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Diabetic peripheral neuropathy, characterized by symptoms such as paresthesia, neuropathic pain, and potential lower limb amputation, poses significant clinical management challenges. Recent studies suggest that chronic hyperglycemia-induced Schwann cells (SCs) apoptosis contributes to neurodegeneration and impaired nerve regeneration, but the detailed mechanisms are still unknown. Our study investigated a mixed-sex type 2 diabetes mellitus (T2DM) rat model using leptin knockout (KO) to simulate obesity and diabetes-related conditions. Through extensive assessments, including mechanical allodynia, electrophysiology, and microcirculation analyses, along with myelin degradation studies in KO versus wild-type rats, we focused on apoptosis, autophagy, and SCs dedifferentiation in the sciatic nerve and examined nerve regeneration in KO rats. KO rats exhibited notable reductions in mechanical withdrawal force, prolonged latency, decreased compound muscle action potential (CMAP) amplitude, reduced microcirculation, myelin sheath damage, and increases in apoptosis, autophagy, and SCs dedifferentiation. Moreover, leptin KO was found to impair peripheral nerve regeneration postinjury, as indicated by reduced muscle weight, lower CMAP amplitude, extended latency, and decreased remyelination and SCs density. These findings underscore the effectiveness of the T2DM rat model in clarifying the impact of leptin KO on SCs apoptosis, dedifferentiation, and demyelination, providing valuable insights into new therapeutic avenues for treating T2DM-induced peripheral neuropathy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Glioblastoma multiforme (GBM) is a malignant tumour with a poor prognosis. Therefore, potential treatment strategies and novel therapeutic targets have gained increased attention. Our data showed that the ethanol extract of Vanilla planifolia stem (VAS) significantly decreased the viability and the colony formation of GBM cells. Moreover, VAS induced the cleavage of MAP1LC3, a marker of autophagy. Further RNA-seq and bioinformatic analysis revealed 4248 differentially expressed genes (DEGs) between VAS-treated GBM cells and the control cells. Protein-protein interactions between DEGs with fold changes less than -3 and more than 5 were further analysed, and we found that 16 and 9 hub DEGs, respectively, were correlated with other DEGs. Further qPCR experiments confirmed that 14 hub DEGs was significantly downregulated and 9 hub DEGs was significantly upregulated. In addition, another significantly downregulated DEG, p21-activated kinase 6 (PAK6), was correlated with the overall survival of GBM patients. Further validation experiments confirmed that VAS significantly reduced the mRNA and protein expression of PAK6, which led to the abolition of cell viability and colony formation. These findings demonstrated that VAS reduced cell viability, suppressed colony formation and induced autophagy and revealed PAK6 and other DEGs as potential therapeutic targets for GBM treatment., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background and Aims: Besides hospital size, clinical diagnosis and severity of patient cases determine the total platelet usage. Therefore, the appropriateness of platelet usage could not be compared simply with the total units of platelet usage in each hospital. This study aimed to objectively monitor and analyze platelet usage after implementing a single-unit issuing policy for each platelet transfusion in our hospital in October 2020., Materials and Methods: We used three objective indices, X, Y, and Z, to monitor platelet usage and compared it with other hospitals. Three indices were generated by dividing the annual total units of platelet usage by the total annual reimbursement, total number of admissions, and average total reimbursement per admission for each hospital., Results: The new indices X and Y alleviated hospital size-dependent differences. Index Y was preferred over X because its value fluctuated less during the COVID-19 pandemic. The Z index was adjusted for the average total reimbursement per admission, and the results showed that more patients with higher disease complexity did not have increased platelet usage during the COVID-19 pandemic. In our hospital (H1), index Z decreased from 2019 to 2021 due to a policy of issuing a single unit for each platelet transfusion., Conclusion: These three objective indices are suitable for peer comparison and monitoring platelet usage in hospitals, irrespective of their size. They could be applied to promote patient blood management and provide an early response to the gradual shortage of blood resources owing to the aging population and declining birth rate in Taiwan., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

The current methods for detecting antiplatelet antibodies are mostly manual and labor-intensive. A convenient and rapid detection method is required for effectively detecting alloimmunization during platelet transfusion. In our study, to detect antiplatelet antibodies, positive and negative sera of random-donor antiplatelet antibodies were collected after completing a routine solid-phase red cell adherence test (SPRCA). Platelet concentrates from our random volunteer donors were also prepared using the ZZAP method and then used in a faster, significantly less labor-intensive process, a filtration enzyme-linked immunosorbent assay (fELISA), for detecting antibodies against platelet surface antigens. All fELISA chromogen intensities were processed using ImageJ software. By dividing the final chromogen intensity of each test serum with the background chromogen intensity of whole platelets, the reactivity ratios of fELISA can be used to differentiate positive SPRCA sera from negative sera. A sensitivity of 93.9% and a specificity of 93.3% were obtained for 50 μL of sera using fELISA. The area under the ROC curve reached 0.96 when comparing fELISA with the SPRCA test. We have successfully developed a rapid fELISA method for detecting antiplatelet antibodies.

Glioblastoma multiforme (GBM) is a grade IV, highly malignant brain tumor. Because of the heterogeneity of GBM, a multitarget drug is a rational strategy for GBM treatment. Histone deacetylase inhibitors (HDACis) regulate the expression of numerous genes involved in cell death, apoptosis, and tumorigenesis. We found that the HDAC4/HDAC5 inhibitor LMK235 at 0.5 µM significantly reduced the cell viability and colony formation of patient-derived, temozolomide-resistant GBM P#5 TMZ-R, U-87 MG, and T98G cells. Moreover, LMK235 also significantly increased TUBA acetylation, which is an indicator of HDAC inhibition. Interestingly, LMK235 induced MAP1LC3 robust readout and puncta accumulation but did not enhance PARP1 cleavage or the proportion of annexin V-positive cells, suggesting that LMK235-induced cell death occurred via autophagy activation. Further RNA-seq analysis after LMK235 treatment showed that 597 different expression genes compared to control. After bioinformatic analysis by KEGG and STRING, we focused on 34 genes and validated their mRNA expression by qPCR. Further validation showed that 2 µM LMK235 significantly reduced the mRNA and protein expression of SCNN1A. Cell viability of SCNN1A -silenced cells were reduced, but cells were rescued while treated with an autophagy inhibitor bafilomycin A1. Conclusively, SCNN1A plays a role in LMK235-induced autophagy and cell death in GBM cells.

Patients with bipolar disorder (BD) exhibit individual variability in the treatment outcome, and genetic background could contribute to BD itself and the treatment outcome. Leptin levels significantly change in BD patients treated with valproate (VPA), but whether LEPR polymorphisms are associated with treatment response is still unknown. This longitudinal study aimed to investigate the associations between LEPR polymorphisms and VPA treatment response in BD patients who were drug naïve at their first diagnosis of BD. The single-nucleotide polymorphisms (SNPs) of LEPR (rs1137101, rs1137100, rs8179183, and rs12145690) were assayed, and the LEPR polymorphism frequencies of alleles and genotypes were not significantly different between the controls ( n = 77) and BD patients ( n = 130). In addition, after the 12-week course of VPA treatment in BD patients, the LEPR polymorphisms showed significant effects on changes in disease severity. Moreover, considering the effect of the LEPR haplotype, the frequency of the CAGG haplotype in BD patients was higher than that in the controls (9.3 vs. 2.9%, p = 0.016), and the LEPR CAGG haplotype was associated with a better treatment response than the other haplotypes in BD patients receiving VPA treatment. Therefore, LEPR polymorphisms might serve as mediators involved in the therapeutic action of VPA treatment.

It is a challenge to obtain sufficient eggs during in vitro fertilization (IVF) in women with impending ovarian failure (IOF)/diminished ovarian reserve (DOR). Although studies have suggested that more than one wave of follicle growth exists, the efficacy of controlled ovulation stimulation (COS) in both follicular and luteal phases of the same ovarian cycle (DuoStim) is not established in women with IOF/DOR. We investigated the efficacy of DuoStim using the intraovarian injection of recombinant human follicle-stimulating hormone (rhFSH) during oocyte retrieval in women with DOR. For luteal-phase stimulation, intraovarian (Group A, N = 28) or superficial subcutaneous (Group B, N = 18) injection of 300 IU rhFSH immediately after oocyte retrieval was administered as the first dose, and intermittent superficial subcutaneous addition of gonadotropins was employed accordingly for further COS in both groups. In Group A, significantly lower Gn doses, a shorter duration of COS, a greater number of antral follicle counts, and an increased number of retrieved mature and total oocytes were noted. Compared with the clinical outcomes of luteal-phase COS, the average daily doses of rhFSH used in Group A were significantly lower. In summary, the novel approach using intraovarian rhFSH injection provides an efficient treatment regimen in women with IOF/DOR.

It is a challenge to obtain enough oocytes during in vitro fertilization (IVF) in women who have a poor ovarian response (POR) in achieving conception. We have adopted the characteristics of the first uterine pass effect, which we pioneered in employing the vaginal administration of gonadotropins in women receiving IVF treatments. In our previous study employing vaginal administration, faster absorption and slower elimination of gonadotropins were demonstrated, and, female subjects presented proper ovarian follicle growth and pregnancy rates. In this study, during 2016-2020, 300 to 675 IU of gonadotropins were administered vaginally every three days in 266 POR women for their controlled ovarian hyperstimulation (COH). The injections were performed with needles angled at 15-30° towards the middle-upper portions of the bilateral vaginal wall, with an injection depth of 1-2 mm. For the COH results, these women, on average, received 3.0 ± 0.9 vaginal injections and a total dose of 1318.4 ± 634.4 IU gonadotropins, resulting in 2.2 ± 1.9 mature oocytes and 1.0 ± 1.2 good embryos. Among these embryos, 0.9 ± 1.0 were transferred to reach a clinical pregnancy rate of 18.1% and a live birth rate of 16.7%. In conclusion, the intermittent vaginal administration of gonadotropins proved to be effective in POR women for their IVF treatments.

Aims: Glioblastoma (GBM) is a highly malignant brain tumor. After treatment with the first-line drug temozolomide, only 50% of patients are responsive. Recent literature shows that the difficulty in treating GBM is mainly due to the heterogeneity of its four major cellular states, which are characterized by differences in EGFR, PDGFRA, CDK4, and NF1. Therefore, development of a multitarget drug is a potential strategy for treating heterogeneous GBM., Main Methods: In this study, the antitumor ability of a potent heat shock protein 90 inhibitor, NVP-AUY922 (AUY922), was evaluated in GBM cell lines (U-87 MG and T98G cells) and patient-derived GBM cell lines [P#5 and P#5 temozolomide-resistant (TMZ-R) cells]., Key Findings: We found that AUY922 significantly reduced cell viability and colony formation in four GBM cell lines. AUY922 also significantly induced apoptosis by increasing PARP1 cleavage and the number of annexin V-positive cells. The autophagy indicators as MAP1LC3B cleavage and MAP1LC3B puncta were increased after AUY922 treatment. AUY922-induced cell death could be partially reversed by pharmacological inhibition of either apoptotic inhibitor or autophagy inhibitor. Moreover, AUY922 reduced the mRNA and protein expressions of EGFR, PDGFRA, CDK4, and NF1, which contribute to the four cellular state subtypes in GBM cells. In addition, the downstream signaling proteins of these four proteins, AKT/p-AKT, MAPK/p-MAPK, and BRAF, were downregulated after AUY922 treatment., Significance: Taken together, AUY922 led to GBM cell death via apoptosis and autophagy, and reduced the mRNA and protein expression of EGFR, PDGFRA, CDK4, and NF1in heterogeneous GBM cells., (Copyright © 2021. Published by Elsevier Inc.)

The uterine first-pass effect occurs when drugs are delivered vaginally. However, the effect of vaginally administered recombinant human follicle-stimulating hormone (rhFSH) on ovarian folliculogenesis and endometrial receptivity is not well established. We aimed to compare the efficacy of rhFSH administered vaginally and abdominally in clinical in vitro fertilization (IVF) treatment, pharmacokinetic study, and animal study. In IVF treatment, the number of oocytes retrieved, endometrial thickness and uterine artery blood perfusion were not different between women who received the rhFSH either vaginally or abdominally. For serum pharmacokinetic parameters, significantly lower Tmax, clearance, and higher AUC and T 1/2 _elimination of rhFSH were observed in women who received rhFSH vaginally, but urine parameters were not different. Immature female rats that received daily abdominal or vaginal injections (1 IU twice daily for 4 days) or intermittent vaginal injections (4 IU every other day for two doses) of rhFSH had more total follicles than the control group. In addition, the serum progesterone and progesterone receptors in the local endometrium were significantly higher in the groups treated with intermittent abdominal or vaginal injection of rhFSH, compared with those who recieved daily injection. In summary, vaginal administration of rhFSH may provide an alternative treatment regimen in women receiving IVF.

Recombinant human thrombomodulin (rhTM), an angiogenesis factor, has been demonstrated to stimulate cell proliferation, keratinocyte migration and wound healing. The objective of this study was to develop nanostructured lipid carrier (NLC) formulations encapsulating rhTM for promoting chronic wound healing. RhTM-loaded NLCs were prepared and characterized. Encapsulation efficiency was more than 92%. The rate of rhTM release from different NLC formulations was influenced by their lipid compositions and was sustained for more than 72 h. Studies on diabetic mouse wound model suggested that rhTM-NLC 1.2 µg accelerated wound healing and was similar to recombinant human epidermal growth factor-NLC (rhEGF-NLC) 20 µg. By incorporating 0.085% carbopol (a highly crosslinked polyacrylic acid polymer) into rhTM NLC, the NLC-gel presented similar particle characteristics, and demonstrated physical stability, sustained release property and stability within 12 weeks. Both rhTM NLC and rhTM NLC-gel improved wound healing of diabetic mice and cell migration of human epidermal keratinocyte cell line (HaCaT) significantly. In comparison with rhTM solution, plasma concentrations of rhTM post applications of NLC and NLC-gel formulations were lower and more sustained in 24 h. The developed rhTM NLC and rhTM NLC-gel formulations are easy to prepare, stable and convenient to apply to the wound with reduced systemic exposure, which may warrant potential delivery systems for the care of chronic wound patients.

In this review, we discuss the chronic care model (CCM) in relation to the diabetes pay-for-performance (P4P) program in Taiwan. We first introduce the 6 components of the CCM and provide a detailed description of each of the activities in the P4P program implemented in Taiwan, mapping them onto the 6 components of the CCM. For each CCM component, the following three topics are described: the definition of the CCM component, the general activities implemented related to this component, and practical and empirical practices based on hospital or local government cases. We then conclude by describing the possible successful features of this P4P program and its challenges and future directions. We conclude that the successful characteristics of this P4P program in Taiwan include its focus on extrinsic and intrinsic incentives ( i.e. , shared care network), physician-led P4P and the implementation of activities based on the CCM components. However, due to the low rate of P4P program coverage, approximately 50% of patients with diabetes cannot enjoy the benefits of CCM-related activities or receive necessary examinations. In addition, most of these CCM-related activities are not allotted an adequate amount of incentives, and these activities are mainly implemented in hospitals, which compared with primary care providers, are unable to execute these activities flexibly. All of these issues, as well as insufficient implementation of the e-CCM model, could hinder the advanced improvement of diabetes care in Taiwan., Competing Interests: Conflict-of-interest statement: We have no financial relationships to disclose., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Previous studies suggested that a disturbance of the dopamine system underlies the pathophysiology of bipolar disorder (BD). In addition, the therapeutic action of medications for treating BD, such as valproate (VPA), might modulate dopamine system activity, but it remains unclear. Here, we aimed to investigate the role of the striatal dopamine transporter (DAT) in BD patients and in social defeat (SD) mice treated with VPA., Methods: We enrolled community-dwelling controls (N = 18) and BD patients (N = 23) who were treated with VPA in a euthymic stage. The striatal DAT availabilities were approached by TRODAT-1 single photon emission computed tomography. We also established a chronic SD mouse model and treated mice with 350 mg/kg VPA for 3 weeks. Behavioral tests were administered, and striatal DAT expression levels were determined., Results: In humans, the level of striatal DAT availability was significantly higher in euthymic BD patients (1.52 ± 0.17 and 1.37 ± 0.23, p = 0.015). Moreover, the level of striatal DAT availability was also negatively correlated with the VPA concentration in BD patients (r = -0.653, p = 0.003). In SD mice, the expression of striatal DAT significantly increased (p < 0.001), and the SD effect on DAT expression was rescued by VPA treatment., Conclusions: The striatal DAT might play a role in the pathophysiology of BD and in the therapeutic mechanism of VPA. The homeostasis of DAT might represent a new therapeutic strategy for BD patients.

Gastrointestinal stromal tumors (GISTs) are frequently driven by auto-activated, mutant KIT and have durable response to KIT tyrosine kinase inhibitor. However, acquired resistance is an increasing clinical issue in GIST patients receiving front-line imatinib therapy. Our previous studies showed the colocalization of KIT with DAPI-stained nuclei in GIST cells without knowing the role of nuclear KIT in GIST tumorigenesis. In this article, we first identified the binding of nuclear KIT to the promoter of NFKB inhibitor beta (NFKBIB) by chromatin immunoprecipitation (ChIP) sequencing and ChIP assays, which was accompanied with enhanced NFKBIB protein expression in GIST cells. Clinically, high NCCN risk GISTs had significantly higher mean expression levels of nuclear phospho-KIT and NFKBIB as compared with those of intermediate or low/very low-risk GISTs. Conversely, downregulation of NFKBIB by siRNA led to RELA nuclear translocation that could bind to the KIT promoter region and subsequently reduced KIT transcription/expression and the viability of GIST cells. These findings were further confirmed by either RELA overexpression or NFKB/RELA inducer, valproic acid, treatment to result in reduced KIT expression and relative cell viability of imatinib-resistant GIST cells. Combining valproic acid with imatinib showed significantly better growth inhibitory effects on imatinib-resistant GIST48 and GIST430 cells in vitro, and in the GIST430 animal xenograft model. Taken together, these results demonstrate the existence of a nuclear KIT-driven NFKBIB-RELA-KIT autoregulatory loop in GIST tumorigenesis, which are potential targets for developing combination therapy to overcome imatinib-resistant of KIT-expressing GISTs.

Insulin-sensitizer treatment with metformin is widely used in polycystic ovary syndrome (PCOS). However, the treatment effectiveness shows individual differences in PCOS patients. Organic cation transporter (OCT) 1 and 2 have been reported to mediate metformin transport in the liver and kidney, respectively. In this study, we investigated the association between the polymorphisms of OCT1 and OCT2 and the treatment effectiveness of metformin in PCOS patients. The single nucleotide polymorphisms (SNPs) of OCT1 (rs683369 and rs628031) and OCT2 (rs316019) were analyzed in 87 PCOS and 113 control women. Oral glucose tolerance tests (OGTTs), which represented metformin treatment response, were conducted at the start of treatment and after six-month treatment. The results demonstrated that the SNP frequencies of OCT1 and OCT2 were not associated with PCOS pathophysiology, and that the polymorphisms of OCT1 and OCT2 were not associated with the OGTT parameters at baseline. However, PCOS patients with the G allele of OCT1 rs683369 and/or with the A allele of OCT1 rs628031 had increased insulin sensitivity compared to those with wild-type genotype after receiving metformin treatment. Moreover, the interactions of metformin*SNP were significant in both OCT1 rs683369 ( p < 0.001) and rs628031 ( p = 0.001) during the treatment period. Taken together, genetic polymorphisms of OCT1 contributed to different metformin treatment responses, and further study is needed to establish personalized treatment programs using a pharmacogenomic algorithm approach in PCOS patients.

The objectives of this study were to perform an economic evaluation of a targeted school-based dental checkup program in northern metropolitan Melbourne, Victoria. A 12-mo retrospective case-control cohort analysis using the decision tree method evaluated the incremental cost-utility and cost-effectiveness ratio (ICUR/ICER) for passive standard care dental services and an outreach pilot intervention completed in 2013. A societal perspective was adopted. A total of 273 children ( n = 273) aged between 3 and 12 y met the inclusion/exclusion criteria: 128 in the standard care group and 145 in the intervention group. The total society costs included health sector costs, patient/family costs, and productivity losses in 2014 Australian dollars. Outcome measures were evaluated using quality-adjusted tooth years (QATY) and the combined deciduous and permanent decayed, missing, and filled teeth prevented (DMFT-prevented). A generic outcome variable was created to determine the impact of the intervention to reach underserved populations based on government concession eligibility (cardholder status). Uncertainties were incorporated using 95% confidence intervals. The mean total society cost per child is $463 and $291 ( P = 0.002), QATY utility difference is 0.283 and 0.293 ( P = 0.937), effectiveness difference is 0.16 and 0.10 ( P = 0.756), and cardholder status is 50.0% and 66.2% ( P = 0.007), respectively, for the standard care and intervention groups. On average per child, there was a cost saving of $172 and improvement of 0.01 QATY, with an additional proportion of 16.2% of cardholder children reached. The calculated ICER was $3,252 per DMFT-prevented. The intervention dominates standard care for QATY and per 1% cardholder reached outcome measures. Our study found the pilot checkup program was largely less costly and more effective compared with the current standard care. Further research is needed to quantify the value of outreach interventions to prevent dental caries development and progression in populations from low socioeconomic status. Knowledge Transfer Statement: The findings of this research demonstrated that an outreach dental program can be less costly and more effective than standard models of dental care. It showed that a school-based dental checkup program is beneficial despite other opinions that dental screening is ineffective as a method to improve public dental health. There is fiscal economic evidence to support broader expansion of similar programs locally and internationally to reduce dental caries for children from low-income families.

The use of autologous fat grafting in breast reconstruction still requires optimization. Fat survival and calcification are the main issues that affect the outcomes of the procedure. In this study, a cell-based therapy utilizing laminin-alginate beads (LABs) as carriers was proposed to promote cell survival and adipogenesis by providing short-term physical support and facilitate nutrient diffusion of the implants. Laminin-modified alginate beads were fabricated by immobilizing laminin onto ring-opened alginate, used to encapsulate 3T3-L1 preadipocytes, and evaluated in vitro and in vivo. LABs as preadipocyte carriers showed better biocompatibility and stability than unmodified alginate beads. Preadipocytes in LABs had higher survival rate and enhanced adipogenesis than those in unmodified alginate beads. In vivo studies showed that LABs gradually degraded and the sites were replaced by newly formed fat tissues, and new blood vessels were also observed. 7T-MRI study mimicking clinical fat grafting showed that LABs carrying adipose stem cells improved the results of conventional fat grafts. Therefore, we believe that LABs represent promising cell carriers and can be potentially used for the reconstruction of breasts or other soft tissues in the future.

Biomaterials are often added to autologous fat grafts both as supporting matrices for the grafted adipocytes and as cell carrier for adipose-derived stem cells (ADSCs). This in vivo study used an autologous fat graft model to test a lamininalginate biomaterial, adipocytes, and ADSCs in immune-competent rats. We transplanted different combinations of shredded autologous adipose tissue [designated "A" for adipose tissue]), laminin-alginate beads [designated "B" for bead], and ADSCs [designated "C" for cell]) into the backs of 15 Sprague-Dawley rats. Group A received only adipocytes, Group B received only laminin-alginate beads, Group AB received adipocytes mixed with laminin-alginate beads, Group BC received laminin-alginate beads encapsulating ADSCs, and Group ABC received adipocytes and laminin-alginate beads containing ADSCs. Seven-tesla magnetic resonance imaging was used to evaluate the rats at the 1st, 6th, and 12th weeks after transplantation. At the 12th week, the rats were sacrificed and the implanted materials were retrieved for gross examination and histological evaluation. The results based on MRI, gross evaluation, and histological data all showed that implants in Group ABC had better resorption of the biomaterial, improved survival of the grafted adipocytes, and adipogenic differentiation of ADSCs. Volume retention of grafts in Group ABC (89%) was also significantly greater than those in Group A (58%) (p < 0.01). Our findings support that the combination of shredded adipose tissue with ADSCs in laminin-alginate beads provided the best overall outcome.

Chitosan nanoparticles modified with 10 and 30% urocanic acid (CUA) via carbodiimide crosslinking were examined for an efficient gene delivery carrier. The CUA gene carrier was characterized by FTIR, TEM, SEM and the in vitro transfection efficiency CUA polyplex was tested with HeLa and 3T3 cells. The loading efficiency of CUA complexes with DNA was assessed at different N/P ratio of 1, 2, 4, 6, 8, and 10. The DNA loading efficiency was found be to >85% for chitosan, CUA10 and CUA30% and the DNA protection ability of CUA10 and CUA30 nanoparticle complexes was confirmed upon incubation with NheI and HindIII. The cell toxicity and cell viability results have supported the non-toxic nature of CUA10 and CUA30 nanoparticles. In vitro transfection efficiency of CUA10 and CUA30 polyplex was tested for EGFP expression in 3T3 and HeLa cells and a relative maximum % transfection of about 10% was confirmed by CUA10 and CUA30 after 96h transfection. The feasibility and biocompatibility of CUA gene carrier in transgenic chickens was also demonstrated. The in vitro transfection and in vivo embryonic viability studies further confirmed the CUA as promising gene carrier because of the improved biocompatibility and DNA protection ability., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Stroke is a leading cause of disability and distress, and often profoundly affects the quality of life of stroke survivors and their carers. With the support of carers, many stroke survivors are returning to live in the community despite the presence of disability and ongoing challenges. The sudden and catastrophic changes caused by stroke affects the mental, emotional and social health of both stroke survivors and carers. The aim of this study is to evaluate a Stroke and Carer Optimal Health Program (SCOHP) that adopts a person-centred approach and engages collaborative therapy to educate, support and improve the psychosocial health of stroke survivors and their carers., Methods: This study is a prospective randomised controlled trial. It will include a total of 168 stroke survivors and carers randomly allocated into an intervention group (SCOHP) or a control group (usual care). Participants randomised to the intervention group will receive nine (8 + 1 booster) sessions guided by a structured workbook. The primary outcome measures for stroke survivors and carers will be health-related quality of life (AQoL-6D and EQ-5D) and self-efficacy (GSE). Secondary outcome measures will include: anxiety and depression (HADS); coping (Brief COPE); work and social adjustment (WSAS); carer strain (MCSI); carer satisfaction (CASI); and treatment evaluation (TEI-SF and CEQ). Process evaluation and a health economic cost analysis will also be conducted., Discussion: We believe that this is an innovative intervention that engages the stroke survivor and carer and will be significant in improving the psychosocial health, increasing independence and reducing treatment-related costs in this vulnerable patient-carer dyad. In addition, we expect that the intervention will assist carers and stroke survivors to negotiate the complexity of health services across the trajectory of care and provide practical skills to improve self-management., Trial Registration: ACTRN12615001046594 . Registered on 7 October 2015.

Background: Chronic kidney disease (CKD) and end-stage kidney disease (ESKD) are serious and growing health problems with enormous impact on psychological and social functioning. Despite high rates of comorbid depression and anxiety in these patient populations, and the adverse impact these have upon treatment adherence, quality of life, social connectedness and healthcare costs there has been little attention focused on the prevention or management of these problems. Thus, our aim was to evaluate the Dialysis Optimal Health Program (DOHP) that adopts a person-centred approach and engages collaborative therapy to educate and support those diagnosed with ESKD who are commencing dialysis., Methods: The study design is a randomised controlled trial. Ninety-six adult patients initiating haemodialysis or peritoneal dialysis will be randomly allocated to either the intervention (DOHP) or usual care group. Participants receiving the intervention will receive nine (8 + 1 booster session) sequential sessions based on a structured information/workbook, psychosocial and educational supports and skills building. The primary outcome measures are depression and anxiety (assessed by the Hospital Anxiety and Depression Scale; HADS). Secondary outcomes include health-related quality of life (assessed by the Kidney Disease Quality of Life instrument; KDQOL), self-efficacy (assessed by General Self-Efficacy Scale) and clinical indices (e.g. albumin and haemoglobin levels). Cost-effectiveness analysis and process evaluation will also be performed to assess the economic value and efficacy of the DOHP. Primary and secondary measures will be collected at baseline and at 3-, 6-, and 12-month follow-up time points., Discussion: We believe that this innovative trial will enhance knowledge of interventions aimed at supporting patients in the process of starting dialysis, and will broaden the focus from physical symptoms to include psychosocial factors such as depression, anxiety, self-efficacy, wellbeing and community support. The outcomes associated with this study are significant in terms of enhancing an at-risk population's psychosocial health and reducing treatment-related costs and associated pressures on the healthcare system., Trial Registration: ANZCTR no. 12615000810516 . Registered on 5 August 2015.

Purpose: KIT mutations, the most prevalent genetic event in gastrointestinal stromal tumors (GIST), are associated with malignant features and poor prognosis. Aggressive GISTs possess a high propensity to spread to the liver. This study aimed to explore the role of KIT mutations in GIST liver metastasis., Experimental Design: A total of 170 GISTs were used to determine the association between KIT mutations and liver metastasis. Immunohistochemistry was performed to assess the correlation of KIT mutations with CXCR4 and ETV1 expression. Genetic and pharmacologic methods were used to study the regulation of CXCR4 and ETV1 by KIT mutations., Results: Codons 557 and 558 in KIT exon 11 were deletion hot spots in GISTs. KIT exon 11 deletions involving codons 557-558 were highly associated with liver metastasis. Overexpression of mutant KIT with exon 11 codons 557-558 deletion (KIT Δ557-558) increased GIST cell motility and liver metastasis. Mechanistically, overexpression of KIT Δ557-558 in GIST cells increased ETV1 and CXCR4 expression. CXCR4 knockdown counteracted KIT Δ557-558-mediated cell migration. Moreover, KIT Δ557-558-induced CXCR4 expression could be abolished by silencing ETV1. The chromatin immunoprecipitation assay showed that ETV1 directly bound to the CXCR4 promoter. After ERK inhibitor PD325901 treatment, the upregulation of ETV1 by KIT Δ557-558 was prevented. In addition, KIT exon 11 codons 557-558 deletion enhanced CXCL12-mediated GIST cell migration and invasion., Conclusions: KIT exon 11 557-558 deletion upregulates CXCR4 through increased binding of ETV1 to the CXCR4 promoter in GIST cells, which thus promotes liver metastasis. These findings highlighted the potential therapeutic targets for metastatic GISTs. Clin Cancer Res; 22(14); 3477-87. ©2016 AACR., (©2016 American Association for Cancer Research.)

Chronic obstructive pulmonary disease (COPD) has a considerable impact on quality of life and well-being of patients. Health state utility value (HSUV) is a recognized measure for health economic appraisals and is extensively used as an indicator for decision-making studies. This study is a systematic review of literature aimed to estimate mean utility value in COPD using meta-analysis and explore degree of heterogeneity in the utility values across a variety of clinical and study characteristic. The literature review covers studies that used EQ-5D to estimate utility value for patient level research in COPD. Studies that reported utility values elicited by EQ-5D in COPD patients were selected for random-effect meta-analysis addressing inter-study heterogeneity and subgroup analyses. Thirty-two studies were included in the general utility meta-analysis. The estimated general utility value was 0.673 (95% CI 0.653 to 0.693). Meta-analyses of COPD stages utility values showed influence of airway obstruction on utility value. The utility values ranged from 0.820 (95% CI 0.767 to 0.872) for stage I to 0.624 (95% CI 0.571 to 0.677) for stage IV. There was substantial heterogeneity in utility values: I(2) = 97.7%. A more accurate measurement of utility values in COPD is needed to refine valid and generalizable scores of HSUV. Given the limited success of the factors studied to reduce heterogeneity, an approach needs to be developed how best to use mean utility values for COPD in health economic evaluation.

Background: Chronic obstructive pulmonary disease (COPD) is a progressive chronic disease that has considerable impact on utility-based health-related quality of life. Utility is a key input of many decision analytic models used for economic evaluations., Objective: To systematically review COPD-related utilities and to compare these with alternative values used in decision models., Methods: The literature review comprised studies that generated utilities for COPD-related stages based on EuroQol five-dimensional questionnaire surveys of patients and of decision models of COPD progression that have been used for economic evaluations. The utility values used in modeling studies and those from the meta-analysis of actual patient-level studies were compared and differences quantified., Results: Twenty decision modeling studies that used utility value as an input parameter were found. Within the same span of publication period, 13 studies involving patient-level utility data were identified and included in the meta-analysis. The estimated mean utility values ranged from 0.806 (95% confidence interval [CI] 0.747-0.866) for stage I to 0.616 (95% CI 0.556-0.676) for stage IV. The utility scores for comparable stages in modeling studies were different (significant difference 0.045 [95% CI 0.041-0.052] for stage III). Modeling studies consistently used higher utility values than the average reported patient-level data., Conclusions: COPD decision analytic models are based on a limited range of utility values that are systematically different from average values estimated using a meta-analysis. A more systematic approach in the application of utility measures in economic evaluation is required to appropriately reflect current literature., (Copyright © 2016 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Extracellular matrix provides both mechanistic and chemical cues that can influence cellular behaviors such as adhesion, migration, proliferation, and differentiation. In this study, a new material, HA-L-Alg, was synthesized by linking developmentally essential ECM constituents hyaluronic acid (HA) and laminin(L) to alginate (Alg). The fabrication of HA-L-Alg was confirmed by FTIR spectroscopy, and it was used to form 3D cell-carrying beads. HA-L-Alg beads had a steady rate of degradation and retained 63.25% of mass after 9 weeks. HA-L-Alg beads showed biocompatibility comparable to beads formed by Alg-only with no obvious cytotoxic effect on the embedded 3T3-L1 preadipocytes. HA-L-Alg encapsulated 3T3-L1 cells were found to have a higher proliferation rate over those in Alg-only beads. These cells also showed better differentiation capacity after 2 weeks of adipogenic induction within HA-L-Alg beads. These results support that HA-L-Alg facilitated cell survival and proliferation, as well as stimulated and maintained cell differentiation. Our results suggest that HA-L-Alg has a great clinical potential to be used as stem cell carrier for adipose tissue engineering. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 669-677, 2016., (© 2015 Wiley Periodicals, Inc.)

Background: Outpatient chemotherapy is a core treatment for haematological malignancies; however, its toxicities frequently lead to distressing/potentially life-threatening side-effects (neutropenia/infection, nausea/vomiting, mucositis, constipation/diarrhoea, fatigue). Early detection/management of side-effects is vital to improve patient outcomes, decrease morbidity and limit lengthy/costly hospital admissions. The ability to capture patient-reported health data in real-time, is regarded as the 'gold-standard' to allow rapid clinical decision-making/intervention. This paper presents the protocol for a Phase 3 multi-site randomised controlled trial evaluating a novel nurse-led Telehealth intervention for remote monitoring/management of chemotherapy side-effects in Australian haematological cancer patients., Methods/design: Two hundred and twenty-two patients will be recruited from two hospitals. Eligibility criteria include: diagnosis of chronic lymphocytic leukaemia/Hodgkin's/non-Hodgkin's lymphoma; aged ≥ 18 years; receiving ≥ 2 cycles chemotherapy. Patients will be randomised 1:1 to either the control or intervention arm with stratification by diagnosis, chemotherapy toxicity (high versus low), receipt of previous chemotherapy and hospital. Patients allocated to the control arm will receive 'Usual Care' whilst those allocated to the intervention will receive the intervention in addition to 'Usual Care'. Intervention patients will be provided with a computer tablet and software prompting twice-daily completion of physical/emotional scales for up to four chemotherapy cycles. Should patient data exceed pre-determined limits an Email alert is delivered to the treatment team, prompting nurses to view patient data, and contact the patient to provide clinical intervention. In addition, six scheduled nursing interventions will be completed to educate/support patients in use of the software. Patient outcomes will be measured cyclically (midpoint and end of cycles) via pen-and-paper self-report alongside review of the patient medical record. The primary outcome is burden due to nausea, mucositis, constipation and fatigue. Secondary outcomes include: burden due to vomiting and diarrhoea; psychological distress; ability to self-manage health; level of cancer information/support needs and; utilisation of health services. Analyses will be intention-to-treat. A cost-effectiveness analysis is planned., Discussion: This trial is the first in the world to test a remote monitoring/management intervention for adult haematological cancer patients receiving chemotherapy. Future use of such interventions have the potential to improve patient outcomes/safety and decrease health care costs by enabling early detection/clinical intervention., Trial Registration: ACTRN12614000516684 . Date registered: 12 March 2014 (registered retrospectively).

Objective: To elicit a patient's willingness to participate in a diabetes pay-for-performance for patient (P4P4P) program using a discrete choice experiment method., Methods: The survey was conducted in March 2013. Our sample was drawn from patients with diabetes at five hospitals in Taiwan (International Classification of Diseases, Ninth Revision, Clinical Modification code 250). The sample size was 838 patients. The discrete choice experiment questionnaire included the attributes monthly cash rewards, exercise time, diet control, and program duration. We estimated a bivariate probit model to derive willingness-to-accept levels after accounting for the characteristics (e.g., severity and comorbidity) of patients with diabetes., Results: The preferred program was a 3-year program involving 30 minutes of exercise per day and flexible diet control. Offering an incentive of approximately US $67 in cash per month appears to increase the likelihood that patients with diabetes will participate in the preferred P4P4P program by approximately 50%., Conclusions: Patients with more disadvantageous characteristics (e.g., elderly, low income, greater comorbidity, and severity) could have less to gain from participating in the program and thus require a higher monetary incentive to compensate for the disutility caused by participating in the program's activities. Our result demonstrates that a modest financial incentive could increase the likelihood of program participation after accounting for the attributes of the P4P4P program and patients' characteristics., (Copyright © 2015 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

We aimed to develop a diabetes mellitus (DM) treatment that could be administered by intramuscular (IM) injection and it lasted for more than 3 days. The objective was to load insulin into the lattice space of hydroxyapatite (HAP) to prevent its release based on a concentration gradient or detachment from the surface, with insulin release being aided by cellular activity. To avoid insulin denaturation during the synthesis of insulin-loaded HAP (insHAP), we developed a single-step insHAP synthesis method by the hydrolysis of brushite. X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) results suggested that insulin could be loaded into the HAP crystal lattice. After IM administration in rats with DM, the synthesized insHAP is thought to be engulfed by macrophages, escape from lysosome/endosome hybrids following disruption by osmotic pressure, and pumped into the extracellular space before entering the blood stream by diffusion. In rats with DM, the normal blood glucose level was maintained for 4 days after a single IM injection of the synthesized insHAP particles. Thus, insHAP may provide a breakthrough in insulin delivery for DM treatment, and may also be used to deliver fluorescent proteins, antibodies, and anticancer drugs.

Our previous study demonstrated NVP-AUY922, a HSP90AA1 inhibitor, could enhance mutant KIT degradation in gastrointestinal stromal tumor (GIST) cells through both proteasome- and autophagy-mediated pathways. Herein, we showed rapamycin, a MTOR inhibitor and autophagy inducer, could reduce total and phospho-KIT expression levels and enhance apoptosis in imatinib-resistant GIST cells. The involvement of autophagy in rapamycin-induced KIT downregulation was further confirmed by co-localization of KIT and autophagosome, and partial recovery of KIT expression level by either siRNA-mediated BECN1 and ATG5 silencing or autophagy inhibitors after rapamycin. Rapamycin and NVP-AUY922 synergistically inhibited GIST cells growth in vitro. The combination of low-dose NVP-AUY922 with rapamycin had comparable effects on reducing KIT expression, increasing MAP1LC3B puncta and tumor necrosis, and inhibiting tumor growth as high-dose NVP-AUY922 did in GIST430 xenograft model. Our results suggest the addition of a MTOR inhibitor may reduce NVP-AUY922 dose requirement and potentially improve its therapeutic index in mutant KIT-expressing GISTs.

Background: Health care provider experiences of the carer have been researched, but little is written about how these can inform development of support programs., Objectives: This study aimed to (1) explore health care provider perceptions of stroke carer roles and support needs and (2) examine carer needs across the stroke care trajectory to assist with development of an Optimal Health Program (OHP) to support carers. This study is part of a staged program of research that will evaluate and refine the OHP., Methods: Four dual-moderated semi-structured focus groups of stroke health care providers across acute, subacute, and community rehabilitation services were conducted. Facilitators used a semi-structured focus group schedule to guide discussion. Sessions were recorded, transcribed, and analyzed using thematic and content analysis., Results: Three key themes emerged: transition, information, and impact of stroke. A number of subthemes highlighted the distinct roles of health care providers and carers. Specific elements of the OHP were identified as having the potential to advance support for carers across the stroke care trajectory., Discussion: Findings support the integration of an OHP for carers within existing stroke care services in Australian public hospital and community settings., Conclusion: This study suggests how health care provider experiences could inform a self-management OHP to assist carers in navigating stroke services and to address their health-related concerns.

Background: Breast-conserving treatment (BCT) leads to a progressive and deteriorating breast deformity. Fatgrafting is ideal for breast reconstruction after BCT. The most frequently utilized technique for fat processing is centrifugation. The PureGraft device (Cytori Therapeutics, San Diego, CA, USA) is a new method that involves washing and filtering the fat to prepare the graft. We compared the subjective and objective outcomes of two fat-processing methods, centrifugation and PureGraft filtration., Methods: Thirty patients underwent breast reconstruction performed by a single surgeon (OM) after BCT in our department between April 2011 and September 2012. The patients were preoperatively divided into two groups randomly: 15 received fatgrafts processed by centrifugation, and 15 received fatgrafts processed by washing in PureGraft bags. The patients were followed up for 12 to 30 months. To measure the subjective outcome, we distributed the BREAST-Q questionnaire to all the patients both preoperatively and 1 year postoperatively. The BCCT.core software evaluated the objective outcome of breast reconstruction by fatgrafting., Results: The Breast-Q results indicated a tremendous improvement in the modules "Satisfaction with Breast" and "Psychosocial Well-being". The "Sexual Well-being" scale also improved. Only the module "Satisfaction with Breasts" significantly differed between groups; patients treated with the PureGraft fat exhibited better outcomes. The BCCT.core results did not significantly differ between the groups., Conclusion: One year postoperatively, the outcomes of the use of PureGraft bags or centrifugation to process fat for breast reconstruction after BCT did not differ. The unpredictability of the results following fatgrafting procedures is likely due to interindividual differences with yet-undisclosed causes.

The study involves design and synthesis of three different elastin like polypeptide (ELP) gene monomers namely ELP1, ELP2 and ELP3 that encode for ELP proteins. The formed ELPs were assessed as an ideal nerve conduit for peripheral nerve regeneration. ELP1 was constructed with a small elongated pentapeptide carrying VPGVG sequence to mimic the natural polypeptide ELP. The ELP2 was designed by the incorporation of 4-penta peptide chains to improve the biocompatibility and mechanical strength. Thus, the third position in unique VPGVG was replaced with alanine to VPAVG and in a similar way modified to VPGKG, VPGEG and VPGIG with the substitution of lysine, glutamic acid and isoleucine. In ELP3, fibronectin C5 domain endowed with REDV sequence was introduced to improve the cell attachment. The ELP1, ELP2 and ELP3 proteins expressed by Escherichia coli were purified by inverse transition cycling (ITC). The purified ELPs were confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting. The Schwann cell (SC) morphology and cell adhesion were assessed by fabrication of ELP membrane cross-linked with glutaraledhyde. The Schwann cell proliferation was measured by WST-1 assay. Immunofluorostaining of Schwann cells was accomplished with SC specific phenotypic marker, S100., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: The study aims to estimate costs required for coordination and case management activities support access to treatment for the three most common eye conditions among Indigenous Australians, cataract, refractive error and diabetic retinopathy., Design: Coordination activities were identified using in-depth interviews, focus groups and face-to-face consultations. Data were collected at 21 sites across Australia. The estimation of costs used salary data from relevant government websites and was organised by diagnosis and type of coordination activity., Setting: Urban and remote regions of Australia., Interventions: Needs-based provision support services to facilitate access to eye care for cataract, refractive error and diabetic retinopathy to Indigenous Australians., Main Outcome Measures: Cost (AUD$ in 2011) of equivalent full time (EFT) coordination staff., Results: The annual coordination workforce required for the three eye conditions was 8.3 EFT staff per 10 000 Indigenous Australians. The annual cost of eye care coordination workforce is estimated to be AUD$21 337 012 in 2011., Conclusions: This innovative, 'activity-based' model identified the workforce required to support the provision of eye care for Indigenous Australians and estimated their costs. The findings are of clear value to government funders and other decision makers. The model can potentially be used to estimate staffing and associated costs for other Indigenous and non-Indigenous health needs., (© 2013 The Authors. Australian Journal of Rural Health © National Rural Health Alliance Inc.)

Objective: To estimate the costs of the extra resources required to close the gap of vision between Indigenous and non-Indigenous Australians., Design: Constructing comprehensive eye care pathways for Indigenous Australians with their related probabilities, to capture full eye care usage compared with current usage rate for cataract surgery, refractive error and diabetic retinopathy using the best available data., Setting: Urban and remote regions of Australia., Interventions: The provision of eye care for cataract surgery, refractive error and diabetic retinopathy., Main Outcome Measures: Estimated cost needed for full access, estimated current spending and estimated extra cost required to close the gaps of cataract surgery, refractive error and diabetic retinopathy for Indigenous Australians., Results: Total cost needed for full coverage of all three major eye conditions is $45.5 million per year in 2011 Australian dollars. Current annual spending is $17.4 million. Additional yearly cost required to close the gap of vision is $28 million. This includes extra-capped funds of $3 million from the Commonwealth Government and $2 million from the State and Territory Governments. Additional coordination costs per year are $13.3 million., Conclusions: Although available data are limited, this study has produced the first estimates that are indicative of the need for planning and provide equity in eye care., (© 2013 The Authors. Australian Journal of Rural Health © National Rural Health Alliance Inc.)

Background: Rehabilitation after spinal cord injury (SCI) has traditionally involved teaching compensatory strategies for identified impairments and deficits in order to improve functional independence. There is some evidence that regular and intensive activity-based therapies, directed at activation of the paralyzed extremities, promotes neurological improvement. The aim of this study is to compare the effects of a 12-week intensive activity-based therapy program for the whole body with a program of upper body exercise., Methods/design: A multicenter, parallel group, assessor-blinded randomized controlled trial will be conducted. One hundred eighty-eight participants with spinal cord injury, who have completed their primary rehabilitation at least 6 months prior, will be recruited from five SCI units in Australia and New Zealand. Participants will be randomized to an experimental or control group. Experimental participants will receive a 12-week program of intensive exercise for the whole body, including locomotor training, trunk exercises and functional electrical stimulation-assisted cycling. Control participants will receive a 12-week intensive upper body exercise program. The primary outcome is the American Spinal Injuries Association (ASIA) Motor Score. Secondary outcomes include measurements of sensation, function, pain, psychological measures, quality of life and cost effectiveness. All outcomes will be measured at baseline, 12 weeks, 6 months and 12 months by blinded assessors. Recruitment commenced in January 2011., Discussion: The results of this trial will determine the effectiveness of a 12-week program of intensive exercise for the whole body in improving neurological recovery after spinal cord injury., Trial Registration: NCT01236976 (10 November 2010), ACTRN12610000498099 (17 June 2010).

Advanced gastrointestinal stromal tumors (GIST), a KIT oncogene-driven tumor, on imatinib mesylate (IM) treatment may develop secondary KIT mutations to confer IM-resistant phenotype. Second-line sunitinib malate (SU) therapy is largely ineffective for IM-resistant GISTs with secondary exon 17 (activation-loop domain) mutations. We established an in vitro cell-based platform consisting of a series of COS-1 cells expressing KIT cDNA constructs encoding common primary±secondary mutations observed in GISTs, to compare the activity of several commercially available tyrosine kinase inhibitors on inhibiting the phosphorylation of mutant KIT proteins at their clinically achievable plasma steady-state concentration (Css). The inhibitory efficacies on KIT exon 11/17 mutants were further validated by growth inhibition assay on GIST48 cells, and underlying molecular-structure mechanisms were investigated by molecular modeling. Our results showed that SU more effectively inhibited mutant KIT with secondary exon 13 or 14 mutations than those with secondary exon 17 mutations, as clinically indicated. On contrary, at individual Css, nilotinib and sorafenib more profoundly inhibited the phosphorylation of KIT with secondary exon 17 mutations and the growth of GIST48 cells than IM, SU, and dasatinib. Molecular modeling analysis showed fragment deletion of exon 11 and point mutation on exon 17 would lead to a shift of KIT conformational equilibrium toward active form, for which nilotinib and sorafenib bound more stably than IM and SU. In current preclinical study, nilotinib and sorafenib are more active in IM-resistant GISTs with secondary exon 17 mutation than SU that deserve further clinical investigation.

Background: Previous studies have evaluated the effects of various health manpower policies but did not include full consideration of the effect of universal health insurance on physician re-distribution. This study examines the effects of implementing National Health Insurance (NHI) on the problem of geographic mal-distribution of health providers in Taiwan., Methods: Data on health providers and population between 1971 and 2001 are obtained from relevant governmental publications in Taiwan. Gini coefficients derived from the Lorenz curve are used under a spline regression model to examine the impact of the NHI on the geographic distribution of health providers., Results: The geographic distribution equality of the three key health providers has improved significantly after the implementation of NHI program. After accounting for the influences of other confounding factors, Gini coefficients of the three key providers have a net reduction of 1.248% for dentists, 0.365% for western medicine physicians, and 0.311% for Chinese medicine physicians. Overall, the absolute values of the three key providers' Gini coefficients also become close to one another., Conclusions: This study found that NHI's offering universal health coverage to all citizens and with proper financial incentives have resulted in more equal geographic distributions among the key health care providers in Taiwan.

Gastrointestinal stromal tumor (GIST) is a prototype of mutant KIT oncogene-driven tumor. Prolonged tyrosine kinase inhibitor (TKI) treatment may result in a resistant phenotype through acquired secondary KIT mutation. Heat shock protein 90 (HSP90AA1) is a chaperone protein responsible for protein maturation and stability, and KIT is a known client protein of HSP90AA1. Inhibition of HSP90AA1 has been shown to destabilize KIT protein by enhancing its degradation via the proteasome-dependent pathway. In this study, we demonstrated that NVP-AUY922 (AUY922), a new class of HSP90AA1 inhibitor, is effective in inhibiting the growth of GIST cells expressing mutant KIT protein, the imatinib-sensitive GIST882 and imatinib-resistant GIST48 cells. The growth inhibition was accompanied with a sustained reduction of both total and phosphorylated KIT proteins and the induction of apoptosis in both cell lines. Surprisingly, AUY922-induced KIT reduction could be partially reversed by pharmacological inhibition of either autophagy or proteasome degradation pathway. The blockade of autophagy alone led to the accumulation of the KIT protein, highlighting the role of autophagy in endogenous KIT turnover. The involvement of autophagy in endogenous and AUY922-induced KIT protein turnover was further confirmed by the colocalization of KIT with MAP1LC3B-, acridine orange- or SQSTM1-labeled autophagosome, and by the accumulation of KIT in GIST cells by silencing either BECN1 or ATG5 to disrupt autophagosome activity. Therefore, the results not only highlight the potential application of AUY922 for the treatment of KIT-expressing GISTs, but also provide the first evidence for the involvement of autophagy in endogenous and HSP90AA1 inhibitor-induced KIT degradation.

Background: Loss of hand function is one of the most devastating consequences of spinal cord injury. Intensive hand training provided on an instrumented exercise workstation in conjunction with functional electrical stimulation may enhance neural recovery and hand function. The aim of this trial is to compare usual care with an 8-week program of intensive hand training and functional electrical stimulation., Methods/design: A multicentre randomised controlled trial will be undertaken. Seventy-eight participants with recent tetraplegia (C2 to T1 motor complete or incomplete) undergoing inpatient rehabilitation will be recruited from seven spinal cord injury units in Australia and New Zealand and will be randomised to a control or experimental group. Control participants will receive usual care. Experimental participants will receive usual care and an 8-week program of intensive unilateral hand training using an instrumented exercise workstation and functional electrical stimulation. Participants will drive the functional electrical stimulation of their target hands via a behind-the-ear bluetooth device, which is sensitive to tooth clicks. The bluetooth device will enable the use of various manipulanda to practice functional activities embedded within computer-based games and activities. Training will be provided for one hour, 5 days per week, during the 8-week intervention period. The primary outcome is the Action Research Arm Test. Secondary outcomes include measurements of strength, sensation, function, quality of life and cost effectiveness. All outcomes will be taken at baseline, 8 weeks, 6 months and 12 months by assessors blinded to group allocation. Recruitment commenced in December 2009., Discussion: The results of this trial will determine the effectiveness of an 8-week program of intensive hand training with functional electrical stimulation., Trial Registration: NCT01086930 (12th March 2010)ACTRN12609000695202 (12th August 2009).

Hyperthermia therapy for cancer has drawn more and more attention these days. In this study, we conducted an in vivo cancer hyperthermia study of the new magnetic hydroxyapatite nanoparticles by a mouse model. The magnetic hydroxyapatite nanoparticles were first made by co-precipitation method with the addition of Fe(2+). Then, magnetic-HAP powder (mHAP) or pure HAP powder (HAP) was mixed with phosphate buffer solution (PBS), respectively. The mixture was injected around the tumor. In order to achieve hyperthermia, the mice were placed into an inductive heater with high frequency and alternating magnetic field. Only the mice which were injected with mHAP and had been treated inside the magnetic field showed dramatic reduction of tumor volume, in the 15-day observation period. No local recurrence was noted. The blood test of mice proved that mHAP powders possessed good biocompatibility and little toxicity when injected subcutaneously. Therefore, our new magnetic hydroxyapatite nanoparticles have demonstrated therapeutic effect in a mouse model with little toxicity. Further study should be done before its application inside the human body.

Background: Potentially inappropriate medication use among the elderly in an outpatient setting has been widely reported. However, the potential association between inappropriate medication use and adverse outcomes is seldom examined., Objectives: To identify the prevalence, risk factors for and adverse outcomes of potentially inappropriate medication use in ambulatory elderly patients with chronic diseases., Methods: Data for this observational cohort study consisted of computerized claims from a tertiary medical centre in Taiwan to the Bureau of National Health Insurance. Consecutive ambulatory elderly patients aged > or = 65 years who received long-term (3-month) prescriptions for treatment of a chronic disease were recruited from 1 to 31 March 2005. The cohort included 5741 elderly patients who received 7538 long-term prescriptions. Patients who required repeat prescriptions were able to be given the same prescription if their conditions were stable. The prevalence of potentially inappropriate medication use and the incidence of adverse outcomes, including emergency visits, hospitalizations and mortality, were documented for up to 6 months after the first day the patient was recruited. Beers' 2002 criteria were used to determine the potential inappropriateness of prescribed medications. Associations between potentially inappropriate medications and adverse outcomes were examined by multivariate logistic regression analyses controlling for possible confounding factors., Results: The prevalence of potentially inappropriate medication use was 23.7% in the studied hospital. The most frequently prescribed potentially inappropriate medications of high severity (i.e. having a high likelihood of being associated with an adverse effect that was clinically significant) were amiodarone, chlorzoxazone, bisacodyl, nifedipine and amitriptyline. Logistic regression analysis revealed that female sex, advanced age, number of chronic diseases and number of medications taken all significantly increased the likelihood of receiving potentially inappropriate medications. The incidence of adverse outcomes in patients with potentially inappropriate medication use in the studied hospital was 25.1%. Multivariate logistic regression analysis revealed that potentially inappropriate medication use was significantly associated with hospitalization., Conclusions: Potentially inappropriate medication use is not a rare event in elderly patients and is associated with higher risk of hospitalization in this age group. In order to reduce the possibility of prescribing inappropriate medications, and therefore to reduce the consequent risk of hospitalization, more attention should be paid when prescribing drugs to, in particular, older female patients with multiple chronic illnesses that require treatment with multiple medications.

The objective of this study was to determine the differential cost between film-based radiology and a hospital-wide picture archiving and communication system (PACS) implemented all at once. The cash flow and running costs of PACS and film-based operation were measured over an 8-year time horizon. When the hospital-wide PACS was implemented over a short period, there was instant conversion into digital film and archives. The net present value (NPV) for PACS operation is US $1,598,698, whereas the NPV for film-based operation is US $2,083,856, indicating a net saving of US $485,157. The payback period is 4 years. The costs of computed radiography and image plates account for 40% of the initial capital expenditure in PACS implementation, followed by computer hardware (30%) and software (9%) costs. Our experience shows that implementation of hospital-wide PACS all at once can produce cost savings. For hospitals intending to go filmless, this study offers a model for financial evaluation of PACS to help in decision making.

Objective: To examine the effects of global budgeting on the distribution of dentists and the use and cost of dental care in Taiwan., Data Sources: (1) Monthly dental claim data from January 1996 to December 2001 for the entire insured population in Taiwan. (2) The 1996-2001 population information for the cities, counties and townships in Taiwan, abstracted from the Taiwan-Fukien Demographic Fact Book., Study Design: Longitudinal, using the autocorrelation model., Principal Findings: Results indicated decline in dental care utilization, particularly after the implementation of dental global budgeting. With few exceptions, dental global budgeting did not improve the distribution of dental care and dentist supply., Conclusions: The experience of the dental global budget program in Taiwan suggested that dental global budgeting might contain dental care utilization and that several conditions might have to be met in order for the reimbursement system to have effective redistributive impact on dental care and dentist supply.