Clinical manifestations of head and neck cancer in pediatric patients, an analysis of 253 cases in a single Brazilian center.

BACKGROUND: Pediatric head and neck cancer (PHNC) is rare and its nonspecific clinical manifestations may often lead to delayed diagnosis. We aimed to describe the signs, symptoms, and clinicopathological characteristics of PHNC. MATERIAL AND METHODS: Medical records were retrospectively reviewed for all PHNC cases diagnosed from 1986 to 2016 affecting patients aged 19-years and younger from a tertiary referral center in Brazil. Demographic variables, anatomical site of primary tumors, histopathological diagnoses, signs and symptoms, and patterns of misdiagnosis were collected and interpreted by statistical and descriptive analysis. RESULTS: A total of 253 PHNC cases were included. The mean age was 9.3 years and male patients were more frequently affected (60.9%). Burkitt lymphoma (23.7%), nasopharyngeal carcinoma (15.8%), and rhabdomyosarcoma (15.4%) were the most common cancer types. The nasopharynx (28.9%), cervical/lymph node region (25.3%), and craniofacial bones (8.3%) were the predominant anatomical sites. Tumor/swelling (68.4%), was the clinical finding often presented. The univariable analysis showed association between tumor histology and clinical variables such as sex (p=0.022), age (p<0.0001), anatomical location (p<0.0001) tumor/swelling (p=0.034), pain (p=0.031), systemic/general manifestations (p=0.004), nasal/breathing alterations (p=0.012), orbital/ocular alterations (p<0.0001). Misdiagnosis such as tonsillitis, otitis, and abscess were frequent. CONCLUSIONS: Although the clinical findings of PHNC are often unspecific, this study provided signs and symptoms with significant correlations between tumor histology. The suspicion of malignancy should be considered when the main signs and symptoms reported here appear and persist, in order to conduct a timely diagnosis.

Effects of lifestyle changes and metformin on salt sensitivity and nitric oxide metabolism in obese salt-sensitive Hispanics.

Salt sensitivity is associated with obesity, and increased cardiovascular morbidity and mortality. We investigated whether treatment of obesity and its associated metabolic abnormalities corrects salt sensitivity and restores impaired nitric oxide (NO) metabolism characteristic of salt sensitivity. Twenty, otherwise, healthy obese salt-sensitive subjects completed a 12-month program of caloric restriction, aerobic exercise and metformin. Two salt sensitivity tests were performed, that is at baseline and end of program. Lifestyle-metformin treatment decreased weight (9.8+/-0.3 kg), body mass index (3.9+/-0.2 kg/m(2)), waist (11.5+/-0.5 cm), systolic blood pressure (SBP) (8.6+/-0.4 mm Hg), diastolic blood pressure (DBP) (5.5+/-0.4 mm Hg), triglyceride (40+/-5 mg/dl), fasting (8.3+/-1 microIU/ml) and post-load (20+/-4 microIU/ml) insulin levels, and salt sensitivity. Going from a high-sodium ( approximately 300 mmol) to a low-sodium diet ( approximately 30 mmol of sodium/day) lowered SBP/DBP by 14.7+/-1.7/7.4+/-0.9 mm Hg at baseline and by 8.6+/-1.9/3.2+/-1.2 mm Hg after treatment (P<0.001). More importantly, blood pressure (BP) sensitivity to customary levels of dietary salt ( approximately 150 mmol of sodium/day) was abolished by the lifestyle-metformin treatment. Differences in SBP/DBP between usual and low salt averaged 11+/-1/8+/-1 mm Hg before treatment, and 3+/-1/1+/-0.5 mm Hg after treatment (P<0.001). At baseline, NO-metabolite excretion was inhibited during high salt; this impairment was corrected by the lifestyle-metformin treatment. In conclusion, acquired correctable factors play an important role in the pathogenesis of salt sensitivity associated with obesity. Correction of salt sensitivity may account for the BP lowering induced by weight reduction. Restoration of the inability to increase or sustain NO production in response to high salt could account for the correction of salt sensitivity induced by the lifestyle-metformin treatment.

Increased blood pressure reactivity to dietary salt in patients with the metabolic syndrome.

The metabolic syndrome is a predictor of type II diabetes mellitus and cardiovascular disease. The mechanisms of the increased blood pressure (BP) in patients with the metabolic syndrome are poorly understood. We investigated if salt-sensitivity is a characteristic of the metabolic syndrome. A total of 301 subjects (87 male subjects, 214 female subjects) of 41.5+/-0.7 years of age completed a salt sensitivity test, and were evaluated for the presence of metabolic syndrome. BP and 24-h sodium excretion were obtained under usual, high- and low-salt intakes. BP reactivity to salt was markedly increased in subjects with the metabolic syndrome; its magnitude was directly related to the severity of the syndrome. Reducing dietary salt from the average usual intake (8.2 g/day) to nearly 2.3 g/day lowered systolic blood pressure (SBP) by 8.7+/-1.3 mm Hg in subjects with four and five traits, 6.0+/-1.1 in those with three traits and failed to modify the BP of subjects with one or no traits of the syndrome (P < 0.0001). Salt restriction reduced the percentage of subjects with metabolic syndrome that were hypertensive (8.2 g/day of salt) from 23.8 to 8.2% (chi2: 23.6; P<0.0001). BP of non-hypertensive subjects with metabolic syndrome was also significantly reduced by salt restriction (7.1+/-1.5 and 4.2+/-1.1 mm Hg in those with four or five traits and three traits, respectively). In conclusion, the metabolic syndrome is a strong clinical predictor of salt sensitivity. The enhanced BP reactivity to dietary salt observed in subjects with the metabolic syndrome, may determine the increased BP levels commonly associated with the syndrome.

NAD(P)H oxidase p22phox gene C242T polymorphism, nitric oxide production, salt sensitivity and cardiovascular risk factors in Hispanics.

Mutations in the NAD(P)H oxidase gene may be associated with abnormal superoxide generation, nitric oxide (NO) availability and cardiovascular diseases. We investigated the prevalence of the NAD(P)H oxidase p22phox gene C242T polymorphism, and its possible association with blood pressure, NO production, salt sensitivity and cardiovascular risk factors in Hispanics. Genotype frequencies were as follows: CC, 52.9%; CT, 40.3%; and TT, 6.8%. There were no significant differences in systolic blood pressure, diastolic blood pressure, age, weight, fasting and post-load glucose levels, LDL and HDL cholesterol, triglyceride and urinary albumin levels in subjects with CC, CT or the TT genotypes. Presence of the T allele was associated with increased salt sensitivity in women, but not in men. NO metabolite excretion was markedly decreased both in women and men with the TT genotype (CC: 868+/-79 micromol/day; CT: 839+/-75 micromol/day; TT: 534+/-78 micromol/day; P<0.05). In conclusion, the prevalence of the NAD(P)H oxidase p22phox gene C242T polymorphism in Venezuelans was comparable to that of Caucasians, but different from that of Chinese and Japanese. Although the T allele was not associated with cardiovascular risk factors, hyperinsulinaemia or hypertension, in women, it appeared to be a genetic susceptibility factor for salt sensitivity. Both in women and men, the p22phox gene may play a role in the genetic control of NO levels.

Endothelial nitric oxide synthase polymorphism, nitric oxide production, salt sensitivity and cardiovascular risk factors in Hispanics.

Mutations in the endothelial nitric oxide synthase (eNOS) gene may be associated with abnormal nitric oxide (NO) production and cardiovascular diseases. In this study, we investigated the prevalence of two eNOS polymorphisms, the Glu298Asp variant on exon 7, and the 4a/b variable number of tandem repeats (VNTR) on intron 4, and their association with blood pressure (BP), NO production, salt sensitivity and cardiovascular risk factors in healthy Venezuelans. The prevalence of both polymorphisms in Venezuelans was comparable to that described for Caucasians, but significantly different from that known for African-Americans and Japanese. The 4a/b genotype was associated with reduced levels of NO metabolites (25% decrease), larger BP lowering in response to salt restriction (9.0 vs 4.8 mmHg, P<0.05), greater prevalence of salt sensitivity (39% in 4a/b and 27% in 4b/b; P<0.05) and with higher LDL-cholesterol levels. The Glu298T polymorphism did not affect NO production, nor it was associated with salt sensitivity. Glu298Asp polymorphism was positively associated with higher weight, triglycerides and LDL-cholesterol. Neither polymorphism was associated with changes in fasting or postload serum glucose, BP, obesity and albuminuria. In conclusion, the prevalence of eNOS polymorphisms is strongly determined by ethnic factors. The 4a/b gene polymorphism could be a genetic susceptibility factor for the BP response to salt intake and for the genetic control of NO production. The reduced NO production in subjects with the 4a/b genotype may be responsible for the increased sensitivity of their BP to salt.

Insulin resistance and upper-normal glucose levels in hypertension: a review.

Reduced insulin-mediated glucose disposal, indicative of insulin resistance, has been demonstrated in lean male hypertensives both with the hyperinsulinaemic euglycaemic clamp and the insulin suppression test. In lean hypertensives, insulin resistance was not accompanied by increases in fasting plasma insulin and glucose levels; but with modest hyperglycaemia and hyperinsulinaemia after a glucose load. Population studies (no stratification) reveal that: (1) insulin sensitivities vary widely in normotensives and hypertensives, (2) there are hypertensives and normotensives with similar degrees of insulin resistance, (3) not all hypertensives are insulin resistant, and (4) insulin resistance does not contribute to the blood pressure level of the hypertensive population. In large cross-sectional studies, the clustering of obesity, dyslipidaemia and type 2 diabetes is largely responsible for the observed associations between insulin or insulin resistance and hypertension. Recent studies indicate a role of glucose in blood pressure control. Glucose has been shown to elevate blood pressure in the presence of endothelial dysfunction and glucose values in the upper-normal range have been shown to be associated with increased cardiovascular mortality. Since endothelial dysfunction is present in hypertensives, dyslipidaemic, obese and in glucose intolerant individuals, lowering of high-normal glucose levels becomes a new, additional therapeutic target in the management of these patients. Hyperglycaemia together with endothelial dysfunction may account for the increased incidence of hypertension in obesity and diabetes mellitus. Because of the strong association between insulin resistance, hyperglycaemia and endothelial dysfunction, and the clustering of risk factors in these subjects, we propose the lowering of high normal glucose levels as part of the therapeutic strategy to prevent cardiovascular and metabolic disease.

Differential blood pressure effects of oral glucose and intravenous L-arginine in healthy lean normotensive and obese hypertensive subjects.

We investigated the role of insulin and glucose in the pathophysiology of hypertension associated with obesity. The comparative effects of an oral glucose load and of an L-arginine infusion on plasma glucose, plasma insulin and blood pressures (BP) were assessed in lean normotensive and in obese hypertensive males. Oral glucose (75 g in 1-2 min) induced a small but significant lowering of BP in lean normotensives, but failed to modify BP in obese hypertensives. L-arginine infusion (30 min, 500 mg/kg total dose) reduced BP; significantly greater reductions in systolic and diastolic BP were observed in obese hypertensives than in the control group. Both oral glucose and L-arginine induced greater increases in plasma insulin in obese hypertensives than in lean normotensives. Endothelial dysfunction which accompanies the insulin resistant state of obesity, glucose intolerance and hypertension, may account for the different BP effects induced by glucose and L-arginine in obese hypertensives and lean normotensives.

Clustering of silent cardiovascular risk factors in apparently healthy Hispanics.

Ischaemic heart disease is one of the leading causes of cardiovascular morbidity and mortality. Because most factors leading to cardiovascular disease have a silent course, early screening is needed for prevention and for halting disease progression. In our centre, a programme was implemented in apparently healthy subjects for the early diagnosis and treatment of factors known to increment the risk of developing cardiovascular and metabolic disease. We present data from the first 153 individuals evaluated. The incidence of modifiable risk factors in our healthy population was as follows: overweight 33% (BMI: 25-30 kg/m(2)), obesity 45% (BMI >30 kg/m(2)), sedentarism 84%, arterial hypertension 15% (>140/90 mm Hg), hyperinsulinaemia 50%, glucose intolerance 14% (>160 mg/dl 120 min after 75 g glucose load), type 2 diabetes mellitus 5%, hypercholesterolaemia 50%, hypertriglyceridaemia 28%, and salt sensitivity 25%. Clustering of three or more cardiovascular risk factors was observed in 59% of the apparently healthy subjects. Obesity was associated with greater clustering of risk factors. The cardiovascular dysmetabolic syndrome was present in 72% of the obese individuals. These findings revealed a very high prevalence of cardiovascular risk factors in apparently healthy Hispanics. Even though these individuals were clinically asymptomatic, they are at increased risk for developing cardiovascular disease and type 2 diabetes mellitus. Mechanisms for the early detection and correction of modifiable risk factors in the healthy population must be implemented. Only through prevention will a reduction in the incidence of cardiovascular atherosclerotic disease and of type 2 diabetes mellitus be achieved.

Hiperinsulinemia y sensibilidad a la sal / Hyperinsulinaemia and salt sensitivity

La enfermedad coronaria es una de las primeras causas de morbilidad y mortalidad cardiovascular. Para su prevención es necesario diagnosticar y corregir con medidas farmacológicas y no farmacológicas los factores de riesgo cardivascular modificables. Nosotros hemos desarrollado un programa de diagnóstico precoz y tratamiento de factores que incrementan a desarrollar enfermedades cardiovasculares y metabólicas, en sujetos "sanos", asintomáticos. Hasta el presente hemos evaluado 153 sujetos. En este trabajo evaluamos la asociación a la sensibilidad a la sal con otros factores de riesgo cardiovascular silente e investigamos los posibles factores predictores de sensibilidad a la sal. La comparación de los sujetos sensibles a la sal (SS), con los sujetos sal resistentes (SR) demostró que los sujetos SS tienen mayor edad, peso corporal, cifras tensionales, niveles elevados de triglicéridos, niveles bajos de HDL-colesterol y de actividad físico. Adicionalmente estudiamos el papel de la hiperinsulinemia y de la hiperglicemia en la sensibilidad a la sal, a través de la medición de la incidencia (porcentaje de individuos SS y SR) y severidad de la sensibilidad a la sal en sujetos hiperinsulinémicos e intolerantes glucosados y/o diabéticos comparándolos con su respectivos controles. No hubo diferencias en la distribución de sensibilidad a la sal entre los diferentes grupos (hiper y normo insulinémicos (insulina en ayunas < 15uUL/ml), glucotolerantes (glicemia en ayunas <110;2 horas post carga < 140 mg/d) y en los intolerantes glucosados y/o diabéticos. La severidad de la sensibilidad a la sal también fue similar entre grupos, de hecho, la reducción de la ingesta de sal de 316ñ13 a 26ñ3 mmol/día, produjo cambios similares en la presión arterial en sujetos hiperinsulinémicos o en sujetos con niveles normoinsulinémicos y en sujetos tolerantes e intolerantes glucosados y/o diabéticos. Adicionalmente no se encontró correlación entre la magnitud de los cambios de la presión arterial inducidos por la sal y los niveles de insulina y glucosa en ayunas, 2 horas después de la carga oral de glucosa o el área bajo la curva de insulina. En conclusión, nuestros resultados sugieren los niveles de glicemia y de insulina del paciente, no determinan su reactividad vascular a los cambios en ingesta de sal

Comparative dopamine-acetylcholine interactions in the ventral and dorsal striatum of rabbit and rat brain.

The dopamine (DA)-acetylcholine (ACh) interactions were investigated in dorsal (nucleus caudate, NC) and ventral (olfactory tubercle, OT) striatal regions, of rats and rabbits. Both regions receive a dense dopaminergic innervation and have high ACh concentrations. Brain slices of NC and OT from both animal species were prelabeled with [3H]choline and superfused. In rat and rabbit OT and NC, higher ACh release per pulse was elicited by lower than higher stimulation frequencies; in addition, rabbit tissues released a greater fraction of tissue [3H]transmitter than rat tissues. Blockade of D2 DA-receptors with sulpiride (1 microM), did not modify ACh release in OT and NC of rats and rabbits; suggesting that the lower ACh release observed in rat tissues is not due to an inhibitory dopaminergic tone on cholinergic neurons. Apomorphine (APO), a D2 DA-receptor agonist, inhibited in a concentration-dependent manner the evoked release of ACh from rat and rabbit NC (maximal inhibition = 90%). In rabbit OT, maximal inhibition induced by APO was 49 +/- 2% and in the rat OT, it was 23 +/- 1%. Sulpiride antagonized APO-induced inhibition of ACh release from rat and rabbit NC; however, it failed to prevent APO-induced inhibition in rat OT, and in the rabbit OT reduced it from 47% to 20 +/- 5%. These results indicate differences in the wiring of DA and cholinergic neurons and terminals in dorsal and ventral striatal structures, as well as between rat and rabbit tissues. Cholinergic ventral striatal structures may not receive a direct DA input, and afferent cholinergic nerve terminals (rather than interneurons) predominate in the ventral striatum.

Differential effects of muscarinic receptor agonists and phorbol ester on muscarinic and D2-dopamine release-modulatory receptors.

The interaction between an active phorbol ester, 4-beta-phobol-12,13-dibutyrate (PDBu), and muscarinic cholinergic receptor (MAChR) agonists on the electrically evoked neurotransmitter release was studied in the striatal and prefrontal cortex (PFC) of the rabbit. MAChR agonists (carbachol and oxotremorine), physostigmine and PDBu enhanced dopamine (DA) release from striatum and prefrontal cortex. Pretreatment with PDBu antagonized the increase in DA release produced by MAChR agonists (M1 receptors). Pretreatment with MAChR agonists and physostigmine also inhibited the action of PDBu on DA release. The inhibition of ACh release from the striatum induced by MAChR agonists (M2 receptors) and by apomorphine (D2-DA receptors) was antagonized by PDBu. MAChR agonists, however, did not antagonize the effects of the D2 agonist on ACh release. In the prefrontal cortex, PDBu produced greater facilitation of DA release than in the striatum, and MAChR agonists were less effective in inhibiting the effects of PDBu on DA release. This study suggests that the facilitation of DA release induced by the MAChR agonists and that induced by PDBu occur via a similar mechanism: stimulation of protein kinase C. PDBu induces a broad-spectrum loss of responsiveness to M1-MAChR and M2-MAChR and to D2-DA release-modulatory receptors, which is probably due to massive protein kinase C stimulation, signaling cell overstimulation. MAChR agonists, on the other hand, would stimulate the protein kinase C in close proximity to the M1 ACh receptor, facilitating DA release but failing to induce broad-spectrum desensitization.