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Introduction/Aims: There are no blood biomarkers to monitor treatment effects in myasthenia gravis (MG) or studies visualizing the acetylcholine receptor (AChR) antibody‐induced membrane attack complex (MAC) at the human muscle membrane. This study aimed to compare levels of complement activation products and native complement components in MG patients and healthy controls (HCs) and to model the AChR antibody‐mediated attacks in human muscle cells. Methods: We assessed the complement components and activation product levels with enzyme‐linked immunosorbent assay and magnetic bead‐based sandwich assays in plasma and sera of 23 MG patients and matched HCs. Receiver operator characteristic (ROC) curve analysis evaluated the diagnostic accuracy. Complement levels were correlated with the myasthenia gravis composite (MGC) scores. AChR+ MG modeling in human muscle cells used sera from nine MG patients and three HCs. Results: MG patients had significantly higher plasma levels of C3a (p <.0001), C5 (p =.0003), and soluble C5b‐9 (sC5b‐9; p <.0001) than HCs. The ROC curve analysis showed a clear separation between MG patients and HCs for plasma C3a (AUC = 0.9720; p <.0001) and sC5b‐9 (AUC = 0.8917, p <.0001). MG patients had higher levels of plasma complement Factor I (FI; p =.0002) and lower properdin levels (p <.0001). The MGC had moderate correlations with plasma Factor B (FB), FI, and Factor H. AChR+ MG patient sera triggered the deposition of MAC and reduced AChRs. Discussion: We suggest validating plasma C3a and sC5b‐9 as blood biomarkers for complement activation in MG. Further, the in vitro study allowed visualization of MAC deposition after applying AChR+ MG sera on human muscle cells. [ABSTRACT FROM AUTHOR]

Summary: A number of clinical treatment modalities involve contact between blood and biomaterials: these include extracorporeal circuits such as hemodialysis, cardiopulmonary bypass, plasmapheresis, and intravascular treatments. Common side effects arising from these treatments are caused by activation of the cascade systems of the blood. Many of these side effects are mediated via the complement system, including thromboinflammatory reactions and rejection of implants. Depending on the composition of the materials, complement activation is triggered via all the activation pathways but is by far mostly driven by the alternative pathway amplification loop. On biomaterial surfaces the alternative pathway amplification is totally unregulated and leads under optimal conditions to deposition of complement fragments, mostly C3b, on the surface leading to a total masking of the underlying surface. In this review, we discuss the mechanism of the complement activation, clinical consequences of the activation, and potential strategies for therapeutic regulation of the activation, using hemodialysis as demonstrator. [ABSTRACT FROM AUTHOR]

Organ transplantation leads to damage of the endothelial glycocalyx of the transplanted organ, and the activated endothelial surface induces thromboinflammation. The result is dysfunction of the transplanted organ, known as ischemia reperfusion injury (IRI). Long‐term graft survival strongly depends on the regulation of IRI. Here the aim is to reconstruct the glycocalyx to regulate blood activation during IRI. Heparin‐conjugated lipid (fHep‐lipid) is synthesized with 0.6, 1.8, 2.7, 4.5, or 8.0 fragmented heparins per lipid to compare their anticoagulation activity. First, liposome and cells are modified with each fHep‐lipid and the surface properties are evaluated. Then the hemocompatibility of the modified human mesenchymal stem cells (hMSCs) is examined in a loop model using human blood. The antithrombin‐binding capacity and anti‐factor Xa activity of the fHep‐lipids depend on the number of conjugated heparins, with efficacy increasing with increasing number of heparins. The modified liposomes are highly negatively charged and show strong anti‐factor Xa activity. In addition, the cell surfaces of human erythrocytes and hMSCs can be uniformly modified with fHep‐lipid. The whole blood studies reveal that fHep‐lipid on hMSCs can prevent generation of thrombin–antithrombin complexes, coagulation markers, and platelet aggregation, whereas unmodified hMSCs trigger activation of the platelet and coagulation systems. [ABSTRACT FROM AUTHOR]

Promising cell therapies using mesenchymal stem cells (MSCs) is proposed for stroke patients. Therefore, we aimed to efficiently accumulate human MSC (hMSC) to damaged brain area to improve the therapeutic effect using poly(ethylene glycol) (PEG)‐conjugated phospholipid (PEG‐lipid) carrying an oligopeptide as a ligand, specific for E‐selectin which is upregulated on activated endothelial cells under hypoxia‐like stroke. Here we synthesized E‐selectin‐binding oligopeptide (ES‐bp) conjugated with PEG spacer having different molecular weights from 1 to 40 kDa. We found that ES‐bp can be immobilized onto the hMSC surface through PEG‐lipid without influence on cell growth and differentiation into adipocytes and osteocytes, respectively. It is also possible to control the immobilization of ES‐bp on hMSC surface (<108 ES‐bp per cell). Immobilized ES‐bp can be continuously immobilized at the outside of cell membrane when PEG‐lipids with PEG 5 and 40 kDa were used. In addition, the modified hMSC can specifically attach onto E‐selectin‐immobilized surface as a model surface of activated endothelium in human blood, indicating the sufficient number of immobilized ES‐bp onto hMSC. Thus, this technique is one of the candidates for hMSC accumulation to cerebral infarction area. [ABSTRACT FROM AUTHOR]

Swedish media regularly indicate that people's confidence in politicians is low. This distrust in or discontent with politicians is often related to rural politics. This paper focuses on the populist tendencies in the representations of politicians in the Swedish rural press during the parliamentary election year of 2014. A discourse analysis of the press material illustrates three closely related and critical themes; politicians are regarded as being urban centred, as doing anything for power, and as acting in an autocratic manner and misusing their power. The discourse analysis also reveals how the critical press material is linked to a moral geography relating space to a specific moral order. Drawing on theories on rural populism, the article shows how the media's references to a rural‐based victimhood, and to an alleged inequality between urbanity and rurality, can morally legitimate and bluntly express their contempt for 'scandalous' politicians, and they can present their critique as rational and justified. [ABSTRACT FROM AUTHOR]

Innate immunity is fundamental to our defense against microorganisms. Physiologically, the intravascular innate immune system acts as a purging system that identifies and removes foreign substances leading to thromboinflammatory responses, tissue remodeling, and repair. It is also a key contributor to the adverse effects observed in many diseases and therapies involving biomaterials and therapeutic cells/organs. The intravascular innate immune system consists of the cascade systems of the blood (the complement, contact, coagulation, and fibrinolytic systems), the blood cells (polymorphonuclear cells, monocytes, platelets), and the endothelial cell lining of the vessels. Activation of the intravascular innate immune system in vivo leads to thromboinflammation that can be activated by several of the system's pathways and that initiates repair after tissue damage and leads to adverse reactions in several disorders and treatment modalities. In this review, we summarize the current knowledge in the field and discuss the obstacles that exist in order to study the cross-talk between the components of the intravascular innate immune system. These include the use of purified in vitro systems, animal models and various types of anticoagulants. In order to avoid some of these obstacles we have developed specialized human whole blood models that allow investigation of the cross-talk between the various cascade systems and the blood cells. We in particular stress that platelets are involved in these interactions and that the lectin pathway of the complement system is an emerging part of innate immunity that interacts with the contact/coagulation system. Understanding the resulting thromboinflammation will allow development of new therapeutic modalities. [ABSTRACT FROM AUTHOR]

There is a growing awareness that complement plays an integral role in human physiology and disease, transcending its traditional perception as an accessory system for pathogen clearance and opsonic cell killing. As the list of pathologies linked to dysregulated complement activation grows longer, it has become clear that targeted modulation of this innate immune system opens new windows of therapeutic opportunity for anti-inflammatory drug design. Indeed, the introduction of the first complement-targeting drugs has reignited a vibrant interest in the clinical translation of complement-based inhibitors. Compstatin was discovered as a cyclic peptide that inhibits complement activation by binding C3 and interfering with convertase formation and C3 cleavage. As the convergence point of all activation pathways and a molecular hub for crosstalk with multiple pathogenic pathways, C3 represents an attractive target for therapeutic modulation of the complement cascade. A multidisciplinary drug optimization effort encompassing rational 'wet' and in silico synthetic approaches and an array of biophysical, structural and analytical tools has culminated in an impressive structure-function refinement of compstatin, yielding a series of analogues that show promise for a wide spectrum of clinical applications. These new derivatives have improved inhibitory potency and pharmacokinetic profiles and show efficacy in clinically relevant primate models of disease. This review provides an up-to-date survey of the drug design effort placed on the compstatin family of C3 inhibitors, highlighting the most promising drug candidates. It also discusses translational challenges in complement drug discovery and peptide drug development and reviews concerns related to systemic C3 interception. [ABSTRACT FROM AUTHOR]

Background In several reports, C3 and C4 have been linked to diabetes and cardiovascular disease (CVD). Here, we investigate this link and the degree of C3 activation in elderly individuals. Methods In this study, C3 and C4 and the activation fragment C3a-desArg were analysed in 1016 subjects aged 70, in which blood pressure, lipid variables and fasting blood glucose were assessed. Results C3 levels were related to all the investigated classical cardiovascular risk factors and the metabolic syndrome (BMI, waist circumference, fat distribution, blood pressure, blood glucose levels, TG) except total cholesterol and LDL cholesterol in a highly significant fashion (Spearman up to 0,5; P < 0.0001). C4 and C3adesArg were associated in the same fashion but less significantly, while the ratios C4/C3 or C3a-desArg/C3 were not, indicating that the association was not directly related to complement activation. The levels C3 and to a lesser degree C4 and C3a-desArg were associated particularly with CRP, but also with E-selectin and ICAM-1. In addition, C3 and C4 levels were shown to decline significantly in 15 female subjects enrolled in a weightreduction programme over 4 months. Conclusion A strong relation between C3, C4 and C3a-desArg levels, adipose tissue and risk factors of CVD was established. The data support that the adipose tissue produces complement components and generates initiators of inflammation, such as C3a and C5a, able to trigger a cyto/chemokine response, in proportion to the amount of adipose tissue. This corroborates the concept that complement contributes to the low-grade inflammation associated with obesity. [ABSTRACT FROM AUTHOR]

During hemodialysis ( HD), microemboli develop in the blood circuit of the apparatus. These microemboli can pass through the venous chamber and enter into the patient's circulation. The aim of this study was to investigate whether it is possible to reduce the risk for exposure of microemboli by altering of the treatment mode. Twenty patients on chronic HD were randomized to a prospective cross-over study of three modes of HD: (a) a dry-stored dialyzer ( F8HPS, Fresenius, steam sterilized) with a low blood level in the venous chamber ( DL), (b) the same dialyzer as above, but with a high level in the venous chamber ( DH), and (c) a wet-stored dialyzer ( Rexeed, Asahi Kasei Medical, gamma sterilized) with a high blood level ( WH). Microemboli measurements were obtained in a continuous fashion during 180 minutes of HD for all settings. A greater number of microemboli were detected during dialysis with the setting DL vs. WH (odds ratio [ OR] 4.07, 95% confidence interval [ CI] 4.03-4.11, P < 0.0001) and DH vs. WH ( OR 1.18, 95% CI 1.17-1.19, P < 0.0001) and less for DH vs. DL ( OR 0.290, 95% CI 0.288-0.293, P < 0.0001). These data indicate that emboli exposure was least when using WH, greater with DH, and most with DL. This study shows that using a high blood level in the venous chamber and wet-stored dialyzers may reduce the number of microemboli. [ABSTRACT FROM AUTHOR]

The aim of this study was to create polymeric materials with known properties to study the preconditions for complement activation. Initially, 22 polymers were screened for complement activating capacity. Based on these results, six polymers (P1-P6) were characterized regarding physico-chemical parameters, for example, composition, surface area, pore size, and protein adsorption from human EDTA-plasma. P2, P4, and reference particles of polystyrene and polyvinyl chloride, were hydrophobic, bound low levels of protein and were poor complement activators. Their accessible surface was limited to protein adsorption in that they had pore diameters smaller than most plasma proteins. P1 and P3 were negatively charged and adsorbed IgG and C1q. A 10-fold difference in complement activation was attributed to the fact that P3 but not P1 bound high amounts of C1-inhibitor. The hydrophobic P5 and P6 were low complement activators. They selectively bound apolipoproteins AI and AIV (and vitronectin), which probably limited the binding of complement activators to the surface. We demonstrate the usefulness of the modus operandi to use a high-throughput procedure to synthesize a great number of novel substances, assay their physico-chemical properties with the aim to study the relationship between the initial protein coat on a surface and subsequent biological events. Data obtained from the six polymers characterized here, suggest that a complement-resistant surface should be hydrophobic, uncharged, and have a small available surface, accomplished by nanostructured topography. Additional attenuation of complement can be achieved by selective enrichment of inert proteins and inhibitors. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part A: , 2011. [ABSTRACT FROM AUTHOR]

Objective. Previous international studies have elucidated signs of poor physical and mental health in women who have sex with women (WSW) and an avoidance of preventive healthcare. When the first Nordic gynecological clinic for WSW was started in Stockholm in 1999, an opportunity to compile information about their physical and psychological health and social situation arose. Design. Retrospective descriptive. Setting and sample. A total of 706 women: 264 patients attending a WSW clinic and 442 women attending the regular gynecological clinic. Methods. Questionnaires. Response rate: WSW 77%, comparison group 40%. Main outcome measures. Possible differences in mental and reproductive health and attendance of preventive healthcare by WSW and heterosexual women. Results. Having had a male sexual partner was reported by 82.3% of the WSW, 39.5% in the last five years and 4.9% in the last year. One-fifth of WSW had been pregnant, and one in ten had given birth. Equally, many had experience of induced abortion. WSW had less experience of gynecological examination and Papanicolaou smear screening. More than one-fifth of WSW had at some time had sexually transmitted infections (STI) and 12.6% reported a history of cervical atypia. WSW remembered dissatisfaction with their sexual lives during their youth and had more frequently sought professional help for their sexuality. Conclusion. WSW attend gynecological examinations to a lesser extent than heterosexual women. The fact that WSW reported having been affected by STI and cervical cell atypia underlines the opinion that they should be advised to attend the same gynecological check-ups and cervical screening programs as heterosexual women. [ABSTRACT FROM AUTHOR]

In 1997–2003, a protocol for treatment of acute myeloid leukaemia (AML) (except promyelocytic leukaemia) was activated in four Swedish health care regions covering 50% of the national population. Based on cytogenetics and clinical findings, patients aged 18–60 yr were assigned to one of three risk groups. In this report we account for the long-term clinical outcome of enrolled patients. Patients received idarubicin and cytarabine in standard doses as induction therapy and consolidation courses included high-dose cytarabine. Allogeneic stem cell transplantation (allo-SCT) from an human leucocyte antigen-identical sibling was recommended in standard and poor-risk patients, whereas unrelated donor transplant was reserved for poor-risk patients. Autologous (auto-SCT) was optional for standard or poor risk patients not eligible for allo-SCT. Two hundred seventy-nine patients with de novo or secondary (9%) AML, median age 51 (18–60) yr, corresponding to 77% of all patients in the population, were included. Twenty (7%) patients were assigned to the good risk group, whereas 150 (54%) and 109 patients (39%) were assigned to standard- and poor-risk groups, respectively. Induction failures accounted for 55 patients; 16 early deaths eight of whom had white blood cell (WBC) >100 at diagnosis, and 39 refractory disease. Thus, complete remission (CR) rate was 80%. At study closure, the median follow-up time of living patients was 90 months. Median survival time from diagnosis in the whole group was 27 months and 4-yr overall survival (OS) rate was 44%. In good, standard, and poor risk groups, 4-yr OS rates were 60, 57 and 24%, respectively. Median relapse-free survival (RFS) time in CR1 was 25 months and RFS at 4 yr was 44%. Four-year RFS rates were significantly ( P < 0.001) different between the three risk groups; 64% in good risk, 51% in standard risk and 27% in poor risk patients. One hundred-ten transplantations were performed in CR1; 74 allo-SCT (50 sibling, 24 unrelated donor), and 36 auto-SCT. Non-relapse mortality was 16% for allo-SCT patients. Outcome after relapse was poor with median time to death 163 d and 4-yr survival rate 17%. Three conclusions were: (i) these data reflect treatment results in a minimally selected population-based cohort of adult AML patients <60 yr old; (ii) a risk-adapted therapy aiming at early allogeneic SCT in patients with a high risk of relapse is hampered by induction deaths, refractory disease, and early relapses; and (iii) high WBC count at diagnosis is confirmed as a strong risk factor for early death but not for relapse. [ABSTRACT FROM AUTHOR]

Objectives Primary adrenocortical insufficiency is mostly caused by an autoimmune destruction of the adrenal cortex. The disease may appear isolated or as a part of an autoimmune polyendocrine syndrome (APS). APS1 is a rare hereditary disorder with a broad spectrum of clinical manifestations. In APS2, primary adrenocortical insufficiency is often combined with autoimmune thyroid disease and/or type 1 diabetes. We analysed mortality and cancer incidence in primary adrenocortical insufficiency patients during 40 years. Data were compared with the general Swedish population. Design and patients A population based cohort study including all patients with autoimmune primary adrenocortical insufficiency (3299) admitted to Swedish hospitals 1964–2004. Measurements Mortality risk was calculated as the standardized mortality ratio (SMR) and cancer incidence as the standardized incidence ratio (SIR). Results A more than 2-fold increased mortality risk was observed in both women (SMR 2·9, 95% CI 2·7–3·0) and men (SMR 2·5, 95% CI 2·3–2·7). Highest risks were observed in patients diagnosed in childhood. SMR was higher in APS1 patients (SMR 4·6, 95% CI 3·5–6·0) compared with patients with APS2 (SMR 2·1, 95% CI 1·9–2·4). Cancer incidence was increased (SIR 1·3, 95% CI 1·2–1·5). When tumours observed during the first year of follow-up were excluded, only the cancer risk among APS1 patients remained increased. Cause-specific cancer incidence analysis revealed significantly higher incidences of oral cancer, nonmelanoma skin cancer, and male genital system cancer among patients. Breast cancer incidence was lower than in the general population. Conclusions Our study shows a reduced life expectancy and altered cancer incidence pattern in patients with autoimmune primary adrenocortical insufficiency. [ABSTRACT FROM AUTHOR]

Heat shock proteins (HSPs) protect cells against stress-associated injury and are overexpressed in several malignant tumors. We aimed to investigate their value as prognostic markers in prostate cancer. A tissue microarray (TMA) was constructed of 289 prostate cancers from radical prostatectomy (RP) specimens with median follow-up of 48.9 months. Slides were immunostained for HSP27, HSP60 and HSP70. Intensity and extent of immunoreactivity (IR) and their product (IRp) was evaluated by two observers. The IRp of HSP27 and HSP60, but not of HSP70, significantly predicted biochemical recurrence (p=0.014, 0.034 and 0.160, respectively). Recurrence-free survival in patients with strong HSP27 and HSP60 staining was shorter than in those with weak expression (p=0.019 and 0.001, respectively). IRp of HSP27 and HSP60 correlated with Gleason score (p<0.01). HSP60 was an independent predictor of biochemical recurrence in multivariate analysis, including extraprostatic extension, margin status, seminal vesicle invasion and Gleason score. Weighted kappa for interobserver agreement of HSP27, HSP60 and HSP70 IR was 0.613–0.823 for intensity and 0.584–0.719 for IRp, but only 0.036–0.244 for extent, raising the question whether staining extent should be estimated on TMA. We conclude that HSP27 and HSP60 are predictors of biochemical recurrence after RP. [ABSTRACT FROM AUTHOR]

Background: A massive destruction of transplanted tissue occurs immediately following transplantation of pancreatic islets from pig to non-human primates. The detrimental instant blood-mediated inflammatory reaction (IBMIR), triggered by the porcine islets, is a likely explanation for this tissue loss. This reaction may also be responsible for mediating an adaptive immune response in the recipient that requires a heavy immunosuppressive regimen. Materials and methods: Low molecular weight dextran sulfate (LMW-DS) and the complement inhibitor Compstatin were used in a combination of in vitro and in vivo studies designed to dissect the xenogeneic IBMIR in a non-human primate model of pancreatic islet transplantation. Adult porcine islets (10 000 IEQs/kg) were transplanted intraportally into three pairs of cynomolgus monkeys that had been treated with LMW-DS or heparin (control), and the effects on the IBMIR were characterized. Porcine islets were also incubated in human blood plasma in vitro to assess complement inhibition by LMW-DS and Compstatin. Results: Morphological scoring and immunohistochemical staining revealed that the severe islet destruction and macrophage, neutrophilic granulocyte, and T-cell infiltration observed in the control (heparin-treated) animals were abrogated in the LMW-DS-treated monkeys. Both coagulation and complement activation were significantly reduced in monkeys treated with LMW-DS, but IgM and complement fragments were still found on the islet surface. This residual complement activation could be inhibited by Compstatin in vitro. Conclusions: The xenogeneic IBMIR in this non-human primate model is characterized by an immediate binding of antibodies that triggers deleterious complement activation and a subsequent clotting reaction that leads to further complement activation. The effectiveness of LMW-DS (in vivo and in vitro) and Compstatin (in vitro) in inhibiting this IBMIR provides the basis for a protocol that can be used to abrogate the IBMIR in pig-human clinical islet transplantation. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies produced by patients with lymphoproliferative diseases sometimes appear as cryoglobulins (CG), immunoglobulins (Ig) that reversibly agglutinate and form immune complexes (IC) when cooled below normal body temperature or through variation in pH and ionic strength. In accordance with our findings of IC-induced cytokine production from peripheral blood mononuclear cells (PBMC) in systemic lupus erythematosus, we investigated whether CG can also induce cytokine production. One IgG and one IgM type I CG from two patients with multiple myeloma and Waldenstrom's macroglobulinaemia were individually purified and added to PBMC cultures. In separate experiments temperature and ionic strength were varied, or Fc γRIIa, Fc γRIII and complement activation were blocked; supernatant cytokine levels were then determined by enzyme-linked immunosorbent assay. CG-induced cytokine production from monocytes varied with precipitation induced by changes in temperature and ionic strength and was mediated via Fc γRIIa- and complement-dependent mechanisms. Complement blockade resulted in increased IgG CG-induced interleukin (IL)-10 production that was inversely correlated with decreased production of tumour necrosis factor- α. CG-induced IL-10 might be a growth factor for malignant B-lymphocytes in CG-associated lymphoproliferative diseases with constant complement consumption. Knowledge of mechanisms underlying CG-induced cytokine production can be useful for designing treatments for type I CG-associated pathology in lymphoproliferative diseases. [ABSTRACT FROM AUTHOR]

To study the effect of vaginal surgery for urinary incontinence and genital descensus on sexual function and quality of life.The day before surgery, 118 women, of whom 41 were admitted for urinary incontinence and 77 for genital descensus, accepted to complete a questionnaire containing questions of uterovaginal symptoms, quality of life, and sexuality. One year later, 101 women, of them 88 were sexually active, accepted to complete the same questionnaire by mail.The women reported improvement in two different scales for quality of life, and there was no difference between surgery for genital descensus and that for urinary stress incontinence. The total score for sexual variables was deteriorated, and the mean frequency of sexual intercourse was reduced. Among women with genital descensus, 14% experienced more urinary incontinence and 13% more dyspareunia after the operation.Although pelvic floor disorders are known to impair sexual function, there was no improvement in sexuality after surgery for urinary incontinence or genital descensus. On the contrary, it seems that sexual function might deteriorate and dyspareunia get worse after vaginal surgery. The explanation for this might be vulnerability to disturbance of vaginal nerve and blood supply of the vaginal wall resulting in impaired sexual arousal and lubrication. [ABSTRACT FROM AUTHOR]

Patients with systemic lupus erythematosus (SLE) have an increased risk of thrombosis. Platelet-induced extracellular phosphorylation of plasma proteins suggests that this is due to persistent activation of the platelets. We examined 30 SLE patients (15 with thrombotic disease), 18 non-SLE patients with deep vein thrombosis (DVT) and 50 healthy controls by analysing β-thromboglobulin, activated factor XI-antithrombin complexes and fibrinogen-bound phosphate. All parameters were elevated in SLE patients, particularly those with thrombosis, but normal in DVT cases and healthy controls. We conclude that thrombotic disease in SLE patients is associated with a persistent systemic platelet activation that may lower the threshold for induction of thrombosis. [ABSTRACT FROM AUTHOR]

Goto M, Groth CG, Nilsson B, Korsgren O. Intraportal pig islet xenotransplantation into athymic mice as an in vivo model for the study of the instant blood-mediated inflammatory reaction. Xenotransplantation 2004; 11: 195–202. © Blackwell Munksgaard, 2004 One of the main obstacles to successful intraportal islet transplantation is the instant blood-mediated inflammatory reaction (IBMIR) elicited by the isolated islets when exposed to fresh human blood. In the present study, we investigated whether intraportal transplantation of pig islets into diabetic athymic mice could be used as a small animal model to study xenogeneic IBMIR in vivo. Adult porcine islets (APIs) or rat islets were implanted into the portal vein or under the renal subcapsular space of diabetic athymic mice. Graft survival and morphology were evaluated by measuring blood glucose levels and by performing immunohistochemical staining, respectively. Transplantation of rat islets, irrespective of implantation site, cured all diabetic athymic mice. APIs transplanted subcapsularly also cured all diabetic athymic mice, while none of the animals transplanted with an equivalent amount of APIs via the portal vein remained normoglycemic for more than 10 days after transplantation. Immunohistochemical staining on day 7 showed that most of intraportally transplanted APIs were entrapped in clots and infiltrated with CD11b+ leukocytes. Intraportal transplantation of APIs into athymic mice induced IBMIR, thus providing a small animal model for studying xenogeneic IBMIR. [ABSTRACT FROM AUTHOR]

Abstract: Studies on vascular hyperacute xenograft rejection (HAR) are usually conducted in vitro on cultured endothelial cells (EC) exposed to human serum, in complex whole organ perfusion models using heparinized blood or in vivo models. Here we describe a new model allowing perfusion of pig vessels with human whole blood without anticoagulants. Segments of the porcine iliac artery were connected to circular polyvinyl chloride (PVC) tubing, whose inner surface was conjugated with immobilized heparin. The vessels were perfused with 7 to 8 ml of fresh, non-anticoagulated human blood by rocking of the tubing device for 5, 15 or 60 min in an incubator at 37°C. Human iliac arteries (n = 4) were perfused with fresh human ABO-compatible blood as controls. Perfusion of human vessels resulted in changes in the blood and plasma parameters similar to those in the PVC control loop. Overall, perfusion of the porcine vessels generated high levels of C3a, sC5b-9 and thrombin–anti-thrombin (TAT). Platelet consumption was near total (97.2 ± 1.2%; “high” responders) in six of 13 vessels perfused and only moderate (55.8 ± 9.9%; “low” responders) in the remaining seven vessels. The “high” responder vessel group showed a significantly higher platelet reduction, neutrophil loss and monocyte consumption and higher C3a and TAT factor at 60 min compared with the human vessels. The “low” responder porcine vessel group also generated significantly higher TAT levels at 60 min compared with the human vessels, but lower levels compared with the “high” responder porcine vessel group. Immunohistochemical examination of perfused porcine vessels revealed binding of human IgM, IgG, IgA, C1q, C3, fibrin and platelets at 5 min. The binding of these proteins was even stronger at 15 and 60 min, and at 60 min C9 could also be detected. Addition of soluble complement receptor 1 (sCR1) to the blood resulted in a significant reduction in C3a and sC5b-9 (P = 0.046 and P = 0.046, respectively). However, sCR1 did not reduce C1q, C3c or C5 staining, but did abolish C9 binding to the endothelium. In conclusion, in vitro perfusion of porcine vessel segments with non-heparinized, fresh human blood triggered events characterizing HAR. The small quantity of blood and xenogenic tissue that is needed makes this model ideal for investigations of the mechanisms and treatments of rejections associated with xenogeneic pig-to-human xenotransplantation. [ABSTRACT FROM AUTHOR]

Objective: To determine the prognosis in 86 new patients with social anxiety disorder. Method: Untreated subjects with social anxiety were recruited by advertising in Stockholm, randomized to 3 months treatment with paroxetine or placebo, and then offered continued specialist care. Metabolizing capacity was determined by genotyping CYP2D6 in the subjects on paroxetine. After a mean 32 months all were contacted for a personal interview. Results: Of the 92 evaluable subjects, 86 (93%) were interviewed. A favourable prognosis was seen in the subjects randomized to paroxetine who chose to continue with serotonergic medication. The least favourable prognosis was in those given placebo who chose not to be treated after the trial. Twenty-four subjects were still symptomatic and dysfunctional and had not sought treatment. Drug-induced adverse effects caused treatment termination in six subjects, one of whom had a poor metabolizing genotype. Conclusion: Due to their condition, some subjects with social anxiety refrain from effective treatments. The efficacy of serotonergic medication was maintained and augmented after a mean period of 32 months. [ABSTRACT FROM AUTHOR]

A mouse monoclonal IgM antibody, directed against human blood group B determinant, was isolated from hybridoma culture growth medium. Chemical analysis indicated presence of N- and O-linked oligosaccharides. The N- and O-linked carbohydrate chains were liberated using two different conditions of reductive alkaline degradation. Structural analysis was carried out on the isolated chains using chemical analysis, 500-MHz ¹H-NMR spectroscopy and fast-atom-bombardment mass spectrometry. The following composite structures of the N-linked chains were found: ["Multiple line equation(s) cannot be represented in ASCII text"]. where R = OH for biantennary structures and R = Neu5Ac α 2-3Gal β 1-4 GlcNAc β 1- or Neu5Ac α 2-3Gal β 1-3[Neu5Ac α 2-6]GlcNAc β 1- for triantennary structures. The O-linked oligosaccharides, found in the light chains, were shown to have the structure Neu5Ac α 2-3Gal β 1-3GalNAc. The native IgM antibody could be separated on a concanavalin- A-Sepharose column into two subfractions, differing in the presence of a high-mannose-type oligosaccharide. [ABSTRACT FROM AUTHOR]

Abnormally high amounts of low molecular weight mannose-rich carbohydrate material were found in the urine of an Angus calf with mannosidosis. At least five oligosaccharide fractions were detected by paper chromatography. The most abundant compound was purified by gel chromatography, zone electrophoresis, and two consecutive preparative paper chromatographic steps. The yield was 10 mg/liter of urine. From structural studies including nuclear magnetic resonance spectroscopy, optical rotation, sugar analysis, methylation analysis, and partial enzymatic degradation the following structure was deduced: α-D-Manp- (1 → 6)-β-D-Manp-(1 → 4)-β-D-GlcNAcp-(1 → 4)-β-D-GlcNAcp-(1 → 4)-D-GlcNAc. This oligosaccharide is distinct from all the oligosaccharides previously described which are excreted by patients with mannosidosis. [ABSTRACT FROM AUTHOR]

The article discusses the role of cultural history museums in educating the public about environmental destruction and environmental protection. It provides an overview of the incidents related to environmental destruction, including the increasing temperature of the Earth, the drought in the Sahel and the flood disasters in Bangladesh and China. It relates the advantages of using the museum as a medium to educate the public in line with the ability of the museum to work with so many senses of its audience, including the sense of sight, sense of hearing, touch and smell. Information is presented on the project of museums in Sweden to spread ecological knowledge.

Recently qualified dentists from a dental school in Stockholm, Sweden (n = 259) and the dental school in Kuopio, Finland (n = 103) were sent a questionnaire designed to obtain information concerning the perceived relevance of their under- graduate education to the practice of dentistry. The response rate was 71 % for Stockholm and 82% for Kuopio. Except for minor differences, probably mainly due to economic resources and traditions in choice of treatment, the graduates in the two countries had comparable views of their basic education. In general, clinical dental subjects were highly valued, while basic science subjects but also subjects in medical and behavioral sciences were given low values. Our results indicate that, although prevention and behavioral sciences are stressed more and more in under- graduate education, the practice of clinical dentistry remains essentially unchanged and restorative dentistry is still very highly valued among recent graduates of these two dental schools. [ABSTRACT FROM AUTHOR]