Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones

Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) by thiazolidinediones (TZDs) improves insulin resistance by increasing insulin-stimulated glucose disposal in skeletal muscle. It remains debatable whether the effect of TZDs on muscle is direct or indirect via adipose tissue. We therefore generated mice with muscle-specific PPARgamma knockout (MuPPARgammaKO) using Cre/loxP recombination. Interestingly, MuPPARgammaKO mice developed excess adiposity despite reduced dietary intake. Although insulin-stimulated glucose uptake in muscle was not impaired, MuPPARgammaKO mice had whole-body insulin resistance with a 36% reduction (P < 0.05) in the glucose infusion rate required to maintain euglycemia during hyperinsulinemic clamp, primarily due to dramatic impairment in hepatic insulin action. When placed on a high-fat diet, MuPPARgammaKO mice developed hyperinsulinemia and impaired glucose homeostasis identical to controls. Simultaneous treatment with TZD ameliorated these high fat-induced defects in MuPPARgammaKO mice to a degree identical to controls. There was also altered expression of several lipid metabolism genes in the muscle of MuPPARgammaKO mice. Thus, muscle PPARgamma is not required for the antidiabetic effects of TZDs, but has a hitherto unsuspected role for maintenance of normal adiposity, whole-body insulin sensitivity, and hepatic insulin action. The tissue crosstalk mediating these effects is perhaps due to altered lipid metabolism in muscle.     

Simultaneous dacryocystography and dacryoscintigraphy using SPECT/CT in the diagnosis of nasolacrimal duct obstruction

Epiphora, an abnormal overflow of tears, is commonly caused by tear drainage system anomalies including nasolacrimal duct obstruction. To assess morphologic abnormalities, dacryocystography by CT is used when CT contrast material is syringed into the lacrimal drainage system. To evaluate the function of the system, dacryoscintigraphy is the most readily available noninvasive method. In the case presented, a 43-year-old man was referred to our clinic with an 8 months' history of indefinite left side epiphora. After performing dacryoscintigraphy, we acquired SPECT/CT images during dacryocystography by CT to establish the surgical indication.     

Gas inertia and ventilatory measurements under pressure: methodological considerations

A bag-in-box apparatus with a spirometer was used to measure the ventilatory minute volume in subjects exercising at air pressures up to 6.8 atm. During rest there was good agreement between minute volumes derived from the expired gas in the bag and the sum of tidal volumes from the spirometer, whereas during exercise the bag volume exceeded the spirometer volume by up to 20%. This was found to be due to the inertia of high density gas in the breathing hoses. Given sufficient flow rate the gas would continue to flow from the box to the bag following end expiration and end inspiration. The spirometer would not record this because it only responds to changes in the sum of box and bag volumes, whereas emptying the bag through a gas meter records the volume of gas actually moved. A model was constructed to investigate the phenomenon. It was concluded that many different conventional setups for respiratory measurements may be subject to this type of error. Solutions to the problem include a collapsible tube section downstream from the subject, pneumotachometers, chest-mounted magnetometers, or inductive plethysmographs.     

The effect of emetine on the immune response of mice

Emetine (33 mg/kg body weight) administered intraperitoneally blocked the immune response of mice to 10⁹ sheep red blood cells (SRBC). The inhibition was almost complete when the drug was administered simultaneously or 24 hr after immunization, while partial inhibition was caused by treatment at 48 and 72 hr. Incorporation of ¹⁴C-leucine and ³H-thymidine by spleen cells isolatedd 4 hr after emetine injection of the mice was strongly decreased. Incorporation was approaching the control level in cells isolated 72–96 hr after emetine administration. However, the incorporation of labeled precursors was less than after SRBC treatment only, even after 72–96 hr.Emetine apparently blocked the development of immune response at an early stage and, in contrast to macromole synthesis, the inhibition of the antibody response was irreversible.     

Optimization of the in vitro and in vivo properties of a novel series of 2,4,5-trisubstituted imidazoles as potent cholecystokinin-2 (CCK2) antagonists

The systematic optimization of the structure of a novel 2,4,5-trisubstituted imidazole-based cholecystokinin-2 (CCK(2)) receptor antagonist afforded analogues with nanomolar receptor affinity. These compounds were now comparable in their potency to the bicyclic heteroaromatic-based compounds 5 (JB93182) and 6 (JB95008), from which the initial examples were designed using a field-point based molecular modeling approach. They were also orally active as judged by their inhibition of pentagastrin stimulated acid secretion in conscious dogs, in contrast to the bicyclic heteroaromatic-based compounds, which were ineffective because of biliary elimination. Increasing the hydrophilicity through replacement of a particular methylene group with an ether oxygen, as in 3-{[5-(adamantan-1-yloxymethyl)-2-cyclohexyl-1H-imidazole-4-carbonyl]amino}benzoic acid (53), had little effect on the receptor affinity but significantly increased the oral potency. Comparison of the plasma pharmacokinetics and the inhibition of pentagastrin-stimulated acid output following bolus intraduodenal administration of both 53 and 6 indicated that 53 was well absorbed, had a longer half-life, and was not subject to the elimination pathways of the earlier series.     

Gr1(+) inflammatory monocytes are required for mucosal resistance to the pathogen Toxoplasma gondii

The enteric pathogen Toxoplasma gondii is controlled by a vigorous innate T helper 1 (Th1) cell response in the murine model. We demonstrated that after oral infection, the parasite rapidly recruited inflammatory monocytes [Gr1(+) (Ly6C(+), Ly6G(-)) F4/80(+)CD11b(+)CD11c(-)], which established a vital defensive perimeter within the villi of the ileum in the small intestine. Mice deficient of the chemokine receptor CCR2 or the ligand CCL2 failed to recruit Gr1(+) inflammatory monocytes, whereas dendritic cells and resident tissue macrophages remained unaltered. The selective lack of Gr1(+) inflammatory monocytes resulted in an inability of mice to control replication of the parasite, high influx of neutrophils, extensive intestinal necrosis, and rapid death. Adoptive transfer of sorted Gr1(+) inflammatory monocytes demonstrated their ability to home to the ileum in infected animals and protect Ccr2(-/-) mice, which were otherwise highly susceptible to oral toxoplasmosis. Collectively, these findings illustrate the critical importance of inflammatory monocytes as a first line of defense in controlling intestinal pathogens.