Richard Mellanby

Diabetes in non-obese diabetic mice is not associated with quantitative changes in CD4+ CD25+ Foxp3+ regulatory T cells

The role of regulatory T cells (Tregs) in maintaining self tolerance has been intensively researched and there is a growing consensus that a decline in Treg function is an important step towards the development of autoimmune diseases, including diabetes. Although we show here that CD25+ cells delay diabetes onset in non‐obese diabetic (NOD) mice, we found, in contrast to previous reports, neither an age‐related decline nor a decline following onset of diabetes in the frequency of CD4+ CD25+ Foxp3+ regulatory T cells. Furthermore, we demonstrate that CD4+ CD25+ cells from both the spleen and pancreatic draining lymph nodes of diabetic and non‐diabetic NOD mice are able to suppress the proliferation of CD4+ CD25– cells to a similar extent in vitro. We also found that pretreatment of NOD mice with anti‐CD25 antibody allowed T cells with a known reactivity to islet antigen to proliferate more in the pancreatic draining lymph nodes of NOD mice, regardless of age. In addition, we demonstrated that onset of diabetes in NOD.scid mice is faster when recipients are co‐administered splenocytes from diabetic NOD donors and anti‐CD25. Finally, we found that although diabetic CD4+ CD25+ T cells are not as suppressive in cotransfers with effectors into NOD.scid recipients, this may not indicate a decline in Treg function in diabetic mice because over 10% of CD4+ CD25+ T cells are non‐Foxp3 and the phenotype of the CD25– contaminating population significantly differs in non‐diabetic and diabetic mice. This work questions whether onset of diabetes in NOD mice is associated with a decline in Treg function.

Multicomponent Reactions for de Novo Synthesis of BODIPY Probes: In Vivo Imaging of Phagocytic Macrophages

Multicomponent reactions are excellent tools to generate complex structures with broad chemical diversity and fluorescent properties. Herein we describe the adaptation of the fluorescent BODIPY scaffold to multicomponent reaction chemistry with the synthesis of BODIPY adducts with high fluorescence quantum yields and good cell permeability. From this library we identified one BODIPY derivative (PhagoGreen) as a low-pH sensing fluorescent probe that enabled imaging of phagosomal acidification in activated macrophages. The fluorescence emission of PhagoGreen was proportional to the degree of activation of macrophages and could be specifically blocked by bafilomycin A, an inhibitor of phagosomal acidification. PhagoGreen does not impair the normal functions of macrophages and can be used to image phagocytic macrophages in vivo.

Incidence of suicide in the veterinary profession in England and Wales.

THERE have been concerns for many years that mortality due to suicide is higher in the veterinary profession than in the general population. For example, a survey of the causes of mortality in British veterinarians reported an increase in mortality from suicide (Kinlen 1983); increased mortality from suicide has also been reported in the American veterinary profession (Blair and Hayes 1980, Miller and Beaumont 1995). The high suicide rate among veterinarians has even led to the publication of an article dealing with how to cope with suicide (Anon 2000). There has been much speculation as to why the incidence of death by suicide is higher in the profession than in the general population. Occupational stress, stigmatisation of mental health disorders within the veterinary profession and a reluctance of veterinarians contemplating suicide to seek medical help, professional and social isolation, and ease of access to lethal drugs have regularly been implicated as factors leading to an increased incidence of suicide (Blair and Hayes 1980, Adkin 2000, Anon 2000, Jeyaretnam and others 2000, Tutt 2000). Despite the concerns about this high incidence, there are very few published data on the number and incidence of suicides by British veterinarians over the past three decades. The aim of this study was to collate data from the Office for National Statistics on the number and incidence of veterinarian suicides, and to compare this incidence with that in the general population and other health care professions. Data on death registrations for all deaths in England and Wales between 1979 to 2000 (with the exception of 1981, which was excluded because the data were incomplete for that particular year) of individuals whose occupation was recorded as veterinarian, where an inquest verdict of suicide (International Classification of Diseases [ICD] codes E950E959) or undetermined cause (‘open verdicts’) (ICD codes E980-E989, excluding E988·8) had been registered, were supplied by the Office for National Statistics. Open verdicts were included because there is evidence that the majority of these are suicides, although data on the number of deaths due to undetermined causes were only available from 1990 onwards (Kelly and Bunting 1998). Similar data were obtained for the death entries where the occupation was recorded as medical practitioner or dental practitioner. The proportional mortality ratio (PMR) is the observed number of suicides divided by the expected number of suicides, expressed as a percentage, and allows the incidence of suicide in a particular occupation to be compared with the general population as well as other occupations. The expected number of deaths was computed by applying the proportion of total deaths due to suicide in the general population to the total deaths in the occupational group of interest (Kelly and Bunting 1998). Consequently, a PMR of suicide of 100 means that the given occupation has the same proportion of all deaths certified as suicide as that of the general population of England and Wales, a PMR of 50 means that the given occupation has half the proportion of all deaths certified as suicide compared with the general population of England and Wales, whereas a PMR of 200 means that the given occupation has double the proportion of all deaths certified as suicide compared with the general population of England and Wales. The proportion of deaths caused by suicide relative to the number of deaths by other causes in the veterinary profession was compared with those for medical and dental practitioners by the chi-squared test with Yates’s correction. Data were considered significant at P<0·05. Table 1 shows the number of suicides and the PMR of male and female veterinarians aged 20 to 74 years, for 1979 to 1980 and 1982 to 1990, and includes data from other health care professions for comparison. Although the actual number of deaths by suicide is lower than for medical or dental practitioners, the PMR for suicide is considerably higher for the veterinary profession and is higher than other health care professions. A similar finding was observed between 1991 and 2000 for male and female veterinarians (Table 2). The most common method of suicide was self-poisoning by solid or liquid substances for both male and female veterinarians (Table 3). Although the absolute number of suicides by veterinarians is relatively small compared with other occupational groups such as farmers and medical practitioners, the PMR for suicide by veterinarians is one of the highest of all occupational groups. The finding of a high PMR in both male and female veterinarians suggests that the number of suicides relative to deaths due to other causes is much higher in the veterinary profession than in the population as a whole, and is higher than in other health care professions such as medical or dental practitioners (Tables 1, 2). Although the PMR was higher for females in both time periods, the small number of female deaths by suicide and other causes means that the higher PMR should be interpreted with caution. While the PMR is one of the most widely used methods to compare the incidence of suicide between various occupations and with the population as a whole, it should be acknowledged that the PMR is affected by the relative frequency of other causes of death. If mortality from all causes is low in a given population, a high PMR from suicide may be observed. A detailed analysis of the age, background, previous health history and type of veterinary job undertaken by the suicide victims was not possible due to the restrictions imposed by the Data Protection Act, which serves to protect an individual’s privacy. However, 10 of the 26 male veterinarian suicides that occurred between 1991 and 2000 were individuals younger than 45 years of age, which suggests that veterinarian suicides are not confined to a restricted age range. There is little evidence to suggest that the incidence of suicide in male veterinarians has increased since 1991 compared with 1979 to 1990. In contrast, the PMR from suicide is much higher for females since 1993 than in 1979 to 1990, but the small numbers of deaths by suicide and by other causes mean that the high PMR from suicide since 1993 should be interpreted with caution. However, an elevated incidence of suicide has Veterinary Record (2005) 157, 415-417

Suicidal behaviour and psychosocial problems in veterinary surgeons: a systematic review.

PurposeRates of suicide are elevated among veterinary surgeons in several countries, yet little is known about contributory factors. We have conducted a systematic review of studies investigating suicidal behaviour and psychosocial problems in veterinary surgeons.MethodsA systematic search of the international research literature was performed in May 2008. Data from 52 studies of non-fatal suicidal behaviour, mental health difficulties, stress and burnout, occupational difficulties, and psychological characteristics of veterinary surgeons were extracted by two independent reviewers and analysed. Studies were rated for quality and greater emphasis placed on findings from higher quality studies.ResultsThe majority of studies were of stress and occupational difficulties experienced by veterinary surgeons. Occupational stressors included managerial aspects of the job, long working hours, heavy workload, poor work-life balance, difficult client relations, and performing euthanasia. Few studies investigated suicidal behaviour or mental health difficulties in the profession. Some studies suggested that young and female veterinarians are at greatest risk of negative outcomes such as suicidal thoughts, mental health difficulties, and job dissatisfaction.ConclusionsThe review highlights the difficulties faced by veterinary surgeons that may contribute to poor mental wellbeing and suicidal behaviour. Future research might include further examination of the influence of euthanasia on attitudes towards suicide and more direct examination of the impact that occupational risk factors might have on suicidal behaviour. Suggestions about the review’s implications for suicide prevention in this group are also made.

Systematic review of the prevalence of suicide in veterinary surgeons

BACKGROUND An accumulating body of research demonstrates that risk of suicide varies between occupational groups. Identification of the occupations at risk, and the factors that contribute to the increased risk of suicide in these groups is essential for the development of effective suicide prevention strategies. There is preliminary evidence to suggest that veterinary surgeons are a group at risk. AIMS To conduct a systematic review of studies of rates and methods of suicide in the veterinary profession. METHODS A systematic search of the international research literature was performed in May 2008. The data from the 19 studies of the prevalence of suicide in the veterinary profession were extracted by two independent reviewers and analysed. RESULTS Between 0 and 43% of veterinary surgeon deaths were due to suicide. In all but one of the 15 studies presenting risk of suicide in veterinary surgeons with a comparison population, an elevated risk was found. The better quality studies with the lowest risk of bias indicated that in the UK, the rate of suicide in the veterinary profession was at least three times the general population rate. Studies of the methods of suicide veterinary surgeons use suggest that self-poisoning and firearms are particularly common. CONCLUSIONS There appears to be an elevated risk of suicide for veterinary surgeons in several countries. Access to means of suicide influences the methods used and may contribute to increased risk.

Long-term outcome of 56 dogs with nasal tumours treated with four doses of radiation at intervals of seven days.

A retrospective study was undertaken on 56 dogs treated for nasal tumours by megavoltage radiotherapy with a hypofractionated schedule consisting of four doses of 9 Gy given at intervals of seven days. The dogs were followed until they died or were euthanased. The clinical signs had improved in 53 of the 56 dogs by the end of the treatment schedule. Mild acute radiation side effects were observed in the majority of the dogs but late radiation side effects were rare. Kaplan-Meier survival analysis revealed a median survival time after the final dose of radiation of 212 days. The oneand two-year survival rates were 45 per cent and 15 per cent. Fifty of the dogs were euthanased because the initial clinical signs recurred.

Cutting Edge: IL-6–Dependent Autoimmune Disease: Dendritic Cells as a Sufficient, but Transient, Source

Mice lacking IL-6 are resistant to autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE), which is driven by CNS-reactive CD4+ T cells. There are multiple cellular sources of IL-6, but the critical source in EAE has been uncertain. Using cell-specific IL-6 deficiency in models of EAE induced by active immunization, passive transfer, T cell transfer, and dendritic cell transfer, we show that neither the pathogenic T cells nor CNS-resident cells are required to produce IL-6. Instead, the requirement for IL-6 was restricted to the early stages of T cell activation and was entirely controlled by dendritic cell–derived IL-6. This reflected the loss of IL-6R expression by T cells over time. These data explain why blockade of IL-6R only achieves protection against EAE if used at the time of T cell priming. The implications for therapeutic manipulation of IL-6 signaling in human T cell–driven autoimmune conditions are considered.

Survey of mistakes made by recent veterinary graduates

To investigate the incidence and types of mistakes made in veterinary practice, and to assess the impact the mistakes had on the veterinarians involved, a questionnaire was sent in November 2002 to all the veterinary graduates of the Universities of Bristol, Edinburgh, Glasgow, London and Liverpool in 2001. One hundred and eight (27 per cent) of 402 questionnaires were returned completed; 87 of 106 respondents (82 per cent) worked frequently or always unsupervised and only 46 (43 per cent) could always rely on support from other veterinarians in the practice. Since starting work, 82 of 105 respondents (78 per cent) stated that they had made a mistake, defined as an erroneous act or omission resulting in a less than optimal or potentially adverse outcome for a patient, and in many cases these mistakes had had a considerable emotional impact on the veterinarians involved. The survey highlights that a large number of recently graduated veterinarians work with little supervision and that many veterinarians beginning their year in practice do not always have access to assistance from other veterinary colleagues.

The transition into veterinary practice: Opinions of recent graduates and final year students

BackgroundThe transition from veterinary student to member of the veterinary profession is known to be challenging. This study aimed to determine and compare the opinions of final year veterinary students and recent graduates on graduate attributes that ease this transition.MethodsThe study was carried out across 3 veterinary schools in the United Kingdom. Paper based or electronic surveys were used. Final year students in the 3 schools were surveyed either electronically (school A) or on paper (schools B and C). Student cohort sizes were 112, 227 and 102 respectively. Recent graduates were contacted either at a reunion event (school A) or electronically from database records (school B and school C). Cohort sizes of contacted graduates were 80, 175 and 91 respectively. Respondents were asked to rate 42 individual attributes on a 5 point Likert scale. Focus groups with final year students and recent graduates and telephone interviews with recent graduates were carried out. Data were analysed by two researchers through a combination of manual coding and thematic analysis. Data were grouped into broad themes then sorted into narrower themes. Data were then searched for counter examples.ResultsResponse rates for final year students were 34% (school A), 36% (school B) and 40% (school C). Response rates for recent graduates were 56% (school A), 20% (school B) and 11% (school C). There was a high level of agreement between the cohorts with respect to communication skills, problem solving and decision making skills, recognition of own limitations and the ability to cope with pressure all rated unanimously important or very important. Business acumen, knowledge of veterinary practice management and research skills were the 3 attributes ranked at the bottom of the list. Nine attributes were identified with a significantly different (p < 0.05) ranking between the cohorts. Final year students ranked veterinary clinical knowledge, knowledge of veterinary public health and zoonotic issues, veterinary legislation and veterinary practice management, commitment to continuing professional development and ability to evaluate information higher than recent graduates. Recent graduates ranked the attributes of integrity, friendliness and compassion higher than final year students.ConclusionsRecent graduates and final year students rate highly the attributes which help foster the client/veterinarian relationship. Recent graduates reflect that a focus on knowledge based attributes is less important once in practice when compared to final year. The study confirms the importance to recent graduates and final year students of attributes considered as non-technical in the transition to working in the veterinary profession.

An early age-related increase in the frequency of CD4+ Foxp3+ cells in BDC2·5NOD mice

Summary The role of regulatory T cells (Treg) in maintaining tolerance to self has been intensively scrutinized, particularly since the discovery of Foxp3 as a Treg‐specific transcription factor. The BDC2·5NOD transgenic mouse is an excellent model of immunoregulation because it has a very low incidence of diabetes despite a highly autoreactive T‐cell repertoire. It has previously been shown that reactivity against islets decreases with age in BDC2·5NOD mice. Here we show that there is a markedly higher frequency of Foxp3+ Treg in the CD4+ subset of 16–20‐week‐old mice compared with 4‐ or 8‐week‐old mice. This phenomenon can be observed in the spleen, thymus, pancreatic draining lymph nodes and the pancreas itself. We show that this early age‐related increase in the frequency of Foxp3+ cells does not occur in wild‐type NOD, BALB/c or C57BL/6 mice. Further, we show that, in contrast to some reports on Treg in wild‐type NOD mice, the suppressive function of BDC2·5NOD Treg from 16‐ to 20‐week‐old mice is intact and comparable to that from 4‐ to 8‐week‐old mice both in vitro and in vivo. Our data offer insights into the long‐term protection of BDC2·5NOD mice from diabetes and an explanation for the age‐related decrease in anti‐islet responses seen in BDC2·5NOD mice.