RADIOMICS BASED ON TWO-DIMENSIONAL AND THREE-DIMENSIONAL ULTRASOUND FOR EXTRATHYROIDAL EXTENSION FEATURE PREDICTION IN PAPILLARY THYROID CARCINOMA.

Aim: To evaluate the diagnostic performance of radiomics features of two-dimensional (2D) and three-dimensional (3D) ultrasound (US) in predicting extrathyroidal extension (ETE) status in papillary thyroid carcinoma (PTC). Patients and Methods: 2D and 3D thyroid ultrasound images of 72 PTC patients confirmed by pathology were retrospectively analyzed. The patients were assigned to ETE and non-ETE. The regions of interest (ROIs) were obtained manually. From these images, a larger number of radiomic features were automatically extracted. Lastly, the diagnostic abilities of the radiomics models and a radiologist were evaluated using receiver operating characteristic (ROC) analysis. We extracted 1693 texture features firstly. Results: The area under the ROC curve (AUC) of the radiologist was 0.65. For 2D US, the mean AUC of the three classifiers separately were: 0.744 for logistic regression (LR), 0.694 for multilayer perceptron (MLP), 0.733 for support vector machines (SVM). For 3D US they were 0.876 for LR, 0.825 for MLP, 0.867 for SVM. The diagnostic efficiency of the radiomics was better than radiologist. The LR model had favorable discriminate performance with higher area under the curve. Conclusion: Radiomics based on US image had the potential to preoperatively predict ETE. Radiomics based on 3D US images presented more advantages over radiomics based on 2D US images and radiologist.

The dose-response effects of uric acid on the prevalence of metabolic syndrome and electrocardiographic left ventricular hypertrophy in healthy individuals.

BACKGROUND AND AIM: Hyperuricemia (HUA) is associated with the prevalence of metabolic syndrome (MetS) and cardiovascular risks in various populations. HUA is also able to induce cardiomyocyte hypertrophy in mouse models. However, the dose-response effects of serum uric acid (SUA) on the prevalence of MetS and electrocardiographic left ventricular hypertrophy (LVH) are unclear. METHODS AND RESULTS: We retrospectively collected data from 18,932 individuals who underwent an annual health examination between 1/1/2016 and 12/31/2016. We excluded those with systemic diseases or missing questionnaires. The primary study endpoints were the prevalence of MetS and LVH, which were defined by the criteria for the Taiwanese population and the "SPRINT" trial. The cohort consisted of 17,913 individuals with a mean age of 31.2 years (SD 7.4) and a mean body mass index of 24.6 kg/m2 (SD 3.6); 87.1% of the individuals were men. The prevalence rates of HUA, MetS, and LVH were 29.5%, 9.4%, and 0.32%, respectively, in the overall study population. The HUA group was predominantly male and had significantly poorer lifestyle choices and greater laboratory cardiometabolic biomarker values than did the normouricemic group. However, the frequencies of physical activity were comparable between the two groups. After adjusting for confounders, SUA was associated with MetS (OR:1.473, 95% CI:1.408-1.540, P < 0.001) and LVH (OR:1.301, 95% CI:1.064-1.591, P = 0.01). CONCLUSION: We demonstrated that the dose-response effects of SUA are associated with the prevalence of MetS and electrocardiographic LVH in healthy individuals from Taiwan. Based on this evidence, future studies should investigate urate-lowering therapy and cardiovascular benefits in individuals with HUA (ClinicalTrials.gov number NCT03473951).

Prefrontal cortical parvalbumin and somatostatin expression and cell density increase during adolescence and are modified by BDNF and sex.

Brain-derived neurotrophic factor (BDNF) is known to play a critical role early in the development of cortical GABAergic interneurons. Recently our laboratory and others have shown protracted development of specific subpopulations of GABAergic interneurons extending into adolescence. BDNF expression also changes significantly across adolescent development. However the role of BDNF in regulating GABAergic changes across adolescence remains unclear. Here, we performed a week-by-week analysis of the protein expression and cell density of three major GABAergic interneurons, parvalbumin (PV), somatostatin (SST) and calretinin (Cal) in the medial prefrontal cortex from prepubescence (week 3) to adulthood (week 12). In order to assess how BDNF and sex might influence the adolescent trajectory of GABAergic interneurons we compared WT as well as BDNF heterozygous (+/-) male and female mice. In both males and females PV expression increases during adolescent development in the mPFC. Compared to wild-types, PV expression was reduced in male but not female BDNF+/- mice throughout adolescent development. This reduction in protein expression corresponded with reduced cell density, specifically within the infralimbic prefrontal cortex. SST expression increased in early adolescent WT females and this upregulation was delayed in BDNF+/-. SST cell density also increased in early adolescent mPFC of WT female mice, with BDNF+/- again showing a reduced pattern of expression. Cal protein expression was also sex-dependently altered across adolescence with WT males showing a steady decline but that of BDNF+/- remaining unaltered. Reduced cell density in on the other hand was observed particularly in male BDNF+/- mice. In females, Cal protein expression and cell density remained largely stable. Our results show that PV, SST and calretinin interneurons are indeed still developing into early adolescence in the mPFC and that BDNF plays a critical, sex-specific role in mediating expression and cell density.

[Effects of early enteral nutrition in the treatment of patients with severe burns].

Objective: To investigate the effects of early enteral nutrition (EEN) in the treatment of patients with severe burns. Methods: Medical records of 52 patients with severe burns hospitalized in the three affiliations of authors from August to September in 2014 were retrospectively analyzed and divided into EEN group (n=28) and non-early enteral nutrition (NEEN) group (n=24) according to the initiation time of enteral nutrition. On the basis of routine treatment, enteral nutrition was given to patients in group EEN within post injury day (POD) 3, while enteral nutrition was given to patients in group NEEN after POD 3. The following items were compared between patients of the two groups, such as the ratio of enteral nutrition intake to total energy intake, the ratio of parenteral nutrition intake to total energy intake, the ratio of total energy intake to energy target on POD 1, 2, 3, 4, 5, 6, 7, 14, 21, and 28, the levels of prealbumin, serum creatinine, blood urea nitrogen, total bilirubin, direct bilirubin, and Acute Physiology and Chronic Health Evaluation Ⅱ (APACHE Ⅱ) score on POD 1, 3, 7, 14, and 28, the first operation time, the number of operations, and the frequencies of abdominal distension, diarrhea, vomiting, aspiration, catheter blockage, and low blood sugar within POD 28. Data were processed with χ(2)test, ttest, Wilcoxon rank sum test, and Bonferroni correction. Results: (1) The ratio of parenteral nutrition intake to total energy intake of patients in group EEN on POD 1 was obviously lower than that in group NEEN (Z=2.078, P<0.05). The ratio of enteral nutrition intake to total energy intake and the ratio of total energy intake to energy target of patients in group EEN on POD 2 and 3 were obviously higher than those in group NEEN (Z=5.766, 6.404, t=4.907, 6.378, P<0.01). The ratio of total energy intake to energy target of patients in group EEN was obviously lower than that in group NEEN on POD 4, 5, 6, and 7 (t=4.635, 2.547, 3.751, 5.373, P<0.05 or P<0.01). On POD 2, 4, 5, 14, 21, and 28, the ratio of enteral nutrition intake to total energy intake of patients in group EEN was obviously higher than the ratio of parenteral nutrition intake to total energy intake within the same group (Z=5.326, 2.046, 2.129, 4.118, 3.174, 3.963, P<0.05 or P<0.01). In group NEEN, the ratio of enteral nutrition to total energy intake of patients on POD 1, 2, and 3 was obviously lower than the ratio of parenteral nutrition intake to total energy intake within the same group (Z=2.591, 2.591, 3.293, P<0.05 or P<0.01), while the ratio of enteral nutrition to total energy intake of patients on POD 14, 21, 28 was obviously higher than the ratio of parenteral nutrition intake to total energy intake within the same group (Z=2.529, 3.173, 3.133, P<0.05 or P<0.01). (2) The prealbumin levels of patients in the two groups were close on POD 1, 3, 7, and 14 (t=1.983, 0.093, 0.832, 1.475, P>0.05). On POD 28, the prealbumin level of patients in group EEN was obviously higher than that in group NEEN (t=3.163, P<0.05). The levels of serum creatinine, blood urea nitrogen, total bilirubin, and direct bilirubin of patients in the two groups at all time points post injury were close (Z=1.340, 0.547, 0.245, 0.387, 0.009, 1.170, 0.340, 1.491, 0.274, 1.953, 0.527, 0.789, 0.474, 1.156, 0.482, 0.268, 0.190, 0.116, 1.194, 0.431, P>0.05). (3) The APACHE Ⅱ scores of patients in group EEN were (22.5±3.1) and (15.6±3.8) points respectively on POD 1 and 3, which were close to (23.6±3.0) and (17.6±4.2) points of patients in group NEEN (t=1.352, 1.733, P>0.05). The APACHE Ⅱ scores of patients in group EEN on POD 7, 14, and 28 were (13.6±3.6), (13.8±4.1), and (15.5±4.1) points, respectively, which were obviously lower than (18.5±3.9), (19.5±4.2) and (20.8±3.8) points of patients in group NEEN (t=4.677, 4.843, 4.792, P<0.05). (4) Within POD 28, the time of the first operation, the number of operations, and the frequencies of abdominal distension, diarrhea, vomiting, aspiration, catheter blockage and hypoglycemia were similar between patients of the two groups (t=0.684, 0.782, Z=0.161, 1.751, 0.525, 0.764, 0.190, 0.199, P>0.05). Conclusions: EEN in the treatment of patients with severe burns potentially increases the energy intake at early stage and improves APACHE Ⅱ score and prealbumin level on POD 28, without increasing frequencies of adverse reactions.

[Synthesis and in vitro characterization of chitosan microspheres/ceramic bovine bone composite scaffold].

OBJECTIVE: The chitosan microspheres encapsulated with bone morphogenetic protein-2 (BMP-2) were prepared by the emulsion cross-linking method. Then the chitosan microspheres were loaded in the ceramic bovine bone (CBB) to achieve the drug delivery system. METHODS: The chemical structure and surface morphology of the drug delivery system were investigated by Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscope (SEM) observation. Characterization preserved the loading capacity and encapsulation efficiency of the BMP-2. The dynamic immersion method was used to examine the in vitro release characteristic of BMP-2. RESULTS: The chitosan microspheres were successfully encapsulated BMP-2 by cross-linking method. The microspheres were micron-sized (5.982 µm) and spherical in shape with smooth surface morphology. From the release experiments, it was found that 5 mg chitosan/BMP-2 soaked for 21 days with a gradual release of BMP-2. The concentration of BMP-2 was (239.1±20.0) mg/L on Day 21. The in vitro experiment showed that this novel drug delivery system could accelerate MC3T3-E1 cells proliferation and osteogenic differentiation. CONCLUSION: The drug delivery system achieves the biological function of BMP-2 and sustaining slow release in bone repair parts. Also it can provide the basis for repair of bone tissue defect treatment and the selection of bone tissue engineering scaffolds.

[Clinical value of changes of SUVmax in series 18F-FDG PET/CT imaging before and after chemotherapy for non-small cell lung cancer].

Objective: To evaluate the clinical value of changes of maximum standardized uptake value (SUVmax) in series 18F-FDG PET/CT imaging before and after chemotherapy for non-small cell lung cancer. Methods: From July 2008 to July 2014, a total of 18 patients with pathological confirmed advanced NSCLC who received systemic chemotherapy were enrolled.18F-FDG PET/CT scans were performed before, 3-4 weeks after 2-4 cycles chemotherapy, 3-4 weeks after the end of chemotherapy for all patients, and added fourth scan for 3 patients 1 year later.The SUVmax of region of interesting was calculated.The histological diagnosis or clinical findings in a 36 months follow-up period served as the standard of control. Results: New metastases foci were found by 18F-FDG PET/CT scans before chemotherapy in 7 of 18 patients.The plans of chemotherapy for 5 patients were changed as therapeutic responses were evaluated according to changes of SUVmax.Targeted therapy was added for 2 patients after the end of chemotherapy.There was a statistically significant difference in outcome of survival analysis between patients performed PET/CT scans and non-performed (P<0.05). Conclusion: Changes of SUVmax in series 18F-FDG PET/CT imaging before and after chemotherapy could be used to evaluate therapeutic response and effectively predict survival in patients with advanced NSCLC.

Biological correlation between glucose transporters, Ki-67 and 2-deoxy-2-[18F]-fluoro-D-glucose uptake in diffuse large B-cell lymphoma and natural killer/T-cell lymphoma.

The purpose of this study was to investigate the association between cellular 2-deoxy-2-[18F]-fluoro-D-glucose ((18)F-FDG) uptake and the expression of several subtypes of glucose transporters (GLUT) and Ki-67 in diffuse large B-cell lymphoma (DLBCL) and natural killer (NK)/T-cell lymphoma (NKTCL). Cell lines were histologically determined to be DLBCL (Raji cells) and NKTCL (Daudi cells), and uptake after pretreatment with (18)F-FDG was determined. Real-time polymerase chain reaction was performed to detect the expression levels of GLUTs 1, 2, 3, 4, and 7 and Ki-67, and to evaluate their association with (18)F-FDG uptake in DLBCL and NKTCL cells. The uptake rates of (18)F-FDG ranged from 18 to 46% (average 30 ± 10.20%) in Raji cells and 25 to 48% (average 35.6 ± 7.57%) in Daudi cells. In DLBCL cells, the expression levels of GLUTs 1, 3, and 7 were significantly correlated with cellular (18)F-FDG uptake rates (Spearman's rank correlation coefficient of 0.667, 0.516, and 0.468, respectively; P < 0.05). In NKTCL cells, the expression levels of GLUTs 1 and 3 were observed to be significantly correlated with cellular (18)F-FDG uptake rates (Spearman's rho of 0.756 and 0.498, respectively; P < 0.05). Ki-67 played no role in (18)F-FDG uptake in Raji or Daudi cells. In conclusion, the data acquired through this preliminary study indicate that GLUT 1 and GLUT 3 contribute to 18F-FDG uptake in DLBCL and NKTCL.

Polymorphisms of CASR gene increase the risk of primary hyperparathyroidism.

OBJECTIVE: To evaluate correlations between polymorphisms of calcium-sensing receptor (CASR) gene [A986S (rs1081725), R990G (rs1042636) and Q1011E (rs1801726)] and the risk of primary hyperparathyroidism (PHPT) among human population. METHODS: Relevant studies were retrieved from online databases using computer-based search strategies, which were then supplemented by manual search strategies. Case-control studies related to our topic were identified based on strict inclusion and exclusion criteria. Statistical analyses were conducted using the Comprehensive Meta-analysis 2.0 (Biostat Inc., Englewood, NJ, USA). RESULTS: We retrieved 202 studies from online databases and other sources initially and eventually enrolled six studies into our meta-analysis. These six studies contained a sum of 693 PHPT patients and 1252 healthy controls. Our meta-analysis results showed that single nucleotide polymorphisms (SNPs) of CASR gene A986S (rs1081725) and R990G (rs1042636), but not Q1011E (rs1801726), may increase the risk of PHPT [A986S (rs1081725): allele model: P = 0.013; dominant model: P = 0.044; R990G (rs1042636): allele model: P = 0.023; dominant model: P = 0.026)]. Subgroup analyses based on ethnicity showed that among Asians, A986S (rs1081725) increased the PHPT risk (P = 0.04) under the allele model, but not under the dominant model. Among Caucasians, there was no association between gene frequencies and PHPT under both the allele and dominant model. In Asians, no significant association was observed between R990G (rs1042636) and PHPT risk, but in Caucasians, R990G (rs1042636) significantly increased the incidence of PHPT [R990G (rs1042636): allele model: P = 0.015; dominant model: P = 0.009)]. CONCLUSION: Our results indicate that SNPs of CASR gene A986S (rs1081725) and R990G (rs1042636) may increase the risk of PHPT, and the polymorphisms can potentially be used as important biological markers for early diagnosis of PHPT.

Analyzing the influence of BDNF heterozygosity on spatial memory response to 17ß-estradiol.

The recent use of estrogen-based therapies as adjunctive treatments for the cognitive impairments of schizophrenia has produced promising results; however the mechanism behind estrogen-based cognitive enhancement is relatively unknown. Brain-derived neurotrophic factor (BDNF) regulates learning and memory and its expression is highly responsive to estradiol. We recently found that estradiol modulates the expression of hippocampal parvalbumin-positive GABAergic interneurons, known to regulate neuronal synchrony and cognitive function. What is unknown is whether disruptions to the aforementioned estradiol-parvalbumin pathway alter learning and memory, and whether BDNF may mediate these events. Wild-type (WT) and BDNF heterozygous (+/-) mice were ovariectomized (OVX) at 5 weeks of age and simultaneously received empty, estradiol- or progesterone-filled implants for 7 weeks. At young adulthood, mice were tested for spatial and recognition memory in the Y-maze and novel-object recognition test, respectively. Hippocampal protein expression of BDNF and GABAergic interneuron markers, including parvalbumin, were assessed. WT OVX mice show impaired performance on Y-maze and novel-object recognition test. Estradiol replacement in OVX mice prevented the Y-maze impairment, a Behavioral abnormality of dorsal hippocampal origin. BDNF and parvalbumin protein expression in the dorsal hippocampus and parvalbumin-positive cell number in the dorsal CA1 were significantly reduced by OVX in WT mice, while E2 replacement prevented these deficits. In contrast, BDNF(+/-) mice showed either no response or an opposite response to hormone manipulation in both behavioral and molecular indices. Our data suggest that BDNF status is an important biomarker for predicting responsiveness to estrogenic compounds which have emerged as promising adjunctive therapeutics for schizophrenia patients.

Establishing a rabbit spinal tumor model for nonvascular interventional therapy through CT-guided percutaneous puncture inoculation.

BACKGROUND AND PURPOSE: An animal spinal tumor model is needed to better simulate the clinical situation and to allow percutaneous puncture, which may provide an experimental platform for the new nonvascular interventional therapies. We established a rabbit spinal tumor model through a CT-guided percutaneous puncture inoculation technique for nonvascular interventional therapy. MATERIALS AND METHODS: VX2 tumor cells were inoculated into the lumbar vertebrae of 32 rabbits through a CT-guided percutaneous puncture technique; then, the development of hind limb paraparesis was observed in the rabbits twice a day. MR imaging and CT were performed on days 14, 21, and 28 postinoculation and at the development of hind limb paraparesis. On days 21 and 28 postinoculation, 2 rabbits, whose imaging suggested successful modeling without hind limb paraparesis, were chosen on each day. The lumbar vertebrae were sampled from 1 rabbit for histopathologic examination, and the other rabbit underwent PET-CT examination before percutaneous vertebroplasty. Finally the lesion vertebrae were sampled for histopathologic examination. RESULTS: The success rate of modeling was 90.6% (29/32) in our study. On day 21 postinoculation, successful modeling was achieved in 21 rabbits, with 19 having no hind limb paraparesis. On day 28 postinoculation, another 7 achieved successful modeling, and only 1 developed hind limb paraparesis. Percutaneous vertebroplasty treatment was successful for the 2 rabbit models. CONCLUSIONS: Establishment of a rabbit spinal tumor model through a CT-guided percutaneous puncture technique and inoculation of VX2 tumor is easy and has a high success rate. The established model can be used to study nonvascular interventional therapies for spinal tumor, including percutaneous vertebroplasty.

Human plasma-derived immunoglobulin G fractionated by an aqueous two-phase system, caprylic acid precipitation, and membrane chromatography has a high purity level and is free of detectable in vitro thrombogenic activity.

BACKGROUND AND OBJECTIVES: Instituto Clodomiro Picado has developed an immunoglobulin G (IgG) plasma fractionation process combining a polyethylene glycol/phosphate aqueous two-phase system (ATPS), caprylic acid precipitation and anion-exchange membrane chromatography. We evaluated the purity and in vitro thrombogenicity of such IgG, in line with current international requirements. MATERIALS AND METHODS: Contributions of the different production steps to reduce thrombogenicity were assessed at 0·2 l-scale, and then the methodology was scaled-up to a 10 l-scale and final products (n = 3) were analysed. Purity, immunoglobulin composition, and subclass distribution were determined by electrophoretic and immunochemical methods. The in vitro thrombogenic potential was determined by a thrombin generation assay (TGA) using a Technothrombin fluorogenic substrate. Prekallikrein activator (PKA), plasmin, factor Xa, thrombin and thrombin-like activities were assessed using S-2302, S-2251, S-2222, S-2238 and S-2288 chromogenic substrates, respectively, and FXI by an ELISA. RESULTS: The thrombogenicity markers were reduced mostly during the ATPS step and were found to segregate mostly into the discarded liquid upper phase. The caprylic acid precipitation eliminated the residual procoagulant activity. The IgG preparations made from the 10 l-batches contained 100% gamma proteins, low residual IgA and undetectable IgM. The IgG subclass distribution was not substantially affected by the process. TGA and amidolytic activities revealed an undetectable in vitro thrombogenic risk and the absence of proteolytic enzymes in the final product. CONCLUSIONS: Fractionating human plasma by an ATPS combined with caprylic acid and membrane chromatography resulted in an IgG preparation of high purity and free of a detectable in vitro thrombogenic risk.

Histone deacetylase inhibitors increase microRNA-146a expression and enhance negative regulation of interleukin-1ß signaling in osteoarthritis fibroblast-like synoviocytes.

OBJECTIVE: MiR-146a exerts negative control on inflammatory responses by suppressing cytokine-induced expression of interleukin-1 receptor-associated kinase-1 (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6) by impairing NF-κB activity and inhibiting the expression of target genes. Recent study suggests that histone deacetylases (HDACs) are involved in the regulation of microRNA (miRNA) expression. Therefore, we determined whether HDAC inhibitors can increase miR-146a expression, thereby inhibiting interleukin-1ß (IL-1ß)-induced signaling in osteoarthritis fibroblast-like synoviocytes (OA-FLS). METHOD: MiRNA expression was analyzed using real-time PCR. IL-1ß-induced downstream signals and cytokine expression were evaluated using Western blotting and ELISA. Transcription factors regulating promoter activation were identified using chromatin immunoprecipitation assays. RESULTS: IL-1ß treatment of OA-FLS induced a mild (1.7-fold) increase in miR-146a expression that was unable to appropriately downregulate IRAK1 and TRAF6 expression. HDAC inhibitors, SAHA (vorinostat), and LBH589 (panobinostat) significantly (6.1- and 5.4-fold) elevated miR-146a expression by increasing the binding of the transcription factor NF-κB to the miR-146a promoter, and negatively regulated IL-1ß-induced IKK/IκB/p65 phosphorylation signaling and IL-6 secretion. The increase in miR-146a expression induced by the HDAC inhibitors was prevented by transfection of miR-146a inhibitor or HDAC1 (class I HDAC), HDAC4 (class IIa HDAC), and HDAC6 (class IIb HDAC) overexpression, suggesting that they were due to inhibition of HDAC activity. CONCLUSIONS: Our study demonstrated that HDAC inhibitor treatment in OA-FLS significantly increased miR-146a expression and mediated markedly negative regulation to inhibit IL-1ß-induced signaling and cytokine secretion. Our results indicate the potential rationale of anti-inflammatory effects for HDAC inhibitors.

Dengue virus inactivation by minipool TnBP/Triton X-45 treatment of plasma and cryoprecipitate.

BACKGROUND AND OBJECTIVES: A minipool solvent/detergent (S/D; 1% TnBP/1% Triton X-45; 31°C) process was developed for viral inactivation of plasma and cryoprecipitate used for transfusion. The goal of this study was to determine the rate and extent of inactivation of dengue virus (DENV) during this process. MATERIALS AND METHODS: DENV-1 was propagated using C6/36 mosquito cells to an infectivity titre close to 9 log and spiked (10% v/v) into individual plasma and cryoprecipitate samples from two distinct donors. Samples were taken right after spiking and during viral inactivation treatment by 1% TnBP-1% Triton X-45 at 31°C. DENV-1 infectivity was assessed on Vero E6 cells by a focus-forming assay (FFA). Culture medium and complement-inactivated plasma were used as experimental controls. Experiments were done in duplicate. RESULTS: DENV-1 infectivity was 7·5 log in spiked plasma and 7·1 and 7·3 log in spiked cryoprecipitate. There was no loss of DENV-1 infectivity in the spiked materials, nor in the controls not subjected to S/D treatment. No infectivity was found in plasma and cryoprecipitate subjected to S/D treatment at the first time-point evaluated (10 min). CONCLUSION: DENV-1 was strongly inactivated in plasma and cryoprecipitate, respectively, within 10 min of 1% TnBP/1% Triton X-45 treatment at 31°C. These data provide a reassurance of the safety of such S/D-treated plasma and cryoprecipitate with regard to the risk of transmission of all DENV serotypes and other flaviviruses.

Changes in diastolic function after exercise training in patients with and without diabetes mellitus after coronary artery bypass surgery. A randomized controlled trial.

BACKGROUND: Left ventricular diastolic dysfunction and diabetes were associated with prognosis after coronary artery bypass surgery (CABG). AIM: This study investigated whether short-term exercise improves diastolic function in patients with and without diabetes mellitus (DM) after CABG and examined the relationship of these changes to exercise capacity. DESIGN: RCT SETTING: Outpatient. POPULATION: Patients with left ventricular ejection fraction ≥50% after CABG were included in this study. METHODS: Participants were randomly assigned to a control (N.=33) or exercise (N.=28) group. The exercise group participated in three-month treadmill exercise training. We evaluated all participants on diastolic function, peak oxygen uptake (VO(2peak)), and concomitant stroke volume. RESULTS: Exercise significantly enhanced VO(2peak) to a similar extent in all patients (P<0.05). Patients with DM improved in arteriovenous oxygen difference ([a-v] O(2) diff) after training (p=0.016), whereas those without DM improved in deceleration time of early filling (p=0.031) with exercise training. The magnitude of improvement in VO(2peak) correlated with the change in (a-v) O(2) diff in patients regardless of DM (r=0.442~0.542) and with baseline (a-v) O(2) diff only in patients with DM (r=-0.480). CONCLUSION: After CABG, all patients showed similar improvements in VO(2peak) with exercise training, mainly through increased (a-v) O(2) diff, but those without DM showed greater improvements in deceleration time. CLINICAL REHABILITATION IMPACT: Exercise training is beneficial for improving exercise capacity associated with restorations of peripheral oxygen utilization in both patients with and without DM.

Modulatory effects of sex steroid hormones on brain-derived neurotrophic factor-tyrosine kinase B expression during adolescent development in C57Bl/6 mice.

Sex steroid hormones and neurotrophic factors are involved in pruning and shaping the adolescent brain and have been implicated in the pathogenesis of neurodevelopmental disorders, including mental illness. We aimed to determine the association between altered levels of sex steroid hormones during adolescent development and neurotrophic signalling in the C57Bl/6 mouse. We first performed a week by week analysis from pre-pubescence to adulthood in male and female C57Bl/6 mice, measuring serum levels of testosterone and oestradiol in conjunction with western blot analysis of neurotrophin expression in the forebrain and hippocampal regions. Second, we manipulated adolescent sex steroid hormone levels by gonadectomy and hormone replacement at the pre-pubescent age of 5 weeks. Young-adult forebrain and hippocampal neurotrophin expression was then determined. Male mice showed significant changes in brain-derived neurotrophic factor (BDNF) expression in the forebrain regions during weeks 7-10, which corresponded significantly with a surge in serum testosterone. Castration and testosterone or di-hydrotestosterone replacement experiments revealed an androgen receptor-dependent effect on BDNF-tyrosine kinase (Trk) B signalling in the forebrain and hippocampal regions during adolescence. Female mice showed changes in BDNF-TrkB signalling at a much earlier time point (weeks 4-8) in the forebrain and hippocampal regions and these did not correspond with changes in serum oestradiol. Ovariectomy actually increased BDNF expression but decreased TrkB phosphorylation in the forebrain regions. 17ß-Oestradiol replacement had no effect, suggesting a role for other ovarian hormones in regulating BDNF-TrkB signalling in the adolescent female mouse brain. These results suggest the differential actions of sex steroid hormones in modulating BDNF-TrkB signalling during adolescence. These data provide insight into how the male and female brain changes in response to altered levels of circulating sex steroid hormones and could help to explain some of the developmental sex differences in the pathogenesis of neurodevelopmental disorders, including mental illness.

Early demyelination of primary A-fibers induces a rapid-onset of neuropathic pain in rat.

Some types of peripheral neuropathic pain are associated with damage to myelin rather than to axons of primary sensory neurons. It is extremely important to develop selective demyelination animal models for understanding neuropathic pain caused by demyelination. We induced a rapid-onset and reversible demyelination of peripheral A-fibers and neuropathic pain behaviors in adult rats by a single injection of cobra venom into the sciatic nerve. The relation between A-fiber demyelination and the abnormal pain behaviors was investigated using this model. Microfilament recordings revealed that cobra venom selectively blocked A-fibers, but not C-fibers. Selective blockade of A-fibers may result from A-fiber demyelination at the site of venom injection as demonstrated by microscope examination. The axons of the demyelinated A-fibers appeared to be otherwise normal. Neuropathic pain behaviors appeared almost immediately after venom injection and lasted about 3 weeks. Electrophysiological studies indicated that venom injection induced loss of conduction in A-fibers, increased sensitivity of C-polymodal nociceptors to innocuous stimuli, and triggered spontaneous activity from both peripheral and central terminals of C-fiber nociceptors. Neurogenic inflammatory responses were also observed in the affected skin via Evan's Blue extravasation experiments. Both antidromic C-fiber spontaneous activity and neurogenic inflammation were substantially decreased by continuous A-fiber threshold electric stimuli applied proximally to the venom injection site. The data suggest that normal activity of peripheral A-fibers may produce inhibitory modulation of C-fiber polymodal nociceptors. Removal of inhibition to C-fiber polymodal nociceptors following demyelination of A-fibers may result in pain and neurogenic inflammation in the affected receptive field.

Impact of solvent/detergent treatment of plasma on transfusion-relevant bacteria.

BACKGROUND: A solvent/detergent (S/D) treatment in a medical device has been developed for pathogen reduction of plasma for transfusion. Impact of S/D on bacterial growth and on the capacity of complement to kill bacteria has been investigated in this study. STUDY DESIGN AND METHODS: A pool of apheresis plasma from four donors was spiked with eight transfusion-relevant bacteria. Plasma was treated with 1% tri(n-butyl) phosphate and 1% Triton X-45 at 31°C for 90 min and then extracted by oil at 31°C for 70 min. Decomplemented plasma and Phosphate Buffer Saline were used as controls. Bacterial count was determined in samples taken immediately after spiking, or after S/D and oil treatment. Similar experiments were conducted using three individual recovered plasma donations. Bacteria growth inhibition tests were performed using discs soaked with plasma samples whether containing the S/D agents or not. RESULTS: The mean reduction factors of Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae due to complement during S/D treatment were >8·75, 4·71, and 4·18 log in pooled plasma and >7·42, 2·24 and >6·08 log in individual plasmas, respectively. Bacillus cereus and Bacillus subtilis were inactivated by S/D (>7·04 and 1·60 log in pooled, and >6·06 and 2·39 in individual plasmas, respectively). Staphylococcus aureus, Staphylococcus epidermidis and Enterobacter cloacae did not multiply during S/D treatment of plasma. Growth inhibition tests revealed an inhibition of three gram-negative bacteria by complement and all gram-positive by S/D. CONCLUSION: The S/D treatment of plasma does not alter the bactericidal activity of complement, and inactivates some gram-positive bacteria.

Comparative study between endoscopic ultrasonography and positron emission tomography-computed tomography in staging patients with esophageal squamous cell carcinoma.

Treatment strategy of esophageal cancer mainly depends on accurate staging. At present, no single ideal staging modality is superior to another in preoperative tumor-node-metastasis (TNM) staging of patients with esophageal cancer. We aimed to investigate the efficacy of endoscopic ultrasonography (EUS) and positron emission tomography-computed tomography (PET-CT) for staging of esophageal cancer. We retrospectively studied 118 consecutive patients with esophageal squamous cell carcinoma who underwent esophagectomy with or without neoadjuvant chemoradiotherapy (CRT) over a near 3-year period between January 2005 and November 2008 at a tertiary hospital in Taiwan. Patients were separated into two groups: without neoadjuvant CRT (group 1, n= 28) and with CRT (group 2, n= 90). Medical records of demographic data and reports of EUS and PET-CT of patients before surgery were reviewed. A database of clinical staging by EUS and PET-CT was compared with one of pathological staging. The accuracies of T staging by EUS in groups 1 and 2 were 85.2% and 34.9%. The accuracies of N staging by EUS in groups 1 and 2 were 55.6% and 39.8%. The accuracies of T and N staging by means of PET-CT scan were 100% and 54.5% in group 1, and were 69.4% and 86.1% in group 2, respectively. In group 2, 38 of 90 patients (42.2%) achieved pathologic complete remission. Among them, two of 34 (5.9%) and 12 of 17 (70.6%) patients were identified as tumor-free by post-CRT EUS and PET-CT, respectively. EUS is useful for initial staging of esophageal cancer. PET-CT is a more reliable modality for monitoring treatment response and restaging. Furthermore, the accuracy of PET-CT with regard to N staging is higher in patients who have undergone CRT than those who have not.

A chromatographically purified human TGF-ß1 fraction from virally inactivated platelet lysates.

BACKGROUND AND OBJECTIVES: TGF-ß1 exerts important physiological functions in osteogenesis and chondrogenesis and may be of therapeutic interest. The aim of this work was to develop a scalable purification process of TGF-ß1 from virally inactivated human platelets. STUDY DESIGN AND METHODS: Apheresis platelet concentrates (N=12) were solvent/detergent (S/D) treated (1% TnBP/1% Triton X-45; 31°C) and the resulting platelet lysates were clarified by oil extraction and centrifugation, then chromatographed on an anion-exchange DEAE-Sepharose Fast-Flow column equilibrated in a PBS buffer, pH 7.5. The column was washed to eliminate unbound proteins and the S/D agents. Bound proteins were eluted using a 1 M NaCl-PBS buffer pH 7.5 (DEAE-eluate). The content in TGF-ß1, PDGF-AB, VEGF, IGF-1, EGF, and b-FGF was measured by ELISA. Proteins, lipids, and S/D agents were assessed. Protein profile was determined by SDS-PAGE under reduced or non-reduced conditions. RESULTS: Most proteins, including albumin and immunoglobulins G, A, and M did not bind to the DEAE column as evidenced also by SDS-PAGE. Essentially all PDGF, VEGF, and IGF were in the breakthrough. The DEAE-eluate contained close to 60% of the TGF-ß1 at a mean concentration of about 102 ng/ml, whereas EGF, b-FGF were at about 0.72 and 0.18 ng/ml, respectively. The content in TnBP and Triton X-45 was <2 ppm. CONCLUSION: A fraction enriched in TGF-ß1 can be prepared from virally inactivated human platelet lysates using an easily scale process. Its interest in regenerative medicine and cell therapy will be evaluated in further studies.

Self-reported functional outcome after surgical intervention in patients with idiopathic normal pressure hydrocephalus.

The goal of this study was to characterize long-term social and functional outcomes in adults treated for idiopathic normal pressure hydrocephalus (NPH). Data for 252 patients treated medically or surgically for idiopathic NPH were obtained through the Hydrocephalus Association Database Project. Data on post-surgical outcomes including improvement in symptoms, the need for in-home care, ability to drive, and employment status were analyzed. Most patients (73.7%) surveyed were treated with a shunt, an endoscopic third ventriculostomy (ETV), or both. More patients who underwent surgery reported driving and being employed compared to those who did not have surgery. Most shunt patients had improvements in gait (81.1%), urinary incontinence (55.9%), and dementia (64.4%). Overall, shunt patients reported more dramatic improvements in quality of life as compared to ETV patients (72.2% versus 55.6%). Treating idiopathic NPH with cerebrospinal fluid diversion facilitates a return to independence through improved functional and social outcomes.