Incidence and risk factors for pulmonary mycosis in kidney transplantation

IntroductionPulmonary mycosis, a severe complication following kidney transplantation, is associated with a high rate of mortality. The incidence of and independent risk factors for its development have not been well studied.MethodsWe retrospectively reviewed 2573 kidney transplant recipients. Patients were divided into case and control groups based on a diagnosis of pulmonary mycosis. The recipient baseline characteristics, posttransplant complications, immunosuppressive regimens and antibiotic usages were analyzed to identify independent risk factors.ResultsThe total incidence of pulmonary mycosis among kidney recipients was 2.1%. Upon univariate analysis, patients in the case group differed significantly from the controls based upon: older age, higher retransplantation rate, longer dialysis time, induction with ATG or anti-CD25 monoclonal antibodies, maintenance treatment with FK506 or MMF, broad-spectrum antibiotics, higher incidences of acute rejection episodes, DGF, impaired liver function, leukopenia, cytomegalovirus infection, and delayed incisional healing (P < .05). Multivariate analysis showed that older age, retransplantation, ATG induction, FK506/MMF, broad-spectrum antibiotics, leukopenia, and delayed incisional healing were independent risk factors for pulmonary mycosis.ConclusionsThe use of more potent immunosuppressive regimens seems to increase the rate of pulmonary mycosis. Patients who have five or more independent risk factors are at high risk for developing pulmonary mycosis.     

An assessment of drug information sheets for diabetic patients: only active involvement by patients is helpful

Insulin/sulphonylurea-treated diabetics attending a busy university diabetic clinic were studied to determine whether issuing drug information sheets and/or age influenced understanding and behaviour regarding their disease and its treatment, especially with respect to avoiding hypoglycaemia. Patients were each asked 10 basic questions (each correct answer scoring 1), stratified by age (20 were less than or equal to 45 years and 91 greater than 45 years). According to a single-blind randomised protocol, they were issued or not issued with drug information sheets (providing information to correctly answer all 10 questions). After 2-3 months, 107 (88 aged greater than 45 years) were retested and asked whether they recalled an information sheet, read it themselves or had it read to them. Whether or not patients received sheets, corresponding mean aggregate scores were very similar in both age groups and there was no correlation with age. Second test scores yielded clinically and statistically significant increments in both the sheet and no sheet groups, respective mean aggregate scores increasing from 4.48 to 5.80 and 5.14 to 6.27 (P less than 0.001). Among patients issued with sheets, 32 who recalled reading them achieved the greatest improvement in mean scores (4.53 to 6.16, P less than 0.001). Active interaction/communication (participation in first test, recall and reading of information sheet) had a favourable educational impact irrespective of age, but merely issuing drug information sheets had no benefit.     

Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma

The mechanisms by which multiple myeloma (MM) cells migrate and home to the bone marrow are not well understood. In this study, we sought to determine the effect of the chemokine SDF-1 (CXCL12) and its receptor CXCR4 on the migration and homing of MM cells. We demonstrated that CXCR4 is differentially expressed at high levels in the peripheral blood and is down-regulated in the bone marrow in response to high levels of SDF-1. SDF-1 induced motility, internalization, and cytoskeletal rearrangement in MM cells evidenced by confocal microscopy. The specific CXCR4 inhibitor AMD3100 and the anti-CXCR4 antibody MAB171 inhibited the migration of MM cells in vitro. CXCR4 knockdown experiments demonstrated that SDF-1-dependent migration was regulated by the P13K and ERK/ MAPK pathways but not by p38 MAPK. In addition, we demonstrated that AMD3100 inhibited the homing of MM cells to the bone marrow niches using in vivo flow cytometry, in vivo confocal microscopy, and whole body bioluminescence imaging. This study, therefore, demonstrates that SDF-1/CXCR4 is a critical regulator of MM homing and that it provides the framework for inhibitors of this pathway to be used in future clinical trials to abrogate MM trafficking.     

Potentiation of antileukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR-ABL- and mutant FLT3-expressing cells

Mediators of PI3K/AKT signaling have been implicated in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). Studies have shown that inhibitors of PI3K/AKT signaling, such as wortmannin and LY294002, are able to inhibit CML and AML cell proliferation and synergize with targeted tyrosine kinase inhi-bitors. We investigated the ability of BAG956, a dual PI3K/PDK-1 inhibitor, to be used in combination with inhibitors of BCR-ABL and mutant FLT3, as well as with the mTOR inhibitor, rapamycin, and the rapamycin derivative, RAD001. BAG956 was shown to block AKT phosphorylation induced by BCR-ABL–, and induce apoptosis of BCR-ABL–expressing cell lines and patient bone marrow cells at concentrations that also inhibit PI3K signaling. Enhancement of the inhibitory effects of the tyrosine kinase inhibitors, imatinib and nilotinib, by BAG956 was demonstrated against BCR-ABL expressing cells both in vitro and in vivo. We have also shown that BAG956 is effective against mutant FLT3-expressing cell lines and AML patient bone marrow cells. Enhancement of the inhibitory effects of the tyrosine kinase inhibitor, PKC412, by BAG956 was demonstrated against mutant FLT3-expressing cells. Finally, BAG956 and rapamycin/RAD001 were shown to combine in a nonantagonistic fashion against BCR-ABL– and mutant FLT3-expressing cells both in vitro and in vivo.     

Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells

An attractive target for therapeutic intervention is constitutively activated, mutant FLT3, which is expressed in a subpopulation of patients with acute myelocyic leukemia (AML) and is generally a poor prognostic indicator in patients under the age of 65 years. PKC412 is one of several mutant FLT3 inhibitors that is undergoing clinical testing, and which is currently in late-stage clinical trials. However, the discovery of drug-resistant leukemic blast cells in PKC412-treated patients with AML has prompted the search for novel, structurally diverse FLT3 inhibitors that could be alternatively used to override drug resistance. Here, we report the potent and selective antiproliferative effects of the novel mutant FLT3 inhibitor NVP-AST487 on primary patient cells and cell lines expressing FLT3-ITD or FLT3 kinase domain point mutants. NVP-AST487, which selectively targets mutant FLT3 protein kinase activity, is also shown to override PKC412 resistance in vitro, and has significant antileukemic activity in an in vivo model of FLT3-ITD(+) leukemia. Finally, the combination of NVP-AST487 with standard chemotherapeutic agents leads to enhanced inhibition of proliferation of mutant FLT3-expressing cells. Thus, we present a novel class of FLT3 inhibitors that displays high selectivity and potency toward FLT3 as a molecular target, and which could potentially be used to override drug resistance in AML.     

Phosphorus Effects of Mesoporous Bioactive Glass on Occlude Exposed Dentin

In recent studies, sealing of exposed dentinal tubules is generally considered as one of the most effective strategies to treat dentin hypersensitivity. Mesoporous bioactive glass (MBG) is a potential material for treating dentin hypersensitivity due to its highly specific areas for dissolution and re-precipitated reaction for reduction in dentin permeability. The groups of commercial products of PerioGlas^®, synthetic MBG and MBG without phosphorus (MBGNP) were compared. The MBG and MBGNP powders were prepared by the sol-gel method and mixed with different calculated ratios of phosphoric acid (PA) and then was brushed onto dentin surfaces. We used X-ray diffractometer (XRD), scanning electronic microscope (SEM), and Fourier transform infrared spectroscopy (FTIR) to investigate the physiochemistry and the occlusion ability of dentinal tubules. The results showed that MBG paste mixed with PA solution has a better ability for occluding dentinal tubules than MBGNP; it has a short reaction time and good operability. The major crystallite phase of MBG agents was monocalcium phosphate monohydrate [Ca(H₂PO₄)₂·H₂O] in the early stages of the reactions. MBG pastes that were mixed with 30% and 40% PA had the ability to create excellent penetration depth greater than 80 μm. These agents have the potential to treat dentin hypersensitivity.     

Feasibility Evaluation of an Interpersonal and Social Rhythm Therapy Group Delivery Model

The effectiveness of psychotherapies, such as interpersonal and social rhythm therapy (IPSRT), is supported by randomized controlled trials. These trials provide minimal direction regarding feasibility of psychotherapy delivery models. The study purpose was to identify factors facilitating implementation and sustainability of an IPRST group for patients with bipolar disorder. Qualitative data were assessed by the normalization process model (NPM). The results demonstrate feasibility of implementation with experienced clinicians, program coordination, and leadership support. Sustainability challenges include aftercare groups, space, and clinician time. The NPM provides a useful framework for evaluation of factors influencing the feasibility of psychotherapy delivery models.     

Bone mineral density enhances use of clinical risk factors in predicting ten-year risk of osteoporotic fractures in Chinese men: the Hong Kong Osteoporosis Study

Summary  

This prospective study aimed to determine the risk factors and the 10-year probability of osteoporotic fracture in Southern Chinese men. The findings show substantial population differences in fracture incidence and risk prediction compared to the FRAX^TM model, and the addition of BMD information to clinical risk factor assessment improved fracture risk prediction in Chinese men.     

Both homo and heterodimers of Marek's disease virus encoded Meq protein contribute to transformation of lymphocytes in chickens

Marek' disease virus serotype-1, also know as Gallid herpesvirus 2 (GaHV-2), elicits T-cell lymphomas in chickens. The GaHV-2 genome encodes an oncoprotein, Meq, with similarity to the Jun/Fos family of proteins. We have previously shown that Meq homodimers are not sufficient to induce lymphomas in chickens. In this study, we investigated the role of Meq heterodimers in the pathogenicity of GaHV-2 by generating a chimeric meq gene, which contains the leucine zipper region of Fos (meqFos). A recombinant virus containing the meqFos gene in place of parental meq, rMd5-MeqFos, was not capable of transforming chicken lymphocytes, indicating that heterodimerization of Meq alone is not sufficient for transformation. In addition, the recovery of the oncogenic phenotype by a recombinant virus encoding one copy each of MeqGCN (homodimer) and MeqFos (heterodimer) conclusively demonstrates that both homo and heterodimerization of Meq are required for oncogenesis.