Symptomatic fracture risk in the renal replacement therapy population.

BACKGROUND: Bone fractures are an important cause of morbidity and mortality in patients on renal replacement therapy (RRT). The aim of this multicentre observational study was to quantify the incidence of radiologically proven bone fracture by anatomical site in prevalent RRT groups and study its relationship to potential risk factors. METHODS: We performed a retrospective analysis of electronic records of all 2096 adults prevalent on RRT in the West of Scotland on 7 July 2010 across all hospitals (except one where inception was 1 August 2011) to identify all subsequent radiologically proven fractures during a median 3-year follow-up. RESULTS: There were 340 fractures, with an incidence of 62.8 per 1000 patient-years. The incidences were 37.6, 99.2 and 57.6 per 1000 patient-years in the transplant, haemodialysis (HD) and peritoneal dialysis (PD) groups, respectively (P < 0.05). In the multivariable model, age and HD (relative to transplant or PD) were independently associated with increased risk of fractures, while primary glomerular disease, increasing serum albumin and taking alfacalcidol or lanthanum were associated with decreased risk. In a multivariable model of only HD patients, age was independently associated with an increased risk of fractures, while glomerular disease, high serum albumin and being on alfacalcidol and lanthanum were associated with decreased risk. In a multivariable model in transplant patients, there were no significant independent predictors of fracture. CONCLUSIONS: The risk of symptomatic bone fracture is high in RRT patients and is ∼2.5 times higher in HD than in renal transplant patients, with the increased risk being independent of baseline factors. Fracture risk increases with age and lower serum albumin and is reduced if the primary renal diagnosis is glomerular disease. The possible protective role of alfacalcidol and lanthanum in HD patients deserves further exploration.

Phosphodiesterase 4 (PDE4) regulation of proinflammatory cytokine and chemokine release from rheumatoid synovial membrane.

BACKGROUND: The cAMP-metabolising enzyme, phosphodiesterase 4 (PDE4), has been implicated in a number of immune responses, including tumour necrosis factor α (TNFα) production. To date, few data have directly addressed whether synovial cytokine and chemokine production is modified by PDE4. OBJECTIVE: Using specific PDE4 inhibitors, roflumilast plus two novel inhibitors, INH 0061 and INH 0062, the authors studied the effect of PDE4 inhibition on proinflammatory cytokine and chemokine release from primary rheumatoid arthritis (RA) synovial digest suspensions and in a macrophage T cell co-culture assay system. RESULTS: All PDE4 inhibitors dose-dependently reduced the release of TNFα from primary synovial membrane cultures (n=5), half maximal inhibitory concentration (IC(50)) 300-30 nM, p<0.05. Similarly, a significant suppression in the release the proinflammatory chemokines, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1α, MIP-1ß (IC(50) 300-30 nM) and regulated upon activation normal T-cell expressed and secreted (RANTES) (IC(50) 3 nM) was also observed, p<0.05. While interleukin 1ß was also reduced, it did not achieve an IC(50). These observations were further confirmed in a macrophage T cell co-culture system, demonstrating the importance of PDE4 pathways in regulating cytokine/chemokine release in a cellular interaction implicated in inflammatory synovitis. Subsequent studies using the human monocytic cell line U937 also demonstrated cytokine regulation with PDE4 knockdown utilising a small interfering RNA approach. CONCLUSION: These data provide direct evidence of PDE4-dependent pathways in human RA synovial inflammatory cytokine and chemokine release and may provide a novel approach in treating chronic autoimmune conditions such as RA.

Costs of congenital rubella syndrome (CRS) in Oman: evidence based on long-term follow-up of 43 children.

As part of the national plan for elimination of rubella and congenital rubella syndrome (CRS), Oman established a national registry of CRS cases. As of May 2005, the registry included 43 surviving CRS cases, with a mean age of 11.9 years. Clinical examinations found that 84% had ocular defects, 84% had auditory/speech defects, 70% had neurological manifestations, and 42% had cardiac defects. Lifetime medical, special education, and rehabilitation costs were assessed. Using a discount rate of 3%, the average direct lifetime cost per surviving CRS patient was estimated at 18,644 US dollars. When including predicted lost productivity due to CRS, the average discounted direct and indirect lifetime costs per surviving CRS patient amounted to 98,734 US dollars.

Global review of health care surveys using lot quality assurance sampling (LQAS), 1984-2004.

We conducted a global review on the use of lot quality assurance sampling (LQAS) to assess health care services, health behaviors, and disease burden. Publications and reports on LQAS surveys were sought from Medline and five other electronic databases; the World Health Organization; the World Bank; governments, nongovernmental organizations, and individual scientists. We identified a total of 805 LQAS surveys conducted by different management groups during January 1984 through December 2004. There was a striking increase in the annual number of LQAS surveys conducted in 2000-2004 (128/year) compared with 1984-1999 (10/year). Surveys were conducted in 55 countries, and in 12 of these countries there were 10 or more LQAS surveys. Geographically, 317 surveys (39.4%) were conducted in Africa, 197 (28.5%) in the Americas, 115 (14.3%) in the Eastern Mediterranean, 114 (14.2%) in South-East Asia, 48 (6.0%) in Europe, and 14 (1.8%) in the Western Pacific. Health care parameters varied, and some surveys assessed more than one parameter. There were 320 surveys about risk factors for HIV/AIDS/sexually transmitted infections; 266 surveys on immunization coverage, 240 surveys post-disasters, 224 surveys on women's health, 142 surveys on growth and nutrition, 136 surveys on diarrheal disease control, and 88 surveys on quality management. LQAS surveys to assess disease burden included 23 neonatal tetanus mortality surveys and 12 surveys on other diseases. LQAS is a practical field method which increasingly is being applied in assessment of preventive and curative health services, and may offer new research opportunities to social scientists. When LQAS data are collected recurrently at multiple time points, they can be used to measure the spatial variation in behavior change. Such data provide insight into understanding relationships between various investments in social, human, and physical capital, and into the effectiveness of different public health strategies in achieving particular behavioral outcomes.

Antenatal rubella serosurvey in Maputo, Mozambique.

OBJECTIVE: To describe the epidemiology of rubella in Mozambique. METHODS: Cross-sectional serosurvey of rubella IgG antibodies among women attending antenatal clinics in Maputo in February-April 2002 to assess the prevalence and titres. RESULTS: Rubella IgG antibodies were detected in 95.3% (95% confidence interval 94.0%-96.6%) of 974 pregnant women. Age and residence did not significantly affect the prevalence of rubella IgG antibodies. However, the mean titre of rubella IgG antibodies was higher in women <20 years of age than in women > or =30 years of age (P < 0.01), and women living in urban areas had higher antibody titres than those living in suburban areas (P < 0.0001). CONCLUSIONS: The seroprevalence of rubella IgG antibodies among pregnant women in Maputo is high. Whether this is due to recent exposure to wild rubella virus or to exposure to rubella virus earlier in life is unclear. Studies on the burden of congenital rubella syndrome could address this matter.

Expression and alternative processing of IL-18 in human neutrophils.

Interleukin-18 (IL-18), a member of the IL-1 cytokine superfamily, is an important regulator of both innate and acquired immune responses. We demonstrate here constitutive expression of IL-18 by human neutrophils. Unexpectedly, we observed that neutrophils from peripheral blood or rheumatoid synovial compartments contained not only pro and mature IL-18, but also several novel smaller-molecular-weight IL-18-derived species. Using specific protease inhibitors, and serine protease gene-targeted mice, we demonstrate that these IL-18-derived products arose through caspase-independent cleavage events mediated by the serine proteases, elastase and cathepsin G. Moreover, we report that the net effect of elastase treatment of mature recombinant IL-18 was to reduce its IFN-gamma-inducing activity. Thus, human neutrophils contain IL-18 and IL-18-derived molecular species that can arise through novel enzymatic processing pathways. Through cytosolic, membrane or secretory expression of such processing enzymes, together with generation of IL-18 itself, neutrophils likely play a critical role in regulating IL-18 activities during early innate immune responses.

Active surveillance for congenital rubella syndrome in Yangon, Myanmar.

OBJECTIVE: Rubella vaccine is not included in the immunization schedule in Myanmar. Although surveillance for outbreaks of measles and rubella is conducted nationwide, there is no routine surveillance for congenital rubella syndrome (CRS). Therefore, we organized a study to assess the burden of CRS. METHODS: From 1 December 2000 to 31 December 2002 active surveillance for CRS was conducted among children aged 0-17 months at 13 hospitals and 2 private clinics in Yangon, the capital city. Children with suspected CRS had a standard examination and a blood sample was obtained. All serum samples were tested for rubella-specific IgM; selected samples were tested for rubella-specific IgG and for rubella RNA by reverse transcriptase-polymerase chain reaction (RT-PCR). FINDINGS: A total of 81 children aged 0-17 months were suspected of having CRS. Of these, 18 children had laboratory-confirmed CRS (7 were IgM positive; 7 were RT-PCR positive; and 10 were IgG positive at > 6 months of age). One additional child who tested positive by RT-PCR and whose mother had had rubella during pregnancy but who had a normal clinical examination was classified as having congenital rubella infection. During 2001-02 no rubella outbreaks were detected in Yangon Division. In the 31 urban townships of Yangon Division, the annual incidence was 0.1 laboratory-confirmed cases of CRS per 1000 live births. CONCLUSION: This is the first population-based study of CRS incidence from a developing country during a rubella-endemic period; the incidence of CRS is similar to endemic rates found in industrialized countries during the pre-vaccine era. Rubella-specific IgG tests proved practical for diagnosing CRS in children aged > 6 months. This is one of the first studies to report on the use of rubella-specific RT-PCR directly on serum samples; further studies are warranted to confirm the utility of this method as an additional means of diagnosing CRS.

A community-based cluster survey on preferences for treatment of diarrhoea and dysentery in Zhengding county, Hebei province, China.

Passive surveillance on the burden of disease due to diarrhoea will underestimate the burden if families use healthcare providers outside the surveillance system. To study this issue, a community-based cluster survey was conducted during October 2001 in the catchment area for a passive surveillance study in Zhengding county, a rural area of northern China. Interviews were conducted at 7 randomly-selected households in each of 39 study villages. The respondents indicated where they sought initial care for cases of diarrhoea or dysentery among children or adults. In the absence of diarrhoea and dysentery cases in the household in the preceding four weeks, the respondents were asked about healthcare use for a hypothetical case. Overall, 80% (95% confidence interval [CI] 67-93%) would chose the village clinic, 11% village pharmacy (95% CI 1-22%), 4% township hospital (95% CI -1-10%), 4% self-treatment (95% CI 1-8%), and 1% county hospital (95% CI 0-2%). Approximately, 84% of patients would seek treatment for diarrhoea and dysentery at centres participating in passive surveillance, suggesting that passive surveillance will provide a relatively accurate assessment of burden of diarrhoea in Zhengding county.

Preferences for treatment of diarrhoea and dysentery in Kaengkhoi district, Saraburi province, Thailand.

To estimate the proportion of cases missed in a passive surveillance study of diarrhoea and dysentery at health centres and hospitals in Kaengkhoi district, Saraburi province, Thailand, a community-based cluster survey of treatment-seeking behaviours was conducted during 21-23 June 2002. Interviews were conducted at 224 households among a study population of 78,744. The respondents reported where they sought care for diarrhoea and dysentery in children aged less than five years and adults aged over 15 years. Health centres or hospitals were the first treatment choice for 78% of children with dysentery (95% confidence interval [CI] 63-94%), 64% of children with diarrhoea (95% CI 54-74%), 61% of adults with dysentery (95% CI 40-82%), and 35% of adults with diarrhoea (95% CI 17-54%). A high degree of heterogeneity in responses resulted in a relatively large design effect (D=3.9) and poor intra-cluster correlation (rho=0.3). The community survey suggests that passive surveillance estimates of disease incidence will need to be interpreted with caution, since this method will miss nearly a quarter of dysentery cases in children and nearly two-thirds of diarrhoea cases in adults.

Diarrhoea episodes and treatment-seeking behaviour in a slum area of North Jakarta, Indonesia.

Visits to household during a census in an impoverished area of north Jakarta were used for exploring the four-week prevalence of diarrhoea, factors associated with episodes of diarrhoea, and the patterns of healthcare use. For 160,261 urban slum-dwellers, information was collected on the socioeconomic status of the household and on diarrhoea episodes of individual household residents in the preceding four weeks. In households with a reported case of diarrhoea, the household head was asked which form of healthcare was used first. In total, 8,074 individuals (5%)--13% of children aged less than five years and 4% of adults--had a diarrhoea episode in the preceding four weeks. The two strongest factors associated with a history of diarrhoea were a diarrhoea episode in another household member in the four weeks preceding the interview (adjusted odds ratio [OR] 11.1; 95% confidence interval [CI] 10.4-11.8) and age less than five years (adjusted OR 3.4; 95% CI 3.2-3.5). Of the 8,074 diarrhoea cases, 1,969 (25%) treated themselves, 1,822 (23%) visited a public-health centre (PHC), 1,462 (18%) visited a private practitioner or a private clinic, 1,318 (16%) presented at a hospital, 753 (9%) bought drugs from a drug vendor, and 750 (9%) used other healthcare providers, such as belian (traditional healers). Children with diarrhoea were most often brought to a PHC, a private clinic, or a hospital for treatment. Compared to children, adults with diarrhoea were more likely to treat themselves. Individuals from households in the lowest-income group were significantly more likely to attend a PHC for treatment of diarrhoea compared to individuals from households in the middle- and higher-income groups.

Rubella serosurveys at three Aravind Eye Hospitals in Tamil Nadu, India.

OBJECTIVE: To determine the susceptibility of female eye hospital staff to rubella infection and the potential risk for hospital-based rubella outbreaks. METHODS: A prospective cohort study on the seroprevalence of rubella IgG antibodies was conducted at three large eye hospitals in Coimbatore, Madurai and Tirunelveli, Tamil Nadu, India, where young children with eye abnormalities attributable to congenital rubella are treated. A total of 1000 female hospital employees aged 18-40 years agreed to participate and gave written informed consent. FINDINGS: The proportions of rubella-seronegative women were: 11.7% at Coimbatore, with a 95% confidence interval (CI) of 8.1-16.5; 15% at Madurai (95% CI = 12.3-18.1), and 20.8 at Tirunelveli (95% CI = 14.7-28.6). For the entire cohort the proportion seronegative was significantly higher among married women (21.5%) than among single women (14.0%) (P = 0.02). Rates of seronegativity were highest among physicians and lowest among housekeepers. All 150 seronegative women in the study sample accepted a dose of rubella vaccine. CONCLUSION: These are the first rubella serosurveys to have been reported from eye hospitals in any country. The relatively high rate of susceptibility indicated a risk of a rubella outbreak, and this was reduced by vaccinating all seronegative women. A policy has been established at all three hospitals for the provision of rubella vaccine to new employees. Other hospitals, especially eye hospitals and hospitals in countries without routine rubella immunization, should consider the rubella susceptibility of staff and the risk of hospital-based rubella outbreaks.

Respiratory syncytial virus infection: denominator-based studies in Indonesia, Mozambique, Nigeria and South Africa.

OBJECTIVE: To assess the burden of respiratory syncytial virus (RSV)-associated lower respiratory infections (LRI) in children in four developing countries. METHODS: A WHO protocol for prospective population-based surveillance of acute respiratory infections in children aged less than 5 years was used at sites in Indonesia, Mozambique, Nigeria and South Africa. RSV antigen was identified by enzyme-linked immunosorbent assay performed on nasopharyngeal specimens from children meeting clinical case definitions. FINDINGS: Among children aged < 5 years, the incidence of RSV-associated LRI per 1000 child-years was 34 in Indonesia and 94 in Nigeria. The incidence of RSV-associated severe LRI per 1000 child-years was 5 in Mozambique, 10 in Indonesia, and 9 in South Africa. At all study sites, the majority of RSV cases occurred in infants. CONCLUSION: These studies demonstrate that RSV contributes to a substantial but quite variable burden of LRI in children aged < 5 years in four developing countries. The possible explanations for this variation include social factors, such as family size and patterns of seeking health care; the proportion of children infected by human immunodeficiency syndrome (HIV); and differences in clinical definitions used for obtaining samples. The age distribution of cases indicates the need for an RSV vaccine that can protect children early in life.

Rubella and congenital rubella syndrome: global update

Se calcula que cada año nacen en el mundo más de 100 000 niños con síndrome de rubéola congénita (SRC). La Organización Mundial de la Salud (OMS) estandarizó en 1998 las definiciones de casos para la vigilancia del SRC y de la rubéola. En 2001, 123 países o territorios notificaron 836 356 casos de rubéola y se espera que el número de países se incremente a medida que se desarrolla, bajo la coordinación de la OMS, una red mundial de laboratorios para la detección del sarampión y la rubéola. Se están realizando investigaciones para mejorar la vigilancia de esta última enfermedad, entre ellas algunos proyectos encaminados a echar a andar la vigilancia y a comparan métodos diagnósticos, así como estudios de epidemiología molecular para lograr entender más a fondo los patrones de circulación del virus de la rubéola en el mundo. En 1996 una encuesta efectuada por la OMS reveló que 78 (36 per ciento) de los 214 países o territorios que habían notificado casos de la enfermedad aplicaban la vacuna contra la rubéola como parte de su régimen de vacunación estándar. Para fines de 2002 un total de 124 de esos 214 (58 per ciento) países o territorios aplicaban la vacuna antirrubeólica cuyo uso depende del nivel de desarrollo económico: 100 per ciento en países industrializados, 71 per ciento en países con economías en transición y 48 per ciento en países en desarrollo. Se dispone de una vacuna inocua y eficaz y se ha demostrado la eficacia de algunas estrategias de vacunación para la prevención de la rubeóla y el SRC. En un trabajo de posición de la OMS se ofrece orientación acerca de lo que entraña, desde el punto de vista programático, emprender la vacunación antirrubeólica. Se trata de una medida cuya efectividad y beneficios superan su costo, pero que exige un continuo fortalecimiento de los servicios de vacunación y sistemas de vigilancia habituales.

Immunogenicity of measles and rubella vaccines in Oman: a prospective clinical trial.

A prospective immunogenicity trial of measles and rubella vaccines was conducted in Oman. Children received measles vaccine at age 9 months and measles-rubella vaccine at age 15 months. Serum specimens were tested for measles-specific IgG and rubella-specific IgG. Of 1025 eligible infants, 881 (86.0%) returned for all five visits and had adequate serum samples for testing. Seroconversion to measles after vaccination at 9 months was 98.1%. At 15 months, 47 (5.3%) of the 881 children were seronegative for measles; of these, 44 (93.6%) seroconverted. At 16 months, 99% of the children seronegative at age 9 months seroconverted after receiving two doses of measles vaccine. At age 15 months, 684 (77.6%) children were seronegative for rubella. Of these, 676 (98.8%) seroconverted by age 16 months. One dose of measles vaccine at age 9 months was highly immunogenic. One dose of measles-rubella vaccine at age 15 months closed the remaining measles immunogenicity gap and resulted in a high rate of rubella seroconversion.

Interleukin-18.

Interleukin-18 (IL-18), a recently described member of the IL-1 cytokine superfamily, is now recognized as an important regulator of innate and acquired immune responses. IL-18 is expressed at sites of chronic inflammation, in autoimmune diseases, in a variety of cancers, and in the context of numerous infectious diseases. This short review will describe the basic biology of IL-18 and thereafter address its potential effector and regulatory role in several human disease states including autoimmunity and infection. IL-18, previously known as interferon-gamma (IFN-gamma)-inducing factor, was identified as an endotoxin-induced serum factor that stimulated IFN-gamma production by murine splenocytes [(1) ]. IL-18 was cloned from a murine liver cell cDNA library generated from animals primed with heat-killed Propionibacterium acnes and subsequently challenged with lipopolysaccharide [(2) ]. Nucleotide sequencing of murine IL-18 predicted a precursor polypeptide of 192 amino acids lacking a conventional signal peptide and a mature protein of 157 amino acids. Subsequent cloning of human IL-18 cDNA revealed 65% homology with murine IL-18 [(3) ] and showed that both contain an unusual leader sequence consisting of 35 amino acids at their N terminus.