Evasion of NKG2D-mediated cytotoxic immunity by sarbecoviruses.

SARS-CoV-2 and other sarbecoviruses continue to threaten humanity, highlighting the need to characterize common mechanisms of viral immune evasion for pandemic preparedness. Cytotoxic lymphocytes are vital for antiviral immunity and express NKG2D, an activating receptor conserved among mammals that recognizes infection-induced stress ligands (e.g., MIC-A/B). We found that SARS-CoV-2 evades NKG2D recognition by surface downregulation of MIC-A/B via shedding, observed in human lung tissue and COVID-19 patient serum. Systematic testing of SARS-CoV-2 proteins revealed that ORF6, an accessory protein uniquely conserved among sarbecoviruses, was responsible for MIC-A/B downregulation via shedding. Further investigation demonstrated that natural killer (NK) cells efficiently killed SARS-CoV-2-infected cells and limited viral spread. However, inhibition of MIC-A/B shedding with a monoclonal antibody, 7C6, further enhanced NK-cell activity toward SARS-CoV-2-infected cells. Our findings unveil a strategy employed by SARS-CoV-2 to evade cytotoxic immunity, identify the culprit immunevasin shared among sarbecoviruses, and suggest a potential novel antiviral immunotherapy.

HLA class I signal peptide polymorphism determines the level of CD94/NKG2-HLA-E-mediated regulation of effector cell responses.

Human leukocyte antigen (HLA)-E binds epitopes derived from HLA-A, HLA-B, HLA-C and HLA-G signal peptides (SPs) and serves as a ligand for CD94/NKG2A and CD94/NKG2C receptors expressed on natural killer and T cell subsets. We show that among 16 common classical HLA class I SP variants, only 6 can be efficiently processed to generate epitopes that enable CD94/NKG2 engagement, which we term 'functional SPs'. The single functional HLA-B SP, known as HLA-B/-21M, induced high HLA-E expression, but conferred the lowest receptor recognition. Consequently, HLA-B/-21M SP competes with other SPs for providing epitope to HLA-E and reduces overall recognition of target cells by CD94/NKG2A, calling for reassessment of previous disease models involving HLA-B/-21M. Genetic population data indicate a positive correlation between frequencies of functional SPs in humans and corresponding cytomegalovirus mimics, suggesting a means for viral escape from host responses. The systematic, quantitative approach described herein will facilitate development of prediction algorithms for accurately measuring the impact of CD94/NKG2-HLA-E interactions in disease resistance/susceptibility.

Allergen Immunotherapy management during vaccinations: An international survey.

Vaccination against viral and bacterial pathogens represents a challenging issue in allergic subjects, mainly concerning patients undergoing allergen immunotherapy (AIT). For this reason, an international survey has been performed involving a panel of experts who responded to a series of questions, also concerning the COVID-19 impact on allergen immunotherapy and vaccinations. The results showed that co-administration of vaccines and AIT requires caution, mainly during the pandemic era. Moreover, the choice of AIT product should be oriented considering also the safety profile.

Evaluación de la arteria alveolo-antral mediante tomografía volumétrica en población mexicana y su relación con levantamiento del piso del seno maxilar / CBCT evaluation of the alveolar antral artery in a mexican cohort and its relationship to maxillary sinus floor lifting

Introducción: El conocimiento de la anatomía de la región maxilar debe ser esencial para el cirujano antes de realizar levantamiento del seno maxilar para evitar complicaciones. La arteria alveolo antral forma una anastomosis intraósea con la arteria infraorbitaria a nivel de la pared antero lateral del seno maxilar, aproximadamente a una distancia de entre 18.9 y 19.6 mm desde el reborde alveolar maxilar. La arteria alveolo antral es la encargada de dar vascularidad a la membrana mucosa del seno maxilar, pared antero lateral del seno y tejido perióstico subyacente.Objetivo: Describir y establecer la frecuencia, diámetro y localización dela anastomosis entre la arteria infraorbitaria y la arteria alveolar posterior superior, llamada arteria alveolo antral y su relación con la cresta ósea alveolar en una población mexicana. Material y métodos: Se realizaun protocolo de estudio observacional, descriptivo y transversal en una población de 1,116 pacientes derecho habientes del Instituto de Seguridad Social y Servicios para los Trabajadores del Estado (ISSSTE), en el oriente de la Ciudad de México, mediante la revisión de estudios de tomografía volumétrica computarizada. Resultados: Se encuentra la anastomosis arterial en el 90 por ciento de los estudios revisados, correspondiente a 1,005 estudios de tomografía.

Introduction: In order to avoid complications, it is essential for surgeonsto have a detailed knowledge of the anatomy of the superior maxillarybone prior to performing any sinus lift procedure. The alveolarantral artery forms an intraosseous anastomosis with the infraorbitalartery at the level of the anterolateral wall of the maxillary antrum at anapproximate distance of between 18.9 and 19.6 mm from the maxillaryalveolar ridge. The alveolar antral artery is responsible for providingvascularity to the mucous membrane of the maxillary sinus, the anteriorlateral wall of the sinus, and the underlying periosteal tissue. Objective:To analyze and establish the frequency, diameter, and locationof the anastomosis between the infraorbital artery and the posteriorsuperior alveolar artery known as the alveolar antral artery, and itsrelationship to the alveolar bone crest in a Mexican cohort. Materialand methods. We conducted a cross-sectional observational descriptivestudy involving a cohort comprised of 1,116 patients of the Institute forSocial Security and Services for State Workers (ISSSTE) on the eastside of Mexico City. The study consisted of a review of CBCT studies.Results: The arterial anastomosis was found in 90% of the 1,005 CBCTstudies reviewed, based on which the following values were determinedfor the distance between the alveolar ridge and the canal of the alveolarantral artery: for the fi rst premolar, 18.24 mm; second premolar,17.35 mm; fi rst molar, 16.96 mm, and for the second molar, 18.75 mm.Conclusions: We established the average measurements for the locationof the vascular bundle in question and the measurements neededto safeguard it along its course, which is important for the preservationand osseointegration of bone grafts placed during maxillary sinus liftprocedures, thus providing a margin of safety not previously reportedin the literature for a Mexican cohort.

Relative cost-effectiveness of using an extensively hydrolyzed casein formula containing the probiotic Lactobacillus rhamnosus GG in managing infants with cow's milk allergy in Spain.

OBJECTIVE: To estimate the cost-effectiveness of using an extensively hydrolyzed casein formula containing the probiotic Lactobacillus rhamnosus GG (eHCF + LGG; Nutramigen LGG) as a first-line management for cow's milk allergy compared with eHCF alone, and amino acid formulae in Spain, from the perspective of the Spanish National Health Service (SNS). METHODS: Decision modeling was used to estimate the probability of immunoglobulin E (IgE)-mediated and non-IgE-mediated allergic infants developing tolerance to cow's milk by 18 months. The models also estimated the SNS cost (at 2012/2013 prices) of managing infants over 18 months after starting a formula as well as the relative cost-effectiveness of each of the formulae. RESULTS: The probability of developing tolerance to cow's milk by 18 months was higher among infants with either IgE-mediated or non-IgE-mediated allergy who were fed eHCF + LGG compared with those fed one of the other formulae. The total health care cost of initially feeding infants with eHCF + LGG was less than that of feeding infants with one of the other formulae. Hence, eHCF + LGG affords the greatest value for money to the SNS for managing both IgE-mediated and non-IgE-mediated cow's milk allergy. CONCLUSION: Using eHCF + LGG instead of eHCF alone or amino acid formulae for first-line management of newly-diagnosed infants with cow's milk allergy affords a cost-effective use of publicly funded resources because it improves outcome for less cost. A randomized controlled study showing faster tolerance development in children receiving a probiotic-containing formula is required before this conclusion can be confirmed.

Barrier-enforcing measures as treatment principle in allergic rhinitis: a systematic review.

BACKGROUND AND OBJECTIVES: Barrier-enforcing measures have been suggested as treatment options for allergic rhinitis. This review identifies and describes the literature on the subject. METHODS: Relevant publications were searched for in the PubMed database (search entries: 'allergic rhinitis' and 'treatment'). The evaluation comprised condition (seasonal or perennial allergic rhinitis), type of intervention, duration of treatment, study design, peer review status or not, number of test subjects, type of allergen exposure, and outcome in terms of effects or not on nasal symptoms of allergic rhinitis. RESULTS: Fifteen studies were either identified in the PubMed database search or from the reference lists of identified publications. Seven were placebo-controlled, randomized, and peer-reviewed, and symptom-reducing effects were reported by all of these reports. Limitations of this review reflect that the remainder of the studies had inferior designs, particularly lack of placebo control. CONCLUSIONS: Barrier-enforcing measures as achieved by nasal administrations of cellulose powder and microemulsions, respectively, have symptom-reducing effects in allergic rhinitis.

A topical microemulsion for the prevention of allergic rhinitis symptoms: results of a randomized, controlled, double-blind, parallel group, multicentre, multinational clinical trial (Nares study).

BACKGROUND: Since barrier protection measures to avoid contact with allergens are being increasingly developed, we assessed the clinical efficacy and tolerability of a topical nasal microemulsion made of glycerol esters in patients with allergic rhinitis. METHODS: Randomized, controlled, double-blind, parallel group, multicentre, multinational clinical trial in which adult patients with allergic rhinitis or rhinoconjunctivitis due to sensitization to birch, grass or olive tree pollens received treatment with topical microemulsion or placebo during the pollen seasons. Efficacy variables included scores in the mini-RQLQ questionnaire, number and severity of nasal, ocular and lung signs and symptoms, need for symptomatic medications and patients' satisfaction with treatment. Adverse events were also recorded. RESULTS: Demographic characteristics were homogeneous between groups and mini-RQLQ scores did not differ significantly at baseline (visit 1). From symptoms recorded in the diary cards, the ME group showed statistically significant better scores for nasal congestion (0.72 vs. 1.01; p = 0.017) and mean total nasal symptoms (0.7 vs. 0.9; p = 0.045). At visit 2 (pollen season), lower values were observed in the mini-RQLQ in the ME group, although there were no statistically significant differences between groups in both full analysis set (FAS) and patients completing treatment (PPS) populations. The results obtained in the nasal symptoms domain of the mini-RQLQ at visit 2 showed the highest difference (-0.43; 95% CI: -0.88 to 0.02) for the ME group in the FAS population. The topical microemulsion was safe and well tolerated and no major discomforts were observed. Satisfaction rating with the treatment was similar between the groups. CONCLUSIONS: The topical application of the microemulsion is a feasible and safe therapy in the prevention of allergic symptoms, particularly nasal congestion. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01478425.

Validation of the first treatment-specific questionnaire for the assessment of patient satisfaction with allergen-specific immunotherapy in allergic patients: the ESPIA questionnaire.

BACKGROUND: Satisfaction with treatment is a patient-reported outcome shown to be associated with the patient's health-related decisions and treatment-related behavior, thereby influencing the chances of successful treatment, and is especially relevant in long-term treatment, such as allergen-specific immunotherapy (AIT). OBJECTIVE: We sought to assess the psychometric properties of the Satisfaction Scale for Patients Receiving Allergen Immunotherapy (ESPIA) questionnaire so as to determine the satisfaction of patients receiving AIT treatment. METHODS: An observational, longitudinal, multicenter study was performed on patients with allergic rhinitis (AR) undergoing AIT treatment. Sociodemographic, clinical, and patient-centered health outcomes data were gathered at the study visits. Feasibility, reliability, validity, and sensitivity to change of the prevalidated version of the ESPIA questionnaire were assessed. RESULTS: Four hundred twenty-nine patients were included (52.2% women, 33.6 years of age, 54.5% of the cases with intermittent AR and 62.5% with moderate AR). Low levels of missing items and ceiling/floor effects were found for the overall score of the ESPIA questionnaire. The overall Cronbach α value and intraclass correlation coefficient were 0.90 and 0.92, respectively. The overall score for the ESPIA questionnaire was strongly associated with months receiving AIT, AR type and intensity, presence of conjunctivitis, self-perceived health status, effect of AR on daily life, and expectations about the AIT treatment. The pattern of correlations obtained with other patient-centered health outcomes was consistent with expectations. The ESPIA questionnaire also showed good sensitivity to change for improved health status. CONCLUSION: The ESPIA questionnaire to assess patient satisfaction with respect to AIT treatment presented satisfactory psychometric properties for its use in clinical practice.

Home-based oral immunotherapy protocol with pasteurized egg for children allergic to hen's egg.

BACKGROUND: In the last decade the use of different types of oral immunotherapy for food-allergic patients has increased with generally satisfactory outcomes. Cow's milk and hen's egg, a common element in the daily diet, have received the main interest. Most of these immunotherapy regimens are performed in the hospital, causing inconvenience for both children and their parents. OBJECTIVES: To assess the efficacy and safety of a home-based oral immunotherapy regimen with raw pasteurized egg. METHODS: The study group comprised children aged 6 years and older with allergy to hen's egg proteins, proven by positive skin prick-tests (SPT) and/orspecific immunoglobulin E (sIgE) and positive open oral food challenge (OOFC) with boiled or raw egg. Patients who met the inclusion criteria and signed the informed consent form underwent egg immunotherapy according to an established schedule. RESULTS: The treatment was given to 31 of the 36 recruited patients: 80.6% of the intention-to-treat population achieved complete tolerance to the maximum dose equivalent to one raw hen's egg, 3.2% achieved incomplete tolerance, and 16.2% did not achieve an acceptable tolerance dose. Most of the latter patients had a positive baseline OOFC with low doses of boiled egg. The average number of reactions per treated patient was 5.8, most of them grades 1 and 2; there were no grade 4 reactions. CONCLUSIONS: This home-based oral immunotherapy protocol proved to effectively induce tolerance to hen's egg in most of the egg-allergic children and its safety profile was acceptable.

Design and recruitment for the GAP trial, investigating the preventive effect on asthma development of an SQ-standardized grass allergy immunotherapy tablet in children with grass pollen-induced allergic rhinoconjunctivitis.

BACKGROUND: Allergic rhinoconjunctivitis is a risk factor for asthma development. Treating the underlying allergy may represent an attractive method of asthma prevention. No regulatory guidance exists in this area, and, to our knowledge, no clinical investigations meeting modern regulatory standards have been published. OBJECTIVE: The objective of this publication is to describe the rationale behind the design of and report on the recruitment for the ongoing pediatric Grazax Asthma Prevention (GAP) trial. METHODS: The trial was designed for assessment of the preventive effect of an SQ-standardized grass allergy immunotherapy tablet (AIT) on asthma development, both during treatment and after the end of treatment. (The standardized quality [SQ] procedure is a standardization procedure comprising 3 components: total potency, major allergen content, and assessment of extract complexity.) The trial design was discussed with several European Competent Authorities. RESULTS: The GAP trial is a multinational, parallel-group, double-blind, placebo-controlled randomized trial. Main eligibility criteria were age of 5 to 12 years, grass pollen-induced allergic rhinoconjunctivitis, no asthma, and no overlapping symptomatic allergies. The children have been randomized 1:1 to receive the grass AIT or placebo once daily for 3 years, followed by a blinded observational period of 2 years. Asthma is assessed by the investigators according to specific diagnostic criteria, used at screening visits before randomization to exclude children with existing asthma, and evaluated at least half-yearly during the trial. Seven months of screening resulted in 812 randomized children at 101 centers in 11 countries. CONCLUSIONS: To our knowledge, the GAP trial represents the first double-blind, placebo-controlled randomized trial to assess the preventive effect of allergen-specific immunotherapy on asthma development. A total of 812 children were successfully recruited into the trial. EudraCT number: 2009-011235-12.

Development of a questionnaire to assess patient satisfaction with allergen-specific immunotherapy in adults: item generation, item reduction, and preliminary validation.

BACKGROUND: Allergen-specific immunotherapy (SIT) is a treatment capable of modifying the natural course of allergy, so ensuring good adherence to SIT is fundamental. Up until now there has not existed an instrument specifically developed to measure patient satisfaction with SIT, although its assessment could help us to comprehend better and improve treatment adherence and effectiveness. The aim of this study was to develop an instrument to measure adult patient satisfaction with SIT. METHODS: Items were generated from a literature review, focus groups with allergic adult patients undergoing SIT, and a meeting with experts. Potential items were administered to allergic patients undergoing SIT in an observational, cross-sectional, multicenter study. Item reduction was based on quantitative and qualitative criteria. A preliminary assessment of feasibility, reliability, and validity of the retained items was performed. RESULTS: An initial pool of 70 items was administered to 257 patients undergoing SIT. Fifty-four items were eliminated resulting in a provisional instrument with 16 items. Factor analysis yielded four factors that were identified as perceived efficacy, activities and environment, cost-benefit balance, and overall satisfaction, explaining 74.8% of variance. Ceiling and floor effects were negligible for overall score. Overall score was associated with the type and intensity of symptoms. CONCLUSION: This is the first attempt to develop a satisfaction with SIT measure from the perspective of the allergic patient, and evidence has been found in favor of its reliability and validity.

Determinación del VPH en cavidad oral: por técnica del hisopo / HPV determination in oral cavity: by hyssop technique

En este estudio nos proponemos determinar la presencia del VPH en cavidad oral por técnica de hisopado. Se utilizó una muestra de 85 pacientes que por medio de exámenes clínicos y cito-histopatológico se determinó la presencia de la infección por VPH en extendidos de Papanicolaou en la cavidad bucal a través de tomas de hisopado faríngeo. De los 85 pacientes estudiados, 49 eran de sexo femenino y 36 masculinos. En el diagnóstico microscópico 7 pacientes resultaron positivos para VPH de los cuales eran 6 mujeres (6 por ciento) y 1 hombre (1 por ciento). La mayor presencia del VPH en nuestro estudio por sexo fue en el femenino con un 6 por ciento, siendo pacientes que presentaban más de 3 a 5 parejas por año, ubicándose entre los 23 y 48 años de edad en la población estudiada, de los cuales el 100 por ciento de ellos refirió inicio precoz de relaciones sexuales antes de los 20 años. La aplicación del tratamiento estadístico de Alfa de Crombach reportó un 71 por ciento de significancia, concluyendo que la técnica de determinación de VPH por hisopado es un exámen fácil, manejo rápido, económico y que puede ser empleado como protocolo para la determinación precoz de lesiones de cavidad oral y su correlación con VPH genital. Esta técnica se podrá incluir como método de pesquisa en población a riesgo a infección de VPH y por ende hacer diagnóstico en etapas premalignas de la enfermedad.

The objective of this study is to determine the presence of the HPV in oral cavity by hyssop technique. We used a sample of 85 patients who by means of clinical examinations and cytology pathology determined the presence of the infection by HVP in extended of Papanicolaou in the oral cavity through takings of hyssop pharyngeal. Of the 85 studied patients, 49 were of feminine sex and 36 masculine ones. In the microscopic diagnosis 7 patients were positive for HVP from which they were 6 women (6 %) and 1 man (1 %). The greater presence of the HVP in our study by sex was in the feminine one with a 6 %, being patient that presented of 3 to 5 pairs per year, being located enters the 23 and 48 years of age in the studied population, of which the 100 % of them referred precocious beginning of sexual relations before the 20 years, the application of the statistical treatment of Alpha of Crombach reported a 71 % of significance, concluding that the technique of hyssop determination of HVP is an easy examination handling, express, economic and that can be used as a protocol for the precocious determination of injuries in oral cavity and its correlation with genital VPH. This technique could be included as method of screening program to VPH infection and therefore at risk be made diagnosis in premalignant stages of the disease.

Monte Carlo simulations of proteins in cages: influence of confinement on the stability of intermediate states.

We study the folding of small proteins inside confining potentials. Proteins are described using an effective potential model that contains the Ramachandran angles as degrees of freedom and does not need any a priori information about the native state. Hydrogen bonds, dipole-dipole-, and hydrophobic interactions are taken explicitly into account. An interesting feature displayed by this potential is the presence of metastable intermediates between the unfolded and native states. We consider different types of confining potentials to describe proteins folding inside cages with repulsive or attractive walls. Using the Wang-Landau algorithm, we determine the density of states and analyze in detail the thermodynamical properties of the confined proteins for different sizes of the cages. We show that confinement dramatically reduces the phase space available to the protein and that the presence of intermediate states can be controlled by varying the properties of the confining potential. Cages with strongly attractive walls destabilize the intermediate states and lead to a two-state folding into a configuration that is less stable than the native structure. However, cages with slightly attractive walls enhance the stability of native structure and induce a folding process, which occurs through intermediate configurations.

Manejo del ganado lechero

En los ultimos años la producción lechera se ha ido intensificado considerablemente en el pais gracias a las iniciativas de la industria de la leche y sus direvados tanto en el sector publico como en el privado. A la par de ello, el consumo de la leche y sus derivados también se ha incrementado. el mercado exigente y la competividad de las industrias han permito que la cría de gando también se intensifique y mejore sustancialmente su menjo a nivel del ganadero.La creación de organizaciones productores de ganaderos lecheros en cada región del paispermitiendo de este modo la generación de fuentes de empleo en el sector agropecuario del país.El docuemnto es un aporte para quienes se dedican a esta actividad

Cavernomas del tronco cerebral: aspectos clínicos y terapéuticos: experiencia personal de tres casos y revisión de la literatura / Cavernoma in the brain stem: clinical and therapeutical aspects: personal experience in 3 cases and a review of literature

Los avances que se han producido en los últimos años, con la introducción de la Resonancia Nuclear Magnética, han permitido conocer la verdadera frecuencia de los cavernomas cerebrales, acercando esta cifra a las publicadas de los estudios de autopsia y que se acepta alrededor del 0,4 por ciento. Así mismo, este avance ha permitido conocer en gran medida su historia natural obteniendo información acerca de sus formas de presentación clínica como el riesgo de hemorragia, la cual se ha constituido en el principal elemento de sostén del tratamiento quirúrgico. Actualmente se estima que este riesgo varía entre un 0,25 por ciento a 1,6 por ciento al año, el cual se ve claramente aumentando en las lesiones de fosa posterior en las que aumenta cerca de treinta veces. De acuerdo a las publicaciones se considera que el tratamiento quirúrgico esta claramente indicado en aquellas lesiones de fosa posterior y en especial si han presentado un episodio de hemorragia previamente. En esta publicación se presentan tres casos personales de cavernomas de tronco cerebral, que presentaron previamente fenómenos hemorrágicos. Los tres pacientes fueron intervenidos quirúrgicamente, obteniéndose la remoción completa de la lesión y de un componente angiomatoso asociado en dos de ellos. El curso postoperatorio en los tres casos ha sido excelente, regresando a sus actividades normales y sin limitaciones, con regresión completaa de sus síntomas y signos preoperatorios

Divertículo de Meckel. Presentación de 15 casos / Meckel Diverticulum: Presentation of 15 cases

El divertículo de meckel es una de las malformaciones congénitas más común del tracto gastrointestinal, se aloja más frecuentemente en la mucosa ideal. Puede ser causante de síntomas como dolor abdominal hemorragia digestiva inferior. Obstrucción intestinal. Se presenta el siguiente estudio, donde se realiza un análisis de 15 casos de pacientes con divertículo de meckel en el Hospital Dr. Domingo Luciani entre los años 1988 y 1998. Se observó que en ninguno de los casos el diagnóstico fue preoperatorio sino que la presentación clínica fue compatible con otros diagnósticos tales como apendicitis aguda, obstrucción intestinal y otras causas de abdomen agudo quirúrgico, inclusive en intervenciones electivas se diagnóstico como hallazgo (histerectomía abdominal), por ello es que el diagnóstico definitivo se realiza por laparoscopia y su tratamiento es la resección de vertículo