Tissue Distribution of Kir7.1 Inwardly Rectifying K Channel Probed in a Knock-in Mouse Expressing a Haemagglutinin-Tagged Protein.

Kir7.1 encoded by the gene in the mouse is an inwardly rectifying K channel present in epithelia where it shares membrane localization with the Na/K-pump. Further investigations of the localisation and function of Kir7.

Molecular Monitoring after Autologous Stem Cell Transplantation and Preemptive Rituximab Treatment of Molecular Relapse; Results from the Nordic Mantle Cell Lymphoma Studies (MCL2 and MCL3) with Median Follow-Up of 8.5 Years.

The main objectives of the present study were to monitor minimal residual disease (MRD) in the bone marrow of patients with mantle cell lymphoma (MCL) to predict clinical relapse and guide preemptive treatment with rituximab. Among the patients enrolled in 2 prospective trials by the Nordic Lymphoma Group, 183 who had completed autologous stem cell transplantation (ASCT) and in whom an MRD marker had been obtained were included in our analysis. Fresh samples of bone marrow were analyzed for MRD by a combined standard nested and quantitative real-time PCR assay for Bcl-1/immunoglobulin heavy chain gene (IgH) and clonal IgH rearrangements.

Uterine, but not ovarian, female reproductive organ involvement at presentation by diffuse large B-cell lymphoma is associated with poor outcomes and a high frequency of secondary CNS involvement.

Involvement of the internal female reproductive organs by diffuse large B-cell lymphoma (DLBCL) is uncommon, and there are sparse data describing the outcomes of such cases. In total, 678 female patients with DLBCL staged with positron emission tomography/computed tomography and treated with rituximab-containing chemotherapy were identified from databases in Denmark, Great Britain, Australia, and Canada. Overall, 27/678 (4%) had internal reproductive organ involvement: uterus (n = 14), ovaries (n = 10) or both (n = 3).

Nanomedicine: a pharma perspective.

Nanotechnology as applied to medicine is not a new field. The first nanomedicines approved for use were developed from research dating back to the 1970s. These liposomal formulations of existing drugs showed improved therapeutic activity and reduced toxicity in the nonclinical model systems.

Phase 1 dose-escalation study of the PARP inhibitor CEP-9722 as monotherapy or in combination with temozolomide in patients with solid tumors.

Purpose: Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme important in DNA repair. PARP-1 activation at points of DNA strand break results in poly(ADP-ribose) polymer formation, opening the DNA structure, and allowing access of other repair enzymes. CEP-9722 inhibits PARP-1 and PARP-2 and is designed to potentiate DNA-damaging chemotherapies.

Effects of octane derivatives on activity of the volume-regulated anion channel in rat pancreatic β-cells.

Background: Saturated free fatty acids (FFAs) have a dual action on pancreatic β-cells, consisting of an initial enhancement and subsequent suppression of glucose-induced electrical activity and insulin release. These stimulatory and inhibitory effects have been attributed, at least in part, to the activation and inhibition, respectively, of the volume-regulated anion channel (VRAC) by FFAs. Both effects were independent of their metabolism.

Cerebrospinal fluid secretion by the choroid plexus.

The choroid plexus epithelium is a cuboidal cell monolayer, which produces the majority of the cerebrospinal fluid. The concerted action of a variety of integral membrane proteins mediates the transepithelial movement of solutes and water across the epithelium. Secretion by the choroid plexus is characterized by an extremely high rate and by the unusual cellular polarization of well-known epithelial transport proteins.

Higher World Health Organization grades of follicular lymphoma correlate with better outcome in two Nordic Lymphoma Group trials of rituximab without chemotherapy.

Abstract A common treatment for follicular lymphoma is rituximab monotherapy. To identify patients for whom this regimen is adequate as first-line therapy, we applied the World Health Organization (WHO) classification for grading follicular lymphoma in a prospective central pathology review of the biopsies of previously untreated patients in two randomized trials of rituximab without chemotherapy. In the first trial (n₁ = 53), higher WHO grades correlated with longer time to next treatment, independently of clinical prognostic factors (p = 0.

A novel surface electrocardiogram-based marker of ventricular arrhythmia risk in patients with ischemic cardiomyopathy.

Background: Better sudden cardiac death risk markers are needed in ischemic cardiomyopathy (ICM). Increased heterogeneity of electrical restitution is an important mechanism underlying the risk of ventricular arrhythmia (VA). Our aim was to develop and test a novel quantitative surface electrocardiogram-based measure of VA risk in patients with ICM: the Regional Restitution Instability Index (R2I2).

The glucokinase activator GKA50 causes an increase in cell volume and activation of volume-regulated anion channels in rat pancreatic β-cells.

Glucokinase plays a key role in the metabolism of glucose by pancreatic β-cells. In this study the effects of the glucokinase activator GKA50 on cell volume and electrical activity in rat β-cells were examined. One micro molar GKA50 caused an increase in β-cell volume in the presence of 4mM glucose.

Functional characterization of bestrophin-1 missense mutations associated with autosomal recessive bestrophinopathy.

Purpose: Autosomal recessive bestrophinopathy (ARB) is a retinal dystrophy affecting macular and retinal pigmented epithelium function resulting from homozygous or compound heterozygous mutations in BEST1. In this study we characterize the functional implications of missense bestrophin-1 mutations that cause ARB by investigating their effect on bestrophin-1's chloride conductance, cellular localization, and stability.

Methods: The chloride conductance of wild-type bestropin-1 and a series of ARB mutants were determined by whole-cell patch-clamping of transiently transfected HEK cells.

Electrical activity in pancreatic islet cells: The VRAC hypothesis.

A major aspect of stimulation of β-cell function by glucose is the induction of electrical activity. The ionic events that underlie β-cell electrical activity are understood in some detail. At sub-stimulatory glucose concentrations, the β-cell is electrically 'silent'.

Epithelial pathways in choroid plexus electrolyte transport.

A stable intraventricular milieu is crucial for maintaining normal neuronal function. The choroid plexus epithelium produces the cerebrospinal fluid and in doing so influences the chemical composition of the interstitial fluid of the brain. Here, we review the molecular pathways involved in transport of the electrolytes Na+, K+, Cl-, and HCO3(-)across the choroid plexus epithelium.

Regulatory volume increase in epithelial cells isolated from the mouse fourth ventricle choroid plexus involves Na(+)-H(+) exchange but not Na(+)-K(+)-2Cl(-) cotransport.

The aim of this study was to determine the ability of choroid plexus epithelial cells to volume regulate when exposed to hypertonic solutions, and furthermore to identify the ion transporters involved in any volume regulation. Experiments were performed on cells freshly isolated, using the enzyme dispase, from the mouse fourth ventricle choroid plexus. Cell volume was measured using a video-imaging method.

Opposing effects of tenidap on the volume-regulated anion channel and K(ATP) channel activity in rat pancreatic beta-cells.

Tenidap (5-chloro-2-hydroxy-3-(thiophene-2-carbonyl)indole-1-carboxamide) is a non-steroidal anti-inflammatory and anti-rheumatic drug with several cellular actions including inhibition of anion transport processes. Since other anion transport inhibitors have been shown to inhibit activity of the volume-regulated anion channel (VRAC), the present study investigated the effects of tenidap on activity of this channel in pancreatic beta-cells. Membrane potential, VRAC currents and input conductance were recorded from single rat beta-cells in primary culture using perforated patch, conventional whole-cell and cell-attached configurations of the patch-clamp technique.

Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa.

Bestrophin-1 is preferentially expressed at the basolateral membrane of the retinal pigmented epithelium (RPE) of the retina. Mutations in the BEST1 gene cause the retinal dystrophies vitelliform macular dystrophy, autosomal-dominant vitreochoroidopathy, and autosomal-recessive bestrophinopathy. Here, we describe four missense mutations in bestrophin-1, three that we believe are previously unreported, in patients diagnosed with autosomal-dominant and -recessive forms of retinitis pigmentosa (RP).

Studies of the mechanism of activation of the volume-regulated anion channel in rat pancreatic beta-cells.

There is evidence that depolarization of the pancreatic beta cell by glucose involves cell swelling and activation of the volume-regulated anion channel (VRAC). However, it is unclear whether cell swelling per se or accompanying changes in intracellular osmolality and/or ionic strength are responsible for VRAC activation. VRAC activity was measured in rat beta cells by conventional or perforated patch whole-cell recording.

Contrasting effects of glycerol and urea transport on rat pancreatic beta-cell function.

Background/aims: Pancreatic beta-cell function is influenced by changes in cell volume. Such volume changes depend on water permeability of the plasma membrane, conferred in part by aquaporins. Islet cells express aquaporin 7 (AQP7), which is permeable to urea and glycerol in addition to water.

HCO 3--dependent volume regulation in alpha-cells of the rat endocrine pancreas.

Ion transport activity in pancreatic alpha-cells was assessed by studying cell volume regulation in response to anisotonic solutions. Cell volume was measured by a video imaging method, and cells were superfused with either 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid-buffered or HCO(3)(-) -buffered solutions. alpha-Cells did not exhibit a regulatory volume increase (RVI) in response to cell shrinkage caused by hypertonic solutions.

NBCe2 exhibits a 3 HCO3(-):1 Na+ stoichiometry in mouse choroid plexus epithelial cells.

The transport stoichiometry of the electrogenic sodium-bicarbonate cotransporter (SLC4A5 or NBCe2) in mouse choroid plexus was examined. Whole-cell recording methods measured the currents carried by the NBCe2, using experimental solutions determined to minimise the contributions of the other ion conductances present. Increases in outward current were observed when 21.

Biallelic mutation of BEST1 causes a distinct retinopathy in humans.

We describe a distinct retinal disorder, autosomal-recessive bestrophinopathy (ARB), that is consequent upon biallelic mutation in BEST1 and is associated with central visual loss, a characteristic retinopathy, an absent electro-oculogram light rise, and a reduced electroretinogram. Heterozygous mutations in BEST1 have previously been found to cause the two dominantly inherited disorders, Best macular dystrophy and autosomal-dominant vitreoretinochoroidopathy. The transmembrane protein bestrophin-1, encoded by BEST1, is located at the basolateral membrane of the retinal pigment epithelium in which it probably functions as a Cl(-) channel.

Kv1 and Kir2 potassium channels are expressed in rat brain endothelial cells.

The endothelial cells of the brain microvasculature, which constitute the blood-brain barrier, secrete K+ into brain interstitial fluid. K+ channels are predicted to have a central role to play in this process. The aim of the following study was to characterise K+ channels in primary cultures of endothelial cells isolated from rat brain microvessels by whole-cell patch clamp and real-time polymerase chain reaction.