Asbestos-induced lung injury in the sheep model: The initial alveolitis

In order to study the cellular and biochemical changes in early asbestosis, three groups of sheep were repeatedly exposed to intratracheal instillations of either saline (controls), low doses of UICC chrysotile asbestos (LD), or high doses of the fibers (HD) until an alveolitis was observed in all HD sheep during the twelfth month of exposure. All sheep were studied bimonthly by transbronchial lung biopsy (LB), bronchoalveolar lavage (BAL), pulmonary function tests (PFT), and chest roentgenograms (CXR). While LBs of the HD sheep demonstrated large accumulations of monocyte-macrophages in the alveolar and interstitial spaces, those of controls and LD sheep did not. In BAL, there was no difference in total and differential cell counts between groups, but the BAL lymphocyte proliferative capacity was clearly depressed in all asbestos-exposed sheep. In the BAL supernatant, total proteins (mainly albumin, beta + gamma globulins) and lactate dehydrogenase were significantly elevated in the HD group only. This alveolitis was associated with a fall in vital capacity, lung compliance, diffusing capacity, and arterial P_O2. Abnormalities on CXR appeared 3 months later. Thus, the cellular and biochemical features of early asbestosis are clearly distinct from those reported in idiopathic pulmonary fibrosis.     

Modulation of allergic and immune complex-induced lung inflammation by bradykinin receptor antagonists

Objective: The effect of bradykinin (B₁ or B₂) receptor antagonists was studied in allergic and immune-complex-induced lung inflammation.Methods: Lungs of BALB/c mice were examined 24 h after induction of lung inflammation, either allergic (ovalbumin-sensitized submitted to two aerosol of antigen, one week apart) or immune-complex induced (intratracheal instillation of IgG antibodies followed by intravenous antigen). The bradykinin B₂ receptor antagonist, HOE-140 or bradykinin B₁ receptor antagonist, R-954 were given intraperitoneally (100 g/kg), 30 min before induction.Results: In allergic inflammation, pre-treatment with R-954 reduced eosinophil infiltration into the lungs, mucus secretion and the airway hyperreactivity to methacholine. Pre-treatment with HOE-140 increased eosinophil infiltration but did not affect the other parameters. In immune-complex inflammation, HOE-140 increased neutrophil infiltration but not their activation nor the hemorrhagic lesions. R-594 pre-treatment did not change the parameters examined.Conclusion: These results show important modulatory effects of bradykinin B₁ and B₂ receptor antagonists in both models of lung inflammation.Received 6 May 2003; returned for revision 22 July 2003; accepted by N. Boughton-Smith 8 October 2003Received 6 May 2003; returned for revision 22 July 2003; accepted by N. Boughton-Smith 8 October 2003     

Impact of transfer delays to rehabilitation in patients with severe trauma

OBJECTIVE: To measure the effect on rehabilitation outcomes of administrative delays in transferring patients from a level I trauma center to inpatient rehabilitation. DESIGN: Retrospective cohort study. SETTINGS: Level I trauma center and an inpatient rehabilitation center in Quebec, Canada. PARTICIPANTS: A total of 289 patients with severe trauma admitted to inpatient rehabilitation from a level I trauma center between 1994 and 1999. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Length of stay (LOS) in rehabilitation, motor and cognitive function at discharge from rehabilitation, interruptions in rehabilitation, and disposition at discharge. RESULTS: Shorter administrative delays were associated with shorter rehabilitation LOS (P<.01) improved cognitive function (P=.02) and had a negative but statistically nonsignificant association with motor function at discharge. No effect was observed for rehabilitation interruptions or dispositions at discharge. CONCLUSIONS: Transferring trauma patients more quickly to inpatient rehabilitation can affect rehabilitation outcomes positively. It can also lead to an economy of resource use in both acute and rehabilitation settings.     

Prevention of in-stent restenosis via reduction of thrombo-inflammatory reactions with recombinant P-selectin glycoprotein ligand-1

The binding of leukocyte P-selectin glycoprotein ligand-1 (PSGL-1) to platelet P-selectin is central to post-angioplasty restenosis. Although intracoronary stents limit the mechanical component of restenosis, they cause marked thrombo-inflammation and neointimal proliferation leading to greater late luminal loss. We sought to demonstrate that P-selectin antagonism, using recombinant PSGL-1 (rPSGL-Ig), is effective in reducing platelet-leukocyte reactions and in-stent restenosis in double-injured porcine coronary arteries. Two weeks after initial injury by angioplasty to the coronary arteries, stents were implanted at the injury-induced lesion site, 15 min after an i.v. bolus administration of a vehicle or rPSGL-Ig (1 mg/kg). Four weeks later, adhesion of (51)Cr-platelets and (111)In-neutrophils and histomorphometric analyses were performed. In-stent residual lumen was almost 3 fold larger in rPSGL-Ig-treated arteries (3.1 +/- 0.4 mm(2)) as compared to control (1.1 +/- 0.2 mm(2)), which correspond to 64% vascular stenosis in control with no change in rPSGL-Ig animals. For a similar injury score, in-stent neointima was significantly reduced by 30 to 40% in the rPSGL-Ig group and quantitative coronary angiography showed a significant 35% reduction in late lumen loss. These effects of rPSGL-Ig were associated with a respective 70% and 53% reduction in platelet and neutrophil adhesion. In conclusion, pretreatment with rPSGL-Ig reduces thrombo-inflammatory responses, neointimal proliferation, and in-stent restenosis. P-selectin antagonism offers a promising therapy to improve clinical outcomes of coronary stenting.     

An interacting systems model of infant habituation

Habituation and related procedures are the primary behavioral tools used to assess perceptual and cognitive competence in early infancy. This article introduces a neurally constrained computational model of infant habituation. The model combines the two leading process theories of infant habituation into a single functional system that is grounded in functional brain circuitry. The HAB model (for Habituation, Autoassociation, and Brain) proposes that habituation behaviors emerge from the opponent, complementary processes of hippocampal selective inhibition and cortical long-term potentiation. Simulations of a seminal experiment by Fantz [Visual experience in infants: Decreased attention familiar patterns relative to novel ones. Science, 146, 668-670, 1964] are reported. The ability of the model to capture the fine detail of infant data (especially age-related changes in performance) underlines the useful contribution of neurocomputational models to our understanding of behavior in general, and of early cognition in particular.     

Profile of endothelin isopeptides and markers of oxidative stress alongside the onset of streptozotocin-type I diabetes in rats

Type I diabetes is associated with vascular endothelial abnormalities. Vasoactive mediators such as endothelins and reactive oxygen species are modulated in diabetic patients. We studied the hemodynamic profile and the release of mediators alongside the onset of streptozotocin-induced type I diabetes in rats. Arterial plasma samples were collected from chronically instrumented, unrestrained and conscious normotensive versus streptozotocin-diabetic rats. Streptozotocin-diabetic rats developed severe hypoinsulinemia and subsequent hyperglycemia within 5 days. Mean arterial blood pressure and heart rate decreased from 107 to 87 mmHg (19%) and from 386 to 282 beats per minute (bpm) (27%), respectively over 21 days. On day 20 post-streptozotocin administration, markers of oxidative stress (reactive oxygen species: hydrogen peroxide, total peroxides) and related vasodilatory nitric oxide metabolites, increased. Plasma concentrations of atrial natriuretic peptide were not affected, while vasocontractile endothelin-1 and big endothelin-1 increased in streptozotocindiabetic rats versus chronically instrumented, unrestrained and conscious normotensive rats. In addition, the ratios of endothelin-1 : big endothelin-1 and nitric oxide : endothelin-1 were increased. The depressed hemodynamic profile may result from an imbalance between vasocontracting and relaxing factors. Their interactions with reactive oxygen species may affect vascular tone and lead to vascular complications prevalent in this pathological condition. Defining the complex regulation and roles of these factors merits further investigations, especially in the later endstages of vascular complications, because the development of these complications is linked to the duration of the diabetic state.     

Locally aggressive solitary fibrous tumor in the infraorbital region: a case report and review of the literature

We describe a case of a soft tissue neoplasm in the infraorbital region of a 31-year-old African-American man that met histologic and immunohistochemical criteria for solitary fibrous tumor. This uncommon spindle cell neoplasm was first described in the pleura, but it has since been reported in many other soft tissue locations. The lesion was locally aggressive and successfully treated by local excision. Solitary fibrous tumor can be locally destructive and can occur in a wide variety of tissues or organs; this is the seventh published case of solitary fibrous tumor in the orofacial region.     

Early lung events following low-dose asbestos exposure

A conscious sheep model recently developed to study sequentially the bronchoalveolar milieu was applied to the investigation of the early lung events following very low dose asbestos exposure. UICC Canadian chrysotile fibers were administered in three monthly intratracheal injections of a suspension of 0 (controls), 1, 2, 4, 8, and 16 mg of asbestos in 50 ml saline. Three sheep per dose were repeatedly exposed to the same monthly doses and all were studied by serial pulmonary function (PF) tests, transbronchial lung biopsies (LB), and bronchoalveolar lavages (BAL). These low-dose exposures did not change the PF tests; routine lung histopathology was not altered except for the observation of occasional fibers in the alveoli, but there was a significantly higher yield in the total BAL cellular due to a marked increase in the macrophage and a small rise in the lymphocyte populations. These changes in the BAL cells occurred without significant changes in the biochemical analyses of the BAL supernatant. These data establish that very low dose asbestos exposure induces migration of macrophages and lymphocytes into the bronchoalveolar milieu. These cells have a major role in the lung defense and have been implicated in the development of asbestos-related diseases.     

A New Care Model Reduces Polypharmacy and Potentially Inappropriate Medications in Long-Term Care

ObjectivesAssess the impact of a new pharmaceutical care model on (1) polypharmacy and (2) potentially inappropriate medication (PIM) use in long-term care facilities (LTCFs).DesignPragmatic quasi-experimental study with a control group. This multifaceted model enables pharmacists and nurses to increase their professional autonomy by enforcing laws designed to expand their scope of practice. It also involves a strategic reorganization of care, interdisciplinary training, and systematic medication reviews.Setting and ParticipantsTwo LTCFs exposed to the model (409 residents) were compared to 2 control LTCFs (282 residents) in Quebec, Canada. All individuals were aged 65 years or older and residing in included LTCFs.MeasuresPolypharmacy (≥10 medications) and PIM (2015 Beers criteria) were analyzed throughout 12 months between March 2017 and June 2018. Groups were compared before and after implementation using repeated measures mixed Poisson or logistic regression models, adjusting for potential confounding variables.ResultsOver 12 months, for regular medications, polypharmacy decreased from 42% to 20% (exposed group) and from 50% to 41% (control group) [difference in differences (DID): 13%, P < .001]. Mean number of PIMs also decreased from 0.79 to 0.56 (exposed group) and from 1.08 to 0.90 (control group) (DID: 0.05, P = .002).Conclusions and ImplicationsCompared with usual care, this multifaceted model reduced the probability of receiving ≥10 medications and the mean number of PIMs. Greater professional autonomy, reorganization of care, training, and medication review can optimize pharmaceutical care. As the role of pharmacists is expanding in many countries, this model shows what could be achieved with increased professional autonomy of pharmacists and nurses in LTCFs.     

Neutrophil function after exposure to polychlorinated biphenyls in vitro.

Polychlorinated biphenyls (PCBs) are known to be immunotoxic, yet the effects on neutrophil (PMN) function are not well characterized. We incubated PMNs isolated from rat peritoneum with a mixture of PCB congeners, Aroclor 1242, in the absence or presence of either phorbol myristate acetate (PMA) to stimulate generation of superoxide anion (O2-) or N-formyl-methionyl-leucyl-phenylalanine (fMLP) to induce degranulation (measured as release of beta-glucuronidase). Aroclor 1242 alone stimulated O2- production at a concentration of 10 micrograms/ml. Significant cytotoxicity was not observed under these conditions. This concentration of Aroclor 1242 also increased O2- generation in PMNs activated with 20 ng PMA/ml. In the presence of a concentration of PMA (2 ng/ml) that by itself did not stimulate production of O2-, 1 microgram Aroclor 1242/ml caused significant generation of O2-, indicating synergy between Aroclor 1242 and PMA. Aroclor 1242 caused release of beta-glucuronidase from quiescent PMNs; however, in PMNs stimulated with fMLP to undergo degranulation, Aroclor 1242 inhibited release of beta-glucuronidase. The effects of two PCB congeners, one that binds to the Ah receptor (3,3', 4,4'-tetrachlorobiphenyl) and one that has little affinity for this receptor (2,2', 4,4'-tetrachlorobiphenyl) were examined. 3,3', 4,4'-Tetrachlorobiphenyl had no effect on PMN function in vitro, whereas 2,2', 4,4'-tetrachlorobiphenyl had effects similar to those observed with Aroclor 1242. These results indicate that PCBs affect PMN function in vitro in a complex manner, stimulating or inhibiting function under different conditions. These effects are apparently not mediated through the Ah receptor.