Reduced cellularity of bone marrow in multiple sclerosis with decreased MSC expansion potential and premature ageing in vitro

Background: Autologous bone-marrow-derived cells are currently employed in clinical studies of cell-based therapy in multiple sclerosis (MS) although the bone marrow microenvironment and marrow-derived cells isolated from patients with MS have not been extensively characterised. Objectives: To examine the bone marrow microenvironment and assess the proliferative potential of multipotent mesenchymal stromal cells (MSCs) in progressive MS. Methods: Comparative phenotypic analysis of bone marrow and marrow-derived MSCs isolated from patients with progressive MS and control subjects was undertaken. Results: In MS marrow, there was an interstitial infiltrate of inflammatory cells with lymphoid (predominantly T-cell) nodules although total cellularity was reduced. Controlling for age, MSCs isolated from patients with MS had reduced in vitro expansion potential as determined by population doubling time, colony-forming unit assay, and expression of β-galactosidase. MS MSCs expressed reduced levels of Stro-1 and displayed accelerated shortening of telomere terminal restriction fragments (TRF) in vitro. Conclusion: Our results are consistent with reduced proliferative capacity and ex vivo premature ageing of bone-marrow-derived cells, particularly MSCs, in MS. They have significant implication for MSC-based therapies for MS and suggest that accelerated cellular ageing and senescence may contribute to the pathophysiology of progressive MS. </jats:sec

Extensive cardiac infiltration in acute T-cell lymphoblastic leukemia:occult extra-medullary relapse and remission after salvage chemotherapy

none5noneBaritussio, Anna; Gately, Amy; Pawade, Joya; Marks, David I.; Bucciarelli-Ducci, ChiaraBaritussio, Anna; Gately, Amy; Pawade, Joya; Marks, David I.; Bucciarelli-Ducci, Chiar

Alemtuzumab-based therapy for Secondary Malignant Histiocytosis arising from Pre-B-ALL

Clinical Practice Points: • Secondary Malignant Histiocytosis (SMH) is an exceedingly rare, life-threatening condition that invariably occurs in the presence of an underlying monoclonal hematologic disorder. Prognosis of SMH remains dismal and there is no established treatment. • We report a case of a patient who developed SMH during induction chemotherapy for his underlying pre-B-ALL, that caused persistently high fevers and was only diagnosed by a marrow while cytopenic in phase 2 induction. He was treated with alemtuzumab-based therapy that reduced the histiocytic infiltration of the bone marrow from 80% to 15% and made him eligible to undergo T-cell replete allogeneic stem transplantation from his sibling. • This report is the first to highlight the role of alemtuzumab, an anti-CD52 monoclonal antibody, in clonal disorders originating from transdifferentiation. • The alemtuzumab-based regimen should be reserved only for carefully selected allogeneic transplant patients. Keywords: Secondary Malignant Histiocytosis (SMH), Pre-B-Cell Acute Lymphoblastic Leukemia (Pre-B-ALL), Transdifferentiation, C/EBPα, PAX

Simplicial quantum dynamics

Present-day quantum field theory can be regularized by a decomposition into quantum simplices. This replaces the infinite-dimensional Hilbert space by a high-dimensional spinor space and singular canonical Lie groups by regular spin groups. It radically changes the uncertainty principle for small distances. Gaugeons, including the gravitational, are represented as bound fermion-pairs, and space-time curvature as a singular organized limit of quantum non-commutativity. Keywords: Quantum logic, quantum set theory, quantum gravity, quantum topology, simplicial quantization.Comment: 25 pages. 1 table. Conference of the International Association for Relativistic Dynamics, Taiwan, 201

One-Antigen Mismatched Related versus HLA-Matched Unrelated Donor Hematopoietic Stem Cell Transplantation in Adults with Acute Leukemia: Center for International Blood and Marrow Transplant Research Results in the Era of Molecular HLA Typing

Approximately 13% of patients lacking an HLA-identical sibling have a one-antigen–mismatched related donor (MMRD). Historically, outcomes from the use of a one-antigen MMRD were considered equivalent to those from the use of a matched unrelated donor (UD). Recent improvements in UD stem cell transplantation (SCT) resulting from better molecular HLA matching justifies investigating whether UD should be preferred over MMRD in adult patients with acute leukemia. Here, we compared the outcomes of MMRD (n = 89) and HLA-A, -B, -C, and -DRB1 allele–matched UD (n = 700) SCT reported to the Center for International Blood and Marrow Transplant Research between 1995 and 2005. The patients underwent transplantation for acute myelogenous leukemia or acute lymphoblastic leukemia in first or second complete remission. Donor type was not associated with hematologic recovery. Univariate and multivariate comparisons of MMRD versus HLA-matched UD transplants showed no statistically significant differences in overall survival, disease-free survival, treatment-related mortality, relapse, or 100-day grade III-IV acute graft-versus-host disease (GVHD). MMRD SCT was associated with a lower rate of chronic GVHD at 1 year (35% vs 47%; P = .03), which was confirmed by multivariate analysis (relative risk, 0.58; 95% confidence interval, 0.39-0.85; P < .01). According to our data, HLA-matched UD and MMRD SCT are associated with comparable survival. Given that less chronic GVHD was observed in the MMRD transplantations, this option, when available, remains the first choice in patients with acute leukemia without an HLA-identical sibling in need of allogeneic SCT

Advising patients seeking stem cell interventions for multiple sclerosis

The topicality of the article. The article shows the impossibility of a clear definition of the ability at a certain stage of human development, as well as their ability changes under the influence of systematic training. The potential identification at early age will improve the efficiency of the process of selection and orientationof sports training and long-term process of athletic improvement. The above-mentioned issues make itpossible to conduct the complex approach to sports selection and orientation of training at all stages oflong-term improvement. Experts recommended the selection and sports orientation is based on geneticmarkers that allow us to determine the genetic inclinations of the children. A new approach to finding the most talented athletes, based on the study of their genetically determined inclinations, one of which is functional asymmetry. The purpose of the research was to study peculiarities of selection of children at the initial stage of training in various sports and to determine generic criteria for the beginners’ selection. The results of the research. In the article the peculiarities of selection of children at the initial stage of training in various sports, defined generalized selection criteria: health status, physical abilities, coordination abilities, body сconstitution, mental warehouse of the individual, motivation. Conclusions. The decision to bringthe student to attend school in a certain sport should be based on a&nbsp;comprehensive assessment. Theparticular importance of an integrated approach in the selection at the initial stage due to the fact thatathletic performance at this stage almost does not contain information about the prospects of a youngathlete.Актуальность. В статье указана невозможность четкого определения способностей на определенном этапе развития человека, а также их способность к изменениям под влиянием систематических тренировок. Определение задатков в раннем возрасте позволит повысить эффективность как процессаотбора и ориентации спортивной подготовки, так и многолетнего процесса спортивного совершенствования. Это обусловливает осуществление комплексного подхода к спортивному отбору и ориентации подготовки на всех этапах многолетнего совершенствования. Специалисты рекомендуют осуществлять отбор и спортивную ориентацию на основании генетических маркеров, которые позво-ляют определить генетические задатки детей. Предложен новый подход к поиску наиболее одаренных спортсменов, основанных на изучении их генетически детерминированных задатков, одним из которых является функциональная асимметрия. Цель исследований – изучить особенности отбора детей на начальном этапе подготовки в различных видах спорта и определить обобщенные критерииотбора начинающих. Результаты исследований. В статье рассмотрены особенности отбора детей на начальном этапе подготовки в различных видах спорта, определены обобщенные критерии отбора начинающих: состояние здоровья, физические, координационные способности, конституция тела, психический склад личности, мотивация. Выводы. Решение о привлечении ребенка к занятиям определенным видом спорта&nbsp;должно основываться на комплексной оценке. Особая важность комплексного подхода при отборе на начальном этапе обусловлена тем, что спортивный результат на этом этапе практически не несет информации о перспективности юного спортсмена.Актуальність. У статті зазначено неможливість чіткого визначення здібностей на певному&nbsp;етапі розвитку людини, а так&nbsp;само їхню здатність до змін під&nbsp;впливом систематичних тренувань. Виявлення задатків у ранньому віці дасть змогу підвищити ефективність процесу відбору й орієнтації спортивної&nbsp;підготовки, багаторічного процесу спортивного вдосконалення. Це обумовлює здійснення&nbsp;комплексного підходу до спортивного відбору та орієнтації&nbsp;підготовки на всіх етапах багаторічного вдосконалення. Фахівці рекомендують виконувати&nbsp;відбір і спортивну орієнтацію&nbsp;на підставі генетичних маркерів, які уможливлюють визначення генетичних задатків дітей. Запропоновано новий підхід до пошуку найбільш обдарованих спортсменів, заснованих на вивченні їхніх генетично&nbsp;детермінованих задатків, одним&nbsp;із яких є функціональнаасиметрія. Мета досліджень –&nbsp;розглянути особливості відбору&nbsp;дітей на початковому етапі підготовки в різних видах спорту&nbsp;та визначити узагальнені критерії відбору початківців. Результати досліджень. У статтірозглянуто особливості відбору&nbsp;дітей на початковому етапі&nbsp;підготовки в різних видах&nbsp;спорту, визначено узагальнення&nbsp;критерії відбору початківців:&nbsp;стан здоровʼя, фізичні, координаційні здібності, конституція&nbsp;тіла, психічний склад особистості, мотивація. Висновки. Рішення про залучення дитини до&nbsp;занять певним видом спорту повинно ґрунтуватися на комплексній оцінці. Особлива важливість комплексного підходу при відборі на початковому етапі обумовлена тим, що спортивний результат на цьому етапі практично не несе інформації про перспективність юного спортсмена

Advising patients seeking stem cell interventions for multiple sclerosis

Given the intuitive potential of stem cell therapy and limitations of current treatment options for progressive multiple sclerosis (MS), it is not surprising that patients consider undertaking significant clinical and financial risks to access stem cell transplantation. However, while increasing evidence supports autologous haematopoietic stem cell transplantation (AHSCT) in aggressive relapsing–remitting MS, interventions employing haematopoietic or other stem cells should otherwise be considered experimental and recommended only in the context of a properly regulated clinical study. Understandably, most neurologists are unfamiliar with AHSCT procedures and the specific requirements for quality assurance and safety standards, as well as post-procedure precautions and follow-up. Consequently they may feel ill-equipped to advise patients. Here, we highlight important points for discussion in consultations with patients considering stem cell ‘tourism’ for MS.</jats:p

Assessment of bone marrow-derived Cellular Therapy in progressive Multiple Sclerosis (ACTiMuS):study protocol for a randomised controlled trial

BACKGROUND: We have recently completed an evaluation of the safety and feasibility of intravenous delivery of autologous bone marrow in patients with progressive multiple sclerosis (MS). The possibility of repair was suggested by improvement in the neurophysiological secondary outcome measure seen in all participants. The current study will examine the efficacy of intravenous delivery of autologous marrow in progressive MS. Laboratory studies performed in parallel with the clinical trial will further investigate the biology of bone marrow-derived stem cell infusion in MS, including mechanisms underlying repair. METHODS/DESIGN: A prospective, randomised, double-blind, placebo-controlled, stepped wedge design will be employed at a single centre (Bristol, UK). Eighty patients with progressive MS will be recruited; 60 will have secondary progressive disease (SPMS) but a subset (n = 20) will have primary progressive disease (PPMS). Participants will be randomised to either early or late (1 year) intravenous infusion of autologous, unfractionated bone marrow. The placebo intervention is infusion of autologous blood. The primary outcome measure is global evoked potential derived from multimodal evoked potentials. Secondary outcome measures include adverse event reporting, clinical (EDSS and MSFC) and self-assessment (MSIS-29) rating scales, optical coherence tomography (OCT) as well as brain and spine MRI. Participants will be followed up for a further year following the final intervention. Outcomes will be analysed on an intention-to-treat basis. DISCUSSION: Assessment of bone marrow-derived Cellular Therapy in progressive Multiple Sclerosis (ACTiMuS) is the first randomised, placebo-controlled trial of non-myeloablative autologous bone marrow-derived stem cell therapy in MS. It will determine whether bone marrow cell therapy can, as was suggested by the phase I safety study, improve conduction in multiple central nervous system pathways affected in progressive MS. Furthermore, laboratory studies performed in parallel with the clinical trial will inform our understanding of the cellular pharmacodynamics of bone marrow infusion in MS patients and the mechanisms underlying cell therapy. TRIAL REGISTRATION: ISRCTN27232902 Registration date 11/09/2012. NCT01815632 Registration date 19/03/201