The role of inhaled endotoxin in the aetiopathogenesis of equine heaves

Soluble lipopolysaccharide (LPS) inhalation challenge induced a dose-dependent bronchoalveolar lavage fluid (BALF) neutrophilia in both heaves-susceptible and control horses, and significant lung dysfunction in the heaves group. The response thresholds were lower for the heaves group, yet were markedly greater than airborne endotoxin exposure during the 5h dusty hay/straw challenge. In addition, there was no significant difference in BALF neutrophil numbers between the 2 groups following challenge with the middle and high LPS dose. There was a significant difference in the airway inflammatory response of the heaves group to 2 separate hay/straw exposures. This response was not related to the level of airborne endotoxin exposure. These findings indicated that inhaled endotoxin is not solely responsible for the induction of naturally occurring heaves.Inhalation challenge of the heaves group with 3 incremental doses of soluble A. fumigatus extract resulted in an increase in a BALF neutrophilia and lung dysfunction, which plateaued following inhalation of the middle dose. Inhalation challenge with LPS-depleted A. fumigatus extract resulted in a significant reduction in airway neutrophil numbers, of a magnitude that was greater than predicted by extrapolation from soluble LPS dose response inhalation experiments. These findings indicated that inhaled endotoxin may act synergistically with mould antigens, and contribute to the pulmonary inflammation observed in heavesInhalation challenge with hay dust suspensions (FIDS), prepared from fine hay dust particles, induced an airway neutrophilia, airway dysfunction and mucus hyper¬ secretion in the heaves group only. Inhalation challenge of the heaves group with the soluble fraction of HDS (SUP) failed to induce the magnitude of response measured following HDS challenge, despite containing almost all of the endotoxin activity of the HDS. These findings supported the involvement of HDS components, other than endotoxin, in the aetiopathogenesis of heaves. Inhalation challenge of the heaves group with the particulate fraction of FIDS (WP) induced only a mild BALF neutrophilia, however a combined challenge with SUP and WP induced a neutrophilic response approaching the magnitude of that following HDS challenge. These findings indicated a synergistic action between the soluble and particulate fractions of HDS.Inhalation challenge of the heaves group with LPS-depleted HDS resulted in a significant reduction in BALF neutrophil numbers, of a magnitude that was greater than predicted by extrapolation from soluble LPS dose response inhalation experiments. Replacement of the depleted LPS resulted in the re-establishment of the original level of BALF neutrophilia. Inhalation challenge of the heaves group with WP reconstituted in LPS solution (containing an equivalent LPS activity to SUP) resulted in a BALF neutrophilia that was not significantly different from that following challenge with combination of WP and SUP. These findings indicated that the endotoxin content of HDS acts synergistically with other HDS components, most notably the particulate fraction

Law, Lawyers, and Legal Practice in Silicon Valley: A Preliminary Report

The Growth of Large Law Firms and Its Effect on the Legal Profession and Legal Education, Symposiu

Law, Lawyers, and Legal Practice in Silicon Valley: A Preliminary Report

The Growth of Large Law Firms and Its Effect on the Legal Profession and Legal Education, Symposiu

Association of ten gastrointestinal and other medical conditions with positivity to faecal occult blood testing in routine screening:a large prospective study of women in England

Background: In 2006, the Bowel Cancer Screening Programme (BCSP) in England began offering biennial faecal occult blood testing (FOBt) at ages 60-69 years. Although FOBt is aimed at detecting colorectal neoplasms, other conditions can affect the result. In a large UK prospective study, we examined associations, both before and after screening, between FOBt-positivity and 10 conditions that are often associated with gastrointestinal bleeding. Methods: By electronically linking BCSP and Million Women Study records, we identified 604,495 women without prior colorectal cancer who participated in their first routine FOBt screening between 2006 and 2012. Regression models, using linked national hospital admission records, yielded adjusted relative risks (RRs) in FOBt-positive versus FOBt-negative women for colorectal cancer, adenoma, diverticular disease, inflammatory bowel disease, haemorrhoids, upper gastrointestinal cancer, oesophagitis, peptic ulcer, anaemia and other haematological disorders. Findings: RRs in FOBt-positive versus FOBt-negative women were 201.3 for colorectal cancer and 197.9 for adenoma within 12 months after screening and 3.5 and 4.9, respectively, 12-24 months after screening; pand#60;0.001 for all RRs. Within 12 months after screening, the RR for inflammatory bowel disease was 26.3, and ranged from 2 to 5 for upper gastrointestinal or haematological disorders. The RRs of being diagnosed with any of the 8 conditions other than colorectal neoplasms before screening and in the 12-24 months after screening, were 1.81 and 1.92, respectively. Conclusions: While fOBt-positivity is associated with a substantially increased risk of colorectal neoplasms after screening, eight other gastrointestinal and haematological conditions are associated with FOBt-positivity, both before and after screening

Alterations in amino acid status in cats with feline dysautonomia

Feline dysautonomia (FD) is a multiple system neuropathy of unknown aetiology. An apparently identical disease occurs in horses (equine grass sickness, EGS), dogs, rabbits, hares, sheep, alpacas and llamas. Horses with acute EGS have a marked reduction in plasma concentrations of the sulphur amino acids (SAA) cyst(e)ine and methionine, which may reflect exposure to a neurotoxic xenobiotic. The aim of this study was to determine whether FD cats have alterations in amino acid profiles similar to those of EGS horses. Amino acids were quantified in plasma/serum from 14 FD cats, 5 healthy in-contact cats which shared housing and diet with the FD cats, and 6 healthy control cats which were housed separately from FD cats and which received a different diet. The adequacy of amino acids in the cats’ diet was assessed by determining the amino acid content of tinned and dry pelleted foods collected immediately after occurrences of FD. Compared with controls, FD cats had increased concentrations of many essential amino acids, with the exception of methionine which was significantly reduced, and reductions in most non-essential amino acids. In-contact cats also had inadequate methionine status. Artefactual loss of cysteine during analysis precluded assessment of the cyst(e)ine status. Food analysis indicated that the low methionine status was unlikely to be attributable to dietary inadequacy of methionine or cystine. Multi-mycotoxin screening identified low concentrations of several mycotoxins in dry food from all 3 premises. While this indicates fungal contamination of the food, none of these mycotoxins appears to induce the specific clinico-pathologic features which characterise FD and equivalent multiple system neuropathies in other species. Instead, we hypothesise that ingestion of another, as yet unidentified, dietary neurotoxic mycotoxin or xenobiotic, may cause both the characteristic disease pathology and the plasma SAA depletion