Donor interleukin-4 promoter gene polymorphism influences allograft rejection after heart transplantation.

BACKGROUND: The cytokine interleukin-4 (IL-4) is secreted mainly by activated T lymphocytes and characterizes the T-helper 2 (Th2) sub-type. In transplantation Th2 cells are believed to induce graft tolerance. Previous studies revealed that patients with a relatively high frequency of IL-4 producing helper T lymphocytes (HTL) before heart transplantation (HTX) had no or less rejection episodes compared with patients with a low frequency of IL-4 producing HTL. Three single nucleotide polymorphisms (SNPs) have been identified in the promoter region of the IL-4 gene, which influence promoter strength. We investigated whether there was a correlation between SNP genotypes in the IL-4 promoter and heart failure, and rejection after HTX. METHODS: Seventy HTX patients, 61 donors, and 36 controls were genotyped for the 3 SNPs by sequencing. RESULTS: Of the SNPs at -285 and -81, only the C and A alleles, respectively, were found in this study. Both alleles were found for the -590 SNP. No relation between patient genotype of the SNP at -590 and heart failure and rejection was found. However, incidence of rejection was significantly lower in patients that received a donor heart with the T-positive genotype compared with patients that received a heart from a T-negative donor. Patients who had the T-negative genotype and received a heart from a T-positive donor, suffered significantly less from rejection than T-negative patients that received a T-negative donor heart. This was not significant in the T-positive patient group. CONCLUSIONS: This indicates that IL-4 production within the donor heart and by cells from the donor is important for reducing incidence of episodes of rejection.     

Effects of repetitive TMS on visually evoked potentials and EEG in the anaesthetized cat: dependence on stimulus frequency and train duration

Repetitive transcranial magnetic stimulation (rTMS) has been shown to alter cortical excitability that lasts beyond the duration of rTMS application itself. High-frequency rTMS leads primarily to facilitation, whereas low-frequency rTMS leads to inhibition of the treated cortex. However, the contribution of rTMS train duration is less clear. In this study, we investigated the effects of nine different rTMS protocols, including low and high frequencies, as well as short and long applications (1, 3 and 10 Hz applied for 1, 5 and 20 min), on visual cortex excitability in anaesthetized and paralysed cats by means of visual evoked potential (VEP) and electroencephalography (EEG) recordings. Our results show that 10 Hz rTMS applied for 1 and 5 min significantly enhanced early VEP amplitudes, while 1 and 3 Hz rTMS applied for 5 and 20 min significantly reduced them. No significant changes were found after 1 and 3 Hz rTMS applied for only 1 min, and 10 Hz rTMS applied for 20 min. EEG activity was only transiently (<20 s) affected, with increased delta activity after 1 and 3 Hz rTMS applied for 1 or 5 min. These findings indicate that the effects of rTMS on cortical excitability depend on the combination of stimulus frequency and duration (or total number of stimuli): short high-frequency trains seem to be more effective than longer trains, and low-frequency rTMS requires longer applications. Changes in the spectral composition of the EEG were not correlated to changes in VEP size.     

Differences in the temporal dynamics of the visual ON and OFF pathways

The temporal structure of spike trains recorded from optic fibers and single units of the lateral geniculate nucleus (LGN) and primary visual cortex of the cat was studied with a novel method of inter-spike interval analysis. ON type relay cells of the LGN exhibited a multimodal interval distribution preferring a distinct interval (fundamental interval) and its multiples during the sustained light response, whereas most OFF cells showed a broad, unimodal distribution. The general pattern of the interval distribution was relatively independent of stimulus size and contrast and the degree of light adaptation. Simultaneously recorded S-potentials originating from the retinal input generally produced only a single peak at the fundamental interval length. Therefore, the multimodal interval distribution of LGN cells seems to be a result of intra-geniculate inhibition. Cortical cells also showed a weak tendency to fire with spike intervals similar to LGN cells. Therefore, the regular firing pattern observed at peripheral stages of the visual pathway can persist at higher levels and might promote the occurrence of oscillatory activity.     

The HIV prevalence among pregnant women in the Amsterdam region (1988–1991)

The objective of the study was to monitor the HIV prevalence in the years 1988–1991 among pregnant women in the Amsterdam region, visitors to an abortion clinic and 3 outpatient infertility clinics. All women attending these clinics were asked to participate in the study on a voluntary basis and were tested with informed consent. The women were questioned about risk-bearing behaviour of themselves and their sexual partner(s). In the period 1988–1991, of the 23,827 eligible pregnant women, 22,165 women participated (93.0%). Twenty-seven women were found to be positive for HIV antibodies (0.12%, 95% CI: 0.08%–0.17%), of whom twenty belonged to a known HIV risk group or had a partner who belonged to one of these groups and 7 women had no known HIV risk. Seventeen of the 27 women had a foreign nationality. The annual HIV prevalence among pregnant women was: 1988: 0.28%; 1989: 0.10%; 1990: 0.10%; 1991: 0.11%. In the years 1990 and 1991, of the 1,128 eligible women visiting the abortion clinic 953 (84.5%) were tested. Eleven women were HIV-seropositive (1.15%, 95% CI: 0.6%–2.0%), of whom 9 were from an AIDS endemic region, 1 woman had a partner from this region and 1 woman had no known HIV risk. Four African women had HIV-2 antibodies. At the 3 outpatient infertility clinics 1 woman was found to be HIV-positive (0.13%; 95% CI: 0.02–0.9). She had no other risk than a partner from an AIDS endemic area. In the Amsterdam region there was a steady and low HIV prevalence (0.1%) among pregnant women through the years 1988–1991. The prevalence in the abortion clinic was ten times higher. The program was able to detect possible high risk groups within the population. Migration and travelling can play an important role in the spread of HIV in the general heterosexual population.     

Physico-chemical properties and stability of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H- dibenz[2,3:6,7]oxepino[4,5-c]pyrrolidine maleate

The physico-chemical properties of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H- dibenz[2,3:6,7]oxepino[4,5-c]pyrrolidine maleate (Org 5222), a new potential antipsychotic compound, were studied by interpretation of its spectra (UV,IR,NMR,mass), X-ray analysis, thermal properties, solubilities and partition coefficient. Analytical methods such as GLC and TLC were developed for use in stability tests. Crystalline Org 5222 was shown to be stable with respect to heat. Only excessive exposure to light was shown to induce degradation of crystalline Org 5222. In solutions of pH 1, 4 and 7 only slight degradation was observed at high temperature or after exposure to light.     

5-HT1B Receptor Polymorphism and Clinical Response to Sumatriptan

The 5-HT₁ receptor agonist, sumatriptan, is highly effective in the treatment of migraine. Some patients, however, do not respond or experience recurrence of the headache. In addition, some patients report chest symptoms after sumatriptan. We investigated whether these different responses could be attributed to genetic diversity of the 5-HT_1B receptor, which most likely mediates the therapeutic action and the coronary side effects of sumatriptan. Allele frequencies of two polymorphisms in the 5-HT_1B receptor gene ( G861C and T-261G ) were investigated in migraine patients with consistently good response to sumatriptan (n=14), with no response (n=12), with recurrence of the headache (n=12), with chest symptoms (n=13), and in patients without chest symptoms (n=27). Allele frequencies (G:0.74; C:0.26 at nt 861 and T:0.39; G:0.61 at nt -261) did not differ between patient groups, indicating that genetic diversity of the 5-HT_1B receptor does not seem to be involved in the different clinical responses to sumatriptan.     

Paired-pulse transcranial magnetic stimulation protocol applied to visual cortex of anaesthetized cat: effects on visually evoked single-unit activity

In this study, we tested the paired-pulse transcranial magnetic stimulation (ppTMS) protocol – a conditioning stimulus (CS) given at variable intervals prior to a test stimulus (TS) – for visually evoked single-unit activity in cat primary visual cortex. We defined the TS as being supra-threshold when it caused a significant increase or decrease in the visually evoked activity. By systematically varying the interstimulus interval (ISI) between 2 and 30 ms and the strength of CS within the range 15–130% of TS, we found a clear dependence of the ppTMS effect on CS strength but little relation to ISI. The CS effect was strongest with an ISI of 3 ms and steadily declined for longer ISIs. A switch from enhancement of intracortical inhibition at short ISIs (2–5 ms, SICI) to intracortical facilitation (ICF) at longer ISIs (7–30 ms), as demonstrated for human motor cortex, was not evident. Whether the CS caused facilitation or suppression of the TS effect mainly depended on the strength of CS and the polarity of the TS effect: within a range of 60–130% a positive correlation between ppTMS and TS effect was evident, resulting in a stronger facilitation if the TS caused facilitation of visual activity, and more suppression if the TS was suppressive by itself. The correlation inverted when CS was reduced to 15–30%. The ppTMS effect was not simply the sum of the CS and TS effect, it was much smaller at weak CS strength (15–50%) but stronger than the sum of CS and TS effects at CS strength 60–100%. Differences in the physiological state between sensory and motor cortices and the interactions of paired synaptic inputs are discussed as possible reasons for the partly different effects of ppTMS in cat visual cortex and human motor cortex.     

Connective tissue growth factor expression and Smad signaling during mouse heart development and myocardial infarction.

Connective tissue growth factor (CTGF) is reported to be a target gene of transforming growth factor beta (TGFbeta) and bone morphogenetic protein (BMP) in vitro. Its physiological role in angiogenesis and skeletogenesis during mouse development has been described recently. Here, we have mapped expression of CTGF mRNA during mouse heart development, postnatal adult life, and after experimental myocardial infarction. Furthermore, we investigated the relationship between CTGF and the BMP/TGFbeta signaling pathway in particular during heart development in mutant mice. Postnatally, CTGF expression in the heart became restricted to the atrium. Strikingly, 1 week after myocardial infarction, when myocytes have disappeared from the infarct zone, CTGF and TGFbeta expression as well as activated forms of TGFbeta but not BMP, Smad effector proteins are colocalized exclusively in the fibroblasts of the scar tissue, suggesting possible cooperation between CTGF and TGFbeta during the pathological fibrotic response.