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The purpose of this study was to evaluate human umbilical cord blood as an alternative to bone marrow in the provision of transplantable stem/progenitor cells for hematopoietic reconstitution. Although no direct quantitative assay for human hematopoietic repopulating cells is at present available, the granulocyte-macrophage progenitor cell (CFU-GM) assay has been used with success as a valid indicator of engrafting capability. We examined greater than 100 collections of human umbilical cord blood for their content of nucleated cells and granulocyte-macrophage, erythroid (BFU-E), and multipotential (CFU-GEMM) progenitor cells, in many cases both before and after cryopreservation. First it was determined that granulocyte-macrophage, erythroid, and multipotential progenitor cells remained functionally viable in cord blood untreated except for addition of anticoagulant for at least 3 days at 4 degrees C or 25 degrees C (room temperature), though not at 37 degrees C, implying that these cells could be satisfactorily studied and used or cryopreserved for therapy after transport of cord blood by overnight air freight carriage from a remote obstetrical service. Granulocyte-macrophage progenitor cells from cord blood so received responded normally to stimulation by purified recombinant preparations of granulocyte-macrophage, granulocyte, and macrophage colony-stimulating factors and interleukin 3. The salient finding, based on analysis of 101 cord blood collections, is that the numbers of progenitor cells present in the low-density (less than 1.077 gm/ml) fraction after Ficoll/Hypaque separation typically fell within the range that has been reported for successful engraftment by bone marrow cells. Another observation of practical importance is that procedures to remove erythrocytes or granulocytes prior to freezing, and washing of thawed cells before plating, entailed large losses of progenitor cells, the yield of unwashed progenitor cells from unfractionated cord blood being many times greater. The provisional inference is that human umbilical cord blood from a single individual is typically a sufficient source of cells for autologous (syngeneic) and for major histocompatibility complex-matched allogeneic hematopoietic reconstitution.

Graft versus host disease (GVHD), mediated by donor T cells, is a significant source of morbidity and mortality following allogeneic stem cell transplantation. Mesenchymal stem cells (MSC) can successfully treat ongoing graft versus host disease, presumably due to their ability to suppress donor T cell proliferation. Little is known about the potential of MSC to prevent GVHD. Here we show that bone marrow-isolated MSC can suppress the development of GVHD if given after donor T cell recognition of antigen. IFN-c was required to initiate MSC efficacy. Recipients of IFN-c -/-T cells did not respond to MSC treatment and succumbed to GVHD. MSC, pre-treated with IFN-c, became immediately active and could suppress GVHD more efficiently than a fivefold-greater number of MSC that were not activated. When given at the time of bone marrow transplantation, activated MSC could prevent GVHD mortality (100% survival, p=0.006). MSC activation was dependent on the magnitude of IFN-c exposure, with increased IFN-c exposure leading to increased MSC suppression of GVHD. Activated MSC present a new strategy for preventing GVHD using fewer MSC. Key words: Mesenchymal stem cell Á GVH disease Á IFN-c See accompanying commentary by Dazzi and Marelli-Berg IntroductionAllogeneic hematopoietic stem cell transplants have the potential to play a significant curative role in the treatment of malignant and non-malignant hematopoietic disorders, autoimmune diseases, and immunological deficiencies, and in the induction of transplantation tolerance [1][2][3][4][5][6][7][8][9][10]. Widespread application of this therapeutic modality is limited due to the morbidity and mortality of graft versus host disease (GVHD), which affects 50% of stem cell transplant recipients [11][12][13][14][15][16]. While grafts highly matched to the recipient, young donors, donor/recipient sex match, and posttransplant immunosuppression are strategies used to reduce the risk of GVHD [17], thus far, the greatest preventative measure has been intentional underutilization of stem cell transplantation. Theoretically, strategies aimed at preventing GVHD would target early initiating factors either during the inflammatory milieu created in the wake of tissue damage from conditioning regimens [18,19] or during T cell antigen recognition and proliferation [20,21]. Once the efferent effector phase occurs, donor T cell-mediated destruction of host tissues occurs and preventive strategies are replaced with treatment regimens [19].Mesenchymal stem cells (MSC) have been used in the efferent phase of GVHD to successfully treat ongoing, acute, steroidresistant GVHD [22,23]. In contrast, when given at the time of BM transplant, for the prevention of GVHD, the incidence of grade III/ IV GVHD was not significantly improved [24], suggesting the [26,27,29,30]. In addition, MSC do not suppress the modest T cell proliferative response to recall antigens [31]. These findings suggest MSC may exert their optimal effects during the events surrounding larger scale T cell activation and proliferat...

et al. Comparison of the effectiveness of inhaler devices in asthma and chronic obstructive airways disease: a systematic review of the literature. Health Technol Assess 2001;5(26). Health Technology Assessment is indexed in Index Medicus/MEDLINE and Excerpta Medica/ EMBASE. Copies of the Executive Summaries are available from the NCCHTA website (see opposite). NHS R&D HTA Programme T he NHS R&D Health Technology Assessment (HTA) Programme was set up in 1993 to ensure that high-quality research information on the costs, effectiveness and broader impact of health technologies is produced in the most efficient way for those who use, manage and provide care in the NHS. Initially, six HTA panels (pharmaceuticals, acute sector, primary and community care, diagnostics and imaging, population screening, methodology) helped to set the research priorities for the HTA Programme. However, during the past few years there have been a number of changes in and around NHS R&D, such as the establishment of the National Institute for Clinical Excellence (NICE) and the creation of three new research programmes: Service Delivery and Organisation (SDO); New and Emerging Applications of Technology (NEAT); and the Methodology Programme. This has meant that the HTA panels can now focus more explicitly on health technologies ('health technologies' are broadly defined to include all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care) rather than settings of care. Therefore the panel structure has been redefined and replaced by three new panels: Pharmaceuticals; Therapeutic Procedures (including devices and operations); and Diagnostic Technologies and Screening. The HTA Programme will continue to commission both primary and secondary research. The HTA Commissioning Board, supported by the National Coordinating Centre for Health Technology Assessment (NCCHTA), will consider and advise the Programme Director on the best research projects to pursue in order to address the research priorities identified by the three HTA panels. The research reported in this monograph was funded as project number 97/23/02. The views expressed in this publication are those of the authors and not necessarily those of the HTA Programme or the Department of Health. The editors wish to emphasise that funding and publication of this research by the NHS should not be taken as implicit support for any recommendations made by the authors. Criteria for inclusion in the HTA monograph series Reports are published in the HTA monograph series if (1) they have resulted from work commissioned for the HTA Programme, and (2) they are of a sufficiently high scientific quality as assessed by the referees and editors. Reviews in Health Technology Assessment are termed 'systematic' when the account of the search, appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the replication of the review by others.

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Rationale: Cohort studies suggest that airflow obstruction is established early in life, manifests as childhood asthma and wheezy bronchitis, and continues into early adulthood. Although an association between childhood asthma and chronic obstructive pulmonary disease (COPD) in later life has been demonstrated, it is unclear if childhood wheezy bronchitis is associated with COPD.Objectives: To investigate whether childhood wheezy bronchitis increases the risk of COPD in the seventh decade.Methods: A cohort of children recruited in 1964 at age 10 to 15 years, which was followed up in 1989, 1995, and 2001, was followed up again in 2014 when at age 60 to 65 years. Discrete time-to-event and linear mixed effects models were used.Measurements and Main Results: FEV 1 and FVC were measured. COPD was defined as post-bronchodilator FEV 1 /FVC ,0.7. Childhood wheezing phenotype was related to 1989, 1995, 2001, and 2014 spirometry data. Three hundred thirty subjects, mean age 61 years, were followed up: 38 with childhood asthma; 53 with childhood wheezy bronchitis; and 239 control subjects (of whom 57 developed adulthood-onset wheeze between ages 16 and 46 yr). In adjusted multivariate analyses, childhood asthma was associated with an increased risk of COPD (odds ratio, 6.37; 95% confidence interval, 3.73-10.94), as was childhood wheezy bronchitis (odd ratio 1.81; 95% confidence interval, 1.12-2.91). The COPD risk increased with childhood asthma, and wheezy bronchitis was associated with reduced FEV 1 that was evident by the fifth decade and not an accelerated rate of FEV 1 decline. In contrast, adulthood-onset wheeze was associated with accelerated FEV 1 decline.Conclusions: Childhood wheezy bronchitis and asthma are associated with an increased risk of COPD and reduced ventilatory function.

There are numerous ways in which people make illegal or unauthorized alterations to urban space. This study identifies and analyzes one that has been largely ignored in social science: explicitly functional and civic-minded informal contributions that I call "do-it-yourself urban design." The research, which began as an investigation into more "traditional" nonpermissable alterations, uncovered these casesfrom homemade bike lanes and street signs to guerrilla gardens and development proposals-that are gaining visibility in many cities, yet are poorly accounted for by existing perspectives in the literature. This article examines the existing theories and evidence from interviews and other fieldwork in 14 cities in order to develop the new analytical category of DIY urban design. I present findings on the creators of these interventions, on their motivations to "improve" the built environment where they perceive government and other development actors to be failing, and on the concentration of their efforts in gentrifying areas. This introduces the possibility of conflict and complicates their impact. I argue that DIY urban design has wide-ranging implications for both local communities and broader urban policy. INTRODUCTIONIn 2010, when the City of Pittsburgh altered the traffic pattern at a hillside intersection in Lawrenceville, an area resident noticed that the change was confusing to some motorists and resulting in fender-benders. Seeing a need for better signage, he put his skills as an artist and illustrator to use, mocking up a design on his computer, using official fonts he had "picked up here and there," printing the design on a home vinyl plotter, and attaching it to an aluminum backing ("based on, you know, municipal criteria and things," he explained to me). The result, a shiny red and white sign reading "Cross Traffic Does Not Stop," was fixed to a pole below the stop sign at the intersection. Two years later it still stands as a valuable addition-as its creator observed, "there's a lot less plastic and glass in the street"-with the only indication of its origins the small lettering at the bottom that read "DIYDPW": the Do-it-Yourself Department of Public Works.This sort of personal improvement to public space is not unique. In Los Angeles, one might find a group of friends painting a new bike lane along a road under cover of night; * Correspondence should be addressed to Gordon Douglas, Dept. of Sociology, University of Chicago, 1126 E. 59th St. Chicago, IL 60637; gdouglas@uchicago.edu. in New York, a woman designing innovative public seating and attaching it to existing infrastructure to make sitting and eating lunch on the street easier; in New Orleans, neighborhood residents writing their personal redevelopment ideas directly on abandoned structures and vacant lots; in Toronto, a man converting magazine racks and corporate advertisements into miniature herb gardens. What is happening? What motivates some citizens effectively to do urban planning and design work themselves?Together, these actions...

This is a review and discussion of studies leading to the first use of human umbilical cord blood, material usually discarded, for the provision of stem/progenitor cells for clinical hematopoietic reconstitution. This prospect arose as a result of extensive studies of the harvesting and cryopreservation of cord blood and of its numerical content of progenitor cells demonstrable in vitro. A male patient with Fanconi anemia (FA) was conditioned with a modified regimen of cyclophosphamide and irradiation that accommodates the abnormally high sensitivity to these agents that is characteristic of FA. Cryopreserved cord blood had been retrieved at birth from a female sibling known from prenatal testing to be unaffected by FA and to be human leukocyte antigen (HLA)-compatible with the prospective sibling recipient. After conditioning and therapeutic infusion of thawed cord blood, successful hematopoietic reconstitution was indicated by the general health of the patient, who had previously required supportive transfusions, by satisfactory hematological criteria and by counts of hematopoietic progenitor cells of various types in the bone marrow. Complete engraftment of the myeloid system with donor cells was evident from cytogenetics, ABO typing, study of DNA polymorphisms, and normal cellular resistance to cytotoxic agents that reveal the fragility of FA cells; the blood contained a residuum of host lymphocytes exhibiting chromosomal damage, but the trend has been towards eliminating these damaged cells. This implies that cord blood from a single individual should provide sufficient reconstituting cells for effective hematopoietic repopulation of an autologous or an HLA-compatible allogeneic recipient.