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.

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.

[Does method of anesthesia modify postoperative ischemia incidence? A study of patients after aortocoronary bypass operations]. / Beeinflusst das Anästhesieverfahren die postoperative Ischämieinzidenz? Eine Untersuchung an Patienten nach aortokoronaren Bypassoperationen.

In the postoperative period after coronary artery bypass graft surgery, the physician's enhanced attention should be focused on the incidence of myocardial ischaemia. The increased stress in the awakening patient as well as the return of autonomous reflexes can be the cause of imbalances in myocardial oxygen supply and uptake. Therefore, a probable influence of the pharmacologic profile of the intraoperatively applied anaesthetics on the incidence of postoperative myocardial ischaemia is of importance for adapting therapy on ICU to minimize any ischaemic risk. After approval by the ethics committee, a prospective randomized study was performed in 40 male patients who underwent coronary artery bypass graft surgery. The aim of the study was to compare balanced anaesthetic techniques performed with fentanyl and halothane, isoflurane and enflurane, respectively, with total intravenous anaesthesia performed with fentanyl and midazolam. An index to classify detection of ischaemia into three categories (ischaemia, probable ischaemia, no ischaemia) was established, based on measurements of myocardial lactate extraction and ST-segment analysis. Simultaneously, measurements of haemodynamic parameters and serum concentrations of catecholamines and intraoperatively applied anaesthetics were taken. In 8% of all measurements (30% of all patients) ischaemia was detected in the observation period and in 37% of all measurements (72.5% of all patients) probable ischaemia was detected. No significant difference was found concerning the incidence of myocardial ischaemia between all groups. The results of this investigation indicate that the application of inhalational anaesthetics for maintaining anaesthesia in coronary artery bypass graft surgery does not increase the risk of postoperative myocardial ischaemia.

Effects of respiratory alkalosis and acidosis on myocardial blood flow and metabolism in patients with coronary artery disease.

BACKGROUND: Variation of the arterial carbon dioxide partial pressure (PaCO2) is not uncommon in anesthetic practice. However, little is known about the myocardial consequences of respiratory alkalosis and acidosis, particularly in patients with coronary artery disease. The aim of the current study was to investigate the effects of variation in PaCO2 on myocardial blood flow (MBF), metabolism, and systemic hemodynamics in patients before elective coronary artery bypass graft surgery. METHODS: In 10 male anesthetized patients, measurements of MBF, myocardial contractility, metabolism, and systemic hemodynamics were made in a randomized sequence at PaCO2 levels of 30, 40, and 50 mmHg, respectively. The MBF was measured using the Kety-Schmidt technique with argon as a tracer. End-diastolic left ventricular pressure and the maximal increase of left ventricular pressure were assessed using a manometer-tipped catheter. RESULTS: The cardiac index significantly changed with varying PaCO2 levels (hypocapnia, - 9%; hypercapnia, 13%). This reaction was associated with inverse changes in systemic vascular resistance index levels. The MBF significantly increased by 15% during hypercapnia, whereas no change was found during hypocapnia. Myocardial oxygen and glucose uptake and the maximal increase of left ventricular pressure were not affected by varying PaCO2 levels. CONCLUSIONS: In anesthetized patients with coronary artery disease, short-term variations in PaCO2 have significant effects on MBF but do not influence global myocardial oxygen and glucose uptake. Changes in systemic hemodynamics associated with respiratory alkalosis and acidosis are caused by changes in systemic vascular resistance rather than by alterations in myocardial contractility.

The influence of isoflurane on peri-operative endocrine and metabolic stress responses.

Trauma and surgery profoundly affect the circulating concentrations of metabolites and so-called stress hormones, and may thereby directly or indirectly influence recovery. This stress response on the other hand is subject to modification by the anaesthetics employed. We investigated the effects of isoflurane on selected stress parameters in 10 patients undergoing major abdominal surgery and compared them to those in 10 patients receiving halothane. Plasma levels of adrenaline, noradrenaline, cortisol, ACTH, and beta-endorphin, as well as glucose, non-esterified fatty acids (NEFA), and lactate were determined during a pre-operative anaesthesia period as well as intra- and post-operatively. The levels of all parameters remained stable or decreased during the pre-operative anaesthesia period. They increased intra- and/or post-operatively, reaching peak values in the recovery period. Although the changes in both groups were basically similar, we observed lower serum concentrations of cortisol and lactate in the isoflurane group. We conclude that isoflurane and halothane have similar effects on peri-operative changes of endocrine and metabolic parameters, and that neither can effectively block the stress response to major surgery. We found no firm evidence for a stimulatory effect of isoflurane on the parameters studied.

[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.

Hepatic and extrahepatic disposition of propofol in patients undergoing coronary bypass surgery.

In order to clarify the relative contribution of the liver to the short term disposition of propofol, hepatic blood flow was measured during induction of anaesthesia with an i.v. bolus dose of propofol 2 mg kg-1. Total clearance of the drug was 2390 (SD 340) ml min-1, hepatic extraction 82% and hepatic clearance 1060 (260) ml min-1. During the 60-min period of observation, hepatic extraction of propofol increased from 79% to 92%. It is concluded that, within 1 h, only 44% of the administered dose is removed by the liver. Consequently, drug accumulation may occur with repeated dosing or infusion of propofol. The increase in extraction results presumably from slow release of propofol from the soy-bean emulsion.

[Continuous measurement of cardiac output based on the Fick principle in cardiac anesthesia]. / Kontinuierliche HZV-Messung nach dem Fickschen Prinzip in der Kardioanaesthesie.

With the development of fiberoptic and pulse oximetry, as well as the development of the more modern methods of oxygen consumption measurements, the online monitoring of Fick cardiac (FCO) output has become possible in the clinical treatment routine. The aim of this study was to compare fiberoptically measured mixed venous oxygen saturation with values from blood samples and continuously determined Fick cardiac output with intermittent thermodilution cardiac output (TCO). Ten patients undergoing coronary artery bypass grafting were measured during the perioperative period. Total body oxygen consumption was determined with a metabolic monitor (Deltatrac Datex) from respiratory gases. Arterial oxygen saturation was assessed by pulse oximetry (Nellcor). Mixed venous oxygen saturation was measured by a balloon tipped pulmonary artery fiberoptic catheter (Opticath) attached to an electronic device based on three wavelengths (Oximetrix cardiac output monitor). Hemoglobin, Methemoglobin and CO-hemoglobin were determined from intermittent blood samples by in vitro analysis. FCO was calculated from corresponding differences in arterial mixed venous oxygen and total body oxygen consumption. TDCO values were calculated from microcomputer recordings of the thermodilution data by monoexponential curve-fitting with respect to baseline drift. A significant systematic difference between FCO and TCO was observed. FCO exceeded TCO on average by 0.42 +/- 0.12 l/min. The limits of confidence (95%) were 0.18 to 0.66 l/min. There was no systematic difference between mixed venous saturation measurements with the fiberoptic system and from blood samples. The cardiac output values derived from fiberoptic and pulse oximetry can be considered sufficiently reliable for clinical purposes.(ABSTRACT TRUNCATED AT 250 WORDS)

[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.

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.

Brachial plexus lesions following cardiac surgery with median sternotomy and cannulation of the internal jugular vein.

There are many possible complications after cannulation of the internal jugular vein (IJV) including injury to the brachial plexus. Neurologic injuries can also occur from sternal splitting. The present study looked at the incidence of brachial plexus lesions after cardiac surgery with and without IJV cannulation. Over 12 months, 815 patients were studied after all types of cardiac surgery. In one half of the group, cannulation of the IJV was avoided when possible. Reducing the incidence of IJV catheterization did not lower the overall incidence of brachial plexus lesions (1.8% to 1.4%). However, there was a higher incidence of neurologic lesions in patients with IJV catheters (3.0% to 0.8%) during the entire study period. All 13 plexus lesions were in the C8-T1 distribution, and seven of the patients had a Horner's syndrome on the same side. No posterior first rib fractures could be detected by radiographs. The brachial plexus lesions were transient but the Horner's syndromes were longer-lasting. It is concluded that the injuries are due to compression and traction of the plexus due to stretching and possibly from hematoma formation from the IJV punctures.

Sufentanil does not block sympathetic responses to surgical stimuli in patients having coronary artery revascularization surgery.

The effects of a moderate dose of sufentanil (1 microgram.kg-1 + 0.015 micrograms.kg-1.min-1) plus nitrous oxide (30% O2/70% N2O) anesthesia (group I; n = 8) and of high-dose sufentanil/O2 anesthesia (10 micrograms.kg-1 + 0.15 micrograms.kg-1.min-1) without N2O (group II; n = 8) on cardiovascular dynamics, myocardial blood flow, myocardial oxygen consumption, myocardial lactate balance, and hypoxanthine release were studied in two groups of male patients scheduled for elective coronary artery bypass surgery. All patients were on maintenance doses of calcium channel blockers and nitrates with the last doses of medications given the morning of operation. All patients were premedicated with flunitrazepam (2 mg orally), piritramide (7.5 mg IM) and promethazine (25 mg IM). Measurements were performed before the induction of anesthesia with the patients premedicated but awake; 20 min after induction of anesthesia with sufentanil plus pancuronium 0.1 mg.kg-1 for muscle relaxation before surgery; and during sternotomy and sternal spread. Sufentanil at either dose decreased mean arterial pressure, as well as cardiac and stroke volume index while heart rate remained unchanged. Following the induction myocardial blood flow and myocardial oxygen consumption decreased 23% (79 ml.min-1.100 g-1 to 61 ml.min-1.100 g-1 and 28% (9.2 ml O2.min-1.100 g-1 to 6.6 ml O2.min-1.100 g-1) in group I and 14% (78 ml.min-1.100 g-1 to 67 ml.min-1.100 g-1 and 18% (8.7 ml O2.min-1.100 g-1 to 7.1 ml O2.min-1.100 g-1) in group II. Myocardial ischemia was seen in one patient of group II (patient No. 4), as indicated by a hypoxanthine release into the coronary sinus, when after the induction MAP decreased from 93 to 67 mm Hg and heart rate increased from 56 to 71 min-1. During sternotomy 8 of 16 patients (50%) developed hypertension and 9 of 16 patients (56%) showed signs of myocardial ischemia, i.e., a lactate and hypoxanthine release.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

[Effect of preoperative continuous nifedipine maintenance medication on hemodynamics and myocardial lactate extraction in coronary surgery patients]. / Einfluss einer präoperativ beibehaltenen Nifedipin-Dauermedikation auf Hämodynamik und myokardiale Laktatextraktion bei koronarchirurgischen Patienten.

The cardioprotective efficacy of preoperatively maintained long-term oral nifedipine application to 21 patients undergoing coronary artery bypass grafting (CABG) was investigated during fentanyl-N2O-anaesthesia. Two groups were defined at random; one group of patients receiving their normal morning doses together with the premedication, the other, who received the last nifedipine medication in the evening before surgery. Measurements where performed: 1. before induction of anaesthesia (reference value), 2. after induction, 3. at skin incision, 4. during sternotomy. There were no significant differences of hemodynamic parameters between the two groups. The hemodynamic parameters heart rate (HR), mean arterial pressure (MAP), cardiac index (CI), and coronary perfusion pressure (CPP) decreased after induction in accordance with the plasma-concentrations of epinephrine and norepinephrine in both groups and increased again during sternotomy with HR and CI remaining below and MAP and CPP rising above the reference value. The nifedipine-plasma-concentrations were significantly higher in the group with the morning dose and just within the minimal therapeutic range before and after induction of anaesthesia. But during skin incision and sternotomy the plasma levels fell below 10 ng/ml, i.e. below the therapeutic level. The incidence of myocardial lactate extraction values greater than 10% was highest immediately after induction of anaesthesia and lowest during sternotomy with one patient in both groups exhibiting negative lactate extraction as a symptom of myocardial ischemia. The results suggest that the preoperatively maintained oral nifedipine medication of 10-20 mg p.o. was not able to provide sufficiently high nifedipine-plasma-levels during sternotomy nor to improve the hemodynamic state in patients with CABG.(ABSTRACT TRUNCATED AT 250 WORDS)