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Background: Current proposed criteria for functional cognitive disorder (FCD) have not been externally validated. We sought to analyse the current perspectives of cognitive specialists in the diagnosis and management of FCD in comparison with neurodegenerative conditions., Methods: International experts in cognitive disorders were invited to assess seven illustrative clinical vignettes containing history and bedside characteristics alone. Participants assigned a probable diagnosis and selected the appropriate investigation and treatment. Qualitative, quantitative and inter-rater agreement analyses were undertaken., Results: Eighteen diagnostic terminologies were assigned by 45 cognitive experts from 12 countries with a median of 13 years of experience, across the seven scenarios. Accurate discrimination between FCD and neurodegeneration was observed, independently of background and years of experience: 100% of the neurodegenerative vignettes were correctly classified and 75%-88% of the FCD diagnoses were attributed to non-neurodegenerative causes. There was <50% agreement in the terminology used for FCD, in comparison with 87%-92% agreement for neurodegenerative syndromes. Blood tests and neuropsychological evaluation were the leading diagnostic modalities for FCD. Diagnostic communication, psychotherapy and psychiatry referral were the main suggested management strategies in FCD., Conclusions: Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details. These characteristics need further validation and operationalisation. Heterogeneous labelling and framing pose clinical and research challenges reflecting a lack of agreement in the field. Careful consideration of FCD diagnosis is advised, particularly in the presence of comorbidities. This study informs future research on diagnostic tools and evidence-based interventions., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Regulatory T cells (Tregs) play a central role in maintenance of immune homeostasis by controlling harmful immune responses to inappropriate antigens and are thought to play a key role in modulating hypersensitivity reactions. Infestation of sheep with Psoroptes ovis results in a pronounced cutaneous hypersensitivity-type response, which appears to be crucial for mite survival. We hypothesize that (i) Tregs are involved in sheep scab lesions and (ii) Treg responses may crucially affect lesion development and subsequent mite survival. Foxp3 is a key transcription factor required for generation and maintenance of Tregs in rodents and humans, and is the most widely used marker for Tregs in these species. In this study, we sequence ovine foxp3 and show that it exhibits a high degree of homology with foxp3 from other species. Using a validated immunohistochemical staining technique, we demonstrate that infestation of sheep with P. ovis results in an influx of Foxp3(+) T cells into the skin. Future work will investigate the regulatory function of ovine Foxp3(+) T cells and determine whether the quality of the Treg response to P. ovis plays a role in individual susceptibility to the mite.

Sheep scab is caused by the noninvasive mite, Psoroptes ovis, which initiates a profound pro-inflammatory skin response leading to lesion development. To investigate these early events between the skin and the parasite, primary ovine epidermal keratinocyte cultures were generated and challenged with mite derived antigens. The kinetics of the mRNA response of these cells were monitored by microarray. The results indicated that the cells responded within 1 h of challenge, with a significant increase in the pro-inflammatory cytokine IL-8. This result was confirmed by real-time RT-PCR, and showed that IL-8 up-regulation was maximal at 1 h but declined to pre-stimulation levels at 24 and 48 h. The IL-8 mRNA response to mite wash antigens containing secretory and/or excretory proteins was also investigated and compared to the response to whole mite antigen. These studies revealed that the mite wash antigen, at a challenge dose of 10 microg/mL, was markedly more potent and induced significantly higher levels of IL-8 mRNA than the same concentration of whole mite antigen. These results are discussed in relation to mite establishment and survival on the ovine host.

Background: Fracture of the distal radius is a common injury. A surgical treatment is external fixation, where metal pins inserted into bone on either side of the fracture are then fixed to an external frame., Objectives: To evaluate the evidence from randomised controlled trials comparing different methods of external fixation for distal radial fractures in adults., Search Strategy: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (June 2007), the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and other databases, conference proceedings and reference lists of articles. No language restrictions were applied., Selection Criteria: Randomised or quasi-randomised controlled clinical trials which compared different methods of external fixation in adults with a distal radial fracture., Data Collection and Analysis: All review authors independently performed study selection. Two authors independently assessed the included trials and performed data extraction., Main Results: Nine small trials involving 510 adults with potentially or evidently unstable fractures, were grouped into five comparisons. The interventional, clinical and methodological heterogeneity of trials precluded data pooling. Only one trial had secure allocation concealment. Two trials comparing a bridging (of the wrist) external fixator versus pins and plaster external fixation found no significant differences in function or deformity. One trial found tendencies for more serious complications but less subsequent discomfort and deformity in the fixator group. Three trials compared non-bridging versus bridging fixation. Of the two trials testing uni-planar non-bridging fixation, one found no significant differences in functional or clinical outcomes; the other found non-bridging fixation significantly improved grip strength, wrist flexion and anatomical outcome. The third trial found no significant findings in favour of multi-planar non-bridging fixation of complex intra-articular fractures. One trial using a bridging external fixator found that deploying an extra external fixator pin to fix the 'floating' distal fragment gave superior functional and anatomical results. One trial found no evidence of differences in clinical outcomes for hydroxyapatite coated pins compared with standard uncoated pins. Two trials compared dynamic versus static external fixation. One trial found no significant effects from early dynamism of an external fixator. The poor quality of the other trial undermines its findings of poorer functional and anatomical outcomes for dynamic fixation., Authors' Conclusions: There is insufficient robust evidence to determine the relative effects of different methods of external fixation. Adequately powered studies could provide better evidence.

Background: Fracture of the distal radius ('broken wrist') is a common clinical problem. It can be treated conservatively, usually involving wrist immobilisation in a plaster cast, or surgically. A key method of surgical fixation is external fixation., Objectives: To evaluate the evidence from randomised controlled trials comparing external fixation with conservative treatment for fractures of the distal radius in adults., Search Strategy: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (September 2006), the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and other databases, conference proceedings and reference lists of articles. No language restrictions were applied., Selection Criteria: Randomised or quasi-randomised controlled clinical trials involving adults with a fracture of the distal radius, which compared external fixation with conservative treatment., Data Collection and Analysis: After independent study selection by all review authors, two authors independently assessed the included trials. Independent data extraction of new trials was performed by two authors. Pooling of data was undertaken where appropriate., Main Results: Fifteen heterogeneous trials, involving 1022 adults with dorsally displaced and potentially or evidently unstable distal radial fractures, were included. While all trials compared external fixation versus plaster cast immobilisation, there was considerable variation especially in terms of patient characteristics and interventions. Methodological weaknesses among these trials included lack of allocation concealment and inadequate outcome assessment. External fixation maintained reduced fracture positions (redisplacement requiring secondary treatment: 7/356 versus 51/338 (data from 9 trials); relative risk 0.17, 95% confidence interval 0.09 to 0.32) and prevented late collapse and malunion compared with plaster cast immobilisation. There was insufficient evidence to confirm a superior overall functional or clinical result for the external fixation group. External fixation was associated with a high number of complications, such as pin-track infection, but many of these were minor. Probably, some complications could have been avoided using a different surgical technique for pin insertion. There was insufficient evidence to establish a difference between the two groups in serious complications such as reflex sympathetic dystropy: 25/384 versus 17/347 (data from 11 trials); relative risk 1.31, 95% confidence interval 0.74 to 2.32., Authors' Conclusions: There is some evidence to support the use of external fixation for dorsally displaced fractures of the distal radius in adults. Though there is insufficient evidence to confirm a better functional outcome, external fixation reduces redisplacement, gives improved anatomical results and most of the excess surgically-related complications are minor.

Aim: To define the views of junior house-officers (JHOs) concerning consent for general surgical conditions., Methods: Questionnaire-based descriptive study on two cohorts of JHOs, separated by 3 years of major national and local directives., Results: From the JHO perspective: (i) there has been a shift away from the JHO being the main signatory, (ii) many JHOs (58% in 2000; 47% in 2003) feel unsupported with respect to obtaining consent, (iii) knowledge concerning any consultant/unit's complication rates was poor (<30%), (iv) knowledge concerning complication rates for several paradigm procedures was also poor, though it improved from 2000 to 2003, (v) there is no formal training in consent., Conclusions: Despite the JHO group of 2003 outperforming that of 2000, there is major scope for improvement from patient, legal, educational and risk-management perspectives.

Protection against an experimental challenge infection by immunization with excretory/secretory products (ES) from Haemonchus contortus, containing predominantly proteins of 15 and 24 kDa, depends on the age of the sheep. Vaccinated sheep 9 and 6 months of age had reduced final worm burdens of 82 and 77, respectively. No reduction in worm burden was found in 3-month-old lambs. Nine-month-old sheep had significantly higher ES-specific serum immunoglobulin (Ig)G1 and IgA during immunizations and after challenge infection than 3-month-old lambs. There was no correlation within the 9-month-old sheep between ES-specific IgA or IgG1 levels and protection, measured as worm burden. However, when the different age groups were combined, negative correlations between percentage protection and ES-specific IgA and IgG1 levels after challenge were found. At the end of the experiment, peripheral blood eosinophils and mast cell counts in abomasal tissue were also significantly higher in the vaccinated and challenged 9-month-old sheep than in the vaccinated and challenged 3-month-old or than in the 9-month-old sheep with challenge, but without vaccination. The responses measured in young lambs were similar to the responses in sheep, but the height of these responses was in general of a lower magnitude.

Studies on the immunoglobulin (Ig)E immune responses to the gastric nematode, Teladorsagia circumcincta, have demonstrated a major high molecular weight allergen (HMWTc). Cross reactive allergens of similar MW were demonstrated for Trichostrongylus colubriformis and Cooperia curticei, but not for Haemonchus contortus. Purification of HMWTc was achieved by gel-filtration chromatography, and nonreducing SDS-PAGE and Western blot analysis revealed two closely associated bands with a molecular weight of approximately 140-150 kDa. Reduction showed four IgE reactive bands of 120, 50, 45 and 30 kDa, and deglycosylation abrogated the immunoreactivity of the 120 and 30 kDa bands. Ultrastructural immunolocalization by electron microscopy revealed that the IgE reactivity was confined to the cuticular surface of the infective (L3) larvae. ELISA studies to determine the IgE anti-HMWTc responses in lambs during their first grazing season, demonstrated significantly higher IgE antibody in lambs with low accumulative faecal egg count (FEC) compared to animals with high accumulative FEC. These studies provide evidence for a protective function of IgE antibody in Teladorsagia infections in lambs.

Lesional area was estimated and lesional mast cells and eosinophils were counted during primary and challenge infestations of sheep with Psoroptes ovis. In addition, circulating basophils and eosinophils and serum P. ovis-specific immunoglobulin IgE antibody were quantified. Expansion of lesional area was significantly less and serum IgE titres significantly greater in challenge than primary infestations. Lesional mast cell hyperplasia and massive eosinophil infiltration accompanied by raised titres of P. ovis antigen-specific IgE antibody were compatible with an IgE-mediated Type-1 allergic reaction, while detection of lesional basophils was suggestive of cutaneous basophil hypersensitivity. The temporal pattern of lesional mastocytosis and eosinophil infiltration and the role of these cells and serum IgE in the immune response is discussed.

A monoclonal antibody to ovine IgE was employed in an ELISA to investigate the IgE antibody responses in serum and gastric lymph to a primary infection of Teladorsagia circumcincta, and following challenge in previously infected sheep. During a primary response, IgE antibody to antigens derived from the infective third stage (L3) and adult (L5) worms were negligible, with low levels of IgE antibody detected in serum and lymph. In contrast, there was a pronounced IgE antibody response in 2/4 sheep to L3 antigens during 2-8 days after challenge of previously infected animals but low levels of IgE antibody to L5 antigens. This response was confirmed in a second but similar experiment, where relatively high levels of IgE antibody was detected to antigens from L3. Antibody levels were higher in lymph than in serum from the same animals, and Western blots of L3 antigen following SDS-PAGE under reducing conditions revealed several bands of MW26-96KD which reacted with the IgE antibody from gastric lymph. Immunohistochemical staining indicated that these IgE antibodies may be reacting with allergens associated with the surface cuticle of the worms.

The IgE response of naive or previously infected sheep to 50,000 infective larvae of Teladorsagia circumcincta was monitored in serum and gastric lymph using a monoclonal antibody generated to recombinant ovine IgE in a dot blot assay. In 4/5 naive sheep, lymph and serum IgE concentrations increased from days 8 and 14 after infection, respectively. In most previously infected sheep, the IgE response to challenge was more rapid, although not necessarily greater than that following a primary infection. IgE concentrations in lymph were some 4-fold higher than in serum indicating that its source was the mucosa or draining nodes.

The distribution of granule-specific sheep mast cell proteinase (SMCP), was assayed by immunocytochemistry and quantified by immunoassay in sheep immune to Haemonchus contortus. Repeated infection with Haemonchus larvae over 10-12 weeks induced a pronounced mucosal mastocytosis, including intraepithelial globule leukocytes (GL), which, 7 days after ceasing this dosing regime, was associated with the inability of incoming larvae to establish within the abomasal mucosa. Loss of this resistance, due to the cessation of stimulation with Haemonchus larvae 84 days previously or to treatment of sheep with corticosteroid, was associated with a marked decline in mast cell density and concentrations of SMCP in abomasal mucosal tissues. Nevertheless, larvae also failed to establish in immune sheep rested from challenge 42 days previously and in which mast cell counts were not significantly different from those of control sheep. A small, but significant, release of SMCP was demonstrated in gastric mucus from immune sheep following larval challenge, whereas little or no SMCP was detected in mucus from naïve animals.

A sensitive and specific enzyme-linked immunosorbent assay (ELISA) was developed for mouse intestinal mast cell proteinase (IMCP). Specificity was demonstrated by the absence of immunoreactivity with extracts of isolated serosal mast cells (SMC), or with high concentrations (50 micrograms/ml) of the antigenically similar rat mast cell proteinases I or II. The small and large intestines in normal mice were the major sources of IMCP, there being little or no IMCP in non-mucosal tissues. Concentrations of IMCP in normal (non-parasitized) mice were low, but were increased 100-1000-fold intestines of mice infected 10 days earlier with Trichinella spiralis. The kinetic response of secreted IMCP into the blood of mice following infection with T. spiralis was also studied. Systemic release of IMCP coincided with the immune expulsion of adult worms from the intestine, and peak concentrations (9.45 micrograms/ml IMCP) occurred 9 days after infection. The tissue distribution of IMCP, its secretion into blood, and its enteric accumulation during parasite infection, are consistent with a mucosal mast cell (MMC) source for IMCP. The results are discussed in the context of similar findings for rat mast cell proteinase II.

Ovine mucosal mast cells and globule leucocytes have been isolated from the abomasum of normal sheep, and from animals challenged with Ostertagia circumcincta. The ultrastructural, morphological and histochemical properties of these cells have been investigated. The granules of ovine mucosal immunoglobulin and a serine esterase. These cells also possess surface immunoglobulin. Cells morphologically intermediate between mucosal mast cells and bulin. Cells morphologically intermediate between mucosal mast cells and globule leucocytes have similar granule and surface properties. These observations, together with quantitative data, indicate that alterations in the granule structure of mucosal mast cells as a consequence of prolonged antigenic challenge give rise to mast cells in the epithelium which, in the past, have been commonly recognized as globule leucocytes.