Croton oil pleurisy induces pulmonary hyperreactivity

Inflammatory process of the airways has been claimed to be relevant to the development of bronchial hyperreactivity in different experimental models. We investigated the consequences of pleural inflammation induced in the guinea-pigs by croton oil injection into the pleural space. Croton oil injection was followed by the development of an inflammatory reaction localized to the pleura as shown by recovery of inflammatory exudate from the pleural cavity of treated animals. An increased number of white cells was observed in the pleural fluid of treated animals as compared to control. Moreover, the croton oil induced inflammation was characterized by development of pulmonary hyperreactivity which involved both airway and vascular smooth muscles. We also studied this phenomenon in an animal model of asthma, such as the actively sensitized guinea-pigs. Polymorphonuclear leukocyte and particularly eosinophil recruitment was increased in this experimental condition and a different trend in the development of the hyperreactive phenomenon was observed. Our data support the relationship between inflammatory process within the pleural space and increased reactivity of pulmonary tissues. The possible involvement of different classes of white cells in this phenomenon has also been discussed.     

Effect of dopamine agonists and antagonists on neurotensin-induced antinociception

In previous reports, we have demonstrated that intracisternal (IC) administration of neurotensin (NT), an endogenous tridecapeptide, produces significant antinociception in a variety of analgesic tests, including the hot-plate test. In addition, many of the central nervous system effects of NT (i.e., hypothermia, gastric cytoprotection) appear to be mediated by brain dopamine (DA) systems. In this study, we evaluated the effect of selected DA agonists and antagonists on NT-induced antinociception in the hot-plate test with mice. Doses, route of administration, and pretreatment interval were determined from the available literature to significantly affect the incidence of DA-dependent behaviors. Pretreatment with chlorpromazine but not haloperidol significantly potentiated NT-induced antinociception. This potentiating effect of chlorpromazine appears not to be due to any intrinsic antinociceptive activity of this agent, chlorpromazine had no significant effect on hot-plate latencies when administered alone. The involvement of DA on NT-induced antinociception was further substantiated by the findings that pretreatment with several DA receptor agonists, including methylphenidate, apomorphine, and d-amphetamine, significantly antagonized the antinociceptive response to IC NT. None of these agents significantly altered the animal's response to the hot-plate when administered alone. The data furnished in the present report suggest that central DA circuits may be involved in the expression of NT-induced antinociception.     

The effect of comorbid illness on mortality outcomes in cardiac surgery

HYPOTHESIS: Comorbid conditions are associated with the risk of death from coronary artery bypass graft surgery. DESIGN: Prospective cohort study data were collected on patient and disease characteristics and comorbid conditions including hypertension, diabetes, obesity, vascular disease, chronic obstructive pulmonary disease, cancer (excluding nonmelanoma skin cancer), dialysis-dependent renal failure, liver disease, and dementia. Statistical analysis used logistic regression for the calculation of adjusted odds ratios (ORs) and 95% confidence intervals (CIs). SETTING: Regional cardiac surgery database. PATIENTS: A total of 27,239 consecutive patients undergoing isolated coronary artery bypass graft surgery. MAIN OUTCOME MEASURE: In-hospital mortality rate. RESULTS: The prevalence of comorbid conditions was as follows: hypertension, 64.3%; diabetes, 30.1%; obesity, 24.6%; severe obesity, 7.2%; vascular disease, 18.3%; chronic obstructive pulmonary disease, 10.9%; peptic ulcer, 7.5%; cancer, 3.8%; renal failure, 1.5%; liver disease, 0.6%; and dementia, 0.1%. After adjustment for patient and disease characteristics, including age, sex, previous cardiac surgery, priority of surgery, degree of left main coronary stenosis, number of diseased coronary arteries, and left ventricular ejection fraction, the following comorbid conditions were significant predictors of in-hospital mortality: diabetes (OR, 1.19; 95% CI, 1.01-1.40; P =.03), vascular disease (OR, 1.67; 95% CI, 1.41-1.97; P<.001), chronic obstructive pulmonary disease (OR, 1.57; 95% CI, 1.29-1.91; P<.001), peptic ulcer (OR, 1.34; 95% CI, 1.05-1.71; P =.02), and dialysis-dependent renal failure (OR, 3.68; 95% CI, 2.65-5.13; P<.001). There was no significant association between in-hospital mortality and hypertension, obesity or severe obesity, cancer, liver disease, or dementia. CONCLUSION: Even after adjustment for other patient and disease characteristics, comorbid conditions (especially diabetes, vascular disease, chronic obstructive pulmonary disease, peptic ulcer disease, and dialysis-dependent renal failure) are associated with significantly increased risk of death after coronary artery bypass graft surgery.     

Looking back at PCPT: looking forward to new paradigms in prostate cancer screening and prevention

OBJECTIVES: Provide a critical summary of the latest interpretation of findings from the Prostate Cancer Prevention Trial (PCPT). METHODS: Findings from PCPT and recently published post-hoc analyses are reviewed. RESULTS: PCPT demonstrated that finasteride can reduce the prevalence of prostate cancer, permitted the first large-scale assessment of the performance characteristics of prostate-specific antigen for prostate cancer screening, and identified new-onset erectile dysfunction as an early predictor of cardiovascular events. CONCLUSIONS: PCPT has and will continue to yield valuable information regarding future strategies for prostate cancer prevention and detection, benign prostatic hyperplasia, and other matters of public health importance.     

Surface contaminants inhibit osseointegration in a novel murine model

Surface contaminants, such as bacterial debris and manufacturing residues, may remain on orthopedic implants after sterilization procedures and affect osseointegration. The goals of this study were to develop a murine model of osseointegration in order to determine whether removing surface contaminants enhances osseointegration. To develop the murine model, titanium alloy implants were implanted into a unicortical pilot hole in the mid-diaphysis of the femur and osseointegration was measured over a five week time course. Histology, backscatter scanning electron microscopy and X-ray energy dispersive spectroscopy showed areas of bone in intimate physical contact with the implant, confirming osseointegration. Histomorphometric quantification of bone-to-implant contact and peri-implant bone and biomechanical pullout quantification of ultimate force, stiffness and work to failure increased significantly over time, also demonstrating successful osseointegration. We also found that a rigorous cleaning procedure significantly enhances bone-to-implant contact and biomechanical pullout measures by two-fold compared with implants that were autoclaved, as recommended by the manufacturer. The most likely interpretation of these results is that surface contaminants inhibit osseointegration. The results of this study justify the need for the development of better detection and removal techniques for contaminants on orthopedic implants and other medical devices.     

Differences in morphology and contractility of the bulbospongiosus and pubococcygeus muscles in nulliparous and multiparous rabbits

In women, birth trauma can result in altered anatomy of supporting structures of the pelvic floor and in the development of urinary incontinence. The goal of this study was to investigate the association between parturition and the morphology and function of perineal and pelvic muscles in the female rabbit. In ten nulliparous and ten multiparous same-age females, we investigated morphological, histological (n = 5 females/group), and contractile characteristics (n = 5 females/group) of the perineal bulbospongiosus (Bsm) and the pelvic pubococcygeus (Pcm) muscles. Bsm and Pcm muscles of multiparous females were significantly lighter, they had a smaller cross-sectional fiber area, and developed significantly lower twitch and tetanic tension force in response to electrical stimulation than muscles of nulliparous females. In female rabbits, multiparity is associated with potentially pathological changes in the morphological and functional characteristics of these perineal and pelvic muscles, possibly as a result of stretching during parturition.     

Ceramide mediates insulin resistance by tumor necrosis factor-alpha in brown adipocytes by maintaining Akt in an inactive dephosphorylated state.

Tumor necrosis factor (TNF)-alpha causes insulin resistance on glucose uptake in fetal brown adipocytes. We explored the hypothesis that some effects of TNF-alpha could be mediated by the generation of ceramide, given that TNF-alpha treatment induced the production of ceramide in these primary cells. A short-chain ceramide analog, C2-ceramide, completely precluded insulin-stimulated glucose uptake and insulin-induced GLUT4 translocation to plasma membrane, as determined by Western blot or immunofluorescent localization of GLUT4. These effects were not produced in the presence of a biologically inactive ceramide analog, C2-dihydroceramide. Analysis of the phosphatidylinositol (PI) 3-kinase signaling pathway indicated that C2-ceramide precluded insulin stimulation of Akt kinase activity, but not of PI-3 kinase or protein kinase C-zeta activity. C2-ceramide completely abolished insulin-stimulated Akt/protein kinase B phosphorylation on regulatory residues Thr 308 and Ser 473, as did TNF-alpha, and inhibited insulin-induced mobility shift in Akt1 and Akt2 separated in PAGE. Moreover, C2-ceramide seemed to activate a protein phosphatase (PP) involved in dephosphorylating Akt because 1) PP2A activity was increased in C2-ceramide- and TNF-alpha-treated cells, 2) treatment with okadaic acid concomitantly with C2-ceramide completely restored Akt phosphorylation by insulin, and 3) transient transfection of a constitutively active form of Akt did not restore Akt activity. Our results indicate that ceramide produced by TNF-alpha induces insulin resistance in brown adipocytes by maintaining Akt in an inactive dephosphorylated state.