Inactivation of L-type calcium channels is determined by the length of the N terminus of mutant beta(1) subunits.

Voltage-dependent calcium channel (Ca(v)) pores are modulated by cytosolic beta subunits. Four beta-subunit genes and their splice variants offer a wide structural array for tissue- or disease-specific biophysical gating phenotypes. For instance, the length of the N terminus of beta(2) subunits has major effects on activation and inactivation rates. We tested whether a similar mechanism principally operates in a beta(1) subunit. Wild-type beta(1a) subunit (N terminus length 60 aa) and its newly generated N-terminal deletion mutants (51, 27 and 18 aa) were examined within recombinant L-type calcium channel complexes (Ca(v)1.2 and alpha(2)delta2) in HEK293 cells at the whole-cell and single-channel level. Whole-cell currents were enhanced by co-transfection of the full-length beta(1a) subunit and by all truncated constructs. Voltage dependence of steady-state activation and inactivation did not depend on N terminus length, but inactivation rate was diminished by N terminus truncation. This was confirmed at the single-channel level, using ensemble average currents. Additionally, gating properties were estimated by Markov modeling. In confirmation of the descriptive analysis, inactivation rate, but none of the other transition rates, was reduced by shortening of the beta(1a) subunit N terminus. Our study shows that the length-dependent mechanism of modulating inactivation kinetics of beta(2) calcium channel subunits can be confirmed and extended to the beta(1) calcium channel subunit.

Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV.

The prognostic relevance of additional cytogenetic findings at diagnosis of chronic myeloid leukemia (CML) is unclear. The impact of additional cytogenetic findings at diagnosis on time to complete cytogenetic (CCR) and major molecular remission (MMR) and progression-free (PFS) and overall survival (OS) was analyzed using data from 1151 Philadelphia chromosome-positive (Ph(+)) CML patients randomized to the German CML Study IV. At diagnosis, 1003 of 1151 patients (87%) had standard t(9;22)(q34;q11) only, 69 patients (6.0%) had variant t(v;22), and 79 (6.9%) additional cytogenetic aberrations (ACAs). Of these, 38 patients (3.3%) lacked the Y chromosome (-Y) and 41 patients (3.6%) had ACAs except -Y; 16 of these (1.4%) were major route (second Philadelphia [Ph] chromosome, trisomy 8, isochromosome 17q, or trisomy 19) and 25 minor route (all other) ACAs. After a median observation time of 5.3 years for patients with t(9;22), t(v;22), -Y, minor- and major-route ACAs, the 5-year PFS was 90%, 81%, 88%, 96%, and 50%, and the 5-year OS was 92%, 87%, 91%, 96%, and 53%, respectively. In patients with major-route ACAs, the times to CCR and MMR were longer and PFS and OS were shorter (P < .001) than in patients with standard t(9;22). We conclude that major-route ACAs at diagnosis are associated with a negative impact on survival and signify progression to the accelerated phase and blast crisis.

A comprehensive analysis of gene expression profiles in distal parts of the mouse renal tubule.

The distal parts of the renal tubule play a critical role in maintaining homeostasis of extracellular fluids. In this review, we present an in-depth analysis of microarray-based gene expression profiles available for microdissected mouse distal nephron segments, i.e., the distal convoluted tubule (DCT) and the connecting tubule (CNT), and for the cortical portion of the collecting duct (CCD; Zuber et al., Proc Natl Acad Sci USA 106:16523-16528, 2009). Classification of expressed transcripts in 14 major functional gene categories demonstrated that all principal proteins involved in maintaining the salt and water balance are represented by highly abundant transcripts. However, a significant number of transcripts belonging, for instance, to categories of G-protein-coupled receptors or serine/threonine kinases exhibit high expression levels but remain unassigned to a specific renal function. We also established a list of genes differentially expressed between the DCT/CNT and the CCD. This list is enriched by genes related to segment-specific transport functions and by transcription factors directing the development of the distal nephron or collecting ducts. Collectively, this in silico analysis provides comprehensive information about relative abundance and tissue specificity of the DCT/CNT and the CCD expressed transcripts and identifies new candidate genes for renal homeostasis.

Sukkamateriaalien vaikutukset jalkaterien ihon kosteuteen ja varvasvälihautumiin

Tutkimuksen tarkoituksena oli selvittää miten erilaiset sukat ja sukkamateriaalit vaikuttavat jalkaterien ihon kosteuteen ja ihomuutoksiin sekä selvittää varusmiesten omahoitotottumuksia ja jalkojen kuntoa. Tutkimus toteutettiin Helsingissä Kaartin jääkärirykmentissä 24.4. - 20.6.2006 ja siihen osallistui 20 aliupseerikurssia suorittavaa varusmiestä. 10 varusmiestä käytti Oy Feelmax Ltd:n Charcoal-varvassukkia ja 10 armeijan perusurheilusukkia kuukauden ajan. Tutkimusstrategia oli kvantitatiivinen ja tiedonhankintamenetelminä olivat strukturoidut ja sekamuotoiset kyselylomakkeet, jalkaterien kliininen tutkimus sekä elektronisilla ihon kosteusmittareilla tapahtuvat kosteusmittaukset. Tulokset esitettiin frekvensseinä ja prosenttiosuuksina. Feelmax- varvassukkia käyttänyt ryhmä tunsi koko tutkimuksen ajan jalkateränsä kuivemmiksi kuin armeijan sukkia käyttäneet. Ryhmien välillä ei ihon kosteudessa mittareilla mitattuna ollut eroa. Molemmilla ryhmillä kosteuden määrä iholla väheni sukkien vaihtovälin tihentyessä. Varvassukkia käyttäneillä oli huomattavasti vähemmän varvasvälihautumia (38 kpl) kuin tavallisia sukkia käyttäneillä (126 kpl). Tutkittavilla oli paljon hiertymiä, koska suurimmalla osalla oli liian suuret kengät. Tutkimusryhmien omahoitotietoudessa oli paljon puutteita ja kaikilla tutkittavilla oli jalkaongelmia. Tulosten perusteella sukkien valinnalla on merkitystä jalkaterien ihon kosteuteen ja ihon kuntoon. Lisäksi varusmiehet tarvitsevat lisätietoa esimerkiksi jalkojen omahoitoluentojen muodossa. Näin vältytään epätoivottujen ja turhien jalkaongelmien leviämiseltä. Oy Feelmax Ltd voi hyödyntää tämän tutkimuksen tutkimustuloksia kehittäessään varvassukkia ja kohdentaa niitä tehokkaammin erilaisille käyttäjäryhmille. Tutkimuksesta saatujen tietojen perusteella Suomen Puolustusvoimat voi kehittää sukkia, kenkiä, varusmiesten jalkojen omahoidon opetusta ja ohjausta, infektioiden torjuntaa ja parantaa näin varusmiesten toimintakykyä ja -valmiutta. Tulokset eivät ole tilastollisesti merkitseviä, joten aihe vaatii lisätutkimuksia suuremmalla tutkimusjoukolla.

Special investigation of the Washington Community School District for the period June 1, 2003 through October 31, 2006

Special investigation of the Washington Community School District for the period June 1, 2003 through October 31, 2006

The SLC2 family of facilitated hexose and polyol transporters.

The SLC2 family of glucose and polyol transporters comprises 13 members, the glucose transporters (GLUT) 1-12 and the H(+)- myo-inositol cotransporter (HMIT). These proteins all contain 12 transmembrane domains with both the amino and carboxy-terminal ends located on the cytoplasmic side of the plasma membrane and a N-linked oligosaccharide side-chain located either on the first or fifth extracellular loop. Based on sequence comparison, the GLUT isoforms can be grouped into three classes: class I comprises GLUT1-4; class II, GLUT6, 8, 10, and 12 and class III, GLUT5, 7, 9, 11 and HMIT. Despite their sequence similarity and the presence of class-specific signature sequences, these transporters carry various hexoses and HMIT is a H(+)/ myo-inositol co-transporter. Furthermore, the substrate transported by some isoforms has not yet been identified. Tissue- and cell-specific expression of the well-characterized GLUT isoforms underlies their specific role in the control of whole-body glucose homeostasis. Numerous studies with transgenic or knockout mice indeed support an important role for these transporters in the control of glucose utilization, glucose storage and glucose sensing. Much remains to be learned about the transport functions of the recently discovered isoforms (GLUT6-13 and HMIT) and their physiological role in the metabolism of glucose, myo-inositol and perhaps other substrates.

Iowa Department of Veterans Affairs, Strategic Plan, 2006-2010

This report outlines the strategic plan for Iowa Department of Veterans Affairs, goals and mission.

Mineralocorticoid receptor is essential for corticosteroid-induced up-regulation of L-type calcium currents in cultured neonatal cardiomyocytes.

Despite the fact that mineralocorticoid receptor (MR) antagonist drugs such as spironolactone and eplerenone reduce the mortality in heart failure patients, there is, thus far, no unambiguous demonstration of a functional role of MR in cardiac cells. The aim of this work was to investigate the activation pathway(s) mediating corticosteroid-induced up-regulation of cardiac calcium current (ICa). In this study, using neonatal cardiomyocytes from MR or glucocorticoid receptor (GR) knockout (KO) mice, we show that MR is essential for corticosteroid-induced up-regulation of ICa. This study provides the first direct and unequivocal evidence for MR function in the heart.

Om det, som bör i achttagas, wid en stads anlägning

Julkaistu: Åbo : tryckt, hos directeruren och kongl. boktr. i Stor. förstendömet Finland, Jacob Merckell , [1753]

Alkuperäisen ulkoasutiedot: [1-2] 3-40 s. ; 4:o

Omistushistoria: Hh: A. R. Cederberg; H Reenpää: Ex libris Heikki Reenpää 1971

Furosemide stimulation of parathormone in humans: role of the calcium-sensing receptor and the renin-angiotensin system

Les interactions entre les systèmes de régulation du sodium et du calcium sont encore mal comprises et leur importance clinique mérite d'être étudiée plus en détail. Les études chez l'animal ont montré qu'il existe des relations entre le taux plasmatique d'hormone parathyroïdienne (PTH) et l'aldostérone ou l'activité de la rénine. Par ailleurs, il a été démontré chez l'animal et chez l'homme que le taux sanguin de PTH augmente rapidement après une injection de furosémide, un diurétique de l'anse ce qui fait penser qu'il existe un lien entre l'effet du furosémide sur le rein et la sécrétion de PTH. Toutefois, à ce jour, le(s) mécanisme(s) impliqués dans ce lien reste(nt) encore inconnu(s). Des résultats plus récents suggèrent que l'effet du furosemide est amoindri par l'administration préalable d'un calcimimétique agissant au niveau du récepteur sensible au calcium (calcium sensing receptor). Pour explorer chez l'homme, les mécanismes possibles du lien entre PTH et effet du furosemide sur le rein, nous avons planifié une étude randomisée croisée contre placebo réalisée chez 18 volontaires sains masculins. Le but principal était d'investiguer le rôle du système rénine-angiotensine et des calcium sensing receptors. L'étude s'est donc réalisée en 2 phases pour chaque sujet. Les participants ont ainsi reçu soit du cinacalcet (60mg) soit un placebo dans une première phase et le placebo ou du cinacalcet dans la 2° phase. Dans chaque phase d'évaluation, une injection de 20 mg de furosemide a été administrée par voie intraveineuse à l'équilibre soit 3 heures après la prise du placebo ou du cinacalcet. Des échantillons de plasma ont été prélevés toutes les 15 minutes pendant 1 heure puis toutes les heures pour le dosage de PTH intacte, calcium, sodium, potassium, magnésium, phosphate, activité de la rénine plasmatique et aldostérone jusqu'à 6h après l'injection de furosémide. L'excrétion urinaire de ces mêmes électrolytes a été mesurée aux mêmes intervalles.