Obesity promotes 7,12-dimethylbenz(a)anthracene-induced mammary tumor development in female zucker rats

INTRODUCTION: High body mass index has been associated with increased risk for various cancers, including breast cancer. Here we describe studies using 7,12-dimethylbenz(a)anthracene (DMBA) to investigate the role of obesity in DMBA-induced mammary tumor susceptibility in the female Zucker rat (fa/fa), which is the most widely used rat model of genetic obesity. METHOD: Fifty-day-old female obese (n = 25) and lean (n = 28) Zucker rats were orally gavaged with 65 mg/kg DMBA. Rats were weighed and palpated twice weekly for detection of mammary tumors. Rats were killed 139 days after DMBA treatment. RESULTS: The first mammary tumor was detected in the obese group at 49 days after DMBA treatment, as compared with 86 days in the lean group (P < 0.001). The median tumor-free time was significantly lower in the obese group (P < 0.001). Using the days after DMBA treatment at which 25% of the rats had developed mammary tumors as the marker of tumor latency, the obese group had a significantly shorter latency period (66 days) than did the lean group (118 days). At the end of the study, obese rats had developed a significantly (P < 0.001) greater mammary tumor incidence (68% versus 32%) compared with the lean group. The tumor histology of the mammary tumors revealed that obesity was associated with a significant (P < 0.05) increase in the number of rats with at least one invasive ductal and lobular carcinoma compared with lean rats. CONCLUSION: Our results indicate that obesity increases the susceptibility of female Zucker rats to DMBA-induced mammary tumors, further supporting the hypothesis that obesity and some of its mediators play a significant role in carcinogenesis

Insulin-Regulated Srebp-1c and Pck1 mRNA Expression in Primary Hepatocytes from Zucker Fatty but Not Lean Rats Is Affected by Feeding Conditions

Insulin regulates the transcription of genes for hepatic glucose and lipid metabolism. We hypothesized that this action may be impaired in hepatocytes from insulin resistant animals. Primary hepatocytes from insulin sensitive Zucker lean (ZL) and insulin resistant Zucker fatty (ZF) rats in ad libitum or after an overnight fasting were isolated, cultured and treated with insulin and other compounds for analysis of gene expression using real-time PCR. The mRNA levels of one insulin-induced (Srebp-1c) and one insulin-suppressed (Pck1) genes in response to insulin, glucagon, and compactin treatments in hepatocytes from ad libitum ZL and ZF rats were analyzed. Additionally, the effects of insulin and T1317 on their levels in hepatocytes from ad libitum or fasted ZL or ZF rats were compared. The mRNA levels of Srebp-1c, Fas, and Scd1, but not that of Insr, Gck and Pck1, were higher in freshly isolated hepatocytes from ad libitum ZF than that from ZL rats. These patterns of Srebp-1c and Pck1 mRNA levels remained in primary hepatocyte cultured in vitro. Insulin's ability to regulate Srebp-1c and Pck1 expression was diminished in hepatocytes from ad libitum ZF, but not ZL rats. Glucagon or compactin suppressed Srebp-1c mRNA expression in lean, but not fatty hepatocytes. However, glucagon induced Pck1 mRNA expression similarly in hepatocytes from ad libitum ZL and ZF rats. Insulin caused the same dose-dependent increase of Akt phosphorylation in hepatocytes from ad libitum ZL and ZF rats. It synergized with T1317 to induce Srebp-1c, and suppressed Pck1 mRNA levels in hepatocytes from fasted, but not that from ad libitum ZF rats. We demonstrated that insulin was unable to regulate its downstream genes' mRNA expression in hepatocytes from ad libitum ZF rats. This impairment can be partially restored in hepatocytes from ZF rats after an overnight fasting, a phenomenon that deserves further investigation

Red wine polyphenols prevent metabolic and cardiovascular alterations associated with obesity in Zucker fatty rats (Fa/Fa)

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Screening for pickiness - a validation study

Picky eating is prevalent in childhood and is associated with negative health outcomes. Therefore early detection of pickiness is pertinent. Because no psychometric measure of picky/fussy eating has been validated, we aimed to examine the screening efficiency of the 6-item ‘Food Fussiness’ (FF) scale from the Children’s Eating Behavior Questionnaire using structured psychiatric interviews (the Preschool Age Psychiatric Interview), providing meaningful cut-off values based on a large, representative sample of Norwegian 6 year olds (n = 752). Screening efficiency was evaluated using receiver operating characteristic curve analysis, revealing excellent discrimination. The cut-point maximizing the sum of sensitivity and specificity for the scale was found at a score of 3.33 for severe cases and 3.00 when both moderate and severe pickiness were included. The results suggest that the FF scale may provide a tool for identification of clinically significant picky eating, although further assessment may be needed to separate moderate from severe cases

Overfeeding, Autonomic Regulation and Metabolic Consequences

The autonomic nervous system plays an important role in the regulation of body processes in health and disease. Overfeeding and obesity (a disproportional increase of the fat mass of the body) are often accompanied by alterations in both sympathetic and parasympathetic autonomic functions. The overfeeding-induced changes in autonomic outflow occur with typical symptoms such as adiposity and hyperinsulinemia. There might be a causal relationship between autonomic disturbances and the consequences of overfeeding and obesity. Therefore studies were designed to investigate autonomic functioning in experimentally and genetically hyperphagic rats. Special emphasis was given to the processes that are involved in the regulation of peripheral energy substrate homeostasis. The data revealed that overfeeding is accompanied by increased parasympathetic outflow. Typical indices of vagal activity (such as the cephalic insulin release during food ingestion) were increased in all our rat models for hyperphagia. Overfeeding was also accompanied by increased sympathetic tone, reflected by enhanced baseline plasma norepinephrine (NE) levels in both VMH-lesioned animals and rats rendered obese by hyperalimentation. Plasma levels of NE during exercise were, however, reduced in these two groups of animals. This diminished increase in the exercise-induced NE outflow could be normalized by prior food deprivation. It was concluded from these experiments that overfeeding is associated with increased parasympathetic and sympathetic tone. In models for hyperphagia that display a continuously elevated nutrient intake such as the VMH-lesioned and the overfed rat, this increased sympathetic tone was accompanied by a diminished NE response to exercise. This attenuated outflow of NE was directly related to the size of the fat reserves, indicating that the feedback mechanism from the periphery to the central nervous system is altered in the overfed state.

Neonatal jaundice and stool production in breast- or formula-fed term infants

It has remained unclear whether the amount of fecal fat excreted in the stool and stool production influences the severity of neonatal jaundice. We determined the relationship between stool production, fecal fat excretion and jaundice in healthy breast-fed (BF) or formula-fed (FF) (near-)term neonates. From postnatal day 1–4, we quantitatively collected stools from 27 FF and 33 BF infants in daily fractions. Stool production and fecal fat contents were related to unconjugated bilirubin (UCB) levels, as determined by transcutaneous bilirubinometry (TcB). Bilirubin concentrations and stool production did not differ between FF and BF neonates during the study period. Neonatal bilirubin levels were not inversely correlated with stool production. FF and BF infants had similar fecal fat excretion rates. The stool production of FF infants was profoundly lower in the present study than in a 1985 study by De Carvalho et al. [J Pediatr (1985) 107:786–790]. We conclude that increased jaundice during the first postnatal days in healthy term neonates can no longer be attributed to breast-feeding and speculate that improved absorbability of formulas since 1985 has contributed to similar fat excretion and stool production in FF and BF neonates in 2007

In Vivo Analysis of MEF2 Transcription Factors in Synapse Regulation and Neuronal Survival

MEF2 (A–D) transcription factors govern development, differentiation and maintenance of various cell types including neurons. The role of MEF2 isoforms in the brain has been studied using in vitro manipulations with only MEF2C examined in vivo. In order to understand specific as well as redundant roles of the MEF2 isoforms, we generated brain-specific deletion of MEF2A and found that Mef2aKO mice show normal behavior in a range of paradigms including learning and memory. We next generated Mef2a and Mef2d brain-specific double KO (Mef2a/dDKO) mice and observed deficits in motor coordination and enhanced hippocampal short-term synaptic plasticity, however there were no alterations in learning and memory, Schaffer collateral pathway long-term potentiation, or the number of dendritic spines. Since previous work has established a critical role for MEF2C in hippocampal plasticity, we generated a Mef2a, Mef2c and Mef2d brain-specific triple KO (Mef2a/c/dTKO). Mef2a/c/d TKO mice have early postnatal lethality with increased neuronal apoptosis, indicative of a redundant role for the MEF2 factors in neuronal survival. We examined synaptic plasticity in the intact neurons in the Mef2a/c/d TKO mice and found significant impairments in short-term synaptic plasticity suggesting that MEF2C is the major isoform involved in hippocampal synaptic function. Collectively, these data highlight the key in vivo role of MEF2C isoform in the brain and suggest that MEF2A and MEF2D have only subtle roles in regulating hippocampal synaptic function

Towards third generation matrix metalloproteinase inhibitors for cancer therapy

The failure of matrix metalloproteinase (MMP) inhibitor drug clinical trials in cancer was partly due to the inadvertent inhibition of MMP antitargets that counterbalanced the benefits of MMP target inhibition. We explore how MMP inhibitor drugs might be developed to achieve potent selectivity for validated MMP targets yet therapeutically spare MMP antitargets that are critical in host protection

Annual variations in the number of malaria cases related to two different patterns of Anopheles darlingi transmission potential in the Maroni area of French Guiana

<p>Abstract</p> <p>Background</p> <p>With an Annual Parasite Incidence (API) of 132.1, in the high and moderate risks zones, the Maroni area of French Guiana has the second highest malaria incidence of South-America after Guyana (API = 183.54) and far above Brazil (API = 28.25). Malaria transmission is occurring despite strong medical assistance and active vector control, based on general WHO recommendations. This situation is generated by two main factors that are the social and cultural characteristics of this border area, where several ethnic groups are living, and the lack of understanding of transmission dynamics of the main mosquito vector, <it>Anopheles darlingi.</it> In this context, entomological data collected in two villages belonging to two different ethnic groups of the French border of the Maroni River, were retrospectively analysed to find out how the mosquito bionomics are related to the malaria transmission patterns.</p> <p>Methods</p> <p>Data were provided by human landing catches of mosquitoes carried out each month for two years in two villages belonging to two ethnic groups, the Amerindians Wayanas and the Aloukous of African origin. The mosquitoes were sorted by species, sex, date, hour and place of collection and processed for <it>Plasmodium sp</it>. parasite detection. The data were compiled to provide the following variables: human biting rates (HBR), parity rates (PR), numbers of infective bites (IB), entomological inoculation rates (EIR) and numbers of infected mosquitoes surviving enough to transmit (IMT). Spatial and temporal differences of variables between locations and during the night were tested by the Kruskall-Wallis analysis of variance to find out significant variations.</p> <p>Results</p> <p>The populations of the main mosquito vector <it>An. darlingi </it>showed significant variations in the spatial and temporal HBR/person/night and HBR/person/hour, IB/person/month and IB/person/hour, and IMT/village/night and IMT/village/hour. In the village of Loca (Aloukous), the IMT peaked from June to August with a very low transmission during the other months. The risks were higher during the first part of the night and an EIR of 10 infective bites per person and per year was estimated. In the village of Twenke (Wayanas), high level of transmission was reported all year with small peaks in March and October. The risk was higher during the second part of the night and an EIR of 5 infective bites per person and per year was estimated.</p> <p>Conclusion</p> <p>For the first time in the past 40 years, the mosquito bionomics was related to the malaria transmission patterns in French Guiana. The peak of malaria cases reported from August to October in the Maroni region is concomitant with the significant peak of <it>An. darlingi </it>IMT, reported from the village of Loca where transmission is higher. However, the persistent number of cases reported all year long may also be related to the transmission in the Amerindian villages. The <it>An. darlingi </it>bionomics for these two close populations were found significantly different and may explain why a uniform vector control method is inadequate. Following these findings, malaria prevention measures adapted to the local conditions are needed. Finally, the question of the presence of <it>An. darlingi </it>sub-species is raised.</p