Por trás da leptina: uma revisão de literatura / Behind the leptin: a literature review / Detrás de leptin: una revisión de la literatura

A obesidade é uma doença crônica, multifatorial, que afeta todas as idades e classes sociais. Esta comorbidade tem avançado em decorrência de diversos fatores e sua prevalência está ancorada em diferentes dimensões como as biológicas, sociais, históricas, comportamentais, saúde pública e política. O presente estudo tem como objetivo caracterizar o gene da leptina, seu produto e de seus receptores, assim como os mecanismos que corroboram com o desenvolvimento da obesidade e seu envolvimento com distúrbios alimentares. A leptina é uma proteína secretada principalmente nos adipócitos, ela reduz o apetite por meio da inibição da formação de neuropeptídeos relacionados ao apetite, como o neuropeptídeo Y e eleva a expressão de neuropeptídeos anorexígenos, como o hormônio liberador de corticotropina, por isso que os altos níveis de leptina reduzem a ingestão alimentar, em contraste com os níveis baixos que induzem hiperfagia. Como a leptina realiza o controle da saciedade e regulação do gasto energético, o indivíduo com disfunção neste gene não desenvolve essa função corretamente. Isso se deve aos SNPs, que de acordo com estudos aumentam a susceptibilidade à obesidade. Além do mais, a leptina pode estar envolvida com processo patológico de alguns distúrbios alimentares, predispondo o paciente às condições como anorexia nervosa e bulimia.

Obesity is a chronic, multifactorial disease that affects all ages and social classes. This comorbidity has advanced as a result of several factors and its prevalence is anchored in different dimensions such as biological, social, historical, behavioral, public health and political. The present study aims to characterize the leptin gene, its product and its receptors, as well as the mechanisms that corroborate the development of obesity and its involvement with eating disorders. Leptin is a protein secreted mainly in adipocytes, it reduces appetite by inhibiting the formation of appetite-related neuropeptides such as neuropeptide Y and elevates the expression of anorexic neuropeptides such as corticotropin-releasing hormone, so high levels of leptin reduce dietary intake, in contrast to low levels that induce hyperphagia. As leptin performs satiety control and regulation of energy expenditure, the individual with dysfunction in this gene does not develop this function properly. This is due to SNPs, which according to studies increase susceptibility to obesity. Furthermore, leptin may be involved with the pathological process of some eating disorders, predisposing the patient to conditions such as anorexia nervosa and bulimia.

La obesidad es una enfermedad crónica multifactorial que afecta a todas las edades y clases sociales. Esta comorbilidad ha avanzado como resultado de diversos factores y su prevalencia está anclada en diferentes dimensiones, como la biológica, la social, la histórica, la conductual, la salud pública y la política. El objetivo de este estudio es caracterizar el gen de la leptina, su producto y sus receptores, así como los mecanismos que corroboran el desarrollo de la obesidad y su participación en los trastornos alimentarios. La leptina es una proteína secretada principalmente en los adipocitos, reduce el apetito inhibiendo la formación de neuropéptidos relacionados con el apetito, como el neuropéptido Y y eleva la expresión de neuropéptidos anorexógenos, como la hormona que libera la corticotropina, razón por la cual los altos niveles de leptina reducen la ingesta dietética, en contraste con los bajos niveles inducir hiperagia. Como la leptina lleva a cabo el control de la saciedad y la regulación del gasto energético, el individuo con disfunción en este gen no desarrolla esta función correctamente. Esto se debe a los SNP, que según los estudios aumentan la susceptibilidad a la obesidad. Además, la leptina puede estar implicada en el proceso patológico de algunos trastornos alimentarios, predisponiéndose al paciente a condiciones tales como anorexia nerviosa y bulimia.

Vaccine-induced immune thrombotic thrombocytopenia post COVID-19 booster vaccination in Brazil: a case series.

Background: The emergence of new variants of SARS-CoV-2 has led to the administration of different booster vaccines to mitigate COVID-19. Vaccines with adenoviral vectors have been rarely associated with vaccine-induced immune thrombotic thrombocytopenia (VITT). Objectives: This study aimed to describe 15 cases of VITT after the third and fourth doses of the COVID-19 vaccine in Brazil. Methods: Cases were reported after all kinds of anti-SARS-CoV-2 booster vaccinations between October 17, 2021, and September 4, 2022. Results: Of the 26 suspected cases, 15 cases of VITT were analyzed. Of these, 10 were classified as definite VITT, 2 as probable, 1 as possible, and 2 as unlikely. The estimated frequency of definite, probable, or possible VITT was 0.33 cases per million. Cases were assigned to ChAdOx1 (13 cases), Ad26.COV2.S (1 case), and BNT162b2 (1 case). None of the patients received an adenoviral vaccine as a primary vaccination. The average age of participants was 34 years, and symptoms usually appeared 8 days after vaccination. Headache was the most common symptom, and cerebral veins were the most affected thrombotic site. The overall mortality risk was 53%. Anti-platelet factor 4 enzyme-linked immunosorbent assay serology was positive in 11 out of 15 patients (73.3%), negative in 2 (13.3%), and missing in 2 (13.3%). Conclusion: The study confirms that VITT is linked to the first exposure to adenoviral vector vaccines. Since January 2023, Brazil has recommended preferably COVID-19 messenger RNA vaccines for individuals aged 18 to 39 years. We suggest that, in the current disease scenario, COVID-19 adenovirus vaccines should not be the first choice for individuals aged <50 years who have not received a previous dose of this type of vaccine.

Exploratory study of humoral and cellular immunity to 17DD Yellow Fever vaccination in children and adults residents of areas without circulation of Yellow Fever Virus.

The present investigation comprised two independent observational arms to evaluate the influence of pre-existing flavivirus humoral immunity and the age-impact on 17DD-YF vaccination immunity. Flavivirus (YFV; DENV; ZIKV) serology and YF-specific cellular immunity was evaluated in 288 children/9Mths-4Yrs and 288 adults/18-49Yrs residents of areas without YFV circulation. Data demonstrated that flavivirus seropositivity at baseline was higher in Adults as compared to Children (26%;87%;67% vs 6%;13%;15%, respectively). The heterologous flavivirus seropositivity (DENV; ZIKV) did not impact the YF-specific cellular immune response at baseline. However, higher levels of NCD4, EMCD8, IFN-MCD8, NCD19 and nCMCD19 were observed in subjects with pre-existing YFV seropositivity. Primary vaccination of YFV-seronegative volunteers led to higher levels of YF-neutralizing antibodies in Adults as compared to Younger Children (9Mths-2Yrs). Although similar seropositivity rates observed amongst Children and Adults at D30-45, lower rates were observed in Younger Children (9Mths-2Yrs) at D365 (94%;95%;100% vs 87%;96%;99%, respectively). A progressive decline in antibody levels were reported at D365, being more expressive in Children as compared to Adults. All age-subgroups exhibited at D30-45 increased levels of eEfCD4, EMCD4, IFN-MCD8 and nCMCD19 together with a decrease of eEfCD8 and CMCD8. While an increase of EMCD8 were observed in all subgroups at D30-45, a declined duration at D365 was reported only in Younger Children (9Mths-2Yrs). Biomarker signatures further support that only Younger Children (9Mths-2Yrs) presented a progressive decline of EMCD8 at D365. Together, these findings demonstrated that regardless the similarities observed in YF-neutralizing antibodies, the age impacts the duration of cellular immune response to primary 17DD-YF vaccination.

Corrigendum: Duration of Humoral and Cellular Immunity 8 Years After Administration of Reduced Doses of the 17DD-Yellow Fever Vaccine.

[This corrects the article DOI: 10.3389/fimmu.2019.01211.].

Duration of Humoral and Cellular Immunity 8 Years After Administration of Reduced Doses of the 17DD-Yellow Fever Vaccine.

The present study aims to determine whether 17DD-YF-specific humoral and cellular immunological memory is maintained 8-years after primary vaccination with subdoses (10,447IU;3,013IU;587IU;158IU;31IU). For this purpose, this follow-up study was carried out in a subset of volunteers (n = 98) originally enrolled in the dose-response study in 2009 and 46 non-vaccinated controls. Our results demonstrated that vaccinees, who had seroconverted following primary vaccination and had not been revaccinated, present similar neutralizing antibodies levels and YF-specific cellular memory, particularly CMCD4 and EMCD8 as compared to the reference full dose (27,476IU). Although, PRNT seropositivity rates were similar across subgroups (94, 82, 83, 94, 80, and 91%, correspondingly), only doses above 587IU elicited similar iterative proportion of seropositivity rates, calculated as a progressive decrease on seropositivity rates along time (89, 80, 80, and 91%, respectively) as compared to 158IU and 31IU (68 and 46%, respectively). Noteworthy were the strong positive correlations ("EMCD4,EMCD8" and "TNFCD8,IFNCD8") observed in most subdoses, except for 31IU. Major similarities underscored the preserved antibody titers and the outstanding levels of EMCD8, relevant correlates of protection for YF-specific immunity. These findings provide evidences to support the regular use of dose sparing strategy for YF vaccine in adults.

Duration of post-vaccination immunity to yellow fever in volunteers eight years after a dose-response study.

In 2009, Bio-Manguinhos conducted a dose-response study with the yellow fever vaccine, administering the vaccine in the usual mean dose of 27,476 IU (full dose, reference) and in tapered doses (10,447 IU, 3013 IU, 587 IU, 158 IU, and 31 IU) by the usual subcutaneous route and usual volume (0.5 mL). Tapered doses were obtained by dilution in the manufacturer's laboratory, and the test batches presented industrial quality. Doses down to 587 IU showed similar immunogenicity to the full dose (27,476, reference), while the 158 IU and 31 IU doses displayed lower immunogenicity. Seropositivity was maintained at 10 months, except in the group that received the 31 IU dose. The current study aims to determine whether yellow fever seropositivity was maintained eight years after YF vaccination in non-revaccinated individuals. According to the current study's results, seropositivity was maintained in 85% of 318 participants and was similar across groups. The findings support the use of the yellow fever vaccine in fractional doses during outbreaks, but each fractional dose should have at least 587 IU. This study also supports the minimum dose required by WHO, 1000 IU. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov NCT 03338231.

Sunitinib treatment in patients with advanced renal cell cancer: the Brazilian National Cancer Institute (INCA) experience.

PURPOSE: The aim of this study was to assess the impact of sunitinib treatment in a non-screened group of patients with metastatic renal cell cancer (mRCC) treated by the Brazilian Unified Health System (SUS) at a single reference institution. MATERIAL AND METHODS: Retrospective cohort study, which evaluated patients with mRCC who received sunitinib between May 2010 and December 2013. RESULTS: Fifty-eight patients were eligible. Most patients were male 41 (71%), with a median age of 58 years. Nephrectomy was performed in 41 (71%) patients with a median interval of 16 months between the surgery and initiation of sunitinib. The most prevalent histological subtype was clear cell carcinoma, present in 52 (91.2%) patients. In 50 patients (86%), sunitinib was the first line of systemic treatment. The main adverse effects were fatigue (57%), hypothyroidism (43%), mucositis (33%) and diarrhea (29%). Grade 3 and 4 adverse effects were infrequent: fatigue (12%), hypertension (12%), thrombocytopenia (7%), neutropenia (5%) and hand-foot syndrome (5%). Forty percent of patients achieved a partial response and 35% stable disease, with a disease control rate of 75%. Median progression free survival was 7.6 months and median overall survival was 14.1 months. CONCLUSION: Sunitinib treatment was active in the majority of patients, especially those with low and intermediate risk by MSKCC score, with manageable toxicity. Survival rates were inferior in this non-screened population with mRCC treated in the SUS.

Sunitinib treatment in patients with advanced renal cell cancer: the Brazilian National Cancer Institute (INCA) experience

ABSTRACT Purpose: The aim of this study was to assess the impact of sunitinib treatment in a non-screened group of patients with metastatic renal cell cancer (mRCC) treated by the Brazilian Unified Health System (SUS) at a single reference institution. Material and Methods: Retrospective cohort study, which evaluated patients with mRCC who received sunitinib between May 2010 and December 2013. Results: Fifty-eight patients were eligible. Most patients were male 41 (71%), with a median age of 58 years. Nephrectomy was performed in 41 (71%) patients with a median interval of 16 months between the surgery and initiation of sunitinib. The most prevalent histological subtype was clear cell carcinoma, present in 52 (91.2%) patients. In 50 patients (86%), sunitinib was the first line of systemic treatment. The main adverse effects were fatigue (57%), hypothyroidism (43%), mucositis (33%) and diarrhea (29%). Grade 3 and 4 adverse effects were infrequent: fatigue (12%), hypertension (12%), thrombocytopenia (7%), neutropenia (5%) and hand-foot syndrome (5%). Forty percent of patients achieved a partial response and 35% stable disease, with a disease control rate of 75%. Median progression free survival was 7.6 months and median overall survival was 14.1 months. Conclusion: Sunitinib treatment was active in the majority of patients, especially those with low and intermediate risk by MSKCC score, with manageable toxicity. Survival rates were inferior in this non-screened population with mRCC treated in the SUS.

Fatores associados à evolução clínica de mulheres com câncer de mama atendidas em um centro de referência no Rio de Janeiro

A sobrevida em pacientes com câncer de mama tem aumentado nos últimos anos graças aos avanços no tratamento e na detecção precoce da doença. Com isso, desfechos intermediários e competitivos ao óbito pelo câncer de mama se tornaram desfechos importantes, a fim de evitar a piora da qualidade de vida, agravamento da doença e óbito por outras causas. Essa dissertação pretende avaliar a influência de fatores socioeconômicos, clínicos, anatomopatológicos e do tratamento na evolução clínica de mulheres com câncer primário de mama. A população de estudo é formada por pacientes do sexo feminino atendidas em um centro de referência em câncer no Rio de Janeiro no período de janeiro de 2003 a dezembro de 2005. O estudo foi dividido em dois artigos, em que o primeiro avaliou os efeitos dos fatores que se associam às diferentes causas de óbito em mulheres com câncer de mama utilizando modelos de riscos competitivos, e o segundo investigou os fatores associados a cada mudança na evolução clínica de mulheres com câncer de mama utilizando modelo multi-estado. No primeiro artigo foram analisadas 2753 mulheres e como desfechos óbito por câncer de mama e óbito não relacionado à doença. Idade avançada, raça/cor não branca, pior estadiamento e tabagismo foram associados à um maior risco de óbito por câncer de mama, enquanto que apenas a idade avançada foi associada à um maior risco de óbito por causa não relacionado à doença.

O segundo artigo analisou 2709 mulheres em relação à transição entre quatro estados: diagnóstico (s1), ativa/capaz de se cuidar (s2), incapaz de se cuidar (s3) e recidiva/metástase/óbito (s4). Fatores como idade avançada, raça/cor não branca, ausência de histórico familiar de câncer, neoplasias ductais e lobulares, bilateralidade do tumor e receptores hormonais negativos, independentemente do estadiamento clínico, foram associados à piora na capacidade funcional e ao agravamento da doença. Os resultados dessa dissertação evidenciam a importância da avaliação de desfechos intermediários e competitivos ao óbito por câncer de mama nos cuidados com as pacientes, para que sejam traçadas estratégias para aumento de sobrevida e melhora da qualidade de vida.

Survival in patients with breast cancer has increased in recent years due to advances in treatment and early detection of disease. Thus, intermediate and competitive outcomes to death by breast cancer have become important outcomes in order to avoid worsening the quality of life, worsening of disease and death from other causes. This dissertation aims to evaluate the influence of socioeconomic, clinical, pathological and treatment factors on clinical evolution in women with primary breast cancer. The study population consists of female patients with a primary diagnosis of breast cancer treated at a referral center for cancer in Rio de Janeiro enrolled from January 2003 to December 2005. The study was divided into two articles, in which the first evaluated the effects of factors that are associated with different causes of death in women with breast cancer using models of competing risks, and the second investigated the factors associated with each change in clinical evolution of women with breast cancer using multi-state model. In the first article were analyzed 2753 women and outcomes as death from breast cancer and death not related to disease. Older age, race / non-white, worse staging and smoking were associated with a higher risk of death from breast cancer, while only older age was associated with a higher risk of death from causes not related to disease.

The second article examined 2709 women in relation to the transition between four states: diagnosis (s1), active / able to take care of self (s2), unable to care of self (s3) and recurrence / metastasis / death (s4). Factors such as older age, race / non-white, no family history of cancer, ductal and lobular neoplasia, bilateral breast cancer and negative hormone receptor, regardless of clinical stage, were associated with worse Performance Status and the worsening of the disease. The results of this dissertation show the importance of the evaluation of intermediate and competitive outcomes to death from breast cancer in the care of the patients, so that strategies can be traced to increased survival and improved quality of life.

Survival data in elderly patients with locally advanced non-small cell lung cancer.

Combined chemoradiation (CRT) is the standard therapy in locally advanced non-small cell lung cancer (NSCLC). Nevertheless, the best approach in the elderly population is still poorly defined. We retrospectively reviewed the charts of elderly (≥ 65 years) patients with unresectable, locally advanced NSCLC, diagnosed at the Brazilian National Cancer Institute between 2003 and 2007. The primary outcome was overall survival (OS), measured from diagnosis until death. Palliative therapy (PT) included best supportive care radiation therapy (RT; ≤ 40 Gy) and palliative chemotherapy. Among patients treated with radical RT, OS was measured from date of treatment beginning until death (OST). One hundred seventy-one patients were included, with median age of 71 years (range 65-90). Thirty-nine percent received PT, 32 % exclusive RT (>40 Gy), and 29 % CRT (concomitant or sequential). Patients treated with RT and CRT had better OS (median 13.7 months [95 % CI 10.9-16.4] and 15.5 months [95 % CI 13.0-17.9]) than PT (median 4.1 months [95 % CI 3.6-4.6]; p < 0.0001). In the multivariate analysis, RT (HR 0.28 [95 % CI 0.18-0.42]; p < 0.0001) and CRT (HR 0.17 [95 % CI 0.1-0.27]; p < 0.0001) were independently correlated to better survival in comparison with PT. Among patients receiving radical RT, the addition of chemotherapy was correlated to longer OST (median 13.8 [95 % CI 10.6-17.0] vs. 10.8 months [95 % CI 8.6-13.1]; p = 0.018). This benefit was confirmed in the multivariate analysis (HR 0.59 [95 % CI 0.36-0.97]; p = 0.039). Elderly patients with locally advanced NSCLC derived significant survival benefit from radical RT and CRT, suggesting that age should not be a contraindication for these aggressive therapeutic strategies.

A adolescência e sua interferência no controle do diabetes mellitus: dificuldades e propostas a partir de uma revisão da literatura / Adolescence and its interference in the diabetes mellitus control: difficulties and proposals after a literature review

O Diabetes Mellitus tipo 1 (DM1) é uma doença que surge comumente durante a infância ou adolescência, acarretando sérias implicações clínicas, psicológicas e sociais na vida do indivíduo. A adolescência é um período crítico na vida dos pacientes com DM1, já que os conflitos típicos dessa fase se somam, nesses indivíduos, às mudanças impostas pela doença. A maioria dos diabéticos apresenta piora do controle metabólico na adolescência, o que não deve ser atribuído apenas a fatores biológicos da puberdade. Além disso grande parte dos profissionais de saúde não está preparada para atender adolescentes diabéticos. Objetivos: identificar na literatura as causas do descontrole metabólico em diabéticos adolescentes, os fatores associados e as intervenções mais eficientes. Material e métodos: foram realizadas buscas em bases de dados por artigos recentes sobre o tema, além da releitura de artigos de relevância. Resultados: identificou-se que vários fatores não biológicos também são relevantes na piora do controle metabólico na adolescência. Os profissionais de saúde devem evitar atitudes autoritárias e críticas, assumindo uma atitude de colaboração com esses pacientes. As metas do tratamento devem ser individualizadas e flexíveis para evitar frustrações e baixa adesão.

Diabetes Mellitus type 1 (DM1) is a disease that usually emerges during childhood or adolescence, bringing serious psychological, clinical and social outcomes in the patient’s life. The adolescence is a critical stage for the a person with DM1, since the normal conflicts of adolescence period adolescence are mounted up to the restraints necessary to achieve proper serum glucose levels. Most of the diabetic patients present a decrease in their metabolic control during adolescence, which is not explained by biologic changes at all. Besides that, a great number of healthcare providers are not able to deal with diabetic youths. Objectives: to identify in the literature reasons of the metabolic control impairment in adolescents, the risk factors as well as the best interventions. Material and Methods: it was carried out researches in health databases for recent articles on this matter, the relevant literature was read carefully and it was documented the reasons for the metabolic control impairment in adolescents with diabetes mellitus, the risk factors and the best interventions to treat them. Results: non-biological reasons were found to be significant to the impairment of the metabolical control that occurs during adolescence. Healthcare providers must have a collaborative attitude with the patients, not be dictatorial when proposing the treatment, nor use criticism or personal judgments. The treatment goals must be flexible and individualized, thereby avoiding low compliance and disappointments.