Pereskia sacharosa Griseb. (Cactaceae) Prevents Lipopolysaccharide-Induced Neuroinflammation in Rodents via Down-Regulating TLR4/CD14 Pathway and GABAA γ2 Activity.

Pereskia sacharosa Griseb. is a plant used in traditional herbal medicine to treat inflammation. We analyzed the phenolic content of P. sacharosa leaves (EEPs) by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and investigated the anti-inflammatory properties of EEPs and its flavonoid fraction (F10) in animal models subjected to acute neuroinflammation induced by bacterial lipopolysaccharide (LPS). Coronal brain sections of C57BL/6JN male mice or Wistar male rats administered with EEPs or F10 before LPS were subjected to in situ hybridization to determine c-fos and CD14 mRNA levels in the hypothalamus or GABAA γ2 mRNA levels in the hippocampus. Theta oscillations were recorded every 6 h in the hippocampus of Wistar rats. In total, five flavonoids and eight phenolic acids were identified and quantified in P. sacharosa leaves. Either EEPs or F10 crossed the blood-brain barrier (BBB) into the brain and reduced the mRNA expression of c-fos, CD14, and GABAA γ2. A decrease in theta oscillation was observed in the hippocampus of the LPS group, while the F10 + LPS group overrode the LPS effect on theta activity. We conclude that the bioactive compounds of P. sacharosa reduce the central response to inflammation, allowing the early return of ambulatory activity and well-being of the animal.

Chemotactic movement of a polarity site enables yeast cells to find their mates.

How small eukaryotic cells can interpret dynamic, noisy, and spatially complex chemical gradients to orient growth or movement is poorly understood. We address this question using Saccharomyces cerevisiae, where cells orient polarity up pheromone gradients during mating. Initial orientation is often incorrect, but polarity sites then move around the cortex in a search for partners. We find that this movement is biased by local pheromone gradients across the polarity site: that is, movement of the polarity site is chemotactic. A bottom-up computational model recapitulates this biased movement. The model reveals how even though pheromone-bound receptors do not mimic the shape of external pheromone gradients, nonlinear and stochastic effects combine to generate effective gradient tracking. This mechanism for gradient tracking may be applicable to any cell that searches for a target in a complex chemical landscape.

A novel stochastic simulation approach enables exploration of mechanisms for regulating polarity site movement.

Cells polarize their movement or growth toward external directional cues in many different contexts. For example, budding yeast cells grow toward potential mating partners in response to pheromone gradients. Directed growth is controlled by polarity factors that assemble into clusters at the cell membrane. The clusters assemble, disassemble, and move between different regions of the membrane before eventually forming a stable polarity site directed toward the pheromone source. Pathways that regulate clustering have been identified but the molecular mechanisms that regulate cluster mobility are not well understood. To gain insight into the contribution of chemical noise to cluster behavior we simulated clustering using the reaction-diffusion master equation (RDME) framework to account for molecular-level fluctuations. RDME simulations are a computationally efficient approximation, but their results can diverge from the underlying microscopic dynamics. We implemented novel concentration-dependent rate constants that improved the accuracy of RDME-based simulations, allowing us to efficiently investigate how cluster dynamics might be regulated. Molecular noise was effective in relocating clusters when the clusters contained low numbers of limiting polarity factors, and when Cdc42, the central polarity regulator, exhibited short dwell times at the polarity site. Cluster stabilization occurred when abundances or binding rates were altered to either lengthen dwell times or increase the number of polarity molecules in the cluster. We validated key results using full 3D particle-based simulations. Understanding the mechanisms cells use to regulate the dynamics of polarity clusters should provide insights into how cells dynamically track external directional cues.

A Randomized Controlled Trial to Compare Analgesia and Functional Improvement After Continuous Neuroablative and Pulsed Neuromodulative Radiofrequency Treatment of the Genicular Nerves in Patients with Knee Osteoarthritis up to One Year After the Intervention.

OBJECTIVES: To compare the analgesic and functional outcomes of continuous neuroablative radiofrequency (CNARF) and pulsed neuromodulative radiofrequency (PNMRF) treatment of genicular nerves up to 1 year after the intervention and to identify predictors associated with a successful outcome (defined as an at least 50% reduction in the pre-interventional visual analog scale [VAS] rating) after genicular radiofrequency treatment. DESIGN: A prospective randomized controlled trial. SETTING: The Pain Department of the Jerez de la Frontera University Hospital, Cadíz, Spain, from January 2018 until May 2019. SUBJECTS: Patients with grade 3-4 gonarthritis suffering from knee pain, with a VAS score ≥5 for >6 months. METHODS: Eligible participants were randomly assigned to receive either CNARF or PNMRF of the superior medial, superior lateral, and inferior medial genicular nerves. The VAS and Western Ontario and McMaster Universities Osteoarthritis (WOMAC) scores were assessed before and at 1, 6, and 12 months after treatment. Medication use was quantified before and at 6 months after the intervention. Potential characteristics associated with the efficacy of radiofrequency intervention were explored by using multivariable statistical models. RESULTS: A total of 188 participants were included. The magnitude and duration of beneficial effect and reduction in analgesic use were significantly greater in the CNARF group. Success at 6 months after radiofrequency treatment decreased with grade 4 gonarthritis; higher pre-interventional VAS score; and concomitant depression, anxiety disorder, and diabetes mellitus. CONCLUSIONS: Therapeutic efficacy and reduction in analgesic consumption were superior after CNARF. Treatment success at 6 months after radiofrequency intervention decreased with more severe gonarthritis; higher pre-interventional pain intensity; and concomitant depression, anxiety disorder, and diabetes mellitus.

Perinatal exposure to octabromodiphenyl ether mixture, DE-79, alters the vasopressinergic system in adult rats.

Polybrominated diphenyl ethers (PBDEs) are persistent environmental pollutants considered as neurotoxicants and endocrine disruptors with important biological effects ranging from alterations in growth, reproduction, and effects on the hypothalamus-pituitary-adrenal axis. The vasopressinergic (AVPergic) system is a known target for pentaBDEs mixture (DE-71) and the structurally similar chemicals, polychlorinated biphenyls. However, the potential adverse effects of mixtures containing octaBDE compounds, like DE-79, on the AVPergic system are still unknown. The present study aims to examine the effects of perinatal DE-79 exposure on the AVPergic system. Dams were dosed from gestational day 6 to postnatal day 21 at doses of 0 (control), 1.7 (low) or 10.2 (high) mg/kg/day, and male offspring from all doses at 3-months-old were subjected to normosmotic and hyperosmotic challenge. Male offspring where later assessed for alterations in osmoregulation (i.e. serum osmolality and systemic vasopressin release), and both vasopressin immunoreactivity (AVP-IR) and gene expression in the hypothalamic paraventricular and supraoptic nuclei. Additionally, to elucidate a possible mechanism for the effects of DE-79 on the AVPergic system, both neuronal nitric oxide synthase immunoreactivity (nNOS-IR) and mRNA expression were investigated in the same hypothalamic nuclei. The results showed that perinatal DE-79 exposure AVP-IR, mRNA expression and systemic release in adulthood under normosmotic conditions and more evidently under hyperosmotic stimulation. nNOS-IR and mRNA expression were also affected in the same nuclei. Since NO is an AVP regulator, we propose that disturbances in NO could be a mechanism underlying the AVPergic system disruption following perinatal DE-79 exposure leading to osmoregulation deficits.

Particle-based simulations of polarity establishment reveal stochastic promotion of Turing pattern formation.

Polarity establishment, the spontaneous generation of asymmetric molecular distributions, is a crucial component of many cellular functions. Saccharomyces cerevisiae (yeast) undergoes directed growth during budding and mating, and is an ideal model organism for studying polarization. In yeast and many other cell types, the Rho GTPase Cdc42 is the key molecular player in polarity establishment. During yeast polarization, multiple patches of Cdc42 initially form, then resolve into a single front. Because polarization relies on strong positive feedback, it is likely that the amplification of molecular-level fluctuations underlies the generation of multiple nascent patches. In the absence of spatial cues, these fluctuations may be key to driving polarization. Here we used particle-based simulations to investigate the role of stochastic effects in a Turing-type model of yeast polarity establishment. In the model, reactions take place either between two molecules on the membrane, or between a cytosolic and a membrane-bound molecule. Thus, we developed a computational platform that explicitly simulates molecules at and near the cell membrane, and implicitly handles molecules away from the membrane. To evaluate stochastic effects, we compared particle simulations to deterministic reaction-diffusion equation simulations. Defining macroscopic rate constants that are consistent with the microscopic parameters for this system is challenging, because diffusion occurs in two dimensions and particles exchange between the membrane and cytoplasm. We address this problem by empirically estimating macroscopic rate constants from appropriately designed particle-based simulations. Ultimately, we find that stochastic fluctuations speed polarity establishment and permit polarization in parameter regions predicted to be Turing stable. These effects can operate at Cdc42 abundances expected of yeast cells, and promote polarization on timescales consistent with experimental results. To our knowledge, our work represents the first particle-based simulations of a model for yeast polarization that is based on a Turing mechanism.

Principles that govern competition or co-existence in Rho-GTPase driven polarization.

Rho-GTPases are master regulators of polarity establishment and cell morphology. Positive feedback enables concentration of Rho-GTPases into clusters at the cell cortex, from where they regulate the cytoskeleton. Different cell types reproducibly generate either one (e.g. the front of a migrating cell) or several clusters (e.g. the multiple dendrites of a neuron), but the mechanistic basis for unipolar or multipolar outcomes is unclear. The design principles of Rho-GTPase circuits are captured by two-component reaction-diffusion models based on conserved aspects of Rho-GTPase biochemistry. Some such models display rapid winner-takes-all competition between clusters, yielding a unipolar outcome. Other models allow prolonged co-existence of clusters. We investigate the behavior of a simple class of models and show that while the timescale of competition varies enormously depending on model parameters, a single factor explains a large majority of this variation. The dominant factor concerns the degree to which the maximal active GTPase concentration in a cluster approaches a "saturation point" determined by model parameters. We suggest that both saturation and the effect of saturation on competition reflect fundamental properties of the Rho-GTPase polarity machinery, regardless of the specific feedback mechanism, which predict whether the system will generate unipolar or multipolar outcomes.

Perinatal exposure to organohalogen pollutants decreases vasopressin content and its mRNA expression in magnocellular neuroendocrine cells activated by osmotic stress in adult rats.

Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are environmental pollutants that produce neurotoxicity and neuroendocrine disruption. They affect the vasopressinergic system but their disruptive mechanisms are not well understood. Our group reported that rats perinatally exposed to Aroclor-1254 (A1254) and DE-71 (commercial mixtures of PCBs and PBDEs) decrease somatodendritic vasopressin (AVP) release while increasing plasma AVP responses to osmotic activation, potentially emptying AVP reserves required for body-water balance. The aim of this research was to evaluate the effects of perinatal exposure to A1254 or DE-71 (30mgkg/day) on AVP transcription and protein content in the paraventricular and supraoptic hypothalamic nuclei, of male and female rats, by in situ hybridization and immunohistochemistry. cFOS mRNA expression was evaluated in order to determine neuroendocrine cells activation due to osmotic stimulation. Animal groups were: vehicle (control); exposed to either A1254 or DE-71; both, control and exposed, subjected to osmotic challenge. The results confirmed a physiological increase in AVP-immunoreactivity (AVP-IR) and gene expression in response to osmotic challenge as reported elsewhere. In contrast, the exposed groups did not show this response to osmotic activation, they showed significant reduction in AVP-IR neurons, and AVP mRNA expression as compared to the hyperosmotic controls. cFOS mRNA expression increased in A1254 dehydrated groups, suggesting that the AVP-IR decrease was not due to a lack of the response to the osmotic activation. Therefore, A1254 may interfere with the activation of AVP mRNA transcript levels and protein, causing a central dysfunction of vasopressinergic system.

BioPrint meets the AI age: development of artificial intelligence-based ADMET models for the drug-discovery platform SAFIRE.

Background: To prioritize compounds with a higher likelihood of success, artificial intelligence models can be used to predict absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of molecules quickly and efficiently. Methods: Models were trained with BioPrint database proprietary data along with public datasets to predict various ADMET end points for the SAFIRE platform. Results: SAFIRE models performed at or above 75% accuracy and 0.4 Matthew's correlation coefficient with validation sets. Training with both proprietary and public data improved model performance and expanded the chemical space on which the models were trained. The platform features scoring functionality to guide user decision-making. Conclusion: High-quality datasets along with chemical space considerations yielded ADMET models performing favorably with utility in the drug discovery process.

Good machine learning practices: Learnings from the modern pharmaceutical discovery enterprise.

Machine Learning (ML) and Artificial Intelligence (AI) have become an integral part of the drug discovery and development value chain. Many teams in the pharmaceutical industry nevertheless report the challenges associated with the timely, cost effective and meaningful delivery of ML and AI powered solutions for their scientists. We sought to better understand what these challenges were and how to overcome them by performing an industry wide assessment of the practices in AI and Machine Learning. Here we report results of the systematic business analysis of the personas in the modern pharmaceutical discovery enterprise in relation to their work with the AI and ML technologies. We identify 23 common business problems that individuals in these roles face when they encounter AI and ML technologies at work, and describe best practices (Good Machine Learning Practices) that address these issues.

A model for migratory B cell oscillations from receptor down-regulation induced by external chemokine fields.

A long-standing paradigm in B cell immunology is that effective somatic hypermutation and affinity maturation require cycling between the dark zone and light zone of the germinal center. The cyclic re-entry hypothesis was first proposed based on considerations of the efficiency of affinity maturation using an ordinary differential equations model for B cell population dynamics. More recently, two-photon microscopy studies of B cell motility within lymph nodes in situ have revealed the complex migration patterns of B lymphocytes both in the preactivation follicle and post-activation germinal center. There is strong evidence that chemokines secreted by stromal cells and the regulation of cognate G-protein coupled receptors by these chemokines are necessary for the observed spatial cell distributions. For example, the distribution of B cells within the light and dark zones of the germinal center appears to be determined by the reciprocal interaction between the level of the CXCR4 and CXCR5 receptors and the spatial distribution of their respective chemokines CXCL12 and CXCL13. Computer simulations of individual-based models have been used to study the complex biophysical and mechanistic processes at the individual cell level, but such simulations can be challenging to parameterize and analyze. In contrast, ordinary differential equations are more tractable, but traditional compartment model formalizations ignore the spatial chemokine distribution that drives B cell redistribution. Motivated by the desire to understand the motility patterns observed in an individual-based simulation of B cell migration in the lymph node, we propose and analyze the dynamics of an ordinary differential equation model incorporating explicit chemokine spatial distributions. While there is experimental evidence that B cell migration patterns in the germinal center are driven by extrinsically regulated differentiation programs, the model shows, perhaps surprisingly, that feedback from receptor down-regulation induced by external chemokine fields can give rise to spontaneous interzonal and intrazonal oscillations in the absence of any extrinsic regulation. While the extent to which such simple feedback mechanisms contributes to B cell migration patterns in the germinal center is unknown, the model provides an alternative hypothesis for how complex B cell migration patterns might arise from very simple mechanisms.

[Septal alcohol ablation in patients with hypertrophic cardiomyopathy]. / Ablación septal con alcohol para tratar miocardiopatía hipertrófica.

OBJECTIVE: to know the clinical and hemodynamic course in septal obstructive hypertrophic cardiomyopathy (SOHC) after alcohol ablation. METHODS: this was an observational, longitudinal study, including 21 patients with SOHC with functional class of the New York Heart Association (CF-NYHA) refractory to treatment and/or = 30 mm Hg gradient at rest or = 60 mm Hg provoked, or have systolic anterior motion or mitral incompetence (MI) > grade II by echocardiography. RESULTS: average age was 50 ± 16 years, males 38.1 %, females 61.9 %; symptoms: angina 42.9 %, dyspnea 85.7 %, syncope 23.8 %. Pre-ablation CF-NYHA was III and IV in 61.9 %; after a year follow-up all of them were class I-II. Pre-ablation, after and one year later, interventricle septum measures were 22.7 ± 4.9 and 20.7 ± 3.1 mm; left ventricular ejection fraction was 65.5 ± 7 %, 62.2 % ± 6.5 % and 68.7 ± 6.2 %; the output gradient of the left ventricle were 106.9 ± 29.9, 44.6 ± 24.3 and 22.0 ± 5.7 mm Hg. Pre-ablation MI grade-III and IV were 33.3 % and 47.6 %; after a year it was grade-0, 52.4 %, grade-I 28.6 %, grade-II, 19 %. There were no hospital mortality. CONCLUSIONS: the alcohol septal ablation in SOHC patients had a high success treatment with a low complication rate.

Objetivo: conocer características demográficas, clínicas y hemodinámicas de los pacientes con ablación con alcohol para tratar la miocardiopatía hipertrófica septal obstructiva (MHSO). Métodos: estudio observacional, longitudinal, descriptivo de 21 pacientes con MHSO resistente a tratamiento o con gradiente = 30 mm Hg en reposo o = 60 mm Hg provocado y con movimiento sistólico anterior o insuficiencia mitral > grado II. Resultados: edad de 50 ± 16 años; hombres 38.1 % y mujeres 61.9 %. Los síntomas fueron angor 42.9 %, disnea 85.7 % y síncope 23.8 %. La clase funcional NYHA preablación fue grados III y IV en 61.9 %; al año todos tenían grados I y II. Preablación y al año, el espesor del septo interventricular fue de 22.7 ± 4.9 y 20.7 ± 3.1 mm. Preablación, después y al año, la fracción de eyección fue de 65.5 ± 7, 62.2 ± 6.5 y 68.7 ± 6.2 %. Preablación, después y al año, el gradiente del tracto de salida del ventrículo izquierdo fue de 106.9 ± 29.9, 44.6 ± 24.3 y 22.0 ± 5.7 mm Hg. Preablación, la insuficiencia mitral fue grados III y IV en 33.3 y 47.6 % y al año fue grados 0 en 52.4 %, I en 28.6 % y II en 19 %. No hubo defunciones intrahospitalarias. Conclusiones: la ablación septal con alcohol en pacientes con MHSO fue exitosa.

[Operative results in cardiovascular surgery of the neonate]. / Resultados inmediatos en cirugía cardiovascular neonatal.

OBJECTIVE: To present our institutional postoperative results in cardiovascular surgery of the neonate, and to give an idea of its contribution to the national problematic knowledge in this area. MATERIAL AND METHODS: A retrospective, descriptive, and observational study was carried out, including all neonates with congenital heart disease who were operated at the Ignacio Chávez National Cardiology Institute in a 7 year period. We made special emphasis in postoperative morbidity and mortality, as well as in the risk factors for early mortality. RESULTS: We operated on 484 neonates with congenital heart disease due to total anomalous pulmonary venous conection, classic transposition of great arteries, pulmonary atresia, and aortic coarctation. Causes for early mortality were cardiac failure, pulmonary hypertension, pulmonary sepsis, and arrhythmias. Operative mortality was 12.2% and was due mainly to congenital heart disease with 5 and 6 RACHS-1 risk score. Risk factors for operative mortality were: age < 15 days, body surface area < 0.20 m2, weight < 4 kg, and univentricular heart physiology. CONCLUSIONS: There is still a high operative mortality for complex neonatal heart disease in this series. Our institutional outcomes can not be extrapolated to the rest of the country, but highlights several challenges that national pediatric health care institutions and associations must assume in order to improve the attention that neonatal patients demand.

[Medical and surgical health care for congenital heart disease: a panoramic vision of the reality in Mexico. Inquiry 2009]. / Atención médico-quirúrgica de las cardiopatías congénitas: una visión panorámica de la realidad en México. Encuesta 2009.

INTRODUCTION: The only way to characterize the Mexican problem related to congenital heart disease care is promoting the creation of a national database for registering the organization, resources, and related activities. MATERIAL AND METHODS: The Health Secretary of Mexico adopted a Spanish registration model to design a survey for obtaining a national Mexican reference in congenital heart disease. This survey was distributed to all directors of medical and/or surgical health care centers for congenital heart disease in Mexico. This communication presents the results obtained in relation to organization, resources and activities performed during the last year 2009. RESULTS: From the 22 health care centers which answered the survey 10 were reference centers (45%) and 12 were assistant centers (55%). All of them are provided with cardiologic auxiliary diagnostic methods. Except one, all centers have at least one bidimentional echocardiography apparatus. There is a general deficit between material and human resources detected in our study. Therapeutic actions for congenital heart disease (70% surgical and 30% therapeutical interventionism) show a clear centralization tendency for this kind of health care in Mexico City, Monterrey and finally Guadalajara. CONCLUSIONS: Due to the participation of almost all cardiac health centers in Mexico, our study provides an important information related to organization, resources, and medical and/or surgical activities for congenital heart disease. The data presented not only show Mexican reality, but allows us to identify better the national problematic for establishing priorities and propose solution alternatives.

[Adequacy assessment of antibiotic prophylaxis in orthopedic and traumatologic surgery]. / Evaluación de la adecuación de la profilaxis antibiótica en cirugía ortopédica y traumatológica.

INTRODUCTION: Antibiotic prophylaxis is an essential strategy for preventing surgical wound infection. This study assesses the adequacy of surgical antibiotic prophylaxis in trauma and orthopedic patients. METHODS: Cross-sectional study including consecutive patients who underwent hip or knee replacement, or spinal surgery. Sample estimation was based on 95% confidence, 5% precision, an overall adequacy of 85%, and assuming a loss of 5%. Thus, 206 patients were required. The appropriateness of the indication, time of administration, administration route, and dose according to the hospital protocol was assessed. The cumulative incidence of surgical site infection at discharge was determined. RESULTS: A total of 221 patients were included, 33.5% men and 66.5% women; mean age was 61.1 (SD=14.1) for men and 67.1 (SD=12.4) for woman (P<0.05). Antibiotic prophylaxis was indicated in all patients. Overall adequacy of prophylaxis according to the hospital protocol was 89.1%. Cumulative incidence of surgical wound infection at discharge was 3.2%. There was no association between the adequacy of antibiotic prophylaxis and surgical site infection (P>0.05). CONCLUSIONS: The adequacy of postoperative antibiotic prophylaxis was high in this study, but it can be improved.

Determinantes sociales de la salud y prevención de infecciones de transmisión sexual en estudiantes de una institución educativa del Perú / Social determinantsof health and prevention of sexually transmitted infections in students of an educational institution in Perú

Objetivo: Establecer la relación entre los determinantes sociales de la salud y prevención de infecciones de transmisión sexual en estudiantes de una Institución Educativa del Perú. Material y métodos: Estudio descriptivo, con enfoque cuantitativo, nivel correlacional y diseño no experimental, donde se contó con una muestra de 144 estudiantes, evaluados mediante un instrumento como el cuestionario estructurado, validado y con un nivel alto de confiabilidad. Resultados: Evidenciaron que la prevención de ITS mostró una relación significativa con las dimensiones biológico, estilo de vida y el sistema sanitario, donde el p valor alcanzado fue de 0,000, así como una correlación positiva media, donde los coeficientes obtenidos fueron 0,500, 0.485 y 0,434 respectivamente. Conclusiones: Predominó una relación significativa, así como una correlación positiva considerable entre las variables evaluadas, por lo mismo que se contó con un p valor de 0.000 y un coeficiente de 0,642 correspondientemente

Objective: To establish the relationship between the social determinants of health and the prevention of sexually transmitted infections in students of an educational institution in Peru. Material and method:descriptive study, with a quantitative approach, correlational level and non-experimental design, where there was a sample of 144 students, evaluated using an instrument such as the structured questionnaire, validated and with a high level of reliability. Results:Showed that STI prevention showed a significant relationship with the biological, lifestyle and health system dimensions, where the p value achieved was 0.000, as well as a mean positive correlation, where the coefficients obtained were 0.500, 0.485 and 0.434 respectively. Conclusions: A significant relationship predominated, as well as a considerable positive correlation between the variables evaluated, for the same reason that there was a p value of 0.000 and a coefficient of 0.642 respectively

Lengthening of proximal implantation site during endovascular repair of thoracic aortic aneurysm: preservation of carotid patency with retrograde trans endograft deployment of a carotid stent.

Endovascular repair of descending thoracic aortic aneurysms with a reduced proximal implantation site represents a technical challenge. Surgical procedures before endovascular exclusion can be necessary to increase the length of the proximal landing site to avoid type 1 endoleaks. We present a case of endovascular exclusion of a descending thoracic aortic aneurysm with the endograft placed proximal to the left common carotid artery. Flow to this arch was preserved reconstructing the carotid ostium with the retrograde implantation of a carotid stent that was placed extending across an orifice created in the deployed endograft by puncture and balloon dilatation.

Effect of the Organization of Rhodopsin on the Association between Transducin and a Photoactivated Receptor.

After photoactivation, rhodopsin (R), a G-protein-coupled receptor, rapidly activates multiple transducin G-proteins (G) in an initial amplification step of phototransduction. G-protein activation requires diffusion-mediated association with an active rhodopsin (R*) at the rod disk membrane. Different organizations of R within the membrane have been revealded by several microscopy studies, including static and freely diffusing situations. However, it is unclear how such different scenarios influence the activation rate of G proteins. Through Monte Carlo simulations, we study the association reaction between a photoactivated rhodopsin and transducin under different reported receptor organizations including (a) R monomers diffusing freely, (b) R forming static dispersed crystalline domains made of rows of dimers, and (c) R arranged in static tracks formed by two adjacent rows of dimers. A key parameter in our simulations is the probability of binding following a collision ( p). For high p, the association rate between R* and G is higher in the freely diffusive system than in the static organizations, but for low collision efficiencies, the static organizations can result in faster association rates than the mobile system. We also observe that with low p, increasing the concentration of R increases the association rate significantly in the dispersed crystals configuration and just slightly in the free diffusive system. In summary, the lateral organization of rhodopsin influences the association rate between R* and G in a manner strongly dependent on the collision efficiency.

[Usefulness of cold ureteral biopsy during radical cystectomy as a predictor of recurrence risk: Review of our series.] / Utilidad de la biopsia fría ureteral durante la cistectomía radical como predictor de riesgo de recidiva: revisión de nuestra serie.

OBJECTIVES: To evaluate the association of positive margins in the intraoperative biopsy during radical cystectomy (RC) with the risk of recurrence in the uretero-ileal anastomosis or upper urinary tract (UUT), and identify potential risk factors for positive ureteral margins. METHODS: A retrospective, descriptive study was performed in patients treated with radical cystectomy due to transitional cell carcinoma (TCC), who underwent a cold biopsy of the ureteral margin at the time of cystectomy. A descriptive analysis and frequency distribution was performed. Fisher's test was used to calculate sensitivity and specificity and a survival analysis was performed. RESULTS: 230 patients were included. Prior to RC, transurethral resection of the bladder tumor and a CT scan were done. The percentage of positive margins was 4.81% for the right ureter and 4.27% for the left. Recurrence was detected in the anastomosis in 2.64% of the cases. In a 0.88% recurrence was found in the UUT (2 cases) at the level of left renal pelvis (1 case) and left kidney (1 case). In the multivariate analysis, neither recurrence in the anastomosis (p=1) or at the UUT (p=1) level during follow-up were significantly associated with the presence of positive margins. An association was found between the pathological biopsy of the right ureter and carcinoma in situ (CIS) of the bladder wall with UUT involvement. We found only association between the cold biopsy of the left ureter and tumor in left UTT. Reimplantation with positive margins was not statistically associated with neither ureteroileal anastomosis or UTT relapse. A relationship was found between the cold biopsy of both ureters and the definitive pathology. CONCLUSIONS: In our study, the presence of positive ureteral margins was not associated with an increased risk of recurrence in the anastomosis or UUT. Although it remains a topic for debate, a strategy to follow may be to adapt ureteral cold biopsies to individual risk, thus perform it in patients with bladder CIS.