Toxicoepidemiology and predictors of death in 2,4-dinitrophenol (DNP) toxicity.

INTRODUCTION: 2,4-Dinitrophenol (DNP) is a highly toxic industrial chemical that is sometimes misused to reduce body fat. Toxicity following ingestion of DNP has recently become more common in the United Kingdom. This research was performed to document the frequency of DNP toxicity as reported to poisons centres in the United States (US) and United Kingdom (UK) and to identify the clinical features associated with fatality. METHODS: Calls to UK and US poisons centres involving systemic exposure to DNP were extracted for the 12 calendar years 2007-2018. These were analysed using univariate and multivariate statistical techniques. RESULTS: There were 204 cases (n = 86, US; n = 118, UK) of systemic DNP exposure identified, of which 86% were under the age of 40 and 71% were males. Over the study period the incidence of reported DNP toxicity was higher in the United Kingdom than the United States (1.78 vs. 0.26 cases per million population) and annual case numbers have increased in both countries since 2011. Case fatality was high and did not differ significantly between countries (US 11.6%; 95% CI: 6.4-20.1%: UK 16.9%; 95% CI: 11.3-24.7%; X2(1) = 1.12, p = 0.29). Univariate analysis demonstrated significant associations between risk of death and the presence of hypoglycaemia (OR = 17.1, 95% CI 1.7-174.3), hypertonia (OR = 12.9, 95% CI 3.5-47.6), acidosis (OR = 12.5, 95% CI 4.8-32.9), raised lactate (OR = 8.3, 95% CI 2.4-28.4), hyperpyrexia (OR = 6.5, 95% CI 2.8-15.2), tachycardia (OR = 6.4, 95% CI 2.5-16.4), agitation or confusion (OR = 6.0, 95% CI 2.6-13.7), hypertension (OR = 5.6, 95% CI 1.9-16.4) and tachypnoea/dyspnoea (OR = 2.8, 95% CI 1.2-6.1). After backwards stepwise logistic regression, the following were retained as significant independent predictors of mortality: acidosis (OR = 5.4, 95% CI: 1.8 - 16.5), tachycardia (OR = 3.6, 95% CI: 1.2 - 11.0), agitation/confusion (OR = 3.4, 95% CI: 1.2 - 9.7) and hyperpyrexia (OR = 2.8, 95% CI: 1.0 - 7.4). DISCUSSION: DNP toxicity is uncommonly reported to poisons centres but has recently become more frequent in the United States and United Kingdom. Tachycardia, hyperpyrexia, acidosis, and agitation/confusion are independent risk factors for mortality and their presence should prompt rapid escalation to an intensive care environment for aggressive supportive treatment and monitoring.

Synthetic cannabinoid receptor agonists: classification and nomenclature.

Introduction: The emergence of novel psychoactive substances has changed the epidemiology of drugs used recreationally throughout Europe and have posed significant challenges for clinicians, researchers and regulators. Synthetic cannabinoid receptor agonists have made up a large proportion of these novel psychoactive substances. Developed for legitimate scientific research, synthetic cannabinoid receptor agonists are potent agonists at CB1 and CB2 receptors and there have been many case reports of severe or fatal toxicity following their recreational use. At least 180 analytically confirmed compounds belonging to this group of drugs have been reported in Europe as of January 2019. Synthetic cannabinoid receptor agonists have a complex molecular structure, consisting of four pharmacophore components termed the 'core', 'tail', 'linker' and 'linked' groups. This structural complexity offers multiple opportunities for chemical modification to evade drug control legislation based on chemical structure, and this explains the large numbers of individual products that have been detected.Objectives: To discuss the chemical structure of synthetic cannabinoid receptor agonists and to describe the different nomenclature used to identify individual compounds thereby increasing understanding of their chemical heterogenicity and the potential relevance of their molecular structure to the risk of toxicity.Methods: The European Database on New Drugs (EDND) and EMCDDA-Europol annual implementation reports (2010-2017) was searched for compounds with known agonist activity at CB1 and/or CB2 receptors. Information on the different names and chemical structures of each compound was extracted and analysed for patterns. PUBMED, Google Scholar and MEDLINE databases were searched, in addition to non-peer reviewed sources, for data on structure, structure-activity relationships and nomenclatures for each compound.Nomenclature of synthetic cannabinoid receptor agonists: The structural complexity of synthetic cannabinoid receptor agonists presents challenges for nomenclature. There are several nomenclature systems in use.Colloquial and clandestine names: Non-scientific names (e.g. AKB-48, 2NEI, XLR-11) have been used to refer to specific compounds and most have probably been invented by vendors, presumably for the purpose of successful marketing of recreational products, however such names do not convey useful information about structure.Systematic chemical names: Each compound has a systematic chemical name that describes its exact structure; however, it is complex, unwieldy, inaccessible to non-chemists and not suitable for routine communication or clinical use.Serial names: Represent iterative designations assigned to compounds produced as a series in a laboratory (e.g. 'WIN-', 'HU-', 'CP-', 'JWH-' and 'AM-'). This nomenclature does not provide structural information or reflect structural similarities between compounds.Systematic abbreviated names: Succinctly describe each compound utilising structural pharmacophores. The chemical motif in each pharmacophore group is assigned a unique code-letter and assembled into a name with the format of 'Linked Group - TailCoreLinker'. Frequently encountered groups include indole and indazole cores, amino-acid-like like groups, most notably methyl-3,3-dimethylbutanoate (MDMB), methanone linker groups and pentyl, 5-fluoropentyl and 4-fluorobenzyl tails. There has been inconsistent usage of this nomenclature, likely due to a lack of consensus and identification of code-letters for several chemical motifs.Emerging compounds and practices: Tricyclic carbazole and γ-carbolinone core analogues have been identified and may represent the next significant structural analogues to emerge onto the recreational market. There is a need to establish basic pharmacological and toxicological data for these analogues.Conclusions: There is a need for international consensus on the nomenclature used to name synthetic cannabinoid receptor agonists to ensure precise and effective communication between professional groups in the clinic and for the purposes of research and regulation, especially with the emergence of analogues of existing compounds and novel structural motifs. A well-defined nomenclature system also supports quick and accurate communication of the structure-activity of these compounds, potentially highlighting compounds that carry a significant risk of toxicity.

A pilot study of bioaerosol reduction using an air cleaning system during dental procedures.

BACKGROUND: Bioaerosols are defined as airborne particles of liquid or volatile compounds that contain living organisms or have been released from living organisms. The creation of bioaerosols is a recognized consequence of certain types of dental treatment and represents a potential mechanism for the spread of infection. OBJECTIVES: The aims of the present study were to assess the bioaerosols generated by certain dental procedures and to evaluate the efficiency of a commercially available Air Cleaning System (ACS) designed to reduce bioaerosol levels. METHODS: Bioaerosol sampling was undertaken in the absence of clinical activity (baseline) and also during treatment procedures (cavity preparation using an air rotor, history and oral examination, ultrasonic scaling and tooth extraction under local anaesthesia). For each treatment, bioaerosols were measured for two patient episodes (with and without ACS operation) and between five and nine bioaerosol samples were collected. For baseline measurements, 15 bioaerosol samples were obtained. For bioaerosol sampling, environmental air was drawn on to blood agar plates using a bioaerosol sampling pump placed in a standard position 20 cm from the dental chair. Plates were incubated aerobically at 37°C for 48 hours and resulting growth quantified as colony forming units (cfu/m³). Distinct colony types were identified using standard methods. Results were analysed statistically using SPSS 12 and Wilcoxon signed rank tests. RESULTS: The ACS resulted in a significant reduction (p = 0.001) in the mean bioaerosols (cfu/m³) of all three clinics compared with baseline measurements. The mean level of bioaerosols recorded during the procedures, with or without the ACS activated respectively, was 23.9 cfu/m³ and 105.1 cfu/m³ (p = 0.02) for cavity preparation, 23.9 cfu/m³ and 62.2 cfu/m³ (p = 0.04) for history and oral examination; 41.9 cfu/m³ and 70.9 cfu/m³ (p = 0.01) for ultrasonic scaling and 9.1 cfu/m³ and 66.1 cfu/m³ (p = 0.01) for extraction. The predominant microorganisms isolated were Staphylococcus species and Micrococcus species. CONCLUSION: These findings indicate potentially hazardous bioaerosols created during dental procedures can be significantly reduced using an air cleaning system.

Antifungal susceptibility of Candida species using the Clinical and Laboratory Standards Institute disk diffusion and broth microdilution methods.

There are conflicting reports on the agreement between the Clinical and Laboratory Standards Institute disk diffusion (M44-A) and reference broth microdilution (M27-A) methods for determination of antifungal susceptibility of yeasts. The antifungal susceptibility of 541 yeasts, the majority of which were from the oral cavity, was determined using these two methods and the accuracy of the disk diffusion method assessed for clinical testing of various Candida species. Of the strains tested, Candida albicans predominated (390 out of 541). The classification of susceptibility determined by the disk diffusion method was largely in concordance with that obtained using the broth dilution method, regardless of species within Candida genus. The overall observed agreement between these two methods was 94.7% for fluconazole and 96.7% for voriconazole was with a 'very major' discrepancy level of 1.5% and 1.7% respectively. This study demonstrates a strong agreement of the simple disk diffusion method with the more labour intensive 'gold standard' broth microdilution method. These findings would support the use of the disk diffusion method in a routine mycology service.

Characterization of Candida albicans infection of an in vitro oral epithelial model using confocal laser scanning microscopy.

INTRODUCTION: Oral candidosis presents as several distinct forms and one of these, chronic hyperplastic candidosis, is distinguished by penetration of the epithelium by Candida. The aim of this study was to use confocal laser scanning microscopy to examine invasion of the oral epithelium by Candida albicans from different oral conditions and to determine whether inherent strain differences exist that could relate to infection type. Reverse transcription-polymerase chain reaction was also used to detect products from virulence gene families. METHODS: C. albicans (n = 19) was used to infect reconstituted human oral epithelium, which was incubated for 12 h. One half of the reconstituted human oral epithelium was then fixed and stained with concanavalin A-Alexa 594, pan-cytokeratin antibody-Alexa 488 and Hoechst nucleic acid dye. RNA was extracted from the remaining tissue for reverse transcription-polymerase chain reaction targeting secreted aspartyl proteinase, phospholipase and agglutinin-like sequence genes of C. albicans. RESULTS: Confocal laser scanning microscopy revealed strain-dependent tissue invasion, with differences evident in surface colonization, C. albicans morphology and the extent and pattern of tissue penetration. Hyphae were seen to directly penetrate epithelial cells and migrate between keratinocytes with yeast budding also evident in the reconstituted human oral epithelium. A relationship between 'high tissue invasion' and expression of secreted aspartyl proteinase genes 4-6 was noted. Interestingly, four of the five 'high invaders' originated from chronic hyperplastic candidosis. CONCLUSIONS: Confocal laser scanning microscopy permitted high resolution analysis of reconstituted human oral epithelium invasion by C. albicans and identified strain differences in the invasion process. Association between extensive hyphal morphology, direct epithelial penetration and high surface colonization were made with the 'highly invasive' strains.

Successful treatment of oral linear IgA disease using mycophenolate.

Linear IgA disease (LAD) is a rare acquired autoimmune bullous disorder, characterized by linear deposition of IgA along the dermoepidermal basement membrane zone. The clinical presentation of LAD consists of vesiculobullous lesions affecting the skin and mucosal surfaces. The present case report presents a rare presentation of this vesiculobullous disorder. Although more than 50% of LAD patients present with oral lesions, there are few reported cases of involvement of the mouth as the sole manifestation. A 79-year-old female presented with a sore mouth and erosions affecting the palate. The symptoms resolved following the provision of mycophenolate, an antiproliferative immunosuppressant which has not previously appeared to have been reported in the long-term successful management of linear IgA disease limited to the mouth. We found that mycophenolate is a useful adjunct to the successful treatment of oral linear IgA when the uses of other immunosuppressants are contraindicated.

Differential invasion of Candida albicans isolates in an in vitro model of oral candidosis.

The study assessed the ability of Candida albicans isolates to invade an in vitro oral tissue model. The extent and pattern of isolate invasion was then correlated with the infection origin of the isolate to identify characteristics that may be restricted to specific forms of oral infection, particularly chronic hyperplastic candidosis (CHC). Reconstituted human oral epithelium was infected with C. albicans isolated from normal oral mucosa (n = 4), CHC (n = 7), non-CHC oral candidoses (n = 4) and squamous cell carcinoma (SCC; n = 4). After infection for 24 h, histological analysis revealed yeast adhesion, hyphal extension, and invasion of the epithelium. Differential patterns of invasion were evident and, whilst consistent for a given isolate, did not relate to the infection origin of the isolate. Two principal patterns of invasion were evident and described as either a 'localised' or a 'uniform' distribution of invading hyphae. Several isolates also exhibited superficial infection with limited hyphal invasion. In conclusion, the use of the in vitro tissue model allowed the assessment of the invasive capabilities of isolates of C. albicans. However, the apparent differences in invasive characteristics did not appear to be related to the clinical origin of isolates.

PCR fingerprinting of Candida albicans associated with chronic hyperplastic candidosis and other oral conditions.

The purpose of this study was to genotype strains of Candida albicans to determine whether specific types were associated with chronic hyperplastic candidosis (CHC). A total of 67 candidal isolates from CHC patients (n = 17) and from patients with other oral conditions (n = 21) were genotyped by PCR fingerprinting employing two interrepeat primer combinations (1245 and 1246 primers or 1251 primer) and a single minisatellite-specific M13 primer. The most suitable primer for fingerprint analysis was found to be primer 1251, yielding well-resolved banding patterns. For the 67 isolates tested, PCR fingerprinting delineated 25 (1245 and 1246 primers), 27 (1251 primer), and 25 (M13 primer) profiles. The majority of C. albicans isolates from multiple sites within the mouth produced identical profiles (six out of nine subjects examined). For patients for whom a series of longitudinal isolates was available, strain persistence for up to 7 years was evident for five out of eight individuals, despite episodes of antifungal therapy. Computer-assisted comparison of the interrepeat PCR fingerprints identified seven distinct profiles that were shared among isolates from different individuals. However, no association was evident among isolates of C. albicans from specific clinical conditions. Eight isolates that were initially identified as C. albicans but having atypical PCR profiles were later confirmed as Candida dubliniensis. In conclusion, the genotypic data do not indicate clonal restriction of C. albicans with respect to CHC. Furthermore, these results have demonstrated that in the majority of individuals, colonizing populations of C. albicans are clonal in nature and exhibit strain persistence.

Identification of Candida dubliniensis, based on ribosomal DNA sequence analysis.

Differentiation of Candida albicans and the recently described C. dubliniensis has proven difficult due to the high degree of phenotypic similarity of these species. The present study examines sequence variations in the ribosomal DNA (rDNA) intergenic transcribed spacer (ITS) regions of C. albicans (n = 5) and C. dubliniensis (n = 7) strains, with a view to identifying sequence differences that would enable consistent differentiation of these two species by restriction fragment length polymorphism (RFLP) analysis. The ITS1 and ITS2 regions, together with the entire 5.8S rRNA gene of the strains, were amplified by the polymerase chain reaction (PCR), using primers ITS1 and ITS4, PCR products from both C. albicans and C. dubliniensis were of similar size (around 540 bp); however, sequence analysis revealed over 20 consistent base differences between the products of the two species. On the basis of sequence variation, the restriction enzyme MspA1 I was selected and used to differentiate the PCR products of C. albicans and C. dubliniensis by RFLP analysis. MspA1 I yielded two discernible fragments from C. albicans PCR products, whilst those from C. dubliniensis appeared undigested, thereby providing an approach to differentiate the two species.

Strain persistence of invasive Candida albicans in chronic hyperplastic candidosis that underwent malignant change.

OBJECTIVES: The aim of this study was to assess persistence and tissue invasion of Candida albicans strains isolated from a 65 year-old patient with chronic hyperplastic candidosis (CHC), that subsequently developed into squamous cell carcinoma (SCC). MATERIALS AND METHODS: C. albicans (n=7) were recovered from the oral cavity of the patient over seven years. Confirmation of CHC and SCC in this patient was achieved by histopathological examination of incisional biopsy tissue. DNA fingerprinting was performed on the seven isolates from the CHC patient together with a further eight isolates from patients with normal oral mucosa (n=2), chronic atrophic candidosis (n=1), SCC (n=1) and CHC (n=4). Genotyping involved the use of inter-repeat PCR using the eukaryotic repeat primer 1251. Characterisation of the tissue invasive abilities of the isolates was achieved by infecting a commercially available reconstituted human oral epithelium (RHE; SkinEthic, Nice, France). After 24 h, C. albicans tissue invasion was assessed by histopathological examination. RESULTS: DNA fingerprinting demonstrated strain persistence of C. albicans in the CHC patient over a seven year period despite provision of systemic antifungal therapy. The strain of C. albicans isolated from this patient was categorised as a high invader within the RHE compared to other isolates. CONCLUSIONS: Candidal strain persistence was evident in a patient with CHC over seven years. This persistence may be due to incomplete eradication from the oral cavity following antifungal therapy or subsequent recolonisation from other body sites or separate exogenous sources. The demonstration of enhanced in vitro tissue invasion by this particular strain may, in part, explain the progression to carcinoma.

Sensitivity of Seescan TV image analysis in discriminating between normal, dysplastic and malignant oral smears.

OBJECTIVE: Smears from premalignant and malignant lesions may contain large proportions of normal cells together with atypical cells; that could reduce the sensitivity of cytologic diagnosis. The present study assessed the performance of the Seescan TV image analysis system (TVIAS) in distinguishing between normal, premalignant and malignant oral smears. The sensitivity of Seescan TVIAS was tested using both white and monochromatic light. STUDY DESIGN: Nuclear area (NA) and corrected integrated optical density (IOD) of 50 Feulgen-stained nuclei were measured in smears collected from normal oral mucosa (n = 6), lesions displaying epithelial dysplasia (n = 5) and invasive squamous cell carcinoma (n = 5) using a Seescan TVIAS with both white and monochromatic light. RESULTS: There was a significant increase (P < .001) in mean IOD for nuclei in smears from dysplastic lesions and carcinomas as compared with normal smears. For smears from carcinomas, the mean NA was significantly elevated as compared with dysplastic (P < .001) and normal smears (P < .01). Mean NA for dysplastic smears was significantly reduced as compared with normal smears. While all smears from premalignant and malignant lesions contained mostly normal nuclei, a significant proportion of abnormal nuclei was identified in each smear. CONCLUSION: Although oral smears contain large amounts of normal cells, the Seescan TVIAS could successfully identify dysplastic and malignant cells on the basis of both IOD and NA values with or without the use of a monochromatic filter.

Phenotypic characterisation of Candida albicans isolated from chronic hyperplastic candidosis.

The phenotypes of 35 Candida albicans isolates from 19 patients with chronic hyperplastic candidosis (CHC) and 35 isolates from 30 patients with non-CHC infections were compared. Typing was based on carbohydrate assimilation, chemical sensitivity and serology. Eight carbohydrate assimilation profiles were evident with the API-20C system and a single profile predominated for isolates from CHC (17 of 19 patients; 89%) and non-CHC (18 of 30 patients; 63%). Chemical sensitivity tests revealed four profiles with no significant difference between CHC and non-CHC isolates. Serotype A predominated for isolates from both CHC (15 of 19 patients; 79%) and non-CHC (25 of 30 patients; 83%) infections. Boric acid resistance was more prevalent in CHC isolates, although a significant difference was not apparent. In summary, there was no overall difference in the phenotypes of isolates from CHC and non-CHC patients, and clonal restriction of CHC isolates was not demonstrated.

Adherence of Candida albicans to oral epithelial cells differentiated by Papanicolaou staining.

OBJECTIVE: To examine the relative adherence of Candida albicans to oral epithelial cells differentiated by Papanicolaou staining. METHODS: Oral epithelial cells were collected from 10 healthy adults (five male, five female) and counted. Equal volumes of oral epithelial cells and candida were mixed and incubated. The epithelial cells from this mix were collected by filtration through 10 microns polycarbonate membrane filters. Cells retained on the membrane filters were stained with crystal violet followed by Papanicolaou stain. The number of yeast attached to each of 100 red, orange, and green staining oral epithelial cells was determined by direct microscopic examination. RESULTS: C albicans had a higher level of adherence (p < 0.001) to red staining oral epithelial cells (mean (SD) number of candida attached to 100 oral epithelial cells 562 (159)) than to cells staining either orange (105 (47)) or green (161 (66)). CONCLUSIONS: Oral epithelial cell variability for candidal adherence is confirmed. The technique provides an opportunity to examine the relation between oral epithelial cell type and oral candidosis in specific groups, such as tobacco smokers, where increased epithelial cell keratinisation and candidal colonisation has been reported.

A novel technique for assessment of adherence of Candida albicans to solid surfaces.

A novel approach for the assessment of adherence of Candida albicans to translucent acrylic material is described. The method uses the inverted microscope to visualise yeast adhering to acrylic surfaces while the test material remains immersed in buffer. Adherent cells were not subjected to surface tension forces that can occur during drying processes, so that an even distribution of yeast with no aggregation occurred. The process of counting attached yeast was subsequently performed without difficulty. From the 11 C albicans isolates examined, two groups were evident with respect to acrylic adherence: one group of four isolates with an adherence level of 400 yeast/mm2 acrylic, and one group of seven isolates with adherence levels of 1000 yeast/mm2 acrylic.

Immunocytochemical detection of Candida albicans in formalin fixed, paraffin embedded material.

AIM: To assess the ability of the commercially available monoclonal antibody 1B12 (BioGenex, San Ramon, USA) to identify C albicans in formalin fixed, paraffin wax embedded material (FFPE). METHODS: Broth cultures of 20 strains of seven Candida species were resuspended in 4% agarose blocks, fixed in formalin for 24 hours, and embedded in paraffin wax. In addition, 16 blocks of FFPE tissue known to contain periodic acid-Schiff positive fungal hyphae were examined. Antigen retrieval involved microwave treatment of specimens in citrate buffer (0.01 M; pH 6.5) before addition of 1B12 antibody for 24 hours. Bound antibody was subsequently detected using a biotinylated link antibody and a peroxidase conjugated streptavidin. RESULTS: Only C albicans strains were 1B12 positive in the agarose blocks. All FFPE tissue blocks were found to contain 1B12 positive hyphal structures, indicating the presence of C albicans. CONCLUSIONS: The ability to identify candida organisms penetrating the lesional tissue in cases of chronic hyperplastic candidosis will help to clarify the role of individual Candida spp in this important form of oral candidosis.

Depressive symptoms and alterations in sucrose taste perception: cognitive bias or a true change in sensitivity?

Previous studies have reported elevated taste thresholds in depressed subjects, but those studies did not control for changes in response bias. The current study used signal detection analyses to address this shortcoming. Sucrose detection thresholds were measured (1) in subjects with high and low Hamilton Depression Rating Scale (HAM-D) scores who did not meet standard criteria for current Major Depressive Episode (MDE); and (2) in subjects who did fulfil standard criteria for MDE. Subjects with low HAM-D scores produced significantly more false alarms than the other two groups, but taste sensitivity, as indexed by d', did not vary significantly across groups. These results suggest that changes in response bias underlie previously reported increases in sucrose taste thresholds in depressed subjects.

Characterisation of the inflammatory cell infiltrate in chronic hyperplastic candidosis of the oral mucosa.

The inflammatory cell infiltrate in biopsy material of chronic hyperplastic candidosis (CHC) from the oral mucosa was characterised using immunocytochemical techniques. Nine specimens were stained for human kappa and lambda immunoglobulin light chains, CD68 antigen (macrophages), lysozyme (macrophages, granulocytes), CD3 antigen (T-lymphocytes), CD20 antigen (B-lymphocytes) and leucocyte common antigen (LCA). In addition, these and a further 13 specimens were also examined for immunoglobulin (Ig)-containing cells (IgA, IgG and IgM). The density of the infiltrate varied considerably between cases; T-lymphocytes were the dominant cell type (53.9%), with fewer B-lymphocytes (8.2%) and macrophages (14.2%). Many Ig-containing cells were seen, and although IgG-containing cells predominated, (60.8%, SD +/- 9.0) there was a high proportion of IgA-containing cells (36.7%, SD +/- 9.1) with few IgM-containing cells (2.5%, SD +/- 3.0). Many neutrophils, together with smaller numbers of T-lymphocytes and macrophages, were seen in the epithelium. It is suggested that mucosal defence to Candida infection involves a cell-mediated reaction in which there is recruitment of macrophages and local production of immunoglobulin with a prominent IgA component.

Opinions of dental consultants on the standard of referral letters in dentistry.

AIM: To ascertain the views of dental consultants on the relative importance of a range of topics relevant to specialist referral. SUBJECTS: 200 randomly selected dental consultants working in the UK in 1995. MAIN OUTCOME MEASURES: Data items which referral letters should contain; standard of referral letters; appropriate reasons for referral; how referrals could be improved; should restrictions be placed on specialist referrals. RESULTS: 161 replies were received. Overall there was only slight variation between specialities with regard to data items, appropriateness of referral and standard of referral letter. The perceived standard of referral letters was adequate or better on 76% of occasions; 21% were deemed to be of a poor standard; 2% were described as appalling. CONCLUSIONS: A Section 63 course on how to refer competently could be of benefit. Consultants were generally not in favour of restricting referrals to them.