Assessment of potential cardiotoxic side effects of mitoxantrone in patients with multiple sclerosis

Previous studies showed that mitoxantrone can reduce disability progression in patients with multiple sclerosis (MS). There is, however, concern that it may cause irreversible cardiomyopathy with reduced left ventricular (LV) ejection fraction (EF) and congestive heart failure. The aim of this prospective study was to investigate cardiac side effects of mitoxantrone by repetitive cardiac monitoring in MS patients. The treatment protocol called for ten courses of a combined mitoxantrone (10 mg/m(2) body surface) and methylprednisolone therapy. Before each course, a transthoracic echocardiogram was performed to determine the LV end-diastolic diameter, the end-systolic diameter and the fractional shortening; the LV-EF was calculated. Seventy-three patients participated (32 males; age 48 +/- 12 years, range 20-75 years; 25 with primary progressive, 47 with secondary progressive and 1 with relapsing-remitting MS) who received at least four courses of mitoxantrone. Three of the 73 patients were excluded during the study (2 patients discontinued therapy; 1 patient with a previous history of ischemic heart disease developed atrial fibrillation after the second course of mitoxantrone). The mean cumulative dose of mitoxantrone was 114.0 +/- 33.8 mg. The mean follow-up time was 23.4 months (range 10-57 months). So far, there has been no significant change in any of the determined parameters (end-diastolic diameter, end-systolic diameter, fractional shortening, EF) over time during all follow-up investigations. Mitoxantrone did not cause signs of congestive heart failure in any of the patients. Further cardiac monitoring is, however, needed to determine the safety of mitoxantrone after longer follow-up times and at higher cumulative doses. Copyright (C) 2005 S. Karger AG, Basel

How does mental health care perform in respect to service users' expectations? Evaluating inpatient and outpatient care in Germany with the WHO responsiveness concept

<p>Abstract</p> <p>Background</p> <p>Health systems increasingly try to make their services more responsive to users' expectations. In the context of the World Health Report 2000, WHO developed the concept of health system <it>responsiveness </it>as a performance parameter. <it>Responsiveness </it>relates to the system's ability to respond to service users' legitimate expectations of non-medical aspects. We used this concept in an effort to evaluate the performance of mental health care in a catchment area in Germany.</p> <p>Methods</p> <p>In accordance with the method WHO used for its <it>responsiveness </it>survey, <it>responsiveness </it>for inpatient and outpatient mental health care was evaluated by a standardised questionnaire. <it>Responsiveness </it>was assessed in the following domains: <it>attention, dignity</it>, <it>clear communication</it>, <it>autonomy, confidentiality, basic amenities, choice </it>of health care provider, <it>continuity</it>, and <it>access to social support</it>. Users with complex mental health care needs (i.e., requiring social and medical services or inpatient care) were recruited consecutively within the mental health services provided in the catchment area of the Hanover Medical School.</p> <p>Results</p> <p>221 persons were recruited in outpatient care and 91 in inpatient care. Inpatient service users reported poor <it>responsiveness </it>(22%) more often than outpatients did (15%); however this was significant only for the domains <it>dignity </it>and <it>communication</it>. The best performing domains were <it>confidentiality </it>and <it>dignity</it>; the worst performing were <it>choice</it>, <it>autonomy </it>and <it>basic amenities </it>(only inpatient care). <it>Autonomy </it>was rated as the most important domain, followed by <it>attention </it>and <it>communication</it>. <it>Responsiveness </it>within outpatient care was rated worse by people who had less money and were less well educated. Inpatient <it>responsiveness </it>was rated better by those with a higher level of education and also by those who were not so well educated. 23% of participants reported having been discriminated against in mental health care during the past 6 months.</p> <p>The results are similar to prior <it>responsiveness </it>surveys with regard to the overall better performance of outpatient care. Where results differ, this can best be explained by certain characteristics that are applicable to mental health care and also by the users with complex needs. The expectations of <it>attention </it>and <it>autonomy</it>, including participation in the treatment process, are not met satisfactorily in inpatient and outpatient care.</p> <p>Conclusion</p> <p><it>Responsiveness </it>as a health system performance parameter provides a refined picture of inpatient and outpatient mental health care. Reforms to the services provided should be orientated around domains that are high in importance, but low in performance. Measuring <it>responsiveness </it>could provide well-grounded guidance for further development of mental health care systems towards becoming better patient-orientated and providing patients with more respect.</p

Genetic Evidence That the Non-Homologous End-Joining Repair Pathway Is Involved in LINE Retrotransposition

Long interspersed elements (LINEs) are transposable elements that proliferate within eukaryotic genomes, having a large impact on eukaryotic genome evolution. LINEs mobilize via a process called retrotransposition. Although the role of the LINE-encoded protein(s) in retrotransposition has been extensively investigated, the participation of host-encoded factors in retrotransposition remains unclear. To address this issue, we examined retrotransposition frequencies of two structurally different LINEs—zebrafish ZfL2-2 and human L1—in knockout chicken DT40 cell lines deficient in genes involved in the non-homologous end-joining (NHEJ) repair of DNA and in human HeLa cells treated with a drug that inhibits NHEJ. Deficiencies of NHEJ proteins decreased retrotransposition frequencies of both LINEs in these cells, suggesting that NHEJ is involved in LINE retrotransposition. More precise characterization of ZfL2-2 insertions in DT40 cells permitted us to consider the possibility of dual roles for NHEJ in LINE retrotransposition, namely to ensure efficient integration of LINEs and to restrict their full-length formation

Imaging Single Retrovirus Entry through Alternative Receptor Isoforms and Intermediates of Virus-Endosome Fusion

A large group of viruses rely on low pH to activate their fusion proteins that merge the viral envelope with an endosomal membrane, releasing the viral nucleocapsid. A critical barrier to understanding these events has been the lack of approaches to study virus-cell membrane fusion within acidic endosomes, the natural sites of virus nucleocapsid capsid entry into the cytosol. Here we have investigated these events using the highly tractable subgroup A avian sarcoma and leukosis virus envelope glycoprotein (EnvA)-TVA receptor system. Through labeling EnvA pseudotyped viruses with a pH-sensitive fluorescent marker, we imaged their entry into mildly acidic compartments. We found that cells expressing the transmembrane receptor (TVA950) internalized the virus much faster than those expressing the GPI-anchored receptor isoform (TVA800). Surprisingly, TVA800 did not accelerate virus uptake compared to cells lacking the receptor. Subsequent steps of virus entry were visualized by incorporating a small viral content marker that was released into the cytosol as a result of fusion. EnvA-dependent fusion with TVA800-expressing cells occurred shortly after endocytosis and delivery into acidic endosomes, whereas fusion of viruses internalized through TVA950 was delayed. In the latter case, a relatively stable hemifusion-like intermediate preceded the fusion pore opening. The apparent size and stability of nascent fusion pores depended on the TVA isoforms and their expression levels, with TVA950 supporting more robust pores and a higher efficiency of infection compared to TVA800. These results demonstrate that surface receptor density and the intracellular trafficking pathway used are important determinants of efficient EnvA-mediated membrane fusion, and suggest that early fusion intermediates play a critical role in establishing low pH-dependent virus entry from within acidic endosomes

Reprogramming triggers endogenous L1 and Alu retrotransposition in human induced pluripotent stem cells

Human induced pluripotent stem cells (hiPSCs) are capable of unlimited proliferation and can differentiate in vitro to generate derivatives of the three primary germ layers. Genetic and epigenetic abnormalities have been reported by Wissing and colleagues to occur during hiPSC derivation, including mobilization of engineered LINE-1 (L1) retrotransposons. However, incidence and functional impact of endogenous retrotransposition in hiPSCs are yet to be established. Here we apply retrotransposon capture sequencing to eight hiPSC lines and three human embryonic stem cell (hESC) lines, revealing endogenous L1, Alu and SINE-VNTR-Alu (SVA) mobilization during reprogramming and pluripotent stem cell cultivation. Surprisingly, 4/7 de novo L1 insertions are full length and 6/11 retrotransposition events occurred in protein-coding genes expressed in pluripotent stem cells. We further demonstrate that an intronic L1 insertion in the CADPS2 gene is acquired during hiPSC cultivation and disrupts CADPS2 expression. These experiments elucidate endogenous retrotransposition, and its potential consequences, in hiPSCs and hESCs