Simulated Microgravity Impairs Human NK Cell Cytotoxic Activity Against Space Radiation-Relevant Leukemic Cells.

Natural killer (NK) cells are important effectors of the innate immune system. Unlike T cells, NK cells do not require antigen-priming, making them an important first-line of defense against malignant cells. Because of the potential for increased cancer risk as a result of astronaut exposure to space radiation, we performed studies to determine whether conditions of microgravity present during spaceflight affects the body's natural defenses against leukemogenesis. Human NK cells were cultured for 48 hours under normal gravity and simulated microgravity (sµG), and cytotoxicity against K-562 (CML) and MOLT-4 (T-ALL) cell lines was measured using standard methodology or under continuous conditions of sµG. Even this brief exposure to sµG markedly reduced NK cytotoxicity against both leukemic cells using standard assay procedures, and these deleterious effects were even more pronounced in continuous sµG. RNA-seq performed on NK cells from two healthy donors provided insight into the mechanism(s) by which sµG reduced cytotoxicity. Given our prior report that human HSC exposed to simulated space radiation gave rise to T-ALL in vivo , the reduced cytotoxicity against MOLT-4 is striking and raises the possibility that µG may add to astronaut risk of leukemogenesis during prolonged missions beyond LEO.

Transplanting FVIII/ET3-secreting cells in fetal sheep increases FVIII levels long-term without inducing immunity or toxicity.

Hemophilia A is the most common X-linked bleeding disorder affecting more than half-a-million individuals worldwide. Persons with severe hemophilia A have coagulation FVIII levels <1% and experience spontaneous debilitating and life-threatening bleeds. Advances in hemophilia A therapeutics have significantly improved health outcomes, but development of FVIII inhibitory antibodies and breakthrough bleeds during therapy significantly increase patient morbidity and mortality. Here we use sheep fetuses at the human equivalent of 16-18 gestational weeks, and we show that prenatal transplantation of human placental cells (107-108/kg) bioengineered to produce an optimized FVIII protein, results in considerable elevation in plasma FVIII levels that persists for >3 years post-treatment. Cells engraft in major organs, and none of the recipients mount immune responses to either the cells or the FVIII they produce. Thus, these studies attest to the feasibility, immunologic advantage, and safety of treating hemophilia A prior to birth.

Immediate effects of acute Mars mission equivalent doses of SEP and GCR radiation on the murine gastrointestinal system-protective effects of curcumin-loaded nanolipoprotein particles (cNLPs).

Introduction: Missions beyond low Earth orbit (LEO) will expose astronauts to ionizing radiation (IR) in the form of solar energetic particles (SEP) and galactic cosmic rays (GCR) including high atomic number and energy (HZE) nuclei. The gastrointestinal (GI) system is documented to be highly radiosensitive with even relatively low dose IR exposures capable of inducing mucosal lesions and disrupting epithelial barrier function. IR is also an established risk factor for colorectal cancer (CRC) with several studies examining long-term GI effects of SEP/GCR exposure using tumor-prone APC mouse models. Studies of acute short-term effects of modeled space radiation exposures in wildtype mouse models are more limited and necessary to better define charged particle-induced GI pathologies and test novel medical countermeasures (MCMs) to promote astronaut safety. Methods: In this study, we performed ground-based studies where male and female C57BL/6J mice were exposed to γ-rays, 50 MeV protons, or 1 GeV/n Fe-56 ions at the NASA Space Radiation Laboratory (NSRL) with histology and immunohistochemistry endpoints measured in the first 24 h post-irradiation to define immediate SEP/GCR-induced GI alterations. Results: Our data show that unlike matched γ-ray controls, acute exposures to protons and iron ions disrupts intestinal function and induces mucosal lesions, vascular congestion, epithelial barrier breakdown, and marked enlargement of mucosa-associated lymphoid tissue. We also measured kinetics of DNA double-strand break (DSB) repair using gamma-H2AX- specific antibodies and apoptosis via TUNEL labeling, noting the induction and disappearance of extranuclear cytoplasmic DNA marked by gamma-H2AX only in the charged particle-irradiated samples. We show that 18 h pre-treatment with curcumin-loaded nanolipoprotein particles (cNLPs) delivered via IV injection reduces DSB-associated foci levels and apoptosis and restore crypt villi lengths. Discussion: These data improve our understanding of physiological alterations in the GI tract immediately following exposures to modeled space radiations and demonstrates effectiveness of a promising space radiation MCM.

Lidocaine Ineffectiveness Suggests New Psychopharmacology Drug Target.

Objectives: The mechanism of many neuropsychiatric disorders remains unknown, but the ineffectiveness of the sodium channel blocker lidocaine has been suggested to be a biomarker for Attention Deficit Hyperactivity Disorder (ADHD) and a severe form of Premenstrual Syndrome (PMS) that is considered psychiatric. We conducted single-arm double-blind clinical trials to test whether lidocaine ineffectiveness can be used as a biomarker to identify people with these conditions and provide a clue as to the molecular mechanism and potential psychopharmacological intervention. Experimental Design: We developed a noninvasive taste test for lidocaine ineffectiveness, validated by comparing lidocaine injections to pain testing in 12 subjects, and assessed it in individuals with ADHD and PMS. Principal Observations: Lidocaine ineffectiveness had a strong association in women with ADHD + PMS in a sample of 53 subjects and controls (p < 0.001). Conclusions: These results suggest the possibility of the biological understanding of the combination of ADHD and PMS that is characteristic of the psychiatric disorder Premenstrual Dysphoric Disorder (PMDD). These results and comparison to family pedigrees of a neuromuscular channelopathy with overlapping symptoms suggest the possibility that the clinical phenotype in PMDD is produced by sensory overstimulation, and amenable to molecular understanding and treatment.

Role of Monotherapy with a P2Y12 Inhibitor for Secondary Prevention in Patients with Established Atherosclerosis.

PURPOSE OF REVIEW: The role of monotherapy with a P2Y12 inhibitor for secondary prevention of cardiovascular diseases has been assessed in several randomized trials. In this article, we summarize the evidence regarding P2Y12 monotherapy for secondary prevention in each one of the major vascular territories. RECENT FINDINGS: Available data including a large recent meta-analysis show no differences in terms of all-cause death, vascular death, stroke, and a minor difference of the risk of myocardial infarction with P2Y12 monotherapy as compared to dual antiplatelet therapy. Overall, mono antiplatelet therapy with aspirin and the P2Y12 inhibitors appear similar in efficacy. However, there are clinical conditions that may suggest one drug regimen over another in secondary prevention. The risk of bleeding must always be weighed in each patient individually for the optimal choice of the antiplatelet regimen.

Resultados de la cirugía endoscópica de la glándula tiroides por vía transaxilar en Perú / Results of transaxillary endoscopic surgery of the thyroid gland in Peru

RESUMEN Objetivo: Describir los resultados de la tiroidectomía endoscópica transaxilar sin insuflación de CO2 en Perú. Material y métodos: Estudio descriptivo, retrospectivo de una serie de casos basado en la revisión de las historias clínicas de los pacientes con tumor tiroideo sometidos a tiroidectomía endoscópica transaxilar sin insuflación de CO entre noviembre 2014 y marzo 2017, en instituciones públicas y privadas del sistema nacional de salud de la ciudad de Lima. Resultados: Se realizaron 24 tiroidectomías endoscópicas, de las cuales 15 fueron hemitiroidectomia, 8 tiroidectomía total y una tiroidectomía subtotal. El tiempo operatorio promedio fue de 193,8 minutos. Las complicaciones más frecuentes fueron el hematoma postoperatorio (12,5%) seguido de la hipocalcemia transitoria (8,3%); ningún caso presentó lesión del plexo braquial. Conclusiones: La tiroidectomía endoscópica por vía transaxilar es un procedimiento seguro, factible de realizar en instituciones de salud que cuenten con el equipamiento de cirugía video endoscópica, que podría indicarse en determinados pacientes.

SUMMARY Objective: To describe the results of transaxillary endoscopic surgery of the thyroid gland without insufflating CO2 in Peru. Methods: A retrospective case series based of chart review of patients with thyroid cancer undergoing transaxillary endoscopic surgery of the thyroid gland without insufflating CO2 from November 2014 to March 2017 in public and private institutions in Lima. Results: 24 transaxillary endoscopic procedures were performed, 15 of which were hemithyroidectomies, 8 were total thyroidectomies and one subtotal thyroidectomy. Mean operating time was 193.8 minutes. The most common complication was post operatory hematoma (12.5%) followed by transient hypocalcemia (8.3%), no lesions of the brachial plexus were observed. Conclusions: Transaxillary endoscopic surgery of the thyroid gland is a safe and feasible procedure to be performed in equipped centers.

[The effectiveness and safety of subcutaneous immunotherapy for inhalable allergens in patients with respiratory allergies after one year of treatment]. / Eficacia y seguridad de la inmunoterapia subcutánea para alérgenos inhalables en pacientes con alergia respiratoria a un año de tratamiento.

BACKGROUND: Allergen-specific immunotherapy is an important therapeutic modality for the management of allergic rhinitis and allergic asthma. OBJECTIVE: To assess the effectiveness and safety of allergen-specific subcutaneous immunotherapy in patients with respiratory allergies at the University Hospital of Puebla after twelve months of treatment. METHODS: A longitudinal, sequential, analytic, quasi-experimental, prolective study. The study was carried out for twelve months with patients of both sexes, aged four to sixty-five years, diagnosed with asthma and/or rhinitis, and with sensitization to aeroallergens. The CARAT and Portnoy questionnaires were collected every two months in order to assess the effectiveness and safety respectively. RESULTS: 47 patients were included: 37 (78.7 %) of them were female. The average age was 29.8 years. 76.6 % of them were diagnosed with allergic rhinitis, and 23.4 % of them were diagnosed with both asthma and allergic rhinitis. The comparison of averages of the initial CARAT questionnaire against the final average by means of a student's t-test showed a t-value of -8.86 and a p-value of < 0.05. A total frequency of local adverse reactions of 19 % and systemic adverse reactions of 2.1 % was reported after 6 and 12 months of treatment. CONCLUSIONS: The assessed scheme of immunotherapy, derived from the Mexican clinical practice guidelines of immunotherapy 2011, is effective with a desirable safety profile.

Antecedentes: La inmunoterapia específica con alérgenos es una importante modalidad terapéutica para el manejo de la rinitis y asma alérgica. Objetivo: Evaluar la eficacia y seguridad de la inmunoterapia subcutánea con alérgenos en pacientes con alergia respiratoria del Hospital Universitario de Puebla posterior a 12 meses de tratamiento. Métodos: Estudio longitudinal, secuencial, analítico, cuasiexperimental, prolectivo. Durante 12 meses se incluyeron pacientes con asma o rinitis, sensibilizados a aeroalérgenos, de cuatro a 65 años y de ambos sexos; bimensualmente se recolectaron los cuestionarios CARAT y Portnoy para evaluar la eficacia y seguridad, respectivamente. Resultados: Se incluyeron 47 pacientes, 37 (78.7 %) mujeres. La edad promedio fue de 29.8 años. El 76.6 % tuvo diagnóstico de rinitis alérgica y 23.4 % de asma y rinitis alérgica. Al comparar el promedio del CARAT inicial contra el promedio final mediante prueba de t de Student se obtuvo un valor de ­8.86 y p < 0.05. Se reportó una frecuencia total de reacciones adversas locales de 19 % y de reacciones adversas sistémicas de 2.1 % a los seis y 12 meses del tratamiento. Conclusiones: El esquema de inmunoterapia evaluado, derivado de la Guía Mexicana de Práctica Clínica de Inmunoterapia 2011, es eficaz con un conveniente perfil de seguridad.

Black American College Students Report Higher Memory of Love for Mothers in Childhood Than White Students.

Cultural differences between Black and White individuals in the South are connected to the inequitable history of the United States. We wondered if these cultural differences would translate to a particularly precious aspect of life: memories of love felt in childhood toward one's parents. Some past studies have shown that Whites score higher on parental attachment measures to parents than Blacks, while other studies show no significant differences. However, no previous study has ever measured memory of feelings of love in relation to differences between ethnicities. In this study, Black (n = 124) and White (n = 125) undergraduates self-reported the strength and frequency of their past feelings of love toward their mother and father in first, sixth, and ninth grade as well as their current feelings of love. Results suggested that Black students reported feeling more love for their mothers in first, sixth, and ninth grades compared to White students. These findings were not explained when we statistically adjusted for age, gender, socioeconomic status, education levels, income, number of years spent living with mother or father, stress, or personality. Therefore, this relationship may be explained by unmeasured or unmeasurable cultural differences. The direction of this effect was in the opposite direction from what we expected based on past attachment research. Given the inequities in U.S. history and the current discussions around ethnicity and race in the United States, the finding that Blacks reported higher remembered feelings of love for their mothers in childhood is intriguing and worthy of dissemination and discussion.

Refractory nausea and vomiting in the setting of well-controlled idiopathic intracranial hypertension.

Summary A 27-year-old woman with a history of recurrent nausea and vomiting in the setting of idiopathic intracranial hypertension (IIH) was admitted for control of unremitting nausea and vomiting. Initial antiemetic therapy included optimisation of IIH therapy by titrating acetazolamide, in addition to using ondansetron and metoclopramide as needed, with minimal relief. She was ultimately treated with palonosetron with complete resolution of her acute nausea. Nausea, often treated with 5-hydroxytryptamine (5-HT3) receptor antagonists, approved for perioperative and chemotherapy-induced nausea, are used off-label to treat nausea and vomiting outside of those settings. The efficacy of different regimens has been compared in the literature and continues to remain controversial. When choosing from different 5-HT3 antagonists there are other considerations, in addition to efficacy to consider: dosing schedule, half-life, time of onset, duration and cost-to-benefit ratio, and although one 5-HT3 antagonist may not have been effective, another one may be. In our case palonosetron, with a significantly longer half-life than other 5-HT3 antagonists, was effective in resolving nausea when compared with the more commonly used ondansetron.