Bioactivity of synthetic peptides from Ecuadorian frog skin secretions against Leishmania mexicana, Plasmodium falciparum, and Trypanosoma cruzi.

Chagas disease, leishmaniasis, and malaria are major parasitic diseases disproportionately affecting the underprivileged population in developing nations. Finding new, alternative anti-parasitic compounds to treat these diseases is crucial because of the limited number of options currently available, the side effects they cause, the need for long treatment courses, and the emergence of drug-resistant parasites. Anti-microbial peptides (AMPs) derived from amphibian skin secretions are small bioactive molecules capable of lysing the cell membrane of pathogens while having low toxicity against human cells. Here, we report the anti-parasitic activity of five AMPs derived from skin secretions of three Ecuadorian frogs: cruzioseptin-1, cruzioseptin-4 (CZS-4), and cruzioseptin-16 from Cruziohyla calcarifer; dermaseptin-SP2 from Agalychnis spurrelli; and pictuseptin-1 from Boana picturata. These five AMPs were chemically synthesized. Initially, the hemolytic activity of CZS-4 and its minimal inhibitory concentration against Escherichia coli, Staphylococcus aureus, and Candida albicans were determined. Subsequently, the cytotoxicity of the synthetic AMPs against mammalian cells and their anti-parasitic activity against Leishmania mexicana promastigotes, erythrocytic stages of Plasmodium falciparum and mammalian stages of Trypanosoma cruzi were evaluated in vitro. The five AMPs displayed activity against the pathogens studied, with different levels of cytotoxicity against mammalian cells. In silico molecular docking analysis suggests this bioactivity may occur via pore formation in the plasma membrane, resulting in microbial lysis. CZS-4 displayed anti-bacterial, anti-fungal, and anti-parasitic activities with low cytotoxicity against mammalian cells. Further studies about this promising AMP are required to gain a better understanding of its activity.IMPORTANCEChagas disease, malaria, and leishmaniasis are major tropical diseases that cause extensive morbidity and mortality, for which available treatment options are unsatisfactory because of limited efficacy and side effects. Frog skin secretions contain molecules with anti-microbial properties known as anti-microbial peptides. We synthesized five peptides derived from the skin secretions of different species of tropical frogs and tested them against cultures of the causative agents of these three diseases, parasites known as Trypanosoma cruzi, Plasmodium falciparum, and Leishmania mexicana. All the different synthetic peptides studied showed activity against one of more of the parasites. Peptide cruzioseptin-4 is of special interest since it displayed intense activity against parasites while being innocuous against cultured mammalian cells, which indicates it does not simply hold general toxic properties; rather, its activity is specific against the parasites.

The Puerto Rico Young Adults' Stress, Contextual, Behavioral & Cardiometabolic Risk (PR-OUTLOOK) Study: Design and Methods.

The Puerto Rico (PR) Young Adults' Stress, Contextual, Behavioral & Cardiometabolic Risk Study (PR-OUTLOOK) is investigating overall and component-specific cardiovascular health (CVH) and cardiovascular disease (CVD) risk factors in a sample of young (age 18-29) Puerto Rican adults in PR (target n=3,000) and examining relationships between individual-, family/social- and neighborhood-level stress and resilience factors and CVH and CVD risk factors. The study is conducting standardized measurements of CVH and CVD risk factors and demographic, behavioral, psychosocial, neighborhood, and contextual variables and establishing a biorepository of blood, saliva, urine, stool, and hair samples. The assessment methods are aligned with other National Heart, Lung, and Blood Institute funded studies: the Puerto Rico Observational Study of Psychosocial, Environmental, and Chronic Disease Trends (PROSPECT) of adults 30-75 years, the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), the Boston Puerto Rican Health Study (BPRHS), and the Coronary Artery Risk Development in Young Adults (CARDIA). PR-OUTLOOK data and its biorepository will facilitate future longitudinal studies of the temporality of associations between stress and resilient factors and CVH and CVD risk factors among young Puerto Ricans, with remarkable potential for advancing the scientific understanding of these conditions in a high-risk but understudied young population.

[Phenotypic and genotypic spectrum of KMT2B dystonia. Description of three Colombian patients]. / Espectro fenotípico y genotípico de la distonía causada por el gen KMT2B. Descripción de tres casos colombianos.

INTRODUCTION: KMT2B-related dystonia is a childhood-onset movement disorder characterized by focal dystonia of the lower extremities progressing to generalized dystonia with predominant cervical, cranial, and laryngeal involvement. So far, fewer than 100 variants have been reported, the vast majority being de novo mutations. The presenting frame of KMT2B dystonia, with dysmorphology features and other complex neurologic symptoms shows the spectrum of KMT2B dystonia as a probable syndromic disease, rather than an isolated early-onset dystonia, which has been the classic view of the condition. CASE REPORTS: We report three patients who presented regression in their neurodevelopment, focal dystonia of the lower limbs with subsequent generalization, in whom two de novo variants were reported in the KMT2B gene, with a mean age of presentation lower than the average reported worldwide. CONCLUSIONS: We describe the largest local series of patients with KMT2B dystonia in Colombia (to our knowledge), which allows us to expand the genotype-phenotype relationship of this genetic dystonia. Although many affected individuals follow a similar disease course, it is important to determine clinical features that may be associated such as neurodevelopmental regression.

TITLE: Espectro fenotípico y genotípico de la distonía causada por el gen KMT2B. Descripción de tres casos colombianos.Introducción. La distonía relacionada con KMT2B es un trastorno del movimiento hipercinético, de inicio en la infancia, caracterizado inicialmente por distonía focal de las extremidades inferiores que progresa a una distonía generalizada con mayor afectación cervical, craneal y laríngea. Hasta el momento se han descrito aproximadamente 100 variantes causantes de enfermedad, y la mayoría son de novo. La presentación clínica de la distonía con hallazgos fenotípicos comunes en los pacientes, asociada a frecuente afectación del neurodesarrollo, afectación intelectual y otros trastornos del movimiento, hace pensar más en el espectro KMT2B como una condición sindrómica, más que en una distonía aislada de inicio temprano, como clásicamente se ha clasificado. Casos clínicos. Se presenta el caso de tres pacientes con regresión del neurodesarrollo, distonía focal de los miembros inferiores con posterior generalización, en quienes se identificaron tres variantes en el gen KMT2B, en dos de los casos de novo (en una de ellas se desconoce la segregación), y dos de ellas comunicadas por primera vez en la bibliografía. La edad media de presentación fue menor a la edad promedio notificada a nivel mundial. Conclusiones. Describimos una serie de pacientes colombianos con distonía DYT-KMT2B (la más grande en nuestro conocimiento a nivel local), lo que nos permite ampliar la relación genotipo-fenotipo de esta distonía genética. Si bien múltiples individuos afectados siguen un curso de enfermedad similar, es importante determinar las características clínicas que pueden estar asociadas, como la regresión del neurodesarrollo y su potencial clasificación como distonía compleja. Describimos, además, dos nuevas variantes asociadas al fenotipo.

Vacunación contra el SARS-CoV-2 en pacientes pediátricos con epilepsia: experiencia de un centro terciario en Colombia / SARS-CoV-2 vaccination in paediatric patients with epilepsy: experience of a tertiary center in Colombia

Objetivo: El objetivo de este estudio es evaluar los efectos de la vacunación contra el SARS-CoV-2 sobre el patrón convulsivo en pacientes pediátricos con epilepsia que acudieron a nuestro centro terciario en la ciudad de Bogotá, Colombia. Pacientes y métodos: Se pidió a los niños con epilepsia que fueron tratados en nuestro centro y que habían recibido la vacuna contra el SARS-CoV-2 y a sus cuidadores que informaran de su experiencia después de la vacunación. Se documentaron la edad, el sexo, la edad de inicio de la epilepsia, la duración de la epilepsia, el tipo de epilepsia, la frecuencia de las convulsiones, el número de medicamentos, el tiempo transcurrido desde la última crisis, los esquemas de vacunación y las convulsiones dos semanas después de la vacunación. Resultados: Se incluyó a 101 pacientes con epilepsia (58%, hombres; y 42%, mujeres). La edad promedio fue de 11 años, el 73% tenía epilepsia focal, y el 27%, generalizada. Veintiuno cumplían los criterios para la epilepsia refractaria y 11 tenían antecedentes personales de convulsiones febriles. Cuarenta y siete pacientes habían sido vacunados con la vacuna de Sinovac; 41, con Pfizer; 12, con Moderna; y uno, con CoronaVac. Tres pacientes presentaron convulsiones 24 horas después de la aplicación de la vacuna sin una relación clara entre la vacunación y la frecuencia de las convulsiones, y un paciente requirió ingreso en el hospital por una convulsión prolongada. Conclusión: La vacunación contra el SARS-CoV-2 en pacientes pediátricos con epilepsia es segura. Aproximadamente el 3% de los pacientes con epilepsia podría eventualmente tener convulsiones en el período posterior a la vacunación.

Aim: The objective of this study is to evaluate effects of SARS-CoV-2 vaccination on seizure pattern in paediatric patients with epilepsy that attended our tertiary center in the city of Bogotá, Colombia. Patients and methods: Children with epilepsy who were treated at our center and have had SARS-CoV-2 vaccination and their caregivers were asked to report their experience following vaccination. We documented age, sex, age at onset of epilepsy, duration of epilepsy, epilepsy type, seizure frequency, number of medications, time from last crisis, vaccination schemes, and seizures two weeks after vaccination. Results: One hundred and one patients with epilepsy were included (58%, male; and 42%, female). The average age was 11 years, 73% had focal epilepsy, and 27%, generalized. Twenty-one fulfilled criteria for refractory epilepsy and 11 had a personal history of febrile seizures. Forty-seven patients had been vaccinated with Sinovac’s vaccine; 41 patients, with Pfizer’s; 12 patients, with Moderna’s; and one, with CoronaVac’s. Three patients presented seizures 24 hours after the application of the vaccine with no clear relation between vaccination and seizure frequency, and one patient required admission to the hospital for a prolonged seizure. Conclusion: Vaccination against SARS-CoV-2 in paediatric patients with epilepsy is safe. Approximately 3% of patients with epilepsy could eventually have seizures in the post-vaccination period.(AU)

El saber hacer de la Indicación Farmacéutica, hacia una farmacia asistencial / The know-how of the Minor Ailments Service, towards a clinical pharmacy

Servicio de Indicación farmacéutica (SIF) es el Servicio Profesional Farmacéutico Asistencial (SPFA) prestado ante la consulta de un PS concreto, para un paciente o cuidador que llega a la farmacia solicitando el remedio más adecuado para el mismo. Es una de las actividades de mayor peso en nuestra profesión. Cuando el farmacéutico comunitario comienza a trabajar la IF de manera protocolizada y siguiendo la metodología, se establece el Servicio de Indicación Farmacéutica. El Estudio Indica+Pro comenzó en 2020 y finaliza este año. Lleva mas de 20.500 registros.Un ejemplo a seguir, son algunas de las experiencias de compañeros del grupo de trabajo de IF que podemos leer en el artículo "Factores y estrategias en la implantación del Servicio de Indicación Farmacéutica en Farmacia Comunitaria" publicado en este mismo número. Es una farmacia comprometida con sus pacientes donde todo el equipo trabaja de forma coordinada y lleva un número sorprendente de registros en el Estudio Indica+Pro. (AU)

SARS-CoV-2 vaccination in paediatric patients with epilepsy: experience of a tertiary center in Colombia. / Vacunación contra el SARS-CoV-2 en pacientes pediátricos con epilepsia: experiencia de un centro terciario en Colombia.

AIM: The objective of this study is to evaluate effects of SARS-CoV-2 vaccination on seizure pattern in paediatric patients with epilepsy that attended our tertiary center in the city of Bogota, Colombia. PATIENTS AND METHODS: Children with epilepsy who were treated at our center and have had SARS-CoV-2 vaccination and their caregivers were asked to report their experience following vaccination. We documented age, sex, age at onset of epilepsy, duration of epilepsy, epilepsy type, seizure frequency, number of medications, time from last crisis, vaccination schemes, and seizures two weeks after vaccination. RESULTS: One hundred and one patients with epilepsy were included (58%, male; and 42%, female). The average age was 11 years, 73% had focal epilepsy, and 27%, generalized. Twenty-one fulfilled criteria for refractory epilepsy and 11 had a personal history of febrile seizures. Forty-seven patients had been vaccinated with Sinovac's vaccine; 41 patients, with Pfizer's; 12 patients, with Moderna's; and one, with CoronaVac's. Three patients presented seizures 24 hours after the application of the vaccine with no clear relation between vaccination and seizure frequency, and one patient required admission to the hospital for a prolonged seizure. CONCLUSION: Vaccination against SARS-CoV-2 in paediatric patients with epilepsy is safe. Approximately 3% of patients with epilepsy could eventually have seizures in the post-vaccination period.

TITLE: Vacunación contra el SARS-CoV-2 en pacientes pediátricos con epilepsia: experiencia de un centro terciario en Colombia.Objetivo. El objetivo de este estudio es evaluar los efectos de la vacunación contra el SARS-CoV-2 sobre el patrón convulsivo en pacientes pediátricos con epilepsia que acudieron a nuestro centro terciario en la ciudad de Bogotá, Colombia. Pacientes y métodos. Se pidió a los niños con epilepsia que fueron tratados en nuestro centro y que habían recibido la vacuna contra el SARS-CoV-2 y a sus cuidadores que informaran de su experiencia después de la vacunación. Se documentaron la edad, el sexo, la edad de inicio de la epilepsia, la duración de la epilepsia, el tipo de epilepsia, la frecuencia de las convulsiones, el número de medicamentos, el tiempo transcurrido desde la última crisis, los esquemas de vacunación y las convulsiones dos semanas después de la vacunación. Resultados. Se incluyó a 101 pacientes con epilepsia (58%, hombres; y 42%, mujeres). La edad promedio fue de 11 años, el 73% tenía epilepsia focal, y el 27%, generalizada. Veintiuno cumplían los criterios para la epilepsia refractaria y 11 tenían antecedentes personales de convulsiones febriles. Cuarenta y siete pacientes habían sido vacunados con la vacuna de Sinovac; 41, con Pfizer; 12, con Moderna; y uno, con CoronaVac. Tres pacientes presentaron convulsiones 24 horas después de la aplicación de la vacuna sin una relación clara entre la vacunación y la frecuencia de las convulsiones, y un paciente requirió ingreso en el hospital por una convulsión prolongada. Conclusión. La vacunación contra el SARS-CoV-2 en pacientes pediátricos con epilepsia es segura. Aproximadamente el 3% de los pacientes con epilepsia podría eventualmente tener convulsiones en el período posterior a la vacunación.

Anthropometric measures and breast cancer risk among Hispanic women in Puerto Rico.

INTRODUCTION: Increased risk of postmenopausal breast cancer associated with anthropometric measures including Body Mass Index (BMI), adult weight gain, and waist circumference has been observed in North American and European populations, but little evidence is available for Hispanic women. Breast cancer is the leading type of cancer, and leading cause of cancer-related deaths among Hispanic women in Puerto Rico (PR). However, compared with the United States, breast cancer incidence rates are lower but increasing more rapidly. PURPOSE: To examine associations between anthropometric characteristics and breast cancer risk in Hispanic women in PR. METHODS: Data from a population-based case-control study in the San Juan metropolitan region (cases = 315; controls = 348) were used to examine associations between anthropometric measures and breast cancer risk, also considering menopausal status and hormone therapy (HT). RESULTS: Among premenopausal participants, there was a significant trend for lower odds of breast cancer with higher BMI and borderline significant with higher waist to height ratio (WHtR). For postmenopausal participants, a significant trend for lower odds of breast cancer was observed with higher WHtR, and waist to hip ratio (WHR), borderline significant with higher BMI, and higher odds with height. Among postmenopausal participants using HT, a significant trend for lower odds of breast cancer was observed with higher waist circumference, WHtR, WHR, and body shape index. CONCLUSION: Our study provides evidence of anthropometric differences in relation to breast cancer risk in PR compared to previous studies. Future studies should include analyses of fat and lean mass distribution, and hormone receptor status to further understand anthropometry and breast cancer risk among Hispanic women.

Cognitive stimulation has potential for brain activation in individuals with Rett syndrome.

BACKGROUND: Knowledge regarding neuropsychological training in Rett syndrome (RS) is scarce. The aim of this study was to assess the outcome and the duration of the effect of cognitive stimulation on topographic electroencephalography (EEG) data in RS. METHODS: Twenty female children diagnosed with RS were included in the analysis. Girls with RS conducted a cognitive task using an eye-tracker designed to evaluate access and choice skills. EEG data were acquired during the experimental procedure including two 10-min baseline stages before and after the task. Topographical changes of several EEG spectral markers including absolute and relative powers, Brain Symmetry Index and entropy were assessed. RESULTS: Topographic significance probability maps suggested statistical decreases on delta activity and increases on beta rhythm associated with the cognitive task. Entropy increased during and after the task, likely related to more complex brain activity. A significant positive interaction was obtained between Brain Symmetry Index and age showing that the improvement of interhemispheric symmetry was higher in younger girls (5-10 years). CONCLUSIONS: According to our findings, significant alterations of brain rhythms were observed during and after cognitive stimulation, suggesting that cognitive stimulation may have effects on brain activity beyond the stimulation period. Finally, our promising results also showed an increase brain symmetry that was especially relevant for the younger group. This could suggest an interaction of the eye-tracking cognitive task; however, further studies in this field are needed to assess the relation between brain asymmetries and age.

Dihydrolipoamide dehydrogenase, pyruvate oxidation, and acetylation-dependent mechanisms intersecting drug iatrogenesis.

In human metabolism, pyruvate dehydrogenase complex (PDC) is one of the most intricate and large multimeric protein systems representing a central hub for cellular homeostasis. The worldwide used antiepileptic drug valproic acid (VPA) may potentially induce teratogenicity or a mild to severe hepatic toxicity, where the underlying mechanisms are not completely understood. This work aims to clarify the mechanisms that intersect VPA-related iatrogenic effects to PDC-associated dihydrolipoamide dehydrogenase (DLD; E3) activity. DLD is also a key enzyme of α-ketoglutarate dehydrogenase, branched-chain α-keto acid dehydrogenase, α-ketoadipate dehydrogenase, and the glycine decarboxylase complexes. The molecular effects of VPA will be reviewed underlining the data that sustain a potential interaction with DLD. The drug-associated effects on lipoic acid-related complexes activity may induce alterations on the flux of metabolites through tricarboxylic acid cycle, branched-chain amino acid oxidation, glycine metabolism and other cellular acetyl-CoA-connected reactions. The biotransformation of VPA involves its complete ß-oxidation in mitochondria causing an imbalance on energy homeostasis. The drug consequences as histone deacetylase inhibitor and thus gene expression modulator have also been recognized. The mitochondrial localization of PDC is unequivocal, but its presence and function in the nucleus were also demonstrated, generating acetyl-CoA, crucial for histone acetylation. Bridging metabolism and epigenetics, this review gathers the evidence of VPA-induced interference with DLD or PDC functions, mainly in animal and cellular models, and highlights the uncharted in human. The consequences of this interaction may have significant impact either in mitochondrial or in nuclear acetyl-CoA-dependent processes.

Long cavity ring fiber mode-locked laser with decreased net value of nonlinear polarization rotation.

We investigate a new configuration of a mode-locked fiber laser by using a nonlinear polarization rotation-based design to generate soliton pulses with low repetition rate. Unlike with previously reported configurations, we introduce a Faraday mirror after the first half of the cavity length to counteract the nonlinear polarization rotation effects. The total cavity length is 437 m including a 400-m long twisted SMF-28 fiber. The fiber was twisted to cancel the linear birefringence and to ensure that the polarization ellipticity is not altered as the pulse travels along the fiber. The strict control of polarization yields a stable relation between the polarization state of the pulses propagating in the cavity and the regimes of generation. Depending on the polarization state we observed three different emission regimes, the single soliton regime (SR), conventional noise-like pulses (NLP) and noise-like square-waveform pulse (NLSWP). In the SR, a 467.2 kHz train of solitons was obtained with pulse duration of 2.9 ps at 1558.7 nm.

The natural history of classic galactosemia: lessons from the GalNet registry.

BACKGROUND: Classic galactosemia is a rare inborn error of carbohydrate metabolism, caused by a severe deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). A galactose-restricted diet has proven to be very effective to treat the neonatal life-threatening manifestations and has been the cornerstone of treatment for this severe disease. However, burdensome complications occur despite a lifelong diet. For rare diseases, a patient disease specific registry is fundamental to monitor the lifespan pathology and to evaluate the safety and efficacy of potential therapies. In 2014, the international Galactosemias Network (GalNet) developed a web-based patient registry for this disease, the GalNet Registry. The aim was to delineate the natural history of classic galactosemia based on a large dataset of patients. METHODS: Observational data derived from 15 countries and 32 centers including 509 patients were acquired between December 2014 and July 2018. RESULTS: Most affected patients experienced neonatal manifestations (79.8%) and despite following a diet developed brain impairments (85.0%), primary ovarian insufficiency (79.7%) and a diminished bone mineral density (26.5%). Newborn screening, age at onset of dietary treatment, strictness of the galactose-restricted diet, p.Gln188Arg mutation and GALT enzyme activity influenced the clinical picture. Detection by newborn screening and commencement of diet in the first week of life were associated with a more favorable outcome. A homozygous p.Gln188Arg mutation, GALT enzyme activity of ≤ 1% and strict galactose restriction were associated with a less favorable outcome. CONCLUSION: This study describes the natural history of classic galactosemia based on the hitherto largest data set.

Estudio CRONO: prevalencia del dolor irruptivo en pacientes con dolor crónico no oncológico en Andalucía, España / CRONO study: prevalence of breakthrough pain in patients with non-cancer chronic pain in Andalusia, Spain

Objetivo: El objetivo de este estudio es evaluar la prevalencia de dolor irruptivo (DI) en pacientes ambulatorios con dolor crónico de origen no oncológico y caracterizar la fisiopatología, localización, intensidad y frecuencia de los episodios de DI. Material y métodos: Estudio observacional, prospectivo y no intervencionista realizado en 16 unidades de dolor ambulatorias de hospitales de Andalucía y Ceuta. Se preguntó a los pacientes consecutivos elegibles si experimentan DI definido como "una exacerbación transitoria del dolor que ocurre espontáneamente, o en relación con un desencadenante predecible o impredecible específico, a pesar del dolor de base estable y controlado". En cada día de la encuesta, los dos primeros pacientes que confirmaron DI fueron preguntados sobre las características clínicas de su PTP (etiología, inicio, intensidad, frecuencia y tratamiento). Resultados: Se realizó un cribaje a un total de 3209 pacientes con dolor crónico no oncológico para identificar a 1118 pacientes con DI, lo que representó una prevalencia del 36 %. Se obtuvieron las características del DI de 350 pacientes: la intensidad media fue de 8,3 (± 1,4) en una Escala Analógica Visual (EVA), con una media de 2 episodios/24 horas (rango 1-5/24 h). El mecanismo del dolor fue mixto en 149 (42,6 %), neuropático en 91 (26 %) y nociceptivo en 72 (20,6 %) de los pacientes. Se encontró correlación positiva entre una mayor intensidad de DI con el nivel de dolor basal (r = 0,243, p < 0,001), y el número de crisis diarias de DI (r = 0,123, p = 0,003), ambas estadísticamente significativas. El 78 % de los pacientes estaba en tratamiento con opioides. Los más frecuentes fueron el citrato de fentanilo (52,6 %) y el tramadol (17,4 %). Conclusiones: La tasa de prevalencia del DI en pacientes con dolor crónico no oncológico es superior a un tercio de los pacientes atendidos en las unidades ambulatorias de dolor hospitalario en España. El DI provoca niveles reducidos de funcionalidad, trastornos psicológicos y un aumento del gasto asistencial. La clave del tratamiento es la individualización

Objective: The aim of this study was to evaluate the prevalence of breakthrough pain (BTP) in ambulatory patients with non-cancer chronic pain in Spain and to characterize physiopathology, location, intensity and frequency of BTP episodes. Methods: Prospective, non-interventional, observational study conducted in 16 pain units of hospitals of Andalusia and Ceuta. Eligible consecutive patients were are asked if they experience BTP defined as "a transient exacerbation of pain that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger, despite stable and controlled background pain". At each survey day, the first two patients reporting BTP were further interrogated on the clinical characteristics of their BTP (etiology, onset, intensity, frequency and treatment). Results: A total of 3,209 patients with non-cancer chronic pain were screened to identify 1,118 patients with BTP, which represented a prevalence of 36 %. BTP characteristics were retrieved from 350 patients: mean BTP intensity was 8.3 (± 1.4) on a Visual Analogue Scale (VAS), with a mean of 2 episodes/24 hour (range 1-5/24 h). Pain mechanism was mixed in 149 (42.6 %), neuropathic in 91 (26 %) and nociceptive in 72 in (20.6 %) of patients. Significant correlation was found between BTP intensity and both higher background pain (r = 0.243, p < 0.001), and daily BTP episodes frequency (r = 0.123, p = 0.003). 78 % of the patients were on opioid treatment. The most frequent were fentanyl citrate (52.6 %) and tramadol (17.4 %). Conclusions: The prevalence rate of BTP in patients with chronic non-oncologic pain is higher than one-third of the patients seen in outpatient hospital pain units in Spain. BTP causes reduced levels of functionality, psychological disorders, and an increase in health care expenditure. Individualization is the key to treatment

Analysis of Chromatin Interactions Mediated by Specific Architectural Proteins in Drosophila Cells.

Chromosome conformation capture assays have been established, modified, and enhanced for over a decade with the purpose of studying nuclear organization. A recently published method uses in situ Hi-C followed by chromatin immunoprecipitation (HiChIP) to enrich the overall yield of significant genome-wide interactions mediated by a specific protein. Here we applied a modified version of the HiChIP protocol to retrieve the significant contacts mediated by architectural protein CP190 in D. melanogaster cells.

Initial conditions for dissipative solitons in a strict polarization-controlled passively mode-locked Er-Fiber laser.

We report the dynamics of dissipative solitons in a ring cavity passively mode-locked fiber laser with a strict control of the polarization state. We study the relation between the polarization state of the pulses propagating in the cavity and the regimes of generation. We have found that at pulse ellipticities between 5° and 15°, the laser generates one bunch of pulses in the cavity, while at higher ellipticities the laser generates multiple bunches. At constant ellipticity we rotated the polarization azimuth and observed a regime transition from the generation of noise-like pulses (NLP) to that of soliton crystal. The NLP regime was found when the azimuth was rotated towards smaller low-power transmission through the polarizer. The number of solitons in the soliton crystal also depended on the azimuth in a straightforward way: the higher the initial transmission, the bigger the number of solitons.

Evolutionarily Conserved Principles Predict 3D Chromatin Organization.

Topologically associating domains (TADs), CTCF loop domains, and A/B compartments have been identified as important structural and functional components of 3D chromatin organization, yet the relationship between these features is not well understood. Using high-resolution Hi-C and HiChIP, we show that Drosophila chromatin is organized into domains we term compartmental domains that correspond precisely with A/B compartments at high resolution. We find that transcriptional state is a major predictor of Hi-C contact maps in several eukaryotes tested, including C. elegans and A. thaliana. Architectural proteins insulate compartmental domains by reducing interaction frequencies between neighboring regions in Drosophila, but CTCF loops do not play a distinct role in this organism. In mammals, compartmental domains exist alongside CTCF loop domains to form topological domains. The results suggest that compartmental domains are responsible for domain structure in all eukaryotes, with CTCF playing an important role in domain formation in mammals.

FAK phosphorylation plays a central role in thrombin-induced RPE cell migration.

The migration of retinal pigment epithelial (RPE) cells is an important step in various pathologic conditions including subretinal neovascularization (SRN), proliferative vitreoretinopathy (PVR) and, importantly, as a consequence of retinal surgery. Therefore, the elucidation of the mechanisms underlying RPE trans-differentiation and migration is essential for devising effective treatments aimed to the prevention of these disorders. A common event in these pathologies is the alteration of the blood-retina barrier (BRB), which allows the interaction of RPE cells with thrombin, a pro-inflammatory protease contained in serum. Our previous work has demonstrated that thrombin induces RPE cell cytoskeletal remodeling and migration, hallmark processes in the development of PVR; however, the molecular mechanisms involved are still unclear. Cell migration requires the disassembly of focal adhesions induced by Focal Adhesion Kinase (FAK) phosphorylation, together with the formation of actin stress fibers. The aim of the present work was to identify thrombin-activated signaling pathways leading to FAK phosphorylation and to determine FAK participation in thrombin-induced RPE cell migration. Results demonstrate that the activation of PAR1 by thrombin induces FAK autophosphorylation at Y397 and the subsequent phosphorylation of Y576/577 within the activation loop. FAK phosphorylation was shown to be under the control of c/nPKC and PI3K/PKC-ζ, as well as by Rho/ROCK, since the inhibition of these pathways prevented thrombin-induced FAK phosphorylation and the consequent disassembly of focal adhesions, in parallel to FAK-dependent actin stress fiber formation and RPE cell migration. These findings demonstrate, for the first time, that thrombin stimulation of RPE cell transformation and migration are regulated by FAK tyrosine phosphorylation. Thus, targeting FAK phosphorylation may provide a strategical basis for PVR treatment.

Patterns of infection and infection-related mortality in patients with steroid-refractory acute graft versus host disease.

This study aimed to characterize the incidence, etiology and outcome of infectious episodes in patients with steroid refractory acute GvHD (SR-GvHD). The cohort included 127 adults treated with inolimomab (77%) or etanercept (23%) owing to acute 2-4 SR-GvHD, with a response rate of 43% on day +30 and a 4-year survival of 15%. The 1-year cumulative incidences of bacterial, CMV and invasive fungal infection were 74%, 65% and 14%, respectively. A high rate (37%) of enterococcal infections was observed. Twenty patients (15.7%) developed BK virus-hemorrhagic cystitis and five percent had an EBV reactivation with only one case of PTLD. One-third of long-term survivors developed pneumonia by a community respiratory virus and/or encapsulated bacteria, mostly associated with chronic GvHD. Infections were an important cause of non-relapse mortality, with a 4-year incidence of 46%. In multivariate analysis, use of rituximab in the 6 months before SCT (hazard ratio; HR 4.2; 95% confidence interval; CI 1.1-16.3), severe infection before SR-GvHD onset (HR 5.8; 95% CI 1.3-26.3) and a baseline C-reactive protein >15 UI/mL (HR 2.9; 95% CI 1.1-8.5) were associated with infection-related mortality. High rates of opportunistic infections with remarkable mortality warrant further efforts to optimize long-term outcomes after SR-GvHD.

Instantaneous frequency measurement of dissipative soliton resonant light pulses.

We measured the instantaneous frequency profile of two different dissipative soliton resonant (DSR) light pulses, the usual flat-top and less-common trapezoid-shaped light pulses. The DSR light pulses were provided by an ytterbium-doped polarization-maintaining fiber ring passively mode-locked laser using the adequately selected amount of net-normal dispersion. We confirmed that the DSR light pulses have a (moderately) low linear chirp across the pulse, except at the edges, where the chirp changes exponentially. This unique instantaneous frequency behavior can be succinctly resumed by the following parameters: linear chirp slope and leading and trailing chirp lifetimes. As the pump power increases, the linear chirp slope decreases, whereas the leading and trailing chirp lifetimes do not show an appreciable change. The results are compared with previous theoretical works.

Polarization evolution of vector wave amplitudes in twisted fibers pumped by single and paired pulses.

Nonlinear polarization dynamics of single and paired pulses in twisted fibers is experimentally and numerically studied. Accompanying a dramatic difference in the output spectrum when a single- or double-amplified soliton pulse is launched in the fiber, the output polarization for the two cases also reveals very different characteristics.

Are natural reservoirs important for cholera surveillance? The case of an outbreak in a Brazilian estuary.

UNLABELLED: Paranaguá Bay is one of the largest estuarine systems on the Southern Brazilian coast. The only recorded cholera outbreak in this region since the early 20th century occurred in 1999 and resulted in 467 cases and at least three reported deaths in a population of approx. 150 000 people. This short communication reports historical, unpublished data related to that outbreak. Water, zooplankton and bivalve samples were collected and evaluated using direct fluorescence assay to determine whether Vibrio cholerae serogroups O1 and O139 were present in the estuarine system at that time. Most of the water (83%) and zooplankton samples (75%) were positive for V. cholerae O1, while V. cholerae O139 was not detected. Shellfish (Mytella sp.) were also positive for V. cholerae O1. These results indicate that the estuary, including biological vectors such as copepods and bivalves, comprise an important reservoir of V. cholerae O1 and a probable waterborne pathway for the disease, in addition to contamination with untreated sewage. SIGNIFICANCE AND IMPACT OF THE STUDY: Despite most of the cholera cases that occurred in Brazil during the 7th pandemic were located in the northern areas of the country, a significant outbreak in Paranaguá, an estuary in the south coast, resulted in at least three deaths in 1999. We report here the detection of Vibrio cholerae O1 in water, zooplankton and bivalve samples during the outbreak, using direct fluorescence assay as an alternative method for the traditional plate culture employed at the time by the Brazilian Sanitary Agency. Results demonstrate that aquatic natural reservoirs comprise a potential route of transmission of cholera, in addition to untreated sewage and routine monitoring is recommended.