Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis.

Importance: The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals. Objective: To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. Design, Setting, and Participants: This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022. Main Outcomes and Measures: For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z < -1.96) or supranormal (z > 1.96) scores. Results: Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [<11.42%]) and similar to that of healthy individuals (<115 individuals [<9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (ß = -0.08; 95% CI, -0.13 to -0.02; P = .02 for false discovery rate) and IQ (ß = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate). Conclusions and Relevance: In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.

Prefrontal γ-Aminobutyric Acid Levels in Never-Medicated Individuals With Chronic Schizophrenia.

This cross-sectional study analyzes spectroscopy data for long-term, never-medicated patients with schizophrenia to examine their levels of γ-aminobutyric acid (GABA) compared with those of healthy controls.

Endothelial mechanisms for inactivation of inflammation-induced hyperpermeability.

Microvascular hyperpermeability is a hallmark of inflammation. Many negative effects of hyperpermeability are due to its persistence beyond what is required for preserving organ function. Therefore, we propose that targeted therapeutic approaches focusing on mechanisms that terminate hyperpermeability would avoid the negative effects of prolonged hyperpermeability while retaining its short-term beneficial effects. We tested the hypothesis that inflammatory agonist signaling leads to hyperpermeability and initiates a delayed cascade of cAMP-dependent pathways that causes inactivation of hyperpermeability. We applied platelet-activating factor (PAF) and vascular endothelial growth factor (VEGF) to induce hyperpermeability. We used an Epac1 agonist to selectively stimulate exchange protein activated by cAMP (Epac1) and promote inactivation of hyperpermeability. Stimulation of Epac1 inactivated agonist-induced hyperpermeability in the mouse cremaster muscle and in human microvascular endothelial cells (HMVECs). PAF induced nitric oxide (NO) production and hyperpermeability within 1 min and NO-dependent increased cAMP concentration in about 15-20 min in HMVECs. PAF triggered phosphorylation of vasodilator-stimulated phosphoprotein (VASP) in a NO-dependent manner. Epac1 stimulation promoted cytosol-to-membrane eNOS translocation in HMVECs and in myocardial microvascular endothelial (MyEnd) cells from wild-type mice, but not in MyEnd cells from VASP knockout mice. We demonstrate that PAF and VEGF cause hyperpermeability and stimulate the cAMP/Epac1 pathway to inactivate agonist-induced endothelial/microvascular hyperpermeability. Inactivation involves VASP-assisted translocation of eNOS from the cytosol to the endothelial cell membrane. We demonstrate that hyperpermeability is a self-limiting process, whose timed inactivation is an intrinsic property of the microvascular endothelium that maintains vascular homeostasis in response to inflammatory conditions.NEW & NOTEWORTHY Termination of microvascular hyperpermeability has been so far accepted to be a passive result of the removal of the applied proinflammatory agonists. We provide in vivo and in vitro evidence that 1) inactivation of hyperpermeability is an actively regulated process, 2) proinflammatory agonists (PAF and VEGF) stimulate microvascular hyperpermeability and initiate endothelial mechanisms that terminate hyperpermeability, and 3) eNOS location-translocation is critical in the activation-inactivation cascade of endothelial hyperpermeability.

Normative modeling of brain morphometry in Clinical High-Risk for Psychosis.

Importance: The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in the majority of individuals at psychosis risk may be nested within the range observed in healthy individuals. Objective: To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high-risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. Design Setting and Participants: Clinical, IQ and FreeSurfer-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1,340 CHR-P individuals [47.09% female; mean age: 20.75 (4.74) years] and 1,237 healthy individuals [44.70% female; mean age: 22.32 (4.95) years] from 29 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. Main Outcomes and Measures: For each regional morphometric measure, z-scores were computed that index the degree of deviation from the normative means of that measure in a healthy reference population (N=37,407). Average deviation scores (ADS) for CT, SA, SV, and globally across all measures (G) were generated by averaging the respective regional z-scores. Regression analyses were used to quantify the association of deviation scores with clinical severity and cognition and two-proportion z-tests to identify case-control differences in the proportion of individuals with infranormal (z<-1.96) or supranormal (z>1.96) scores. Results: CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z-scores, and all ADS vales. The proportion of CHR-P individuals with infranormal or supranormal values in any metric was low (<12%) and similar to that of healthy individuals. CHR-P individuals who converted to psychosis compared to those who did not convert had a higher percentage of infranormal values in temporal regions (5-7% vs 0.9-1.4%). In the CHR-P group, only the ADSSA showed significant but weak associations (|ß|<0.09; PFDR<0.05) with positive symptoms and IQ. Conclusions and Relevance: The study findings challenge the usefulness of macroscale neuromorphometric measures as diagnostic biomarkers of psychosis risk and suggest that such measures do not provide an adequate explanation for psychosis risk.

Dysconnectivity in Schizophrenia Revisited: Abnormal Temporal Organization of Dynamic Functional Connectivity in Patients With a First Episode of Psychosis.

BACKGROUND AND HYPOTHESIS: Abnormal functional connectivity between brain regions is a consistent finding in schizophrenia, including functional magnetic resonance imaging (fMRI) studies. Recent studies have highlighted that connectivity changes in time in healthy subjects. We here examined the temporal changes in functional connectivity in patients with a first episode of psychosis (FEP). Specifically, we analyzed the temporal order in which whole-brain organization states were visited. STUDY DESIGN: Two case-control studies, including in each sample a subgroup scanned a second time after treatment. Chilean sample included 79 patients with a FEP and 83 healthy controls. Mexican sample included 21 antipsychotic-naïve FEP patients and 15 healthy controls. Characteristics of the temporal trajectories between whole-brain functional connectivity meta-states were examined via resting-state functional MRI using elements of network science. We compared the cohorts of cases and controls and explored their differences as well as potential associations with symptoms, cognition, and antipsychotic medication doses. STUDY RESULTS: We found that the temporal sequence in which patients' brain dynamics visited the different states was more redundant and segregated. Patients were less flexible than controls in changing their network in time from different configurations, and explored the whole landscape of possible states in a less efficient way. These changes were related to the dose of antipsychotics the patients were receiving. We replicated the relationship with antipsychotic medication in the antipsychotic-naïve FEP sample scanned before and after treatment. CONCLUSIONS: We conclude that psychosis is related to a temporal disorganization of the brain's dynamic functional connectivity, and this is associated with antipsychotic medication use.

Manejo de discontinuidad pélvica debido a fractura de acetábulo mediante cirugía de revisión de artroplastia de cadera y reemplazo de componente acetabular por anillo de Burch-Schneider: reporte de un caso / Treatment for pelvic discontinuity due to acetabular fracture by means of hip arthroplasty revision surgery and acetabular component replacement using a Burch-Schneider ring: a case report

Introducción. La discontinuidad pélvica es una complicación de la artroplastia total de cadera que consiste en la separación de la hemipelvis superior e inferior a través del acetábulo.Presentación del caso. Hombre de 74 años con antecedente de artroplastia total de cadera izquierda que requirió 4 cirugías de revisión de artroplastia, quien consultó al servicio de urgencias de un hospital de segundo nivel de atención de Sogamoso (Colombia) por dolor y limitación de la movilidad de la cadera izquierda durante 7 días luego de haber sufrido trauma por caída de su propia altura en la que el miembro inferior izquierdo recibió la fuerza del impacto. En el examen físico, se evidenció limitación de los arcos de movilidad de la cadera izquierda, por lo que se realizó una radiografía de cadera, en la que se observó fractura del acetábulo, y una tomografía computarizada de cadera, en la que se evidenciaron signos de aflojamiento del componente acetabular y fractura del acetábulo (tipo IIIB según clasificación de Paprosky). Teniendo en cuenta lo anterior, se diagnosticó discontinuidad pélvica y se realizó cirugía de revisión de artroplastia y reemplazo del componente acetabular por un anillo de Burch-Schneider. El paciente tuvo una adecuada evolución posoperatoria con seguimiento a 3 meses. Conclusión. Si bien hay múltiples opciones para el manejo de la discontinuidad pélvica, no hay consenso sobre cuál es la mejor; sin embargo, el uso de componentes acetabulares de refuerzo como el anillo de Burch-Schneider fue una opción con buenos resultados posoperatorios en este caso

Introduction: Pelvic discontinuity is a complication of total hip arthroplasty, consisting of a structural bone defect of the acetabulum with separation of the upper and lower hemipelvis. Case presentation: A 74-year-old male patient with a history of total left hip arthroplasty and 4 arthroplasty revision surgeries visited the emergency department of a secondary care hospital due to pain and limited mobility of the left hip over a period of 7 days after having suffered a fall from his own height in which the left lower limb received the force of the impact. Physical examination showed limitation of the range of motion of the left hip, so a hip X-ray was performed, showing a fracture of the acetabulum. A computed tomography of the hip revealed signs of loosening of the acetabular component and fracture of the acetabulum (type IIIB according to the Paprosky classification). In view of the above, pelvic discontinuity was diagnosed and revision arthroplasty and replacement of the acetabular component with a Burch-Schneider ring was performed. The patient had an adequate postoperative progression and follow-up at 3 months.Conclusion: Although there are multiple options for the treatment of pelvic discontinuity, currently, there is no conclusive data regarding the best therapeutic option. However, the use of reinforcement acetabular components, such as the Burch-Schneider ring, was an option with good postoperative outcomes in this case

White matter alterations and the conversion to psychosis: A combined diffusion tensor imaging and glutamate 1H MRS study.

INTRODUCTION: Widespread white matter abnormalities and alterations in glutamate levels have been reported in patients with schizophrenia. We hypothesized that alterations in white matter integrity and glutamate levels in individuals at clinical high risk (CHR) for psychosis are associated with the subsequent development of psychosis. METHODS: Participants included 33 antipsychotic naïve CHR (Female 7/Male 26, Age 19.55 (4.14) years) and 38 healthy controls (Female 10/Male 28, Age 20.92 (3.37) years). Whole brain diffusion tensor imaging for fractional anisotropy (FA) and right frontal white matter proton magnetic resonance spectroscopy for glutamate levels were acquired. CHR participants were clinically followed for 2 years to determine conversion to psychosis. RESULTS: CHR participants that transitioned to psychosis (N = 7, 21%) were characterized by significantly lower FA values in the posterior thalamic radiation compared to those who did not transition and healthy controls. In the CHR group that transitioned to psychosis only, positive exploratory correlations between glutamate levels and FA values of the posterior thalamic radiation and the retrolenticular part of the internal capsule and a negative correlation between glutamate levels and the cingulum FA values were found. CONCLUSION: The results of the present study highlight that alterations in white matter structure and glutamate are related with the conversion to psychosis.

Striatal glutamate, subcortical structure and clinical response to first-line treatment in first-episode psychosis patients.

INTRODUCTION: Recent studies have observed that patients with treatment-resistant schizophrenia as well as patients with schizophrenia who do not respond within a medication trial exhibit excess activity of the glutamate system. In this study we sought to replicate the within-trial glutamate abnormality and to investigate the potential for structural differences and treatment-induced changes to improve identification of medication responders and non-responders. METHODS: We enrolled 48 medication-naïve patients in a 4-week trial of risperidone and classified them retrospectively into responders and non-responders using clinical criteria. Proton magnetic resonance spectroscopy and T1-weighted structural MRI were acquired pre- and post-treatment to quantify striatal glutamate levels and several measures of subcortical brain structure. RESULTS: Patients were classified as 29 responders and 19 non-responders. Striatal glutamate was higher in the non-responders than responders both pre- and post-treatment (F1,39 = 7.15, p = .01). Volumetric measures showed a significant group x time interaction (t = 5.163, <1%FDR), and group x time x glutamate interaction (t = 4.23, <15%FDR) were seen in several brain regions. Striatal volumes increased at trend level with treatment in both groups, and a positive association of striatal volumes with glutamate levels was seen in the non-responders. CONCLUSIONS: Combining anatomic measures with glutamate levels offers the potential to enhance classification of responders and non-responders to antipsychotic medications as well as to provide mechanistic understanding of the interplay between neuroanatomical and neurochemical changes induced by these medications. Ethical statement The study was approved by the Ethics and Scientific committees of the Instituto Nacional de Neurología y Neurocirugía in Mexico City. All participants over 18 years fully understood and signed the informed consent; in case the patient was under 18 years, informed consent was obtained from both parents. Participants did not receive a stipend.

Pasting and Dough Rheological Properties of Ackee (Blighia sapida) Aril Flour: A Contribution to the Search for Wheat Flour Substitutes.

Wheat is one of the most widely used cereals in the world. However, studies consider wheat flour doughs to be of low nutritional quality, as there is now greater public awareness of celiac disease and gluten intolerance. Therefore, consumers are demanding healthier and more varied food products. Consequently, wheat flour is being replaced fully or partially by flours from other sources with higher quality. Hence, the main objective of this work was to report the effect of blending wheat flour with ackee aril flour, until the total replacement of wheat flour, on pasting and dough rheological properties. Five different levels of blending were analyzed: wheat to ackee aril flour mass ratios of 100 : 0, 75 : 25, 50 : 50, 25 : 75, and 0 : 100. Pasting properties (pasting temperature, peak viscosity, ease of cooking, swelling power, final viscosity at 50 °C, and thixotropy) were analyzed; and steady-state shear measurements were used to obtain consistency coefficients (K) and flow behavior indexes (n) after data was fitted to the Power Law and Herschel-Bulkley models. The gradual addition of the ackee aril flour fraction produced an increase in ash, fat, protein, and fiber content; while water and carbohydrate content showed the opposite behavior in the obtained composite flour. Consequently, the partial or full replacement of wheat flour changed the rheological properties of the produced doughs, as well as the quality of the final product. These changes were mostly related to the protein and carbohydrate content of the ackee aril flour fraction. In general, doughs showed a pseudoplastic behavior with thixotropy whose viscosity decreased as the addition of ackee aril flour was increased. Pasting properties of blends involving 25 %-75 % ackee aril flour demonstrate the feasibility of including these flours in products subjected to high processing temperatures such as canned products or even to produce chips and pasta.

Striatal Glutathione in First-episode Psychosis Patients Measured In Vivo with Proton Magnetic Resonance Spectroscopy.

Deficits of brain glutathione (GSH), the most abundant and primary antioxidant in living tissue, and associated redox imbalance are postulated to be implicated in schizophrenia. This pilot clinical study compared the levels of striatal GSH, measured in vivo with proton magnetic resonance spectroscopy (1H MRS) at 3T, in 10 drug-naïve, first-episode psychosis (FEP) patients with those in 9 matched healthy control subjects. The results revealed a significant GSH deficit in FEP patients (0.92 ± 0.24 × 10-3) compared to the healthy control group (1.10 ± 0.10 × 10-3) (U = 25.00, p = 0.02), as well as a positive correlation between GSH levels and the Positive Symptoms subscale of the PANSS in the FEP group (ρ = 0.96; p <0.001). These preliminary findings suggest a possible role of striatal oxidative stress in early-stage psychosis that warrants further scrutiny and confirmation in larger studies.

Endothelial cAMP deactivates ischemia-reperfusion-induced microvascular hyperpermeability via Rap1-mediated mechanisms.

Approaches to reduce excessive edema due to the microvascular hyperpermeability that occurs during ischemia-reperfusion (I/R) are needed to prevent muscle compartment syndrome. We tested the hypothesis that cAMP-activated mechanisms actively restore barrier integrity in postischemic striated muscle. We found, using I/R in intact muscles and hypoxia-reoxygenation (H/R, an I/R mimic) in human microvascular endothelial cells (HMVECs), that hyperpermeability can be deactivated by increasing cAMP levels through application of forskolin. This effect was seen whether or not the hyperpermeability was accompanied by increased mRNA expression of VEGF, which occurred only after 4 h of ischemia. We found that cAMP increases in HMVECs after H/R, suggesting that cAMP-mediated restoration of barrier function is a physiological mechanism. We explored the mechanisms underlying this effect of cAMP. We found that exchange protein activated by cAMP 1 (Epac1), a downstream effector of cAMP that stimulates Rap1 to enhance cell adhesion, was activated only at or after reoxygenation. Thus, when Rap1 was depleted by small interfering RNA, H/R-induced hyperpermeability persisted even when forskolin was applied. We demonstrate that 1) VEGF mRNA expression is not involved in hyperpermeability after brief ischemia, 2) elevation of cAMP concentration at reperfusion deactivates hyperpermeability, and 3) cAMP activates the Epac1-Rap1 pathway to restore normal microvascular permeability. Our data support the novel concepts that 1) different hyperpermeability mechanisms operate after brief and prolonged ischemia and 2) cAMP concentration elevation during reperfusion contributes to deactivation of I/R-induced hyperpermeability through the Epac-Rap1 pathway. Endothelial cAMP management at reperfusion may be therapeutic in I/R injury.NEW & NOTEWORTHY Here, we demonstrate that 1) stimulation of cAMP production deactivates ischemia-reperfusion-induced hyperpermeability in muscle and endothelial cells; 2) VEGF mRNA expression is not enhanced by brief ischemia, suggesting that VEGF mechanisms do not activate immediate postischemic hyperpermeability; and 3) deactivation mechanisms operate via cAMP-exchange protein activated by cAMP 1-Rap1 to restore integrity of the endothelial barrier.

Nivel cognitivo y habilidad procedimental de la delimitación de las líneas oclusales en prótesis completa en estudiantes de odontología / Cognitive level and procedural skill of the delimitation of the occlusal lines in full denture in dental students

Conocer el nivel de relación entre los aspectos cognitivos y procedimentales en el diseño y delimitación de las líneas para la confección del rodete de oclusión y contorno en prótesis completa, en estudiantes de odontología. Materiales y métodos. La muestra estuvo conformada por 134 estudiantes, de los cuales 51 fueron del sexo masculino. Se evaluó el aspecto cognitivo mediante un examen escrito, el cual fue calificado de 0 a 20 para luego subdividirlo en cinco grupos. El mismo sistema de evaluación se aplicó sobre los trabajos de diseño y graficación realizado sobre los modelos de trabajo y placas bases. Resultados. En aprestamiento procedimental no se encontró asociación significativa con el grado de conocimiento, sin embargo, un mayor número de alumnos obtuvieron un buen grado de conocimientos y la mayoría obtuvo un buen nivel de aprestamiento procedimental. En el grado de conocimiento con relación al nivel de aprestamiento procedimental no se encontró una asociación estadísticamente significativa por sexo. Al evaluar grado de conocimiento según edad se encontraron diferencias significativas, en el grupo de 19-24 años se observó un mayor grado de conocimientos. En la evaluación del nivel de aprestamiento procedimental para el grupo de teoría, no se encontró asociación estadísticamente significativa al igual que en edad y sexo. Conclusiones. Es importante reforzar el conocimiento teórico de la confección de las líneas para la realización del rodete de oclusión y contorno, ya que este es un procedimiento básico para la correcta preparación de una prótesis completa...

To know the level of relationship between cognitive and procedural aspects in the design and delimitation of the lines for the confection of the occlusion rim and the contour in full denture, in dental students. Materials and methods. The sample was formed by 134 students, of which 51 were male. The cognitive aspect was evaluated by means of a written examination which was qualified from 0 to 20, and then it was subdivided into five groups. The same evaluation system was applied for the design work and charting on the models of work and base plaques. Results. In procedural readiness not significant association was found with the degree of knowledge, however, a greater number of students obtained a good degree of knowledge and most of them obtained a good level of procedural readiness. On the degree of knowledge in relation to the level of procedural readiness there was not a statisticallysignificant association by sex; however women provided a good level of knowledge and a level of readiness in comparison with men. In assessing the degree of knowledge according to age it was a significant higher prevalence of students from 19-24 years of age with a good degree of knowledge. In the assessment of the level of procedural for the theory group readiness, no significant association was found just that in age and sex. Conclusions. It is important to strengthen the theoretical knowledge of making lines for the confection of the occlusion rim and contour, since this is a basic procedure for the correct preparation of a full denture...

Functional significance of cytosolic endothelial nitric-oxide synthase (eNOS): regulation of hyperpermeability.

Endothelial NOS (eNOS)-derived NO is a key factor in regulating microvascular permeability. We demonstrated previously that eNOS translocation from the plasma membrane to the cytosol is required for hyperpermeability. Herein, we tested the hypothesis that eNOS activation in the cytosol is necessary for agonist-induced hyperpermeability. To study the fundamental properties of endothelial cell monolayer permeability, we generated ECV-304 cells that stably express cDNA constructs targeting eNOS to the cytosol or plasma membrane. eNOS-transfected ECV-304 cells recapitulate the eNOS translocation and permeability properties of postcapillary venular endothelial cells (Sánchez, F. A., Rana, R., Kim, D. D., Iwahashi, T., Zheng, R., Lal, B. K., Gordon, D. M., Meininger, C. J., and Durán, W. N. (2009) Proc. Natl. Acad. Sci. U.S.A. 106, 6849-6853). We used platelet-activating factor (PAF) as a proinflammatory agonist. PAF activated eNOS by increasing phosphorylation of Ser-1177 and inducing dephosphorylation of Thr-495, increasing NO production, and elevating permeability to FITC-dextran 70 in monolayers of cells expressing wild-type and cytosolic eNOS. PAF failed to increase permeability to FITC-dextran 70 in monolayers of cells transfected with eNOS targeted to the plasma membrane. Interestingly, this occurred despite eNOS Ser-1177 phosphorylation and production of comparable amounts of NO. Our results demonstrate that the presence of eNOS in the cytosol is necessary for PAF-induced hyperpermeability. Our data provide new insights into the dynamics of eNOS and eNOS-derived NO in the process of inflammation.

El desarrollo humano y la calidad de vida integrados en un Modelo de Gestión Urbana para Barranquilla (Colombia) / Human development and quality of life integrated in an urban management model for Barranquilla (Colombia)

Este artículo tiene como objetivo enmarcar el tema del desarrollo humano y la calidad de vida dentro de la problemática urbana en una ciudad como Barranquilla (Colombia) y la urgente necesidad que existe en ésta por cumplir unos criterios de habitabilidad y convivencia social en un marco de desarrollo sostenible. Para esto se describen los problemas de la salud y su relación con el espacio urbano en la ciudad, luego se presenta el concepto de Desarrollo Humano y Calidad de Vida, así como de Habitabilidad. Se termina sugiriendo una perspectiva de análisis que integre todo lo anterior coherentemente al concepto de sostenibilidad, como una alternativa de generar una mayor calidad de vida, mayor desarrollo humano y mayor habitabilidad en la ciudad...

This article intends to place the topic of human development and quality of life within the urban problematic in Barranquilla, Colombia, and the urgent necessity to meet some habitability and convivential criteria, within a sustainable development framework. In order to accomplish this, health problems and their relationship with the urban space in the city are described, next the concept of Human Development and Quality of Life, and habitability in Barranquilla are presented. It finishes suggesting a new perspective of analysis which coherently integrates all the afore said to the sustainability concept, as an alternative to generate better quality of life, higher human development and higher habitability in the city...

La autonomía municipal plena en el marco de la nueva constitución política de Bolivia. Caso: Gobierno Municipal de la Ciudad de La Paz

La investigación basado en análisis de encuestas afirma que los Concejeros y Funcionarios del Gobierno Municipal de la ciudad de La Paz como: AMDEPAZ, FAM y el Ministerio de Autonomías, están de acuerdo en que el Gobierno Municipal debe recaudar su organización institucional a través de la reformulación de la Ley de Municipalidades 2028, ya que es la que norma el actuar del municipio y establecer las condiciones para la implantación de la "Autonomía Municipal Plena"

Independent regulation of periarteriolar and perivenular nitric oxide mechanisms in the in vivo hamster cheek pouch microvasculature.

OBJECTIVE: We tested the hypothesis that differential stimulation of nitric oxide (NO) production can be induced in pre- and postcapillary segments of the microcirculation in the hamster cheek pouch. MATERIALS AND METHODS: We applied acetylcholine (ACh) or platelet-activating factor (PAF) topically and measured perivascular NO concentration ([NO]) with NO-sensitive microelectrodes in arterioles and venules of the hamster cheek pouch. We also measured NO in cultured coronary endothelial cells (CVEC) after ACh or PAF. RESULTS: ACh increased periarteriolar [NO] significantly in a dose-dependent manner. ACh at 1 microM increased [NO] from 438.1+/-43.4 nM at baseline to 647.9+/-66.3 nM, while 10 microM of ACh increased [NO] from baseline to 1,035.0+/-59.2 nM (P<0.05). Neither 1 nor 10 microM of ACh changed perivenular [NO] in the hamster cheek pouch. PAF, at 100 nM, increased perivenular [NO] from 326.6+/-50.8 to 622.8+/-41.5 nM. Importantly, 100 nM of PAF did not increase periarteriolar [NO]. PAF increased [NO] from 3.6+/-2.1 to 455.5+/-19.9 in CVEC, while ACh had no effect. CONCLUSIONS: We conclude that NO production can be stimulated in a differential manner in pre- and postcapillary segments in the hamster cheek pouch. ACh selectively stimulates the production of NO only in arterioles, while PAF stimulates the production of NO only in venules.

Internalization of eNOS via caveolae regulates PAF-induced inflammatory hyperpermeability to macromolecules.

Endothelial nitric oxide (NO) synthase (eNOS) is thought to regulate microvascular permeability via NO production. We tested the hypotheses that the expression of eNOS and eNOS endocytosis by caveolae are fundamental for appropriate signaling mechanisms in inflammatory endothelial permeability to macromolecules. We used bovine coronary postcapillary venular endothelial cells (CVECs) because these cells are derived from the microvascular segment responsible for the transport of macromolecules in inflammation. We stimulated CVECs with platelet-activating factor (PAF) at 100 nM and measured eNOS phosphorylation, NO production, and CVEC monolayer permeability to FITC-dextran 70 KDa (Dx-70). PAF translocated eNOS from plasma membrane to cytosol, induced changes in the phosphorylation state of the enzyme, and increased NO production from 4.3+/-3.8 to 467+/-22.6 nM. PAF elevated CVEC monolayer permeability to FITC-Dx-70 from 3.4+/-0.3 x 10(-6) to 8.5+/-0.4 x 10(-6) cm/s. The depletion of endogenous eNOS with small interfering RNA abolished PAF-induced hyperpermeability, demonstrating that the expression of eNOS is required for inflammatory hyperpermeability responses. The inhibition of the caveolar internalization by blocking caveolar scission using transfection of dynamin dominant-negative mutant, dyn2K44A, inhibited PAF-induced hyperpermeability to FITC-Dx-70. We interpret these data as evidence that 1) eNOS is required for hyperpermeability to macromolecules and 2) the internalization of eNOS via caveolae is an important mechanism in the regulation of endothelial permeability. We advance the novel concept that eNOS internalization to cytosol is a signaling mechanism for the onset of microvascular hyperpermeability in inflammation.

Hyperglycemia impairs glucose and insulin regulation of nitric oxide production in glucose-inhibited neurons in the ventromedial hypothalamus.

Physiological changes in extracellular glucose, insulin, and leptin regulate glucose-excited (GE) and glucose-inhibited (GI) neurons in the ventromedial hypothalamus (VMH). Nitric oxide (NO) signaling, which is involved in the regulation of food intake and insulin signaling, is altered in obesity and diabetes. We previously showed that glucose and leptin inhibit NO production via the AMP-activated protein kinase (AMPK) pathway, while insulin stimulates NO production via the phosphatidylinositol-3-OH kinase (PI3K) pathway in VMH GI neurons. Hyperglycemia-induced inhibition of AMPK reduces PI3K signaling by activating the mammalian target of rapamycin (mTOR). We hypothesize that hyperglycemia impairs glucose and insulin-regulated NO production in VMH GI neurons. This hypothesis was tested in VMH neurons cultured in hyperglycemic conditions or from streptozotocin-induced type 1 diabetic rats using NO- and membrane potential-sensitive dyes. Neither decreased extracellular glucose from 2.5 to 0.5 mM, nor 5 nM insulin increased NO production in VMH neurons in either experimental condition. Glucose- and insulin-regulated NO production was restored in the presence of the AMPK activator, 5-aminoimidazole-4-carboxamide-1-b-4-ribofuranoside or the mTOR inhibitor rapamycin. Finally, decreased glucose and insulin did not alter membrane potential in VMH neurons cultured in hyperglycemic conditions or from streptozotocin-induced rats. These data suggest that hyperglycemia impairs glucose and insulin regulation of NO production through AMPK inhibition. Furthermore, glucose and insulin signaling pathways interact via the mTOR pathway.

Endothelial nitric oxide synthase is a molecular vascular target for the Chinese herb Danshen in hypertension.

Danshen, a Chinese herb, reduces hypertension in Oriental medicine. We hypothesized that Danshen acts partially through endothelial nitric oxide synthase (eNOS) signaling mechanisms. We tested the hypothesis using tanshinone II(A), an active ingredient of Danshen, and the two-kidney, one-clip renovascular hypertension model in hamsters. Oral tanshinone (50 microg/100 g body wt) reduced mean arterial pressure (MAP) from 161.2 +/- 6.9 to 130.0 +/- 7.8 mmHg (mean +/- SE; P < 0.05) in hypertensive hamsters. MAP in sham-operated hamsters was 114.3 +/- 9.2 mmHg. Topical tanshinone at 1 microg/ml and 5 microg/ml increased normalized arteriolar diameter from 1.00 to 1.25 +/- 0.08 and 1.57 +/- 0.11, respectively, and increased periarteriolar nitric oxide concentration from 87.1 +/- 11.3 to 146.9 +/- 23.1 nM (P < 0.05) at 5 microg/ml in hamster cheek pouch. N(G)-monomethyl-L-arginine inhibited tanshinone-induced vasodilation. Hypertension reduced eNOS protein relative to sham-operated control. Tanshinone prevented the hypertension-induced reduction of eNOS and increased eNOS expression to levels higher than sham-operated control in hamster cheek pouch. Topical tanshinone increased normalized arteriolar diameter from 1.0 to 1.47 +/- 0.08 in the cremaster muscle of control mice and to 1.12 +/- 0.13 in cremasters of eNOS knockout mice. In ECV-304 cells transfected with eNOS-green fluorescent protein, tanshinone increased eNOS protein expression 1.35 +/- 0.05- and 1.85 +/- 0.07-fold above control after 5-min and 1-h application, respectively. Tanshinone also increased eNOS phosphorylation 1.19 +/- 0.07- and 1.72 +/- 0.20-fold relative to control after 5-min and 1-h application. Our data provide a basis to understand the action of a Chinese herb used in alternative medicine. We conclude that eNOS stimulation is one mechanism by which tanshinone induces vasodilation and reduces blood pressure.