Ankyrin-G regulates forebrain connectivity and network synchronization via interaction with GABARAP.

GABAergic circuits are critical for the synchronization and higher order function of brain networks. Defects in this circuitry are linked to neuropsychiatric diseases, including bipolar disorder, schizophrenia, and autism. Work in cultured neurons has shown that ankyrin-G plays a key role in the regulation of GABAergic synapses on the axon initial segment and somatodendritic domain of pyramidal neurons, where it interacts directly with the GABAA receptor-associated protein (GABARAP) to stabilize cell surface GABAA receptors. Here, we generated a knock-in mouse model expressing a mutation that abolishes the ankyrin-G/GABARAP interaction (Ank3 W1989R) to understand how ankyrin-G and GABARAP regulate GABAergic circuitry in vivo. We found that Ank3 W1989R mice exhibit a striking reduction in forebrain GABAergic synapses resulting in pyramidal cell hyperexcitability and disruptions in network synchronization. In addition, we identified changes in pyramidal cell dendritic spines and axon initial segments consistent with compensation for hyperexcitability. Finally, we identified the ANK3 W1989R variant in a family with bipolar disorder, suggesting a potential role of this variant in disease. Our results highlight the importance of ankyrin-G in regulating forebrain circuitry and provide novel insights into how ANK3 loss-of-function variants may contribute to human disease.

Efficient parameter estimation in multiresponse models measuring radioactivity retention.

After incorporation of radioactive substances, workers are routinely checked by bioassays (isotopic activity excreted via urine, measurements of radionuclides retained in the whole body or in the lungs, etc.). From the results, the isotopic activity incorporated by the worker is inferred, as well as the values of other parameters related to the metabolism of the incorporated substance, using the 'response function'. This function depends on several factors and it is usually obtained by solving a system of linear differential equations, resulting from the compartmental model which describes the human body (or a part of it). The possibility of using different types of bioassays from the same worker improves estimation of some of the parameters that characterize the solution of the system of equations, specially the unknown incorporated activity to the system. The transfer coefficients are usually considered to be known, using the values that are published in the corresponding International Commission of Radiological Protection (ICRP) publication. In the present study some practical cases will be presented, and optimal design criteria are developed that allow taking the bio-samples at the most informative times. The methodology presented here requires solving the models of element distribution in the human organism as a function of time, for which the recently updated models recommended by the ICRP have been used. Initially thought for workers in facilities dealing with radioactive substances, the study results, procedures and conclusions can be applied to other clinical or laboratory settings, and to the design of action protocols in case of environmental public exposure.

Improving efficiency of viability-qPCR for selective detection of infectious HAV in food and water samples.

AIM: To improve the efficacy of intercalating dyes to distinguishing between infectious and inactivated hepatitis A virus (HAV) in food. METHODS AND RESULTS: Different intercalating dyes were evaluated for the discrimination between infectious and thermally inactivated HAV suspensions combining with the RT-qPCR proposed in the ISO 15216. Among them, PMAxx was the best dye in removing the RT-qPCR signal from inactivated HAV. Applied to lettuce and spinach, PMAxx-Triton pretreatment resulted in complete removal of the RT-qPCR signal from inactivated HAV. Likewise, this study demonstrates that this pretreatment is suitable for the discrimination of inactivated HAV in shellfish without further sample dilution. In mussels and oysters, the developed viability RT-qPCR method reduced the signal of inactivated HAV between 1·7 and 2·2 logs at high inoculation level, and signal was completely removed at low inoculation level. CONCLUSIONS: This study showed that the use of PMAxx is an important improvement to assess HAV infectivity by RT-qPCR. It was shown that PMAxx-Triton pretreatment is suitable for the analysis of infectious HAV in complex food samples such as vegetables and shellfish. SIGNIFICANCE AND IMPACT OF THE STUDY: The PMAxx-Triton pretreatment can be easily incorporated to the ISO norm for infectious virus detection.

Seasonal influenza in octogenarians and nonagenarians admitted to a general hospital: epidemiology, clinical presentation and prognostic factors.

OBJECTIVE: Seasonal influenza is responsible for high annual morbidity and mortality worldwide, especially in elderly patients. The aim of the study was to analyse the epidemiological, clinical and prognostic features of influenza in octogenarians and nonagenarians admitted to a general hospital, as well as risk factors associated with mortality. METHODS: Retrospective, cross-sectional, descriptive study in patients admitted and diagnosed with influenza by molecular biology in the General University Hospital of Alicante from 1 January to 31 April 2015. RESULTS: A total of 219 patients were diagnosed with influenza in the study period: 55 (25.1%) were ≤64 years-old; 77 (35.2%) were aged 65-79; 67 (30.6%) were aged 80-89 years; and 20 (9.1%) were aged ≥90 years. Most flu episodes were caused by influenza A (n=181, 82.6%). Patients aged 80 years or older had lower glomerular filtration rate (mean: 49.7 mL/min vs. 62.2 mL/min; p=0.006), a greater need for non-invasive mechanical ventilation (22% vs 9.3%; p=0.02), greater co-morbidity due to cardiac insufficiency (40.5% vs. 16.4%; p<0.001) and chronic renal disease (32.9 vs. 20%, p=0.03), and greater mortality (19% vs. 2.9%; p<0.001). In a multivariate analysis, mortality was higher in those aged 80 or over (adjusted odds ratio [ORa] 9.2, 95% confidence interval [CI] 1.65-51.1), those who had acquired the flu in a long-term care facility (ORa 11.9, 95% CI 1.06-134), and those with hyperlactataemia (ORa 1.89, 95% CI 1.20-3.00). CONCLUSIONS: Seasonal influenza is a serious problem leading to elevated mortality in octogenarian and nonagenarian patients admitted to a general hospital.

Effectiveness of a programme to reduce the burden of catheter-related bloodstream infections in a tertiary hospital.

The objective of this study was to assess the effectiveness of a catheter-related bloodstream infection (CR BSI) reduction programme and healthcare workers' compliance with recommendations. A 3-year surveillance programme of CR BSIs in all hospital settings was implemented. As part of the programme, there was a direct observation of insertion and maintenance of central venous catheters (CVCs) to determine performance. A total of 38 education courses were held over the study period and feedback reports with the results of surveillance and recommendations were delivered to healthcare workers every 6 months. A total of 6722 short-term CVCs were inserted in 4982 patients for 58 763 catheter-days. Improvements of compliance with hand hygiene was verified at the insertion (87·1-100%, P < 0·001) and maintenance (51·1-72·1%, P = 0·029) of CVCs; and the use of chlorhexidine for skin disinfection was implemented at insertion (35·7-65·4%, P < 0·001) and maintenance (33·3-45·9%, P < 0·197) of CVCs. There were 266 CR BSI incidents recorded with an annual incidence density of 5·75/1000 catheter-days in the first year, 4·38 in the second year [rate ratio (RR) 0·76, 95% confidence interval (CI) 0·57-1·01] and 3·46 in the third year (RR 0·60, 95% CI 0·44-0·81). The education programme clearly improved compliance with recommendations for CVC handling, and was effective in reducing the burden of CR BSIs.

New model for sustainable management of pressurized irrigation networks. Application to Bembézar MD irrigation district (Spain).

Pressurized irrigation networks require large amounts of energy for their operation which are linked to significant greenhouse gas (GHG) emissions. In recent years, several management strategies have been developed to reduce energy consumption in the agricultural sector. One strategy is the reduction of the water supplied for irrigation but implies a reduction in crop yields and farmer's profits. In this work, a new methodology is developed for sustainable management of irrigation networks considering environmental and economic criteria. The multiobjective non-dominated Sorting Genetic Algorithm (NSGA II) has been selected to obtain the optimum irrigation pattern that would reduce GHG emissions and increase profits. This methodology has been applied to Bembézar Margen Derecha (BMD) irrigation district (Spain). Irrigation patterns that reduce GHG emissions or increase actual profits are obtained. The best irritation pattern reduces the current GHG emissions in 8.56% with increases the actual profits in 14.56%. Thus, these results confirm that simultaneous improvements in environmental and economic factors are possible.

Impacts of irrigation network sectoring as an energy saving measure on olive grove production.

In recent years, improving water use efficiency has been one of the most important challenges for the agricultural sector. However, such improvements have led to the installation of pressurized irrigation systems which generally require more energy to operate, especially in plantations on sloping and mountainous lands. Thus, the reduction of energy use in these systems has also become a major issue. Irrigation network sectoring has been proposed as one of the most effective energy saving measures. Typically, however, the potential benefits of this management strategy have been evaluated by means of theoretical approaches in networks that were originally designed to supply water on demand and not after water application in real irrigation districts designed following sectoring strategies. In this work, this measure is applied to an irrigation district devoted to olive grove production in a mountainous area that was designed according to this management strategy. With this aim, the WEBSO (Water and Energy Based Sectoring Operation) algorithm, which was developed in a previous work, has been modified in order to take into account the specific characteristics of the irrigation district and its actual management, as well as to analyze sensitivity to several irrigation water depths in terms of both energy demand and yields. An economic analysis of the potential benefits of this management strategy is also carried out. The results show that this measure has lead to a nearly 30% reduction in energy consumption, while increasing farmers' profits by 13% compared to traditional on-demand operations.

Molecular characterization of sewage-borne pathogens and detection of sewage markers in an urban stream in Caracas, Venezuela.

Molecular characterization of two sewage-borne pathogens identified hepatitis A virus (HAV) subgenotype IA and Giardia duodenalis assemblages A and B as predominant genotypes circulating in an urban area of Venezuela. This study reveals epidemiological features of human pathogens of worldwide distribution and the efficacy of molecular methods for accurate assessment of sewage pollution.

Optimizing the test power for a radiation retention model in the human body.

The model that describes the retention in lungs of radioisotope particles is studied in this paper, considering the situation of an accident in facilities that handle radioactive materials. Optimal times to make the bioassays are computed for D- and c-optimality, and efficiencies for the computed designs are provided and compared. Moreover, the test power is checked by means of simulations and replications. After that the inverse of the Fisher information matrix is compared to an estimation of the covariance matrix of the parameters. Finally, a study taking into consideration the randomness of the designs space is performed.

Saccade velocity is reduced in presymptomatic spinocerebellar ataxia type 2.

OBJECTIVE: A characteristic feature of spinocerebellar ataxia type 2 (SCA2) is saccadic slowing at early disease stages. We sought to determine whether this sign is detectable before clinical manifestation and quantifies the disease progression throughout life in linear fashion. METHODS: In a specialized ataxia clinic, 54 presymptomatic carriers of SCA2 polyglutamine expansions and 56 relatives without mutation were documented with regard to their maximal saccade velocity (MSV). RESULTS: Among the control individuals, a significant effect of aging on MSV was observed. After elimination of this age influence through a matched-pair approach, a presymptomatic decrease of MSV could be shown. The MSV reduction was stronger in carriers of large expansions. In the years before calculated disease manifestation, the MSV impairment advanced insidiously. CONCLUSION: Saccade velocity is a sensitive SCA2 endophenotype that reflects early pontine degeneration and may be a useful diagnostic parameter before the onset of ataxia. SIGNIFICANCE: Future neuroprotective therapies of polyglutamine neurodegeneration may be assessed by MSV from earliest to prefinal disease stages.

Detection and characterization of waterborne gastroenteritis viruses in urban sewage and sewage-polluted river waters in Caracas, Venezuela.

The detection and molecular characterization of pathogenic human viruses in urban sewage have been used extensively to derive information on circulating viruses in given populations throughout the world. In this study, a similar approach was applied to provide an overview of the epidemiology of waterborne gastroenteritis viruses circulating in urban areas of Caracas, the capital city of Venezuela in South America. Dry season sampling was conducted in sewers and in a major river severely polluted with urban sewage discharges. Nested PCR was used for detection of human adenoviruses (HAds), while reverse transcription plus nested or seminested PCR was used for detection of enteroviruses (HuEVs), rotaviruses (HRVs), noroviruses (HuNoVs), and astroviruses (HAstVs). HRVs were fully characterized with genotype-specific primers for VP4 (genotype P), VP7 (genotype G), and the rotavirus nonstructural protein 4 (NSP4). HuNoVs and HAstVs were characterized by sequencing and phylogenetic analysis. The detection rates of all viruses were >or=50%, and all sampling events were positive for at least one of the pathogenic viruses studied. The predominant HRV types found were G1, P[8], P[4], and NSP4A and -B. Genogroup II of HuNoVs and HAstV type 8 were frequently detected in sewage and sewage-polluted river waters. This study reveals relevant epidemiological data on the distribution and persistence of human pathogenic viruses in sewage-polluted waters and addresses the potential health risks associated with transmission of these viruses through water-related environmental routes.

Saccade velocity is reduced in presymptomatic spinocerebellar ataxia type 2

A characteristic feature of spinocerebellar ataxia type 2 (SCA2) is saccadic slowing at early disease stages. We sought to determine whether this sign is detectable before clinical manifestation and quantifies the disease progression throughout life in linear fashion. In a specialized ataxia clinic, 54 presymptomatic carriers of SCA2 polyglutamine expansions and 56 relatives without mutation were documented with regard to their maximal saccade velocit Spinocerebellar ataxia type 2 Among the control individuals, a significant effect of aging on MSV was observed. After elimination of this age influence through a matched-pair approach, a presymptomatic decrease of MSV could be shown. The MSV reduction was stronger in carriers of large expansions. In the years before calculated disease manifestation, the MSV impairment advanced insidiously.Saccade velocity is a sensitive SCA2 endophenotype that reflects early pontine degenerationPolyglutamine expansion and may be a useful diagnostic parameter before the onset of ataxia. Significance: Future neuroprotective therapies of polyglutamine neurodegeneration may be assessed by MSV from earliest to prefinal disease stages...(AU)

Clinical and pathological factors associated with the development of hepatocellular carcinoma in patients with hepatitis virus-related cirrhosis: a long-term follow-up study.

AIMS: Hepatocellular carcinoma (HCC) represents >90% of primary liver neoplasms and develops mainly in patients with liver cirrhosis. Risk factor identification for the development of HCC in patients with cirrhosis possesses great clinical relevance due to its high incidence and poor prognosis when detected at advanced stages. The aim of this study was to identify HCC development-associated risk factors in a cohort of patients with hepatitis virus-related chronic liver disease and cirrhosis. MATERIALS AND METHODS: Patients with a diagnosis of hepatitis virus-related cirrhosis between January 1980 and January 2000 were included. Patients were followed with an abdominal ultrasound and the determination of alpha-fetoprotein levels, a physical examination, and routine biochemical tests every 3-6 months. The end point of the study was defined as the development of HCC. Liver histology was evaluated according to the French METAVIR Cooperative Study Group (METAVIR) score. RESULTS: Two hundred and eighty-two patients met the inclusion criteria; most of these (86%) had a serologic diagnosis of hepatitis C virus, and only 14% had hepatitis B virus at the time of the diagnosis of cirrhosis, whereas 56 and 37% were classified as Child A and B, respectively, and only 7% as Child C. Histological activity was mild in 59% of patients, and moderate and severe in 41%. The mean annual incidence was 1.87%, and 22 and 35% of patients developed HCC at 10 and 15 years of follow-up, respectively. The diagnosis of HCC was made by histopathology in 37% and by tumoural lesion-associated alpha-fetoprotein elevation confirmed by imaging studies in 63%. In multivariate analysis, we found three variables associated with HCC: moderate to severe histological activity; a platelet count <105x10(3)/mm(3), and alpha-fetoprotein >5 ng/ml. The patients were divided into two groups according to regression coefficient: low and high risk; patients assigned to the low-risk group showed 5-, 10- and 15-year HCC incidences of 3.4, 6.4 and 6.4%, respectively, in contrast to patients from the high-risk group, who showed incidences of 17.8, 33.5 and 56.8%, respectively. CONCLUSIONS: We found three HCC-associated variables: histological activity, platelet count and alpha-fetoprotein levels. Patients considered as high risk for developing HCC must be considered candidates for closer follow-up.

Optimal design and mathematical model applied to establish bioassay programs.

Bioassays can be used to estimate the initial intake I for the case of an acute intake exposure for an individual worker. To evaluate the effective dose, apart from I, we need to know other parameters such as activity median aerodynamic diameter (AMAD) or the fraction absorption ( f(1)) in the blood from the GI tract, but in an accident situation these parameters are often unknown. The bioassay measurement values can be used to estimate by fitting the parameters unknown. In this paper, optimal designs for the estimation of the unknown parameters are developed. The efficiency of the design will depend on the number of samples and the measurement accuracy. The method described applies D-optimality that maximises the determinant of the Fisher information matrix to find the best moments where the bioassay measurements should be taken. It requires obtaining the analytical solution of the biokinetic model as a function of the parameters to be fitted. The method has been implemented in a computer program.

In vitro activity of new fluoroquinolones and linezolid against non-tuberculous mycobacteria.

The objective of the study was to determine the activity of new fluoroquinolones and linezolid against 108 clinical isolates of different species of non-tuberculous mycobacteria isolated in Spain. Gatifloxacin and moxifloxacin were found to be more effective than levofloxacin. Mycobacterium kansasii was more susceptible to the fluoroquinolones tested than M. avium complex and M. fortuitum was more susceptible than M. chelonae. Linezolid was more active against M. kansasii than against M. avium complex. A better understanding of the relationship between the in vitro activity of these compounds and their usefulness in the treatment of these infections is needed. The new fluoroquinolones exhibit good activity against M. kansasii and M. fortuitum and linezolid is active against M. kansasii.