Early immune anergy towards recall antigens and mitogens in patients at onset of septic shock.

The pathology of sepsis is typically characterized by an infection and excessive initial inflammation including a cytokine storm, followed by a state of immune suppression or paralysis. This classical view of a two peak kinetic immune response is currently controversially discussed. This study was a sub-study of the randomized clinical Trial SISPCT registered with www.clinicaltrials.gov (NCT00832039, Registration date: 29/01/2009). Blood samples from 76 patients with severe sepsis and septic shock were incubated for 48 h at 37 °C in vitro with bacterial or fungal recall-antigens or specific mitogen antigens within 24 hours of sepsis onset. Recall-antigen stimulation led to a severe dampening of normal cytokine release. This immunologic anergy was similarly observed after mitogen stimulation. Moreover, patients under hydrocortisone therapy or with lowered arterial oxygen tension had further reductions in cytokine levels upon B- and T-cell mitogen stimulation. This investigation reveals an early onset of immunoparalysis during sepsis. This immune incompetence in mounting an adequate response to further infections includes previously sensitized pathogens, as seen with recall-antigens. Also, the immune-suppressive role of hydrocortisone and low PaO2 is highlighted. Aside from early broad-spectrum antimicrobial therapy, our findings reinforce the need for maximal immunological support and protection against further infections at the onset of sepsis.

The identification and management of substance use disorders in anesthesiologists.

PURPOSE: The purpose of this article is to review current evidence for the identification and management of substance use disorders in anesthesiologists and to describe an approach to return to practice. PRINCIPAL FINDINGS: Anesthesiologists experience substance use disorders at a rate reported to be 2.7 times that of other physicians. Effective evidence-based treatment is available for physicians with substance use disorders, including anesthesiologists. Significant barriers preventing access to such treatment still exist, some of which are specific to the physician cohort. Standard of care should involve ongoing monitoring of substance use disorders in a chronic disease management paradigm. The outcomes for anesthesiologists treated and monitored for a substance use disorder are similar to those for other physicians and significantly superior to those for the general population. Return to work is possible and is most effectively managed in an occupational health risk management model. CONCLUSION: The treatment of substance use disorders in anesthesiologists is effective, and a safe return to practice is possible in a majority of cases. National guidelines are needed to ensure equitable access to high-quality treatment and recovery monitoring for all Canadian physicians.

Functional changes in neutrophils and psychoneuroendocrine responses during 105 days of confinement.

The innate immune system as one key element of immunity and a prerequisite for an adequate host defense is of emerging interest in space research to ensure crew health and thus mission success. In ground-based studies, spaceflight-associated specifics such as confinement caused altered immune functions paralleled by changes in stress hormone levels. In this study, six men were confined for 105 days to a space module of ~500 m(3) mimicking conditions of a long-term space mission. Psychic stress was surveyed by different questionnaires. Blood, saliva, and urine samples were taken before, during, and after confinement to determine quantitative and qualitative immune responses by analyzing enumerative assays and quantifying microbicide and phagocytic functions. Additionally, expression and shedding of L-selectin (CD62L) on granulocytes and different plasma cytokine levels were measured. Cortisol and catecholamine levels were analyzed in saliva and urine. Psychic stress or an activation of the psychoneuroendocrine system could not be testified. White blood cell counts were not significantly altered, but innate immune functions showed increased cytotoxic and reduced microbicide capabilities. Furthermore, a significantly enhanced shedding of CD62L might be a hint at increased migratory capabilities. However, this was observed in the absence of any acute inflammatory state, and no rise in plasma cytokine levels was detected. In summary, confinement for 105 days caused changes in innate immune functions. Whether these changes result from an alert immune state in preparation for further immune challenges or from a normal adaptive process during confinement remains to be clarified in future research.

520-d Isolation and confinement simulating a flight to Mars reveals heightened immune responses and alterations of leukocyte phenotype.

During interplanetary exploration, chronic stress caused by long term isolation and confinement in the spacecraft is one of the major concerns of physical and psychological health of space travelers. And for human on Earth, more and more people live in an isolated condition, which has become a common social problem in modern western society. Collective evidences have indicated prolonged chronic stress could bring big influence to human immune function, which may lead to a variety of health problems. However, to what extent long-term isolation can affect the immune system still remains largely unknow. A simulated 520-d Mars mission provided an extraordinary chance to study the effect of prolonged isolation. Six healthy males participated in this mission and their active neuroendocrine and immune conditions were studied with saliva and blood samples from all participants on chosen time points during the isolation period. As a typical neuroendocrine parameter, stress hormone cortisol was measured in the morning saliva samples. Immune phenotype changes were monitored through peripheral leukocyte phenotype analysis. Using an ex vivo viral infection simulation assay we assessed the immune response changes characterized by the ability to produce representative endogenous pro-inflammatory cytokines. The results of this study revealed elevated cortisol levels, increased lymphocyte amount and heightened immune responses, suggesting that prolonged isolation acting as chronic stressors are able to trigger leukocyte phenotype changes and poorly controlled immune responses.

Five days of head-down-tilt bed rest induces noninflammatory shedding of L-selectin.

Head-down-tilt bed rest (HDTBR) is a popular model, simulating alterations of gravitation during space missions. The aim of this study was to obtain a better insight into the complexly orchestrated regulations of HDTBR-induced immunological responses, hypothesizing that artificial gravity can mitigate these HDTBR-related physiological effects. This crossover-designed 5 days of HDTBR study included three protocols with no, or daily 30 min of centrifugation or 6 × 5 min of centrifugation. Twelve healthy, male participants donated blood pre-HDTBR, post-HDTBR, and twice during HDTBR. Cellular immune changes were assessed either by enumerative and immune cell phenotyping assays or by functional testing of responses to either recall antigens or receptor-dependent activation by chemotactic agents N-formyl-methionyl-leucyl-phenylalanine (fMLP) and with TNF-α. The expression of the adhesion molecule L-selectin (CD62L) on the surface of granulocytes and its shedding into plasma samples were measured. In parallel, other humoral factor, such as interleukin-6 and interleukin-8, parameters of endothelial damage (glycocalyx) were determined. Hematocrit and hemoglobin were significantly increased during HDTBR. Although immune functional tests did not indicate a change in the immune performance, the expression of CD62L on resting granulocytes was significantly shed by 50% during HDTBR. Although the latter is normally associated to an activation of inflammatory innate immune responses and during interaction of granulocytes with the endothelium, CD62L shedding was, however, not related either to a systemic inflammatory alteration or to shedding of the endothelial glycocalyx during bed rest. This suggests a noninflammatory or "mechanical" shedding related to fluid shifts during head-down intervention and not to an acute inflammatory process.

Psychoneuroendocrine alterations during 5 days of head-down tilt bed rest and artificial gravity interventions.

This study aimed to investigate psychological stress and endocrine responses during 5 days of head-down tilt bed rest (HDTBR) with or without the impact of artificial gravity (AG). Participants were assigned to one of three bed-rest-protocols either with (i) no centrifugation, (ii) continuous 30 min (AG1) or (iii) discontinuous 6 × 5 min (AG2) centrifugation periods at 1G in the center of mass periods. Centrifugations were performed daily in one session. Questionnaires for assessing psychological stress and the corresponding biological sample collection were performed before, during and after HDTBR or centrifugation. Overall, questionnaires showed no significant changes of anxiety or emotional stress during HDTBR. In the AG1-group, salivary cortisol levels were significantly higher after centrifugation irrespective of the progress of the HDTBR and day of intervention. The AG2-group showed higher cortisol concentrations after centrifugation only on the first days of head-down tilt but no more on day 5 of HDTBR. During bed rest, urine epinephrine excretion increased in all groups, but showed the highest day concentrations in the AG1-group, which were also significantly higher when compared with AG2. These results indicate that 5 days of HDT alone is not a major stressor and accordingly resulted only in moderate changes of neuroendocrine responses over time. However, daily centrifugation for a continuous duration of 30 min induced a significant neuroendocrine response, which was not subject to a habituation as compared with daily but intermittent centrifugation for 6 × 5 min. Discontinuous centrifugation is better tolerated and associated with lower adrenocortical stress responses during HDTBR.

[Quality of results of therapy of acute respiratory failure : changes over a period of two decades]. / Ergebnisqualität der Therapie des akuten Lungenversagens : Veränderungen über einen Zeitraum von 2 Jahrzehnten.

Progress in intensive care (ICU) treatment of acute respiratory distress syndrome (ARDS) over the last 20 years includes the introduction of extracorporeal membrane oxygenation (ECMO) for CO2 removal and the widespread use of evidence-based lung-protective ventilatory strategies. Little is known, however, about whether these changes have resulted in improvements in short-term and long-term outcome of acute respiratory distress syndrome (ARDS) within the two decades after introduction. In a retrospective study 167 long-term survivors of severe ARDS who were transferred to the clinic for anesthesiology of the University of Munich, Campus Großhadern by means of specialized intensive care unit (ICU) transport teams and treated over a period of 20 years (1985-2005) were evaluated to investigate whether significant improvements in outcome as a consequence of the above mentioned progress in ARDS therapy have occurred. The ARDS patient cohort studied was characterized with regard to demographic variables, initial acute physiology and chronic health evaluation (APACHE) II score, duration of ICU treatment, the duration of mechanical ventilation and mortality. Data on long-term outcome were collected in a subcohort (n = 125) of patients who responded to mailed questionnaires and included health-related quality of life (HRQL, SF-36 questionnaire), symptoms of post-traumatic stress disorder (PTSD), traumatic memories from ICU treatment (PTSS-10 instrument) and current state of employment. During the observation period no significant changes regarding patient age (39 ± 16 years, mean ± SD), disease severity on admission to the ICU (APACHE II scores 22 ± 5), duration of ICU treatment (47 ± 39 days) or duration of mechanical ventilation (39 ± 38 days) were found. Overall ICU mortality during the two decades was 37.3 % (range 25.0 %-38.1 %) between 1995 and 2001 and a non-significant increase in values between 36.8 % and 58.3 % during the time interval from 2002 und 2005. The paO2/FIO2-ratio on ICU admittance improved significantly between 1990 and 2000 (69 ± 5 between 1990 and 1994 versus 101 ± 12 between 1995 and 2000, p < 0.01) and remained nearly unchanged thereafter. Long-term outcome was evaluated on average 5.0 ± 3.1 years after discharge from the ICU. During the time period between 1985 and 1994 survivors of ARDS showed significant impairments in all 8 categories of the SF-36 HRQL instrument when compared to an age and sex-matched normal population with maximal differences regarding physical function (z = -1.01), general health perception (z = -1.17) and mental health (z = -1.3). Patients who were treated from 1995 to 2005 were still impaired in 7 out of 8 categories of HRQL but reported significantly better mental health (49.6 ± 16.5 vs. 68.6 ± 17.8, p < 0,01) and better physical function than individuals from the previous decade (49.6 ± 16.5 vs. 73.4 ± 27.5, p = 0,03). The difference of mental health was no longer significant when compared to a healthy age and sex matched control group (p = 0.14) but the difference in physical function still was (z = -0.48, p < 0.01). The incidence of severe post-traumatic stress defined as a PTSS-10 score ≥ 35 was 20.4 % and remained unchanged throughout the 2 decades of observation. The PTSS-10 scores correlated with the number of traumatic memories present (r = 0.43, p < 0.01, n = 125). More than 50 % of long-term survivors were able to return to full time work with no significant changes during the 2 decades of observation. The introduction of new modalities of ARDS treatment were associated with higher paO2/FIO2-ratios on ICU admittance but had no effect on short-term outcomes including duration of ICU therapy, mechanical ventilation or mortality. The ARDS patients are still at risk for post-traumatic stress and persistent impairments in HRQL. Apart from some improvements in HRQL, the outcome of ARDS therapy remained largely unchanged during two decades.

A corticoid-sensitive cytokine release assay for monitoring stress-mediated immune modulation.

The human immune system is orchestrated in a complex manner and protects the host against invading organisms and controls adequate immune responses to different antigen challenges in an endo-, auto- and paracrine-regulated fashion. The variety and intensity of immune responses are known to be dependent on stress-sensitive neural, humoral and metabolic pathways. The delayed-type hypersensitivity (DTH) skin test was a validated and standardized measure applied in clinical studies to monitor the integral function of cellular immune responses in vivo. The DTH skin test was, however, phased out in 2002. To obtain insight into the mechanisms of stress-sensitive immune reactions, we have developed an alternative in-vitro assay which allows the evaluation of antigen-dependent cellular immune responses triggered by T lymphocytes. The change in the concentration of proinflammatory cytokines in supernatant of the blood-antigen mixture is of particular interest to mirror the degree and adequacy of cellular immune responses. In this study we report that the proinflammatory cytokines interleukin (IL)-2, interferon (IFN)-γ and tumour necrosis factor (TNF)-α show a time-dependent increase upon ex-vivo bacterial, viral and fungal antigen stimulations. Furthermore, evidence is provided that this assay is sensitive to mirror stress hormone-mediated immune modulation in humans as shown either after hydrocortisone injection or after acute stress exposure during free fall in parabolic flight. This in-vitro test appears to be a suitable assay to sensitively mirror stress hormone-dependent inhibition of cellular immune responses in the human. Because of its standardization and relatively simple technical handling, it may also serve as an appropriate research tool in the field of psychoneuroendocrinology in clinical as in field studies.

A new cytokine release assay: a simple approach to monitor the immune status of HIV-infected patients.

PURPOSE: To test a new assay based on an ex vivo cytokine release from whole blood for the monitoring of immune changes in human immunodeficiency virus (HIV)-infected patients. METHODS: A pilot study of outpatients with HIV infection (n = 9) at a large academic hospital who were divided into three groups: HIV-infected patients on highly active antiretroviral therapy (HAART) with a CD4(+) cell count >350/µL (group I) or a CD4(+) cell count <350/µL (group II) and HIV-infected HAART-naïve subjects with a CD4(+) cell count >350/µL (group III). All groups were compared with healthy volunteers (n = 3). The ex vivo cytokine release assay was performed in a three-step process: (1) blood collection, (2) whole-blood ex vivo incubation over 48 h without or with a standard set of well-defined recall antigens as comparable to those used formerly in the skin delayed-type hypersensitivity (DTH) test, (3) cytokine determination from the assay supernatant. RESULTS: Under stimulated conditions, untreated HIV-infected patients with a CD4(+) count >350/µL had similar interleukin-2 (IL-2) levels in the supernatant of the whole-blood incubation to HIV-infected patients on HAART with a low CD4(+) count. Both groups revealed lower IL-2 levels in the supernatant than HIV-infected patients on HAART and with a CD4(+) count >350/µL or healthy volunteers. The determination of interferon-γ and tumour necrosis factor-α in the supernatant showed a similar arrangement of cytokines between groups. CONCLUSIONS: Our results suggest that this cytokine release assay could be a suitable tool to mirror the immunological responsiveness of patients with HIV infection in a gradual manner; further studies are required in order to assess its value in HAART monitoring.

Effects of cryopreservation with polyethylene glycol on the expression of CD11b and CD62L on the surface of polymorphonuclear leukocytes.

In experimental and clinical studies, expression of surface adhesion molecules such as ß2-integrine (CD11b) and L-selectin (CD62L) on polymorphonuclear leukocyte (PMNL) are investigated to assess certain crucial innate immune functions. Because the expression of CD11b and CD62L on PMNL can alter they cannot be quantified reliably when the time between blood draw and measurements is prolonged. Goals of this study were to test effects of cryopreservation on the expression of CD11b and CD62L on human PMNLs either under native conditions as well as after stimulation-dependant adhesion molecules´ expression pattern. CD11b and CD62L expression on PMNL can be cryopreserved with 10% of PEG-solution for at least one month at -60 degree C. This was observed in native, unstimulated as well as in stimulated cell-preparations. CD11b is very stable in contrast to CD62L expression which appears to be more susceptible to alteration due to freezing-thawing. However, the relative stimulus-dependant changes of activation can still be reflected.

Effects of exercise stress on the endocannabinoid system in humans under field conditions.

The effects of physical exercise stress on the endocannabinoid system in humans are almost unexplored. In this prospective study, we investigated in a crossover design and under field conditions at different altitudes the effects of physical exercise on the endocannabinoid system (ECS) in 12 trained healthy volunteers. For determination of alterations on the ECS three different protocols were analyzed: Protocol A (physical exercise at lower altitude) involved strenuous hiking below 2,100 m, whereas Protocol B (physical exercise by active ascent to high altitude) involved hiking up to 3,196 m, an accommodation at the cottage and a descent the next day. Protocol C (passive ascent) included a helicopter ascent to 3,196 m, an overnight stay at this altitude and a flight back to the base camp the following day. The cumulative hiked altitude in Protocol A and B was comparable (~1,650 m). The blood EC concentrations of anandamide increased significantly in Protocol A/B from baseline (T0) 0.12 ± 0.01/0.16 ± 0.02 (mean ± SEM) to 0.27 ± 0.02/0.42 ± 0.02 after exercise (T1) (p < 0.05). Anandamide levels in Protocol C remained stable at 0.20 ± 0.02. We conclude that the ECS is activated upon strenuous exercise whereas the combination with hypoxic stress further increases its activity. The reduced partial pressure of oxygen at high altitude alone did not affect this system. In summary, physical exercise activates the endocannabinoid system, whereas the combination with high altitude enhances this activation. This discloses new perspectives to adaptation mechanisms to physical exercise.

Without 'informed consent'? Ethics and ancient mummy research.

Ethical issues are of foremost importance in modern bio-medical science. Ethical guidelines and socio-cultural public awareness exist for modern samples, whereas for ancient mummy studies both are de facto lacking. This is particularly striking considering the fact that examinations are done without informed consent or that the investigations are invasive due to technological aspects and that it affects personality traits. The aim of this study is to show the pro and contra arguments of ancient mummy research from an ethical point of view with a particular focus on the various stakeholders involved in this research. Relevant stakeholders in addition to the examined individual are, for example, a particular researcher, and the science community in general, likely descendents of the mummy or any future generation. Our broad discussion of the moral dilemma of mummy research should help to extract relevant decision-making criteria for any such study in future. We specifically do not make any recommendations about how to rate these decision-factors, since this is highly dependent on temporal and cultural affiliations of the involved researcher. The sustainability of modern mummy research is dependent on ethical orientation, which can only be given and eventually settled in an interdisciplinary approach such as the one we attempt to present here.

A beta-adrenergic antagonist reduces traumatic memories and PTSD symptoms in female but not in male patients after cardiac surgery.

BACKGROUND: Epinephrine enhances emotional memory whereas beta-adrenoceptor antagonists (beta-blockers, BBs) impair it. However, the effects of BB administration on memory are sex dependent. Therefore, we predicted differential effects of epinephrine and the BB metoprolol given to male and female patients after cardiac surgery (CS) on traumatic memories and post-traumatic stress disorder (PTSD) symptoms. METHOD: We performed a prospective observational study and determined the number of standardized traumatic memories (NTRM) and PTSD symptom intensity in cardiac surgical patients at 1 day before surgery, and at 1 week and 6 months after the procedure. PTSD symptoms and NTRM were quantified using validated questionnaires. Metoprolol could be administered any time post-operatively. RESULTS: Baseline NTRM was not significantly different between male (n=95) and female patients (n=33). One week after CS, the NTRM in male patients was significantly higher. Metoprolol had no significant effect in either sex. At 6 months, females with metoprolol (n=18) showed a significantly lower NTRM and significantly lower PTSD symptom scores than females without BBs (n=15, p=0.02). By contrast, the totally administered dosage of epinephrine correlated with NTRM in males (r=0.33, p<0.01) but not in females (r=0.21, p=0.29). CONCLUSIONS: beta-Adrenergic stimulation with epinephrine enhances memory for adverse experiences in males but not in females whereas beta-blockade selectively reduces memory for post-operative adverse events and PTSD symptoms in females.

Recurrence rates in Ontario physicians monitored for major depression and bipolar disorder.

OBJECTIVE: Physicians with recurrent conditions that may affect job performance are sometimes referred for monitoring to help ensure compliance with treatment, ongoing remission of illness, and patient safety. Little is known about recurrence rates among doctors monitored for mood disorders. Our primary objective was to describe recurrence rates among Ontario physicians monitored for recurrent unipolar depression and bipolar disorder (BD). Our secondary objective was to explore predictors of recurrence. METHOD: We used a retrospective cohort design to describe the time to recurrence, defined as either stopping work owing to symptoms or any re-emergence of symptoms meeting a pre-established clinical threshold. Our exploratory analysis of recurrence predictors included age, sex, psychiatric diagnosis, psychiatric comorbidity, medical comorbidity, number of past episodes, past hospitalizations, and family history of psychiatric disorder. RESULTS: During a median observation of 24 months, 36% (18 of 50) of physicians stopped work owing to recurrence of symptoms, with the median time to stopping work being 11 months. As well, 52% (26 of 50) had a re-emergence of clinical symptoms, with the median time to any level of symptom re-emergence being 13 months. Physicians with psychiatric comorbidity stopped work sooner (hazard ratio [HR] 3.53; 95% CI 1.24 to 10.03, P = 0.01) and had more rapid symptom re-emergence (HR 2.96; 95% CI 1.34 to 6.52, P = 0.004) than those without comorbidity. The most common psychiatric comorbidity was a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, anxiety disorder. CONCLUSION: Recurrence rates are high among Ontario physicians referred for formal monitoring of recurrent unipolar depression and BD, and are markedly hastened by the presence of psychiatric comorbidity.

Enhanced anandamide plasma levels in patients with complex regional pain syndrome following traumatic injury: a preliminary report.

The complex regional pain syndrome (CRPS) is a disabling neuropathic pain condition that may develop following injuries of the extremities. The pathogenesis of this syndrome is not clear; however, it includes complex interactions between the nervous and the immune system resulting in chronic inflammation, pain and trophic changes. This interaction may be mediated by chronic stress which is thought to activate the endogenous cannabinoid (endocannabinoid) system (ECS). We conducted an open, prospective, comparative clinical study to determine plasma level of the endocannabinoid anandamide by high-performance liquid chromatography and a tandem mass spectrometry system in 10 patients with CRPS type I versus 10 age- and sex-matched healthy controls. As compared to healthy controls, CRPS patients showed significantly higher plasma concentrations of anandamide. These results indicate that the peripheral ECS is activated in CRPS. Further studies are warranted to evaluate the role of the ECS in the limitation of inflammation and pain.

Risk and outcome analysis of renal replacement therapies in patients after cardiac surgery with pre-operatively normal renal function.

Peri-operative acute renal failure requiring renal replacement therapy is common (5-30%) after cardiac surgery and associated with a mortality of approximately 50%. Pre-operative renal impairment seems to be the most important risk factor for frank postoperative renal failure. To help evaluate the risk factors, we conducted a prospective observational trial of 1574 consecutive patients with normal pre-operative renal function (creatinine < 110 micromol.l(-1)). Renal failure was defined as the need for renal replacement therapy. After univariate analysis of previously described risk factors, those who differed significantly between patients with or without renal failure were enrolled into a multivariate classification and regression tree (CART) statistical model that identifies the most 'predictive' risk factors and creates a ranked list of these. In patients with pre-operatively normal renal function, a serum level of lactate > 1.1 mmol.l(-1) in the first 24 h after the operation was the strongest predictor for the development of renal failure.

Parabolic flight primes cytotoxic capabilities of polymorphonuclear leucocytes in humans.

BACKGROUND: Previously performed in vitro studies suggested that gravitational stress may alter functions of immune cells. This study investigated the in vivo effects of parabolic flight manoeuvres as a short-term model of micro- and hypergravity on the cytotoxic and microbicidal polymorphonuclear leucocyte (PMN) functions as the key element of innate immunity. MATERIAL AND METHODS: Twenty-one healthy male volunteers underwent 30 subsequent parabolic flight manoeuvres. Each manoeuvre produced 22-s periods of nearly weightlessness close to <<0g>>, with each parabola starting with a pull-up and ending with a pull-out (hypergravity) at 1.8 g for about 20 s each. Blood samples were drawn 24 h prior to take off (T0), after 25-30 parabolas (T1), and 24 h (T2) and 48 h (T3) after flight for determination of (i) leucocyte number and subpopulations, (ii) PMNs' capabilities to produce hydrogen peroxide (H(2)O(2)) and to adhere and phagocytose particles and (iii) plasma cytokines known to prime PMN functions [interleukin-8 (IL-8), tumour necrosis factor-alpha (TNF-alpha), granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF)]. RESULTS: Parabolic flight induced an increase in leucocyte number with a significant elevation of the PMN fraction. The spontaneous H(2)O(2) production by PMNs did not change; however, the capability of PMNs to produce H(2)O(2) in response to soluble stimuli [N-formyl-methionyl-leucyl-phenylalanine (fMLP), fMLP and TNF-alpha, calcium ionophore (A23187), phorbol myristate acetate (PMA)] was increased. Adhesive and phagocytic properties of PMNs were not altered. Regarding priming cytokines, IL-8 and G-CSF were significantly elevated. CONCLUSIONS: Our data indicate that parabolic flight induces priming of the cytotoxic capabilities of PMNs without affecting microbicidal functions.

Characteristics and outcomes of doctors in a substance dependence monitoring programme in Canada: prospective descriptive study.

OBJECTIVE: To describe the characteristics at enrollment and outcomes of doctors in a substance dependence monitoring programme in Canada. DESIGN: Prospective descriptive study. SETTING: Provincial physician health programme, Canada. PARTICIPANTS: All 100 doctors consecutively admitted to a substance dependence monitoring programme and followed until completion of monitoring or on leaving the programme. MAIN OUTCOME MEASURE: Relapse during long term monitoring for five years. RESULTS: Ninety per cent of the doctors enrolled on the programme were men, 66% were married or living with a partner, 44% had had previous treatment for substance dependence, and 36% had had previous psychiatric treatment. Smokers were over-represented compared with the general population of US doctors (38% v 5%). During the monitoring period 71% of participants had no known relapse. An additional 14% went on to complete the programme, after some form of relapse. In total, 85% of the doctors successfully completed the programme. CONCLUSION: In this cohort of doctors enrolled on the Ontario Physician Health Program for substance dependence, most were men who were dependent on alcohol or opioids. Smokers were over-represented compared with the general population of US doctors. Eighty five per cent successfully completed the programme.

Diffusion generated T1 and T2 contrast.

In MR images of porous organic samples (such as roots or wood) in water media, the sample is often surrounded by a bright ring, with a corresponding decreased T1 value in T1 maps. When the medium is removed, or contrast agents are added, the ring disappears, indicating that the signal does not originate in the outer layers of the sample, but from the medium itself. It can be shown that this "bright ring effect" is only observed when the medium experiences a reduction in T1 when permeating the sample. In order to investigate this effect, a computer model was used to simulate the diffusion of magnetisation between regions that exhibit different relaxation constants. Using this model, the origin of the signal increase was found to be an inflow effect, as diffusion transports relaxed magnetisation from the boundary regions of the sample into the surrounding medium. In the case of the "bright ring" around the plants described above, a mixing of short T1 values from within the sample and long T1 values within the medium occurs, yielding a "transition region" between the two values. There, a signal increase can be observed at T1 weighted images, compared to the signal from the medium beyond this transition region. The width of the transition region is on the order of magnitude of the diffusion displacement that is calculated from the T1 value as diffusion time. In addition to causing the bright ring around the plant samples, this diffusion effect also limits the resolution of the relaxation time maps. This effect is not limited to T1 relaxation but also applies to T2 relaxation. However, at high B0 field strengths such as those used in this study (11.7 T), a T2 effect is not usually observed due to the considerably shorter T2 times in plants (about 50 ms, compared to T1 times of higher than 1 s). Because the diffusion length during this T2 relaxation is short with respect to the resolution of the imaging experiments, no T2 ring effect is seen.

Implementation of sustainable sanitation in existing urban areas: long-term strategies for an optimised solution.

If technologies for decentralised sanitation and reuse (DESAR) and for natural stormwater management should at least partially replace existing systems, then intensive reconstruction work becomes essential. A conversion can only be realised successively over a long period due to high construction and financial expenses and requires new strategies. This paper presents the development and practical implementation of a mathematical tool to find an optimised strategy for the realisation of alternative and more decentralised drainage and sanitation concepts in existing urban areas. The succession of construction measures (e.g. the implementation of decentralised greywater recycling) for the whole period of consideration is determined based upon a mathematical optimisation model on the condition that the favoured future state is known. The model describes the complex interdependencies of the urban water and nutrient cycle and enables the minimisation of both financial efforts and ecological impacts on the way toward the future state. The results of the implementation for a rural area in Germany show that the mathematical optimisation is an adequate instrument to support decision-making processes in finding strategies for the realisation of sustainable urban water management.