Disruption of mGluR5 in parvalbumin-positive interneurons induces core features of neurodevelopmental disorders.

Alterations in glutamatergic transmission onto developing GABAergic systems, in particular onto parvalbumin-positive (Pv(+)) fast-spiking interneurons, have been proposed as underlying causes of several neurodevelopmental disorders, including schizophrenia and autism. Excitatory glutamatergic transmission, through ionotropic and metabotropic glutamate receptors, is necessary for the correct postnatal development of the Pv(+) GABAergic network. We generated mutant mice in which the metabotropic glutamate receptor 5 (mGluR5) was specifically ablated from Pv(+) interneurons postnatally, and investigated the consequences of such a manipulation at the cellular, network and systems levels. Deletion of mGluR5 from Pv(+) interneurons resulted in reduced numbers of Pv(+) neurons and decreased inhibitory currents, as well as alterations in event-related potentials and brain oscillatory activity. These cellular and sensory changes translated into domain-specific memory deficits and increased compulsive-like behaviors, abnormal sensorimotor gating and altered responsiveness to stimulant agents. Our findings suggest a fundamental role for mGluR5 in the development of Pv(+) neurons and show that alterations in this system can produce broad-spectrum alterations in brain network activity and behavior that are relevant to neurodevelopmental disorders.

A novel protocol allowing oral delivery of a protein complement inhibitor that subsequently targets to inflamed colon mucosa and ameliorates murine colitis.

While there is evidence of a pathogenic role for complement in inflammatory bowel disease, there is also evidence for a protective role that relates to host defence and protection from endotoxaemia. There is thus concern regarding the use of systemic complement inhibition as a therapeutic strategy. Local delivery of a complement inhibitor to the colon by oral administration would ameliorate such concerns, but while formulations exist for oral delivery of low molecular weight drugs to the colon, they have not been used successfully for oral delivery of proteins. We describe a novel pellet formulation consisting of cross-linked dextran coated with an acrylic co-polymer that protects the complement inhibitor CR2-Crry from destruction in the gastrointestinal tract. CR2-Crry containing pellets administered by gavage, were characterized using a therapeutic protocol in a mouse model of dextran sulphate sodium (DSS)-induced colitis. Oral treatment of established colitis over a 5-day period significantly reduced mucosal inflammation and injury, with similar therapeutic benefit whether or not the proton pump inhibitor, omeprazole, was co-administered. Reduction in injury was associated with the targeting of CR2-Crry to the mucosal surface and reduced local complement activation. Treatment had no effect on systemic complement activity. This novel method for oral delivery of a targeted protein complement inhibitor will reduce systemic effects, thereby decreasing the risk of opportunistic infection, as well as lowering the required dose and treatment cost and improving patient compliance. Furthermore, the novel delivery system described here may provide similar benefits for administration of other protein-based drugs, such as anti-tumour necrosis factor-α antibodies.

ANOVA to Compare Three Methods to Track COVID-19 in Nine Countries / ANOVA en la comparación de tres métodos para rastrear COVID-19 en nueve países

ABSTRACT A new coronavirus denominated first 2019-nCoV and later SARS-CoV-2 was found in Wuhan, China in December of 2019. This paper compares three mathematical methods: nonlinear regression, SIR, and SEIR epidemic models, to track the covid-19 disease in nine countries affected by the SARS-CoV-2 virus, to help epidemiologists to know the disease trajectory, considering initial data in the pandemic, mainly 100 days from the beginning. To evaluate the results obtained with the three methods one-way ANOVA is applied. The average of predicted infected cases with SARS-CoV-2, obtained with the mentioned methods was: for United States of America 1,098,508, followed by Spain with 226,721, Italy with 202,953, France with 183,897 United Kingdom with 182,190, Germany with 159,407, Canada with 58,696, Mexico with 50,366 and Argentina with 4,860 in average. The one-way ANOVA does not show a significant difference among the results of the projected infected cases by SARS-CoV-2, using nonlinear regression, SIR, and SEIR epidemic methods. The above could mean that initially any method can be used to model the pandemic course.

RESUMEN Un nuevo coronavirus denominado primero 2019-nCoV y más tarde SARS-CoV-2 fue encontrado en Wuhan, China en diciembre de 2019. El objetivo de este trabajo es comparar tres métodos matemáticos: regresión no lineal, modelos epidemiológicos SIR y SEIR, para rastrear la enfermedad del COVID-19 en nueve países infectados por el virus SARS-CoV-2, con el propósito de ayudar al epidemiólogo a conocer el curso de la pandemia, considerando principalmente sus primeros 100 días. Para evaluar los resultados obtenidos de la aplicación de los tres métodos, se aplicó ANOVA de una vía. El número promedio de casos infectados con SARS-CoV-2, obtenidos con los tres métodos descritos son: para Estados Unidos 1,098,508, seguido de España con 226,721, Italia con 202,953, Francia con 183,897 Reino Unido con 182,190, Alemania con 159,407, Canadá con 58,696, México con 50,366 y Argentina con 4,860 en promedio. El ANOVA de una vía no muestra diferencias significativas entre los resultados de los casos infectados proyectados por SARS-CoV-2, utilizando la regresión no lineal y los métodos SIR and SEIR. Lo anterior podría señalar que cualquiera de los tres métodos estudiados puede modelar el curso de la pandemia en las condiciones descritas para cada uno.

[Octreotide in the treatment of angiodysplasia in patients with advanced chronic renal failure]. / Tratamiento con octreotide en pacientes con angiodisplasia e insuficiencia renal crónica avanzada.

Angiodysplasia is an important cause of gastrointestinal bleeding in patients with chronic renal failure. Octreotide, a long-acting synthetic somatostatin analogue that reduces splachnic blood flow have been used to treat esophageal varicose hemorrhage, but its efficacy for bleeding vascular ecstasies is awaiting support. We present three patients with chronic renal failure (two with diabetic nephropaty and the third with mesangiocapilar glomerulonephritis and hepatic cirrosis), seric creatinine 3-4,5 mg/dl, and recurrent gastrointestinal bleeding due to diffuse angiodysplasia and vascular ecstasies, diagnosed by oral endoscopy, colonoscopy and video capsule. They all were treated with octreotide, administered subcutanesly 0.1 mg twice a day for six months, with significantly decreased blood requirements in all of them, as well as the occurrence of bleeding episodes. It was well tolerated and none side-effects occurred in any subject. In our experience, octreotide is an effective and safe drug in bleeding angiodysplasia and ecstasies vascular of the gastrointestinal tract in patients with chronic renal failure, and it may be a good option especially in patients who are not candidates for surgery or endoscopic treatment due to inaccessible sites, spread of the lesion, old age and/or concomitant disorders.

Design, fabrication and metrological evaluation of wearable pressure sensors.

Pressure sensors are valuable transducers that are necessary in a huge number of medical application. However, the state of the art of compact and lightweight pressure sensors with the capability of measuring the contact pressure between two surfaces (contact pressure sensors) is very poor. In this work, several types of wearable contact pressure sensors are fabricated using different conductive textile materials and piezo-resistive films. The fabricated sensors differ in size, the textile conductor used and/or the number of layers of the sandwiched piezo-resistive film. The intention is to study, through the obtaining of their calibration curves, their metrological properties (repeatability, sensitivity and range) and determine which physical characteristics improve their ability for measuring contact pressures. It has been found that it is possible to obtain wearable contact pressure sensors through the proposed fabrication process with satisfactory repeatability, range and sensitivity; and that some of these properties can be improved by the physical characteristics of the sensors.

Rapid differential endogenous plasminogen activator expression after acute middle cerebral artery occlusion.

BACKGROUND AND PURPOSE: During focal cerebral ischemia, the microvascular matrix (ECM), which participates in microvascular integrity, is degraded and lost when neurons are injured. Loss of microvascular basal lamina antigens coincides with rapid expression of select matrix metalloproteinases (MMPs). Plasminogen activators (PAs) may also play a role in ECM degradation by the generation of plasmin or by MMP activation. METHODS: The endogenous expressions of tissue-type plasminogen activator (tPA), urokinase (uPA), and PA inhibitor-1 (PAI-1) were quantified in 10-microm frozen sections from ischemic and matched nonischemic basal ganglia and in the plasma of 34 male healthy nonhuman primates before and after middle cerebral artery occlusion (MCA:O). RESULTS: Within the ischemic basal ganglia, tissue uPA activity and antigen increased significantly within 1 hour after MCA:O (2P<0.005). tPA activity transiently decreased 2 hours after MCA:O (2P=0.01) in concert with an increase in PAI-1 antigen (2P=0.001) but otherwise did not change. The transient decrease in free tPA antigen was marked by an increase in the tPA-PAI-1 complex (2P<0.001). No significant relations to neuronal injury or intracerebral hemorrhage were discerned. CONCLUSIONS: The rapid increase in endogenous PA activity is mainly due to significant increases in uPA, but not tPA, within the ischemic basal ganglia after MCA:O. This increase and an increase in PAI-1 coincided with latent MMP-2 generation and microvascular ECM degeneration but not neuronal injury.

Activated microvessels express vascular endothelial growth factor and integrin alpha(v)beta3 during focal cerebral ischemia.

Both vascular endothelial growth factor (VEGF) and integrin alpha(v)beta3 play roles in angiogenesis. In noncerebral vascular systems, VEGF can induce endothelial integrin alpha(v)beta3 expression. However, it is unknown whether VEGF, like integrin alpha(v)beta3, appears in the initial response of microvessels to focal brain ischemia. Their coordinate expression in microvessels of the basal ganglia after middle cerebral artery occlusion (MCAO) in the nonhuman primate model was examined quantitatively. Cells incorporating deoxyuridine triphosphate (dUTP+) by the polymerase I reaction at 1 hour (n = 3), 2 hours (n = 3), and 7 days (n = 4) after MCAO defined the ischemic core (Ic) and peripheral regions. Both VEGF and integrin alpha(v)beta3 were expressed by activated noncapillary (7.5- to 30.0-microm diameter) microvessels in the Ic region at 1 and 2 hours after MCAO. At 7 days after MCAO, the number of VEGF+, integrin alpha(v)beta3+, or proliferating cell nuclear antigen-positive microvessels had decreased within the Ic region. The expressions of VEGF, integrin alpha(v)beta3, and proliferating cell nuclear antigen were highly correlated on the same microvessels using hierarchical log-linear statistical models. Also, VEGF and subunit alpha(v) messenger ribonucleic acids were coexpressed on selected microvessels. Here, noncapillary microvessels are activated specifically early during a focal cerebral ischemic insult and rapidly express VEGF and integrin alpha(v)beta3 together.

Rapid loss of microvascular integrin expression during focal brain ischemia reflects neuron injury.

The integrity of cerebral microvessels requires the close apposition of the endothelium to the astrocyte endfeet. Integrins alpha1beta1 and alpha6beta4 are cellular matrix receptors that may contribute to cerebral microvascular integrity. It has been hypothesized that focal ischemia alters integrin expression in a characteristic time-dependent manner consistent with neuron injury. The effects of middle cerebral artery occlusion (MCAO) and various periods of reperfusion on microvasclar integrin alpha1beta1 and alpha6beta4 expression were examined in the basal ganglia of 17 primates. Integrin subunits alpha1 and beta1 colocalized with the endothelial cell antigen CD31 in nonischemic microvessels and with glial fibrillary acidic protein on astrocyte fibers. Rapid, simultaneous, and significant disappearance of both integrin alpha1 and beta1 subunits and integrin alpha6beta4 occurred by 2 hours MCAO, which was greatest in the region of neuron injury (ischemic core, Ic), and progressively less in the peripheral (Ip) and nonischemic regions (N). Transcription of subunit beta1 mRNA on microvessels increased significantly in the Ic/Ip border and in multiple circular subregions within Ic. Microvascular integrin alpha1beta1 and integrin alpha6beta4 expression are rapidly and coordinately lost in Ic after MCAO. With loss of integrin alpha1beta1, multiple regions of microvascular beta1 mRNA up-regulation within Ic suggest that microvessel responses to focal ischemia are dynamic, and that multiple cores, not a single core, are generated. These changes imply that microvascular integrity is modified in a heterogeneous, but ordered pattern.

Matrix metalloproteinases increase very early during experimental focal cerebral ischemia.

Microvascular integrity is lost during focal cerebral ischemia. The degradation of the basal lamina and extracellular matrix are, in part, responsible for the loss of vascular integrity. Matrix metalloproteinases (MMPs) may play a primary role in basal lamina degradation. By using a sensitive modification of gelatin zymography, the authors investigated the activity of MMP-2 and MMP-9 in frozen 10-microm sections of ischemic and nonischemic basal ganglia and plasma samples of 27 non-human primates after middle cerebral artery occlusion/reperfusion (MCAO/R) for various periods. The gelatinolytic activities were compared with parallel cell dUTP incorporation in the ischemic zones of adjacent sections. In the brain, the integrated density of MMP-2 increased significantly by 1 hour after MCAO and was persistently elevated thereafter. Matrix metalloproteinase-2 expression was highly correlated with the extent of neuron injury and the number of injured neurons (r = 0.9763, SE = 0.004, 2P < 0.0008). Matrix metalloproteinase-9 expression only was significantly increased in subjects with hemorrhagic transformation. In plasma, only MMP-9 increased transiently at 2 hours of MCAO. These findings highlight the early potential role of MMP-2 in the degradation of basal lamina leading to neuronal injury, and an association of MMP-9 with hemorrhagic transformation after focal cerebral ischemia.

Early follicular phase hormone levels in relation to patterns of alcohol, tobacco, and coffee use.

OBJECTIVE: To examine the effects of alcohol, caffeine, and tobacco use on early follicular phase FSH, LH, E2, and sex hormone-binding globulin (SHBG). DESIGN: Cross-sectional study. SETTING: Academic medical center. PATIENT(S): Four hundred ninety-eight women selected from the general population, ages 36-45, who were not currently pregnant, breast feeding, or using exogenous hormones. INTERVENTION(S): A general questionnaire assessing demography, anthropometry, and smoking habits and a standardized dietary questionnaire assessing food and beverage frequencies, including sources of alcohol and caffeine. MAIN OUTCOME MEASURE(S): FSH, LH, E2, and SHBG levels measured during the early follicular phase of the menstrual cycle. RESULT(S): Significant associations observed in a univariate analysis included age > or =40 and current smoking associated with higher FSH; higher body mass index (BMI) associated with lower SHBG levels; and daily alcohol use, cholesterol consumption greater than the median, and coffee use >1 cup/d associated with higher E2 levels. In a multivariate model, total caffeine use was significantly associated with E2 levels after adjustment for age, BMI, total calories, current smoking, alcohol, cholesterol consumption, and day of sampling. Early follicular phase E2 increased from 28.2 pg/mL for women consuming < or =100 mg of caffeine to 45.2 pg/mL for women consuming > or =500 mg of caffeine per day, about a 70% increase. CONCLUSION(S): Coffee consumption and total caffeine use may increase early follicular phase E2 levels independent of related habits of alcohol or tobacco use.

Influence of oral contraceptives on the acute effect of amphetamine on the hepatic endoplasmic reticulum of the rat.

The interaction between amphetamine and synthetic oral contraceptive steroids have been studied in the female rat. A progestational agent, quingestanol acetate, and a standard combination contraceptive (quingestanol acetate/ethynyl estradiol) were given with and without the concurrent administration of amphetamine. Steroid treatments increased the activity of some drug-metabolizing enzymes (aminopyrine N-demethylase, coumarin 3- hydroxylase, hexobarbital oxidase). Other parameters measured remained unaltered (glucose-6-phosphatase, aniline hydroxylase, cytochrome c reductase, cytochrome P 450, microsomal protein and phospholipid contents). Amphetamine treatment alone raised some drug-metabolizing enzymes (coumarin 3-hydroxylase, hexobarbital oxidase), increased microsomal phospholipid content and de novo synthesis, but elicited no effect on other enzymes measured. Amphetamine and quingestanol acetate given together significantly increased some drug metabolizing enzymes while the simultaneous treatment with combined steroids and amphetamine showed the most pronounced action. These experiments thus revealed that at least in the liver of the female rat, amphetamine elicited no overt hepatotoxicity, rather, brought about a weak inductive action of drug metabolizing enzymes. The application of steroid hormones also raised drug metabolism and the interaction between amphetamine and contraceptive steroids showed additive effects.

On the registration of time and the patterning of speech movements.

In order to study speech coordination we frequently average kinematic and other physiological signals. The averages are assumed to be more representative of the underlying patterns of production than individual records. In this note we outline different approaches to averaging and present a new nonlinear normalization technique that offers better information than ensemble averaging, linear normalization, or feature alignment methods. We suggest that this technique provides a clear estimation of pattern shape while preserving information on the variation over time.

Optimal glottal configuration for ease of phonation.

Recent experimental studies have shown the existence of optimal values of the glottal width and convergence angle, at which the phonation threshold pressure is minimum. These results indicate the existence of an optimal glottal configuration for ease of phonation, not predicted by the previous theory. In this paper, the origin of the optimal configuration is investigated using a low dimensional mathematical model of the vocal fold. Two phenomena of glottal aerodynamics are examined: pressure losses due to air viscosity, and air flow separation from a divergent glottis. The optimal glottal configuration seems to be a consequence of the combined effect of both factors. The results agree with the experimental data, showing that the phonation threshold pressure is minimum when the vocal folds are slightly separated in a near rectangular glottis.

[Turner's phenotype in a male with deficit of ACTH and gonadotropins (author's transl)]. / Fenotipo Turner en un varón con déficit de gonadotropinas y ACTH.

A case of male Turner's syndrome in a 23-year-old patient is reported. Clinical features included total eunuchoidism, shield-like chest, cubitus valgus, lymphedema in the extremities (hands and feet) and a shortened fourth metacarpal. Hormonal studies revealed very low levels of gonadotropins, cortisol, testosterone and HGH, and normal values for PRL and TSH. Gonadotropin levels did not change after the administration of 100 micrograms LH-RH and 500 micrograms LH-RH every 8 hours during 5 days. Testosterone levels increased when HCG was given. Deficit of ACTH release was demonstrated after the administration of metopyrone, ACTH and 0.1 UI insulin per kilogram of body weight to induce hypoglycemia. Hypoglycemia with insulin and arginine did not determine an increase of GH levels, instead of previous estrogen therapy. These results reveal a hypophyseal hormonal defect in relation to ACTH, LH, FSH and GH release. Hormone abnormalities found in the present case have not been previously described.

[Mountain chinchilla (Lagostomus maximus maximus Blainv) meat. Biological value]. / Carne de vizcacha (Lagostomus maximus maximus Blainv). Valor biológico.

In order to establish the vizcacha meat quality as food, the percentual chemical composition, cholesterol content and values of some fatty acids were determined. Assays were performed using Wistar rats for estimation of Net Protein Utilization (UPN), True Digestibility (TD) and Biological Value (BV). The results obtained were: protein, 23.87 g/100 g; total lipids, 3.74g/100g and a low content of cholesterol of 50 mg/100g. From the analysis of the fatty acids composition it is noticed a remarkable high proportion of insatured C18 fatty acids. The nitrogen availability calculated from UPN studies gave a value of 60.50 +/- 9.7, a TD of 85.00 +/- 13.20 and a BV of 70.60. Considering on the whole the results here obtained and the optimal approval of this product by man, it is inferred that vizcacha meat constitutes a good base for the production of foods suitable to be manufactured as can products. An adequate promotion of this product will be needed for its introduction in new markets.

Hexane abatement and spore emission control in a fungal biofilter-photoreactor hybrid unit.

The performance of a fungal perlite-based biofilter coupled to a post-treatment photoreactor was evaluated over 234 days in terms of n-hexane removal, emission and deactivation of fungal spores. The biofilter and photoreactor were operated at gas residence times of 1.20 and 0.14min, respectively, and a hexane loading rate of 115±5gm(-3)h(-1). Steady n-hexane elimination capacities of 30-40gm(-3)h(-1) were achieved, concomitantly with pollutant mineralization efficiencies of 60-90%. No significant influence of biofilter irrigation frequency or irrigation nitrogen concentration on hexane abatement was recorded. Photolysis did not support an efficient hexane post-treatment likely due to the short EBRT applied in the photoreactor, while overall hexane removal and mineralization enhancements of 25% were recorded when the irradiated photoreactor was packed with ZnO-impregnated perlite. However, a rapid catalyst deactivation was observed, which required a periodic reactivation every 48h. Biofilter irrigation every 3 days supported fungal spore emissions at concentrations ranging from 2.4×10(3) to 9.0×10(4)CFUm(-3). Finally, spore deactivation efficiencies of ≈98% were recorded for the photolytic and photocatalytic post-treatment processes. This study confirmed the potential of photo-assisted post-treatment processes to mitigate the emission of hazardous fungal spores and boost the abatement performance of biotechnologies.

Treatment of O2-free toluene emissions by anoxic biotrickling filtration.

Toluene biotrickling filtration under anoxic denitrifying conditions was evaluated in two identical bioreactors (R1 and R2) operated at liquid recycling rates of 1.3, 2.7 and 5.3 m h−1 and liquid renewal rates of 0 and 0.17 d−1. R1 and R2 achieved a similar maximum elimination capacity (EC ∼30 g m−3 h−1) at the same toluene inlet load (∼50 g m−3 h−1), which was approximately 7 times higher compared with available literature on continuous toluene removal under anoxic conditions. Nevertheless, higher metabolite accumulation was observed in the bioreactor operated without periodical liquid phase renewal (R2), leading to intermittent drops in its toluene removal performance. This is the first work operating an anoxic biotrickling filter at empty bed residence time of 3 min, which is comparable with those employed in conventional aerobic systems. A characterization of the metabolites accumulated in the liquid phase revealed a dynamic metabolite production and degradation.