Prevalence and outcome of lymphopenia in the Paediatric Intensive Care Unit: A prospective observational study.

AIM: Leukopenia (lymphopenia or neutropenia) may be an important marker of altered immunity and risk in children with critical illness. We aimed to evaluate the prevalence, course, and outcome of leukopenia in children admitted to Paediatric Intensive Care Unit (PICU). METHODS: All consecutive children (n = 200) admitted to PICU for any reason except malignancy or pre-existing immune deficiency were enrolled during June-August 2018. RESULTS: Median (interquartile range) age was 2.2 (0.6-8.5) years. About 52% (n = 103) had undergone a surgical procedure; 34% (n = 68) being cardiac surgery. Among medical illnesses, respiratory disorders were the most common (n = 39, 20%). Laboratory confirmed infections were present in 63 (31.5%) children. Leukopenia was identified in 135 (67.5%) children in the first week; 117 (58.5%) had only lymphopenia, 16 (8%) had both lymphopenia and neutropenia, and 2 (1%) had only neutropenia. In 69 children who had follow-up blood counts, lymphopenia resolved in 33 (48%) within 48 h and in another 20 (29%) by 4 days, and in a further 10 (14%) by 7 days. Children with lymphopenia had higher frequency of cardiac surgery, longer cardiopulmonary bypass time, greater need for invasive ventilation and vasopressor/inotrope therapy, and a higher probability of organ failure on day 4 and longer hospital stay. CONCLUSION: In critically ill children, lymphopenia is very common, often transient, but may be associated with unfavourable outcomes. Further studies with follow-up of blood counts in a larger sample are required to determine the course and outcomes of lymphopenia.

Establishing and prioritizing research questions for the prevention, diagnosis and treatment of hair loss (excluding alopecia areata): the Hair Loss Priority Setting Partnership.

BACKGROUND: Hair and scalp problems are common. Unfortunately, many uncertainties exist around the most effective management and treatment strategies for these disorders. OBJECTIVES: To identify uncertainties in hair-loss management, prevention, diagnosis and treatment that are important to both people with hair loss and healthcare professionals. METHODS: A Hair Loss Priority Setting Partnership was established between patients, their carers and relatives, and healthcare professionals to identify the most important uncertainties in hair loss. The methodology of the James Lind Alliance was followed to ensure a balanced, inclusive and transparent process. RESULTS: In total, 2747 treatment uncertainties were submitted by 912 participants; following exclusions 884 uncertainties relating to hair loss (excluding alopecia areata) were analysed. Questions were combined into 'indicative uncertainties' following a structured format. A series of ranking exercises further reduced this list to a top 25 that was taken to a final prioritization workshop where the top 10 priorities were agreed. CONCLUSIONS: We present the top 10 research priorities for hair loss (excluding alopecia areata) to guide researchers and funding bodies to support studies important to both patients and clinicians.

Establishing and prioritizing research questions for the treatment of alopecia areata: the Alopecia Areata Priority Setting Partnership.

BACKGROUND: Alopecia areata (AA) is a common hair loss disorder that results in patchy to complete hair loss. Many uncertainties exist around the most effective treatments for this condition. OBJECTIVES: To identify uncertainties in AA management and treatment that are important to both service users (people with hair loss, carers and relatives) and healthcare professionals. METHODS: An AA priority setting partnership was established between patients, their carers and relatives, and healthcare professionals to identify the most important uncertainties in AA. The methodology of the James Lind Alliance was followed to ensure a balanced, inclusive and transparent process. RESULTS: In total, 2747 treatment uncertainties were submitted by 912 participants, of which 1012 uncertainties relating to AA (and variants) were analysed. Questions were combined into 'indicative uncertainties' following a structured format. A series of ranking exercises further reduced this list to a top 25 that were taken to a final prioritization workshop where the top 10 priorities were agreed. CONCLUSIONS: We present the top 10 research priorities for AA to guide researchers and funding bodies to support studies important to both patients and clinicians.

Dysregulation of follicle development in a mouse model of premature ovarian insufficiency.

Premature ovarian insufficiency (POI) occurs in 1% of reproductive-age women. The ovarian manifestation ranges from the presence of a variable population of follicles (follicular) to the absence of follicles (afollicular), and in the majority of cases the cause is unknown. A transgenic mouse model of follicular POI, the Double Mutant (DM), arises from oocyte-specific deletion of Mgat1 and C1galt1 required for the generation of O- and N-glycans. DM females are subfertile at 6 weeks, infertile by 9 weeks and exhibit POI by 12 weeks of age. In this study we investigate the cause of the reduced fertility at 6 weeks and infertility at 9 weeks of DM females. Ovary sections were used to analyse follicle and corpora lutea (CL) numbers, apoptosis, and levels of laminin and 3ß-hydroxysteroid dehydrogenase using immunohistochemistry. After POI, DM females unexpectedly remained sexually receptive. At both 6 and 9 weeks, DM ovaries contained more primary follicles, however, at 9 weeks DM follicles were proportionally healthier, revealed by TUNEL analysis compared with Controls. In 9 week DM ovaries (collected post-mating), secondary follicles had theca and basal lamina structure abnormalities, whilst preovulatory follicles failed to ovulate resulting in the presence of numerous luteinised unruptured follicles, indicative of ovulation failure. Finally, DM ovaries contained more regressing CL with decreased luteal cell apoptosis indicative of a defect in CL regression. Identifying these follicular modifications have provided insight into the aetiology of a model of POI and highlight targets to investigate with the hope of developing new fertility treatments.

Corticosterone Contributes to Diet-Induced Reprogramming of Post-Metamorphic Behavior in Spadefoot Toads.

Stressful experiences in early life can have phenotypic effects that persist into, or manifest during, adulthood. In vertebrates, such carryover effects can be driven by stress-induced secretion of glucocorticoid hormones, such as corticosterone, which can lead to developmental reprogramming of hypothalamic-pituitary-adrenal/interrenal axis activity and behavior. Nutritional stress in the form of early life nutrient restriction is well known to modify later life behaviors and stress activity through corticosterone-related mechanisms. However, it is not known whether corticosterone is also mechanistically involved in carryover effects induced by a different form of nutritional variation: the use of alternate or entirely novel types of dietary resources. The plains spadefoot (Spea bombifrons) presents an excellent system for testing this question, since larvae of this species have evolved to use 2 alternate diet types: an ancestral detritus-based diet and a more novel diet of live shrimp. While previous work has shown that feeding on the novel shrimp diet influences juvenile (i.e., post-metamorphic) behavior and corticosterone levels, it is unclear whether these diet-induced carryover effects are mediated by diet-induced corticosterone itself. To test for the mechanistic role of corticosterone in diet-induced carryover effects, we experimentally treated S. bombifrons larvae with exogenous corticosterone and measured subsequent effects on juvenile behavior and corticosterone levels. We found that while shrimp-fed larvae had elevated corticosterone levels, treatment of larvae with corticosterone itself had effects on juvenile behavior that partially resembled those carryover effects induced by the shrimp diet, such as altered food seeking and higher locomotor activity. However, unlike carryover effects caused by the shrimp diet, larval corticosterone exposure did not affect juvenile corticosterone levels. Overall, our study shows that corticosterone-related mechanisms are likely involved in carryover effects induced by a novel diet, yet such diet-induced carryover effects are not driven by corticosterone alone.

Owners' views of canine nutrition, weight status and wellbeing and their implications for the veterinary consultation.

OBJECTIVES: To investigate owners' views around canine nutrition and wellbeing, how these beliefs may differ according to the weight status of the dog and the implications for owner support approaches. MATERIALS AND METHODS: A researcher-mediated questionnaire collected quantitative and qualitative data via structured interviews with dog owners (n=147) attending a country park in the East Midlands, UK, with a specific focus on views around canine nutrition and wellbeing. RESULTS: Forty-four percent of owners cited "past experience" when determining what to feed, and only 9% of owners cited the veterinarian as a source of this information. When comparing chosen verbal description versus non-sequential body condition score images of the dog, only 22% of owners with overweight animals matched perceived verbal and visual appraisals, compared with 89% of owners of ideal weight dogs. Owners cited a good diet and regular exercise as important factors for canine wellbeing, but companionship with other dogs as the least important factor. CLINICAL SIGNIFICANCE: Owners report being aware of the important association between canine nutrition and wellbeing, but their considered importance of factors influencing dog wellbeing may be influenced by their perceived weight status of the animal. Veterinarians may need to reframe owner discourse such that there is more routine discussion around weight and nutrition at every consultation. Furthermore, the use of non-sequential body condition score images could be a useful tool for a more considered opinion of canine weight status by owners.

Risk factors associated with hair loss, ulceration, and swelling at the hock in freestall-housed UK dairy herds.

The objective of this study was to identify the risk factors associated with 3 presentations of hock lesions (hair loss, ulceration, and swelling) in freestall-housed lactating cattle. By independent identification and scoring of, and analysis of the factors associated with, hair loss, ulceration, and swelling, the aim was to identify whether risk factors were common to all 3, or differed among the presentations. A cross-sectional study was conducted on 76 herds in the UK during the winter housing period of 2007 to 2008, with a total of 3,691 cows examined for hock lesions. A randomly selected sample of approximately 50 cows in each herd were scored for body condition, lameness, cleanliness, rising behavior, and lesions at the hocks. For all cows, hair loss, ulceration, and swelling were scored separately on 4-point scales, with both left and right hocks scored. Based on a review of the literature, potential risk factors were identified and measured, collected from milk-recording data, or obtained through interviews with the farmers. Risk factors associated with hocks lesions in cattle were examined using data from the 2,982 cows housed in the 63 freestall-housed herds visited. Risk factors for each of the 3 lesion presentations were considered separately in multilevel logistic regression models, with moderate or severe hair loss, any degree of ulceration, and moderate or severe swelling as the outcome variables. Thirty risk factors were identified, none of which were common to all 3 lesion presentations. Five risk factors (locomotion score, number of days of winter housing, mean milk yield, freestall base material, and herd size) were common to both hair loss and ulceration. The stall bedding material was a common risk factor for both hair loss and swelling. A further 8, 5, and 11 risk factors were unique to hair loss, ulceration, and swelling, respectively. The existence of several differential risk factors between the 2 lesion presentations suggests that ulceration may not always be a direct extension of hair loss, as has been implied in previous scoring systems. Of the 12 risk factors associated with swelling, only 1 was common to another lesion presentation, which suggests that swelling may have a different etiology than hair loss and ulceration. The variables associated with the lesions indicate the importance of factors that affect the lying and rising behavior of the animal, including freestall structure and design, and the lying surface.

The effect of antigenic competition on various manifestations of humoral antibody formation and cellular immunity.

The effect of antigenic competition on various parameters of humoral antibody formation and cellular immunity was studied in mice. Several pairs of antigens were employed in the investigation of the competitive aspects of induction of humoral antibody formation. Induction of a primary immune response to hemocyanin in Swiss white female mice moderately suppressed the induction of both 19S and 7S antibody formation to goose or rat erythrocytes. Suppression of 7S antibody formation was maximal when a time interval of 1-3 days separated the sequence of injections, although suppression was noted for intervals of up to 14 days. The induction of a primary immune response to rat RBC, the second of the two antigens in sequence, also suppressed The induction of both 19S and 7S antibody formation to goose RBC when appropriate intervals of 1-3 days were employed between injections. The induction of a secondary immune response to rat RBC totally suppressed the primary induction of both 19S and 7S antibody formation to goose RBC administered in the appropriate time sequence. Subsequently, it was shown that the secondary immune response to the suppressed antigen (goose RBC) elicited 30 days after induction of a primary immune response (5 days after secondary immunization with rat RBC) was characterized by deficient 19S and 7S antibody production. These levels were suppressed even in comparison with a normal primary immune response to this antigen. The results were interpreted in part on the basis of a deficiency of formation of primed cells associated with immunological memory. Alternatively, evidence was obtained for the development of a split type of immunological tolerance in 6 of 10 animals studied, since a total suppression of 7S antibody production was obtained in association with deficient 19S antibody synthesis (titers < 1/10). The induction of a primary immune response to several antigens in A/J female mice suppressed the processes of cellular immunity as manifested by prolonged survival of skin grafts from C57 BL/6J female donors. These results were interpreted as evidence for the existence and utilization of processing cells by the initial immune stimulus yielding a deficiency of cells available for processing the second antigen administered in sequence.

Balancing the needs and preferences of humans against concerns for fishes: how to handle the emerging ethical discussions regarding capture fisheries?

How can stakeholders within the fisheries community engage in constructive ethical discussions? Drawing on experiences from previous debates surrounding the human use of animals, this paper presents a proactive approach whereby stakeholders can create a framework for ethical discussion of capture fisheries.

The ethics and role of AI with fresh and frozen semen in dogs.

The use of artificial insemination (AI) with fresh semen has resulted in many benefits for the management of dog breeding, but there are disadvantages that can sometimes be overlooked. Furthermore, poorer quality semen arising as a result of cryopreservation necessitates uterine insemination, which raises the potential for surgical insemination. A number of significant ethical concerns have been raised by key stakeholders (such as The Kennel Club and the Royal College of Veterinary Surgeons) about AI per se, but particularly about the use of surgical insemination. This paper discusses the technological development of AI and explores a number of the ethical issues raised by its application to dog breeding. An Ethical Matrix method is used to map the potential ethical issues for key interest groups, namely dogs, breeders, owners, veterinarians and wider society. There are national variations in the way in which institutions have evaluated potential ethical impacts, and this is reflected in the different regulatory frameworks governing the use of AI in dogs. In order to facilitate decision-making and reduce some of the ethical risks associated with this technology, the veterinary research community could take several proactive steps including: (i) clarifying clinical decision-making processes, (ii) enhancing informed choice among clients and (iii) increasing the knowledge-base of potential impacts of AI.

"Who's been a good dog?" - Owner perceptions and motivations for treat giving.

Complex relationships commonly exist between owners and their companion animals, particularly around feeding behaviour with an owner's affection or love for their animal most pronounced through the provision of food. It is notable that the pet food market is experiencing strong year-on-year growth in sales of dog and cat treats. Recognising the impact of treat giving in pet nutrition, the objective of the study was to investigate owner attitudes and motivations towards feeding treats (shop bought and other) to their dogs. A researcher-mediated questionnaire consisting of both quantitative and qualitative questions was used to interview dog owners (n=280) at two locations: an out-of-town retail park and a country park in the East Midlands. Owners almost unanimously viewed the word 'treat' within a nutritional context, as opposed to a new toy or other pleasure. The majority (96%) of owners interviewed reported feeding treats to their dog, with 69% feeding shop-bought treats on a daily basis. A wide range of treats was reportedly given by owners and the majority of owners interviewed fed multiple treat types. No association was found between owner age and frequency of shop-bought treats fed (P=0.659) nor between owner age and frequency of food given to the dog from the owner's plate (P=0.083). A wide range of foods which would not be considered balanced for the animal's nutritional requirements was viewed as a treat by some dog owners. A range of positive and negative views around the feeding of treats were expressed by dog owners, with some citing beneficial effects while others were clearly aware of the association between treat feeding and potential weight gain/obesity. Owner views included themes around positive reinforcement and responsibility but also reflected relational aspects of the human-animal bond. The results of the study show that treat giving is commonplace in feeding regimes and that treats are embedded in the feeding behaviour of many dog owners. However, the different views expressed around the motivations for, and feeding of, dog treats, reinforce the need to better understand owner psychology linked to this area, and the role this may play in the growing pet obesity epidemic.

Diagnosis of old inferior myocardial infarction by body surface isopotential mapping.

Body surface isopotential maps obtained from 28 patients with old inferior wall myocardial infarction were compared with maps from 120 normal subjects. The 12 lead electrocardiogram of 8 of the 28 patients (29 percent) with inferior wall infarction was normal or showed only nondiagnostic ST-T wave abnormalities at the time the isopotential maps were obtained. In all patients with inferior wall infarction the isopotential map showed a minimum (area of negative potentials) on the inferior or right thoracic surface during the early portions of the QRS complex. This finding was observed in patients with normal or nonspecific abnormalities in the 12 lead electrocardiogram as well as those with QRS abnormalities. By contrast, the minimum during the early QRS complex in normal subjects was located on the right upper back and shoulder region...

Effects of pregnancy on the maternal lymphoid system in mice.

The effects of pregnancy on the lymphocyte populations in the mouse have been studied. Though cell numbers decreased in the thymus and increased in the lymph nodes draining the parauterine area, no significant changes were seen in the proportions of thymus derived (theta allo-antigen positive) and bone marrow derived (Fc receptor positive) lymphocytes. The humoral response to sheep erythrocytes was suppressed during both syngeneic and allogeneic pregnancies following a decline coincidental with that of thymic mitotic activity. Though the observed immunosuppression could be explained by a selective lymphocyte depletion, it appears more likely to be a nonspecific effect of the steroid milieu of pregnancy.

Negative affective consequences of thinking about disease detection behaviors.

It was proposed that thinking about disease-detection behavior would lead to more negative moods than thinking about health-promotion behavior. Detection behaviors produce more negative moods because they can threaten perceptions of good health. In a laboratory study, the initial mood states of 121 participants recruited from undergraduates and the general community were measured using a neutral-words rating procedure. Then participants were randomly assigned to think about performing a disease-detection behavior or a health-promotion behavior. Subsequently, they wrote down their responses to the behavior and evaluated these as either positive, negative, or neutral. Finally, the participant's mood was remeasured using both a neutral words-rating procedure and a more traditional bipolar rating measure. Results indicated that thought about disease-detection behavior produced more negative affective responses and more negative mood change than did thought about health-promotion behavior.

The effects of expectancy and alcohol on cognitive-motor performance.

Previous studies have found equivocal evidence for expectancy effects on cognitive-motor performance. The effects of expectancy and alcohol on a dual tracking and reaction-time task analogous to some driving skills, and on choice reaction-time, were studied in a balanced-placebo design (n = 90). A dose of alcohol achieving 80 mg/100 ml (high dose) had large effects on both tasks, but a low dose (40 mg/100 ml) had no significant effects. Expecting alcohol led to subjects who received the high dose performing significantly better on the primary tracking task than subjects expecting placebo (but also receiving the high alcohol dose). By contrast, on a secondary reaction-time task, subjects who had received placebo performed worse 100-130 minutes after drinking, if they had expected alcohol. All groups felt more drunk than baseline and expecting alcohol made subjects feel more able to perform, whatever drink they had received. The implications of these findings for the nature of expectancy effects on performance and the relationship between expectations and strategy are discussed.

An in vivo model for screening peptidomimetic inhibitors of gelatinase A.

Gelatinase A, a matrix metalloproteinase, is frequently associated with human solid tumors, and its secretion and activation in the tumor milieu is considered important in the process of angiogenesis, invasion, and metastasis. Consequently, metalloproteinase inhibitors may be of value in the therapy of cancer as well as other disease states involving tissue remodeling and release of biologically active peptide/protein by proteolytic cleavage. Here we describe the development of a rapid screening assay for in vivo activity of peptidomimetic inhibitors of gelatinase A that involves assessment of inhibition of an enzyme-substrate reaction in a circumscribed body compartment, the mouse pleural cavity. As examples of the utility of this assay, in vivo activity of the aryl sulfonamide, sulfamyl urea, morpholino and carboxylic acid functionality at the P3' position of a series of hydroxamic acid inhibitors was examined after administration both intraperitoneally (ip) (to approximate systemic administration) and orally. For up to 2 h after ip administration, all inhibitors tested showed marked activity (> 90% inhibition) at 17 mumol/kg (approximately 10 mg/kg). This activity declined in a dose-responsive manner to insignificant levels at 0.67 mumol/kg (approximately 0.4 mg/kg). Aryl sulfonamides showed significant inhibition (> 50%) for up to 7 h after administration. A higher dosage (136 mumol/kg, approximately 80 mg/kg) was required to reveal oral activity, which was observed only with morpholino compounds (> 50% inhibition). Thus, the model described may be of value in the identification of orally active gelatinase A inhibitors.

Influence of ivermectin on cellular and humoral immune responses of lambs.

In view of the extensive use of anthelmintics in sheep and the fact that their activity may in part depend upon the immune system, we were interested to determine if ivermectin had any influence on aspects of the sheep immune response. Ten parasite-free 6-month-old lambs were drenched with ivermectin and 1 day later were given intravenously human erythrocytes and subcutaneously ovalbumin. Ten other lambs with injected antigens were not drenched and served as controls. Both groups were bled at intervals for cells and serum. The procedure was repeated on day 28. Lymphocytes from the drenched lambs, cultured in vitro in RPMI plus 50% autologous serum collected up to 7 and 14 days after the first and second antigen injections respectively, had decreased blastogenic activity compared with lymphocytes from control lambs. Similar results were obtained with lymphocytes cultured in RPMI 1640 supplemented with 50% autologous serum plus concanavalin A (Con A) or phytohaemagglutinin (PHA). When washed, lymphocytes were cultured in RPMI 1640 supplemented with 5% foetal calf serum (FCS) or 5% FCS plus Con A or PHA, decreased blastogenesis was observed but blastogenesis depression was not as marked as that observed with autologous serum. Similar antibody responses were seen for the drenched and control groups in response to the two injections of both antigens except that after the second injection, there was a significant reduction in antibody response to ovalbumin in the ivermectin-treated lambs. There were no differences in serum complement or serum nitric oxide levels between the two groups at any stage, but insulin-like growth factor-1 levels were significantly reduced in serum of the ivermectin-treated group, 4 days after each drench. Growth hormone levels were consistently significantly higher 22 days after both drenchings. There was no difference in mean body weight increase between the groups during the experiment.

Verbal expectancies and performance after alcohol.

New verbal expectancies about the effects of alcohol were experimentally induced in subjects by suggesting in writing and verbally that food had positive, negative, or neutral effects on performance after alcohol. Subjects (n = 120, male) received this suggestion, food (fed or fasted), and alcohol (alcohol or placebo) in a between-subjects design. Alcohol impaired reaction time and tracking (with a secondary reaction-time task). Food reduced this impairment. The verbal expectancy manipulation had no effect on performance, although it had a marginally significant effect on rated ability to perform. It is concluded that verbal expectancy effects about alcohol influence verbal or social behaviours more easily than cognitive processes.

The role of the physiotherapist in the management of repetitive strain injury.

A review of current literature concerning the aetiology, diagnosis, role and involvement of physiotherapists in the treatment of repetitive strain injury (R.S.I.) is presented as a basis for investigation. To determine the modes of treatment used by physiotherapists in the management of R.S.I. and to analyse their efficacy, a questionnaire was designed. Forty centres were surveyed and the results are presented. Information concerning the most commonly encountered conditions, treatment given, and physiotherapists' opinions on prevention, patient education and further training in RSI management was also sought. An attempt is made to define the role of the physiotherapist in the recognition, treatment and education aspects of over-use injury, and recommendations for further research and physiotherapy involvement are presented.