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Major Barrier (major + barrier)
Selected AbstractsAccess to essential drugs in Guyana: a public health challenge,,INTERNATIONAL JOURNAL OF HEALTH PLANNING AND MANAGEMENT, Issue 1 2010Enrique Seoane-Vazquez Abstract Guyana's pharmaceutical sector faces major challenges that limit access to essential drugs. This study analyzes Guyana's drug policy and regulation, public financing, and drug procurement and delivery. The study also identifies main barriers to drug access and proposes alternatives to strengthen the country's public health functions. Data were collected from the country's regulatory agencies, public procurement agency, pharmacies, wholesalers, and pharmaceutical companies. The information was supplemented with interviews with a convenient sample of Guyanese health authorities and stakeholders. Data were also compiled from scientific databases, and web pages of the country's Ministries of Health, Commerce and Finance, the Bureau of Statistics, and international organizations. Major barriers to drug access include: (1) lack of national drug policy and regulation, and limited role of the regulatory authority; (2) inefficient drug selection and irrational drug use; (3) insufficient financial resources and lack of drug pricing policy; (4) inefficient planning and managing public supply system; (5) deficient epidemiological and information systems; and (6) inadequate infrastructures and human resources shortage. Improving drug access in Guyana requires the strengthening of the country's public health functions and the implementation of a national drug policy and pricing policy, streamlining the drug financing, procurement, and planning and managing drug supply; and adequate infrastructures and human resources. Copyright © 2008 John Wiley & Sons, Ltd. [source] Barriers to the self-care of type 2 diabetes from both patients' and providers' perspectives: literature reviewJOURNAL OF NURSING AND HEALTHCARE OF CHRONIC ILLNE SS: AN INTERNATIONAL INTERDISCIPLINARY JOURNAL, Issue 1 2009Sandra PY Pun MHA Aim., To review systematically the literature about barriers to diabetes self-care from both patients' and healthcare providers' perspectives. Background., Diabetes mellitus is a global health concern due to rapidly increasing prevalence. The healthcare costs for diabetes care and related complications are high. Tight glycaemic control achieved by intensive therapy has been shown to lower the risk of complications. Despite the provision of comprehensive management programmes, patients are often unable to achieve the desired outcomes. It is essential to understand the barriers to diabetes self-care in order to promote successfully self-care behaviours. Methods., A search of OVID Medline (R), CINAHL, Cochrane Library and British Nursing Index was carried out during 1986,2007 using keywords: Type 2 Diabetes Mellitus, self care, patient compliance, patient adherence and barriers to diabetes self care. Manual searching of relevant nursing journals and sourcing of secondary research extended the search. Results., A total of 16 original research papers using various methods including survey, descriptive correlational, sequential explanatory mixed-method and qualitative exploratory design were reviewed. In total, over 8900 patients and 4550 healthcare providers were recruited from over 28 countries in these studies. Major barriers identified included psychosocial, socioeconomic, physical, environmental and cultural factors. Conclusions., Healthcare providers can enhance patient empowerment and participation with family support to achieve feasible targets. Better health care delivery systems and reforms that improve affordability, accessibility, and efficiency of care are essential for helping both providers and patients to meet desirable standards of diabetes care. Relevance to clinical practice., Understanding barriers to diabetes self-care is the first step in facilitating providers to identify their role in enabling patients to overcome these barriers. Healthcare providers can develop strategies to clarify and individualise treatment guidelines, implement continuing education, improve communication skills, and help motivate patients to achieve desired behavioral changes. [source] Health care for childhood cancer survivorsCANCER, Issue 4 2004Insights, perspectives from a Delphi panel of young adult survivors of childhood cancer Abstract BACKGROUND Most children diagnosed with cancer are surviving into adulthood but are not receiving adequate or appropriate follow-up health care. However, to the authors' knowledge, there is little literature published to date exploring potential barriers to long-term risk-based follow-up care for young adult survivors of childhood cancer. METHODS In the current study, using a modified Delphi technique, young adult cancer survivors identified barriers to utilizing appropriate follow-up care and offered suggestions for ways to enhance health care in this young adult population. RESULTS Major barriers to health care were found to be a lack of knowledge on the part of both physicians and survivors regarding long-term health issues related to cancer. Suggestions to enhance care included self-advocacy training for survivors and advanced training for primary care physicians who may treat childhood cancer survivors as they transition into adulthood. CONCLUSIONS The results of the current study are consistent with reports that young adult survivors of childhood cancer need or desire information regarding their medical histories, psychosocial support, and social advocacy. Cancer 2004;100:843,50. © 2004 American Cancer Society. [source] A review of basal insulinsDIABETIC MEDICINE, Issue 11 2003Anthony H. Barnett Abstract Tight glycaemic control (ideally, HbA1c < 7%) is central to reducing the risk of long-term complications of diabetes. This approach, for both Type 1 and Type 2 diabetes, commonly involves the use of basal insulin, and must be achieved with minimal risk of hypoglycaemia (particularly nocturnal episodes). Indeed, concern around hypoglycaemia is a major barrier to achieving tight glycaemic control, and is a common problem with those protracted-acting insulins most frequently used in clinical practice for basal insulin supply. Other drawbacks include inter- and intra-patient variability that compromises dosing reproducibility and unsuitability for single daily dosing. New long-acting human insulin analogues with action profiles designed to overcome these problems are now available in clinical practice or are under evaluation in clinical trials. Clinical evidence suggests efficacy and safety advantages for these analogues over NPH insulin (the most commonly used basal insulin), and may bring closer the goal of tight glycaemic control in patients with diabetes. [source] Neuropeptides and appetite controlDIABETIC MEDICINE, Issue 8 2002J. P. H. Wilding Abstract Obesity is important in the aetiology of type 2 diabetes, and presents a major barrier to its successful prevention and management. Obesity develops when energy intake exceeds energy expenditure over time. A complex system has evolved to maintain energy homeostasis, but this is biased towards weight gain. Meal size is controlled by a series of short-term hormonal and neural signals that derive from the gastrointestinal tract, such as cholecystokinin whereas others may initiate meals, such as the recently discovered hormone, ghrelin. Other hormones such as insulin and leptin, together with circulating nutrients, indicate long-term energy stores. All these signals act at several central nervous system (CNS) sites but the pathways converge on the hypothalamus, which contains a large number of peptide and other neurotransmitters that influence food intake. As energy deficit is most likely to compromise survival, it is not surprising that the most powerful of these pathways are those that increase food intake and decrease energy expenditure when stores are depleted. When energy stores are low, production of leptin from adipose tissue, and thus circulating leptin concentrations fall, leading to increased production of hypothalamic neurotransmitters that strongly increase food intake, such as neuropeptide Y (NPY), galanin and agouti-related protein (AGRP) and decreased levels of ,-melanocyte-stimulating hormone (,-MSH), cocaine and amphetamine-regulated transcript (CART) and neurotensin that reduce food intake and increase energy expenditure. The finding that mutations in leptin and POMC lead to severe early onset obesity in bumans has highlighted the importance of these peptides in humans. This new understanding may eventually lead to new treatments for obesity that will be of particular benefit in the prevention and treatment of type 2 diabetes. Diabet. Med. 19, 619,627 (2002) [source] The Dialoguer: An Interactive Bilingual Interface to a Network Operating SystemEXPERT SYSTEMS, Issue 3 2001Emad Al-Shawakfa We have developed a bilingual interface to the Novell network operating system, called the Dialoguer. This system carries on a conversation with the user in Arabic or English or a combination of the two and attempts to help the user use the Novell network operating system. Learning to use an operating system is a major barrier in starting to use computers. There is no single standard for operating systems which makes it difficult for novice users to learn a new operating system. With the proliferation of client,server environments, users will eventually end up using one network operating system or another. These problems motivated our choice of an area to work in and they have made it easy to find real users to test our system. This system is both an expert system and a natural language interface. The system embodies expert knowledge of the operating system commands and of a large variety of plans that the user may want to carry out. The system also contains a natural language understanding component and a response generation component. The Dialoguer makes extensive use of case frame tables in both components. Algorithms for handling a bilingual dialogue are one of the important contributions of this paper along with the Arabic case frames. [source] The application of an empowerment modelHUMAN FACTORS AND ERGONOMICS IN MANUFACTURING & SERVICE INDUSTRIES, Issue 4 2001Eric Molleman In this study we applied an empowerment model that focuses on (a) the need for empowerment in light of organizational strategy, (b) job design issues such as job enlargement and job enrichment that facilitate empowerment, and (c) the abilities, and (d) the attitudes of workers that make empowerment work. We applied the model in the manufacturing department of a firm that produces catheters for medical use and interviewed managers and supporting staff and surveyed 231 operators. The leading performance indicators in this firm are efficiency and quality. The reassignment of 12 out of 33 tasks was believed to contribute to these organizational objectives. For most workers, their abilities and their attitudes toward empowerment proved to be no major barrier to the reallocation of these tasks. However, for temporary workers, mainly working in a "short shift," the leeway to learn skills is limited, which probably impedes empowerment. The study shows that our model helps to diagnose the need for empowerment, to design work structures that facilitate empowerment, and to select appropriate human resource management practices. Further validation in other organizational settings is desirable. © 2001 John Wiley & Sons, Inc. [source] Barriers to kidney transplants in Indonesia: a literature reviewINTERNATIONAL NURSING REVIEW, Issue 1 2009P.N. Bennett rn Background:, People living with chronic kidney disease will require renal dialysis or a kidney transplant to maintain life. Although Indonesia has a developing healthcare industry, Indonesia's kidney transplant rates are lower than comparable nations. Purpose:, To explore the healthcare literature to identify barriers to kidney transplants in particular in relation to Indonesia. Methods:, Healthcare databases were searched (CINAHL, Medline, EBSCOhostEJS, Blackwell Synergy, Web of Science, PubMed, Google Scholar and Proquest 5000) using the search terms: transplant, kidney disease, renal, dialysis, haemodialysis, Indonesia and nursing. The search was limited to English and Indonesian language data sources from 1997 to 2007. Reference lists of salient academic articles were hand searched. Results:, The results of our search identified six articles that met our criteria. Costs are the major barrier to kidney transplant in Indonesia, followed by cultural beliefs, perception of the law, lack of information and lack of infrastructure. In addition, kidney disease prevention strategies are required. Conclusions:, There are many complex socio-economic, geographical, legal, cultural and religious factors that contribute to low kidney transplant rates in Indonesia. Although an increase in transplantation rates will require strategies from various agencies, healthcare professionals, including nurses, can play a role in overcoming some barriers. Community education programmes, improving their own education levels and by increasing empowerment in nursing we may contribute to improved kidney transplant rates in Indonesia. [source] Maximizing Clinical Research Participation in Vulnerable Older Persons: Identification of Barriers and MotivatorsJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 8 2008Edward R. Marcantonio MD OBJECTIVES: To identify barriers and motivators to participation in long-term clinical research by high-risk elderly people and to develop procedures to maximize recruitment and retention. DESIGN: Quantitative and qualitative survey. SETTING: Academic primary care medicine and pre-anesthesia testing clinics. PARTICIPANTS: Fifty patients aged 70 and older, including 25 medical patients at high risk of hospitalization and 25 patients with planned major surgery. MEASUREMENTS: Fifteen- to 20-minute interviews involved open- and closed-ended questions guided by an in-depth script. Two planned study protocols were presented to each participant. Both involved serial neuropsychological assessments, blood testing, and magnetic resonance brain imaging (MRI); one added lumbar puncture (LP). Participants were asked whether they would be willing to participate in these protocols, rated barriers and incentives to participation, and were probed with open-ended questions. RESULTS: Of 50 participants (average age 78, 44% male, 40% nonwhite), 32 (64%) expressed willingness to participate in the LP-containing protocol, with LP cited as the strongest disincentive. Thirty-eight (76%) expressed willingness to participate in the protocol without LP, with phlebotomy and long interviews cited as the strongest disincentives. Altruism was a strong motivator for participation, whereas transportation was a major barrier. Study visits at home, flexible appointment times, assessments shorter than 75 minutes, and providing transportation and free parking were strategies developed to maximize study participation. CONCLUSION: Vulnerable elderly people expressed a high rate of willingness to participate in an 18-month prospective study. Participants identified incentives and barriers that enabled investigators to develop procedures to maximize recruitment and retention. [source] A Curriculum to Teach Internal Medicine Residents to Perform House Calls for Older AdultsJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 8 2007Jennifer L. Hayashi MD Physician house calls are an important but underused mode of delivering health care to a growing population of homebound elderly patients. One major barrier to internal medicine physicians making house calls is a lack of training in this setting. This article describes a needs assessment survey of residents from nine internal medicine residency programs for a house call curriculum that combines a longitudinal clinical experience with Internet-based learning. Implementation of the curriculum was begun in July 2006, and data will be collected and results evaluated for at least 2 years. Several educational outcomes from the intervention are anticipated, including increased learner knowledge of house call medicine, improved learner confidence in making house calls, and program director satisfaction with the curriculum. This early work lays the foundation for determining the effect of a carefully designed curriculum on the number of practicing internists with the skills, knowledge, and attitudes necessary to meet the growing need for physician house calls. [source] The status of training and education in information and computer technology of Australian nurses: a national surveyJOURNAL OF CLINICAL NURSING, Issue 20 2008Robert Eley Aims and objectives., A study was undertaken of the current knowledge and future training requirements of nurses in information and computer technology to inform policy to meet national goals for health. Background., The role of the modern clinical nurse is intertwined with information and computer technology and adoption of such technology forms an important component of national strategies in health. The majority of nurses are expected to use information and computer technology during their work; however, the full extent of their knowledge and experience is unclear. Design., Self-administered postal survey. Methods., A 78-item questionnaire was distributed to 10,000 Australian Nursing Federation members to identify the nurses' use of information and computer technology. Eighteen items related to nurses' training and education in information and computer technology. Results., Response rate was 44%. Computers were used by 86·3% of respondents as part of their work-related activities. Between 4,17% of nurses had received training in each of 11 generic computer skills and software applications during their preregistration/pre-enrolment and between 12,30% as continuing professional education. Nurses who had received training believed that it was adequate to meet the needs of their job and was given at an appropriate time. Almost half of the respondents indicated that they required more training to better meet the information and computer technology requirements of their jobs and a quarter believed that their level of computer literacy was restricting their career development. Nurses considered that the vast majority of employers did not encourage information and computer technology training and, for those for whom training was available, workload was the major barrier to uptake. Nurses favoured introduction of a national competency standard in information and computer technology. Conclusions., For the considerable benefits of information and computer technology to be incorporated fully into the health system, employers must pay more attention to the training and education of nurses who are the largest users of that technology. Relevance to clinical practice., Knowledge of the training and education needs of clinical nurses with respect to information and computer technology will provide a platform for the development of appropriate policies by government and by employers. [source] Towards a sustainable theory of health-related stigma: lessons from the HIV/AIDS literatureJOURNAL OF COMMUNITY & APPLIED SOCIAL PSYCHOLOGY, Issue 6 2006Harriet Deacon Abstract Stigma has been identified as a major barrier to health care and quality of life in illness management. But unfortunately there is no common theoretical perspective on stigma. We need a sustainable theory of health-related stigma. This would start with a coherent definition of stigma that brings together both individual and social dimensions of this complex phenomenon. It would reassesses the existence of ,types' of stigma and explain how stigma relates to disadvantage. A sustainable theory would help researchers to move from theory into practice: to develop a comprehensive measurement tool for stigma and related disadvantage, and inform design, monitoring and evaluation of anti-stigma interventions. This paper draws on two recent literature reviews on HIV/AIDS stigma to introduce several key issues in developing a sustainable theory of stigma. We suggest limiting the definition of stigma to the process of othering, blaming and shaming (often called symbolic stigma). We argue that there is value in analytically separating stigma from discrimination in order to better understand the relationship between them. We also suggest the need to understand discrimination caused by stigma as only one element of stigma-related disadvantage. Copyright © 2006 John Wiley & Sons, Ltd. [source] Promoting development and use of systematic reviews in a developing countryJOURNAL OF EVALUATION IN CLINICAL PRACTICE, Issue 6 2009Reza Yousefi-Nooraie MD Abstract Introduction, One major barrier to develop health systems is the limited capacity for conducting research and implementation of research findings. We assessed the views of researchers, decision makers and research policy makers on how the development and usage of evidence from systematic reviews can be promoted in a country with limited resources. Methods, We surveyed 131 participants in six systematic review workshops for their views on important items influencing the production and usage of systematic reviews in a developing country. They were also asked to propose interventions to deal with potential barriers. We analysed the quantitative data using multidimensional scaling methods, and the qualitative data using content analysis approach. Results, We identified seven clusters of items that contribute to the promotion of conducting and using systematic reviews. For each cluster a set of interventions are proposed that health care decision makers and research policy makers may use for promoting conduct and use of systematic reviews. The clusters are ,importance for policy makers', ,access to international research', ,priority and support for systematic reviews', ,competency and willingness of researchers to conduct reviews', ,importance for end-users', ,quality of local primary research' and ,visibility and access to local research'. Discussion, The proposed interventions focus on national level initiatives for making the systematic reviews ,wanted' and improving the capacity to conduct research. Our findings emphasize the essential role of policy makers for promoting systematic reviews. They demonstrate that many barriers stem from the lower quality of and lack of access to primary research originating from developing countries. [source] Incremental identification of fluid multi-phase reaction systemsAICHE JOURNAL, Issue 4 2009Claas Michalik Abstract Despite their importance, rigorous process models are rarely available for reaction and especially multi-phase reaction systems. The high complexity of these systems, which is due to the superposed effects of mass transfer and intrinsic reaction, is the major barrier for the development of process models. A methodology that allows thesystematic decomposition of mass transfer and chemical reaction and thus enables the efficient identification of multi-phase reaction systems is proposed in this work. The method is based on the so-called Incremental Identification Method, recently presented by Brendel et al., Chem Eng Sci. 2006;61:5404-5420. The method allows to easily test the identifiability of a system based on the available measurement data. If identifiability is given, the intrinsic reaction kinetics can be identified in a sound and numerically robust manner. These benefits are illustrated using a simulated 2-phase enzyme reaction system. © 2009 American Institute of Chemical Engineers AIChE J, 2009 [source] Biostability and pharmacokinetics of LJP 920, an octameric Gal (,1,3) Gal conjugate for the inhibition of xenotransplantation rejectionJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2001Lee Jia Antibodies to an ,-galactosyl saccharide structure present in human serum are associated with hyperacute rejection and delayed xenograft rejection after pig-to-primate xenotransplantation. To overcome this major barrier to the xenotransplantation, LJP 920, a galactosyl ,1,3 galactose (Gal (,1,3) Gal) coupled to a non-immunogenic platform at a valency of eight Gal (,1,3) Gal molecules/platform, was synthesized to clear circulating antibodies and to inhibit their production by B cells that produce these antibodies. Herein we report on the stability of LJP 920 in biological media and its pharmacokinetic profile. Incubation of LJP 920 with mouse serum or liver microsomes at 37°C for 2 days showed no indication of degradation of the conjugate as detected by a reversed-phase HPLC method, indicating that the conjugate is not subject to enzymatic metabolism. After intravenous administration of LJP 920 to mice at the doses of 20 and 100 mg kg,1, LJP 920 serum concentration decreased rapidly, showing a biphasic pattern, with a distribution half-life of 3 min and an elimination half-life of more than 30 min, respectively. The serum-to-erythrocyte concentration ratio of LJP 920 was 33- and 36-fold excess at 0.5 and 5 min, respectively, after intravenous administration (100 mg kg,1). Both Cmax and AUC values increased in a dose-proportional manner. LJP 920 displayed a great distribution to well-perfused tissues. It was eliminated mainly through renal excretion in the unchanged form, which accounted for 23% of the total amount within 8 h of dosing. [source] The Peritoneal Microcirculation in Peritoneal DialysisMICROCIRCULATION, Issue 5 2001BENGT RIPPE ABSTRACT This paper deals with the peritoneal microcirculation and with peritoneal exchange occurring in peritoneal dialysis (PD). The capillary wall is a major barrier to solute and water exchange across the peritoneal membrane. There is a bimodal size-selectivity of solute transport between blood and the peritoneal cavity, through pores of radius ,40,50 Å as well as through a very low number of large pores of radius ,250 Å. Furthermore, during glucose-induced osmosis during PD, nearly 40% of the total osmotic water flow occurs through molecular water channels, termed "aquaporin-1." This causes an inequality between 1,, and the sieving coefficient for small solutes, which is a key feature of the "threepore model" of peritoneal transport. The peritoneal interstitium, coupled in series with the capillary walls, markedly modifies small-solute transport and makes large-solute transport asymmetric. Thus, although severely restricted in the blood-to-peritoneal direction, the absorption of large solutes from the peritoneal cavity occurs at a high clearance rate (,1 mL/min), largely independent of molecular radius. True absorption of macromolecules to the blood via lymphatics, however, seems to be occurring at a rate of ,0.2 mL/min. Several controversial issues regarding transcapillary and transperitoneal exchange mechanisms are discussed in this paper. [source] Refill adherence and polypharmacy among patients with type 2 diabetes in general practicePHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 11 2009Rykel van Bruggen PhD Abstract Background and Aims Non-adherence is considered a major barrier to better outcomes of diabetes care. A relationship has been established between polypharmacy and patients' adherence. This study aims to investigate the occurrence of polypharmacy and non-adherence in general practice, their mutual relationship and the association between adherence and the intermediate outcomes of diabetes care. Materials and Methods We used the baseline and follow-up data of a randomised controlled trial (RCT) that compared usual care with care in accordance with a locally adapted national guideline. This study took place in the Netherlands and involved 30 general practices and 1283 patients. We obtained a complete medication profile of all participants and calculated the number of prescribed drugs and the adherence indices (AI) for oral blood glucose, blood pressure and cholesterol lowering drugs. Patients with an adherence index <,0.8 were considered non-adherent. Clustering at practice level and case-mix were taken into account. Results Approximately 80% of the participating patients demonstrated an adherence index ,,0.8 for oral blood glucose, blood pressure and cholesterol lowering drugs. In the intervention group, increase of drug prescriptions exceeded that of controls (1.1,±,2.0 vs. 0.6,±,1.5, p,<,0.001, adjusted p,<,0.05). There was evidence of an inverse relationship between the number of drugs that had been prescribed during the last 6 months of the study and patients' adherence to blood pressure lowering medications (adjusted OR 0.84, 95%CI 0.78,0.91). After one year, HbA1c and total cholesterol levels were significantly lower in adherent patients. Conclusion During the intervention the mean number of drug prescriptions increased in both the study groups. This did not result in a lower adherence to blood glucose and cholesterol lowering medications. Given the relationship between the number of medications and patients' adherence to blood pressure lowering drugs, it may be wise to discuss adherence before prescribing multiple drug regimens. Copyright © 2009 John Wiley & Sons, Ltd. [source] Functional genomics of phosphate antiport systems of plastidsPHYSIOLOGIA PLANTARUM, Issue 4 2003Ulf-Ingo Flügge Plant cells require a co-ordination of metabolism between their major compartments, the plastids and the cytosol, in particular as certain metabolic pathways are confined to either compartments. The inner envelope membrane of the plastids forms the major barrier for metabolite exchange and is the site for numerous transport proteins, which selectively catalyse metabolite exchanges characteristic for green and/or non-green tissues. This report is focused on the molecular biology, evolution and physiological function of the family of phosphate translocators (PT) from plastids. Until now, four distinct subfamilies have been identified and characterized, which all share inorganic phosphate as common substrate, but have different spectra of counter exchange substrates to fulfil the metabolic needs of individual cells and tissues. The PTs are named after their main transported substrate, triose phosphate (TPT), phosphoenolpyruvate (PPT), glucose 6-phosphate (GPT) and xylulose 5-P (XPT). All PTs belong to the TPT/nucleotide sugar transporter (NST) superfamily, which includes yet uncharacterized PT homologues from plants and other eukaryotes. Transgenic plants or mutants with altered transport activity of some of the PTs have been generated or isolated. The analysis of these plant lines revealed new insights in the co-ordination and flexibility of plant metabolism. [source] Correction of mucopolysaccharidosis type IIIA somatic and central nervous system pathology by lentiviral-mediated gene transferTHE JOURNAL OF GENE MEDICINE, Issue 9 2010Chantelle McIntyre Abstract Background The hallmark of lysosomal storage disorders (LSDs) is microscopically demonstrable lysosomal distension. In mucopolysaccharidosis type IIIA (MPS IIIA), this occurs as a result of an inherited deficiency of the lysosomal hydrolase sulphamidase. Consequently, heparan sulphate, a highly sulphated glycosaminoglycan, accumulates primarily within the cells of the reticulo-endothelial and monocyte-macrophage systems and, most importantly, neurones. Children affected by MPS IIIA experience a severe, progressive neuropathology that ultimately leads to death at around 15 years of age. Methods MPS IIIA pathology was addressed in a mouse model using two separate methods of therapeutic gene delivery. A lentiviral vector expressing murine sulphamidase was delivered to 6-week-old MPS IIIA affected mice either by intravenous injection, or by intraventricular infusion. Therapeutic outcomes were assessed 7 months after gene transfer. Results After intravenous gene delivery, liver sulphamidase was restored to approximately 30% of wild-type levels. The resultant widespread delivery of enzyme secreted from transduced cells to somatic tissues via the peripheral circulation corrected most somatic pathology. However, unlike an earlier study, central nervous system (CNS) pathology remained unchanged. Conversely, intraventricular gene delivery resulted in widespread sulphamidase gene delivery in (and reduced lysosomal storage throughout) the brain. Improvements in behaviour were observed in these mice, and interestingly, pathological urinary retention was prevented. Conclusions The CNS remains the last major barrier to effective therapy for children affected by LSDs. The blood,brain barrier (BBB) limits the uptake of lysosomal enzymes from the peripheral circulation into the CNS, making direct gene delivery to the brain a reasonable, albeit more challenging, therapeutic option. Future work will further assess the relative advantages of directly targeting the brain with somatic gene delivery with sulphamidase modified to increase the efficiency of transport across the BBB. Copyright © 2010 John Wiley & Sons, Ltd. [source] ,-Catenin dysregulation in cancer: interactions with E-cadherin and beyond,THE JOURNAL OF PATHOLOGY, Issue 2 2010Qun Lu Abstract Stable E-cadherin-based adherens junctions are pivotal in maintaining epithelial tissue integrity and are the major barrier for epithelial cancer metastasis. Proteins of the p120ctn subfamily have emerged recently as critical players for supporting this stability. The identification of the unique juxtamembrane domain (JMD) in E-cadherin that binds directly to ,-catenin/NPRAP/neurojungin (CTNND2) and p120ctn (CTNND1) provides a common motif for their interactions. Recently, crystallographic resolution of the JMD of p120ctn further highlighted possibilities of intervening between interactions of p120ctn subfamily proteins and E-cadherin for designing anti-cancer therapeutics. For most epithelial cancers, studies have demonstrated a reduction of p120ctn expression or alteration of its subcellular distribution. On the other hand, ,-catenin, a primarily neural-enriched protein in the brain of healthy individuals, is up-regulated in all cancer types that have been studied to date. Two research articles in the September 2010 issue of The Journal of Pathology increase our understanding of the involvement of these proteins in lung cancer. One reports the identification of rare p120ctn (CTNND1) gene amplification in lung cancer. One mechanism by which ,-catenin and p120ctn may play a role in carcinogenesis is their competitive binding to E-cadherin through the JMD. The other presents the first vigorous characterization of ,-catenin overexpression in lung cancer. Unexpectedly, the authors observed that ,-catenin promotes malignant phenotypes of non-small cell lung cancer by non-competitive binding to E-cadherin with p120ctn in the cytoplasm. Looking towards the future, the understanding of ,-catenin and p120ctn with and beyond their localization at the cell,cell junction should provide further insight into their roles in cancer pathogenesis. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Invited Commentary for Castillo et al. Gene amplification of the transcription factor DP1 and CTNND1 in human lung cancer, Journal of Pathology, 2010; 222: 89,98. And for Zhang et al. ,-Catenin promotes malignant phenotype of non-small cell lung cancer by non-competative binding to E-cadherin with p120ctn in cytoplasm. Journal of Pathology, 2010; 222: 76,88. [source] Rural,Urban Differences in Primary Care Physicians' Practice Patterns, Characteristics, and IncomesTHE JOURNAL OF RURAL HEALTH, Issue 2 2008William B. Weeks MD ABSTRACT:,Context:Low salaries and difficult work conditions are perceived as a major barrier to the recruitment of primary care physicians to rural settings. Purpose: To examine rural,urban differences in physician work effort, physician characteristics, and practice characteristics, and to determine whether, after adjusting for any observed differences, rural primary care physicians' incomes were lower than those of urban primary care physicians. Methods: Using survey data from actively practicing office-based general practitioners (1,157), family physicians (1,378), general internists (2,811), or pediatricians (1,752) who responded to the American Medical Association's annual survey of physicians between 1992 and 2002, we used linear regression modeling to determine the association between practicing in a rural (nonmetropolitan) or urban (standard metropolitan statistical area) setting and physicians' annual incomes after controlling for specialty, work effort, provider characteristics, and practice characteristics. Findings: Rural primary care physicians' unadjusted annual incomes were similar to their urban counterparts, but they tended to work longer hours, complete more patient visits, and have a much greater proportion of Medicaid patients. After adjusting for work effort, physician characteristics, and practice characteristics, primary care physicians who practiced in rural settings made $9,585 (5%) less than their urban counterparts (95% confidence intervals: ,$14,569, ,$4,602, P < .001). In particular, rural practicing general internists and pediatricians experienced lower incomes than did their urban counterparts. Conclusions: Addressing rural physicians' lower incomes, longer work hours, and greater dependence on Medicaid reimbursement may improve the ability to ensure that an adequate supply of primary care physicians practice in rural settings. [source] Phenotype, Distribution and Alloreactive Properties of Memory T Cells from Cynomolgus MonkeysAMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2010Ognjenka Nadazdin The high frequency of memory T cells present in primates is thought to represent a major barrier to tolerance induction in transplantation. Therefore, it is crucial to characterize these memory T cells and determine their functional properties. High numbers of memory T cells were detected in peripheral blood and all lymphoid tissues except lymph nodes, which were essentially the site of naïve T cells. The majority of CD8+ memory T cells were effector memory cells located in the blood and bone marrow while most CD4+ memory T cells were central memory cells present in the spleen. Next, memory T cells from over 100 monkeys were tested for their response to alloantigens by ELISPOT. Memory alloreactivity mediated via direct but not indirect allorecognition was detected in all animals. The frequency of allospecific memory T cells varied dramatically depending upon the nature of the responder/stimulator monkey combination tested. MHC gene matching was generally associated with a low-memory alloreactivity. Nevertheless, low anamnestic alloresponses were also found in a significant number of fully MHC-mismatched monkey combinations. These results show that selected donor/recipient combinations displaying a low memory alloresponsiveness can be found. These combinations may be more favorable for transplant tolerance induction. [source] Critical Role for IL-6 in Hypertrophy and Fibrosis in Chronic Cardiac Allograft RejectionAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2009J. A. Diaz Chronic cardiac allograft rejection is the major barrier to long term graft survival. There is currently no effective treatment for chronic rejection except re-transplantation. Though neointimal development, fibrosis, and progressive deterioration of graft function are hallmarks of chronic rejection, the immunologic mechanisms driving this process are poorly understood. These experiments tested a functional role for IL-6 in chronic rejection by utilizing serial echocardiography to assess the progression of chronic rejection in vascularized mouse cardiac allografts. Cardiac allografts in mice transiently depleted of CD4+ cells that develop chronic rejection were compared with those receiving anti-CD40L therapy that do not develop chronic rejection. Echocardiography revealed the development of hypertrophy in grafts undergoing chronic rejection. Histologic analysis confirmed hypertrophy that coincided with graft fibrosis and elevated intragraft expression of IL-6. To elucidate the role of IL-6 in chronic rejection, cardiac allograft recipients depleted of CD4+ cells were treated with neutralizing anti-IL-6 mAb. IL-6 neutralization ameliorated cardiomyocyte hypertrophy, graft fibrosis, and prevented deterioration of graft contractility associated with chronic rejection. These observations reveal a new paradigm in which IL-6 drives development of pathologic hypertrophy and fibrosis in chronic cardiac allograft rejection and suggest that IL-6 could be a therapeutic target to prevent this disease. [source] Proteasome Inhibition Causes Apoptosis of Normal Human Plasma Cells Preventing Alloantibody ProductionAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2009D. K. Perry Antibody production by normal plasma cells (PCs) against human leukocyte antigens (HLA) can be a major barrier to successful transplantation. We tested four reagents with possible activity against PCs (rituximab, polyclonal rabbit antithymocyte globulin (rATG), intravenous immunoglobulin (IVIG) and the proteasome inhibitor, bortezomib) to determine their ability to cause apoptosis of human bone marrow-derived PCs and subsequently block IgG secretion in vitro. IVIG, rituximab and rATG all failed to cause apoptosis of PCs and neither rituximab nor rATG blocked antibody production. In contrast, bortezomib treatment led to PC apoptosis and thereby blocked anti-HLA and antitetanus IgG secretion in vitro. Two patients treated with bortezomib for humoral rejection after allogeneic kidney transplantation demonstrated a transient decrease in bone marrow PCs in vivo and persistent alterations in alloantibody specificities. Total IgG levels were unchanged. We conclude that proteasome activity is important for PC longevity and its inhibition may lead to new techniques of controlling antibody production in vivo. [source] The big ecological questions inhibiting effective environmental management in AustraliaAUSTRAL ECOLOGY, Issue 1 2009S. R. MORTON Abstract The need to improve environmental management in Australia is urgent because human health, well-being and social stability all depend ultimately on maintenance of life-supporting ecological processes. Ecological science can inform this effort, but when issues are socially and economically complex the inclination is to wait for science to provide answers before acting. Increasingly, managers and policy-makers will be called on to use the present state of scientific knowledge to supply reasonable inferences for action based on imperfect knowledge. Hence, one challenge is to use existing ecological knowledge more effectively; a second is to tackle the critical unanswered ecological questions. This paper identifies areas of environmental management that are profoundly hindered by an inability of science to answer basic questions, in contrast to those areas where knowledge is not the major barrier to policy development and management. Of the 22 big questions identified herein, more than half are directly related to climate change. Several of the questions concern our limited understanding of the dynamics of marine systems. There is enough information already available to develop effective policy and management to address several significant ecological issues. We urge ecologists to make better use of existing knowledge in dialogue with policy-makers and land managers. Because the challenges are enormous, ecologists will increasingly be engaging a wide range of other disciplines to help identify pathways towards a sustainable future. [source] Many faces of graft- versus -host diseaseAUSTRALASIAN JOURNAL OF DERMATOLOGY, Issue 1 2010Pablo F Peñas ABSTRACT Allogeneic haematopoietic stem cell transplantation is increasingly used in the treatment of malignant and non-malignant disorders. Despite ongoing advances in the field, morbidity and mortality related to graft- versus -host disease remains a major barrier to its application. Graft- versus -host disease is a difficult-to-diagnose disease. Dermatologists are involved due to its diverse cutaneous expression. In order to appropriately diagnose, classify and treat this complex disease, knowledge of its expanding cutaneous expression is required. This review provides a synopsis of the clinical manifestations of acute, lichenoid and sclerodermatous phases of graft- versus -host disease with a look at the current evidence surrounding its differential diagnosis. [source] Regional differences among employed nurses: A Queensland studyAUSTRALIAN JOURNAL OF RURAL HEALTH, Issue 4 2009Tim Henwood Abstract Objective:,To ascertain differences in the working lives of geographically dispersed nurses. Design:,Cross-sectional. Setting:,Registered, enrolled and assistants-in-nursing members of the Queensland Nurses' Union employed in nursing in Queensland, Australia. Participants:,A total of 3000 members of the Union, equally stratified by sector (public, private, aged care). Among them, 1192 responded and 1039 supplied postcodes matching the Australian Standard Geographical Classification. Main outcome measures:,Statistically significant differences in working lives of nurses employed in different geographical locations. Results:,Nurses in outer regional/remote/very remote localities are more likely to be employed as permanent full-time staff and self-report higher levels of work stress. These levels could be explained by: lack of replacement staff for leave, longer working and on call hours and lack of support for new staff. Distance remains a major barrier to accessing continuing professional education. However, outer regional/remote/very remote nurses were more likely to be provided employer support for professional education. Inner regional nurses were more likely to work part time, would work more hours if offered and were more likely to have taken a break from nursing as a result of family commitments. Conclusion:,The data confirm that current policies are not addressing the differences in the working lives of geographically dispersed nurses. Policies addressing orientation, mentoring and workloads should be implemented to address these issues. [source] Plant invasions , the role of mutualismsBIOLOGICAL REVIEWS, Issue 1 2000DAVID M. RICHARDSON ABSTRACT Many introduced plant species rely on mutualisms in their new habitats to overcome barriers to establishment and to become naturalized and, in some cases, invasive. Mutualisms involving animalmediated pollination and seed dispersal, and symbioses between plant roots and microbiota often facilitate invasions. The spread of many alien plants, particularly woody ones, depends on pollinator mutualisms. Most alien plants are well served by generalist pollinators (insects and birds), and pollinator limitation does not appear to be a major barrier for the spread of introduced plants (special conditions relating to Ficus and orchids are described). Seeds of many of the most notorious plant invaders are dispersed by animals, mainly birds and mammals. Our review supports the view that tightly coevolved, plant-vertebrate seed dispersal systems are extremely rare. Vertebrate-dispersed plants are generally not limited reproductively by the lack of dispersers. Most mycorrhizal plants form associations with arbuscular mycorrhizal fungi which, because of their low specificity, do not seem to play a major role in facilitating or hindering plant invasions (except possibly on remote islands such as the Galapagos which are poor in arbuscular mycorrhizal fungi). The lack of symbionts has, however, been a major barrier for many ectomycorrhizal plants, notably for Pinus spp. in parts of the southern hemisphere. The roles of nitrogen-fixing associations between legumes and rhizobia and between actinorhizal plants and Frankia spp. in promoting or hindering invasions have been virtually ignored in the invasions literature. Symbionts required to induce nitrogen fixation in many plants are extremely widespread, but intentional introductions of symbionts have altered the invasibility of many, if not most, systems. Some of the world's worst invasive alien species only invaded after the introduction of symbionts. Mutualisms in the new environment sometimes re-unite the same species that form partnerships in the native range of the plant. Very often, however, different species are involved, emphasizing the diffuse nature of many (most) mutualisms. Mutualisms in new habitats usually duplicate functions or strategies that exist in the natural range of the plant. Occasionally, mutualisms forge totally novel combinations, with profound implications for the behaviour of the introduced plant in the new environment (examples are seed dispersal mutualisms involving wind-dispersed pines and cockatoos in Australia; and mycorrhizal associations involving plant roots and fungi). Many ecosystems are becoming more susceptible to invasion by introduced plants because: (a) they contain an increasing array of potential mutualistic partners (e.g. generalist frugivores and pollinators, mycorrhizal fungi with wide host ranges, rhizobia strains with infectivity across genera); and (b) conditions conducive for the establishment of various alienalien synergisms are becoming more abundant. Incorporating perspectives on mutualisms in screening protocols will improve (but not perfect) our ability to predict whether a given plant species could invade a particular habitat. [source] Entrapment of dispersed pancreatic islet cells in CultiSpher-S macroporous gelatin microcarriers: Preparation, in vitro characterization, and microencapsulationBIOTECHNOLOGY & BIOENGINEERING, Issue 6 2001S. Del Guerra Abstract Immunoprotection of pancreatic islets for successful allo- or xenotransplantation without chronic immunosuppression is an attractive, but still elusive, approach for curing type 1 diabetes. It was recently shown that, even in the absence of fibrotic overgrowth, other factors, mainly insufficient nutrition to the core of the islets, represent a major barrier for long-term survival of intraperitoneal microencapsulated islet grafts. The use of dispersed cells might contribute to solve this problem due to the conceivably easier nutritional support to the cells. In the present study, purified bovine islets, prepared by collagenase digestion and density gradient purification, and dispersed bovine islet cells, obtained by trypsin and DNAsi (viability > 90%), were entrapped into either 2% (w/v) sodium alginate (commonly used for encapsulation purposes) or (dispersed islet cells only) macroporous gelatin microcarriers (CulthiSpher-S, commonly used for the production of biologicals by animal cells). Insulin release studies in response to glucose were performed within 1 week and after 1 month from preparation of the varying systems and showed no capability of dispersed bovine islet cells within sodium alginate microcapsules to sense glucose concentration changes. On the contrary, bovine islet cells entrapped in CulthiSpher-S microcarriers showed maintained capacity of increasing insulin secretion upon enhanced glucose concentration challenge. In this case, insulin release was approximately 60% of that from intact bovine islets within sodium alginate microcapsules. MTT and hematoxylineosin staining of islet cell-containing microcarriers showed the presence of viable and metabolically active cells throughout the study period. This encouraging functional data prompted us to test whether the microcarriers could be immunoisolated for potential use in transplantation. The microcarriers were embedded within 3% sodium alginate, which was then covered with a poly-L-lysine layer and a final outer alginate layer. Maintained insulin secretion function of this system was observed, which raises the possibility of using microencapsulated CulthiSpher-S microcarriers, containing dispersed pancreatic islet cells, in experimental transplantation studies. © 2001 John Wiley & Sons, Inc. Biotechnol Bioeng 75: 741,744, 2001. [source] Feasibility of prophylaxis and immune tolerance induction regimens in haemophilic children using fully implantable central venous cathetersBRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2008Maria Elisa Mancuso Summary Venous access represents the major barrier to the feasibility of prophylaxis and immune tolerance induction (ITI) in haemophilic children. Ports improve treatment feasibility, but their duration is limited by infectious complications. This study aimed at evaluating whether or not ports allow haemophilic children to maintain the treatment regimen in the long term. Children were prospectively followed-up and underwent port removal either for complications or transition to peripheral veins. Of 27 ports (17 used for prophylaxis and 10 for ITI), 25 were removed after a median of 3·3 years. Inhibitor children showed a younger age at port insertion (P = 0·02), an earlier occurrence of infections (P = 0·006) at a higher rate (P = 0·00001) and an earlier removal for infection (P = 0·05) than non-inhibitor patients. Daily port use was associated with earlier infections at a higher rate compared to less frequent use (P = 0·02). Port removal after a median of 0·8 years prevented ITI completion in 50% of children, while it hampered the maintenance of prophylaxis in 27% of patients. This study showed that ports improved the feasibility of prophylaxis in the majority of non-inhibitor children, while they were not suitable for inhibitor children who require a prolonged ITI regimen with daily infusions. [source] | |||||||||||||||||||||||||||||||||||||||||||