POPULATION PHARMACOKINETICS OF CONTINUOUS INFUSION OF FACTOR VIII IN HEMOPHILIA-A PATIENTS UNDERGOING ORTHOPEDIC SURGERY

Objective: to develop a population pharmacokinetic model taking into account blood losses during and after orthopedic surgery in adult hemophilia A patients receiving infusion of coagulation factor VIII, and to evaluate the influence of potential covariates.Methods: Factor VIII pharmacokinetic parameters were calculated from 24 patients. Among them, 7 were HIV+. The observations were analyzed with the mixed-effects compartment pharmacokinetic package NONMEM and the first-order conditional estimation method. To evaluate the stability and robustness of the final model the bootstrap method was used.Results: During the model-building process, central volume of distribution (V1) was related to body weight (P = 0.0263) and viral status (P = 0.0078). Moreover, the peripheral volume of distribution was related to body weight (P=0.0362). In the final model, only the viral status was significant for V1 when compared with the base model. Posterior predictive checks and robustness analysis showed that the model adequately described the pharmacokinetic parameters. The HIV covariate accounted for 29.8% of the unexplained variation across patients for V1. V1 increased by 33.3% in HIV+ patients compared to HIV- patients.Conclusion: A population pharmacokinetic model taking into account blood losses during and after orthopedic surgery was developed. The 33.3% increase in V1 observed in HIV+ patients explained the need for higher doses in these patients.Â

Observation of a narrow structure in the pp elastic scattering at T{sub kin} = 2.11 GeV

The angular dependences of the pp elastic scattering analyzing power, spin correlation, depolarization transfer were measured in the angular range from 60{degrees} to 97{degrees} CM at 14 energies between 1.96 and 2 .23 GeV. At fixed angles two maxima were observed in the analyzing Power energy dependence, both below and above 2.11 GeV. Furthermore a rapid decrease Of the spin correlation Parameter at 90{degrees} CM occurs around this energy. The observables allow determination of the absolute values of three nonvanishing pp amplitudes at 90{degrees}. The energy dependence of the spin-single amplitude shows a shoulder centered at 2.11 GeV, while the spin-triplet amplitudes are decreasing functions of energy snowing no evidence of structure. All experimental data are listed in tables and their energy dependences are shown in figures

Targeting the delivery of systemically administered haematopoietic stem / progenitor cells to the inflamed colon using hydrogen peroxide and platelet microparticle pre-treatment strategies

AbstractHaematopoietic stem and progenitor cell (HSC) therapy may be promising for the treatment of inflammatory bowel disorders (IBDs). However, clinical success remains poor, partly explained by limited HSC recruitment following systemic delivery. The mechanisms governing HSC adhesion within inflamed colon, and whether this event can be enhanced, are not known. An immortalised HSC-like line (HPC7) was pre-treated with hydrogen peroxide (H2O2), activated platelet releasate enriched supernatant (PES) or platelet microparticles (PMPs). Subsequent adhesion was monitored using adhesion assays or in vivo ischaemia–reperfusion (IR) and colitis injured mouse colon intravitally. Integrin clustering was determined confocally and cell morphology using scanning electron microscopy. Both injuries resulted in increased HPC7 adhesion within colonic mucosal microcirculation. H2O2 and PES significantly enhanced adhesion in vitro and in the colitis, but not IR injured, colon. PMPs had no effect on adhesion. PES and PMPs induced clustering of integrins on the HPC7 surface, but did not alter their expression. Adhesion to the colon is modulated by injury but only in colitis injury can this recruitment be enhanced. The enhanced adhesion induced by PES is likely through integrin distribution changes on the HPC7 surface. Improving local HSC presence in injured colon may result in better therapeutic efficacy for treatment of IBD

Cancer cell–derived microparticles bearing P-selectin glycoprotein ligand 1 accelerate thrombus formation in vivo

Recent publications have demonstrated the presence of tissue factor (TF)–bearing microparticles (MPs) in the blood of patients suffering from cancer. However, whether these MPs are involved in thrombosis remains unknown. We show that pancreatic and lung cancer cells produce MPs that express active TF and P-selectin glycoprotein ligand 1 (PSGL-1). Cancer cell–derived MPs aggregate platelets via a TF-dependent pathway. In vivo, cancer cell–derived MPs, but not their parent cells, infused into a living mouse accumulate at the site of injury and reduce tail bleeding time and the time to occlusion of venules and arterioles. This thrombotic state is also observed in mice developing tumors. In such mice, the amount of circulating platelet-, endothelial cell–, and cancer cell–derived MPs is increased. Endogenous cancer cell–derived MPs shed from the growing tumor are able to accumulate at the site of injury. Infusion of a blocking P-selectin antibody abolishes the thrombotic state observed after injection of MPs or in mice developing a tumor. Collectively, our results indicate that cancer cell–derived MPs bearing PSGL-1 and TF play a key role in thrombus formation in vivo. Targeting these MPs could be of clinical interest in the prevention of thrombosis and to limit formation of metastasis in cancer patients

Optimising monitoring in the management of Crohn's disease: a physician's perspective.

Management of Crohn's disease has traditionally placed high value on subjective symptom assessment; however, it is increasingly appreciated that patient symptoms and objective parameters of inflammation can be disconnected. Therefore, strategies that objectively monitor inflammatory activity should be utilised throughout the disease course to optimise patient management. Initially, a thorough assessment of the severity, location and extent of disease is needed to ensure a correct diagnosis, identify any complications, help assess prognosis and select appropriate therapy. During follow-up, clinical decision-making should be driven by disease activity monitoring, with the aim of optimising treatment for tight disease control. However, few data exist to guide the choice of monitoring tools and the frequency of their use. Furthermore, adaption of monitoring strategies for symptomatic, asymptomatic and post-operative patients has not been well defined. The Annual excHangE on the ADvances in Inflammatory Bowel Disease (IBD Ahead) 2011 educational programme, which included approximately 600 gastroenterologists from 36 countries, has developed practice recommendations for the optimal monitoring of Crohn's disease based on evidence and/or expert opinion. These recommendations address the need to incorporate different modalities of disease assessment (symptom and endoscopic assessment, measurement of biomarkers of inflammatory activity and cross-sectional imaging) into robust monitoring. Furthermore, the importance of measuring and recording parameters in a standardised fashion to enable longitudinal evaluation of disease activity is highlighted.Peer reviewe

Primary intestinal lymphangiectasia (Waldmann's disease)

Primary intestinal lymphangiectasia (PIL) is a rare disorder characterized by dilated intestinal lacteals resulting in lymph leakage into the small bowel lumen and responsible for protein-losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia. PIL is generally diagnosed before 3 years of age but may be diagnosed in older patients. Prevalence is unknown. The main symptom is predominantly bilateral lower limb edema. Edema may be moderate to severe with anasarca and includes pleural effusion, pericarditis or chylous ascites. Fatigue, abdominal pain, weight loss, inability to gain weight, moderate diarrhea or fat-soluble vitamin deficiencies due to malabsorption may also be present. In some patients, limb lymphedema is associated with PIL and is difficult to distinguish lymphedema from edema. Exsudative enteropathy is confirmed by the elevated 24-h stool α1-antitrypsin clearance. Etiology remains unknown. Very rare familial cases of PIL have been reported. Diagnosis is confirmed by endoscopic observation of intestinal lymphangiectasia with the corresponding histology of intestinal biopsy specimens. Videocapsule endoscopy may be useful when endoscopic findings are not contributive. Differential diagnosis includes constrictive pericarditis, intestinal lymphoma, Whipple's disease, Crohn's disease, intestinal tuberculosis, sarcoidosis or systemic sclerosis. Several B-cell lymphomas confined to the gastrointestinal tract (stomach, jejunum, midgut, ileum) or with extra-intestinal localizations were reported in PIL patients. A low-fat diet associated with medium-chain triglyceride supplementation is the cornerstone of PIL medical management. The absence of fat in the diet prevents chyle engorgement of the intestinal lymphatic vessels thereby preventing their rupture with its ensuing lymph loss. Medium-chain triglycerides are absorbed directly into the portal venous circulation and avoid lacteal overloading. Other inconsistently effective treatments have been proposed for PIL patients, such as antiplasmin, octreotide or corticosteroids. Surgical small-bowel resection is useful in the rare cases with segmental and localized intestinal lymphangiectasia. The need for dietary control appears to be permanent, because clinical and biochemical findings reappear after low-fat diet withdrawal. PIL outcome may be severe even life-threatening when malignant complications or serous effusion(s) occur