Long-term outcome in patients with non-valvular atrial fibrillation on dabigatran: a prospective cohort study

ABSTRACT

Introduction: Most studies on thromboembolic and bleeding risk in patients with non-valvular atrial fibrillation (NVAF) exposed to non-vitamin K oral anticoagulants stem from interrogation of insurance databases.

Areas covered: We studied 742 consecutive patients with NVAF who started treatment with dabigatran in three hospitals in Italy. Average follow-up was 1.80 years.

Mean age was 76.2 years. CHA₂DS₂VASc score was 0–1 in 37 (5%), 2 in 97 (13%) and ≥ 3 in 604 (82%) patients. NVAF was permanent in 349 (48%). Overall, 76% of patients remained on treatment over the entire follow-up period. Among 180 patients who discontinued permanently, the most frequent reasons were dyspepsia (33.9%), bleeding (17.8%), and renal worsening (12.1%). About 48% and 74% of permanent discontinuations occurred during the first 6 and 12 months of treatment, respectively. Rates of major events (per 100 patient-years) were 0.75 for stroke, 0.31 for myocardial infarction, 1.50 for all-cause death, and 1.80 for major bleedings. The rate of intracranial bleedings was 0.45 and that of major gastrointestinal bleedings was 0.75.

Expert opinion: This prospective cohort study confirms the low incidence of stroke, major bleeding and intracranial bleeding, and a 76% persistence with treatment, in patients with NVAF treated with dabigatran over about 2 years.     

Amniotic fluid and bone marrow derived mesenchymal stem cells can be converted to smooth muscle cells in the cryo-injured rat bladder and prevent compensatory hypertrophy of surviving smooth muscle cells

PURPOSE: Wound healing of the cryo-injured bladder can bring about organ remodeling because of incomplete reconstitution of depleted smooth muscle cells. Stem cell transplantation could be beneficial to improve smooth muscle cell regeneration and/or modulate the remodeling process. The repair of bladder injury using adult-type stem cells would be useful for adult urological patients but unsuited for neonatal patients, in whom major benefits are likely to derive from fetal-type stem cells. MATERIALS AND METHODS: The smooth muscle cell differentiation potential of fetal-type vs adult-type stem cells was evaluated by injecting green fluorescent protein labeled mesenchymal stem cells from rat amniotic fluid or bone marrow, respectively, in cryo-injured rat bladder walls. RESULTS: At 30 days after transplantation only a few fetal-type or adult-type mesenchymal stem cells gave rise to enteric or vascular smooth muscle cells, whereas most mesenchymal stem cells appeared incapable of specific differentiation. In vitro co-culture experiments of smooth muscle cells with fetal-type or adult-type mesenchymal stem cells selectively labeled with distinct fluorochromes showed the presence of hybrid cells, suggesting that some mesenchymal stem cells can undergo cell fusion. Surprisingly the major effect of rat bone marrow or amniotic fluid mesenchymal stem cell transplantation seemed to be preventing cryo-injury induced hypertrophy of surviving smooth muscle cells. CONCLUSIONS: In this model stem cell transplantation has a limited effect on smooth muscle cell regeneration. Instead it can regulate post-injury bladder remodeling, possibly via a paracrine mechanism.     

Low incidence of secondary neoplasia after autotransplantation for lymphoproliferative disease: the role of pre-transplant therapy

Abstract:  To asses the real contribution of pre-transplantation treatment in the incidence of secondary neoplasia after autologous transplant for lymphoproliferative disorders, we used stringent inclusion/exclusion criteria. One hundred and forty-two patients out of 323 that underwent autologous transplantation for lymphoproliferative disorders were studied. The risk factors that were evaluated with univariate and multivariate analysis included: gender, sex, age, diagnosis, radiotherapy, and chemotherapy prior to conditioning regimen, disease status at peripheral blood stem-cell transplantation (PBSCT) and type of harvest. Three patients developed secondary myelodysplastic syndrome/acute myeloid leukemia (sMDS/AML) and three patients developed solid neoplasia. By univariate analysis diagnosis chronic lymphocytic leukemia and use of fludarabine and monoclonal antibodies were the only variables significantly associated with the development of sMDS/AML. By multivariate analysis, the variables associated with sMDS/AML were the use of fludarabine and disease status at PBSCT. By univariate analysis, we found that radiotherapy and the use of monoclonal antibodies were significantly associated with the development of secondary solid neoplasia. Multivariate analysis confirmed that the only two variables significantly associated with new cancers were radiotherapy and prior treatment with monoclonal antibodies. We report the lowest incidence of sMDS/AML after autologous stem-cell transplantation for lymphoproliferative malignancies. Major reasons could be ascribed to the stringent inclusion/exclusion criteria used to establish the real incidence of sMDS/AML because of chemo-radiotherapy used before transplant procedure. The low incidence of secondary solid tumors could be caused by the absence of total body irradiation as part of the conditioning regimen or the short follow-up.     

Cobalt protoporpyhrin reduces caspase-3,-7 enzyme activity in neonatal porcine islets, but does not inhibit cell death induced by TNF-alpha

Apoptotic phenomena observed in vitro following isolation and following transplantation contribute significantly to islet graft loss. Strategies to reduce apoptosis of islet tissue prior to and posttransplantation may improve graft survival and function and reduce the amount of tissue necessary to achieve insulin independence. The expression of cytoprotective proteins is one such strategy that may prolong islet survival. In this light, heme-oxygenase 1 (HO-1) upregulation has been studied in both allo- and xenotransplantation models. In this study, the effect of HO-1 on apoptosis in neonatal porcine islet-like cell clusters (NPICC) was assessed. In in vitro assessments of NPICC apoptosis, NPICC showed a high sensitivity to apoptotic stimulation using a combination of TNF-alpha and cycloheximide. Stimulation with TNF-alpha alone was sufficient to induce reproducible apoptotic responses as demonstrated by caspase-3,-7 activation and subdiploid DNA analysis. Dose-dependent, high-level HO-1 protein expression was achieved following culture of NPICC in medium containing either cobalt protoporphyrin (CoPP) or cobalt mesoporphyrin (CoMP). CoPP treatment resulted in the reduction of caspase-3,-7 enzyme activity following TNF-alpha stimulation. However, such an effect was not associated with a reduction in the levels of cell death. Indeed, the inhibition of caspase enzyme activity resulted in decreased PARP-1 cleavage, which may lead to heightened levels of necrosis in treated NPICC cultures, possibly explaining the observed commitment of NPICC to the death pathway.     

Absence of epidermal growth factor receptor gene mutations in patients with hormone refractory prostate cancer not responding to gefitinib

BACKGROUND: Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in human cancers are associated with increased sensitivity to anilinoquinazoline EGFR inhibitors. To our knowledge no data have been reported on EGFR gene mutations in hormone refractory prostate cancer (HRPC). METHODS: Between March 2003 and December 2004, 23 patients with HRPC received 250 mg oral gefitinib daily in addition to antiandrogen plus luteinizing hormone-releasing hormone (LH-RH) analog for at least 2 months or until disease progression. Patients with unresected prostate cancer prospectively underwent trans-rectal biopsy of primary tumor (before starting gefitinib treatment). RESULTS: None of the patients demonstrated PSA or objective response to gefitinib. We sequenced exons 18-21 of the EGFR TK domain from genomic DNA isolated from 8 HRPC patients. No patient showed EGFR TK domain mutations. CONCLUSIONS: Our results show EGFR mutations did not occur in these patients suggesting that gefitinib is unlikely to be effective in patients with tumors not harboring specific EGFR TK domain.     

Electronic media communication with friends from 2002 to 2006 and links to face-to-face contacts in adolescence: an HBSC study in 31 European and North American countries and regions

Objective:  

Because the potential for electronic media communication (EMC) has increased greatly, it is of interest to describe trends in EMC between adolescents and their friends and to investigate whether EMC facilitate or supersede face-to-face contacts among peers.     

Different mechanisms of inhibition of nerve terminals by botulinum and snake presynaptic neurotoxins

The different mode of action on peripheral nerve terminals of the botulinum neurotoxins and of the snake presynaptic phospholipase A2 neurotoxins is reviewed here. These two groups of toxins are highly toxic because they are neurospecific and at the same time are enzymes that can modify many substrate molecules before being inactivated. The similarity of symptoms they cause in humans derives from the fact that both botulinum neurotoxins (seven serotypes named A-G) and snake presynaptic PLA2 neurotoxins block the nerve terminals and that peripheral cholinergic terminals are major targets. Given this general similarity of targets and clinical symptoms, the specific molecular and cellular mechanisms at the basis of their action are very different. This difference appears evident from the beginning of intoxication, i.e. neurotoxins binding to peripheral nerve terminals and proceeds with the different site of actions and molecular targets.