Characteristics of Early Paget's Disease in SQSTM1 Mutation Carriers: Baseline Analysis of the ZiPP Study Cohort.

Mutations in SQSTM1 are strongly associated with Paget's disease of bone (PDB), but little is known about the clinical characteristics of those with early disease. Radionuclide bone scans, biochemical markers of bone turnover, and clinical characteristics were analyzed in SQSTM1 mutation carriers who took part in the Zoledronic acid in the Prevention of Paget's disease (ZiPP) study. We studied 222 individuals, of whom 54.9% were female, with mean ± SE age of 50.1 ± 0.6 years. Twelve SQSTM1 mutations were observed, including p.Pro392Leu, which was present in 141 of 222 (63.5%) subjects. Bone scan examination revealed evidence of PDB in 20 subjects (9.0%), ten of whom (50%) had a single affected site. Participants with lesions were older than those without lesions but the difference was not significant (53.6 ± 9.1 versus 49.8 ± 8.9; p = .07). The mean age of participants with lesions was not significantly different from the age at which their parents were diagnosed with PDB (55 years versus 59 years, p = .17). All individuals with lesions were asymptomatic. Serum concentrations of total alkaline phosphatase (ALP) normalized to the upper limit of normal in each center were higher in those with lesions (0.75 ± 0.69 versus 0.42 ± 0.29 arbitary units; p < .0001). Similar findings were observed for other biochemical markers of bone turnover, but the sensitivity of ALP and other markers in detecting lesions was poor. Asymptomatic PDB is present in about 9% of SQSTM1 mutation carriers by the fifth decade. Further follow-up of this cohort will provide important information on the natural history of early PDB and its response to treatment. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Zoledronate in the prevention of Paget's (ZiPP): protocol for a randomised trial of genetic testing and targeted zoledronic acid therapy to prevent SQSTM1-mediated Paget's disease of bone.

INTRODUCTION: Paget's disease of bone (PDB) is characterised by increased and disorganised bone remodelling affecting one or more skeletal sites. Complications include bone pain, deformity, deafness and pathological fractures. Mutations in sequestosome-1 (SQSTM1) are strongly associated with the development of PDB. Bisphosphonate therapy can improve bone pain in PDB, but there is no evidence that treatment alters the natural history of PDB or prevents complications. The Zoledronate in the Prevention of Paget's disease trial (ZiPP) will determine if prophylactic therapy with the bisphosphonate zoledronic acid (ZA) can delay or prevent the development of PDB in people who carry SQSTM1 mutations. METHODS AND ANALYSIS: People with a family history of PDB aged >30 years who test positive for SQSTM1 mutations are eligible to take part. At the baseline visit, participants will be screened for the presence of bone lesions by radionuclide bone scan. Biochemical markers of bone turnover will be measured and questionnaires completed to assess pain, health-related quality of life (HRQoL), anxiety and depression. Participants will be randomised to receive a single intravenous infusion of 5 mg ZA or placebo and followed up annually for between 4 and 8 years at which point baseline assessments will be repeated. The primary endpoint will be new bone lesions assessed by radionuclide bone scan. Secondary endpoints will include changes in biochemical markers of bone turnover, pain, HRQoL, anxiety, depression and PDB-related skeletal events. ETHICS AND DISSEMINATION: The study was approved by the Fife and Forth Valley Research Ethics Committee on 22 December 2008 (08/S0501/84). Following completion of the trial, a manuscript will be submitted to a peer-reviewed journal. The results of this trial will inform clinical practice by determining if early intervention with ZA in presymptomatic individuals with SQSTM1 mutations can prevent or slow the development of bone lesions with an adverse event profile that is acceptable. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

A practical guide to pre-trial simulations for Bayesian adaptive trials using SAS and BUGS.

It is often unclear what specific adaptive trial design features lead to an efficient design which is also feasible to implement. Before deciding on a particular design, it is generally advisable to carry out a simulation study to characterise the properties of candidate designs under a range of plausible assumptions. The implementation of such pre-trial simulation studies presents many challenges and requires considerable statistical programming effort and time. Despite the scale and complexity, there is little existing literature to guide the implementation of such projects using commonly available software. This Teacher's Corner article provides a practical step-by-step guide to implementing such simulation studies including how to specify and fit a Bayesian model in WinBUGS or OpenBUGS using SAS, and how results from the Bayesian analysis may be pulled back into SAS and used for adaptation of allocation probabilities before simulating subsequent stages of the trial. The interface between the two software platforms is described in detail along with useful tips and tricks. A key strength of our approach is that the entire exercise can be defined and controlled from within a single SAS program.

Chapter 4. The Relationship Between the European and North American Societies for Pediatric Gastroenterology, Hepatology and Nutrition.

This chapter is based on the memories of those who shaped the relationship between the European and the North American Societies for Pediatric Gastroenterology, Hepatology and Nutrition. The first joint meeting of the 2 Societies took place in Paris in 1978, followed by 1 in New York in 1985, 1 in Amsterdam in 1990, 1 in Houston in 1994, and the last one in Toulouse in 1998. The formation of the Federation of the International Societies for Pediatric Gastroenterology, Hepatology and Nutrition (FISPGHAN) preceded the First World Congress of all Societies, which took place in Boston in 2000. The success of this meeting was followed by world congresses in Paris in 2004, Iguassu in 2008, Taiwan in 2012, and Montreal in 2016. NASPGHAN and ESPGHAN jointly took on the direction of the Journal of Pediatric Gastroenterology and Nutrition in 1991. Communication between the 2 Societies is extremely active, with members participating in many joint projects.

Long-Term Randomized Trial of Intensive Versus Symptomatic Management in Paget's Disease of Bone: The PRISM-EZ Study.

It has been suggested that normalization of bone turnover may improve clinical outcome in Paget's disease of bone (PDB) by preventing complications such as fractures and the development of osteoarthritis. Here we investigated the long-term effects of a treatment strategy that aimed to normalize bone turnover in PDB with that of symptomatic treatment. The study group comprised 502 subjects who were enrolled into a 3-year extension of the Paget's Disease: Randomized Trial of Intensive versus Symptomatic Management (PRISM) study. Intensive bisphosphonate therapy was continued in 270 of these subjects with the aim of normalizing bone turnover using zoledronic acid as the treatment of first choice. Symptomatic treatment continued in 232 subjects in whom bisphosphonates were only given for the treatment of bone pain. The primary outcome was fracture and secondary outcomes were orthopedic procedures, quality of life, and bone pain, adjusted for baseline characteristics. Serum total alkaline phosphatase (ALP) concentrations were significantly lower in the intensive group on entry to the study and the differences between groups increased as the study progressed. There were no clinically important differences in quality of life measures or bone pain between the treatment groups. Intensive treatment was associated with a nonsignificant increase in fracture risk (hazard ratio = 1.90; 95% CI, 0.91 to 3.98; p = 0.087), orthopedic procedures (1.81; 95% CI, 0.71 to 4.61; p = 0.214), and serious adverse events (relative risk 1.28; 95% CI, 0.96 to 1.42). We conclude that long-term intensive bisphosphonate therapy confers no clinical benefit over symptomatic therapy and is associated with a nonsignificant increase in the risk of fractures, orthopedic events, and serious adverse events. The results of this study suggest that in patients with established PDB, bisphosphonate therapy should focus on control of symptoms rather than suppression of bone turnover. © 2016 American Society for Bone and Mineral Research.

Presence of commensal house dust mite allergen in human gastrointestinal tract: a potential contributor to intestinal barrier dysfunction.

BACKGROUND: Abnormal gut barrier function is the basis of gut inflammatory disease. It is known that house dust mite (HDM) aero-allergens induce inflammation in respiratory mucosa. We have recently reported allergen from Dermatophagoides pteronyssinus (Der p1) to be present in rodent gut. OBJECTIVE: To examine whether Der p1 is present in human gut and to assess its effect on gut barrier function and inflammation. DESIGN: Colonic biopsies, gut fluid, serum and stool were collected from healthy adults during endoscopy. Der p1 was measured by ELISA. Effect of HDM was assessed on gut permeability, tight-junction and mucin expression, and cytokine production, in presence or absence of cysteine protease inhibitors or serine protease inhibitors. In vivo effect of HDM was examined in mice given oral HDM or protease-neutralised HDM. Role of HDM in low-grade inflammation was studied in patients with IBS. RESULTS: HDM Der p1 was detected in the human gut. In colonic biopsies from healthy patients, HDM increased epithelial permeability (p<0.001), reduced expression of tight-junction proteins and mucus barrier. These effects were associated with increased tumour necrosis factor (TNF)-α and interleukin (IL)-10 production and were abolished by cysteine-protease inhibitor (p<0.01). HDM effects did not require Th2 immunity. Results were confirmed in vivo in mice. In patients with IBS, HDM further deteriorated gut barrier function, induced TNF-α but failed to induce IL-10 secretion (p<0.001). CONCLUSIONS: HDM, a ubiquitous environmental factor, is present in the human gut where it directly affects gut function through its proteolytic activity. HDM may be an important trigger of gut dysfunction and warrants further investigation.

Intestinal colonization and programming of the intestinal immune response.

Initial bacterial colonization of the gut is a vital component of the development of the gastrointestinal tract, particularly mucosal immune protection, during the neonatal period. Newborn infants in their protected intrauterine environment are suddenly thrust into a highly contaminated extrauterine state. Although mucosal host defenses have developed in utero during fetal maturation because of the stimulation of ingested trophic factors in amniotic fluid, actual active protection only occurs when colonizing bacteria stimulate the gut mucosal barrier. Colonization evolves over a period of about 1 year and is dependent on the mode of delivery, use of perinatal antibiotics, age at birth, and infant feeding. A fully colonized gut consists of 10(14) bacteria, establishes a symbiotic relationship with the host and insures normal development and immune homeostasis. Colonizing bacteria can also affect the epithelial mucosal barrier and the innate and adaptive immune systems. Disruption of normal colonization, dysbiosis, is associated with increased expression of disease. Evidence exists that the use of probiotics with dysbiosis may prevent disease expression.

Compositional requirements of follow-up formula for use in infancy: recommendations of an international expert group coordinated by the Early Nutrition Academy.

The follow-up formula (FUF) standard of Codex Alimentarius adopted in 1987 does not correspond to the recently updated Codex infant formula (IF) standard and current scientific knowledge. New Zealand proposed a revision of the FUF Codex standard and asked the non-profit Early Nutrition Academy, in collaboration with the Federation of International Societies for Paediatric Gastroenterology, Hepatology, and Nutrition (FISPGHAN), for a consultation with paediatric nutrition experts to provide scientific guidance. This global expert group strongly supports breastfeeding. FUF are considered dispensable because IF can substitute for breastfeeding throughout infancy, but FUF are widely used and thus the outdated current FUF standard should be revised. Like IF, FUF serve as breast milk substitutes; hence their marketing should respect appropriate standards. The compositional requirements for FUF for infants from 6 months onwards presented here were unanimously agreed upon. For some nutrients, the compositional requirements for FUF differ from those of IF due to differing needs with infant maturation as well as a rising contribution of an increasingly diversified diet with advancing age. FUF should be fed with adequate complementary feeding that is also appropriate for partially breastfed infants. FUF could be fed also after the age of 1 year without safety concerns, but different compositional requirements should be applied for optimal, age-adapted milk-based formulations for young children used only after the age of 1 year. This has not been considered as part of this review and should be the subject of further consideration.

The messages they send: e-mail use by adolescents with and without a history of specific language impairment (SLI).

BACKGROUND: Contemporary adolescents use e-mail for a variety of purposes, including peer communication and education. Research into these uses has focused on typically developing individuals; much less is known about the use of e-mail by exceptional youth. AIMS: The present study examined the structure and form of e-mail messages sent by adolescents with and without a history of specific language impairment (SLI). METHODS & PROCEDURES: Thirty-eight adolescents with a history of SLI and 56 typically developing (TD) peers were assessed on measures of nonverbal abilities, core language skills and literacy skills (reading and spelling). The participants were asked to compose an e-mail reply to a standard e-mail sent by an experimenter. These reply e-mails were coded for linguistic structure, readability and spelling errors. Two adult raters, blind to the participants' language ability, judged how understandable the e-mails were, how grammatically correct the e-mails were, and also the sender's command of the English language. OUTCOMES & RESULTS: Adolescents with a history of SLI produced e-mails that were similar to those sent by their TD peers in terms of structure and readability. However, they made significantly more spelling errors. Furthermore, the adult raters considered the messages from participants with a history of SLI to be of poorer standard than those sent by their TD peers. CONCLUSIONS & IMPLICATIONS: The findings suggest that the e-mail messages of adolescents with a history of SLI provide indicators of the sender's language and literacy skills. Implications for intervention and technology development are discussed.

Effect of Bifidobacterium animalis subsp lactis supplementation in preterm infants: a systematic review of randomized controlled trials.

OBJECTIVE: To systematically evaluate and update evidence on the efficacy and safety of Bifidobacterium animalis subsp lactis CNCM I-3446 supplementation in preterm infants. MATERIALS AND METHODS: The Cochrane Library and MEDLINE databases and major pediatric conference proceedings were searched in December 2008 for randomized controlled trials (RCTs). The company that manufactures B lactis was contacted for unpublished data. The review was restricted to RCTs performed in preterm infants <37 weeks of gestation and/or with a birth weight <2500 g. RESULTS: Four RCTs involving 324 infants met the inclusion criteria. Compared with controls, B lactis supplementation has the potential to increase fecal bifidobacteria counts and to reduce Enterobacteriaceae and Clostridium spp counts. It also can reduce stool pH and fecal calprotectin concentrations, increase fecal immunoglobulin A and short-chain fatty acid concentrations, and decrease intestinal permeability. Compared with controls, B lactis supplementation had no effect on the risk of necrotizing enterocolitis stage > or = 2 (3 RCTs, n = 293, risk ratio [RR] 0.53, 95% CI 0.16-1.83), risk of sepsis (2 RCTs, 397 cultures, RR 0.6, 95% CI 0.07-5.2), and use of antibiotics (2 RCTs, n = 255, RR 0.67, 95% CI 0.28-1.62). The power of these studies, however, does not allow for a definitive statement regarding a reduced risk of necrotizing enterocolitis. B lactis supplementation did have some effects on anthropometric parameters. No adverse events associated with B lactis supplementation were reported. CONCLUSIONS: Evidence regarding the potential beneficial effects of B lactis supplementation in preterm infants is encouraging. Further studies to assess clinically relevant outcomes are needed.

Breast milk as the gold standard for protective nutrients.

In this introductory overview, I explore the observation that breast milk is the gold standard for protective nutrients fed to newborn infants and present clinical evidence of its strong protective effect against age-related infectious gastroenteritis. The composition of breast milk changes according to the newborn infant's needs for passive protection. In addition, substances in breast milk can actively stimulate development of the newborn's host defenses to provide continued mucosal protection after breastfeeding is terminated. Later I present several specific examples of the development of intestinal host defenses due to breastfeeding. An important function of early breastfeeding is its anti-inflammatory effect on the immature, excessive inflammatory response in newborns. Several components of breast milk can reduce the inflammatory response to stimuli in the newborn intestine. These include transforming growth factor (TGF)-beta, interleukin (IL)-10, erythropoietin, and lactoferrin. These components of breast milk can act individually or in concert to contain the neonatal immature anti-inflammatory response.

Educational and interpersonal uses of home computers by adolescents with and without specific language impairment.

Many uses of new media entail processing language content, yet little is known about the relationship between language ability and media use in young people. This study compares educational versus interpersonal uses of home computers in adolescents with and without a history of specific language impairment (SLI). Participants were 55 17-year-olds with SLI and 72 typically developing peers. Measures of frequency and ease of computer use were obtained as well as assessments of participants' psycholinguistic skills. Results showed a strong preference for interpersonal computer use in both groups. Virtually all participants engaged with interpersonal new media, finding them relatively easy to use. In contrast, one third of adolescents with SLI did not use educational applications during a typical week. Regression analyses revealed that lower frequency of educational use was associated with poorer language and literacy skills. However, in adolescents with SLI, this association was mediated by perceived ease of use. The findings show that language ability contributes to new media use and that adolescents with SLI are at a greater risk of low levels of engagement with educational technology.

Estimating the spatial scale of herbicide and soil interactions by nested sampling, hierarchical analysis of variance and residual maximum likelihood.

An unbalanced nested sampling design was used to investigate the spatial scale of soil and herbicide interactions at the field scale. A hierarchical analysis of variance based on residual maximum likelihood (REML) was used to analyse the data and provide a first estimate of the variogram. Soil samples were taken at 108 locations at a range of separating distances in a 9 ha field to explore small and medium scale spatial variation. Soil organic matter content, pH, particle size distribution, microbial biomass and the degradation and sorption of the herbicide, isoproturon, were determined for each soil sample. A large proportion of the spatial variation in isoproturon degradation and sorption occurred at sampling intervals less than 60 m, however, the sampling design did not resolve the variation present at scales greater than this. A sampling interval of 20-25 m should ensure that the main spatial structures are identified for isoproturon degradation rate and sorption without too great a loss of information in this field.

The Knee Arthroplasty Trial (KAT) design features, baseline characteristics, and two-year functional outcomes after alternative approaches to knee replacement.

BACKGROUND: The aim of continued development of total knee replacement systems has been the further improvement of the quality of life and increasing the duration of prosthetic survival. Our goal was to evaluate the effects of several design features, including metal backing of the tibial component, patellar resurfacing, and a mobile bearing between the tibial and femoral components, on the function and survival of the implant. METHODS: A pragmatic, multicenter, randomized, controlled trial involving 116 surgeons in thirty-four centers in the United Kingdom was performed; 2352 participants were randomly allocated to be treated with or without a metal backing of the tibial component (409), with or without patellar resurfacing (1715), and/or with or without a mobile bearing (539). Randomization to more than one comparison was allowed. The primary outcome measures were the Oxford Knee Score (OKS), Short Form-12, EuroQol-5D, and the need for additional surgery. The results up to two years postoperatively are reported. RESULTS: Functional status and quality-of-life scores were low at baseline but improved markedly across all trial groups following knee replacement (mean overall OKS, 17.98 points at baseline and 34.82 points at two years). Most of the change was observed at three months after the surgery. Six percent of the patients had additional knee surgery within two years. There was no evidence of differences in clinical, functional, or quality-of-life measures between the randomized groups at two years. CONCLUSIONS: Patients have substantial improvement following total knee replacement. This is the first adequately powered randomized controlled trial, of which we are aware, in which the effects of metal backing, patellar resurfacing, and a mobile bearing were investigated. We found no evidence of an effect of these variants on the rate of early complications or on functional recovery up to two years after total knee replacement.

Relapse after emergency department discharge for acute asthma.

OBJECTIVES: The objectives were to determine patient and treatment-response factors associated with relapse after emergency department (ED) treatment for acute asthma. METHODS: Subjects aged 18-55 years who were treated for acute asthma in 20 Canadian EDs prospectively underwent a structured ED interview and telephone contact 2 weeks later. RESULTS: Of 695 enrolled patients, 604 (86.9%) were discharged from the ED; follow-up was available in 529 (87.5%); 63% were female and the median age was 29 years. Most patients were discharged on oral (70.8%) and inhaled (60.1%) corticosteroids (CS); 2-week treatment adherences were 93.3 and 80.9%, respectively. Relapse occurred in 9.2% at 1 week (95% confidence interval [CI] = 7.1% to 12.0%) and 13.9% (95% CI = 11% to 17%) at 2 weeks. In multivariable modeling, factors associated with relapse were ethnicity (risk ratio [RR] white = 0.66; 95% CI = 0.52 to 0.83); female gender (RR = 1.57; 95% CI = 1.14 to 2.09); any ED visits in the past 2 years (RR = 1.47; 95% CI = 1.18 to 1.80); ever admitted for asthma treatment (RR = 1.83; 95% CI = 1.09 to 2.84); use of combined inhaled CS plus long-acting beta(2)-agonists (RR = 1.39; 95% CI = 1.07 to 1.78) and of oral CS (RR = 1.35; 95% CI = 1.12 to 1.59) at the time of ED presentation. CONCLUSIONS: Ethnicity (white), female gender, prior ED visits and admissions for asthma, and recent treatments (especially oral CS) were associated with asthma relapse, which remains relatively common. Future research is required to target this high-risk group.

Microbial degradation of organophosphorus compounds.

Synthetic organophosphorus compounds are used as pesticides, plasticizers, air fuel ingredients and chemical warfare agents. Organophosphorus compounds are the most widely used insecticides, accounting for an estimated 34% of world-wide insecticide sales. Contamination of soil from pesticides as a result of their bulk handling at the farmyard or following application in the field or accidental release may lead occasionally to contamination of surface and ground water. Several reports suggest that a wide range of water and terrestrial ecosystems may be contaminated with organophosphorus compounds. These compounds possess high mammalian toxicity and it is therefore essential to remove them from the environments. In addition, about 200,000 metric tons of nerve (chemical warfare) agents have to be destroyed world-wide under Chemical Weapons Convention (1993). Bioremediation can offer an efficient and cheap option for decontamination of polluted ecosystems and destruction of nerve agents. The first micro-organism that could degrade organophosphorus compounds was isolated in 1973 and identified as Flavobacterium sp. Since then several bacterial and a few fungal species have been isolated which can degrade a wide range of organophosphorus compounds in liquid cultures and soil systems. The biochemistry of organophosphorus compound degradation by most of the bacteria seems to be identical, in which a structurally similar enzyme called organophosphate hydrolase or phosphotriesterase catalyzes the first step of the degradation. organophosphate hydrolase encoding gene opd (organophosphate degrading) gene has been isolated from geographically different regions and taxonomically different species. This gene has been sequenced, cloned in different organisms, and altered for better activity and stability. Recently, genes with similar function but different sequences have also been isolated and characterized. Engineered microorganisms have been tested for their ability to degrade different organophosphorus pollutants, including nerve agents. In this article, we review and propose pathways for degradation of some organophosphorus compounds by microorganisms. Isolation, characterization, utilization and manipulation of the major detoxifying enzymes and the molecular basis of degradation are discussed. The major achievements and technological advancements towards bioremediation of organophosphorus compounds, limitations of available technologies and future challenge are also discussed.

Evaluation of simplifying assumptions on pesticide degradation in soil.

There is evidence that degradation of pesticides in simple laboratory systems may differ from that in the field, but it is not clear which of the simplifications inherent in laboratory studies present serious shortcomings. Laboratory experiments evaluated several simplifying assumptions for a clay loam soil and contrasting pesticides. Degradation of cyanazine [2-(4-chloro-6-ethylamino-1,3,5-triazin-2-ylamino)-2-methylpropiononitrile] and bentazone [3-isopropyl-1H-2,1,3-benzothiadiazin-4(3H)-one 2,2-dioxide] at fluctuating temperature and moisture was predicted reasonably well based on parameters derived from degradation under constant conditions. There was a tendency for slower degradation of cyanazine and bentazone in soil aggregates of 3 to 5 mm in diameter (DT50 at 15 degrees C and 40% maximum water holding capacity of 25.1 and 58.2 d, where DT50 is the time for 50% decline of the initial pesticide concentration) than in soil sieved to <3 mm (DT50 of 19.1 and 37.6 d), but the differences were not significant for most datasets. Degradation of cyanazine, isoproturon [3-(4-isopropylphenyl)-1,1-dimethylurea], and chlorotoluron [3-(3-chloro-p-tolyl)-1,1-dimethylurea] was measured in soil amended with different amounts of lignin. The effect of lignin on degradation was small despite considerable differences in sorption. The DT50 values of cyanazine, isoproturon, and chlorotoluron were 16.2, 18.6, and 33.0 d, respectively, in soil without lignin and 19.0, 23.4, and 34.6 d, respectively, in soil amended with 2% lignin. Degradation of bentazone and cyanazine in repacked soil columns was similar under static and flow conditions with 50.1 and 47.2% of applied bentazone and 74.7 and 73.6% of applied cyanazine, respectively, degraded within 20 d of application. Thus, the assumptions underpinning laboratory to field extrapolation tested here were considered to hold for our experimental system. Additional work is required before general conclusions can be drawn.

Leaching of pesticides from biobeds: effect of biobed depth and water loading.

Pesticides may be released to farmyard surfaces as a result of spillages, leakages, and the decontamination of tractors and sprayers. Biobeds can be used to intercept and treat contaminated runoff, thus minimizing losses to the environment. Previous studies using lined and unlined biobeds showed that water management was the limiting factor for both systems. While lined biobeds effectively retained pesticides, the system rapidly became water logged and degradation was slow. Studies using unlined biobeds showed that >99% of the applied pesticides were removed by the system, with a significant proportion degraded within 9 months. However, peak concentrations of certain pesticides (Koc < 125) were unacceptable to the regulatory authorities. These experiments were designed to optimize the design and management of unlined biobeds. Experiments performed to investigate the relationship between biobed depth and water loading showed that biobeds need to have a minimum depth of 1-1.5 m. The surface area dimension of the biobed depends on the water loading, which is controlled by the nature and frequency of pesticide handling activities on the farm. Leaching losses of all but the most mobile (Koc < 15) pesticides were <0.32% of the applied dose from 1.5 m deep biobeds subject to a water loading of 1175 L m(-2). These were reduced to <0.06% when a water loading of 688 L m(-2) was applied and down to <0.0001% for a water loading of 202 L m(-2). On the basis of these data, a 1.5 m deep biobed, subject to a maximum water loading of 1121 L m(-2) and with a surface area of 40 m(2) should be able to treat < or =44000 L of pesticide waste and washings such that the average concentration of all pesticides, other than those classified as very mobile, does not exceed 5 microg L(-1). This level of treatment can be improved by further reduction in the hydraulic loading.

Bacterial colonization and the development of intestinal defences.

In humans, intestinal defences develop during gestation and, at full term, have the capacity to respond in an appropriate manner to infectious agents and foreign antigens. Before an active protective response can occur, however, the gut must first be exposed to colonizing bacteria. Colonization with diverse intestinal microbes is necessary for the development of important gut defenses such as the synthesis and secretion of polymeric immunoglobulin A and the generation of a balanced T helper (Th) cell response. Insights into normal immune physiological development of the gut have been made by studying the germ-free animal and intestinal defenses. These studies have provided insights into the physiology of immune responses. Two important immunological functions are the secretion of polymeric immunoglobulin A to protect the intestinal surface against harmful stimuli and inhibition of the systemic response to commensal bacteria and food proteins (eg, oral tolerance) to prevent chronic inflammation. Neither function exists in the germ-free state, but rapidly develops after conventionalization (colonization) of the germ-free animal. In the present review, the importance of bacterial colonization on the appearance of normal mucosal immune function and to the clinical consequences of inadequate colonization to the development of disease will be discussed. For example, excessive Th2 activity can lead to atopy, whereas Th1 predominance is found in conditions such as Helicobacter pylori gastritis and Crohn's disease. With the eradication of infectious diseases in developed countries in the past three decades, the incidence of atopic and autoimmune diseases has increased. This epidemiological observation has been explained by the 'hygiene hypothesis', which suggests that a reduction in microbial burden by public health measures has contributed to an immunological imbalance in the intestine. A family of pattern recognition receptors (Toll-like receptors) on gut lymphoid and epithelial cells mediates innate immune responses to bacterial molecular patterns and, thereby, orchestrates acquired immunity. As the role of bacterial communication within the gut (bacterial-epithelial cross-talk) is clarified, physicians should be able to modulate gut immune responses, for example, by the use of probiotics.

Effect of different soil textures on leaching potential and degradation of pesticides in biobeds.

Biobeds can be used to intercept pesticide-contaminated runoff from the mixing/washdown area, creating optimum conditions for sorption and biodegradation such that the amount of pesticide reaching adjacent water bodies is significantly reduced. The biobed is built on the farm using locally available materials, which include, straw, compost, and topsoil. The topsoil acts as the inoculum for the system and is likely to vary in terms of its physical, chemical, and microbiological characteristics from one farm to another. This study therefore investigated the effects of using different soil types on the degradation and leaching potential from biobeds. Three contrasting topsoils were investigated. Leaching studies were performed using isoproturon, dimethoate, and mecoprop-P, which were applied at simulated disposal rates to 1.5 m deep biobeds. Annual average concentrations were similar for each soil type with leaching losses of even the most mobile (Koc = 12-25) pesticide <1.64% of the applied dose. Greater than 98% of the retained pesticides were degraded in all matrices. Degradation studies investigated the persistence of individual pesticides and pesticide mixtures in the different matrices. DT50 values for isoproturon, chlorothalonil, mecoprop-P, and metsulfuron-methyl applied at 4 times the maximum approved rate were similar across the biomix types and were all less than or equal to reported DT50 values for soil treated at approved rates. When applied as a mixture, DT50 values in each biomix increased, indicating that interactions between pesticides are possible. However, DT90 values of <167 days were obtained in all circumstances, indicating a negligible risk of accumulation. Studies therefore indicate that substrate will have little impact on biobed performance so it should be possible to use local soils in the construction process.