Carsten Kruschinski

Circulating soluble urokinase plasminogen activator receptor is stably elevated during the first week of treatment in the intensive care unit and predicts mortality in critically ill patients

IntroductionsuPAR is the soluble form of the urokinase plasminogen activator receptor (uPAR), which is expressed in various immunologically active cells. High suPAR serum concentrations are suggested to reflect the activation of the immune system in circumstances of inflammation and infection, and have been associated with increased mortality in different populations of non-intensive care patients. In this study we sequentially analyzed suPAR serum concentrations within the first week of intensive care in a large cohort of well characterized intensive care unit (ICU) patients, in order to investigate potential regulatory mechanisms and evaluate the prognostic significance in critically ill patients.MethodsA total of 273 patients (197 with sepsis, 76 without sepsis) were studied prospectively upon admission to the medical intensive care unit (ICU), on Day 3 and Day 7, and compared to 43 healthy controls. Clinical data, various laboratory parameters as well as investigational inflammatory cytokine profiles were assessed. Patients were followed for approximately one year.ResultsUpon admission to the ICU suPAR serum concentrations were elevated in critically ill patients as compared with healthy controls. In sepsis patients suPAR levels were higher than in non-sepsis patients (with or without systemic inflammatory response syndrome (SIRS)). During the first week after admission to the ICU serum suPAR concentrations remained stably elevated. suPAR serum concentrations measured upon admission were closely and independently correlated to various laboratory parameters, specifically biomarkers of inflammation (tumor necrosis factor (TNF), C-reactive protein (CRP)), hepatic and renal dysfunction. High suPAR levels at admission and at Day 3 were a strong independent predictor for both ICU and long-term mortality in critically ill patients.ConclusionsIn sepsis and non-sepsis patients suPAR serum concentrations are increased upon admission to the ICU, likely reflecting the activation state of the immune system, and remain stably elevated in the initial course of treatment. Low suPAR levels are a positive predictor of ICU- and overall survival in critically ill patients, including sepsis and non-sepsis patients. Aside from its value as a promising new prognostic biomarker, both experimental and clinical studies are required in order to understand the specific effects and regulatory mechanisms of suPAR in SIRS and sepsis, and may reveal new therapeutic options.

Inhibition of CD26/Dipeptidyl Peptidase IV Enhances CCL11/Eotaxin-Mediated Recruitment of Eosinophils In Vivo

Chemokines mediate the recruitment of leukocytes to the sites of inflammation. N-terminal truncation of chemokines by the protease dipeptidyl peptidase IV (DPPIV) potentially restricts their activity during inflammatory processes such as allergic reactions, but direct evidence in vivo is very rare. After demonstrating that N-terminal truncation of the chemokine CCL11/eotaxin by DPPIV results in a loss of CCR3-mediated intracellular calcium mobilization and CCR3 internalization in human eosinophils, we focused on the in vivo role of CCL11 and provide direct evidence for specific kinetic and rate-determining effects by DPPIV-like enzymatic activity on CCL11-mediated responses of eosinophils. Namely, it is demonstrated that i.v. administration of CCL11 in wild-type F344 rats leads to mobilization of eosinophils into the blood, peaking at 30 min. This mobilization is significantly increased in DPPIV-deficient F344 rats. Intradermal administration of CCL11 is followed by a dose-dependent recruitment of eosinophils into the skin and is significantly more effective in DPPIV-deficient F344 mutants as well as after pharmacological inhibition of DPPIV. Interestingly, CCL11 application leads to an up-regulation of DPPIV, which is not associated with negative feedback inhibition via DPPIV-cleaved CCL11(3–74). These findings demonstrate regulatory effects of DPPIV for the recruitment of eosinophils. Furthermore, they illustrate that inhibitors of DPPIV have the potential to interfere with chemokine-mediated effects in vivo including but not limited to allergy.

CD26 (dipeptidyl-peptidase IV)-dependent recruitment of T cells in a rat asthma model

CD26 truncates several chemokines as well as neuropeptides and influences immune responses via modulation of cell adhesion and T cell activation, suggesting an involvement of CD26 in asthmatic and airway inflammation. Therefore, Fischer 344 (F344), Brown Norway (BN) and Lewis (LEW) rat strains, which differ in their CD26‐like enzymatic activity, were compared using an asthma model. Additionally, two CD26‐deficient mutant F344 rat substrains were included and compared to the wild‐type F344 substrain. Immunization was performed twice with ovalbumin (OVA), and 2 weeks later the rats were challenged with OVA intratracheally Flow cytometry (FACS) analysis of different leucocyte subsets as well as enzyme‐linked immunosorbent assay (ELISA) for IgE levels in the blood and bronchoalveolar lavage (BAL) were performed 24 h after challenge. LEW rats with the lowest CD26 activity among the rat strains investigated here displayed significantly reduced CD4+ T cell numbers in the BAL compared to wild‐type F344 and BN rats. Moreover, in asthma, the ratio of CD26+ to CD26– T cell receptor (TCR)‐positive cells increased significantly in F344 and LEW but not BN rats. Most intriguingly, in both CD26‐deficient F344 rat substrains the number of CD4+ T lymphocytes was markedly reduced compared to wild‐type F344. The decrease in T cell recruitment observed in the CD26‐deficient rats was associated with significantly reduced OVA‐specific IgE‐titres. This is the first report to show a remarkably reduced T cell recruitment in rat strains that either lack or exhibit reduced CD26‐like enzymatic activity, suggesting a role for CD26 in the pathogenesis of asthma via T cell‐dependent processes such as antibody production.

Age-dependent development of the splenic marginal zone in human infants is associated with different causes of death

Infants are more susceptible to infections caused by T cell- independent type 2 (TI-2) polysaccharide antigens of certain encapsulated bacteria. Immune responses against this type of antigen are related to the splenic marginal zone (MZ). However, only few data exist on the age-dependent developmental stages of the human spleen in early childhood and on their association with different diseases. Therefore, the present study aimed to investigate spleens of a large number of children at very young ages (12 days to 32 months), derived from autopsy cases. Immunohistochemical labeling was performed on paraffin sections of 34 spleens using a panel of monoclonal antibodies. The shape and size of the white pulp compartments were examined and correlated to the cause of death of the children. Results show that the development of the different compartments was statistically age-dependent, but no clear-cut time point for the maturity of each compartment was seen. Furthermore, the MZ was significantly more often missing when sudden infant death (SID) and/or infection were the cause of death, compared with other violent or traumatic reasons that served as controls. This association supports the concept that an immature state of the spleen and especially of the MZ might contribute to the increased susceptibility to bacterial infections in young infants.

Postnatal Life Events Affect the Severity of Asthmatic Airway Inflammation in the Adult Rat

Genetic and hygienic factors influence susceptibility to asthma. In autoimmune and inflammatory diseases, additional effects of the psychosocial environment have been demonstrated that might also play a role in asthma. In this study, the impact of different early postnatal stressors on an OVA-induced model of asthma was tested in adulthood. Fischer 344 rats were subjected to either repeated handling stimulation (HA), maternal separation (MS), or were left undisturbed in their first 4 wk of life. Behavioral differences were characterized at the age of 4 mo. At 5 mo of age, immunological cellular and serologic changes were investigated and experimental asthma was induced. Results show significantly increased exploratory behavior and reduced anxiety in HA rats compared with MS and controls. Without further behavioral or immunological challenges, HA animals exhibited an increased ex vivo NK cell cytotoxicity but no other obvious immunological differences. After induction of asthma, in contrast, MS animals exhibited proinflammatory effects in leukocyte subset composition including increased eosinophil numbers, whereas levels of IgE and the allergy-specific cytokine IL-13 were reduced compared with HA. There was a most remarkable increase of adrenocorticotropin in HA animals, comparing pre- to postchallenge plasma levels. These data demonstrate for the first time that early postnatal stimulative or adverse experiences exert long-lasting changes of the “neuroendocrinoimmune” interface in adulthood, resulting in either protective or aggravating mechanisms in allergic airway disease. Thus, in addition to genetic and hygienic factors, nongenetically acquired individual differences contribute to the pathobiology of asthma.

A Survey to Assess Family Physicians’ Motivation to Teach Undergraduates in Their Practices

Background In Germany, family physicians (FPs) are increasingly needed to participate in undergraduate medical education. Knowledge of FPs’ motivation to teach medical students in their practices is lacking. Purpose To describe a novel questionnaire that assesses the motivation of FPs to teach undergraduates in their practices and to show the results of a subsequent survey using this instrument. Methods The questionnaire was developed based on a review of the literature. Previously used empirical instruments assessing occupational values and motivation were included. A preliminary version was pretested in a pilot study. The resulting 68-item questionnaire was sent to 691 FPs involved in undergraduate medical education. Reliability was assessed and subgroups were analyzed with regard to differences in motivation. Results A total of 523 physicians in n = 458 teaching practices participated (response rate 75.7%). ‘Helping others’ and ‘interest’ were revealed as the predominant motives. Responses showed a predominantly intrinsic motivation of the participating FPs. Their main incentives were an ambition to work as a medical preceptor, to generally improve undergraduate education and to share knowledge. Material compensation was of minor importance. Time restraints were indicated as a barrier by some FPs, but were not a general concern. Conclusion German FPs involved in medical education have altruistic attitudes towards teaching medical students in their practices. Motivational features give an important insight for the recruitment of FP preceptors as well as for their training in instructional methods.

Clinical relevance of the distance between the cochlea and the facial nerve in cochlear implantation.

Hypothesis To elucidate possible mechanisms of facial nerve costimulation after cochlear implantation that are supposed to result from the close cochlea to facial nerve contact. Background One of the postoperative complications of cochlear implantation is facial muscle twitching, which has preferentially been found in otosclerotic patients. It impairs hearing benefits because of deactivation of electrodes and can still not be adequately prevented. Methods A total of 13 temporal bones were dissected to quantify where the labyrinthine portion of the facial nerve is closest to the scala tympani, the placement site of the cochlear implantation electrode array. After the typical operative procedures to find out the number of electrodes lying closest to the facial nerve were performed, a cochlear implantation array was inserted into four specimens. The clinical records of 14 otosclerotic patients were investigated to correlate these results with the position of in vivo deactivated electrodes. Results The closest distance between the scala tympani and the nerve was only 0.33 mm (±0.14). On average, after insertion of 23 electrode resp. marking rings, the facial nerve was reached. This is clinically the position of most frequently deactivated electrodes to prevent postoperative facial nerve costimulation. Conclusions These investigations support the hypothesis that a direct current spread at the site of the facial nerve crossing the cochlear basal turn is most likely the reason for postoperative facial muscle twitching facilitated in otospongiotic bone. Prevention could therefore be achieved by cochlear implantation designs and surgical techniques that take into consideration the site of closest contact.

Attitudes of medical students towards general practice: Effects of gender, a general practice clerkship and a modern curriculum.

Aims: Planning a career in general practice depends on positive attitudes towards primary care. The aim of this study was to compare attitudes of medical students of a Modern Curriculum at Hannover Medical School with those of the Traditional Curriculum before (pre) and after (post) a three-week clerkship in general practice. In parallel, we aimed to analyse several other variables such as age and gender, which could influence the attitudes. Methods: Prospective survey of n=287 5th-year students. Attitudes (dependent variable, Likert-scale items) as well as socio-demographic characteristics (age, gender, rural/urban background), school leaving examination grades, former qualifications, experiences in general practice and career plans were requested. Attitudes were analysed separately according to these characteristics (e.g. career plans: general practitioner (GP)/specialist), curriculum type and pre/post the clerkship in general practice. Bi- and multivariate statistical analysis was used including a factor analysis for grouping of the attitude items. Results: Most and remarkable differences of attitudes were seen after analysis according to gender. Women appreciated general practice more than men including a greater interest in chronic diseases, communication and psychosocial aspects. The clerkship (a total of n=165 students of the “post” survey could be matched) contributed to positive attitudes of students of both gender, whereas the different curricula did not show such effects. Conclusions: Affective learning goals such as a positive attitude towards general practice have depended more on characteristics of students (gender) and effects of a clerkship in general practice than on the curriculum type (modern, traditional) so far. For the development of outcomes in medical education research as well as for the evolution of the Modern Curriculum such attitudes and other affective learning goals should be considered more frequently.

Fracture risk of patients suffering from dizziness: A retrospective cohort study

Abstract Background: Dizziness is known to be associated with the risk of falls. However, there is not much evidence for the increase of fractures caused by dizziness. Objectives: The aim of the study was to investigate whether the symptom of dizziness is associated with an increased fracture rate. Methods: We performed a retrospective cohort study using a population-based administrative database in the Province of Quebec, Canada. A cohort of n = 2 442 patients with at least one diagnosis of dizziness was compared to n = 16 125 unexposed patients. The main outcome measure was any kind of first fracture after the index date of dizziness. Results: Analysis revealed a moderate effect of dizziness as an independent contributing factor to fractures (adjusted hazard ratio (HR) 1.26, 95% confidence interval 1.03 to 1.55). A fracture in the year before the index date was highly associated with the incidence of a subsequent fracture (HR 2.69, 2.09 to 3.47), and fractures were less frequent in women (HR 0.70, 0.60–0.82). Analysis further revealed that dizziness (HR 1.31, 1.05–1.64) and prior fractures (HR 2.41, 1.81–3.22) were associated with non-osteoporotic fractures, which were also less frequent in women (HR 0.59, 0.50–0.71). The incidence of fractures in sites typical for osteoporosis correlated with a precedent fracture (HR 3.91, 2.31–6.63), but not with dizziness (HR 1.10, 0.69–1.75). Conclusion: Besides the ‘typical’ elderly female patient being at risk of osteoporotic fractures, male patients suffering from dizziness should be carefully evaluated, and prevention strategies should be considered to minimise their risk of suffering non-osteoporotic fractures.

Attitudes towards General Practice: a comparative cross-sectional survey of 1st and 5th year medical students

Objective: Positive attitudes towards General Practice can be understood as a prerequisite for becoming a General Practitioner (GP) and for collaboration with GPs later on. This study aimed to assess attitudes of medical students at the beginning and the end of medical school. Methods: A total of 160 1st year students at Hannover Medical School were surveyed. Their attitudes were compared to those of 287 5th year students. Descriptive, bi- and multivariate analyses were performed to investigate influences of year of study and gender. Results: Year of study and gender both were associated with the attitudes towards General Practice. The interest in General Practice and patient-orientation (communication, care of older patients with chronic diseases) was higher in 1st year students compared to more advanced students. Female students valued such requirements more than male students, the differences in attitudes between the years of study being more pronounced in male students. Conclusion: Despite some limitations caused by the cross-sectional design, the attitudes towards General Practice competencies changed to their disadvantage during medical school. This suggests a formative influence of the strategies used in medical education. Educational strategies, however, could be used to bring about a change of attitudes in the other direction.