Status epilepticus: impact of therapeutic coma on outcome.

OBJECTIVES: Therapeutic coma is advocated in guidelines for management of refractory status epilepticus; this is, however, based on weak evidence. We here address the specific impact of therapeutic coma on status epilepticus outcome. DESIGN: Retrospective assessment of a prospectively collected cohort. SETTING: Academic hospital. PATIENTS: Consecutive adults with incident status epilepticus lasting greater than or equal to 30 minutes, admitted between 2006 and 2013. MEASUREMENTS AND MAIN RESULTS: We recorded prospectively demographics, clinical status epilepticus features, treatment, and outcome at discharge and retrospectively medical comorbidities, hospital stay, and infectious complications. Associations between potential predictors and clinical outcome were analyzed using multinomial logistic regressions. Of 467 patients with incident status epilepticus, 238 returned to baseline (51.1%), 162 had new disability (34.6%), and 67 died (14.3%); 50 subjects (10.7%) were managed with therapeutic coma. Therapeutic coma was associated with poorer outcome in the whole cohort (relative risk ratio for new disability, 6.86; 95% CI, 2.84-16.56; for mortality, 9.10; 95% CI, 3.17-26.16); the effect was more important in patients with complex partial compared with generalized convulsive or nonconvulsive status epilepticus in coma. Prevalence of infections was higher (odds ratio, 3.81; 95% CI, 1.66-8.75), and median hospital stay in patients discharged alive was longer (16 d [range, 2-240 d] vs 9 d [range, 1-57 d]; p < 0.001) in subjects managed with therapeutic coma. CONCLUSIONS: This study provides class III evidence that therapeutic coma is associated with poorer outcome after status epilepticus; furthermore, it portends higher infection rates and longer hospitalizations. These data suggest caution in the straightforward use of this approach, especially in patients with complex partial status epilepticus.

Role of vitamin D deficiency in extraskeletal complications : predictor of health outcome or marker of health status?

The relationship of vitamin D with extraskeletal complications, such as cardiovascular disease, cancer, and autoimmune disease, is of major interest considering its roles in key biological processes and the worldwide high prevalence of vitamin D deficiency. However, the causal relationships between vitamin D and most extraskeletal complications are weak. Currently, a heated debate over vitamin D is being conducted according to two hypotheses. In this review, we first present the different arguments that suggest a major role of vitamin D in a very broad type of extraskeletal complications (hypothesis #1). We then present results from recent meta-analyses of randomized controlled trials indicating a lack of association of vitamin D with major extraskeletal complications (hypothesis #2). We discuss different issues (e.g., causality, confounding, reverse causation, misclassification, and Mendelian randomization) that contribute to the favoring of one hypothesis over the other. While ultimately only one hypothesis is correct, we anticipate that the results from the ongoing randomized controlled trials will be unlikely to reconcile the divided experts.

Blueberry production in Chile: current status and future developments

Chile has become a major actor in the blueberry industry as the most important supplier of off-season fresh fruit for the northern hemisphere. Blueberry exports passed from US$ 30 million (around 4,000 tons) in 2000 to US$ 380 million (94,000 tons) in 2011. The characteristics of the major blueberry growing regions (North, Central, South-central and South) are presented in terms of acreage, varieties, management practices, extension of the harvest season, and soil and climatic conditions. Most fruit is from highbush varieties, picked by hand and exported fresh by boat to United States. Largest proportion of fruit is exported from mid December to late January, which coincides with lowest prices. The south-central region (latitudes 34º50' to 38º15' S) was in 2007 the most important one with 5,075 ha (51.1% of area planted). Among the challenges for the Chilean blueberry industry in the near future are: 1. Lower profitability due to lower rates of currency exchange and higher costs, 2 - Greater scarcity and higher cost of labor, 3.- Need for higher productivity and sustainable production practices, 4- Fruit of high and consistent quality, and 5.- Greater investment in research. As a case study the article presents three approaches that can help identify areas with low availability of labor and improve its efficiency. The article shows the use of geomatic tools to establish labor availability, application of growth regulators to reduce crop load, increase fruit size and improve harvest efficiency, and the use of shakers to harvest fresh fruit for long distance markets. More research is needed to improve yields, reduce costs and give greater economical and ecological sustainability to the Chilean blueberry industry.

Assessing positive mental health in people with chronic physical health problems: correlations with socio-demographic variables and physical health status

Background: A holistic perspective on health implies giving careful consideration to the relationship between physical and mental health. In this regard the present study sought to determine the level of Positive Mental Health (PMH) among people with chronic physical health problems, and to examine the relationship between the observed levels of PMH and both physical health status and socio-demographic variables. Methods: The study was based on the Multifactor Model of Positive Mental Health (Lluch, 1999), which comprises six factors: Personal Satisfaction (F1), Prosocial Attitude (F2), Self-control (F3), Autonomy (F4), Problem-solving and Self-actualization (F5), and Interpersonal Relationship Skills (F6). The sample comprised 259 adults with chronic physical health problems who were recruited through a primary care center in the province of Barcelona (Spain). Positive mental health was assessed by means of the Positive Mental Health Questionnaire (Lluch, 1999). Results: Levels of PMH differed, either on the global scale or on specific factors, in relation to the following variables: age: global PMH scores decreased with age (r=-0.129; p=0.038); b) gender: men scored higher on F1 (t=2.203; p=0.028) and F4 (t=3.182; p=0.002), while women scored higher on F2 (t -3.086; p=0.002) and F6 (t=-2.744; p=0.007); c) number of health conditions: the fewer the number of health problems the higher the PMH score on F5 (r=-0.146; p=0.019); d) daily medication: polymedication patients had lower PMH scores, both globally and on various factors; e) use of analgesics: occasional use of painkillers was associated with higher PMH scores on F1 (t=-2.811; p=0.006). There were no significant differences in global PMH scores according to the type of chronic health condition. The only significant difference in the analysis by factors was that patients with hypertension obtained lower PMH scores on the factor Autonomy (t=2.165; p=0.032). Conclusions: Most people with chronic physical health problems have medium or high levels of PMH. The variables that adversely affect PMH are old age, polypharmacy and frequent consumption of analgesics. The type of health problem does not influence the levels of PMH. Much more extensive studies with samples without chronic pathology are now required in order to be able to draw more robust conclusions.

Oncogenic K-Ras segregates at spatially distinct plasma membrane signaling platforms according to its phosphorylation status

Activating mutations in the K-Ras small GTPase are extensively found in human tumors. Although these mutations induce the generation of a constitutively GTP-loaded, active form of K-Ras, phosphorylation at Ser181 within the C-terminal hypervariable region can modulate oncogenic K-Ras function without affecting the in vitro affinity for its effector Raf-1. In striking contrast, K-Ras phosphorylated at Ser181 shows increased interaction in cells with the active form of Raf-1 and with p110α, the catalytic subunit of PI 3-kinase. Because the majority of phosphorylated K-Ras is located at the plasma membrane, different localization within this membrane according to the phosphorylation status was explored. Density-gradient fractionation of the plasma membrane in the absence of detergents showed segregation of K-Ras mutants that carry a phosphomimetic or unphosphorylatable serine residue (S181D or S181A, respectively). Moreover, statistical analysis of immunoelectron microscopy showed that both phosphorylation mutants form distinct nanoclusters that do not overlap. Finally, induction of oncogenic K-Ras phosphorylation - by activation of protein kinase C (PKC) - increased its co-clustering with the phosphomimetic K-Ras mutant, whereas (when PKC is inhibited) non-phosphorylated oncogenic K-Ras clusters with the non-phosphorylatable K-Ras mutant. Most interestingly, PI 3-kinase (p110α) was found in phosphorylated K-Ras nanoclusters but not in non-phosphorylated K-Ras nanoclusters. In conclusion, our data provide - for the first time - evidence that PKC-dependent phosphorylation of oncogenic K-Ras induced its segregation in spatially distinct nanoclusters at the plasma membrane that, in turn, favor activation of Raf-1 and PI 3-kinase.

Effect of Maraviroc Intensification on HIV-1-Specific T Cell Immunity in Recently HIV-1-Infected Individuals

Background The effect of maraviroc on the maintenance and the function of HIV-1-specific T cell responses remains unknown. Methods Subjects recently infected with HIV-1 were randomized to receive anti-retroviral treatment with or without maraviroc intensification for 48 weeks, and were monitored up to week 60. PBMC and in vitro-expanded T cells were tested for responses to the entire HIV proteome by ELISpot analyses. Intracellular cytokine staining assays were conducted to monitor the (poly)-functionality of HIV-1-specific T cells. Analyses were performed at baseline and week 24 after treatment start, and at week 60 (3 months after maraviroc discontinuation). Results Maraviroc intensification was associated with a slower decay of virus-specific T cell responses over time compared to the non-intensified regimen in both direct ex-vivo as well as in in-vitro expanded cells. The effector function profiles of virus-specific CD8+ T cells were indistinguishable between the two arms and did not change over time between the groups. Conclusions Maraviroc did not negatively impact any of the measured parameters, but was rather associated with a prolonged maintenance of HIV-1-specific T cell responses. Maraviroc, in addition to its original effect as viral entry inhibitor, may provide an additional benefit on the maintenance of virus-specific T cells which may be especially important for future viral eradication strategies.

Estimating the Ontogenetic Status of an Enantiornithine Bird from the Lower Barremian of El Montsec, Central Pyrenees, Spain.

An Enantiornithes specimen from El Montsec was initially described as an immature individual based upon qualitative traits such as its relatively large orbit and overall proportions of the skull and the postcranium. In this study we re-evaluate the precise determination of the ontogenetic stage of this individual, establishing a cross-talk among taphonomic, anatomic, and morphometric data. The exceptional preservation of the specimen has allowed pondering ontogenetic influence versus preservational bias in features like the external patterns of bone surfaces, instead of being aprioristically considered due to taphonomic alterations only. The rough texture of the periosteal bone associated with pores in the distal, proximal and mid-shaft areas of the humeral shaft, indicates a subadult stage when compared with long bones of modern birds. Forelimb proportions of embryo and juvenile Enanthiornithes are equivalent to those of adult individuals of other taxa within this clade, though this is not a reliable criterion for establishing a precise ontogenetic stage. The El Montsec specimen may be attributed a close adulthood, yet only if growth regimes in Enantiornithes are considered equivalent to those in Neornithes birds.

A definition and classification of status epilepticus - Report of the ILAE Task Force on Classification of Status Epilepticus.

The Commission on Classification and Terminology and the Commission on Epidemiology of the International League Against Epilepsy (ILAE) have charged a Task Force to revise concepts, definition, and classification of status epilepticus (SE). The proposed new definition of SE is as follows: Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1 ). It is a condition, which can have long-term consequences (after time point t2 ), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. This definition is conceptual, with two operational dimensions: the first is the length of the seizure and the time point (t1 ) beyond which the seizure should be regarded as "continuous seizure activity." The second time point (t2 ) is the time of ongoing seizure activity after which there is a risk of long-term consequences. In the case of convulsive (tonic-clonic) SE, both time points (t1 at 5 min and t2 at 30 min) are based on animal experiments and clinical research. This evidence is incomplete, and there is furthermore considerable variation, so these time points should be considered as the best estimates currently available. Data are not yet available for other forms of SE, but as knowledge and understanding increase, time points can be defined for specific forms of SE based on scientific evidence and incorporated into the definition, without changing the underlying concepts. A new diagnostic classification system of SE is proposed, which will provide a framework for clinical diagnosis, investigation, and therapeutic approaches for each patient. There are four axes: (1) semiology; (2) etiology; (3) electroencephalography (EEG) correlates; and (4) age. Axis 1 (semiology) lists different forms of SE divided into those with prominent motor systems, those without prominent motor systems, and currently indeterminate conditions (such as acute confusional states with epileptiform EEG patterns). Axis 2 (etiology) is divided into subcategories of known and unknown causes. Axis 3 (EEG correlates) adopts the latest recommendations by consensus panels to use the following descriptors for the EEG: name of pattern, morphology, location, time-related features, modulation, and effect of intervention. Finally, axis 4 divides age groups into neonatal, infancy, childhood, adolescent and adulthood, and elderly.

Innate and Adaptive Immunity in Orolabial Herpes Simplex

Oral mucosa is a frequent site of primary herpes simplex virus type 1 (HSV-1) infection, whereas intraoral recurrent disease is very rare. Instead, reactivation from latency predominantly results in asymptomatic HSV shedding to saliva or recurrent labial herpes (RLH) with highly individual frequency. The current study aimed to elucidate the role of human oral innate and acquired immune mechanisms in modulation of HSV infection in orolabial region. Saliva was found to neutralize HSV-1, and to protect cells from infection independently of salivary antibodies. Neutralization capacity was higher in saliva from asymptomatic HSV-seropositive individuals compared to subjects with history of RLH or seronegative controls. Neutralization was at least partially associated with salivary lactoferrin content. Further, lactoferrin and peroxidase-generated hypothiocyanite were found to either neutralize HSV-1 or interfere with HSV-1 replication, whereas lysozyme displayed no anti-HSV-1 activity. Lactoferrin was also shown to modulate HSV-1 infection by inhibiting keratinocyte proliferation. RLH susceptibility was further found to be associated with Th2 biased cytokine responses against HSV, and a higher level of anti- HSV-IgG with Th2 polarization, indicating lack of efficiency of humoral response in the control of HSV disease. In a three-dimensional cell culture, keratinocytes were found to support both lytic and nonproductive infection, suggesting HSV persistence in epithelial cells, and further emphasizing the importance of peripheral immune control of HSV. These results suggest that certain innate salivary antimicrobial compounds and Th1 type cellular responses are critically important in protecting the host against HSV disease, implying possible applications in drug, vaccine and gene therapy design.

A Population-Based Model to Consider the Effect of Seasonal Variation on Serum 25(OH)D and Vitamin D Status.

Background. We elaborated a model that predicts the centiles of the 25(OH)D distribution taking into account seasonal variation. Methods. Data from two Swiss population-based studies were used to generate (CoLaus) and validate (Bus Santé) the model. Serum 25(OH)D was measured by ultra high pressure LC-MS/MS and immunoassay. Linear regression models on square-root transformed 25(OH)D values were used to predict centiles of the 25(OH)D distribution. Distribution functions of the observations from the replication set predicted with the model were inspected to assess replication. Results. Overall, 4,912 and 2,537 Caucasians were included in original and replication sets, respectively. Mean (SD) 25(OH)D, age, BMI, and % of men were 47.5 (22.1) nmol/L, 49.8 (8.5) years, 25.6 (4.1) kg/m(2), and 49.3% in the original study. The best model included gender, BMI, and sin-cos functions of measurement day. Sex- and BMI-specific 25(OH)D centile curves as a function of measurement date were generated. The model estimates any centile of the 25(OH)D distribution for given values of sex, BMI, and date and the quantile corresponding to a 25(OH)D measurement. Conclusions. We generated and validated centile curves of 25(OH)D in the general adult Caucasian population. These curves can help rank vitamin D centile independently of when 25(OH)D is measured.

Could machine learning improve the prediction of pelvic nodal status of prostate cancer patients? Preliminary results of a pilot study.

We tested and compared performances of Roach formula, Partin tables and of three Machine Learning (ML) based algorithms based on decision trees in identifying N+ prostate cancer (PC). 1,555 cN0 and 50 cN+ PC were analyzed. Results were also verified on an independent population of 204 operated cN0 patients, with a known pN status (187 pN0, 17 pN1 patients). ML performed better, also when tested on the surgical population, with accuracy, specificity, and sensitivity ranging between 48-86%, 35-91%, and 17-79%, respectively. ML potentially allows better prediction of the nodal status of PC, potentially allowing a better tailoring of pelvic irradiation.

Practice variability and efficacy of clonazepam, lorazepam, and midazolam in status epilepticus: A multicenter comparison.

OBJECTIVE: Benzodiazepines (BZD) are recommended as first-line treatment for status epilepticus (SE), with lorazepam (LZP) and midazolam (MDZ) being the most widely used drugs and part of current treatment guidelines. Clonazepam (CLZ) is also utilized in many countries; however, there is no systematic comparison of these agents for treatment of SE to date. METHODS: We identified all patients treated with CLZ, LZP, or MDZ as a first-line agent from a prospectively collected observational cohort of adult patients treated for SE in four tertiary care centers. Relative efficacies of CLZ, LZP, and MDZ were compared by assessing the risk of developing refractory SE and the number of antiseizure drugs (ASDs) required to control SE. RESULTS: Among 177 patients, 72 patients (40.62%) received CLZ, 82 patients (46.33%) LZP, and 23 (12.99%) MDZ; groups were similar in demographics and SE characteristics. Loading dose was considered insufficient in the majority of cases for LZP, with a similar rate (84%, 95%, and 87.5%) in the centers involved, and CLZ was used as recommended in 52% of patients. After adjustment for relevant variables, LZP was associated with an increased risk of refractoriness as compared to CLZ (odds ratio [OR] 6.4, 95% confidence interval [CI] 2.66-15.5) and with an increased number of ASDs needed for SE control (OR 4.35, 95% CI 1.8-10.49). SIGNIFICANCE: CLZ seems to be an effective alternative to LZP and MDZ. LZP is frequently underdosed in this setting. These findings are highly relevant, since they may impact daily practice.