Assessing the state of consciousness for individual patients using complex, statistical stimuli.

Patients with prolonged disorders of consciousness (PDOC) are often unable to communicate their state of consciousness. Determining the latter is essential for the patient's care and prospects of recovery. Auditory stimulation in combination with neural recordings is a promising technique towards an objective assessment of conscious awareness. Here, we investigated the potential of complex, acoustic stimuli to elicit EEG responses suitable for classifying multiple subject groups, from unconscious to responding. We presented naturalistic auditory textures with unexpectedly changing statistics to human listeners. Awake, active listeners were asked to indicate the change by button press, while all other groups (awake passive, asleep, minimally conscious state (MCS), and unresponsive wakefulness syndrome (UWS)) listened passively. We quantified the evoked potential at stimulus onset and change in stimulus statistics, as well as the complexity of neural response during the change of stimulus statistics. On the group level, onset and change potentials classified patients and healthy controls successfully but failed to differentiate between the UWS and MCS groups. Conversely, the Lempel-Ziv complexity of the scalp-level potential allowed reliable differentiation between UWS and MCS even for individual subjects, when compared with the clinical assessment aligned to the EEG measurements. The accuracy appears to improve further when taking the latest available clinical diagnosis into account. In summary, EEG signal complexity during onset and changes in complex acoustic stimuli provides an objective criterion for distinguishing states of consciousness in clinical patients. These results suggest EEG-recordings as a cost-effective tool to choose appropriate treatments for non-responsive PDOC patients.

Mice lacking the AMPA GluR1 receptor exhibit striatal hyperdopaminergia and 'schizophrenia-related' behaviors.

There is growing evidence implicating dysfunctional glutamatergic neurotransmission and abnormal interactions between the glutamate and dopamine (DA) systems in the pathophysiology of various neuropsychiatric disorders including schizophrenia. The present study evaluated knockout (KO) mice lacking the L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) GluR1 receptor subunit for a range of behaviors considered relevant to certain symptoms of schizophrenia. KO showed locomotor hyperactivity during exposure to open field and in response to a novel object, but normal activity in a familiar home cage. Open field locomotor hyperactivity in KO was effectively normalized to WT levels by treatment with the DA antagonist and neuroleptic haloperidol, while locomotor stimulant effects of the NMDA receptor antagonist MK-801 were absent in KO. Social behaviors during a dyadic conspecific encounter were disorganized in KO. KO showed deficits in prepulse inhibition of the acoustic startle response. In vivo chronoamperometric measurement of extracellular DA clearance in striatum demonstrated retarded clearance in KO. These data demonstrate behavioral abnormalities potentially pertinent to schizophrenia in GluR1 KO, together with evidence of dysregulated DA function. Present findings provide novel insight into the potential role of GluR1, AMPA receptors and glutamate x DA interactions in the pathophysiology of schizophrenia and other neuropsychiatric conditions.

Er:YAG laser ablation of cerebellar and cerebral tissue.

With the availability of suitable fibres, the Er:YAG laser has become an indispensable tool for invasive neurosurgical applications as a source of precise ablation. The aim of this study was to investigate the ablative effects of the Er:YAG laser on brain tissue. The response of neuronal tissue to 2.94 microns Er:YAG laser irradiation was investigated on excised rat brain specimens. Ablation craters were created in cerebral and cerebellar tissues using 0.3, 0.5 and 1.0 J single pulses of 150 microseconds duration. The corresponding average irradiances were 37.7 J/cm2, 62.9 J/cm2 and 125.8 J/cm2, respectively. Craters were checked qualitatively, crater dimensions were measured and compared, and volume of ablated tissue was estimated. Laser-induced crater dimensions were found to be significantly different at different energy levels applied. Moreover, dimensions of craters on cerebral and cerebellar tissues were significantly different in terms of dimensions. We observed that with the Er:YAG laser ablation craters were created with practically no thermal damage to adjacent tissues. The differences observed in the response of cerebral and cerebellar cortical tissues were dependent on the anatomical and chemical differences.

Effect of inhaled low molecular weight heparin on methacholine-induced bronchoconstriction.

OBJECTIVES: Recent studies have shown that inhaled standard heparin exhibits protection towards various bronchoconstrictor stimuli in asthma including methacholine. Low molecular weight heparins (LMWH) (4000-5000 daltons) have higher bioavailability than standard heparins (12,000-16,000 daltons). It is possible that the anti-asthmatic activity of heparin may be molecular weight-dependent. The purpose of the present investigation was to study the effect of LMWH on methacholine-induced bronchoconstriction and to compare the effect of LMWH with that of standard heparin. SUBJECTS: Fifteen subjects (7 male, 8 female, mean age: 33 +/- 13 years, range: 20-65) with mild asthma were studied. METHOD: Methacholine bronchial provocation tests were performed in a single-blind, crossover, randomized order and repeated 45 minutes after placebo or aerosolized standard heparin (1.000 U/kg) or aerosolized LMWH (Enoksaparin, Clexane, 0.8 mg/kg). RESULTS: There was no significant difference in baseline FEV1 values between study days. The standard heparin and enoksaparin inhibited bronchoconstriction induced by methacholine. The geometric mean log PD20 values after placebo, standard heparin, and enoksaparin were 0.24 +/- 0.57 (1.74) mg/ml, 0.79 +/- 0.59 (6.17 mg/ml), 0.76 +/- 0.57 (5.75 mg/ml), respectively (p < 0.0009). Three subjects in standard heparin group and two subjects in enoksaparin group showed increased hyperreactivity, the others showed decreased bronchial hyperreactivity. The degree of protection offered by standard heparin and enoksaparin did not show any statistical difference. CONCLUSIONS: These data suggest that both inhaled LMWH and inhaled standard heparin play inhibitory roles in methacholine-induced bronchoconstriction.

Acute purulent exacerbation of chronic obstructive pulmonary disease and Chlamydia pneumoniae infection.

In order to investigate the role of bacteria, including Mycoplasma pneumoniae and especially Chlamydia pneumoniae in acute purulent exacerbations of chronic obstructive pulmonary disease (COPD), we examined sputum specimens and acute and convalescent sera taken 26 d apart from 49 outpatients experiencing an acute purulent exacerbation of COPD. The sera were tested for antibodies to C. pneumoniae with the microimmunofluorescence test, and for antibodies to M. pneumoniae with the indirect fluorescence antibody test. Routine microbiologic culture of sputum yielded potentially pathogenic microorganisms in 12 of the 49 patients (24%). Three patients (6%) showed serologic evidence of recent M. pneumoniae infection. Seven patients showed high IgG titers of >/= 1:1,024 to C. pneumoniae, and an additional four had a fourfold increase in IgG titer, suggesting reinfection with C. pneumoniae. Sputum from two of these 11 patients also grew Streptococcus pneumoniae, and one grew Moraxella catarrhalis. Patients with and without serologic evidence of current C. pneumoniae infection showed no significant differences in clinical features or pulmonary function. The high incidence of infection with C. pneumoniae (the sole causal agent in 16% of cases, and the causal agent with other agents in 6%) provides insight into the importance of this organism among agents leading to exacerbations of COPD in Turkey.

Effect of inhaled cyclosporin on the rat airway: histologic and bronchoalveolar lavage assessment.

Airway inflammation plays a pivotal role in asthma. Over the last 10 years, evidence has accumulated for the potential role of lymphocytes in airway inflammation. Since cyclosporin A (Cyc-A) can profoundly influence lymphocyte activation, it is appropriate to consider this drug as a novel antiasthmatic. The effect of inhalation of low doses of Cyc-A on airway inflammation remains unclear. The purpose of this study was to investigate the bronchoalveolar lavage (BAL), peripheral blood cell profiles, and lung biopsy specimens in Cyc-A-pretreated rats. Twenty-nine rats (8 controls, 10 ovalbumin sensitized, and 11 Cyc-A inhaling and ovalbumin sensitized) were included in the study. A commercial intravenous Cyc-A solution was given as a single dose of 20 mg/kg 1 h prior to inhalation of ovalbumin via nebulizer. The total number of BAL cells significantly increased in rats inhaling Cyc-A when compared with ovalbumin-sensitized rats (2.37 +/- 2.34 x 10(6)/ml and 1.01 +/- 0.49 x 10(6)/ml respectively, p < 0.05). There was a significant increase in the percentage of lymphocytes (14.5 +/- 8.5 versus 27.4 +/- 7.4%, p < 0.03), a nonsignificant increase in the percentage of eosinophils (0.8 +/- 1.0 versus 3.0 +/- 4.6%), and a significant decrease in the percentage of polymorphonuclear leukocytes (9.4 +/- 6.9 versus 3.4 +/- 3.8%, p < 0.01) and macrophages (75.4 +/- 5.1 versus 50.2 +/- 11.8%, p < 0.02) in BAL in the ovalbumin-sensitized group as compared with controls. Differential cell counts revealed a higher percentage of neutrophils and macrophages in the BAL of Cyc-A-pretreated rats than in that of the ovalbumin-sensitized group (26.3 +/- 26.8 versus 3.4 +/- 3.8%, p < 0.01 and 66.1 +/- 7.7 versus 50.2 +/- 11.8%, p < 0.02). There was a nonsignificant decrease of lymphocytes and eosinophils in the Cyc-A-pretreated group when compared with the ovalbumin-sensitized group (27.4 +/- 7.4 versus 21.1 +/- 12.4 and 3.0 +/- 4.6% versus 2.4 +/- 2.6%). The peripheral blood total white blood cell count decreased in the ovalbumin-sensitized and Cyc-A-pretreated groups as compared with the control group (2,520 +/- 1,098/mm3, 3,591 +/- 2,251/mm3, and 5,975 +/- 2,787/mm3, respectively, p < 0.01). In addition, peripheral eosinophilia was detected in the Cyc-A-pretreated group when compared with controls and the ovalbumin-sensitized group (6.9 +/- 4.7, 2.4 +/- 1.1, and 2.6 +/- 2.4%, respectively, p < 0.01). Light-microscopic examination of the airways revealed prominent eosinophilia in tracheal, bronchial, and bronchiolar sections in the ovalbumin-sensitized group: counts were 1.8 +/- 2.3/HPF, 10.3 +/- 11.4/HPF, 63.3 +/- 45.0/HPF, respectively. Cyc-A resulted in a decrease of the eosinophil counts/HPF to 0/HPF in trachea (p < 0.05), to 4.3 +/- 9.4/HPF in bronchi (p < 0.02), to 19.4 +/- 38.4 in bronchioles (p < 0.004). In conclusion, the present study supports the theory that locally administered inhaled low-dose Cyc-A is effective on inflammatory cells of sensitized airways and peripheral cells. It may therefore be useful in elucidating the inflammatory mechanisms involved in asthma.

Comparison of noninvasive positive pressure ventilation with standard medical therapy in hypercapnic acute respiratory failure.

STUDY OBJECTIVE: To compare the efficacy of standard medical therapy (ST) and noninvasive mechanical ventilation additional to standard medical therapy in hypercapnic acute respiratory failure (HARF). DESIGN: Single center, prospective, randomized, controlled study. SETTING: Pulmonary medicine directed critical care unit in a university hospital. PATIENTS: Between March 1993 and November 1996, 30 HARF patients were randomized to receive ST or noninvasive positive pressure ventilation (NPPV) in addition to ST. INTERVENTIONS: NPPV was given with an air-cushioned face via a mechanical ventilator (Puritan Bennett 7200) with initial setting of 5 cm H2O continuous positive airway pressure and 15 cm H2O pressure support. RESULTS: At the time of randomization, patients in the ST group had (mean+/-SD) PaO2 of 54+/-13 mm Hg, PaCO2 of 67+/-11 mm Hg, pH of 7.28+/-0.02, and respiratory rate of 35.0+/-5.8 breaths/min. Patients in the NPPV group had PaO2 of 55+/-14, PaCO2 of 69+/-15, pH of 7.27+/-0.07, and respiratory rate of 34.0+/-8.1 breaths/min. With ST, there was significant improvement of only respiratory rate (p < 0.05). However, with NPPV, PaO2 (p < 0.001), PaCO2 (p < 0.001), pH (p < 0.001), and respiratory rate (p < 0.001) improved significantly compared with baseline. Six hours after randomization, pH (p < 0.01) and respiratory rate (p < 0.01) in NPPV patients were significantly better than with ST. Hospital stay for NPPV vs ST patients was, respectively, 11.7+/-3.5 and 14.6+/-4.7 days (p < 0.05). One patient in the NPPV group required invasive mechanical ventilation. The conditions of six patients in the ST group deteriorated and they were switched to NPPV; this was successful in four patients, two failures were invasively ventilated. CONCLUSION: This study suggests that early application of NPPV in HARF patients facilitates improvement, decreases need for invasive mechanical ventilation, and decreases the duration of hospitalization.

Effect of inhaled heparin on adenosine-induced bronchial hyperreactivity.

Glycosaminoglycan heparin possesses multiple noncoagulant properties including antiinflammatory actions. We have previously shown that heparin attenuates the methacholine-induced bronchoconstriction in humans. In contrast to methacholine, a stimulus that induces airway constriction mainly by "direct" stimulation of airway smooth muscle cells, adenosine airway responsiveness reflects "indirectly" induced airway narrowing via inflammatory mediators or neural reflex mechanisms. Whether heparin modulates bronchial hyperreactivity induced by adenosine, is not well known. We investigated the effect of inhaled heparin on adenosine-induced bronchoconstriction and compared the inhibitory role of heparin on the adenosine challenge test with that on the methacholine challenge test. Fifteen subjects (7 males, 8 females) with mild asthma were included in the study. Bronchial provocation tests were performed in a single-blind, crossover, randomized order, and repeated 45 minutes after placebo or aerosolized heparin inhalation (1,000 U/kg). The heparin increased the geometric mean log methacholine PD20 value from 0.47 +/- 0.16 (2.95 mg/ml) to 0.96 +/- 0.10 (8.91 mg/ml), (P < 0.0009) in 15 patients and the geometric mean log adenosine PD20 values from 1.59 +/- 0.23 (38.9 mg/ml) to 1.98 +/- 0.14 (97.7 mg/ml) (NS) in 7 patients whose baseline adenosine PD20 levels were less than 200 mg/ml. The degree of protection by heparin against adenosine-induced bronchoconstriction was not correlated with that against methacholine-induced bronchoconstriction (r = 0.60, NS). The data suggest that inhaled heparin may have an inhibitory effect on the methacholine bronchial challenge, and thus, most likely directs its effect against smooth muscle. Heparin caused less attenuation of a challenge with adenosine and probably does not affect mast cell degranulation.

IL-8 in pleural effusion.

Interleukin-8 (IL-8) is a recently described potent chemotactic factor that may be involved in the pathogenesis of pleural effusions. To understand the actual mechanisms mediating the inflammatory response, changes in cellular components and IL-8 level in pleural fluid of different aetiologies were evaluated. Thirty-four patients (19 male, 15 female) with a mean age of 46 +/- 22 years (range 16-92) were included in the study. Of these, 13 had tuberculous pleural effusion, seven had empyema/parapneumonic pleural effusion, and 14 had malignant pleural effusion (seven adenocarcinoma, three ovarian carcinoma, two lymphoma, one chronic myeloid leukaemia, and one small cell carcinoma) with positive cytology. Differential cell counts in the pleural fluid were obtained using cytocentrifuge preparations. The concentrations of IL-8 in pleural fluid were measured by the ELISA method. Interleukin-8 was detected in all 34 pleural fluid samples. The serum IL-8 level was analysed only in the empyema/parapneumonic pleural effusion group. The mean IL-8 levels of tuberculous, empyema/parapneumonic, and malignant pleural effusions were 1420 +/- 1049 pg ml-1, 4737 +/- 2297 pg ml-1, and 1574 +/- 1079 pg ml-1, respectively. The IL-8 levels in the empyema/parapneumonic group were significantly raised over malignant and tuberculous groups (P < 0.02). The mean pleural fluid neutrophil counts in tuberculous, empyema/parapneumonic and malignant pleural effusions were 315 +/- 575 cells mm-3, 11,136 +/- 12,452 cells mm-3, and 635 +/- 847 cells mm-3, respectively (P < 0.003). There was a significant positive correlation between pleural IL-8 levels and neutrophil counts (r = 0.46, P < 0.006). The levels of IL-8 in paired samples of serum and pleural fluid in the empyema/parapneumonic effusion group were compared, and the concentration of IL-8 was higher in the pleural effusion than serum (means, 4737 +/- 2297 pg ml-1 and 130.0 +/- 62.5 pg ml-1, respectively, P < 0.03). There was a significant negative correlation between IL-8 concentrations in serum and pleural fluid (r = -0.80, P < 0.03). This data suggests that production of IL-8 in pleural effusion may play a key role in initiation and maintenance of inflammatory reactions, especially in empyema/parapneumonic pleural effusions. It may offer the basis for introduction of novel anti-inflammatory agents in treatment.

Analysis of pleural effusions using flow cytometry.

Flow cytometry allows a rapid and accurate analysis of the cells in serous fluids. The aim of this study was to evaluate the use of flow cytometric analysis in malignant pleural effusions. 26 patients (13 females, 13 males; mean age 52 +/- 19 years; range 16-82) were included in the study. 15 had malignant pleural effusions (7 adenocarcinoma, 2 lymphoma, 2 chronic myeloid leukemia, 1 ovarian carcinoma, 1 small cell lung carcinoma, 1 squamous cell lung carcinoma and empyema, and 1 malignant mesothelioma) with positive cytology. 2 had benign effusions associated with malignancy (1 squamous cell lung carcinoma and congestive heart failure, and 1 neuroblastoma and hypoproteinemia). 9 had benign effusions (3 tuberculosis, 1 congestive heart failure, 3 parapneumonic pleural effusion, 1 benign mesothelioma, and 1 pulmonary embolism). Flow cytometric analysis of pleural effusions revealed an increased DNA index in malignant effusions: 1.32 +/- 0.44 versus 0.88 +/- 0.23 in benign effusions (p < 0.04). The cell cycle distribution of cells such as G1/G0 and S in malignant effusions did not differ from that of benign pleural effusions; however G2+M increased significantly in malignant effusions (p < 0.03). Using analysis of mononuclear immunophenotyping, CD3+, CD4+, and CD8+ cells did not show any significant difference between the two groups. The lymphocyte activation marker CD38 was positive in 57.6 +/- 11.5% of malignant fluid cells and 38.5 +/- 6.2% of benign fluid cells (p < 0.04). The mean carcinoembryonic antigen levels in malignant and benign pleural effusions were 98.7 +/- 157.3 and 0.9 +/- 1.2 ng/ml, respectively (p < 0.03). In conclusion, the results of our study indicate that finding cells with an abnormal DNA content strongly supports the diagnosis of malignant pleural effusions. Additionally, mononuclear cell phenotypes have to be taken into consideration for malignant pleural effusions, particularly activated T cells. We recommend that flow cytometry should be performed if the cytology is equivocal.

Ofloxacin-induced vasculitis.

We describe a patient with hypersensitivity vasculitis due to ofloxacin therapy; the vasculitis was associated with elevated transaminase and IgA levels. Cyclophosphamide and intravenous pulse prednisolone resulted in clinical improvement.

Effect of inhaled heparin on methacholine-induced bronchial hyperreactivity.

Although heparin is used as an anticoagulant, its biologic function has remained unclear since the 1920s. Glycosaminoglycan heparin possesses multiple noncoagulant properties, including anti-inflammatory actions, and it is possible that heparin may inhibit airway hyperreactivity. Thus, the purpose of the present investigation was to study the effect of inhaled heparin on methacholine-induced bronchoconstriction. Thirteen subjects (7 women, 6 men) with mild asthma were included in the study. Bronchial provocation tests were performed in a single-blind, crossover, randomized order and repeated 45 min after placebo or aerosolized heparin inhalation (1,000 U/kg). The heparin inhibited bronchoconstriction induced by methacholine. In the methacholine challenge test, heparin treatment resulted in an increase in the mean PD20 over placebo: 5.26 +/- 4.80 mg/mL vs 10.57 +/- 5.72 mg/mL (p < 0.0002). These data suggest that inhaled heparin may have an inhibitory role on methacholine bronchial challenge, possibly via a direct effect on smooth muscle.

Role of the adhesion molecule ICAM-1 in asthma.

Cells need to interact with one another for the inflammatory response to occur. The intercellular adhesion molecule-1 (ICAM-1), a member of the immunoglobulin supergene family, plays an important role in inflammation, and circulating ICAM-1 has been reported to be elevated in patients with some inflammatory disorders. To study the influence of asthma on circulating ICAM-1 levels, we measured concentrations of circulating ICAM-1 in patients with asthma. Fifteen patients (6 male, 9 female, mean age: 30 +/- 7 years) and 5 controls (2 male, 3 female, mean age: 25 +/- 6 years) were included in the study. Daily peak flow rates and symptom scores were monitored over a week in all patients and methacholine challenge tests were performed in 7 patients. The spirometric analysis of asthmatic patients demonstrated mean FEV1: 2.57 +/- 0.97 L (74.9 +/- 17.7% predicted), mean FEV1/FVC: 70.1 +/- 9.6%, mean bronchodilator response: 19.2 +/- 8.4%. The mean morning peak flow rate was 331.0 +/- 122.2 L/min, the mean evening peak flow rate 389.0 +/- 118.5 L/min, the mean peripheral eosinophil count 268 +/- 451/mm3, and the mean serum IgE level 327.4 +/- 238.2 IU/ml. The mean serum ICAM-1 levels of asthmatic patients and controls were 429 +/- 133 ng/ml and 405.0 +/- 81.0 ng/ml, respectively. There was no statistical difference between these levels. Furthermore, we could find no correlation between serum ICAM-1 levels and FEV1, serum IgE levels, peak flow rates, and symptom scores, or methacholine PD20 values in asthmatic patients. The results of this study suggest that serum ICAM-1 levels are not increased in asthmatic patients over controls and do not correlate with clinical asthma status.

Comparison of the bronchodilator efficacy of nebulized pirenzepine and ipratropium bromide in patients with airway obstructive lung disease.

Ipratropium bromide (IB) is a non-selective muscarinic antagonist, whose bronchodilator efficacy has been shown in reversible and irreversible obstructive airway diseases. Pirenzepine is a M1 receptor antagonist and effective in vagally-induced bronchoconstriction. To investigate the bronchodilator efficacy of nebulized pirenzepine, we compared nebulized pirenzepine with nebulized IB and nebulized isotonic saline (placebo). Eighteen patients with reversible and 18 patients with irreversible obstructive airway disease were studied. Nebulized isotonic saline (placebo), 100 mcg nebulized pirenzepine and 125 mcg nebulized IB were given on three consecutive days. Spirometry was performed prior to nebulization and repeated at 5, 30, 60, 90 and 120 minutes following nebulized medication. A dose of 125 mcg IB resulted in a significant increase in FEV1 in patients with both reversible or irreversible bronchoconstriction (p < 0.00001, p < 0.03). IB at the same dose resulted in an increase in FVC in patients with irreversible bronchoconstriction (p < 0.001) and an increase in FEF25-75 in patients with reversible bronchoconstriction (p < 0.0003). Pirenzepine therapy resulted in no significant change in the same parameters. It is concluded that nebulized pirenzepine at a dose of 100 mcg does not have bronchodilator effect in patients with reversible or irreversible bronchoconstriction.

Septic pulmonary emboli secondary to internal jugular vein phlebitis (postanginal sepsis) caused by Eikenella corrodens.

Postanginal sepsis is the term used to describe the life-threatening infection caused by suppurative phlebitis of the internal jugular vein secondary to infection of the parapharyngeal spaces. This begins with a history of pharyngitis followed by infection of the parapharyngeal spaces, septic pulmonary embolism, and septicemia caused by hematogenous dissemination of the infection. The oral anaerobes are the most common pathogens associated with this syndrome. Recently, we managed 2 patients who had septic pulmonary embolism from postanginal sepsis syndrome caused by Eikenella corrodens. Previously, E. corrodens has not been described in association with this syndrome. The clinical presentation, anatomic, bacteriologic, and management aspects of postanginal sepsis syndrome are reviewed based on our experience with these 2 cases. In patients with clinical evidence of septic pulmonary embolism, particularly in the nonintravenous drug abusers, postanginal sepsis and septic jugular phlebitis have to be considered as a source of septic pulmonary embolism.