APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease.

BACKGROUND: Variants in APOE and PSEN1 (encoding apolipoprotein E and presenilin 1, respectively) alter the risk of Alzheimer's disease. We previously reported a delay of cognitive impairment in a person with autosomal dominant Alzheimer's disease caused by the PSEN1 E280A variant who also had two copies of the apolipoprotein E3 Christchurch variant (APOE3 Ch). Heterozygosity for the APOE3 Ch variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the PSEN1 E280A variant is prevalent. METHODS: We analyzed data from 27 participants with one copy of the APOE3 Ch variant among 1077 carriers of the PSEN1 E280A variant in a kindred from Antioquia, Colombia, to estimate the age at the onset of cognitive impairment and dementia in this group as compared with persons without the APOE3 Ch variant. Two participants underwent brain imaging, and autopsy was performed in four participants. RESULTS: Among carriers of PSEN1 E280A who were heterozygous for the APOE3 Ch variant, the median age at the onset of cognitive impairment was 52 years (95% confidence interval [CI], 51 to 58), in contrast to a matched group of PSEN1 E280A carriers without the APOE3 Ch variant, among whom the median age at the onset was 47 years (95% CI, 47 to 49). In two participants with the APOE3 Ch and PSEN1 E280A variants who underwent brain imaging, 18F-fluorodeoxyglucose positron-emission tomographic (PET) imaging showed relatively preserved metabolic activity in areas typically involved in Alzheimer's disease. In one of these participants, who underwent 18F-flortaucipir PET imaging, tau findings were limited as compared with persons with PSEN1 E280A in whom cognitive impairment occurred at the typical age in this kindred. Four studies of autopsy material obtained from persons with the APOE3 Ch and PSEN1 E280A variants showed fewer vascular amyloid pathologic features than were seen in material obtained from persons who had the PSEN1 E280A variant but not the APOE3 Ch variant. CONCLUSIONS: Clinical data supported a delayed onset of cognitive impairment in persons who were heterozygous for the APOE3 Ch variant in a kindred with a high prevalence of autosomal dominant Alzheimer's disease. (Funded by Good Ventures and others.).

New threats in the recovery of large carnivores inhabiting human-modified landscapes: the case of the Cantabrian brown bear (Ursus arctos).

Understanding mortality causes is important for the conservation of endangered species, especially in small and isolated populations inhabiting anthropized landscapes where both natural and human-caused mortality may hinder the conservation of these species. We investigated the mortality causes of 53 free-ranging brown bears (Ursus arctos) found dead between 1998 and 2023 in the Cantabrian Mountains (northwestern Spain), a highly human-modified region where bears are currently recovering after being critically threatened in the last century. We detected natural traumatic injuries in 52.63% and infectious diseases in 39.47% of the 38 bears for which the mortality causes were registered, with 21.05% of these cases presenting signs of both infectious diseases and traumas. More specifically, almost 30% of the bears died during or after intraspecific fights, including sexually selected infanticide (10.53%). In addition, primary infectious diseases such as infectious canine hepatitis, distemper, clostridiosis and colibacillosis caused the death of 15.79% of the bears. The number of direct human-caused deaths (i.e., shooting, poisoning, snare) decreased over the study period. This study also reveals three new mortality causes triggered by pathogens, two of which-Clostridium novyi and verotoxigenic Escherichia coli-not previously described in ursids, and the other one, canine distemper virus, never reported in brown bears as cause of death. New management strategies for the conservation of Cantabrian bears, which are urgently needed due to the rapid expansion of the population, should consider the mortality causes described in this study and must promote further research to elucidate how the high prevalence of infectious diseases may threaten the current recovery of the population.

Plasma p-tau217 predicts in vivo brain pathology and cognition in autosomal dominant Alzheimer's disease.

INTRODUCTION: Plasma-measured tau phosphorylated at threonine 217 (p-tau217) is a potential non-invasive biomarker of Alzheimer's disease (AD). We investigated whether plasma p-tau217 predicts subsequent cognition and positron emission tomography (PET) markers of pathology in autosomal dominant AD. METHODS: We analyzed baseline levels of plasma p-tau217 and its associations with amyloid PET, tau PET, and word list delayed recall measured 7.61 years later in non-demented age- and education-matched presenilin-1 E280A carriers (n = 24) and non-carrier (n = 20) family members. RESULTS: Carriers had higher plasma p-tau217 levels than non-carriers. Baseline plasma p-tau217 was associated with subsequent amyloid and tau PET pathology levels and cognitive function. DISCUSSION: Our findings suggest that plasma p-tau217 predicts subsequent brain pathological burden and memory performance in presenilin-1 E280A carriers. These results provide support for plasma p-tau217 as a minimally invasive diagnostic and prognostic biomarker for AD, with potential utility in clinical practice and trials. HIGHLIGHTS: Non-demented presenilin-1 E280A carriers have higher plasma tau phosphorylated at threonine 217 (p-tau217) than do age-matched non-carriers. Higher baseline p-tau217 is associated with greater future amyloid positron emission tomography (PET) pathology burden. Higher baseline p-tau217 is associated with greater future tau PET pathology burden. Higher baseline p-tau217 is associated with worse future memory performance.

Sex differences in blood biomarkers and cognitive performance in individuals with autosomal dominant Alzheimer's disease.

INTRODUCTION: Plasma tau phosphorylated at threonine 217 (P-tau217) and neurofilament light (NfL) have emerged as markers of Alzheimer's disease (AD) pathology. Few studies have examined the role of sex in plasma biomarkers in sporadic AD, yielding mixed findings, and none in autosomal dominant AD. METHODS: We examined the effects of sex and age on plasma P-tau217 and NfL, and their association with cognitive performance in a cross-sectional study of 621 Presenilin-1 E280A mutation carriers (PSEN1) and non-carriers. RESULTS: As plasma P-tau217 levels increase, cognitively unimpaired female carriers showed better cognitive performance than cognitively unimpaired male carriers. Yet, as disease progresses, female carriers had a greater plasma NfL increase than male carriers. There were no sex differences in the association between age and plasma biomarkers among non-carriers. DISCUSSION: Our findings suggest that, among PSEN1 mutation carriers, females had a greater rate of neurodegeneration than males, yet it did not predict cognitive performance. HIGHLIGHTS: We examined sex differences in plasma P-tau217 and NfL in Presenilin-1 E280A (PSEN1) mutation carriers and non-carriers. Female carriers had a greater plasma NfL increase, but not P-tau217, than male carriers. As plasma P-tau217 levels increase, cognitively unimpaired female carriers showed better cognitive performance than cognitively unimpaired male carriers. The interaction effect of sex by plasma NfL levels did not predict cognition among carriers.

Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred.

INTRODUCTION: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. METHODS: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies. RESULTS: 13 variants had p<1×10-7 or p<1×10-5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14. DISCUSSION: Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.

Opportunities and Challenges of Computed Tomography Coronary Angiography in the Investigation of Chest Pain in the Emergency Department-A Narrative Review.

Chest pain is one of the most common presentations to emergency departments. However, only 5.1% will be diagnosed with an acute coronary syndrome, representing considerable time and expense in the diagnosis and investigation of the patients eventually found not to be suffering from an acute coronary syndrome. PubMed and Medline databases were searched with variations of the terms "chest pain", "emergency department", "computed tomography coronary angiography". After review, 52 articles were included. Computed tomography coronary angiography (CTCA) is a class I endorsement for investigating chest pain in major international societal guidelines. CTCA offers excellent sensitivity and negative predictive value in identifying patients with coronary disease, with prognostic data impacting patient management. If CTCA is to be applied to all comers, it is pertinent to discuss the advantages and potential pitfalls if use in the Australian system is to be increased.

Comparison of Carotid Intima-Media Thickness in Children and Adults With and Without Obesity: A Hysteresis Model.

OBJECTIVE: To describe a third-degree polynomial function (hysteresis) of the effect size of age, obesity, and insulin sensitivity over the carotid intima-media thickness (c-IMT), in the pediatric and adult groups. METHODS: A quasi-experimental study with fixed factor analysis of age (children aged 8-12 years, n = 73; adults aged 21-45 years, n = 82) and obesity (yes, n = 76; no, n = 79) was conducted to analyze the effect on the c-IMT and Matsuda insulin sensitivity index values. This quasi-experimental design was analyzed with robust regression modeling. RESULTS: The additive effect of obesity, independent of age, was evident in the case of the c-IMT values. There was no interaction effect, but a significant difference between participants with normal weight and those with obesity was found (P < .0001). The difference between adults and children was also significant, but the effect size was smaller. A model was created based on age, Tanner stage, and obesity using the c-IMT and Matsuda insulin sensitivity index values. A linear function fit as R2, and the cubic function estimated parameters like a polynomial model. CONCLUSION: This practical study design showed that children with obesity displayed the same levels of carotid intima-media abnormalities as adults with obesity. The polynomial shape of the model suggests potentially poor outcomes that resemble the hysteresis process and may predict chronic cardiometabolic events during early adulthood.

Evaluation and perceptions of a nursing discharge plan among nurses from different healthcare settings in Spain.

PURPOSE: The exchange of information between different healthcare settings through a nursing discharge plan is essential for safe care. However, the factors contributing to achieving the most efficient exchange have not been well studied. This study aimed to evaluate and explore the perceptions of a nursing discharge plan from the perspective of nurses in different healthcare settings. METHODS: A mixed methods approach comprising a specifically designed ad hoc questionnaire (n = 437) and a focus group session (n = 8). FINDINGS: Overall, 66.1% out of 437 nurses, and especially those working in nursing homes, were satisfied with the nursing discharge plan. Lack of time to complete the report and poor information about both nursing diagnoses and patients' social assessment were identified as problem areas. Some proposals emerged from the focus group: providing sufficient time for its completion, giving the nursing discharge plan a more flexible structure permitting more open-ended responses, requiring more information to be provided about the social and psychological situation of the patients, training nurses to use standardized language to avoid possible misinterpretations, and getting nurses from the different health care settings to work together in designing continuity of care plans. Elderly and low-income patients are found to need greater attention when filling out nursing discharge plans. CONCLUSIONS: The study has revealed key aspects that need to be improved and some recommendations in implementing the nursing discharge plan in our health area. These include that there should be more time provided to complete the NDP, and also specific details regarding the format, structure, content of the information that is communicated, and the prioritization of the patient profile.

Resilience and job satisfaction among out-of-hospital emergency medical service professionals: A cross-sectional multi-centric study.

AIM: We aim to describe the relationship between job satisfaction and compare levels of resilience among out-of-hospital emergency medical service professionals. BACKGROUND: The study of the impact of the working environment on health professionals has raised great interest. Job-related variables and resilience can be a protective factor against stressful and demanding events at work. METHODS: A cross-sectional survey comprising sociodemographic and job-related variables was conducted among 406 workers (doctors, nurses, psychologists, and ambulance technicians) from the out-of-hospital emergency medical system in Spain. Resilience was self-reported using the Connor-Davidson Resilience Scale. RESULTS: Nursing professionals were less resilient compared with ambulance technicians (score difference 1.709, p = .008). As age increased, resilience was lower (r = -.118). Professionals with higher resilience scores were more satisfied in their work (OR = 1.06, 95% CI: 1.02-1.11), and professionals with higher psychological strength, gained from working with other colleagues, also showed greater job satisfaction (OR = 5.47, 95% CI: 2.55-11.73). CONCLUSION: There was a positive association between resilience, job satisfaction and collaborative work. Professionals with greater psychological strength, gained from working with other colleagues, also showed higher levels of job satisfaction. IMPLICATIONS FOR NURSING MANAGEMENT: Managers can use these results to influence the work environment to enhance job satisfaction and hence improve the resilience of the out-of-hospital emergency health care professionals.

Discovery of 6-substituted thieno[2,3-d]pyrimidine analogs as dual inhibitors of glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase in de novo purine nucleotide biosynthesis in folate receptor expressing human tumors.

We discovered 6-substituted thieno[2,3-d]pyrimidine compounds (3-9) with 3-4 bridge carbons and side-chain thiophene or furan rings for dual targeting one-carbon (C1) metabolism in folate receptor- (FR) expressing cancers. Synthesis involved nine steps starting from the bromo-aryl carboxylate. From patterns of growth inhibition toward Chinese hamster ovary cells expressing FRα or FRß, the proton-coupled folate transporter or reduced folate carrier, specificity for uptake by FRs was confirmed. Anti-proliferative activities were demonstrated toward FRα-expressing KB tumor cells and NCI-IGROV1 ovarian cancer cells. Inhibition of de novo purine biosynthesis at both 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase and glycinamide ribonucleotide formyltransferase (GARFTase) was confirmed by metabolite rescue, metabolomics and enzyme assays. X-ray crystallographic structures were obtained with compounds 3-5 and human GARFTase. Our studies identify first-in-class C1 inhibitors with selective uptake by FRs and dual inhibition of enzyme targets in de novo purine biosynthesis, resulting in anti-tumor activity. This series affords an exciting new platform for selective multi-targeted anti-tumor agents.

Decrease of Postchemotherapy Complications With the Use of Probiotics in Children With Acute Lymphoblastic Leukemia.

INTRODUCTION: During the administration of antineoplastic drugs, acute complications because of toxicity occur, determining their hospital readmission, visits to the emergency department, use of antimicrobials, and possibilities of presenting systemic infections, impacting on their life quality. METHODS: Through a prospective cohort, 60 children with acute lymphoblastic leukemia were followed-up for 30 days after the hospital discharge because of chemotherapy administration, those patients were previously included in a single-blinded study in which 30 (group 1) received Lactobacillus rhamnosus GG probiotic during the administration of chemotherapy. The remaining 30 patients did not receive probiotics (group 2). There were evaluated gastrointestinal symptoms, such as diarrhea, dyspepsia, abdominal distension, meteorism, constipation, nausea, and vomit, development of infections, antibiotic use, number of emergency department visits, number of hospitalizations, and sepsis diagnosis. STATISTICAL ANALYSIS: To assess the impact of the use of probiotics, the difference in proportions between both study groups was evaluated. RESULTS: Gastrointestinal manifestations (nausea, vomiting, diarrhea, constipation) occurred in 30% of patients in group 1 versus 63% of group 2 (P=0.009). Nine of 30 patients (30.0%) in group 1 went to the emergency room, versus 33.3% of group 2 (P=0.7). Antimicrobials were used in 8 subjects (26.6%) in group 1 versus 6 subjects (53.3%) in group 2 (P=0.03) suspected of an infectious disease. Four (13.3%) group 1 patients were hospitalized versus 30% of group 2 (P=0.1). Two subjects (6.6%) in group 1 had sepsis versus 7 (23.3%) in group 2 (P=0.07).Conclusions:The results indicate that the use of probiotics can be a great alternative in the improvement of gastrointestinal symptoms and the adverse effects associated with chemotherapy.

Immunogenicity of Intramuscular Fractional Dose of Inactivated Poliovirus Vaccine.

BACKGROUNDS: Intradermal (id) fractional inactivated poliovirus vaccine ([fIPV] one fifth of normal IPV dose) is safe and immunogenic; however, id administration is perceived as difficult. We compared fIPV immunogenicity administered id or intramuscularly (im). METHODS: This noninferiority trial was conducted among polio vaccine-naive Cuban infants who received 2 IPV doses at 4 and 8 months of age. Infants were randomized into 4 arms: (A) fIPV, 0.1 mL im; (B) fIPV, 0.2 mL im; (C) fIPV, 0.1mL id; and (D) IPV, 0.5 mL im. Blood collected before and after vaccinations was tested for poliovirus-neutralizing antibodies. RESULTS: A total of 196 of 214 (91.6%) enrolled children completed study. Seroconversion after 2 IPV doses in each arm were as follows: (A) 97.3% (90.6-99.7), 98.7% (92.7-99.9), and 90.5% (81.5-96.1) for serotypes 1, 2, and 3, respectively; (B) 97.2% (90.3-99.7), 100%, 95.8% (88.3-99.1) for serotypes 1, 2, and 3, respectively; (C) 89.3% (71.8-97.7), 92.9% (76.5-99.1), 82.1% (63.1-93.9) for serotypes 1, 2, and 3, respectively; and (D) 100%, 100%, 100% for serotypes 1, 2, and 3, respectively. Seroconversion with fIPV im was noninferior to fIPV id for all serotypes. CONCLUSIONS: We demonstrated noninferiority of fIPV im compared with id when administered at 4 and 8 months of age. Further investigations in an earlier infant schedule should be pursued to explore fIPV im as option for dose-sparing strategy in countries reluctant to use fIPV id due to programmatic difficulties of id administration.

Influence of the 2012 European Guidelines in Diagnosis and Follow-up of Coeliac Children With Selective IgA Deficiency.

OBJECTIVES: The aim of the study was to describe diagnostic criteria used in children with coeliac disease (CD) and selective IgA deficiency; to determine if the publication of the 2012 ESPGHAN criteria prompted any changes; to evaluate the evolution of serological markers. METHODS: Multicenter, retrospective, descriptive study of a cohort of children under 15 years with selective IgA deficiency diagnosed with CD (January 2006 to December 2016). Demographic, clinical, genetic, histological and IgG-based antibodies were collected at diagnosis and follow-up. RESULTS: Eighty-six children were included, 60 diagnosed after the guide. Two groups were established: G1 (n = 63) and G2 (n = 23) with or without diagnostic biopsy respectively. In G1: 87.3% were symptomatic, 87.3% had human leukocyte antigan (HLA) DQ2/DQ8 typing (all positive), all had IgG serology positive (71.5% ATG, 35% EMA, 19% DPG, 9.5% AGA), and all had villous atrophy (Marsh-Oberhuber 2-3). Follow-up data were available in 58 children, 34 after 2 years on a gluten-free diet. Fifty-two percentage remained ATG IgG-positive despite good dietary adherence and symptom remission. Regarding G2: all were diagnosed post-2012, had typical symptoms, HLA DQ2/DQ8 positive and ATG IgG × 10 ULN. Additionally, EMA IgG was performed in 14 (60%), all positive. CONCLUSIONS: In our cohort of children with selective IgA deficiency and diagnosed with CD, children without a diagnostic biopsy suggests that IgG serology was considered the equivalent as IgA isotype, even when this is not addressed in the aforementioned guidelines. Great heterogeneity was observed in the IgG serology used at diagnosis. After 2 years of a gluten-free diet, half of children remained with a positive serology.

Cardiac performance after an endurance open water swimming race.

PURPOSE: Endurance exercise competitions have shown a transient negative effect on global right ventricular (RV) performance. Most published studies are based on terrestrial sports. The aim of our study was to evaluate the cardiac effects after an open water swimming race. METHODS: We evaluated 33 healthy swimmers (mean age 40.9 ± 7.2) participating in a 9.5 km open water swimming race. All subjects underwent a standard transthoracic echocardiography including an evaluation of dimensions and myocardial ventricular deformation. Echocardiography was performed 24 h before and within the first hour of arrival at the finish line. Cardiac troponin I (cTn I), NT-ProBNP and leukocytes were also evaluated. RESULTS: No changes in left ventricle (LV) ejection fraction or LV global longitudinal strain were observed. A significant increase in RV end-diastolic area (RVEDA) was noted after the race (RVEDA at baseline 15.12 ± 1.86; RVEDA after race 16.06 ± 2.27, p < 0.05), but no changes were seen in RV fractional area change or RV global longitudinal strain. Cardiac biomarkers and leukocytes significantly increased. No association was detected between the increase in cTn I or NT-proBNP and the RV acute dilatation or LV performance. A significant association was observed between cTn I and leukocytes (r = 0.375, p < 0.05). CONCLUSIONS: An acute RV dilatation but without an impairment in RV deformation was observed after participating in an endurance swimming race. The correlation between the increase in cTn I and leukocytes, but not with ventricular performance, may support the hypothesis of an exercise-induced increase in myocardial sarcolemmal permeability due to an inflammatory response rather than myocardial injury.

Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr).

INTRODUCTION: A small percentage of Alzheimer's disease (AD) cases are caused by genetic mutations with autosomal dominant inheritance. We report a family with a novel variant in PSEN1. METHODS: We performed clinical and genetic evaluation of 93 related individuals from a Colombian admixed population. 31 individuals had whole-genome sequencing. RESULTS: Genetic analysis revealed a missense variant in PSEN1 (NM_000021.3: c.1247T>C p.Ile416Thr), which originated on an African haplotype and segregated with AD logarithm of the odds score of 6. Their clinical phenotype is similar to sporadic AD except for earlier age at onset: the mean age at onset for mild cognitive impairment was 47.6 years (standard deviation 5.83) and for dementia 51.6 years (standard deviation 5.03). DISCUSSION: Ile416Thr is a novel pathogenic variant that causes AD in the sixth decade of life. The history of the region that included slave importation and admixtures within a confined geographic locale represents a "mini-population bottleneck" and subsequent emergence of a rare dominant mutation.

Does Simultaneous Administration of Bivalent (Types 1 and 3) Oral Poliovirus Vaccine and Inactivated Poliovirus Vaccine Induce Mucosal Cross-immunity to Poliovirus Type 2?

Background: Inactivated poliovirus vaccine (IPV) alone does not induce mucosal immunity. However, it was hypothesized that administration of IPV together with bivalent (types 1+3) oral poliovirus vaccine (bOPV) may stimulate mucosal cross-immunity to poliovirus type 2 (PV2). Methods: Cuban infants were randomized to receive either one dose of IPV (Arm A); one dose of IPV with bOPV (Arm B) at about 6 months of age or no vaccine (Arm C). Subjects were challenged with one dose of trivalent OPV (tOPV); they were about 7 months old in arms A and B, and about 3 months old in arm C at a time of the tOPV challenge. Sera were collected before vaccination and 30 days after tOPV challenge and tested for presence of poliovirus neutralizing antibodies; stool samples were collected at days 0, 7, 14, 21 and 49 post-challenge and tested for presence of poliovirus. Results: We enrolled 333 children. Excretion of PV2 following tOPV challenge was highest on day 7 (75 [CI 95% = 65-82%], 68 [CI 95% = 58-75%] and 73 [CI 95% = 63-80%] for study arms A, B, and C respectively); excretion decreased with every subsequent stool sampling; no significant differences either in proportion of PV2 excretion or in its duration were observed between study arms. Conclusions: There was no reduction in excretion of PV2 after tOPV challenge in children who had received IPV with bOPV when compared to those who had received IPV alone or no vaccine. Polio eradication program cannot assume any PV2 mucosal response with the current polio immunization schedule. Clinical Trials Registration: The trial was registered with the Australian New Zealand Clinical Trials Registry and allocated trial number ACTRN12616000169448.

Effect of Eicosapentaenoic Acid on Body Composition and Inflammation Markers in Patients with Head and Neck Squamous Cell Cancer from a Public Hospital in Mexico.

INTRODUCTION: Head and neck cancer patients are at high risk of anorexia-cachexia syndrome and literature shows that Eicosapentaenoic acid (EPA) could regulate it. We aim to determine the EPA effect on body composition and pro-inflammatory markers in patients with head neck cancer. MATERIALS AND METHODS: A randomized single-blind placebo-controlled clinical trial was conducted in patients with head and neck squamous cell cancer who received a polymeric diet with 2 g of EPA or a standard polymeric diet for six weeks before antineoplastic treatment. We assessed body composition by bioelectrical impedance analysis and determined IL-1ß, IL-6, TNF-α and IFN-γ, CRP, serum proteins, and blood count at baseline and at the end of the study. RESULTS: 32 patients received EPA (2 g/day) and 32 became controls. A decrease in serum levels of IL-1ß, IL-6, TNF-α, and IFN-γ was observed in the experimental group, as well as regulation of body weight (-0.3 ± 5.9 vs. -2.1 ± 3.7), lean body mass (-0.2 ± 3.8 vs. -1.3 ± 3.6), body fat mass (0.2 ± 3.5 vs. -1.2 ± 3.8), and quality of life (10 ± 33 vs. 5 ± 34). CONCLUSION: Supplementing with 2 g/day of EPA to head and neck cancer patient during antineoplastic treatment regulates serum pro-inflammatory cytokines, body weight, lean body mass, and improve quality of life.

Boosting Immune Responses Following Fractional-Dose Inactivated Poliovirus Vaccine: A Randomized, Controlled Trial.

BACKGROUND: Fractional-dose administration of inactivated poliovirus vaccine (fIPV) could increase IPV affordability and stretch limited supplies. We assessed immune responses following fIPV administered intradermally, compared with full-dose IPV administered intramuscularly, among adults with a history of oral poliovirus vaccine (OPV) receipt. METHODS: We conducted a randomized, controlled noninferiority trial in Cuba. fIPV or IPV were administered on days 0 and 28; serum was collected on days 0, 7, 28, and 56 for analysis by a neutralization assay. The primary end point was seroconversion or a ≥4-fold rise in antibody titer. The noninferiority limit was 10%. The secondary end point was safety, assessed by the number and intensity of adverse reactions. RESULTS: A total of 503 of 534 enrolled participants (94.2%) completed all study requirements. Twenty-eight days after the first dose, 94.8%, 98.0%, and 98.0% of fIPV recipients had an immune response to poliovirus types 1, 2, and 3, respectively, compared with 98.1% (P = .06), 98.0% (P = 1.00), and 99.2% (P = .45) in the IPV arm. Noninferiority was achieved on days 7, 28, and 56 for all serotypes. No serious adverse events were reported. CONCLUSION: fIPV induced similar boosting immune responses, compared with full-dose IPV. This suggests that fIPV would be an effective strategy to boost population immunity in an outbreak situation. CLINICAL TRIALS REGISTRATION: ACTRN12615000305527.

In Vivo Characterization of an AHR-Dependent Long Noncoding RNA Required for Proper Sox9b Expression.

Xenobiotic activation of the aryl hydrocarbon receptor (AHR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) prevents the proper formation of craniofacial cartilage and the heart in developing zebrafish. Downstream molecular targets responsible for AHR-dependent adverse effects remain largely unknown; however, in zebrafish sox9b has been identified as one of the most-reduced transcripts in several target organs and is hypothesized to have a causal role in TCDD-induced toxicity. The reduction of sox9b expression in TCDD-exposed zebrafish embryos has been shown to contribute to heart and jaw malformation phenotypes. The mechanisms by which AHR2 (functional ortholog of mammalian AHR) activation leads to reduced sox9b expression levels and subsequent target organ toxicity are unknown. We have identified a novel long noncoding RNA (slincR) that is upregulated by strong AHR ligands and is located adjacent to the sox9b gene. We hypothesize that slincR is regulated by AHR2 and transcriptionally represses sox9b. The slincR transcript functions as an RNA macromolecule, and slincR expression is AHR2 dependent. Antisense knockdown of slincR results in an increase in sox9b expression during both normal development and AHR2 activation, which suggests relief in repression. During development, slincR was expressed in tissues with sox9 essential functions, including the jaw/snout region, otic vesicle, eye, and brain. Reducing the levels of slincR resulted in altered neurologic and/or locomotor behavioral responses. Our results place slincR as an intermediate between AHR2 activation and the reduction of sox9b mRNA in the AHR2 signaling pathway.

Retinoid-X-receptors (α/ß) in melanocytes modulate innate immune responses and differentially regulate cell survival following UV irradiation.

Understanding the molecular mechanisms of ultraviolet (UV) induced melanoma formation is becoming crucial with more reported cases each year. Expression of type II nuclear receptor Retinoid-X-Receptor α (RXRα) is lost during melanoma progression in humans. Here, we observed that in mice with melanocyte-specific ablation of RXRα and RXRß, melanocytes attract fewer IFN-γ secreting immune cells than in wild-type mice following acute UVR exposure, via altered expression of several chemoattractive and chemorepulsive chemokines/cytokines. Reduced IFN-γ in the microenvironment alters UVR-induced apoptosis, and due to this, the survival of surrounding dermal fibroblasts is significantly decreased in mice lacking RXRα/ß. Interestingly, post-UVR survival of the melanocytes themselves is enhanced in the absence of RXRα/ß. Loss of RXRs α/ß specifically in the melanocytes results in an endogenous shift in homeostasis of pro- and anti-apoptotic genes in these cells and enhances their survival compared to the wild type melanocytes. Therefore, RXRs modulate post-UVR survival of dermal fibroblasts in a "non-cell autonomous" manner, underscoring their role in immune surveillance, while independently mediating post-UVR melanocyte survival in a "cell autonomous" manner. Our results emphasize a novel immunomodulatory role of melanocytes in controlling survival of neighboring cell types besides controlling their own, and identifies RXRs as potential targets for therapy against UV induced melanoma.