Coagulation-fibrinolysis system in poststroke patients receiving antiplatelet medication

BACKGROUND AND PURPOSE: We studied the activities of the coagulation-fibrinolysis system in the chronic stage of poststroke patients and the effect of antiplatelet medication on the system. METHODS: We determined fibrinogen, antithrombin III, thrombin-antithrombin III complex, tissue plasminogen activator antigen, plasminogen activator inhibitor-1, plasmin-alpha 2 plasmin inhibitor complex, and D-dimer in plasma from 153 poststroke patients in the chronic phase (ie, 33 patients not receiving antiplatelet medication, 78 patients receiving 200 mg/d ticlopidine, and 42 patients receiving 40 mg/d aspirin), and compared the results in control subjects and among the treatment groups. RESULTS: The concentrations of fibrinogen, thrombin-antithrombin III complex, antithrombin III, plasmin-alpha 2 plasmin inhibitor complex, and tissue plasminogen activator were slightly but significantly increased in all treatment groups compared with control subjects (P < .01) but did not differ among the treatment groups. The plasminogen activator inhibitor-1 levels were significantly elevated in patients not receiving antiplatelet medication compared with control subjects (P < .01), whereas they were in the normal range and significantly lower in patients receiving ticlopidine or aspirin than in patients not receiving antiplatelet medication (P < .01). The plasminogen activator inhibitor-1 levels were significantly lower in patients whose platelet aggregation was inhibited by antiplatelet medication than in patients with uninhibited platelet aggregability (P < .05). CONCLUSIONS: These findings suggest that coagulation-fibrinolysis markers are mildly increased in poststroke patients in the chronic phase and that antiplatelet medication is effective in reducing the elevated plasminogen activator inhibitor-1 levels.     

FATIGUE CRACK GROWTH IN SEVERAL CERAMIC MATERIALS

Fatigue crack growth tests of five ceramic materials were carried out in order to investigate the general characteristics of cyclic and static fatigue crack growth in ceramics. A cyclic effect was found in Si₃N₄, Al₂O₃ and TiB₂, where the main fracture mechanism was intergranular separation, and stress shielding due to grain bridging occurred near the crack tip. On the other hand, no cyclic effect was observed in Sic and ZrO₂, where the main fracture mechanism was transgranular fracture. The fatigue crack growth curves reduced to a unique curve by using the parameter K_up/E, regardless of the kind of ceramics studied.     

Analysis of the in vitro cytokine production by liver-infiltrating T cells of patients with autoimmune hepatitis

The pathogenic mechanisms underlying the development of autoimmune hepatitis (AIH) are still unclear. Since AIH is associated with the presence of various autoantibodies and certain HLA subtypes, it is likely that T and B cells play a major role in this disease. In this study we have determined the functional capacities of in vivo preactivated liver-infiltrating T cells (LTC) from patients with AIH. As controls we used LTC from patients with non-autoimmune hepatitis (non-AIH). Our results show that preactivated LTC from patients with AIH predominantly (190/255 clones) reside in the CD4+ population, whereas LTC in non-AIH are dominated by the CD8+ phenotype (148/254 clones). In view of this finding we have investigated the cytokine secretion patterns of 102 randomly chosen CD4+ T cell clones from six patients with AIH. As controls we have used 58 CD4+ LTC from 11 patients with non-AIH. All clones were stimulated by lectin and irradiated accessory cells and subsequent cytokine production was evaluated. LTC from patients with AIH have a lower interferon-gamma (IFN-gamma)/IL-4 ratio compared with LTC from non-AIH. Although clones from some patients with AIH produced very high amounts of IL-4 in vitro, this was not a constant finding. These results show that in vivo preactivated LTC from patients with AIH are mostly CD4+ T cells that produce more IL-4 than IFN-gamma. In contrast, LTC from patients with non-AIH are dominated by CD8+ and CD4+ T cells that produce significantly less IL-4 than IFN-gamma. Thus, liver-infiltrating T cells from patients with AIH and non-AIH belong to different functional T cell subsets. This may have implications for the regulation of humoral and cellular immune responses in inflammatory liver disease.     

Failure characteristics of osteoporotic vertebral bodies monitored by acoustic emission

The third lumbar vertebrae of nine elderly subjects (average age, 81.4 +/- 6.7 years) graded osteoporotic and the second to fifth lumbar vertebrae of a 37-year-old man graded as normal were used to investigate microdamage accumulation during quasi-static compression loading with an acoustic emission detection system. Mechanical parameters (apparent elastic modulus, stress, and strain) and acoustic emission event count rates were measured simultaneously. The normalized mean value of any mechanical parameters of normal group was significantly high with respect to that of osteoporotic group. The normalized mean value of cumulative acoustic emission event counts to maximum stress of the normal vertebrae was substantially small with respect to that of the osteoporotic vertebrae (p < 0.0005, z-test). Postloading microradiographs displayed fracture lines adjacent to the end plates in six vertebrae of osteoporotic group. These results are consistent with the hypotheses that microdamages of osteoporotic vertebral bodies are generated and accumulate at lower strains than those of normal vertebrae at a specific site.     

Adenylate cyclases in keratinocytes: FRSK cells express types I, II, III, IV, VI and VIII, and 1,25(OH)2D3, retinoic acid and TPA augment forskolin-induced cyclic AMP accumulation in the absence of altered isozyme expression

BACKGROUND: Polyketides are a large and structurally diverse group of natural products that include antibiotics, antifungal agents and immunosuppressant compounds. Polyketides are biosynthesised in filamentous bacteria on modular polyketide synthases (PKSs) in which each cycle of chain extension requires a different 'module' of enzymatic activities. The recently proposed dimeric model for modular PKSs predicts that even a single-module PKS should be catalytically active in the absence of other PKS components. Researchers are also interested in manipulating the stereochemical outcome of polyketide chain extension using genetic engineering of domains within each module. RESULTS: We have constructed a minimal modular PKS from the erythromycin-producing PKS (DEBS) of Saccharopolyspora erythraea. The diketide synthase (DKS1-2) consists of a single chimaeric extension module, derived from the DEBS module 1 ketoacyl-ACP synthase (KS), sandwiched between a loading module and a chain-terminating thioesterase. When DKS1-2 was expressed in S. erythraea, the strain preferentially6 accumulated the diketide (2R, 3S)-2-methyl-3-hydroxy pentanoic acid. CONCLUSIONS: These results demonstrate that, as predicted, even a single-module PKS is catalytically active in the absence of other DEBS proteins. In its normal context, the ketosynthase domain KS1 is thought to generate a (2S)-2methyl-3-hydroxy intermediate by epimerising the initial product of carbon-carbon chain formation, the (2R)-2-methyl-3-ketoester. The observed formation of the alternative (2R)-methyl-3-hydroxy product catalysed by DKS1-2 provides strong support for this proposal, and indicates how targeted alteration of stereospecificity can be achieved on a modular PKS.     

Numerical simulation with experimental verification of the fracture behavior in granite under confining pressures based on the tension-softening model

The use of the tension-softening model for analyzing fracture processes of rock is examined with special reference to the effect of confining pressure on the fracture extension. Tension-softening curves are measured by means of theJ-based technique from unconfined tests performed on compact tension (CT) specimens of granite. On the basis of the determined tension-softening relation, numerical analyses are executed using a boundary element method (BEM) to simulate fracture of the granite under confining pressures. Numerical results are compared to the experimental results of two series of tests for which CT specimens and thick-walled cylindrical specimens were loaded to failure under confining pressures ranging from 0 to 26.5 MPa. It is shown that the BEM analyses can predict the observed fracture behavior. Based on the results, it is demonstrated that the tension-softening relation provides a suitable model to analyze the fracture process in the rock. The source mechanism for the pressure sensitive fracture is discussed by examining the growth of the fracture process zone.     

Muscle sympathetic nerve activity during cold pressor test in patients with cerebrovascular accidents

BACKGROUND AND PURPOSE: Autonomic dysfunction is frequently present in patients with cerebrovascular accidents (CVA). However, the pathophysiological mechanisms of these disorders are not clear. The purpose of the study was to assess the effects of CVA on the autonomic nervous system. METHODS: In eight male patients with a history of CVA with damage of the cortical or subcortical structures, we measured the cold pressor response during recording of muscle sympathetic nerve activity (MSNA) from the peroneal nerve on the hemiplegic side. We also studied 10 age-matched male control subjects. Tests were performed before, during, and after immersion of the nonhemiplegic hand in ice water for a period of 3 minutes in each phase. We also recorded changes in heart rate (HR), arterial blood pressure, skin temperature of the middle finger, and perception of pain using the Borg's score. RESULTS: During the control period, the mean burst count of MSNA in CVA (57.2 +/- 3.9 beats/100 HR) was higher than in control subjects (36.3 +/- 3.2 beats/100 HR) (P<.05). Total MSNA (the mean burst amplitude per minute times burst rate) increased significantly in CVA and control during the immersion period by 79.9 +/- 18.4% and 133.1 +/- 25.6%, respectively. The percent change in total MSNA in CVA was attenuated during immersion compared with control subjects. The HR and skin temperature responses as well as the Borg's score were similar in both groups during control, hand immersion, and recovery periods. CONCLUSIONS: The present results suggest that increased MSNA in CVA may be due to damage of cortical or subcortical structures or stroke-related changes in other areas or nonspecific changes that cause continuous increase in basal MSNA.     

Interaction of beta-lactam antibiotics with H+/peptide cotransporters in rat renal brush-border membranes

Two H+/peptide cotransporters, PEPT1 and PEPT2, are expressed in the kidney, mediating the renal tubular reabsorption of oligopeptides and beta-lactam antibiotics. We examined the interactions of beta-lactam antibiotics with peptide transporters in rat renal brush-border membranes by evaluating the inhibitory potencies of the antibiotics against glycylsarcosine transport. Western blot analysis revealed that PEPT1 and PEPT2 were expressed in the renal brush-border membranes with the apparent molecular masses of 75 and 105 kDa, respectively. Using renal brush-border membrane vesicles, the uphill transport of glycylsarcosine was observed in the presence of an inward H+ gradient and an inside-negative membrane potential. Two transport systems with high affinity (Km of 50 microM) and low affinity (Km of 1.2 mM) appeared kinetically to mediate the glycylsarcosine uptake. The inhibition constants of the antibiotics for glycylsarcosine transport were more closely correlated with those in stable LLC-PK1 cells transfected with rat PEPT2 rather than PEPT1 cDNA. The beta-lactam antibiotics with an alpha-amino group showed trans-stimulation effects on the glycylsarcosine uptake, suggesting that these antibiotics and glycylsarcosine share a common peptide transporter. However, the antibiotics lacking an alpha-amino group failed to show the trans-stimulation effect. It is concluded that amino-beta-lactam antibiotics at therapeutic concentrations interact predominantly with PEPT2 localized in the brush-border membranes of rat kidney.     

Elevated levels of lung surfactant protein A in sera from patients with idiopathic pulmonary fibrosis and pulmonary alveolar proteinosis

An enzyme-linked immunosorbent assay using monoclonal antibodies to human lung surfactant protein A (SP-A) was applied to sera from patients with lung diseases. We examined whether SP-A appears in the sera of patients with diseases that are known to cause alterations in surfactant composition in bronchoalveolar lavage fluids, and we characterized the SP-A that was found. The level of SP-A in sera from 57 healthy volunteers was 45 +/- 3 ng/ml (mean +/- SEM). The levels in patients with idiopathic pulmonary fibrosis (IPF) (205 +/- 23 ng/ml, n = 32) and pulmonary alveolar proteinosis (PAP) (285 +/- 23 ng/ml, n = 6) were significantly higher than those in healthy control subjects (p < 0.01), whereas those of sarcoidosis (n = 16), pneumonia (n = 14), and tuberculosis (n = 14) were 52 +/- 27 ng/ml, 65 +/- 11 ng/ml, and 49 +/- 23 ng/ml, respectively. Electrophoresis and immunoblotting analysis demonstrated that the fraction isolated from serum of a patient with PAP or IPF by anti-SP-A immunoaffinity column chromatography consisted chiefly of human IgG and IgM, and that it also contained SP-A. Furthermore, IgG was found in preparation of purified human SP-A. SP-A was demonstrated to bind to nonimmune IgG coated onto microtiter wells. Gel filtration analysis revealed that serum SP-A was eluted at fractions of larger molecular size than was the purified SP-A. These findings suggest that SP-A appears in the bloodstream as a complex with immunoglobulin in IPF and in PAP.