Reduced costs with bisoprolol treatment for heart failure - An economic analysis of the second Cardiac Insufficiency Bisoprolol Study (CIBIS-II)

Background Beta-blockers, used as an adjunctive to diuretics, digoxin and angiotensin converting enzyme inhibitors, improve survival in chronic heart failure. We report a prospectively planned economic analysis of the cost of adjunctive beta-blocker therapy in the second Cardiac Insufficiency BIsoprolol Study (CIBIS II). Methods Resource utilization data (drug therapy, number of hospital admissions, length of hospital stay, ward type) were collected prospectively in all patients in CIBIS . These data were used to determine the additional direct costs incurred, and savings made, with bisoprolol therapy. As well as the cost of the drug, additional costs related to bisoprolol therapy were added to cover the supervision of treatment initiation and titration (four outpatient clinic/office visits). Per them (hospital bed day) costings were carried out for France, Germany and the U.K. Diagnosis related group costings were performed for France and the U.K. Our analyses took the perspective of a third party payer in France and Germany and the National Health Service in the U.K. Results Overall, fewer patients were hospitalized in the bisoprolol group, there were fewer hospital admissions perpatient hospitalized, fewer hospital admissions overall, fewer days spent in hospital and fewer days spent in the most expensive type of ward. As a consequence the cost of care in the bisoprolol group was 5-10% less in all three countries, in the per them analysis, even taking into account the cost of bisoprolol and the extra initiation/up-titration visits. The cost per patient treated in the placebo and bisoprolol groups was FF35 009 vs FF31 762 in France, DM11 563 vs DM10 784 in Germany and pound 4987 vs pound 4722 in the U.K. The diagnosis related group analysis gave similar results. Interpretation Not only did bisoprolol increase survival and reduce hospital admissions in CIBIS II, it also cut the cost of care in so doing. This `win-win' situation of positive health benefits associated with cost savings is Favourable from the point of view of both the patient and health care systems. These findings add further support for the use of beta-blockers in chronic heart failure

Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein–protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families

Lésions cancéreuse et pré-cancéreuse sur oesophage de Barrett : Etude clinique, endoscopique et histologique

14 patients porteurs d'udénocarcinome œsophagien entouré de muqueuse de type cylindrique (Barrett) ont été investigués sur le plan clinique, endoscopique et ont été soumis à une étude histologique spéciale destinée à caractériser l'environnement muqueux de cette lésion maligne. Pratiquement tous les patients se plaignaient de dysphagie, de perte pondérale et avaient présenté antérieurement des symptômes de reflux gastro-œsophagien. Les aspects tumoraux ont été variables: envahissement superficiel (I), crois" sance exopilytique (4), multifocale (1), ulcération maligne distale (4) ou ulcération sténosante (4). Les biopsies prélevées au niveau de la tumeur et dans l'épithélium cylindrique type Barrett environnant ont révélé des adénocarcinomes peu ou modérément différencié. La muqueuse de type cardial (MC) était présente chez tous les patients avec des degrés de dysplasie sévère ou modérée observés sur toutes les biopsies. Ces changements dysplasiques ont été observés dans un peu plus de la moitié des biopsies de muqueuse type cylindrique avec métaplasie intestinale (MCMI) et manquaient au niveau des muqueuses de type fundique (MF). Ces résultats ont été comparés avec les données histologiques de 200 biopsies endoscopiques prélevées chez 50 patients porteurs d'endobrachyœsophage sans lésion maligne. Des changements dysplasiques ont été observés sur 18 % du matériel biopsique: 16 % de muqueuse type cardial (MC) et 2 % de muqueuse type cylindrique avec métaplasie intestinale (MCMI). Les résultats de l'étude en microscopie optique correspondent aux résultats préliminaires d'une étude de cinétique cellulaire actuellement en cours: le marquage cellulaire avec autoradiographie montre au niveau de la muqueuse cylindrique péri-tumorale une expansion du comportement prolifératif sur la muqueuse de type cardial (MC), et seulement sporadiquement sur la muqueuse de type cylindrique avec métaplasie intestinale (MCMI) et jamais au niveau de la muqueuse de type fundique (MF)

Follow-up of blood donors positive for hepatitis B surface antigen

From 1973 to 1977 in Amsterdam the incidence of hepatitis B surface antigen (HBsAg) in blood donations from new donors was 0.224 and from known donors 0.034%. 65 donors, previously found positive for HBsAg, were re-examined. Persistence of HBsAg in new donors (28 of 31) occurred significantly (p less than 0.0005) more often than in known donors (15 of 34). All carriers were classified into HBeAg (21%) or anti-HBe (79%) by a sensitive Elisa technique. Abnormal liver function tests (LFTs) were observed in 30% of the carriers and were significantly (p less than 0.005) more often found in HBeAg than in anti-HBe-positive carriers. When the LFTs remained abnormal, in almost all (8 of 9) carriers moderate to severe histological liver disease was diagnose

Tumor necrosis factor unresponsiveness after surgery in bile duct-ligated rats

In obstructive jaundice, postoperative complications are related to gut-derived endotoxemia and possibly mediated by cytokines such as tumor necrosis factor (TNF) and interleukin-6 (IL-6). This study investigated the course of IL-6 and TNF after surgery in bile duct-ligated rats (BDL) treated with and without an enteral endotoxin binder (cholestyramine). Endotoxin in rat plasma was determined by blocking cytokine production in whole blood cell cultures stimulated by rat plasma using antibodies directed against the endotoxin (CD14) receptor. Surgery elicited a significant IL-6 response in saline-treated BDL rats (BDL-SAL). TNF, however, remained at its low preoperative levels. Cholestyramine treatment resulted in undetectable preoperative TNF and IL-6 levels, but levels of both cytokines were significantly raised after surgery. Endotoxin, as determined by the CD14 blockade test, was identified in the BDL-SAL group, before (time 0) and after surgery (2 and 4 h), whereas in the cholestyramine group endotoxin was only present at 2 h after surgery. The lack of a postoperative plasma TNF response in the BDL-SAL group in the continuous presence of endotoxin suggests endotoxin tolerance for TNF production in obstructive jaundic

Liver failure induces a systemic inflammatory response. Prevention by recombinant N-terminal bactericidal/permeability-increasing protein.

The observed increased susceptibility of patients with fulminant hepatic failure for local and systemic infections has been hypothesized to be due to a failure for the hepatic clearance function and subsequent leaking of endogenous endotoxins into the systemic circulation. However, experimental evidence for such a systemic inflammation during liver failure due to endogenous endotoxemia is lacking. Therefore, we designed a study to clarify whether circulating endotoxins due to liver failure could lead to the development of systemic inflammations. In a rat model for liver failure induced by a two-thirds partial hepatectomy, we evaluated the course of circulating tumor necrosis factor and interleukin-6, changes in blood chemistry and hemodynamics, and histopathological changes in the lungs. Partially hepatectomized animals, but not sham-operated animals, demonstrated cardiac failure, increased levels of creatinin and urea, metabolic acidosis, high plasma levels of tumor necrosis factor and interleukin-6, and an influx of PMNs in the lungs-together indicating the development of a systemic inflammatory response. Continuous infusion of recombinant N-terminal bactericidal/permeability-increasing protein (rBPI23), a well described endotoxin-neutralizing protein, prevented these inflammatory reactions. Ex vivo experiments with rat plasma samples confirmed the presence of circulating endotoxins in partially hepatectomized rats as opposed to those treated with rBPI23. Thus, our results indicate that the early phase of liver failure induces a systemic inflammatory response triggered by circulating endotoxins, which can be prevented by perioperative infusion of rBPI23