The Ca2+-gated channel TMEM16A amplifies capillary pericyte contraction and reduces cerebral blood flow after ischemia

Pericyte-mediated capillary constriction decreases cerebral blood flow in stroke after an occluded artery is unblocked. The determinants of pericyte tone are poorly understood. We show that a small rise in cytoplasmic Ca²⁺ concentration ([Ca²⁺]_i) in pericytes activated chloride efflux through the Ca²⁺-gated anion channel TMEM16A, thus depolarizing the cell and opening voltage-gated calcium channels. This mechanism strongly amplified the pericyte [Ca²⁺]_i rise and capillary constriction evoked by contractile agonists and ischemia. In a rodent stroke model, TMEM16A inhibition slowed the ischemia-evoked pericyte [Ca²⁺]_i rise, capillary constriction, and pericyte death; reduced neutrophil stalling; and improved cerebrovascular reperfusion. Genetic analysis implicated altered TMEM16A expression in poor patient recovery from ischemic stroke. Thus, pericyte TMEM16A is a crucial regulator of cerebral capillary function and a potential therapeutic target for stroke and possibly other disorders of impaired microvascular flow, such as Alzheimer’s disease and vascular dementia.     

The effect of socio-economic status and ethnicity on the comparative oral health of Asian and White Caucasian 12-year-old children

OBJECTIVE: To investigate the oral health of 12-year-old children of different deprivation but similar fluoridation status from South Asian and White Caucasian ethnic groups. DESIGN: An epidemiological survey of 12-year-old children using BASCD criteria, with additional tooth erosion, ethnic classification and postcode data. CLINICAL SETTING: Examinations were completed in schools in Leicestershire and Rutland, England, UK. Participants A random sample of 1,753 12-year-old children from all schools in the study area. MAIN OUTCOME MEASURES: Caries experience was measured using the DMFT index diagnosed at the caries into dentine (D3) threshold, and tooth erosion using the index employed in the Children's Dental Health UK study reported in 1993. RESULTS: The overall prevalence of caries was greater in White than Asian children, but varied at different levels of deprivation and amongst different Asian religious groups. There was a significant positive association between caries and deprivation for White children, but the reverse was true for non-Muslim Asians. White Low Deprivation children had significantly less tooth erosion, but erosion experience increased with decreasing deprivation in non-Muslim Asians. CONCLUSIONS: Oral health is associated with ethnicity and linked to deprivation on an ethnic basis. The intra-Asian dental health disadvantage found in the primary dentition of Muslim children is perpetuated into the permanent dentition.     

Orthodontic retention: why when and how?

Retention is normally required after active orthodontic tooth movement to hold the teeth in their new positions. This article reviews the principles of orthodontic retention and describes common retention regimes and appliances.     

Thrombospondin mediates the cytoadherence of Plasmodium falciparum- infected red cells to vascular endothelium in shear flow conditions

Cerebral malaria is thought to involve specific attachment of Plasmodium falciparum-infected knobby red cells to venular endothelium. The nature of surface ligands on host endothelial cells that may mediate cytoadherence is poorly understood. We have investigated the effects of soluble thrombospondin, rabbit antiserum raised against thrombospondin, and human immune serum on cytoadherence of parasitized erythrocytes in ex vivo mesocecum vasculature. Preincubation of infected red cells with soluble thrombospondin or human immune serum inhibits binding of infected red cells to rat venular endothelium. Infusion of the microcirculatory preparation with rabbit antithrombospondin antibodies before perfusion of parasitized erythrocytes also resulted in decreased cytoadherence. In addition, incubation of infected cells with human immune sera obtained from malaria patients significantly inhibited the observed cytoadherence. Our results indicate that thrombospondin mediates binding of infected red cells to venular endothelium and may thus be involved in the pathogenesis of cerebral malaria.     

Issues of Daily Living for Persons with Mental Illness

Abstract

The essential elements of well being and health include an adequate income from meaningful employment, healthful diet, comfortable and safe housing, and good health. Well being also includes being able to improve one's life through education and the building of good relationships. The absence of these elements is faced by people who have experienced mental illness, and thus, in addition to being challenged by the illness, they are also challenged by the social consequences which are the result of the absence of the elements of well being. This paper elaborates on these issues and the difficulties faced by people with mental illness. People who experience mental illness are challenged not only by their illness, but also by the social consequences, which follow or even exacerbate their illness. The impact of poverty, homelessness, inadequate and unsafe housing, low quality or no physical health care, and lack of or interrupted education and unemployment on the lives of mental health consumers/survivors is incalculable. These social consequences are the “side effects” which result from the inadequate system of care for persons with mental illness. This paper further expands upon these challenges of daily living for those who struggle with mental illness.     

Ex vivo expansion with stem cell factor and interleukin-11 augments both short-term recovery posttransplant and the ability to serially transplant marrow

The characterization of many cytokines involved in the control of hematopoiesis has led to intense investigation into their potential use in ex vivo culture to expand progenitor numbers. We have established the optimum ex vivo culture conditions that allow substantial amplification of transient engrafting murine stem cells and which, simultaneously, augment the ability to sustain serial bone marrow transplantation (BMT). Short-term incubation of unfractionated BM cells in liquid culture with stem cell factor (SCF) and interleukin-11 (IL- 11) produced a 50-fold amplification of clonogenic multipotential progenitors (CFU-A). Following such ex vivo expansion, substantially fewer cells were required to rescue lethally irradiated mice. When transplanted in cell doses above threshold for engraftment, BM cells expanded ex vivo resulted in significantly more rapid hematopoietic recovery. In a serial transplantation model, unmanipulated BM was only able to consistently sustain secondary BMT recipients, but BM expanded ex vivo has sustained quaternary BMT recipients that remain alive and well more than 140 days after 4th degree BMT. These results show augmentation of both short-term recovery posttransplant and the ability to serially transplant marrow by preincubation in culture with SCF and IL-11.     

Systemic hematologic effects of PEG-rHuMGDF-induced megakaryocyte hyperplasia in mice

PEG-rHuMGDF injected daily in normal mice causes a rapid dose-dependent increase in megakaryocytes and platelets. At the same time that platelet numbers are increased, the mean platelet volume (MPV) and platelet distribution width (PDW) can be either decreased, normal, or increased depending on the dose and time after administration. Thus, PEG-rHuMGDF at a low dose causes decreases in MPV and PDW, MGDF at an intermediate dose causes an initial increase followed by a decrease in MPV and PDW, and PEG-rHuMGDF at higher doses causes an increase in MPV and PDW followed by a gradual normalization of these platelet indices. In addition to the expected thrombocytosis after 7 to 10 days of daily injection of high doses of PEG-rHuMGDF, a transient decrease in peripheral red blood cell numbers and hemoglobin is noted accompanied in the bone marrow by megakaryocytic hyperplasia, myeloid hyperplasia, erythroid and lymphoid hypoplasia, and deposition of a fine network of reticulin fibers. Splenomegaly, an increase in splenic megakaryocytes, and extramedullary hematopoiesis accompany the hematologic changes in the peripheral blood and marrow to complete a spectrum of pathologic features similar to those reported in patients with myelofibrosis and megakaryocyte hyperplasia. However, all the PEG-rHuMGDF-initiated hematopathology including the increase in marrow reticulin is completely and rapidly reversible upon the cessation of administration of PEG-rHuMGDF. Thus, transient hyperplastic proliferation of megakaryocytes does not cause irreversible tissue injury. Furthermore, PEG-rHuMGDF completely ameliorates carboplatin-induced thrombocytopenia at a low-dose that does not cause the hematopathology associated with myelofibrosis.