[Sustained upgaze in a patient who ingested high doses of bupropion. Report of one case]. / Supraversión de la mirada en intoxicación mortal por bupropión.

Upgaze or sustained elevation of the eyes, is an alteration of ocular motility initially described in hypoxic coma. We report a 65-year-old woman admitted with hypotension and alteration of sensorium due to the ingestion of 9.5 g of Bupropion. She presented two seizures of short duration, without epileptic activity on the EEG. She had a persistent asynchronous myoclonus in extremities, tachycardia and prolonged Q-t. She suffered a cardiac arrest caused by asystole, which recovered quickly in five minutes. At that moment, upgaze appeared, associated with a persistent ocular opening, which persisted for days, but finally disappeared, without remission of coma. A magnetic resonance imaging done at the eighth day, showed hyperintensity of the oval center and corpus callosum which disappeared in a new imaging study done 30 days later, where images of hypoxia in the basal nuclei and cortex appeared. The patient died forty seven days after admission. Up-gaze is an ominous oculomotor alteration linked to an important but incomplete damage in the cerebral cortex, a condition that perverts some sequences of the ocular opening, reversing the Bell phenomenon and producing eyelid retraction.

Sleep biosignature of Type 2 diabetes: a case-control study.

AIM: To determine whether or not the sleep disturbances associated with Type 2 diabetes affect the structure of sleep. METHODS: We designed a case-control study in 76 patients with Type 2 diabetes and 76 control subjects without Type 2 diabetes, matched by age, gender, BMI and waist and neck circumferences. A subgroup of 32 patients with Type 2 diabetes was also matched with 64 control subjects without Type 2 diabetes according to apnoea-hypopnoea index score. Examination included an overnight full polysomnography. RESULTS: No differences in the percentage of time spent in either rapid eye movement or non-rapid eye movement sleep were observed between groups; however, patients with Type 2 diabetes had more microarousal events during sleep than control subjects [41.4 (total range 4.0-104.4) vs 20.7 (total range 1.3-94.5) events/h; P < 0.001]. These differences were mainly observed during the non-rapid eye movement sleep [7.4 (total range 0-107.2) vs 0.2 (total range 0-65.2) events/h; P < 0.001]. In addition, sleep variables related to oxygen saturation measures, such as the percentage of time spent with oxygen saturation ≤90%, were significantly greater during the rapid eye movement sleep in patients with Type 2 diabetes [20.3 (total range 0-99.2) vs. 10.5 (total range 0-94.0)%; P = 0.047]. This pattern was maintained in the subgroup of patients matched by apnoea-hypopnaea index. Finally, stepwise regression analyses showed that apnoea-hypopnoea index, the presence of Type 2 diabetes and fasting plasma glucose value were independently associated with the number of microarousals (R2 =0.667). CONCLUSIONS: Type 2 diabetes is associated with an altered sleep structure, with different effects according to rapid eye movement (increase in nocturnal hypoxia) or non-rapid eye movement (increase in sleep fragmentation) sleep.

Cryptic Caribbean species of Scorpaena (Actinopterygii: Scorpaeniformes) suggested by cytogenetic and molecular data.

Cytogenetic and molecular analyses enabled identification of two cytotypes among individuals of the spotted scorpion fish Scorpaena plumieri from Margarita Island, Venezuela. Cytotype 1 was characterized by 48 subtelo-acrocentric chromosomes and fundamental number (number of chromosome arms; FN) equalled 48, while cytotype 2 was characterized by two metacentric and 46 subtelo-acrocentric chromosomes and FN was 50. These cytotypes also differed in the location of the ribosomal gene clusters and in the distribution of the constitutive heterochromatin. Moreover, fish from the cytotypes 1 and 2 were found to belong to distinct mitochondrial lineages. The presence of two S. plumieri cytotypes from two lineages separated by high genetic distance suggests that they correspond to sympatric cryptic species.

Association of IgG immunoglobulin and subclasses level with the severity of chromoblastomycosis due to Fonsecaea pedrosoi and therapeutic response to itraconazole.

Chromoblastomycosis (CBM) is a chronic, suppurative, granulomatous mycosis of the skin and subcutaneous tissues. The aim of this study was to evaluate the association between IgG antibody levels and the severity of CBM and therapeutic response of patients to itraconazole. A longitudinal study was conducted in patients with CBM due to Fonsecaea pedrosoi and in healthy subjects with chromomycin skin test (CST)+. The dosage of anti-F. pedrosoi IgG antibody performed in 47 healthy individuals with CST+ showed positivity in 97.5 %, with an average titer of 2,109 [standard deviation (SD) + 3,676)] and a mean optical density (OD) of 1.174 (SD + 0.456), showing positive correlation with the induration area of the CST (mm(2)). The level of antibodies in 55 patients with CBM expressed in OD and titration showed that, before treatment, patients with severe disease had higher levels of IgG, IgG1, IgG2, and IgG3 when compared with moderate or mild disease (p < 0.05). According to the time of treatment, the mean antibody titers of IgG, IgG1, and IgG2 were reduced after treatment (p < 0.05). In the assessment of therapeutic response, there was reduction of IgG3 and IgG titers in patients with rapid response (p < 0.05) and IgG2 on rapid and intermediate response (p < 0.05). There was clear evidence of what are the risk factors for exposure to F. pedrosoi in the daily lives of these subjects, with prospects of preventive measures for the target population. The immunological analysis shows that the antibody anti-F. pedrosoi did not exhibit a protective role against infection caused by this agent.

Strokes and their relationship with sleep and sleep disorders.

INTRODUCTION: In the current population, strokes are one of the most important causes of morbidity and mortality, to which new risk factors are increasingly being attributed. Of late, there is increased interest in the relationship between sleep disorders and strokes as regards risk and prognosis. DEVELOPMENT: This article presents the changes in sleep architecture and brain activity in stroke patients, as well as the interaction between stroke and sleep disorders, including those which may also influence the outcome and recovery from strokes. The different treatments discussed in the literature are also reviewed, as correct treatment of such sleep disorders may not only improve quality of life and reduce after-effects, but can also increase life expectancy. CONCLUSIONS: Sleep disorders are becoming increasingly associated with stroke. In addition to being a risk factor, they can also interfere in the outcome and recovery of stroke patients. This article aims to present an exhaustive and current review on strokes and their relationship with sleep alterations and sleep disorders.

Melatonin in sleep disorders.

Melatonin is the main hormone involved in the control of the sleep-wake cycle. It is easily synthesisable and can be administered orally, which has led to interest in its use as a treatment for insomnia. Moreover, as production of the hormone decreases with age, in inverse correlation with the frequency of poor sleep quality, it has been suggested that melatonin deficit is at least partly responsible for sleep disorders. Treating this age-related deficit would therefore appear to be a natural way of restoring sleep quality, which is lost as patients age. However, despite the undeniable theoretical appeal of this approach to insomnia, little scientific evidence is available that supports any benefit of this substitutive therapy. Furthermore, the most suitable dose ranges and pharmaceutical preparations for melatonin administration are yet to be clearly defined. This review addresses the physiology of melatonin, the different pharmaceutical preparations, and data on its clinical usefulness.

Thriving in Oxygen While Preventing ROS Overproduction: No Two Systems Are Created Equal.

From 2.5 to 2.0 billion years ago, atmospheric oxygen concentration [O2] rose thousands of times, leading to the first mass extinction. Reactive Oxygen Species (ROS) produced by the non-catalyzed partial reduction of O2 were highly toxic eliminating many species. Survivors developed different strategies to cope with ROS toxicity. At the same time, using O2 as the final acceptor in respiratory chains increased ATP production manifold. Thus, both O2 and ROS were strong drivers of evolution, as species optimized aerobic metabolism while developing ROS-neutralizing mechanisms. The first line of defense is preventing ROS overproduction and two mechanisms were developed in parallel: 1) Physiological uncoupling systems (PUS), which increase the rate of electron fluxes in respiratory systems. 2) Avoidance of excess [O2]. However, it seems that as avoidance efficiency improved, PUSs became less efficient. PUS includes branched respiratory chains and proton sinks, which may be proton specific, the mitochondrial uncoupling proteins (UCPs) or unspecific, the mitochondrial permeability transition pore (PTP). High [O2] avoidance also involved different strategies: 1) Cell association, as in biofilms or in multi-cellularity allowed gas-permeable organisms (oxyconformers) from bacterial to arthropods to exclude O2. 2) Motility, to migrate from hypoxic niches. 3) Oxyregulator organisms: as early as in fish, and O2-impermeable epithelium excluded all gases and only exact amounts entered through specialized respiratory systems. Here we follow the parallel evolution of PUS and O2-avoidance, PUS became less critical and lost efficiency. In regard, to proton sinks, there is fewer evidence on their evolution, although UCPs have indeed drifted in function while in some species it is not clear whether PTPs exist.

[Treating acute postoperative pain: evaluation of results on the surgical ward]. / Atencióón del dolor agudo postoperatorio: evaluación de resultados en las salas de hospitalizacidón quirúrgicas.

OBJECTIVE: To describe management of acute postoperative pain on the surgical ward. To study the relationship between pain and a variety of surgical procedures and approaches. To determine the level of information patients received, their expectations, and their satisfaction with treatment of postoperative pain. PATIENTS AND METHODS: Cross-sectional observational study by survey and review of patient records. We studied 234 patients, including all who were hospitalized for more than 24 hours after scheduled or emergency operations. The main variables recorded were pain intensity at rest and during movement, including on the day after surgery, and the surgical procedure and approach. RESULTS: The prevalence of pain (>3 on a numerical scale) on the surgical ward was 33% at rest and 66% during movement. The prevalence of intense pain (>6 on the numerical scale) was 1.7% at rest and 7.3% during movement. Factors related to greater pain intensity were timing, that is, the first day after surgery, when 74.4% of patients experienced their most intense pain; type of surgery and approach (P<.004); and expecting to experience moderate or intense pain (P<.001). CONCLUSIONS: Recording the prevalence of postoperative pain on a surgical ward provides information about the real situation of acute postoperative pain control. Pain on movement is a principal indicator for detecting groups of patients for whom analgesic protocols could be improved. Type of surgery and approach is a fundamental factor to consider when comparing the results of analgesic protocols.

Saliva as a source of HCMV DNA in allogeneic stem cell transplantation patients.

OBJECTIVE: The purpose of this study was to investigate the use of saliva for the identification of human cytomegalovirus (HCMV) in allogeneic hematopoietic stem cell transplant patients by real time PCR compared with blood. MATERIALS AND METHODS: Saliva and blood samples were sampled weekly in 30 allogeneic hematopoietic stem cell transplant patients until 100 days after transplant. Total genomic DNA, extracted from saliva and whole-blood samples, was used for HCMV real time PCR. Nonparametric tests were performed, and P value

[Varicella outbreak in a village in Uruguay]. / Estudio de un brote de varicela en un pueblo del Uruguay.

UNLABELLED: A varicella outbreak occurred in a Uruguayan village that introduced the varicella vaccine in 1999 with currently high vaccination rates. AIM: To investigate the cause of the outbreak, vaccine effectiveness, and to describe the measures adopted. MATERIAL AND METHODS: Cases that occurred in the kindergarten and schools in the village were investigated. Vaccination cards were examined, history of chickenpox and clinical characteristic of the current episode were obtained and the outcome of the measures was evaluated. An estimate was made of the vaccine's effectiveness. RESULTS: 37 cases of varicella were reported, 14 occurring in previously vaccinated children, in a one total population of 313 children. The global effectiveness of the vaccine was 80%, and 100% for severe cases. A shift of cases towards older ages was demonstrated; vaccinated children had a trend of less fever and lower number of lesions. Immunization of healthy unvaccinated children, mainly adolescents stopped the outbreak. COMMENTS: The vaccine proved to be highly effectiveness. In an outbreak situation, immunization policies should consider "catch up" vaccination in non-immunized adolescents without a previous history of varicella.

A mutation in mitochondrial 12S rRNA, A827G, in Argentinean family with hearing loss after aminoglycoside treatment.

Mutations in mitochondrial DNA (mtDNA) have been found to be associated with sensorineural hearing loss. We report the clinical, genetic, and molecular characterization of one Argentinean family with aminoglycoside-induced impairment in two of their members. Clinical evaluation revealed the variable phenotype of hearing impairment including audiometric configuration in these subjects. Mutational analysis of the mtDNA in these pedigrees showed the presence of homoplasmic 12S rRNA A827G mutation, which has been associated with hearing impairment. The A827G mutation is located at the A-site of the mitochondrial 12S rRNA gene which is highly conserved in mammals. It is possible that the alteration of the tertiary or quaternary structure of this rRNA by the A827G mutation may lead to mitochondrial dysfunction, thereby playing a role in the pathogenesis of hearing loss and aminoglycoside hypersensitivity. However, incomplete penetrance of hearing impairment indicates that the A827G mutation itself is not sufficient to produce clinical phenotype.

Melatonin in sleep disorders. / Melatonina en los trastornos de sueño.

Melatonin is the main hormone involved in the control of the sleep-wake cycle. It is easily synthesisable and can be administered orally, which has led to interest in its use as a treatment for insomnia. Moreover, as production of the hormone decreases with age, in inverse correlation with the frequency of poor sleep quality, it has been suggested that melatonin deficit is at least partly responsible for sleep disorders. Treating this age-related deficit would therefore appear to be a natural way of restoring sleep quality, which is lost as patients age. However, despite the undeniable theoretical appeal of this approach to insomnia, little scientific evidence is available that supports any benefit of this substitutive therapy. Furthermore, the most suitable dose ranges and pharmaceutical preparations for melatonin administration are yet to be clearly defined. This review addresses the physiology of melatonin, the different pharmaceutical preparations, and data on its clinical usefulness.

Sterility and Safety Validation for Transport Packaging of Organs and Tissues.

The bags used in the transport of organs and tissues must be sterile, nontoxic, pyrogen free, and must serve as a barrier throughout their useful life. The goal of this study was to show the sterility, safety, and functionality of the bags subjected to irradiation, through validated procedures and techniques. The selected sterilization method was the use of gamma radiation. The sterilization dose was determined based on validated standards for the sterilization of medical products, ISO 11137-2: 2013 and ISO/TS 13004: 2013, using the Verification Dose Maximum method on samples belonging to 3 manufacturing lots. The ISO 10993-5: 2009 standard was used in the cytotoxicity tests, by means of extracts test and quantitative technique of MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. The tests to determine the expiration date of the kit were performed by ASTM F1980, accelerated aging, and ASTM D3078 to evaluate hermeticity. The irradiation dose validated to reach the required sterility safety level was 22.5 kGy. The constituent materials and the sterilization method do not generated cellular toxicity, and the product was not modified during the simulated time of 5 years. Sterilization by irradiation is a method that leaves no residue, does not harm the properties of the material because it is conducted in cold, and as the sterilizing agent, the energy absorbed by the product is highly penetrating and can be treated in its final packaging, with no risk of postcontamination. It is for this reason that it is prioritized over other methods of sterilization.

Sensitization of retinoids and corticoids to epigenetic drugs in MYC-activated lung cancers by antitumor reprogramming.

Components of the SWI/SNF chromatin remodeling complex, including BRG1 (also SMARCA4), are inactivated in cancer. Among other functions, SWI/SNF orchestrates the response to retinoid acid (RA) and glucocorticoids (GC) involving downregulation of MYC. The epigenetic drugs SAHA and azacytidine, as well as RA and GC, are currently being used to treat some malignancies but their therapeutic potential in lung cancer is not well established. Here we aimed to determine the possible therapeutic effects of azacytidine and SAHA (A/S) alone or in combination with GC plus RA (GC/RA) in lung cancers with either BRG1 inactivation or MYC amplification. In vitro, responses to GC/RA treatment were more effective in MYC-amplified cells. These effects were mediated by BRG1 and involved a reprogramming towards prodifferentiation gene expression signatures and downregulation of MYC. In MYC-amplified cells, administration of GC/RA enhanced the cell growth inhibitory effects of A/S which, in turn, accentuated the prodifferentiation features promoted by GC/RA. Finally, these treatments improved overall survival of mice orthotopically implanted with MYC-amplified, but not BRG1-mutant, cells and reduced tumor cell viability and proliferation. We propose that the combination of epigenetic treatments with retinoids and corticoids of MYC-driven lung tumors constitute a strategy for therapeutic intervention in this otherwise incurable disease.

BRG1/SMARCA4 is essential for neuroblastoma cell viability through modulation of cell death and survival pathways.

Neuroblastoma (NB) is a neoplasm of the sympathetic nervous system, and is the most common solid tumor of infancy. NBs are very heterogeneous, with a clinical course ranging from spontaneous regression to resistance to all current forms of treatment. High-risk patients need intense chemotherapy, and only 30-40% will be cured. Relapsed or metastatic tumors acquire multi-drug resistance, raising the need for alternative treatments. Owing to the diverse mechanisms that are responsible of NB chemoresistance, we aimed to target epigenetic factors that control multiple pathways to bypass therapy resistance. We found that the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4/BRG1) was consistently upregulated in advanced stages of NB, with high BRG1 levels being indicative of poor outcome. Loss-of-function experiments in vitro and in vivo showed that BRG1 is essential for the proliferation of NB cells. Furthermore, whole-genome transcriptome analysis revealed that BRG1 controls the expression of key elements of oncogenic pathways such as PI3K/AKT and BCL2, which offers a promising new combination therapy for high-risk NB.

Synthesis of a heterogeneous artificial metallolipase with chimeric catalytic activity.

A solid-phase strategy using lipase as a biomolecular scaffold to produce a large amount of Cu(2+)-metalloenzyme is proposed here. The application of this protocol on different 3D cavities of the enzyme allows creating a heterogeneous artificial metallolipase showing chimeric catalytic activity. The artificial catalyst was assessed in Diels-Alder cycloaddition reactions and cascade reactions showing excellent catalytic properties.

Dealing with inter-expert variability in retinopathy of prematurity: A machine learning approach.

BACKGROUND AND OBJECTIVE: Understanding the causes of disagreement among experts in clinical decision making has been a challenge for decades. In particular, a high amount of variability exists in diagnosis of retinopathy of prematurity (ROP), which is a disease affecting low birth weight infants and a major cause of childhood blindness. A possible cause of variability, that has been mostly neglected in the literature, is related to discrepancies in the sets of important features considered by different experts. In this paper we propose a methodology which makes use of machine learning techniques to understand the underlying causes of inter-expert variability. METHODS: The experiments are carried out on a dataset consisting of 34 retinal images, each with diagnoses provided by 22 independent experts. Feature selection techniques are applied to discover the most important features considered by a given expert. Those features selected by each expert are then compared to the features selected by other experts by applying similarity measures. Finally, an automated diagnosis system is built in order to check if this approach can be helpful in solving the problem of understanding high inter-rater variability. RESULTS: The experimental results reveal that some features are mostly selected by the feature selection methods regardless the considered expert. Moreover, for pairs of experts with high percentage agreement among them, the feature selection algorithms also select similar features. By using the relevant selected features, the classification performance of the automatic system was improved or maintained. CONCLUSIONS: The proposed methodology provides a handy framework to identify important features for experts and check whether the selected features reflect the pairwise agreements/disagreements. These findings may lead to improved diagnostic accuracy and standardization among clinicians, and pave the way for the application of this methodology to other problems which present inter-expert variability.

A simple method for quantifying IgM of low molecular weight.

A new and simple method for quantitation of IgM of low molecular weight in sera by radial immunodiffusion in 7% agar gel is described. The test is easy to perform and permits exact determination of low molecular weight IgM concentration down to very small quantities (1 mg%). Results obtained with the method described agree with previously used assay procedures and offer the advantage of convenience and rapidity.