Protease Activated Receptor-2 Contributes to Heart Failure

Heart failure is a major clinical problem worldwide. Previous studies have demonstrated an important role for G protein-coupled receptors, including protease-activated receptors (PARs), in the pathology of heart hypertrophy and failure. Activation of PAR-2 on cardiomyocytes has been shown to induce hypertrophic growth in vitro. PAR-2 also contributes to myocardial infarction and heart remodeling after ischemia/reperfusion injury. In this study, we found that PAR-2 induced hypertrophic growth of cultured rat neonatal cardiomyocytes in a MEK1/2 and p38 dependent manner. In addition, PAR-2 activation on mouse cardiomyocytes increased expression of the pro-fibrotic chemokine MCP-1. Furthermore, cardiomyocyte-specific overexpression of PAR-2 in mice induced heart hypertrophy, cardiac fibrosis, inflammation and heart failure. Finally, in a mouse model of myocardial infarction induced by permanent ligation of the left anterior descending coronary artery, PAR-2 deficiency attenuated heart remodeling and improved heart function independently of its contribution to the size of the initial infarct. Taken together, our data indicate that PAR-2 signaling contributes to the pathogenesis of hypertrophy and heart failure.     

Strongyloidiasis in Canadian Far East war veterans

A survey was done of Canadians who had been interned by the Japanese during World War II to assess the prevalence of latent infection with Strongyloides stercoralis in this group. Packages containing three mail-in kits and a questionnaire were sent to 992 men, 694 (70%) of whom responded. Larvae were found in the stool specimens of four of the respondents. Examination of stool specimens after formalin-ether concentration was the most successful method of detecting Strongyloides larvae. The Baermann concentration technique yielded negative results in all four men. Three of the four cases of strongyloidiasis were detected after sampling of three fecal specimens. In the fourth case additional specimens were requested on the basis of data derived from the questionnaire. The most frequently cited clinical manifestations were abdominal pain, weight loss, diarrhea and rashes.     

Nuclear envelope‐associated dynein drives prophase centrosome separation and enables Eg5‐independent bipolar spindle formation

The microtubule motor protein kinesin‐5 (Eg5) provides an outward force on centrosomes, which drives bipolar spindle assembly. Acute inhibition of Eg5 blocks centrosome separation and causes mitotic arrest in human cells, making Eg5 an attractive target for anti‐cancer therapy. Using in vitro directed evolution, we show that human cells treated with Eg5 inhibitors can rapidly acquire the ability to divide in the complete absence of Eg5 activity. We have used these Eg5‐independent cells to study alternative mechanisms of centrosome separation. We uncovered a pathway involving nuclear envelope (NE)‐associated dynein that drives centrosome separation in prophase. This NE‐dynein pathway is essential for bipolar spindle assembly in the absence of Eg5, but also functions in the presence of full Eg5 activity, where it pulls individual centrosomes along the NE and acts in concert with Eg5‐dependent outward pushing forces to coordinate prophase centrosome separation. Together, these results reveal how the forces are produced to drive prophase centrosome separation and identify a novel mechanism of resistance to kinesin‐5 inhibitors.     

Aging alterations in the modulation of central dopaminergic cilioinhibition by etorphine in the marine mussel,Mytilus edulis: Decrease in the inhibition of presynaptic dopamine release

1. This report further demonstrates that etorphine influences presynaptic dopamine release, which in turn centrally modulates peripheral cilioinhibition. 2. In older animals cilioinhibition has become enhanced due to a lack of responsiveness to endogenous opioids which results in greater dopamine release, causing a higher level of cilioinhibition as demonstrated by challenging the visceral ganglia with etorphine or destroying the dopaminergic component with 6-hydroxydopamine. 3. Only the central cilioinhibitory, not the peripheral inhibitory response, mechanism appears to be altered in older animals. Thus, the alteration appears in the central integrative mechanisms involved with regulating ciliary activity. 4. The KCl-stimulated release of dopamine is unaltered in both young and old organisms, whereas the opiate inhibition of the KCl-stimulated release of dopamine is reduced in older organisms. Thus, the aging-associated alteration is associated with a specific process. 5. The reduction of opioid influence and the resulting enhanced cilioinhibitory activity may make the organisms more susceptible to environmental stress.     

Semipermeable polymer tubes provide a microenvironment for in vivo analysis of dorsal root regeneration

The regeneration of lesioned axons is critically influenced by the local microenvironment. In this study, semipermeable polymer tubes were used to provide a defined microenvironment in vivo to analyze the regeneration of dorsal root axons under various conditions in the adult rat. Cut dorsal root fibers grew across a 2.7 mm gap within enclosed polymer tubes by 4 weeks. The pattern of axonal outgrowth was dramatically influenced by mechanical factors such as the inner surface topography of the polymer tube. Tubes containing various molecular and cellular substrates were also used to study their effect on dorsal root regeneration.     

Effect of dose schedule of vitamin E and hydroxethylruticide on intestinal toxicity induced by adriamycin

CDF1 mice receiving Adriamycin, 12 mg/kg IP develop a toxic GI mucositis. The mean survival in CDF1 mice after Adriamycin injection was found to be 6.5 +/- 2.0 weeks and could be increased by alcohol or acetate Vitamin E pretreatment (with 2 g/kg qDx7d) to 22.06 +/- 12.3 weeks or by treatment with Venoruton after Adriamycin (qDx7 with 1.5 g/kg) to 23.7 +/- 12.7 weeks. Other schedules were ineffective or harmful. The ability of Venoruton to enhance survival when given after Adriamycin encouraged us to proceed to tumor bearing mice. The maximum survival with CDF1 mice bearing 5 X 10(6) L1210 cells was 1 +/- 0.2 week which could be increased to 2.17 +/- 0.8 weeks with optimal dose Adriamycin (10 mg/kg). Optimum survival with Venoruton and a single dose of Adriamycin was 2.45 +/- 0.91 weeks with Venoruton, 1.5 g, qd X 14, and 12 mg/kg Adriamycin. Treatment of L1210 bearing mice with Adriamycin, 10 mg/kg on days 1 and 8, yielded a survival of 2.23 +/- 0.7 weeks. An equitoxic regimen of Adriamycin, 11 mg/kg on days 1 and 9, plus Venoruton, 1.5 g, qd X 14, increased survival 30% to 3.08 +/- 2.9 weeks. Venoruton is a promising agent to increase the therapeutic index of Adriamycin.     

Crystalline inclusions in Bacillus thuringiensis

Crystalline inclusion bodies resembling those seen in Clostridium cochlearium were detected in cultures of Bacillus thuringiensis infected with bacteriophage.     

Relation of Catalase to Substrate Utilization by Mycoplasma pneumoniae

No catalase activity was detected in four strains of glucose-grown Mycoplasma pneumoniae at any time during the replication of the organism. Exogenous catalase dramatically increased the O(2) uptake with glycerol, presumably by releasing inhibition caused by hydrogen peroxide. The effect of added catalase on the O(2) uptake of washed organisms with glucose as substrate was moderate and variable in degree. The production of hydrogen peroxide was demonstrated by the quantitative enzymatic assay for inorganic peroxide and by the fact that added pyruvate, which is non-enzymatically oxidized by H(2)O(2) to acetic acid and CO(2) could mimic the action of catalase.