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3.
Geroscience ; 2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32648237

RESUMO

Immunostimulation by chronic infection has been linked to an increased risk for different non-communicable diseases, which in turn are leading causes of death in high- and middle-income countries. Thus, we investigated if a positive serostatus for pathogens responsible for common chronic infections is individually or synergistically related to reduced overall survival in community dwelling elderly. We used data of 365 individuals from the German MEMO (Memory and Morbidity in Augsburg Elderly) cohort study with a median age of 73 years at baseline and a median follow-up of 14 years. We examined the effect of a positive serostatus at baseline for selected pathogens associated with chronic infections (Helicobacter pylori, Borrelia burgdorferi sensu lato, Toxoplasma gondii, cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1/2, and human herpesvirus 6) on all-cause mortality with multivariable parametric survival models. We found a reduced survival time in individuals with a positive serostatus for Helicobacter pylori (accelerated failure time (AFT) - 15.92, 95% CI - 29.96; - 1.88), cytomegalovirus (AFT - 22.81, 95% CI - 36.41; - 9.22) and Borrelia burgdorferi sensu lato (AFT - 25.25, 95% CI - 43.40; - 7.10), after adjusting for potential confounders. The number of infectious agents an individual was seropositive for had a linear effect on all-cause mortality (AFT per additional infection - 12.42 95% CI - 18.55; - 6.30). Our results suggest an effect of seropositivity for Helicobacter pylori, cytomegalovirus, and Borrelia burgdorferi sensu lato on all-cause mortality in older community dwelling individuals. Further research with larger cohorts and additional biomarkers is required, to assess mediators and molecular pathways of this effect.

4.
J Vis Exp ; (160)2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32597860

RESUMO

fDrug research for the treatment of lung infections is progressing towards predictive in vitro models of high complexity. The multifaceted presence of bacteria in lung models can re-adapt epithelial arrangement, while immune cells coordinate an inflammatory response against the bacteria in the microenvironment. While in vivo models have been the choice for testing new anti-infectives in the context of cystic fibrosis, they still do not accurately mimic the in vivo conditions of such diseases in humans and the treatment outcomes. Complex in vitro models of the infected airways based on human cells (bronchial epithelial and macrophages) and relevant pathogens could bridge this gap and facilitate the translation of new anti-infectives into the clinic. For such purposes, a co-culture model of the human cystic fibrosis bronchial epithelial cell line CFBE41o- and THP-1 monocyte-derived macrophages has been established, mimicking an infection of the human bronchial mucosa by P. aeruginosa at air-liquid interface (ALI) conditions. This model is set up in seven days, and the following parameters are simultaneously assessed: epithelial barrier integrity, macrophage transmigration, bacterial survival, and inflammation. The present protocol describes a robust and reproducible system for evaluating drug efficacy and host responses that could be relevant for discovering new anti-infectives and optimizing their aerosol delivery to the lungs.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32594187

RESUMO

Early life stress influences adult psychopathology and is associated with an increase in the propensity for drug use/seeking throughout the lifespan. Animal models corroborate that stress exposure exacerbates maladaptive reactivity to stressful stimuli while also shifting the rewarding properties of many drugs of abuse, including nicotine (NIC), a stimulant commonly misused by adolescents. Interestingly, NIC treatment can also normalize some stress-induced behavioral deficits in adult rodents; however, little is known about NIC's therapeutic efficacy following stress experienced during adolescence. The goal of the following experiments was to elucidate NIC's ability to buffer the negative consequences of stress exposure, and to further assess behavioral responsivity while on the drug. Given that stress often occurs in both physical and non-physical forms, we employed the vicarious social defeat stress (VSDS) model which allows for investigation of both physical (PS) and emotional stress (ES) exposure. After 10 days, exposure to PS and ES decreased interaction with a social target in the social interaction test (SIT), confirming social avoidance. Groups were further divided and given NIC (0.0 or 160 mg/L) in their drinking water. After 1 month of NIC consumption, the mice were exposed to the SIT, elevated plus maze (EPM), and the forced swim test (FST), respectively. NIC-treated mice showed a reversal of stress-induced deficits in the EPM and FST. Surprisingly, the mice did not show improvement in the SIT regardless of treatment condition. Together, these data confirm NIC's ability to normalize some stress-induced behavioral deficits; however, NIC's effects on social behavior need further investigation.

6.
PLoS One ; 15(5): e0233056, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32396546

RESUMO

The content and composition of seed storage proteins is largely responsible for wheat end-use quality. They mainly consist of polymeric glutenins and monomeric gliadins. According to their electrophoretic mobility, gliadins and glutenins are subdivided into several fractions. Glutenins are classified as high molecular weight or low molecular weight glutenin subunits (HMW-GSs and LMW-GSs, respectively). LMW-GSs are encoded by multigene families located at the orthologous Glu-3 loci. We designed a set of 16 single-nucleotide polymorphism (SNP) markers that are able to detect SDS-PAGE alleles at the Glu-A3 and Glu-B3 loci. The SNP markers captured the diversity of alleles in 88 international reference lines and 27 Mexican cultivars, when compared to SDS-PAGE and STS markers, however, showed a slightly larger percent of multiple alleles, mainly for Glu-B3. SNP markers were then used to determine the Glu-1 and Glu-3 allele composition in 54 CIMMYT historical lines and demonstrated to be useful tool for breeding programs to improve wheat end product properties.


Assuntos
Glutens/genética , Triticum/genética , Alelos , Sequência de Bases , Pão , DNA de Plantas/genética , Genes de Plantas , Marcadores Genéticos , Glutens/química , Peso Molecular , Melhoramento Vegetal , Polimorfismo de Nucleotídeo Único , Subunidades Proteicas , Sitios de Sequências Rotuladas
7.
Arch. bronconeumol. (Ed. impr.) ; 56(4): 218-224, abr. 2020. tab, graf
Artigo em Inglês | IBECS-Express | ID: ibc-FGT-3321

RESUMO

OBJECTIVE: (I) Analyze the effect of altitude above the sea level on the mortality rate in patients undergoing invasive mechanical ventilation. (II) Validate the traditional equation for adjusting PaO2/FiO2 according to the altitude. DESIGN: A prospective, observational, multicenter and international study conducted during August 2016. PATIENTS: Inclusion criteria: (I) age between 18 and 90 years old, (II) admitted to intensive care unit (ICU) situated at the same altitude above the sea level (AASL) in which the patients has stayed, at least, during the previous 40 days and (III) received invasive MV for at least 12 h. MATERIAL AND METHODS: All variables were registered the day of intubation (day 0). Patients were followed until death, ICU discharge or day 28. PaO2/FiO2 ratio was adjusted by the AASL according to: PaO2/FiO2 * (barometric pressure/760). Categorical variables were compared with χ2 and Cochran-Mantel-Haenszel test. Continuous variables with Mann-Whitney. Correlation between continuous variables was analyzed graphically and analytically. Logistic regression model was constructed to identify factors associated to mortality. Kapplan-Meier method was used to estimate the probability of survival according to the altitude. A 2-side p value < 0.05 was consider significant. RESULTS: 249 patients (< 1500 m n = 55; 1500 to < 2500 m n = 20; 2500 to < 3500 m n=155 and ≥ 3500 m n=19) were included. Adjusted and non-adjusted PaO2/FiO2 were correlated with several respiratory and non respiratory variables. None discordances between non adjusted and adjusted PaO2/FiO2 were identified. However, several correlations were appreciated only in patients situated < 1500 m or in > 1500 m. Seventy-nine patients died during the ICU stayed (32%). The mortality curve was not affected by the altitude above the sea level. Variables independently associated to mortality are: PEEP, age, systolic arterial blood pressure, and platelet count. AUROC: 0.72. CONCLUSION: In acclimatized patients undergoing invasive mechanical ventilation, the traditional equation for adjusting PaO2/FiO2 according the elevation above the sea level seems to be inaccurate and the altitude above the sea level does not affect the mortality risk


OBJETIVO: 1) Analizar el efecto de la altitud por encima del nivel del mar en la tasa de mortalidad de pacientes sometidos a ventilación mecánica invasiva, y 2) Validar la ecuación tradicional de ajuste de PaO2/FiO2, de acuerdo con la altitud. DISEÑO: Estudio internacional prospectivo, observacional y multicéntrico realizado durante agosto de 2016. PACIENTES: Criterios de inclusión: 1 Edad comprendida entre 18 y 90 años, 2 Haber sido ingresado en una unidad de cuidados intensivos (UCI) situada a la misma altitud por encima del nivel del mar (AASL) en la cual el paciente haya estado durante al menos los 40 días previos al estudio, y 3) Haber recibido ventilación mecánica (VM) durante al menos 12 h. MATERIALES Y MÉTODOS: Todas las variables se registraron el día de la intubación (día 0). El seguimiento se realizó hasta la muerte del paciente, el alta de la UCI o el día 28. El cociente PaO2/FiO2 se ajustó según los criterios de la AASL de acuerdo con: PaO2/FiO2 * (presión barométrica/760). Las variables categóricas se compararon mediante la prueba de χ2 y el test Cochran-Mantel-Haenszel, y las variables continuas con el test de Mann-Whitney. La correlación entre las variables continuas se analizó de forma gráfica y analítica. Para identificar los factores asociados a la mortalidad se elaboró un modelo de regresión logística. Se utilizó el método de Kaplan-Meier para estimar la probabilidad de supervivencia de acuerdo con la altitud. Un valor de p < 0,05 en la prueba bilateral se consideró como significativo. RESULTADOS: Se incluyeron 249 pacientes (< 1.500 m, n = 55; 1.500 a < 2.500 m, n = 20; 2.500 a < 3.500 m, n = 155 y ≥ 3.500 m, n = 19). El cociente PaO2/FiO2 mostró correlación con las variables graves tanto respiratorias como no respiratorias. No se registraron discordancias entre el cociente PaO2/FiO2 ajustado y sin ajustar. Únicamente se observaron diversas correlaciones entre los pacientes situados a < 1.500 m o a > 1.500 m. Setenta y nueve pacientes (32%) murieron durante la estancia en la UCI. La altitud sobre el nivel del mar no afectó a la curva de mortalidad. Las variables asociadas de forma independiente con la mortalidad fueron la presión positiva al final de la espiración (PEEP), la edad, la presión arterial sistólica y el recuento de plaquetas. El área bajo la curva ROC (AUROC) fue de 0,72. CONCLUSIÓN: En pacientes aclimatados sometidos a ventilación mecánica invasiva la ecuación tradicional para ajustar el cociente PaO2/FiO2, de acuerdo con la elevación sobre el nivel del mar parece inexacta. Por otro lado, la altitud por encima del nivel del mar no afecta al riego de mortalidad

8.
J Agric Food Chem ; 68(20): 5521-5528, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32275419

RESUMO

Grain protein composition is important in wheat quality and may influence the amino acidic sequence of bioactive peptides obtained from this feedstock. However, the genetic basis modulating the amino acid profile in durum wheat is not well-understood. Therefore, strong and weak gluten strength durum wheat genotypes were evaluated for their amino acid composition along grain filling. Strong gluten strength lines showed higher expression levels of low-molecular-weight glutenin-related genes between 21 and 35 days post-anthesis (DPA) and exhibited up to 43.5% more alanine than the weak lines at 42 DPA, which was supported by the higher expression levels of putative alanine amino transferase genes in strong genotypes. Therefore, with the involvement of chemistry and molecular biology, the results present here may influence the science of wheat.

9.
J Dent Educ ; 84(4): 438-448, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32314384

RESUMO

The aim of this study was to evaluate the feasibility and preliminary outcomes of immersive integrated experiential and didactic courses in strengthening competency-based global health learning in dental education. To address global inequities in oral health and student interest in global health, the Harvard School of Dental Medicine introduced two global health courses in 2017-18. The first was a didactic course in the core predoctoral curriculum, and the second, in collaboration with the Inter-American Center for Global Health, was a five-day elective experiential learning course in rural Costa Rica. The experiential course was an extension of the didactic course. All 33 second-year dental students completed the didactic course, and three of those students completed the experiential course. A pre-post survey and a six-month follow-up survey on self-reported knowledge based on course learning objectives were administered. The experiential course students also completed journals and interviews for qualitative analysis. Thirty-two students completed the pre-post didactic course surveys, for a response rate of 94%. There was a 100% response rate on the pre-post didactic surveys by those students who participated in the experiential learning course. While the experiential learning group scored similarly to the class average before the didactic course, they had higher scores than the class averages both immediately after and at the six-month follow-up. All three students reported that the experiential learning course was "extremely effective" in building on what they learned in the didactic course. Qualitative analysis of the journals and interviews suggested enhanced learning from the combination of didactic and experiential methods. These preliminary results support the Global Health Learning Helix Model, a theoretical competency-based teaching model for ethical student global health engagement to better prepare the future generation in tackling oral health disparities both locally and worldwide.


Assuntos
Aprendizagem Baseada em Problemas , Estudantes de Odontologia , Currículo , Educação em Odontologia , Saúde Global , Humanos
10.
PLoS One ; 15(4): e0231974, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32320435

RESUMO

The impact of sex-specific body fat distribution on the susceptibility to five chronic infections, helicobacter pylori and human herpesviruses 3 to 6 (i.e. varicella-zoster, Epstein-Barr, cytomegalo- and human herpesvirus 6), has not previously been examined. In the present study, seropositivity was determined via multiplex serology in serum samples of study participants collected in 2006/08 and 2013/14 during the follow-up examinations F4 (n = 3080) and FF4 (n = 2279) of the German population-based baseline KORA S4 survey. We quantified the severity of overall and abdominal obesity by body mass index, body adiposity index, waist circumference, waist-to-hip ratio, and waist-to-height ratio. Using sex-specific logistic spline-models, cross-sectional and longitudinal associations between obesity measures and seropositivity of the previously mentioned infections were investigated. Overall and abdominal fat content were significantly associated with seropositivity of varicella-zoster virus in both cross-sectional and longitudinal analyses among women. In addition, a non-significant inverse relationship with Epstein-Barr virus seroprevalence in both sexes and a trend towards a positive association with human herpesvirus 6 seropositivity in women were observed. Therefore, in women total body fat may be associated with VZV-seropositivity and may influence the reactivation of the varicella-zoster virus, independent of adipose tissue distribution.


Assuntos
Infecções/sangue , Infecções/complicações , Obesidade/complicações , Adulto , Idoso , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Soroepidemiológicos , Inquéritos e Questionários
11.
Front Immunol ; 11: 128, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32153562

RESUMO

There are several unmet needs in modern immunology. Among them, vaccines against parasitic diseases and chronic infections lead. Trypanosoma cruzi, the causative agent of Chagas disease, is an excellent example of a silent parasitic invasion that affects millions of people worldwide due to its progression into the symptomatic chronic phase of infection. In search for novel vaccine candidates, we have previously introduced Traspain, an engineered trivalent immunogen that was designed to address some of the known mechanisms of T. cruzi immune evasion. Here, we analyzed its performance in different DNA prime/protein boost protocols and characterized the systemic immune response associated with diverse levels of protection. Formulations that include a STING agonist, like c-di-AMP in the boost doses, were able to prime a Th1/Th17 immune response. Moreover, comparison between them showed that vaccines that were able to prime polyfunctional cell-mediated immunity at the CD4 and CD8 compartment enhanced protection levels in the murine model. These findings contribute to a better knowledge of the desired vaccine-elicited immunity against T. cruzi and promote the definition of a vaccine correlate of protection against the infection.

12.
Int J Mol Sci ; 21(6)2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32188077

RESUMO

Although the advent of combined antiretroviral therapy has substantially improved the survival of HIV-1-infected individuals, non-AIDS-related diseases are becoming increasingly prevalent in HIV-1-infected patients. Persistent abnormalities in coagulation appear to contribute to excess risk for a broad spectrum of non-AIDS defining complications. Alterations in coagulation biology in the context of HIV infection seem to be largely a consequence of a chronically inflammatory microenvironment leading to endothelial cell (EC) dysfunction. A possible direct role of HIV-1 proteins in sustaining EC dysfunction has been postulated but not yet investigated. The HIV-1 matrix protein p17 (p17) is secreted from HIV-1-infected cells and is known to sustain inflammatory processes by activating ECs. The aim of this study was to investigate the possibility that p17-driven stimulation of human ECs is associated with increased production of critical coagulation factors. Here we show the involvement of autophagy in the p17-induced accumulation and secretion of von Willebrand factor (vWF) by ECs. In vivo experiments confirmed the capability of p17 to exert a potent pro-coagulant activity soon after its intravenous administration.

13.
Behav Brain Res ; 384: 112548, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32061748

RESUMO

Ketamine, a dissociative anesthetic and psychedelic compound, has revolutionized the field of psychopharmacology by showing robust, and rapid-acting antidepressant activity in patients suffering from major depressive disorder (MDD), suicidal tendencies, and treatment-resistant depression (TRD). Ketamine's efficacy, however, is transient, and patients must return to the clinic for repeated treatment as they experience relapse. This is cause for concern because ketamine is known for its abuse liability, and repeated exposure to drugs of abuse often leads to drug abuse/dependence. Though the mechanism(s) underlying its antidepressant activity is an area of current intense research, both clinical and preclinical evidence shows that ketamine's effects are mediated, at least in part, by molecular adaptations resulting in long-lasting synaptic changes in mesolimbic brain regions known to regulate natural and drug reward. This review outlines our limited knowledge of ketamine's neurobiological and biochemical underpinnings mediating its antidepressant effects and correlates them to its abuse potential. Depression and addiction share overlapping neural circuitry and molecular mechanisms, and though speculative, repeated use of ketamine for the treatment of depression could lead to the development of substance use disorder/addiction, and thus should be tempered with caution. There is much that remains to be known about the long-term effects of ketamine, and our lack of understanding of neurobiological mechanisms underlying its antidepressant effects is a clear limiting factor that needs to be addressed systematically before using repeated ketamine in the treatment of depressed patients.

14.
Gastroenterology ; 158(6): 1762-1775.e9, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32001321

RESUMO

BACKGROUND & AIMS: Hepatitis B virus (HBV) infection persists because the virus-specific immune response is dysfunctional. Therapeutic vaccines might be used to end immune tolerance to the virus in patients with chronic infection, but these have not been effective in patients so far. In patients with chronic HBV infection, high levels of virus antigens might prevent induction of HBV-specific immune responses. We investigated whether knocking down expression levels of HBV antigens in liver might increase the efficacy of HBV vaccines in mice. METHODS: We performed studies with male C57BL/6 mice that persistently replicate HBV (genotype D, serotype ayw)-either from a transgene or after infection with an adeno-associated virus that transferred an overlength HBV genome-and expressed HB surface antigen at levels relevant to patients. Small hairpin or small interfering (si)RNAs against the common 3'-end of all HBV transcripts were used to knock down antigen expression in mouse hepatocytes. siRNAs were chemically stabilized and conjugated to N-acetylgalactosamine to increase liver uptake. Control mice were given either entecavir or non-HBV-specific siRNAs and vaccine components. Eight to 12 weeks later, mice were immunized twice with a mixture of adjuvanted HBV S and core antigen, followed by a modified Vaccinia virus Ankara vector to induce HBV-specific B- and T-cell responses. Serum and liver samples were collected and analyzed for HBV-specific immune responses, liver damage, and viral parameters. RESULTS: In both models of HBV infection, mice that express hepatocyte-specific small hairpin RNAs or that were given subcutaneous injections of siRNAs had reduced levels of HBV antigens, HBV replication, and viremia (1-3 log10 reduction) compared to mice given control RNAs. Vaccination induced production of HBV-neutralizing antibodies and increased numbers and functionality of HBV-specific, CD8+ T cells in mice with low, but not in mice with high, levels of HBV antigen. Mice with initially high titers of HBV and knockdown of HBV antigen expression, but not mice with reduced viremia after administration of entecavir, developed polyfunctional, HBV-specific CD8+ T cells, and HBV was eliminated. CONCLUSIONS: In mice with high levels of HBV replication, knockdown of HBV antigen expression along with a therapeutic vaccination strategy, but not knockdown alone, increased numbers of effector T cells and eliminated the virus. These findings indicate that high titers of virus antigens reduce the efficacy of therapeutic vaccination. Anti-HBV siRNAs and therapeutic vaccines are each being tested in clinical trials-their combination might cure chronic HBV infection.

15.
Behav Brain Res ; 383: 112508, 2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-32017978

RESUMO

Two decades ago, the observation of a rapid and sustained antidepressant response after ketamine administration provided an exciting new avenue in the search for more effective therapeutics for the treatment of clinical depression. Research elucidating the mechanism(s) underlying ketamine's antidepressant properties has led to the development of several hypotheses, including that of disinhibition of excitatory glutamate neurons via blockade of N-methyl-d-aspartate (NMDA) receptors. Although the prominent understanding has been that ketamine's mode of action is mediated solely via the NMDA receptor, this view has been challenged by reports implicating other glutamate receptors such as AMPA, and other neurotransmitter systems such as serotonin and opioids in the antidepressant response. The recent approval of esketamine (Spravato™) for the treatment of depression has sparked a resurgence of interest for a deeper understanding of the mechanism(s) underlying ketamine's actions and safe therapeutic use. This review aims to present our current knowledge on both NMDA and non-NMDA mechanisms implicated in ketamine's response, and addresses the controversy surrounding the antidepressant role and potency of its stereoisomers and metabolites. There is much that remains to be known about our understanding of ketamine's antidepressant properties; and although the arrival of esketamine has been received with great enthusiasm, it is now more important than ever that its mechanisms of action be fully delineated, and both the short- and long-term neurobiological/functional consequences of its treatment be thoroughly characterized.

17.
Arch Bronconeumol ; 56(4): 218-224, 2020 Apr.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31582181

RESUMO

OBJECTIVE: (i) Analyze the effect of altitude above the sea level on the mortality rate in patients undergoing invasive mechanical ventilation. (ii) Validate the traditional equation for adjusting PaO2/FiO2 according to the altitude. DESIGN: A prospective, observational, multicenter and international study conducted during August 2016. PATIENTS: Inclusion criteria: (i) age between 18 and 90 years old, (ii) admitted to intensive care unit (ICU) situated at the same altitude above the sea level (AASL) in which the patients has stayed, at least, during the previous 40 days and (iii) received invasive MV for at least 12h. MATERIAL AND METHODS: All variables were registered the day of intubation (day 0). Patients were followed until death, ICU discharge or day 28. PaO2/FiO2 ratio was adjusted by the AASL according to: PaO2/FiO2*(barometric pressure/760). Categorical variables were compared with χ2 and Cochran-Mantel-Haenszel test. Continuous variables with Mann-Whitney. Correlation between continuous variables was analyzed graphically and analytically. Logistic regression model was constructed to identify factors associated to mortality. Kapplan-Meier method was used to estimate the probability of survival according to the altitude. A 2-side p value <0.05 was consider significant. RESULTS: 249 patients (<1500m n=55; 1500 to <2500m n=20; 2500 to <3500m n=155 and ≥3500m n=19) were included. Adjusted and non-adjusted PaO2/FiO2 were correlated with several respiratory and non respiratory variables. None discordances between non adjusted and adjusted PaO2/FiO2 were identified. However, several correlations were appreciated only in patients situated <1500m or in >1500m. Seventy-nine patients died during the ICU stayed (32%). The mortality curve was not affected by the altitude above the sea level. Variables independently associated to mortality are: PEEP, age, systolic arterial blood pressure, and platelet count. AUROC: 0.72. CONCLUSION: In acclimatized patients undergoing invasive mechanical ventilation, the traditional equation for adjusting PaO2/FiO2 according the elevation above the sea level seems to be inaccurate and the altitude above the sea level does not affect the mortality risk.

18.
J Gastrointest Surg ; 24(5): 1149-1157, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31273553

RESUMO

BACKGROUND: Guidelines recommend colectomy for appendiceal carcinoid tumors larger than 2 cm, but physicians debate whether colectomy would be beneficial in treating smaller tumors. We sought to determine when colectomy confers a survival advantage over appendectomy. METHODS: Appendiceal carcinoid patients in the US Surveillance, Epidemiology, and End Results (SEER) database (1988-2011) were stratified by age group, gender, TNM stage, tumor grade, and race. Kaplan-Meier and logistic regression analyses relating grade, stage, and receipt of colectomy to overall and cancer-specific survival were performed. RESULTS: Of 817 patients who underwent surgical extirpation of an appendiceal carcinoid, 338 (41%) had appendectomy alone and 479 (59%) had additional colectomy. Surprisingly, patients who underwent colectomy had worse cancer-specific survival (HR 1.98, 95% CI 1.32-2.98, p = 0.001) than those who underwent appendectomy, and colectomy did not confer a survival advantage over appendectomy in any subset analysis including low-grade or high-grade tumors, smaller or larger than 2 cm, or node-positive, non-metastatic tumors. Even when accounting for stage and grade, colectomy was not associated with significantly better survival rates. Furthermore, as colectomy frequency has increased over the last decade, the 5-year survival rate has trended down. The main predictors of cancer-specific mortality in carcinoid patients were high-grade (grades 3-4) and high-stage (node positive or metastatic) tumors. CONCLUSIONS: Survival in patients with carcinoid tumor of the appendix is primarily determined by tumor grade and stage. Our study found no survival advantage to colectomy over appendectomy in a large cohort of patients with the disease. Further investigation is necessary prior to recommending change of practice for patients with appendiceal carcinoid tumors.

19.
J Dent Educ ; 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31818984

RESUMO

The aim of this study was to evaluate the feasibility and preliminary outcomes of immersive integrated experiential and didactic courses in strengthening competency-based global health learning in dental education. To address global inequities in oral health and student interest in global health, the Harvard School of Dental Medicine introduced two global health courses in 2017-18. The first was a didactic course in the core predoctoral curriculum, and the second, in collaboration with the Inter-American Center for Global Health, was a five-day elective experiential learning course in rural Costa Rica. The experiential course was an extension of the didactic course. All 33 second-year dental students completed the didactic course, and three of those students completed the experiential course. A pre-post survey and a six-month follow-up survey on self-reported knowledge based on course learning objectives were administered. The experiential course students also completed journals and interviews for qualitative analysis. Thirty-two students completed the pre-post didactic course surveys, for a response rate of 94%. There was a 100% response rate on the pre-post didactic surveys by those students who participated in the experiential learning course. While the experiential learning group scored similarly to the class average before the didactic course, they had higher scores than the class averages both immediately after and at the six-month follow-up. All three students reported that the experiential learning course was "extremely effective" in building on what they learned in the didactic course. Qualitative analysis of the journals and interviews suggested enhanced learning from the combination of didactic and experiential methods. These preliminary results support the Global Health Learning Helix Model, a theoretical competency-based teaching model for ethical student global health engagement to better prepare the future generation in tackling oral health disparities both locally and worldwide.

20.
Sci Rep ; 9(1): 16362, 2019 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-31704965

RESUMO

The contribution of natural killer (NK) cells to the clearance of hepatic viral infections is well recognized. The recently discovered heterogeneity of NK cell populations renders them interesting targets for immune interventions. Invariant natural killer T (iNKT) cells represent a key interaction partner for hepatic NK cells. The present study addressed whether characteristics of NK cells in the liver can be shaped by targeting iNKT cells. For this, the CD1d-binding pegylated glycolipid αGalCerMPEG was assessed for its ability to modulate the features of NK cells permanently or transiently residing in the liver. In vivo administration resulted in enhanced functionality of educated and highly differentiated CD27+ Mac-1+ NK cells accompanied by an increased proliferation. Improved liver homing was supported by serum-derived and cellular factors. Reduced viral loads in a mCMV infection model confirmed the beneficial effect of NK cells located in the liver upon stimulation with αGalCerMPEG. Thus, targeting iNKT cell-mediated NK cell activation in the liver represents a promising approach for the establishment of liver-directed immune interventions.

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