Greater risk of hip fracture in hemodialysis than in peritoneal dialysis.

UNLABELLED: Several differences may have existed between patients treated with peritoneal dialysis and hemodialysis because of the difference in dialysis modality. This nationwide population-based cohort study demonstrated that patients on hemodialysis had an increased risk of hip fracture compared to patients on peritoneal dialysis; the hazard ratio was 1.52. INTRODUCTION: Numerous debates on which dialysis modality is "superior" have taken place in recent decades. However, no large-scale study has ever mentioned about the relationship between dialysis modality and risk of hip fracture. METHODS: We identified 64,124 incident end-stage renal disease patients from the National Health Insurance Research Database in Taiwan between 1998 and 2008, including 59,457 (92.72%) hemodialysis (HD) and 4,667 (7.28%) peritoneal dialysis (PD) patients. After 8:1 propensity score matching, 31,554 patients, of whom 28,048 were HD and 3,506 were PD patients, were included in the study. We conducted the Cox proportional hazards model to examine the effects of dialysis modality and other variables on hip fracture risk. RESULTS: A total of 2,587 hip fractures were identified in 64,124 dialysis patients. The incidence rate of hip fracture was 13.60 per 1000 patient-years in the HD group and 6.25 in the PD group. Dialysis modality, sex, age, presence of cardiovascular disease, diabetes, medication with antiepileptic drugs, diuretics, steroids, and vitamin D had statistically significant associations with hip fracture. Patients on HD had an increased risk of hip fracture compared to patients on PD; the hazard ratio (HR) was 1.52 (95% CI: 1.09-2.12, P = 0.02). CONCLUSIONS: In this population-based cohort study, HD had a greater hip fracture risk compared to PD; the HR was 1.52. We should focus more on reducing the risk of hip fractures in hemodialysis patients.

A tryptophan metabolite, kynurenine, promotes mast cell activation through aryl hydrocarbon receptor.

BACKGROUND: Tryptophan metabolites have been suggested to play a role in immune modulation, wherein those have recently been shown to be endogenous ligands of aryl hydrocarbon receptor (AhR; a unique cellular chemical sensor). However, the involvement of tryptophan metabolites and AhR in modulating mast cell function remains to be fully defined. We therefore investigated that the functional impacts of tryptophan metabolites on human and mouse mast cell responses in vitro and their functional importance in vivo. METHODS: Three tryptophan metabolites, kynurenine (KYN), kynurenic acid (KA) and quinolinic acid (QA), were examined in terms of their effect on IgE-mediated responses in mouse bone marrow-derived mast cells (BMMCs) and in human peripheral blood-derived cultured mast cells (HCMCs) and on in vivo anaphylactic responses. For evaluation of AhR involvement, we examined the responses of mast cells from AhR-null or AhR-wild-type mice with the use of a known AhR antagonist, CH223191. RESULTS: Kynurenine, but not KA and QA, enhanced IgE-mediated responses, including degranulation, LTC4 release, and IL-13 production in BMMCs through the activation of PLCγ1, Akt, MAPK p38, and the increase of intracellular calcium. KYN also enhanced cutaneous anaphylaxis in vivo. These enhancing effects of KYN were not observed in AhR-deficient BMMCs and could be inhibited by CH223191 in BMMCs. Further, KYN had similar enhancing effects on HCMCs, which were inhibited by CH223191. CONCLUSION: The AhR-KYN axis is potentially important in modulating mast cell responses and represents an example of AhR's critical involvement in the regulation of allergic responses.

Microstructural remodeling of articular cartilage following defect repair by osteochondral autograft transfer.

OBJECTIVE: To assess collagen network alterations occurring with flow and other abnormalities of articular cartilage at medial femoral condyle (MFC) sites repaired with osteochondral autograft (OATS) after 6 and 12 months, using quantitative polarized light microscopy (qPLM) and other histopathological methods. DESIGN: The collagen network structure of articular cartilage of OATS-repaired defects and non-operated contralateral control sites were compared by qPLM analysis of parallelism index (PI), orientation angle (α) relative to the local tissue axes, and retardance (Γ) as a function of depth. qPLM parameter maps were also compared to ICRS and Modified O'Driscoll grades, and cell and matrix sub-scores, for sections stained with H&E and Safranin-O, and for Collagen-I and II. RESULTS: Relative to non-operated normal cartilage, OATS-repaired regions exhibited structural deterioration, with low PI and more horizontal α, and unique structural alteration in adjacent host cartilage: more aligned superficial zone, and reoriented deep zone lateral to the graft, and matrix disorganization in cartilage overhanging the graft. Shifts in α and PI from normal site-specific values were correlated with histochemical abnormalities and co-localized with changes in cell organization/orientation, cloning, or loss, indicative of cartilage flow, remodeling, and deterioration, respectively. CONCLUSIONS: qPLM reveals a number of unique localized alterations of the collagen network in both adjacent host and implanted cartilage in OATS-repaired defects, associated with abnormal chondrocyte organization. These alterations are consistent with mechanobiological processes and the direction and magnitude of cartilage strain.

Experimental characterization of the stagnation layer between two obliquely merging supersonic plasma jets.

We present spatially resolved measurements characterizing the stagnation layer between two obliquely merging supersonic plasma jets. Intrajet collisionality is very high, but the interjet ion-ion mean free path is of the order of the stagnation layer thickness of a few centimeters. Fast-framing camera images show a double-peaked emission profile transverse to the stagnation layer, with the central emission dip consistent with a density dip in the interferometer data. We demonstrate that our observations are consistent with collisional oblique shocks.

Attitudes toward menstruation in females with schizophrenia or schizoaffective disorders in Taiwan.

OBJECTIVE: The aims of this cross-sectional, case-controlled, observational study were to examine attitudes toward menstruation in female patients with schizophrenia or schizoaffective disorder and in a control group, and to explore the associations between attitudes toward menstruation and psychopathology, menstrual regularity during antipsychotic treatment, and menstrual distress symptoms. METHODS: Fifty-eight patients treated with anti-psychotic medications for at least the previous 6 months were placed in irregular (irregular menstrual cycle) (n = 31) and regular (regular menstrual cycle) (n = 27) groups. Sixty-two, age-matched, healthy female participants with regular menstrual cycles were enrolled as a control group. Psychopathology was assessed by psychiatrists using the Positive and Negative Syndrome Scale (PANSS). The Menstrual Attitude Questionnaire (MAQ) was used to assess attitudes toward menstruation, and symptom checklists based on the Moos Menstruation Distress Questionnaire (MMDQ) were used to assess menstrual distress symptoms. RESULTS: Patients with psychotic disorders (both irregular and regular groups) had more negative attitudes toward menstruation than the control group. In the Schizophrenia group, there was no association between the severity of psychotic symptoms and their influence on attitudes toward menstruation. Moreover, regular menstrual cycles during antipsychotic treatment and fewer menstrual distress symptoms were the two main predictors for more positive attitudes toward menstruation in the patient group. CONCLUSION: This is one of the first studies to explore the relationship between psychotic symptoms and attitudes toward menstruation. The findings provide more support for the assumption that attitudes toward menstruation are derived from a woman's perception of her bodily experience rather than a psychiatric disorder.

Simulations of magnetic field generation in unmagnetized plasmas via beat-wave current drive.

This work describes the scientific basis and associated simulation results for the magnetization of an unmagnetized plasma via beat-wave current drive. Two-dimensional electromagnetic particle-in-cell simulations have been performed for a variety of angles between the injected waves to demonstrate beat-wave generation in agreement with theoretical predictions of the beat-wave wave vector and saturation time, revealing new 2D effects. The simulations clearly demonstrate electron acceleration by the beat waves and resultant current drive and magnetic field generation. The basic process depends entirely on the angle between the parent waves and the ratio of the beat-wave phase velocity to the electron thermal velocity. The wave to magnetic energy conversion efficiency of the cases examined is as high as 0.2%. The technique could enable novel plasma experiments in which the use of magnetic coils is infeasible.

High bone marrow angiopoietin-1 expression is an independent poor prognostic factor for survival in patients with myelodysplastic syndromes.

BACKGROUND: Angiogenic factors have an essential role in normal and pathologic angiogenesis. However, the clinical implication of angiogenic factor expression in myelodysplastic syndromes (MDS) remains unclear. METHODS: In this study, we sought to investigate the prognostic impact of the expression of genes encoding angiopoietin-1 (Ang-1), Ang-2, the receptor Tie2, vascular endothelial growth factor-A (VEGF-A) and VEGF-C in the bone marrow (BM) in 208 patients with newly diagnosed primary MDS. RESULTS: BM Ang-1 expression was significantly higher in MDS patients, especially those with higher-risk subtypes, than in normal controls. With a median follow-up time of 32.9 months, the disease transformed to acute leukaemia more frequently in the patients bearing higher Ang-1 expression than in those with lower expression (31.5% vs 18.6%, P=0.023). The MDS patients with higher Ang-1 expression had shorter overall survival than those with lower expression (median 20.8±4.5 months vs 63.3±17.8 months, P<0.001). Multivariate analyses showed that higher Ang-1 expression was an independent unfavourable prognostic factor for overall survival. There was no impact of the expression of other angiogenic factors on survival. CONCLUSION: BM Ang-1 expression may serve as a new biomarker to predict clinical outcome in MDS patients.

A retrospective study of pulmonary infarction in patients with systemic lupus erythematosus from southern Taiwan.

Since large-scale reports of pulmonary infarction in systemic lupus erythematosus (SLE) are limited, a retrospective study was performed for this manifestation in 773 hospitalized patients in southern Taiwan from 1999 to 2009. Pulmonary infarction was defined as the presence of pulmonary embolism, persistent pulmonary infiltrates, and characteristic clinical symptoms. Demographic, clinical, laboratory, and radiological images data were analyzed. There were 12 patients with pulmonary embolism and 9 of them had antiphospholipid syndrome (APS). Six patients (19 to 53 years, average 38.2 ± 12.6) with 9 episodes of lung infarction were identified. All cases were APS and four episodes had coincidental venous thromboembolism. There were four episodes of bilateral infarction and seven episodes of larger central pulmonary artery embolism. Heparin therapy was routinely prescribed and thrombolytic agents were added in two episodes. Successful recovery was noted in all patients. In conclusion, there was a 0.8% incidence of pulmonary infarction in patients with SLE, all with the risk factor of APS. Differentiation between pulmonary infarction and pneumonia in lupus patients should be made; they have similar chest radiography with lung consolidation but require a different clinical approach in management. Although this report is a retrospective study with relatively small numbers of lupus patients with lung infarcts, our observation might provide beneficial information on the clinical features and radiological presentations during the disease evolution of pulmonary infarction in SLE with APS.

The immune response against myelin basic protein in two strains of rat with different genetic capacity to develop experimental allergic encephalomyelitis.

After challenge with guiena pig basic protein (GPBP) Lewis (Le) rats, which are homozygous for the immune response experimental allergic encephalomyelitis (Ir-EAE) gene, developed positive delayed skin tests against GPBP and the 43 residue encephalitogenic fragment (EF); in addition, Le rat lymph node cells (LNC) were stimulated and produced migration inhibitory factor (MIF) when incubated in vitro with these antigens. In contrast Brown Norway (BN) rats, which lack the Ir-EAE gene, did not develop delayed skin tests to EF and their LNC were not stimulated and did not produce MIF when incubated in vitro with EF. These observations indicate that the Ir-EAE gene controls a T-cell response against the EF. Le rats produced measurable anti-BP antibody by radioimmunoassay after primary challenge. Although no antibody was detectable in BN rats by radioimmunoassay, radioimmunoelectrophoresis indicated that a small amount of antibody was formed after primary immunization. After boosting intraperitoneally, both strains of rat exhibited a rise in anti-BP antibody; which was greater in Le rats. In both strains of rat the anti-BP antibody reacted with a portion of the molecule other than the EF. Since EF primarily evokes a T cell response, it is suggested that the EF portion of the BP molecule may contain a helper determinant in antibody production.

Mitogen-activated protein kinase kinase antagonized fas-associated death domain protein-mediated apoptosis by induced FLICE-inhibitory protein expression.

Fas and Fas-associated death domain (FADD) play a critical role in the homeostasis of different cell types. The regulation of Fas and FADD-mediated cell death is pivotal to many physiological functions. The activation of T lymphocytes by concanavalin A (Con A) inhibited Fas-mediated cell death. We identified that among the several activation signals downstream of Con A stimulation, mitogen-activated protein (MAP) kinase kinase (MKK) was the major kinase pathway that antagonized Fas-triggered cell death. MKK1 suppressed FADD- but not caspase-3- induced apoptosis, indicating that antagonism occurred early along the Fas-initiated apoptotic cascade. We further demonstrated that activation of MKK1 led to expression of FLIP, a specific inhibitor of FADD. MKK1 inhibition of FADD-induced cell death was abrogated if induction of FLIP was prevented, indicating that FLIP mediates MKK1 suppression of FADD-mediated apoptosis. Our results illustrate a general mechanism by which activation of MAP kinase attenuates apoptotic signals initiated by death receptors in normal and transformed cells.

Targeting vesicles to specific sites on the plasma membrane: the role of the sec6/8 complex.

The delivery of secretory vesicles to appropriate docking and fusion sites on the plasma membrane is crucial for many cellular functions, including formation of synapses, exocytosis of neurotransmitter, establishment and maintenance of cell polarity, cell growth and plasma membrane wound healing. Cell-biological, genetic and biochemical approaches have identified crucial proteins and protein interactions important for vesicle docking and fusion. However, a description of the molecular mechanisms underlying vesicle targeting to specific membrane-fusion sites remains elusive. This review discusses a set of proteins that might direct vesicles to specific domains of the plasma membrane.

Distinct domains of syntaxin are required for synaptic vesicle fusion complex formation and dissociation.

Membrane fusion resulting in neurotransmitter secretion forms the basis of neural communication. Three multimeric complexes of the protein syntaxin are important in this process: syntaxin and n-sec1; syntaxin, VAMP, and SNAP-25; and syntaxin, VAMP, SNAP-25, alpha SNAP, and NSF (20S complex). In this report, we demonstrate that unique, yet overlapping, domains of syntaxin are required to form these complexes. The formation of higher order heteromultimers has a set of structural requirements distinct from those required for dimeric interactions. Dissociation of the 20S complex by NSF following ATP hydrolysis requires amino-terminal regions of syntaxin that are outside of the binding domains for the 20S constituent proteins. These data are consistent with the hypothesis that conformational changes in syntaxin, resulting from protein-protein interactions and ATP hydrolysis by NSF, mediate neurotransmitter release.

Specificity and regulation of a synaptic vesicle docking complex.

Synaptic vesicles are proposed to dock at the presynaptic plasma membrane through the interaction of two integral membrane proteins of synaptic vesicles, VAMP and synaptotagmin, and two plasma membrane proteins, syntaxin and SNAP-25. We have characterized the binding properties of these proteins and observed SNAP-25 potentiation of VAMP 2 binding to syntaxins 1a and 4 but not syntaxins 2 or 3. n-sec1, a neuron-specific syntaxin-binding protein, bound syntaxin with nanomolar affinity, forming a complex that is distinct from the previously identified 7S and 20S syntaxin-containing complexes. This suggests that syntaxin exists in at least three states: bound to n-sec1, in a 7S particle, and in a 20S particle. Recombinant n-sec1 inhibited VAMP or SNAP-25 binding to syntaxin. We propose that the specific associations of VAMP, SNAP-25, and syntaxin mediate vesicle docking and that a syntaxin/n-sec1 complex precedes and/or regulates formation of these complexes.

The mammalian brain rsec6/8 complex.

rsec6 and rsec8 are two components of a 17S complex in mammalian brain that is homologous to the yeast 834 kDa Sec6/8/15 complex which is essential for exocytosis. Purification and partial amino acid sequencing of the mammalian rsec6/8 complex reveals that it is composed of eight novel proteins with a combined molecular weight of 743 kDa. The complex is broadly expressed in brain and displays a plasma membrane localization in nerve terminals. Membrane associated rsec6/8 complex coimmunoprecipitates with syntaxin, a plasma membrane protein critical for neurotransmission. These data suggest a role for the mammalian rsec6/8 complex in neurotransmitter release via interactions with the core vesicle docking and fusion apparatus.

Subunit composition, protein interactions, and structures of the mammalian brain sec6/8 complex and septin filaments.

Both the sec6/8 complex and septin filaments have been implicated in directing vesicles and proteins to sites of active membrane addition in yeast. The rat brain sec6/8 complex coimmunoprecipitates with a filament composed of four mammalian septins, suggesting an interaction between these complexes. One of the septins, CDC10, displays broad subcellular and tissue distributions and is found in postmitotic neurons as well as dividing cells. Electron microscopic studies showed that the purified rat brain septins form filaments of 8.25 nm in diameter; the lengths of the filaments are multiples of 25 nm. Glutaraldehyde-fixed rat brain sec6/8 complex adopts a conformation resembling the letter "T" or "Y". The sec6/8 and septin complexes likely play an important role in trafficking vesicles and organizing proteins at the plasma membrane of neurons.

Modulation of transcriptional regulation by LEF-1 in response to Wnt-1 signaling and association with beta-catenin.

Wnt signaling is thought to be mediated via interactions between beta-catenin and members of the LEF-1/TCF family of transcription factors. Here we study the mechanism of transcriptional regulation by LEF-1 in response to a Wnt-1 signal under conditions of endogenous beta-catenin in NIH 3T3 cells, and we examine whether association with beta-catenin is obligatory for the function of LEF-1. We find that Wnt-1 signaling confers transcriptional activation potential upon LEF-1 by association with beta-catenin in the nucleus. By mutagenesis, we identified specific residues in LEF-1 important for interaction with beta-catenin, and we delineated two transcriptional activation domains in beta-catenin whose function is augmented in specific association with LEF-1. Finally, we show that a Wnt-1 signal and beta-catenin association are not required for the architectural function of LEF-1 in the regulation of the T-cell receptor alpha enhancer, which involves association of LEF-1 with a different cofactor, ALY. Thus, LEF-1 can assume diverse regulatory functions by association with different proteins.

Inhibition of angiogenesis in human glioblastomas by chromosome 10 induction of thrombospondin-1.

Glioblastoma multiforme is distinguished from its less malignant astrocytoma precursors by intense angiogenesis and frequent loss of tumor suppressor genes on chromosome 10. Here we link these traits by showing that when a wild-type chromosome 10 was returned to any of three human glioblastoma cell lines U251, U87, or LG11, they lost their ability to form tumors in nude mice and switched to an antiangiogenic phenotype, as measured by the inhibition of capillary endothelial cell migration and of corneal neovascularization. This change in angiogenesis was directly due to the increased secretion of a potent inhibitor of angiogenesis, thrombospondin-1, because: (a) neutralizing thrombospondin completely relieved the inhibition; (b) the inhibitory activity of thrombospondin was not dependent on transforming growth factor beta; and (c) chromosome 10 introduction did not alter secreted inducing activity. The inducing activity was dependent on vascular endothelial cell growth factor and had an ED50 of 10 microg/ml in media conditioned by parental cells and 9-13 microg/ml in media conditioned by chromosome 10 revertants. Normal human astrocytes were also antiangiogenic due to secreted thrombospondin. The effect of chromosome 10 on thrombospondin production in vitro was reflected in patient material. Normal brain and lower grade astrocytomas known to retain chromosome 10 stained strongly for thrombospondin, but 12 of 13 glioblastomas, the majority of which lose chromosome 10, did not. These data indicate that the loss of tumor suppressors on chromosome 10 contributes to the aggressive malignancy of glioblastomas in part by releasing constraints on angiogenesis that are maintained by thrombospondin in lower grade tumors.

Genetic alterations and their clinical implications in older patients with acute myeloid leukemia.

A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with acute myeloid leukemia (AML). However, comprehensive studies regarding the impact of genetic alterations in this group of patients are limited. In this study, we compared relevant mutations in 21 genes between AML patients aged 60 years or older and those younger and exposed their prognostic implications. Compared with the younger patients, the elderly had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A and TP53 mutations but a lower frequency of WT1 mutations. The older patients more frequently harbored one or more adverse genetic alterations. Multivariate analysis showed that DNMT3A and TP53 mutations were independent poor prognostic factors among the elderly, while NPM1 mutation in the absence of FLT3/ITD was an independent favorable prognostic factor. Furthermore, the status of mutations could well stratify older patients with intermediate-risk cytogenetics into three risk groups. In conclusion, older AML patients showed distinct genetic alterations from the younger group. Integration of cytogenetics and molecular mutations can better risk-stratify older AML patients. Development of novel therapies is needed to improve the outcome of older patients with poor prognosis under current treatment modalities.