Differential roles of hypoxia and innate immunity in juvenile and adult dermatomyositis.

Dermatomyositis (DM) can occur in both adults and juveniles with considerable clinical differences. The links between immune-mediated mechanisms and vasculopathy with respect to development of perifascicular pathology are incompletely understood. We investigated skeletal muscle from newly diagnosed, treatment-naïve juvenile (jDM) and adult dermatomyositis (aDM) patients focusing on hypoxia-related pathomechanisms, vessel pathology, and immune mechanisms especially in the perifascicular region. Therefore, we assessed the skeletal muscle biopsies from 21 aDM, and 15 jDM patients by immunohistochemistry and electron microscopy. Transcriptional analyses of genes involved in hypoxia, as well as in innate and adaptive immunity were performed by quantitative Polymerase chain reaction (qPCR) of whole tissue cross sections including perifascicular muscle fibers.Through these analysis, we found that basic features of DM, like perifascicular atrophy and inflammatory infiltrates, were present at similar levels in jDM and aDM patients. However, jDM was characterized by predominantly hypoxia-driven pathology in perifascicular small fibers and by macrophages expressing markers of hypoxia. A more pronounced regional loss of capillaries, but no relevant activation of type-1 Interferon (IFN)-associated pathways was noted. Conversely, in aDM, IFN-related genes were expressed at significantly elevated levels, and Interferon-stimulated gene (ISG)15 was strongly positive in small perifascicular fibers whereas hypoxia-related mechanisms did not play a significant role.In our study we could provide new molecular data suggesting a conspicuous pathophysiological 'dichotomy' between jDM and aDM: In jDM, perifascicular atrophy is tightly linked to hypoxia-related pathology, and poorly to innate immunity. In aDM, perifascicular atrophy is prominently associated with molecules driving innate immunity, while hypoxia-related mechanisms seem to be less relevant.

Arterial-alveolar CO2 equilibration in exercising dogs during prolonged rebreathing.

Arterial-alveolar equilibration of CO2 during exercise was studied by normoxic CO2 rebreathing in six dogs prepared with a chronic tracheostomy and exteriorized carotid loop and trained to run on a treadmill. In 153 simultaneous measurements of PCO2 in arterial blood (PaCO2) and end-tidal gas (PE'CO2) obtained in 46 rebreathing periods at three levels of mild-to-moderate steady-state exercise, the mean PCO2 difference (PaCO2-PE'CO2) was -1.0 +/- 1.0 (SD) Torr and was not related to O2 uptake or to the level of PaCO2 (30-68 Torr). The small negative PaCO2-PE'CO2 is attributed to the lung-to-carotid artery transit time delay which must be taken into account when both PaCO2 and PE'CO2 are continuously rising during rebreathing (average rate 0.22 Torr/s). Assuming that blood-gas equilibrium for CO2 was complete, a lung-to-carotid artery circulation time of 4.6 s accounts for the observed uncorrected PaCO2-PE'CO2 of -1.0 Torr. The results are interpreted to indicate that in rebreathing equilibrium PCO2 in arterial blood and alveolar gas are essentially identical. This conclusion is at variance with previous studies in exercising humans during rebreathing but is in full agreement with our recent findings in resting dogs.

ColoPulse tablets perform comparably in healthy volunteers and Crohn's patients and show no influence of food and time of food intake on bioavailability.

ColoPulse tablets are an innovative development in the field of oral drug delivery and are characterized by a colon-specific release. Until now ColoPulse dosage forms (only capsules) have been studied in healthy volunteers having a standardized breakfast three hours after administration but not in specific patient groups and not with a shorter interval between administration and breakfast. Information on bioavailability and release characteristics of ColoPulse tablets in Crohn's patients and the influence of food and time of food intake is a prerequisite to properly design future clinical studies with active substances in these patients. In the current cross-over study bioavailability and drug release characteristics of ColoPulse tablets were compared in healthy volunteers and in Crohn's patients in remission. Furthermore the influence of food and time of food intake on the in vivo drug release behavior of ColoPulse tablets was investigated. In this study the dual label isotope strategy was used which means that a ColoPulse tablet containing (13)C-urea and an uncoated, immediate release tablet containing (15)N2-urea were taken simultaneously. Breath and urine samples were collected during the test day for isotope analysis. The appearance of the stable isotopes in breath and/or urine provides information on the site of release from the dosage form, release characteristics and bioavailability. Both tablets were administered on two different days in a cross-over design: the first day with a breakfast (non-standardized) one hour after administration and the second day with a standardized breakfast three hours after administration of the tablets. There was no difference in instructions for administration between both days. Results of 16 healthy volunteers and 14 Crohn's patients were evaluated. At least 86% (51 out of 59) of all ColoPulse tablets administered in this study released their contents at the desired intestinal region. There was no significant difference in bioavailability between healthy volunteers and Crohn's patients on both days (day 1 75.8% vs 90.2%, p=0.070 and day 2 83.4% vs 91.4%, p=0.265). There was also no significant influence of food and time of food intake on bioavailability in healthy volunteers (75.8% and 83.4%, p=0.077) and in Crohn's patients (90.2% and 91.4%, p=0.618) when day 1 and day 2 were compared. Release characteristics did not significantly differ between healthy volunteers and Crohn's patients. However, food and time of food intake had some, clinically non-relevant, influence on the release characteristics within both groups which is in line with the fact that food affects gastro-intestinal transit times. This study shows that ColoPulse tablets enable the site-specific delivery of drugs or other compounds (e.g. diagnostics) deep in the ileo-colonic region of the intestine of Crohn's patients in a comparable amount and rate as in healthy volunteers. Food and time of food intake had no relevant influence on bioavailability. In conclusion ColoPulse delivery systems are promising and deserve further research for local therapy with immunosuppressive drugs in Crohn's patients in the near future.

Clinical trial of a leucotriene B4 receptor antagonist, BIIL 284, in patients with rheumatoid arthritis.

BACKGROUND: Several clinical and experimental lines of evidence suggest that leucotriene B4 (LTB4), an arachidonic acid derivative with potent proinflammatory properties, plays a key role in the pathophysiology of rheumatoid arthritis (RA). OBJECTIVE: To evaluate the efficacy and safety of BIIL 284, an oral long-acting LTB4 receptor antagonist, as monotherapy for the treatment of patients with active RA. METHODS: This was a multi-centre, randomised, double-blind, placebo-controlled trial of patients with active RA of 3 months' duration. A total of 342 patients were randomised to receive 5 mg, 25 mg or 75 mg of BIIL 284 or placebo. The primary end point was the percentage of patients achieving an American College of Rheumatology (ACR) 20. RESULTS: Although a higher percentage of ACR 20 responders was observed in the groups treated with 25 mg and 75 mg of BIIL 284 compared with those treated with placebo, no statistically significant differences were found between any of the three active treatment groups compared with the placebo group with regard to the primary or secondary end points. All trial treatments were safe and well tolerated. CONCLUSIONS: This clinical trial demonstrates that treatment of patients with active RA with a potent oral long-acting LTB4 receptor antagonist produced only modest improvements in disease activity. The results of this trial support the conclusion that LTB4 is not a major contributor to the inflammatory process in RA.

Short-term carnitine supplementation does not augment LCPomega3 status of vegans and lacto-ovo-vegetarians.

OBJECTIVE: Long-chain polyunsaturated omega-3 fatty acids (LCPomega3) synthesis, notably that of docosahexaenoic acid (DHA), from the precursor alpha-linolenic acid (ALA) proceeds with difficulty. We investigated whether carnitine supplementation augments the LCPomega3 status of apparently healthy vegans and lacto-ovo-vegetarians, who are expected to have low carnitine status. METHODS: Group A (n = 11) took 990 mg/day l-carnitine from weeks 1-4, and 990 mg/day l-carnitine + 4 mL/day linseed oil from weeks 5-8. Group B (n = 9) took 4 mL/day linseed oil from weeks 1-4, and 4 mL/day linseed oil + 990 mg/day l-carnitine from weeks 5-8. Fatty acid compositions of red blood cells, platelets, plasma cholesterol esters and plasma triglycerides were measured in the fasting state at baseline, and after 4 and 8 weeks. RESULTS: Carnitine supplementation increased plasma free and total carnitine concentrations with 30 and 25%, respectively, but did not affect eicosapentaenoic acid (EPA) and DHA contents of any of the investigated compartments. EPA and DHA changes were negatively related to initial carnitine status. CONCLUSIONS: Our results suggest that carnitine is not an important limiting factor, if any, for LCPomega3 synthesis in vegans and lacto-ovo-vegetarians. This conclusion is also likely to apply to omnivores. The most efficient means to augment EPA and particularly DHA status remains consumption of LCPomega3 from e.g. fish or supplements.

[High-frequency jet ventilation through a modified stomach tube in endobronchial 192 Iridium irradiation]. / Hochfrequente Jet-Ventilation über eine modifizierte Magensonde bei endobronchialer 192Iridium-Bestrahlung.

A case of sufficient high-frequency jet ventilation with a tip-cut nasogastric tube in a patient requiring endobronchial 192iridium irradiation is described. In order to allow the endotracheal introduction of a bronchoscope together with an 192iridium applicator during anesthesia with mechanical ventilation, the nasogastric tube was used instead of an endotracheal tube for jet ventilation. Using a frequency of 60/min and a fresh-gas flow of 15 l/min, FIO2 = 1.0, normocapnic, normoxemic ventilation could be achieved during the whole procedure. It is concluded that the method can be considered as an alternative in patients with narrow airways, provided that airway-pressure monitoring and bronchoscopy to confirm the position of the tube are employed.

[Unusual malpositioning of internal jugular vein catheter (author's transl)]. / Ungewöhnliche Fehllage eines V. jugularis interna-Katheters.

An unusual positioning of a central venous catheter via left internal jugular vein into a branch of left vena pericardiacophrenica within the pericardium is reported. The dangers of this malposition are discussed and measures for prevention suggested.

Gas exchange efficacy of high-frequency oscillatory ventilation studied by helium washout from dog lungs.

The gas exchange efficacy of high-frequency oscillatory ventilation (HFOV) was assessed from an analysis of helium washout from lungs in anesthetized paralyzed supine dogs. Piston stroke volumes (Vs) were varied from 20 to 40 ml, frequencies (f), from 10 to 40 Hz and mean airway opening pressures from 2 to 10 cm H2O. The time course of washout could be described as the sum of three exponential components. Based on a series model comprising a proximal and a distal lung compartment, two component conductances, a 'distal' conductance (Gd) and a 'proximal' conductance (Gp) and an overall conductance of the lung (Gl) could be calculated. Gd, Gp and Gl increased with f up to a maximum value remaining constant or decreasing at higher f; the frequency at which the maximum occurred depending on Vs and on the diameter of the endotracheal tube (ET). With increasing Vs generally the G values increased, but decreased at higher f with the smaller ET. The insoluble inert gas washout is shown to be a useful method for assessing the ventilatory gas exchange conductance of lungs during HFOV.

Pulmonary gas exchange during high-frequency ventilation in dogs.

Steady-state gas exchange was studied in anesthetized paralyzed dogs subjected to high-frequency ventilation (HFV) to determine the effects of oscillation frequency (f 10-40 Hz) and stroke volume (Vs 20-40 ml) on gas exchange efficiency. Alveolar gas fractions were measured by rapid withdrawal of lung gas while oscillations and the bias flow circuit were interrupted. Alveolar ventilation (VA) calculated from steady-state CO2 elimination and FACO2 was found to exhibit a frequency-dependent maximum. Similarly, PaCO2 increased and PaO2 decreased again when f exceeded a critical level. VA was 13% of total ventilation (f . Vs) at 10 Hz (40 ml Vs) decreasing to about 4% at 40 Hz. Blood - gas differences for O2 (PA - Pa) were about 6 torr and close to zero for CO2 (Pa - PA). Lung volume assessed from He wash-out was increased with f and Vs. O2 uptake and CO2 elimination were significantly enhanced by HFV as a function of Vs. Because the effective VT was essentially unknown, the apparent gas exchange inefficiency at high f and Vs values may be due to the functional characteristics of the apparatus rather than a general feature of HFV.

[Mean equipotent blood pressure-lowering concentrations of halothane, isoflurane and enflurane during balanced anesthesia differ from conventional MAC-values]. / Aquipotente mittlere blutdrucksenkende Konzentrationen von Halothan, Isofluran und Enfluran während balancierter Anaesthesie differieren von den konventionellen MAC-Werten.

Balanced anesthesia is a technique that allows control of blood pressure in patients with coronary artery disease. In order to evaluate the relative requirements of volatile anesthetics during basic opioid analgesia, 51 patients with unimpaired left ventricular function who were undergoing coronary artery bypass grafting during balanced anesthesia were investigated. They were randomly assigned to three groups, i.e. halothane (H), isoflurane (I), and enflurane (E). Permanent medications were maintained up to 12 h preoperatively. After premedication with flunitrazepam, promethazine and piritramide, anesthesia was induced with 7 micrograms/kg fentanyl, 0.3 mg/kg etomidate, and 0.1 mg/kg pancuronium and continued with fentanyl infusion (0.1 microgram/kg-1 min-1). Volatile anesthetics were applied in oxygen/air and adjusted to keep the mean arterial blood pressure within +/- 20% of the preoperative value. End-expiratory concentrations of volatile anesthetics were measured (Capnomac, DATEX) and averaged over time. The mean ages of the patients in the different groups were 60 +/- 7.6 years (H), 59 +/- 7.1 years (I), and 60 +/- 6.9 years (E). Four patients in the halothane group, six in the isoflurane group, and five in the enflurane group took beta-blockers preoperatively. The cumulative doses of fentanyl were: H = 0.80 +/- 0.17 mg, I = 0.85 +/- 0.16 mg, and E = 0.83 +/- 0.16 mg at the time of skin incision and H = 1.20 +/- 0.26 mg, I = 1.38 +/- 0.19 mg, and E = 1.24 +/- 0.25 mg at the beginning of extracorporeal circulation.2+ which are possibly the reason for the high O2-MAC value, which may be abolished during balanced anesthesia. However, both the negative inotropic and the vasodilatory effects of enflurane are more likely explanations for the results. It is concluded that 0.5 to 1.0 MAC of halothane, isoflurane, or enflurane used as equipotent components of balanced anesthesia for blood pressure control during aorto-coronary bypass grafting may differ considerably from the conventional MAC concept.

[Non-invasive Doppler-ultrasound determination of cardiac output. Results and experiences with the ACCUCOM]. / Nicht-invasive Doppler-Ultraschallmessung des Herzzeitvolumens. Ergebnisse und Erfahrungen mit dem ACCUCOM.

Because of the invasiveness of the method, the determination of cardiac output (CO) by the thermodilution technique is not without a certain risk to the patient. Previous studies have suggested that noninvasive Doppler technology could be used to determine the velocity of blood in the aorta. With knowledge of the diameter of the aorta, CO can be calculated. The newly developed ACCUCOM (Datascope Corp.) measures CO noninvasively by Doppler ultrasound. However, there is not much information as to how the ACCUCOM performs in clinical practice. The present study was designed to compare the determination of CO by the ACCUCOM with that by thermodilution. CO was determined simultaneously in 12 anesthetized patients scheduled for abdominal or orthopedic surgery. There was a significant but not very tight linear correlation (r = 0.82) between ACCUCOM and reference measurements. The ACCUCOM underestimated CO on the average by 32%. In order to analyze the ACCUCOM tracking of relative changes in CO, in 6 out of 12 patients CO was also determined during cardiac stimulation by isoprenaline (0.5-1.0 microgram.min-1) IV. The resulting increase in CO was detected reliably using the ACCUCOM. It was, however, significantly overestimated by the Doppler technique (average increase = 58%) as compared to the reference method (average increase = 42%). These results suggest the possibility of major deviations in determining CO with the ACCUCOM.(ABSTRACT TRUNCATED AT 250 WORDS)

Gas mixing in dog lungs studied by single-breath washout of He and SF6.

Simultaneously measured helium (He) and sulfur hexafluoride (SF6) single-breath washout was studied in 16 anesthetized paralyzed dogs ventilated with a special hydraulically operated ventilatory servo system. After equilibration of lung gas with 1% He and 1% SF6, the maneuver consisting of inspiration of a test gas-free mixture at constant rate (VI), a variable time of breath holding, and an expiration at constant rate (VE), was performed. Fractional concentrations of He and SF6, recorded against expired volume, were analyzed in terms of slope of the alveolar plateau (S) and series (Fowler) dead space (VD). In control conditions (VI = 0.5 l/s, VE = 0.1 l/s) S was about 10% of alveolar-to-inspired concentration difference per liter expirate both for He and SF6. Both SHe and SSF6 were inversely related to VI and VE, the relative changes being more pronounced with varying VE. SHe/SSF6 was higher or lower than unity depending on VI and VE. Both SHe and SSF6 decreased with increasing preinspiratory lung volume. Breath holding up to 10 s slightly decreased SHe and SSF6 while SHe/SSF6 was unchanged. The contribution of continuing gas exchange to S assessed from comparative measurements using the reversed (single breath washin) technique ranged from 6 to 23% in the various conditions. The VDHe/VDSF6 ratio was 0.84 and was little affected in the various settings. Results indicate that the substantial alveolar gas inhomogeneity in the dog lung and the mechanism accounting for S are little diffusion dependent. By exclusion sequential filling and emptying of lung units is believed to constitute the most important mechanism responsible for the sloping alveolar plateau.

Cerebral effects of anaesthesia and hypothermia.

Cerebral blood flow, cerebral oxygen and glucose consumption, and cerebral lactate and pyruvate release were measured; spectral analysis of the EEG was recorded in 10 male patients who had coronary artery bypass surgery. The measurements were taken to evaluate the effects of fentanyl-midazolam anaesthesia during normothermia and during hypothermic nonpulsatile cardiopulmonary bypass at 26 degrees C venous blood temperature, when a temperature-corrected PaCO2-value of 5.3 kPa was maintained. Anaesthesia with fentanyl 7 micrograms/kg and midazolam 200 micrograms/kg as induction doses, followed by infusions of fentanyl 0.15 micrograms/kg/minute and midazolam 3 micrograms/kg/minute, was characterised by a decrease in fast-wave activity and an increase in high-amplitude, slow-wave activity in the EEG. There was also a decrease in cerebral blood flow (38%), oxygen consumption (22%) and glucose consumption (25%), while lactate and pyruvate production remained unchanged. Hypothermia of 26 degrees C venous blood temperature suppressed EEG almost completely and decreased oxygen and glucose consumption by a further 61% and 54%, respectively, with no changes in lactate and pyruvate production while cerebral blood flow increased by 145%. These results show that the effects of fentanyl-midazolam anaesthesia on cerebral metabolism are enhanced during hypothermic cardiopulmonary bypass while the influence of anaesthesia on cerebral blood flow is overshadowed by the practice of a temperature-corrected acid-base management.

Helium and SF6 washout from dog lungs during high-frequency ventilation.

Simultaneous washout of He and SF6 was studied in anesthetized paralyzed dogs (mean body weight 19 kg) subjected to high-frequency ventilation at varying frequencies (10-40 Hz), stroke volumes (20-40 ml), lung volumes (0.8-1.2 L) and fresh gas flow rates (7-13 L/min). The washout curves could be analyzed into three exponential components for both test gases. The rate constants of the intermediate and slow components were slightly but significantly higher for He than for SF6 while the fast component was the same for the two test gases. The data were analyzed on the basis of a series lung model with a dead space compartment and two serially arranged alveolar compartments. The He/SF6 ratio of the effective conductances for gas transfer between the alveolar compartments averaged 1.15 +/- 0.08 (SD). Since this ratio is much closer to unity, predicted for convective transport, than 6 to 7, predicted for diffusive transport, it is concluded that during high-frequency ventilation gas transport in peripheral airways occurs by both convection and diffusion, convection being quantitatively more important.