Overcoming T-cell exhaustion in LCH: PD-1 blockade and targeted MAPK inhibition are synergistic in a mouse model of LCH.

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207+ dendritic cells (DCs) with persistent MAPK pathway activation. Standard-of-care chemotherapies are inadequate for most patients with multisystem disease, and optimal strategies for relapsed and refractory disease are not defined. The mechanisms underlying development of inflammation in LCH lesions, the role of inflammation in pathogenesis, and the potential for immunotherapy are unknown. Analysis of the immune infiltrate in LCH lesions identified the most prominent immune cells as T lymphocytes. Both CD8+ and CD4+ T cells exhibited "exhausted" phenotypes with high expression of the immune checkpoint receptors. LCH DCs showed robust expression of ligands to checkpoint receptors. Intralesional CD8+ T cells showed blunted expression of Tc1/Tc2 cytokines and impaired effector function. In contrast, intralesional regulatory T cells demonstrated intact suppressive activity. Treatment of BRAFV600ECD11c LCH mice with anti-PD-1 or MAPK inhibitor reduced lesion size, but with distinct responses. Whereas MAPK inhibitor treatment resulted in reduction of the myeloid compartment, anti-PD-1 treatment was associated with reduction in the lymphoid compartment. Notably, combined treatment with MAPK inhibitor and anti-PD-1 significantly decreased both CD8+ T cells and myeloid LCH cells in a synergistic fashion. These results are consistent with a model that MAPK hyperactivation in myeloid LCH cells drives recruitment of functionally exhausted T cells within the LCH microenvironment, and they highlight combined MAPK and checkpoint inhibition as a potential therapeutic strategy.

Effects of laropiprant on nicotinic acid-induced flushing in patients with dyslipidemia.

Niacin (nicotinic acid) is not optimally used mainly because of flushing, a process mediated primarily by prostaglandin D(2), which leads to poor patient compliance and suboptimal dosing. This phase II dose-ranging study was designed to assess whether the prostaglandin D(2) receptor 1 antagonist laropiprant (LRPT; MK-0524) would (1) reduce extended-release niacin (ERN)-induced flushing in dyslipidemic patients and (2) support a novel accelerated ERN dosing paradigm: initiating ERN at 1 g and advancing rapidly to 2 g. In part A of the study, 154 dyslipidemic patients were randomized to LRPT 150 mg/day or placebo in a 9-week, 2-period crossover study. Patients who completed part A (n = 122) entered part B (after a 2-week washout), together with additional patients who entered part B directly (n = 290). Part B patients were randomized to placebo, ERN 1 g (Niaspan, no previous titration), or ERN 1 g coadministered with LRPT 18.75, 37.5, 75, or 150 mg for 4 weeks, with doubling of the respective doses for the remaining 4 weeks. Patients treated with LRPT plus ERN experienced significantly less ERN-induced flushing than those treated with ERN alone during the initiation of treatment (ERN 1 g, week 1) and the maintenance treatment (ERN 1 to 2 g, weeks 2 to 8). All doses of LRPT were maximally effective in inhibiting niacin-induced flushing. LRPT did not alter the beneficial lipid effects of ERN. LRPT plus ERN was well tolerated. In conclusion, the significant reduction in ERN-induced flushing provided by LRPT plus ERN supports an accelerated ERN dose-advancement paradigm to achieve rapidly a 2-g dose in dyslipidemic patients.

Donación de óvulos posterior a detorsión de ovario isquémico por pedículo torcido debido a quiste paratubárico / Oocyte donation following ischemic ovarian detorsion for twisted pedicle due to paratubal cyst

RESUMEN La torsión anexial es secundaria a quistes ováricos generalmente benignos. La cirugía habitual es la salpingooferectomía. Sin embargo, para mantener la función ovárica se recomienda una cirugía mínimamente invasiva con detorsión y conservación del ovario independientemente de su apariencia. Presentamos el caso de una mujer de 19 años con diagnóstico de quiste a pedículo torcido, a quien se realizó detorsión laparoscópica del pedículo torcido y exéresis del quiste paratubárico con preservación de ovario, a pesar del aspecto isquémico. La paciente presentó evolución favorable y participó en un programa de ovodonación, obteniéndose ovocitos del ovario antes afectado en cantidad y calidad similar al ovario no afectado. La detorsión ovárica laparoscópica y conservación del ovario comprometido independientemente de su apariencia es un procedimiento seguro y eficaz para preservar la fertilidad.

Tuberculosis genital en el tercer trimestre del embarazo. Comunicación de un caso y revisión de la literatura / Tuberculosis genital en el tercer trimestre del embarazo. Comunicación de un caso y revisión de la literatura

RESUMEN La tuberculosis es una de las principales causas de muerte generada por un agente infeccioso a nivel mundial. Generalmente su afectación es pulmonar, pero bajo ciertas circunstancias puede diseminarse a través de vía linfática o sanguínea y afectar tejidos u órganos distantes. En el embarazo puede ocasionar múltiples complicaciones maternas y neonatales. A pesar de ser un problema importante de salud pública, en la actualidad no existe suficiente evidencia en las guías sobre la epidemiologia, flujograma diagnóstico y tratamiento de la tuberculosis genital en el embarazo. Se presenta un caso de tuberculosis genital en el tercer trimestre del embarazo con evolución tórpida, dificultad para el diagnóstico y retraso en la instauración del tratamiento.

ABSTRACT Tuberculosis is one of the main causes of death generated by an infectious agent worldwide. It usually affects the lungs, but under certain circumstances it can spread through the lymphatic or blood routes and affect distant tissues or organs. In pregnancy it can cause multiple maternal and neonatal complications. Despite being an important public health problem, there is currently insufficient evidence in the guidelines on the epidemiology, diagnostic flow chart and treatment of genital tuberculosis in pregnancy. A case of genital tuberculosis in the third trimester of pregnancy with a torpid evolution is presented, with difficulty in diagnosis and delay in the establishment of treatment.

Effects of ezetimibe/simvastatin on lipoprotein subfractions in patients with primary hypercholesterolemia: an exploratory analysis of archived samples using two commercially available techniques.

BACKGROUND: Cholesterol-rich lipoproteins, including low-density lipoprotein cholesterol (LDL-C), intermediate-density lipoprotein cholesterol (IDL-C), and very-low-density lipoprotein cholesterol (VLDL-C), are known to promote atherosclerosis. Ezetimibe/simvastatin (E/S) is an efficacious lipid-lowering treatment that inhibits both the intestinal absorption and biosynthesis of cholesterol. OBJECTIVE: The aim of the current analysis was to compare the effects of ezetimibe and simvastatin monotherapy and E/S treatment on lipoprotein subfractions and LDL particle size in patients with primary hypercholesterolemia. METHODS: This was an exploratory (hypothesis generating) analysis of archived plasma samples drawn from patients in a multicenter, randomized, double-blind, placebo-controlled, parallel-arm study. After a washout and diet/placebo run-in, patients with hypercholesterolemia (LDL-C, > or =145- < or =250 mg/dL; triglycerides, < or =350 mg/dL) were randomized equally to 1 of 10 daily treatments for 12 weeks: E/S (10/10, 10/20, 10/40, or 10/80 mg), simvastatin monotherapy (10, 20, 40, or 80 mg), ezetimibe monotherapy (10 mg), or placebo. A subset of patients had lipid subfraction measurements taken at baseline (week 0) and postrandomization (week 12). Plasma samples were used to quantify cholesterol associated with VLDL subfractions (VLDLI+2 and VLDL3), IDL, and 4 LDL subfractions (LDL1-4) via the Vertical Auto Profile II method. LDL-C particle size was determined using segmented gradient gel electrophoresis. The primary end point was median percent change in subfraction cholesterol for E/S versus ezetimibe or simvastatin monotherapy, pooled across doses. RESULTS: Of the 1528 patients randomized in the original study, 1397 (91%) had lipid subfraction measurements taken. E/S was associated with significant reductions in VLDL-CI+2, VLDL-C3, IDL-C, LDL-C1, LDL-C2, and LDL-C3 versus ezetimibe, simvastatin, and placebo. E/S resulted in near-additive reductions in VLDL-CI+2, VLDL-C3, IDL-C, LDL-C1, LDL-C2, and LDL-C3 versus ezetimibe and simvastatin monotherapy. Of the subfractions examined, with regard to E/S, the greatest reductions were observed in IDL-C and LDL-C1, LDL-C2, and LDL-C3. When compared with placebo, ezetimibe, simvastatin, and E/S did not shift the distribution of LDL particles toward a larger, more buoyant LDL subclass pattern. CONCLUSION: E/S was more effective than ezetimibe and simvastatin monotherapy in reducing atherogenic lipoprotein subfractions in these patients with primary hypercholesterolemia.

Características maternas y resultados perinatales en mujeres peruanas infectadas con COVID-19: Un estudio observacional y transversal / Maternal characteristic and perinatal outcomes among peruvian women infected with COVID-19. An observational and cross-sectional study

Objetivo: Determinar las características maternas de mujeres infectadas con COVID-19 y de sus neonatos nacidos en el Hospital de atención referencia Covid-19 (HRDT) entre abril y setiembre del 2020. Material y Métodos: Estudio observacional y transversal realizado en el HRDT que incluyó 703 pacientes obstétricas con COVID-19. Resultados: La edad promedio fue de 27 años. El 35.7 % fueron nulíparas y el 95% fueron asintomáticas para COVID-19. Tuvieron COVID-19 leve, moderado y severo el 3%,1% y 1%; respectivamente. Los síntomas más frecuentes fueron tos (84,85%) y anosmia (39,39%). Los signos más comunes fueron Taquipnea (60.61%) y dificultad respiratoria (51,52 %). La gasometría, dímero-D y ferritina sérica estuvieron alterados en el 71%, 54% y 30%; respectivamente. Las complicaciones médicas más frecuentes fueron: sepsis (2,28%), neumonía (2,13%), insuficiencia respiratoria (2,13%) y shock séptico (1,14%). Las complicaciones obstétricas más frecuentes fueron Rotura prematura de membranas (6,69%), preeclampsia severa (5,41%), síndrome abortivo (3.27%) y trabajo de parto pretérmino (2,56%). El 73,9% de partos fue por Cesárea. El 0,99 % de pacientes requirió unidad de cuidados intensivos y la letalidad materna fue del 0,2%. El 85,7% de neonatos fueron a término y el 97,2 % tuvo APGAR a los 5 minutos ≥7. Hubo 4 muertes neonatales (0,64%) y 16 óbitos (2,58%). Hubo 8 RT-PCR positivas en neonatos (1,3%). Conclusión: La mayoría de pacientes fueron nulíparas, menores de 35 años y asintomáticas para COVID-19. La mayoría de neonatos nacieron por cesárea y evolucionaron favorablemente. Hubo dos muertes maternas, 16 óbitos fetales y 4 muertes neonatales.

Objetive: To determine the maternal characteristics of women infected with COVID-19 and their neonates born in the COVID-19 referral hospital (HRDT) between April and September 2020.Material and Methods: Observational and cross-sectional study carried out in the HRDT that included 703 obstetric patients with COVID-19. Results: The average age was 27 years. 35.7% were nulliparous and 95% were asymptomatic for COVID-19. 3%, 1% and 1% had mild, moderate and severe COVID-19; respectively. The most frequent symptoms were cough (84.85%) and anosmia (39.39%). The most common signs were tachypnea (60.61%) and respiratory distress (51.52%). Blood gas, D-dimer, and ferritin were altered in 71%, 54%, and 30%; respectively. The most frequent medical complications were: sepsis (2.28%), pneumonia (2.13%), respiratory failure (2.13%) and septic shock (1.14%). The most frequent obstetric complications were premature rupture of membranes (6.69%), severe preeclampsia (5.41%), abortive syndrome (3.27%) and preterm labor (2.56%). 73.9% of deliveries were by Caesarean section. 0.99% of patients required intensive care unit and maternal mortality was 0. 2%. 85.7% of neonates were at term and 97.2% had APGAR ≥7 at 5 minutes. There were 4 neonatal deaths (0.64%) and 16 deaths (2,58%). There were 8 positive RT-PCR in neonates (1.3%). Conclusion: The majority of patients were nulliparous, under 35 years of age and asymptomatic for COVID-19. Most of the newborns were born by cesarean section and evolved favorably. There were two maternal deaths, 16 stillbirths, and 4 neonatal deaths.

A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia.

OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety profile of ezetimibe/simvastatin(EZE/SIMVA) combination tablet, relative to ezetimibe (EZE) and simvastatin (SIMVA) monotherapy, in patients with primary hypercholesterolemia. METHODS: This was a randomized, multicenter, double-blind, placebo-controlled, factorial design study After a 6- to 8-week washout period and 4-week, single-blind, placebo run in, hypercholesterolemic patients (low-density lipoprotein cholesterol [LDL-C], 145-250 mg/dL; triglycerides [TG], < or =350 mg/dL) were randomized equally to 1 of 10 daily treatments for 12 weeks: EZE/SIMVA 10/10, 10/20, 10/40, or 10/80 mg; SIMVA 10, 20, 40, or 80 mg; EZE 10 mg; or placebo. The primary efficacy analysis was mean percent change from baseline in LDL-C to study end point Secondary end points included percent changes in other lipid variables and C-reactive protein [CRP]. RESULTS: There were 1528 patients randomized to treatment (792 women, 736 men); mean (SD) age ranged from 54.9 (112) years to 56.4 (10.6) years across pooled treatment groups. The treatment groups were well balanced for baseline demographics. Pooled EZE/SIMVA was associated with greater reductions in LDL-C than pooled SIMVA or EZE alone (P < 0.001). Depending on dose, EZE/SIMVA was associated with reductions in LDL-C of -44.8% to -602%, non-high-density lipoprotein cholesterol of -40.5% to -55.7%, and TG of -22.5% to -30.7%; high-density lipoprotein cholesterol increased by 5.5% to 9.8%. EZE/SIMVA was associated with greater reductions in CRP and remnant-like particle-cholesterol than SIMVA alone (P < 0.001). More patients receiving EZE/SIMVA versus SIMVA achieved LDL-C concentrations <100 mg/dL (78.6% vs 45.9%; P < 0.001). EZE/SIMVA was generally well tolerated, with a safety profile similar to SIMVA monotherapy There were no significant differences between EZE/SIMVA and SIMVA in the incidence of consecutive liver transaminase levels > or =3 times the upper limit of normal (ULN) (1 .5% for EZE/SIMVA and 1.1% for SIMVA; P = NS) or creature kinase levels > or =10 times ULN (0.0% for EZE/SIMVA and 02% for SIMVA; P = NS). CONCLUSION: The EZE/SIMVA tablet was a highly effective and well-tolerated LDL-C-lowering therapy in this study of patients with primary hypercholesterolemia.

Lesiones por quemadura en la embarazada / Injuries from burn in pregnant women

Fundamento: las quemaduras en la embarazada constituyen un reto para el equipo multidisciplinario que se ocupa de su tratamiento. Estas lesiones en dependencia de su extensión, profundidad y el tiempo de gestación de las pacientes, pueden comprometer tanto la vida de la madre como la del feto. Objetivo: determinar la morbi-mortalidad por quemaduras en las embarazadas y la conducta seguida en dependencia del tiempo de gestación, en las pacientes atendidas con estas características en el Servicio de Caumatología del Hospital Universitario Manuel Ascunce Domenech de la ciudad de Camagüey desde el año 2001 hasta el 2010. Método: se realizó un estudio observacional, descriptivo y transversal. El universo estuvo conformado por 585 mujeres que sufrieron quemaduras durante este período, la muestra no probabilística la conformaron 16 pacientes las cuales estaban en estado de gestación. Resultados: Se encontraban en el segundo trimestre de su embarazo siete gestantes para un 43.75 %, y del total de las lesionadas cuatro eran grandes quemaduras. El índice de menos grave representó el 50 % del total de las lesionadas. Con el 68.75 % de las embarazadas se siguió una conducta expectante. Conclusiones: La mayoría de las gestantes estaban clasificadas como menos graves. El estado materno al egreso fue satisfactorio en la totalidad de las pacientes, no así el estado fetal.

Background: burns in pregnant women are a challenge for the multidisciplinary team dealing with their treatment. These lesions depending on its size, depth and time of gestation of patients, may compromise the life of the mother and the fetus. Objective: to determine the morbidity and mortality due to burns in pregnant women and the management followed depending on gestation time, in patients treated with these features in the Burns unit at the University Hospital Manuel Ascunce Domenech in Camagüey city from 2001 to 2010. Method: an observational, descriptive and cross-sectional study was conducted. The universe was constituted by 585 women who suffered burns during this period; 16 pregnant patients were taken through a non probabilistic sampling. Results: seven pregnant women were in the second trimester of their pregnancy for a 43.75 %, from the total of the injured four had large burns. The less serious rate represented 50 % of the total number of the injured. With the 68.75 % of pregnant women an expectant management was followed. Conclusions: the majority of pregnant women were classified as less serious. The maternal state when discharge from hospital was satisfactory in all patients, unlike the fetal state.

The upper GI safety and tolerability of oral alendronate at a dose of 70 milligrams once weekly: a placebo-controlled endoscopy study.

OBJECTIVE: Alendronate (10 mg daily) has been shown in long term clinical trials to be an effective treatment for postmenopausal osteoporosis. A weekly dosing regimen of alendronate is preferred by both patients and physicians, as it has the potential to provide greater convenience and enhance compliance. In a 1-yr clinical trial, alendronate (70 mg once weekly) was equally efficacious and at least as well tolerated as the 10-mg daily dose in the treatment of postmenopausal osteoporosis, despite the higher unit dosage required. We conducted a randomized, double blind, placebo- and active-controlled endoscopy study to confirm the results of this clinical trial. We hypothesized that mean endoscopic gastric erosion scores would be similar in subjects receiving alendronate (70 mg once weekly) and those receiving a placebo. METHODS: Two hundred seventy-seven subjects (90 men and 187 women) were randomized to one of three treatment groups: 1) alendronate (70 mg once weekly) for 10 wk (N = 126), 2) placebo (once weekly) for 10 wk (N = 126), or 3) placebo (once weekly) for 10 wk followed by aspirin (650 mg q.i.d.) for the last week as the positive control (N = 25). Esophagogastroduodenoscopy was performed 5 to 7 days after the last dose of alendronate or matching placebo. RESULTS: The mean gastric erosion scores (Lanza scale) were similar in subjects given alendronate (70 mg once weekly) and those given a placebo (0.32 vs 0.35, respectively; 95% CI for difference = -0.22-0.16, p = 0.75), whereas scores in both groups were significantly lower than in those given aspirin (3.09; p < 0.001). Endoscopic gastroduodenal ulcers occurred in no alendronate (0%), two placebo (1.7%), and five aspirin (23.8%) subjects. The mean erosion scores in the esophagus and duodenum of alendronate and placebo subjects were also similar. The incidences of upper GI symptoms were similar in the alendronate and placebo subjects and did not suggest a relationship with endoscopic lesions. CONCLUSIONS: Alendronate (70 mg once weekly) was not associated with any increase in endoscopic lesions in the upper GI tract relative to a placebo.

Creación de un instrumento para evaluar la calidad de vida en niños con Retinosis Pigmentaria / Devising a way to evaluate life quality in children suffering from Pigmentary Retinosis

Se confeccionó un instrumento para evaluar la calidad de vida en el niño con Retinosis Pigmentaria, para ello se tomó el criterio de 19 expertos a los que se les entregó una planilla con 19 variables para valorar su efectividad y se les pidió que sugirieran otras. Los jueces evaluaron las variables ofertadas y sugirieron incluir otras. Como resultado se obtuvieron 20 variables agrupadas en tres escalas analógicas visuales, una para niños en forma de dibujos caricaturizados y otra para padres y médicos con consignas verbales. Se añadió además una pregunta abierta que explora Calidad de vida de forma global, y otra que interrogó acerca de otras preocupaciones que pudiera tener el paciente.

An instrument was made to evaluate the quality of life in children suffering from pigmentary retinosis, for that reason the criterion of 19 especialits was taken into account, they received a list with 19 variants to value its effectiveness and they were asked to suggest others. The judges evaluated the offered variables and they suggested to include others. As a result 20 variables were obtained contained in three visual analogical scales. One, in caricatural drawings form, for children and another with verbal watchwords for parents and doctors. It was also added an open question that explores quality of life in aglobal way and another one that interrogated about other concern that the patient could have.

El dibujo libre en el niño con Retinosis Pigmentaria / Free drawing in children with Pigmentary Retinosis

Se realizó un estudio observacional descriptivo en el Centro Provincial de Retinosis Pigmentaria con el objetivo de describir las características del dibujo libre en el niño con Retinosis Pigmentaria. El universo estuvo constituido por los pacientes en etapa escolar y adolescencia temprana con esta enfermedad. La muestra intencional fue de 41 pacientes. En los dibujos realizados se apreció un predominio del uso de 3 a 6 colores con la combinación de colores cálidos sin relleno en la figura, prevalecieron las combinaciones realistas, al igual que el trazado fuerte e inestable con combinación de trazado fuerte y débil. Se apreció coherencia y originalidad en los dibujos. Predominó el paisaje campestre. Los colores más representados en los dibujos fueron rojo, amarillo y azul. Entre los hallazgos más importantes se encuentra que en cuanto a la forma los dibujos tienen puntos de contacto con los de los niños con patologías que expresan inmadurez en la coordinación viso-motora. El tema de los dibujos se corresponde con lo encontrado por otros autores con respecto al dibujo del niño cubano.

A descriptive observational study was carried out in the Provincial Center of Retinosis with the objective of describing the characteristic of the free drawing in children with pigmentary retinosis. This group was constituted by the patients in school stage and in early adolescence with this illness. The intentional sample belonged to 41 patients. It was appreciated predominant use of 3 or 6 colours in the drawings they carried out as well as the combination of warm colours without refilling in the figure, the realistic combinations prevailed, the same as the strong and unstable traced with combination of strong and weak traced. It was appreciated coherence and originality in the drawings. The country landscape prevailed. The colours more represented in drawings were red, yellow and blue. Among the most important discoveries are the drawings taking into account their form, which have points of contact with those drawings of the children with pathologies that express immaturity in the visual and motion coordination. The topics of the drawings is corresponded with the found it by the other authors with respect to drawings of Cuban children.