Population-based analysis of the impact of trauma on longer-term functional outcomes.

BACKGROUND: Functional outcome measures are important as most patients survive trauma. The aim of this study was to describe the long-term impact of trauma within a healthcare region from a social perspective. METHODS: People active in work or education and admitted to hospitals in Central Norway in the interval 1 June 2007 to 31 May 2010 after sustaining trauma were included in the study. Clinical data were linked to Norwegian national registers of cause of death, sickness and disability benefits, employment and education. Primary outcome measures were receipt of medical benefits and time to return to preinjury work level. Secondary outcome measures were mortality within 30 days or during follow-up. RESULTS: Some 1191 patients were included in the study, of whom 193 (16·2 per cent) were severely injured (Injury Severity Score greater than 15). Five years after injury, the prevalence of medical benefits was 15·6 per cent among workers with minor injuries, 22·3 per cent in those with moderate injuries and 40·5 per cent among workers with severe injuries. The median time after injury until return to work was 1, 4 and 11 months for patients with minor, moderate and severe injuries respectively. Twelve patients died within 30 days and an additional 17 (1·4 per cent) during follow-up. CONCLUSION: Patients experiencing minor or major trauma received high levels of medical benefits; however, most recovered within the first year and resumed preinjury work activity. Patients with severe trauma were more likely to receive medical benefits and have a delayed return to work. Registration number: NCT02602405 (http://www.clinicaltrials.gov).

[New aspects of immunotherapy in multiple sclerosis]. / Neues aus der Immuntherapie bei Multipler Sklerose.

The spectrum of therapeutic options for immunotherapy of multiple sclerosis is continuously broadening. After the approval of cladribine and ocrelizumab in Europe, two new drugs are now available with ocrelizumab being the first approved option for treatment of primary progressive multiple sclerosis; however, the increased use of highly effective therapies is accompanied by a rise in severe side effects. During recent months, special attention was paid to the new progressive multifocal leukoencephalopathy (PML) risk assessment in natalizumab-treated patients, cardiac side effects of fingolimod, cases of idiopathic thrombocytopenic purpura and listeria meningitis associated with alemtuzumab and cases of daclizumab-treated patients with liver failure or encephalitis. These case reports highlight the importance of careful monitoring of all patients treated with immunomodulatory therapies.

Trauma care in a combined rural and urban region: an observational study.

BACKGROUND: The available information on trauma care in mixed rural-urban areas with scattered populations is limited. The aim of this study is to describe epidemiology, resource use, transfers and outcomes for trauma care within such an area, prior to implementation of a formal trauma system. METHODS: A multicentre observational study including potential severely injured patients from June 2007 to May 2010. All patients received by trauma teams at seven acute care hospitals (ACH) and one major trauma centre (MTC) were included. Major trauma was defined as Injury Severity Score (ISS) > 15. RESULTS: A total of 2323 patients were included. ACH received 1330 patients and delivered definite care to 85% of these. Only 329 (14%) patients were major trauma of which 134 (41%) were initially received at an ACH. Nine per cent of patients were transferred between hospitals. After inter-hospital transfers, 79% of all major trauma patients received definite care at the MTC. Helicopter emergency services admitted 52% of major trauma and performed 68% of inter-hospital transfers from ACH to MTC. Forty-eight patients (2%) died within 30 days. CONCLUSION: In a region with a dispersed network of hospitals, geographical challenges, and low rate of major trauma cases, efforts should be made to identify patients with major trauma for treatment at a MTC as early as possible. This can be done by implementing triage and transfer guidelines, maintaining competence at ACHs for initial stabilization, and sustaining an organization for effective inter-facility transfers.

[Clinical trials in children--between the expectations of scientific requirements, the assurance of proven treatment and ethical demands]. / Klinische Prüfung an Kindern im Spannungsfeld zwischen wissenschaftlichen Anforderungen, der Sicherstellung der korrekten Behandlung und ethischen Aspekten.

Regulation (EC) No. 1901/2006 of the European Parliament and the Council dated 12 December 2008 on medicinal products for paediatric use is the result of a survey by the European Commission, concluding that children in the European Union are inadequately treated with medicinal products. The Regulation is addressed to the pharmaceutical industry with the intention to place medicinal products on the market and to the Member States to register all information on medicinal products for the treatment of children. The pharmaceutical industry will be obliged to conduct clinical trials in children for new medicinal products and medicinal products still under patent. This will be supported by incentives and rewards. As a consequence of the requirement to conduct clinical trials in children the framework and conditions have to be defined and ethical considerations have to be respected.

[Control of aspirin effect in chronic cardiovascular patients using two whole blood platelet function assays. PFA-100 and Multiplate]. / Vollblutaggregometrie zur Kontrolle der Wirksamkeit von Azetylsalizylsäure bei Patienten mit koronarer Herzkrankheit. Vergleich von PFA-100 und Multiplate.

In this study two aspirin sensitive platelet function tests which are based on the analysis of whole blood were evaluated and correlated with each other. In vitro bleeding time was determined using the PFA-100 analyzer (Dade Behring, Marburg, Germany) using the collagen/epinephrine cartridge and citrated blood. Whole blood aggregometry was performed using the Multiplate analyzer (Dynabyte medical, Munich, Germany) using hirudin blood (25 mug/ml). Aggregatin was triggered using arachidonic acid (ASPItest), collagen (COLtest) or TRAP-6 (thrombin receptor activating peptide, TRAPtest). Following informed consent citrated blood and hirudin blood was drawn from 76 cardiovascular patients which were on long-term aspirin therapy (aspirin patients). In addition hirudin blood was drawn from 57 healthy blood donors for assessment of whole blood aggregometry. PFA-100 closure times of the aspirin patients were 273 +/- 49 s. Based on the cut-off of 170 s a non response to the aspirin therapy was detected in 5 of 76 patients. Whole blood aggregation was comparable in the aspirin patients vs the blood donors AUC values in the TRAP test, whereas in COLtest and ASPItest significantly reduced aggregations were detected (p < 0.05). Of the five patients that had a normal PFA-100 closure time only one had normal aggregation in ASPItest, and also only one had a normal aggregation in COLtest. The high rate of response to the aspirin therapy which was found in PFA-100 and ASPItest can be explained by the assumed high level of compliance of the cohort. In the applied tests different patients were stratified as aspirin-non-responders. This highlights the importance of the assay conditions for the diagnosis of an aspirin-non-response.

In vivo activation of antigen-specific CD4 T cells.

Physical detection of antigen-specific CD4 T cells has revealed features of the in vivo immune response that were not appreciated from in vitro studies. In vivo, antigen is initially presented to naïve CD4 T cells exclusively by dendritic cells within the T cell areas of secondary lymphoid tissues. Anatomic constraints make it likely that these dendritic cells acquire the antigen at the site where it enters the body. Inflammation enhances in vivo T cell activation by stimulating dendritic cells to migrate to the T cell areas and display stable peptide-MHC complexes and costimulatory ligands. Once stimulated by a dendritic cell, antigen-specific CD4 T cells produce IL-2 but proliferate in an IL-2--independent fashion. Inflammatory signals induce chemokine receptors on activated T cells that direct their migration into the B cell areas to interact with antigen-specific B cells. Most of the activated T cells then die within the lymphoid tissues. However, in the presence of inflammation, a population of memory T cells survives. This population is composed of two functional classes. One recirculates through nonlymphoid tissues and is capable of immediate effector lymphokine production. The other recirculates through lymph nodes and quickly acquires the capacity to produce effector lymphokines if stimulated. Therefore, antigenic stimulation in the presence of inflammation produces an increased number of specific T cells capable of producing effector lymphokines throughout the body.

Developmental apraxia arising from neonatal brachial plexus palsy.

OBJECTIVE: To determine whether motor unit activation is impaired in patients with persisting disability arising from neonatal brachial plexus palsy (NBPP). BACKGROUND: In NBPP patients, the authors previously found more extensive muscle reinnervation than might have been anticipated from the clinical examination. METHODS: Motor skills were tested in a group of nine boys and seven girls with prior NBPP, who then underwent physiologic investigation of proximal and distal muscles in their affected and unaffected arms. The latter tests comprised measurements of maximal evoked muscle compound action potential (M-wave) amplitude, maximal voluntary torque, twitch torque, and twitch interpolation. A group of 17 children of similar ages served as control subjects. RESULTS: In the NBPP group, motor skills were diminished and voluntary torque was reduced relative to M-wave amplitude and twitch torque. Moreover, interpolated twitches could be demonstrated in some NBPP patients but not in control subjects. CONCLUSION: Persisting disability in NBPP patients is due, at least in part, to impaired motor unit activation. The authors suggest that the impairment is a form of developmental apraxia caused by defective motor programming in early infancy.

B cell receptor expression level determines the fate of developing B lymphocytes: receptor editing versus selection.

During B lymphocyte development, antibody genes are assembled by DNA recombination. Successful cell surface expression of IgM promotes developmental progression. However, when antigen receptors bind autoantigen, development is blocked and ongoing antibody gene recombination occurs, which often alters antibody specificity in a process called receptor editing. We demonstrate here a significant role of developmental block and receptor editing in B cell receptor quality control. During development a functional, non-self-reactive receptor undergoes receptor editing if its expression is below a certain threshold. Doubling the receptor gene dose promotes development in the absence of autoantigen, but allows editing when autoantigen is present. Thus, both underexpressed and harmful B cell receptors can undergo correction by receptor editing.

Platelet function analysis with PFA-100 in patients medicated with acetylsalicylic acid strongly depends on concentration of sodium citrate used for anticoagulation of blood sample.

Our data from 214 patients after cessation of long-term therapy with 100 mg/d ASA demonstrate that the determination of platelet-related primary hemostasis in citrated whole blood with PFA-100 is a reliable and sensitive method for the detection of ASA-induced platelet dysfunction. However, the sensitivity of the method is strongly dependent on concentration of sodium citrate used as anticoagulant. The results of PFA-100 testing show a clearly enhanced sensitivity for ASA when blood samples were collected with 0.129 M rather than 0.106 M sodium citrate. According to sample stability, PFA-100 results can only be confirmed up to 1 hour postcollection when blood was anticoagulated with 0.129 M but not with 0.106 M sodium citrate. Therefore, we recommend that testing with PFA-100 in patients with suspected ASA-induced platelet dysfunction should be performed exclusively in blood collected in buffered 0.129 M sodium citrate.

Antigen-experienced CD4 T cells display a reduced capacity for clonal expansion in vivo that is imposed by factors present in the immune host.

It is thought that protective immunity is mediated in part by Ag-experienced T cells that respond more quickly and vigorously than naive T cells. Using adoptive transfer of OVA-specific CD4 T cells from TCR transgenic mice as a model system, we show that Ag-experienced CD4 T cells accumulate in lymph nodes more rapidly than naive T cells after in vivo challenge with Ag. However, the magnitude of clonal expansion by Ag-experienced T cells was much less than that of naive T cells, particularly at early times after primary immunization. Ag-experienced CD4 T cells quickly reverted to the slower but more robust clonal expansion behavior of naive T cells after transfer into a naive environment. Conversely, the capacity for rapid clonal expansion was acquired by naive CD4 T cells after transfer into passively immunized recipients. These results indicate that rapid in vivo response by Ag-experienced T cells is facilitated by Ag-specific Abs, whereas the limited capacity for clonal expansion is imposed by some other factor in the immune environment, perhaps residual Ag.

B-cell-receptor-dependent positive and negative selection in immature B cells.

This review touches on only a small part of the complex biology of B cells, but serves to illustrate the point that the antigen receptor is the most important of many cell-surface receptors affecting cell-fate decisions. Receptor expression is necessary, but not sufficient, for cell survival. It is also essential that a B cell's antigen-receptor specificity be appropriate for its environment. The need to balance reactivity with self tolerance has resulted in an intricate feedback control (affected by both the recombinase and cell survival) that regulates independent selection events at the level of the receptor and the cell.

Psychological abuse: implications for adjustment and commitment to leave violent partners.

The contribution of psychological abuse, beyond that of physical abuse, to battered women's psychological adjustment and their intentions to terminate their abusive relationships was examined. Sixty-eight battered women residing in shelters for battered women provided information on their: (1) physical and psychological abuse; (2) psychological symptomatology; (3) strategies for coping with and perceptions of control over partner violence; and (4) intentions to return to their abusive partners. Multiple regression analyses indicated that frequency and severity of physical abuse was not a significant predictor of posttraumatic stress disorder (PTSD) symptomatology nor of women's intentions to terminate their abusive relationships. However, psychological abuse was a significant predictor of both PTSD symptomatology and intentions to permanently leave abusive partners even after controlling for the effects of physical abuse. PTSD symptomatology moderated the relationship between psychological abuse and intentions to terminate the abusive relationships: resolve to leave the abusive partner as a function of level of psychological abuse was significant only among women characterized by low levels of PTSD symptomatology. Greater use of emotion-focused coping strategies, absolutely and relative to problem-focused coping, had direct effects on PTSD symptomatology. However, neither coping nor perceptions of control moderated the effects of psychological abuse on psychological adjustment. The results of the investigation suggested that psychological abuse and ensuing PTSD symptomatology are important variables to assess among physically battered women.

Denervation and reinnervation in congenital brachial palsy.

Motor unit number estimation (MUNE) was shown to be useful in assessing the neurophysiological status of 18 subjects with congenital brachial palsy. This was especially so since conventional M-wave measurements may give misleading impressions as to the extent of motor axon regeneration. In most subjects the involvement of sensory nerve fibers indicated that the traumatic lesions included postganglionic segments of the fibers, with or without preganglionic damage. In a minority the lesions were purely preganglionic. Digital sensory nerve involvement was more in a mediolateral direction, consistent with greater damage to the uppermost elements in the brachial plexus. In 5 individuals, MUNE and sensory testing showed that there had been trauma to the supposedly unaffected arm. Discrepancies between sensory and motor results suggested that reinnervation of the biceps brachii muscle was greater than that of the intrinsic muscles of the hand. In one subject examined serially, reinnervation of the hand muscles was detected by 10 months and continued in the hypothenar muscles for the next 6 years.

Antigen-specific CD4+ T cells that survive after the induction of peripheral tolerance possess an intrinsic lymphokine production defect.

Injection of soluble foreign antigen without an adjuvant induces a state of antigen-specific immunological unresponsiveness. We investigated the cellular mechanisms that underlie this form of peripheral tolerance by physically tracking a small population of ovalbumin (OVA) peptide/I-Ad-specific, CD4+ T cell receptor (TCR) transgenic T cells following adoptive transfer into normal recipients. Injection of OVA peptide in the absence of adjuvant caused the antigen-specific T cells to proliferate for a brief period after which most of the T cells disappeared. The remaining OVA-specific T cells had converted to a memory phenotype but were poorly responsive in vivo as evidenced by a failure to accumulate in the draining lymph nodes following immunization with OVA peptide in adjuvant. These surviving T cells possessed a long-lasting, but reversible, defect in Il-2 and TNF-alpha production and in vivo proliferation, but did not gain capacity to produce Th2-type cytokines or suppress the clonal expansion of T cells specific for another antigen. Therefore, some antigen-specific T cells survive this peripheral tolerance protocol but are functionally unresponsive due to an intrinsic activation defect.

Self-reactive B lymphocytes overexpressing Bcl-xL escape negative selection and are tolerized by clonal anergy and receptor editing.

Self-reactive B cells Tg for both a bcl-xL death inhibitory gene and an Ig receptor recognizing hen egg lysozyme (HEL-Ig) efficiently escaped developmental arrest and deletion in mice expressing membrane-bound self-antigen (mHEL). In response to the same antigen, Tg HEL-Ig B cells not expressing bcl-xL were deleted, while cells expressing bcl-2 were arrested at the immature B stage. Bcl-xL Tg B cells escaping negative selection were anergic in both in vitro and in vivo assays and showed some evidence for receptor editing. These studies suggest that Bcl-x may have a distinct role in controlling survival at the immature stage of B cell development and demonstrate that tolerance is preserved when self-reactive B cells escape central deletion.

Direct evidence that functionally impaired CD4+ T cells persist in vivo following induction of peripheral tolerance.

A small population of CD4+ OVA-specific TCR transgenic T cells was tracked following the induction of peripheral tolerance by soluble Ag to address whether functionally unresponsive, or anergic T cells, persist in vivo for extended periods of time. Although injection of OVA peptide in the absence of adjuvant caused a transient expansion and deletion of the Ag-specific T cells, a population that showed signs of prior activation persisted in the lymphoid tissues for several months. These surviving OVA-specific T cells had long-lasting, but reversible defects in their ability to proliferate in lymph nodes and secrete IL-2 and TNF-alpha in vivo following an antigenic challenge. These defects were not associated with the production of Th2-type cytokines or the capacity to suppress the clonal expansion of a bystander population of T cells present in the same lymph nodes. Therefore, our results provide direct evidence that a long-lived population of functionally impaired Ag-specific CD4+ T cells is generated in vivo after exposure to soluble Ag.

A natural immunological adjuvant enhances T cell clonal expansion through a CD28-dependent, interleukin (IL)-2-independent mechanism.

The adoptive transfer of naive CD4(+) T cell receptor (TCR) transgenic T cells was used to investigate the mechanisms by which the adjuvant lipopolysaccharide (LPS) enhance T cell clonal expansion in vivo. Subcutaneous administration of soluble antigen (Ag) resulted in rapid and transient accumulation of the Ag-specific T cells in the draining lymph nodes (LNs), which was preceded by the production of interleukin (IL)-2. CD28-deficient, Ag-specific T cells produced only small amounts of IL-2 in response to soluble Ag and did not accumulate in the LN to the same extent as wild-type T cells. Injection of Ag and LPS, a natural immunological adjuvant, enhanced IL-2 production and LN accumulation of wild-type, Ag-specific T cells but had no significant effect on CD28-deficient, Ag-specific T cells. Therefore, CD28 is critical for Ag-driven IL-2 production and T cell proliferation in vivo, and is essential for the LPS-mediated enhancement of these events. However, enhancement of IL-2 production could not explain the LPS-dependent increase of T cell accumulation because IL-2-deficient, Ag-specific T cells accumulated to a greater extent in the LN than wild-type T cells in response to Ag plus LPS. These results indicate that adjuvants improve T cell proliferation in vivo via a CD28-dependent signal that can operate in the absence of IL-2.

A role for inflammatory cytokines in the productive activation of antigen-specific CD4+ T-cells.

The mechanisms of action of immunological adjuvants were studied using a system in which the behavior of adoptively transferred CD4+ T-cell receptor transgenic T-cells could be directly monitored following antigen administration. These studies revealed that adjuvant-induced inflammatory cytokines promote immunity by enhancing the clonal expansion, persistence and differentiation of antigen-activated CD4+ T-cells.

[Who were the healers in medieval Trondheim?]. / Hvem var helbredere i middelalderens Trondheim?

When Trondheim celebrated its millenium in 1997, this also marked a 1000 year-old medical tradition. In medieval times, sick and disabled people made their pilgrimage to the Nidaros cathedral and the grave of Saint Olav (995-1030). Working from the assumption that every organized society develops rituals and rules to deal with disease and death, we have looked for evidence of what kind of healers one would expect there were in medieval Trondheim up to the reformation in 1537. Sources include reports from archaeological excavations, written material of both medieval and more recent origin, buildings and objects, and living traditions. Three kinds of healer traditions can be identified: The popular and "wise" folk healers were based on traditional pre-Christian mythology and belief in natural forces. The charitable clerics emerged with Christianity. The "professional" wound healers evolved from the needs of the military, later to merge with the early barber surgeons. Traces of scientific traditions, the Salerno school and early European university medicine can be found in local texts, but there is no evidence of any university educated doctor practising in Trondheim before the 17th century.

Negative and positive dimensions of schizotypal personality disorder.

The positive (perceptual-cognitive) and negative (social-interpersonal) dimensions of schizotypal personality traits were examined in biological relatives of individuals with Axis I disorder. The subjects were young adult offspring from three contrasting parental groups, including schizophrenic disorder, affective disorder, and normal controls. Cognitive correlates, including digit span (presumed to assess working memory) and P3 amplitudes, were also examined. Preliminary results showed that positive and negative dimensions were distinguished by different prevalence patterns in the offspring subjects, and by a different pattern of correlations with cognitive measures. Negative dimensions were more frequent in offspring from the schizophrenic parental group than in the offspring from affective disorder and normal control parental groups. Digits forward and backward, and P3 amplitude decrements, characterized a subset of offspring with negative features from the schizophrenic parental group. Positive dimensions did not differ between the psychiatric parental groups, and did not covary with digit span or P3 amplitude assessments. These results support the view that positive and negative dimensions may reflect separable pathophysiologic processes.