Analysis of orthologous gene expression between human pulmonary adenocarcinoma and a carcinogen-induced murine model

Human adenocarcinoma (AC) is the most frequently diagnosed human lung cancer, and its absolute incidence is increasing dramatically. Compared to human lung AC, the A/J mouse-urethane model exhibits similar histological appearance and molecular changes. We examined the gene expression profiles of human and murine lung tissues (normal or AC) and compared the two species' datasets after aligning approximately 7500 orthologous genes. A list of 409 gene classifiers (P value <0.0001), common to both species (joint classifiers), showed significant, positive correlation in expression levels between the two species. A number of previously reported expression changes were recapitulated in both species, such as changes in glycolytic enzymes and cell-cycle proteins. Unexpectedly, joint classifiers in angiogenesis were uniformly down-regulated in tumor tissues. The eicosanoid pathway enzymes prostacyclin synthase (PGIS) and inducible prostaglandin E(2) synthase (PGES) were joint classifiers that showed opposite effects in lung AC (PGIS down-regulated; PGES up-regulated). Finally, tissue microarrays identified the same protein expression pattern for PGIS and PGES in 108 different non-small cell lung cancer biopsies, and the detection of PGIS had statistically significant prognostic value in patient survival. Thus, the A/J mouse-urethane model reflects significant molecular details of human lung AC, and comparison of changes in orthologous gene expression may provide novel insights into lung carcinogenesis.     

Oxygen uptake-heart rate relationship in élite wheelchair racers

The American College of Sports Medicine (ACSM) recommends that, as a general rule for health purposes, individuals should exercise at 40%–85% of their maximal oxygen uptakes. Moreover, it has been suggested that 55%–90% of the maximal heart rate may be used as an alternative estimate of these percentage maximal oxygen uptake values. The present study examined the relationship between percentage peak heart rate (% HR_peak) and percentage peak oxygen uptake (% ) during steady-state incremental intensity wheelchair propulsion of 16 élite, male wheelchair racers (WR). Oxygen uptake was determined during each submaximal exercise stage and heart rate (HR) was continuously monitored. The was subsequently determined using a separate protocol. Linear regression equations of % HR_peak versus % for each participant included % HR_peak values corresponding to 40%, 60%, 80% and 85% . The linear regression equation, derived as the group mean of the slope and intercept terms determined for each individual, was: . The group mean of the individual correlation coefficients for the relationship was 0.99. The values of % HR_peak for each of the % values below 85% were significantly greater (P<0.01) than those suggested by the ACSM. This suggests that the ACSM guidelines below 85% , based on % HR_peak, may underestimate the relative exercise intensity (i.e. % ) in the WR population. However, in élite level WR, % HR_peak can be recommended as an alternative estimate of % at wheelchair propulsion intensities of 85% or more. Electronic Publication     

Lethal Myocardial Ischemic Injury

The biologic changes occurring in severely ischemic myocytes in vivo as the affected cells pass through the phase of reversible to the phase of lethal or irreversible injury are reviewed with special emphasis on the effect of ischemia on the production and utilization of highenergy phosphate, the destruction of the adenine nucleotide pool, and the appearance of signs of damage to the plasma membrane of the sarcolemma. Evidence is presented that indicates that the events occurring in severe ischemia in vivo are essentially identical to those found in total ischemia in vitro except that the biologic changes of ischemia develop more slowly in total ischemia in vitro than in severe ischemia in vivo. The slower time course of injury, together with the uniformity of injury provided by total ischemia in vitro, may allow for more precise identification of potential lethal cellular events in ischemic injury. The production of highenergy phosphates (HEP) from anaerobic glycolysis have been estimated in both in vivo and in vitro ischemia by the measurement of lactate accumulation, and total HEP utilization has been estimated from the depletion of stores of preformed HEP. The results show that between 80% and 90% of the HEP utilized by ischemic dog left ventricle is produced by anaerobic glycolysis. The onset of irreversibility is associated with marked depletion of the HEP and adenine nucleotide pools of the tissue and the cessation of energy production via glycolysis. The cessation of anaerobic glycolysis may be caused by the low sarcoplasmic, adenosine triphosphate (ATP) concentration of the dying myocyte. In addition to the foregoing changes, irreversibly injured tissue exhibits both ultrastructural and functional evidence of disruption of the plasmalemma of the sarcolemma. The possible relationships, causal and otherwise, between severe HEP depletion and membrane damage are discussed. Both HEP depletion (ATP < 3-8% of control) and membrane damage are considered to be objective signs of the presence of irreversible myocardial ischemic injury. However, at the present time, there is no proof that these changes are causally related either to each other or to cell death in severe in vivo ischemia.     

Phagocytosis in the light-damaged albino rat eye: Light and electron microscopic study

Retinal photoreceptor degeneration was induced by exposing albino rats to fluorescent illumination at elevated environmental temperatures. Fine carbon particles were injected intravenously or directly into the vitreous body or anterior chamber of the eye. The resulting pattern of invasion, migration, and egression of carbon-filled phagocytes in eyes with degenerated retinas was reconstructed from a time sequence series of light and electron microscopic tissue sections. Retinal debris, such as damaged photoreceptor outer segments and carbon particles, was most frequently removed by two populations of cells possessing phagocytic properties: mononuclear cells of vascular origin and pigment epithelial cells. After retinal damage, mononuclear cells appeared first in the vitreous body and later, in time sequence, progressively deeper in the inner plexiform layer and out to the bipolar nuclear layer, where they were seen within, or partially within, retinal capillaries. After intravenous carbon injection, however, marked phagocytes were not seen in the retina. Carbon-filled phagocytic cells were observed in the choroidal connective tissue and blood vessels after intravenous injection, but not after intravitreal injections of carbon. Therefore, retinal phagocytes did not appear to leave the eye through the choroidal circulation. Pigment epithelial cells proliferated by mitotic activity, occurred as single cells separated from Bruch's membrane, and were seen among the degenerated outer segments. After direct exposure to carbon particles, pigment cell phagosomes contained both carbon and lamellated discs of degenerated outer segments. Whether these cells exited from the eye through retinal capillaries or returned to Bruch's membrane to reestablish continuity in the pigment epithelium could not be determined.     

Vinylpyrrolidone-co-(meth)acrylic acid inserts for ocular drug delivery: synthesis and evaluation

Copolymeric hydrogels constituting of vinylpyrrolidone and methacrylic or acrylic acid repeat units have been prepared and investigated for their ability to act as controlled release vehicles in ophthalmic drug delivery. The materials were synthesized by radical-induced polymerization in the presence of N,N'-methylenebisacrylamide crosslinker, and the influences of network composition and drug solubility upon the swelling properties, adhesion behavior, and drug release characteristics were studied. In vitro release experiments showed that some of these materials could be useful vehicles for the delivery of drugs such as pilocarpine or chloramphenicol, while in vivo studies, using the rabbit model, confirmed their high potential for the controlled ocular delivery of pilocarpine hydrochloride.     

Short-circuiting autoimmune disease by target-tissue-derived nitric oxide

A previous report from this laboratory suggested that expression of skeletal-muscle-derived, inducible nitric oxide synthase (iNOS), is associated with resistance to the autoimmune model of myasthenia gravis (MG) demonstrated by Wistar Furth rats following the passive transfer of antibody reactive with the nicotinic acetylcholine receptor (AChR). The study reported below demonstrates an association between increased expression of iNOS/NO in Wistar Furth rats and the induction of programmed cell death (apoptosis) in both macrophages and CD4+ T cells that attempt to traffic through targeted muscles. It is concluded that production of muscle-derived NO is protective in experimental MG, and in part, dictates the severity of eventual immunopathology.     

Interpersonal stressors and resources as predictors of parental adaptation following pediatric traumatic injury

The authors examined the relationship of preinjury interpersonal resources and stressors to parental adaptation following pediatric traumatic brain injury (TBI) and orthopedic injury. Parents of children with severe TBI (n = 53), moderate TBI (n = 56), and orthopedic injuries (n = 80) were assessed soon after injury, 6 and 12 months after the initial evaluation, and at an extended follow-up with a mean of 4 years postinjury. General linear model analyses provide support for both main and moderating effects of stressors and resources on parental adjustment. Support from friends and spouse was associated with less psychological distress, whereas family and spouse stressors were associated with greater distress. The results also reveal a marked decline in injury-related stress over follow-up for families in the severe TBI group who reported a combination of high stressors and high resources. The decline suggests that interpersonal resources attenuated long-term family burden because of severe TBI. The findings are discussed in terms of their implications for intervention following TBI.     

Defects in regulation of apoptosis in caspase-2-deficient mice

During embryonic development, a large number of cells die naturally to shape the new organism. Members of the caspase family of proteases are essential intracellular death effectors. Herein, we generated caspase-2-deficient mice to evaluate the requirement for this enzyme in various paradigms of apoptosis. Excess numbers of germ cells were endowed in ovaries of mutant mice and the oocytes were found to be resistant to cell death following exposure to chemotherapeutic drugs. Apoptosis mediated by granzyme B and perforin was defective in caspase-2-deficient B lymphoblasts. In contrast, cell death of motor neurons during development was accelerated in caspase-2-deficient mice. In addition, caspase-2-deficient sympathetic neurons underwent apoptosis more effectively than wild-type neurons when deprived of NGF. Thus, caspase-2 acts both as a positive and negative cell death effector, depending upon cell lineage and stage of development.