Reaudit report on the City of St. Charles, Iowa for the period July 1, 2005 through June 30, 2006

Reaudit report on the City of St. Charles, Iowa for the period July 1, 2005 through June 30, 2006

Why human islets die? analysis of death signaling pathways during isolation and following cytokine treatments

RESUME Le diabète de type 1 se définit comme un désordre métabolique d'origine auto-immune qui aboutit à la destruction progressive et sélective de la cellule ß-pancréatique sécrétrice d'insuline. Cette maladie représente 10 % des cas de diabète enregistrés dans la population mondiale, et touche les jeunes de moins de 20 ans. Le traitement médical par insulinothérapie corrige le manque d'hormone mais ne prévient pas les nombreuses complications telles que les atteintes cardiaques, neurologiques, rénales, rétiniennes, et les amputations que la maladie provoque. Le remplacement de la cellule ß par transplantation d'îlots de Langerhans est une alternative prometteuse au traitement médical du diabète de type 1. Cependant la greffe d'îlots est encore un traitement expérimental et ne permet pas un contrôle efficace de la glycémie au long terme chez les patients transplantés, et les raisons de cet échec restent mal comprises. L'obstacle immédiat qui se pose est la purification d'un nombre suffisant d'îlots viables et la perte massive de ces îlots dans les premières heures suite à la greffe. Cette tendance presque systématique de la perte fonctionnelle du greffon immédiatement après la transplantation est connue sous le terme de « primary graft non-function » (PNF). En effet, la procédure d'isolement des îlots provoque la destruction des composantes cellulaires et non cellulaires du tissu pancréatique qui jouent un rôle déterminant dans le processus de survie de l'îlot. De plus, la transplantation elle-même expose les cellules à différents stress, notamment le stress par les cytokines inflammatoires qui encourage la mort cellulaire par apoptose et provoque par la suite le rejet de la greffe. L'ensemble de ces mécanismes aboutit a une perte de la masse d'îlot estimée a plus de 60%. Dans ce contexte, nous nous sommes intéressés à définir les voies majeures de stress qui régissent cette perte massive d'îlot par apoptose lors du processus d'isolement et suite à l'exposition immédiate aux cytokines. L'ensemble des résultats obtenus indique que plusieurs voies de signalisation intracellulaire sont recrutées qui s'activent de manière maximale très tôt lors des premières phases de l'isolement. La mise en culture des îlots deux jours permet aux voies activées de revenir aux taux de base. De ce fait nous proposons une stratégie dite de protection qui doit être 1) initiée aussitôt que possible lors de l'isolement des îlots pancréatiques, 2) devrait probablement bloquer l'activation de ces différentes voies de stress mis en évidence lors de notre étude et 3) devrait inclure la mise en culture des îlots purifiés deux jours après l'isolement et avant la transplantation. RESUME LARGE PUBLIC Le diabète est une maladie qui entraîne un taux anormalement élevé de sucre (glucose) dans le sang du à une insuffisance du pancréas endocrine à produire de l'insuline, une hormone qui régule la glycémie (taux de glucose dans le sang). On distingue deux types majeurs de diabètes; le diabète de type 1 ou juvénile ou encore appelé diabète maigre qui se manifeste souvent pendant l'enfance et qui se traduit par une déficience absolue en insuline. Le diabète de type 2 ou diabète gras est le plus fréquent, et touche les sujets de plus de 40 ans qui souffrent d'obésité et qui se traduit par une dysfonction de la cellule ß avec une incapacité à réguler la glycémie malgré la production d'insuline. Dans le diabète de type 1, la destruction de la cellule ß est programmée (apoptose) et est majoritairement provoquée par des médiateurs inflammatoires appelés cytokines qui sont produites localement par des cellules inflammatoires du système immunitaire qui envahissent la cellule ß-pancréatiques. Les cytokines activent différentes voies de signalisation parmi lesquelles on distingue celles des Mitogen-Activated Protein Kinase (MAPKs) composées de trois familles de MAPKs: ERK1/2, p38, et JNK, et la voie NF-κB. Le traitement médical par injections quotidiennes d'insuline permet de contrôler la glycémie mais ne prévient pas les nombreuses complications secondaires liées à cette maladie. La greffe d'îlots de Langerhans est une alternative possible au traitement médical, considérée avantageuse comparée a la greffe du pancréas entier. En effet l'embolisation d'îlots dans le foie par injection intraportale constitue une intervention simple sans complications majeures. Néanmoins la technique de préparation d'îlots altère la fonction endocrine et cause la perte massive d'îlots pancréatiques. De plus, la transplantation elle-même expose la cellule ß à différents stress, notamment le stress par les cytokines inflammatoires qui provoque le rejet de greffon cellulaire. Dans la perspective d'augmenter les rendements des îlots purifiés, nous nous sommes intéressés à définir les voies majeures de stress qui régissent cette perte massive d'îlot lors du processus d'isolement et suite à l'exposition immédiate aux cytokines après transplantation. L'ensemble de ces résultats indique que le stress induit lors de l'isolement des îlots et celui des cytokines recrute différentes voies de signalisation intracellulaire (JNK, p38 et NF-κB) qui s'additionnent entre-elles pour altérer la fonction et la viabilité de l'îlot. De ce fait une stratégie doit être mise en place pour bloquer toute action synergique entre ces différentes voies activées pour améliorer la viabilité et la fonction de la cellule ß lors du greffon cellulaire. SUMMARY Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the progressive and selective destruction of the pancreatic ß-cells that secrete insulin, leading to absolute insulin deficiency. T1DM accounts for about 10% of all diabetes cases, affecting persons younger than 20 years of age. Medical treatment using daily exogenous insulin injection corrects hormone deficiency but does not prevent devastating complications such as heart attack, neuropathy, kidney failure, blindness, and amputation caused by the disease. Pancreatic islet transplantation (PIT) is one strategy that holds promise to cure patients with T1DM, but purified pancreatic islet grafts have failed to maintain long-term glucose homeostasis in human recipients, the reasons for this failure being still poorly understood. There is however a more immediate problem with islet grafting that is dependent upon poor islet recovery from donors and early islet loss following the first hours of grafting. This tendency of islet grafts to fail to function within a short period after transplantation is termed primary graft non-function (PNF). Indeed, the islet isolation procedure itself destroys cellular and non-cellular components of the pancreas that may play a role in supporting islet survival. Further, islet transplantation exposes cells to a variety of stressful stimuli, notably pro-inflammatory cytokines that encourage ß-cell death by apoptosis and lead to early graft failure. Altogether these mechanisms lead to an estimated loss of 60% of the total islet mass. Here, we have mapped the major intracellular stress signaling pathways that may mediate human islet loss by apoptosis during isolation and following cytokine attack. We found that several stress pathways are maximally activated from the earliest stages of the isolation procedure. Culturing islet for two days allow for the activated pathways to return to basal levels. We propose that protective strategies should 1) be initiated as early as possible during isolation of the islets, 2) should probably target the activated stress pathways that we uncovered during our studies and 3) should include culturing islets for two days post-isolation and prior transplantation.

Origine et évolution de la réhabilitation psychosociale

The main historical stages of the social rehabilitation of the mentally-ill patients show that the psychiatric hospital centred approach has been progressively cast off and therefore the creation of intermediate institutions and ambulatory care integrated in the city has been favoured. This has allowed the progressive development of the psychosocial rehabilitation. This reorientation of the medical practice towards the community was based on two specific and corollary approaches: the deinstitutionalisation and the rehabilitation, which have the common objective to facilitate the return of the patient in the natural social community. The psychosocial rehabilitation includes the deinstitutionalisation and the return to the community, in a holistic approach aiming at compensating for the psychosocial handicap induced by the mental illness. The concept of the psychosocial rehabilitation itself has been progressively elaborated over time. The initial enthusiasm was followed by a period of progressive disillusion, which was finally followed by the development of the psychosocial rehabilitation as a true specific clinical discipline, a topic in medical education and in scientific research

Reaudit letter to the City of Ottumwa for the period July 1, 2005 through June 30, 2006, as well as certain issues applicable to the year ended June 30, 2005 and subsequent periods

Reaudit letter to the City of Ottumwa for the period July 1, 2005 through June 30, 2006, as well as certain issues applicable to the year ended June 30, 2005 and subsequent periods

Report on the Unemployment Insurance Tax Redesign Project administered by Iowa Workforce Development for the period July 1, 2002 through June 30, 2009

Report on the Unemployment Insurance Tax Redesign Project administered by Iowa Workforce Development for the period July 1, 2002 through June 30, 2009

Audit report on the Honey Creek Resort operated by Central Group Management, LLC for the period from inception (September 18, 2008) to June 30, 2009

Audit report on the Honey Creek Resort operated by Central Group Management, LLC for the period from inception (September 18, 2008) to June 30, 2009

Report on a review of the funding for construction of the Lewis and Clark Interpretive Center at Lewis and Clark State Park in Monona County for the period February 25, 1999 through December 31, 2008

Report on a review of the funding for construction of the Lewis and Clark Interpretive Center at Lewis and Clark State Park in Monona County for the period February 25, 1999 through December 31, 2008

Report on payments made subsequent to recipients’ dates of death under the Medicaid program administered by the Department of Human Services for the period July 1, 2006 through December 31, 2008

Report on payments made subsequent to recipients’ dates of death under the Medicaid program administered by the Department of Human Services for the period July 1, 2006 through December 31, 2008

Special investigation of the City of Truro for the period January 1, 2003 through February 18, 2009

Special investigation of the City of Truro for the period January 1, 2003 through February 18, 2009

Report on the City of Hills Fire Department, also known as Hills Fire Fighters, for the period July 1, 2006 through September 30, 2009

Report on the City of Hills Fire Department, also known as Hills Fire Fighters, for the period July 1, 2006 through September 30, 2009

Report on a review of the Transportation Enhancement Program of the Iowa Department of Transportation for projects closed out during the period July 1, 2007 through June 30, 2009

Report on a review of the Transportation Enhancement Program of the Iowa Department of Transportation for projects closed out during the period July 1, 2007 through June 30, 2009

Period-Luminosity-Colour distribution and classification of Galactic oxygen-rich LPVs I. Luminosity calibrations

The absolute K magnitudes and kinematic parameters of about 350 oxygen-rich Long-Period Variable stars are calibrated, by means of an up-to-date maximum-likelihood method, using HIPPARCOS parallaxes and proper motions together with radial velocities and, as additional data, periods and V-K colour indices. Four groups, differing by their kinematics and mean magnitudes, are found. For each of them, we also obtain the distributions of magnitude, period and de-reddened colour of the base population, as well as de-biased period-luminosity-colour relations and their two-dimensional projections. The SRa semiregulars do not seem to constitute a separate class of LPVs. The SRb appear to belong to two populations of different ages. In a PL diagram, they constitute two evolutionary sequences towards the Mira stage. The Miras of the disk appear to pulsate on a lower-order mode. The slopes of their de-biased PL and PC relations are found to be very different from the ones of the Oxygen Miras of the LMC. This suggests that a significant number of so-called Miras of the LMC are misclassified. This also suggests that the Miras of the LMC do not constitute a homogeneous group, but include a significant proportion of metal-deficient stars, suggesting a relatively smooth star formation history. As a consequence, one may not trivially transpose the LMC period-luminosity relation from one galaxy to the other.

Research Activities Credit Annual Report for the Period July 1, 2009 – December 31, 2009

Annual report on individuals and companies that claim the Iowa Research Activities Tax Credit. The report includes the total amount of Regular Research Activities Tax Credit claims, the total amount of Supplemental Research Activities Tax Credit claims, the total amount of Research Activities Tax Credit claims paid as refunds, the amounts of Research Activities Tax Credits claimed against corporate income tax and against individual income tax, and the names of taxpayers and the amounts claimed for taxpayers that claimed in excess of $500,000 of Research Activities Tax Credits.

Report on a special investigation of the City of Crawfordsville for the period July 1, 1999 through February 28, 2009

Report on a special investigation of the City of Crawfordsville for the period July 1, 1999 through February 28, 2009

Report on the eligibility requirements for the Medicaid program administered by the Department of Human Services for the period July 1, 2006 through December 31, 2008

Report on the eligibility requirements for the Medicaid program administered by the Department of Human Services for the period July 1, 2006 through December 31, 2008