Glycine supplementation extends lifespan of male and female mice.

Diets low in methionine extend lifespan of rodents, though through unknown mechanisms. Glycine can mitigate methionine toxicity, and a small prior study has suggested that supplemental glycine could extend lifespan of Fischer 344 rats. We therefore evaluated the effects of an 8% glycine diet on lifespan and pathology of genetically heterogeneous mice in the context of the Interventions Testing Program. Elevated glycine led to a small (4%-6%) but statistically significant lifespan increase, as well as an increase in maximum lifespan, in both males (p = 0.002) and females (p < 0.001). Pooling across sex, glycine increased lifespan at each of the three independent sites, with significance at p = 0.01, 0.053, and 0.03, respectively. Glycine-supplemented females were lighter than controls, but there was no effect on weight in males. End-of-life necropsies suggested that glycine-treated mice were less likely than controls to die of pulmonary adenocarcinoma (p = 0.03). Of the 40 varieties of incidental pathology evaluated in these mice, none were increased to a significant degree by the glycine-supplemented diet. In parallel analyses of the same cohort, we found no benefits from TM5441 (an inhibitor of PAI-1, the primary inhibitor of tissue and urokinase plasminogen activators), inulin (a source of soluble fiber), or aspirin at either of two doses. Our glycine results strengthen the idea that modulation of dietary amino acid levels can increase healthy lifespan in mice, and provide a foundation for further investigation of dietary effects on aging and late-life diseases.

Association of KRAS polymorphisms with risk for lung adenocarcinoma accompanied by atypical adenomatous hyperplasias.

The pulmonary adenoma susceptibility 1 (Pas1) gene affects susceptibility to the development of lung adenomas in mice with a subset of the adenomas progressing to adenocarcinoma (ADC). In this study, genotype distributions for 10 polymorphisms in the human counterparts for three mouse candidate Pas1 genes, KRAS, CASC1/LAS1 and LRMP, were examined in a hospital-based case-control study consisting of 364 lung ADC cases and 253 controls. All the ADC cases were subjected to lobectomy and subsequent pathological investigation of atypical adenomatous hyperplasia (AAH), a putative precursor for peripheral lung ADC, including bronchioloalveolar carcinoma, in the resected lobes. Eighty-one (22%) of the ADC cases carried at least one AAH lesion in addition to the primary ADC and 34 (9%) of them carried multiple AAH lesions. None of the 10 polymorphisms examined showed significant associations with overall lung ADC risk (P > 0.05). However, minor allele carriers for two polymorphisms in the KRAS gene, KRAS-1 and -6, showed significantly increased odds ratios (ORs) for ADC accompanied by multiple AAHs [OR = 3.0; 95% confidence interval (CI) = 1.4-6.2, P = 0.004 and OR = 2.4; 95% CI = 1.1-4.7, P = 0.02, respectively]. Minor haplotypes including the minor allele for the KRAS-6 polymorphism showed increased ORs for ADC accompanied by multiple AAHs, and KRAS transcripts from the minor allele for this polymorphism were more abundantly detected in lung tissues than those from the major allele. Thus, KRAS polymorphisms were indicated to be involved in risk for the development of AAHs that progress to ADC by causing differential KRAS oncogene expression in the lungs.

Atypical adenomatous hyperplasia of the lung: a probable forerunner in the development of adenocarcinoma of the lung.

An increasingly large body of work suggests that atypical adenomatous hyperplasia (AAH) of the lung may be a forerunner of pulmonary adenocarcinoma. Recognizing this fact, the World Health Organization now acknowledges the existence of AAH while noting difficulties that may be encountered in distinguishing AAH from the nonmucinous variant of bronchioloalveolar carcinoma. Regrettably, a universally acceptable definition of morphologic criteria for the diagnosis of AAH has not been achieved. This review of the literature examines the epidemiology, gross appearance, light microscopic findings, morphometry, immunohistochemistry, and molecular features of AAH and suggests a set of histopathologic features that may help the practicing pathologist identify this intriguing lesion. These features include the following: irregularly bordered focal proliferations of atypical cells spreading along the preexisting alveolar framework; prominent cuboidal to low columnar alveolar epithelial cells with variable degree of atypia but less than that seen in adenocarcinoma; increased cell size and nuclear-cytoplasmic ratio with hyperchromasia and prominent nucleoli, generally intact intercellular attachment of atypical cells with occasional empty-looking spaces between them without high cellularity and without tufting or papillary structures; and slight thickening of the alveolar walls on which the AAH cells have spread, with some fibrosis but without scar formation or significant chronic inflammation of the surrounding lung tissue. Several lines of evidence indicate that AAH is a lesion closely associated with adenocarcinoma of the lung, suggesting AAH may be involved in the early stage of a complex multistep carcinogenesis of pulmonary adenocarcinoma.

Abscess disease, caseous lymphadenitis, and pulmonary adenomatosis in imported sheep.

The occurrence of abscess disease, caseous lymphadenitis, and pulmonary adenomatosis in sheep in Denmark is reported for the first time. Subcutaneous abscesses were observed in imported 4- to 5-month-old lambs of the Lacaune breed 10 days after arrival in Denmark. Abscesses were mostly located in the head, neck and shoulder regions close to the regional lymph nodes. Bacteriological examinations revealed growth of Staphylococcus aureus ssp. anaerobius in all animals with subcutaneously located abscesses containing a viscous white-yellow odourless mass. In addition, Corynebacterium pseudotuberculosis was isolated from abscesses in one animal and lesions consistent with pulmonary adenomatosis were found in four animals.