Removal of Trypanosoma cruzi by white cell-reduction filters: an electronmicroscopic study

White cell (WBC)-reduction filters have been shown to be effective in removing infectious agents from infected blood products. In this study, the mechanisms of Trypanosoma cruzi (T. cruzi) retention by WBC-reduction filters were assessed. Human packed red blood cell (PRBC) and platelet concentrate (PC) samples were contaminated with T. cruzi organisms (Y strain; 3.4 x 10(6)/ml), and then filtered using WBC-reduction experimental filters that provided about 3 log10 WBC removal. Transmission electron microscopy sections showed that T. cruzi parasites were removed from contaminated PRBC and PC samples primarily by mechanical mechanism without interacting with filter fibbers or blood cells. In addition, we found that T. cruzi parasites were also removed by a direct fibber adhesion. These data indicate that T. cruzi parasites are removed from infected blood not only by mechanical mechanism but also by biological mechanism probably mediated by parasite surface proteins.

Echinacea intake induces an immune response through altered expression of leucocyte hsp70, increased white cell counts and improved erythrocyte antioxidant defences

Objective: To study the effect of Echinacea tablets on the expression of leucocyte heat shock protein 70 (hsp70), erythrocyte haemolysis, plasma antioxidant status, serum chemistry, haematological values and plasma alkylamide concentrations. Method: Eleven healthy individuals (26-61 years of age) were evaluated at baseline (day 1) and on day 15 after consuming two commercially blended Echinacea tablets daily for 14 days. Results: Echinacea supplementation enhanced the fold increase in leucocyte hsp70 expression after a mild heat shock (P=0.029). White cell counts (WCC) were also increased (P=0.043). We also observed a preventative effect against free radical induced erythrocyte haemolysis (P=0.006) indicative of an antioxidant effect. Conclusion: The pilot study suggests that Echinacea may invoke an immune response through altered expression of hsp70 and increased WCC.

Treatment of persistent rejection with methotrexate in stable patients submitted to heart transplantation

OBJECTIVE:To evaluate the use of methotrexate for the treatment of recurrent rejection in heart transplant recipients. METHODS: We studied 6 patients submitted to heart transplantation that showed rejection grade > or = 3A (ISHLT) in two consecutives endomyocardial biopsy specimens. The dose was 11.26±3.75mg/week. The evaluated data were: ventricular function, endomyocardial biopsy, white cell count and number of rejection episodes before and after methotrexate administration. RESULTS: There was a reduction in the number of rejection episodes (5.17±1.47 before methotrexate; 2.33±1.75 after 6 months and 3.17±2.99 after 12 months of treatment, p=0.0193). The ventricular function was normal with ejection fraction of 76.5±4.80 before and 75.6±4.59 after methotrexate (p=0.4859). One patient did not finish the treatment because he showed signs of rejection associated with severe pericardial effusion. Five patients had a reduction in the white cell count (8,108±23.72 before and 5650±1350 after methotrexate, p=0.0961). One pulmonary infection with complete resolution after antibiotic treatment was observed. CONCLUSION: Methotrexate in low doses is an effective adjunct therapy in the treatment of recurrent rejection after heart transplantation.

Mechanisms of B cell survival induced by BAFF, APRIL and their receptors

RESUME : BAFF est un membre de 1a famille du TNF qui contrôle l'homéostasie des lymphocytes B. BAFF lie les récepteurs TACI, BCMA et BAFF-R sur les cellules B, tandis qu'APRIL, son proche homologue, lie seulement TACI et BCMA. BAFF et APRIL sont des protéines transmembranaires pouvant -être relâchées sous forme de cytokines trimériques solubles suite à un clivage protéolytique. Le BAFF soluble peut s'assembler en 60-mère. Les rôles physiologiques des BAFF membranaires et solubles sont inconnnus. Nous avons étudié la capacité de diverses formes de BAFF et APRIL à activer différents récepteurs. BAFF-R répond à toutes les formes dé BAFF, tandis que TACI nécessite du BAFF ou de l'APRIL membranaire ou oligomérisé pour être activé et pour transmettre des signaux de survie dans les lymphocytes B primaires. TACI ne répond pas aux ligands trimériques bien qu'il puisse les lier. TACI est essentiel pour la réponse humorale aux antigènes présentant des épitoges répétitifs, une réponse qui est indépendante des lymphocytes T (réponse TI-2). Des souris exprimant moins de BAFF ont un pourcentage modérément réduit de lymphocytes B et leur réponse TI-2 est atténuée. Par contre, des souris qui n'expriment que du BAFF membranaire ont encore moins de cellules B mais répondent efficacement aux antigènes TI-2. Ces résultats suggèrent que le BAFF soluble est impliqué dans le maintien de la population des lymphocytes B, alors que le BAFF membranaire peut activer TACI lors d'are réponse TI-2. Le BAFF 60-mère est un autre activateur potentiel de TACI in vivo. Le BAFF 60-mère existe dans des surnageants de cellules productrices de BAFF mais n'est pas détecté dans le plasma de souris saines, même lorsqu'elles présentent des niveaux élevés de BAFF. BAFF 60-mère est néanmoins présent dans le plasma de souris transgéniques pour BAFF et de souris déficientes en TACI. Comme ces deux lignées présentent des signes d'autoimmunité, ces résultats suggèrent que la présence de BAFF 60-mère pourrait être liée à des conditions pathologiques. Summary : The TNF family ligand BAFF is essential for B cell homeostasis. BAFF binds to the receptors TACI, BCMA and BAFF-R on B cells, whereas its close homolog APRIL binds to TACI and BCMA only. BAFF and APRIL are transmembrane proteins, which can be proteolytically processed to release trimeric soluble cytokines. Soluble BAFF 3-mer can further assemble in a 60-mer. The physiological roles of membrane-bound and soluble BAFF are unknown. We studied the ability of various forms of BAFF and APRIL to signal through different receptors. BAFF-R responded to all forms of BAFF, but TACI required membrane-bound, cross-licked or oligomeric BAFF or APRIL in order to transmit productive signals in primary B cells. TACI was unresponsive to trimeric ligands, although it could bind them. TACI is essential for T-cell independent antibody responses to antigens with repetitive epitopes (TI-2 responses). Mice expressing lower than normal levels of BAFF displayed a moderate B cell reduction and impaired TI-2 responses, whereas mice expressing membrane-bound BAFF displayed severe B cell reduction, but unimpaired TI-2 responses. These results suggest that processed BAFF is involved in the maintenance of the B cell pool and that membrane-bound BAFF can activate TACI during T-cell independent humoral responses. BAFF 60-mer is another potential activator of TACI in vivo. BAFF 60-mer was detected in the supernatant of BAFF-producing cells, but not in the plasma of healthy mice with either norma1 or elevated BAFF levels. It was however present in sera of BAFF transgenic mice and TACI-/- mice, both of which suffer from autoimmunity, suggesting that GAFF 60-mer may be linked to pathogenic conditions.

A novel cell compatible impingement system to study in vitro drug absorption from dry powder aerosol formulations

A modified Astra type multistage liquid impinger (MSLI) with integrated bronchial cell monolayers was used to study deposition and subsequent drug absorption on in vitro models of the human airway epithelial barrier. Inverted cell culture of Calu-3 cells on the bottom side of cell culture filter inserts was integrated into a compendial MSLI. Upside down cultivation did not impair the barrier function, morphology and viability of Calu-3 cells. Size selective deposition with subsequent absorption was studied for three different commercially available dry powder formulations of salbutamol sulphate and budesonide. After deposition without size separation the absorption rates from the aerosol formulations differed but correlated with the size of the carrier lactose particles. However, after deposition in the MSLI, simulating relevant impaction and causing the separation of small drug crystals from the carrier lactose, the absorption rates of the three formulations were identical, confirming the bioequivalence of the three formulations.

Ex vivo evaluation of a Taylor-Couette flow, immobilized heparinase I device for clinical application

Efficient and safe heparin anticoagulation has remained a problem for continuous renal replacement therapies and intermittent hemodialysis for patients with acute renal failure. To make heparin therapy safer for the patient with acute renal failure at high risk of bleeding, we have proposed regional heparinization of the circuit via an immobilized heparinase I filter. This study tested a device based on Taylor-Couette flow and simultaneous separation/reaction for efficacy and safety of heparin removal in a sheep model. Heparinase I was immobilized onto agarose beads via cyanogen bromide activation. The device, referred to as a vortex flow plasmapheretic reactor, consisted of two concentric cylinders, a priming volume of 45 ml, a microporous membrane for plasma separation, and an outer compartment where the immobilized heparinase I was fluidized separately from the blood cells. Manual white cell and platelet counts, hematocrit, total protein, and fibrinogen assays were performed. Heparin levels were indirectly measured via whole-blood recalcification times (WBRTs). The vortex flow plasmapheretic reactor maintained significantly higher heparin levels in the extracorporeal circuit than in the sheep (device inlet WBRTs were 1.5 times the device outlet WBRTs) with no hemolysis. The reactor treatment did not effect any physiologically significant changes in complete blood cell counts, platelets, and protein levels for up to 2 hr of operation. Furthermore, gross necropsy and histopathology did not show any significant abnormalities in the kidney, liver, heart, brain, and spleen.

Granulocyte-colony-stimulating factor mobilizes bone marrow stem cells in patients with subacute ischemic stroke: the Stem Cell Trial of Recovery EnhanceMent After Stroke (STEMS) Pilot Randomized, Controlled Trial (ISRCTN 16784092)

Background and Purpose - Loss of motor function is common after stroke and leads to significant chronic disability. Stem cells are capable of self-renewal and of differentiating into multiple cell types, including neurones, glia, and vascular cells. We assessed the safety of granulocyte-colony-stimulating factor (G-CSF) after stroke and its effect on circulating CD34 stem cells. Methods - We performed a 2-center, dose-escalation, double-blind, randomized, placebo-controlled pilot trial (ISRCTN 16784092) of G-CSF (6 blocks of 1 to 10 g/kg SC, 1 or 5 daily doses) in 36 patients with recent ischemic stroke. Circulating CD34 stem cells were measured by flow cytometry; blood counts and measures of safety and functional outcome were also monitored. All measures were made blinded to treatment. Results - Thirty-six patients, whose mean SD age was 768 years and of whom 50% were male, were recruited. G-CSF (5 days of 10 g/kg) increased CD34 count in a dose-dependent manner, from 2.5 to 37.7 at day 5 (area under curve, P0.005). A dose-dependent rise in white cell count (P0.001) was also seen. There was no difference between treatment groups in the number of patients with serious adverse events: G-CSF, 7/24 (29%) versus placebo 3/12 (25%), or in their dependence (modified Rankin Scale, median 4, interquartile range, 3 to 5) at 90 days. Conclusions - ”G-CSF is effective at mobilizing bone marrow CD34 stem cells in patients with recent ischemic stroke. Administration is feasible and appears to be safe and well tolerated. The fate of mobilized cells and their effect on functional outcome remain to be determined. (Stroke. 2006;37:2979-2983.)

The effect of laparoscopy access and antibiotics on the outcome of severe bacterial peritonitis in rats

Introduction: Treatment of severe bacterial peritonitis, especially by videolaparoscopy, is still a matter of investigation. The aim of the present study was to evaluate the effect of videolaparoscopy and laparotomy access with or without antibiotics on the outcome of severe bacterial peritonitis in rats. Materials and Methods: Sixty-four male Wistar rats were equally assigned to 8 groups: Sham surgery (SHAM), SHAM+antibiotics (SHAM+AB), cecal ligation and puncture (CLP), CLP+AB, CLP+videolaparoscopy (VLAP), CLP+laparotomy (LAP), VLAP+AB, and LAP+AB. All treated animals were submitted to an evaluation of bacteremia, white cell counts, and cytokine determinations: interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha (TNF-alpha). The groups treated with antibiotics received gentamicin and metronidazole. Survival was monitored over a period of 7 days. Results: Peritonitis induced by CLP was severe, with IL-1, IL-6, and TNF-alpha levels and lethality being significantly higher compared to the SHAM group. The IL-6 levels in the VLAP group were significantly higher compared to the CLP and VLAP+AB groups, and the TNF-alpha levels in the VLAP and LAP+AB groups were significantly higher compared to the LAP group. The survival time was significantly higher in the CLP+AB and VLAP+AB groups, when compared to the CLP group. There was no significant difference in bacteremia and lethality rates between the resources employed for treatment of peritonitis. Conclusions: Although the use of laparoscopic access itself exacerbates the inflammatory response, the combination with antibiotics minimizes this effect and increases the survival time. However, all of the resources used for treating severe peritonitis, when applied alone or in combination, have an equivalent influence on bacteremia and lethality rates.

Eosinophilic pneumonitis induced by aerosol-administered diesel oil and pyrethrum to mice

Objective. To confirm the episode of eosinophilic pneumonitis that occurred in March 2001 in Manaus, Amazon, northern Brazil, as secondary to home aerosolization with 2% cypermethrin diluted in diesel compared with the more conventional 1% cypermethrin and soybean solution used in prophylaxis of dengue. Methods. Four groups of Swiss mice were kept in polycarbonate cages aerosolized with one of the following solutions: diesel, diesel and cypermethrin, soy oil and cypermethrin, and saline. Three and 6 days after exposure, resistance and compliance of the respiratory system and white cell kinetics in peripheral blood and lung tissue were analyzed. Results. The group exposed to diesel and cypermethrin showed higher respiratory system resistance (p < 0.001), lower compliance (p = 0.03), and increased eosinophils in blood (p = 0.03) and lung tissue (p = 0.005) compared with the other groups. There was an increase of neutrophils in the blood of all experimental groups on the third day after exposure (p < 0.001). Conclusions. We concluded that diesel associated with cypermethrin induced lung hyperresponsiveness in this experimental model and was associated with increased polymorphonuclear cells (eosinophils and neutrophils) in blood and lungs. This effect is strongest on the third day after exposure. These results are similar to the episode that occurred in Manaus in 2001 and suggest that diesel plus cypermethrin home aerosolization for arbovirosis prophylaxis should be revised.

Avaliação da monitorização diária da proteína C-Reativa no doente crítico

RESUMO: O objectivo desta Tese de Doutoramento foi estudar o valor da Proteína CReactiva(PCR) como marcador de infecção e sepsis. Por definição, um marcador da infecção não está presente se o doente não está infectado, deve aparecer concomitantemente ou idealmente preceder a instalação da infecção, deve desaparecer com a instituição de terapêutica antimicrobiana adequada e permanecer elevado se a infecção for refractária ao tratamento. Do ponto de vista biológico, a PCR é o protótipo das proteínas de fase aguda, com uma marcada elevação da sua concentração sérica em resposta a diversos estímulos inflamatórios em particular infecções bacterianas. A sua concentração sérica depende apenas da intensidade do estímulo e da velocidade de síntese hepática, não sendo influenciada por nenhum factor ou tratamento a não ser que este tenha influência directa sobre o estímulo desencadeante, o que a torna um marcador de infecção com grande potencial. Nesta Tese comparou-se a PCR com marcadores clássicos de infecção, temperatura e contagem leucocitária, em diversas situações clínicas analisando doentes com infecções documentadas e doentes controlos, sem infecção. Globalmente os resultados dos trabalhos desta Tese mostram que a PCR é um bom marcador de infecção de acordo com a definição previamente apresentada. Em conjunto com a restante avaliação clínica e laboratorial, a monitorização diária da PCR nos doentes sem infecção mostrou ser útil como sentinela da infecção, isto é, apresenta valores baixos nos doentes sem infecção e sobe precocemente nos doentes que desenvolvem uma infecção. Nos doentes com infecção documentada revelou um ser bom marcador de resposta à terapêutica e evolução clínica, diminuindo naqueles que melhoravam e persistindo elevada nos que tinham mau prognóstico, bem assim como identificar diferentes perfis evolutivos. Em suma, a monitorização diária da PCR mostrou utilidade ao longo de todo o internamento na Unidade de Cuidados Intensivos, quer na presença quer na ausência de infecção. Deste todo, a monitorização diária da PCR pode a possibilitar uma utilização mais racional e judiciosa da terapêutica antimicrobiana, contribuindo dessa forma para uma diminuição da toxicidade e da pressão antibiótica, menor risco de emergência de resistências e finalmente diminuição dos custos. Uma vez que, os doentes internados nas Unidades de Cuidados Intensivos apresentam as mesmas doenças que os restantes doentes admitidos no hospital apenas se distinguindo pela sua maior gravidade, poder-se-á extrapolar que a PCR também é potencialmente um bom marcador de infecção nestes doentes. ----------------ABSTRACT: The aim of this PhD Thesis was to assess the value of C-Reactive Protein (CRP) as a marker of infection and sepsis. A marker of infection should be absent in a non-infected patient, should increase alongside or ideally precede the development of an infection, and finally should assess the therapeutic response, that is to say decrease or even disappear with adequate antimicrobial therapy or on the opposite remain elevated if the infection is refractory to the prescribed treatment. The biology of CRP makes it the prototype of acute phase proteins, with marked and sharp elevations of its serum concentration in response to several inflammatory stimulus in particular bacterial infections. Besides, CRP level depends only of the intensity of the stimulus and the rate of hepatic synthesis. Its concentration is not modified by any therapy or intervention. Only those interventions affecting the inflammatory process responsible for the acute phase reaction can change the CRP level. These properties make CRP a potentially good marker of infection. In this Thesis the value of CRP was studied in comparison to traditional markers of infection, like temperature and white cell count, in different clinical situations analysing patients with documented infections and a control group without infection. The aggregated results of the analysis presented in this Thesis illustrate that CRP could be used as a marker of infection. In conjunction with other clinical and laboratory manifestations of sepsis, daily CRP measurement in patients without infection was useful in prediction of infection as its concentration remains low in patients without infection whereas if an infection appears its levels raise markedly. In addition, in patients with documented infections CRP was useful as a marker of therapeutic response and follow-up, with marked decreases in patients with good outcome and remaining elevated in those with poor prognosis, as well as the recognition of different patterns of evolution. In summary, daily CRP measurement was helpful in critical ill patients along the entire Intensive Care Unit stay, both in the presence and in the absence of infection. As a result, daily CRP measurement can assure a better and more rational use of antibiotics and consequently contribute to a decrease in the antibiotic toxicity and demand, reducing the risks of emergence of resistant strains aas well as costs. Provided that patients admitted to an Intensive Care Unit presented the same clinical diagnosis as those admitted to the wards but with higher severity, one can speculate that CRP is also a potentially good marker of infection in these of patients.

Severe stroke: patient profile and predictors of favorable outcome.

Summary.  Background:  Severe stroke carries high rates of mortality and morbidity. The aims of this study were to determine the characteristics of patients who initially presented with severe ischemic stroke, and to identify acute and subacute predictors of favorable clinical outcome in these patients. Methods:  An observational cohort study, Acute Stroke Registry and Analysis of Lausanne (ASTRAL), was analyzed, and all patients presenting with severe stroke - defined as a National Institute of Health Stroke Scale score of ≥ 20 on admission - were compared with all other patients. In a multivariate analysis, associations with demographic, clinical, pathophysiologic, metabolic and neuroimaging factors were determined. Furthermore, we analyzed predictors of favorable outcome (modified Rankin scale score of ≤ 3 at 3 months) in the subgroup of severe stroke patients. Results:  Of 1915 consecutive patients, 243 (12.7%) presented with severe stroke. This was significantly associated with cardio-embolic stroke mechanism (odds ratio [OR] 1.74, 95% confidence interval [CI] 1.19-2.54), unknown stroke onset (OR 2.35, 95% CI 1.14-4.83), more neuroimaging signs of early ischemia (mostly computed tomography; OR 2.65, 95% CI 1.79-3.92), arterial occlusions on acute imaging (OR 27.01, 95% CI 11.5-62.9), fewer chronic radiologic infarcts (OR 0.43, 95% CI 0.26-0.72), lower hemoglobin concentration (OR 0.97, 95% CI 0.96-0.99), and higher white cell count (OR 1.05, 95% CI 1.00-1.11). In the 68 (28%) patients with favorable outcomes despite presenting with severe stroke, this was predicted by lower age (OR 0.94, 95% CI 0.92-0.97), preceding cerebrovascular events (OR 3.00, 95% CI 1.01-8.97), hypolipemic pretreatment (OR 3.82, 95% CI 1.34-10.90), lower acute temperature (OR 0.43, 95% CI 0.23-0.78), lower subacute glucose concentration (OR 0.74, 95% CI 0.56-0.97), and spontaneous or treatment-induced recanalization (OR 4.51, 95% CI 1.96-10.41). Conclusions:  Severe stroke presentation is predicted by multiple clinical, radiologic and metabolic variables, several of which are modifiable. Predictors in the 28% of patients with favorable outcome despite presenting with severe stroke include hypolipemic pretreatment, lower acute temperature, lower glucose levels at 24 h, and arterial recanalization.

Syndrome de Cogan : à propos d'un cas et brève revue de la littérature [Cogan's Syndrome]

We report the case of a 20-year-old woman, with no medical history, who in a short period of time developed the association of a bilateral vestibulocochlear deficit and a nonsyphilitic interstitial keratitis, the usual clinical presentation of Cogan's syndrome. This rare disease was named after David Cogan, the ophthalmologist to whom we owe the description of the first series of cases. The precise aetiology of Cogan's syndrome has yet to be defined, but clinical and biological evidence point toward an immunopathological process. Some authors distinguish between a typical and an atypical form of Cogan's syndrome, the former being associated with interstitial keratitis, the latter with other forms of ocular involvement. The diagnosis of Cogan's syndrome is mainly a clinical one, the association of a bilateral vestibulocochlear deficit and a non-syphilitic keratitis being almost specific. Cogan's syndrome is frequently associated with general signs and cardiovascular, neurological, rheumathological and digestive involvement. Laboratory data usually show nonspecific inflammatory signs (elevation of the white cell count and of the erythrocyte sedimentation rate). The mortality of the disease is essentially determined by its cardiovascular involvement, mostly aortic insufficiency, which should therefore actively be sought for in every patient. It is useful to emphasise that the typical form of Cogan's syndrome carries a higher risk regarding the development of aortic insufficiency, whereas the atypical form is more often associated with a systemic vasculitis. Treatment is mandatory, based upon corticosteroids, and must sometimes be intensified by the administration of a steroid-sparing immunosuppressive drug. Although our patient perfectly met the diagnostic criteria of Cogan's syndrome, the vestibular symptoms preceded the visual complaints, the reverse temporal sequence being more often reported in the literature. Systemic signs and cardiovascular involvement are frequently seen in Cogan's syndrome, but were notably absent in our patient. Blood samples showed inflammatory signs, whereas both lumbar puncture and cerebral MRI were normal, which is the usual pattern encountered in Cogan's syndrome. Following the rapid initiation of immunosuppressive therapy (Prednisone), the visual symptoms due to the bilateral keratitis resolved in a matter of days, whereas the vestibulocochlear deficit was only partly - but dramatically - reduced. This is in accordance with literature data, showing that a severe and permanent auditory deficit occurs at some time in the majority of patients suffering from Cogan's syndrome. Tapering off Prednisone unfortunately reactivated the audiovestibular and ocular symptoms of the disease in our patient so that a steroid-sparing immunosuppressive drug had to be added (azathioprine, followed by mycophenolate mofetil because the patient developed hepatic intolerance). Only after these therapeutic measures could the disease be stabilised. With this case report, we would like to emphasise the importance of rapidly identifying the clinical picture of Cogan's syndrome, so that immunosuppressive therapy can be started without delay, which may significantly reduce both morbidity and mortality of this disease.

Susceptibility to exacerbation in chronic obstructive pulmonary disease

Background Although we know that exacerbations are key events in chronic obstructive pulmonary disease (COPD), our understanding of their frequency, determinants, and effects is incomplete. In a large observational cohort, we tested the hypothesis that there is a frequent-exacerbation phenotype of COPD that is independent of disease severity. Methods We analyzed the frequency and associations of exacerbation in 2138 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End points (ECLIPSE) study. Exacerbations were defined as events that led a care provider to prescribe antibiotics or corticosteroids (or both)or that led to hospitalization (severe exacerbations). Exacerbation frequency was observed over a period of 3 years. Results Exacerbations became more frequent (and more severe) as the severity of COPD increased; exacerbation rates in the first year of follow-up were 0.85 per person for patients with stage 2 COPD (with stage defined in accordance with Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages), 1.34 for patients with stage 3, and 2.00 for patients with stage 4. Overall, 22% of patients with stage 2 disease, 33% with stage 3, and 47% with stage 4 had frequent exacerbations (two or more in the first year of follow-up). The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations. The frequent-exacerbation phenotype appeared to be relatively stable over a period of 3 years and could be predicted on the basis of the patient"s recall of previous treated events. In addition to its association with more severe disease and prior exacerbations, the phenotype was independently associated with a history of gastroesophageal reflux or heartburn, poorer quality of life, and elevated white-cell count. Conclusions Although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype. This has implications for the targeting of exacerbation-prevention strategies across the spectrum of disease severity. (Funded by GlaxoSmithKline; ClinicalTrials .gov number, NCT00292552.)

CSF lactate for accurate diagnosis of community-acquired bacterial meningitis.

CSF lactate measurement is recommended when nosocomial meningitis is suspected, but its value in community-acquired bacterial meningitis is controversial. We evaluated the diagnostic performance of lactate and other CSF parameters in a prospective cohort of adult patients with acute meningitis. Diagnostic accuracy of lactate and other CSF parameters in patients with microbiologically documented episodes was assessed by receiver operating characteristic (ROC) curves. The cut-offs with the best diagnostic performance were determined. Forty-five of 61 patients (74%) had a documented bacterial (n = 18; S. pneumoniae, 11; N. meningitidis, 5; other, 2) or viral (n = 27 enterovirus, 21; VZV, 3; other, 3) etiology. CSF parameters were significantly different in bacterial vs. viral meningitis, respectively (p < 0.001 for all comparisons): white cell count (median 1333 vs. 143/mm(3)), proteins (median 4115 vs. 829 mg/l), CSF/blood glucose ratio (median 0.1 vs. 0.52), lactate (median 13 vs. 2.3 mmol/l). ROC curve analysis showed that CSF lactate had the highest accuracy for discriminating bacterial from viral meningitis, with a cutoff set at 3.5 mmol/l providing 100% sensitivity, specificity, PPV, NPV, and efficiency. CSF lactate had the best accuracy for discriminating bacterial from viral meningitis and should be included in the initial diagnostic workup of this condition.