S100A8/A9 Drives Neuroinflammatory Priming and Protects against Anxiety-like Behavior after Sepsis.

Sepsis commonly results in acute and chronic brain dysfunction, which dramatically increases the morbidity associated with this common disease. Chronic brain dysfunction in animal models of sepsis survival is linked to persistent neuroinflammation and expression of multiple cytokines. However, we have found previously that microglia predominantly upregulate the damage associated molecule S100A8/A9 after sepsis. In this article, we show that S100A8/A9 is increased in the brains of patients who died of sepsis and that S100A8 is expressed in astrocytes and myeloid cells. Using a mouse model of sepsis survival, we show that S100A8/A9 is persistently expressed in the brain after sepsis. S100A9 expression is necessary for recruitment of neutrophils to the brain and for priming production of reactive oxygen species and TNF-α secretion in microglia and macrophages. However, despite improving these indices of chronic inflammation, S100A9 deficiency results in worsened anxiety-like behavior 2 wk after sepsis. Taken together, these results indicate that S100A8/A9 contributes to several facets of neuroinflammation in sepsis survivor mice, including granulocyte recruitment and priming of microglial-reactive oxygen species and cytokine production, and that these processes may be protective against anxiety behavior in sepsis survivors.

Associations of the consumer food environment with eating behaviours and BMI.

OBJECTIVE: To examine cross-sectional associations of four aspects of the consumer food environment - price, availability, marketing and product placement - with BMI and fruit and vegetable intake. DESIGN: This cross-sectional study measured the consumer food environment using grocery store audits and surveys. Outcomes were measured through surveys and physical exams. Multivariable linear regression models were run; models were all adjusted for age, neighbourhood, education, race/ethnicity and financial burden. SETTING: Non-proportional quota sample of four socio-economically and racial/ethnically diverse neighbourhoods in Chicago, IL. PARTICIPANTS: Women (n 228) aged 18-44 years. RESULTS: Participants who reported seeing healthy food marketing had a higher vegetable intake (ß = 0·24, 95 % CI 0·06, 0·42). There was some suggestive evidence that participants who shopped at stores that were more expensive (ß = -0·90, 95 % CI -1·94, 0·14) had lower BMI, but this association was not statistically significant. Multivariable regression models did not indicate any significant association between any measure of the consumer food environment and fruit intake. CONCLUSIONS: Our findings add to the growing interest in the role of the consumer food environment in health behaviours. Further research is needed to better understand the role of price and marketing characteristics on eating behaviours and BMI.

Phosphorylated self-peptides alter human leukocyte antigen class I-restricted antigen presentation and generate tumor-specific epitopes.

Human leukocyte antigen (HLA) class I molecules present a variety of posttranslationally modified epitopes at the cell surface, although the consequences of such presentation remain largely unclear. Phosphorylation plays a critical cellular role, and deregulation in phosphate metabolism is associated with disease, including autoimmunity and tumor immunity. We have solved the high-resolution structures of 3 HLA A2-restricted phosphopeptides associated with tumor immunity and compared them with the structures of their nonphosphorylated counterparts. Phosphorylation of the epitope was observed to affect the structure and mobility of the bound epitope. In addition, the phosphoamino acid stabilized the HLA peptide complex in an epitope-specific manner and was observed to exhibit discrete flexibility within the antigen-binding cleft. Collectively, our data suggest that phosphorylation generates neoepitopes that represent demanding targets for T-cell receptor ligation. These findings provide insights into the mode of phosphopeptide presentation by HLA as well as providing a platform for the rational design of a generation of posttranslationally modified tumor vaccines.

Cord blood adiponectin and leptin are associated with a lower risk of stunting during infancy.

Undernutrition is responsible for up to 45% of deaths in children under five, with low- and middle-income countries disproportionately affected. Adipokines are known modulators of metabolism and have been linked to growth rates and neurocognition during infancy. We examined the relationship(s) between cord blood adiponectin and leptin and both longitudinal growth and cognition during the first year of life using generalized estimating equations. Infants were classified as underweight (weight-for-age z-score [WAZ]), stunted (height-for-age z-score [HAZ]) or wasted (weight-for-height z-score [WHZ]) using WHOAnthro software. Cord blood adiponectin and leptin levels were highly correlated (r = 0.35, P < 0.0001) and positively associated with birth WAZ (r = 0.34 and r = 0.45, P < 0.0001, respectively). Adipokines were independently, inversely associated with weight gain. Infants in the highest quintile of adipokine production had a lower risk of being stunted, while neither was associated with lower WAZ or WHZ in final adjusted models. Cognition was not found to be independently related to cord blood leptin or adiponectin. The negative association with adipokines and rate of weight gain during infancy may reflect heightened nutritional status at birth rather than a direct hormonal influence. The relationship between leptin or adiponectin and longitudinal length gains suggests that both adipokines may promote linear growth during infancy.

A Look at COVID-19 Global Health Situation, 1-Year Post Declaration of the Pandemic.

The new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic on 11 March 2020 by the World Health Organization (WHO). The impacts of COVID-19 have changed over the past year globally. There were 116 million confirmed cases of COVID-19 in more than 220 countries, including 2.5 million deaths, as reported at the end of the first week of March 2021. Throughout this time, different variants of SARS-CoV-2 have emerged. In early March, the United States of America (USA) led in both confirmed cases and casualties, while India followed in the number of confirmed cases and Brazil in the number of deaths. Vaccines are available in the USA and worldwide to help combat COVID-19. The level of preparedness among multisectoral communities played a role in transmission rates; therefore, lessons learned from past outbreaks, alongside this pandemic, are crucial in establishing policies and regulations to reduce and/or prevent the spread. This narrative literature review provides an update on the global spread of the COVID-19 outbreak, and the current impact of the pandemic 1-year after the declaration, preparedness, and mitigation efforts since the outbreak.

Post-acute Sequelae in COVID-19 Survivors: an Overview.

In the acute phase of SARS-CoV-2 infection, varying degrees of clinical manifestations have been noticed in patients. Some patients who recovered from the infection developed long-term effects which have become of interest to the scientific and medical communities, as it relates to pathogenesis and the multidisciplinary approach to treatment. Long COVID (long-term or long-haul) is the collective term used to define recovered individuals of SARS-CoV-2 infection who have presented with persistent COVID symptoms, as well as the emergence of disorders and complications. Following the review of literature from major scientific databases, this paper investigated long COVID and the resulting post-sequela effects on survivors, regardless of initial disease severity. The clinical manifestations and multisystem complications of the disease specifically, cardiovascular, neurologic and psychologic, hematologic, pulmonary, dermatologic, and other ailments were discussed. Patients with chronic COVID-19 were found to experience heart thrombosis leading to myocardial infarction, inflammation, lung fibrosis, stroke, venous thromboembolism, arterial thromboembolism, "brain fog", general mood dysfunctions, dermatological issues, and fatigue. As the disease continues to progress and spread, and with the emergence of new variants the management of these persisting symptoms will pose a challenge for healthcare providers and medical systems in the next period of the pandemic. However, more information is needed about long COVID, particularly concerning certain patient populations, variability in follow-up times, the prevalence of comorbidities, and the evolution of the spread of infection. Thus, continued research needs to be conducted concerning the disease pathology to develop preventative measures and management strategies to treat long COVID.

The efficacy assessment of convalescent plasma therapy for COVID-19 patients: a multi-center case series.

Convalescent plasma (CP) transfusion has been indicated as a promising therapy in the treatment for other emerging viral infections. However, the quality control of CP and individual variation in patients in different studies make it rather difficult to evaluate the efficacy and risk of CP therapy for coronavirus disease 2019 (COVID-19). We aimed to explore the potential efficacy of CP therapy, and to assess the possible factors associated with its efficacy. We enrolled eight critical or severe COVID-19 patients from four centers. Each patient was transfused with 200-400 mL of CP from seven recovered donors. The primary indicators for clinical efficacy assessment were the changes of clinical symptoms, laboratory parameters, and radiological image after CP transfusion. CP donors had a wide range of antibody levels measured by serology tests which were to some degree correlated with the neutralizing antibody (NAb) level. No adverse events were observed during and after CP transfusion. Following CP transfusion, six out of eight patients showed improved oxygen support status; chest CT indicated varying degrees of absorption of pulmonary lesions in six patients within 8 days; the viral load was decreased to a negative level in five patients who had the previous viremia; other laboratory parameters also tended to improve, including increased lymphocyte counts, decreased C-reactive protein, procalcitonin, and indicators for liver function. The clinical efficacy might be associated with CP transfusion time, transfused dose, and the NAb levels of CP. This study indicated that CP might be a potential therapy for severe patients with COVID-19.

Mannan-MUC1-pulsed dendritic cell immunotherapy: a phase I trial in patients with adenocarcinoma.

PURPOSE: Tumor antigen-loaded dendritic cells show promise for cancer immunotherapy. This phase I study evaluated immunization with autologous dendritic cells pulsed with mannan-MUC1 fusion protein (MFP) to treat patients with advanced malignancy. EXPERIMENTAL DESIGN: Eligible patients had adenocarcinoma expressing MUC1, were of performance status 0 to 1, with no autoimmune disease. Patients underwent leukapheresis to generate dendritic cells by culture ex vivo with granulocyte macrophage colony-stimulating factor and interleukin 4 for 5 days. Dendritic cells were then pulsed overnight with MFP and harvested for reinjection. Patients underwent three cycles of leukapheresis and reinjection at monthly intervals. Patients with clinical benefit were able to continue with dendritic cell-MFP immunotherapy. RESULTS: Ten patients with a range of tumor types were enrolled, with median age of 60 years (range, 33-70 years); eight patients were of performance status 0 and two of performance status 1. Dendritic cell-MFP therapy led to strong T-cell IFNgamma Elispot responses to the vaccine and delayed-type hypersensitivity responses at injection sites in nine patients who completed treatments. Immune responses were sustained at 1 year in monitored patients. Antibody responses were seen in three patients only and were of low titer. Side effects were grade 1 only. Two patients with clearly progressive disease (ovarian and renal carcinoma) at entry were stable after initial therapy and went on to further leukapheresis and dendritic cell-MFP immunotherapy. These two patients have now each completed over 3 years of treatment. CONCLUSIONS: Immunization produced T-cell responses in all patients with evidence of tumor stabilization in 2 of the 10 advanced cancer patients treated. These data support further clinical evaluation of this dendritic cell-MFP immunotherapy.

Regional distribution of T-tubule density in left and right atria in dogs.

BACKGROUND: The peculiarities of transverse tubule (T-tubule) morphology and distribution in the atrium-and how they contribute to excitation-contraction coupling-are just beginning to be understood. OBJECTIVES: The objectives of this study were to determine T-tubule density in the intact, live right and left atria in a large animal and to determine intraregional differences in T-tubule organization within each atrium. METHODS: Using confocal microscopy, T-tubules were imaged in both atria in intact, Langendorf-perfused normal dog hearts loaded with di-4-ANEPPS. T-tubules were imaged in large populations of myocytes from the endocardial surface of each atrium. Computerized data analysis was performed using a new MatLab (Mathworks, Natick, MA) routine, AutoTT. RESULTS: There was a large percentage of myocytes that had no T-tubules in both atria with a higher percentage in the right atrium (25.1%) than in the left atrium (12.5%) (P < .02). The density of transverse and longitudinal T-tubule elements was low in cells that did contain T-tubules, but there were no significant differences in density between the left atrial appendage, the pulmonary vein-posterior left atrium, the right atrial appendage, and the right atrial free wall. In contrast, there were significant differences in sarcomere spacing and cell width between different regions of the atria. CONCLUSION: There is a sparse T-tubule network in atrial myocytes throughout both dog atria, with significant numbers of myocytes in both atria-the right atrium more so than the left atrium-having no T-tubules at all. These regional differences in T-tubule distribution, along with differences in cell width and sarcomere spacing, may have implications for the emergence of substrate for atrial fibrillation.

A phase 2, single-arm study of an autologous dendritic cell treatment against mucin 1 in patients with advanced epithelial ovarian cancer.

BACKGROUND: Mucin 1 antigen, highly expressed by epithelial ovarian cancer (EOC), is a potential target for immunotherapy. A previous successful phase 1 trial was conducted in patients with adenocarcinoma who were injected with Cvac, autologous monocyte-derived dendritic cells (DCs) incubated with mannosylated mucin 1 protein (M-FP). The present study was a phase 2 trial of Cvac in patients with advanced EOC. METHODS: Eligible patients had EOC with progressive disease, defined as an increase in CA125 of ≥ 25% in 1 month. The primary endpoint was CA125 response or stabilization. Peripheral blood mononuclear cells were collected by leukapheresis and cultured to generate DCs. The DC were incubated with M-FP, and after washing were prepared for injection into the patient intradermally every 4 weeks for 3 doses, then every 10 weeks for up to 12 months. RESULTS: All 28 patients recruited were evaluable for safety and 26 for efficacy. All had undergone surgery and platinum-based chemotherapy, and 57% of patients received ≥ 3 chemotherapy regimens. There were no Grade 3 or 4 toxicities considered related to Cvac. Four patients showed CA125 response or stabilization (2 patients with major responses, 1 minor response, 1 stabilization) of median duration 10.3 months (5.3-16.3 months). An additional patient had > 25% CA125 reduction (not confirmed). CONCLUSIONS: Cvac immunotherapy was well tolerated. Clinical activity in EOC was evident based on decline or stabilization of CA125 in some patients, supporting ongoing development of Cvac in ovarian carcinoma and planning of additional trials of patients in remission is currently underway.