Inflammatory cytokines,socioeconomic status,and acute stress responsivity

Socioeconomic status is a major determinant of coronary heart disease (CHD). Proinflammatory cytokines are implicated in the etiology of CHD, and are also sensitive to emotional stress. We hypothesised that concentration of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 receptor antagonist (IL-1Ra) would be inversely related to socioeconomic status, and that cytokine responses to stress would be associated with SES. One hundred and twenty-five middle-aged men and 105 women from the Whitehall II epidemiological cohort were tested, and socioeconomic status was indexed by grade of employment, with participants divided into high, intermediate, and low status groups. Plasma concentrations at rest of TNF-alpha, IL-1Ra, and IL-6 (women only) were associated with socioeconomic status, with lower levels in the high status group, but the effect was non-linear. There was no relationship between socioeconomic status and cytokine responses to stress, but sex differences were observed, with men showing greater TNF-alpha, and women greater IL-6 and IL-1Ra increases. The role of inflammatory cytokines in mediating psychosocial influences on CHD is discussed.     

Intravenous dexamethasone‐cyclophosphamide pulse therapy in comparison with oral methylprednisolone‐azathioprine therapy in patients with pemphigus: Results of a multicenter prospectively randomized study

Background: Pemphigus is a potentially life‐threatening autoimmune blistering skin disease usually treated with high‐dose corticosteroids in combination with immunosuppressive drugs. In a multicenter, prospectively randomized study we compared efficacy and side effects of a dexamethasone‐cyclophosphamide (D/C) pulse therapy with a methylprednisolone‐azathioprine (M/A) therapy in 22 patients with newly diagnosed pemphigus vulgaris and pemphigus foliaceus. Patients and methods: The 11 patients of the M/A group were treated with daily doses of methylprednisolone (initially 2 mg/kg body weight) and azathioprine (2 – 2,5 mg/kg body weight) which were subsequently tapered. D/C pulse therapy in 11 patients consisted of intravenous administration of 100 mg dexamethasone/d on 3 consecutive days along with cyclophosphamide (500 mg) on day one. Pulses were initially repeated every 2 – 4 weeks and then at increasing intervals. In between the pulses, oral cyclophosphamide (50 mg) was given daily for 6 months. Results: Within 24 months after treatment initiation, 5/11 patients of the D/C group had a remission (complete remissions after discontinuation of therapy in 3 patients) and 6/11 patients had a progression. In the M/A group, there were remissions in 9/11 patients (complete remissions after discontinuation of therapy in 3 patients) and progression in 1/11 patients. There were more relapses in M/A therapy after remission than in D/C therapy. Side effects were more common in the M/A group. These differences were not significant (p > 0,05). Conclusion: Because of the high number of progressions in patients treated with D/C therapy, we can not confirm the encouraging results of earlier reports about pulse D/C therapy. Nevertheless D/C therapy seemed to be better tolerated and, in case of primary efficacy, was associated with fewer recurrences than M/A therapy.     

A humanized tumor necrosis factor receptor 1 (TNFR1)-specific antagonistic antibody for selective inhibition of tumor necrosis factor (TNF) action

Tumor necrosis factor (TNF) is a recognized pathogenic mediator in a number of chronic and acute inflammatory diseases. Antibodies targeting TNF have significantly improved therapy of chronic inflammatory diseases, in particular rheumatoid arthritis. Despite this success, anti-TNF treatment shows clinical efficacy only in part of the patients and is often transient, necessitating the development of alternative reagents to combat TNF action. We here describe humanization and functional properties of a TNFR1-specific, monovalent antibody fragment, designated IZI-06.1, which binds to the cysteine-rich domain 1 of TNFR1 with high affinity and competes ligand binding. IZI-06.1 serves as a receptor-selective inhibitor of proapoptotic and antiapoptotic TNF actions, revealed from complete blockage of TNFR1-dependent apoptosis and interleukin-6 induction in Kym 1 and HeLa cells, respectively, whereas TNFR2-mediated signals remained intact, evident from TNF and interleukin-2-mediated costimulation of interferon-gamma production in T cells. Accordingly, IZI-06.1 is a TNFR1-selective TNF antagonist and holds great promise to be developed into a clinically applicable therapeutic. IZI-06.1 could be a useful therapeutic alternative in all diseases already known to clinically respond to anti-TNF treatment and particularly in those diseases, where anti-TNF treatment has failed because of complete blockade of TNF action.     

Lead poisoning following ingestion of pieces of lead roofing plates: pica-like behavior in an adult

A 37-year-old man was admitted to hospital after complaining of abdominal pain for the past two weeks. On admission the abdominal radiograph showed multiple radio-opaque flecks dispersed throughout the gastrointestinal tract. Blood testing showed hemoglobin level 8.7 g/dL and a blood lead level of 112.4 microg/dL. The family interview revealed that the patient had pica-like behavior since childhood. He was a site foreman and had been ingesting pieces of roofing plates for a few weeks. The patient was treated with laxatives and CaNa(2)EDTA therapy was initiated. The blood lead level then dropped to 69.9 microg/dL. The patient received two subsequent courses of oral succimer and the blood lead level decreased to 59 microg/dL 21 days after the first course. The follow-up abdominal X-ray 20 days after the first examination was normal. Four months later, an outpatient follow-up visit showed a blood lead level within normal limits (14.5 microg/dL) and a psychiatric follow-up was initiated. Lead poisoning following the ingestion of lead-containing foreign bodies is particularly rare in adults, while it is sometimes observed in children. Pica behavior is a well-identified risk factor of lead intoxication in children but is quite exceptional in adults, where it is usually considered to be a psychiatric condition. Other unusual sources of lead poisoning include the ingestion of lead bullets, ceramic lead glaze or glazed earthenware, lead-contaminated candies, ethnic or herbal remedies.     

Retrieval of DNA from the faces of children aged 0-5 years: a technical note

Approximately 21% of children suffer from some form of physical abuse. It is hypothesized that when an individual hits a child some of that person's DNA will be deposited onto the child's skin. As yet, no one has reported a method of sampling DNA from the skin of this vulnerable group of individuals. We have sampled DNA from several facial areas of 30 children aged 5 years of age and under. The results show that it is possible to swab the faces of this age group without distressing them or contaminating the samples. Additionally the results indicate that the DNA obtained is almost entirely that of the subject, with little nondonor DNA being observed.     

What do tachycardiomyopathy belong to?: reply

We thank Dr Pieroni and colleagues for their response to theposition statement from the     

Foetal growth determines cerebral ventricular volume in infants The Generation R Study

The cerebral ventricular system is a marker of brain development and a predictor of neurodevelopmental outcome. In premature or dysmature neonates, neuroanatomical structures including the ventricular system appear to be altered. The present study aims to provide information on the association between foetal growth and neonatal cerebral ventricular size in the normal population. Within the Generation R Study, a population-based cohort study, we used three-dimensional cranial ultrasound to determine lateral ventricular volume in 778 term infants aged 4-12 weeks. Foetal growth characteristics were repeatedly measured in early, mid- and late pregnancy and analysed in relation to ventricular volume divided by head circumference. Results revealed positive associations between foetal head circumference in late pregnancy and log-transformed ventricular volume (beta=0.077, 95% confidence interval (0.017; 0.136), equivalent to a 7.7% increase in ventricular volume per standard deviation of head circumference). Similarly, in a per week-longer gestational duration, ventricular volume in infancy was 6.0% larger. Multilevel modelling demonstrated that reduced growth of foetal head circumference and biparietal diameter during pregnancy were associated with decreased ventricular volume in infancy. In conclusion, foetal maturation is positively associated to cerebral ventricular size in term infants. Larger ventricular size in term infants needs to be distinguished from ventricular enlargement due to intraventricular haemorrhage or white matter damage in premature or dysmature infants. Moreover, the naturally occurring enlargement of ventricles during infancy should be considered in interpreting reports on increased ventricular volumes in several neuropsychiatric disorders.     

Impaired transcallosally mediated motor inhibition in adults with attention-deficit/hyperactivity disorder is modulated by methylphenidate

Using transcranial magnetic stimulation (TMS) in children with ADHD, an impaired transcallosally mediated motor inhibition (ipsilateral silent period, iSP) was found, and its restoration was correlated with improvement of hyperactivity under medication with methylphenidate (MPH). Hyperactivity has been reported to decrease during transition into adulthood, although some motor dysfunction might persist. As one underlying neurophysiological process, a development-dependent normalization of motor cortical excitability might be postulated. In order to test this hypothesis, we measured the iSP in 21 adult ADHD patients and twenty-one sex- and age-matched healthy controls. In 16 of these patients, a second TMS was performed under treatment with MPH. Our results indicate a persistence of impaired transcallosally mediated motor cortical inhibition (shortened duration) in ADHD adults, which was correlated with clinical characteristics of hyperactivity and restlessness, and was restored by MPH. In contrast to ADHD in childhood, the iSP latency was not impaired, suggesting a partial development-dependent normalization of motor cortical excitability in ADHD adults. ISP duration appears to be a sensitive parameter for the assessment of disturbed intercortical inhibition in adults with ADHD.     

Intracortical motor inhibition and facilitation in adults with attention deficit/hyperactivity disorder

Using transcranial magnetic stimulation (TMS), disturbed facilitatory and inhibitory motor functions were recently found to correlate with motor hyperactivity in children with ADHD. Since hyperactivity seems to become reduced in ADHD during the transition to adulthood, a normalization of motor cortical excitability might be assumed. Therefore, we investigated the same inhibitory and facilitatory TMS paradigms in ADHD adults as we had previously examined in children. Motor cortical excitability was tested with TMS paired-pulse protocols in 21 ADHD adults and 21 age- and gender-matched healthy controls. In contrast to our results in ADHD children, no group-specific differences in amplitude changes of motor evoked potentials for inhibitory inter-stimulus intervals (ISI) (3, 100, 200 and 300 ms) or for facilitatory ISIs (13, 50 ms) could be detected. In ADHD adults, disturbed facilitatory and inhibitory motor circuits as found in ADHD children could not be shown, probably due to a development-dependent normalization of motor cortical excitability.