Arg506–Gln mutation in factor V and risk of thrombosis during pregnancy

Seventy women with thrombosis in pregnancy were investigated for the presence of APC resistance and the associated Arg⁵⁰⁶–Gln mutation in coagulation factor V. The mutation was found in 46% of the investigated women. Carriers of the mutation were more prone to develop thrombosis in the first pregnancy (OR (odds ratio) = 3.41; P  < 0.05) and had a higher probability of recurrence (OR = 3.86; P  < 0.05) compared to non-carriers. The incidence of miscarriage was not related to the mutation but its probability increased in women with thrombosis in a second or subsequent pregnancy ( P  < 0.025). Negative dynamics of APC response during pregnancy was observed in 20/22 women; eight of them developed APC resistance de novo . The suppression of APC response was independent of the mutation.     

Coronary venous retroinfusion of deferoxamine reduces infarct size in pigs

The efficacy of coronary venous retroinfusion of the iron chelator deferoxamine was studied in 24 pentobarbital-anesthetized open chest pigs with a 60 min occlusion of the left anterior descending coronary artery followed by 3 h of reperfusion. Eight retrogradely treated pigs were given 10 mg/kg body weight of deferoxamine by way of the anterior interventricular vein and eight systemically treated pigs received the same doses of deferoxamine intravenously. Drug infusions lasted for 5 min, beginning 15 min before reperfusion. Eight control pigs received systemic intravenous saline solution. Myocardial area at risk and necrotic area were assessed by the monastral blue dye and the triphenyltetrazolium chloride staining method, respectively. There were no significant differences in hemodynamics or regional myocardial function (sonomicrometry) among the groups. Infarct size expressed as percent of risk area was 73.9 +/- 13.5% in the control group, 70.6 +/- 16.4% in the systemically treated group and 48.5 +/- 21.4% (p less than 0.05) in the retrogradely treated group. In conclusion, deferoxamine significantly reduced infarct size after coronary occlusion only when given regionally by way of the coronary vein. Because there was no significant hemodynamic effect caused by deferoxamine infusion, it is suggested that this drug prevents postischemic reperfusion injury by a direct cardioprotective effect.     

Stimulation of T-cell cytokine production and NK-cell function by IL-2, IFN-alpha and histamine treatment during remission of non-Hodgkin's lymphoma

Limited therapeutic options remain for patients with relapsing lymphoma following chemotherapy and autologous stem cell transplantation (ASCT), hence motivating investigations of complementary treatments. The aim of the present study was to evaluate feasibility and immunological effects of an immunotherapy schedule administered during chemotherapy-induced remission of aggressive non-Hodgkińs lymphoma (NHL). Repeated cycles of rIL-2, rIFN-alpha and histamine were administered to a patient with a grade III follicle center cell lymphoma, following relapse and high-dose chemotherapy with stem cell support. T-cell cytokine production and repertoire alterations were monitored by flow cytometry together with assessment of natural killer (NK) cell-mediated cytotoxicity. The treatment schedule induced significant increases in frequencies of CD4+ T cells expressing intracellular IFN-gamma or IL-4, thus a T helper (Th) 1 and Th 2 type of response were observed. CD8+T cells showed enhancement mainly of TNF-alpha production. Such induction of T-cell effector functions was accompanied by an augmentation of NK-cell cytotoxicity and a pronounced reduction of possibly regulatory CD57 expressing lymphocytes. The results indicate synergistic T- and NK-cell activation by tolerable doses of the combined immunotherapy, administered during remission after chemotherapy and ASCT in NHL.     

Self-care techniques for acute episodes of low back pain

Guidelines recommend minimal medical intervention for acute non-specific low back pain. However, patients often request strategies to reduce symptoms and recover quickly. Self-care techniques that do not contradict current evidence-based recommendations may be suggested. Self-care techniques can reduce costs and iatrogenic complications that can occur with medical treatment. They may also increase the patient's perception of control and improve long-term outcome. A shift in paradigm for the health care provider and the patient is required for self-care to be successful. These issues, as well as self-care approaches such as medication, exercises, modalities and mind-body techniques are discussed. Practice points for each approach are given.     

Cardiac effects of treatment with quinidine and digoxin, alone and in combination

Systolic time intervals (QS2-I and LVET-I) and echocardiographically determined ejection fraction and velocity of circumferential fiber shortening were recorded in 10 healthy volunteers as measures of inotropic effect during maintenance treatment with 4 consecutive drug regimens: (1) quinidine, 1,200 mg/day; (2) digoxin, average dose 0.31 mg/day; (3) the combination of (1) and (2); and (4) digoxin alone (average dose 0.65 mg/day) to provide the same steady-state serum concentration of digoxin as during the period with combination of digoxin and quinidine. The steady-state serum concentration of digoxin during the low-dose regimen increased from 0.72 +/- 0.15 (mean +/- standard deviation [SD]) to 1.63 +/- 0.28 nmol/liter when quinidine was added. With the high dose of digoxin alone, the serum digoxin level reached 1.68 +/- 0.50 nmol/liter. Skeletal muscle digoxin concentrations during these periods were 27.7 +/- 8.3, 48.7 +/- 16.2, and 51.6 +/- 23.6 nmol/kg of dry weight, respectively. The skeletal muscle to serum concentration ratio of digoxin decreased significantly during quinidine treatment. Systolic time intervals were significantly prolonged by quinidine alone and shortened by digoxin alone, the latter effect being dose-dependent. Subtracting the effect of quinidine itself, the induced increase in digoxin level caused a significant increase in inotropic effect. When these corrected values were compared with those attained during the period with the same steady-state digoxin concentration but in the absence of quinidine, no significant differences were found. Echocardiographically measured ejection fraction and velocity of circumferential fiber shortening showed trends for similar drug effects, as did the systolic time intervals. This study, performed under steady-state conditions, demonstrates that the quinidine-induced increase in steady-state serum digoxin concentration will, with due consideration to quinidine's own pharmacodynamic properties, be accompanied by increased cardiac effects. This indicates that quinidine is not interfering with active receptor sites in the heart for digoxin.     

A comparison of sympathoadrenal activity and cardiac performance at rest and during exercise in patients with ventricular demand or atrial synchronous pacing

Cardiac sympathetic function was assessed by measuring the coronary sinus overflow of noradrenaline and dopamine at rest and during supine exercise in eight patients with high degree atrioventricular block treated with dual chamber pacemakers (DDD). Patients exercised (30-60 W) during both ventricular inhibited (VVI) and atrial synchronous (VAT) pacing. During exercise cardiac output increased less markedly in the VVI mode than in the VAT mode. The cardiac output response was entirely stroke volume dependent in the VVI mode and mainly heart rate dependent in the VAT mode. Coronary sinus noradrenaline concentrations were higher in the VVI mode at rest and during exercise. Noradrenaline overflow from the heart was enhanced during VVI pacing and increased from about 100 pmol/min (17 ng/min) at rest to 1087 pmol/min during exercise (60 W) in the VVI mode and 545 pmol/min in the VAT mode. Dopamine overflow from the heart was less than 5 pmol/at rest but increased 2-5 fold during exercise. Also arterial concentrations of catecholamine increased more during exercise in the VVI mode, but the differences between pacing modes were less pronounced. Circulating adrenaline seems to be of little importance for cardiac function under these conditions; in healthy individuals the arterial concentrations of adrenaline attained in this study have small effects. Cardiac noradrenaline overflow correlated with pulmonary capillary venous pressures and atrial rates in both pacing modes, indicating a relation between cardiac sympathetic activity and cardiac function. Enhanced cardiac release of noradrenaline may increase cardiac contractility and thereby partially compensate for the lack of heart rate responsiveness to exercise during VVI pacing.     

Selective inhibition of 11 beta-hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycemic mice strains

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) has been proposed as a new target for type 2 diabetes drugs. The aim of the present study was to assess the effects of inhibition of 11 beta-HSD1 on blood glucose levels, glucose tolerance, and insulin sensitivity in mouse models of type 2 diabetes. BVT.2733 is an isoform-selective inhibitor of mouse 11 beta-HSD1. Hyperglycemic and hyperinsulinemic ob/ob, db/db, KKAy, and normal C57BL/6J mice were orally administered BVT.2733 (200 mg/kg.d, twice daily). In hyperglycemic, but not in normal mice, BVT.2733 lowered circulating glucose (to 50-88% of control) and insulin (52-65%) levels. In oral glucose tolerance tests in ob/ob and KKAy mice, glucose concentrations were 65-75% of vehicle values after BVT.2733 treatment, and in KKAy mice insulin concentrations were decreased (62-74%). Euglycemic, hyperinsulinemic clamps demonstrated decreased endogenous glucose production (21-61%). Analysis of hepatic mRNA in KKAy mice showed reduced phosphoenolpyruvate carboxykinase mRNA (71%). A slight reduction in food intake was observed in ob/ob and KKAy mice. Cholesterol, triglycerides, and free fatty acid levels were decreased to 81-86% in KKAy mice after a 4-h fast. The results support previous suggestions that selective 11 beta-HSD1 inhibitors lower blood glucose levels and improve insulin sensitivity in different mouse models of type 2 diabetes.     

Characterization of the MHC class I cross-presentation pathway for cell-associated antigens by human dendritic cells

Major histocompatibility complex (MHC) class I presentation of exogenous antigens is the mechanism enabling professional antigen-presenting cells (APCs) to induce CD8+ T-cell responses against viruses and tumors that do not have access to the classical MHC class I pathway. We have characterized the uptake, processing, and MHC class I cross-presentation by human dendritic cells (DCs) of cell-associated antigens derived from physiologically relevant sources, namely, vaccinia virus-infected apoptotic and necrotic cells. We show that cross-presentation is a rapid process, detectable within 2 to 4 hours after uptake of dead cells, and that proteolysis by cathepsin D in an acidic endosomal compartment is essential for cross-presentation. The presentation is abolished when the phagocytic or macropinocytic functions of the cells are inhibited and is dependent on transporter associated with antigen processing, sensitive to brefeldin A, and requires functional proteasomes. Altogether, these data suggest that antigens derived from apoptotic and necrotic cells require access to the cytosol to intersect with the conventional MHC class I pathway for presentation of cytosolic proteins.     

Occurrence and significance of hemolytic streptococci groups b-u in human infectious disease.

245 strains of hemolytic streptococci, isolated from 225 patients with infectious diseasses, were grouped serologically according to Lancefield. About 40% belonged to group B and half of them were found in the genito-urinary tract. Another 40% belonged to the groups C and G, half of them being found in the respiratory tract and often as the only potentially pathogenic organism. About 10% of the isolates belonged to other of the groups E to T, including M streptococci, and were found under similar circumstances as the C and G isolates. The last 10% could not be referred to any of the groups A-U. In 4 cases group B streptococci were found as the only potentially pathogenic organism in typical erysipelas, and in 4 cases of septicemia the only bacterial finding from blood was a streptococcus of the groups B, C or G. In these cases, as in most others in which an etiological significance could be ascribed to steptococci of other groups than A, the patient was in a bad general condition, due to very high age, agranulocytosis, ethylism or narcomania.     

High mobility group box chromosomal protein 1, a DNA binding cytokine,induces arthritis

OBJECTIVE: To examine the potential role of high mobility group box chromosomal protein 1 (HMGB-1) in the pathogenesis of arthritis. METHODS: Mice were injected intraarticularly with 1 microg or 5 microg of HMGB-1. Joints were dissected on days 4, 7, and 28 after injection and were evaluated histopathologically and immunohistochemically. To investigate the importance of different white blood cell populations for the development of arthritis, in vivo cell depletion procedures were performed. In addition, spleen cells were cultured in the presence of HMGB-1, and nuclear factor kappaB (NF-kappaB) activation was detected by electrophoretic mobility shift assay. RESULTS: Injection of recombinant HMGB-1 (rHMGB-1) into different mouse strains resulted in an overall frequency of arthritis in 80% of the animals. The inflammation was characterized by mild to moderate synovitis and lasted for at least 28 days. The majority of cells found in the inflamed synovium were Mac-1+ macrophages, whereas only a few CD4+ lymphocytes were detected. Pannus formation was observed in some cases 7 and 28 days after HMGB-1 injection. No significant differences were found with respect to incidence and severity of arthritis between mice depleted of monocytes, granulocytes, or lacking T/B lymphocytes. However, combined removal of monocytes and neutrophils resulted in a 43% lower incidence of arthritis. Mice rendered deficient in the interleukin-1 (IL-1) receptor did not develop inflammation upon challenge with HMGB-1. In vitro data corroborate this finding, showing that rHMGB-1 activated NF-kappaB, a major pathway leading to IL-1 production. CONCLUSION: Our results indicate that HMGB-1 is not a mere expression of inflammatory responses, but on its own, it triggers joint inflammation by activating macrophages and inducing production of IL-1 via NF-kappaB activation.