[Inhaled levodopa: from evidence to experience]. / Levodopa inhalada: de la evidencia a la experiencia.

Most patients with Parkinson's disease experience motor fluctuations or 'off' periods, which impact on their daily activities, increase their disability and diminish their quality of life. They suffer from these fluctuations despite multiple adjustments to the schedules, doses and intake of medication. In this context, on-demand or rescue treatments are necessary to attempt to improve 'off' periods, with drugs that have the pharmacokinetic advantage of a much faster onset of action because their routes of administration are not oral. There are currently three on-demand therapies for the treatment of fluctuations: subcutaneous apomorphine, inhaled levodopa and sublingual apomorphine. Of the three alternatives, subcutaneous apomorphine generally has the fastest onset of action, sublingual apomorphine provides the longest clinical effect, and inhaled levodopa has the most favourable side effect profile. Each of these drugs has its own characteristics: the time before onset of action, the duration of action and different side effect profiles. The choice for each patient will depend on their individual needs and circumstances. To mark the first year of the introduction of inhaled levodopa, we review these therapies, focusing on the experience with this new dosage form of levodopa.

TITLE: Levodopa inhalada: de la evidencia a la experiencia.La mayoría de los pacientes con enfermedad de Parkinson sufren fluctuaciones motoras o períodos off, que impactan en sus actividades cotidianas, aumentan su discapacidad y empeoran su calidad de vida. A pesar de realizar múltiples ajustes en los horarios, en las dosis y en las tomas de medicación, no se consigue que estén libres de estas fluctuaciones. Es en este contexto en el que son necesarios los tratamientos a demanda o de rescate para tratar de mejorar los períodos off, con fármacos que tienen la ventaja farmacocinética de un inicio de acción mucho más rápido debido a que sus vías de administración no son orales. En la actualidad existen tres terapias a demanda para el tratamiento de las fluctuaciones: apomorfina subcutánea, levodopa inhalada y apomorfina sublingual. En general, la apomorfina subcutánea tiene un inicio de efecto más rápido, la apomorfina sublingual ofrece el efecto clínico más prolongado y la levodopa inhalada tiene el perfil de efectos secundarios más favorable entre las tres opciones. Cada uno de estos medicamentos tiene características únicas: tiempo de inicio, duración de acción y diferentes perfiles de efectos secundarios. La elección para cada paciente dependerá de sus necesidades y circunstancias individuales. Aprovechando el primer año de la introducción de la levodopa inhalada, revisamos estas terapias, centrándonos en la experiencia acumulada con esta nueva presentación galénica de levodopa.

Glomangioma: rare case of a painful lump in the upper lip.

Glomus tumours in the lip are extremely rare with only 13 cases, including this one, recorded in the English language that we know of. We report a 45-year-old woman with a firm, mildly painful lump in her upper lip. Excisional biopsy examination and histopathological analysis showed it to be a subtype of glomus tumour called a glomangioma.

Detection of N-glycolylneuraminic acid biomarkers in sera from patients with ovarian cancer using an engineered N-glycolylneuraminic acid-specific lectin SubB2M.

N-glycolylneuraminic acid (Neu5Gc)-containing glycans are a prominent form of aberrant glycosylation found in human tumor cells and have been proposed as cancer biomarkers. The B subunit of the subtilase cytotoxin (SubB) produced by Shiga toxigenic Escherichia coli recognises Neu5Gc containing glycans. We have previously engineered this lectin, SubB2M, for greater specificity and enhanced recognition of Neu5Gc-containing glycans. Here we further explore the utility of SubB2M to detect Neu5Gc tumor biomarkers in sera from patients with ovarian cancer. Using surface plasmon resonance (SPR) we show that SubB2M can detect the established ovarian cancer biomarker, CA125, in a highly sensitive and specific fashion in the context of human serum. These studies established conditions for screening serum samples from patients with ovarian cancer for Neu5Gc glycans. We found that serum from patients with all stages of ovarian cancer had significantly elevated mean levels of Neu5Gc glycans compared to normal controls. Serum from patients with late stage disease (stages IIIC, IV) had uniformly elevated levels of Neu5Gc glycans. Detection of Neu5Gc-glycans using SubB2M has the potential to be used as a diagnostic ovarian cancer biomarker, as well as a tool for monitoring treatment and disease progression in late stage disease.

Síndrome de Holt-Oram y Trastorno del Espectro Autista. A propósito de un caso / Holt-Oram syndrome and autism spectrum disorder. About a case

El Síndrome de Holt-Oram o displasia atriodigital es un trastorno de herencia autosómica dominante con un 100% de penetrancia que afecta a uno de cada 100000 nacimientos, causado por la mutación del gen TBX5 (12q24.1), responsable de la cardiogénesis y de la formación de los miembros superiores, por lo que se caracteriza por la presencia de anomalías y malformaciones esqueléticas y cardiológicas. Se describe el caso de un varón de 8 años con diagnóstico de Síndrome de Holt-Oram y de Trastorno del Espectro Autista

Holt-Oram syndrome or atrio-digital dysplasia is an autosomal dominant disorder inheritance with 100% penetrance that affects one in every 100,000 births, caused by the mutation of the TBX5 gene (12q24.1), responsible for cardiogenesis and of the formation of superior limbs, reason why it is characterized by the presence of anomalies and skeletal and cardiological malformations. We describe the case of a 8-year-old male with a diagnosis of Holt-Oram Syndrome and Autism Spectrum Disorder

Contextual modulation of primary visual cortex by auditory signals.

Early visual cortex receives non-feedforward input from lateral and top-down connections (Muckli & Petro 2013 Curr. Opin. Neurobiol. 23, 195-201. (doi:10.1016/j.conb.2013.01.020)), including long-range projections from auditory areas. Early visual cortex can code for high-level auditory information, with neural patterns representing natural sound stimulation (Vetter et al. 2014 Curr. Biol. 24, 1256-1262. (doi:10.1016/j.cub.2014.04.020)). We discuss a number of questions arising from these findings. What is the adaptive function of bimodal representations in visual cortex? What type of information projects from auditory to visual cortex? What are the anatomical constraints of auditory information in V1, for example, periphery versus fovea, superficial versus deep cortical layers? Is there a putative neural mechanism we can infer from human neuroimaging data and recent theoretical accounts of cortex? We also present data showing we can read out high-level auditory information from the activation patterns of early visual cortex even when visual cortex receives simple visual stimulation, suggesting independent channels for visual and auditory signals in V1. We speculate which cellular mechanisms allow V1 to be contextually modulated by auditory input to facilitate perception, cognition and behaviour. Beyond cortical feedback that facilitates perception, we argue that there is also feedback serving counterfactual processing during imagery, dreaming and mind wandering, which is not relevant for immediate perception but for behaviour and cognition over a longer time frame.This article is part of the themed issue 'Auditory and visual scene analysis'.

Induction of endoplasmic reticulum stress by deletion of Grp78 depletes Apc mutant intestinal epithelial stem cells.

Intestinal epithelial stem cells are highly sensitive to differentiation induced by endoplasmic reticulum (ER) stress. Colorectal cancer develops from mutated intestinal epithelial stem cells. The most frequent initiating mutation occurs in Apc, which results in hyperactivated Wnt signalling. This causes hyperproliferation and reduced sensitivity to chemotherapy, but whether these mutated stem cells are sensitive to ER stress induced differentiation remains unknown. Here we examined this by generating mice in which both Apc and ER stress repressor chaperone Grp78 can be conditionally deleted from the intestinal epithelium. For molecular studies, we used intestinal organoids derived from these mice. Homozygous loss of Apc alone resulted in crypt elongation, activation of the Wnt signature and accumulation of intestinal epithelial stem cells, as expected. This phenotype was however completely rescued on activation of ER stress by additional deletion of Grp78. In these Apc-Grp78 double mutant animals, stem cells were rapidly lost and repopulation occurred by non-mutant cells that had escaped recombination, suggesting that Apc-Grp78 double mutant stem cells had lost self-renewal capacity. Although in Apc-Grp78 double mutant mice the Wnt signature was lost, these intestines exhibited ubiquitous epithelial presence of nuclear ß-catenin. This suggests that ER stress interferes with Wnt signalling downstream of nuclear ß-catenin. In conclusion, our findings indicate that ER stress signalling results in loss of Apc mutated intestinal epithelial stem cells by interference with the Wnt signature. In contrast to many known inhibitors of Wnt signalling, ER stress acts downstream of ß-catenin. Therefore, ER stress poses a promising target in colorectal cancers, which develop as a result of Wnt activating mutations.

Metabolic Syndrome After Liver Transplantation: Five-Year Prevalence and Risk Factors.

Survival after orthotopic liver transplantation (OLT) has increased over the last decades, focusing on the metabolic complications that contribute to patient morbidity and mortality. The aim of our study was to describe the prevalence of metabolic syndrome (MS), its components, and its associated factors in patients who underwent OLT in a hospital in Spain. From November 2001 to January 2014, we performed 415 transplantations in 386 patients. We analyzed 204 patients with a minimum follow-up of 1 year (77.6% were male and the mean age was 54.2+/-9.5 years). The most frequent etiology was alcohol (41%), followed by hepatitis C virus (29.1%). The indication was decompensated cirrhosis in 51.8% and hepatocellular carcinoma in 34%. According to modified National Cholesterol Education Program-Adult Treatment Panel-III (NCEP-ATP III) criteria, 5 years post-transplantation MS was diagnosed in 38.2% of patients. Significant independent predictors of post-transplantation MS on logistic regression analysis were as follows: pretransplantation obesity (odds ratio [OR], 3.09; P = .056), 1-year post-transplantation obesity (OR, 3.95; P = .009), pretransplantation diabetes (OR, 4.63; P = .001), 1-year post-transplantation diabetes (OR, 3.01; P = .015), 1-year post-transplantation hypertension (OR, 1.85; P = .176), and hypertriglyceridemia at the first year after transplantation (OR, 2.32; P = .063). In our center the prevalence of MS at 5 years after OLT is slightly lower than published. The most important risk factors were obesity and diabetes (both pretransplantation and the first year post-transplantation).

Dose escalation in brachytherapy for cervical cancer: impact on (or increased need for) MRI-guided plan optimisation.

OBJECTIVE: The aim of this study was to assess the impact of dose escalation on the proportion of patients requiring MR image-guided optimisation rather than standard Manchester-based CT-guided planning, and the level of escalation achievable. METHODS: 30 patients with cervical cancer treated with external beam radiotherapy and image-guided brachytherapy (IGBT) had MR images acquired at the first fraction of IGBT. Gross tumour volume and high-risk clinical target volume (HR CTV) were contoured and treatment plans retrospectively produced for a range of total 2-Gy equivalent (EQD2) prescription doses from 66 Gy(α/ß=10) to 90 Gy(α/ß=10) (HR CTV D90). Standard Manchester system-style plans were produced, prescribed to point A and then optimised where necessary with the aim of delivering at least the prescription dose to the HR CTV D90 while respecting organ-at-risk (OAR) tolerances. RESULTS: Increasing the total EQD2 from 66 Gy(α/ß=10) to 90 Gy(α/ß=10) increased the number of plans requiring optimisation from 13.3% to 90%. After optimisation, the number of plans achieving the prescription dose ranged from 93.3% (66 Gy(α/ß=10)) to 63.3% (90 Gy(α/ß=10)) with the mean ± standard deviation for HR CTV D90 EQD2 from 78.4 ± 12.4 Gy(α/ß=10) (66 Gy(α/ß=10)) to 94.1 ± 19.9 Gy(α/ß=10) (90 Gy(α/ß=10)). CONCLUSION: As doses are escalated, the need for non-standard optimised planning increases, while benefits in terms of increased target doses actually achieved diminish. The maximum achievable target dose is ultimately limited by proximity of OARs. ADVANCES IN KNOWLEDGE: This work represents a guide for other centres in determining the highest practicable prescription doses while considering patient throughput and maintaining acceptable OAR doses.

Cutaneous mucormycosis infection by Absidia in two consecutive liver transplant patients.

Mucormycosis, although an infrequent fungal infection, has a high mortality in patients undergoing orthotopic liver transplantation. We present two cases of cutaneous Absidia mucormycosis in two successive patients undergoing liver transplantation in our hospital. In our literature search, we encountered only one published case of Absidia infection in liver transplantation.

Early and extended therapy for recurrent hepatitis C after liver transplantation.

BACKGROUND: End-stage cirrhosis due to hepatitis C virus (HCV) is one of the most common indications for orthotopic liver transplantation (OLT). Recurrence is universal and more aggressive than before OLT. The aim of this study was to evaluate the efficacy and tolerability of antiviral therapy in recurrent HCV after OLT. Therapy was started even with mild fibrosis (F < 2) and extended until 72 weeks, if it was possible. METHODS: Between November 2001 and December 2010, 279 OLTs were performed in 262 patients in our hospital; 81 (31%) for HCV-related cirrhosis. Nineteen patients were excluded because they died in the first 6 months. We treated 28 of 62 HVC patients. RESULTS: Twenty-eight patients met the indication for antiviral therapy: 21 male (75%) and 7 female (25%), with a mean age of 56 years (range, 40 to 68 years). All the patients had histologically proven recurrence liver disease: F1, 19 patients (68%); F2, 4 patients (14%), and F3, 45 patients (18%). The mean time to recurrence was 23 months, with a range of 3 to 90 months. Adverse effects (leukopenia in 82% and anemia in 79%) were treated with granulocyte colony-stimulating factor (GCSF) and erythropoietin (EPO), and dose reduction. Four patients (14%) were withdrawn from the treatment because of adverse effects. Nineteen patients achieved early virologic response (68%), and the sustained virologic response was 54% (15 of 28 patients). Five patients died (18%). CONCLUSION: Improving sustained virologic response in HCV liver transplant patients is a key goal. Antiviral therapy is safe and effective treating HCV recurrence after OLT. Starting this therapy in an early stage of hepatitis C recurrence, extending antiviral therapy (72 weeks), and avoiding dose reduction of antiviral drugs could help to achieve higher rates of sustained virological response.

Indications and effectiveness of the mammalian target of rapamycin in liver transplantation.

BACKGROUND: The mammalian target of rapamycin (mTOR) inhibitors are new immunosuppressive drugs for organ transplantation. They are interesting for liver transplantation because of their absence of nephrotoxicity and potential antitumor effects, because calcineurin inhibitors (CNI) are associated with renal dysfunction post-CNI and tumors. We sought to analyze the indications, safety, and efficacy of mTOR among liver transplant patients at our center. METHODS: We retrospectively identified patients who were treated with mTOR for their indications for liver transplantation, type of immunosuppressive therapy, acute rejection episodes, and evolution of kidney function. RESULTS: We identified 43 (19.02%) patients treated with mTOR including 35 (81.4%) males and 8 (18.6%) females of overall average age of 56.7 (range, 44-68). In 30% of patients, the drug was introduced for kidney failure, and in 23% for actual or a high risk of hepatocellular carcinoma (HCC) recurrence. The average time to introduction of the mTOR was 6.4 months (range, 1-46). The final immunosuppressive regimen was mTOR alone (73%), or mTOR plus CNI (23%), or mTOR plus mycophenolate mofetil (4%). The average values of creatinine and urea were lower after conversion to mTOR (P < .05) with a 6.9% incidence of acute rejection episodes. CONCLUSION: The mTOR immunosuppressive drugs are safe for liver transplant patients, effectively controlling renal dysfunction. They can be used in other indications, such as neurotoxicity, de novo tumors, and high risk of HCC recurrence. More studies are needed to clarify their long-term effectiveness.

Covered metal stents for the treatment of biliary complications after orthotopic liver transplantation.

BACKGROUND: Biliary complications, a major source of morbidity after orthotopic liver transplantation (OLT), are increasingly being treated by endoscopic retrograde cholangiopancreatography (ERCP). Endoscopic management has been shown to be superior to percutaneous therapy and surgery. Covered self-expandable metal stents (CSEMSs) may be an alternative to the current endoscopic standard treatment with periodic plastic stent replacement. OBJECTIVE: To assess the safety and efficacy of temporary CSEMS insertion for biliary complications after OLT. METHODS: From November 2001 to December 2009, the 242 OLT performed in 226 patients included 67 cases that developed post-OLT leaks or strictures (29.6%), excluding ischemic biliary complications. CSEMSs were used in 22 patients (33%), 18 male and 4 female, with an overall median age of 55 years (range, 29-69). In-house OLT patients underwent an index ERCP at 26 days (range, 8-784) after OLT. Their records were reviewed to determine ERCP findings, technical success, and clinical outcomes. RESULTS: ERCP with sphincterotomy was performed in all 22 patients, revealing 18 with biliary strictures alone (82%), 3 with strictures and leaks (14%), and 1 with strictures and choledocholithiasis (4%). All strictures were anastomotic. All patients had 1-2 plastic stents inserted across the anastomosis (11 had prior balloon dilation); stones were successfully removed, for an initial technical success rate of 100% (22/22). CSEMSs, were placed at the second ERCP in 14 patients, at the third in 7, and at the fourth in 1. With a median follow-up of 12.5 months (range, 3-25) after CSEMS removal, 21/22 patients (95.5%) remain stricture free and one relapsed, requiring repeat CSEMS insertion. Four patients experienced pain after CSEMS insertion. At CSEMS removal, migration was noted in 5 cases, into either the distal duodenum (n=4) or the proximal biliary tree (n=1), and embedding was seen in 1 case. There were no serious complications; no patients needed hepatojejunostomy. CONCLUSIONS: ERCP is a safe first-line approach for post-OLT biliary complications. It was highly successful in a population with anastomotic leaks and strictures. The therapeutic role of ERCP to manage biliary complications after OLT in the long term is not well known. In our experience, the high rate (close to 95%) of efficacy and its relative safety allowed us to use CSEMS to manage refractory biliary post-OLT strictures. CSEMS insertion may preclude most post-OLT hepatojejunostomies.

A retrospective study of pediatric endoscopy as performed in an adult endoscopy unit.

Gastrointestinal endoscopy is a safe, efficient technique with minimal complications, and a useful diagnostic tool for the pediatric population. Under ideal conditions endoscopies for children should be performed by experienced pediatric endoscopists. In this study we report our experience with pediatric endoscopy at the general adult endoscopy unit in our hospital. Our goal is to quantify the number of endoscopies performed in children, as well as their indications and findings, the type of sedation or anesthesia used, and the time waiting for the test to occur. Our experience demonstrates that endoscopists in a general adult gastroenterology department, working together with pediatricians, may perform a relevant number of endoscopies in children in a fast, safe, effective manner.

Risk of development of the metabolic syndrome after orthotopic liver transplantation.

Longer survival for orthotopic liver transplantation (OLT) patients over the last decade has focused emphasis on the metabolic complications that contribute to patient morbidity and mortality. The aim of our study was to analyze the prevalence of the metabolic syndrome (MS) and other risk factors after OLT among our patients at 1 year follow-up. From 2001 to 2008, we performed OLT in 210 patients with 62 exclusions leaving 148 patients for the study. We recorded age, gender, liver disease, smoking status, pre- and post-OLT body mass index, pre- and post-OLT arterial blood pressure, pre- and post-OLT fasting blood glucose, pre- and post-OLT high-density lipoproteins and triglycerides, family history of diabetes, hepatitis B and C virus status, immunosuppressive therapy, and corticosteroid bolus for rejection episodes. The MS was defined according to modified ATP III criteria. At month 12 after OLT, 29/148 patients (19.6%) developed the MS. The associated factors were obesity and hyperlipidemia pre-OLT, familial and personal history of diabetes as well as alcoholic cirrhosis. By multivariate analysis, pre-OLT body mass index (odds ratio, 3.7 [1.3-10.5]) and pre-OLT diabetes (odds ratio, 2.9 [1.1-7.9]) were independent risk factors.

Estudio retrospectivo sobre la endoscopia pediátrica desarrollada en un servicio de endoscopias de adultos / A retrospective study of pediatric endoscopy as performed in an adult endoscopy unit

La endoscopia gastrointestinal es una técnica segura y eficientecon mínimas complicaciones, así como una útil herramienta diagnósticaen la población pediátrica. En condiciones ideales, las endoscopiasen niños deberían ser realizadas por endoscopistas pediátricosexperimentados. En este estudio reportamos nuestraexperiencia en la realización de endoscopias pediátricas en la Unidadde Endoscopias general de adultos de nuestro hospital.El objetivo es cuantificar la cantidad de endoscopias realizadasen niños, así como las indicaciones y hallazgos de las mismas, eltipo de sedación o anestesia empleado y el tiempo de espera parala realización de la prueba. Nuestra experiencia demuestra que losendoscopistas de un servicio de gastroenterología general de adultos,en colaboración con pediatras, pueden realizar un númeroimportante de endoscopias a niños, de forma rápida, segura y eficaz(AU)

Gastrointestinal endoscopy is a safe, efficient technique withminimal complications, and a useful diagnostic tool for the pediatricpopulation. Under ideal conditions endoscopies for childrenshould be performed by experienced pediatric endoscopists. Inthis study we report our experience with pediatric endoscopy atthe general adult endoscopy unit in our hospital. Our goal is toquantify the number of endoscopies performed in children, as wellas their indications and findings, the type of sedation or anesthesiaused, and the time waiting for the test to occur. Our experiencedemonstrates that endoscopists in a general adult gastroenterologydepartment, working together with pediatricians, mayperform a relevant number of endoscopies in children in a fast,safe, effective manner(AU)