The functioning of oxygen concentrators in resource-limited settings: a situation assessment in two countries.

SETTING: The paediatric wards of hospitals in Malawi and Mongolia. OBJECTIVE: To describe oxygen concentrator functioning in two countries with widespread, long-term use of concentrators as a primary source of oxygen for treating children. DESIGN: A systematic assessment of concentrators in the paediatric wards of 15 hospitals in Malawi and nine hospitals in Mongolia. RESULTS: Oxygen concentrators had been installed for a median of 48 months (interquartile range [IQR] 6-60) and 36 months (IQR 12-96), respectively, prior to the evaluation in Malawi and Mongolia. Concentrators were the primary source of oxygen. Three quarters of the concentrators assessed in Malawi (28/36) and half those assessed in Mongolia (13/25) were functional. Concentrators were found to remain functional with up to 30 000 h of use. However, several concentrators were functioning very poorly despite limited use. Concentrators from a number of different manufacturers were evaluated, and there was marked variation in performance between brands. Inadequate resources for maintenance were reported in both countries. CONCLUSION: Years after installation of oxygen concentrators, many machines were still functioning, indicating that widespread use can be sustained in resource-limited settings. However, concentrator performance varied substantially. Procurement of high-quality and appropriate equipment is critical, and resources should be made available for ongoing maintenance.

Oxygen is an essential medicine: a call for international action.

Hypoxaemia is commonly associated with mortality in developing countries, yet feasible and cost-effective ways to address hypoxaemia receive little or no attention in current global health strategies. Oxygen treatment has been used in medicine for almost 100 years, but in developing countries most seriously ill newborns, children and adults do not have access to oxygen or the simple test that can detect hypoxaemia. Improving access to oxygen and pulse oximetry has demonstrated a reduction in mortality from childhood pneumonia by up to 35% in high-burden child pneumonia settings. The cost-effectiveness of an oxygen systems strategy compares favourably with other higher profile child survival interventions, such as new vaccines. In addition to its use in treating acute respiratory illness, oxygen treatment is required for the optimal management of many other conditions in adults and children, and is essential for safe surgery, anaesthesia and obstetric care. Oxygen concentrators provide the most consistent and least expensive source of oxygen in health facilities where power supplies are reliable. Oxygen concentrators are sustainable in developing country settings if a systematic approach involving nurses, doctors, technicians and administrators is adopted. Improving oxygen systems is an entry point for improving the quality of care. For these broad reasons, and for its vital importance in reducing deaths due to lung disease in 2010: Year of the Lung, oxygen deserves a higher priority on the global health agenda.

Oxygen concentrators: a practical guide for clinicians and technicians in developing countries.

Hypoxaemia is a common problem causing child deaths in developing countries, but the cost-effective ways to address hypoxaemia are ignored by current global strategies. Improving oxygen supplies and the detection of hypoxaemia has been shown to reduce death rates from childhood pneumonia by up to 35%, and to be cheaper per life saved than other effective initiatives such as conjugate pneumococcal vaccines. Oxygen concentrators provide the cheapest and most consistent source of oxygen in health facilities where power supplies are reliable. To implement and sustain oxygen concentrators requires strengthening of health systems, with clinicians, teachers, administrators and technicians working together. Programmes built around the use of pulse oximetry and oxygen concentrators are an entry point for improving quality of care, and are a unique example of successful integration of appropriate technology into clinical care. This paper is a practical and up-to-date guide for all involved in purchasing, using and maintaining oxygen concentrators in developing countries.

Isoniazid preventive therapy for people living with HIV: public health challenges and implementation issues.

Isoniazid preventive therapy (IPT) is recognised as an important component of collaborative tuberculosis (TB) and human immunodeficiency virus (HIV) activities to reduce the burden of TB in people living with HIV (PLHIV). However, there has been little in the way of IPT implementation at country level. This failure has resulted in a recent call to arms under the banner title of the 'Three I's' (infection control to prevent nosocomial transmission of TB in health care settings, intensified TB case finding and IPT). In this paper, we review the background of IPT. We then discuss the important challenges of IPT in PLHIV, namely responsibility and accountability for the implementation, identification of latent TB infection, exclusion of active TB and prevention of isoniazid resistance, length of treatment and duration of protective efficacy. We also highlight several research questions that currently remain unanswered. We finally offer practical suggestions about how to scale up IPT in the field, including the need to integrate IPT into a package of care for PLHIV, the setting up of operational projects with the philosophy of 'learning while doing', the development of flow charts for eligibility for IPT, the development and implementation of care prior to antiretroviral treatment, and finally issues around procurement, distribution, monitoring and evaluation. We support the implementation of IPT, but only if it is done in a safe and structured way. There is a definite risk that 'sloppy' IPT will be inefficient and, worse, could lead to the development of multidrug-resistant TB, and this must be avoided at all costs.

Management of asthma in children in low-income countries.

Asthma is a common disease in children living in low-income countries. Asthma is diagnosed in children, especially those aged over 2 years, who have wheezing episodes that improve after a bronchodilator is given (bronchodilator response test). Children are classified as having either intermittent or persistent asthma and treated according to the severity of the disease with either an inhaled bronchodilator (reliever) or a combination of an inhaled bronchodilator and inhaled corticosteroid (controller). Treatment is best given by inhalation, and as children under 5 years cannot coordinate their breathing with the multidose inhaler, spacers are required. These can be made locally from plastic bottles. Care givers need to be educated about how to manage asthma and should receive a written management plan on the management of the child's asthma. Children should be examined to see if they are allergic to especially airborne allergens, and if these are present they should be removed from the environment. Adult smoking worsens childhood asthma, and care givers need to be given support with smoking cessation. Regular planned follow-up is needed to ensure that the asthma is well controlled and the lowest dose of inhaled corticosteroid is used. Inhaled bronchodilators and corticosteroids must become freely available and should be inexpensive in low-income countries in order to treat childhood asthma correctly.

Management of pneumonia in the child aged 0 to 8 weeks.

The group of children with the highest mortality from pneumonia is the group aged 8 weeks and younger. This group of infants is more likely to present with non-specific signs of disease, and the pneumonia is caused by a wider spectrum of organisms. For these reasons, infants aged < or = 8 weeks have to be carefully assessed, taking into account the characteristics peculiar to this age. Due to the seriousness of the pneumonia, they are only classified into three categories: very severe pneumonia, severe pneumonia and cough or cold. All infants aged < or = 8 weeks diagnosed with severe or very severe pneumonia must be hospitalised, as they require parenteral antibiotics for at least 8 days and need careful monitoring. The monitoring needs to be adapted, as they are more likely to have problems with body temperature and serum glucose control. Careful plans have to be formulated to ensure that these infants recover fully and are integrated into the well baby clinics. In the triage of sick children, it is those aged < or = 8 weeks who should receive the most urgent attention.

Management of pneumonia in the child 2 to 59 months of age.

The mortality from pneumonia is reduced when children with pneumonia requiring antibiotics are identified and the severity of the pneumonia assessed. Children presenting with a cough or difficult breathing have pneumonia if fast breathing is present. The severity of pneumonia is classified by the presence of chest wall indrawing, inability to drink or feed well, decreased level of consciousness or convulsions, amongst others. Using these easily observed signs, pneumonia can be classified into four grades of severity: no pneumonia (cough or cold), pneumonia, severe pneumonia and very severe pneumonia. The classification into one of these four grades of severity is extremely useful as it identifies which children require antibiotics, which antibiotics and who requires hospitalisation and supplementary oxygen. This simple case management of pneumonia can be successfully taught to any cadre of health care worker, and where implemented has been shown to reduce childhood mortality from pneumonia.

Assessing the child with cough or difficult breathing.

In most low-income countries, clinical assessment is the only tool available to distinguish an upper respiratory infection (cough or cold) from pneumonia requiring antibiotics. The severity of the pneumonia, determined from the clinical signs, will determine which patients require more potent antibiotic regimens and supplementary oxygen. Careful assessment of the respiratory rate, chest in-drawing, ability to feed normally, cyanosis and level of consciousness are used to make the diagnosis of pneumonia and determine the severity. Co-morbid disease such as malnutrition, measles, HIV infection and malaria increase mortality due to pneumonia, and signs of these diseases must be looked for so that appropriate treatment can be started. This article carefully describes the signs that should be looked for in children presenting with a cough or difficult breathing to any health care worker.

Management of the child with cough or difficult breathing.

Childhood respiratory disease creates considerable morbidity and mortality, especially amongst children living in low-income countries. Of the more than 10 million children who die annually from preventable diseases, pneumonia is responsible for 18.1%, while in low-income countries this percentage rises to 26%. It is calculated that 90% of these deaths from preventable diseases occur in 42 countries. Even in the face of the human immunodeficiency virus (HIV) epidemic, pneumonia is still responsible for 21% of deaths. HIV-infected children are at greatest risk for developing and dying from pneumonia. By the introduction of low cost standardised case management strategies for the management of pneumonia, increasing immunisation, reducing risk factors such as poor nutrition and environmental smoking and promoting breast-feeding, it is estimated that the death rate from pneumonia can be reduced by 50%. In this series the epidemiology of childhood acute respiratory infections (ARI) and the recognition and management of childhood pneumonia in resource-poor settings will be highlighted as well as the scientific justification for the standard case management of childhood pneumonia. As cases of pneumonia are better managed, other childhood respiratory diseases such as asthma and tuberculosis (TB) will be discovered, which also require a standard approach to management. The management of asthma and TB in resource-poor settings will also be discussed.

Management of tuberculosis in children in low-income countries.

Children become infected when they are exposed to infectious adults with smear-positive tuberculosis (TB). Most children become infected, but few progress to disease (TB). Children at greatest risk of developing disease are those younger than 5 years of age, HIV-infected and severely malnourished. TB is diagnosed in a child when the child has been exposed to an infectious case, has symptoms and a radiological picture suggestive of TB. Children are treated by the DOTS strategy, and can be treated with 6- or 8-month regimens. HIV-infected children are treated with the same regimens. Children under 5 years of age exposed to an infectious case or infected with TB (tuberculin skin test positive) who are asymptomatic must receive preventive chemotherapy (isoniazid for 6 months). Babies born to mothers with active TB must be managed carefully, as they could have congenital TB, and if they do not have TB they will need preventive chemotherapy for 6 months. BCG is indicated in all children soon after birth, except for those with symptomatic HIV infection. The main aim of any TB programme is to prevent the spread of TB, and also the spread to children, which is best achieved by early detection and treatment of adults with smear-positive TB.

Autoantigens of the nuclear pore complex.

The nuclear envelope (NE) is one of many intracellular targets of the autoimmune response in patients with autoimmune liver disease, systemic lupus erythematosus, and related conditions. In eukaryotic organisms the NE consists of five interconnected regions: an outer nuclear membrane (ONM) that is continuous with the endoplasmic reticulum, an intermembrane or perinuclear space, an inner nuclear membrane (INM) with a unique set of integral membrane proteins, the underlying nuclear lamina, and the pore domains that are regions where the ONM and INM come together. The pore domains are sites of regulated continuity between the cytoplasm and nucleus that are occupied by supramolecular structures, termed nuclear pore complexes (NPCs). Human autoantibodies identified to date bind to specific components in three of the five NE compartments. Autoantigen targets include the lamins A, B, and C of the nuclear lamina, gp210, p62 complex proteins, Nup153, and Tpr within the NPC, and LBR, MAN1, LAP1, and LAP2 that are integral proteins of the INM. Autoantibodies to these NE targets have been shown to be correlated with various autoimmune diseases such as primary biliary cirrhosis, other autoimmune liver diseases and systemic rheumatic diseases. Now that the proteome of the NE is more clearly defined, other autoantibodies to components in this cell compartment are likely to be defined.

The nuclear pore complex protein Tpr is a common autoantigen in sera that demonstrate nuclear envelope staining by indirect immunofluorescence.

We studied the autoantigen targets of 75 human sera that had antibodies to the nuclear envelope (NE) as identified by indirect immunofluorescence (IIF) on HEp-2 cells. Several different IIF staining patterns could be identified when antibodies to different components of the nuclear membrane (NM) and nuclear pore complexes (NuPC) were identified: a smooth membrane pattern characteristic of antibodies to nuclear lamins, a punctate pattern typical of antibodies to the nuclear pore complex and more complex patterns that included antibodies to nuclear and cytoplasmic organelles. Western immunoblotting of isolated nuclear and NE proteins and immunoprecipitation of radiolabelled recombinant proteins prepared by using the full-length cDNAs of the Translocated promoter region (Tpr), gp210 and p62 were used to identify specific autoantibody targets. Fifty-two of the 75 (70%) sera bound to Tpr, 25 (33%) bound to lamins A, B or C, 15 (20%) reacted with gp210 and none reacted with p62. Sixteen (21%) did not react with any of the NE components tested in our assays. The clinical features of 37 patients with anti-NE showed that there were 34 females and three males with an age range of 16-88 years (mean 59 years). The most frequent clinical diagnosis (9/37 = 24%) was autoimmune liver disease (ALD; two with primary biliary cirrhosis), followed by seven (19%) with systemic lupus erythematosus (SLE), four (11%) with a motor and/or sensory neuropathy, three (8%) with anti-phospholipid syndrome (APS), two with systemic sclerosis (SSc), two with Sjögren's syndrome (SjS), and others with a variety of diagnoses. This report indicates that Tpr, a component of the NuPC, is a common target of human autoantibodies that react with the NE.

Nuclear envelope dynamics.

The nuclear envelope (NE) provides a semi permeable barrier between the nucleus and cytoplasm and plays a central role in the regulation of macromolecular trafficking between these two compartments. In addition to this transport function, the NE is a key determinant of interphase nuclear architecture. Defects in NE proteins such as A-type lamins and the inner nuclear membrane protein, emerin, result in several human diseases that include cardiac and skeletal myopathies as well as lipodystrophy. Certain disease-linked A-type lamin defects cause profound changes in nuclear organization such as loss of peripheral heterochromatin and redistribution of other nuclear envelope components. While clearly essential in maintenance of nuclear integrity, the NE is a highly dynamic organelle. In interphase it is constantly remodeled to accommodate nuclear growth. During mitosis it must be completely dispersed so that the condensed chromosomes may gain access to the mitotic spindle. Upon completion of mitosis, dispersed NE components are reutilized in the assembly of nuclei within each daughter cell. These complex NE rearrangements are under precise temporal and spatial control and involve interactions with microtubules, chromatin, and a variety of cell-cycle regulatory molecules.

Nuclear envelope defects associated with LMNA mutations cause dilated cardiomyopathy and Emery-Dreifuss muscular dystrophy.

Nuclear lamin A and C alleles that are linked to three distinct human diseases have been expressed both in HeLa cells and in fibroblasts derived from Lmna null mice. Point mutations that cause dilated cardiomyopathy (L85R and N195K) and autosomal dominant Emery-Dreifuss muscular dystrophy (L530P) modify the assembly properties of lamins A and C and cause partial mislocalization of emerin, an inner nuclear membrane protein, in HeLa cells. At the same time, these mutant lamins interfere with the targeting and assembly of endogenous lamins and in this way may cause significant changes in the molecular organization of the nuclear periphery. By contrast, lamin A and C molecules harboring a point mutation (R482W), which gives rise to a dominant form of familial partial lipodystrophy, behave in a manner that is indistinguishable from wild-type lamins A and C, at least with respect to targeting and assembly within the nuclear lamina. Taken together, these results suggest that nuclear structural defects could contribute to the etiology of both dilated cardiomyopathy and autosomal dominant Emery-Dreifuss muscular dystrophy.

Case management of childhood pneumonia in developing countries: recent relevant research and current initiatives.

Acute respiratory infections (ARI), mostly pneumonia, are one of the leading causes of death in young children in developing countries, accounting for 28% of childhood mortality. This paper provides a summary of the research and technical development efforts made in the last 15 years which contributed to improving the effectiveness of the case management strategy to reduce mortality from pneumonia in children in developing countries. Community intervention studies provided strong evidence that the strategy was feasible and effective in producing a substantial impact on pneumonia mortality. Clinical studies provided the rationale for improving the sensitivity and specificity of key signs of pneumonia, and for enhancing the therapeutic efficacy of standard home treatment. Research also provided data to deal with the problem of the clinical overlap of pneumonia and malaria in children. Technological initiatives succeeded in making appropriate diagnostic and therapeutic devices available. An important body of socio-cultural knowledge about family practices regarding pneumonia and ARI in children was built up and provided orientation on effective communication between health workers and families about home care of children with ARI. Health systems research focused on methods for surveillance of bacterial drug resistance and methodologies for evaluating the control programmes. Despite advances in the development of vaccines against respiratory bacteria and in the prevention of risk factors for pneumonia in children, case management will continue to be a central strategy for preventing mortality. Current international research initiatives are looking into measures that can improve the referral of severe pneumonia and effective management of severe pneumonia at first level hospitals.

Function and assembly of nuclear pore complex proteins.

Nuclear pore complexes (NPCs) are extremely elaborate structures that mediate the bidirectional movement of macromolecules between the nucleus and cytoplasm. The current view of NPC organization features a massive symmetrical framework that is embedded in the double membranes of the nuclear envelope. It embraces a central channel of as yet ill-defined structure but which may accommodate particles with diameters up to 26 nm provided that they bear specific import/export signals. Attached to both faces of the central framework are peripheral structures, short cytoplasmic filaments, and a nuclear basket assembly, which interact with molecules transiting the NPC. The mechanisms of assembly and the nature of NPC structural intermediates are still poorly understood. However, mutagenesis and expression studies have revealed discrete sequences within certain NPC proteins that are necessary and sufficient for their appropriate targeting. In addition, some details are emerging from observations on cells undergoing mitosis where the nuclear envelope is disassembled and its components, including NPC subunits, are dispersed throughout the mitotic cytoplasm. At the end of mitosis, all of these components are reutilized to form nuclear envelopes in the two daughter cells. To date, it has been possible to define a time course of postmitotic assembly for a group of NPC components (CAN/Nup214, Nup153, POM121, p62 and Tpr) relative to the integral inner nuclear membrane protein LAP2 and the NPC membrane glycoprotein gp210. Nup153, a dynamic component of the nuclear basket, associates with chromatin towards the end of anaphase coincident with, although independent of, the inner nuclear membrane protein, LAP2. Assembly of the remaining proteins follows that of the nuclear membranes and occurs in the sequence POM121, p62, CAN/Nup214 and gp210/Tpr. Since p62 remains as a complex with three other NPC proteins (p58, p54, p45) during mitosis, and CAN/Nup214 maintains a similar interaction with its partner, Nup84, the relative timing of assembly of these additional four proteins may also be inferred. These observations suggest that there is a sequential association of NPC proteins with chromosomes during nuclear envelope reformation and the recruitment of at least eight of these precedes that of gp210. These findings support a model in which it is POM121 rather than gp210 that defines initial membrane-associated NPC assembly intermediates and which may therefore represent an essential component of the central framework of the NPC.

Amino-terminal sequences that direct nucleoporin nup153 to the inner surface of the nuclear envelope.

Nup153 is a large O-linked glycoprotein that is a component of the basket-like structure that forms the nucleoplasmic face of nuclear pore complexes (NPCs). The Nup153 molecule has a tripartite structure consisting of N- and C-terminal domains flanking a central zinc finger domain. All of the targeting and assembly information contained within Nup153 is contributed by the N-domain. In fact this region of the molecule can target a cytosolic protein, pyruvate kinase, to the nucleoplasmic face of the NPC. The zinc finger and C-terminal domains appear to have no role in these targeting and assembly activities. Deletion analysis reveals that there are two distinct regions within the Nup153 N-domain that contain different targeting functions. One of these is directly involved in assembly into the NPC while a second overlapping region may target Nup153, as well as other reporter molecules, to the inner face of the nuclear envelope.

Filariasis in an upland population in the Philippines.

An epidemiological survey of filariasis was undertaken among the Mangyan villages of Mindoro, Philippines. The prevalence of microfilaremia was 10.2%. There were two foci of the disease; one in the northeast and the other in the southeast. The prevalence of lymphedema was very low. The prevalence of chronic productive cough was high and was associated with the presence of microfilaria.