An in vivo neuroimmune organoid model to study human microglia phenotypes.

Microglia are specialized brain-resident macrophages that play crucial roles in brain development, homeostasis, and disease. However, until now, the ability to model interactions between the human brain environment and microglia has been severely limited. To overcome these limitations, we developed an in vivo xenotransplantation approach that allows us to study functionally mature human microglia (hMGs) that operate within a physiologically relevant, vascularized immunocompetent human brain organoid (iHBO) model. Our data show that organoid-resident hMGs gain human-specific transcriptomic signatures that closely resemble their in vivo counterparts. In vivo two-photon imaging reveals that hMGs actively engage in surveilling the human brain environment, react to local injuries, and respond to systemic inflammatory cues. Finally, we demonstrate that the transplanted iHBOs developed here offer the unprecedented opportunity to study functional human microglia phenotypes in health and disease and provide experimental evidence for a brain-environment-induced immune response in a patient-specific model of autism with macrocephaly.

Prognostic Role of Neutrophil, Monocyte and Platelet to Lymphocyte Ratios in Advanced Ovarian Cancer According to the Time of Debulking Surgery.

Despite a multimodal radical treatment, mortality of advanced epithelial ovarian cancer (AEOC) remains high. Host-related factors, such as systemic inflammatory response and its interplay with the immune system, remain underexplored. We hypothesized that the prognostic impact of this response could vary between patients undergoing primary debulking surgery (PDS) and those undergoing interval debulking surgery (IDS). Therefore, we evaluated the outcomes of two surgical groups of newly diagnosed AEOC patients according to the neutrophil, monocyte and platelet to lymphocyte ratios (NLR, MLR, PLR), taking median ratio values as cutoffs. In the PDS group (n = 61), low NLR and PLR subgroups showed significantly better overall survival (not reached (NR) vs. 72.7 months, 95% confidence interval [CI]: 40.9-95.2, p = 0.019; and NR vs. 56.1 months, 95% CI: 40.9-95.2, p = 0.004, respectively) than those with high values. Similar results were observed in progression free survival. NLR and PLR-high values resulted in negative prognostic factors, adjusting for residual disease, BRCA1/2 status and stage (HR 2.48, 95% CI: 1.03-5.99, p = 0.043, and HR 2.91, 95% CI: 1.11-7.64, p = 0.03, respectively). In the IDS group (n = 85), ratios were not significant prognostic factors. We conclude that NLR and PLR may have prognostic value in the PDS setting, but none in IDS, suggesting that time of surgery can modulate the prognostic impact of baseline complete blood count (CBC).

Competitive binding of HIF-1α and CITED2 to the TAZ1 domain of CBP from molecular simulations.

Many intrinsically disordered proteins (IDPs) are involved in complex signalling networks inside the cell. Their particular binding modes elicit different types of responses that can be subtly regulated. Here we study the binding of two disordered transactivation domains from proteins HIF-1α and CITED2, whose binding to the TAZ1 domain of CBP is critical for the hypoxic response. Experiments have shown that both IDPs compete for their shared partner, and that this competition is mediated by the formation of a ternary intermediate state. Here we use computer simulations with a coarse-grained model to provide a detailed molecular description of this intermediate. We find that the conserved LP(Q/E)L motif may have a critical role in the displacement of HIF-1α by CITED2 and show a possible mechanism for the transition from the intermediate to the bound state. We also explore the role of TAZ1 dynamics in the binding. The results of our simulations are consistent with many of the experimental observations and provide a detailed view of the emergent properties in the complex binding of these IDPs.

New Global Referencing Approach in a Camera-LCD Micro Positioning System.

In any precision manufacturing process, positioning systems play a very important role in achieving a quality product. As a new approach to current systems, camera-LCD positioning systems are a new technology that can provide substantial improvements enabling better accuracy and repeatability. However, in order to provide stability to the system a global positioning system is required. This paper presents an improvement of a positioning system based on the treatment of images on an LCD in which a new algorithm with absolute reference has been implemented. The method is based on basic geometry and linear algebra applied to computer vision. The algorithm determines the spiral center using an image taken at any point. Consequently, the system constantly knows its position and does not lose its reference. Several modifications of the algorithm are proposed and compared. The simulation and test of the algorithm provide an important improvement in the reliability and stability of the positioning system providing errors of microns for the calculation of the global position used by the algorithm.

Multiparametric magnetic resonance imaging-guided salvage radiotherapy in prostate cancer.

AIM: To analyse the efficacy and toxicity of postprostatectomy SRT in patients with a BCR evaluated with mpMRI. BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) has the ability to detect the site of pelvic recurrence in patients with biochemical recurrence (BCR) after radical prostatectomy (RP). However, we do not know the oncological outcomes of mpMRI-guided savage radiotherapy (SRT). RESULTS: Local, lymph node, and pelvic bone recurrence was observed in 13, 4 and 2 patients, respectively. PSA levels were significantly lower in patients with negative mpMRI (0.4 ng/mL [0.4]) vs. positive mpMRI (2.2 ng/mL [4.1], p = 0.003). Median planning target volume doses in patients with visible vs. non-visible recurrences were 76 Gy vs. 70 Gy. Overall, mean follow-up was 41 months (6-81). Biochemical relapse-free survival (bRFS) at 3 years was 82.3% and 82.5%, respectively, for the negative and positive mpMRI groups (p = 0.800). Three-year rates of late grade ≥2 urinary and rectal toxicity were 14.8% and 1.9%, respectively; all but one patient recovered without sequelae. CONCLUSION: SRT to the macroscopic recurrence identified by mpMRI is a feasible and well-tolerated option. In this study, there were no differences in bRFS between MRI-positive and MRI-negative patients, indicating effective targeting of MRI-positive lesions.

Do Patients Feel Well Informed in a Radiation Oncology Service?

Information received by cancer patients has gained importance in recent decades. The aim of this study was to evaluate the perception of information received by oncological patients in a radiotherapy department and to measure the importance of the other information sources. A cross-sectional study was conducted, evaluating patients who received radiotherapy. All the patients were asked two questionnaires: the EORTC QLQ-INFO26 module evaluating their satisfaction with received information, and a questionnaire analyzing other sources of information search. One hundred patients between 27 and 84 years were enrolled. Breast cancer (26 %) was the commonest cancer. Patients felt better informed about the medical tests and secondly about the performed treatment. The younger patients were those who were more satisfied with the information received and patients with no formal education felt less satisfied, with statistically significant differences. Patients did not seek external information; at the most, they asked relatives and other people with cancer. Patients were satisfied with the received information, although a high percentage would like more information. In general, patients did not search for external information sources. Age and educational level seem to influence in the satisfaction with the received information.

Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through the cAMP/PKA pathway.

Heterozygous loss-of-function (LoF) mutations in SETD1A, which encodes a subunit of histone H3 lysine 4 methyltransferase, cause a neurodevelopmental syndrome and increase the risk for schizophrenia. Using CRISPR-Cas9, we generate excitatory/inhibitory neuronal networks from human induced pluripotent stem cells with a SETD1A heterozygous LoF mutation (SETD1A+/-). Our data show that SETD1A haploinsufficiency results in morphologically increased dendritic complexity and functionally increased bursting activity. This network phenotype is primarily driven by SETD1A haploinsufficiency in glutamatergic neurons. In accordance with the functional changes, transcriptomic profiling reveals perturbations in gene sets associated with glutamatergic synaptic function. At the molecular level, we identify specific changes in the cyclic AMP (cAMP)/Protein Kinase A pathway pointing toward a hyperactive cAMP pathway in SETD1A+/- neurons. Finally, by pharmacologically targeting the cAMP pathway, we are able to rescue the network deficits in SETD1A+/- cultures. Our results demonstrate a link between SETD1A and the cAMP-dependent pathway in human neurons.

Prevalence of depressive symptoms in new Mexico Hispanic and non-Hispanic white elderly.

OBJECTIVE: To evaluate the prevalence rates, risk factors, and pattern of depressive symptoms in elderly Hispanic and non-Hispanic Whites (NHWs). METHODS: This survey was a community-based, cross-sectional survey of randomly selected Medicare recipients living in Bernalillo County (Albuquerque, New Mexico). The survey's objective was to examine the health and health-related issues of Hispanic and NHW elderly persons (> or =65 years of age). As part of the survey, participants were administered the Geriatric Depression Scale-short form (GDS). RESULTS: Complete data were available on 798 subjects with a mean age of 73.7 years, age range 65-96. The prevalence of a GDS score > or =6 was: Hispanic males, 9.5%; Hispanic females, 19.2%; NHW males, 5.4%; and NHW females, 8.7%. Hispanics (P=.001) and women (P=.003) had higher prevalence rates. Sociodemographic variables, health, social support, and the activities of daily living (ADLs) were significantly related to symptoms. English skills (P<.0001) and birthplace (P=.011) were associated with symptoms in Hispanics. Significant differences were found in the response patterns between Hispanics and NHWs. Logistic regression analyses showed that ethnic differences were largely explained by differences in the level of education and income among Hispanics and NHWs. CONCLUSION: A difference was seen in the prevalence rates of depressive symptoms between Hispanic and NHW elderly persons and between men and women. In addition to the traditional risk factors for depressive symptoms, we found that ethnic differences in prevalence rates can be largely explained by education and income differences in the two groups.

Prognostic factors in pediatric sepsis study, from the Spanish Society of Pediatric Intensive Care.

BACKGROUND: Sepsis and septic shock represent up to 30% of admitted patients in pediatric intensive care units, with a mortality that can exceed 10%. The objective of this study is to determine the prognostic factors for mortality in sepsis. METHODS: Multicenter prospective descriptive study with patients (aged 7 days to 18 years) admitted to the pediatric intensive care units for sepsis, between January 2011 and April 2012. RESULTS: Data from 136 patients were collected. Eighty-seven were male (63.9%). The median age was a year and a half (P25-75 0.3-5.5 years). In 41 cases (30.1%), there were underlying diseases. The most common etiology was Neisseria meningitidis (31 cases, 22.8%) followed by Streptococcus pneumoniae (16 patients, 11.8%). Seventeen cases were fatal (12.5%). In the statistical analysis, the factors associated with mortality were nosocomial infection (P = 0.004), hypotension (P <0.001) and heart and kidney failure (P < 0.001 and P = 0.004, respectively). The numbers of leukocytes, neutrophils and platelets on admission were statistically lower in the group that died (P was 0.006, 0.013 and <0.001, respectively). Multivariate analysis showed that multiple organ failure, neutropenia, purpura or coagulopathy and nosocomial infection were independent risk factors for increased mortality (odds ratio: 17, 4.9, 9 and 9.2, respectively). CONCLUSIONS: Patients with sepsis and multiorgan failure, especially those with nosocomial infection or the presence of neutropenia or purpura, have a worse prognosis and should be monitored and treated early.

Emotional responses to APO E genotype disclosure for Alzheimer disease.

The purpose of our study is to assess the emotional responses to disclosing APO E genotype to asymptomatic older adults at increased risk for Alzheimer disease (AD). This is a longitudinal cohort study of volunteer subjects who were aged 50 years or over, asymptomatic for (AD), had a family history of AD, passed a psychological assessment, and participated in pre- and post-test genetic counseling and three follow-up visits over 10 months. We analyzed responses by three emotional constructs: depressed, worried, and relieved. Three hundred and twenty-eight subjects were screened, 76 received their APO E genotype. When emotional responses occurred it was immediate, between baseline and the 1 month follow-up. Emotional reactions did not change significantly past 1 month. Our results suggest that for emotionally stable persons, disclosing results of their APO E genotype, high risk subjects did not report more depression or worry and low risk subjects felt relieved by knowing the results. Future studies should evaluate the risks of disclosure to family members involved in the diagnostic work-up of a relative and include subjects from a broader range of emotional stability and socioeconomic background.

Cefalea postpunción en pacientes jóvenes y "ambulatorios", comparando dos tipos de agujas para anestesia espinal en cirugía de extremidad inferior / Post puncture headache in young ambulatory patients, comparing two different kinds of spinal anesthesia needles for lower limb surgery

El propósito de esta investigación clínica comparativa experimental fue corroborar la incidencia de cefalea postpunción en pacientes jóvenes y "ambulatorios", sometidos a cirugía de extremidad inferior bajo anestesia espinal, comparando una aguja traumática vs. una aguja atraumática. Se estudiaron 308 pacientes con rango de edad de 18 a 45 años, divididos en dos grupos: Grupo A (Problema, n=154), con aguja traumática Quincké No. 26 y Grupo B (Control, n=154), con aguja atraumática Whitacre No. 25 El procedimiento anestésico se desarrolló sin eventualidades. La cefalea postpunción fue valorada con los criterios de Corbey y cols.. Hubo 3 (1.9 por ciento) pacientes en el grupo A con cefalea postpunción Grado II , y 2 (1.3 por ciento) pacientes en el grupo B con cefalea postpunción Grado II, (p=0.70). El tratamiento de la cefalea postpunción fue a base de medidas higiénicas y analgésicos no opiáceos, ninguno de los casos ameritó manejo con parche hemático. Concluimos que existe diferencia estadísticamente significativa en la incidencia de cefalea postpunción con la utilización de agujas atraumáticas, presentándose en menor porcentaje.

Ropivacaína vs bupivacaína por vía espinal / Spinal ropivacaine vs bupivacaine

Esta investigación clínica comparativa experimental, se realizó con el propósito de comprobar la eficacia de la ropivacaína simple al 0.5 por ciento en anestesia espinal, en pacientes sometidos a cirugía ortopédica de extremidad inferior, comparándola con bupivacaína simple al 0.5 por ciento. Se estudiaron 140 pacientes de 18 a 90 años, con estado físico A.S.A. 1 y 2, divididos en dos grupos de manera aleatoria: Grupo A (Problema, n=70), anestesia espinal con ropivacaína simple al 0.5 por ciento (15 mg.); Grupo B (Control, n=70), anestesia espinal con bupivacaína simple al 0.5 por ciento (15 mg.). La calidad de la anestesia fue valorada con tres parámetros: 1) nivel sensitivo y tolerancia al torniquete neumático; 2) bloqueo motor; 3) apreciación subjetiva del cirujano. En el 77.1 por ciento del total de pacientes se utilizó torniquete neumático (n=108). La calidad de la anestesia fue adecuada en los setenta pacientes del Grupo B y en sesenta y ocho del Grupo A. En dos pacientes del Grupo A la anestesia fue inadecuada, p=0.24, por medio de la prueba de la "Probabilidad exacta de Fisher". No hubo complicaciones en relación con el procedimiento anestésico en ninguno de los pacientes. Conclusión: la eficacia de la ropivacaína simple al 0.5 por ciento para anestesia espinal en pacientes sometidos a cirugía ortopédica de extremidad inferior, es similar a la de la bupivacaína simple al 0.5 por ciento.