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Biomedical subjects

P D Arkwright

Publications and source records attributed to P D Arkwright.

At least 19 recordsLinked to original sources
PubMed2006

Effect of childhood eczema and asthma on parental sleep and well-being: a prospective comparative study.

BACKGROUND: The psychological impact of childhood atopic eczema on parents and carers is poorly quantified. Objectives To compare the impact of caring for a child with atopic eczema vs. asthma on parents' sleep and well-being. METHODS: Ninety-two parents of 55 children who had moderate to severe atopic eczema or asthma took part in this prospective, questionnaire-based study. It was conducted at regional eczema and asthma outpatient clinics within a U.K. tertiary paediatric hospital. The main outcome measures were the number and duration of parents' sleep disturbances, as well as their anxiety and depression scores. RESULTS: Mothers caring for children with atopic eczema lost a median of 39 min of sleep per night and fathers lost 45 min sleep per night. This compared with a median of 0 min sleep lost by parents who had children with asthma (P < 0.001). These differences were independent of the age of the children, and whether the child came from a single-parent or two-parent family. There was a direct correlation between the severity of sleep disturbance and the level of maternal anxiety (rho = 0.58; P = 0.002) and depression (rho = 0.73; P < 0.001), as well as the level of paternal anxiety (rho = 0.59; P = 0.01). CONCLUSIONS: Compared with looking after a child with chronic asthma, caring for a child with chronic atopic eczema was associated with greater parental sleep disturbances. Disruption to parental sleep correlated with anxiety levels and, in the case of mothers, depression scores.

Anxiety↗
PubMed2006

Killed Mycobacterium vaccae suspension in children with moderate-to-severe atopic dermatitis: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: The hygiene hypothesis is often proposed to explain the high prevalence of atopy in the western world. Dysregulation of the immune system may result from inadequate exposure to micro-organisms such as mycobacteria. A small trial suggested that a killed extract of Mycobacterium vaccae ameliorates atopic dermatitis (AD). OBJECTIVES: To confirm in a large clinical trial whether killed M. vaccae ameliorates AD in 5-16-year-old children. METHODS: This was a randomized, placebo-controlled, double-blind, multi-centre study of the effect of intradermal injection of killed M. vaccae (0.1 or 1 mg) on patients, aged 5-16, with moderate-to-severe AD. Patients were followed up for 24 weeks. The primary end point was the change in severity of AD at 12 weeks, assessed using the six area, six-sign, atopic dermatitis (SASSAD) score. Secondary end points included changes in disease extent, patient's global assessment and children's dermatology life quality index. RESULTS: There were 166 patients randomized. The mean SASSAD score fell to a similar degree at week 12 in all treatment arms: from 33 to 24, (26%) in the high-dose group, from 30 to 23 (25%) in the low-dose group and from 36 to 27 (24%) in the placebo group (P>0.05). Secondary end points followed the same trend. Adverse events were generally those expected to occur in this population. Injection site reactions occurred in 32 patients at week 4. CONCLUSIONS: M. vaccae was no more effective than the placebo in ameliorating the severity of AD.

Adolescent↗
PubMed2005

Past mortality from infectious diseases and current burden of allergic diseases in England and Wales.

This study documents the changes in mortality in England and Wales over the last 100 years as a possible explanation for our increasingly allergy-prone Western society. A total of 53 million computerized recorded deaths, which occurred from 1901 to 2000 were analysed retrospectively. Childhood mortality decreased by 98%, from 40.6% of total annual deaths in 1901 to 0.9% in 2000. In 1901, 36.2% of all deaths and 51.5% of childhood deaths were from infectious diseases. By contrast in 2000, 11.6% of all deaths and only 7.4% of childhood deaths were from infectious diseases. Infectious diseases were a significant cause of childhood mortality in British cities until about 40 years ago. Several factors, including vaccination, antibiotics and improved sanitation have contributed to this trend. Survival of individuals with heightened immunity to infections may have led to natural selection of allergy-prone individuals in England and Wales. However, the relationship between changes in rates of infection and allergy is complex and not fully understood.

Adolescent↗
PubMed2005

Effect of Mycobacterium vaccae on cytokine responses in children with atopic dermatitis.

The increasing prevalence of atopic diseases over the last few decades is thought to be due to reduced exposure to environmental microbes that normally down-regulate allergic responses (hygiene hypothesis). We have shown previously that administration of the environmental microbe Mycobacterium vaccae ameliorates atopic dermatitis in school-age children at 3 months post-treatment. The present study tested the hypothesis that M. vaccae suppresses Th2-type cytokine activity and increases transforming growth factor (TGF)-beta(1) immunomodulatory activity in these children. Interleukin (IL)-4, IL-5, TGF-beta(1) and interferon (IFN)-gamma activity were assessed in resting and stimulated peripheral blood mononuclear cells (PBMC) isolated from 12 of the children who received M. vaccae in our original clinical trial. A cDNA expression array was used to examine a broader range of cytokine pathway transcripts. There were no significant changes in either Th2-type or TGF-beta(1) activity. A 5- to 10-fold increase in Th1-type activity was found at 1 month post-M. vaccae administration (P < 0.05), but it had returned to baseline by 3 months. The results do not support the hypothesis that M. vaccae reduces Th2-type or increases TGF-beta(1) activity of PBMC isolated from children with atopic dermatitis. The transient surge in IFN-gamma at 1 month is unlikely to explain any improvement in eczema score at 3 months.

Adolescent↗
PubMed2004

A new analytical system for quantification scratching behaviour in mice.

BACKGROUND: Scratching behaviour is an important component of human atopic dermatitis. The duration of scratching determines the extent of skin damage and thus the rash, but quantification of this is difficult. Establishment of a method for measuring the duration of scratching is important in order to make objective assessments of the factors that may cause the itch and also the efficacy of new antipruritic drugs. OBJECTIVES: A novel method for assessing the duration of scratching in mice was evaluated, based on the time course changes in the distance between the animal's hind limbs and the back of the neck during scratching behaviour. METHODS: Compound 48/80 was administered intradermally to the back of ICR mice and their scratching behaviour was recorded on digital videotape. The distance between the back and the hind limb was measured continuously using an image analysis system. RESULTS: Measurement of the frequency and duration when the mouse's hind limb came into contact with the back of the neck provided an accurate method of quantitating scratching behaviour. CONCLUSIONS: This system provides a new method of quantifying scratching behaviour in a mouse.

Animals↗
PubMed2003

Effect of Mycobacterium vaccae on atopic dermatitis in children of different ages.

BACKGROUND: Exposure to environmental microorganisms is associated with variations in the prevalence and severity of atopic diseases. We have previously shown that administration of a Mycobacterium vaccae suspension significantly reduced the severity of atopic dermatitis (AD) in children aged 5-18 years. OBJECTIVES: This study aimed to extend these observations to younger children. METHODS: Fifty-six children aged 2-6 years with moderate to severe AD were enrolled in a randomized, double-blind, placebo-controlled trial and given one intradermal injection of either killed M. vaccae suspension or buffer solution (placebo). Skin surface area affected and dermatitis severity score were assessed before and 1, 3 and 6 months after treatment. RESULTS: Although a 38-54% reduction in surface area affected by dermatitis was noted at all time points after M. vaccae administration (P = 0.005), this improvement was not significantly different from that observed in the placebo group. Meta-analysis of this and our previous cohort (97 children aged 2-18 years) showed that M. vaccae was associated with a significant improvement in clinical severity at all ages, whereas within the placebo group, younger but not older children showed a similar improvement. CONCLUSIONS: Despite a reduction in clinical severity associated with M. vaccae at all ages, no benefit could be found after administering M. vaccae to children with AD aged 2-6 years when compared with placebo. M. vaccae may offer greater benefit in children over 5 years old, whose AD appears less likely to regress spontaneously.

Adolescent↗
PubMed2002

Hyper IgD syndrome (HIDS) associated with in vitro evidence of defective monocyte TNFRSF1A shedding and partial response to TNF receptor blockade with etanercept.

Hereditary periodic fever syndromes comprise a group of distinct disease entities linked by the defining feature of recurrent febrile episodes. Hyper IgD with periodic fever syndrome (HIDS) is caused by mutations in the mevalonate kinase (MVK) gene. The mechanisms by which defects in the MVK gene cause febrile episodes are unclear and there is no uniformly effective treatment. Mutations of the TNFRSF1A gene may also cause periodic fever syndrome (TRAPS). Treatment with the TNFR-Fc fusion protein, etanercept, is effective in some patients with TRAPS, but its clinical usefulness in HIDS has not been reported. We describe a 3-year-old boy in whom genetic screening revealed a rare combination of two MVK mutations producing clinical HIDS as well as a TNFRSF1A P46L variant present in about 1% of the population. In vitro functional assays demonstrated reduced receptor shedding in proband's monocytes. The proband therefore appears to have a novel clinical entity combining Hyper IgD syndrome with defective TNFRSF1A homeostasis, which is partially responsive to etanercept.

Antigens, CD↗
PubMed2002

Transient lymphopenia in acutely unwell young infants.

The clinical outcome of 42 acutely unwell infants <3 months old with lymphopenia was retrospectively compared with that of 42 controls. Lymphopenic infants were significantly more likely to require active resuscitation and intensive care, independent of total leucocyte count, gender, degree of prematurity, and diagnosis.

Acute Disease↗
PubMed2001

V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations.

Severe combined immunodeficiency (SCID) comprises a heterogeneous group of primary immunodeficiencies, a proportion of which are due to mutations in either of the 2 recombination activating genes (RAG)-1 and -2, which mediate the process of V(D)J recombination leading to the assembly of antigen receptor genes. It is reported here that the clinical and immunologic phenotypes of patients bearing mutations in RAGs are more diverse than previously thought and that this variability is related, in part, to the specific type of RAG mutation. By analyzing 44 such patients from 41 families, the following conclusions were reached: (1) null mutations on both alleles lead to the T-B-SCID phenotype; (2) patients manifesting classic Omenn syndrome (OS) have missense mutations on at least one allele and maintain partial V(D)J recombination activity, which accounts for the generation of residual, oligoclonal T-lymphocytes; (3) in a third group of patients, findings were only partially compatible with OS, and these patients, who also carried at least one missense mutation, may be considered to have atypical SCID/OS; (4) patients with engraftment of maternal T cells as a complication of a transplacental transfusion represented a fourth group, and these patients, who often presented with a clinical phenotype mimicking OS, may be observed regardless of the type of RAG gene mutation. Analysis of the RAG genes by direct sequencing is an effective way to provide accurate diagnosis of RAG-deficient as opposed to RAG-independent V(D)J recombination defects, a distinction that cannot be made based on clinical and immunologic phenotype alone.

Alleles↗
PubMed2001

Cytokine promoter gene polymorphisms and idiopathic recurrent pregnancy loss.

Approximately one in 300 women experience recurrent pregnancy loss (RPL), the aetiology of which is unknown in at least 40% of cases. Previously, some studies have shown increased production of pro-inflammatory cytokines (tumour necrosis factor-alpha and interferon-gamma) and reduced production of anti-inflammatory cytokines (interleukin-10) by circulating blood lymphocytes isolated from these patients when compared with controls. The reasons for this are unclear. The production of these cytokines are partly under genetic control. This study investigated whether polymorphisms in these three cytokine genes known to be associated with either high or low production, are associated with idiopathic RPL. No association was found. It may be that genetic factors are not a major determinant of cytokine production during pregnancy, or alternatively it may be that the observed differences in cytokine production by peripheral lymphocytes do not accurately indicate what is occurring at the local maternofoetal interface during successful and abortive pregnancies.

Abortion, Habitual↗
PubMed2001

Children with atopic dermatitis who carry toxin-positive Staphylococcus aureus strains have an expansion of blood CD5- B lymphocytes without an increase in disease severity.

Toxin-positive strains of Staphylococcus aureus (T + S. aureus) are present on the skin of some but not all patients with atopic dermatitis. Many staphylococcal toxins are superantigens, which can stimulate the immune response and thus may potentially lead to the very high levels of IgE characteristic of this condition, as well as exacerbating the clinical disease. The aim of this study was to determine whether the presence of T + S. aureus on the skin of children with atopic dermatitis was associated with in vivo evidence of a heightened humoral immune response, higher IgE levels and more severe clinical disease. Toxin gene expression in S. aureus isolated from the eczematous lesions of 28 children with atopic dermatitis was assessed by PCR. Clinical and immune data were also collected from this cohort. Thirteen of the 28 children (46%) were colonized with T + S. aureus strains. The presence of T + S. aureus was associated with a significant expansion in peripheral blood CD5- B cells (P = 0.01), and the more toxin types identified the greater the B-cell expansion (P = 0.002). However, in this cohort of children with atopic dermatitis, despite th in vivo expansion of B cells in children harbouring T + S. aureus, there was no associated increase in IgE levels or in clinical disease severity scores.

Adolescent↗
PubMed2001

Intradermal administration of a killed Mycobacterium vaccae suspension (SRL 172) is associated with improvement in atopic dermatitis in children with moderate-to-severe disease.

BACKGROUND: Although a doubling in the prevalence of atopic disease, including atopic dermatitis, in the Western world over the last few generations has been paralleled by a marked reduction in infectious diseases, especially tuberculosis, it is unclear whether this increase in atopy is causally related to reduced exposure to mycobacteria. OBJECTIVES: The aim of this study was to determine whether administration of mycobacterial antigens to atopic individuals might ameliorate their disease. METHODS: Forty-one children aged 5 to 18 years with moderate-to-severe atopic dermatitis were enrolled in a randomized, double-blind, placebo-controlled trial, where they were given either one intradermal injection of killed Mycobacterium vaccae (SRL 172) or buffer solution (placebo). Changes in skin surface area affected by dermatitis and dermatitis severity score were assessed before treatment and at 1 and 3 months after treatment. RESULTS: Children treated with SRL 172 showed a mean 48% (95% CI, 32%-65%) reduction in surface area affected by dermatitis compared with a mean 4% (95% CI, -29% to 22%) reduction for the placebo group (P <.001) and a median 68% (interquartile range, 46%-85%) reduction in dermatitis severity score compared with 18% (interquartile range, -2% to 34%) for the placebo group (P <.01) at 3 months after treatment. There were no untoward effects of the treatment, apart from a local reaction in 13 of the 21 children, which occurred 1 month after SRL 172 administration and settled spontaneously. CONCLUSION: SRL 172 was associated with an improvement in the severity of the dermatitis in children with moderate-to-severe disease.

Adolescent↗
PubMed2001

Atopic dermatitis is associated with a low-producer transforming growth factor beta(1) cytokine genotype.

BACKGROUND: Atopic dermatitis (AD) is associated with hyperresponsiveness of lymphocytes to allergens. In acute AD only T(H)2-type lymphocytes are activated, whereas in more chronic forms of AD, the activity of both T(H)1- and T(H)2-type lymphocytes increases. IL-10 and transforming growth factor beta(1) (TGF-beta(1)) are immunosuppressive cytokines that inhibit the activity of both T(H) cell types in human subjects. OBJECTIVE: The aim of this study was to determine whether children with moderately severe chronic AD had IL10 or TGFB1 genotypes known to be associated with low cytokine production. METHODS: Using amplification refractory mutation screening PCR, we examined TGFB1 and IL10 gene polymorphisms, which are known to affect cytokine production, in 68 children with moderately severe AD and in 50 nonatopic children. RESULTS: The odds ratio of children with AD having a low TGFB1 producer genotype was 4.8 (95% CI, 2.4--9.7) compared with the control subjects (P <.0001). There were no differences in the frequency of IL10 gene polymorphisms between groups. CONCLUSION: TGFB1 genotype may partly explain the strong genetic predisposition to AD.

Adolescent↗
PubMed2000

Cytomegalovirus infection in infants with autoimmune lymphoproliferative syndrome (ALPS).

Fas-mediated apoptosis may be one of the effector pathways leading to the elimination of virus-infected cells. Cytomegalovirus (CMV) infection in two brothers with Fas deficiency associated with autoimmunity and benign lymphoproliferation (ALPS) provided a unique opportunity to study the clinical course of CMV infection in children with defective apoptosis. The clinical courses of two brothers with autosomal dominant ALPS who were infected with CMV in the neonatal period are described. CMV was detected from throat and urine culture from the brothers. ALPS was confirmed by in vitro anti-CD95 MoAb-induced T lymphocyte apoptosis assay and subsequent sequencing and identification of mutations in the Fas gene. A de novo mutation in the Fas gene, leading to a truncated cytoplasmic Fas product, was associated with autosomal dominant ALPS in a mother and her two sons. Both boys had evidence of CMV infection acquired early in infancy which cleared by the age of 2-3 years. There were no neurodevelopmental sequelae. The natural history of CMV infection in two infants with ALPS was similar to that described in normal children.

Adolescent↗
PubMed2000

Atopic eczema is associated with delayed maturation of the antibody response to pneumococcal vaccine.

The aim of this study was to investigate a previously undocumented observation, that children with atopic eczema under 9 years of age tended to have a poor antibody response to Pneumococcal vaccination. Thirty-five children (mean age 8.8 years, range 3-16 years) with moderate to severe atopic eczema but no history of systemic infection were studied retrospectively. Pneumococcal antibody responses after immunization with Pneumovax II were compared with a hospital control group consisting of 36 children (mean age 6.0 years, range 3-16 years) with recurrent upper respiratory tract infections. Only 17% of children with atopic eczema aged 3-8 years responded to Pneumovax. This response was significantly poorer than that of the controls (57%) (odds ratio 0.20, 95% confidence interval (CI) 0.05-0.84, P = 0.03). There were no significant differences in the levels of total IgG2, the component of IgG associated with protective antibody responses to Pneumococcus between the two groups. Delay in maturation of the total IgG and IgG2 antibody response to Pneumococcus is a feature in this group of children with moderately severe atopic eczema.

Adolescent↗