Epstein-Barr virus infection after adolescence and human herpesvirus 6A as risk factors for multiple sclerosis.

BACKGROUND AND PURPOSE: Infections with human herpesvirus 6A (HHV-6A) and Epstein-Barr virus (EBV) have been linked to multiple sclerosis (MS) development. For EBV, late infection has been proposed as a risk factor, but serological support is lacking. The objective of this study was to investigate how age affects the EBV and HHV-6A associated risks of developing MS. METHODS: In this nested case-control study, Swedish biobanks were accessed to find pre-symptomatically collected blood samples from 670 individuals who later developed relapsing MS and 670 matched controls. A bead-based multiplex assay was used to determine serological response against EBV and HHV-6A. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. RESULTS: Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20-29 and 30-39 years (p for trend 0.020). The age of transition was estimated to be 18.8 years. In contrast, HHV-6A was associated with increased MS risk in all age groups (total cohort odds ratio 2.1, 95% confidence interval 1.6-2.7). CONCLUSIONS: This study suggests EBV infection after adolescence and age independent HHV-6A infection as risk factors for MS.

Heterogeneous photochemistry relevant to the troposphere: H(2)O(2) production during the photochemical reduction of NO(2) to HONO on UV-illuminated TiO(2) surfaces.

Bleached out: The detection of an oxidized co-product, hydrogen peroxide, during an important tropospheric reaction, combined with the detection of photoaccelerated surface nitrate formation (a competing pathway), allows a likely mechanism to be proposed (see figure) which explains previously observed experimental stoichiometries.

Reduction of NO2 to nitrous acid on illuminated titanium dioxide aerosol surfaces: implications for photocatalysis and atmospheric chemistry.

TiO2, a component of atmospheric mineral aerosol, catalyses the reduction of NO2 to nitrous acid (HONO) when present as an aerosol and illuminated with near UV light under conditions pertinent to the troposphere.

Clinical manifestations and diagnosis of neuroborreliosis.

Lyme borreliosis has in a few years turned out to be a health problem not only in the United States, but also in many European countries. When it affects the nervous system, Lyme borreliosis acts as the great disease imitator. Because of this characteristic it is often difficult to diagnose on clinical grounds. Patients with neuroborreliosis might appear within all medical disciplines. Clinical markers, such as preceding tick bite and/or ECM, are important clues to the diagnosis. Mononuclear pleocytosis and elevated CSF protein are present in most patients with neuroborreliosis. Final evidence for the diagnosis is the demonstration of specific antibodies in serum and/or CSF. Measurement of antibody titers should be carried out in both serum and CSF, since these methods are complementary when trying to obtain a serological diagnosis of neuroborreliosis.

Open the black box: paradoxes and lacunas in Swedish health care reforms.

The idea of using contracting-out as a means for improving public administration dates back to the 1850s, but was then found to be infeasible. The same idea has now become a major building-block in Sweden's health care reforms. Driven by a productivity-focused political discourse and the premises of neoclassical economics, these reforms ignore motivational structures among health care staff. The result may be a delegitimizing of the welfare state from within--either through the extinction of care rationality and its replacement by wage rationality, or, at worst, through the spread of a commercial spirit among health care staff and/or staff frustration at the unavoidable downward adjustments in remuneration rates. The author points to three strategic choices that arise when insights from a labor-process perspective are taken into consideration.

Origins of authority: the organization of medical care in Sweden.

Earlier research by Gardell and Gustafsson indicates a general discrepancy between perceived needs and organizational structure in Swedish somatic hospitals; the work organization directs the work process as if cure and medical treatment were the only appropriate goals in almost all kinds of health care settings. The standard organizational model for general hospitals, here named "the acute care model"--which is a merger of medical and administrative hierarchies--forces great segments of the staff into a work content that is neither appropriate for patients' needs nor satisfying for the personnel. The present study is a historical-sociological discourse in which the structural antecedents of the acute care model are traced. It gives an exposé of the main stages in the formation of the Swedish health care system from the middle ages to the present. In 1864 a regulation of the hospital boards was issued. This meant the definite consolidation of the acute care model and was in line with earlier developments, which were characterized by an incremental interorganizational activity demarcation that divided the core of institutional care into three branches: somatic hospitals, mental hospitals, and homes for the elderly. The driving forces in the formation of the total health care system are shown to be closely related to premedical and extramedical factors, such as military needs, mercantilism, and the emergence of the middle class.

[Systemic sclerosis]. / Systemisk skleros.

Systemic sclerosis is a generalised connective tissue disorder characterised clinically by thickening and fibrosis of the skin and by the involvement of such internal organs as the kidneys, lungs, heart and gastro-intestinal tract. Although the aetiology of systemic sclerosis is unknown, its prevalence has been reported to be increased in workers exposed to silica. Most pathogenic findings in patients with systemic sclerosis involve changes in the vascular system, immunological anomalies and disturbances in the regulation of fibroblast function. Two subsets are recognised according to the degree of skin involvement: the limited cutaneous form, usually confined to acral features; and diffuse cutaneous scleroderma, manifesting involvement both of the trunk and extremities. The latter subset is characterised by more rapid progression of skin and visceral involvement, poorer prognosis and manifestly reduced survival. No adequate therapy has been found, and optimal use of the available therapies necessitates accurate subset assignment of the patient in order to be able to assess the stage of disease in relation to vascular, immunological and fibroblast function changes.

Eosinophil activation in systemic sclerosis.

Circulating levels of eosinophil cationic protein (ECP) were increased 4-fold in patients with systemic sclerosis (SSc) compared with those in healthy control subjects. There was no correlation between the ECP concentrations and laboratory indices of inflammatory activity or visceral involvement. Mean ECP levels were higher in patients with a history of occupational exposure to silica, even though patients who had no such history also had ECP levels higher than normal. The patients had increased bronchoalveolar levels of ECP, which correlated with impaired lung functioning. Skin infiltration with activated eosinophils and extracellular deposits of ECP were present in skin biopsy samples from the SSc patients. We conclude that eosinophil activation is part of the inflammatory process in SSc.

Increase in activated T cells and reduction in suppressor inducer T cells in systemic sclerosis.

Blood lymphocytes from 37 patients with systemic sclerosis were characterised using monoclonal antibodies in a two colour flow cytometric (fluorescence activated cell sorter (FACS)) analysis. The ratio of helper CD4+ to suppressor/cytotoxic CD8+ T cells was raised in patients compared with that in 30 healthy controls owing to decreased CD8+ cells. In the patients CD4+ and CD8+ cells displayed an increased expression of the activation marker HLA-DR. The relative number of CD11b+ CD8+ lymphocytes (suppressor T cells) was normal, but the calculated absolute counts of this cell type were slightly reduced. The proportions and absolute numbers of suppressor inducer T cells, defined as CD45R+ CD4+ cells, were on average only half the levels observed in controls. These findings were not related to the inflammatory activity as measured by acute phase plasma proteins or serum immunoglobulins. Activated T cells were seen at all stages of the sclerotic process and especially during the early stages of the disease and in patients who had suffered occupational exposure to silica dust. A high proportion of activated T cells was also linked with impaired small intestine function but not with the degree of skin or lung involvement. A loss of suppressor inducer T cells was more pronounced later in the disease and in patients with the CREST (calcinosis, Raynaud's phenomenon, oesophageal dysmotility, sclerodactyly, telangiectasia) syndrome. These data provide further evidence for an involvement of T cell mediated immunity in the perpetuation of systemic sclerosis.

Increased expression of platelet-derived growth factor type B receptors in the skin of patients with systemic sclerosis.

The expression of B-type receptors for platelet-derived growth factor (PDGF) was investigated in skin biopsy samples from patients with systemic sclerosis (SSc), by immunohistochemical staining using monoclonal antibodies specific for the receptor. Whereas skin from healthy individuals lacked expression of PDGF-B receptors, receptor expression was seen in sclerodermatous skin lesions from 13 of 14 patients. Increased receptor expression was observed in dermal vessels, as well as on many stromal fibroblast-like cells close to these vessels. PDGF-B receptor expression was most pronounced within and around dermal vessels in which perivascular infiltrates of Leu-4-positive T lymphocytes and HLA-DR-positive, RFD7-positive activated macrophages were present. Both perivascular inflammatory cell infiltrates and PDGF-B receptor expression were generally also seen in macroscopically normal areas of the skin of the SSc patients, indicating that the observed phenotypic alterations may precede the macroscopically observable features of scleroderma in the skin. The observed induction of PDGF-B receptors, together with indirect indications of increased synthesis and release of PDGF, would be compatible with altered PDGF-mediated control of connective tissue cell growth as part of the molecular basis for development of the skin lesions in SSc.

Non-invasive assessment of systolic left ventricular function in systemic sclerosis.

Systemic sclerosis is a multisystemic disorder, also affecting the heart. To evaluate its influence on systolic left ventricular (LV) function, we investigated 30 consecutive patients (age 54.5 +/- 2.4 years, 15 men and 15 women) and 48 controls matched for age and sex. All subjects were investigated by phonocardiography, pulse curve recordings, M-mode echocardiography, and by pulsed and continuous wave Doppler. Heart rate, blood pressure and peripheral resistance did not differ, but patients weighed less than controls (P less than 0.01). Systolic time intervals indicated systolic impairment, with an increased pre-ejection period to LV ejection time (LVET) ratio (0.37 +/- 0.02 vs 0.30 +/- 0.01 P less than 0.001), and also an increased isovolumic contraction time to LVET ratio (0.17 +/- 0.02 vs 0.12 +/- 0.01, P less than 0.02). The latter difference remained when LVET was adjusted for heart rate. Echocardiographic E-point to septal separation was increased in patients (8.3 +/- 1.3 vs 4.8 +/- 0.3 mm, P = 0.001), also after adjustment for LV dimension (P = 0.0001), while septal fractional thickening was decreased (P less than 0.01). End systolic wall stress (P = 0.0002) and stress to volume ratio (P = 0.03) were lower in systemic sclerosis. Peak LV emptying rate was also lower in the patient group when measured by echocardiography (P = 0.03). There was no difference between groups regarding LV dimensions, fractional shortening or mean velocity of circumferential fibre shortening. While aortic Doppler peak emptying rate did not differ between groups, it occurred later in systole in the patient group (P less than 0.01) as did peak velocity (P = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Non-invasive evaluation of long-term cardiac effects of captopril in systemic sclerosis.

Impairment of left ventricular (LV) function has previously been reported in patients with systemic sclerosis (SScl). An intermittent vasospastic process in the myocardium may contribute to the development of myocardial dysfunction. Vasodilators may therefore be potentially useful in the treatment of cardiac dysfunction in patients with SScl. This study was designed to evaluate the long-term effects of captopril on the myocardial function of patients with SScl. Twenty-two patients with SScl (15 patients with diffuse scleroderma and 7 patients with CREST syndrome, i.e. calcinosis. Raynaud's phenomenon, oesophageal hypomotility, sclerodactyly, telangiectasia) were investigated by means of Doppler and echophonocardiography before and after treatment with captopril (1.3 mg kg-1 body weight d-1) for 11-15 months. There were no significant differences in heart rate, systolic and diastolic blood pressure, end-systolic blood pressure, total peripheral resistance or LV diameters before or after treatment. However, captopril treatment exerted significant effects on LV function: the pre-ejection period (PEP) and the ratio of pre-ejection period to LV ejection time decreased significantly (P less than 0.05). Mitral E-point septal separation decreased significantly (P less than 0.01), even after adjustment for LV end-diastolic diameter (P less than 0.01). The ejection fraction increased significantly (P less than 0.05), and the isovolumic relaxation time decreased (P less than 0.01). The left atrial emptying index increased (P less than 0.01). The Doppler peak late to early ventricular filling velocity decreased (P less than 0.05), and the isovolumic index was also reduced (P less than 0.05). We conclude that both systolic and diastolic LV function indices improved in patients with SScl after captopril treatment for a mean period of 1 year. The effects of captopril might be due to vasodilation of the myocardial vessels and/or a direct effect on the renin-angiotensin system of the heart.

Cold-induced reversible myocardial ischaemia in systemic sclerosis.

The effect of cold provocation on myocardial perfusion was studied in 21 patients with systemic sclerosis and 8 healthy controls. The cold provocation was designed not to cause a pain reaction, and no rise in heart rate/blood pressure product occurred during provocation. Myocardial perfusion was assessed by measurement of thallium uptake by imaged single photon emission computed tomography. No patient had clinical evidence of cardiac involvement, but abnormal electrocardiographic (ECG) findings were found in 5. In 12 patients cold-induced reversible perfusion defects were found; 9 of these also had permanent defects. A further 3 patients had permanent perfusion defects but no reversible defects. The permanent and/or reversible perfusion defects were not related to age among the patients and were not seen in any of the healthy controls, whose age distribution was similar. The reversible and permanent defects were not related to other features of systemic sclerosis, nor to the ECG findings. It is concluded that abnormalities in myocardial perfusion are common in systemic sclerosis and may be present without apparent clinical myocardial involvement. A cold-induced vasopastic process in the myocardial circulation might contribute to the development of the patchy myocardial fibrosis seen in patients with systemic sclerosis.

Short-term kinetics of the humoral anti-C1q response in SLE using the ELISPOT method: fast decline in production in response to steroids.

Twenty four systemic lupus erythaematosus patients and 17 patients with other diagnoses were investigated regarding the presence of cells producing C1q reactive antibodies in peripheral blood mononuclear cells using the ELISPOT technique. These results were then compared with parallel serum levels of C1q reactive antibodies. Current production of anti-C1q was almost entirely confined to the systemic lupus erythaematosus group. Longitudinal analysis of anti-C1q ELISPOT positive patients showed rapid changes in the number of anti-C1q producing cells, but only slowly changing serum levels of the corresponding antibodies in response to glucocorticoids. In one systemic lupus erythaematosus patient prednisolone treatment had a selective effect on this autoantibody production, as the production of anti-C1q spot forming cells rapidly dropped to zero, at the same time as the number of total spot-forming cells showed only less change. In another patient, self-limiting connective tissue disease was associated with temporal occurrence of IgM anti-C1q. We believe, from these data, that the ELISPOT method for determination of current antibody production may be of particular value in longitudinal evaluation of disease course and therapeutic effects in systemic lupus erythaematosus and other rheumatic diseases.

Phenotypic and functional activation of alveolar macrophages, T lymphocytes and NK cells in patients with systemic sclerosis and primary Sjögren's syndrome.

OBJECTIVES: Attempts to differentiate between the pathogenesis of the severe pulmonary manifestations observed in systemic sclerosis (SSc) and the mild form in primary Sjögren's syndrome (pSS) were performed by studying cell populations recovered during bronchoalveolar lavage (BAL). METHODS AND RESULTS: Two-colour flow cytometric analysis of BAL fluid lymphocytes showed a similar degree of phenotypic activation (DR+) of CD4+ and CD8+ T lymphocyte subsets and CD16+ NK cells in patients with SSc (n = 13) and pSS (n = 11) groups and healthy controls (n = 11). Alveolar macrophages expressed the CD14 antigen at significantly increased densities in patients with SSc. Alveolar macrophage activation in SSc was also suggested by increased IL-6 concentrations in neat BAL fluid and increases in macrophage production of TNF alpha and EGF in vitro. SSc patients also had increased proportions of neutrophils and eosinophils in BAL fluid. No correlations were found between any cellular subsets or cytokine levels in BAL fluid and lung status at the time of lavage in SSc or pSS patients or the subsequent course of the pulmonary function in SSc patients. CONCLUSION: It is concluded that the phenotypical activation of alveolar helper/inducer (DR+CD4+) and suppressor/cytotoxic (DR+CD8+) T lymphocytes and NK (DR+CD16+) cells is not a prerequisite for the development of lung fibrosis in SSc or bronchial hyper-responsiveness in pSS. Alveolar macrophage activation may contribute to the development of lung fibrosis in SSc.