Factors determining the maintenance dose of warfarin in Chinese patients

Chinese patients are reportedly more sensitive than Caucasians to the anticoagulant effect of warfarin. We examined warfarin dose requirements and their determinants in 151 Chinese out-patients on stable maintenance dose of warfarin with international normalized ratio of 2 to 2.5. Mean daily warfarin requirement was 3.3 +/- 1.4 mg, much lower than reported doses in Caucasian patients. The most important determinant was age (r = -0.43, p < 0.001), with progressively lower warfarin requirement with increasing age (p = 0.0001). There was a weaker association with body weight (r = 0.20, p = 0.01). Patients with chronic rheumatic heart disease tended to require a smaller dose than those with heart valve replacements (2.94 +/- 1.24 vs. 3.69 +/- 1.42 mg, p < 0.01). We confirm that Chinese patients require a smaller dose of warfarin for the same degree of anticoagulation. Age is the most important factor affecting dose requirement, although body weight and underlying disease also play a role.      

Antibody Reactivity Against Thyroid Peroxidase and Myeloperoxidase in Autoimmune Thyroiditis and Systemic Vasculitis

Potential cross-reactivity between thyroid peroxidase (TPO) and myeloperoxidase (MPO) molecules was evaluated by analysing the binding of 199 TPO antibody- and 145 MPO antibody- positive sera to TPO and MPO molecules. Sera from six patients with autoimmune thyroiditis (AITD) and four patients with systemic vasculitis (SV) with different TPO-MPO antibody findings were then chosen for further analyses. All six patients with AITD had TPO antibodies in enzyme immunoassay (EIA) and four of them had simultaneously MPO antibodies in EIA. In AITD patients antibody binding to TPO could not be inhibited by adding native MPO to the serum diluent, suggesting that the possible cross-reactive epitopes were exposed in the denaturated MPO molecule. Similarly, the MPO ab reactivity of patients with systemic vasculitis could not be inhibited by native TPO. To study whether TPO and MPO antibodies recognize linear epitopes, the binding of antibodies to synthetic TPO and MPO peptides was analysed. Several TPO and MPO peptides were reactive, including peptides reacting with both TPO and MPO antibody-positive sera. One of the most cross-reactive peptides contained AA 586–601 in TPO, showing also particularly high AA homology (88%) with MPO (AA 594–609). The results suggest that TPO and MPO molecules contain cross-reactive epitopes that are exposed in denaturated molecules and may thus cause false positive antibody findings in solid phase EIA assays.     

Enhancing Web-Based Mindfulness Training for Mental Health Promotion With the Health Action Process Approach: Randomized Controlled Trial

Background

With increasing evidence demonstrating the effectiveness of Web-based interventions and mindfulness-based training in improving health, delivering mindfulness training online is an attractive proposition.

Objective

The aim of this study was to evaluate the efficacy of two Internet-based interventions (basic mindfulness and Health Action Process Approach enhanced mindfulness) with waitlist control. Health Action Process Approach (HAPA) principles were used to enhance participants’ efficacy and planning.

Methods

Participants were recruited online and offline among local universities; 321 university students and staff were randomly assigned to three conditions. The basic and HAPA-enhanced groups completed the 8-week fully automated mindfulness training online. All participants (including control) were asked to complete an online questionnaire pre-program, post-program, and at 3-month follow-up.

Results

Significant group by time interaction effect was found. The HAPA-enhanced group showed significantly higher levels of mindfulness from pre-intervention to post-intervention, and such improvement was sustained at follow-up. Both the basic and HAPA-enhanced mindfulness groups showed better mental well-being from pre-intervention to post-intervention, and improvement was sustained at 3-month follow-up.

Conclusions

Online mindfulness training can improve mental health. An online platform is a viable medium to implement and disseminate evidence-based interventions and is a highly scalable approach to reach the general public.

Trial Registration

Chinese Clinical Trial Registry (ChiCTR): ChiCTR-TRC-12002954; http://www.chictr.org/en/proj/show.aspx?proj=3904 (Archived by WebCite at http://www.webcitation.org/6VCdG09pA).     

Hematopoietic stem cells in the blood after stem cell factor and interleukin-11 administration: evidence for different mechanisms of mobilization

Peripheral blood stem cells and progenitor cells, collected during recovery from exposure to cytotoxic agents or after cytokine administration, are being increasingly used in clinical bone marrow transplantation. To determine factors important for mobilization of both primitive stem cells and progenitor cells to the blood, we studied the blood and splenic and marrow compartments of intact and splenectomized mice after administration of recombinant human interleukin-11 (rhlL-11), recombinant rat stem cell factor (rrSCF), and IL-11 + SCF. IL-11 administration increased the number of spleen colony- forming units (CFU-S) in both the spleen and blood, but did not increase blood long-term marrow-repopulating ability (LTRA) in intact or splenectomized mice. SCF administration increased the number of CFU- S in both the spleen and blood and did not increase the blood or splenic LTRA of intact mice, but did increase blood LTRA to normal marrow levels in splenectomized mice. The combination of lL-11 + SCF syngeristically enhanced mobilization of long-term marrow-repopulating cells from the marrow to the spleen of intact mice and from the marrow to the blood of splenectomized mice. These data, combined with those of prior studies showing granulocyte colony-stimulating factor mobilization of long-term marrow repopulating cells from the marrow to the blood of mice with intact spleens, suggest different cytokine- induced pathways for mobilization of primitive stem cells.     

Distinct evolutionary trajectories of primary high‐grade serous ovarian cancers revealed through spatial mutational profiling

High‐grade serous ovarian cancer (HGSC) is characterized by poor outcome, often attributed to the emergence of treatment‐resistant subclones. We sought to measure the degree of genomic diversity within primary, untreated HGSCs to examine the natural state of tumour evolution prior to therapy. We performed exome sequencing, copy number analysis, targeted amplicon deep sequencing and gene expression profiling on 31 spatially and temporally separated HGSC tumour specimens (six patients), including ovarian masses, distant metastases and fallopian tube lesions. We found widespread intratumoural variation in mutation, copy number and gene expression profiles, with key driver alterations in genes present in only a subset of samples (eg PIK3CA, CTNNB1, NF1). On average, only 51.5% of mutations were present in every sample of a given case (range 10.2–91.4%), with TP53 as the only somatic mutation consistently present in all samples. Complex segmental aneuploidies, such as whole‐genome doubling, were present in a subset of samples from the same individual, with divergent copy number changes segregating independently of point mutation acquisition. Reconstruction of evolutionary histories showed one patient with mixed HGSC and endometrioid histology, with common aetiologic origin in the fallopian tube and subsequent selection of different driver mutations in the histologically distinct samples. In this patient, we observed mixed cell populations in the early fallopian tube lesion, indicating that diversity arises at early stages of tumourigenesis. Our results revealed that HGSCs exhibit highly individual evolutionary trajectories and diverse genomic tapestries prior to therapy, exposing an essential biological characteristic to inform future design of personalized therapeutic solutions and investigation of drug‐resistance mechanisms. © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

1141170685Tumor-infiltrating lymphocytes contain higher proportion of FOXP3+ T lymphocytes from cervical cancer than that from cervical intraepithelial zneoplasm

Ovine uterine serpin (OvUS) is the major progesterone-induced protein in the uterus of the pregnant sheep. This protein is a member of the serine proteinase inhibitor superfamily and it has been proposed to down-regulate uterine immune function during pregnancy to protect the fetus. In vitro experiments have shown that both the native and the recombinant (r) form of the protein can inhibit mitogen-induced lymphocyte proliferation and growth of canine primary osteogenic sarcoma cells, mouse lymphoma cells, human prostatic adenocarcinoma cells (PC-3 cell line) and bovine preimplantation embryos. The mechanism by which OvUS inhibits cell proliferation is still unknown. Accordingly, experiments were conducted to test whether rOvUS exerts its anti-proliferative action through apoptosis. In the first experiment, the anti-proliferative effect of rOvUS on PC-3 cells was tested to determine the minimal concentration effective at inhibiting proliferation. Proliferation was inhibited by concentrations of OvUS at 8 μg/mL and higher. The incorporation of [³H]thymidine was 4043, 3998, 3464, 2785, 2827, 2310, and 2332 dpm for 0, 0.5, 2, 8, 32, 125, and 250 μg/mL, respectively. In the second experiment, PC-3 cells were cultured for 48 hr with 50, 100 and 200 μg/mL of rOvUS or ovalbumin. Cells were then fixed and apoptotic cells identified using the TUNEL assay to detect DNA fragmentation. There was no effect of OvUS at any concentration tested on the percent of cells that were apoptotic. Percent apoptosis was 1.3% for control cells, 3.8%, 4.8% and 2% for cells cultured with 50, 100 and 200 μg/mL rOvUS, and 2% for cells cultured with 200 μg/mL ovalbumin. Results confirm that OvUS inhibits proliferation of PC-3 cells and indicate that inhibition does not involve induction of apoptosis. Further experiments are warranted to elucidate the anti-proliferative mechanism of action of OvUS.     

Circulating noradrenaline and β-adrenergic receptors in children with congestive heart failure

This study was designed to investigate changes in plasma catecholamine concentrations and the number of β-adrenoceptors (β-AR) of circulating lymphocyte in 94 noncyanotic congenital heart patients, in 43 patients with congestive heart failure, β-AR density was significantly lower ( p < 0.001) and plasma noradrenergic levels were significantly higher ( p < 0.001) compared with corresponding values in 51 patients without heart failure. A significant negative correlation between lymphocyte β-AR density and plasma noradrenergic levels was observed ( r =−0.61, p < 0.001). The degree of left-to-right shunt and pulmonary pressure was correlated directly with noradrenaline level and inversely with lymphocyte β-AR density. Both plasma noradrenaline level and lymphocyte β-AR density return to normal in children with heart failure after surgical repair. Our results support the idea that changes in noradrenaline level and lymphocyte β-adrenoceptor density occur concurrently with the presence and severity of heart failure in children.