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AbstractObjective: The marked increase in the prevalence of obesity in the United States has recently been attributed to the increased fructose consumption. To determine if and how fructose might promote obesity in an animal model, we measured body composition, energy intake, energy expenditure, substrate oxidation, and several endocrine parameters related to energy homeostasis in mice consuming fructose.Research Methods and Procedures: We compared the effects of ad libitum access to fructose (15% solution in water), sucrose (10%, popular soft drink), and artificial sweetener (0% calories, popular diet soft drink) on adipogenesis and energy metabolism in mice.Results: Exposure to fructose water increased adiposity, whereas increased fat mass after consumption of soft drinks or diet soft drinks did not reach statistical significance (n = 9 each group). Total intake of energy was unaltered, because mice proportionally reduced their caloric intake from chow. There was a trend toward reduced energy expenditure and increased respiratory quotient, albeit not significant, in the fructose group. Furthermore, fructose produced a hepatic lipid accumulation with a characteristic pericentral pattern.Discussion: These data are compatible with the conclusion that a high intake of fructose selectively enhances adipogenesis, possibly through a shift of substrate use to lipogenesis.

The use of alcohol has been associated with both an increased risk of acquisition of HIV‐1 infection and an increased rate of disease progression among those already infected by the virus. The potential for alcohol to exacerbate the effects of HIV infection is especially important in the central nervous system (CNS) because this area is vulnerable to the combined effects of alcohol and HIV infection. The effects of alcohol on glial cells are mediated through receptors such as Toll‐like receptor 4 and N‐methyl‐d‐aspartate receptor. This causes the activation of signaling molecules such as interleukin‐1 receptor‐associated kinase and various members of the P38 mitogen‐activated protein kinase family and subsequent activation of transcription factors such as nuclear factor‐kappa beta and activator protein 1. The eventual outcome is an increase in pro‐inflammatory cytokine production by glial cells. Alcohol also induces higher levels of NADPH oxidase in glial cells, which leads to an increased production of reactive oxygen species (ROS). Viral invasion of the CNS occurs early after infection, and HIV proteins have also been demonstrated to increase levels of pro‐inflammatory cytokines and ROS in glial cells through activation of some of the same pathways activated by alcohol. Both cell culture systems and animal models have demonstrated that concomitant exposure to alcohol and HIV/HIV proteins results in increased levels of expression of pro‐inflammatory cytokines such as interleukin‐1 beta and tumor necrosis factor‐alpha, along with increased levels of oxidative stress. Clinical studies also suggest that alcohol exacerbates the CNS effects of HIV‐1 infection. This review focuses on the mechanisms by which alcohol causes increased CNS damage in HIV‐1 infection.

Thirty-two pregnant Long-Evans rats were divided into 10 groups of 3 or 4 pregnant rats, and each rat was given a single dose of 4 ml ethanol/kg (20 ml/kg of a 20% solution) between d 6 and 15 of gestation. An 11th group of 50 pregnant rats received distilled water and served as controls. Offspring body weights were decreased in groups of rats given ethanol as compared to controls (3.0-3.6 g, versus 3.9 g for controls). Total litter weight was decreased in dams given ethanol on d 6. Skeletal variants were seen in 13-78% of the offspring given ethanol, compared to 0.6% of the controls. Variations may be considered as additional signs of embryotoxicity. Malformations such as hydronephrosis, pelvic kidney, microcephalus, cranioschisis, and microphthalmia occurred in 72-100% of the ethanol treated offspring, as compared to 12% of controls. Hydronephrosis was most frequent on d 9 or 14, pelvic kidney on d 8 and 11, and microphthalmia from d 10-12. Cranioschisis was maximal on d 7, 11, and 15, and microcephalic offspring were most frequently born to dams given ethanol on d 7 or 14. Skeletal defects were usually single entities, while soft-tissue anomalies occurred in a consistent pattern. These results suggest that ethanol is a stage-specific teratogen in the rat at comparable exposure levels attained by many humans.

We have recently demonstrated that eight, daily flurothyl-induced generalized clonic seizures, followed by a four week stimulus-free interval, results in a long-lasting reduction in generalized seizure threshold and a change in the type of seizure expressed in response to flurothyl from clonic to tonic. There is a progressive increase in the probability that a mouse will express a tonic seizure during the four week interval, suggesting that prior flurothyl seizures initiate a proepileptogenic process that requires time to develop. In this study, the immunohistochemical detection of the c-fos protein (Fos) was used to evaluate whether seizure-induced epileptogenesis resulted in regional differences in the degree of neuronal activation. Fos immunoreactivity was examined 1.5 h following either a single generalized seizure, the last of eight consecutive daily seizures or a retest seizure evoked two weeks after the last of eight seizures. In each condition, generalized seizure behaviours were elicited in C57BL/6 mice using flurothyl and classified as either "forebrain" (face and forelimb clonus) or "brainstem" (running/bouncing, treading, tonic extension). The spatial distribution of Fos induction was compared on the basis of the seizure phenotype and the seizure history. The predominant differences in Fos distribution were found to be related to the type of seizure expressed regardless of the seizure history. Furthermore, the different motor components that make up a "brainstem" seizure could not be distinguished by the pattern of Fos labelling suggesting that multiple convulsive behaviours are mediated by one anatomical system. Finally, Fos induction in the ventromedial hypothalamic nucleus preceded and predicted the change in seizure type from "forebrain" to "brainstem". These data support the concept that separate anatomical systems mediate the expression of the two generalized seizure phenotypes. In addition, the ventromedial nucleus of the hypothalamus may be a point of interaction between the systems and may play a role in seizure-induced neural reorganization.

To establish a mouse model of alcohol-driven hepatocellular carcinoma (HCC) that develops in livers with alcoholic liver disease (ALD).Adult C57BL/6 male mice received multiple doses of chemical carcinogen diethyl nitrosamine (DEN) followed by 7 wk of 4% Lieber-DeCarli diet. Serum alanine aminotransferase (ALT), alpha fetoprotein (AFP) and liver Cyp2e1 were assessed. Expression of F4/80, CD68 for macrophages and Ly6G, MPO, E-selectin for neutrophils was measured. Macrophage polarization was determined by IL-1β/iNOS (M1) and Arg-1/IL-10/CD163/CD206 (M2) expression. Liver steatosis and fibrosis were measured by oil-red-O and Sirius red staining respectively. HCC development was monitored by magnetic resonance imaging, confirmed by histology. Cellular proliferation was assessed by proliferating cell nuclear antigen (PCNA).Alcohol-DEN mice showed higher ALTs than pair fed-DEN mice throughout the alcohol feeding without weight gain. Alcohol feeding resulted in increased ALT, liver steatosis and inflammation compared to pair-fed controls. Alcohol-DEN mice had reduced steatosis and increased fibrosis indicating advanced liver disease. Molecular characterization showed highest levels of both neutrophil and macrophage markers in alcohol-DEN livers. Importantly, M2 macrophages were predominantly higher in alcohol-DEN livers. Magnetic resonance imaging revealed increased numbers of intrahepatic cysts and liver histology confirmed the presence of early HCC in alcohol-DEN mice compared to all other groups. This correlated with increased serum alpha-fetoprotein, a marker of HCC, in alcohol-DEN mice. PCNA immunostaining revealed significantly increased hepatocyte proliferation in livers from alcohol-DEN compared to pair fed-DEN or alcohol-fed mice.We describe a new 12-wk HCC model in adult mice that develops in livers with alcoholic hepatitis and defines ALD as co-factor in HCC.

Summary In cats anaesthetized with pentobarbitone, the fluid spaces in and around the brain stem were perfused from the third ventricle to the foramen magnum with artificial cerebrospinal fluid (c.s.f.) flowing usually at the rate of 5 ml/minute. Test solutions were substituted for the artificial c.s.f. without switching artifact for periods varying from 5 to 60 seconds. Observations were made on respiratory excursions, end‐expiratory % CO2 and arterial blood pressure. Perfusion with sucrose solution equiosmolar with the c.s.f. produced no respiratory or cardiovascular response. Replacement of sodium with potassium (60 to 133 mm) resulted in a prompt but mild respiratory stimulation and a delayed fall in blood pressure associated with a slowing of the heart beat. Replacement of sodium with magnesium (40 to 131 mm) resulted in a late prolonged apneustic depression of breathing and in an early but slight reduction in blood pressure. Procaine (1 to 50 mg/ml) elicited a respiratory response similar to that of excess magnesium; however, an initial rise in blood pressure to as high as 200 mmHg was evoked with procaine. Nicotine (0·05 to 0·5 mg/ml) produced an immediate brief bradypnea followed by a vigorous and slowly reversing hyperpnea accompanied most often by a fall in blood pressure. Tachyphylaxis was observed in the response to nicotine. Noradrenaline (0·001 and 0·1 mg/ml) did not produce any effect, and it did not alter the responses elicited by procaine and nicotine given by perfusion either simultaneous with or subsequent to the noradrenaline. Acetylcholine (0·5 mg/ml) produced weak transient respiratory stimulation and a small fluctuation in blood pressure which disappeared in repeated tests. Methacholine (1 mg/ml) caused a brief hyperpnea and a fall in blood pressure both of which were abolished after atropine (0·2 mg) was injected into the third ventricle. Pilocarpine (10 mg/ml) elicited no change in respiration or blood pressure. Respiratory and cardiovascular effects produced by strychnine (1 mg/ml) were attributable nonspecifically to convulsive movements of the animal. Ethamivan (1 mg/ml) produced a single deep breath and a slowly reversing rise in blood pressure. Cyanide (0·5 mg/ml) barely stimulated the respiration but it produced a long lasting rise in blood pressure. Ethyl alcohol (0·1 ml/ml) elicited brisk though brief respiratory stimulation and a short lasting fall in blood pressure. It was shown that the effects of procaine and nicotine were not qualitatively altered when the perfusion effluent was collected through a ventral craniotomy instead of the cisterna magna. It is concluded that the brain surfaces are insensitive to the substances tested and that the observed effects resulted from movement of the agents into the brain parenchyma.

The purpose of the current study was to ascertain whether ethyl nitrite could be detected in vitro from the reaction of ethanol with peroxynitrite, as well as after administration of ethanol to mice. Ethyl nitrite analyte was determined by using gas chromatography--mass spectrometry with headspace analysis with the use of a solid-phase microextraction device. Peroxynitrite was allowed to react with ethanol under a variety of conditions in vitro. Ethyl nitrite was generated when peroxynitrite was allowed to react with ethanol. Male, inbred short-sleep mice were injected intraperitoneally with either ethanol [5.2 g/kg; 15.0% (weight/volume) ethanol in saline] or a 50:50 mixture of deuterium-labeled ethanol (D5-ethanol) and ethanol. Blood samples, as well as whole brain and liver sections, were obtained from mice 30 min later for determination of ethanol, D5-ethanol, ethyl nitrite, and deuterium-labeled ethyl nitrite (D5-ethyl nitrite). Time courses for the appearance of ethyl nitrite in blood samples, as well as in whole brain and liver sections, obtained from mice were carried out. After ethanol administration, ethyl nitrite was detected and quantitated in mouse blood, brain, and liver. A small fraction of ethyl nitrite was present. When a 50:50 mixture of ethanol and D5-ethanol was given to animals, both ethyl nitrite and D5-ethyl nitrite were found in blood and brain in approximately the same ratio as that of ethanol and D5-ethanol. The level of D5-ethyl nitrite in liver was more than twice that of ethyl nitrite, indicating a possible isotope effect in the metabolism of ethyl nitrite. Ethyl nitrite is a new metabolite of ethanol in vivo. The mechanism of ethyl nitrite formation is most likely the reaction of ethanol with peroxynitrite generated in vivo from nitric oxide.