru. Selected patients for surgery after adequate screening are photographed, and their cleft deformity is recorded. Scheduled patients or their parents, when they are minors, sign an informed consent form. Patients operated on in any given day are examined and photographed 1 day after surgery, before discharge. Between 30 and 35 patients are operated on at each mission site. About 2 weeks after the mission, patients are checked and photographed, and the outcome of surgery is recorded. Complications that may occur are recorded and treated by the CIRPLAST team as soon as possible. Almost all operations are performed under general endotracheal anesthesia coupled by local anesthesia containing a vasoconstrictor, to reduce bleeding and facilitate tissue dissection. All wounds of the lip and palate are closed with absorbable sutures, to avoid the need for suture removal. After cleft lip surgery, patients go to the recovery room for monitoring by nurses until they recover completely., Results: A total of 6108 cleft lip and palate repairs, primary and secondary, were performed by CIRPLAST in 141 missions, between May 12, 1994, and October 15, 2014. The medical records of the 5162 patients (84.5%) who returned for follow-up (ranging from 12 days to 9 years) were reviewed retrospectively. Between 45% and 70% of the patients operated on a mission have returned for early follow-up and some the following year. There were 3176 males (51.9%) and 2932 females (48.1%). The incidence of isolated lip clefts was 1546 patients (25.3%); of isolated palate clefts, 2223 patients (36.4%); and combined defects, 2339 patients (38.3%). Of the 5162 patients who returned for follow-up, 377 patients (7.3%) had complications. Lip wound dehiscence was present in 58 patients (15.4). Palate fistula formation in 33 patients (8.8%): 24 (6.4%) after primary palate closure, and 9 (2.4%) after previous fistula closure. Infection occurred in 37 cleft lip patients (9.8%). Hypertrophic lip scars were seen in 56 patients (14.9%). Bleeding occurred in the recovery room after palatoplasty in 48 patients (12.7%), and in most cases, it was contained by applying pressure. No blood transfusions were used. Residual deformities of varying degree of the nose and/or lip occurred in 145 patients (38.5%). All required reoperation for correction. There were no intraoperative deaths in this series., Conclusions: During the past 20 years, the CIRPLAST team has offered free surgery with good outcomes and few complications, to more than 6000 cleft lip and/or palate patients in remote areas of Peru.

Background: HLA class I molecules are divided into classic (Ia) and nonclassic (Ib). Nonclassic HLA molecules (E, F, and G) have acquired relevance owing to their immunomodulatory properties and possible repercussions for induction of tolerance in organ transplantation. The objective of this study was to identify the impact of these molecules on transplant success or failure., Methods: A systematic review of literature was performed with the use of MeSH terms in Pubmed. Clinical trials, randomized clinical trials, case-control studies, and reviews from the past 15 years were included., Results: HLA-E*0103/E*0103 genotype is associated with lower risk of graft-versus-host disease, decreased mortality, and greater disease-free survival after bone marrow transplantation. There were no significant associations between HLA-F and clinical outcomes in any of the studies. Elevated serum levels of HLA-G were associated with a lower incidence of rejection in hepatic and renal transplantation during the 1st year and lower T-cell response after bone marrow, liver, and kidney transplantation. Detection of mRNA of HLA-G1 was also associated with less graft rejection., Conclusions: Current literature suggests that nonclassic HLA Ib molecules play an important role in immunotolerance in organ transplantation; however, more studies are required to predict outcomes related to specific genotypes.

Progress in transplantation has relied on similar human leukocyte antigen (HLA) matching between the donor and the patient, while the role of other immunologic factors like non-HLA markers including minor histocompatibility antigens (miHA) are currently in the forefront. miHA are polymorphic proteins that vary even in monozygotic twins. The best known is the H-Y antigen, but there are also other autosomal miHA and MICA (MHC class I chain-related gene A). miHA have been well studied in transplantation of hematopoietic precursors, but not in solid organ transplantation. The most important studies in this field relate to incompatibility of H-Y antigen as a risk factor in kidney transplantation, although the findings are still inconclusive. This review presents the role of minor histocompatibility antigens in solid organ transplantation, especially of the kidney., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Serotonin (5-HT), the endogenous nonselective 5-HT receptor agonist, activates the inositol 1,4,5-triphosphate/calcium (InsP3/Ca2+) signaling pathway and exerts both stimulatory and inhibitory actions on cAMP production and GnRH release in immortalized GnRH neurons. The high degree of similarity between the signaling and secretory responses elicited by GnRH and 5-HT prompted us to target specific 5-HT receptor subtypes to deconvolute the complex actions of these agonists on signal transduction and GnRH release. Specific mRNA transcripts for 5-HT1A, 5-HT2C, 5-HT4, and 5-HT7 were identified in immortalized GnRH neurons (GT1-7). The rate of firing of spontaneous action potentials (APs) by hypothalamic GnRH neurons and cAMP production and pulsatile GnRH release in GT17 cells were profoundly inhibited during activation of the Gi-coupled 5-HT1A receptor. Treatment with a selective agonist to activate the Gq-coupled 5-HT2C receptor increased the rate of firing of spontaneous APs, stimulated InsP3 production and caused a delayed increase in GnRH release. Selective activation of the Gs-coupled 5-HT4 receptor also increased the rate of firing of APs, stimulated cAMP production, and caused a sustained and robust increase in GnRH release. The ability of 5-HT receptor subtypes expressed in GnRH neurons to activate single or multiple G proteins in a time- and dose-dependent manner differentially regulates the phospholipase C/InsP3/Ca2+, and adenylyl cyclase/cAMP signaling pathways, and thereby regulates the frequency and amplitude of pulsatile GnRH release. This process, in conjunction with the modulation of spontaneous electrical activity of the GnRH neuron, contributes to the control of the pulsatile mode of neuropeptide secretion that is characteristic of GnRH neuronal function in vivo and in vitro.

Immortalized GnRH neurons (GT1-7) express receptors for estrogen [estrogen receptor-alpha and-13(ERa and ERI3)] and progesterone (progesterone receptor A) and exhibit positive immunostaining for both intracellular and plasma membrane ERs. Exposure of GT1-7 cells to picomolar estradiol concentrations for 5-60 min caused rapid, sustained,and dose-dependent inhibition of cAMP production. In contrast, treatment with nanomolar estradiol concentrations for 60 min increased cAMP production. The inhibitory and stimulatory actions of estradiol on cAMP formation were abolished by the ER antagonist, ICI 182,780. The estradiol-induced inhibition of cAMP production was prevented by treatment with pertussis toxin, consistent with coupling of the plasma membrane ER to an inhibitory G protein. Coimmunoprecipitation studies demonstrated an estradiol-regulated stimulatory interaction between ERa and G,3 that was prevented by the ER antagonist, ICI 182,780. Exposure of perifused GT1-7 cells and hypothalamic neurons to picomolar estradiol levels increased the GnRH peak interval, shortened peak duration, and increased peak amplitude. These findings indicate that occupancy of the plasma membrane-associated ERs expressed in GT1-7 neurons by physio-logical estradiol levels causes activation of a G, protein and modulates cAMP signaling and neuropeptide secretion.

The pulsatile secretion of gonadotropin-releasing hormone (GnRH) from normal and immortalized hypothalamic GnRH neurons is highly calcium-dependent and is stimulated by cAMP. It is also influenced by agonist activation of the endogenous GnRH receptor (GnRH-R), which couples to G(q/11) as indicated by release of membrane-bound alpha(q/11) subunits and increased inositol phosphate/Ca(2+) signaling. Conversely, GnRH antagonists increase membrane-associated alpha(q/11) subunits and abolish pulsatile GnRH secretion. GnRH also stimulates cAMP production but at high concentrations has a pertussis toxin-sensitive inhibitory effect, indicative of receptor coupling to G(i). Coupling of the agonist-activated GnRH-R to both G(s) and G(i) proteins was demonstrated by the ability of nanomolar GnRH concentrations to reduce membrane-associated alpha(s) and alpha(i3) levels and of higher concentrations to diminish alpha(i3) levels. Conversely, alpha(i3) was increased during GnRH antagonist and pertussis toxin treatment, with concomitant loss of pulsatile GnRH secretion. In cholera toxin-treated GnRH neurons, decreases in alpha(s) immunoreactivity and increases in cAMP production paralleled the responses to nanomolar GnRH concentrations. Treatment with cholera toxin and 8-bromo-cAMP amplified episodic GnRH pulses but did not affect their frequency. These findings suggest that an agonist concentration-dependent switch in coupling of the GnRH-R between specific G proteins modulates neuronal Ca(2+) signaling via G(s)-cAMP stimulatory and G(i)-cAMP inhibitory mechanisms. Activation of G(i) may also inhibit GnRH neuronal function and episodic secretion by regulating membrane ion currents. This autocrine mechanism could serve as a timer to determine the frequency of pulsatile GnRH release by regulating Ca(2+)- and cAMP-dependent signaling and GnRH neuronal firing.

In immortalized GnRH neurons, cAMP production is elevated by increased extracellular Ca2+ and the Ca2+ channel agonist, BK-8644, and is diminished by low extracellular Ca2+ and treatment with nifedipine, consistent with the expression of adenylyl cyclase type I (AC I). Potassium-induced depolarization of GT1-7 neurons causes a dose-dependent monotonic increase in [Ca2+]i and elicits a bell-shaped cAMP response. The inhibitory phase of the cAMP response is prevented by pertussis toxin (PTX), consistent with the activation of G(i)-related proteins during depolarization. Agonist activation of the endogenous GnRH receptor in GT1-7 neurons also elicits a bell-shaped change in cAMP production. The inhibitory action of high GnRH concentrations is prevented by PTX, indicating coupling of the GnRH receptors to G(i)-related proteins. The stimulation of cAMP production by activation of endogenous LH receptors is enhanced by low (nanomolar) concentrations of GnRH but is abolished by micromolar concentrations of GnRH, again in a PTX-sensitive manner. These findings indicate that GnRH neuronal cAMP production is maintained by Ca2+ entry through voltage-sensitive calcium channels, leading to activation of Ca2+-stimulated AC I. Furthermore, the Ca2+ influx-dependent activation of AC I acts in conjunction with AC-regulatory G proteins to determine basal and agonist-stimulated levels of cAMP production.

The authors present their experience with 15 years of organizing cleft lip and palate surgical volunteer missions in Latin America. The history, basic principles, and objectives of Operation San Jose, a volunteer goodwill program from Christus St. Joseph Hospital in Houston, Texas, are covered. This report addresses the different problems encountered and solutions found. Following the principles set by Operation San Jose, CIRPLAST is a Peruvian foundation for plastic surgery that travels to remote areas in Peru, operating on patients with cleft lip and palate deformities. This report highlights the importance of working with local plastic surgeons and their residents, and emphasizes that the program should be organized by and the operations performed by accredited plastic surgeons and with the auspices and support of the national plastic surgery society and the local medical board. Operation San Jose promotes the creation of long-term benefits by offering a program to teach local surgeons cleft lip and palate repair techniques and to set up guidelines to organize local surgeons so that they can continue this effort by treating their own patients in their own countries.

Episodic hormone secretion is a characteristic feature of the hypothalamo-pituitary-gonadal system, in which the profile of gonadotropin release from pituitary gonadotrophs reflects the pulsatile secretory activity of GnRH-producing neurons in the hypothalamus. Pulsatile release of GnRH is also evident in vitro during perifusion of immortalized GnRH neurons (GT1-7 cells) and cultured fetal hypothalamic cells, which continue to produce bioactive GnRH for up to 2 months. Such cultures, as well as hypothalamic tissue from adult rats, express GnRH receptors as evidenced by the presence of high-affinity GnRH binding sites and GnRH receptor transcripts. Furthermore, individual GnRH neurons coexpress GnRH and GnRH receptors as revealed by double immunostaining of hypothalamic cultures. In static cultures of hypothalamic neurons and GT1-7 cells, treatment with the GnRH receptor antagonist, [D-pGlu1, D-Phe2, D-Trp(3,6)]GnRH caused a prominent increase in GnRH release. In perifused hypothalamic cells and GT1-7 cells, treatment with the GnRH receptor agonist, des-Gly10-[D-Ala6]GnRH N-ethylamide, reduced the frequency and increased the amplitude of pulsatile GnRH release, as previously observed in GT1-7 cells. In contrast, exposure to the GnRH antagonist analogs abolished pulsatile secretion and caused a sustained and progressive increase in GnRH release. These findings have demonstrated that GnRH receptors are expressed in hypothalamic GnRH neurons, and that receptor activation is required for pulsatile GnRH release in vitro. The effects of GnRH agonist and antagonist analogs on neuropeptide release are consistent with the operation of an ultrashort-loop autocrine feedback mechanism that exerts both positive and negative actions that are necessary for the integrated control of GnRH secretion from the hypothalamus.

Agonist activation of cholinergic receptors expressed in perifused hypothalamic and immortalized GnRH-producing (GT1-7) cells induced prominent peaks in GnRH release, each followed by a rapid decrease, a transient plateau, and a decline to below basal levels. The complex profile of GnRH release suggested that acetylcholine (ACh) acts through different cholinergic receptor subtypes to exert stimulatory and inhibitory effects on GnRH release. Whereas activation of nicotinic receptors caused a transient increase in GnRH release, activation of muscarinic receptors inhibited basal GnRH release. Nanomolar concentrations of ACh caused dose-dependent inhibition of cAMP production that was prevented by pertussis toxin (PTX), consistent with the activation of a plasma-membrane Gi protein. Micromolar concentrations of ACh also caused an increase in phosphoinositide hydrolysis that was inhibited by the M1 receptor antagonist, pirenzepine. In ACh-treated cells, immunoblot analysis revealed that membrane-associated G(alpha q/11) immunoreactivity was decreased after 5 min but was restored at later times. In contrast, immunoreactive G(alpha i3) was decreased for up to 120 min after ACh treatment. The agonist-induced changes in G protein alpha-subunits liberated during activation of muscarinic receptors were correlated with regulation of their respective transduction pathways. These results indicate that ACh modulates GnRH release from hypothalamic neurons through both M1 and M2 muscarinic receptors. These receptor subtypes are coupled to Gq and Gi proteins that respectively influence the activities of PLC and adenylyl cyclase/ion channels, with consequent effects on neurosecretion.

In order to evaluate the role of glutamate in prolactin secretion, we examined the effects of N-methyl-D,L-aspartic acid (NMDA) receptor antagonists on serum prolactin levels at both resting and restraint-stress conditions in female rats at estrus. NMDA increased basal serum prolactin levels. Administration of the selective NMDA receptor antagonist, cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755) (5 and 10 mg/kg i.p.), to rats under resting conditions enhanced basal prolactin levels. A low dose of CGS 19755 (3 mg/kg) was unable to modify the hormone serum level. Under stress conditions the pretreatment with CGS 19755 (3 and 5 mg/kg) prevented the increase in serum prolactin levels. This effect was reversed by NMDA (60 mg/kg s.c.). The NMDA receptor antagonist (5 mg/kg) decreased the median eminence concentration of the dopamine metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), without modifying dopamine content. To examine the probable link between serotonin (5-HT) and glutamate in prolactin release, the 5-HT2A/5-HT2C receptor antagonist, ritanserin, was used. Under resting conditions, a dose of 5 mg/kg s.c. blocked the NMDA-induced prolactin release. In rats submitted to restraint, ritanserin decreased the prolactin response and NMDA was unable to correct the stress serum prolactin levels. The 5-HT1A receptor agonist, 8-hidroxypropyl-amino tetralin (8-OH-DPAT) (3 mg/kg s.c.), increased basal serum prolactin levels and restored serum prolactin in stressed animals pretreated with CGS 19755 (5 mg/kg). The present data strongly suggest that the glutamatergic system participates in the regulation of prolactin secretion. A stimulation tone seems to be exerted via the tuberoinfundibular dopaminergic system, and the prolactin release evoked by restraint apparently involves glutamate/NMDA receptors linked to a serotoninergic pathway.

The dopaminergic nerve terminals in rat striatum appear to be an important target for progesterone (Pg) and the excitatory amino acid glutamate. In the present study the possible interaction between glutamate and Pg upon [3H]DA release in striatal slices from rats in proestrus was examined. [3H]DA release was augmented by NMDA in a concentration-dependent manner. The presence of Pg (400 nM) in the perfusion medium produced an amplification of the responses to NMDA (50 microM) as shown by significant increase in the tritium outflow. The NMDA selective antagonists AP-7 (100 microM) and MK-801 (0.1 microM) prevented the effects of both NMDA and NMDA plus Pg on [3H]DA release. In contrast, the AMPA/kainate receptor antagonist CNQX (10 and 20 microM) was ineffective. Furthermore, AP-7 (100 microM) attenuated the enhancing effect of 400 nM Pg on [3H]DA release evoked by 28 mM K+. The antagonist was unable to alter the effect produced by K+ alone. These results indicate a specific action of Pg on dopaminergic terminals mediated by NMDA receptors and suggest a close interaction between glutamate and dopamine systems in the striatum, apparently modulated by progesterone.

Glutamate has been shown to stimulate noradrenaline (NA) release from hypothalamic nerve terminals. In the present study, we evaluated the possible interaction between the excitatory amino acid glutamate and gamma-aminobutyric acid (GABA), an inhibitory transmitter, on noradrenaline (NA) release from mediobasal hypothalamus (MBH) of adult male rats. Hypothalamic slices loaded in vitro with 3H-NA were superfused and exposed to glutamate, N-methyl-D-aspartic acid (NMDA), or kainate (KA). We found that 3H-NA release evoked by the excitatory amino acids glutamate and NMDA was dramatically decreased by GABA. The facilitatory effects of NMDA and KA were prevented concentration-dependently by the GABAB receptor antagonist 2-hydroxy saclofen which restored the NMDA effect. In addition, baclofen blocked K(+)-induced 3H-NA release. Activation of GABAA receptors by muscimol and THIP was ineffective. In conclusion, glutamate and GABA, through GABAB receptors, may interact to modulate NA release from the rat mediobasal hypothalamus.

1. The present review discusses the proposed roles of the amino acids glutamate and GABA in the central regulation of luteinizing hormone-releasing hormone (LHRH) and in luteinizing hormone (LH) secretion. 2. Descriptions of the mechanisms of action of these neurotransmitters have focused on two diencephalic areas, namely, the preoptic-anterior hypothalamic area where the cell bodies of LHRH neurons are located, and the medial basal hypothalamus which contains the nerve endings of the LHRH system. Increasing endogenous GABA concentration by drugs, GABA agonists, or blockade of glutamatergic neurotransmission by selective antagonists in rats and non-human primates prevents ovulation and pulsatile LH release, and blunts the LH surges induced by estrogen or an estrogen-progesterone combination. In contrast, glutamate and different glutamate agonists such as NMDA, AMPA and kainate, can increase LHRH/LH secretion. 3. The simultaneous enhancement of glutamatergic activity and a decrease of GABAergic tone may positively influence the maturation of the pituitary-gonadal system in rats and non-human primates. Administration of glutamate receptor agonists has been shown to significantly advance the onset of puberty. Conversely, glutamate antagonists or increased endogenous GABA levels may delay the onset of puberty. The physiological regulation of LHRH/LH secretion may thus involve a GABA-glutamate interaction and a cooperative action of the various types of ionotropic glutamate receptors. 4. The inhibitory actions of GABA on LH release and ovulation may be exerted at the level of afferent nerve terminals that regulate LHRH secretion. A likely candidate is noradrenaline, as suggested by the synaptic connections between noradrenergic nerve terminals and GABAergic interneurons in the preoptic area. Recent experiments have provided complementary evidence for the physiological balance between inhibitory and excitatory transmission resulting in modulation of the action of noradrenaline to evoke LHRH release.

The present study was designed to analyze the effects of glutamate (GLU) and its agonists on the release of noradrenaline (NA) from the mediobasal region of rat hypothalamus (MBH). Slices from hypothalamus were loaded in vitro with 3H-NA and thereafter exposed to GLU and the glutamate agonists N-methyl-D-aspartic acid (NMDA) and kainate (KA), in superfusion chambers. GLU evoked a significant 3H-NA release in a concentration-dependent manner. The EC50 was 35 mM. 6-Cyano-7-nitro-quinoxaline-2,3-dione (CNQX), a non-NMDA selective antagonist, and amino-7-phosphonoheptanoic acid (AP 7), a NMDA selective antagonist, both decreased the GLU-evoked response to about 50% of its value. NMDA, superfused in Mg(2+)-free Krebs-Ringer, exhibited a greater potency than GLU with an EC50 = 124 microM. KA was also able to evoke 3H-NA release, although overall responses to KA were lower than those of NMDA. The maximal response to KA was a 36% increase of release at a concentration of 200 microM. The effect of KA was blunted by CNQX. NMDA-induced 3H-NA release was progressively altered with age. In old rats (16-18 months) and middle-aged rats (10 months), responses to 200 microM NMDA were decreased respect to young (4 months) male rats. These results show that NMDA and KA receptors mediate the excitatory effects of GLU on NA release from nerve terminals in the MBH and suggest that GLU, in association with NA, participates in the complex mechanisms that regulate neuroendocrine functions.(ABSTRACT TRUNCATED AT 250 WORDS)

Histamine (HA) stimulates prolactin secretion via H1 and H2 receptors. In the present study, we examined the role of a third subtype of receptor recently described in brain, the H3-HA receptor, on prolactin secretion in male rats. R(-)alpha-methyl-HA (alpha-MHA), a selective H3 receptor agonist, was injected into the lateral ventricle of the brain in freely moving rats. alpha-MHA produced a dose-dependent (1-5 micrograms) and long-lasting increase in plasma prolactin levels. This increase was observed from 15 to 60 min after injection of alpha-MHA. Its stimulatory action was prevented by thioperamide (20 micrograms i.v.t), a selective H3 antagonist. This compound, injected intraventricularly, lacked effect by itself on basal plasma prolactin levels. Neither pyrilamine (H1 antagonist; 60 micrograms i.v.t.) nor ranitidine (H2 antagonist; 60 micrograms i.v.t.) affected alpha-MHA-induced prolactin release. The stimulatory effect was still present when brain HA was depleted by alpha-fluoromethylhistidine (30 mg/kg i.p.). Our findings suggest that alpha-MHA evokes prolactin release by activation of postsynaptic H3 receptors.

Inoculation of 2 groups of dogs with 1 X 10(9) and 4 X 10(9) Leptospira interrogans serovar icterohaemorrhagiae produced disease varying from transient fever to uremia and death. Clinical signs of disease in the severely affected dogs were fever, dehydration, depression, and icterus. Laboratory changes in serum of infected dogs included increased urea nitrogen, creatinine, phosphorus, alkaline phosphatase, total bilirubin, aspartate aminotransferase, and alanine aminotransferase. Chloride concentration decreased in the serum of dogs with severe disease. The icterus in the infected dogs did not appear to be related to hemolytic anemia.