Resistencia a los inhibidores de la integrasa en niños con el virus de la inmunodeficiencia humana por transmisión vertical: primeros casos en Uruguay / Resistance to integrase inhibitors in children with vertically-transmitted human immunodeficiency virus: First cases in Uruguay

La resistencia a los antirretrovirales (ARV) es un problema de salud pública. Con el uso de inhibidores de la integrasa (INSTI) en pediatría, también comienzan a aparecer resistencias. El objetivo de esta comunicación es describir 3 casos con resistencia a los INSTI. Se describen 3 pacientes pediátricos con transmisión vertical del virus de la inmunodeficiencia humana (VIH). Iniciaron ARV de lactantes y preescolares, con mala adherencia al tratamiento, cursaron con diferentes planes secundarios a comorbilidades asociadas y fallas virológicas por resistencia. Los 3 casos clínicos describen la rápida aparición de resistencia frente a la falla virológica y el compromiso de los INSTI. La adherencia debe ser supervisada para detectar precozmente el aumento de la viremia. La falla virológica en un paciente tratado con raltegravir obliga a un rápido cambio de esquema ARV, ya que continuar utilizándolo podría favorecer nuevas mutaciones y resistencia a los INSTI de segunda generación.

Antiretroviral (ARV) drug resistance is a public health issue. Resistance has also been observed in the case of integrase strand transfer inhibitors (INSTIs) used in pediatrics. The objective of this article is to describe 3 cases of INSTI resistance. These are the cases of 3 children with vertically-transmitted human immunodeficiency virus (HIV). They were started on ARVs as infants and preschoolers, with poor treatment adherence, and had different management plans due to associated comorbidities and virological failure due to resistance. In the 3 cases, resistance developed rapidly as a result of virological failure and INSTI involvement. Treatment adherence should be monitored so that any increase in viremia can be detected early. Virological failure in a patient treated with raltegravir forces to a rapid change in ARV therapy because its continued use may favor new mutations and resistance to second-generation INSTIs.

Resistance to integrase inhibitors in children with vertically-transmitted human immunodeficiency virus: First cases in Uruguay. / Resistencia a los inhibidores de la integrasa en niños con el virus de la inmunodeficiencia humana por transmisión vertical: primeros casos en Uruguay.

Antiretroviral (ARV) drug resistance is a public health issue. Resistance has also been observed in the case of integrase strand transfer inhibitors (INSTIs) used in pediatrics. The objective of this article is to describe 3 cases of INSTI resistance. These are the cases of 3 children with vertically-transmitted human immunodeficiency virus (HIV). They were started on ARVs as infants and preschoolers, with poor treatment adherence, and had different management plans due to associated comorbidities and virological failure due to resistance. In the 3 cases, resistance developed rapidly as a result of virological failure and INSTI involvement. Treatment adherence should be monitored so that any increase in viremia can be detected early. Virological failure in a patient treated with raltegravir forces to a rapid change in ARV therapy because its continued use may favor new mutations and resistance to second-generation INSTIs.

La resistencia a los antirretrovirales (ARV) es un problema de salud pública. Con el uso de inhibidores de la integrasa (INSTI) en pediatría, también comienzan a aparecer resistencias. El objetivo de esta comunicación es describir 3 casos con resistencia a los INSTI. Se describen 3 pacientes pediátricos con transmisión vertical del virus de la inmunodeficiencia humana (VIH). Iniciaron ARV de lactantes y preescolares, con mala adherencia al tratamiento, cursaron con diferentes planes secundarios a comorbilidades asociadas y fallas virológicas por resistencia. Los 3 casos clínicos describen la rápida aparición de resistencia frente a la falla virológica y el compromiso de los INSTI. La adherencia debe ser supervisada para detectar precozmente el aumento de la viremia. La falla virológica en un paciente tratado con raltegravir obliga a un rápido cambio de esquema ARV, ya que continuar utilizándolo podría favorecer nuevas mutaciones y resistencia a los INSTI de segunda generación.

Clinical and research applications of a brain tumor tissue bank in the age of precision medicine.

Marked progress has been made recently in the treatment of patients with central nervous system (CNS) tumors, especially gliomas. However, because of the relative rarity of these tumors compared with other malignancies, advances in the molecular/genetic analysis leading to future targeted treatments rely on systematic, organized tissue banking. Several large multi-institutional efforts have utilized major tissue banks that have yielded valuable information that may lead to a better understanding of the pathogenesis of CNS tumors. This manuscript portrays best practices for the establishment and maintenance of a well-organized CNS tumor bank. In addition, annotation for clinical and research needs is explained. The potential benefits to clinical care, as well as basic science and translational research are also described.

Insulin access to skeletal muscle is impaired during the early stages of diet-induced obesity.

OBJECTIVE: Insulin must move from the blood to the interstitium to initiate signaling, yet access to the interstitium may be impaired in cases of insulin resistance, such as obesity. This study investigated whether consuming a short- and long-term high-fat diet (HFD) impairs insulin access to skeletal muscle, the major site of insulin-mediated glucose uptake. METHODS: Male mongrel dogs were divided into three groups consisting of control diet (n = 16), short-term (n = 8), and long-term HFD (n = 8). Insulin sensitivity was measured with intravenous glucose tolerance tests. A hyperinsulinemic euglycemic clamp was performed in each animal at the conclusion of the study. During the clamp, lymph fluid was measured as a representation of the interstitial space to assess insulin access to muscle. RESULTS: Short- and long-term HFD induced obesity and reduced insulin sensitivity. Lymph insulin concentrations were approximately 50% of plasma insulin concentrations under control conditions. Long-term HFD caused fasting plasma hyperinsulinemia; however, interstitial insulin concentrations were not increased, suggesting impaired insulin access to muscle. CONCLUSIONS: A HFD rapidly induces insulin resistance at the muscle and impairs insulin access under basal insulin concentrations. Hyperinsulinemia induced by a long-term HFD may be a compensatory mechanism necessary to maintain healthy insulin levels in muscle interstitium.

Exenatide Treatment Alone Improves ß-Cell Function in a Canine Model of Pre-Diabetes.

BACKGROUND: Exenatide's effects on glucose metabolism have been studied extensively in diabetes but not in pre-diabetes. OBJECTIVE: We examined the chronic effects of exenatide alone on glucose metabolism in pre-diabetic canines. DESIGN AND METHODS: After 10 weeks of high-fat diet (HFD), adult dogs received one injection of streptozotocin (STZ, 18.5 mg/kg). After induction of pre-diabetes, while maintained on HFD, animals were randomized to receive either exenatide (n = 7) or placebo (n = 7) for 12 weeks. ß-Cell function was calculated from the intravenous glucose tolerance test (IVGTT, expressed as the acute insulin response, AIRG), the oral glucose tolerance test (OGTT, insulinogenic index) and the graded-hyperglycemic clamp (clamp insulinogenic index). Whole-body insulin sensitivity was assessed by the IVGTT. At the end of the study, pancreatic islets were isolated to assess ß-cell function in vitro. RESULTS: OGTT: STZ caused an increase in glycemia at 120 min by 22.0% (interquartile range, IQR, 31.5%) (P = 0.011). IVGTT: This protocol also showed a reduction in glucose tolerance by 48.8% (IQR, 36.9%) (P = 0.002). AIRG decreased by 54.0% (IQR, 40.7%) (P = 0.010), leading to mild fasting hyperglycemia (P = 0.039). Exenatide, compared with placebo, decreased body weight (P<0.001) without altering food intake, fasting glycemia, insulinemia, glycated hemoglobin A1c, or glucose tolerance. Exenatide, compared with placebo, increased both OGTT- (P = 0.040) and clamp-based insulinogenic indexes (P = 0.016), improved insulin secretion in vitro (P = 0.041), but had no noticeable effect on insulin sensitivity (P = 0.405). CONCLUSIONS: In pre-diabetic canines, 12-week exenatide treatment improved ß-cell function but not glucose tolerance or insulin sensitivity. These findings demonstrate partial beneficial metabolic effects of exenatide alone on an animal model of pre-diabetes.

Elevated nocturnal NEFA are an early signal for hyperinsulinaemic compensation during diet-induced insulin resistance in dogs.

AIMS/HYPOTHESIS: A normal consequence of increased energy intake and insulin resistance is compensatory hyperinsulinaemia through increased insulin secretion and/or reduced insulin clearance. Failure of compensatory mechanisms plays a central role in the pathogenesis of type 2 diabetes mellitus; consequently, it is critical to identify in vivo signal(s) involved in hyperinsulinaemic compensation. We have previously reported that high-fat feeding leads to an increase in nocturnal NEFA concentration. We therefore designed this study to test the hypothesis that elevated nocturnal NEFA are an early signal for hyperinsulinaemic compensation for insulin resistance. METHODS: Blood sampling was conducted in male dogs to determine 24 h profiles of NEFA at baseline and during high-fat feeding with and without acute nocturnal NEFA suppression using a partial A1 adenosine receptor agonist. RESULTS: High-fat feeding increased nocturnal NEFA and reduced insulin sensitivity, effects countered by an increase in acute insulin response to glucose (AIR(g)). Pharmacological NEFA inhibition after 8 weeks of high-fat feeding lowered NEFA to baseline levels and reduced AIR(g) with no effect on insulin sensitivity. A significant relationship emerged between nocturnal NEFA levels and AIR(g). This relationship indicates that the hyperinsulinaemic compensation induced in response to high-fat feeding was prevented when the nocturnal NEFA pattern was returned to baseline. CONCLUSIONS/INTERPRETATION: Elevated nocturnal NEFA are an important signal for hyperinsulinaemic compensation during diet-induced insulin resistance.

Supplementation of α-linolenic acid improves serum adiponectin levels and insulin sensitivity in patients with type 2 diabetes.

OBJECTIVE: ω-3 Polyunsaturated α-linolenic acid (ALA) supplementation has not been studied in the setting of adiponectin levels and insulin sensitivity (IS) improvements in patients with type 2 diabetes mellitus (T2DM) by hyperinsulinemic-euglycemic clamp (HEC). The aim of this study was to examine the influence of ω-3 ALA on IS and adiponectin. METHODS: We conducted a randomized study in patients with T2DM and assessed IS using HEC. Twenty patients with T2DM were included and randomly assigned to receive 3 g/d of ALA or placebo for 60 d, in a double-blind design. The assessment of IS by HEC was performed at baseline and after 60 d in all patients; blood samples were taken for the measurement of serum lipids, glucose, insulin, adiponectin, and cytokines. The primary outcome variables were an increase of both glucose infusion rate (GIR) in steady state and glucose metabolization (M) by HEC. The secondary outcomes were an increase in adiponectin levels and a decrease in fasting plasma glucose, glycated hemoglobin, homeostasis model assessment-estimated insulin resistance (HOMA-IR) index, lipids and cytokines. The study was conducted at an academic medical center. RESULTS: The ALA group improved IS corrected for fat-free mass (M/FFM; P = 0.04). Both groups showed increased adiponectin after 60 d (P = 0.01), however, the increase for the ALA group was greater (P = 0.04). In the ALA group, adiponectin was positively correlated with GIR (r = 0.76; P = 0.01) and M/FFM (r = 0.62; P = 0.06), and negatively correlated with HOMA-IR (r = -0.61; P = 0.03). CONCLUSION: ω-3 ALA supplementation improved glucose homeostasis and was associated with an increase in adiponectin. Improvement in the overall metabolic profile with ω-3 ALA suggests a potential clinical utility for this agent and requires further investigation.

Increase in visceral fat per se does not induce insulin resistance in the canine model.

OBJECTIVES: To determine whether a selective increase of visceral adipose tissue content will result in insulin resistance. METHODS: Sympathetic denervation of the omental fat was performed under general inhalant anesthesia by injecting 6-hydroxydopamine in the omental fat of lean mongrel dogs (n = 11). In the conscious animal, whole-body insulin sensitivity was assessed by the minimal model (SI ) and the euglycemic hyperinsulinemic clamp (SICLAMP ). Changes in abdominal fat were monitored by magnetic resonance. All assessments were determined before (Wk0) and 2 weeks (Wk2) after denervation. Data are medians (upper and lower interquartile). RESULTS: Denervation of omental fat resulted in increased percentage (and content) of visceral fat [Wk0: 10.2% (8.5-11.4); Wk2: 12.4% (10.4-13.6); P < 0.01]. Abdominal subcutaneous fat remained unchanged. However, no changes were found in SI [Wk0: 4.7 (mU/l)(-1) min(-1) (3.1-8.8); Wk2: 5.3 (mU/l)(-1) min(-1) (4.5-7.2); P = 0.59] or SICLAMP [Wk0: 42.0 × 10(-4) dl kg(-1) min(-1) (mU/l)(-1) (41.0-51.0); Wk2: 40.0 × 10(-4) dl kg(-1) min(-1) (mU/l) (-1) (34.0-52.0); P = 0.67]. CONCLUSIONS: Despite a selective increase in visceral adiposity in dogs, insulin sensitivity in vivo did not change, which argues against the concept that accumulation of visceral adipose tissue contributes to insulin resistance.

Growth hormone attenuates myocardial fibrosis in rats with chronic pressure overload-induced left ventricular hypertrophy.

1. The role of growth hormone (GH) in cardiac remodelling and function in chronic and persistent pressure overload-induced left ventricular hypertrophy has not been defined. The aim of the present study was to assess short-term GH treatment on left ventricular function and remodelling in rats with chronic pressure overload-induced hypertrophy. 2. Twenty-six weeks after induction of ascending aortic stenosis (AAS), rats were treated with daily subcutaneous injections of recombinant human GH (1 mg/kg per day; AAS-GH group) or saline (AAS-P group) for 14 days. Sham-operated animals served as controls. Left ventricular function was assessed by echocardiography before and after GH treatment. Myocardial fibrosis was evaluated by histological analysis. 3. Before GH treatment, AAS rats presented similar left ventricular function and structure. Treatment of rats with GH after the AAS procedure did not change bodyweight or heart weight, both of which were higher in the AAS groups than in the controls. After GH treatment, posterior wall shortening velocity (PWSV) was lower in the AAS-P group than in the control group. However, in the AAS-GH group, PWSV was between that in the control and AAS-P groups and did not differ significantly from either group. Fractional collagen (% of total area) was significantly higher in the AAS-P and AAS-GH groups compared with control (10.34 +/- 1.29, 4.44 +/- 1.37 and 1.88 +/- 0.88%, respectively; P < 0.05) and was higher still in the AAS-P group compared with the AAS-GH group. 4. The present study has shown that short-term administration of GH to rats with chronic pressure overload-induced left ventricular hypertrophy induces cardioprotection by attenuating myocardial fibrosis.

Zinc supplementation does not inhibit basal and metoclopramide-stimulated prolactinemia secretion in healthy men.

Dopamine (DA) and zinc (Zn++) share common mechanisms in their inhibition of prolactin (PRL) secretion. Both substances are present in the same brain areas, where Zn++ is released together with DA, suggesting a modulatory effect of Zn++ on dopaminergic receptors. The aim of the present study was to evaluate the effect of Zn++ supplementation on basal and PRL secretion stimulated by metoclopramide (MCP), a dopaminergic antagonist. Seven healthy men were evaluated in controlled study, where MCP (5 mg) was given intravenously, before and after 3 months of oral Zn++ (25 mg) administration. Our results indicate that chronic Zn++ administration does not change basal or MCP-stimulated plasma PRL secretion suggesting that, in humans, Zn++ does not interfere on PRL secretion mediated through dopaminergic receptors.

Prolactin and zinc in dialysis patients.

The objectives of the present study were to investigate the frequencies of hyperprolactinemia and hypozincemia in patients undergoing hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD), the associations between blood levels of zinc (Zn2+) and hormones, and dietary zinc intake amount and its relation to zincemia. We studied 28 patients (14 HD and 14 CAPD) who had their blood levels of Zn2+, prolactin (PRL), parathyroid hormone (PTH), and gonadotropins (LH, FSH) evaluated. Thirteen patients had dietary nutrient amounts evaluated from a 3-d nutritional record. Hyperprolactinemia occurred in 29% patients (HD = CAPD), hypozincemia in 62% (20% HD and 42% CAPD), and low dietary Zn2+ intake in 90% of patients. No correlation among blood concentration of Zn2+ and PRL, PTH, LH, and FSH were observed in the two modalities of dialysis or between zincemia and Zn2+ ingestion. We concluded that the occurrence of hyperprolactinemia and hypozincemia were not related to dialysis modality and that zincemia did not reflect the observed low dietary intake of Zn2+.

Revisäo de 2.564 punçöes aspirativas de tireóide: ênfase em doenças näo-neoplásticas / Review of 2564 fine needle aspiration of thyroid: with emphasis on non-neoplastic disease

Mediante estudo retrospectivo, os autores revisaram 2.564 casos de punçäo aspirativa por agulha fina (PAAF) da glândula tireóide de pacientes do Hospital das Clínicas da Faculdade de Medicina de Botucatu-UNESP registrados entre 1989 e 1995. Foram observados 1.911 casos de diagnósticos näo-neoplásticos, 134 de neoplásticos e 519 de materiais inadequados ao dagnóstico citológico, sendo que, dentro do critério "näo-neoplástico", foram encontrados 1.244 diagnósticos de Bócio Colóide, 337 de Tireoidites e 323 de Doença de Graves. A PAAF mostrou ser um método diagnóstico útil também nas doenças tireóideas näo-neoplásticas, incluindo os processos difusos como as Tireoidites e a Doença de Graves