Primary intraocular lymphoma.

Primary intraocular lymphoma (PIOL) is an ocular malignancy that is a subset of primary central system lymphoma (PCNSL). Approximately one-third of PIOL patients will have concurrent PCNSL at presentation, and 42-92% will develop PCNSL within a mean of 8-29 months. Although rare, the incidence has been rising in both immunocompromised and immunocompetent populations. The majority of PIOL is diffuse large B-cell lymphoma, though rare T-cell variants are described. Recently, PIOL has been classified by main site of involvement in the eye, with vitreoretinal lymphoma as the most common type of ocular lymphoma related to PCNSL. Diagnosis remains challenging for ophthalmologists and pathologists. PIOL can masquerade as noninfectious or infectious uveitis, white dot syndromes, or occasionally as other neoplasms such as metastatic cancers. Laboratory diagnosis by cytology has been much aided by the use of immunocytochemistry, flow cytometry, biochemical finding of interleukin changes (IL10:IL6 ratio > 1), and cellular microdissection with polymerase chain reaction amplification for clonality. Use of several tests improves the diagnostic yield. Approaches to treatment have centered on systemic methotrexate-based chemotherapy, often with cytarabine (Ara-C) and radiotherapy. Use of intravitreal chemotherapy with methotrexate (0.4 mg/0.1 mL) is promising in controlling ocular disease, and intravitreal rituximab (anti-CD20 monoclonal antibody) has also been tried. Despite these advances, prognosis remains poor

Single to Double Hump Transition in the Equilibrium Distribution Function of Relativistic Particles

We unveil a transition from single peaked to bimodal velocity distribution in a relativistic fluid under increasing temperature, in contrast with a non-relativistic gas, where only a monotonic broadening of the bell-shaped distribution is observed. Such transition results from the interplay between the raise in thermal energy and the constraint of maximum velocity imposed by the speed of light. We study the Bose-Einstein, the Fermi-Dirac, and the Maxwell-J\"uttner distributions, all exhibiting the same qualitative behavior. We characterize the nature of the transition in the framework of critical phenomena and show that it is either continuous or discontinuous, depending on the group velocity. We analyze the transition in one, two, and three dimensions, with special emphasis on two-dimensions, for which a possible experiment in graphene, based on the measurement of the Johnson-Nyquist noise, is proposed.Comment: 5 pages, 5 figure

Reviewing the literature on access to prompt and effective malaria treatment in Kenya: implications for meeting the Abuja targets

<p>Abstract</p> <p>Background</p> <p>Effective case management is central to reducing malaria mortality and morbidity worldwide, but only a minority of those affected by malaria, have access to prompt effective treatment.</p> <p>In Kenya, the Division of Malaria Control is committed to ensuring that 80 percent of childhood fevers are treated with effective anti-malarial medicines within 24 hours of fever onset, but this target is largely unmet. This review aimed to document evidence on access to effective malaria treatment in Kenya, identify factors that influence access, and make recommendations on how to improve prompt access to effective malaria treatment. Since treatment-seeking patterns for malaria are similar in many settings in sub-Saharan Africa, the findings presented in this review have important lessons for other malaria endemic countries.</p> <p>Methods</p> <p>Internet searches were conducted in PUBMED (MEDLINE) and HINARI databases using specific search terms and strategies. Grey literature was obtained by soliciting reports from individual researchers working in the treatment-seeking field, from websites of major organizations involved in malaria control and from international reports.</p> <p>Results</p> <p>The review indicated that malaria treatment-seeking occurs mostly in the informal sector; that most fevers are treated, but treatment is often ineffective. Irrational drug use was identified as a problem in most studies, but determinants of this behaviour were not documented. Availability of non-recommended medicines over-the-counter and the presence of substandard anti-malarials in the market are well documented. Demand side determinants of access include perception of illness causes, severity and timing of treatment, perceptions of treatment efficacy, simplicity of regimens and ability to pay. Supply side determinants include distance to health facilities, availability of medicines, prescribing and dispensing practices and quality of medicines. Policy level factors are around the complexity and unclear messages regarding drug policy changes.</p> <p>Conclusion</p> <p>Kenya, like many other African countries, is still far from achieving the Abuja targets. The government, with support from donors, should invest adequately in mechanisms that promote access to effective treatment. Such approaches should focus on factors influencing multiple dimensions of access and will require the cooperation of all stakeholders working in malaria control.</p

Barriers to prompt and effective malaria treatment among the poorest population in Kenya

<p>Abstract</p> <p>Background</p> <p>Prompt access to effective malaria treatment is central to the success of malaria control worldwide, but few fevers are treated with effective anti-malarials within 24 hours of symptoms onset. The last two decades saw an upsurge of initiatives to improve access to effective malaria treatment in many parts of sub-Saharan Africa. Evidence suggests that the poorest populations remain least likely to seek prompt and effective treatment, but the factors that prevent them from accessing interventions are not well understood. With plans under way to subsidize ACT heavily in Kenya and other parts of Africa, there is urgent need to identify policy actions to promote access among the poor. This paper explores access barriers to effective malaria treatment among the poorest population in four malaria endemic districts in Kenya.</p> <p>Methods</p> <p>The study was conducted in the poorest areas of four malaria endemic districts in Kenya. Multiple data collection methods were applied including: a cross-sectional survey (n = 708 households); 24 focus group discussions; semi-structured interviews with health workers (n = 34); and patient exit interviews (n = 359).</p> <p>Results</p> <p>Multiple factors related to affordability, acceptability and availability interact to influence access to prompt and effective treatment. Regarding affordability, about 40 percent of individuals who self-treated using shop-bought drugs and 42 percent who visited a formal health facility reported not having enough money to pay for treatment, and having to adopt coping strategies including borrowing money and getting treatment on credit in order to access care. Other factors influencing affordability were seasonality of illness and income sources, transport costs, and unofficial payments. Regarding acceptability, the major interrelated factors identified were provider patient relationship, patient expectations, beliefs on illness causation, perceived effectiveness of treatment, distrust in the quality of care and poor adherence to treatment regimes. Availability barriers identified were related to facility opening hours, organization of health care services, drug and staff shortages.</p> <p><b>Conclusions</b></p> <p>Ensuring that all individuals suffering from malaria have prompt access to effective treatment remains a challenge for resource constrained health systems. Policy actions to address the multiple barriers of access should be designed around access dimensions, and should include broad interventions to revitalize the public health care system. Unless additional efforts are directed towards addressing access barriers among the poor and vulnerable, malaria will remain a major cause of morbidity and mortality in sub-Saharan Africa.</p

The C-Terminal Domain of the Arabinosyltransferase Mycobacterium tuberculosis EmbC Is a Lectin-Like Carbohydrate Binding Module

The D-arabinan-containing polymers arabinogalactan (AG) and lipoarabinomannan (LAM) are essential components of the unique cell envelope of the pathogen Mycobacterium tuberculosis. Biosynthesis of AG and LAM involves a series of membrane-embedded arabinofuranosyl (Araf) transferases whose structures are largely uncharacterised, despite the fact that several of them are pharmacological targets of ethambutol, a frontline drug in tuberculosis therapy. Herein, we present the crystal structure of the C-terminal hydrophilic domain of the ethambutol-sensitive Araf transferase M. tuberculosis EmbC, which is essential for LAM synthesis. The structure of the C-terminal domain of EmbC (EmbCCT) encompasses two sub-domains of different folds, of which subdomain II shows distinct similarity to lectin-like carbohydrate-binding modules (CBM). Co-crystallisation with a cell wall-derived di-arabinoside acceptor analogue and structural comparison with ligand-bound CBMs suggest that EmbCCT contains two separate carbohydrate binding sites, associated with subdomains I and II, respectively. Single-residue substitution of conserved tryptophan residues (Trp868, Trp985) at these respective sites inhibited EmbC-catalysed extension of LAM. The same substitutions differentially abrogated binding of di- and penta-arabinofuranoside acceptor analogues to EmbCCT, linking the loss of activity to compromised acceptor substrate binding, indicating the presence of two separate carbohydrate binding sites, and demonstrating that subdomain II indeed functions as a carbohydrate-binding module. This work provides the first step towards unravelling the structure and function of a GT-C-type glycosyltransferase that is essential in M. tuberculosis. Author Summary Top Tuberculosis (TB), an infectious disease caused by the bacillus Mycobacterium tuberculosis, burdens large swaths of the world population. Treatment of active TB typically requires administration of an antibiotic cocktail over several months that includes the drug ethambutol. This front line compound inhibits a set of arabinosyltransferase enzymes, called EmbA, EmbB and EmbC, which are critical for the synthesis of arabinan, a vital polysaccharide in the pathogen's unique cell envelope. How precisely ethambutol inhibits arabinosyltransferase activity is not clear, in part because structural information of its pharmacological targets has been elusive. Here, we report the high-resolution structure of the C-terminal domain of the ethambutol-target EmbC, a 390-amino acid fragment responsible for acceptor substrate recognition. Combining the X-ray crystallographic analysis with structural comparisons, site-directed mutagenesis, activity and ligand binding assays, we identified two regions in the C-terminal domain of EmbC that are capable of binding acceptor substrate mimics and are critical for activity of the full-length enzyme. Our results begin to define structure-function relationships in a family of structurally uncharacterised membrane-embedded glycosyltransferases, which are an important target for tuberculosis therapy

The decline in paediatric malaria admissions on the coast of Kenya

<p>Abstract</p> <p>Background</p> <p>There is only limited information on the health impact of expanded coverage of malaria control and preventative strategies in Africa.</p> <p>Methods</p> <p>Paediatric admission data were assembled over 8.25 years from three District Hospitals; Kilifi, Msambweni and Malindi, situated along the Kenyan Coast. Trends in monthly malaria admissions between January 1999 and March 2007 were analysed using several time-series models that adjusted for monthly non-malaria admission rates and the seasonality and trends in rainfall.</p> <p>Results</p> <p>Since January 1999 paediatric malaria admissions have significantly declined at all hospitals. This trend was observed against a background of rising or constant non-malaria admissions and unaffected by long-term rainfall throughout the surveillance period. By March 2007 the estimated proportional decline in malaria cases was 63% in Kilifi, 53% in Kwale and 28% in Malindi. Time-series models strongly suggest that the observed decline in malaria admissions was a result of malaria-specific control efforts in the hospital catchment areas.</p> <p>Conclusion</p> <p>This study provides evidence of a changing disease burden on the Kenyan coast and that the most parsimonious explanation is an expansion in the coverage of interventions such as the use of insecticide-treated nets and the availability of anti-malarial medicines. While specific attribution to intervention coverage cannot be computed what is clear is that this area of Kenya is experiencing a malaria epidemiological transition.</p

Factors influencing implementation of the Ministry of Health-led private medicine retailer programmes on malaria in Kenya

<p>Abstract</p> <p>Background</p> <p>Kenya has experienced a number of retail sector initiatives aimed at improving access to antimalarial medicines. This study explored stakeholders' perceptions of the role of private medicine retailers (PMRs), the value and feasibility of programme goals, perceived programme impact, factors influencing implementation and recommendations in three districts of Kenya.</p> <p>Methods</p> <p>This study was part of a larger evaluation of PMR programmes, including quantitative and qualitative components. The qualitative research was conducted to assess implementation processes and actors' experiences in the programmes, through focus group discussions with trained PMRs and mothers of children under five years, and in-depth interviews with programme managers, trainers and co-trainers.</p> <p>Results</p> <p>PMRs were perceived to provide rapid cheap treatment for non-serious conditions and used as a deliberate and continuously evaluated choice between different treatment sources. All stakeholders supported programme goals and most PMRs described increased customer satisfaction, more rational purchasing of medicine stock and increased medicine sales after participation. Factors undermining programme implementation included a lack of MoH resources to train and monitor large numbers of PMRs, the relative instability of outlets, medicines stocked and retail personnel, the large number of proprietary brands and financial challenges to retailers in stocking antimalarial medicines, and their customers in buying them. Unambiguous national support and a broad range of strategies are important to strengthen the feasibility of change in OTC antimalarial use.</p> <p>Conclusions</p> <p>Understanding the context and implementation processes of PMR programmes and the perspectives of key actors are critical to identifying measures to support their effective implementation. Financial barriers underlie many described challenges, with important implications for policies on subsidies in this sector. In spite of barriers to implementation, increased exposure to programme activities promoted trust and improved relationships between PMRs and their clients and trainers, strengthening feasibility of such interventions. Public information can strengthen PMR training programmes by engaging local communities and may facilitate performance monitoring of PMRs by their clients.</p

Dynamics of a Quantum Phase Transition and Relaxation to a Steady State

We review recent theoretical work on two closely related issues: excitation of an isolated quantum condensed matter system driven adiabatically across a continuous quantum phase transition or a gapless phase, and apparent relaxation of an excited system after a sudden quench of a parameter in its Hamiltonian. Accordingly the review is divided into two parts. The first part revolves around a quantum version of the Kibble-Zurek mechanism including also phenomena that go beyond this simple paradigm. What they have in common is that excitation of a gapless many-body system scales with a power of the driving rate. The second part attempts a systematic presentation of recent results and conjectures on apparent relaxation of a pure state of an isolated quantum many-body system after its excitation by a sudden quench. This research is motivated in part by recent experimental developments in the physics of ultracold atoms with potential applications in the adiabatic quantum state preparation and quantum computation.Comment: 117 pages; review accepted in Advances in Physic

Unified treatment of spin torques using a coupled magnetisation dynamics and three-dimensional spin current solver

A three-dimensional spin current solver based on a generalised spin drift-diffusion description, including the bulk and interfacial spin Hall effects, is integrated with a magnetisation dynamics solver. The resulting model is shown to simultaneously reproduce the spin-orbit torques generated using the spin Hall effect, spin pumping torques generated by magnetisation dynamics in multilayers, as well as the spin transfer torques acting on magnetisation regions with spatial gradients, whilst field-like and spin-like torques are reproduced in a spin valve geometry. Two approaches to modelling interfaces are analysed, one based on the spin mixing conductance and the other based on continuity of spin currents where the spin dephasing length governs the absorption of transverse spin components. In both cases analytical formulas are derived for the spin-orbit torques in a heavy metal / ferromagnet bilayer geometry, showing in general both field-like and damping-like torques are generated. The limitations of the analytical approach are discussed, showing that even in a simple bilayer geometry, due to the non-uniformity of the spin currents, a full three-dimensional treatment is required. The model is further applied to the analysis of the spin Hall angle in Pt by reproducing published experimental ferromagnetic resonance data in the bilayer geometry

Retail sector distribution chains for malaria treatment in the developing world: a review of the literature

BACKGROUND: In many low-income countries, the retail sector plays an important role in the treatment of malaria and is increasingly being considered as a channel for improving medicine availability. Retailers are the last link in a distribution chain and their supply sources are likely to have an important influence on the availability, quality and price of malaria treatment. This article presents the findings of a systematic literature review on the retail sector distribution chain for malaria treatment in low and middle-income countries. METHODS: Publication databases were searched using key terms relevant to the distribution chain serving all types of anti-malarial retailers. Organizations involved in malaria treatment and distribution chain related activities were contacted to identify unpublished studies. RESULTS: A total of 32 references distributed across 12 developing countries were identified. The distribution chain had a pyramid shape with numerous suppliers at the bottom and fewer at the top. The chain supplying rural and less-formal outlets was made of more levels than that serving urban and more formal outlets. Wholesale markets tended to be relatively concentrated, especially at the top of the chain where few importers accounted for most of the anti-malarial volumes sold. Wholesale price mark-ups varied across chain levels, ranging from 27% to 99% at the top of the chain, 8% at intermediate level (one study only) and 2% to 67% at the level supplying retailers directly. Retail mark-ups tended to be higher, and varied across outlet types, ranging from 3% to 566% in pharmacies, 29% to 669% in drug shops and 100% to 233% in general shops. Information on pricing determinants was very limited. CONCLUSIONS: Evidence on the distribution chain for retail sector malaria treatment was mainly descriptive and lacked representative data on a national scale. These are important limitations in the advent of the Affordable Medicine Facility for Malaria, which aims to increase consumer access to artemisinin-based combination therapy (ACT), through a subsidy introduced at the top of the distribution chain. This review calls for rigorous distribution chain analysis, notably on the factors that influence ACT availability and prices in order to contribute to efforts towards improved access to effective malaria treatment