Phorbol ester impairs electrical excitation of rat pancreatic beta-cells through PKC-independent activation of K(ATP) channels

BACKGROUND: Phorbol 12-myristate 13-acetate (PMA) is often used as an activating phorbol ester of protein kinase C (PKC) to investigate the roles of the kinase in cellular functions. Accumulating lines of evidence indicate that in addition to activating PKC, PMA also produces some regulatory effects in a PKC-independent manner. In this study, we investigated the non-PKC effects of PMA on electrical excitability of rat pancreatic β-cells by using patch-clamp techniques. RESULTS: In current-clamp recording, PMA (80 nM) reversibly inhibited 15 mM glucose-induced action potential spikes superimposed on a slow membrane depolarization and this inhibition can not be prevented by pre-treatment of the cell with a specific PKC inhibitor, bisindolylmaleimide (BIM, 1 μM). In the presence of a subthreshold concentration (5.5 mM) of glucose, PMA hyperpolarized β-cells in a concentration-dependent manner (0.8–240 nM), even in the presence of BIM. Based on cell-attached single channel recordings, PMA increased ATP-sensitive K(+) channel (K(ATP)) activity. Based on inside-out patch-clamp recordings, PMA had little effect on K(ATP) activity if no ATP was in the bath, while PMA restored K(ATP) activity that was suppressed by 10 μM ATP in the bath. In voltage-clamp recording, PMA enhanced tolbutamide-sensitive membrane currents elicited by repetitive ramp pulses from -90 to -50 mV in a concentration-dependent manner, and this potentiation could not be prevented by pre-treatment of cell with BIM. 4α-phorbol 12,13-didecanoate (4α-PDD), a non-PKC-activating phorbol ester, mimicked the effect of PMA on both current-clamp and voltage-clamp recording configurations. With either 5.5 or 16.6 mM glucose in the extracellular solution, PMA (80 nM) increased insulin secretion from rat islets. However, in islets pretreated with BIM (1 μM), PMA did not increase, but rather reduced insulin secretion. CONCLUSION: In rat pancreatic β-cells, PMA modulates insulin secretion through a mixed mechanism: increases insulin secretion by activation of PKC, and meanwhile decrease insulin secretion by impairing β-cell excitability in a PKC-independent manner. The enhancement of K(ATP) activity by reducing sensitivity of K(ATP) to ATP seems to underlie the PMA-induced impairment of β-cells electrical excitation in response to glucose stimulation

Bone morphogenetic protein-2 functions as a negative regulator in the differentiation of myoblasts, but not as an inducer for the formations of cartilage and bone in mouse embryonic tongue

<p>Abstract</p> <p>Background</p> <p>In vitro studies using the myogenic cell line C2C12 demonstrate that bone morphogenetic protein-2 (BMP-2) converts the developmental pathway of C2C12 from a myogenic cell lineage to an osteoblastic cell lineage. Further, in vivo studies using null mutation mice demonstrate that BMPs inhibit the specification of the developmental fate of myogenic progenitor cells. However, the roles of BMPs in the phases of differentiation and maturation in skeletal muscles have yet to be determined. The present study attempts to define the function of BMP-2 in the final stage of differentiation of mouse tongue myoblast.</p> <p>Results</p> <p>Recombinant BMP-2 inhibited the expressions of markers for the differentiation of skeletal muscle cells, such as myogenin, muscle creatine kinase (MCK), and fast myosin heavy chain (fMyHC), whereas BMP-2 siRNA stimulated such markers. Neither the recombinant BMP-2 nor BMP-2 siRNA altered the expressions of markers for the formation of cartilage and bone, such as osteocalcin, alkaline phosphatase (ALP), collagen II, and collagen X. Further, no formation of cartilage and bone was observed in the recombinant BMP-2-treated tongues based on Alizarin red and Alcian blue stainings. Neither recombinant BMP-2 nor BMP-2 siRNA affected the expression of inhibitor of DNA binding/differentiation 1 (Id1). The ratios of chondrogenic and osteogenic markers relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH, a house keeping gene) were approximately 1000-fold lower than those of myogenic markers in the cultured tongue.</p> <p>Conclusions</p> <p>BMP-2 functions as a negative regulator for the final differentiation of tongue myoblasts, but not as an inducer for the formation of cartilage and bone in cultured tongue, probably because the genes related to myogenesis are in an activation mode, while the genes related to chondrogenesis and osteogenesis are in a silencing mode.</p

Monivammapotilaan kivunhoito

Tämän opinnäytetyön tarkoituksena oli kartoittaa monivammapotilaan kivunhoitoa ennen sairaalaan tuloa, sairaalassa ja kotona systemaattista kirjallisuuskatsausta soveltaen. Tavoitteena on edistää monivammapotilaan kivunhoitoa. Opinnäytetyöhön valikoitui analysoitavaksi 38 (=n) julkaisua. Monivammapotilaan kivunhoito vaatii moniammatillista osaamista ja yhteistyötä. Kivunhoidon oleellisena osana on kivun arviointi. Kipua voidaan arvioida erilaisin mittarein, kuten sanallinen asteikko (VRS), numeroasteikko (NRS) ja visuaalianalogiasteikko (VAS). Potilaan ollessa tajuton, kivunarviointi muuttuu haasteellisemmaksi, sillä silloin mittareita ei voida käyttää. Monivammapotilaan kipua hoidetaan pääsääntöisesti lääkkeillä. Keskeisimpiä lääkkeitä ovat tulehduskipulääkkeet, parasetamoli ja opioidit. Lääkkeettömiä kivunhoitomuotoja kuten asentohoito, fysikaaliset hoitomuodot, hengitysharjoitukset, musiikin kuuntelu, rentoutumis- ja mielikuvaharjoitukset, käytetään myös, mutta ne ovat tehokkaampia yhdistettynä lääkkeelliseen kivunhoitoon. Lääkehoito koostuu monen lääkeryhmän yhdistelmistä eli multimodaalisesta kivunhoidosta. Puudutteet ovat keskeinen osa monivammapotilaan kivunhoitoa, sillä ne vähentävät huomattavasti opioidien käyttöä. Kivunhoito on tasapainoilua potilaan kivuttomuuden ja kivunhoidon haittavaikutuksien välillä. Potilaan kivunhoito jatkuu koko hoidon ajan, myös kotiutumisen jälkeen. Kivunhoito on potilaan oikeus eikä ole olemassa mitään pätevää syytä jättää kipua hoitamatta. Monivammapotilaat ovat todella kivuliaita, joten kivun hoidon tutkiminen ja kehittäminen on tärkeää. Tehokkaalla kivunhoidolla voidaan ehkäistä kivun kroonistumista.The purpose of this thesis is to improve multi-trauma patients pain management before coming to a hospital, in hospital and at home by using a systematic literature review. The aim is to improve multi-trauma patient’s pain management. There was 38(=n) publications chosen for this thesis. The pain management of a multi-trauma patient requires multi-professional expertise and cooperation. An essential part of pain management is assessment of pain. The pain can be assessed with different kind of rating scales for example verbal rating scale (VRS), numeric rating scale (NRS) and visual analog scale (VAS). When patient is being unconscious assessment of pain becomes challenging so the rating scales cannot be used. The pain of a multi-trauma patient is mainly managed with medicine. The most common medicines are inflammatory drugs, paracetamol and opioids. Drug-free pain management formats such as position management, physical therapies, breathing exercises, listening to music, relaxing and imagination exercises are used but they are more effective combined with medicinal pain management. Medication consist of the combination of different drug groups called multimodal pain management. Regional anesthetics are a key part of the pain management of a multi-trauma patient because regional anesthetics reduce remarkably the use of opioids. Pain management is balancing between painless and side effects pain management. The pain management of the patient goes through the whole care also after discharging from hospital. Pain management is the patients right and there is no competent reason to not treat the pain. Multi-trauma patients are in a high amount of pain so the study and development of pain management is really important. With efficient pain management you can anticipate chronical pain

A Statistical Study of Gamma-Ray Emitting Solar Flares Observed with Yohkoh

Gamma-ray emitting solar flares observed with Yohkoh were analyzed from a statistical viewpoint. The four-band hard X-ray (15--95 keV) photometric data, taken with the Hard X-ray Telescope onboard Yohkoh, were utilized in combination with the spectro-photometric gamma-ray (0.2--30 MeV) data obtained with the Gamma-Ray Spectrometer. The GOES class was also incorporated. Out of 2788 X-ray flares observed from 1991 October to 2001 December, 178 events with strong hard X-ray emission were selected. Among them, 40 flares were further found to show significant gamma-ray emission. A fractal dimension analysis and multi-band color--color plots of the 40 flares suggest that their soft X-ray to MeV gamma-ray spectral energy distributions involve at least four independent parameters. These are: (1) the overall flare size; (2) the relative intensities of the thermal vs. non-thermal signals; (3) the gamma-ray to hard X-ray intensity ratio; and (4) the hard X-ray spectral slope. These results are examined for possible selection effects. Also, the meanings of the third parameter are briefly considered.Comment: 23 pages, 7 figures, PASJ accepte

Criterion and Construct Validity of the CogState Schizophrenia Battery in Japanese Patients with Schizophrenia

BACKGROUND: The CogState Schizophrenia Battery (CSB), a computerized cognitive battery, covers all the same cognitive domains as the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery but is briefer to conduct. The aim of the present study was to evaluate the criterion and construct validity of the Japanese language version of the CSB (CSB-J) in Japanese patients with schizophrenia. METHODOLOGY/PRINCIPAL FINDINGS: Forty Japanese patients with schizophrenia and 40 Japanese healthy controls with matching age, gender, and premorbid intelligence quotient were enrolled. The CSB-J and the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J) were performed once. The structure of the CSB-J was also evaluated by a factor analysis. Similar to the BACS-J, the CSB-J was sensitive to cognitive impairment in Japanese patients with schizophrenia. Furthermore, there was a significant positive correlation between the CSB-J composite score and the BACS-J composite score. A factor analysis showed a three-factor model consisting of memory, speed, and social cognition factors. CONCLUSIONS/SIGNIFICANCE: This study suggests that the CSB-J is a useful and rapid automatically administered computerized battery for assessing broad cognitive domains in Japanese patients with schizophrenia

SORL1 Is Genetically Associated with Late-Onset Alzheimer’s Disease in Japanese, Koreans and Caucasians

To discover susceptibility genes of late-onset Alzheimer’s disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values ,261025 were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P=7.3361027 in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P=1.7761029) and rs3781834 (P=1.0461028). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P=1.7161025) and rs744373 near BIN1 (P = 1.3961024). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations