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Obesity and high-fat (HF) diet are associated with over activation of the endocannabinoid system (ECS). We have demonstrated that maternal HF diet induces early obesity and modulates cannabinoid signaling in visceral (VIS) and subcutaneous (SUB) white adipose tissue (WAT) in weanling rat offspring. We hypothesized that perinatal maternal HF diet would program the expression of ECS in adipose tissue in a long-term way in parallel to alterations in epigenetic markers and sex hormone signaling. Progenitor female rats received control diet (C, 9% fat) or isocaloric high-fat diet (HF, 28% fat) for 8 weeks before mating, gestation, and lactation. All pups were weaned to C diet and they were euthanized at 180 days old. Maternal HF diet induced overweight and increased SUB WAT mass of male and female adult offspring. Maternal HF diet induced hypertrophy of VIS and SUB adipocytes only in female offspring associated with increased type 1 cannabinoid receptor protein (CB1) and mRNA (Cnr1) levels. These changes were associated with increased estrogen receptor α binding to Cnr1 promoter in SUB WAT of adult female offspring, which may contribute to higher expression of Cnr1. Increased CB1 signaling in adipose tissue might contribute to higher adiposity programmed by maternal HF diet because endocannabinoids stimulate the accumulation of fat in the adipose tissue. Our findings provide molecular insights into sex-specific targets for anti-obesity therapies based on the endocannabinoid system.

Neuromedin B, a bombesin-like peptide, and its receptor, are expressed in white adipose tissue with undefined roles. Female mice with disruption of neuromedin B receptor (NB-R) exhibited partial resistance to diet-induced obesity leading to our hypothesis that NB-R is involved in adipogenesis. Here, we showed that adipose stem/stromal cells (ASC) from perigonadal fat of female NB-R-knockout mice, exposed to a differentiation protocol in vitro, accumulated less lipid (45%) than wild type, suggesting reduced capacity to differentiate under adipogenic input. To further explore mechanisms, preadipocytes 3T3-L1 cells were incubated in the presence of NB-R antagonist (PD168368) during the first 3 days in culture. Cells were analyzed in the end of the treatment (Day 3) and later when fully differentiated (Day 21). NB-R antagonist induced lower number of cells at day 3 and 21 (33–39%), reduced cell proliferation at day 3 (−53%) and reduced lipid accumulation at day 21 (−86%). The mRNA expressions of several adipocyte differentiation markers were importantly reduced at both days: Cebpb and Pparg and Fabp4, Plin-1 and Adipoq, and additionally Lep mRNA at day 21. The antagonist had no effect when incubated with mature 3T3-L1 adipocytes. Therefore, genetically disruption of NB-R in mice ASC or pharmacological antagonism of NB-R in 3T3-L1 cells impairs adipogenesis. The mechanisms suggested by results in 3T3-L1 cells involve reduction of cell proliferation and of early gene expressions, leading to decreased number of mature adipocytes. We speculate that NB-R antagonism may be useful to limit the increase in adiposity due to pre-adipocyte differentiation.

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease of unknown cause that occurs sporadically, but it can also occur in families and so named as Familial Pulmonary Fibrosis (FPF). Some forms of FPF overlaps IPF features, namely the radiological and histological pattern of usual interstitial pneumonia (UIP). Genetic and environmental factors commonly play an important role in the pathogenesis of FPF and the most commonly identified mutations involve the telomerase complex. Here, we report a rare case of FPF in a male at the age of 44, in whom genetic testing showed heterozygous variants for the telomerase reverse transcriptase gene (TERT). Our report highlights the importance of compiling a thorough family history in younger patients identified with UIP serving as a resource for identifying the current and future genetic links to disease. Families with UIP hold a great promise in defining UIP pathogenesis, potentially suggesting targets for the development of future therapies. Keywords: Familial pulmonary fibrosis, Idiopathic pulmonary fibrosis, TERT, Telomerase gene mutations

Hypolipidemic effects of cinnamon (Cinnamomum zeylanicum) have been described in humans and in experimental animals. Hypothyroidism is frequently associated with hyperlipidemia. Here we investigated the effects of chronic ingestion of cinnamon on lipid metabolism of hypothyroid male Wistar rats. Rats received methimazole for 7 weeks, and treated either with cinnamon as powder added to the chow or aqueous extract of cinnamon, during the last 4 weeks of protocol, and compared to untreated hypothyroid and euthyroid rats. Cinnamon intake reduced body mass increasing fat mass and reducing body protein content of hypothyroid rats. Cinnamon ingestion did not revert the hypercholesterolemia of hypothyroid rats and promoted a further reduction in serum T3, suggesting a worsening of the hypothyroid condition. Our results indicate that the beneficial effects of cinnamon on lipid metabolism are impaired in hypothyroidism.

The giant anteater (Myrmecophaga tridactyla) is a vulnerable species from Central and South America, and is considered possibly extinct in Belize, Guatemala, El Salvador, and Uruguay. Due to the species’ conservation and reproductive importance, this research aimed to characterize the morphology, histochemical, immunohistochemical, and ultrastructural feature of the giant anteater prostate gland. For this, we collected 11 giant anteater prostate glands and performed macroscopic, morphological, histochemical, immunohistochemical, and ultrastructural analysis. Nine prostate glands from an adult subject and two from young subjects were studied. Grossly, the adult giant anteater prostate gland is divided in two distinct zones, the central zones (composed mainly of ducts) and the peripheral zones (of acini formed by secretory cells). The secretory cells showed positive periodic acid–Schiff staining. Furthermore, the immunohistochemical characterization revealed a similar human prostate pattern, with p63 staining basal cells, uroplakin III (UPIII) superficial cells of prostatic urethra, androgen receptor (AR) expressing nucleus of secretory and stromal cells, and prostatic specific antigen (PSA) staining prostatic epithelial cells. Overall, our research provided an in-depth morphological description of the giant anteater’s prostate gland, providing valuable information for futures studies focused on giant anteater conservation.

Background: Sarcoidosis is a systemic granulomatous disease of unknown etiology. Epidemiological studies of different populations are essential because clinical presentation, organ involvement, disease severity, and prognosis vary significantly according to region and population. The aim of this study was to assess epidemiological and clinical characteristics, staging factors, and clinical course in patients with sarcoidosis from a tertiary hospital in Oporto, Portugal. Methods: A retrospective analysis of patients with sarcoidosis and at least 2 years of follow-up evaluated at the Centro Hospitalar de São João between 2000 and 2014. Results: We identified 409 patients with sarcoidosis (females, 58.9%; mean age at diagnosis, 38.9 ± 13.4 years; smokers, 14.4%]. All the patients were diagnosed according to the ERS/ATS/WASOG consensus statement and 64.1% had evidence of noncaseating epithelioid cell granulomas in biopsy specimens. Bronchoalveolar lavage was performed as part of the diagnostic work-up in 289 patients and 90.2% had lymphocytosis (CD4/CD8 ratio â¥Â 3.5 in 60.9% of cases). Exertion dyspnea, cough, and constitutional symptoms were the most common presenting symptoms; 10.1% of patients were asymptomatic, 22.8% had Löfgren syndrome, and 50.5% had extrathoracic involvement. Radiographic stages of disease according to the Scadding criteria were as follows: stage 0 (5.2%), stage I (33.7%), stage II (47.0%), stage III (8.4%), and stage IV (5.7%). Impaired respiratory function was observed in 45.6% patients and was mostly mild. Systemic treatment was administered in 58.6% of cases. Overall, 45.3% of patients experienced disease resolution. Conclusion: The epidemiological and clinical characteristics of this cohort of patients with sarcoidosis from the Oporto region in northern Portugal revealed epidemiological and clinical characteristics that were generally similar to those described in other Western Europe populations and in the US ACCESS study. However, we found a higher proportion of patients who progressed to chronic forms. Keywords: Sarcoidosis, Oporto, Löfgren syndrome, Extrathoracic involvement, Scadding criteria

Cinnamon supplementation has been associated with an improvement in glucose disposal and a reduction in fat mass in type 2 diabetes. Maternal nutrition during lactation impacts the health of the offspring throughout life. We hypothesize that cinnamon intake by lactating rats affects maternal physiology, leading to hormonal and metabolic changes in their offspring. To investigate this hypothesis, dams received aqueous cinnamon extract (400 mg cinnamon kg-1 body mass day-1 ) or water orally, during lactation.; Results: Maternal cinnamon intake did not affect the body mass gain or food intake of dams or their offspring, although it decreased visceral white adipose tissue mass in dams and in their adult offspring of both sexes. Cinnamon-treated dams exhibited no differences in serum insulin, adiponectin, leptin or estradiol levels, although they presented higher serum progesterone. At weaning, cinnamon male pups exhibited lower insulinemia, whereas cinnamon female pups exhibited lower glycemia. Interestingly, in adulthood, only the female offspring exhibited an altered hormonal profile, with reduced serum leptin, adiponectin and insulin levels accompanied by lower glycemia.; Conclusion: The present study demonstrates that maternal cinnamon intake during lactation promotes mild changes in dams and can trigger sex-specific metabolic programming in pups that lasts into adulthood. © 2017 Society of Chemical Industry.; © 2017 Society of Chemical Industry.

Neuromedin B (NB) and gastrin-releasing peptide (GRP) are bombesin-like peptides, found in the gastrointestinal tube and pancreas, among other tissues. Consistent data proposed that GRP stimulates insulin secretion, acting directly in pancreatic cells or in the release of gastrointestinal hormones that are incretins. However, the role of NB remains unclear. We examined the glucose homeostasis in mice with deletion of NB receptor (NBR-KO). Female NBR-KO exhibited similar fasting basal glucose with lower insulinemia (48.4%) and lower homeostasis model assessment of insulin resistance index (50.5%) than wild type (WT). Additionally, they were more tolerant to oral glucose, demonstrated by a decrease in the area under the glucose curve (18%). In addition, 15 min after an oral glucose load, female and male NBR-KO showed lower insulin serum levels (45.6 and 26.8%, respectively) than WT, even though blood glucose rose to similar levels in both groups. Single injection of NB, one hour before the oral glucose administration, tended to induce higher serum insulin in WT (28.9%, p=0.3), however the same did not occur in NBR-KO. They showed no changes in fasting insulin content in pancreatic islets by immunohistochemistry, however, the fasting serum levels of glucagon-like peptide, a potent incretin, exhibited a strong trend to reduction (40%, p=0.07). Collectively, mice with deletion of NB receptor have lower insulinemia, especially in response to oral glucose, and females also exhibited a better glucose tolerance, suggesting the involvement of NB and its receptor in regulation of insulin secretion induced by incretins, and also, in insulin sensitivity.

Metabolic syndrome (MetS) and thyroid dysfunction are common in clinical practice. The objectives of this review are to discuss some proposed mechanisms by which thyroid dysfunctions may lead to MetS, to describe the bidirectional relationship between thyroid hormones (THs) and adiposity and finally, to resume a list of recent studies in humans that evaluated possible associations between thyroid hormone status and MetS or its clinical components. Not solely THs, but also its metabolites regulate metabolic rate, influencing adiposity. The mechanisms enrolled are related to its direct effect on adenosine triphosphate (ATP) utilization, uncoupling synthesis of ATP, mitochondrial biogenesis, and its inotropic and chronotropic effects. THs also act controlling core body temperature, appetite, and sympathetic activity. In a bidirectional way, thyroid function is affected by adiposity. Leptin is one of the hallmarks, but the pro-inflammatory cytokines and also insulin resistance impact thyroid function and perhaps its structure. MetS development and weight gain have been positively associated with thyroid-stimulating hormone (TSH) in several studies. Adverse glucose metabolism may be related to hyperthyroidism, but also to reduction of thyroid function or higher serum TSH, as do abnormal serum triglyceride levels. Hypo- and hyperthyroidism have been related to higher blood pressure (BP), that may be consequence of genomic or nongenomic action of THs on the vasculature and in the heart. In summary, the interaction between THs and components of MetS is complex and not fully understood. More longitudinal studies controlling each of all confounding variables that interact with endpoints or exposure factors are still necessary.

Scope Non-alcoholic fatty liver disease (NAFLD) among adolescents has been related to fructose intake. Additionally, maternal high-fat diet (mHFD) increases the offspring susceptibility to NAFLD at adulthood. Here, it is hypothesized that mHFD may exacerbate the fructose impact in adolescent male rat offspring, by changing the response of contributing mechanisms to liver injury. Methods and results Female Wistar rats receive standard (mSTD: 9% fat) or high-fat diet (mHFD: 29% fat) prior mating throughout pregnancy and lactation. After weaning, offspring receive standard chow and, from the 25th to 45th day, receive water or fructose-drinking water (15%). At 46 days old, fructose groups show increased adiposity, increased serum and hepatic triglycerides, regardless of maternal diet. Fructose aggravates the hepatic imbalance of redox state already exhibited by mHFD offspring. The hepatic activation of cellular repair pathways by fructose, such as unfolded protein response and macroautophagy, is disrupted only in mHFD offspring. Fructose does not change the liver morphology of mSTD offspring. However, it intensifies the liver injury already present in mHFD offspring. Conclusion Fructose intake during adolescence accelerates the emergence of NAFLD observed previously at the adult life of mHFD offspring, and reveals a differentiated hepatic response to metabolic insult, depending on the maternal diet.

Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) which varies in prevalence across the world, depending on disease definition, diagnostic methods, exposure type and intensity, geographical environments, agricultural and industrial practices, and host risk factors. This study aimed to deepen knowledge about HP's clinical characteristics, diagnosis and functional and imaging features in a cohort of HP patients from the North of Portugal. To achieve this goal, a retrospective assessment of the clinical and diagnostic data was carried out, and patients were classified and compared according to disease presentation (acute, sub-acute and chronic HP forms). Of the 209 HP patients included (mean age 58.3 ± 16.0 years), 52.6% were female and 73.7% presented a chronic form. Most patients had prior exposure to birds (76.6%). Dyspnoea and cough were the most frequently experienced symptoms, but no statistically significant differences were found between groups (p = 0.089, p = 0.418, respectively). Fever was most common in acute HP form (p < 0.001). The most common patterns found in Chest CT were ground glass (p = 0.002) in acute/subacute presentation, and reticulation (p < 0.001) in chronic form, while mosaic attenuation, although was also frequently observed, no statistically significant differences were found between groups (p = 0.512). The most common functional pattern was restrictive (38% of patients, 73.7% with chronic HP form). Bronchoalveolar lavage lymphocytes were higher in acute and subacute forms although not reaching statistical significance (p = 0.072), with lowest CD4/CD8 ratio (p = 0.001) in acute forms. Thus, given the significant disease heterogeneity, further studies with different populations and ambient exposures are needed to achieve a better stratification of the exposure risk, to provide proper implementation of avoidance methods and a precise diagnostic and therapeutic approach. Martins N. would like to thank the Portuguese Foundation for Science and Technology (FCT-Portugal) for the Strategic project ref. UID/BIM/04293/2013 and ?NORTE2020?Programa Operacional Regional do Norte? (NORTE-01-0145-FEDER-000012).

Perinatal maternal high-fat diet (HFD) increases susceptibility to obesity and fatty liver diseases in adult offspring, which can be attenuated by the potent hypolipidaemic action of fish oil (FO), ann-3 PUFA source, during adult life. Previously, we described that adolescent HFD offspring showed resistance to FO hypolipidaemic effects, although FO promoted hepatic molecular changes suggestive of reduced lipid accumulation. Here, we investigated whether this FO intervention only during the adolescence period could affect offspring metabolism in adulthood. Then, female Wistar rats received isoenergetic, standard (STD: 9 % fat) or high-fat (HFD: 28·6 % fat) diet before mating, and throughout pregnancy and lactation. After weaning, male offspring received the standard diet; and from 25 to 45 d old they received oral administration of soyabean oil or FO. At 150 d old, serum and hepatic metabolic parameters were evaluated. Maternal HFD adult offspring showed increased body weight, visceral adiposity, hyperleptinaemia and decreased hepatic pSTAT3/STAT3 ratio, suggestive of hepatic leptin resistance. FO intake only during the adolescence period reduced visceral adiposity and serum leptin, regardless of maternal diet. Maternal HFD promoted dyslipidaemia and hepatic TAG accumulation, which was correlated with reduced hepatic carnitine palmitoyl transferase-1a content, suggesting lipid oxidation impairment. FO intake did not change serum lipids; however, it restored hepatic TAG content and hepatic markers of lipid oxidation to STD offspring levels. Therefore, we concluded that FO intake exclusively during adolescence programmed STD offspring and reprogrammed HFD offspring male rats to a healthier metabolic phenotype in adult life, reducing visceral adiposity, serum leptin and hepatic TAG content in offspring adulthood.

Nutrition at early stages of life contributes to the alarming incidence of childhood obesity, insulin resistance and hepatoesteatosis. Cinnamaldehyde, major component of cinnamon, increases insulin sensitivity and modulates adiposity and lipid metabolism. The aim of this study was to analyze the impact of cinnamaldehyde treatment during adolescence in a rat model of early obesity. Litter size reduction was used to induce overfeeding and early obesity. At postnatal day 30 (adolescence), the male Wistar rats received cinnamaldehyde by gavage (40 mg/kg of body weight/day) for 29 days and were studied at the end of treatment at 60 days old or 4 months thereafter (180 days old). At 60 days of age, the treatment with cinnamaldehyde promoted reduced visceral adiposity, serum triacylglycerol, and attenuation of energy efficiency and insulin resistance. In the liver, it reduced lipid synthesis, stimulated autophagy and reduced ER stress. At 180 days of age, animals treated with cinnamaldehyde during the adolescence exhibited normalization of visceral adiposity and energy efficiency, and attenuation of hyperphagia, serum hypertriglyceridemia and hepatic triacylglycerol content, with molecular markers indicative of reduced hepatic synthesis. However, the beneficial effect observed at 60 days of age on glucose homeostasis, autophagy and ER stress was lost. Therefore, the cinnamaldehyde supplementation during the adolescence has short- and long-term metabolic beneficial effects, highlighting its potential as an adjuvant in the treatment of early obesity.

Taxifolin possesses gastroprotective property but is characterized by low water solubility, is instabile in alkaline medium, and is degraded by the intestinal bacteria flora. The purpose of the work was therefore to produce a gastroadhesive formulation to prolong taxifolin residence time and release in the stomach. We first demonstrated that taxifolin is stable in simulated gastric fluid with or without pepsin and mucus, and is able to cross pig gastric mucus layer and stomach mucosa. Next, gastromucoadhesive microparticles composed of Syloid® AL-1 mesoporous silica, chitosan and HPMC were produced using spray-drying. Microparticles were characterized by a spherical shape and a mean volume-equivalent diameter around 12 μm. The optimized microparticles were able to release taxifolin and to adhere to pig stomach mucosa for 5 h.

Maternal diet plays a critical role in health development. Perinatal overnutrition induces metabolic dysfunctions and obesity in the offspring. Obesity is associated with endocannabinoid system (ECS) over activation and oxidative stress. Liver ECS activation induces hepatic steatosis, inflammation and fibrosis while the antagonism of cannabinoid receptors ameliorates these alterations. Here, we investigated the effect of perinatal maternal high-fat diet (HF, 29% of calories as fat) on the ECS and antioxidant system in liver of male and female adult rat offspring (180 days old). Maternal HF diet increased hepatic cannabinoid receptors, ECS metabolizing enzymes and triglyceride content, with male offspring more affected. ECS changes are likely independent of estradiol serum levels but associated with increased hepatic content of estrogen receptor, which can stimulate the expression of ECS components. Differently, maternal HF diet decreased the activity of the antioxidant enzymes glutathione peroxidase, superoxide dismutase and catalase, and increased oxidative stress markers in both sexes. Alterations in the redox homeostasis were associated with mitochondria damage but not with liver fibrosis. Our data suggest that maternal HF diet induces ECS over activation in adulthood, and that male offspring are at higher risk to develop liver disease compared with female rats.

Scope Maternal high-fat diet (HFD) promotes obesity and metabolic disturbances in offspring at weaning and adult life. We investigated metabolic consequences of maternal HFD in adolescent rat offspring and the potential benefic effects of fish oil (FO) (n-3 polyunsaturated fatty acid source). Methods and results Female rats received isocaloric, standard diet (STD: 9% fat) or HFD (28.6%) before mating, and throughout pregnancy and lactation. After weaning, male offspring received standard diet and, from 25th to 45th day, received oral administration of soybean oil (SO) or FO. HFD offspring showed higher body weight and adiposity, which was not attenuated by FO. In STD offspring, FO reduced serum triglyceride and cholesterol, as expected, but not in HFD offspring. Liver of HFD offspring groups showed increased free cholesterol and FO-treated HFD group showed lower expression of Abcg8, suggesting decreased cholesterol biliary excretion. HFD offspring presented higher hepatic expression of lipogenic markers, Srebf1 mRNA and acetyl CoA carboxylase (ACC). Serum n-3 PUFA were decreased in FO-treated HFD compared to FO-treated STD offspring, which may explain the reduced hypolipidemic FO effect. Conclusion Maternal HFD impaired the ability of FO to reduce adiposity and serum lipids in adolescent offspring, suggesting a potential predisposition to future development of metabolic disorders.

The relationship between primary hematologic disease and rheumatologic manifestations is well known, especially acute lymphocytic leukemia, lymphomas, plasma cell dyscrasias and myelodysplastic syndrome (MDS). Currently, more has been described about autoimmune manifestations in chronic myelomonocytic leukemia (CMML). Many different clinical scenarios may lead a patient with MDS/CMML initially to seek a rheumatological unit. Autoimmune features such as polymyalgia rheumatic symptoms, myositis, neutrophilic dermatosis, cutaneous vasculitis and positive antinuclear antibodies (ANA) are some examples of clinical presentation of MDS/CMML. Moreover, peripheral cytopenias are a common initial presentation both for systemic lupus erythematous (SLE) and MDS/CMML. The aim of this study was to describe a case of an elderly woman with thrombocytopenia and positivity of antibodies to anti-extractable nuclear antigens (anti-ENA) as initial manifestation of CMML mimicking SLE, and to present some clues that encourage the clinician to perform a bone marrow study in such a clinical scenario.

The hypothalamus-pituitary-thyroid (HPT) axis determines the set point of thyroid hormone (TH) production. Hypothalamic thyrotropin-releasing hormone (TRH) stimulates the synthesis and secretion of pituitary thyrotropin (thyroid-stimulating hormone, TSH), which acts at the thyroid to stimulate all steps of TH biosynthesis and secretion. The THs thyroxine (T4) and triiodothyronine (T3) control the secretion of TRH and TSH by negative feedback to maintain physiological levels of the main hormones of the HPT axis. Reduction of circulating TH levels due to primary thyroid failure results in increased TRH and TSH production, whereas the opposite occurs when circulating THs are in excess. Other neural, humoral, and local factors modulate the HPT axis and, in specific situations, determine alterations in the physiological function of the axis. The roles of THs are vital to nervous system development, linear growth, energetic metabolism, and thermogenesis. THs also regulate the hepatic metabolism of nutrients, fluid balance and the cardiovascular system. In cells, TH actions are mediated mainly by nuclear TH receptors (210), which modify gene expression. T3 is the preferred ligand of THR, whereas T4, the serum concentration of which is 100-fold higher than that of T3, undergoes extra-thyroidal conversion to T3. This conversion is catalyzed by 5'-deiodinases (D1 and D2), which are TH-activating enzymes. T4 can also be inactivated by conversion to reverse T3, which has very low affinity for THR, by 5-deiodinase (D3). The regulation of deiodinases, particularly D2, and TH transporters at the cell membrane control T3 availability, which is fundamental for TH action. © 2016 American Physiological Society. Compr Physiol 6:1387-1428, 2016.

Background Cinnamon has several effects on energy metabolism. However, no data exist on the impact of cinnamon intake on thyroid hormone serum concentrations and action, since thyroid hormones (THs) play a major role in metabolism. Results Male rats were treated with cinnamon water extract (400 mg kg(-1) body weight, 25 days). Cinnamon supplementation resulted in a lower serum total T3 level accompanied by normal serum T4 and TSH levels. The cinnamon-treated rats did not exhibit significant differences in TSHβ subunit, TRβ or deiodinase type 2 mRNA expression in the pituitary. In the liver, cinnamon did not change the TRβ protein expression or the deiodinase type 1 mRNA expression, suggesting that there were no changes in T3 signaling or metabolism in this organ. However, mitochondrial GPDH, a target gene for T3 in the liver, exhibited no changes in mRNA expression, although its activity level was reduced by cinnamon. In the cardiac ventricle, T3 action was markedly reduced by cinnamon, as demonstrated by the lower TRα mRNA and protein levels, reduced SERCA2a and RyR2 and increased phospholamban mRNA expression. Conclusion This study has revealed that TH action is a novel target of cinnamon, demonstrating impairment of T3 signaling in the cardiac ventricles. © 2015 Society of Chemical Industry.

Maternal nutritional imbalances trigger developmental adaptations involving early epigenetic mechanisms associated with adult chronic disease. Maternal high-fat (HF) diet promotes obesity and hypothalamic leptin resistance in male rat offspring at weaning and adulthood. Leptin resistance is associated with over activation of the endocannabinoid system (ECS). The ECS mainly consists of endocannabinoids derived from n-6 fatty acids and cannabinoid receptors (CB1 coded by Cnr1 and CB2 coded by Cnr2). The CB1 activation in hypothalamus stimulates feeding and appetite for fat while CB2 activation seems to play an immunomodulatory role. We demonstrated that maternal HF diet increases hypothalamic CB1 in male offspring while increases CB2 in female offspring at birth, prior to obesity development. However, the molecular mechanisms behind these changes remain unexplored. We hypothesized that maternal HF diet would down-regulate leptin signaling and up-regulate Cnr1 mRNA levels in the hypothalamus of the offspring at birth, associated with sex-specific changes in epigenetic markers and sex steroid signaling. To test our hypothesis, we used progenitor female rats that received control diet (C, 9% fat) or isocaloric high-fat diet (HF, 28% fat) from 8 weeks before mating until delivery. Blood, hypothalamus and carcass from C and HF male and female offspring were collected for biochemical and molecular analyses at birth. Maternal HF diet down-regulated the transcriptional factor STAT3 in the hypothalamus of male and female offspring, but induced hypoleptinemia only in males and decreased phosphorylated STAT3 only in female offspring. Because leptin acts through STAT3 pathway to inhibit central ECS, our results suggest that leptin pathway impairment might contribute to increased levels of Crn1 mRNA in hypothalamus of both sex offspring. Besides, maternal HF diet increased the histone acetylation percentage of Cnr1 promoter in male offspring and increased the androgen receptor binding to the Cnr1 promoter, which can contribute to higher expression of Cnr1 in newborn HF offspring. Maternal HF diet increased plasma n6 to n3 fatty acid ratio in male offspring, which is an important risk factor to metabolic diseases and might indicate an over activation of endocannabinoid signaling. Thus, although maternal HF diet programs a similar phenotype in adult offspring of both sexes (obesity, hyperphagia and higher preference for fat), here we showed that molecular mechanisms involving leptin signaling, ECS, epigenetic markers and sex hormone signaling were modified prior to obesity development and can differ between newborn male and female offspring. These observations may provide molecular insights into sex-specific targets for anti-obesity therapies.

Studies with foods, known to promote health benefits in addition to the nutritive value, show that their consumption by pregnant and/or lactating females could induce negative outcomes to the offspring. It is well characterized that cinnamon intake promotes benefits to energy homeostasis. The present study aimed to analyze the effects of the consumption of an aqueous extract of cinnamon by lactating female rats on the endocrine-metabolic outcomes in the adult offspring. Lactating dams (Wistar rats) were supplemented with cinnamon aqueous extract (400 mg/kg body weight/day) for the entire lactating period. The male adult offspring were evaluated at 180 days old (CinLac). The offspring presented visceral obesity (P = 0.001), hyperleptinemia (P = 0.002), and hyperinsulinemia (P = 0.016). In the liver, CinLac exhibited reduced p-IRβ (P = 0.018) suggesting insulin resistance. However, phosphorylation of IRS1 (P = 0.041) and AKT (P = 0.050) were increased. JAK2 (P = 0.030) and p-STAT3 (P = 0.015) expressions were higher, suggesting that the activation of IRS1/AKT in the CinLac group could have resulted from the increased activation of leptin signaling. Although we observed no changes in the gluconeogenic pathway, the CinLac group exhibited lower hepatic glycogen content (P = 0.005) accompanied by increased p-GSK3β (P = 0.011). In addition, the CinLac group showed increased hepatic triacylglycerol content (P = 0.049) and a mild steatosis (P = 0.001), accompanied by reduced PPARα mRNA expression (P = 0.005). We conclude that maternal intake of aqueous extract of cinnamon induces long-term molecular, metabolic, and hormonal changes in the adult progeny, including visceral obesity, higher lipid accumulation, and lower glycogen content in the liver.

The aim of this study was to evaluate the bond strength between the fibre post and root dentin after different cleaning protocols to remove eugenol from dentin. The residues and elemental composition of dentin were analysed using SEM and EDS. Bovine incisor roots were obturated with eugenol-based sealer. The post space was prepared, and the roots were divided into the following groups according to the cleaning protocol: unfilled (negative control), saline solution (positive control), 70% ethanol, acetone and 70% isopropyl alcohol. The fibre posts were cemented and push-out test realised. Chemical analysis of the dentin was performed using SEM and EDS. The bond strength values were analysed by anova/Fisher's and were as follows: negative control (7.30 ± 2.77) = 70% ethanol (6.64 ± 2.91) = 70% isopropyl alcohol (5.01 ± 3.15) = acetone (4.42 ± 1.53) >positive control (1.29 ± 0.56). It was concluded that 70% ethanol may be a good cleaning protocol to remove eugenol from dentin.

The modern concept of thyroid disruptors includes synthetic chemicals and bioactive compounds from food that interfere with any aspect of the hypothalamus–pituitary–thyroid axis, thyroid hormone biosynthesis and secretion, blood and transmembrane transport, metabolism and local actions of thyroid hormones. This review highlights relevant disruptors that affect populations through their diet: directly from food itself (fish oil and polyunsaturated fatty acids, pepper, coffee, cinnamon and resveratrol/grapes), through vegetable cultivation (pesticides) and from containers for food storage and cooking (bisphenol A, phthalates and polybrominated diphenyl ethers). Due to the vital role of thyroid hormones during every stage of life, we review effects from the gestational period to adulthood, including evidence fromin vitrostudies, rodent models, human trials and epidemiological studies.

Early life inadequate nutrition triggers developmental adaptations and adult chronic disease. Maternal high-fat (HF) diet promotes visceral obesity and hypothalamic leptin resistance in male rat offspring at weaning and adulthood. Obesity is related to over active endocannabinoid system (ECS). The ECS consists mainly of endogenous ligands, cannabinoid receptors (CB1 and CB2), and the enzymes fatty acid anandamide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). We hypothesized that perinatal maternal HF diet would regulate offspring ECS in hypothalamus and brown adipose tissue (BAT) at birth, prior to visceral obesity development, and program food preference and energy expenditure of adult offspring. Female rats received control diet (C, 9% fat) or isocaloric high-fat diet (HF, 28% fat) for 8 weeks before mating, and throughout gestation and lactation. We evaluated C and HF offspring at birth and adulthood. At birth, maternal HF diet decreased leptinemia and increased hypothalamic CB1, orexin-A, and proopiomelanocortin while it decreased thyrotropin-releasing hormone (Trh) in male pups. Differentially, maternal HF diet increased hypothalamic CB2 in female pups. In BAT, maternal HF diet decreased CB1 and increased CB2 in male and female pups, respectively. Besides presenting different molecular ECS profile at birth, HF adult offspring developed overweight, higher adiposity and high-fat diet preference, independently of the sex, but only males presented hyperleptinemia and higher energy expenditure. In conclusion, maternal HF diet alters ECS components and energy metabolism targets in hypothalamus and BAT of offspring at birth, in a sex-specific manner, which may contribute for hyperphagia, food preference and higher adiposity later in life.

We present a new data set of annual historical (1750–2014) anthropogenic chemically reactive gases (CO, CH4, NH3, NOx, SO2, NMVOCs), carbonaceous aerosols (black carbon – BC, and organic carbon – OC), and CO2 developed with the Community Emissions Data System (CEDS). We improve upon existing inventories with a more consistent and reproducible methodology applied to all emission species, updated emission factors, and recent estimates through 2014. The data system relies on existing energy consumption data sets and regional and country-specific inventories to produce trends over recent decades. All emission species are consistently estimated using the same activity data over all time periods. Emissions are provided on an annual basis at the level of country and sector and gridded with monthly seasonality. These estimates are comparable to, but generally slightly higher than, existing global inventories. Emissions over the most recent years are more uncertain, particularly in low- and middle-income regions where country-specific emission inventories are less available. Future work will involve refining and updating these emission estimates, estimating emissions' uncertainty, and publication of the system as open-source software.

Background This study aimed to investigate the pathophysiology of hepatic microcirculatory dysfunction in non-alcoholic fatty liver disease (NAFLD). Methods In Wistar rats, NAFLD model was induced by 20 weeks of high-fat diet (HFD) feeding. Rolling and adhesion of leukocytes and tissue perfusion in hepatic microcirculation were examined using in vivo microscopic and laser speckle contrast imaging (LSCI), respectively. Oxidative stress and inflamatory parameters were analysed by TBARs, catalase enzyme activity, RT-PCR and ELISA. The participation of advanced glycation end-products (AGE) and its receptor RAGE was evaluated by the measurement of gene and protein expression of RAGE by RT-PCR and Western-blot, respectively and by liver and serum quantification of fluorescent AGEs. Results Wistar rats fed high-fat diet (HFD) showed increase in epididymal and abdominal fat content, systolic arterial blood pressure, fasting blood glucose levels, hepatic triglycerides and cholesterol, and impairment of glucose and insulin metabolisms. Liver histology confirmed the presence of steatosis and ultrasound analysis revealed increased liver size and parenchymal echogenicity in HFD-fed rats. HFD causes significant increases in leukocyte rolling and adhesion on hepatic microcirculation and decrease in liver microvascular blood flow. Liver tissue presented increase in oxidative stress and inflammtion. At 20 weeks, there was a significantly increase in AGE content in the liver and serum of HFD-fed rats and an increase in RAGE gene expression in the liver. Conclusion The increase in liver AGE levels and microcirculatory disturbances could play a role in the pathogenesis of liver injury and are key components of NAFLD.

The inhibition of maternal prolactin production in late lactation leads to metabolic syndrome and hypothyroidism in adult offspring. Physical training is a therapeutic strategy that could prevent or reverse this condition. We evaluated the effects of a short-duration low-intensity running wheel training program on the metabolic and hormonal alterations in rats. Lactating Wistar rats were treated with bromocriptine (Bro, 1 mg twice a day) or saline on days 19, 20, and 21 of lactation, and the training of offspring began at 35 days of age. Offspring were divided into sedentary and trained controls (C-Sed and C-Ex) and sedentary and trained Bro-treated rats (Bro-Sed and Bro-Ex). Chronic exercise delayed the onset of weight gain in Bro-Ex offspring, and the food intake did not change during the experimental period. At 180 days, visceral fat mass was higher (+46%) in the Bro-Sed offspring than in C-Sed and Bro-Ex rats. As expected, running capacity was higher in trained animals. Most parameters observed in the Bro-Sed offspring were consistent with hypothyroidism and metabolic syndrome and were reversed in the Bro-Ex group. Chronic exercise did not influence the muscle glycogen in the C-Ex group; however, liver glycogen was higher (+30%) in C-Ex group and was unchanged in both Bro offspring groups. Bro-Ex animals had higher plasma lactate dehydrogenase levels, indicating skeletal muscle damage and intolerance of the training program. Low-intensity chronic training is able to normalize many clinical aspects in Bro animals; however, these animals might have had a lower threshold for exercise adaptation than the control rats.

Thyroid hormones are important modulators of lipid metabolism because the liver is a primary hormonal target. The hypolipidaemic effects of thyroid hormones result from the balance between direct and indirect actions resulting in stimulation of lipid synthesis and lipid oxidation, which favours degradation pathways. Originally, it was believed that thyroid hormone activity was only transduced by alteration of gene transcription mediated by the nuclear receptor thyroid hormone receptors, comprising the classic action of thyroid hormone. However, the discovery of other effects independent of this classic mechanism characterised a new model of thyroid hormone action, the non-classic mechanism that involves other signalling pathways. To date, this mechanism and its relevance have been intensively described. Considering the increasing evidence for non-classic signalling of thyroid hormones and the major influence of these hormones in the regulation of lipid metabolism, we reviewed the role of thyroid hormone in cytosolic signalling cascades, focusing on the regulation of second messengers, and the activity of effector proteins and the implication of these mechanisms on the control of hepatic lipid metabolism.

Made available in DSpace on 2018-11-26T17:12:11Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-01-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) The aim of this study was to investigate the relationship between antibiotic residues found in the muscle of cage-farm-raised Nile tilapia (Oreochromisniloticus), the occurrence of resistant bacteria, and the sanitary practices adopted by farmers in Ilha Solteira reservoir, Brazil. Nine fish (three small fish, 40-200 g; three medium-sized fish, 200-500 g; and three large fish, 500-800 g) were collected from four cage farms every three months from April 2013 to January 2014. Ten antibiotic residues were determined using liquid chromatography-mass spectrometry, and bacteria were isolated and tested for antibiotic resistance to determine the multiple antibiotic resistance (MAR) index. Only three antibiotics (oxytetracycline, tetracycline, and florfenicol) were detected in the muscle of Nile tilapia, and their residues were the highest in small fish; however, the MAR index was higher in large fish. In addition, a direct positive relationship between the MAR index and the concentration of antibiotic residues in Nile tilapia was found. Overall, the adoption of prophylactic management practices improved the sanitary status of cage farms, reducing bacterial infections and hampering the development of antibiotic-resistant bacteria. Inst Biol, Sao Paulo, SP, Brazil Univ Sao Paulo, Ctr Nucl Energy Agr, Piracicaba, SP, Brazil Inst Fisheries, Votuporanga, SP, Brazil Sao Paulo State Univ, Ctr Aquaculture, Jaboticabal, SP, Brazil Inst Agron, Votuporanga, SP, Brazil Sao Paulo State Univ, Ctr Aquaculture, Jaboticabal, SP, Brazil FAPESP: 2011/18179-1

Aims To understand how thyroid hormone (TH) regulates tissue-specific gene expression in patients with the syndrome of resistance to TH (RTHβ), we used a mouse model that replicates the human RTHβ, specifically the ∆ 337T mutation in the thyroid hormone receptor β (THRβ). Main methods We investigated the expression of key TH target genes in the pituitary and liver of TRβ ∆ 337T and wild type THRβ mice by qPCR before and after a T 3 suppression test consisting of the administration of increasing concentrations of T 3 to hypothyroid mice. Key findings Pituitary Tshb and Cga expression decreased and Gh expression increased in TRβ ∆ 337T mice after T 3 suppression. The stimulation of positively regulated TH genes was heterogeneous in the liver. Levels of liver Me1 and Thsrp were elevated in TRβ ∆ 337T mice after T 3 administration. Slc16a2 and Gpd2 did not respond to T 3 stimulation in the liver of TRβ ∆ 337T mice whereas Dio1 response was lower than that observed in WT mice. Moreover, although Chdh and Upd1 genes were negatively regulated in the liver, the expression of these genes was elevated after T 3 suppression. We did not observe significant changes in THRα expression in the liver and pituitary, while THRβ levels were diminished in the pituitary and increased in the liver. Significance Using a model expressing a THRβ unable to bind T3, we showed the expression pattern of liver negative and positive regulated genes by T3.

OBJECTIVES: To evaluate the effect of Carbopol gel formulations containing pilocarpine on the morphology and morphometry of the vaginal epithelium of castrated rats. METHODS: Thirty-one female Wistar-Hannover rats were randomly divided into four groups: the control Groups I (n=7, rats in persistent estrus; positive controls) and II (n=7, castrated rats, negative controls) and the experimental Groups, III (n=8) and IV (n=9). Persistent estrus (Group I) was achieved with a subcutaneous injection of testosterone propionate on the second postnatal day. At 90 days postnatal, rats in Groups II, III and IV were castrated and treated vaginally for 14 days with Carbopol gel (vehicle alone) or Carbopol gel containing 5% and 15% pilocarpine, respectively. Next, all of the animals were euthanized and their vaginas were removed for histological evaluation. A non-parametric test with a weighted linear regression model was used for data analysis (p

Maternal nutritional status affects the future development of offspring. Both undernutrition and overnutrition in critical periods of life (gestation or lactation) may cause several hormonal changes in the pups and programme obesity in the adult offspring. We have shown that hyperleptinaemia during lactation results in central leptin resistance, higher adrenal catecholamine secretion, hyperthyroidism, and higher blood pressure and heart rate in the adult rats. Here, we evaluated the effect of a maternal isocaloric high-fat diet on breast milk composition and its impact on leptinaemia, energy metabolism, and adrenal and thyroid function of the offspring at weaning. We hypothesised that the altered source of fat in the maternal diet even under normal calorie intake would disturb the metabolism of the offspring. Female Wistar rats were fed a normal (9% fat; C group) or high-fat diet (29% fat as lard; HF group) for 8 weeks before mating and during pregnancy and lactation. HF mothers presented increased total body fat content after 8 weeks (+27%, P < 0.05) and a similar fat content at the end of lactation. In consequence, the breast milk from the HF group had higher concentration of protein (+18%, P < 0.05), cholesterol (+52%, P < 0.05) and triglycerides (+86%, P < 0.05). At weaning, HF offspring had increased body weight (+53%, P < 0.05) and adiposity (2 fold, P < 0.05), which was associated with lower β3-adrenoreceptor content in adipose tissue (-40%, P < 0.05). The offspring also presented hyperglycaemia (+30%, P < 0.05) and hyperleptinaemia (+62%, P < 0.05). In the leptin signalling pathway in the hypothalamus, we found lower p-STAT3/STAT3 (-40%, P < 0.05) and SOCS3 (-55%, P < 0.05) content in the arcuate nucleus, suggesting leptin resistance. HF offspring also had higher adrenal catecholamine content (+17%, P < 0.05), liver glycogen content (+50%, P < 0.05) and hyperactivity of the thyroid axis at weaning. Our results suggest that a high fat diet increases maternal body fat and this additional energy is transferred to the offspring during lactation, since at weaning the dams had normal fat and the pups were obese. The higher fat and protein concentrations in the breast milk seemed to induce early overnutrition in the HF offspring. In addition to storing energy as fat, the HF offspring had a larger reserve of glycogen and hyperglycaemia that may have resulted from increased gluconeogenesis. Hyperleptinaemia may stimulate both adrenal medullary and thyroid function, which may contribute to the development of cardiovascular diseases. These early changes induced by the maternal high-fat diet may contribute to development of metabolic syndrome.

Early weaning is associated with changes in the developmental plasticity. Here, we studied the adipocytes morphology, adipokines expression or content in adipose tissue as well as adrenal and thyroid function of neonate and adult offspring primed by early weaning. After birth, lactating rats were divided into 2 groups: EW (early weaning) – dams were wrapped with a bandage to block access to milk during the last 3 days of lactation, and Control – dams whose pups had free access to milk throughout lactation (21 days). At postnatal day (PN) 21, EW pups had lower visceral and subcutaneous adipocyte area ( − 67.7% and − 62%, respectively), body fat mass ( − 26%), and leptin expression in visceral adipocyte ( − 64%) but higher leptin expression in subcutaneous adipocyte (2.9-fold increase). Adrenal evaluations were normal, but neonate EW pups presented lower serum T3 ( − 55%) and TSH ( − 44%). At PN 180, EW offspring showed higher food intake, higher body fat mass (+21.6%), visceral and subcutaneous adipocyte area (both 3-fold increase), higher leptin (+95%) and ADRβ3 (2-fold increase) content in visceral adipose tissue, and higher adiponectin expression in subcutaneous adipose tissue (+47%) but lower in visceral adipose tissue ( − 40%). Adult EW offspring presented higher adrenal catecholamine content (+31%), but no changes in serum corticosterone or thyroid status. Thus, early weaning primed for hypothyroidism at weaning, which can be associated with the adipocyte hypertrophy at adulthood. The marked changes in catecholamine adrenal content and visceral adipocyte ADRB3 are generally found in obesity, contributing to the development of other cardiovascular and metabolic disturbances.

Introduction: Integrated PET/CT has become a fundamental tool in the preoperative assessment of non-small cell lung cancer (NSCLC) providing useful anatomical and metabolic information to characterize tumoral lesions and to detect unsuspected metastatic disease. Aim: To compare the agreement between clinical and pathological staging before and after the use of PET/CT. Material and methods: Retrospective study of patients with NSCLC who underwent potentially curative surgery throughout 10.5 years. Cohen's kappa coefficient was used to evaluate staging agreement. Results: One hundred and fifty patients were evaluated, 78% males, with a mean age of 65 (±9.6) years. Thirteen percent were submitted to neoadjuvant chemotherapy. PET/CT was performed in 41%. Global agreement between clinical and pathological staging was 51% (kappa = 0.3639). There was a statistically significant difference between the staging results in patients who underwent PET/CT, when compared to the subgroup who did not (p = 0.003). For those with PET/CT false negatives occurred in less 39%, false positives in more 12% and clinical and pathological staging coincided in more 27%. The overall results reflected an improvement in the agreement between clinical and pathological staging in the PET/CT subgroup (67%, kappa = 0.5737 vs 40%, kappa = 0.2292). PET/CT accuracy was enhanced when patients re-staged after neoadjuvant therapy were excluded and a substantial staging agreement was obtained for those who had the exam only for staging purposes (73%, kappa = 0.6323). Conclusion: Inclusion of PET/CT in NSCLC preoperative assessment improved the accuracy of the clinical staging, with a good level of agreement with pathological staging. Resumo: Introdução: A PET/TC integrada tornou-se num instrumento fundamental na avaliação pré-operatória do cancro do pulmão de não pequenas células (CPNPC), fornecendo informação anatómica e metabólica com utilidade na caracterização das lesões tumorais e na deteção da doença metastática. Objetivo: Comparar a concordância entre o estadiamento clínico e o patológico antes e depois da utilização da PET/TC. Material e métodos: Estudo retrospetivo envolvendo doentes com CPNPC submetidos a cirurgia potencialmente curativa num período de 10,5 anos. O coeficiente de kappa de Cohen foi utilizado para avaliar a concordância entre os resultados. Resultados: Foram incluídos 150 doentes, 78% do sexo masculino, com uma idade média de 65 (± 9,6) anos. Treze por cento foram submetidos a quimioterapia neoadjuvante. A PET/TC foi efetuada em 41%. A concordância global entre o estadiamento clínico e o patológico foi de 51% (kappa = 0,3639). Verificou-se uma diferença estatisticamente significativa quanto aos resultados do estadiamento nos doentes que efetuaram PET/TC em comparação com o subgrupo que não efetuou o exame (p = 0,003). Nos doentes com PET/TC os falsos negativos ocorreram menos 39%, os falsos positivos em mais 12% e o estadiamento clínico e patológico foi coincidente em mais 27% dos casos. Estes resultados refletiram uma melhoria da concordância entre o estadiamento clínico e o patológico no subgrupo com PET/TC (67%, kappa = 0,5737 vs 40%, kappa = 0,2292). A acuidade da PET/TC foi aumentada quando os doentes submetidos a terapêutica neoadjuvante foram excluídos, obtendo-se uma concordância substancial naqueles que efetuaram o exame apenas com o objetivo de estadiamento (73%, kappa = 0,6323). Conclusão: A inclusão da PET/TC na avaliação pré-operatória do CPNPC melhorou a acuidade do estadiamento clínico, permitindo uma boa concordância com o estadiamento patológico. Keywords: Non-small cell lung cancer, PET/CT, Staging, Palavras-chave: Cancro do pulmão de não pequenas células, PET/TC, Estadiamento

Resumo: Introdução: A PET/TC integrada tornou-se num instrumento fundamental na avaliação pré-operatória do cancro do pulmão de não pequenas células (CPNPC), fornecendo informação anatómica e metabólica com utilidade na caracterização das lesões tumorais e na deteção da doença metastática. Objetivo: Comparar a concordância entre o estadiamento clínico e o patológico antes e depois da utilização da PET/TC. Material e métodos: Estudo retrospetivo envolvendo doentes com CPNPC submetidos a cirurgia potencialmente curativa num período de 10,5 anos. O coeficiente de kappa de Cohen foi utilizado para avaliar a concordância entre os resultados. Resultados: Foram incluídos 150 doentes, 78% do sexo masculino, com uma idade média de 65 (± 9,6) anos. Treze por cento foram submetidos a quimioterapia neoadjuvante. A PET/TC foi efetuada em 41%. A concordância global entre o estadiamento clínico e o patológico foi de 51% (kappa = 0,3639). Verificou-se uma diferença estatisticamente significativa quanto aos resultados do estadiamento nos doentes que efetuaram PET/TC em comparação com o subgrupo que não efetuou o exame (p = 0,003). Nos doentes com PET/TC os falsos negativos ocorreram menos 39%, os falsos positivos em mais 12% e o estadiamento clínico e patológico foi coincidente em mais 27% dos casos. Estes resultados refletiram uma melhoria da concordância entre o estadiamento clínico e o patológico no subgrupo com PET/TC (67%, kappa = 0,5737 vs 40%, kappa = 0,2292). A acuidade da PET/TC foi aumentada quando os doentes submetidos a terapêutica neoadjuvante foram excluídos, obtendo-se uma concordância substancial naqueles que efetuaram o exame apenas com o objetivo de estadiamento (73%, kappa = 0,6323). Conclusão: A inclusão da PET/TC na avaliação pré-operatória do CPNPC melhorou a acuidade do estadiamento clínico, permitindo uma boa concordância com o estadiamento patológico. Abstract: Introduction: Integrated PET/CT has become a fundamental tool in the preoperative assessment of non small lung cancer (NSCLC) providing useful anatomical and metabolic information to characterize tumoral lesions and to detect unsuspected metastatic disease. Aim: To compare the agreement between clinical and pathological staging before and after the use of PET/CT. Material and methods: Retrospective study of patients with NSCLC who underwent potentially curative surgery throughout 10.5 years. Cohen's kappa coefficient was used to evaluate staging agreement. Results: One hundred and fifty patients were evaluated, 78% males, with a mean age of 65 (±9.6) years. Thirteen percent were submitted to neoadjuvant chemotherapy. PET/CT was performed in 41%. Global agreement between clinical and pathological staging was 51% (kappa=0.3639). There was a statistically significant difference between the staging results in patients who underwent PET/CT, when compared to the subgroup who did not (p=0.003). For those with PET/CT false negatives occurred in less 39%, false positives in more 12% and clinical and pathological staging coincided in more 27%. The overall results reflected an improvement in the agreement between clinical and pathological staging in the PET/CT subgroup (67%, kappa=0.5737 vs 40%, kappa=0.2292). PET/CT accuracy was enhanced when patients re-staged after neoadjuvant therapy were excluded and a substantial staging agreement was obtained for those who had the exam only for staging purposes (73%, kappa=0.6323). Conclusion: Inclusion of PET/CT in NSCLC preoperative assessment improved the accuracy of the clinical staging, with a good level of agreement with pathological staging. Palavras-chave: Cancro do pulmão de não pequenas células, PET/TC, Estadiamento, Keywords: Non small cell lung cancer, PET/CT, Staging

Thyroid hormone and leptin are essential regulators of energy homeostasis. Both hormones stimulate energy expenditure but have opposite effects on appetite. The mechanisms behind food intake regulation in thyroid dysfunctions are poorly understood. It has been shown that hypothyroid rats exhibited impaired leptin anorexigenic effect and signaling in total hypothalamus, even though they were hypophagic. It was hypothesized that hypothyroidism modulates the expression of neuropeptides: orexigenic neuropeptide Y (NPY) and anorexigenic proopiomelanocortin (POMC), independently of inducing nuclei-specific changes in hypothalamic leptin signaling.Adult male rats were rendered hypothyroid by administration of 0.03% methimazole in the drinking water for 21 days. Protein content of NPY, POMC, and leptin signaling (the signal transducer and activator of transcription 3 [STAT3] pathway) were evaluated by Western blot, and mRNA levels by real time reverse transcription polymerase chain reaction in arcuate (ARC), ventromedial (VMN), and paraventricular (PVN) hypothalamic nuclei isolated from euthyroid (eu) and hypothyroid (hypo) rats. Leptin anorexigenic effect was tested by recording food intake for two hours after intracerebroventricular (i.c.v.) administration of leptin. Statistical differences were considered significant at p ≤ 0.05.Hypothyroidism was confirmed by decreased serum triiodothyronine, thyroxine, and increased thyrotropin, in addition to increased levels of pro-TRH mRNA in PVN and Dio2 mRNA in the ARC of hypo rats. Hypothyroidism decreased body weight and food intake associated with decreased protein content of NPY and increased content of POMC in the ARC. Conversely, hypothyroidism induced central resistance to the acute anorexigenic effect of leptin, since while euthyroid rats displayed reduced food intake after leptin i.c.v. injection, hypothyroid rats showed no response. Hypothyroid rats exhibited decreased leptin receptor (ObRb) protein content in ARC and VMN but not in PVN nucleus. ObRb protein changes were concomitant with decreased phosphorylated STAT3 in the ARC, and decreased total STAT3 in VMN and PVN. However, hypothyroidism did not affect mRNA levels of Lepr or Stat3 in the hypothalamic nuclei.Experimental hypothyroidism induced a negative energy balance accompanied by decreased NPY and increased POMC protein content in the ARC, resulting in predominance of anorexigenic pathways, despite central leptin resistance and impairment of the leptin signaling cascade in a nuclei-specific manner.

Neuropeptide Y (NPY) inhibits TRH neurons in fed state, and hypothalamic NPY higher expression during fasting has been proposed to be involved in fasting-induced suppression of the hypothalamus-pituitary–thyroid (HPT) axis. We investigated the role of central Y5 receptors in the control of thyrotropin (TSH) and thyroid hormone (TH) secretion. Fed and fasting rats received twice daily central injections (3rd ventricle) of Y5 receptor antagonist (CGP71683; 15nmol/rat) for 72h. Fasted rats also received a single central injection of CGP71683 (15nmol/rat) at the end of 72h of fasting. In fed rats, Y5 receptor blockade reduced total food intake by 32% and body mass by almost 10% (p

n-3 polyunsaturated fatty acids (n-3 PUFA) from fish oil (FO) exert important lipid-lowering effects, an effect also ascribed to thyroid hormones (TH) and TH receptor β1 (TRβ1)-specific agonists. n-3 PUFA effects are mediated by nuclear receptors, such as peroxisome proliferator-activated receptors (PPAR) and others. In this study, we investigated a role for TH signaling in n-3 PUFA effects. Euthyroid and hypothyroid adult rats (methimazole-treated for 5 weeks) received FO or soybean oil (control) by oral administration for 3 weeks. In euthyroid rats, FO treatment reduced serum triglycerides and cholesterol, diminished body fat, and increased protein content of the animals. In addition, FO-treated rats exhibited higher liver expression of TRβ1 and mitochondrial α-glycerophosphate dehydrogenase (mGPD), at protein and mRNA levels, but no alteration of glutathione S-transferase or type 1 deiodinase. In hypothyroid condition, FO induced reduction in serum cholesterol and increase in body protein content, but lost the ability to reduce triglycerides and body fat, and to induce TRβ1 and mGDP expression. FO did not change PPARα liver abundance regardless of thyroid state; however, hypothyroidism led to a marked increase in PPARα liver content but did not alter TRβ1 or TRα expression. The data suggest that part of the effect of n-3 PUFA from FO on lipid metabolism is dependent on TH signaling in specific steps and together with the marked upregulation of PPARα in liver of hypothyroid rats suggest importantin vivoconsequences of the cross-talking between those fatty acids and TH pathways in liver metabolism.

Mice bearing the genomic mutation Δ337T on the thyroid hormone receptor β (TRβ) gene present the classical signs of resistance to thyroid hormone (TH), with high serum TH and TSH. This mutant TR is unable to bind TH, remains constitutively bound to co-repressors, and has a dominant negative effect on normal TRs. In this study, we show that homozygous (TRβΔ337T) mice for this mutation have reduced body weight, length, and body fat content, despite augmented relative food intake and relative increase in serum leptin. TRβΔ337T mice exhibited normal glycemia and were more tolerant to an i.p. glucose load accompanied by reduced insulin secretion. Higher insulin sensitivity was observed after single insulin injection, when the TRβΔ337T mice developed a profound hypoglycemia. Impaired hepatic glucose production was confirmed by the reduction in glucose generation after pyruvate administration. In addition, hepatic glycogen content was lower in homozygous TRβΔ337T mice than in wild type. Collectively, the data suggest that TRβΔ337T mice have deficient hepatic glucose production, by reduced gluconeogenesis and lower glycogen deposits. Analysis of liver gluconeogenic gene expression showed a reduction in the mRNA of phosphoenolpyruvate carboxykinase, a rate-limiting enzyme, and of peroxisome proliferator-activated receptor-γ coactivator 1α, a key transcriptional factor essential to gluconeogenesis. Reduction in both gene expressions is consistent with resistance to TH action via TRβ, reproducing a hypothyroid phenotype. In conclusion, mice carrying the Δ337T-dominant negative mutation on the TRβ are leaner, exhibit impaired hepatic glucose production, and are more sensitive to hypoglycemic effects of insulin.

There are data about the immunomodulatory properties of some macrolides in cryptogenic organizing pneumonia (COP) as an alternative to corticosteroids in mild disease or as adjuvant to standard therapy.A sixty-year-old female, with a controlled intrinsic asthma, presented with COP and recurrent respiratory exacerbations despite corticosteroid and immunossupressant therapy. Azithromycin (500 mg, on alternate days) as an adjuvant to steroids was then started, with clinical and functional improvement and regression of lung infiltrates. Withdrawal of steroids was possible in one year, without evidence of relapse in the next six months. Azithromycin was maintained (three times per week) with no documentation of adverse side effects.This clinical case reinforces the potential role of macrolides anti-inflammatory properties in COP as corticosteroids adjuvant therapy. Resumo: Existem dados na literatura sobre o uso das propriedades imunomoduladoras de alguns macrólidos no tratamento da pneumonia organizativa criptogénica (COP) como alternativa aos corticoesteróides na doença ligeira ou como adjuvantes da terapêutica padrão.Os autores descrevem o caso de uma mulher de 60 anos de idade, com asma intrínseca controlada, que apresentou uma COP e exacerbações respiratórias de repetição, apesar da corticoterapia e terapêutica imunossupressora instituídas. Após início de azitromicina (500 mg, dias alternados), como adjuvante da corticoterapia, verificou-se melhoria clínica e funcional e regressão dos infiltrados pulmonares. A suspensão dos corticoesteróides foi possível no período de um ano, sem evidência de recidiva nos seis meses seguintes. A azitromicina foi mantida (3 vezes/semana) sem documentação de efeitos laterais adversos.Este caso clínico reforça o potencial papel das propriedades anti-inflamatórias dos macrólidos na COP, como terapêutica adjuvante dos corticoesteróides. Keywords: Cryptogenic organizing pneumonia, Macrolides, Azithromycin, Antibiotic therapy, Palavras-chave: Pneumonia organizativa criptogénica, Macrólidos, Azitromicina, Antibioterapia

Hyperleptinemia during lactation programs for higher serum leptin in 30-day-old and adult rats, associated with metabolic changes. Here we evaluated the inhibition of serum leptin at 29 and 30 days on the metabolic phenotype of rats programmed with leptin during lactation. Pups from Wistar rats were saline-injected or leptin-injected from postnatal day 1 to day 10. At 29 and 30 days old, animals were injected with anti-leptin antibody (LA and CA) or saline (LS and CS). In adult animals, higher visceral (+53%) and total fat mass (+33%), hyperleptinemia (+67%), hypertriglyceridemia (+47%), and hypoadiponectinemia (-44%) observed in LS group compared to CS were prevented by immunoneutralization of leptin, since LA group had those parameters values similar to CS group. However, immunoblockade of leptin in normal animals led to the same metabolic changes seen in leptin-treated animals, in addition to lower serum adiponectin (-77% vs. CS) and higher insulin resistance index (+37%). Liver sirtuin1 (SIRT1) was higher (+41%) only in LA group, suggesting a role for SIRT1 in the prevention of leptin programming. Hypothalamic OBR was lower and SOCS3 higher in LS group and these changes were normalized in LA group. In conclusion, blocking leptin action one week after weaning seems to revert most of the alterations observed in rats programmed by neonatal hyperleptinemia. Higher liver SIRT1 expression may be one of the mechanisms involved, leading to a better glucose and lipid metabolism. Our data suggest that the lack or the excess of leptin programs an adverse metabolic phenotype in adulthood.

Previous studies have proposed a role for neuromedin B (NB), a bombesin-like peptide, in the control of body weight homeostasis. However, the nature of this role is unclear. The actions of NB are mediated preferentially by NB-preferring receptors (NBRs). Here we examined the consequences of targeted deletion of NBRs in female mice on body weight homeostasis in mice fed a normolipid diet (ND) or a high-fat diet (HFD) for 13 weeks. Body weight and food ingestion of neuromedin B receptor knockout (NBR-KO) mice fed a normolipid diet showed no difference in relation to wild-type (WT). However, the high-fat diet induced an 8.9- and 4.8-fold increase in body weight of WT and NBR-KO, respectively, compared to their controls maintained with a normolipid diet, even though the mice ingested the same amount of calories, regardless of genotype. Comparing mice fed the high-fat diet, NBR-KO mice accumulated approximately 45% less fat depot mass than WT, exhibited a lower percentage of fat in their carcasses (19.2 vs. 31.3%), and their adipocytes were less hypertrophied. Serum leptin and leptin mRNA in inguinal and perigonadal fat were lower in HFD NBR-KO than HFD WT, and serum adiponectin was similar among HFD groups and unaltered in comparison to ND-fed mice. HFD-fed WT mice developed glucose intolerance but not the HFD-fed NBR-KO mice, although they had similar glycaemia and insulinaemia. NBR-KO and WT mice on the normolipid diet showed no differences in any parameters, except for a trend to lower insulin levels. Therefore, disruption of the neuromedin B receptor pathway did not change body weight homeostasis in female mice fed a normolipid diet; however, it did result in partial resistance to diet-induced obesity.

Previous studies have shown that alterations in thyroid status may lead to changes in serum leptin and adiponectin, both in humans and rodents. The mechanisms, especially for adiponectin, are unclear. In the present study, we investigated the effect of triiodothyronine (T3) on the expression of adiponectin mRNA and the release of leptin and adiponectin by white adipose tissue (WAT) explants obtained from epididymal (visceral) or inguinal (subcutaneous) depots from normal rats. We also analyzed the effects of other known regulators of adiponectin and leptin release, such as rosiglitazone and dexamethasone. T3 acted directly at rat WAT explants in a depot-specific manner and in a unique fashion to each hormone. T3 was able to inhibit leptin release only by epididymal explants, and to reduce adiponectin mRNA expression only in inguinal explants. However, T3 was incapable of modifying adiponectin release by both explants. Additionally, rosiglitazone exhibited an inhibitory effect on adiponectin release by both WAT explants, even though adiponectin mRNA was importantly upregulated only in inguinal explants. Rosiglitazone acted as an inhibitor of leptin release by both studied fat depots, while only epididymal explants responded to the stimulatory effect of dexamethasone on leptin release. Therefore, the present model of isolated rat white adipose tissue explants highlights the fact that the regulation of hormonal production by white adipose tissue depends on the type of depot and its anatomical location. In this context, our results show for the first time a potential inhibitory effect of T3 on adiponectin mRNA expression specifically on WAT from a subcutaneous depot.

Thyroid hormone (TH) regulates many cardiac genes via nuclear thyroid receptors, and hyperthyroidism is frequently associated with atrial fibrillation. Electrical activity propagation in myocardium depends on the transfer of current at gap junctions, and connexins (Cxs) 40 and 43 are the predominant junction proteins. In mice, Cx40, the main Cx involved in atrial conduction, is restricted to the atria and fibers of the conduction system, which also express Cx43. We studied cardiac expression of Cx40 and Cx43 in conjunction with electrocardiogram studies in mice overexpressing the dominant negative mutant thyroid hormone receptor-β Δ337T exclusively in cardiomyocytes [myosin heavy chain (MHC-mutant)]. These mice develop the cardiac hypothyroid phenotype in the presence of normal serum TH. Expression was also examined in wild-type mice rendered hypothyroid or hyperthyroid by pharmacological treatment. Atrial Cx40 mRNA and protein levels were decreased (85 and 55%, respectively; P < 0.001) in MHC-mt mice. Atrial and ventricular Cx43 mRNA levels were not significantly changed. Hypothyroid and hyperthyroid animals showed a 25% decrease and 40% increase, respectively, in Cx40 mRNA abundance. However, MHC-mt mice presented very low Cx40 mRNA expression regardless of whether they were made hypothyroid or hyperthyroid. Atrial depolarization velocity, as represented by P wave duration in electrocardiograms of unanesthetized mice, was extremely reduced in MHC-mt mice, and to a lesser extent also in hypothyroid mice (90 and 30% increase in P wave duration). In contrast, this measure was increased in hyperthyroid mice (19% decrease in P wave duration). Therefore, this study reveals for the first time that Cx40 mRNA is up-regulated by TH acting in cardiac atria via the TH receptor and that this may be one of the mechanisms contributing to atrial conduction alterations in thyroid dysfunctions.Cardiac-specific expression of a mutant thyroid hormone receptor unable to bind thyroid hormone profoundly reduces atrial connexin 40 expression in association with prolonged atrial conduction.

Neuromedin B (NB), a neuropeptide highly concentrated in pituitary, has been proposed to be an inhibitor of thyrotropin (TSH) secretion. Previous study showed that mice with disruption of neuromedin B receptor (NBR-KO) have higher TSH release in response to thyrotropin-releasing hormone (TRH), although TSH seems to have decreased bioactivity. Here we examined in NBR-KO mice the response of TSH to thyroid hormone (TH) deprivation, obtained by methimazole treatment, or excess, obtained by acute and chronic TH administration. In response to hypothyroidism NBR-KO mice exhibited a lower magnitude increase in serum TSH compared to wild-type (WT) mice (1.7 vs. 3.3-times increase compared to euthyroid values, respectively, P 0.001). One hour after a single T4 injection (0.4μg/100 g BW), WT and NBR-KO hypothyroid mice presented similar degree of serum TSH reduction (54%, P 0.05). However, 3 h after T4 administration, WT mice presented serum TSH similar to hypothyroid baseline, while NBR-KO mice still had decreased serum TSH (30% reduced in comparison to hypothyroid baseline P 0.05). T3 treatment of euthyroid mice for 21 days, with progressively increasing doses, significantly reduced serum TSH similarly in WT and NBR-KO mice. Also, serum T4 exhibited the same degree of suppression in WT and NBR-KO. In conclusion, disruption of neuromedin B receptor did not interfere with the sensitivity of thyroid hormone-mediated suppression of TSH release, but impaired the ability of thyrotroph to increase serum TSH in hypothyroidism, which highlights the importance of NB in modulating the set point of the hypothalamus–pituitary–thyroid axis at hypothyroidism.

Made available in DSpace on 2013-09-27T14:54:07Z (GMT). No. of bitstreams: 1 WOS000267218200025.pdf: 446263 bytes, checksum: 7232c4fbcfe19ade6252554576e5cb49 (MD5) Previous issue date: 2008-01-01 Made available in DSpace on 2013-09-30T18:15:24Z (GMT). No. of bitstreams: 1 WOS000267218200025.pdf: 446263 bytes, checksum: 7232c4fbcfe19ade6252554576e5cb49 (MD5) Previous issue date: 2008-01-01 Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-20T13:31:44Z No. of bitstreams: 1 WOS000267218200025.pdf: 446263 bytes, checksum: 7232c4fbcfe19ade6252554576e5cb49 (MD5) Made available in DSpace on 2014-05-20T13:31:44Z (GMT). No. of bitstreams: 1 WOS000267218200025.pdf: 446263 bytes, checksum: 7232c4fbcfe19ade6252554576e5cb49 (MD5) Previous issue date: 2008-01-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) We examined the genotoxic and mutagenic effects of a crude extract of Clusia alata ( a potential medicinal plant) on peripheral leukocyte and bone marrow cells of mice, using the comet and chromosome aberration assays. Extracts at doses of 1000, 1500 and 2000 mg/kg were administered by gavage, and a positive control, N-nitroso-N-ethylurea (50 mg/kg) was injected intraperitoneally. Peripheral blood leukocytes were collected 4 and 24 h after the treatments for the comet assay, and bone marrow cells were collected 24 h after the treatments, for the chromosome aberration assay. The comet assay showed that C. alata extract causes an increase in damage to DNA in the peripheral blood leukocytes, but it was significant only with the 2000 mg/kg dose after 24 h; the extract also induced a small but significant increase in the mean number of chromosome aberrations in the bone marrow cells at doses of 1500 and 2000 mg/kg. No evidence of a significant decrease in the mitotic index was observed. Acute consumption of high concentrations of C. alata extract produced some mutagenic effects in bone marrow cells. Univ Estadual Paulista, Fac Filosofia & Ciencias, Dept Fonoaudiol, Marilia, SP, Brazil Univ Fed Amapa, Lab Pesquisa Farmacos, Macapa, AP, Brazil Univ Estadual Paulista, Fac Filosofia & Ciencias, Dept Fonoaudiol, Marilia, SP, Brazil CNPq: 306544/2006-7 FAPESP: 06/57514-2

Leptin has been shown to modulate deiodinase type 1 (D1) and type 2 (D2) enzymes responsible for thyroxine (T4) to triiodothyronine (T3) conversion. Previously, it was demonstrated that a single injection of leptin in euthyroid fed rats rapidly increased liver, pituitary, and thyroid D1 activity, and simultaneously decreased brown adipose tissue (BAT) and hypothalamic D2 activity. We have now examined D1 and D2 activities, two hours after a single subcutaneous injection of leptin (8 microg/100 g BW) into hypo- and hyperthyroid rats. In hypothyroid rats, leptin did not modify pituitary, liver and thyroid D1, and thyroid D2 activity, while pituitary D2 was decreased by 41% (p