False-positive results of galactomannan assays in patients administered glucose-containing solutions.

Galactomannan (GM) is a polysaccharide cell wall component released by Aspergillus spp., and an immunoenzymatic GM assay is used for the diagnosis of invasive pulmonary aspergillosis. We evaluated the cause of strong positivity for GM in patients with no typical signs of aspergillosis. Repeat assays were performed using different instruments and reagent lots, but there were no differences in results among the assays. Patients with strongly positive GM results were investigated. Medication histories revealed that 14 of 23 patients had been administered total parenteral nutrition solution from one manufacturer and 4 patients had been administered dextrose solution from a different manufacturer before being tested. The results of GM assays conducted on samples of dextrose solution and the glucose fraction of the total parenteral nutrition solution were strongly positive, confirming the causes of the false-positive reactions. We hypothesize that a trace amount of GM was introduced into the glucose-containing solutions because glucoamylase, which is necessary for the saccharification step of glucose synthesis, was derived from Aspergillus niger. To enhance patient care and prevent unnecessary antifungal prescriptions, healthcare providers and manufacturers of healthcare products need to be aware of the possibility of false-positive reactions for GM.

Drug use evaluation of opioid analgesics in pain management among patients with hematopoietic stem cell transplantation.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) patients usually experience mucositis, musculoskeletal pain associated with high-dose chemotherapy, radiation, post-HSCT infection, or graft-versus-host disease. Pain management is important for the patients' quality of life. We evaluated appropriate opioid analgesic use in HSCT patients to propose effective pain management strategies. METHODS: A retrospective analysis was conducted using electronic medical records of adult patients with HSCT treated with opioids for moderate to severe pain at Seoul National University Bundang Hospital. The numeric rating scale (NRS) was used in pain management. NRS scores of 4‒10 correspond to moderate to severe pain. Appropriate opioid analgesic use was evaluated following published cancer pain management guidelines. RESULTS: In total, 119 cases were evaluated, including 369 episodes of moderate to severe pain. Mucositis-related, musculoskeletal, and headache pain occurred in 62.6%, 25.8%, and 6.0% of episodes, respectively. Frequently used opioids were intravenous tramadol (84.9%), fentanyl patch (73.9%), and intravenous morphine sulfate (68.9%). Intravenous and topical administrations were used for mucosal pain. In total, 95.0% of patients received appropriate short-acting opioids for initial pain management, 80.5% received appropriate doses of short-acting opioids, appropriate opioids dose adjustment was done after first assessment in 95.5% of patients, and 85.6% were converted to appropriate long-acting opioids. CONCLUSION: Short-acting opioid analgesic use for initial pain management and dose adjustment after assessment were appropriate. However, initial and conversion dosages recommended by guidelines may be difficult to implement considering the severity of HSCT patients. Pain management guidelines specific for HSCT patients should be developed in the future.

Association between preoperative use of antithrombotic medications and intraoperative transfusion in older patients undergoing cancer surgery.

BACKGROUND: Management of antiplatelet agents and other chronic anticoagulation medications in patients scheduled for surgery can reduce intraoperative bleeding complications. However, few studies on the association of antithrombotics, relative to their duration of action, with intraoperative transfusion have been conducted. We aimed to determine the association of recent use of antithrombotics, relative to their duration of action, with intraoperative transfusion in elderly people undergoing cancer surgery. METHODS: The study subjects were patients aged 65 years or older who were scheduled for cancer surgery and presented for comprehensive geriatric assessment. We reviewed the baseline patient characteristics obtained from electronic medical records and the patients' preoperative medication history, including anticoagulants, antiplatelet agents, and streptokinase/streptodornase. RESULTS: A total of 475 cancer patients were included. Multivariate analysis showed that long-acting anticoagulant therapy before surgery was a significant risk factor for intraoperative transfusion. Long-acting anticoagulants increased the risk of transfusion approximately 15.9-fold (95% CI 1.9-136.2). The attributable risk of long-acting anticoagulants to transfusion was approximately 93.7%. Also, low body mass index (BMI) and hepato-pancreato-biliary (HPB) surgery were significantly associated with intraoperative transfusion. The adjusted odds ratios for low BMI (<18.5 kg/m2) and HPB surgery (reference: lower gastrointestinal surgery) were 5.3 (95% CI 1.8-15.4) and 4.9 (95% CI 1.9-12.5), respectively. CONCLUSIONS: It was found that the perioperative use of long-acting anticoagulants was associated with an increased risk of intraoperative transfusion, further highlighting the importance of medication optimization for elderly patients with cancer surgery.

The influence of a patient counseling training session on pharmacy students' self-perceived communication skills, confidence levels, and attitudes about communication skills training.

BACKGROUND: The ability to communicate effectively is an essential skill for a pharmacist. However, the curricula of most pharmacy schools in South Korea do not include communication skills training (CST). This study aims to evaluate the effects of CST in pharmacy education. METHODS: This study was a comparison of pre- and post-intervention surveys completed by sixty fifth-year pharmacy students who participated in communication skills and patient counseling training during the spring 2017 semester. The students were asked to respond to 49 questions addressing 4 self-assessment categories: communication skills (24), attitudes (19), and confidence levels (2) at the beginning and end of the CST, and their perception of CST (4) after completing the course. The training session included lectures, small group work, role play, videos, and performance feedback by a tutor. Data were analyzed using the paired t-test with Bonferroni's correction for multiple comparisons. The open-ended questions were analyzed using inductive content analysis. RESULTS: The pharmacy students' self-assessment of their communication skills, attitudes toward the communication course, and confidence levels showed significant improvement after the CST. Most students (96.7%) indicated the necessity of a pharmacy communication curriculum. They responded that CST is helpful for effective communication with patients (33.3%) and other healthcare professionals (31.7%). Role-playing was reported as the most preferred learning method (58.3%). CONCLUSIONS: CST significantly impacted pharmacy students' skills, attitudes, and confidence levels related to communication skills and patient counseling. These findings indicate that communications training should be included in the regular curriculum of pharmacy schools.

Clinical outcomes and risk factors of thromboprophylaxis with rivaroxaban versus aspirin in patients undergoing hip arthroplasty in low-incidence population: A nationwide study in Korea.

PURPOSE: We aimed to evaluate the efficacy and safety of rivaroxaban in thromboprophylaxis compared with those of aspirin in real-world patients who underwent hip arthroplasty using nationwide claims data. METHODS: Patients aged more than or equal to 18 years with at least one hip arthroplasty including total and partial hip replacements and hip replacement revisions during July 2009 to June 2013 were identified from the Health Insurance Review and Assessment (HIRA) database. The study outcome was incidence rate of thromboembolic events and anticoagulation-related major bleeding within 90 days of hip arthroplasty. RESULTS: The incidence of overall venous thromboembolism (VTE) within 90-day postsurgery was significantly higher in the aspirin cohort than it was in the rivaroxaban cohorts. Bleeding events associated with pharmacological thromboprophylaxis in patients who received rivaroxaban were not significantly different from that in aspirin-treated patients. In aspirin cohorts, 65.7% of patients received less than 3-week treatment while about half received a less than 14-day treatment, and 31.7% received more than 3-week treatment in the rivaroxaban cohort. CONCLUSIONS: This study demonstrates that rivaroxaban was more effective in preventing VTE following hip arthroplasty without raising bleeding risks in clinical settings. Age more than or equal to 80 years, women, and a history of thromboembolism were the risk factors of VTE incidence.

Impact of pharmacists' interventions on physicians' decision of a knowledge-based renal dosage adjustment system.

Background Early interventions with clinical decision support system (CDSS) guidance have ensured appropriate drug dosing for patients with renal impairment. However, the low rates of physician compliance with CDSS alerts have been reported. Objective We investigated whether designated pharmacist interventions were associated with physician' acceptance of the knowledge-based renal dosage adjustment system (K-RDS) for patients with reduced renal function. Setting A retrospective, single-center study was conducted using a healthcare information system at a tertiary teaching hospital. Methods This study compared physicians' acceptance of the K-RDS with and without designated pharmacists. The severity of prescription errors and the impact of service provided by the pharmacist were evaluated using the validated method developed by Overhage and Lukes. From April to June 2017, we enrolled patients who were ≥ 20 years of age and admitted with an estimated glomerular filtration rate under 50 ml/min on medications that required dose adjustments. Main outcomes measure The number of dosing alerts of the K-RDS and physicians' acceptance rates were compared between a control group guided by the central pharmacy only and a group with assigned designated pharmacists. The factors associated with the physicians' acceptance rate were also analyzed using a multivariate logistic regression method. The impact of service provided by the pharmacist were considered as 'highly significant' (categories: 1-2). Severity of prescription errors were defined as 'serious' if they corresponded to categories 1-2 of the Overhage and Lukes scale for severity, and interventions were relevant if they corresponded to categories 1-3 in the impact of  service provided by the pharmacist scale. Results Among 1363 prescription interventions, 491 (36.0%) were performed by designated pharmacists. The K-RDS alert acceptance rate by the physicians was 54.4% in the designated pharmacist group and 47.0% in the control group (p = 0.0233). The statistically significant association was found in the designated pharmacists group in 'highly significant' service provided by the pharmacist (p < 0.001, OR 1.772; 95% CI 1.362-2.305) and 'serious' severity of prescription errors (p = 0.012, OR 1.657; 95% CI 1.116-2.460). The presence of designated pharmacists (OR 1.353, p = 0.0272), patient's gender (OR 0.758, p = 0.0016), department specialty (OR 0.659, p < 0.0001), eGFR (OR 1.538 if < 10 ml/min; OR 1.519 if 10-40 ml/min, p < 0.0001), and medications (OR 6.058-43.992 depending on the medication category, p < 0.0001) were significant factors affecting physicians' acceptance. Conclusion Pharmacists' interventions effectively improved physicians' acceptance of the K-RDS alerts.

Association of pre-operative medication use with post-surgery mortality and morbidity in oncology patients receiving comprehensive geriatric assessment.

BACKGROUND: Comprehensive geriatric assessment (CGA) has become a predictor for elderly cancer patients in post-surgical complications, including post-discharge institutionalization and mortality. AIMS: To determine whether pre-operative medication use is associated with post-operative morbidity and mortality in oncology patients receiving CGA. METHODS: Patients aged 65 years or older who were scheduled for cancer surgery and presented for CGA were included in the present study. Baseline characteristics of patients were collected from electrical medical records, and pre-operative medication review was performed. The primary outcome was death within 30 days after surgery and post-discharge institutionalization. RESULTS: A total of 475 cancer patients were included. Among them, three patients died within 30 days after surgery and 14 patients were discharged to another institution. All patients who died within 30 days after surgery had polypharmacy with marginal significance (P = 0.087). Multivariate analysis models were constructed using significant factors for post-surgery institutionalization from univariate analysis: Model I (polypharmacy and transfusion), Model II (polypharmacy and infection), and Model III (polypharmacy, transfusion, and infection). Infection was the most significant factor. Its adjusted odds ratio was as large as 11.1 and attributable risk was almost 91%. In pre-surgery medication use, only polypharmacy showed significant association with post-discharge institutionalization. Attributable risk of polypharmacy was around 75%. CONCLUSIONS: It is possible that pre-operative medication use has impact on death and post-discharge institutionalization in geriatric oncology patients, further highlighting the importance of medication optimization for elderly patients with cancer surgery.

Development of dietary pattern evaluation tool for adults and correlation with Dietary Quality Index.

BACKGROUND/OBJECTIVES: As the prevalence of chronic diseases has risen, the need for straightforward diagnostic tools for monitoring nutrition status to improve nutrition counseling and disease prevention has likewise increased. This study developed an easily usable dietary behavior pattern diagnosis checklist and investigated its correlation with dietary quality index. SUBJECTS/METHODS: A draft dietary pattern evaluation tool was generated by analyzing previous studies. The draft questionnaire comprised 61 questions for assessing dietary habits. A survey was administered to 320 adults (19 to 64 years old) using the dietary pattern evaluation tool and 24-hour-recall method between March and May of 2014 in Jeonbuk province and the metropolitan area. Principal component analysis with varimax rotation was performed to identify dietary behavior patterns. Nutritional analysis was conducted using CAN-Pro 4.0, and the Diet Quality Index-International (DQI-I) was calculated to assess dietary quality. The correlation between dietary pattern scores and DQI-I scores was also analyzed. RESULTS: The factor analysis resulted in a total of 34 questions mapped to four main dietary behavior patterns: "high fat and calorie" pattern (12 questions), "overeating/binge" pattern (nine questions), "dietary impulse" pattern (eight questions), and "unbalanced food intake" pattern (five questions). The four dietary behavior patterns were negatively correlated with DQI-I adequacy and total scores (P < 0.01). CONCLUSIONS: The dietary pattern evaluation tool developed in this study can be used to diagnose a client's dietary behavior problems and is available as a nutrition counseling tool in the field.

Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP.

The Hippo signaling pathway converges on YAP to regulate growth, differentiation, and regeneration. Previous studies with overexpressed proteins have shown that YAP is phosphorylated by its upstream kinase, Lats1/2, on multiple sites, including an evolutionarily conserved 14-3-3-binding site whose phosphorylation is believed to inhibit YAP by excluding it from the nucleus. Indeed, nuclear localization of YAP or decreased YAP phosphorylation at this site (S168 in Drosophila, S127 in humans, and S112 in mice) is widely used in current literature as a surrogate of YAP activation even though the physiological importance of this phosphorylation event in regulating endogenous YAP activity has not been defined. Here we address this question by introducing a Yap(S112A) knock-in mutation in the endogenous Yap locus. The Yap(S112A) mice are surprisingly normal despite nuclear localization of the mutant YAP protein in vivo and profound defects in cytoplasmic translocation in vitro. Interestingly, the mutant Yap(S112A) mice show a compensatory decrease in YAP protein levels due to increased phosphorylation at a mammalian-specific phosphodegron site on YAP. These findings reveal a robust homeostatic mechanism that maintains physiological levels of YAP activity and caution against the assumptive use of YAP localization alone as a surrogate of YAP activity.

Sonic hedgehog in the notochord is sufficient for patterning of the intervertebral discs.

The intervertebral discs, located between adjacent vertebrae, are required for stability of the spine and distributing mechanical load throughout the vertebral column. All cell types located in the middle regions of the discs, called nuclei pulposi, are derived from the embryonic notochord. Recently, it was shown that the hedgehog signaling pathway plays an essential role during formation of nuclei pulposi. However, during the time that nuclei pulposi are forming, Shh is expressed in both the notochord and the nearby floor plate. To determine the source of SHH protein sufficient for formation of nuclei pulposi we removed Shh from either the floor plate or the notochord using tamoxifen-inducible Cre alleles. Removal of Shh from the floor plate resulted in phenotypically normal intervertebral discs, indicating that Shh expression in this tissue is not required for disc patterning. In addition, embryos that lacked Shh in the floor plate had normal vertebral columns, demonstrating that Shh expression in the notochord is sufficient for pattering the entire vertebral column. Removal of Shh from the notochord resulted in the absence of Shh in the floor plate, loss of intervertebral discs and vertebral structures. These data indicate that Shh expression in the notochord is sufficient for patterning of the intervertebral discs and the vertebral column.

Bmp2, Bmp4 and Bmp7 are co-required in the mouse AER for normal digit patterning but not limb outgrowth.

Outgrowth and patterning of the vertebrate limb requires a functional apical ectodermal ridge (AER). The AER is a thickening of ectodermal tissue located at the distal end of the limb bud. Loss of this structure, either through genetic or physical manipulations results in truncation of the limb. A number of genes, including Bmps, are expressed in the AER. Previously, it was shown that removal of the BMP receptor Bmpr1a specifically from the AER resulted in complete loss of hindlimbs suggesting that Bmp signaling in the AER is required for limb outgrowth. In this report, we genetically removed the three known AER-expressed Bmp ligands, Bmp2, Bmp4 and Bmp7 from the AER of the limb bud using floxed conditional alleles and the Msx2-cre allele. Surprisingly, only defects in digit patterning and not limb outgrowth were observed. In triple mutants, the anterior and posterior AER was present but loss of the central region of the AER was observed. These data suggest that Bmp ligands expressed in the AER are not required for limb outgrowth but instead play an essential role in maintaining the AER and patterning vertebrate digits.

Hedgehog signaling is required for formation of the notochord sheath and patterning of nuclei pulposi within the intervertebral discs.

The vertebrae notochord is a transient rod-like structure that produces secreted factors that are responsible for patterning surrounding tissues. During later mouse embryogenesis, the notochord gives rise to the middle part of the intervertebral disc, called the nucleus pulposus. Currently, very little is known about the molecular mechanisms responsible for forming the intervertebral discs. Here we demonstrate that hedgehog signaling is required for formation of the intervertebral discs. Removal of hedgehog signaling in the notochord and nearby floorplate resulted in the formation of an aberrant notochord sheath that normally surrounds this structure. In the absence of the notochord sheath, small nuclei pulposi were formed, with most notochord cells dispersed throughout the vertebral bodies during embryogenesis. Our data suggest that the formation of the notochord sheath requires hedgehog signaling and that the sheath is essential for maintaining the rod-like structure of the notochord during early embryonic development. As notochord cells form nuclei pulposi, we propose that the notochord sheath functions as a "wrapper" around the notochord to constrain these cells along the vertebral column.

Degeneration and regeneration of the intervertebral disc: lessons from development.

Degeneration of the intervertebral discs, a process characterized by a cascade of cellular, biochemical, structural and functional changes, is strongly implicated as a cause of low back pain. Current treatment strategies for disc degeneration typically address the symptoms of low back pain without treating the underlying cause or restoring mechanical function. A more in-depth understanding of disc degeneration, as well as opportunities for therapeutic intervention, can be obtained by considering aspects of intervertebral disc development. Development of the intervertebral disc involves the coalescence of several different cell types through highly orchestrated and complex molecular interactions. The resulting structures must function synergistically in an environment that is subjected to continuous mechanical perturbation throughout the life of an individual. Early postnatal changes, including altered cellularity, vascular regression and altered extracellular matrix composition, might set the disc on a slow course towards symptomatic degeneration. In this Perspective, we review the pathogenesis and treatment of intervertebral disc degeneration in the context of disc development. Within this scope, we examine how model systems have advanced our understanding of embryonic morphogenesis and associated molecular signaling pathways, in addition to the postnatal changes to the cellular, nutritional and mechanical microenvironment. We also discuss the current status of biological therapeutic strategies that promote disc regeneration and repair, and how lessons from development might provide clues for their refinement.

The development of a korean drug dosing database.

OBJECTIVES: This report describes the development process of a drug dosing database for ethical drugs approved by the Korea Food & Drug Administration (KFDA). The goal of this study was to develop a computerized system that supports physicians' prescribing decisions, particularly in regards to medication dosing. METHODS: The advisory committee, comprised of doctors, pharmacists, and nurses from the Seoul National University Bundang Hospital, pharmacists familiar with drug databases, KFDA officials, and software developers from the BIT Computer Co. Ltd. analyzed approved KFDA drug dosing information, defined the fields and properties of the information structure, and designed a management program used to enter dosing information. The management program was developed using a web based system that allows multiple researchers to input drug dosing information in an organized manner. The whole process was improved by adding additional input fields and eliminating the unnecessary existing fields used when the dosing information was entered, resulting in an improved field structure. RESULTS: A total of 16,994 drugs sold in the Korean market in July 2009, excluding the exclusion criteria (e.g., radioactivity drugs, X-ray contrast medium), usage and dosing information were made into a database. CONCLUSIONS: The drug dosing database was successfully developed and the dosing information for new drugs can be continually maintained through the management mode. This database will be used to develop the drug utilization review standards and to provide appropriate dosing information.

Multiphasic and tissue-specific roles of sonic hedgehog in cloacal septation and external genitalia development.

Malformations of the external genitalia are among the most common congenital anomalies in humans. The urogenital and anorectal sinuses develop from the embryonic cloaca, and the penis and clitoris develop from the genital tubercle. Within the genital tubercle, the endodermally derived urethral epithelium functions as an organizer and expresses sonic hedgehog (Shh). Shh knockout mice lack external genitalia and have a persistent cloaca. This identified an early requirement for Shh, but precluded analysis of its later role in the genital tubercle. We conducted temporally controlled deletions of Shh and report that Shh is required continuously through the onset of sexual differentiation. Shh function is divisible into two temporal phases; an anogenital phase, during which Shh regulates outgrowth and patterning of the genital tubercle and septation of the cloaca, and a later external genital phase, during which Shh regulates urethral tube closure. Disruption of Shh function during the anogenital phase causes coordinated anorectal and genitourinary malformations, whereas inactivation during the external genital phase causes hypospadias. Shh directs cloacal septation by promoting cell proliferation in adjacent urorectal septum mesenchyme. Additionally, conditional inactivation of smoothened in the genital ectoderm and cloacal/urethral endoderm shows that the ectoderm is a direct target of Shh and is required for urethral tube closure, highlighting a novel role for genital ectoderm in urethragenesis. Identification of the stages during which disruption of Shh results in either isolated or coordinated malformations of anorectal and external genital organs provides a new tool for investigating the etiology of anogenital malformations in humans.

In the limb AER Bmp2 and Bmp4 are required for dorsal-ventral patterning and interdigital cell death but not limb outgrowth.

The apical ectodermal ridge (AER) in the vertebrate limb is required for limb outgrowth and patterning. To investigate the role BMP ligands expressed in the AER play in limb development we selectively inactivated both Bmp2 and Bmp4 in this tissue. The autopods of mice lacking both of these genes contained extra digits, digit bifurcations and interdigital webbing due to a decrease in programmed cell death and an increase in cell proliferation in the underlying mesoderm. Upon removal of Bmp2 and Bmp4 in the AER, no defects in proximal-distal patterning were observed. At the molecular level, removal of Bmp2 and Bmp4 in the AER caused an increase in Fgf expression, which correlated with an increase in both the width and length of the AER. Investigation of Engrailed-1 (En1) expression in the AER of limb buds in which Bmp2 and Bmp4 had been removed indicated that En1 expression was absent from this tissue. Our data suggests that AER expression of Bmp2 and Bmp4 is required for digit and dorsal-ventral patterning but surprisingly not for limb outgrowth.

Biological characterization of long-term cultured human mesenchymal stem cells.

Human mesenchymal stem cells (hMSCs) have generated a great deal of interest in clinical applications. The reason is that they may have the plasticity needed to differentiate into multiple lineages and the ability to expand ex vivo. For the therapeutic applications of hMSCs to be of practical use, it is crucial to assess the efficacy and safety of hMSCs in long-term ex vivo expansion. In this study, we cultured hMSCs by population doubling (PD) 60, and investigated their growth, osteogenic and adipogenic differential abilities, change of surface markers, telomerase activity, telomere length, and gene expression related to tumorigenesis. An in vivo tumorigenesis assay was also carried out. In long-term expanded hMSCs, the cells became aged above PD 30 and their adipogenic and osteogenic differentiation potential decreased. Telomerase activity unchanged whereas telomere length decreased and karyotypes were not changed. Gene expressions related to tumorigenesis decreased in proportion as the PD of hMSCs increased. In vivo transplantation of long-term cultured hMSCs to nude mice did not result in tumor formation. These findings suggest that diverse tests for cellular therapy should be considered during the ex vivo culture of hMSCs, particularly when a prolonged and extended propagation period is required.

Identification of nucleus pulposus precursor cells and notochordal remnants in the mouse: implications for disk degeneration and chordoma formation.

A classically identified "notochordal" cell population in the nucleus pulposus is thought to regulate disk homeostasis. However, the embryonic origin of these cells has been under dispute for >60 years. Here we provide the first direct evidence that all cell types in the adult mouse nucleus pulposus are derived from the embryonic notochord. Additionally, rare isolated embryonic notochord cells remained in the vertebral column and resembled "notochordal remnants," which in humans have been proposed to give rise to a rare type of late-onset cancer called chordoma. Previously, this cell type had not been identified in the mouse model system. The development and characterization of a mouse model that can be used to fate map nucleus pulposus precursor cells in any mutant background will be useful for uncovering the cellular and molecular mechanisms of disk degeneration. In addition, the identification of notochordal remnants in mice is the first step towards generating an in vivo model of chordoma.

Gene expression profile of cytokine and growth factor during differentiation of bone marrow-derived mesenchymal stem cell.

Mesenchymal stem cells (MSCs), which are adherent stromal cells of a nonhematopoietic origin, have the ability to give rise to various differentiated cell types. MSCs regulate localization, self-renewal and differentiation of hematopoietic stem cells (HSCs) due to MSCs' secretion of cytokines and growth factors, the cell-to-cell interactions and the influence of the extracellular matrix proteins. Using RT-PCR analysis, we examined the expression levels of cytokines and growth factors from MSCs and their differentiated cell types, including osteoblasts, adipocytes and endothelial cells. Cytokine and growth factor genes, including IL-6, IL-8, IL-11, IL-12, IL-14, IL-15, LIF, G-CSF, GM-CSF, M-SCF, FL and SCF, were found to be expressed in the MSCs. In contrast, there was no IL-1alpha, IL-1beta, or IL-7 expression observed. The IL-12, IL-14, G-CSF, and GM-CSF mRNA expression levels either disappeared or decreased after the MSCs differentiated into osteoblasts, adipocytes, and endothelial cells. Among the differentiated cells derived from MSCs, osteoblasts, adipocytes, and endothelial cells expressed the osteopontin, aP2, and the VEGFR-2 gene, respectively. These profiles could help determine future clinical applications of MSCs and their derivatives for cell therapy.

In vitro trans-differentiation of rat mesenchymal cells into insulin-producing cells by rat pancreatic extract.

Recent reports have suggested that mesenchymal cells derived from bone marrow may differentiate into not only mesenchymal lineage cells but also other lineage cells. There is possibility for insulin-producing cells (IPCs) to be differentiated from mesenchymal cells. We used self-functional repair stimuli of stem cells by partial injury. Rat pancreatic extract (RPE) from the regenerating pancreas (2 days after 60% pancreatectomy) was treated to rat mesenchymal cells. After the treatment of RPE, they made clusters like islet of Langerhans within a week and expressed four pancreatic endocrine hormones; insulin, glucagon, pancreatic polypeptide, and somatostatin. Moreover, IPCs released insulin in response to normal glucose challenge. Here we demonstrate that the treatment of RPE can differentiate rat mesenchymal cells into IPCs which can be a potential source for the therapy of diabetes.