Resumo em Inglês:

ABSTRACT Obesity is a complex and multifactorial disease that is influenced by physiological, environmental, socioeconomic, and genetic factors. In recent decades, this serious disease has impacted a large number of adolescents as a result of lifestyle factors. A lack of exercise and the consumption of excessive calories from an inadequate diet are the main contributors to adolescent obesity. However, genetic and hormonal factors might also play a role. The short- and long-term consequences of this disease include chronic issues such as type 2 diabetes and cardiovascular disorders and an increase in early mortality rates. Although it is a serious disease, obesity in adolescents can be controlled with diet and exercise. When these lifestyle changes do not obtain the expected results, we can intensify the treatment by adding medication to the practice of diet and exercise. Additionally, for more severe cases, bariatric surgery can be an option. The purpose of this review is to clarify the current epidemiology, risks, and comorbidities and discuss news about the main treatments and the necessary improvements in this context.

Resumo em Inglês:

ABSTRACT Objective: Obesity is characterized by a state of chronic, low-intensity systemic inflammation frequently associated with insulin resistance and dyslipidemia. Materials and methods: Given that chronic inflammation has been implicated in the pathogenesis of mood disorders, we investigated if chronic obesity that was initiated early in life – lasting through adulthood – could be more harmful to memory impairment and mood fluctuations such as depression. Results: Here we show that pre-pubertal male rats (30 days old) treated with a high-fat diet (40%) for 8-months gained ~50% more weight when compared to controls, exhibited depression and anxiety-like behaviors but no memory impairment. The prefrontal cortex of the obese rats exhibited an increase in the expression of genes related to inflammatory response, such as NFKb, MMP9, CCl2, PPARb, and PPARg. There were no alterations in genes known to be related to depression. Conclusion: Long-lasting obesity with onset in prepuberal age led to depression and neuroinflammation but not to memory impairment.

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ABSTRACT Objective: Feeding restriction in rats alters the oscillators in suprachiasmatic, paraventricular, and arcuate nuclei, hypothalamic areas involved in food intake. In the present study, using the same animals and experimental protocol, we aimed to analyze if food restriction could reset clock genes ( Clock, Bmal1 ) and genes involved in lipid metabolism ( Pgc1a, Pparg, Ucp2 ) through nutrient-sensing pathways ( Sirt1, Ampk, Nampt ) in peripheral tissues. Materials and methods: Rats were grouped according to food access: Control group (CG, food ad libitum ), Restricted night-fed (RF-n, food access during 2 h at night), Restricted day-fed (RF-d, food access during 2 h in the daytime), and Day-fed (DF, food access during 12 h in the daytime). After 21 days, rats were decapitated at ZT3 (0900-1000 h), ZT11 (1700-1800 h), or ZT17 (2300-2400 h). Blood, liver, brown (BAT) and peri-epididymal (PAT) adipose tissues were collected. Plasma corticosterone and gene expression were evaluated by radioimmunoassay and qPCR, respectively. Results: In the liver, the expression pattern of Clock and Bmal1 shifted when food access was dissociated from rat nocturnal activity; this phenomenon was attenuated in adipose tissues. Daytime feeding also inverted the profile of energy-sensing and lipid metabolism-related genes in the liver, whereas calorie restriction induced a pre-feeding increased expression of these genes. In adipose tissues, Sirt1 expression was modified by daytime feeding and calorie restriction, with concomitant expression of Pgc1a , Pparg , and Ucp2 but not Ampk and Nampt . Conclusion: Feeding restriction reset clock genes and genes involved in lipid metabolism through nutrient-sensing-related genes in rat liver, brown, and peri-epididymal adipose tissues.

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ABSTRACT Objective: People with Down's syndrome (DS) have a higher risk of developing type 1 diabetes mellitus (T1D) and may have specific clinical features compared to T1D patients without DS. This study evaluated the clinical and laboratory aspects of T1D in children and adolescents with DS in an admixed population. Subjects and methods: A case-control study comparing patients with T1D and DS (T1D+DS) to patients with T1D without DS (T1D controls) from two tertiary academic Hospitals in São Paulo, Brazil. Results: The sample consisted of 9 patients with T1D+DS and 18 T1D age and sex-matched controls. Anti-glutamic acid decarboxylase 65 antibodies were positive in 7/7 of the 9 T1D+DS patients, confirming the presence of diabetes autoimmunity in this group. Mean age at diagnosis of T1D was 4.9 ± 3.9 years in the T1D+DS group and 6.4 years ± 3 in the T1D control group; early diagnosis (<2 years old) occurred in three T1D+DS patients but only in one T1D control patients, both suggesting lower age of diagnosis in T1D+DS group, although without statistical significance (p = 0.282 and p = 0.093, respectively). The T1D+DS group presented lower total insulin dose (0.7 IU/kg/day ± 0.2) and HbA1c (7.2% ± 0.6) than the control group (1.0 IU/kg/day ± 0.3 and 9.1% ± 0.7, respectively) (p = 0.022 and p = 0.047, respectively). Conclusion: We confirmed the autoimmune etiology of diabetes in people with DS in this admixed population. T1D+DS patients developed diabetes earlier and achieved better metabolic control with a lower insulin dose than T1D controls. These findings are in agreement with previous studies in Caucasian populations.

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ABSTRACT Objectives: The purpose of this study was to investigate the heterogeneity of the association between glycemic variability and oxidative stress markers in T1DM patients under daily life insulin treatment. Subjects and methods: We studied, in a cross-sectional analysis, 76 T1DM patients without clinical chronic diabetes complications and 22 healthy individuals. Were evaluated the short-term glycemic variability (STGV), long-term glycemic variability (LTGV), oxidative stress markers [8-isoprostaglandin-F2α (Ur-8-iso-PGF2α), nitric oxide (NO), thiobarbituric acid reactive substances (TBARS) and erythrocytes reduced/oxidized glutathione (GSH/GSSG)] and biochemical dosages (glycaemia, HbA1c, lipidogram, albuminuria). Results: Plasmatic NO was positively associated with LTGV (last year average of HbA1c) (8.7 ± 1.6% or 71 ± 18 mmol) (rS: 0.278; p: 0.042). Plasmatic TBARS, erythrocytes GSH/GSSH and Ur-8-iso-PGF-2α didn't show correlation with glycemic variability. GSH/GSSG was inversely correlated with LDL-cholesterol (rS: - 0.417; p: 0.047) and triglycerides (rS: −0.521; p: 0.013). Albuminuria was positive correlated with age (rS: 0.340; p: 0.002), plasmatic NO (rS: 0.267; p 0.049) and TBARS (rS: 0.327; p: 0.015). Conclusion: In daily life insulin treatment, young T1DM patients have higher plasmatic NO than healthy subjects. However, the correlation between glycemic variability and oxidative stress markers is heterogeneous. Lipid profile and albuminuria are associated with different oxidative stress markers. These data collaborate to explain the controversial results in this issue.

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ABSTRACT Objective: Although thyroid microcarcinoma (TMC) usually has a favorable prognosis, some patients present a higher risk of disease recurrence or persistence. Thus, we aimed at identifying possible risk factors associated with an incomplete response to therapy in TMC. Subjects and methods: This was a retrospective study of 517 patients with TMC treated with total thyroidectomy, with or without radioactive iodine (RAI) therapy, reclassified after 1.1 ± 0.4 years according to the response to treatment into “favorable” (excellent/indeterminate) or “unfavorable” (biochemical/structural incomplete) responses. We evaluated participants' age, sex, tumor size, histological variants, multifocality, presence of vascular/lymphatic/perineural invasion, extrathyroidal extension, metastatic lymph nodes (LN), and distant metastasis. The effect of RAI therapy on the response range was analyzed in a given subgroup. Results: The mean age observed was 46.4 ± 12.0 years, and 89.7% were female. We noted 97.5% with papillary carcinoma, 27.8% with multifocality and 11.2% with LN metastasis. Although the majority of patients had a low risk of recurrence/persistence (78%), 75% were submitted to RAI therapy. Incomplete response (20.7%) was associated with multifocality (p=0.041; OR=1.619) and metastatic LN (p=0.041; OR=1.868). These variables were strongly correlated (p=0.000; OR=3.283). No cut-off of tumor size was identified as a predictor of incomplete response by the receiver operating curve analysis. RAI treatment did not influence the response of patients with multifocality or LN metastasis. Conclusion: Multifocality and LN metastasis are independent risk factors for incomplete response in TMC patients and are strongly correlated. Additional RAI therapy was not associated with a more favorable response in these subgroups.

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ABSTRACT Objective: To evaluate the association between some indicators of adiposity and markers of metabolic disorder, evaluate their performance in predicting metabolic syndrome (MetS), and identify their cutoff values among older adults, both in the overall sample and according to sex. Subjects and methods: Cross-sectional study in 159 older men and women. MetS was defined according to the harmonized criteria. The assessments included waist circumference (WC), waist-to-height ratio (WHtR), conicity index (C index), lipid accumulation product (LAP), visceral adiposity index (VAI), body mass index (BMI), A body shape index (ABSI), area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. Results: LAP and WHtR resulted in the largest AUC values (>0.80). In both sexes, the best indicators were LAP, WC, and WHtR. Both LAP and WHtR presented the highest Youden's index values in the overall sample, with cutoff values of approximately 46.9 (sensitivity 75.0%, specificity 76.7%) and 0.56 (sensitivity 79.3%, specificity 69.8%), respectively. When analyzed by sex, BMI, WC, WHtR, and LAP yielded the highest Youden's index values for the prediction of MetS in older women. Conclusion: The indicators LAP, WC, and WHtR performed well in identifying the presence of MetS in older women and could be used to individually or collectively assess and monitor MetS.

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ABSTRACT Objective: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide. The aim this study was to investigate the association of diabetes with severity and mortality among hospitalized patients with COVID-19 in Wuhan, China. Subjects and methods: This retrospective, single-center case study enrolled a total of 564 patients diagnosed with COVID-19 at the Seventh Hospital of Wuhan City, between January 20 and March 15, 2020. Results: Among the 564 patients with confirmed COVID-19, 509 (85.1%) were discharged and 55 (9.8%) died. The median age was 59 years (range, 10-93 years). A total of 85 (15.1%) patients were diagnosed with diabetes on admission (median age, 65.0 [range, 34-91] years). Patients with diabetes had significantly higher proportions of critical cases (24 [28.2%] vs. 66 [13.8%]) and in-hospital mortality (17 [20%] vs. 38 [7.9%]). Moreover, patients with diabetes presented abnormal levels of multiple indicators concerning lymphopenia, inflammation, heart, liver, kidney, and lung function on admission, while diabetic patient group still display higher troponin T (TnT) levels when approaching discharge. The Kaplan-Meier survival curve indicated a trend toward poorer survival in diabetic patients compared to non-diabetic patients, also evidenced by abnormal laboratory biomarker changes regarding multiple system impairments among COVID-19 patients with diabetes with in-hospital death. Conclusion: The detailed clinical investigation of 564 hospitalized patients with COVID-19 indicated a considerable association between diabetes and COVID-19 severity or mortality. Thus, more intensive treatment may be considered for COVID-19 patients with diabetes, especially regarding to cardiac injury.

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ABSTRACT Objective: To evaluate whether there is a relationship between diet quality and bone health in a group of elderly Brazilian women. Subjects and methods: A cross-sectional study was performed with 105 elderly women. Participants were evaluated regarding diet quality (good, needing improvement, and poor) and its relationship with bone mineral density (BMD), bone-specific alkaline phosphatase (BSAP), and C-telopeptide (CTX). Results: Fifty eight participants (55.2%) presented a poor-quality diet and 47 (44.8%) required dietary improvements, while no subjects presented a good quality diet. The group requiring dietary improvements had lower CTX [0.35 (0.05;1.09) vs. 0.52 (0.10;1.45); p = 0.03)] and BSAP (38.7 ± 12.9 U/L vs. 46.10 ± 15.2 U/L; p < 0.01) levels than the poor-quality diet group. Groups did not differ in terms of BMD. Conclusion: In this group of elderly Brazilian women, there was a relationship between diet quality and bone health, where worse diet quality was associated with higher levels of bone remodelling markers.

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ABSTRACT Objective: We aimed to investigate the role of testosterone to estradiol ratio in predicting the effectiveness of human chorionic gonadotropin and testosterone treatments in male hypogonadism. Materials and methods: Thirty-six male patients with hypogonadotropic hypogonadism were included in the study. Seventeen (47.2%) patients received weekly recombinant human choriogonadotropin alpha (hCG) treatment (group-1) and 19 (52.8%) received testosterone replacement therapy (T treatment) every 21 days (group-2). Under these treatments, adequate frequency of morning erection (≥3/week), testosterone to estradiol ratio (T/E), and testicular volume changes were analyzed. Results: The mean age of the patients was 28.5 ± 8.7 years. When the frequency of morning erection (≥3/week) was specified as adequate, the cut-off value for effective T/E ratio was found to be 12.0 (sensitivity 93.8%, specificity 90.0%). There was no significant difference between the treatment groups in terms of total testosterone levels, T/E ratio, or frequency of morning erections (≥3/week) (p > 0.05). However, there was a statistically significant difference between the groups in terms of median left-right testicular volume in favor of group-1 (p < 0,05). Conclusion: In patients with hypogonadism who are under treatment, elevated estradiol-induced erectile dysfunction symptoms may persist even if serum testosterone levels are normal. Testosterone to estradiol ratio can be used as a predictive value in the effective treatment of hypogonadotropic hypogonadism with hCG and T.

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ABSTRACT Objective: To analyze the association of clinical, anatomical, and ultrasound (US) characteristics of malignancies in Bethesda III or IV (III-B or IV-B) thyroid nodules. Subjects and methods: The association between malignancies and the following variables were analyzed: III-B or IV-B, age < 55 years and ≥ 55 years, sex, family history of thyroid cancer, history of irradiation, nodule size, and ACR TI-RADS classification in 62 participants who underwent thyroidectomy. Results: Of the 62 participants, 87.1% (54/62) were women, 74.2% were < 55 years old, 95.2% had no family history of thyroid cancer, 56.5% had nodules < 2 cm in size, 62.9% were IV-B, and 69.4% were ACR TI-RADS 4. Thirty-two patients had thyroid carcinoma, and 30 had benign histology. Among all factors associated with malignancy, only ACR TI-RADS 5 classification on US was found to be statistically significant (p = 0.014), while III-B with architectural atypia cytological classification was the only one significantly associated with benign status (p = 0.004). Conclusion: Only a high risk of malignancy as assessed using US was able to refine the indication for molecular tests in a group of patients with indeterminate nodules. We found 85% (53/62) of III-B or IV-B thyroid nodules would benefit from available molecular diagnostic tests.

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ABSTRACT Objective: Patients with cystic fibrosis (CF) have a high incidence of pubertal and growth delay. In girls with CF, pubertal delay has an important psychological impact. Still, only a few studies have explored the occurrence of pubertal delay in girls with CF. The aims of this study were to compare the pubertal development of girls with CF compared with healthy controls regarding Tanner staging and pelvic ultrasound and, in girls with CF, correlate the findings with those of spirometry, body mass index, Shwachman-Kulczycki score (SKS), and genotyping. Subjects and methods: This was a cross-sectional, case-control study including 35 girls with CF aged 6-17 years and following up at the Pediatric Pulmonology Outpatient Clinic of a tertiary hospital. These patients were compared with 59 healthy controls who had undergone pelvic ultrasound as part of another study conducted by the same group. Girls with CF were consecutively enrolled in the study during their annual routine check-up visit. Data collected in the CF group included spirometry and anthropometric results, SKS values, bone age, occurrence of current cystic fibrosis-related diabetes (CFRD) and Pseudomonas aeruginosa colonization, history of meconium ileus, genotype, ultrasound parameters, and Tanner stage. Results: Pelvic ultrasound findings and Tanner stage reflected less pubertal development in girls with CF compared with healthy controls. Pubertal stage in patients with CF who presented CFRD (3.17 ± 1.16), had chronic colonization by Pseudomonas aeruginosa (3.10 ± 1.10), or were homozygous for the F508del mutation (1.91 ± 1.30) was more delayed than in controls (3.41 ± 1.41). Tanner stage correlated with age at menarche, bone age, and anthropometric and ultrasound data. Conclusions: Girls with CF presented a delay in pubertal development evaluated by Tanner stage and ultrasound parameters, which was more evident in the presence of comorbidities.

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ABSTRACT Objective: Flash glucose monitoring (FGM) is increasingly used in type 1 diabetes mellitus (T1D) management. This study aimed to assess glycated hemoglobin (HbA1c) and body mass index (BMI) in the first year of FGM use in patients with T1D and to identify predictive factors of benefit associated with its use. Subjects and methods: Retrospective study of T1D patients, using FGM for ≥ 6 months and under intensive insulin therapy with multiple daily injections. Results: In 179 patients with a median (Md) age of 43.0 years (P25 31.0; P75 52.0) and disease duration of 18.0 years (P25 10.0; P75 28.0), initial HbA1c was 7.9% (P25 7.2; P75 8.8) and initial BMI was 24.0 kg/m2 (P25 21.9; P75 26.2). With FGM, HbA1c improved significantly to 7.6% (P25 7.0; P75 8.3) at 6 months and 7.7% (P25 6.95; P75 8.5) at 12 months (p < 0.05), with more patients with HbA1c < 7% (16.1% vs 22.5%) and fewer patients with HbA1c ≥ 8% (49.1% vs 35.8%) (p < 0.05). Initial HbA1c 8.0-8.9% (HR 1.886; 95% CI 1.321-2.450) and ≥ 9.0% (HR 3.108, 95% CI 2.454-3.761) predicted greater HbA1c reduction. BMI increased significantly, especially between 6 and 12 months (BMI Md 23.8 [P25 21.9; P75 26.2] kg/m2 and 24.0 [P25 22.0; P75 26.2] kg/m2, respectively) (p < 0.05). Overweight (HR 4.319, 95% CI 3.185-5.453) and obesity (HR 8.112, 95% CI 3.919-12.306) predicted greater weight gain. Conclusions: FGM use was associated with significant improvement in HbA1c, mainly in patients with worse previous glycemic control. It was also associated with increased BMI, especially if baseline BMI ≥ 25 kg/m2, so weight control strategies should be emphasized.

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SUMMARY Acromegaly caused by ectopic growth hormone-releasing hormone (GHRH)-secreting tumor is exceedingly rare. We report a case of acromegaly secondary to GHRH secretion by an incidentally diagnosed pulmonary neuroendocrine tumor (NET) and review 47 similar cases in literature. A 22-year-old male patient presented with symptoms of pituitary apoplexy. Magnetic resonance imaging (MRI) showed apoplexy of a pituitary adenoma. Routinely prior to surgery, a chest radiography was performed which revealed a mass in the left lung. During investigation, the patient was diagnosed with metastatic GHRH-secreting pulmonary NET. In retrospect, it was noted that the patient had pituitary hyperplasia 20 months prior to the MRI which showed the presence of a pituitary adenoma. The histological findings confirmed somatotroph hyperplasia adjacent to somatotropinoma. This case suggests that GHRH secretion can be associated with pituitary hyperplasia, which may be followed by pituitary adenoma formation.

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SUMMARY Treatment-refractory hypothyroidism is a common clinical finding. Substantial causes include poor compliance and intake failure as well as gastrointestinal diseases, such as inflammatory bowel disease and short bowel syndromes. Increasing oral dosage of levothyroxine (LT4) is not always effective. Therefore, alternative routes of administration are necessary. In this report, we evaluate alternative treatment modalities for refractory hypothyroidism and present a 28-year-old woman with intestinal drug malabsorption successfully treated by subcutaneous LT4 administration. In this patient, a parenteral form of LT4, 500 μg/5 ml, was administered subcutaneously in a split dosage regimen. Blood hormone levels returned to normal within a few days and remained stable over an 8-month follow-up period.

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SUMMARY Severe hypercalcemia is a medical emergency that requires immediate and aggressive management. Primary hyperparathyroidism (PHPT) often causes severe hypercalcemia. Volume resuscitation, parenteral salmon calcitonin, and administration of intravenous bisphosphonates are common measures used to stabilize patients. However, the use of these measures is inadequate in several patients and may even be contraindicated in individuals with renal insufficiency or severe systemic illness. This study demonstrated the efficacy and safety of denosumab in patients with severe hypercalcemia due to PHPT, when immediate surgery was not feasible. We present four patients with severe hypercalcemia due to PHPT. Immediate surgery was not feasible because the patients had severe systemic illness, such as seizures and altered sensorium (case 1); acute severe pancreatitis (cases 2 and 3); or coronavirus disease 2019 pneumonia (case 4). Intravenous normal saline and parenteral salmon calcitonin were inadequate for controlling hypercalcemia. Intravenous bisphosphonates were avoided because of severe systemic illness in all cases and impaired renal function in three cases. Denosumab was administered to control hypercalcemia and allow the stabilization of patients for definitive surgical management. Following denosumab administration, serum calcium levels normalized, and general condition improved in all patients. Three patients underwent parathyroidectomy after two weeks and another patient after eight weeks. The use of denosumab for the management of severe hypercalcemia due to PHPT is efficacious and safe in patients when immediate surgical management is not feasible due to severe systemic illness.