Pseudomonas elastase acts as a virulence factor in burned hosts by Hageman factor-dependent activation of the host kinin cascade.

Purified Pseudomonas elastase injected subcutaneously into the skin of an Evans blue dye-injected (intravenously) guinea pig caused dye leakage similar to that observed when histamine or bradykinin was injected in the same animal. The histamine-induced dye leakage was ablated in antihistamine-treated guinea pigs, but elastase- and bradykinin-induced dye leakages were not. Local injections of specific inhibitors of the host Hageman factor-dependent bradykinin-generating pathway given immediately prior to elastase injection reduced dye leakage in a dose-related manner. Elastase-related dye release was enhanced when angiotension-converting enzyme inhibitor, a substance which prevents host enzymes from breaking down bradykinin, was injected prior to elastase injection. We conclude that Pseudomonas elastase generates bradykinin in the infected host via a Hageman factor-dependent pathway.     

Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis

The nuclear bile acid receptor FXR has been proposed to play a central role in the feedback repression of the gene encoding cholesterol 7 alpha-hydroxylase (CYP7A1), the first and rate-limiting step in the biosynthesis of bile acids. We demonstrate that FXR directly regulates expression of fibroblast growth factor-19 (FGF-19), a secreted growth factor that signals through the FGFR4 cell-surface receptor tyrosine kinase. In turn, FGF-19 strongly suppresses expression of CYP7A1 in primary cultures of human hepatocytes and mouse liver through a c-Jun N-terminal kinase (JNK)-dependent pathway. This signaling cascade defines a novel mechanism for feedback repression of bile acid biosynthesis and underscores the vital role of FXR in the regulation of multiple pathways of cholesterol catabolism in the liver.     

Blastocystis hominis as a contributing risk factor for development of iron deficiency anemia in pregnant women

Intestinal parasitic infection increases the risk of developing iron deficiency anemia (IDA) during pregnancy. The objective of this study was to assess Blastocystis hominis as a contributing risk factor for development of IDA in pregnant women. A total of 200 fecal specimens from 120 pregnant women with IDA (mean Hb?=?9.6 g/dl), and 80 non-anemic controls were examined for Blastocystis. Fecal specimens were examined by the formalin/ethyl-acetate concentration technique, iron hematoxylin staining, modified Ziehl-Neelsen acid-fast staining, and by the in vitro cultivation technique for Blastocystis. Frequency of Blastocystis infection, detected microscopically and by the in vitro culture technique, was significantly higher in IDA study group (n?=?48; 40%) compared to non-anemic controls (n?=?5; 6.3%; P?相似文献   

mtDNA haplogroup J: a contributing factor of optic neuritis

Optic neuritis frequently occurs in multiple sclerosis (MS), and shares several similarities with the optic neuritis of Leber's hereditary optic neuropathy (LHON), which is mainly due to maternally transmitted mitochondrial DNA (mtDNA) mutations. Our report shows for the first time that a mitochondrial DNA background could influence the clinical expression of MS. One European mtDNA haplogroup was found only in MS patients with optic neuritis but not in MS patients without visual symptoms. Therefore, we hypothesize that mtDNA haplogroup J might constitute a risk factor for optic neuritis occurrence when it is coincidentally associated with MS, but not be a risk factor for developing MS per se as suggested previously.     

Chromosomal aberrations as a contributing factor for tumor promotion in the mouse skin

Tumor promotion in mouse skin can be dissected in two stages: stage I (conversion) and stage II. Whereas for stage II clonal expansion of transformed cells is believed to play a major role, the mechanism(s) underlying conversion is still a matter of debate. Because conversion can be achieved upon treatment with phorbol ester tumor promoters prior to initiation, it is unlikely to represent simply proliferative stimulation of initiated cells (due to epigenetic changes induced). Since tumor promoters exert clastogenic activities and, on the other hand, the clastogen methyl methanesulfonate proved to be convertogenic, the possibility arises that chromosomal changes are involved in conversion. Based on this hypothesis, several findings concerning the action of tumor promoters and the process of tumor promotion in the mouse skin system are discussed and interpreted: the frequency, reversibility, and transient nature of conversion, dependence of tumor promotion on DNA synthesis, induction of DNA breaks by tumor promoters, and the protecting effect of scavengers of free radicals. A model is presented suggesting tumor formation in mouse skin (and other systems) to proceed in discrete, genetically determined steps. Initiation is considered to be due to the induction of point mutations in a dominant-acting oncogene that becomes thereupon activated, whereas the decisive event in the conversion stage of tumor promotion is the induction of numerical and/or structural chromosomal changes with the consequence of loss or inactivation of gene(s) involved in suppression of the tumor phenotype.     

Activation of the tissue factor pathway of blood coagulation in patients with chronic urticaria

BACKGROUND: In patients with chronic urticaria (CU), plasma shows signs of thrombin generation and autologous plasma skin tests score positive in as many as 95% of cases. OBJECTIVE: To evaluate the initiators of blood coagulation that lead to thrombin generation and fibrinolysis in CU. METHODS: Activated factor VII, activated factor XII, fragment F(1+2), and D-dimer plasma levels were measured in 37 patients with CU and 37 controls. Skin specimens from 10 patients with CU and 10 controls were tested for tissue factor immunohistochemically. RESULTS: Mean F(1+2) levels were higher in patients than controls (2.54 [SD 2.57] nmol/L vs 0.87 [0.26] nmol/L; P < .001); disease activity was moderate or severe in 9 of 11 (82%) and 9 of 26 (35%) patients showing high or normal F(1+2) levels, respectively (P < .025). Mean D-dimer plasma levels were higher in patients than controls (329 [188] ng/mL vs 236 [81] ng/mL; P < .01); disease activity was moderate or severe in 6 of 8 (75%) and 11 of 29 (38%) showing elevated or normal plasma D-dimer levels (P = NS). Factor VIIa levels were higher in patients than controls (2.86 ng/mL [0.66] vs 1.97 ng/mL [0.65]; P < .001). Activated factor VII and F(1+2) levels were correlated (r = 0.529; P = .008). Tissue factor reactivity was observed only in CU skin specimens. CONCLUSION: The extrinsic pathway of clotting cascade is activated in CU. Disease severity is associated with the activation of the coagulation cascade. CLINICAL IMPLICATIONS: The involvement of the coagulation pathway in CU opens new perspectives for a better understanding of the pathogenesis and, possibly, for the treatment of this disease.     

Hydrogen peroxide as an irrigation solution in arthroplasty - a potential contributing factor to the development of aseptic loosening

The reason for revision of primary total hip arthroplasty is quoted as aseptic loosening in 60.6% of cases between 1979 and 2003 in the Swedish National Hip Arthroplasty Registry. Much research effort has been directed toward enhancing the bone-cement interface of total joint arthroplasties, in an attempt to reduce this complication. Haemostatic agents have been popularized as effective means of retarding the development of potentially harmful debris interposition adjacent to, and blood lamination patterns within, the methylmethacrylate. Such agents include hydrogen peroxide (H(2)O(2)), local freezing saline, saline at room temperature and adrenaline solution. One main concern with the use of hydrogen peroxide is whether it affects the material properties of bone cement such that in the long term it contributes to aseptic loosening. This would have enormous clinical consequences. Preliminary studies indicate that porosity increases and that the tensile strength and yield stresses are reduced by up to a factor of 10 by contaminating samples with increasing concentrations of hydrogen peroxide. We postulate that the current use of hydrogen peroxide as an irrigation solution in arthroplasty contributes to the development of aseptic loosening.     

Role of coagulation factor XIII (FXIII) in angiogenesis and tissue repair

Factor FXIII (FXIII) is a plasma transglutaminase that catalyzes the cross link formation between fibrin chains to stabilize the clot. Beside it s function in hemostasis FXIII has a role in wound healing and embryo implantation--processes that involve angiogenesis. In this review we discuss the role of FXIII in angiogenesis and the molecular mechanisms underlying its pro-angiogenic effect. In addition, FXIII role in wound repair is discussed.     

High levels of coagulation factor XI as a risk factor for venous thrombosis

BACKGROUND: Factor XI, a component of the intrinsic pathway of coagulation, contributes to the generation of thrombin, which is involved in both the formation of fibrin and protection against fibrinolysis. A deficiency of factor XI is associated with bleeding, but a role of high factor XI levels in thrombosis has not been investigated. METHODS: We determined factor XI antigen levels in the patients enrolled in the Leiden Thrombophilia Study, a large population-based, case-control study (with a total of 474 patients and 474 controls) designed to estimate the contributions of genetic and acquired factors to the risk of deep venous thrombosis. Odds ratios were calculated as a measure of relative risk. RESULTS: The age- and sex-adjusted odds ratio for deep venous thrombosis in subjects who had factor XI levels above the 90th percentile, as compared with those who had factor XI levels at or below that value, was 2.2 (95 percent confidence interval, 1.5 to 3.2). There was a dose-response relation between the factor XI level and the risk of venous thrombosis. Adjustment of the odds ratios for other risk factors such as oral-contraceptive use, homocysteine, fibrinogen, factor VIII, female sex, and older age did not alter the result. Also, when we excluded subjects who had known genetic risk factors for thrombosis (e.g., protein C or S deficiency, antithrombin deficiency, the factor V Leiden mutation, or the prothrombin G20210A mutation), the odds ratio remained the same, indicating that the risk of venous thrombosis associated with elevated levels of factor XI was not the result of one of the known risk factors for thrombosis. CONCLUSIONS: High levels of factor XI are a risk factor for deep venous thrombosis, with a doubling of the risk at levels that are present in 10 percent of the population.     

Tissue factor-dependent coagulation is preferentially up-regulated within arterial branching areas in a baboon model of Escherichia coli sepsis

Endothelium plays a critical role in the pathobiology of sepsis by integrating systemic host responses and local rheological stimuli. We studied the differential expression and activation of tissue factor (TF)-dependent coagulation on linear versus branched arterial segments in a baboon sepsis model. Animals were injected intravenously with lethal doses of Escherichia coli or saline and sacrificed after 2 to 8 hours. Whole-mount arterial segments were stained for TF, TF-pathway inhibitor (TFPI), factor VII (FVII), and markers for endothelial cells (ECs), leukocytes, and platelets, followed by confocal microscopy and image analysis. In septic animals, TF localized preferentially at branches, EC surface, leukocytes, and platelet aggregates and accumulated in large amounts in the subendothelial space. FVII strongly co-localized with TF on ECs and leukocytes but less so with subendothelial TF. TFPI co-localized with TF and FVII on endothelium and leukocytes but not in the subendothelial space. Focal TF increases correlated with fibrin deposition and increased endothelial permeability to plasma proteins. Biochemical analysis confirmed that aortas of septic baboons expressed more TF mRNA and protein than controls. Branched segments contained higher TF protein levels and coagulant activity than equivalent linear areas. These data suggest that site-dependent endothelial heterogeneity and rheological factors contribute to focal procoagulant responses to E. coli.     

Sleep apnea syndrome: is it a contributing factor to the sex differential in mortality?

Sleep apnea syndrome is a relatively common disease, with an overwhelmingly male predominance. The female:male ratio is about 1:15-20, depending on the specific age group. In light of findings linking sleep apnea syndrome to essential hypertension, it is hypothesized that the syndrome may contribute to the sex differential in mortality. In most of the developed countries women have longer life expectancy than men even after adjustment for various lifestyles and biologica variables Mortality from heart disease accounts for 40% of the total sex differential. The fact that the 2-5 fold sex differential for heart disease mortality is reduced to much lesser extent by multivariate adjustment than the sex differential for mortality from all causes, and that it is minimally affected by the exclusion of all persons with a history of chronic diseases, indicates that other risk factors should be sought. I propose the hypothesis that Sleep Apnea Syndrome (SAS), which almost exclusively affects males, contributes to the sex differential in mortality from coronary heart disease. Sleep Apnea Syndrome is a relatively common disease. It is the most preponderant finding among patients referred to diagnostic sleep laboratories, particularly among patients complaining of excessive daytime sleepiness. Its incidence among the adult male population (age greater than 21 years) was estimated to be at least 1-1.5%. It is considerably higher than that, at least 5 to 7 fold, in the 40 to 60 years age group, and in specific high-risk populations such as the morbidly obese. The female:male ratio is about 1:15-20, depending on the specific age group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Recapitulating development: a template for periodontal tissue engineering

The induction of bone formation by the soluble osteogenic molecular signals of the transforming growth factor-beta (TGF-beta) superfamily is a critical issue to periodontologists, molecular biologists, and tissue engineers alike, because preclinical studies in primates and clinical trials have demonstrated the bone induction capacity of bone morphogenetic and osteogenic proteins (BMPs/OPs) in clinical context. BMPs/OPs, pleiotropic members of the TGF-beta superfamily, induce de novo endochondral bone formation as a recapitulation of embryonic development and act as soluble signals for tissue morphogenesis sculpting the multicellular mineralized structures of the periodontal tissues with functionally oriented periodontal ligament fibers inserting into newly formed cementum. This paper reviews the induction of the complex tissue morphologies of the periodontal tissues in the nonhuman primate Papio ursinus with furcation defects treated with doses of naturally derived and recombinantly produced human BMPs/OPs. Periodontal tissue regeneration develops as a mosaic structure in which the OPs of the TGF-beta superfamily singly, synergistically, and synchronously initiate and maintain tissue induction and morphogenesis.     

Coagulation abnormalities in stroke--disseminated intravascular coagulation as a complication of subarachnoid hemorrhage

To determine the pathogenesis of the symptomatic vasospasm (SV) following subarachnoid hemorrhage (SAH), we compared the difference in coagulation activity between 52 aneurysmal patients with SV and 20 patients without SV. The hypercoagulable state was scored according to the Disseminated Intravascular Coagulation (DIC) scoring system. Our clinical studies showed that severe SAH following aneurysmal rupture caused the hypercoagulable state and there was a good correlation between the degree of the hypercoagulable state, the severity of SV and outcome of the aneurysmal patients. We stressed in this report that the monitoring of the blood coagulation and fibrinolytic activities is very important in severe SAH and that the hypercoagulable state after SAH plays an important role on the occurrence of SV.     

Increased erythrocyte aggregation in ovarian hyperstimulation syndrome: a possible contributing factor in the pathophysiology of this disease

BACKGROUND: Many theories regarding the pathophysiology leading to ovarian hyperstimulation syndrome (OHSS) have been proposed and tested. Increased erythrocyte aggregation is associated with capillary slow flow and tissue hypoxaemia. We performed this study in order to assess the degree of erythrocyte aggregation in the peripheral blood of individuals with OHSS and undergoing controlled ovarian stimulation (COH). METHODS: Twenty women with severe OHSS, 20 women undergoing COH under IVF protocol, and 20 healthy matched controls were recruited for this prospective study. Blood samples were drawn for determination of erythrocyte aggregation as well as haematological indices. The percentage of slide covered by the cells ('erythrocyte percentage': EP) was determined using a simple slide test and image analysis. Lower EP values correspond to higher degrees of aggregation. RESULTS: The respective measures of EP were 59.2 +/- 3.0, 42.0 +/- 3.0 and 35.0 +/- 2.4% micro m for the controls, women with COH and OHSS (P < 0.01 between controls and the two stimulation groups). CONCLUSIONS: The degree of erythrocyte aggregation is enhanced in the peripheral venous blood of patients with both COH and OHSS. This finding, known to cause capillary leak, may contribute to the pathophysiology of the OHSS.     

Difference in the intratumoral distributions of extracellular‐fluid and intravascular MR contrast agents in glioblastoma growth

Contrast enhancement by an extracellular‐fluid contrast agent (CA) (Gd‐DOTA) depends primarily on the blood–brain‐barrier permeability (bp ), and transverse‐relaxation change caused by intravascular T₂ CA (superparamagnetic iron oxide nanoparticles, SPIONs) is closely associated with the blood volume (BV). Pharmacokinetic (PK) vascular characterization based on single‐CA‐using dynamic contrast‐enhanced MRI (DCE‐MRI) has shown significant measurement variation according to the molecular size of the CA. Based on this recognition, this study used a dual injection of Gd‐DOTA and SPIONs for tracing the changes of bp and BV in C6 glioma growth (Days 1 and 7 after the tumor volume reached 2 mL). bp was quantified according to the non‐PK parameters of Gd‐DOTA‐using DCE‐MRI (wash‐in rate, maximum enhancement ratio and initial area under the enhancement curve (IAUC)). BV was estimated by SPION‐induced ΔR₂* and ΔR₂. With validated measurement reliability of all the parameters (coefficients of variation ≤10%), dual‐contrast MRI demonstrated a different region‐oriented distribution between Gd‐DOTA and SPIONs within a tumor as follows: (a) the BV increased stepwise from the tumor center to the periphery; (b) the tumor periphery maintained the augmented BV to support continuous tumor expansion from Day 1 to Day 7; (c) the internal tumor area underwent significant vascular shrinkage (i.e. decreased ΔR₂ and ΔR₂) as the tumor increased in size; (d) the tumor center showed greater bp ‐indicating parameters, i.e. wash‐in rate, maximum enhancement ratio and IAUC, than the periphery on both Days 1 and 7 and (e) the tumor center showed a greater increase of bp than the tumor periphery in tumor growth, as suggested to support tumor viability when there is insufficient blood supply. In the MRI–histologic correlation, a prominent BV increase in the tumor periphery seen in MRI was verified with increased fluorescein isothiocyanate–dextran signals and up‐regulated immunoreactivity of CD31–VEGFR. In conclusion, the spatiotemporal alterations of BV and bp in glioblastoma growth, i.e. augmented BV in the tumor periphery and increased bp in the center, can be sufficiently evaluated by MRI with dual injection of extracellular‐fluid Gd chelates and intravascular SPION.     

Effects of different progestin regimens in hormone replacement therapy on blood coagulation factor VII and tissue factor pathway inhibitor

BACKGROUND: Long-term hormone replacement therapy (HRT) reduces cardiovascular risk, but an early increased risk was reported in women with coronary heart disease. In such women the arterial intima can express tissue factor, and changes in coagulation factor VII (factor VII) and tissue factor pathway inhibitor (TFPI) may be deleterious. METHODS: We measured factor VII clotting activity, activated factor VII, and concentrations of factor VII and TFPI during 12 months in healthy post-menopausal women randomized to: (i). cyclic oral estrogen/progestin (n = 25); (ii). long-cycle oral estrogen/quarterly progestin (n = 32); (iii). continuous oral estrogen/progestin (n = 21); (iv). continuous oral estrogen/intrauterine progestin (n = 22); (v). no HRT (n = 26). Blood was collected at baseline, 3, 6 and 12 months. Additional sampling was done before progestin intake in the long cycle group. RESULTS: No variations were observed in the reference group. There was a substantial decrease in TFPI concentrations in the HRT groups irrespective of the type of progestin. In women receiving long-cycle treatment, all factor VII measures increased during the unopposed estrogen periods, and the increase was reversed after progestin intake. The integrated response, AUC, for TFPI was significantly lower in the HRT groups compared with the reference group. CONCLUSION: The observed changes may increase the early thrombotic risk associated with HRT use.