The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Long-term effects of medical management on growth and weight in individuals with urea cycle disorders

Low protein diet and sodium or glycerol phenylbutyrate, two pillars of recommended long-term therapy of individuals with urea cycle disorders (UCDs), involve the risk of iatrogenic growth failure. Limited evidence-based studies hamper our knowledge on the long-term effects of the proposed medical management in individuals with UCDs. We studied the impact of medical management on growth and weight development in 307 individuals longitudinally followed by the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD). Intrauterine growth of all investigated UCDs and postnatal linear growth of asymptomatic individuals remained unaffected. Symptomatic individuals were at risk of progressive growth retardation independent from the underlying disease and the degree of natural protein restriction. Growth impairment was determined by disease severity and associated with reduced or borderline plasma branched-chain amino acid (BCAA) concentrations. Liver transplantation appeared to have a beneficial effect on growth. Weight development remained unaffected both in asymptomatic and symptomatic individuals. Progressive growth impairment depends on disease severity and plasma BCAA concentrations, but cannot be predicted by the amount of natural protein intake alone. Future clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth in UCDs

Adaptative changes of metabolic zonation in liver cirrhosis

Le métabolisme des hépatocytes diffère en fonction de leur localisation proximale (zone périportale) ou distale (périvenulaire) le long des sinusoïdes hépatiques. Certaines voies métaboliques ont une localisation préférentielle, voire exclusive, dans une zone acinaire, soit périportale, soit périvenulaire. Cette hétérogénéité fonctionnelle des hépatocytes est appelée « zonation métabolique ». Grâce à ce système, les voies métaboliques agissent de manière séquentielle et complémentaire le long du sinusoïdes. La direction du flux sanguins dans le sinusoïde semble jouer un rôle prépondérant dans l’organisation de cette zonation métabolique. La technique de cytochimie quantitative et de microdensitométrie développée au laboratoire permet de mesurer de façon précise l’activité de différentes enzymes au niveau de la cellule hépatique individuelle, tout en corrélant directement cette activité enzymatique avec l’histologie et les lésions pathologiques éventuelles. Le principe de la technique consiste en une mesure in situ, par microspectrophotométrie, du produit final de réactions cytochimiques sur sections cryocongelées de tissus hépatiques. Nous avons démontré le reproductibilité et la spécificité de la technique, également appliquée à l’examen de biopsies humaines telles qu’obtenues par ponction à l’aiguille. La zonation métabolique s’établit pogressivement en période postnatale, et ce développement ontogénique explique les différences d’activité observées tant chez l’homme que chez l’animal en fonction de l’âge. Afin de déterminer si la zonation métabolique décrite dans le parenchyme hépatique normal persistait également dans le nodule cirrhotique, nous avons développé au laboratoire différents modèles de cirrhoses expérimentales, et nous avons étudié également du foie humain cirrhotique en provenance de patients transplantées pour cirrhose biliaire. la zonation métabolique persiste dans le module cirrhotique malgré les bouleversements architecturaux qui caractérisent la cirrhose. La zonation métabolisque s’établit entre le centre et la périphérie des nodules cirrhotiques, plaidant pour une organisation fonctionnelle du nodule comparable à celle de l’acinus. Néanmoins, la zonation diffère dans la cirrhose toxique (CC14) par rapport à une cirrhose biliaire (ligature des voies biliaires) : dans le premier modèle, le centre du nodule exprime une activité de type périportale, plaidant pour une direction centrifuge du flux sanguin dans les sinusoïdes du nodule. Dans la cirrhose biliaire expérimentale et humaine, l’activité de type périportale se retrouve en périphérie du nodule, plaidant pour une direction centripète du flux sanguin sinusoïdal. La perte de la zonation métabolique et de la sous-spécialisation hépatocytaire pourrait être un facteur déterminant de la décompensation fonctionnelle hépatique dans la cirrhose terminaleHepatocytes differ in their composition and metabolism according to their own localization along the liver cell plate, close or distal to the portal tract. This heterigenous distribution of liver metabolism is called “liver metabolic zonation”, and seems to play a key role in achieving physiological concentrations of solutes and optimal composition of the blood leaving the organ. The zonal distribution of enzymes is a very efficient means to combine complementary metabolic pathways, acting sequentially along the liver cell plate. Antagonist metabolic processes occur in different hepatocytes. This liver cell heterogeneity may be partially pre-determined, according to the anatomy of the organ, and to the distribution of cellular receptors. Beside this predetermination, the hepatocyte metabolism is also influenced by its microenvironment, which varies along the sinusoid due to uptake and release of substances by the liver cells themselves. We have developed in our laboratory a technique of quantitative histochemistry, using microdensitometry to measure the activities of several enzymes in individual liver cells on frozen liver sections. This technique allows direct correlation of enzyme activities with adjacent histology. We choose to measure the activities of 5 different enzymes, representative of major metabolic pathways carbohydrate metabolism (glucose-6-phosphatase dehydrogenase, mitochondrial, more active in the perivenual zone), drug metabolism (NADPH dehydrogenase and alcohol dehydrogenase, microsome and cytosol, more active in the perivenular zone) and oxidative metabolism (succinate dehydrogenase, mitochondria, more active in the periportal zone). The technique of quantitative histochemisty was first validated in animals, and we thereafter demonstrated its applicability to human clinical biopsy samples. In preliminary experiments, we demonstrated that the liver metabolic zonation described in animals is also observed in human liver. However, activities and “zonation” pattern was different in infants as compared with older children and adults, and we concluded that age differences could influence the zonation pattern observed. To investigate further this possibility, zonal changes of enzyme activities with age were systematically analyzed from birth in growing rats Periportal and perivenular activities of SDH and NADPH increased with age during the first postnatal weeks. The increase was more important for SDH in the periportal zone and for DN in the perivenular zone, so that the distribution gradient became more prominent with time, giving birth to the “adult” type of zonation pattern. G6P activity decreased after birth in the perivenular zone while increasing concomitantly in the periportal zone, this evolution being responsible for a maximal distribution gradient, with a ratio of periportal to perivenular activity of 2.27, at day 26. G6P activity decreased then slowly in both zones to reach lower adult values. In these animals, marked changes in zonal enzyme activities were observed at the time of weaning, reflecting changes in nutriment intake from a high fat/low carbohydrate diet (maternal milk) to the laboratory diet rich in carbohydrate, lowering the need for glucose production. Liver metabolic zonation incirrhosis: Pathological conditions affecting the liver do not necessarily impair immediately the liver function itself, and cirrhosis may even develop without liver insufficiency. In view of the key role played by the metabolic zonation in maintaining optimal liver function, we hypothesized that a liver metabolic zonation should be preserved in compensated cirrhosis, despite the intense architectural changes observed in this condition. This would suggest adaptive changes of the metabolic zonation from an “acinar” zonation pattern towards a new zonation pattern and enzyme distribution across the cirrhotic nodule. To answer this question, the zonal metabolism was investigated by quantitative histochemistry in various human and animal models of cirrhosis. In a first experiment, cirrhosis of the liver was induced in growing rats by chronic administration of CC1 4 and phenobarbitone. Enzyme activities were deeply affected by this treatment, especially G6P and SDH in the perivenular zone. When cirrhosis had developed, treatment was discontinued, and enzyme activities returned to control values. However, a new pattern of metabolic zonation was observed in the cirrhotic nodules: the distribution gradient of activities was now established between the periphery and centre of the cirrhotic nodule. The “nodule periphery” zone displayed activities similar to the control perivenular zone, whilst activities at the nodule centre were similar to the control periportal activities. This zonation pattern may suggest that the blood flows in the nodule from the centre to the periphery. Because in this model hepatocyte damage are mainly observed in the perivenular zone, we suggested that a different cirrhotic zonation pattern would be observed in a biliary cirrhosis, in which initial liver damages are found in the periportal zone. To investigate this possibility, we developed and animal model of pediatric biliary cirrhosis: Bile duct ligation and excision was performed in growing rats, and zonal metabolism analyzes after the development of cirrhosis (mean of 35 days). A metabolic zonation persisted for all enzymes analyzed in this model. As hypothesized, the zonation pattern in this model was exactly the reserve as that observed in the CCl 4 model of cirrhosis. Enzyme activities displayed at the nodule periphery were similar to control periportal activities, whilst at the nodule centre, they corresponded to control perivenular activities. To further confirm this finding in human pathology, we analyzed liver biopsy samples from children with extra-hepatic biliary atresia compensated cirrhosis, and compared the zonation observed to that of normal human liver obtained after graft reduction during transplantation. In these extra-hepatic biliary atresia livers, a similar zonation pattern was observed as in the animal model of bile duct ligation, with a periportal like activity at the nodule periphery and a perivenular like activity at the nodule centre. We conclude from these studies that quantitative histochemistry is a reproducible means to investigate the metabolism of individual liver cells and to correlate directly enzyme activities with pathological damages. The liver metabolic zonation described in animals is also observed in human livers, and this physiological organisation plays a key role in adjusting the final composition of fluids leaving the liver. Ontogenic changes of metabolic zonation are observed in both animals and human, and these changes may affect differently activities of the same enzyme in different part of the liver acinus. A metabolic zonation persists in liver cirrhosis, despite the intense architectural changes disrupting the acinus. In toxic cirrhosis, the metabolic zonation is established between the centre and periphery a perivenular like activity. A mirror image of metabolic zonation is observed in animal and human biliary cirrhosis, reflecting a different type of injury which in these models interest mainly the periportal area. Study of liver metabolic zonation may therefore be a useful tool to determine the site of the initial liver damage in cryptogenic cirrhosis. Loss of metabolic zonation in cirrhosis may e an important step towards the development of functional impairment, by disrupting the sequential complementary metabolic activities along the liver cell plateThèse d'agrégation de l'enseignement supérieur (faculté de médecine) -- UCL, 199

Growth factors in children with end-stage liver disease before and after liver transplantation: a review

Growth failure is a common observation in children with end-stage liver disease (ESLD). The liver is an important endocrine organ producing potent anabolic growth factors such as IGF-I (insulin-like growth factor-I) and its major binding-proteins, called IGFBP-1, -2 and -3. Circulating IGF-I and IGFBP-3 levels are low in children with chronic liver failure despite increased GH secretion. This discrepancy suggests that GH resistance is present in chronic liver failure and is mainly due to the associated malnutrition. The advent of orthotopic liver transplantation (OLT) has dramatically improved the life expectancy of children with ESLD. Nevertheless, the growth of 15-20% of the children in recent studies remains poor after successful transplantation. Several factors such as age and height deficit at the time of OLT, etiology of the liver disease and graft function as well as the dose and mode of administration of glucocorticoids have been implicated in the lack of complete catch-up growth following surgery. Few studies have explored the possibility that anomalies in the GH-IGF-I cascade could explain growth retardation. However, it is unlikely that major anomalies of the GH-IGF-I axis contribute to impaired growth. Treatment with GH alone or in combination with IGF-I before or after OLT may improve the growth of children. Randomized multi-center studies are needed to address this issue

Post-transplant lymphoproliferative disorder with supraglottic involvement.

OBJECTIVE: Transplant patients with primary Epstein-Barr virus (EBV) infection may develop post-transplant lymphoproliferative disorder (PTLD). Since many infants are seronegative at the time of transplantation, PTLD is a major concern for paediatric transplant centres. First manifestations of PTLD are frequently observed in the ENT area with adenoidal and/or tonsillar involvement. DESIGN: Retrospective study of two cases of PTLD with confirmed supraglottic involvement, their management and outcome. Only patients with pathologically and immunologically demonstrated B-cell proliferation were diagnosed as PTLD. RESULT: Two infants developed an acute stridor during PTLD respectively 8 and 10 months after orthotopic liver transplantation (OLT). These infants were seronegative for EBV at the time of transplantation. IgM anti-EBV and/or detection of EBV genome by polymerase chain reaction were positive. Laryngeal examination revealed hypopharyngeal and/or supraglottic mucosal hyperplasia. Immunostaining of laryngeal biopsy was positive for latent membrane protein-1 (LMP1). Patients were treated by a reduction in immunosuppression as far as tolerated with the intent to recover natural immune response by the patient over the proliferation of EBV-infected cells. Complete remission of PTLD was observed in these two cases. CONCLUSION: Tonsillar hypertrophy and adenoid enlargement are the most encountered features of PTLD in OLT occurring in the ENT area. Acute stridor with supraglottic involvement may also be observed in PTLD and must be promptly diagnosed as the prognosis of this disorder is related to rapid reduction in immunosuppression and consequently to the recovering of a natural immune response against the EBV infection

Acute tonsillitis as the first manifestation of post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication that may follow orthotopic liver transplantation (OLT) in children. The first symptoms are often in the ear, nose, or throat (ENT) area. This abnormal proliferation of lymphoid cells is related to Epstein-Barr virus (EBV) infection in immunocompromised children. The incidence of PTLD, EBV status before OLT and at the diagnosis of PTLD, delay between OLT and PTLD, localization, pathological investigations, and the treatment and evolution of PTLD were prospectively evaluated in 77 pediatric liver transplant recipients. Eight patients (10%) developed PTLD, all with an ENT presentation. Seven had acute nonbacterial tonsillitis (with a negative throat swab), and 1 had a pharyngolaryngeal localization at the time of the diagnosis. Four patients had associated involvement outside the ENT area. All patients were EBV-seronegative at the time of OLT; 6 underwent seroconversion at the time of diagnosis, and 2 within 9 and 20 months of diagnosis. All patients presented with low-grade PTLD. All patients with acute tonsillitis associated with EBV seroconversion underwent immediate tonsillectomy, and immunosuppression was decreased as much as tolerated. This therapeutic protocol led to complete recovery in all patients. After OLT in children, nonbacterial tonsillar inflammation or hypertrophy associated with an EBV infection is often the first manifestation of PTLD. Tonsillectomy combined with tapering of immunosuppression offers the best chance for a complete recovery

Bone marrow transplantation from an unrelated donor for Fanconi's anaemia: two unusual complications.

An eight-year-old boy with Fanconi's anaemia received a bone marrow transplantation from an unrelated donor. Sustained engraftment was achieved, but he developed major complications including acute grade III graft-versus-host disease, autoimmune haemolytic anaemia with positive Coombs' test and free antibodies against Rhesus group, and a virus-associated haemophagocytic syndrome; this latter complication was successfully treated with acyclovir. Sixteen months after transplantation he has full haematopoietic reconstitution, but with persisting mild autoimmune haemolysis