Statin exposure and the risk of dementia in individuals with hypercholesterolaemia.

OBJECTIVES: This study aimed to examine the association between statin exposure and dementia risk in individuals with hypercholesterolaemia using data from the NHIS-HEALS database between 2002 and 2015. METHODS: Subjects were classified into statin exposure and statin nonexposure groups according to medication possession ratio. Dementia was defined as those with primary diagnostic dementia codes such as F00-F03, G30, G31.1, G31.9 or G31.82. Cox proportional hazards regression models were adopted after stepwise adjustment for confounders to investigate the prospective association between statin exposure and dementia risk. RESULTS: During the follow-up period (median follow-up 11.7 years), 711 cases of dementia occurred, accounting for 11.5% of the total study population (statin exposure group, 8.2%; statin nonexposure group, 12.9%). Compared to the statin nonexposure group, fully adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) for overall dementia in the statin exposure group were 0.63 (0.43-0.91) and 0.62 (0.50-0.78) in men and women, respectively. Compared to the statin nonexposure group, the HRs (95% CIs) for Alzheimer's disease and related dementia, vascular dementia and other types of dementia in the statin exposure group were 0.54 (0.32-0.91), 2.45 (0.69-8.68) and 0.59 (0.32-1.07), respectively, in men and 0.53 (0.38-0.73), 1.29 (0.42-3.96) and 0.70 (0.51-0.96), respectively, in women. CONCLUSIONS: Hypercholesterolaemic individuals exposed to statin had a lower risk of overall dementia and Alzheimer's disease and related dementia in both sexes, and a lower risk of other types of dementia in women, than subjects who were not exposed to statins.

Survival of oral mucosal melanoma according to treatment, tumour resection margin, and metastases.

Because of the poor prognosis and of oral mucosal melanoma, and patients' short survival, large, randomised, clinical studies are difficult. We have investigated its demographic characteristics and analysed the effect of treatment, resection margins, and metastases on survival. We recorded age, sex, site of primary tumour, and types of treatment, survival, and metastases in 74 patients treated at the Department of Oral and Maxillofacial Surgery, Seoul National University Dental Hospital. Survival was analysed based on bony invasion, depth of invasion, and resection margins, and we found that it varied depending on the primary site (p=0.002), and declined with liver (p=0.001) or brain (p=0.033) metastases. The two-year survival according to the primary site was as follows: palate 85% (n=32), anterior maxillary gingiva 53% (n=13), mandible 58% (n=13), and posterior maxillary gingival 74% (n=10) and buccal mucosa 50% (n=4). The two-year survival was 34% (n=8) in patients with liver metastases and 23% (n=7) in patients with brain metastases. In cases of bony invasion (p=0.005), depth of invasion (p=0.042), unclear resection margin (p=0.023), or higher T stages (p=0.009), the survival declined considerably. Neck dissection did not affect survival (p=0.343). Survival of the patients given chemotherapy was significantly lower (p=0.013) and the two-year survival was 54.0%. The patients given radiotherapy showed no significant difference in survival compared with those not given radiotherapy (p=0.107). In conclusion, primary site, bony invasion, resection margins, depth of invasion and systemic metastases were critical to predict prognosis and selection of treatment of oral mucosal melanoma.

Utilidad clínica de la PET/TC ósea doble fase con 18F-fluoruro de sodio (18F-NaF) para valorar la respuesta terapéutica de las metástasis óseas del cáncer de mama: informe de un caso / Clinical usefulness of two-phase 18F-sodium-fluoride (18F-NaF) bone PET/CT for evaluating treatment response of bone metastases from breast cancer: case reportien

Reportamos el caso de una paciente con cáncer de mama, en la que la PET/TC ósea doble fase con 18F-fluoruro de sodio (18F-NaF) resultó de utilidad para detectar metástasis óseas ocultas y valorar la respuesta al tratamiento. La paciente fue estudiada con PET/TC ósea en doble fase de una lesión de nuevo desarrollo detectada en la gammagrafía posterior a la intervención. En las imágenes PET/TC de perfusión y óseas, se encontraron captaciones en las fases de perfusión y ósea, puntualmente incrementadas en el sacro y la vértebra L5, sugerentes de metástasis óseas del cáncer de mama, por lo que se aplicó a la paciente terapia paliativa. En las imágenes de PET/TC ósea en doble fase, realizadas a los 3y 6meses, las imágenes de perfusión reflejaron más claramente la mejora de la captación de la lesión que las imágenes de la fase ósea en los análisis visual y semicuantitativo. Por tanto, se utilizaron las imágenes de la fase de perfusión para esclarecer la respuesta a la terapia con mayor prontitud que las imágenes de la fase ósea. Se trata del primer caso que refleja la utilidad clínica de la PET/TC ósea con 18F-NaF, con la técnica de imagen de perfusión, para evaluar las metástasis óseas y la respuesta terapéutica de las lesiones óseas metastásicas

We report the case of a breast cancer patient in whom a two-phase 18F-sodium-fluoride (18F-NaF) bone PET/CT was useful for detecting hidden bone metastases and assessing treatment response. The patient underwent a two-phase bone PET/CT to evaluate a newly developed lesion found on bone scintigraphy following surgery. In the perfusion and bone phase PET/CT images, focally increased perfusion and bony uptake were found in the sacrum and L5 vertebra, suggesting bone metastases of breast cancer. Therefore, the patient subsequently underwent palliative treatment. In another twoPET/CT studies (each including two-phase bone images) performed after 3and 6months of follow-up, the perfusion phase images showed an improvement of the lesion uptake more clearly than in the bone phase images in the visual and semi-quantitative analyses, and thus the perfusion phase images were more useful for clarifying the treatment response earlier than the bone phase images. This is the first case showing the clinical usefulness of 18F-NaF bone PET/CT with the perfusion imaging technique for evaluating bone metastases and the therapeutic response of metastatic bone lesions

Online estimation of optimal operating conditions for simulated moving bed chromatographic processes.

A new approach for determining optimal operating conditions for simulated moving bed chromatographic processes is presented. The method is based on recursive online estimation and requires only rough initial estimates. It is based on a simple foot point model of the moving concentration fronts and an online measurement of the corresponding retention times in the different zones of the plant. A mathematical representation of the adsorption isotherms is not required. The method is validated experimentally for the separation of bicalutamide enantiomers.

A DNA priming and protein boosting immunization scheme to augment immune responses against parvovirus in ducks.

AIMS: To evaluate the effect of a DNA priming and protein boosting immunization scheme in ducks. METHODS AND RESULTS: Pekin ducks were immunized with pTCY/VP2 DNA vaccine; on day 14 (D14) after primary immunization, the ducks were boosted with either the same vaccine (DNA + DNA) or the rVP2 vaccine (DNA + rVP2). CpG oligodeoxynucleotides containing three copies of GACGTT motifs were used as the adjuvant in the vaccines. Compared with unimmunized controls, both immunization schemes significantly increased the titre of antigen-specific antibodies, lymphocyte proliferation index, percentage of CD4+ and CD8+ cells in peripheral blood mononuclear cells (PBMCs) and mRNA expression of interferon (IFN)-α, IFN-γ, interleukin (IL)-6 and IL-12 in antigen-stimulated PBMCs. Furthermore, compared with the DNA + DNA homologous scheme, the DNA + rVP2 heterologous scheme significantly increased lymphocyte proliferation, percentage of CD4+ and CD8+ cells in PBMCs and upregulation of mRNA expression of cytokines 2 weeks after the boost (D28). CONCLUSIONS: The DNA + rVP2 immunization scheme enhanced immune responses, mainly Th1 type, against parvovirus in ducks. SIGNIFICANCE AND IMPACT OF THE STUDY: The DNA priming and protein boosting heterologous immunization strategy can be applied to develop vaccines against viral infections in ducks. It can potentially be used in breeding ducks because of long-term immunity may confer protection for ducklings.

Direct bilirubin is associated with low-density lipoprotein subfractions and particle size in overweight and centrally obese women.

BACKGROUND AND AIMS: Bilirubin has antioxidant and anti-inflammatory properties; serum bilirubin levels have been known to be inversely associated with cardiovascular disease. However, the effects of different bilirubin subtypes on cardiometabolic traits are unknown. In this study, we aimed to determine whether direct bilirubin is more strongly correlated with small, dense low-density lipoprotein (sdLDL) compared to other bilirubin subtypes. We also investigated which LDL subfractions exhibited the highest correlation with direct bilirubin. METHODS AND RESULTS: A total of 288 overweight and centrally obese women were included in this study. The Pearson correlation and Steiger's Z test were used to compare the correlation coefficients between bilirubin subtypes and lipoproteins. Multiple linear regression analyses were used to evaluate the independent association between direct bilirubin and mean LDL particle size. Only direct bilirubin levels were significantly associated with the sdLDL subfraction and mean LDL particle size. Mean LDL particle size exhibited a significantly stronger correlation with direct bilirubin than sdLDL, percent sdLDL, and the sdLDL:large LDL ratio. Regression analysis showed that direct bilirubin was significantly associated with mean LDL particle size, according to both the stepwise method (ß = 11.445, P value = 0.002) and the enter method (ß = 11.655, P value = 0.002). CONCLUSIONS: Direct bilirubin is more strongly correlated with the sdLDL subfraction compared with total and indirect bilirubin, and is independently associated with mean LDL particle size in overweight and centrally obese women.

Is calcium phosphate augmentation a viable option for osteoporotic hip fractures?

The use of calcium phosphate bone cement has been described to allow for retention of reduction. Therefore, we evaluated whether augmentation with resorbable calcium phosphate could improve fracture stability in osteoporotic hip fractures. The results showed that augmentation with calcium phosphate cement significantly improved the stability of intertrochanteric fractures. INTRODUCTION: The aim with this study was to measure whether augmentation with resorbable calcium phosphate cement could improve fracture stability in osteoporotic hip fractures. METHODS: We retrospectively reviewed 82 patients who underwent closed reduction and internal fixation with proximal femoral nail (PFN) for unstable intertrochanteric fractures between 2014 and 2017. In 42 of 82 patients, patients were treated with a PFN alone (group I). These patients were compared with 40 patients for whom the same device combined with calcium phosphate cement for augmentation was used (group II). Questionnaire surveys or telephone interviews were conducted and patients completed a self-report Harris hip score (HHS) and visual analog scale (VAS) scores. Radiographic outcomes including mean sliding distance of screw, femoral shortening, and varus collapse were compared. Postoperative complications were compared. RESULTS: Clinical outcomes at 6 months after surgery were equivalent in both groups. Screw sliding, femoral shortening, and varus collapse were all significantly reduced in the cemented group at the last follow-up (p < 0.001, p = 0.005, p < 0.001, respectively). A total of 9 (21%) complications occurred in group I. In contrast, 2 (5%) complications were seen in group II (p = 0.029). CONCLUSIONS: Augmentation with calcium phosphate cement significantly improved the stability of intertrochanteric fractures fixed with a PFN and reduced overall failure rates. We believe augmentation with resorbable calcium phosphate cement for osteoporotic hip fractures is a reasonable option in selected patients.

Correlation between intraoperative proximal segment rotation and post-sagittal split ramus osteotomy relapse: a three-dimensional cone beam computed tomography study.

This study evaluated the effects of proximal segment rotation and the extent of mandibular setback on post-sagittal split ramus osteotomy (SSRO) relapse using three-dimensional (3D) analysis. Thirty-one patients diagnosed with a skeletal class III malocclusion who underwent SSRO alone were enrolled in this study. The movements of the mandibular condyles were assessed using cone beam computed tomography (CBCT) and a 3D imaging program at ≤1 month before the operation (T0), 1 week after the operation (T1), and 6 months (T2) and 1year (T3) postoperative. Yaw and roll were increased at T1 as compared to T0. However, the proximal segments reverted to their original positions between T2 and T3. There was a positive correlation between the extent of the posterior movement of the mandible and relapse at 6 months and 1year postoperative. Although the proximal bone segments showed displacement in three dimensions at T1, they reverted to their original positions over time. In addition, although there was a positive correlation between the extent of the posterior movement of the mandible and the occurrence of post-surgical relapse at 6 months and 1year post-surgery, the rotation of the proximal bone segment during surgery had no relationship with postoperative relapse.

Runx3 plays a critical role in restriction-point and defense against cellular transformation.

The restriction (R)-point decision is fundamental to normal differentiation and the G1-S transition, and the decision-making machinery is perturbed in nearly all cancer cells. The mechanisms underlying the cellular context-dependent R-point decision remain poorly understood. We found that the R-point was dysregulated in Runx3-/-mouse embryonic fibroblasts (MEFs), which formed tumors in nude mice. Ectopic expression of Runx3 restored the R-point and abolished the tumorigenicity of Runx3-/-MEFs and K-Ras-activated Runx3-/-MEFs (Runx3-/-;K-RasG12D/+). During the R-point, Runx3 transiently formed a complex with pRb and Brd2 and induced Cdkn1a (p21Waf1/Cip1/Sdi1; p21), a key regulator of the R-point transition. Cyclin D-CDK4/6 promoted dissociation of the pRb-Runx3-Brd2 complex, thus turning off p21 expression. However, cells harboring oncogenic K-Ras maintained the pRb-Runx3-Brd2 complex and p21 expression even after introduction of Cyclin D1. Thus, Runx3 plays a critical role in R-point regulation and defense against cellular transformation.

Immunologic regulatory effects of human umbilical cord blood-derived mesenchymal stem cells in a murine ovalbumin asthma model.

BACKGROUND: Mesenchymal stem cells (MSCs) have multiple immunomodulatory properties and hold therapeutic potential for inflammatory diseases. However, the therapeutic and immunologic effects of human umbilical cord blood-derived MSCs (huMSCs) remain largely unexamined for asthma. OBJECTIVE: This study was to investigate the immunomodulatory properties of huMSCs in an ovalbumin (OVA)-induced murine asthma model. METHODS: Mice were injected intraperitoneally with OVA and an aluminium hydroxide adjuvant. huMSCs were administered via the tail vein (5×105 cells/100 uL) to female BALB/c mice prior to the initial OVA challenge. The effects of huMSCs were assessed by investigating airway hyperresponsiveness, histological changes, inflammatory cell numbers, serum allergen-specific antibodies, cytokine production in spleen, lung tissue, and bronchoalveolar lavage (BAL) fluid as well as expansion of regulatory T cells. RESULTS: Administration of huMSCs significantly reduced methacholine bronchial hyperresponsiveness and eosinophil counts in BAL cells. Similarly, there was a significant decrease in serum OVA-specific IgE and IgG1 levels along with Th2 cytokine production (IL-4, IL-5, and IL-13) in the lung and spleen tissues, whereas increased percentage of regulatory T cells was observed after treatment with huMSCs. CONCLUSIONS: Our results suggest that huMSC treatment reduces OVA-induced allergic inflammation, which could be mediated by regulatory T cells.

Pre-existing invasive fungal infection is not a contraindication for allogeneic HSCT for patients with hematologic malignancies: a CIBMTR study.

Patients with prior invasive fungal infection (IFI) increasingly proceed to allogeneic hematopoietic cell transplantation (HSCT). However, little is known about the impact of prior IFI on survival. Patients with pre-transplant IFI (cases; n=825) were compared with controls (n=10247). A subset analysis assessed outcomes in leukemia patients pre- and post 2001. Cases were older with lower performance status (KPS), more advanced disease, higher likelihood of AML and having received cord blood, reduced intensity conditioning, mold-active fungal prophylaxis and more recently transplanted. Aspergillus spp. and Candida spp. were the most commonly identified pathogens. 68% of patients had primarily pulmonary involvement. Univariate and multivariable analysis demonstrated inferior PFS and overall survival (OS) for cases. At 2 years, cases had higher mortality and shorter PFS with significant increases in non-relapse mortality (NRM) but no difference in relapse. One year probability of post-HSCT IFI was 24% (cases) and 17% (control, P<0.001). The predominant cause of death was underlying malignancy; infectious death was higher in cases (13% vs 9%). In the subset analysis, patients transplanted before 2001 had increased NRM with inferior OS and PFS compared with later cases. Pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT but significant survivorship was observed. Consequently, pre-transplant IFI should not be a contraindication to allogeneic HSCT in otherwise suitable candidates. Documented pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT. However, mortality post transplant is more influenced by advanced disease status than previous IFI. Pre-transplant IFI does not appear to be a contraindication to allogeneic HSCT.

Dynamic prognostic value of the revised international prognostic scoring system following pretransplant hypomethylating treatment in myelodysplastic syndrome.

This study aimed to analyze the use of the revised International Prognostic Scoring System (IPSS-R) assessed after hypomethylating treatment (HMT) for patients with myelodysplastic syndrome (MDS) undergoing an allogeneic stem cell transplantation (SCT). Among 115 patients who received pre-SCT HMT, comparison analysis of the prognostic values between the IPSS-R at the time of HMT (IPSS-R@HMT) and at the time of SCT after HMT (IPSS-R@SCT) showed a significantly higher predictive power for overall survival (OS) of the latter. Alteration in IPSS-R risk occurred in 60%, while the patients with 'down-staged' IPSS-R@SCT showed better OS compared with those with 'unchanged' or 'up-staged' risk. On multivariate analysis in all 201 patients, IPSS-R@SCT, monosomal karyotype, treatment failure to pre-SCT treatment, and high hematopoietic cell transplantation-comorbidity index were independently associated with OS. Constructed using these factors, the MDS Transplantation Prognostic Scoring System (MTPSS) identified four risk groups with 4-year OS of 76.4% in low, 61.4% in intermediate-1 and 21.9% in intermediate-2 risk groups, whereas all in the high risk group died within 2 years after SCT (P<0.001). Our study emphasizes the need for further studies aiming to evaluate a transplantation prognostic model such as the MTPSS to make appropriate decisions for transplantation in MDS.

RAC-LATS1/2 signaling regulates YAP activity by switching between the YAP-binding partners TEAD4 and RUNX3.

The tumor-suppressor RUNX3 has a critical role in a lineage determination, cell cycle arrest and apoptosis. Lozenge (Lz), a Drosophila homolog of mammalian RUNX family members, has integral roles in these processes and specifically in eye cell fate determination. To elucidate the genetic modifiers of Lz/RUNX3, we performed a large-scale functional screen in a fly mutant library. The screen revealed genetic interactions between the Lz, Rac and Hippo pathways. Analysis of interactions among these genes revealed that the defective phenotype resulting from activation of Yki, an end point effector of the Hippo pathway, was suppressed by Lz and enhanced by Rac-Trio. Molecular biological analysis using mammalian homologs reveled that LATS1/2-mediated YAP phosphorylation-facilitated dissociation of the YAP-TEAD4 complex and association of the YAP-RUNX3 complex. When cells were stimulated to proliferate, activated RAC-TRIO signaling inhibited LATS1/2-mediated YAP phosphorylation; consequently, YAP dissociated from RUNX3 and associated with TEAD, thereby replacing the YAP-RUNX3 complex with YAP-TEAD. RUNX3 contributed to both association and dissociation of YAP-TEAD complex, most likely through the formation of the YAP-TEAD-RUNX3 ternary complex. Ectopic expression of RUNX3 in MKN28 gastric cancer cells reduced tumorigenicity, and the tumor-suppressive activity of RUNX3 was associated with its ability to interact with YAP. These results identify a novel regulatory mechanism, mediated by the Hippo and RAC-TRIO pathways, that changes the binding partner of YAP.

Tuberculosis before hematopoietic stem cell transplantation in patients with hematologic diseases: report of a single-center experience.

BACKGROUND: Few reports discuss the optimal management of patients diagnosed with tuberculosis (TB) before scheduled stem cell transplantation (SCT), who then proceed with transplantation. METHODS: We found 13 patients with TB before SCT (proven, n = 9; probable, n = 3; possible, n = 1) in the medical records of our institution. RESULTS: Most of the patients had pulmonary TB (n = 8; disseminated, n = 2; extrapulmonary, n = 3). Eight of 9 patients with proven disease had SCT after at least 100 days of anti-tuberculous medication, ranging from 103 to 450 days. None of those patients suffered TB-related events after SCT. However, 1 patient with proven pulmonary TB who underwent SCT after only 40 days of anti-tuberculous therapy subsequently died of TB meningitis. Patients with possible and probable disease had their transplants after 6-176 days of anti-tuberculous medication, and all were alive at the time of analysis. The entire duration of anti-tuberculous medication was 12 months in most cases. With a follow-up duration ranging from 0.7 to 87.5 months, 4 patients died, but TB was the cause of death in only 1 case. CONCLUSION: In conclusion, for proven cases of TB, SCT after >100 days of anti-tuberculous medication is probably feasible and safe, in terms of TB control, in patients with various hematologic diseases.