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Objectives: Individuals with congenital isolated growth hormone deficiency (IGHD) in Northeastern Brazil have a normal lifespan with a prolonged healthspan. We hypothesize that their increased healthspan is accompanied by a reduced cognitive decline during aging. We have recently shown that these individuals have a similar total cognitive function and better attention and executive function than controls. These data were obtained using a Portuguese version of the Literacy Independent Cognitive Assessment (LICA) instrument, whose translation to facilitate cognitive research in Portuguese-speaking countries is described here., Subjects and Methods: In the first stage, a psychologist and a psychiatrist translated the LICA instrument from English into Portuguese, and an English teacher proofread the translation. The second stage included its synthesis and cultural adaptation, carried out by Brazilian authors, and changes in some words and images. The third stage involved an evaluation round with two referees (independent psychologists). The fourth stage involved a back translation of the instrument, which demonstrated > 95% agreement with the original version. The fifth stage included a study to verify the understanding of the questionnaire by responders. In the sixth stage, an endocrinologist and a psychiatrist approved the final Portuguese version of the instrument, which was then administered to 15 individuals with IGHD and 15 controls older than 50 years., Results: The LICA instrument was applied 59 times (5 times in the pilot study, 24 in the variability studies, and 30 in the experimental step). The interobserver and intraobserver variabilities were 99% and 96%, respectively. Cronbach's alpha was 0.76, indicating good reliability. The mean (± standard deviation) duration of the application was 39 ± 8.6 and 48.5 ± 5.8 minutes in literate and illiterate individuals, respectively., Conclusion: The Portuguese version of the LICA instrument was valuable for the cognitive assessment of individuals with Itabaianinha syndrome., Competing Interests: Disclosure: R. Salvatori serves on the advisory board for Novo Nordisk.

Background: The somatotrophic axis, including hypothalamic growth hormone (GH)-releasing hormone (GHRH), pituitary GH and circulating IGF-I, is critical for body size. However, the local production of GH/IGF-I (and IGF-II) and other peptides is relevant for other body functions, such as vascular, brain, and retinal function. The consequences of GH deficiency (GHD) on the retinal structure are still unclear, possibly reflecting the heterogeneity of patients and the different types of assessment in previous publications. Our purpose was to assess quantitative measures of the vascular and neural components of the retina in subjects with severe congenital isolated GHD (IGHD)., Methods: A cross-sectional study was carried out in 25 adult IGHD subjects and 25 age- and gender-matched controls. Interview, physical examination, laboratory data, optical coherence tomography (OCT) and OCT angiography (OCTA) were performed., Results: OCT revealed no difference in the areas of the nerve fiber layer average, nor in the areas of superior, inferior, or nasal quadrants, between the two groups. However, areas of the temporal quadrant (p = 0.041), the optical disc (p = 0.042), the cup (p < 0.0001), as well as the cup/disc ratio (p < 0.0001), were higher in IGHD subjects than controls. The rim area was smaller (p = 0.002), although still normal. In OCTA, there was no difference in the minimum foveal thickness, central fovea, foveal avascular zone, and retinal density in any assessed area., Conclusions: In conclusion, congenital IGHD does not affect quantitative measures of the vascular and neural retina, and it is associated with increased optical disc in this genetically homogeneous cohort., (© 2022. The Author(s).)

Reduced inflammation, increased insulin sensitivity, and protection against cancer are shared between humans and mice with GH/IGF1 deficiency. Beyond hormone levels, miRNAs are important regulators of metabolic changes associated with healthy aging. We hypothesized that GH deficiency in humans alters the abundance of circulating miRNAs and that a subset of those miRNAs may overlap with those found in GH-deficient mice. In this study, subjects with untreated congenital isolated GH deficiency (IGHD; n = 23) and control subjects matched by age and sex (n = 23) were recruited and serum was collected for miRNA sequencing. Serum miRNAs from young (6 month) and old (22 month) Ames dwarf (df/df) mice with GH deficiency and their WT littermates (n = 5/age/genotype group) were used for comparison. We observed 14 miRNAs regulated with a genotype by age effect and 19 miRNAs regulated with a genotype effect independent of age in serum of IGHD subjects. These regulated miRNAs are known for targeting pathways associated with longevity such as mTOR, insulin signaling, and FoxO. The aging function was overrepresented in IGHD individuals, mediated by hsa-miR-31, hsa-miR-146b, hsa-miR-30e, hsa-miR-100, hsa-miR-181b-2, hsa-miR-195, and hsa-miR-181b-1, which target the FoxO and mTOR pathways. Intriguingly, miR-181b-5p, miR-361-3p, miR-144-3p, and miR-155-5p were commonly regulated in the serum of humans and GH-deficient mice. In vitro assays confirmed target genes for the main up-regulated miRNAs, suggesting miRNAs regulated in IGHD individuals can regulate the expression of age-related genes. These findings indicate that systemic miRNAs regulated in IGHD individuals target pathways involved in aging in both humans and mice., (© 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Purposes: Increasing evidence suggests that the FGF-Klotho endocrine system and the somatotropic system (pituitary and extra-pituitary GH) may have important metabolic and immune relationships, thus contributing to the pathophysiology of aging-related disorders, including diabetes, atherosclerosis, and cancer. The status of these interactions in isolated GH deficiency (IGHD) is unknown. The objective of this study was to assess the response of both FGF21 and β-Klotho levels to a standard meal in a homogeneous group of adults with congenital untreated IGHD due to a homozygous mutation in the GHRH receptor gene., Methods: In a cross-sectional study, we measured the levels of FGF21 and β-Klotho, before and 30, 60, 120, and 180 min after a standardized test meal in 20 (11 males) IGHD and 20 (11 males) age-matched controls. Areas under the curves (AUC) of FGF21 and β-Klotho were calculated., Results: Baseline levels of FGF21 were similar, but baseline levels of β-Klotho were lower in IGHD subjects. The IGHD individuals exhibited lower AUC for FGF21 and β-Klotho levels than control subjects. There was a positive correlation between IGF1 and β-Klotho levels in the pooled groups. No correlation was found between IGF1 and FGF21 levels., Conclusions: Subjects with lifetime, untreated IGHD exhibit reduced FGF21 and β-Klotho levels response to a mixed meal. This difference may have consequences on metabolism and aging.

Objectives: Cerebrovascular disease (CeVD) is a major cause of death and disability. The role of the GH/IGF-I axis on CeVD risk is controversial. Patients with GH deficiency (GHD) in the setting of hypopituitarism often exhibit CeVD predisposing factors, like low nitric oxide generation, endothelial dysfunction, increased visceral fat mass, increased levels of LDL cholesterol, and increased intima-media thickness, a surrogate marker of atherosclerosis. However, several confounders such as the primary hypothalamic-pituitary lesion, hormonal replacement therapies, consequences of surgery and radiotherapy, may influence this relationship. Therefore, we decided to assess cerebral vasoreactivity, a surrogate marker of CeVD, in adult subjects with untreated isolated GHD (IGHD) due to the same homozygous null mutation in the GHRH receptor gene., Methods: A cross-sectional study was carried out in 25 adult IGHD subjects and 25 age- and gender-matched controls. Interview, physical examination, laboratory data, intima-media thickness measurement, and transcranial Doppler were performed. The intracranial hemodynamics (mean flow velocity, pulsatility and resistance indexes) were measured, and the response to the vasodilatory stimulus by breath-holding maneuver (breath-holding index) was calculated., Results: IGHD and control groups were similar in Framingham risk score and intima-media thickness. Similarly, there was no difference in mean flow velocity, pulsatility, resistance, and breath-holding index., Conclusions: Lifetime, untreated IGHD does not cause impaired cerebral vasoreactivity.

Context: GH and IGF-1 are crucial for attainment of normal body size and regulation of food intake, nutrient storage, and insulin sensitivity. Enteroendocrine connections exist between the GH-IGF-1 axis and insulin, ghrelin, and glucagon-like peptide 1 (GLP-1). The status of these connections in GH deficiency (GHD) is unknown., Objective: To study the enteroendocrine connections before and after a standard meal test in a homogeneous population of adults with congenital untreated isolated GHD (IGHD) due to a mutation in the GHRH receptor gene., Design: In a cross-sectional study of 20 individuals with IGHD and 20 control subjects, we measured glucose, insulin, ghrelin, and GLP-1 before and 30, 60, 120, and 180 minutes after a standardized test meal. Homeostasis model assessment index of insulin resistance (HOMA-IR) and homeostasis model assessment (HOMA)-β were calculated. Participants scored feelings of hunger, fullness, and prospective food consumption on a visual analog scale., Main Outcome Measures: Area under the curve (AUC) values of glucose, insulin, ghrelin, GLP-1, hunger, fullness, and prospective food consumption., Results: Fasting HOMA-IR and HOMA-β were lower in individuals with IGHD than in control subjects (P = 0.002 and P = 0.023, respectively). AUC was higher for hunger (P < 0.0001), glucose (P = 0.0157), ghrelin (P < 0.0001), and GLP-1 (P < 0.0001) and smaller for fullness (P < 0.0001) in individuals with IGHD compared with control subjects. There was no difference in AUC for prospective food consumption or insulin., Conclusions: Untreated IGHD is associated with increased GLP-1 secretion and reduced postprandial ghrelin and hunger attenuation in response to a mixed meal. These enteroendocrine connections can result in a favorable outcome in terms of environmental adaptation and guaranteeing appropriate food intake and can confer metabolic benefits., (Copyright © 2019 Endocrine Society.)

Growth hormone (GH) and the insulin-like growth factor I (IGF-I) have cell proliferative and differentiation properties. Whether these hormones have a role in mutagenesis is unknown. Nevertheless, severe IGF-I deficiency seems to confer protection against the development of neoplasms. Here, we report five cases of adult patients with severe and congenital isolated GH deficiency (IGHD) due to the c.57+1G>A mutation in the GHRH receptor gene, who developed tumors. Four GH-naïve subjects presented skin tumors: a 42-year-old man with a fibroepithelial polyp, a 53-year-old woman and two men (59 and 56 years old) with epidermoid skin cancers. One of these died from it after three surgeries and radiotherapy. The fifth patient was a 25-year-old woman, who had intermittently received GH replacement therapy (GHRT) from age 11 to 18, who developed an ependymoma extending from the fourth ventricle to the end of the thoracic spine. She underwent three surgical procedures, without obvious evidence of tumor recurrence during the six years follow up. These observations suggest that severe IGHD does not protect completely from development of tumors., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Several acquired or congenital hypothalamic abnormalities may cause growth failure (GF). We described two of these congenital abnormalities. First, a case of CHARGE syndrome, an epigenetic disorder mostly caused by heterozygous mutations in the gene encoding CHD7, a chromatin remodeling protein, causing several malformations, some life-threatening, with additional secondary hypothalamus-hypophyseal dysfunction, including GF. Second, a cohort of individuals with genetic isolated severe GH deficiency (IGHD), due to a homozygous mutation in the GH-releasing hormone (GHRH) receptor gene described in Itabaianinha County, in northeast Brazil. In this IGHD, with marked reduction of serum concentrations of IGF-I, and an up regulation of IGF-II, GF is the principal finding in otherwise normal subjects, with normal quality of life and longevity. This IGHD may unveil the effects of GHRH, pituitary GH and IGF-I, IGF-II and local GH and growth factor on the size and function of body and several systems. For instance, anterior pituitary hypoplasia, and impairment of the non-REM sleep may be due to GHRH resistance. Proportionate short stature, doll facies, high-pitched pre-pubertal voice, and reduced muscle mass reflect the lack of the synergistic effect of pituitary GH and IGF-I in bones and muscles. Central adiposity may be due to a direct effect of the lack of GH. Brain, eyes and immune system may also involve IGF-II and local GH or growth factors. A concept of physiological hierarchy controlling body size and function by each component of the GH system may be drawn from this model., (Copyright © 2017. Published by Elsevier Ltd.)

Purpose: Computed tomograms of the mandibles of 285 patients with indications for dental implants were evaluated at a private clinic., Materials and Methods: This study involved the evaluation of 285 cone-beam computed tomograms of patients 50 to 75 years of age who were referred to the clinic for the evaluation for implant placement images with visible C3 and C5 vertebrae that were obtained using the same I-Cat tomographic device (Imaging Sciences-Kavo, Hatfield, PA). Atheromas in the carotid space were visualized using paraxial images., Results: Data were analyzed using Student t and χ 2 tests, with a significance level of a P value less than or equal to .05. Atheromas in the carotid space were observed in 17.89% of patients; a significant difference in the incidence of atheromas was observed between men (24.27%) and women (14.29%; P = .034). However, no significant correlation was found between the frequency of occurrence of atheromas and the affected side of the carotid bifurcation (right or left) in women (P = .431) or men (P = .558)., Conclusion: Based on these results, cone-beam computed tomography could be a useful tool for the diagnosis of atheroma., (Copyright © 2016 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: To identify and describe the morphology and location of the canalis sinuosus (CS) and make correlations with gender, age, and distance of this canal to important adjacent structures on the region, thus mapping the anatomy of this structure., Methodology: A total of 100 cone beam computed tomography (CBCT) examinations were collected from the files of a dental clinic in the Municipality of Belém, Pará, Brazil, and analyzed to identify the site of bifurcation, the diameter of CS right after such bifurcation and in its terminal portion as well as the direction of its course and the distance to the alveolar bone crest region. The anatomical views were evaluated using InVivoDental software on sagittal, axial, and coronal sections, and the results were submitted to Fisher's exact test, Kendall correlation coefficients, Mann-Whitney tests, and T tests., Results: CS was present in 88 % of the sample. There were no statistically significant changes in the presence of CS regarding gender, age and direction of course. A strong positive correlation between CS's diameter on its initial and terminal portions was observed (p < 0.0001). There was a statistically significant change in the distance to alveolar bone crest related to gender, which is higher in men (p = 0.0303)., Conclusion: In the sample, CS was frequent and similar in both genders, with course distance to the alveolar bone crest and termination in different locations that ought to be analyzed on CBCT prior to surgical procedures.

Leaf-cutter ant species (Atta spp.) are key pests of cultivated crops in the Neotropics, and recent studies have demonstrated that workers of Atta spp., particularly of Atta sexdens rubropilosa, exhibit aggressive behavior among nestmates when in contact with the sesquiterpene beta-eudesmol, found in leaves of Eucalyptus maculata. However, the underlying mechanism sparking this behavior pattern has yet to be investigated. This work aimed to elucidate the mechanism by which this substance elicits aggression in workers of A. sexdens rubropilosa. The results, thus obtained, showed that beta-eudesmol is able to modify the chemical composition of the workers cuticle, impairing nestmate recognition, triggering alarm behavior and leading to nestmate aggression.