IP-10 and type 1 diabetes: a question of time and location

Chemokines are key signal molecules that attract cells of the host immune system to the site of a potential threat. Virus infections usually induce a massive chemokine and cytokine burst and therefore recruit a large plethora of leukocytes to the site of infection with the goal to restrict and abrogate viral spread. The down side of this massive excitation of the human defense system is non-specific activation of potentially self-reactive lymphocytes. Coupled with an antigen-specific event, for example molecular mimicry between host components and viral proteins, autoimmunity might be the consequence in susceptible individuals. However, activated immune components with autoaggressive potential must find their target and must remain in one site sufficiently long in order to cause chronic tissue damage. In this review we will focus on the influence of the chemokine IP-10 (CXCL10) on the trafficking of autoaggressive cells during the immunopathogenesis of type 1 diabetes (T1D) and explain why IP-10 can have a dual effect on T1D depending on time and location of expression.     

Knowledge and attitudes towards preimplantation genetic diagnosis in Germany

BACKGROUND: Preimplantation genetic diagnosis (PGD) is a technique which is often related to emotional debates because of its ethical and social implications. Worldwide there are different forms of legislation; Germany constitutes an interesting case because of the historical background concerning eugenics and dealing with handicapped persons at the time of national socialism. PGD is currently not legal but there are still polarized positions and legalization remains an issue. Studies about the attitudes of the general population towards PGD are rare. METHODS: Data were collected in a representative survey carried out in November 2003. Subjects were 2110 persons in Germany aged 18-50 years. RESULTS AND CONCLUSIONS: Respondents had little knowledge about PGD. There were incorrect assumptions about the diagnostic possibilities and a lack of basic genetic knowledge. A tendency towards a general acceptance of PGD for medical indications was found. Non-medical indications such as sex selection were generally not accepted. It could be observed that respondents who already had a notion about PGD overestimated the diagnostic possibilities and would eventually use PGD in the future more than respondents who had never heard about PGD before.     

Paracetamol inhibits replicative DNA synthesis and induces sister chromatid exchange and chromosomal aberrations by inhibition of ribonucleotide reductase

Effects of paracetamol have been studied in a hydroxyurea (HU)-resistant mouse mammary tumour cell line TA3H2, shown to overproduce the small subunit of ribonucleotide reductase. These TA3H2 cells were much more resistant than the TA3H (wild-type) cells towards the inhibitory effect of paracetamol on cell growth, IC50 0.55 mM paracetamol for the wild-type compared to 2.7 mM for the HU-resistant cells. The reduced cell growth was due to an inhibition of replicative DNA synthesis, judged from an increased percentage of cells in S-phase measured by flow cytometry. Furthermore, in the wild-type cells, the increase in the number of cells in S phase was already observed at 0.1 mM while in the HU-resistant cell line this effect was first seen at 3.0 mM paracetamol. HU inhibits ribonucleotide reductase by destroying a tyrosyl free radical located on the small subunit of the enzyme. By electron paramagnetic resonance we demonstrate that paracetamol added to crude cell extracts of HU-resistant cells also immediately destroys this radical. These results show that paracetamol reduces DNA synthesis by a specific inhibition of ribonucleotide reductase. A concentration-dependent induction of sister chromatid exchanges was found both with paracetamol (1.0-10 mM) and HU (0.3-3 mM) in wild-type cells whereas no such increase was observed in HU-resistant cells. Paracetamol (1 mM for 2 h) also increased the number of chromosomal aberrations CAs in wild-type cells (i.e. chromatid breaks and chromatid exchanges). The frequency of CAs was not increased in HU-resistant cells at paracetamol concentrations up to 10 mM.(ABSTRACT TRUNCATED AT 250 WORDS)     

CYP1B1 mutations in French patients with early-onset primary open-angle glaucoma

Introduction: Primary open-angle glaucoma (POAG) is a leading cause of visual impairment worldwide and a complex genetic disorder that affects mostly adults. Mutations in the MYOCILIN (MYOC) and OPTINEURIN genes account for rare forms with a Mendelian inheritance and for <5% of all POAG cases. The CYP1B1 gene, a member of the cytochrome P450 gene family, is a major cause of primary congenital glaucoma (PCG), a rare and severely blinding disease with recessive inheritance. However, CYP1B1 mutations have also been associated with cases of juvenile-onset glaucoma in some PCG families or shown to modify the age of onset of glaucoma linked to a MYOC mutation in a large family.

Objective: To investigate the role of CYP1B1 mutations in POAG predisposition, irrespective of the presence of a MYOC mutation.

Methods and subjects: CYP1B1 coding region variation was characterised by denaturing high performance liquid chromatography (DHPLC) and sequencing in 236 unrelated French Caucasian POAG patients and 47 population-matched controls.

Results: Eleven (4.6%) patients carried one or two mutated CYP1B1 gene(s) and no MYOC mutation. They showed juvenile or middle-age onset of disease (median age at diagnosis, 40 years, range 13–52), significantly earlier than in non-carrier patients. Apart from one, all mutations detected in POAG patients were previously associated with PCG.

Conclusion: CYP1B1 mutations might pose a significant risk for early-onset POAG and might also modify glaucoma phenotype in patients who do not carry a MYOC mutation.

     

Sex ratio of the mutation frequencies in haemophilia A: coagulation assays and RFLP analysis.

Coagulation and RFLP data from 41 families with an isolated haemophilia A patient were used to estimate the sex ratio of mutation frequencies (nu/mu). Based on the results of coagulation assays in all the female relatives investigated, nu/mu was estimated to be 12.1 by the maximum likelihood method (95% confidence interval 3.8 to 62.5). In order to avoid the possible influence of germline mosaicism, an additional analysis was performed in which only the results in the mothers and grandmothers of an isolated patient were included. The nu/mu ratio was then estimated to be 5.2 (95% confidence interval 1.8 to 15.1). Because an estimate of nu/mu based on all available RFLP data can easily be biased in favour of males, we set up a model in which only information on the grandparental derivation of the patient's X chromosome was used, irrespective of the generation in which the mutation actually occurred. In this way nu/mu was estimated to be minimally 4. The probability of carriership for mothers of an isolated haemophilia A patient amounts to 86% with a sex ratio of 5.2. Although this would imply that 14% of the mothers are not carriers of the disease in the classical sense, they may be mosaic for the mutation and, therefore, also at risk of transmitting the mutation more than once.     

Bicycle helmet ventilation and comfort angle dependence

Five modern bicycle helmets were studied to elucidate some of the variations in ventilation performance, using both a heated manikin headform and human subjects (n=7). Wind speed and head angle were varied to test their influence on the measured steady-state heat exchange (cooling power) in the skull section of the headform. The cooling power transmitted by the helmets varied from about 60% to over 90% of that of the nude headform, illustrating the range of present manufacturer designs. Angling the head forward by 30° was found to provide better cooling power to the skull (up to 25%) for three of the helmets and almost equal cooling power in the remaining two cases. Comparisons of skull ventilation at these angles with human subjects strongly supported the headform results.     

A staphylococcal radioimmunoassay for detection of antibodies toMycoplasma pneumoniae

A radioimmunoassay (RIA) which depends on the property of protein A ofStaphylococcus aureus to combine with the Fc-fragment of immunoglobulins was developed.This technique was employed to measure antibodies in human and various animal sera. It could be demonstrated that the staphylococcal RIA was at least as sensitive as the previously described radioimmunoprecipitation technique in detecting antibodies toM.pneumoniae in human sera. In addition, antibodies toM.pneumoniae could be demonstrated in sera of hamsters intranasally inoculated with the organisms. Antibodies could also be demonstrated in rabbit sera after immunization withM.pneumoniae. The test proved to be considerably more sensitive than conventional tests for detection of antibodies to the organisms. The test requires only small amounts of reagents and is relatively inexpensive.The results were presented in a preliminary form at the annual meeting of the Local Branch of the American Society for Microbiology, Frankfurt, March 1976 and the 77th ordinary meeting of the Society for General Microbiology, Glasgow, September 1976     

Agouti-related peptide-expressing neurons are mandatory for feeding

Multiple hormones controlling energy homeostasis regulate the expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus. Nevertheless, inactivation of the genes encoding NPY and/or AgRP has no impact on food intake in mice. Here we demonstrate that induced selective ablation of AgRP-expressing neurons in adult mice results in acute reduction of feeding, demonstrating direct evidence for a critical role of these neurons in the regulation of energy homeostasis.