Convergent dopamine and ALK4 signaling to PCBP1 controls FosB alternative splicing and cocaine behavioral sensitization.

ΔfosB is an alternatively spliced product of the FosB gene that is essential for dopamine-induced reward pathways and that acts as a master switch for addiction. However, the molecular mechanisms of its generation and regulation by dopamine signaling are unknown. Here, we report that dopamine D1 receptor signaling synergizes with the activin/ALK4/Smad3 pathway to potentiate the generation of ΔFosB mRNA in medium spiny neurons (MSNs) of the nucleus accumbens (NAc) via activation of the RNA-binding protein PCBP1, a regulator of mRNA splicing. Concurrent activation of PCBP1 and Smad3 by D1 and ALK4 signaling induced their interaction, nuclear translocation, and binding to sequences in exon-4 and intron-4 of FosB mRNA. Ablation of either ALK4 or PCBP1 in MSNs impaired ΔFosB mRNA induction and nuclear translocation of ΔFosB protein in response to repeated co-stimulation of D1 and ALK4 receptors. Finally, ALK4 is required in NAc MSNs of adult mice for behavioral sensitization to cocaine. These findings uncover an unexpected mechanism for ΔFosB generation and drug-induced sensitization through convergent dopamine and ALK4 signaling.

Adult medial habenula neurons require GDNF receptor GFRα1 for synaptic stability and function.

The medial habenula (mHb) is an understudied small brain nucleus linking forebrain and midbrain structures controlling anxiety and fear behaviors. The mechanisms that maintain the structural and functional integrity of mHb neurons and their synapses remain unknown. Using spatiotemporally controlled Cre-mediated recombination in adult mice, we found that the glial cell-derived neurotrophic factor receptor alpha 1 (GFRα1) is required in adult mHb neurons for synaptic stability and function. mHb neurons express some of the highest levels of GFRα1 in the mouse brain, and acute ablation of GFRα1 results in loss of septohabenular and habenulointerpeduncular glutamatergic synapses, with the remaining synapses displaying reduced numbers of presynaptic vesicles. Chemo- and optogenetic studies in mice lacking GFRα1 revealed impaired circuit connectivity, reduced AMPA receptor postsynaptic currents, and abnormally low rectification index (R.I.) of AMPARs, suggesting reduced Ca2+ permeability. Further biochemical and proximity ligation assay (PLA) studies defined the presence of GluA1/GluA2 (Ca2+ impermeable) as well as GluA1/GluA4 (Ca2+ permeable) AMPAR complexes in mHb neurons, as well as clear differences in the levels and association of AMPAR subunits with mHb neurons lacking GFRα1. Finally, acute loss of GFRα1 in adult mHb neurons reduced anxiety-like behavior and potentiated context-based fear responses, phenocopying the effects of lesions to septal projections to the mHb. These results uncover an unexpected function for GFRα1 in the maintenance and function of adult glutamatergic synapses and reveal a potential new mechanism for regulating synaptic plasticity in the septohabenulointerpeduncular pathway and attuning of anxiety and fear behaviors.

Feasibility Study of Experimental Protocol for the Time-Dependent Mechanical Response of Synthetic Tibia.

In this research, an experimental biomechanics construct was developed to reveal the mechanics of distal tibial fracture by submitting synthetic tibiae to cyclic loading, resulting in a combined stress state due to axial compression and bending loads. The synthetic tibia was fixed at the knee but allowed to rotate in the coronal and sagittal planes at the ankle. The first three loading regimes lasted for 4000 cycles/each, and the final until ultimate failure. After 12k±80 cycles, the observed failure patterns closely resembled distal tibial fractures. The collected data during cyclic loading were fitted into a phenomenological model to deduce the time-dependent response of the synthetic tibiae. Images were also collected and analyzed using digital image correlation to deduce the full-field state of strain. The latter revealed that longitudinal strain contours extended in the proximal-distal direction. The transverse strain contours exemplified a medial-to-lateral distribution, attributed to the combined contributions of the Poisson's effect and the flexural deformation from axial and bending components of the applied load, respectively. The experimental construct, full-field characterization, and data analysis approaches can be extended to elucidate the effect of different fixation devices on the overall mechanical behavior of the bone and validate computational models in future research.

An Effective Framework for Deep-Learning-Enhanced Quantitative Microwave Imaging and Its Potential for Medical Applications.

Microwave imaging is emerging as an alternative modality to conventional medical diagnostics technologies. However, its adoption is hindered by the intrinsic difficulties faced in the solution of the underlying inverse scattering problem, namely non-linearity and ill-posedness. In this paper, an innovative approach for a reliable and automated solution of the inverse scattering problem is presented, which combines a qualitative imaging technique and deep learning in a two-step framework. In the first step, the orthogonality sampling method is employed to process measurements of the scattered field into an image, which explicitly provides an estimate of the targets shapes and implicitly encodes information in their contrast values. In the second step, the images obtained in the previous step are fed into a neural network (U-Net), whose duty is retrieving the exact shape of the target and its contrast value. This task is cast as an image segmentation one, where each pixel is classified into a discrete set of permittivity values within a given range. The use of a reduced number of possible permittivities facilitates the training stage by limiting its scope. The approach was tested with synthetic data and validated with experimental data taken from the Fresnel database to allow a fair comparison with the literature. Finally, its potential for biomedical imaging is demonstrated with a numerical example related to microwave brain stroke diagnosis.

Symptoms of Anxiety in Mothers During the COVID-19 Lockdown: A Structural Equation Model Approach.

The COVID-19 global pandemic has forced millions of people to stay confined at home, increasing symptoms of anxiety and stress levels. Women who are also mothers, for their part, not only face the demands of motherhood but must combine working life with family life locked down in their homes. Main objective was to develop an explanatory model of the psychological consequences of COVID-19 and parental and perceived stress in mothers. A total of 261 mothers were evaluated coinciding with the lockdown imposed by the Spanish Government. The model displayed adequate indices and it was found that symptoms of anxiety in mothers increased the levels of perceived stress. The model allows to understand the close relationships between the psychological consequences of lockdown and stress in mothers. Understanding these relationships will help to prepare and direct psychological interventions in this population in the case of a possible new surge.

Cytoreductive Surgery With or Without HIPEC After Neoadjuvant Chemotherapy in Ovarian Cancer: A Phase 3 Clinical Trial.

BACKGROUND: Cytoreductive surgery (CRS) and administration of hyperthermic intraperitoneal chemotherapy (HIPEC) have shown their efficacy in multiple malignancies and also could offer a prognostic benefit for patients with advanced ovarian cancer. METHODS: A prospective, single-center, parallel-group, randomized phase 3 clinical trial analyzed patients with a diagnosis of carcinomatosis from ovarian cancer treated with neoadjuvant systemic chemotherapy (NACT). In this trial, 71 patients were randomized to receive CRS alone (36 patients) or CRS with HIPEC (35 patients) using cisplatin (75 mg/m2 for 60 min at 42 °C). The primary end point was disease-free survival (DFS). Overall survival (OS), morbidity, and quality of life (QoL) were the secondary end points. RESULTS: During a median follow-up period of 32 months, the median DFS was 12 months in the control group (CRS) and 18 months in the experimental group (CRS and HIPEC). The findings showed HIPEC to be an independent protective factor against the development of recurrence (hazard ratio [HR], 0.12, 95 % confidence interval [CI], 0.02-0.89; p = 0.038). The median OS was 45 months in the control group and 52 months in the experimental group. The respective morbidity rates for any grade (1 to 5) were respectively 58.3 % and 45.7 % (p > 0.05), with a mortality rates of 2.8 % and 2.9 % (p > 0.05). In the dimensions evaluated, CRS with or without HIPEC had no impact on QoL. CONCLUSIONS: For patients who had advanced ovarian cancer treated with NACT, CRS and HIPEC was associated with better DFS and OS, but without a difference in postoperative morbidity, mortality, or in the QoL evaluation.

COVID-19 in children: clinical and epidemiological spectrum in the community.

Most publications on pediatric COVID-19 in Spain were performed at the beginning of the pandemic when some diagnostic tools were not widely available. This study aims to show the real spectrum of the infection based on wide detection of cases due to symptoms and contact tracing. A descriptive and analytical observational study was performed including pediatric cases (0 to 14 years) from the region of Aragón between May 12 and October 31, 2020. Diagnostics was by PCR detection of viral RNA, rapid antigen detection test, or positive IgG serology. There were 5933 positive children included. Of them, 49.03% were women. The mean age was 7.53 ± 4.28 years. The source of infection could not be determined in 17.8% of cases. As for the rest, was determined to be within the family environment in 67.8%. The percentage of asymptomatic patients was 50.3%. Among symptomatic patients, fever (58.1%) and cough (46.7%) were the most frequent symptoms. Hospitalization was required in 0.52% of infected, intensive care unit admission was on 0.05%, and there was one death (0.02%). Children under the age of one presented some symptoms more frequently (71.6% vs 48.5%; OR 2.68; 95% CI 2.08 to 3.45; p < 0.001) and required more hospitalizations (3.9% vs 0.34%; OR 11.52; 95% CI 5.65 to 23.52; p < 0.001).Conclusion: In our environment, SARS-CoV-2 infection is like other mild respiratory viral infections in the population under the age of 15. The contagion occurs mainly in the family environment, the number of asymptomatic is high, being the symptoms mild and the complications very infrequent. What is Known: • Pediatric infection produced by SARS-CoV-2 has manifested as a mild disease in relation to adult age, although with higher affectation at the youngest ages. • Nearly all studies on epidemiology and clinical spectrum of the disease were conducted with patients diagnosed at the beginning of the pandemic. By then, diagnostic tools were only available in hospitals and in emergency units. What is New: • Once diagnostic means were available in primary care medicine and were used not only for the diagnosis of clinical symptoms of the patient, but for the tracing of case contacts, a much more precise approach to the epidemiology and clinical manifestations of the disease was allowed, as described in this study.

Efficacy of mindfulness-based interventions in cognitive function in the elderly people: a systematic review and meta-analysis.

OBJECTIVES: The main objective was to determine the efficacy of Mindfulness-Based Interventions in improving the cognitive function of older adults (healthy adults or adults with mild cognitive impairment). METHODS: A search was conducted in 4 databases. The effect sizes were extracted to perform a meta-analysis of the cognitive functions, as well as subgroup meta-analyses according to each domain: attention, memory and executive function. RESULTS: The meta-analysis of cognitive functions showed an average effect size of g = .07, 95% CI [-.013; .160], p = .09, with the following values for each domain: g = .02, 95% CI [-.167; .204] for attention; g = .06, 95% CI [-.148; .262] for memory; and g = .14, 95% CI [-.042; .329] for executive function. CONCLUSION: The MBI had a null global effect. The attention and memory results showed a null effect size and a small effect size was found for executive function. The methodological quality of the studies, however, was poor, so the results need to be interpreted with caution.

Acute renal disease in patients with ovarian peritoneal carcinomatosis treated with cytoreduction and HIPEC: the influence of surgery and the cytostatic agent used.

BACKGROUND: The main objective of this study was to evaluate the differences between cisplatin and paclitaxel in the development of postoperative renal toxicity, using as a reference the RIFLE (Risk, Injury, Insufficiency, Loss, and End-stage renal function) and AKIN (Acute Kidney Injury Network) criteria in patients with primary or recurrent ovarian cancer with peritoneal dissemination treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: One hundred fifty-two patients who were treated between December 2007 and June 2017 were analyzed. RESULTS: Patients who received previous platinum-based chemotherapy had higher baseline creatinine levels than those who had not (p = 0.05). A total of 11 (7.2%) and 4 (2.6%) patients developed an acute renal dysfunction (ARD) during the postoperative period of cytoreduction and HIPEC according to the RIFLE and AKI criteria respectively. RIFLE detects a higher rate of ARD due to different parameters such as GFR (7.2% versus 2.6%, p = 0.016). Performing ostomy (p = 0.007; OR: 39.320; 95% CI = 2.74-56.13) and using of cisplatin during HIPEC treatment (p = 0.017; OR = 13.619; 95% IC = 1.600-25.95) were factors independently related to a higher rate of ARD. CONCLUSION: ARD has a multifactorial origin. Cisplatin was associated with the development of a higher rate of ARD than paclitaxel. Diagnosis of ARD did not correlate with worse survival figures.

Olfactory and taste disorders in healthcare workers with COVID-19 infection.

PURPOSE: Severe acute respiratory syndrome caused by COVID-19 has spread globally for the last few months. Healthcare workers (HCW) are overexposed and infection rates are higher than in the rest of the population. Strict clinical assessment is paramount to detect suspicious cases. In this context, olfactory or taste dysfunction (OTD) appears as an early and frequent symptom. Evaluating its presence in early stages plays an important role nowadays. METHODS: We performed a descriptive observational single-center study among 256 HCW at Hospital Universitario de Fuenlabrada affected by COVID-19 and confirmed using RT-PCR. A telephonic interview was performed, after obtaining oral informed consent. RESULTS: OTD was present in up to 70% of the cases as an early symptom, including mild-to-severe cases. The extent of these sensory deficits lasted an average of 11 days. In 26% of the patients, these sensory alterations persisted for over a month. CONCLUSION: OTD is reported as an early symptom among HCW with SARS-CoV-2 infection. Its strong association with test positivity is useful in the management of the infection and should be enough to indicate preventive isolation. We consider that OTD needs to be included in clinical screening questionnaires in HCW.

Gaps in beliefs and practice in dyslipidaemia management in Japan, Germany, Colombia and the Philippines: insights from a web-based physician survey.

BACKGROUND: Implementing evidence-based management of dyslipidaemia is a challenge worldwide. OBJECTIVES: To understand physician beliefs and behaviour and identify uncertainties in dyslipidaemia management across four world regions. METHODS: Web-based survey of 1758 physicians in Japan, Germany, Colombia and the Philippines who were selected randomly from existing databases. Key inclusion criteria were 1) for cardiologists and diabetes/endocrinology specialists: ≥50 dyslipidaemia patients examined in the last month; 2) for specialists in neurology/neurosurgery/stroke medicine: ≥50 dyslipidaemia patients and ≥ 20 patients with a history of ischaemic stroke examined in the last month; and 3) for specialists in nephrology and general medicine: based at centres with ≥20 beds and ≥ 50 dyslipidaemia patients examined in the last month. The self-report survey covered dyslipidaemia management, target low-density lipoprotein cholesterol (LDL-C) levels in different patient groups, and statin safety. All physicians gave voluntary consent and all data were anonymised. Analysis was solely descriptive. RESULTS: The survey highlighted key areas of uncertainty in dyslipidaemia management in the four countries. These related to LDL-C targets in different patient groups, the safety of low LDL-C levels, the safety of statins, especially for effects on cognitive, renal and hepatic function and for haemorrhagic stroke risk, and lipid management strategies in patients with chronic kidney disease, including those with concomitant hypertriglyceridaemia. CONCLUSIONS: This survey of physicians in Japan, Germany, Colombia and the Philippines has identified key gaps in knowledge about dyslipidaemia management. These relate to the safety of low LDL-C levels, the safety of statins, and lipid management of chronic kidney disease. The findings from this survey highlight the need for further education to improve the implementation of guideline recommendations for dyslipidaemia management.

Periodontal Disease, Inflammatory Cytokines, and PGE2 in Pregnant Patients at Risk of Preterm Delivery: A Pilot Study.

Periodontal disease is an infection that, in pregnant women, can act as a risk factor for preterm delivery by increasing local and systemic inflammatory responses. Objective. To analyze the presence of periodontal disease, proinflammatory cytokines, and prostaglandin E 2 (PGE2) in pregnant patients at high risk for preterm delivery. Materials and Methods. Pilot study for a case-control study. We included 46 pregnant patients (23 patients at risk of preterm delivery as cases and 23 patients without risk of preterm delivery as controls). We excluded patients who received periodontal treatment, antibiotics, or antimicrobials over the last 3 months as well as those with infections or diseases such as diabetes or hypercholesterolemia. The patients underwent a periodontal assessment, and their levels of cytokines (interleukin- [IL-] 2, IL-6, IL-10, and tumor necrosis factor- [TNF-] α) and prostaglandin E2 (PGE2) were quantified. Results. Patients with periodontal disease showed higher levels of cytokines (IL-2, IL-6, IL-10, and TNF-α) and PGE 2 . Patients at high risk for preterm birth showed higher IL levels compared with patients at low risk for preterm delivery. PGE 2 increased with the severity of periodontal disease. PGE 2 was higher in patients at low risk for preterm delivery, although this difference was not significant. Conclusion. Periodontal disease can increase the systemic inflammatory response as well as the levels of PGE 2 and inflammatory cytokines in pregnant patients.

Genetic analysis of porcine circovirus type 2 from pigs affected with PMWS in Chile reveals intergenotypic recombination.

BACKGROUND: Porcine circovirus type 2 (PCV2) is a very small, non-enveloped and icosahedral virus, with circular single stranded DNA genome. This virus is the most ubiquitous and persistent pathogen currently affecting the swine industry worldwide. PCV2 has been implicated as the major causative agent of postweaning multisystemic wasting syndrome (PMWS), a disease which is characterized by severe immunosuppressive effects in the porcine host. Worldwide PCV2 isolates have been classified into four different genotypes, PCV2a, PCV2b, PCV2c and PCVd. The goal of this work was to conduct the first phylogenetic analysis of PCV2 in Chile. METHODS: PCV2 partial ORF2 sequences (462 nt) obtained from 29 clinical cases of PMWS in 22 Chilean intensive swine farms, covering over the 90% of the local pork-production, were analyzed. RESULTS: 14% and 52% of sequences belonged to the genotypes PCV2a and PCV2b, respectively. Surprisingly, 34% of sequences were PCV2a/PCV2d recombinant viruses. CONCLUSIONS: Our findings suggested that a novel cluster of Chilean sequences emerged resulting from intergenotypic recombination between PCV2a and PCV2d.

Failed Minimally Invasive Staged Treatment of a Giant Symptomatic Aortic Perigraft Hygroma after Open Aortic Repair.

BACKGROUND: Perigraft hygromas or seromas are an unusual finding and/or complication after open aortic repair. METHODS AND RESULTS: We present a case of an 82-year-old man with a previous urgent aortic bifurcated graft for abdominal aortic aneurysm rupture. He received several treatments due to abdominal compartment syndrome, requiring a Bogota Bag and colostomy derivation. He was finally discharged home and lost on follow-up. Eight years after this procedure, he presented to the urgency department with an abdominal mass and pain. Urgent computed tomography (CT) scan revealed a giant bilobed aortic sac, corresponding with a huge hygroma. A 3-stage minimally invasive procedure was scheduled due to hostile abdomen. Six months after successful treatment, patient came with fever and abdominal pain. He was diagnosed with graft infection and aortoenteric fistula and was treated with explantation and silver in situ repair. CONCLUSIONS: Aortic hygroma or seromas after open repair should be treated by open means whenever possible. Endovascular techniques could be a valid option in selected patients; however, further evidence is needed.

[Screening for malnutrition among hospitalized patients in a Colombian University Hospital]. / Frecuencia de riesgo de desnutrición según la Escala de Tamizado para Desnutrición (MST) en un servicio de Medicina Interna.

BACKGROUND: On admission, 30 to 50% of hospitalized patients have some degree of malnutrition, which is associated with longer length of stay, higher rates of complications, mortality and greater costs. AIM: To determine the frequency of screening for risk of malnutrition in medical records and assess the usefulness of the Malnutrition Screening Tool (MST). MATERIAL AND METHODS: In a cross-sectional study, we searched for malnutrition screening in medical records, and we applied the MST tool to hospitalized patients at the Internal Medicine Wards of San Ignacio University Hospital. RESULTS: Of 295 patients included, none had been screened for malnutrition since hospital admission. Sixty one percent were at nutritional risk, with a higher prevalence among patients with HIV (85.7%), cancer (77.5%) and pneumonia. A positive MST result was associated with a 3.2 days increase in length of hospital stay (p = 0.024). CONCLUSIONS: The prevalence of malnutrition risk in hospitalized patients is high, but its screening is inadequate and it is underdiagnosed. The MST tool is simple, fast, low-cost, and has a good diagnostic performance.

Isolation of lactic acid bacteria from swine milk and characterization of potential probiotic strains with antagonistic effects against swine-associated gastrointestinal pathogens.

Probiotics are usually isolated from the gastrointestinal tract of humans and animals. The search of probiotics in human milk is a recent field of research, as the existence of the human milk microbiome was discovered only about a decade ago. To our knowledge, no reports regarding the potential probiotic effect of bacteria from swine milk have been published. In this work, we isolated several lactic acid bacteria from swine milk and evaluated them for them potential as probiotics. Among the isolated strains, Lactobacillus curvatus TUCO-5E showed antagonistic effects against swine-associated gastrointestinal pathogens. TUCO-5E was able to reduce the growth of enterotoxigenic and enterohemorrhagic Escherichia coli strains as well as pathogenic salmonella. In vitro exclusion and displacement assays in intestinal epithelial cells showed a remarkable antagonistic effect for L. curvatus TUCO-5E against Salmonella sp. strain TUCO-I7 and Salmonella enterica ATCC 13096. Moreover, by using a mouse model of Salmonella infection, we were able to demonstrate that preventative administration of L. curvatus TUCO-5E for 5 consecutive days was capable of decreasing the number of Salmonella enterica serovar Typhimurium in the liver and spleen of treated mice, compared with the controls, and prevented dissemination of the pathogen to the blood stream. Therefore, we have demonstrated here that swine milk is an interesting source of beneficial bacteria. In addition, the results of this work suggest that L. curvatus TUCO-5E is a good candidate to study in vivo the protective effect of probiotics against intestinal infection and damage induced by Salmonella infection in the porcine host.

Evidence of involvement of the mannose receptor in the internalization of Streptococcus pneumoniae by Schwann cells.

BACKGROUND: The ability of S. pneumoniae to generate infections depends on the restrictions imposed by the host's immunity, in order to prevent the bacterium from spreading from the nasopharynx to other tissues, such as the brain. Some authors claim that strains of S. pneumoniae, which fail to survive in the bloodstream, can enter the brain directly from the nasal cavity by axonal transport through the olfactory and/or trigeminal nerves. However, from the immunological point of view, glial cells are far more responsive to bacterial infections than are neurons. This hypothesis is consistent with several recent reports showing that bacteria can infect glial cells from the olfactory bulb and trigeminal ganglia. Since our group previously demonstrated that Schwann cells (SCs) express a functional and appropriately regulated mannose receptor (MR), we decided to test whether SCs are involved in the internalization of S. pneumoniae via MR. RESULTS: Immediately after the interaction step, as well as 3 h later, the percentage of association was approximately 56.5%, decreasing to 47.2% and 40.8% after 12 and 24 h, respectively. Competition assays by adding a 100-fold excess of mannan prior to the S. pneumoniae infection reduced the number of infected cells at 3 and 24 h. A cytochemistry assay with Man/BSA-FITC binding was performed in order to verify a possible overlap between mannosylated ligands and internalized bacteria. Incubation of the SCs with Man/BSA-FITC resulted in a large number of intracellular S. pneumoniae, with nearly complete loss of the capsule. Moreover, the anti-pneumococcal antiserum staining colocalized with the internalized man/BSA-FITC, suggesting that both markers are present within the same endocytic compartment of the SC. CONCLUSIONS: Our data offer novel evidence that SCs could be essential for pneumococcal cells to escape phagocytosis and killing by innate immune cells. On the other hand, the results also support the idea that SCs are immunocompetent cells of the PNS that can mediate an efficient immune response against pathogens via MR.

Quality of Life and Clinical Impairment in Spanish Adolescent Anorexia Nervosa Patients.

Eating disorders have serious physical, mental and social consequences that can affect the quality of life of the sufferer. This study aimed to evaluate the relationship between the severity of ED-related psychopathology and clinical impairment in adolescents with anorexia nervosa (AN) as well as their perception of health-related quality of life. Eighty-six Spanish young women with AN completed a set of questionnaires assessing eating disorder pathology, clinical impairment, and quality of life. The set included the following instruments: the Eating Disorder Examination Questionnaire, Clinical Impairment Assessment, Short Form-12 Item Health Survey, and the Eating Disorder-Specific Heath-Related Quality of Life instrument. Descriptive and regression analyses were applied to identify associations between variables. Higher scores on clinical impairment domains were associated with greater impairment of mental and physical health. Moreover, clinical impairment domains and concerns due to ED were related to a lower quality of life. In conclusion, adolescents with AN have a poor quality of life. Moreover, the findings suggest that the clinical features of impairment may serve as severity indicators of quality of life.