A chordoma is an uncommon tumor that originates from the remnants of the notochord and most commonly involves the cranial and caudal regions of the axial skeleton. Chordoma has been described in laboratory animals such as dogs, rats, minks, and ferrets. This report describes a case of a chordoma in the tail of a ferret. Grossly, a grayish-white, expansile, subcutaneous soft-tissue mass was observed in the tail. Histopathologically, the mass was a loosely placed, nodular, unencapsulated neoplasm within the dermis. In the mass, tumor lobules were intermingled with fibrous tissues. Fibrous tissues contained abundant extracellular basophilic material that was consistent with mucin. The tumor was composed of a close pack of adipocyte-like vacuolated cells (physaliferous cells). The cells were centrally or eccentrically located round nuclei and eosinophilic cytoplasm with large vacuoles. Immunohistologically, neoplastic cells were positive for vimentin and S-100 protein. Based on histopathologic findings and special staining characteristics, this case was diagnosed as chordoma.
Chordoma; ferret; physaliferous cells; pathology
Allostatic load (AL) measures overall physiological wear and tear on one's body, as a preclinical marker of pathophysiologic processes that precede the onset of disease. We studied the association of dietary habits with AL.
Consecutive patients visiting a tertiary hospital Health Promotion Center from September 2009 to February 2010, older than 20 years with metabolic syndrome were selected for study (n = 204). By multivariable linear regression analysis, we investigated the association of various dietary habits evaluated by questionnaires.
In male, multivariable linear regression showed a significant negative association between fat preference and AL with BMI ≥ 30 (1st quartile [Q] vs. 2Q: β = -3.71; 95% confidence interval [CI], -6.26 to -1.16), a significant negative association between salt preference and AL with BMI 25-30 (β = -1.36; 95% CI, -2.46 to -0.26), a negative association between appetite control and AL with BMI < 25 (1Q vs. 3Q: β = -1.54; 95% CI, -3.00 to -0.096), a significant positive association between appetite control and AL with BMI 25-30 (1Q vs. 3Q: β = 1.30; 95% CI, 0.12 to 2.48), and a significant positive association between eating in response to food cues and AL in males with BMI 25-30 (1Q vs. 4Q: β = 1.09; 95% CI, 0.020 to 2.15).
Our results suggest that metabolic syndrome patients should be discouraged from eating fat and eating in response to food cues, and should be educated about nutrition and balanced diet.
Allostasis; Metabolic Syndrome; Food Habits; Food Preferences
Abnormalities during brain development are thought to cause psychiatric illness and other neurodevelopmental disorders. However, developmental processes such as neurogenesis continue in restricted brain regions of adults, and disruptions of these processes could contribute to the phenotypes of neurodevelopmental disorders. As previously reported, we show that Disc1 knockdown specifically in adult-born dentate gyrus (DG) neurons results in increased mTOR signaling, hyper-excitability and neuronal structure deficits. Disc1 knockdown also resulted in pronounced cognitive and affective deficits, which could be reversed when the affected DG neurons were inactivated. Importantly, reversing increases in mTOR signaling with an FDA approved inhibitor, both prevented and treated these behavioral deficits, even when associated structural deficits were not reversed. Our findings suggest that a component of the affective and cognitive phenotypes in neurodevelopmental disorders may be caused by disruptions in adult-born neurons. Consequently, treatments directed at this cell population may have a significant impact on these phenotypes.
Adult neurogenesis, a process of generating mature neurons from adult neural stem cells, proceeds concurrently with ongoing neuronal circuit activity and is modulated by various physiological and pathological stimuli. The niche mechanism underlying activity-dependent regulation of sequential steps of adult neurogenesis remains largely unknown. Here we report that neuronal activity decreases the expression of secreted frizzled-related protein 3 (sFRP3), a naturally secreted Wnt inhibitor highly expressed by adult dentate gyrus granule neurons. Sfrp3 deletion activates quiescent radial neural stem cells and promotes newborn neuron maturation, dendritic growth and spine formation in the adult mouse hippocampus. Furthermore, sfrp3 reduction is essential for activity-induced adult neural progenitor proliferation and acceleration of new neuron development. Our study identifies sFRP3 as an inhibitory niche factor from local mature dentate granule neurons that regulates multiple phases of adult hippocampal neurogenesis and suggests a novel activity-dependent mechanism governing adult neurogenesis via acute release of tonic inhibition.
AIM: To evaluate the possibility of an association between polyethylene glycol (PEG) and acute renal failure (ARF) in elderly patients using a health insurance claims database.
METHODS: We conducted a population-based case-crossover study using information obtained from Korean Health Insurance Review and Assessment Service (HIRA) claims from January 1, 2005 to December 31, 2005 (Seoul, Korea). The study population consisted of elderly patients who received PEG prior to experiencing their first ARF-related hospitalization from April 1, 2005 to December 31, 2005. For each patient, one case and two control periods were matched. PEG use in a 2- or 4-wk window period prior to hospitalization for ARF was compared with PEG use in two earlier 2- or 4-wk control window periods. Conditional logistic regression analysis was used to estimate odds ratios (ORs) and 95% CI, adjusting for concomitant uses of diuretics, angiotensin converting enzyme inhibitors, non-steroidal anti-inflammatory drugs, antibiotics, anti-cancer drugs, and contrast media.
RESULTS: Within the HIRA database which contained 1 093 262 elderly patients, 1156 hospitalized ARF cases were identified. Among these cases, PEG was prescribed to 17 (1.5%) patients before hospitalization. The adjusted ORs when applying the 2- and 4-wk window periods were 0.4 (95% CI: 0.03-5.24) and 2.1 (95% CI: 0.16-27.78), respectively.
CONCLUSION: No increased risk of ARF was found in elderly PEG users. However, based on the limited number of study subjects, further analysis should be performed to confirm these results.
Polyethylene glycol; Acute renal failure; Adverse drug reaction; Health insurance claims database; Case-crossover
We aimed to determine the characteristic adverse events (AEs) of iodinated contrast media (IOCM) and to compare the safety profiles of different IOCM. This study used the database of AEs reports submitted by healthcare professionals from 15 Regional Pharmacovigilance Centers between June 24, 2009 and December 31, 2010 in Korea. All reports of IOCM, including iopromide, iohexol, iopamidol, iomeprol, ioversol, iobitridol and iodixanol, were analyzed. Safety profiles were compared between different IOCM at the system organ level using the proportional reporting ratio (PRR) and 95% confidence interval (95% CI). Among a total of 48,261 reports, 6,524 (13.5%) reports were related to the use of IOCM. Iopromide (45.5%), iohexol (16.9%), iopamidol (14.3%) and iomeprol (10.3%) were identified as frequently reported media. 'Platelet, bleeding & clotting disorders' (PRR, 29.6; 95%CI, 1.9-472.6) and 'urinary system disorders' (PRR, 22.3; 95% CI, 17.1-29.1) were more frequently reported for iodixanol than the other IOCM. In conclusion, the frequency of AEs by organ class was significantly different between individual media. These differences among different IOCM should be considered when selecting a medium among various IOCM and when monitoring patients during and after its use to ensure optimum usage and patient safety.
Contrast Media; Adverse Drug Reaction Reporting Systems; Patient Safety
Vascular smooth muscle cells (VSMCs) undergo phenotypic changes in response to vascular injury such as angioplasty. Protein kinase G (PKG) has an important role in the process of VSMC phenotype switching. In this study, we examined whether rosiglitazone, a peroxisome proliferator-activated receptor (PPAR)-γ agonist, could modulate VSMC phenotype through the PKG pathway to reduce neointimal hyperplasia after angioplasty. In vitro experiments showed that rosiglitazone inhibited the phenotype change of VSMCs from a contractile to a synthetic form. The platelet-derived growth factor (PDGF)-induced reduction of PKG level was reversed by rosiglitazone treatment, resulting in increased PKG activity. This increased activity of PKG resulted in phosphorylation of vasodilator-stimulated phosphoprotein at serine 239, leading to inhibited proliferation of VSMCs. Interestingly, rosiglitazone did not change the level of nitric oxide (NO) or cyclic guanosine monophosphate (cGMP), which are upstream of PKG, suggesting that rosiglitazone influences PKG itself. Chromatin immunoprecipitation assays for the PKG promoter showed that the activation of PKG by rosiglitazone was mediated by the increased binding of Sp1 on the promoter region of PKG. In vivo experiments showed that rosiglitazone significantly inhibited neointimal formation after balloon injury. Immunohistochemistry staining for calponin and thrombospondin showed that this effect of rosiglitazone was mediated by modulating VSMC phenotype. Our findings demonstrate that rosiglitazone is a potent modulator of VSMC phenotype, which is regulated by PKG. This activation of PKG by rosiglitazone results in reduced neointimal hyperplasia after angioplasty. These results provide important mechanistic insight into the cardiovascular-protective effect of PPARγ.
cGMP-dependent protein kinase; Rosiglitazone; Smooth muscle cells
Practitioners of family medicine are essential to primary care practices in Korea. Resident training staffs in Korean family medicine departments have a crucial role in producing well-trained family physicians. This study assesses the aspects of satisfaction and difficulties of Korean family medicine resident training staffs.
We surveyed the resident training staffs of various Korean family medicine departments using an online survey tool. The survey used in this study was modified from previously used questionnaires. Respondents rated items using a five-point Likert scale and a 0-10 visual analogue scale.
The response rate was 43.9% (122/278). The mean satisfaction score with regard to current family medicine residency programs was 7.59 out of 10. Resident training staffs found the administrative aspects of their role to be the most difficult. There were considerable differences in the reported difficulties of resident training according to the differing characteristics of each staff member, including age, sex, type of hospital, number of staff members, role as chief, and duration of staff. Most respondents (91.9%) cited a need for faculty development programs.
Korean family medicine resident training staffs need faculty development programs for the improvement of resident training. For the strengthening of core competencies among resident training staffs, faculty development programs or courses should be designed and implemented in Korea.
Faculty Development; Survey; Family Medicine Teacher; Faculty Developmental Program
Ceramides are the main lipid component of the stratum corneum and are a structurally heterogeneous and complex group of sphingolipids of which sphingoid bases are the basic structural constituents. Altered levels of sphingoid bases have been reported in skin conditions that involve dryness and barrier disruption, including atopic dermatitis.
The purpose of this study was to investigate the altered levels of sphingoid bases in psoriatic epidermis and their relationship with the clinical severity of the psoriasis.
Samples from the lesional and non-lesional epidermis were obtained from eight psoriasis patients. Levels of sphingosine and sphinganine were analyzed by high-performance liquid chromatography. The expression of ceramide synthase and ceramidase proteins, which are related to sphingosine and sphinganine metabolism, were measured using Western blot analysis.
Levels of sphingosine and sphinganine in the lesional epidermis were significantly higher than those in the non-lesional epidermis. Although there was no altered ceramide synthase and ceramidase, there was a highly significant positive correlation between the % change of ceramidase, the degradative enzyme of ceramide into sphingosine, and the Psoriasis Area Severity Index (PASI) score.
The levels of sphingosine and sphinganine were significantly increased in psoriatic epidermis and the % change of ceramidase was positively correlated with the clinical severity of psoriasis.
Ceramidases; Dihydroceramide desaturase; Psoriasis; Sphinganine; Sphingosine
How extrinsic stimuli and intrinsic factors interact to regulate continuous neurogenesis in the postnatal mammalian brain is unknown. Here we show that regulation of dendritic development of newborn neurons by Disrupted-in-Schizophrenia 1 (DISC1) during adult hippocampal neurogenesis requires neurotransmitter GABA-induced, NKCC1-dependent depolarization through a convergence onto the AKT-mTOR pathway. In contrast, DISC1 fails to modulate early postnatal hippocampal neurogenesis when conversion of GABA-induced depolarization to hyperpolarization is accelerated. Extending the period of GABA-induced depolarization, or maternal deprivation stress, restores DISC1-dependent dendritic regulation through mTOR pathway during early postnatal hippocampal neurogenesis. Furthermore, DISC1 and NKCC1 interact epistatically to affect risk for schizophrenia in two independent case control studies. Our study uncovers an interplay between intrinsic DISC1 and extrinsic GABA signaling, two schizophrenia susceptibility pathways, in controlling neurogenesis and suggests critical roles of developmental tempo and experience in manifesting the impact of susceptibility genes on neuronal development and risk for mental disorders.
We present the development and characterization of nanoparticles loaded with a custom phosphor; we exploit these nanoparticles to perform quantitative measurements of the concentration of oxygen within three-dimensional (3-D) tissue cultures in vitro and blood vessels in vivo. We synthesized a customized ruthenium (Ru)-phosphor and incorporated it into polymeric nanoparticles via self-assembly. We demonstrate that the encapsulated phosphor is non-toxic with and without illumination. We evaluated two distinct modes of employing the phosphorescent nanoparticles for the measurement of concentrations of oxygen: 1) in vitro, in a 3-D microfluidic tumor model via ratiometric measurements of intensity with an oxygen-insensitive fluorophore as a reference, and 2) in vivo, in mouse vasculature using measurements of phosphorescence lifetime. With both methods, we demonstrated micrometer-scale resolution and absolute calibration to the dissolved oxygen concentration. Based on the ease and customizability of the synthesis of the nanoparticles and the flexibility of their application, these oxygen-sensing polymeric nanoparticles will find a natural home in a range of biological applications, benefiting studies of physiological as well as pathological processes in which oxygen availability and concentration play a critical role.
Nanoparticle; Oxygen–sensing; Ruthenium phosphor; Poly(urethane acrylate nonionomer)(PUAN); Tissue engineering; Vascular oxygen concentration
Entamoeba histolytica, which causes amoebic colitis and occasionally liver abscess in humans, is able to induce host cell death. However, signaling mechanisms of colon cell death induced by E. histolytica are not fully elucidated. In this study, we investigated the signaling role of NOX in cell death of HT29 colonic epithelial cells induced by E. histolytica. Incubation of HT29 cells with amoebic trophozoites resulted in DNA fragmentation that is a hallmark of apoptotic cell death. In addition, E. histolytica generate intracellular reactive oxygen species (ROS) in a contact-dependent manner. Inhibition of intracellular ROS level with treatment with DPI, an inhibitor of NADPH oxidases (NOXs), decreased Entamoeba-induced ROS generation and cell death in HT29 cells. However, pan-caspase inhibitor did not affect E. histolytica-induced HT29 cell death. In HT29 cells, catalytic subunit NOX1 and regulatory subunit Rac1 for NOX1 activation were highly expressed. We next investigated whether NADPH oxidase 1 (NOX1)-derived ROS is closely associated with HT29 cell death induced by E. histolytica. Suppression of Rac1 by siRNA significantly inhibited Entamoeba-induced cell death. Moreover, knockdown of NOX1 by siRNA, effectively inhibited E. histolytica-triggered DNA fragmentation in HT29 cells. These results suggest that NOX1-derived ROS is required for apoptotic cell death in HT29 colon epithelial cells induced by E. histolytica.
Entamoeba histolytica; host cell death; HT29 colon epithelial cell; reactive oxygen species (ROS); NADPH oxidase 1 (NOX1)
Pancreatic cancer is the fourth commonest cause of cancer-related deaths in the world. However, no adequate therapy for pancreatic cancer has yet been found. In this study, the antitumor activity of cytokine-induced killer (CIK) cells against the human pancreatic cancer was evaluated in vitro and in vivo. Human peripheral blood mononuclear cells were cultured with IL-2-containing medium in anti-CD3 for 14 days. The resulting populations of CIK cells comprised 94% CD3+, 4% CD3-CD56+, 41% CD3+CD56+, 11% CD4+, and 73% CD8+. This heterogeneous cell population was called cytokine-induced killer (CIK) cells. At an effector-target cell ratio of 100:1, CIK cells destroyed 51% of AsPC-1 human pancreatic cancer cells, as measured by the 51Cr-release assay. In addition, CIK cells at doses of 3 and 10 million cells per mouse inhibited 42% and 70% of AsPC-1 tumor growth in nude mouse xenograft assays, respectively. This study suggests that CIK cells may be used as an adoptive immunotherapy for pancreatic cancer patients.
Pancreatic cancer; Adoptive immunotherapy; Cytokine-induced killer cells
Disrupted-in Schizophrenia 1 (DISC1), a susceptibility gene for major mental disorders, encodes a scaffold protein that has a multifaceted impact on neuronal development. How DISC1 regulates different aspects of neuronal development is not well understood. Here we show that Fasciculation and Elongation Protein Zeta-1 (FEZ1) interacts with DISC1 to synergistically regulate dendritic growth of newborn neurons in the adult mouse hippocampus, and that this pathway complements a parallel DISC1-NDEL1 interaction that regulates cell positioning and morphogenesis of newborn neurons. Furthermore, genetic association analysis of two independent cohorts of schizophrenia patients and healthy controls reveals an epistatic interaction between FEZ1 and DISC1, but not between FEZ1 and NDEL1, for risk of schizophrenia. Our findings support a model in which DISC1 regulates distinct aspects of neuronal development through its interaction with different intracellular partners and such epistasis may contribute to increased risk for schizophrenia.
Chronic heart failure accounts for a great deal of the morbidity and mortality in the aging population. Evidence-based treatments include angiotensin-2 receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACE-I), beta-blockers, and aldosterone antagonists. Underutilization of these treatments in heart failure patients were frequently reported, which could lead to increase morbidity and mortality. The aim of this study was to evaluate the utilization of evidence-based treatments and their related factors for elderly patients with chronic heart failure.
This is retrospective observational study using the Korean National Health Insurance claims database. We identified prescription of evidence based treatment to elderly patients who had been hospitalized for chronic heart failure between January 1, 2005, and June 30, 2006.
Among the 28,922 elderly patients with chronic heart failure, beta-blockers were prescribed to 31.5%, and ACE-I or ARBs were prescribed to 54.7% of the total population. Multivariable logistic regression analyses revealed that the prescription from outpatient clinic (prevalent ratio, 4.02, 95% CI 3.31–4.72), specialty of the healthcare providers (prevalent ratio, 1.26, 95% CI, 1.12–1.54), residence in urban (prevalent ratio, 1.37, 95% CI, 1.23–1.52) and admission to tertiary hospital (prevalent ratio, 2.07, 95% CI, 1.85–2.31) were important factors associated with treatment underutilization. Patients not given evidence-based treatment were more likely to experience dementia, reside in rural areas, and have less-specialized healthcare providers and were less likely to have coexisting cardiovascular diseases or concomitant medications than patients in the evidence-based treatment group.
Healthcare system factors, such as hospital type, healthcare provider factors, such as specialty, and patient factors, such as comorbid cardiovascular disease, systemic disease with concomitant medications, together influence the underutilization of evidence-based pharmacologic treatment for patients with heart failure.
Congestive heart failure; Drug utilization evaluation; Elderly; Type 2 angiotensin receptor antagonists; Angiotensin-converting enzyme antagonists; Beta-adrenergic blockers
Background and Objectives
Poor homing efficiency is one of the major limitations of current stem cell therapy. Magnetic bionanoparticles (MPs) obtained from Magnetospirillum sp. AMB-1 have a lipid bilayer membrane and ferromagnetic properties. We evaluated a novel priming strategy using MPs to enhance the homing of transplanted progenitor cells to target tissue.
Materials and Methods
Effects of MP on proliferation, viability, and migration of late human endothelial progenitor cells (EPCs) were examined in vitro. Additionally, effects of MP on gene and protein expression related to survival and adhesion were evaluated. Homing and angiogenic efficiency of MP transferred late EPCs was evaluated in nude mouse hindlimb ischemia model.
Below threshold concentration, MP transfer did not influence proliferation or survival of late EPCs, but enhanced migration and trans-endothelial migration of late EPCs toward magnet. Below threshold concentration, MP transfer did not influence gene and protein expression related to survival. In the mouse hindlimb ischemia model, late EPCs treated with high dose MP (5 ug/mL) showed enhanced homing of injected late EPCs in the ischemic limb by magnet, compared to low dose MP (1 ug/mL) treated late EPCs. In addition, high dose MP transferred EPC showed significantly better improvement of perfusion in ischemic limb compared to untreated EPC.
MP transfer with magnet application can be a promising novel strategy to enhance homing efficacy and outcomes of current stem cell therapy.
Nanoparticles; Stem cells; Ischemia
Brain-derived neurotrophic factor (BDNF) induces synaptic potentiation at both neuromuscular junctions (NMJs) and synapses of the central nervous system through a Ca2+-dependent pathway. The molecular mechanism underlying BDNF-induced synaptic potentiation, especially the regulation of Ca2+ dynamics, is not well understood. Using the Xenopus NMJ in culture as a model system, we show that pharmacological inhibition or morpholino-mediated knockdown of Xenopus TRPC1 (XTRPC1) significantly attenuated the BDNF-induced potentiation of the frequency of spontaneous synaptic responses at the NMJ. Functionally, XTRPC1 was required specifically in postsynaptic myocytes for BDNF-induced Ca2+ elevation and full synaptic potentiation at the NMJ, suggesting a previously under-appreciated postsynaptic function of Ca2+ signaling in neurotrophin-induced synaptic plasticity, in addition to its well-established role at presynaptic sites. Mechanistically, blockade of the p75 neurotrophin receptor abolished BDNF-induced postsynaptic Ca2+ elevation and restricted BDNF-induced synaptic potentiation, while knockdown of the TrkB receptor in postsynaptic myocytes had no effect. Our study suggests that BDNF-induced synaptic potentiation involves coordinated presynaptic and postsynaptic responses and identifies TRPC1 as a molecular mediator for postsynaptic Ca2+ elevation required for BDNF-induced synaptic plasticity.
Site-specific delivery of drugs while minimizing unwanted distribution has been one of the pursued goals in cancer therapy. In this endeavor, we have developed targeted polymeric nanoparticles called amphiphilic urethane acrylate nonionomer (UAN) for encapsulation of diverse water-insoluble drugs and diagnostic agents, as well as for simple and reproducible surface conjugation of targeting ligands. Using monoclonal antibodies or lymphocyte function-associated antigen-1 (LFA-1) I domain engineered for varying affinities to intercellular adhesion molecule (ICAM)-1, we were able to deliver UAN nanoparticles to human cancer cells with the efficiency dependent on the strength of the molecular interactions and the degree of ICAM-1 expression on cell surface. Compared to non-specific uptake of free drugs, targeted delivery of UAN nanoparticles carrying equal amount of drugs produced more potent cytotoxicity. Notably, without the targeting ligands attached, UAN nanoparticles were largely precluded from non-specific uptake by the cells, resulting in much lower toxicity. The versatility of our UAN nanoparticles in both payload encapsulation and presentation of targeting ligands may facilitate developing a robust platform for evaluating various combinations of cancer drugs and molecular interactions toward developing effective cancer therapy formulations.
self-assembled nanoparticle; targeted nanoplatform; adhesion molecule; tumor targeting; drug delivery; payload encapsulation
Attending conferences is important for doctors and residents in family medicine. Nevertheless, departments of family medicine at many hospitals find it difficult to hold regular conferences. Holding joint videoconferences between Family Medicine Departments of several hospitals through a videoconferencing system could solve this problem. Therefore, Family Medicine Departments of Seoul National University Hospital, Seoul National University Bundang Hospital, and Kangwon National University Hospital decided to hold regular joint videoconferences via a videoconferencing system. Eighty-one joint videoconferences were held from April 1 to October 29, 2010. PowerPoint slideshows were transferred to the other two locations in the same resolution as presenter's monitor. Image and voice of the speaker were transferred in real time and in acceptable quality. Joint videoconferences are feasible, satisfactory and useful for medical education, especially when individual family medicine departments are small and lack resources to hold face-to-face conferences. We expect that more family medicine departments will choose to participate in implementing similar joint videoconferencing systems in the future.
Videoconference; Medical Education; Family Medicine
Entamoeba histolytica is an enteric tissue-invading protozoan parasite that can cause amebic colitis and liver abscess in humans. E. histolytica has the capability to kill colon epithelial cells in vitro; however, information regarding the role of calpain in colon cell death induced by ameba is limited. In this study, we investigated whether calpains are involved in the E. histolytica-induced cell death of HT-29 colonic epithelial cells. When HT-29 cells were co-incubated with E. histolytica, the propidium iodide stained dead cells markedly increased compared to that in HT-29 cells incubated with medium alone. This pro-death effect induced by ameba was effectively blocked by pretreatment of HT-29 cells with the calpain inhibitor, calpeptin. Moreover, knockdown of m- and µ-calpain by siRNA significantly reduced E. histolytica-induced HT-29 cell death. These results suggest that m- and µ-calpain may be involved in colon epithelial cell death induced by E. histolytica.
Entamoeba histolytica; host cell death; calpain; HT-29 colon epithelial cells
Disrupted-in-Schizophrenia 1 (DISC1), a susceptibility gene for major mental illnesses, regulates multiple aspects of embryonic and adult neurogenesis. Here we show that DISC1 suppression in newborn neurons of the adult hippocampus leads to over-activated signaling of AKT, another schizophrenia susceptibility gene. Mechanistically, DISC1 directly interacts with KIAA1212, an AKT binding partner that enhances AKT signaling in the absence of DISC1, and DISC1 binding to KIAA1212 prevents AKT activation in vitro. Functionally, multiple genetic manipulations to enhance AKT signaling in adult-born neurons in vivo exhibit similar defects as DISC1 suppression in neuronal development that can be rescued by pharmacological inhibition of mammalian target of rapamycin (mTOR), an AKT downstream effector. Our study identifies AKT-mTOR signaling pathway as a critical DISC1 target in regulating neuronal development and provides a framework for understanding how multiple susceptibility genes may functionally converge onto a common pathway in contributing to the etiology of certain psychiatric disorders.
Health risk appraisal (HRA) is a tool for determining health risk factors and motivating individuals to maintain a healthy lifestyle. We performed this study to describe the HRA algorithm and evaluate the accuracy of an HRA program for 10-yr mortality prediction in Korean men. We used data derived from periodic health examinations of 116,927 male public officials and school personnel aged 20 or older. Risk age and the difference between risk age and calendar age were calculated. We obtained the hazard ratio (HR) of 10-yr mortality according to the calculated age difference. Of the 116,927 subjects, 1,900 (1.6%) died during the 10 yr after the 1992 medical examinations. The HR of 10-yr mortality increased significantly with age difference. Compared with the HR in the reference group (age difference below 2 yr), the HR in the group with a 2- to 6-yr age difference was 1.20 (95% confidence interval [CI]: 1.05 to 1.38) and HR in the group with more than 7-yr age difference was 1.35 (95% CI: 1.14 to 1.75). Risk age is a relatively good predictor of 10-yr mortality in Korean men and may be useful in identifying high-risk middle-aged men for health interventions.
Health Status Indicators; Validity; Mortality; Men; Health Risk Appraisal
The secretion of insulin from pancreatic β-cells is triggered by the influx of Ca2+ through voltage-dependent Ca2+ channels. The resulting elevation of intracellular calcium ([Ca2+]i) triggers additional Ca2+ release from internal stores. Less well understood are the mechanisms involved in Ca2+ mobilization from internal stores after activation of Ca2+ influx. The mobilization process is known as calcium-induced calcium release (CICR). In this study, our goal was to investigate the existence of and the role of caffeine-sensitive ryanodine receptors (RyRs) in a rat pancreatic β-cell line, INS-1 cells. To measure cytosolic and stored Ca2+, respectively, cultured INS-1 cells were loaded with fura-2/AM or furaptra/AM. [Ca2+]i was repetitively increased by caffeine stimulation in normal Ca2+ buffer. However, peak [Ca2+]i was only observed after the first caffeine stimulation in Ca2+ free buffer and this increase was markedly blocked by ruthenium red, a RyR blocker. KCl-induced elevations in [Ca2+]i were reduced by pretreatment with ruthenium red, as well as by depletion of internal Ca2+ stores using cyclopiazonic acid (CPA) or caffeine. Caffeine-induced Ca2+ mobilization ceased after the internal stores were depleted by carbamylcholine (CCh) or CPA. In permeabilized INS-1 cells, Ca2+ release from internal stores was activated by caffeine, Ca2+, or ryanodine. Furthermore, ruthenium red completely blocked the CICR response in permeabilized cells. RyRs were widely distributed throughout the intracellular compartment of INS-1 cells. These results suggest that caffeine-sensitive RyRs exist and modulate the CICR response from internal stores in INS-1 pancreatic β-cells.
INS-1; Caffeine; Ryanodine; Calcium release; CICR
Immunophilins, including FK506-binding proteins (FKBPs), are protein chaperones with peptidyl-prolyl isomerase (PPIase) activity. Initially identified as pharmacological receptors for immunosuppressants to regulate immune responses via isomerase independent mechanisms, FKBPs are most highly expressed in the nervous system where their physiological function as isomerases remains unknown. We demonstrate that FKBP12 and FKBP52 catalyze cis/trans isomerization of regions of TRPC1 implicated in controlling channel opening. FKBP52 mediates stimulus-dependent TRPC1 gating through isomerization, which is required for chemotropic turning of neuronal growth cones to netrin-1 and myelin-associated glycoprotein and for netrin-1/DCC-dependent midline axon guidance of commissural interneurons in the developing spinal cord. By contrast, FKBP12 mediates spontaneous opening of TRPC1 through isomerization and is not required for growth cone responses to netrin-1. Our study demonstrates a novel physiological function of proline isomerases in chemotropic nerve guidance through TRPC1 gating and may have significant implication in clinical applications of immunophilin-related therapeutic drugs.
Oxidative stress induced by chronic hyperglycemia in type 2 diabetes plays a crucial role in progressive loss of β-cell mass through β-cell apoptosis. Glucagon like peptide-1 (GLP-1) has effects on preservation of β-cell mass and its insulin secretory function. GLP-1 possibly increases islet cell mass through stimulated proliferation from β-cell and differentiation to β-cell from progenitor cells. Also, it probably has an antiapoptotic effect on β-cell, but detailed mechanisms are not proven. Therefore, we examined the protective mechanism of GLP-1 in β-cell after induction of oxidative stress. The cell apoptosis decreased to ~50% when cells were treated with 100 µM H2O2 for up to 2 hr. After pretreatment of Ex-4, GLP-1 receptor agonist, flow cytometric analysis shows 41.7% reduction of β-cell apoptosis. This data suggested that pretreatment of Ex-4 protect from oxidative stress-induced apoptosis. Also, Ex-4 treatment decreased GSK3β activation, JNK phosphorylation and caspase-9, -3 activation and recovered the expression of insulin2 mRNA in β-cell lines and secretion of insulin in human islet. These results suggest that Ex-4 may protect β-cell apoptosis by blocking the JNK and GSK3β mediated apoptotic pathway.
Apoptosis; Exendin-4; Glucagon-Like Peptide 1; Oxidative Stress; Insulin-Secreting Cells