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Introduction: Prefrontal serotonin plays a role in the expression of flexible behavior during reversal learning tasks as its depletion delays reversal learning. However, the mechanisms by which serotonin modulates the prefrontal cortex functions during reversal learning remain unclear. Nevertheless, serotonin has been shown to modulate theta activity during spatial learning and memory., Methods: We evaluated the effects of prefrontal serotonin depletion on theta activity in the prefrontal infralimbic, prelimbic, and orbitofrontal (IL, PL, and OFC) subregions of male rats during a spatial reversal learning task in an aquatic T-maze., Results: Prefrontal serotonin depletion delayed spatial reversal learning and increased theta activity power in the PL and OFC. Furthermore, animals with serotonin depletion had increased functional coupling between the OFC and the IL and PL cortices compared with the control group., Discussion: These results indicate that serotonin regulates reversal learning through modulation of prefrontal theta activity by tuning both the power and functional synchronization of the prefrontal subregions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Estrada-Reyes, Cervantes-Alfaro, López-Vázquez and Olvera-Cortés.)

Incidental visuospatial learning acquired under incidental conditions is more vulnerable to aging than in the intentional case. The theta and gamma correlates of the coding and retrieval of episodic memory change during aging. Based on the vulnerability of incidental coding to aging, different theta and gamma correlates could occur under the incidental versus intentional coding and retrieval of visuospatial information. Theta and gamma EEG was recorded from the frontotemporal regions, and incidental/intentional visuospatial learning was evaluated in young (25-60 years old) and elderly (60-85 years old) participants. The EEG recorded during encoding and retrieval was compared between incidental low-demand, incidental high-demand, and intentional conditions through an ANCOVA considering the patient's gender, IQ, and years of schooling as covariates. Older adults exhibited worse performances, especially in place-object associations. After the intentional study, older participants showed a further increase in false-positive errors. Higher power at the theta and gamma bands was observed for frontotemporal derivations in older participants for both encoding and retrieval. Under retrieval, only young participants had lower power in terms of errors compared with correct responses. In conclusion, the different patterns of power and coherence support incidental and intentional visuospatial encoding and retrieval in young and elderly individuals. The correlates of power with behavior are sensitive to age and performance.

Background: Health care systems are increasingly screening for unmet social needs. The association between patient-reported social needs and health care utilization is not well understood., Objective: To investigate the association between patient-reported social needs, measured by the Protocol for Responding to and Assessing Patients' Assets, Risks, and Experiences (PRAPARE), and inpatient and emergency department (ED) utilization., Design: This cohort study analyzed merged 2017-2019 electronic health record (EHR) data across multiple health systems., Participants: Adult patients from a federally qualified health center (FQHC) in central North Carolina who completed PRAPARE as part of a primary care visit with behavioral health services., Main Measures: The count of up to 12 unmet social needs, aggregated as 0, 1, 2, or 3 + . Outcomes include the probability of an ED visit and hospitalization 12 months after PRAPARE assessment, modeled by logistic regressions controlling for age, sex, race, ethnicity, comorbidity burden, being uninsured, and prior utilization in the past 12 months., Key Results: The study population consisted of 1924 adults (38.7% male, 50.1% Black, 36.3% Hispanic, 55.9% unemployed, 68.2% of patients reported 1 + needs). Those with more needs were younger, more likely to be unemployed, and experienced greater comorbidity burden. 35.3% of patients had ED visit(s) and 36.3% had hospitalization(s) 1 year after PRAPARE assessment. In adjusted analysis, having 3 + needs was associated with a percentage point increase in the predicted probability of hospitalization (average marginal effect 0.06, SE 0.03, p < 0.05) compared with having 0 needs. Similarly, having 2 needs (0.07, SE 0.03, p < 0.05) or 3 + needs (0.06, SE 0.03, p < 0.05) was associated with increased probability of ED visits compared to 0 needs., Conclusions: Patient-reported social needs were common and associated with health care utilization patterns. Future research should identify interventions to address unmet social needs to improve health and avoid potentially preventable escalating medical intervention., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: To establish the influence of overweight/obesity, medicated hypothyroidism, and medicated non-syndromic hypogrowth on maxillary and mandibular growth., Materials and Methods: The relation between 10 craniofacial anthropometric measurements and hypothyroidism (n = 216), overweight/obesity (n = 108), and non-syndromic hypogrowth (n = 250) were evaluated in patients aged 1-19 years and a control group of healthy patients (n = 587). A subgroup analysis was performed at the peak growth in all groups., Results: Patients with overweight/obesity and hypothyroidism showed increased craniofacial growth, while hypogrowth patients showed differences in zygomatic width and nasal base growth. Females with hypothyroidism and non-syndromic hypogrowth showed decreased head circumference at peak growth. Several anthropometric measurements were increased in patients with overweight/obesity, including head circumference. When all age groups were analyzed, overweight/obese and hypothyroidism patients showed increased zygomatic width while decreased hypogrowth. Overall, most craniofacial anthropometric measurements in overweight/obese patients were increased. Finally, the peak growth in males with hypothyroidism and subjects with non-syndromic hypogrowth was delayed compared to the control group (p < 0.05)., Conclusions: Children and adolescents with overweight/obesity and endocrine disorders showed alterations in craniofacial growth. Clinicians must be aware that the growth peak in these patients may be delayed when planning maxillary and mandibular orthopedic treatment., (© 2023. The Author(s).)

Objective: To evaluate the relationship between social needs and metformin use among adults with type 2 diabetes (T2D)., Research Design and Methods: In a prospective cohort study of adults with T2D (n = 722), we linked electronic health record (EHR) and Surescripts (Surescripts, LLC) prescription network data to abstract data on patient-reported social needs and to calculate metformin adherence based on expected refill frequency using a proportion of days covered methodology., Results: After adjusting for demographics and clinical complexity, two or more social needs (-0.046; 95% CI -0.089, 0.003), being uninsured (-0.052; 95% CI -0.095, -0.009) and while adjusting for other needs, being without housing (-0.069; 95% CI -0.121, -0.018) and lack of access to medicine/health care (-0.058; 95% CI -0.115, -0.000) were associated with lower use., Conclusions: We found that overall social need burden and specific needs, particularly housing and health care access, were associated with clinically significant reductions in metformin adherence among patients with T2D., (© 2023 by the American Diabetes Association.)

Objective: Identify the prevalence of food insecurity (FI) and compare sociodemographic, mental, physical, behavioral, and environmental risk factors for FI among students at a private university, community college, and historically black college or university (HBCU)., Participants: Adult students attending a private university, community college, or HBCU ( n  = 4,140) located within the southeastern United States., Methods: Using an online survey (2017-2019), FI, sociodemographic, mental, physical, behavioral, and environmental data were collected to understand their association with FI., Results: Up to 37.1% of students experienced FI. Identifying as black, other/multi-racial, having poor sleep, federal loans, depressive symptoms, high stress, social isolation, or a chronic condition were associated with FI. These associations varied by institution., Conclusions: FI is prevalent within diverse post-secondary institutions that serve traditional and nontraditional students with risk factors varying between institutions. The prevalence of FI and risk factors can inform institutional policy responses to ameliorate the effects of FI.

Increases in power and frequency of hippocampal theta activity have been related to efficient place learning and memory acquisition in hippocampal-dependent tests. The complex medial septum-diagonal band of Broca (MS/DBB) is the pacemaker of hippocampal theta activity, influenced by the ascending synchronizing system, and modulated by serotonergic raphe medial afferents, acting on cholinergic and GABAergic septal neurons. The suppression of hippocampal theta expression and the modulation of hippocampal learning and memory are attributed to serotonin. To simultaneously test these hypotheses, a daily local serotonin increase was induced by citalopram (CIT) infusion (100 µM, 0.88 µl, 0.2 µl/m) 15 min before training in the Morris water maze. The theta activity was recorded in the MS/DBB, dentate gyrus (DG) and CA1 of one group infused with artificial cerebrospinal liquid (ACL) and the other with CIT on Days 1-6 of training. After a probe trial (Day 7) and one resting day, the treatments were reversed (Days 8-11). The CIT MS/DBB infusion in the first 6 training days reduced the efficiency of spatial learning in association with reduced power in the DG, reduced MS/DBB-DG coherence, increased DG-CA1 coherence, and a lack of a negative correlation between MS/DBB power and swam distances. No effect of the CIT occurred once the information was acquired under ACL training. These results support a role of serotonin, in acting on the MS/DBB in the fine tuning of hippocampal learning and memory efficiency through the modulation of learning-related theta activity power and septohipocampal synchronization., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Objectives: The aim of this study was to analyze indirect costs of vaginal and laparoscopic routes for hysterectomy to determine whether this makes a difference in total costs when considering route for surgery., Methods: A five-year observational retrospective cohort study was conducted in an academic tertiary care center. A total of 517 patients scheduled for total laparoscopic hysterectomy (n = 137) and vaginal hysterectomy (n = 380) for benign conditions between January 1, 2008 and December 31, 2012 meeting inclusion criteria were reviewed., Results: Indirect costs were higher in the vaginal hysterectomy group compared to the laparoscopic hysterectomy group (mean cost €3,239.86 vs. €1,371.58; cost increase of €1,868.28; p < .001). Indirect costs due to lost-work-productivity were the most important, represented by 97.7% in the vaginal group and 93.6% in the laparoscopic group., Conclusion: Among women undergoing hysterectomy for benign disease, laparoscopic hysterectomy appears to be superior to vaginal hysterectomy when indirect costs are analyzed in a five-year temporal horizon. Laparoscopic hysterectomy is a good alternative to vaginal hysterectomy when technically feasible as both present comparable advantages. The surgical approach to hysterectomy should be decided in light of the relative benefits and hazards, which will depend on clinical circumstances and surgical expertise., (© 2022 by SLS, Society of Laparoscopic & Robotic Surgeons.)

Objectives: RNASEH1 gene has recently been associated with type 1 diabetes (T1D) in Colombia. The purpose of this study was to fine mapping the putative functional variant in RNASEH1 and testing its interaction with HLA tagSNPs., Methods: Two-hundred nuclear families with T1D were included in this study. Probands were tested for GAD65 and IA-2 autoantibodies. Genotyping was performed using 20 coding tagSNPs uncovered through Sanger sequencing (N = 96), in addition to 23 tagSNPs chosen from 1000genomes to cover the extent of the gene region. Also, 45 tagSNPs for classic HLA alleles associated with T1D were also genotyped. The transmission disequilibrium test (TDT) was used to test for association and a multiple testing correction was made using permutation. Interaction between RNASEH1 variants and HLA was evaluated by means of the M-TDT test., Results: We identified 20 variants (15 were novel) in the 96 patients sequenced. None of these variants were in linkage disequilibrium. In total, 43 RNASEH1 variants were genotyped in the 200 families. Association between T1D and rs7607888 was identified (P = .002). Haplotype analysis involving rs7607888 variant revealed even stronger association with T1D (most significative P = .0003). HLA tagSNPs displayed stronger associations (OR = 6.39, 95% CI = 4.33-9.44, P-value = 9.74E-28). Finally, we found several statistically significant interactions of HLA variants with rs7607888 (P-value ranged from 8.77E-04 to 5.33E-12)., Conclusion: Our results verify the association of rs7607888 in RNASEH1 gene with T1D. It is also shown in the interaction between RNASEH1 and HLA for conveying risk to T1D in Northwest Colombia. Work is underway aiming to identify the actual classic HLA alleles associated with the tagSNPs tested here., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Type 1 diabetes (T1D) is a complex disease with a higher incidence in Europeans than other populations. The Colombians Living in Medellin (CLM) is admixed with ancestry contributions from Europeans, Native Americans (NAT) and Africans (AFR)., Aim: Our aim was to analyze the genetic admixture component at candidate T1D loci in Colombian individuals with the disease., Methods: Seventy-four ancestry informative markers (AIMs), which tagged 41 T1D candidate loci/genes, were tested by studying a cohort of 200 Northwest Colombia diseased individuals. T1D status was classified by testing for glutamic acid decarboxylase (GAD-65 kDa) and protein tyrosine-like antigen-2 auto-antibodies in serum samples. Candidate loci/genes included HLA , INS , PTPN22 , CTLA4 , IL2RA , SUMO4 , CLEC16A , IFIH1 , EFR3B , IL7R , NRP1 and RNASEH1 , amongst others. The 1,000 genome database was used to analyze data from 94 individuals corresponding to the reference CLM. As the data did not comply with a normal distribution, medians were compared between groups using the Mann-Whitney U -test., Results: Both T1D patients and individuals from CLM displayed mainly European ancestry (61.58 vs 62.06) followed by Native American (27.34 vs 27.46) and to a lesser extent the AFR ancestry (10.28 vs 10.65) components. However, compared to CLM, ancestry of T1D patients displayed a decrease of NAT ancestry at gene EFR3B (24.30 vs 37.10) and an increase at genes IFIH1 (32.07 vs 14.99) and IL7R (52.18 vs 39.18). Also, for gene NRP1 (36.67 vs 0.003), we observed a non-AFR contribution (attributed to NAT). Autoimmune patients (positive for any of two auto-antibodies) displayed lower NAT ancestry than idiopathic patients at the MHC region (20.36 vs 31.88). Also, late onset patients presented with greater AFR ancestry than early onset patients at gene IL7R (19.96 vs 6.17). An association analysis showed that, even after adjusting for admixture, an association exists for at least seven such AIMs, with the strongest findings on chromosomes 5 and 10 (gene IL7R , P = 5.56 × 10 -6 and gene NRP1 , P = 8.70 × 10 -19 , respectively)., Conclusion: Although Colombian T1D patients have globally presented with higher European admixture, specific T1D loci have displayed varying levels of Native American and AFR ancestries in diseased individuals., Competing Interests: Conflict-of-interest statement: None to declare., (©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.)

Clinical Decision Support System (CDSS) has been implemented to support physicians about the medical prescription of genetic testing. CDSS is based on open source software. A CDSS for prescribing these genetic tests in BRCA1 and BRCA2 and preventing gynecological cancer risks has been designed and performed in the 'Virgen del Rocío' University Hospital. Clinical evidence demonstrates that BRCA1 and BRCA2 mutations can develop gynecological cancer, but genetic testing has a high cost to the healthcare system. The developed technological architecture integrates open source tools like Mirth Connect and OpenClinica. The system allows general practitioners and gynecologists to classify patients as low risk (they do not require a specific treatment) or high risk (they should be attended by the Genetic Council), According to their genetic risk, recommending the prescription of genetic tests. The aim main of this paper is the evaluation of the developed CDSS, getting positive outcomes.

Introduction: The HLA region strongly associates with autoimmune diseases, such as type 1 diabetes. An alternative way to test classical HLA alleles is by using tag SNP. A set of tag SNP for several classical HLA alleles has been reported as associated with susceptibility or resistance to this disease in Europeans. Objective: We aimed at validating the methodology based on tag SNP focused on the inference of classical HLA alleles, and at evaluating their association with type 1 diabetes mellitus in a sample of 200 families from Antioquia. Materials and methods: We studied a sample of 200 families from Antioquia. Each family had one or two children with T1D. We genotyped 13 SNPs using tetra-primer ARMS-PCR or PCRRFLP. In addition, we tested the validity of the tag SNP reported for Europeans in 60 individuals from a population of Colombians living in Medellín (CLM) from the 1000 Genomes Project database. Statistical analyses included the Hardy-Weinberg equilibrium, the transmission disequilibrium and the linkage disequilibrium tests. Results: The linkage disequilibrium was low in reported tag SNP and classical HLA alleles in this CLM population. Association analyses revealed both risk and protection factors to develop type 1 diabetes mellitus. Appropriate tag SNPs for the CLM population were determined by using the genotype information available in the 1000 Genome Project database. Conclusions: Although linkage disequilibrium patterns in this CLM population were different from those reported in Europeans, we did find strong evidence of the role of HLA in the development of type 1 diabetes mellitus in the study population.

Background: In a previous work, we found linkage and association of type 1 diabetes (T1D) to a 12 known gene region at chromosome 2p25 in Colombian families. Here, we present further work on this candidate region., Materials and Methods: Seventeen SNPs located on the 12 candidate genes, in 100 familial trios set, were tested by ARMS-tetraprimer-PCR or PCR-RFLP. Five extra SNPs in the vicinity of rs10186193 were typed. A replica phase included 97 novel familial trios, in whom diabetes-related auto-antibodies (AABs) were tested in sera of the patients. In addition to transmission disequilibrium tests, haplotype analyses were carried out using the unphased software., Results: SNP rs10186193 (at RNASEH1 gene) showed association with T1D (P = 0.005). The additional five SNPs revealed that rs7607888 (P = 2.03 × 10 -7 ), rs55981318 (P = 0.018), and rs1136545 (P = 1.93 × 10 -9 ) were also associated with T1D. Haplotype analysis showed association for rs55981318-rs10186193 (P = 0.0005), rs7563960-rs7607888 (P = 0.0007), rs7607888-rs1136545 (P = 9.21 × 10 -10 ), and rs1136545-rs11538545 (P = 6.67 × 10 -8 ). In contrast, the new set of 97 familial trios tested for SNPs rs55981318, rs10186193, and rs7607888 did not support the previous finding; however, by combining the sample (197 trios), evidence of association of T1D with rs55981318 and rs7607888 was conclusive. In addition, a two-loci haplotype analysis of the combined sample showed significant association of RNASEH1 with T1D (P = 3.1 × 10 -5 )., Conclusion: In conclusion, our analyses suggest that RNASEH1 gene variants associate with susceptibility/protection to T1D in Colombia.

Background: Benchmark data from the Trauma Quality Improvement Program (TQIP) identified an opportunity for improvement in our trauma programme. Our unexpected return to the intensive care unit (ICU) was found to be higher than the national averages and we also noticed that our readmission rate had increased. We chose to address these complications as continuous quality improvement projects. It was hypothesized that restructuring the workflow of the trauma advanced practice providers (APPs) to focus on the delivery of comprehensive clinical care would decrease return to ICU and readmission rates of trauma patients., Methods: The development of the APP programme occurred from 2012 to 2014. First, APP daily shifts were extended to mirror the resident physicians' coverage. Second, the APPs' original job description was expanded from 'task-oriented' workflow to providing comprehensive clinical care. Third, the APPs were involved in the evaluation and decision-making process for transferring trauma patients from the ICU. Finally, the APPs implemented a new discharge process that included all information in a standardized format and a follow-up phone call 24-48 hours after discharge. The trauma registry at our verified, academic level I trauma center was use to assess our ICU and hospital readmission rates during the time we instituted the new APP workflow programme., Results: In 2012, our ICU readmission rate was 5.7% (TQIP=1.9%) but then decreased to 4.4% in 2013 (TQIP=2.5%) and 2.1% in 2014 (TQIP=2.8%). Our hospital readmission rate was 2.0% in 2012 but then decreased to 1.38% and 0.96% over the next 2 years., Conclusions: After extending the APP service coverage, implementing a comprehensive clinical care model and standardizing the discharge process, our unplanned return to ICU rates have decreased to below the TQIP national average and hospital readmission rates have also decreased by half., Level of Evidence: III., Competing Interests: Competing interests: None declared.

Clinical evidence demonstrates that BRCA 1 and BRCA2 mutations can develop a gynecological cancer but genetic testing has a high cost to the healthcare system. Besides, several studies in the literature indicate that performing these genetic tests to the population is not cost-efficient. Currently, our physicians do not have a system to provide them the support for prescribing genetic tests. A Decision Support System for prescribing these genetic tests in BRCA1 and BRCA2 and preventing gynecological cancer risks has been designed, developed and deployed in the Virgen del Rocío University Hospital (VRUH). The technological architecture integrates a set of open source tools like Mirth Connect, OpenClinica, OpenCDS, and tranSMART in addition to several interoperability standards. The system allows general practitioners and gynecologists to classify patients as low risk (they do not require a specific treatment) or high risk (they should be attended by the Genetic Council). On the other hand, by means of this system we are also able to standardize criteria among professionals to prescribe these genetic tests. Finally, this system will also contribute to improve the assistance for this kind of patients.

Becker's nevus syndrome is part of the epidermal nevus syndromes and has been described with a phenotype that includes Becker's nevus, ipsilateral breast hypoplasia, and variable skeletal malformations. It is more frequent in males than in females (5 : 1) but is more relevant in females. The diagnosis is clinically based and the skin lesion must be present and no other numbered criteria have been established, but with more criteria being present the possibility of the diagnosis is higher. Regarding the treatment of breast hypoplasia, the use of antiandrogen medication has demonstrated adequate clinical response in a dose of 50 mg/day of spironolactone., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper.

Background: Protein tyrosine phosphatase, non-receptor type 22 (lymphoid) (PTPN22), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and interferon induced with helicase C domain 1 (IFIH1) are among the confirmed type 1 diabetes (T1D) susceptibility genes in several populations. The aim of this study was to evaluate the role of PTPN22, CTLA4, and IFIH1 gene variants in the development of T1D in a Colombian population., Methods: Associations of PTPN22, CTLA4, and IFIH1 variants with T1D were investigated in a sample of 197 nuclear families, including 205 affected children, in the Colombian population. Three to four single nucleotide polymorphisms (SNPs) were analyzed per gene: rs2476600, rs2476601, rs1217418, and rs2488457 for PTPN22; rs1990760, rs3747517, and rs10930046 for IFIH1; and rs231775, rs3087243, and rs231779 for CTLA4. A transmission disequilibrium test was performed for the global sample, in addition to stratified analysis considering autoimmunity, age at onset, and parent of origin. Haplotypes per gene were also analyzed., Results: There was no significant transmission distortion for CTLA4. Conversely, SNPs rs10930046 (IFIH1) and rs2476601 (PTPN222) exhibited significant transmission distortion of the C and T alleles, respectively, from parents to affected children (odds ratio [OR] 0.57 and 1.83, respectively). In addition, decreased transmission of the C allele for rs10930046 occurred preferentially from mothers. Stratification analysis revealed that this association was maintained in individuals who were positive for autoantibodies and in those with an age of diagnosis <5 years., Conclusion: The results show that IFIH1 and PTPN22 are associated with T1D in Colombian families., (© 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.)

Docosahexaeonic acid (DHA) is the final compound in the omega-3 polyunsaturated fatty acids (PUFA) synthetic pathway and the most abundant PUFA found in the brain. DHA plays an essential role in the development of the brain, and the intakes in pregnancy and early life affect growth and cognitive performance later in childhood. Recently, it has been proposed that dietary intake of DHA could be a non-pharmacological interventional strategy for the treatment of seizures in humans. However, to date, the experimental approaches to study the antiepileptic effect of DHA have been exclusively restricted to rodent models during short-to-medium periods of treatment. The purpose of the present study was to test the chronic anticonvulsivant effects of DHA supplementation in zebrafish from the pre-spawning stage to aging, taking advantage of our recently described kainate-induced seizure model using this animal. To that end, two groups of adult female zebrafish were fed with standard or 200mg/kg DHA-enriched diets during 1 month previous to the spawning, and offspring subdivided in two categories, and subsequently fed with standard or DHA diets, generating 4 groups of animals that were aged until 20 months. Afterward, KA was intraperitoneally administered and epileptic score determined. All the DHA-enriched groups presented antiepileptic effects compared to the control group, showing that DHA presents an anticonvulsant potential. Among the studied groups, zebrafish fed with DHA from the pre-spawning stage to aging presented the best antiepileptic profile. These results show a neuroprotective benefit in zebrafish fed with DHA-enriched diet before birth and during the whole life., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Glutamate is the major excitatory neurotransmitter of the central nervous system in vertebrates. Excitotoxicity, caused by over-stimulation of the glutamate receptors, is a major cause of neuron death in several brain diseases, including epilepsy. We describe here how behavioural seizures can be triggered in adult zebrafish by the administration of kainate and are very similar to those observed in rodent models. Kainate induced a dose-dependent sequence of behavioural changes culminating in clonus-like convulsions. Behavioural seizures were suppressed by DNQX (6,7-dinitroquinoxaline-2,3-dione) dose-dependently, whilst MK-801 (a non-competitive NMDA receptor antagonist) had a lesser effect. Kainate triggers seizures in adult zebrafish, and thus this species can be considered as a new model for studying seizures and subsequent excitotoxic brain injury., (© 2011 NEURON BPh. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

N-Heterocyclic carbene (NHC) ligands have attracted great interest over the last decade for their use in the design of homogenous catalysts. NHC-based metal complexes have interesting potential biomedical applications, such as in antimicrobial and cancer therapy, which are beginning to be explored more fully. We have studied here the oxidant activities of a series of Ru(II) complexes in vitro and zebrafish (Danio rerio) have been used as a model in vivo to investigate and characterize the toxicity of some of these compounds. Dual behavior was observed for the NHC-based complexes as they behaved as antioxidants at low concentrations but showed pro-oxidant capacity at higher concentrations. Zebrafish embryos were exposed to Ru(II) complexes under several different conditions (0 or 24 h postfertilization, with or without the chorion) and various parameters, such as viability, edema, heart rate, blood coagulation, pigmentation, scoliosis, malformation, and hatching, were tested. In general, zebrafish embryos were not harmed by exposure to Ru(II) complexes whatever the experimental conditions. Several toxicity profiles were observed depending upon the chemical structure of the compound in question. Their characteristics as pro-oxidant and/or antioxidant agents together with their biosafety may point to their having biomedical applications as antitumoral or neuroprotective drugs.

The frequency and functionality of peripheral blood invariant (iNKT) cells and their subsets, as well as other regulatory T-cell subsets, were evaluated in patients with type 1A diabetes mellitus (DM1), Hashimoto's disease, and Graves' disease. In addition to healthy individuals (HC), patients with type 2 diabetes mellitus (DM2) were included as controls because this disease has a different physiopathology. A similar frequency of total iNKT cells, as well as their subsets, existed among HC and the different study groups. Similar results were reported when we compared the frequency of CD4(+)/CD25(high) T cells, CD8(+)/CD28(negative) T cells, and gamma-delta T cells among HC and study groups, whereas patients with DM2 exhibited a higher frequency of CD8(+)/CD28(negative) T cells compared with HC and DM1. Also, patients with DM2 exhibited a lower frequency of CD4(negative) and CD4(+) iNKT cells expressing tumor necrosis factor-alpha (TNF-alpha) than HC. We did not observe significant differences in the frequency of iNKT cells expressing interleukin-4 or interferon-gamma among study groups and controls. Our findings support a normal frequency and function of peripheral blood iNKT cells in different endocrine autoimmune diseases, but an abnormal expression of TNF-alpha by circulating iNKT cells from patients with DM2.

The zebrafish (Danio rerio) is rapidly gaining ground as a disease model. However, until now, the use of this species with human pathogens has been restricted to just three bacteria; no studies involving viruses that infect humans are recorded. In this study, the zebrafish was used as a model of herpes simplex virus type 1 (HSV-1) infection of the nervous system. Fish infected using viral culture supernatants showed detectable HSV-1 DNA concentrations 1-4 days after inoculation, indicating that this virus can experimentally infect and persist in this host. The kinetics of infection was dose dependent, especially in the head. Histological immunodetection of HSV-1 glycoproteins confirmed the presence of HSV-1 in the organs studied; infection led to histopathological changes. Moreover, the suppression of the immune system by cyclophosphamide and the antiviral effect of acyclovir were demonstrated. The infection of the encephalon was studied in detail, and the time course of viral colonization recorded. Immunofluorescence studies provided immunoreactive evidence of viral antigens in the encephalon and spinal cord. Viruses cleared from infected brains showed the ability to infect human neuroblastoma cells. This study is the first to demonstrate HSV-1 infection in the zebrafish and manifests the potential use of this species in herpesvirus studies.

The activating protein-1 transcription factor, in particular the Jun proteins play critical roles in the regulation of cell proliferation and tumor progression. To study the potential clinical relevance of interfering with JunB expression, we generated retroviruses expressing short hairpin RNA. Reduction of JunB levels causes increased proliferation and tumorigenicity in wild-type murine fibroblasts, whereas in c-Jun knockout cells p53-independent cell cycle arrest and apoptosis are induced. Using melanoma-derived B16-F10 cancer cells the combination of JunB knockdown and c-Jun/JNK inactivation leads to cell cycle arrest and apoptosis-inducing factor-dependent apoptosis. Furthermore, the combined treatment extends survival of mice inoculated with the tumor cells. These results indicate that in the absence of c-Jun, JunB can act as a tumor promoter and inactivation of both, c-Jun and JunB, could provide a valuable strategy for antitumor intervention.

Dopamine (DA)-serotonin interactions dealing with learning and memory functions have been apparent from experimental approaches over the past decade. However, since the former evidence showing that these cerebral neurotransmitter systems are involved in the regulation of the same cognitive processes, few experimental studies have been done to further clarify the nature of DA-serotonin interactions for cognitive processes sharing common brain structures. Nevertheless, a regulatory role of 5-HT/DA interactions in cognition and the prefrontal cortex (PFC) and the striatum as a neuroanatomical substrate for these DA/5-HT interactions, are now recognized. Experimental evidence indicates that pharmacological disruption of serotonin neurotransmission results in a facilitative effect on the processing of mnemonic information by cerebral regions under strong, functional DA modulation, such as the striatum and the PFC; on the other hand, increased serotonin neurotransmission appears to have a detrimental effect on cognitive functions integrated in these structures. These effects seem to occur through the interaction of different pre- and postsynaptic DA and serotonin receptor subtypes acting as opposite systems underlying cognitive abilities. Some studies, focused on DA-serotonin interactions underlying the pathophysiology of neurological and psychiatric diseases, which evolve with cognitive dysfunctions in human beings, have shown that drugs that are able to modify DA or serotonin neurotransmission may exert beneficial effects on cognitive functions, even though improvement of motor, mood and behavioural disturbances are the main objectives of pharmacological treatment of these diseases. The complete significance of DA-serotonin interactions in cognitive functions could be addressed by future experimental and clinical studies.

Disseminated herpes simplex virus type 1 (HSV-1) infection during pregnancy is poorly described even though it is associated with high maternal and fetal morbidity and neonatal mortality in humans. In a previous paper using mice as a model, the authors demonstrated that HSV-1 is transmitted hematogenously from mother to offspring, the virus colonizing the central nervous system and provoking high mortality. In the present study, viral DNA levels in latently infected mothers were investigated during pregnancy and after delivery in mice. Samples from different organs were obtained before gestation (latency), three times during pregnancy (17, 4.5, and 1 day before delivery), and four times after delivery (1 day, 1 week, 1 and 2 months). A dramatic decrease in viral DNA concentration was observed during pregnancy, especially in the nervous system, with postnatal recovery to latent levels. All the brain regions studied showed similar trends. The viral copy numbers detected in mothers at delivery +1 day were independent of viral inoculum size. The spread of the virus to the above organs was examined immunohistochemically and, in general, more intense viral staining was observed after delivery in each. Because immunoglobulin levels can be modified by infections during pregnancy, the authors examined the levels of specific HSV-1 antibodies. Variation in HSV-1 DNA concentration was found to be associated with changes in the full spectrum of immunoglobulins (but especially immunoglobulin M [IgM]) over pregnancy, whereas at delivery -1 day a significant inverse relationship between immunoglobulins and HSV-1 DNA was observed. IgGs provided protection during the postnatal phase.

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus that causes severe disease and death in newborn humans but, to date, it remains unclear how neonatal infection occurs. We show here that the vertical transmission of HSV-1 in mice is mainly hematogenous and involves the colonization of the neonate central nervous system (CNS). HSV-1 DNA was mainly detected in the blood and CNS of the offspring born to latently infected mothers; no significant differences were seen between the viral DNA concentrations in the blood of these mothers and their female progeny (either neonate or adult). The administration of acyclovir during gestation reduced or eliminated both the maternal and the neonatal viral DNA in the blood. Embryo transfer was performed to ensure (as far as possible) that only vertical hematogenous infection took place. Immunohistochemical analysis detected viral proteins in the encephalon of the offspring. Immunofluorescence studies provided immunoreactive evidence of HSV-1 proteins in the neurons of the hippocampus and showed that these viruses can molecularly reactivate after hyperthermia. Neonatal HSV-1 infection therefore appears to be mainly caused by hematogenous vertical transmission, and the viruses that colonize the offspring CNS are capable of molecular reactivation after a period of latency.

Herpes simplex virus type 1 (HSV-1) causes disease in humans and animals. Infection usually occurs via the neural route and possibly occurs via the hematogenous route. The latter, however, is the main route by which immunosuppressed individuals and neonates are infected. Gender-dependent differences in the incidence and severity of some viral infections have been reported. To detect differences between the sexes with respect to HSV-1 colonization and disease, the characteristics of both acute and latent infections in hematogenously infected male and female mice were compared. In acute infection, the female mice had a poorer outcome: HSV-1 colonization was more effective, especially in the gonads and brain. In the encephalon, the midbrain had the highest viral load. In latent infection, brain viral loads were not significantly different with respect to sex. Significant differences were seen, however, in the blood and trigeminal ganglia: HSV-1 seroprevalence was observed in females, with no virus detected in males. In brain dissections, only the cerebral cortex of the females had viral loads statistically higher than those observed in the males. The spread of the virus to several organs of interest during acute infection was examined immunohistochemically. Female mice showed greater viral immunostaining, especially in the adrenal cortex, gonads, and midbrain. In male mice, HSV-1 was detected predominantly in the adrenal cortex. It was also found that apolipoprotein E promotes virus colonization of the ovaries, the APOE gene dose being directly related to viral invasiveness.

Neural stem cells are defined as clonogenic cells with self-renewal capacity and the ability to generate all neural lineages (multipotentiality). Cells with these characteristics have been isolated from the embryonic and adult central nervous system. Under specific conditions, these cells can differentiate into neurons, glia, and non-neural cell types, or proliferate in long-term cultures as cell clusters termed "neurospheres". These cultures represent a useful model for neurodevelopmental studies and a potential cell source for cell replacement therapy. Because no specific markers are available to unequivocally identify neural stem cells, their functional characteristics (self-renewal and multipotentiality) provide the main features for their identification. Here, we review the experimental and ultrastructural studies aimed at identifying the morphological characteristics and the antigenic markers of neural stem cells for their in vitro and in vivo identification.

Background: So far there have been no reports on the expression pattern of DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) in human breast cells and its relationship to the estrogen receptors, ER-alpha and ER-beta, and the androgen receptor (AR)., Methods: In this study we evaluated, by immunohistochemistry and Western blot analysis, the presence and distribution of DAX-1 in benign breast disease (BBD), in situ carcinoma (CIS), and ductal and lobular breast carcinomas., Results: In BBD and breast carcinomas, DAX-1 was present in both the nuclei and the cytoplasm of epithelial cells, although in infiltrative carcinomas the percentage of nuclear immunoreaction was higher than in CIS. An important relation was observed between DAX-1 and AR expression and between this orphan receptor and nodal status., Conclusion: DAX-1 might modify the AR and ER-beta intracellular location, and because a direct positive relation between the expression of these three receptors was found it could be assumed that the presence of DAX-1 in neoplastic cells might indicate a possible failure of endocrine therapies.

The aim of this study was to evaluate the presence and distribution of retinoid X receptors (RXRs) alpha, beta, and gamma in normal, hyperplastic (nodular, basal cell, and atrophic hyperplasia), and carcinomatous human prostates in order to elucidate the relationship among these receptors and the onset and development of prostatic adenocarcinoma. RXRalpha and RXRgamma were immunodetected in all samples of normal, nodular, and basal cell hyperplasia, as well as carcinomatous prostates. In atrophic glands, the expression of both receptors was found in 22.5% of samples. Positive immunostaining for RXRbeta was observed in 53.3% of normal prostates, 100% of samples showed basal cell hyperplasia, and were negative in nodular and atrophic hyperplasia. In prostatic adenocarcinoma, only 3 of 25 samples (the 3 diagnosed as well-differentiated) were positive for RXRbeta. Results suggest that diminished RXRbeta expression might be related to prostate cancer progression and because the responsiveness to retinoic acid treatments depends on the expression of different receptors, it is important to study their expression before therapy.

p53, p21, and Rb are proteins with an important role in cell-cycle control. The expression and distribution of these gene products and the apoptotic rate were studied in the marbled-newt testis along the annual cycle to know the role of these factors in the control of spermatogenesis and glandular tissue formation. The study was carried out using Western blot analysis and immunohistochemistry. The results differed from those, previously reported in mammals showing constant spermatogenesis. Greater expression of p53 and p21 was found in the quiescence period and was detected in PCGs (primordial germ cells), spermatogonia, follicular, interstitial cells, and glandular tissue. Greater expression of Rb and phosph-Rb was present in the proliferation period, in PCGs, and spermatogonia. Apoptosis was only detected in secondary spermatogonia (quiescence and spermiogenesis periods) and primary spermatocytes (proliferation and spermiogenesis periods). In the quiescence period, the increase in p53 expression activates p21 expression, which inhibits Rb phosphorylation and arrests the cell cycle in G1. In the proliferation period and, in a lesser degree, in the spermiogenesis period, the expressions of p53 and p21 decrease and phosph-Rb increases, enhancing cell proliferation. These gene products do not seem to be related to apoptosis., (Copyright 2002 Wiley-Liss, Inc.)

Retinoid acid receptors (RXR-alpha, -beta, -gamma) and Farnesoid X-activated receptor (FXR) expression in the testis of the marbled newt were investigated with special attention to the changes during the annual testicular cycle, using light microscopy immunohistochemistry and Western blot analysis. The annual testicular cycle of the marbled newt (Triturus marmoratus marmoratus) comprises three periods: (a) proliferative period (germ cell proliferation from primordial germ cells to round spermatids, April-June); (b) spermiogenesis period (July-September); and (c) quiescence period (interstitial and follicular cells form the glandular tissue, October-April). In the proliferative period, primordial germ cells and primary spermatogonia immunostained intensely to the three types of RXRs and also to FXR. In the other periods, immunostaining to these antibodies was weak or absent. Secondary spermatogonia stained weakly to the four antibodies in the proliferative period, and only to FXR, also weakly, in the spermiogenesis period. Immunoreactive primary spermatocytes were weakly labeled with the RXR antibodies in the proliferative period. Spermatids and spermatozoa did not stain to any antibody in any period. Follicular cells only immunostained to RXR-gamma and only in the quiescence period when they are forming the glandular tissue, together with the interstitial cells. As follicular cells, interstitial cells only immunostained in the quiescence period; however, they immunoreacted to the three types of RXRs. These findings suggest that in the newt, RXRs and FXR are involved in spermatogenesis control by regulating the proliferation of primordial germ cells and spermatogonia. In addition, RXR-gamma seems to be also involved in the development of the glandular (steroidogenic) tissue., (Copyright 2002 Wiley-Liss, Inc.)

Expression of androgen receptor (AR), estrogen receptor alpha (ER-alpha) and estrogen receptor beta (ER-beta) in the testis of the marbled newt (Triturus marmoratus marmoratus) was investigated, with special attention to changes during the annual testicular cycle, using light microscopy immunohistochemistry and Western blot analysis. Primordial germ cells, primary and secondary spermatogonia and spermatocytes showed a positive reaction to the 3 receptor antibodies during the annual reproductive cycle. Follicular cells were positive to AR, ER-alpha and ER-beta during the spermiogenesis and quiescence periods in the glandular tissue. Interstitial cells showed reactivity to AR, ER-alpha and ER-beta in the spermiogenesis and the quiescence periods, and presented no labelling to these receptors in the proliferative period. These findings suggest that, as in mammals, there is an androgen-estrogen regulation of the function and development of the newt testis.

Objectives: To determine the possible antiemetic effect of propofol as the single agent for intravenous anesthesia in children undergoing strabismus surgery, in comparison with other techniques., Patients and Method: Eighty ASA I and II patients between 3 and 10 years, divided into 4 groups of 20, were studied prospectively. Groups I, II and III were premedicated with dehydrobenzylperidol (90 micrograms/kg) i.m. Group I then received sleep doses of thiopental and N2O. Group II received propofol, sleep doses, and N2O. Groups III and IV received sleep doses of propofol followed by intravenous perfusion (10 mg/kg/h)., Results: Half the patients in group I experienced postoperative vomiting, more than in groups II, III and IV (p < 0.05). The incidence of vomiting in group II was 30%. Groups III and IV experienced less vomiting (5-10%) than did groups I and II (p < 0.05). The incidence of bradycardia during surgery was higher in groups III and IV (p < 0.05); medical treatment was not required., Conclusions: Propofol used as the single agent for induction and maintenance of anesthesia offers clear advantages in reducing emesis after strabismus surgery.