Recombinant human activated protein C improves pulmonary function in ovine acute lung injury resulting from smoke inhalation and sepsis

Objective: To investigate the effects of recombinant human activated protein C (rhAPC) on pulmonary function in acute lung injury (ALI) resulting from smoke inhalation in association with a bacterial challenge. Design: Prospective, randomized, controlled, experimental animal study with repeated measurements. Setting: Investigational intensive care unit at a university hospital. Subjects: Eighteen sheep (37.2 +/- 1.0 kg) were operatively prepared and randomly allocated to either the sham, control, or rhAPC group (n = 6 each). After a tracheotomy had been performed, ALI was produced in the control and rhAPC group by insufflation of 4 sets of 12 breaths of cotton smoke. Then, a 30 mL suspension of live Pseudomonas aeruginosa bacteria (containing 2-5 x 10(11) colony forming units) was instilled into the lungs according to an established protocol. The sham group received only the vehicle, i.e., 4 sets of 12 breaths of room air and instillation of 30 mL normal saline. The sheep were studied in the awake state for 24 hrs and were ventilated with 100% oxygen. RhAPC (24 mu g/kg/hr) was intravenously administered. The infusion was initiated 1 hr post-injury and lasted until the end of the experiment. The animals were resuscitated with Ringer's lactate solution to maintain constant pulmonary artery occlusion pressure. Measurements and Main Results., In comparison with nontreatment in controls, the infusion of rhAPC significantly attenuated the fall in PaO2/FiO(2) ratio (control group values were 521 +/- 22 at baseline [BL], 72 +/- 5 at 12 hrs, and 74 +/- 7 at 24 hrs, vs. rhAPC group values of 541 +/- 12 at BL, 151 +/- 29 at 12 hours [p < .05 vs. control], and 118 +/- 20 at 24 hrs), and significantly reduced the increase in pulmonary microvascular shunt fraction (Qs/Qt; control group at BL, 0.14 +/- 0.02, and at 24 hrs, 0.65 +/- 0.08; rhAPC group at BL, 0.24 +/- 0.04, and at 24 hrs, 0.45 +/- 0.02 [p < .05 vs. control]) and the increase in peak airway pressure (mbar; control group at BL, 20 +/- 1, and at 24 hrs, 36 +/- 4; rhAPC group at BL, 21 +/- 1, and at 24 hrs, 28 +/- 2 [p < .05 vs. control]). In addition, rhAPC limited the increase in lung 3-nitrotyrosine (after 24 hrs [%]: sham, 7 +/- 2; control, 17 +/- 1; rhAPC, 12 +/- 1 [p < .05 vs. control]), a reliable indicator of tissue injury. However, rhAPC failed to prevent lung edema formation. RhAPC-treated sheep showed no difference in activated clotting time or platelet count but exhibited less fibrin degradation products (1/6 animals) than did controls (4/6 animals). Conclusions. Recombinant human activated protein C attenuated ALI after smoke inhalation and bacterial challenge in sheep, without bleeding complications.

TRALI in 2 cases of leukemia

We describe transfusion-related acute lung injury (TRALI) in 2 acute leukemia cases to increase awareness of this under reported serious transfusion complication syndrome in multitransfused patients. There are a number of reports in multitransfused patients with nonmalignant disorders. However, reports of pediatric oncology patients are few, suggesting a lack of recognition or misdiagnosis of the syndrome. A disproportionately high number of fatalities in children is recorded in the literature. This highlights the need for increased awareness and appropriate treatment of this serious complication of transfusion. Although TRALI is initially a clinical diagnosis, the laboratory investigation is vital as it contributes to defining the pathogenesis of the syndrome and importantly facilitates the effective management of implicated donations and donors. An investigational strategy for suspected cases is presented and the results are discussed in the context of current proposed mechanisms for TRALI. As each transfused blood product is associated with a potential risk of TRALI, more frequent reports in patients receiving large volume or recurrent transfusion would be expected.

Outcome measurement in Australian rehabilitation environments

Objective: To determine the frequency and pattern of methods of outcome assessment used in Australian physical rehabilitation environments. Design: Postal survey. Methods: A questionnaire on service type, staffing, numbers of adults treated and outcome measures used for 7 conditions related to injury and road trauma as well as stroke and neuromuscular disorders was sent to 973 services providing adult physical rehabilitation treatment. Results: Questionnaires were completed by 440 service providers for a response rate of 45%, similar to that reported in a recent European survey reported in this journal. A small number of measures were reported as in use by most respondents, while a large number of measures were used by a few respondents. Measures of physical changes were used more frequently than those of generic well-being or quality of life. Ease of use and reporting to other professionals were cited as the most important reasons in selection of outcome measures. Conclusion: This Australian-wide survey detected considerable heterogeneity in outcome measurement procedures used in rehabilitation environments. While the goal of measurement may vary between providers and differ between conditions, the results highlight opportunities for harmonization, benchmarking and measurement of health-related quality of life.

Nitric oxide synthase inhibition in sepsis? Lessons learned from large-animal studies

Nitric Oxide (NO) plays a controversial role in the pathophysiology of sepsis and septic shock. Its vasodilatory effects are well known, but it also has pro- and antiinflammatory properties, assumes crucial importance in antimicrobial host defense, may act as an oxidant as well as an antioxidant, and is said to be a vital poison for the immune and inflammatory network. Large amounts of NO and peroxynitrite are responsible for hypotension, vasoplegia, cellular suffocation, apoptosis, lactic acidosis, and ultimately multiorgan failure. Therefore, NO synthase (NOS) inhibitors were developed to reverse the deleterious effects of NO. Studies using these compounds have not met with uniform success however, and a trial using the nonselective NOS inhibitor N-G-methyl-L-arginine hydrochloride was terminated prematurely because of increased mortality in the treatment arm despite improved shock resolution. Thus, the issue of NOS inhibition in sepsis remains a matter of debate. Several publications have emphasized the differences concerning clinical applicability of data obtained from unresuscitated, hypodynamic rodent models using a pretreatment approach versus resuscitated, hyperdynamic models in high-order species using posttreatment approaches. Therefore, the present review focuses on clinically relevant large-animal studies of endotoxin or living bacteria-induced, hyperdynamic models of sepsis that integrate standard day-today care resuscitative measures.

Comparison of surfactant lipids between pleural and pulmonary lining fluids

Saturated phospholipids (PCs), particularly dipalmitoylphosphatidylcholine (DPPC), predominate in surfactant lining the alveoli, although little is known about the relationship between saturated and unsaturated PCs on the outer surface of the lung, the pleura. Seven healthy cats were anesthetized and a bronchoalveolar lavage (BAL) was performed, immediately followed by a pleural lavage (PL). Lipid was extracted from lavage fluid and then analyzed for saturated, primarily dipalmitoylphosphatidylcholine (DPPC), and unsaturated PC species using high-performance liquid chromatography (HPLC) with combined fluorescence and ultraviolet detection. Dilution of epithelial lining fluid (ELF) in lavage fluids was corrected for using the urea method. The concentration of DPPC in BAL fluid (85.3 +/- 15.7 mu g/mL) was significantly higher (P=0.021) than unsaturated PCs (similar to 40 mu g/mL). However, unsaturated PCs (similar to 34 mu g/mL), particularly stearoyl-linoleoyl-phosphatidylcholine (SLPC; 17.4 +/- 6.8), were significantly higher (P = 0.021) than DPPC (4.3 +/- 1.8 mu g/mL) in PL fluid. These results show that unsaturated PCs appear functionally more important in the pleural cavity, which may have implications for surfactant replenishment following pleural disease or thoracic surgery. (c) 2005 Published by Elsevier Ltd.

Physiological consequences of early-life insult

The most commonly observed severe lung injuries in early life are the respiratory distress syndrome in premature infants and the acute respiratory distress syndrome in children. Both diseases are characterised by alveolar instability, fluid filled airspace and some degree of airway obstruction. In the acute phase, collapsed alveoli can be reopened with positive end-expiratory pressure and lung recruitment. New insight into the physiology of lung recruitment suggests that the shape of the pressure–volume curve is defined by the change in rate of alveolar opening and closing. Reduced lung volumes and severe ventilation maldistribution are found in the acute phase but may persist during childhood. Any severe lung injury in this early phase of life can cause significant structural and functional damage to the developing lung. Follow-up studies of children with chronic lung disease have shown that the functional abnormalities will improve but may still be present in later childhood.

Investigation of factors related to employment outcome following traumatic brain injury: a critical review and conceptual model

Purpose : The purpose of this article is to critically review the literature to examine factors that are most consistently related to employment outcome following traumatic brain injury (TBI), with a particular focus on metacognitive skills. It also aims to develop a conceptual model of factors related to employment outcome. Method : The first stage of the review considered 85 studies published between 1980 and December 2003 which investigated factors associated with employment outcome following TBI. English-language studies were identified through searches of Medline and PsycINFO, as well as manual searches of journals and reference lists. The studies were evaluated and rated by two independent raters (Kappa = 0.835) according to the quality of their methodology based upon nine criteria. Fifty studies met the criteria for inclusion in the second stage of the review, which examined the relationship between a broad range of variables and employment outcome. Results : The factors most consistently associated with employment outcome included pre-injury occupational status, functional status at discharge, global cognitive functioning, perceptual ability, executive functioning, involvement in vocational rehabilitation services and emotional status. Conclusions : A conceptual model is presented which emphasises the importance of metacognitive, emotional and social environment factors for improving employment outcome.

Perinatal outcomes with laser surgery for twin-twin transfusion syndrome

The aim of this tertiary hospital-based cohort study was to determine and compare perinatal outcome and neonatal morbidities of pregnancies with twin-twin transfusion syndrome (TTTS) before and after the introduction of a treatment program with laser ablation of placental communicating vessels. Twenty-seven pregnancies with Stage II-IV TTTS treated with amnioreduction were identified (amnioreduction group). The data were compared with that obtained from the first 31 pregnancies with Stage II-IV TTTS managed with laser ablation of placental communicating vessels (laser group). Comparisons were made for perinatal survival and neonatal morbidities including abnormalities on brain imaging. The median gestation at therapy was similar between the two groups (20 vs. 21 weeks, p = .24), while the median gestation at delivery was significantly greater in the laser treated group (34 vs. 28 weeks, p = .002). The perinatal survival rate was higher in the laser group (77.4% vs. 59.3%, p = .03). Neonatal morbidities including acute respiratory distress, chronic lung disease, requirement for ventilatory assistance, patent ductus arteriosus, hypotension, and oliguric renal failure had a lower incidence in the laser group. On brain imaging, ischemic brain injury was seen in 12% of the amnioreduction group and none of the laser group of infants (p = .01). In conclusion, these findings indicate that perinatal outcomes are improved with less neonatal morbidity for monochorionic pregnancies with severe TTTS treated by laser ablation of communicating placental vessels when compared to treatment by amnioreduction.

Gene-expression profiling reveals distinct expression patterns for classic versus variant Merkel cell phenotypes and new classifier genes to distinguish Merkel cell from small-cell lung carcinoma

Merkel cell carcinoma (MCC) is a rare aggressive skin tumor which shares histopathological and genetic features with small-cell lung carcinoma (SCLC), both are of neuroendocrine origin. Comparable to SCLC, MCC cell lines are classified into two different biochemical subgroups designated as 'Classic' and 'Variant'. With the aim to identify typical gene-expression signatures associated with these phenotypically different MCC cell lines subgroups and to search for differentially expressed genes between MCC and SCLC, we used cDNA arrays to pro. le 10 MCC cell lines and four SCLC cell lines. Using significance analysis of microarrays, we defined a set of 76 differentially expressed genes that allowed unequivocal identification of Classic and Variant MCC subgroups. We assume that the differential expression levels of some of these genes reflect, analogous to SCLC, the different biological and clinical properties of Classic and Variant MCC phenotypes. Therefore, they may serve as useful prognostic markers and potential targets for the development of new therapeutic interventions specific for each subgroup. Moreover, our analysis identified 17 powerful classifier genes capable of discriminating MCC from SCLC. Real-time quantitative RT-PCR analysis of these genes on 26 additional MCC and SCLC samples confirmed their diagnostic classification potential, opening opportunities for new investigations into these aggressive cancers.