bluuebunny/crossref_metadata_2025 huggingface dataset:
A practice survey on vasopressor and inotropic drug therapy in Scandinavian intensive care units
Authors: Oldner A. , Rossi P. , Karason S. , Åneman A. ,   for the Scandinavian Critical Care Trials Group
Published: December 2004

Background: This practice survey was performed to analyse the indications for use of vasopressor/inotropic drugs, preferred drugs and doses as well as concomitant monitoring and desired haemodynamic target values in Scandinavian ICUs. An internet‐based reporting system was implemented.

Methods: A total of 223 ICUs were identified in the Scandinavian countries and invited to participate in a one‐day point‐prevalence study. An internet‐based database was constructed and a practice survey protocol designed to identify haemodynamic monitoring, indications for vasopressor/inotropic drug‐therapy, fluids used for volume loading, pretreatment circulatory state, actual and targeted haemodynamic variables. Patients were eligible for the study if on vasopressor/inotropic drug‐therapy for more than 4 h.

Results: A total of 114 ICUs participated. A total of 114 adult patients matched the inclusion criteria. Sixty‐seven per cent of the patients had received vasopressor/inotropic drug‐treatment for >24 h and 32% received more than one drug. Arterial hypotension (92%) and oliguria (50%) were most common indications. Fluid loading prior to therapy was reported in 87% of patients. Dopamine (47%) and noradrenaline (44%) were the most commonly used drugs followed by dobutamine (24%). No other drug exceeded 6%. Non‐catecholamine drugs were rarely used even in cardiac failure patients. Invasive arterial pressure was monitored in 95% of patients, pulmonary artery catheters were used in 19%. Other cardiac output monitoring techniques were used in 8.5% of the patients.

Conclusion: Dopamine and noradrenaline seem to be the most commonly used inotropic/vasopressor drugs in Scandinavia. Traditional indications for inotropic/vasopressor support as hypotension and oliguria seem to be most common. Invasive monitoring was used in almost all patients, whereas a limited use of pulmonary artery catheters was noted. The internet‐based reporting system proved to be an efficient tool for data collection.
Recombinant human erythropoietin in preoperative autologous blood donation did not influence the haemoglobin recovery after surgery
Authors: Åvall A. , Hyllner M. , Bengtson J. P. , Carlsson L. , Bengtsson A.
Published: December 2004

Background: Recombinant human erythropoietin in combination with preoperative autologous blood donation is an established regime for avoiding allogenic blood transfusions. The aim of the study was to determine endogenous erythropoietin production and haemoglobin recovery after preoperative autologous blood donation and surgery, with or without recombinant human erythropoietin treatment.

Methods: Thirty‐eight patients having total hip joint replacement surgery were randomised to receive either autologous blood transfusion (control group) or autologous transfusion plus preoperative recombinant human erythropoietin treatment (EPO group). Haemoglobin, haematocrit, erythropoietin and reticulocyte concentrations were repeatedly analysed, before, during, and after surgery.

Results: No significant differences were found between the groups regarding haemoglobin, haematocrit, and erythropoietin, but the reticulocyte count increased significantly more in the EPO group. There was no difference in the requirement for allogeneic blood transfusions between the groups. The baseline haemoglobin was >13 g dL−1 in all but four patients.

Conclusions: In patients with normal preoperative haemoglobin levels, recombinant human erythropoietin treatment did not improve haemoglobin levels, or reduce the need for allogenic blood transfusion. There were no differences in serum erythropoietin concentrations between the groups. We question whether recombinant human erythropoietin treatment facilitates preoperative autologous blood donation in patients with normal haemoglobin levels.
Aseptic meningitis during combined continuous spinal and epidural analgesia*
Authors: Kasai T. , Yaegashi K. , Hirose M. , Fujita T. , Tanaka Y.
Published: December 2004

Continuous spinal analgesia (CSA) offers considerable advantages: (1) it requires 10% of the local anesthetic; (2) it may be instituted after patient positioning, thus minimizing the potential for cardiovascular instability; and (3) with low doses of dilute short‐acting local anesthetic, the recovery period is shortened (1). Continuous spinal analgesia has been used for various procedures such as surgery and cancer pain control. However, CSA has not gained wide popularity because of its possible complications, such as headache, nerve injury, infection and accidental removal or migration of the catheter. Although real possibilities, these complications have been rarely documented. We describe an episode of aseptic meningitis during combined CSA and EA.
Resistive load of laryngeal mask airway and proseal laryngeal mask airway in mechanically ventilated patients
Authors: Natalini G. , Rosano A. , Lanza G. , Martinelli E. , Pletti C. , Bernardini A.
Published: December 2004

Background:  The ProSeal Laryngeal Mask Airway (PLMA) ventilation tube is narrower and shorter than the standard Laryngeal Mask Airway (LMA) and is without the vertical bars at the end of the tube. In this randomized, crossover study, PLMA and LMA resistances were compared.

Methods:  Respiratory mechanics was calculated in 26 anesthetized, mechanically ventilated patients with both LMA and PLMA. The laryngeal mask positioning was fiberoptically evaluated. Differences in the respiratory mechanics of the LMA and the PLMA were attributed to the differences between the laryngeal masks.

Results:  In the total study population the airway resistance was 1.5  ±  2.6 hPa.l−1.s−1 (P = 0.005) higher with the PLMA than with the LMA. During the PLMA use, the peak expiratory flow reduced by 0.02 ± 0.05 l min−1 (P = 0.046), the expiratory resistance increased by 0.6 ± 1.3 hPa.l−1.s−1 (P = 0.022), and the time constant of respiratory system lengthened by 0.09 ± 0.18 s (P = 0.023). These differences doubled when the LMA was better positioned than the PLMA, whereas they disappeared when the PLMA was positioned better than the LMA.

Conclusions:  The standard LMA offers a lower resistive load than the PLMA. Moreover, the fitting between the laryngeal masks and the larynx, as fiberoptically evaluated, plays a major role in determining the resistive properties of these devices.
Detection of organ ischemia during hemorrhagic shock
Authors: Kvarstein G. , Mirtaheri P. , Tønnessen T. I.
Published: December 2004

Background:  In a porcine hemorrhagic shock model we aimed to determine: (a) whether blood flow to the intestine and kidney was more reduced than cardiac output; (b) whether parameters of anaerobic metabolism correlated with regional blood flow; and (c) whether metabolic parameters in intestine, kidney and skeletal muscles detected a compromized metabolic state at an earlier stage than did systemic parameters.

Methods:  In an animal research laboratory at a university hospital six domestic pigs were subjected to volume‐controlled hemorrhage. Every 30 min samples of blood were withdrawn. Systemic and regional hemodynamic parameters and tissue levels of PCO2 were monitored. Whole body and organ‐specific oxygen consumption (VO2) and veno‐arterial (VA) differences of lactate, glucose, potassium (K+), PCO2, H+ and base excess (BE) were calculated every 30 min.

Results:  With progressive hemorrhage, intestinal blood flow decreased to the same extent as cardiac output, whereas the reduction in renal blood flow was more pronounced. We found a concomitant reduction in VO2 (onset of supply dependent metabolism) in intestine, kidney and skeletal muscles. In muscular tissue PCO2 increased to levels three times higher than baseline, while renal and intestinal PCO2 increased eightfold.

Supply dependency was associated with a concomitant increase in VA CO2 and VA H+. Also, VA lactate increased, mostly in intestine and least in skeletal muscle. Intestinal and renal VA K+ increased, while muscular VA K+ decreased. Arterial lactate and H+ increased considerably, whereas arterial BE decreased.

Conclusion:  With progressive hemorrhage, renal blood flow, but not intestinal and skeletal muscle blood flow, was reduced more than cardiac output. Supply dependent oxygen metabolism (VO2) and organ acidosis occurred simultaneously in the three organs, despite differences in blood flow reductions. Organ ischemia coincided with a pronounced change in arterial lactate and systemic acid base parameters.
Effects of intra‐abdominal CO2‐insufflation on normal and impaired myocardial function: an experimental study
Authors: Greim C. A. , Broscheit J. , Kortländer J. , Roewer N. , Schulte am Esch J.
Published: December 2004

Background:  Intra‐abdominal pressure (IAP) elevation during CO2‐pneumoperitoneum increases cardiac afterload and may enhance dysfunction of the already compromized heart. This study focused on the effects of acute IAP increases on left and right ventricular loadings and contractility in the heart with impaired global function.

Methods:  Impairment of myocardial function (IMF) was pharmacologically induced in 16 pigs by administration of halothane and propranolol, while baseline arterial pressure was maintained by intravenous phenylephrine. Intra‐abdominal pressure was gradually increased by 10 mmHg up to 30 mmHg in the supine position (IMF group 1, n = 8) or in a head‐down tilted position (IMF group 2, n = 8). In two control groups with normal myocardial function, IAP was also increased in the supine position or the head‐down tilted position. Cardiac function in all groups was assessed by epicardial echocardiography, intraventricular pressure measurements and pulmonary artery catheterization.

Results:  The increase in IAP was accompanied by a transient rise in LV end‐systolic wall stress and reduced cardiac output significantly by 16–24% in all groups. In the IMF groups, LV end‐diastolic transmural pressure increased by 34–60% to peak values of 24 mmHg, while cross‐sectional LV end‐diastolic areas remained unchanged. Increases in right ventricular end‐diastolic volume and decreases in right ventricular ejection fraction as well as in cardiac output were most pronounced at IAP 20 mmHg and significantly stronger in both IMF groups than in the control groups (P < 0.001).

Conclusion:  Following the acute elevation of IAP, the right ventricular volume load shifted more extensively in the IMF groups than in the animals with normal myocardial function. Myocardial function in the impaired heart may worsen during IAP elevation due to right ventricular load alterations rather than a LV afterload increase.
Citation classics in anaesthesia and pain journals: a literature review in the era of the internet
Authors: Terajima K. , Åneman A.
Published: December 2004

Background: The number of citations an article receives reflects its scientific impact. The introduction of internet‐based resources to search and access articles has made it possible to review even whole scientific areas. This study identifies the top 50 most‐cited articles over the last 25 years in speciality journals dedicated to anaesthesia and pain, respectively.

Methods: Twenty‐two journals listed in The Science Citation Index Expanded™ in the field of anaesthesiology and nine major medical journals were screened using the cited reference option to identify articles cited more than 100 times between 1986 and 2002. The top 50 articles in speciality journals and the top 10 articles in major medical journals concerning anaesthesia and pain were retrieved for further analysis.

Results:  The most‐cited articles in speciality journals were published from 1986 to 1997 and received a mean of 222 (anaesthesia) and 279 (pain) citations. Sixty‐seven institutions produced the most‐cited articles and of those 28 were located outside North America. The articles were published in six journals led by the Journal of Pain (50 articles) and Journal of Anaesthesiology (39 articles). Forty‐seven articles were classified as related to clinical experience, 33 were review articles, and 20 discussed basic science.

Conclusion:  To make an article a possible ‘citation classic’ in anaesthesiology, it should be published in one of six leading journals and originate from an established institute in North America. Internet resources to publish and cite the literature have to date not advanced any article published in the last 5 years to the top 100 list.
Influences on serum concentrations of morphine, M6G and M3G during routine clinical drug monitoring: A prospective survey in 300 adult cancer patients
Authors: Klepstad P. , Dale O. , Kaasa S. , Zahlsen K. , Aamo T. , Fayers P. , Borchgrevink P. C.
Published: December 2004

Background:  In order to make treatment decisions physicians should have knowledge about the relations between patient characteristics and drug disposition. Dose, route of administration, gender, age and renal function are reported to influence the serum concentrations of morphine, morphine‐6‐glucurnide (M6G) and morphine‐3‐glucuronide (M3G) during chronic treatment of cancer pain. These factors, however, are not evaluated in studies with a sample size sufficient to explore predictive factors.

Methods:  Three hundred consecutive morphine users admitted because of a malignant disease were recruited. The relations of serum concentrations of morphine, M6G and M3G to patient characteristics (gender, age, weight, renal function, liver function, dose, route of administration) were explored, and regression analysis performed to investigate whether these characteristics predicted serum concentrations obtained during routine clinical drug monitoring.

Results:  Morphine dose was associated with serum concentrations of morphine (r = 0.69), M6G (r = 0.76) and M3G (r = 0.76). Oral morphine resulted in higher dose‐adjusted M6G and M3G serum concentrations compared with s.c. morphine. Creatinine serum concentrations correlated with serum concentrations of M6G and M3G. Dose and route of administration predicted morphine serum concentrations, while dose and renal function predicted M6G and M3G serum concentrations. Age was an additional factor predicting M3G concentrations. Dose was the only factor that explained a clinically significant part of the observed variability.

Conclusion:  Patient characteristics predict only minor parts of the variability of morphine, M3G and M6G serum concentrations observed during routine clinical drug‐monitoring in cancer patients.
Effects of different steroid treatment on reperfusion‐associated production of reactive oxygen species and arrhythmias during coronary surgery
Authors: Volk T. , Schmutzler M. , Engelhardt L. , Pantke U. , Laule M. , Stangl K. , Grune T. , Wernecke K. ‐D. , Konertz W. , Kox W. J.
Published: December 2004

Background:  During conventional cardiac surgery ischemia and reperfusion may cause excessive production of reactive oxygen species leading to tissue damage including early arrhythmias. We therefore assessed the kinetics of markers of radical stress including oxidized and reduced glutathione (GSSG/GSH), oxidized proteins (PCG) and malondialdehyde (MDA), and tested the hypothesis that different steroid treatments inhibit these markers and early reperfusion‐associated supraventricular and ventricular extrasystolic beats.

Methods:   In a randomized, controlled, blinded, prospective trial 36 patients received a preoperative infusion of methylprednisolone (MP, 15 mg kg−1, n = 12), tirilazad mesylate (TM, 10 mg kg−1, n = 12) or placebo (PL, NaCl, n = 12). Coronary sinus and arterial blood was drawn at baseline and 2, 5, 15, 30, 60 and 240 min after aortic declamping. Holter‐ECG analysis was used to identify arrhythmias.

Results:  Cardiac GSSG release occurred very early ( < 15 min) and was not significantly attenuated by either drug treatment. Cardiac PCG production showed biphasic increases, lasted > 4 h and was significantly reduced only by TM. Cardiac MDA release was short ( < 30 min) and significantly reduced by MP and TM. Neither treatment had a significant influence on the early occurrence of ventricular or supraventricular arrhythmias. The number of patients needing cardioversions or defibrillations also were not different.

Conclusions:  The results indicate that cardiac production of reactive oxygen species occurs after reperfusion in humans and is not inhibited by steroid treatment. Steroid treatment effectively reduces lipid peroxidation during cardiac surgery but has no influence on arrhythmias.
Intraoperative changes in arterial oxygenation during volume‐controlled mechanical ventilation in modestly obese patients undergoing laparotomies with general anesthesia
Authors: Yoshino J. , Akata T. , Takahashi S.
Published: December 2004

Background:   In obese patients, arterial oxygenation can be greatly impaired during general anesthesia. Both avoidance of denitrogenation and application of positive end‐expiratory pressure (PEEP) during mechanical ventilation may be effective in preventing such impairment of arterial oxygenation.

Methods:  We studied 28 obese/overweight and seven non‐obese (BMI < 25 kg · m−2) patients who underwent laparotomies with general anesthesia (i.e. isoflurane with or without nitrous oxide). During anesthesia, their lungs were mechanically ventilated at a rate of 10 breaths · min−1 with a constant flow, inspiratory‐to‐expiratory ratio 1 : 2, and tidal volume ∼10 ml · kg−1. The obese/overweight patients were allocated to four different groups in terms of denitrogenation and application of PEEP (7 cm H2O) during the ventilation (n = 7 each). In the non‐obese patients, their denitogenated lungs were ventilated without application of PEEP. Arterial gas analyses were performed before induction of anesthesia, and 30, 90, 150 and 210 min after tracheal intubation. The ratio of PaO2 to FiO2 was calculated as an index of arterial oxygenation.

Results:  No significant changes in the PaO2/FiO2 ratio were observed throughout the study in the non‐obese patients and in the obese/overweight patients whose non‐denitrogenated lungs were ventilated with PEEP. In the obese/overweight patients whose lungs were ventilated after denitrogenation or without application of PEEP, significant decreases in the PaO2/FiO2 ratio were observed 30 and 90 min after tracheal intubation.

Conclusions:  In obese or overweight patients under general anesthesia, it may be advisable to avoid denitrogenation and apply PEEP during mechanical ventilation in order to minimize the impairment of arterial oxygenation.
Cardiac complications after elective major vascular surgery
Authors: Kertai M. D. , Klein J. , Van Urk H. , Bax J. J. , Poldermans D.
Published: December 2004

Cardiac complications are the major cause of perioperative and late mortality and morbidity in patients undergoing elective major vascular surgery. This review focuses on the pathophysiology of perioperative complications, risk assessment and risk reduction strategies, all related to cardiovascular disease. Patients without cardiac risk factors are considered to be at low risk and no additional evaluation for coronary artery disease is recommended; β‐adrenergic blockers may reduce perioperative cardiac events; patients with one or more risk factors represent an intermediate to high‐risk population. β‐Adrenergic blockers should be prescribed to all patients and coronary revascularization should be reserved for patients who have a clearly defined need for revascularization independent of the need for vascular surgery.
Is there a risk of sensitization and allergy to chlorhexidine in health care workers?
Authors: Garvey L. H. , Roed‐Petersen J. , Husum B.
Published: December 2004

Background:  In Denmark, chlorhexidine is the standard disinfectant in most hospitals and health care workers are repeatedly exposed to it. The aim of this study was to establish whether there is a risk of sensitization and allergy to chlorhexidine from this type of exposure.

Methods:  Two hundred and forty‐eight doctors, nurses and auxiliary staff were invited to participate in the study. One hundred and four individuals took part in the full study including skin tests and a questionnaire and a further 74 individuals filled in the questionnaire giving a total of 178 questionnaires (72%). Patch tests with chlorhexidine gluconate 1% and chlorhexidine acetate 1% were performed looking for type IV (delayed type) allergy. A prick test with chlorhexidine gluconate 0.5% and an intradermal test with chlorhexidine 0.0002% were performed looking for type I (immediate type) allergy.

Results:  There were no positive tests in any of the 104 individuals tested (99% confidence interval 0–4.9%). There was a predominance of females in both groups and the overall median age was 42 years (28–63). No one in the group not tested reported to have a verified or suspected allergy to chlorhexidine.

Conclusion:  In this first study to examine the risk of type I and type IV allergy to chlorhexidine in health care workers with daily exposure to chlorhexidine, we did not identify allergies to chlorhexidine in any of the 104 individuals tested or in the additional 74 individuals who completed the questionnaire. We conclude that an allergy to chlorhexidine in health care workers is likely to be rare.
The work, duties and prestige of Finnish anesthesiologists: patients’ view
Authors: Tohmo H. , Pälve H. , Illman H.
Published: December 2004

Background:  Patients' awareness of the medical qualifications and duties of anesthesiologists outside the operating theatres may be limited. How are anesthesiologists ranked with regard to prestige and academic qualifications among other hospital employees?

Methods:  One hundred and sixty operative patients were interviewed in one tertiary care center and another secondary care center in Finland.

Results:  Nearly all (90%) of the patients knew that anesthesiologists are medical doctors and that they work in operation theatres (87%). Many patients thought that anesthesiologists do not work in pain clinics (41%), obstetric departments (36%) and in the departments of radiology (68%), in ambulances (58%) and in research work (46%). Anesthesiologists were ranked second after surgeons with regard to prestige among health service professionals.

Conclusions:  Patients knew the medical qualification of anesthesiologists very well. The work of anesthesiologists was highly appreciated, but the duties outside the operation theatres were poorly known.
Low plasma glutamine after multiple trauma: relationship with intracellular glutamine in polymorphonuclear neutrophils during prolonged ICU stay
Authors: Engel J. M. , Mühling J. , Weiss S. , Löhr T. , Simonis Y. , Menges T. , Hempelmann G.
Published: December 2004

Background: Aim of the study was to evaluate whether low plasma glutamine (GLN) is related to low intracellular GLN in stress‐affected cells such as polymorphonuclear neutrophil (PMN). We hypothesized, that because low plasma GLN is assumed to have an impact on clinical outcome, stress‐affected cells may also show low GLN contents.

Methods: Thirty‐nine consecutive severely injured trauma patients staying at least 10 days at a surgical intensive care unit (ICU) of a university hospital were separated into two groups: group one (n = 16) with low plasma GLN (< 420 µmol/l in average during ICU stay), and group two (n = 23) with normal plasma GLN. Initial blood samples for GLN analyses were collected within 24 h of admission at ICU. Further blood samples were taken on days 5 and 10 at 08:00 hours.

Results: Patients in both groups showed no differences regarding demographic data, surgical interventions or infections. Acute physiology and chronic health evaluation (APACHE) II and the sequential organ failure assessment (SOFA) score and mortality rate were also comparable. During the study period, intracellular PMN GLN contents and concentrations did not differ between both groups. On the first day, intracellular PMN GLN content in the low plasma GLN group peaked at 5.01 ± 3.06 × 10−16 mol and in normal plasma GLN group at 4.73 ± 2.57 × 10−16 mol above the level of healthy individuals. In both groups, content decreased significantly towards the end of the observation period (group one: 2.79 ± 1.59 × 10−16 mol and group two: 2.63 ± 1.71 × 10−16 mol). A correspondent course could be observed for cell volumes. In contrast, variation of intracellular GLN concentrations remained within the reference range throughout the observation period: group one 836 ± 510 µmol/l on day 1 and 582 ± 331 µmol/l on day 10, and group two 788 ± 428 µmol/l on day 1 and 548 ± 356 µmol/l on day 10. No correlation between plasma GLN and intracellular GLN was found in either group.

Conclusion: No association between low plasma GLN and low intracellular GLN in PMN was found in a cohort of severely injured trauma patients with a minimum stay of 10 days at ICU.
Effective pain relief from intra‐articular saline with or without morphine 2 mg in patients with moderate‐to‐severe pain after knee arthroscopy: a randomized, double‐blind controlled clinical study
Authors: Rosseland L. A. , Stubhaug A. , Grevbo F. , Reikerås O. , Breivik H.
Published: December 2004

Background: Intra‐articular (IA) morphine has given good and prolonged pain relief in some studies when given at the end of arthroscopic procedures in the knee joint. However, similar studies have not been able to document any local analgesic effect of morphine. A large number of the negative studies have not demonstrated any assay sensitivity. We have documented that around 40% of patients have only very mild or no pain after arthroscopic procedures in the knee joint. This obviously is a confounding factor, reducing assay sensitivity when all patients are included in IA morphine studies.

Method: By leaving a soft catheter IA in 57 patients and including only patients who developed moderate‐to‐severe pain within 1 h after an arthroscopic procedure in the knee joint under general anaesthesia, we included 40 patients. These patients had a mean pre‐treatment baseline pain of about 50/100 on a 100‐mm visual analogue scale (VAS) for pain intensity. A randomized, double‐blind controlled comparison of saline 10 ml with or without morphine 2 mg followed. Test drugs were administered through the IA catheter. Pain intensity and pain relief, consumption of rescue analgesics and global evaluation of effect and adverse effects were measured up to 36 h thereafter.

Results: Pain intensity decreased from about 50 to about 10–15/100 in both groups and the sum of pain intensity differences at 2 and 22 h was not significantly different between the two groups. Global evaluation of effects and adverse effects, as well as consumption of rescue analgesics during 36 h after arthroscopic procedures, were also similar in the two groups.

Conclusions: Only 70% of 57 patients had pain of moderate‐to‐severe intensity within 1 h after an arthroscopic procedure of the knee joint under general anaesthesia. IA injection of saline 10 ml and saline 10 ml with morphine 2 mg were both associated with pain relief. These findings may have implications for interpretations of a majority of published studies on IA morphine.
Chronic intraperitoneal endotoxin treatment in rats induces resistance to d‐tubocurarine, but does not produce up‐regulation of acetylcholine receptors
Authors: Hinohara H. , Morita T. , Okano N. , Kunimoto F. , Goto F.
Published: December 2004

Background: Chronic systemic inflammation resulting from intraperitoneal Eschevichia coli endotoxin administration or Corynebacterium injections induces tolerance to non‐depolarizing neuromuscular blockers in rodents. Although this has been explained as up‐regulation of muscle acetylcholine receptors (AChR), the numbers of involved receptors have not been documented. The aim of this study was to determine the effects of chronic endotoxin administration on rat muscle AChR.

Methods: One day after one, seven, or 14 daily intraperitoneal doses of lipopolysaccharide endotoxin (0 or 0.5 mg kg−1), we studied in vivo dose–response relationships for d‐tubocurarine (d‐Tc) and AChR binding using [125I]α‐bungarotoxin as a ligand.

Results: One day after seven and 14 daily intraperitoneal doses of endotoxin, the effective dose of d‐Tc required to suppress the twitch response to 50% of the control (ED50) was significantly increased compared with that of time‐matched control rats (146.5 ± 38.2 vs. 76.1 ± 9.0 µg kg−1 for seven doses; 116.4 ± 51.3 vs. 74.4 ± 9.6 µg kg−1 for 14 doses, P < 0.05). However, this was not associated with an increase in the number of AChR in the anterior tibial muscle or diaphragm.

Conclusions: Mechanisms other than AChR up‐regulation might be responsible for the increased d‐Tc requirement during chronic intraperitoneal endotoxin administration.
Epidemiology and natural course of social fears and social phobia
Authors: Wittchen H.‐U. , Fehm L.
Published: December 2004

Objective: To summarize epidemiological studies providing data on prevalence, incidence, comorbidity, natural course, risk factors and consequences of social phobia (SP).

Method: Data from cross‐sectional studies and prospective longitudinal studies in particular are considered.

Results: These studies portray SP as a frequent mental disorder, which begins typically in early adolescence, and is highly comorbid with other anxiety disorders, as well as secondary depression and substance abuse disorders. Several possible risk factors have already been identified for the onset and unfavorable course of SP; some of them have been tested in prospective longitudinal studies. SP is a chronic disorder when compared with other mental disorders and when subclinical symptomatic levels are considered. Impairment caused by SP is considerable and increases over a patient's life span. The negative impact of SP is not only reflected in subjective well‐being and reduced quality of life but also in social role functioning, and it impacts negatively on career progression.

Conclusion: Prospective longitudinal studies in representative samples drawn from the general population provide information that allows the overall direct and indirect costs of the disorder (treatment costs, disability, social welfare) to be determined, and enables an improvement in long‐term care strategies as well as preventive efforts to be established.
The impairments caused by social phobia in the general population: implications for intervention
Authors: Kessler R. C.
Published: December 2004

Objective: Although social phobia is common, treatment remains low. In order to gauge public health implications of this low treatment, information is needed on the impairments caused by social phobia.

Method: A computer literature review searched for the terms ‘social anxiety disorder’ and ‘social phobia’ in the MEDLINE and PsycLIT databases. New analyses were carried out in the US National Comorbidity Survey.

Results: The literature shows that social phobia has serious effects on role functioning and quality of life. These effects are least severe for pure non‐generalized social phobia and most severe for comorbid generalized social phobia with avoidant personality disorder. The most direct impairments involve social interactions and information processing errors in these interactions. Indirect effects are even more important. Three indirect effects are highlighted: effects on secondary mental (e.g. depression), substance (e.g. alcoholism) and physical (e.g. cardiovascular disease) disorders; effects on normative role transitions (e.g. educational attainment); and effects on help‐seeking.

Conclusion: Given the early age of onset and impacts on secondary disorders and early adult life course transitions, the greatest public health impact of increasing treatment of social phobia is likely to be achieved by developing programs targeted at early identification and treatment through schools.
Neuroanatomical circuits modulating fear and anxiety behaviors
Authors: Charney D. S.
Published: December 2004

Objective:  Our understanding of the neurobiology of anxiety disorders, although not complete, has advanced significantly with the development and application of genetic, neuroimaging and neurochemical approaches.

Method:  The neuroanatomical basis of anxiety disorders is reviewed with particular focus on the amygdala and the temporal and prefrontal cortex. The functional anatomical correlates of anxiety disorders such as panic disorder, specific phobias and post‐traumatic stress disorder are also discussed.

Results:  Functional neuroimaging studies in patients with anxiety disorders have shown neurophysiological abnormalities during symptom provocation tests, implicating the limbic, paralimbic and sensory association regions. The involvement of neurotransmitters such as serotonin and norepinephrine in depressive disorders is well established. Antidepressants that affect these neurotransmitter systems have also been shown to be useful in the treatment and management of patients with anxiety disorders. The role of serotonin and norepinephrine in the pathophysiology of anxiety disorders is reviewed. In addition, the involvement of the stress hormone corticotropin‐releasing hormone, the peptide cholecystokinin and the amino acid transmitter γ‐amino butyric acid in anxiety disorders is reviewed.

Conclusion:  The inconsistency in the results of biologic investigations of anxiety disorders highlights the importance of addressing the neurobiologic heterogeneity inherent within criteria‐based, psychiatric diagnoses. Understanding of this heterogeneity will be facilitated by the continued development and application of genetic, neuroimaging and neurochemical approaches that can refine anxiety disorder phenotypes and elucidate the genotypes associated with these disorders. Application of these experimental approaches will also facilitate research aimed at clarifying the mechanisms of anti‐anxiety therapies.
The neurobiology of social anxiety disorder: the relevance of fear and anxiety
Authors: Marcin M. S. , Nemeroff C. B.
Published: December 2004

Objective: Social anxiety disorder (SAD) is a ubiquitous anxiety disorder. Despite being the third most common psychiatric disorder, little is known about the interaction between genetic predisposition and environmental factors in the development of SAD. The available literature on SAD has been compared with data on the genetics and environmental impact on the phenotypic expression of fear and anxiety, and its implicated neurobiology, in order to explore the neurobiology of SAD as understood through the neurochemical dysregulation expressed in fear and anxiety.

Method:A systematic review of the literature was employed for the years from 1966 to 2001.

Results:SAD does indeed have much overlap with fear and anxiety. This is best demonstrated by the interactions of the noradrenergic and serotonergic systems with each other and the hypothalamic–pituitary–adrenal axis.

Conclusion:SAD may well be understood as one potential outcome for predisposed individuals who are exposed to the proverbial ‘second hit’, or environmental insult, in childhood. Behavioral inhibition may be an early expression of this predisposition, with natural progression to SAD occurring via a disruption of neurochemical homeostasis. Through animal and human data it has become evident that fear and anxiety have shared, as well as distinct, neurochemical and neuroanatomical pathways. These similarities are expressed as symptoms and objective signs that are common to many individuals with social anxiety disorder.
Family and high‐risk studies of social anxiety disorder
Authors: Merikangas K. R. , Lieb R. , Wittchen H.‐U. , Avenevoli S.
Published: December 2004

Objective:  To present data on the role of familial factors in the etiology of social anxiety disorder.

Method:  Findings presented from a family/high‐risk study (the Yale Family Study) and a prospective community study of youth (the Munich Early Developmental Stages of Psychopathology (EDSP) Study).

Results:  The Yale Family Study demonstrated a substantial degree of familial aggregation of social anxiety disorder and specificity with respect to other anxiety subtypes among adult relatives. The Yale high‐risk component and the EDSP Study confirm the association between parental and offspring social anxiety, but did not yield consistent evidence for an association between familial environmental factors and social anxiety.

Conclusion:  Future studies are needed to examine mechanisms for the specificity of social anxiety disorder aggregation, to identify vulnerability factors for its development and to pinpoint environmental conditions that may enhance or suppress expression of underlying vulnerability.
The lifelong course of social anxiety disorder: a clinical perspective
Authors: Keller M. B.
Published: December 2004

Social anxiety disorder (SAD) is among the most frequently observed psychiatric disorders, with estimates of approximately 10% of people likely to suffer from the disorder during their lifetime. However, despite causing significant impairment of normal functioning, this disorder is often mistaken as shyness and remains under‐recognized and under‐treated. Following onset in adolescence, patients with generalized SAD often experience a lifelong and unremitting mental disorder characterized by severe anxiety and disability. Typical duration of the illness is far in excess of that seen in panic disorder, and prospective, long‐term, naturalistic studies have indicated that only one‐third of individuals attain remission from SAD within 8 years, compared with over two‐thirds of those with panic disorder. Comorbidity of other anxiety disorders, depression and personality disorders are common in SAD and associated with more pronounced impairment and a poorer long‐term outcome. Effective treatment for SAD is available but use is low and may remain suboptimal, despite the development of pharmacotherapeutic agents with anxiolytic and antidepressant properties and the efficacy of psychotherapeutic approaches. Increased knowledge of the course of SAD highlights the need to examine the role of available treatments, administered individually or in combination, as acute, continuation or maintenance therapy to maximize the chances of remission and long‐term benefit for patients.
Pharmacotherapy of social phobia
Authors: Davidson J. R. T.
Published: December 2004

Objective:  To review placebo‐controlled medication trials in social phobia (SP).

Method:  Published and/or presented placebo‐controlled trials of medication were reviewed and summarized.

Results:  Phenelzine is effective in 60–70% of patients with SP and always superior to placebo. Although reversible inhibitors of monoamine oxidase type A (RIMAs) are safer, their benefits are unpredictable. SSRIs, fluvoxamine, paroxetine and sertraline are superior to placebo in generalized SP. Gabergic drugs are useful, e.g. clonazepam, gabapentin and pregabalin. Promising effects have been found with venlafaxine, a serotonin–norepinephrine reuptake inhibitor, and the results of larger studies should be forthcoming in the next 2 years. Drugs such as buspirone, tricyclics and beta‐blockers are either ineffective or have limited use. SP is a chronic disorder, and early termination of successful pharmacotherapy is associated with a greater likelihood of relapse. Studies with paroxetine, clonazepam, sertraline and brofaromine show that continued treatment is associated with better maintenance of response. Special populations that require further study include children, those with comorbid Axis I disorders and the population with discrete (non‐generalized) SP.

Conclusion:  MAOI and SSRI are most uniformly effective in treating SP. Clonazepam and gabapentin may also be useful. Other drugs are of more limited value. Long‐term treatment is recommended to reduce rates of relapse.
Non‐pharmacologic treatments for social anxiety disorder
Authors: Zaider T. I. , Heimberg R. G.
Published: December 2004

Objective:  The purpose of this paper is to present a review of research on the efficacy of psychotherapeutic interventions for children, adolescents and adults with social anxiety disorder. Data are presented on the relative efficacy of cognitive‐behavioral therapies (CBTs), pharmacotherapy and combination treatments. We also discuss research on specific clinical conditions that are likely to influence treatment success.

Method:  Relevant studies were identified through literature searches, reference lists and research databases.

Results:  Non‐pharmacologic treatments for social anxiety disorder, particularly CBTs, have gained substantial empirical support over the last two decades. However, questions remain about how to maximize the benefit of available treatments.

Conclusion:  New directions for future research in this area are discussed.
Necrotic Feature of the Trophoblasts Lacking HLA‐G Expression in Normal and Pre‐eclamptic Placentas
Authors: Sageshima Noriko , Ishitani Akiko , Omura Motoko , Akasaki Masayoshi , Umekage Hideshi , Katabuchi Hidetaka , Okamura Hitoshi , Hatake Katsuhiko
Published: December 2004

PROBLEM:  Human leukocyte antigen (HLA)‐G is thought to be expressed in all placental extravillous trophoblasts (EXTs). In pre‐eclamptic placentas, a lack of HLA‐G expression on EXTs had been found, and deduced as a possible cause of pre‐eclampsia. However, a subset of EXTs lacking expression of HLA‐G can also be found in normal placenta. Therefore, we sought to compare these cells in normal and pre‐eclamptic placentas.

METHODS OF STUDY:  Frozen sections of normal and pre‐eclamptic placentas were examined by immunohistochemical staining using HLA‐G monoclonal antibody 87G, histochemical enzymatic analysis of succinate dehydrogenase (SDH) and ultrastructural analysis.

RESULTS:  A subset of EXTs lacking HLA‐G expression was found in both normal and pre‐eclamptic placentas. These cells showed necrotic features such as the swelling of cells, eosin‐achromatophilia, the loss of SDH activity and swelling mitochondria. Cells from both tissues were identical with regard to these features.

CONCLUSION:  The features of the EXTs lacking HLA‐G expression indicated they had undergone necrosis and thus could not express HLA‐G protein. Therefore, an alternative interpretation to the lack of HLA‐G expression in pre‐eclamptic placentas is that it is the result of cell death and not the cause.
Estrogen and Progesterone Modulate Monocyte Cell Cycle Progression and Apoptosis
Authors: Thongngarm T. , Jenkins J. K. , Ndebele K. , McMurray R. W.
Published: December 2004

PROBLEM:  Pregnancy is characterized by dramatic immunologic changes most commonly characterized as suppression of cell‐mediated immunity. Mechanisms of this immunosuppression are obscure but may be caused by increases in pregnancy‐associated sex steroids such as 17‐β‐estradiol or progesterone.

METHOD OF STUDY:  Using five myelomonocytic cell lines in various stages of differentiation, the effects of 17‐β‐estradiol and progesterone on cell cycling, apoptosis, and bcl‐2 expression in randomly cycling cells before and after lipopolysaccharide (LPS) activation were examined.

RESULTS:  Lipopolysaccharide alone inhibited cell cycle progression in THP‐1 monocyte‐like cells and U‐937 histiocyte‐like cells. Estrogen alone produced cell cycle arrest in all myelomonocytic cells except HL‐60 pro‐myelocyte‐like cells. Progesterone had effects predominantly on pro‐myelocytic‐like HL‐60 cells, inducing apoptosis. Estrogen and progesterone both decreased levels of bcl‐2 in KG‐1α, HL‐60, and THP‐1 cells. LPS partially antagonized both estrogen‐induced THP‐1 apoptosis and its suppression of bcl‐2 protein.

CONCLUSIONS:  Sex steroid‐induced effects on cell cycle transition and apoptosis are potential mechanisms by which pregnancy‐induced cell‐mediated immune suppression may occur. Further investigation should provide a better understanding of pregnancy‐induced immune changes and, perhaps, sex‐based differences in monocyte function and immunologic responses.
Natural Killer (NK) Cell Receptors' Repertoire in Couples with Recurrent Spontaneous Abortions
Authors: Varla‐Leftherioti Marighoula , Spyropoulou‐Vlachou Maria , Niokou Demetra , Keramitsoglou Theodora , Darlamitsou Areti , Tsekoura Christina , Papadimitropoulos Miltiadis , Lepage Virginia , Balafoutas Christos , Stavropoulos‐Giokas Catherine
Published: December 2004

PROBLEM:  Natural killer (NK) cell receptors (NKRs) have been suggested to protect trophoblast, but their function at the fetomaternal interface remains unknown. To investigate if the outcome of pregnancy depends on women's NKRs, we studied the NKR repertoire in couples with recurrent spontaneous abortions (RSA).

METHODS:  Twenty‐six childless couples with ≥2 abortions, characterized by alloimmune abnormalities, and 26 control couples were genotyped for five killer immunoglobulin‐like receptors (KIR) and two CD94/NKG receptors, known to have as ligands human leukocyte antigen (HLA) class I molecules with trophoblastic expression: inhibitory 2DL1,2,3 and activating 2DS1,4 KIRs, inhibitory NKG2A and activating NKG2C. Detected repertoires of women and partners were compared between the two groups.

RESULTS:  Less aborters than controls were found to have all three inhibitory KIRs (30.77% versus 69.23%, P = 0.01), some of them had only one inhibitory KIR (19.23% versus 3.85%, P = 0.08) and most of them were lacking inhibitory KIRs possessed by their husbands (57.69% versus 15.38%, P = 0.001).

CONCLUSIONS:  Women with alloimmune abortions have a limited inhibiting KIR repertoire and such miscarriages may occur because trophoblastic HLA class I molecules are recognized by decidual NK cells lacking the appropriate inhibitory KIRs.
Intracellular Expression of CD69 in Endometrial and Peripheral T cells Represents a Useful Marker in Women with Recurrent Miscarriage: Modulation After Allogeneic Leukocyte Immunotherapy
Authors: Ramhorst R. , García V. , Agriello E. , Corigliano A. , Etchepareborda E. , Irigoyen M. , Pasanante Gómez , Fainboim L.
Published: December 2004

PROBLEM:  To characterize in fertile women and women with recurrent spontaneous abortions (RSA) the expression and functional status of T cells expressing the CD69 molecule.

METHOD OF STUDY:  We analyzed by flow cytometry in peripheral blood and endometrium from fertile and RSA women, the surface and cytoplasmic expression of CD69 on gated T cells. In addition, we investigated by three‐color flow cytometry the expression of cytokines, and subsets of memory T cells.

RESULTS:  In T cells, CD69 was restricted to the intracellular compartment with a higher frequency in RSA than in fertile women (68.2 ± 12% versus 23.7 ± 22%, P < 0.001, and 20 ± 9.5% versus 2.1 ± 3.8%, P < 0.005, in endometrium and peripheral blood, respectively). In contrast, the number of interferon‐γ+ (IFN‐γ+) secreting cells was higher (16 ± 5% versus 6 ± 1%) in fertile women. All 11 RSA women alloimmunized with parental leukocytes reached values of CD3+ CD69+ cells similar to those observed in fertile women.

CONCLUSIONS:  CD69 might represent a useful marker in the diagnosis and the follow up of RSA patients.
The Cellular Immune Response of Children is Specifically Decreased Against their Parents but not Vice versa, Independent of Pregnancy, age, or HLA or HY Antigens
Authors: Brune Thomas , Riepe Felix G. , Garritsen Henk , Exeler Rita , Louwen Frank , Harms Erik
Published: December 2004

PROBLEM:  The fetal immune response against the mother and the father is specifically altered. Up to now it is unclear whether the immune response between adult children and their parents is also specifically altered.

METHODS:  Seven female and seven male adults and five male and five female newborns and all their parents were enrolled in the study. Cyotoxicity, apoptosis and proliferation properties of the parents' lymphocytes were measured against those of their children and vice versa using two‐way mixed lymphocyte cultures (MLCs).

RESULTS:  The immune response of adult children against both their parents is reproducibly decreased compared with that of both parents against their children in cytotoxicity, apoptosis and proliferation, independent of sex or age.

CONCLUSION:  The cellular immune response of children is decreased against both their parents but not vice versa independent of pregnancy, age, or HLA or HY antigens. This might be acquired during pregnancy or genetically determined.