Unravelling the operation of organic artificial neurons for neuromorphic bioelectronics.

Organic artificial neurons operating in liquid environments are crucial components in neuromorphic bioelectronics. However, the current understanding of these neurons is limited, hindering their rational design and development for realistic neuronal emulation in biological settings. Here we combine experiments, numerical non-linear simulations, and analytical tools to unravel the operation of organic artificial neurons. This comprehensive approach elucidates a broad spectrum of biorealistic behaviors, including firing properties, excitability, wetware operation, and biohybrid integration. The non-linear simulations are grounded in a physics-based framework, accounting for ion type and ion concentration in the electrolytic medium, organic mixed ionic-electronic parameters, and biomembrane features. The derived analytical expressions link the neurons spiking features with material and physical parameters, bridging closer the domains of artificial neurons and neuroscience. This work provides streamlined and transferable guidelines for the design, development, engineering, and optimization of organic artificial neurons, advancing next generation neuronal networks, neuromorphic electronics, and bioelectronics.

Domain collapse and active site ablation generate a widespread animal mitochondrial seryl-tRNA synthetase.

Through their aminoacylation reactions, aminoacyl tRNA-synthetases (aaRS) establish the rules of the genetic code throughout all of nature. During their long evolution in eukaryotes, additional domains and splice variants were added to what is commonly a homodimeric or monomeric structure. These changes confer orthogonal functions in cellular activities that have recently been uncovered. An unusual exception to the familiar architecture of aaRSs is the heterodimeric metazoan mitochondrial SerRS. In contrast to domain additions or alternative splicing, here we show that heterodimeric metazoan mitochondrial SerRS arose from its homodimeric ancestor not by domain additions, but rather by collapse of an entire domain (in one subunit) and an active site ablation (in the other). The collapse/ablation retains aminoacylation activity while creating a new surface, which is necessary for its orthogonal function. The results highlight a new paradigm for repurposing a member of the ancient tRNA synthetase family.

Shared Reflection to Maximize Resources and Minimize Costs: The Reflecting Team Applied to a Hospital Environment.

Severe mental illness entails multiple hospital admissions and a large use of public resources. The Reflecting Team (RT), together with other dialogue strategies, place in a single therapeutic space, the patient, his family and a team of professionals to find together a solution to a situation of stagnation. The aim of this study was to evaluate feasibility and cost-effectiveness of a RT intervention in psychiatric inpatients in a public hospital. Six RT were performed, and clinical variables were collected retrospectively for six months pre-RT and post-RT. Both number of hospital admissions and total time spent in the psychiatric acute unit show a significant decrease. All computed cost showed statistically significant reduction. The results suggest RT might be a good strategy to introduce a positive change in the treatment of those psychiatric cases in which the patient and family find themselves caught in a system that seems to offer stale and ineffective help to problems that have become chronic.

Bile acid changes after metabolic surgery are linked to improvement in insulin sensitivity.

BACKGROUND: Metabolic surgery is associated with a prompt improvement in insulin resistance, although the mechanism of action remains unknown. The literature on bile acid changes after metabolic surgery is conflicting, and insulin sensitivity is generally assessed by indirect methods. The aim of this study was to investigate the relationship between improvement in insulin sensitivity and concentration of circulating bile acids after biliopancreatic diversion (BPD) and Roux-en-Y gastric bypass (RYGB). METHODS: This was a prospective observational study of nine patients who underwent BPD and six who had RYGB. Inclusion criteria for participation were a BMI in excess of 40 kg/m2 , no previous diagnosis of type 2 diabetes and willingness to participate. Exclusion criteria were major endocrine diseases, malignancies and liver cirrhosis. Follow-up visits were carried out after a mean(s.d.) of 185·3(72·9) days. Fasting plasma bile acids were assessed by ultra-high-performance liquid chromatography coupled with a triple quadrupole mass spectrometer, and insulin sensitivity was measured by means of a hyperinsulinaemic-euglycaemic clamp. RESULTS: A significant increase in all bile acids, as well as an amelioration of insulin sensitivity, was observed after metabolic surgery. An increase in conjugated secondary bile acids was significantly associated with an increase in insulin sensitivity. Only the increase in glycodeoxycholic acid was significantly associated with an increase in insulin sensitivity in analysis of individual conjugated secondary bile acids. CONCLUSION: Glycodeoxycholic acid might drive the improved insulin sensitivity after metabolic surgery.

Ongoing and cumulative pregnancy rate after cleavage-stage versus blastocyst-stage embryo transfer using vitrification for cryopreservation: impact of age on the results.

PURPOSE: To determine if blastocyst transfer increases the ongoing and cumulative pregnancy rates, compared with day 3 embryo transfer, in women of all ages when at least 4 zygotes are obtained. METHODS: Prospective study including patients undergoing a first IVF/ICSI treatment and assigned to cleavage stage (n = 46) or blastocyst (n = 58) embryo transfer. Supernumerary embryos were vitrified and patients failing to achieve an ongoing pregnancy after fresh embryo transfer would go through cryopreserved cycles. The main outcome measure was the ongoing pregnancy rate after the fresh IVF/ICSI transfer and the cumulative ongoing pregnancy rate. Results were also analyzed according to age (under 35 and 35 or older). RESULTS: A majority of patients (96.6 %) had a blastocyst transfer when at least 4 zygotes were obtained. The ongoing pregnancy rate was significantly higher in the day-5 group compared with the day-3 group (43.1 % vs. 24 %, p = 0.041). The cumulative ongoing pregnancy rate was higher (but not significantly) with blastocyst than with cleavage stage embryos (56.8 % vs. 43.4 %, p = 0.174). When analysed by age, patients 35 or older showed significantly higher ongoing pregnancy rate (48.4 % vs. 19.3 %, p = 0.016) and cumulative ongoing pregnancy rate (58 % vs. 25.8 %, p = 0.01) in the day-5 group compared to the day-3 group, while no such differences were observed in women under 35. CONCLUSIONS: Blastocyst transfer can be suggested whenever there are at least 4 zygotes. While there are no differences in women under 35, the benefit of this option over cleavage stage transfer could be significant in women 35 or older.

Should obesity be a limiting factor for clozapine treatment?

OBJECTIVE: Clozapine is the first choice in drug-resistant schizophrenia but also causes important weight changes. This might discourage clinicians concerned about the risk of developing health problems. To assess this issue we measured change in body mass index (cBMI) induced by clozapine at 18 and 56 weeks. METHODS: Baseline body weight and height were measured and weight weekly thereafter during the first 18 weeks of treatment. After that, measurements were made monthly. Steady clozapine dose, clozapine and norclozapine blood concentrations, concomitant medication, gender and age were recorded. RESULTS: At 18 weeks (n=76) mean cBMI was 1.83 kg/m(2). Baseline BMI was inversely correlated with cBMI. At 56 weeks (n=57) cBMI was 2.67 kg/m(2) and was inversely correlated with basal BMI. Multiple regression analysis replicated the results. When split with BMI categories, obese patients had lesser risk for further weight gain. CONCLUSIONS: Obesity should not discourage clinicians from starting clozapine in drug-resistant patients.

Vitrification can modify embryo cleavage stage after warming. Should we change endometrial preparation?

PURPOSE: Studies have shown that embryo metabolism and cell cleavage after warming vitrified embryos is faster than after thawing frozen embryos. We study vitrified embryo transfer (VET) results depending on the developmental stage of warmed embryos and the duration of progesterone treatment before embryo transfer. METHODS: We designed a prospective study, patients were randomized in two groups, starting progesterone three (D + 3) or four days (D + 4) before embryo transfer. We recruited 88 patients with embryos vitrified on day 3. RESULTS: We didn't find statitistical differences in pregnancy rate when we transferred embryos in D + 3 vs D + 4 (38.2 % vs 40.5 % p ≥ 0.05). The day after warming, 54.6 % of embryos had developed to morula or early blastocyst, 32.4 % to cleavage stage and 13 % didn't cleave. Transfers were with morula/blastocysts stage embryos (52.1 %; n:37), cleavage stage embryos (18.3 %; n:13) or mixed (29.6 %; n:21). Implantation rate was significantly higher in morula/blastocyst stage than in cleavage stage or mixed transfers (44 %, 22 % and 16.3 %; p = 0.011). Pregnancy and implantation rates were significantly higher in morula/blastocyst transfers on D + 4 than on D + 3 (68.7 % and 64.7 % vs 33.3 %, and 33.3 %, p = 0.033 and p = 0.034). CONCLUSIONS: Our findings suggest that a majority of embryos will develop to morula/blastocyst stage after warming. VET results with morula/blastocysts, and after four days of progesterone supplementation, are better than with cleavage stage embryos.

The reduction of the metabolyc syndrome in Navarra-Spain (RESMENA-S) study: a multidisciplinary strategy based on chrononutrition and nutritional education, together with dietetic and psychological control.

INTRODUCTION: The high prevalence of metabolic syndrome (MS) in Spain requires additional efforts for prevention and treatment. OBJECTIVE: The study RESMENA-S aims to improve clinical criteria and biomarkers associated with MS though an integral therapy approach. METHODS: The study is a randomized prospective parallel design in which is expected to participate a total of 100 individuals. The RESMENA-S group (n = 50) is a personalized weight loss (30% energy restriction) diet, with a macronutrient distribution (carbohydrate / fat / protein) of 40/30/30, high meal frequency (7 / day), low glycemic index/load and high antioxidant capacity as well as a high adherence to the Mediterranean diet. The control group (n = 50) is assigned to a diet with the same energy restriction and based on the American Heart Association pattern. Both experimental groups are under dietary and psychological control during 8 weeks. Likewise, for an additional period of 16 weeks of self-control, is expected that volunteers will follow the same pattern but with no dietary advice. RESULTS: Anthropometrical data and body composition determinations as well as blood and urine samples are being collected at the beginning and end of each phase. This project is registered at www.clinicaltrials.gov with the number NCT01087086 and count with the Research Ethics Committee of the University of Navarra approval (065/2009). CONCLUSIONS: Intervention trials to promote the adoption of dietary patterns and healthy lifestyle are of great importance to identify the outcomes and nutritional mechanisms that might explain the link between obesity, metabolic syndrome and associated complications.

Serological evidence of Bartonella henselae infection in healthy people in Catalonia, Spain.

Cat scratch disease (CSD), bacillary angiomatosis, hepatic peliosis and some cases of bacteraemia, endocarditis, and osteomyelitis are directly caused by some species of the genus Bartonella. The purpose of this study was to determine the prevalence of IgG antibodies against Bartonella henselae in healthy people and to identify the epidemiological factors involved. Serum samples from 218 patients were examined by indirect immunofluorescence assay (IFA). Significance levels for univariate statistical analysis were determined by the Mann-Whitney U test, chi2 test and Fisher's exact test. Of 218 patients, 99 were female and 119 male, with a median age of 34.36 years (range 0-91 years). Nineteen (8.7%) reacted with B. henselae antigens. Of all the factors concerning the seroprevalence rate being studied (age, sex, contact with animals, residential area), only age was statistically significant. Our serological data seems to indicate that B. henselae is present in Catalonia and could be transmitted to humans.

Determination of conjugated linoleic acid in human plasma by fast gas chromatography.

A new method for the determination of the main isomers of conjugated linoleic acid (CLA) in human and animal plasma was developed by gas chromatography coupled to flame ionization detection (GC-FID). The new method introduces three main advantages in comparison to the current available methodologies: firstly it does not require previous lipid extraction, secondly the chromatographic separation of CLA isomers was performed on an Rtx-2330 column significantly shorter and thinner than the typical long highly polar capillary columns in use that allows a faster analysis than in current methodologies, and thirdly the amount of sample needed to perform the analyses was substantially lower than the amount used in current routine methodologies. Its application to human plasma and rat plasma showed to be robust and reliable for quick and correct identification of the main CLA isomers in particular, and the total fatty acid profile in general, in routine analysis.

Compliance with the European and national nutritional objectives in a Mediterranean population.

OBJECTIVE: To analyze compliance with the current European and Spanish nutritional objectives in a representative sample from Catalonia, a Spanish Mediterranean region; and to examine relationships between diet and plasma fatty acid composition. DESIGN: Cross-sectional nutritional survey. SETTING: Population based random sample derived from the Catalan Nutrition Survey. SUBJECTS: A total of 516 healthy adult men (n=203) and women (n=313). METHODS: Dietary habits were assessed by means of a quantitative food frequency questionnaire. A physical exam included height, weight, waist and hip circumferences, and a fasting blood draw. RESULTS: Gender differences were observed in nutrient and energy intakes. Women showed a better compliance with the nutritional recommendations for monounsaturated fatty acid (MUFA) and polyunsaturated fatty acid (PUFA) than did men. Men showed a better compliance for saturated fatty acid (SFA) and carbohydrate than did women. However, the SFA:MUFA:PUFA ratio was similar in both gender (1.6:2.3:1.0 for men; 1.7:2.5:1.0 for women). The highest compliance was observed for nutritional goals of sodium, calcium and fruit and vegetable intakes for both genders. In addition, the present study showed that levels of certain fatty acids in plasma are clearly associated with dietary intake of foods rich in these components. The highest correlations were found for n-3 long chain polyunsaturated fatty acids with blue fish intake in both men and women (r (men)=0.36 and r (women)=0.42; P<0.001). CONCLUSIONS: The diet followed in Catalonia seems to ensure compliance with most of the intermediate nutritional objectives for the Spanish population. However, a reduction in the SFA intake and an increase in the carbohydrate intake could be recommended in order to reduce the current prevalence of overweight and obesity in this Mediterranean region. SPONSORSHIP: This study was supported by the Catalan Department of Health, the Nutrition Catalan Centre of the Institute of Catalan Studies, and Mercadona SA.

Determination of phospholipid fatty acids in biological samples by solid-phase extraction and fast gas chromatography.

A new method for the determination of phospholipid fatty acids in biological samples, combination of solid-phase extraction (SPE) and fast gas chromatography (GC) was developed. Its application to human plasma and human erythrocytes showed to be robust and reliable for quick and correct identification in routine analysis.

[Validity of the non-mydriatic camera for diabetic retinopathy screening and analysis of retinopathy risk indicators]. / Validez de la cámara no midriática en el cribado de la retinopatía diabética y análisis de indicadores de riesgo de la retinopatía.

PURPOSE: Analysis of the validity of the non-mydriatic camera in detecting diabetic retinopathy and severity levels which can be referred to the ophthalmologist. Analysis of risk indicators of diabetic retinopathy which help increase the sensitivity of the screening: development time of prolonged diabetes (more than 20 years); poor metabolic control (HbA1C > 10%). METHOD: A cross-sectional study was designed to determine the validity of a diagnostic test (non-mydriatic fundus camera Topcon model TRC-NW6S). As criteria for evaluation we used validity indicators, predictive values, indicators of clinical use, and concordance. SETTING: Primary Care. Patients with severe cataracts were excluded. The sample size was 376 eyes of 188 type-2 diabetic patients. RESULTS: With reference to the distribution of diabetic retinopathy we found that 41.25% had a variable level of retinopathy. The validity indicators analysed improved as the number of fundus fields studied increased, obtaining sensitivity levels of greater than 75%; specificity greater than 95%; positive predictive values greater than 90% and almost perfect concordance when two or three fundus fields were used. CONCLUSIONS: The analysis of retinal photography in digital format can be considered a valid method with respect to the gold standard, and the severity indicators analysed can play a guiding role in obtaining greater prevalences of derivable diabetic retinopathy, but cannot be used as an isolated test for making clinical decisions.

Identification of iduronate-2-sulfatase in mouse pancreatic islets.

The lysosomal enzyme iduronate-2-sulfatase (IDS) is expressed in pancreatic islets and is responsible for degradation of proteoglycans, such as perlecan and dermatan sulfate. To determine the role of IDS in islets, expression and regulation of the gene and localization of the enzyme were investigated in mouse pancreatic islets and clonal cells. The Ids gene was expressed in mouse islets and beta- and alpha-clonal cells, in which it was localized intracellularly in lysosomes. The transcriptional expression of Ids in mouse islets increased with glucose in a dose-dependent manner (11.5, 40.2, 88, and 179% at 5.5, 11.1, 16.7, and 24.4 mM, respectively, P < 0.01 for 16.7 and 24.4 mM glucose vs. 3 mM glucose). This increase was not produced by glyceraldehyde (1 mM) or 6-deoxyglucose (21.4 mM) and was blocked by the addition of mannoheptulose (21.4 mM). Neither insulin content nor secretory response to glucose (16.7 mM) was altered in mouse islets infected with lentiviral constructs carrying the IDS gene in sense orientation. Furthermore, no decrease in islet cell viability was observed in mouse islets carrying lentiviral contracts compared with controls. However, insulin content was reduced (35% vs. controls, P < 0.001) in islets infected with IDS antisense construct, while the secretory response of those islets to glucose was maintained. Inhibition of IDS by antisense infection led to an increase in lysosomal size and a high rate of insulin granule degradation via the crinophagic route in pancreatic beta-cells. We conclude that IDS is localized in lysosomes in pancreatic islet cells and expression is regulated by glucose. IDS has a potential role in the normal pathway of lysosomal degradation of secretory peptides and is likely to be essential to maintain pancreatic beta-cell function.

Azo dye oxidation with hydrogen peroxide catalysed by manganese 1,4,7-triazacyclononane complexes in aqueous solution.

A kinetic and mechanistic study is reported of the oxidation of a number of azonaphthol dyes with hydrogen peroxide in aqueous solution, catalysed by some mono and dinuclear manganese(IV) complexes of 1,4,7-trimethyl-1,4,7-triazacyclononane (Me3TACN). The results of UV-Vis investigations, augmented by EPR and ESI-MS studies, are described for a series of experiments in which concentrations, pH and ionic strength have been varied. The reactions are characterised by an induction period followed by a relatively rapid oxidation. For the dinuclear manganese complex 2, these are consistent with an initial perhydrolysis of the manganese complex involving both the dye anion and HO2-, to give mononuclear manganese species and the operation of a catalytic cycle incorporating MnIIIL(OH)3, O = MnVL(OH)2 and MnIVL(OH)3 (L = Me3TACN) (cf. the reactions of peroxidase enzymes). ESI-MS results provide evidence for the formation and reaction (with the dye) of MnIVL(OH)3. With the mononuclear manganese complex MnIVL(OMe)3, there is a short lag-phase attributed to perhydrolysis by HO2- followed by the same catalytic cycle.

Intrinsic changes on automatism, conduction, and refractoriness by exercise in isolated rabbit heart.

We have studied the intrinsic modifications on myocardial automatism, conduction, and refractoriness produced by chronic exercise. Experiments were performed on isolated rabbit hearts. Trained animals were submitted to exercise on a treadmill. The parameters investigated were 1) R-R interval, noncorrected and corrected sinus node recovery time (SNRT) as automatism index; 2) sinoatrial conduction time; 3) Wenckebach cycle length (WCL) and retrograde WCL, as atrioventricular (A-V) and ventriculoatrial conduction index; and 4) effective and functional refractory periods of left ventricle, A-V node, and ventriculoatrial retrograde conduction system. Measurements were also performed on coronary flow, weight of the hearts, and thiobarbituric acid reagent substances and glutathione in myocardium, quadriceps femoris muscle, liver, and kidney, to analyze whether these substances related to oxidative stress were modified by training. The following parameters were larger (P < 0.05) in trained vs. untrained animals: R-R interval (365 +/- 49 vs. 286 +/- 60 ms), WCL (177 +/- 20 vs. 146 +/- 32 ms), and functional refractory period of the left ventricle (172 +/- 27 vs. 141 +/- 5 ms). Corrected SNRT was not different between groups despite the larger noncorrected SNRT obtained in trained animals. Thus training depresses sinus chronotropism, A-V nodal conduction, and increases ventricular refractoriness by intrinsic mechanisms, which do not involve changes in myocardial mass and/or coronary flow.