Longitudinal analysis of the effect of water hardness on atopic eczema: evidence for gene-environment interaction.

BACKGROUND: Several studies have identified an association between water hardness and atopic eczema (AE); however, there is a paucity of longitudinal data in early life. OBJECTIVES: To examine whether water hardness is associated with an increased risk of AE and skin barrier dysfunction in infants and to assess effect modification by filaggrin (FLG) loss-of-function variants. METHODS: We performed a longitudinal analysis of data from infants in the Enquiring About Tolerance (EAT) study, who were enrolled at 3 months and followed up until 36 months of age. RESULTS: Of 1303 infants enrolled in the EAT study, 91·3% (n = 1189) attended the final clinic visit and 94·0% (n = 1225) of participants' families completed the 36-month questionnaire. In total, 761 (58·4%) developed AE by 36 months. There was no overall association between exposure to harder (> 257 mg L-1 CaCO3 ) vs. softer (≤ 257 mg L-1 CaCO3 ) water: adjusted hazard ratio (HR) 1·07, 95% confidence interval (CI) 0·92-1·24. However, there was an increased incidence of AE in infants with FLG mutations exposed to hard water (adjusted HR 2·72, 95% CI 2·03-3·66), and statistically significant interactions between hard water plus FLG and both risk of AE (HR 1·80, 95% CI 1·17-2·78) and transepidermal water loss (0·0081 g m-2 h-1 per mg L-1 CaCO3 , 95% CI 0·00028-0·016). CONCLUSIONS: There is evidence of an interaction between water hardness and FLG mutations in the development of infantile AE.

The role of skin and gut microbiota in the development of atopic eczema.

Conventional culture-based studies have suggested that a reduction in microbial exposure in early life predisposes to atopic eczema and allergies. However, molecular microbiological methods have shown that conventional culture fails to grow around 80% of the bacterial flora. More recent work reviewed in this paper has employed next generation sequencing to study the influence of the gut and skin microbiota, both with regard to the risk of developing atopic eczema but also the role of pathogenic and commensal bacteria in established disease. Birth cohorts investigating the gastrointestinal tract reported reduced faecal microbiota diversity among those who later developed atopic eczema, using gel electrophoresis, real-time PCR or 16S ribosomal RNA gene pyrosequencing. However, the inverse association with reduced faecal bacterial diversity was not confirmed in cross-sectional studies among patients with established atopic eczema. Only two studies investigated the cutaneous microbiota in a longitudinal study design and both were unable to provide evidence that Staphylococcus aureus colonisation precedes the development of atopic eczema. Next generation sequencing has confirmed the cross-sectional association between atopic eczema and S. aureus colonisation. The two studies that used this approach have also shown that disease flares are associated with a significant fall in skin microbiota diversity and an increase in the relative abundance of both S. aureus and epidermidis. Interestingly, S. aureus elimination does not appear to be the main reason why atopic eczema improves after a flare and antimicrobial and anti-inflammatory therapy enhances bacterial diversity. Further, well-phenotyped birth cohorts that take key confounders, such as antibiotic exposure, into account are required.

Patients' ability to treat anaphylaxis using adrenaline autoinjectors: a randomized controlled trial.

BACKGROUND: Previous work has shown patients commonly misuse adrenaline autoinjectors (AAI). It is unclear whether this is due to inadequate training, or poor device design. We undertook a prospective randomized controlled trial to evaluate ability to administer adrenaline using different AAI devices. METHODS: We allocated mothers of food-allergic children prescribed an AAI for the first time to Anapen or EpiPen using a computer-generated randomization list, with optimal training according to manufacturer's instructions. After one year, participants were randomly allocated a new device (EpiPen, Anapen, new EpiPen, JEXT or Auvi-Q), without device-specific training. We assessed ability to deliver adrenaline using their AAI in a simulated anaphylaxis scenario six weeks and one year after initial training, and following device switch. Primary outcome was successful adrenaline administration at six weeks, assessed by an independent expert. Secondary outcomes were success at one year, success after switching device, and adverse events. RESULTS: We randomized 158 participants. At six weeks, 30 of 71 (42%) participants allocated to Anapen and 31 of 73 (43%) participants allocated to EpiPen were successful - RR 1.00 (95% CI 0.68-1.46). Success rates at one year were also similar, but digital injection was more common at one year with EpiPen (8/59, 14%) than Anapen (0/51, 0%, P = 0.007). When switched to a new device without specific training, success rates were higher with Auvi-Q (26/28, 93%) than other devices (39/80, 49%; P < 0.001). CONCLUSIONS: AAI device design is a major determinant of successful adrenaline administration. Success rates were low with several devices, but were high using the audio-prompt device Auvi-Q.

Assessing the efficacy of oral immunotherapy for the desensitisation of peanut allergy in children (STOP II): a phase 2 randomised controlled trial: a critical appraisal.

AIM: Anagnostou et al. investigated the efficacy of oral immunotherapy (OIT) in treating peanut allergy. SETTING AND DESIGN: An unmasked randomized controlled crossover trial of 7-16 year olds with double-blind placebo-controlled food challenge (DBPCFC)-proven peanut allergy. The first phase compared an active group undergoing 26 weeks of OIT with daily ingestion of peanut protein vs. a control group avoiding peanuts. Both groups underwent DBPCFC to peanut at 26 weeks. In the second phase the control group was then offered OIT for 26 weeks. STUDY EXPOSURE: Participants undergoing OIT attended hospital every 2 weeks to initiate and increase their daily peanut protein dose through nine stages (2, 5, 12·5, 25, 50, 100, 200, 400 and 800 mg - about five peanuts), subsequently maintaining consumption at the highest tolerated dose. Primary outcome The primary outcome compared the proportions of active- and control-group participants able to ingest a cumulative dose of 1400 mg of peanut protein (about 10 peanuts) during their DBPCFC at the end of the first phase without reacting. Secondary outcomes Further outcomes included the proportion of participants who tolerated the top maintenance dosage of 800 mg protein up to 26 weeks; the proportion of the control group who were desensitized or tolerated daily ingestion of 800 mg protein in the second phase; threshold changes in no observed adverse effect level after OIT (NOAEL: defined as the highest dose of peanut protein tolerated in milligrams of protein during challenge or immunotherapy); change in quality of life; number and type of adverse events; and immunological parameters (basophil reactivity, peanut-specific IgE, total IgE and skin-prick test). RESULTS: Primary outcome Twenty-four of 39 (62%) of the active group were able to tolerate the 1400 mg of peanut protein during their DBPCFC after 26 weeks of OIT, compared with none of the 46 control participants (P < 0·001). Secondary outcomes Twenty-five of 46 (54%) of the control group had a negative 1400-mg peanut protein challenge at the end of phase 2. Combining the two groups, 49 of 85 children (58%) were desensitized. Thirty-three of 39 (85%) active participants in phase one and 42 of 46 (91%) control participants in phase two tolerated 800 mg of OIT daily - a combined result of 75 of 85 (88%) trial participants. The median absolute change in NOAEL between baseline and 26 weeks was 1345 mg (P = 0·002), or a 25·5-fold increase (P < 0·001) for the active group. Both the active and control groups demonstrated a significant improvement (decrease) in Food Allergy Quality of Life scores after OIT in the under-13-year-old participants: -1·61 and -1·41, respectively (both P < 0·001). Mild side-effects predominated, with 54 (57%) reporting abdominal pain and 31 (33%) reporting vomiting. However, 21 (22%) also reported wheezing and one (1%) laryngeal oedema. One participant received adrenaline by self-administration on two occasions for wheezing. CONCLUSIONS: Anagnostou et al. concluded that OIT successfully induced desensitization in challenge-proven peanut-allergic children and resulted in a clinically and socially meaningful increase in tolerated peanut protein. Quality of life improved after intervention and there was a good safety profile.

Organophosphate poisoning.

The present review discusses the structure of the anticholinesterase organophosphates (OPs), which are used predominantly as insecticides. OP poisoning can occur in a variety of situations and can be accidental or suicidal. It is common in developing countries. The cholinergic syndrome is caused by acetylcholinesterase inhibition, and diagnosis is based on the clinical signs and symptoms as well as the measurement of inhibition of erythrocyte acetylcholinesterase and/or plasma cholinesterase activity. Antidotal treatment is with atropine, an enzyme reactivator such as pralidoxime and diazepam. Anticholinesterase OPs may produce effects other than the acute cholinergic syndrome, including the intermediate syndrome. Later effects may include organophosphorus-induced delayed neuropathy. Certain OPs are exploited for their anticholinesterase effects, including defoliants such as 'DEF', herbicides such as glyphosate, fire retardants and industrial intermediates. The toxicology of this group is heterogeneous and they may or may not possess anticholinesterase activity.

The histopathology of rat lung following exposure to zinc oxide/hexachloroethane smoke or installation with zinc chloride followed by treatment with 70% oxygen.

The effects of inhaled zinc oxide/hexachloroethane smoke (11,580 mg x min/m3) and intratracheally instilled zinc chloride (2.5 mg/kg body weight) have been studied in rat lung. The effects of subsequent treatment with 70% oxygen have been studied after both procedures. Both the inhalation of the smoke and instillation of zinc chloride produced similar effects that included pulmonary edema, alveolitis and, at a later stage, some fibrosis. After zinc chloride instillation, the pathological changes largely spared the periphery of the lung, while following smoke inhalation they were more diffuse. Subsequent oxygen administration had little effect on the development or progression of the pathological changes.

The acute intravenous and oral toxicity in mice, rats and guinea-pigs of 4-dimethylaminophenol (DMAP) and its effects on haematological variables.

The single dose oral toxicity of 4- dimethylaminophenol (DMAP) was examined in mice, rats and guinea-pigs and the intravenous toxicity in mice. The oral LD50 in female mice was 946 mg kg-1, in male rats, 780 mg kg-1, in female rats 689 mg kg-1 and in female guinea-pigs 1032 mg kg-1. The intravenous LD50 in female mice was 70 mg kg-1. Dosing with DMAP at the maximum tolerated dose produced Heinz body haemolytic anaemia in rats and Heinz bodies unaccompanied by anaemia in mice. Rats showed biochemical and histological evidence of renal tubular changes.

An investigation of possible models for the production of progressive pulmonary fibrosis in the rat. The effects of repeated intratracheal instillation of bleomycin.

Pulmonary fibrosis is a common later sequel to damage to the lung caused by a wide variety of agents. Bleomycin is an antineoplastic drug used in the treatment of squamous cell carcinomas and lymphomas. It is known to cause pulmonary fibrosis is both man and experimental animals. Bleomycin, dissolved in saline, was given by intratracheal instillation (dose = 0.5 U/animal; dose vol. = 0.5 ml/animal) to groups of at least 5 rats. Groups received either a single dose or 2, 3 or 4 doses each given a week apart. They were then sacrificed at periods of up to 90 days after the last dose. Subsequent histology revealed varying degrees of alveolitis, type II pneumocyte hyperplasia, alterations to alveolar structure including obliteration, degeneration, collapse and enlargement with significant interstitial fibrosis. The lesion appeared to be diffusely distributed throughout the lung. After a single dose or 2 doses regression of the lesion was observed with time following dosing whereas with 3 or 4 doses of bleomycin the changes increased progressively in extent and severity. Three or more doses of intratracheal instilled bleomycin appear to be a good model of progressive pulmonary fibrosis in the rat.

Comparative acute systemic toxicity of sodium arsenite and dichloro(2-chlorovinyl)arsine in rabbits.

The acute intravenous toxicity of sodium arsenite and dichloro(2-chlorovinyl)arsine (lewisite) has been compared in rabbits to provide a quantitative and qualitative model for future assessment of treatments of lewisite poisoning. The LD50 of sodium arsenite was 7.6 mg.kg-1; that for lewisite was 1.8 mg.kg-1. On the basis of arsenic content the former was 6.5 times less toxic than the latter. Significant differences in tissue arsenic content and pathology were found between the 2 materials. Histologically, changes were observed in the lungs and gall bladder after lewisite injection but not after sodium arsenite. It was concluded that use of sodium arsenite is not a suitable substitute model for lewisite poisoning.

The biochemical and pathological changes produced by the intratracheal instillation of certain components of zinc-hexachloroethane smoke.

Zinc chloride which is formed by igniting a mixture of zinc oxide and hexachloroethane in the production of white smokes has been shown to produce oedema when given to rats as a single instillation. The oedematous reaction, as assessed by histopathology and measurements of alveolar surface protein in lavage fluid, is variable, dose-dependent, and maximal at 3 days but at sub-lethal doses it regresses after 7 days. The parent compound, zinc oxide, does not produce these effects. In some animals there is evidence of a fibrogenic response at 7 days post-exposure although it is currently unknown whether or not this effect is progressive.

The absorption by human volunteers of glutamic acid from monosodium glutamate and from a partial enzymic hydrolysate of casein.

Peripheral plasma concentrations of glutamic and aspartic acids and alanine were measured after ingestion of monosodium glutamate or a pancreatic hydrolysate of casein by human volunteers. The doses of each material were such that they contained similar amounts of glutamic acid. Plasma glutamic acid concentrations rose promptly after the monosodium glutamate but mean peak concentrations were well below those likely to cause neurological damage. Plasma aspartic acid concentrations also rose after the monosodium glutamate but the behaviour of plasma alanine concentrations suggested that intestinal transamination of glutamic acid was insufficient to cause an appreciable rise in alanine concentration in the peripheral plasma. Significant increments in plasma glutamic acid concentrations did not occur after the pancreatic hydrolysate of casein and it is probable that competition for absorptive mechanisms by other amino acids, both free and peptide-bound, causes absorption of glutamic acid to be slower from mixtures of peptides and amino acids than from monosodium glutamate itself.

Percutaneous toxicity of ethylene glycol monomethyl ether and of dipropylene glycol monomethyl ether in the rat.

The subacute percutaneous toxicity of dipropylene glycol monomethyl ether (DPM) in male rats dosed 5 days/week for 4 weeks under both occluded and unoccluded conditions has been assessed and compared to the percutaneous toxicity of ethylene glycol monomethyl ether (EGM). DPM caused no significant changes in the clinical chemistry, haematology, or pathology, whereas EGM caused changes in the haematology and clinical chemistry, and both testicular and bone marrow damage at doses of 1000 mg/kg per day.

Acute toxicity of T2 toxin in rats, mice, guinea pigs, and pigeons.

The acute intravenous, intragastric, subcutaneous, intraperitoneal and intratracheal toxicity of T2 toxin has been studied in rats, mice, guinea-pigs, and pigeons. The acute LD50 values obtained varied between 1.0 and 14 mg X kg-1, there being little difference between the various routes in any given species. T2 caused vomiting in pigeons at doses of one fifth or less the LD50. In rats doses of 3.0 and 5.0 mg X kg-1 T2 produced lymphopenia, reticulocytosis, and in the highest dose groups normoblastaemia. Additionally, changes in plasma alkaline phosphatase and aspartate aminotransferase activities were seen. Histological changes were observed in lymphoid organs and were most severe in the thymus, lymph nodes, and Peyer's patches. The spleen was less severely affected. Gastrointestinal changes consisting of dead and dying lymphoid cells throughout the lamina propria were seen together with, in some cases, mucosal ulceration. The time course of the development and of the reversal of the changes was followed.

Histological changes produced by exposure of rabbits and rats to smokes produced from red phosphorus.

Rabbits and rats were exposed to single doses of smoke from pyrotechnic mixtures containing red phosphorus. The survivors were observed for up to 14 days. Most of the histological changes observed were found in the respiratory tract and they included abnormalities in the larynx and trachea, alveolitis and, in a few cases, frank pneumonia.

The induction of methaemoglobin by p-aminophenones.

Four aminophenones were administered to dogs. Orally p-aminopropiophenone (PAPP) was the most effective methaemoglobin former, while p-aminoheptanoylphenone (PAHpP) was the least effective. p-Aminovalerylphenone (PAVP) and p-aminohexanoylphenone (PAHP) were of intermediate efficacy. With oral PAPP, PAVP and PAHP there was no clear cut relationship between acyl chain length and the timing of peak mean methaemoglobin levels. When PAPP or PAHP were administered intravenously the latter produced lower and later peak methaemoglobin levels than the former.

A repeated dose study of the toxicity of technical grade dibenz-(b.f.)-1,4 oxazepine in mice and hamsters.

The repeated dose inhalation toxicology of technical grade dibenz-(b.f.)-1,4 oxazepine (CR) was studied in mice and hamsters. The animals were exposed 5 days/week for 18 weeks and retained until 1 year after the start of exposure. CR, at high doses, affected survival of both species, nevertheless the material produced little specific organ-directed toxicity.

The acute oral and intravenous toxicity of p-aminopropiophenone (PAPP) to laboratory rodents.

The acute toxicity of p-aminopropiophenone (PAPP) to three species of laboratory animals has been investigated using solutions in dimethylsulphoxide (DMSO) for intravenous and oral (intragastric) administration. In addition, methaemoglobinaemia and Heinz-body haemolytic anaemia are described.

Pathological changes produced by exposure of rabbits and rats to smokes from mixtures of hexachloroethane and zinc oxide.

Rabbits and rats were exposed to single doses of hexachloroethane zinc smoke and observed for up to 14 days. Changes in the respiratory tract included acute inflammation and in some cases necrosis of the laryngeal and tracheal mucosa. Pulmonary oedema and pneumonitis were observed in decedent animals. Animals that survived to the end of the experiment, showed similar but much less florid changes in the respiratory tract.

A repeated dose study of the toxicity of CR applied to the skin of mice.

Dibenz (b,f)-1-4 oxazepine (CR) was applied to the skin of C3H and Porton-strain mice, daily for 12 weeks. After a further 80 weeks the animals were sacrificed and examined grossly and histologically. The results were compared with appropriate solvent and untreated controls. No abnormalities were found that could be ascribed to CR, but a high incidence of fatty infiltration of the liver in 1 strain of mice might have been due to the solvent in which CR was dissolved, namely acetone. There were marked differences in the incidence of several lesions in the 2 strains of mice, alveologenic carcinoma being much more common in the Porton mice. CR appeared to have little effect on the skin but both the test and solvent groups of male Porton mice shared an increased incidence of acanthosis.

Methemoglobinogenic potential of primaquine and its mutagenicity in the Ames test.

Single doses of primaquine did not produce methemoglobinemia in beagle bitches. Repeated daily administration for 12 days produced a gradually rising level of methemoglobin over that time period, unaccompanied by depletion of erythrocytic reduced glutathione. Primaquine was mutagenic in the Ames test in Salmonella typhimurium strain TA 1537, with or without S9, using a liquid preincubation assay. Primaquine was non-mutagenic in this assay to strains TA 1535, TA 1538, TA 98 and TA 100, regardless of the presence or absence of S9. In the standard overpour Ames test, the drug was non-mutagenic in all 5 Salmonella strains, both with and without S9 metabolic activation.