Hepatitis B virus-specific T-cell responses during IFN administration in a small cohort of chronic hepatitis B patients under nucleos(t)ide analogue treatment.

The effect of pegylated interferon-α (IFN) add-on therapy on HBV-specific T-cell responses was evaluated in 12 patients with stable, undetectable hepatitis B virus (HBV) load under nucleos(t)ide analogue therapy. Peripheral blood mononuclear cells were isolated at week 0, 4, 8, 12, 24 and 48 of IFN add-on therapy. Quantity and quality of circulating HBV S- and core-specific CD4 and CD8 T cells were analysed ex vivo by flow cytometry. HBV S- and core-specific CD4 T-cell numbers modestly increased within 8 weeks of IFN administration (P = 0.0391 and P = 0.0195), whereas HBV-specific CD8 T cells in general showed only minor changes under IFN add-on therapy. Functionality of HBV-specific CD4 but not CD8 T cells positively correlated with serum transaminase activity. In addition, we observed an increase in CD4 T cells producing tumour necrosis factor-α (TNFα) without antigen restimulation (P = 0.0039), which correlated with elevated transaminases. During IFN add-on therapy, two patients developed an anti-HBs seroconversion, only one of whom showed a relevant increase in HBV-specific T cells. In conclusion, IFN add-on therapy of chronic hepatitis B increased HBV-specific T-cell responses and affected a previously unrecognized TNFα-monofunctional CD4 T-cell population. Although the observed T-cell responses did not correlate with HBsAg seroconversion, we expect additional insights into the immunopathogenesis of hepatitis B, following the characterization of the newly identified TNF α-monofunctional T-cell population.

Dental caries and microbiota in children with black stain and non-discoloured dental plaque.

AIM: We aimed to assess caries experience and microbiota in systemically healthy children with black stain (BS) and non-discoloured plaque. METHODS: Forty-six children with BS and 47 counterparts with non-discoloured plaque aged 7.9 ± 1.3 years were clinically examined. Dental caries was scored using WHO criteria. Samples of BS and non-discoloured dental plaque were collected from tooth surfaces. The DNA of the samples was extracted and real-time PCR was performed to determine the total number of bacteria and the species Streptococcus mutans, S. sobrinus, Lactobacillus sp., Actinomyces naeslundii, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia and Fusobacterium nucleatum. RESULTS: Children with BS had lower DMFT (p = 0.013), lower DT values (p = 0.005) and a tendency to lower caries prevalence (p = 0.061) than children with non-discoloured plaque. Plaque samples of the BS group contained higher numbers of A. naeslundii (p = 0.005) and lower numbers of F. nucleatum (p = 0.001) and Lactobacillus sp. (p = 0.001) compared to the non-discoloured plaque samples of the control group. Comparing the children with BS and non-discoloured plaque, higher counts for A. naeslundii (p = 0.013) were observed in caries-free children with BS while in caries-affected children with BS, lower counts of F. nucleatum (p = 0.007) were found. Counts of Lactobacillus sp. were higher in non-discoloured plaque samples than in BS of caries-free and caries-affected children. CONCLUSION: Results suggest that the different microbial composition of BS might be associated with the lower caries experience in affected subjects. The role of black-pigmented bacteria associated with periodontitis needs further studies.

Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo.

The pro-inflammatory cytokine interleukin (IL)-6 (refs. 1-5) can bind to cells lacking the IL-6 receptor (IL-6R) when it forms a complex with the soluble IL-6R (sIL-6R) (trans signaling). Here, we have assessed the contribution of this system to the increased resistance of mucosal T cells against apoptosis in Crohn disease (CD), a chronic inflammatory disease of the gastrointestinal tract. A neutralizing antibody against IL-6R suppressed established experimental colitis in various animal models of CD mediated by type 1 T-helper cells, by inducing apoptosis of lamina propria T cells. Similarly, specific neutralization of sIL-6R in vivo by a newly designed gp130-Fc fusion protein caused suppression of colitis activity and induction of apoptosis, indicating that sIL-6R prevents mucosal T-cell apoptosis. In patients with CD, mucosal T cells showed strong evidence for IL-6 trans signaling, with activation of signal transducer and activator of transcription 3, bcl-2 and bcl-xl. Blockade of IL-6 trans signaling caused T-cell apoptosis, indicating that the IL-6-sIL-6R system mediates the resistance of T cells to apoptosis in CD. These data indicate that a pathway of T-cell activation driven by IL-6-sIL-6R contributes to the perpetuation of chronic intestinal inflammation. Specific targeting of this pathway may be a promising new approach for the treatment of CD.

Treatment of allergic airway inflammation and hyperresponsiveness by antisense-induced local blockade of GATA-3 expression.

Recent studies in transgenic mice have revealed that expression of a dominant negative form of the transcription factor GATA-3 in T cells can prevent T helper cell type 2 (Th2)-mediated allergic airway inflammation in mice. However, it remains unclear whether GATA-3 plays a role in the effector phase of allergic airway inflammation and whether antagonizing the expression and/or function of GATA-3 can be used for the therapy of allergic airway inflammation and hyperresponsiveness. Here, we analyzed the effects of locally antagonizing GATA-3 function in a murine model of asthma. We could suppress GATA-3 expression in interleukin (IL)-4-producing T cells in vitro and in vivo by an antisense phosphorothioate oligonucleotide overlapping the translation start site of GATA-3, whereas nonsense control oligonucleotides were virtually inactive. In a murine model of asthma associated with allergic pulmonary inflammation and hyperresponsiveness in ovalbumin (OVA)-sensitized mice, local intranasal administration of fluorescein isothiocyanate-labeled GATA-3 antisense oligonucleotides led to DNA uptake in lung cells associated with a reduction of intracellular GATA-3 expression. Such intrapulmonary blockade of GATA-3 expression caused an abrogation of signs of lung inflammation including infiltration of eosinophils and Th2 cytokine production. Furthermore, treatment with antisense but not nonsense oligonucleotides induced a significant reduction of airway hyperresponsiveness in OVA-sensitized mice to levels comparable to saline-treated control mice, as assessed by both enhanced pause (PenH) responses and pulmonary resistance determined by body plethysmography. These data indicate a critical role for GATA-3 in the effector phase of a murine asthma model and suggest that local delivery of GATA-3 antisense oligonucleotides may be a novel approach for the treatment of airway hyperresponsiveness such as in asthma. This approach has the potential advantage of suppressing the expression of various proinflammatory Th2 cytokines simultaneously rather than suppressing the activity of a single cytokine.

Analysis of oscillations of the visual sensitivity.

At the subjective threshold, repeated flash test stimuli are perceived by the observer on only 50% of occasions, since the detectability of a single light stimulus fluctuates with time. For the analysis of these fluctuations we have recorded sequences of positive ("seen") and negative ("not seen") responses, stimulating at 10 sec intervals for 50 min. These records, reflecting the time course of detectability, show periodic fluctuations. The frequencies of these fluctuations have been estimated by autocorrelation and Fourier analysis of the records. For 19 subjects they yielded spectra with preferential period durations between 0.5 and 2, respectively 5 and 15 min in 15 cases, and some spectra are noisy.

Reproductive performance in South Australian dairy herds.

Herd breeding records (161) were examined from a random 10% sample of dairy farms (96) in South Australia with more than 40 cows and suitable breeding records for 1988 and/or 1989. Of these farms, 53 (55.2%) had a year-round calving pattern, 42 (43.8%) claimed to be seasonal and one was changing from a year-round to a seasonal pattern. Only 14.6% of farmers observed oestrous behaviour outside milking times and 18.8% used tailpaint. Overall, the average proportion of unobserved heats was estimated to be 32%. Artificial insemination (AI) was carried out on 85.4% of farms (16.7% used AI alone and 68.7% also used bulls) of which 32.9% used commercial technicians and 67.1% were do-it-yourself operators. Overall, the average 30-day submission rate was 59.9% and the average 49-day non-return to service rate was 58.9%. Investigation into the probable causes of suboptimal reproductive performance gave a tentative diagnosis of inefficient oestrous detection, deferral of service, inadequate nutrition, poor AI technique, insufficient bulls, and venereal/other diseases in 69.1, 32.1, 27.2, 28.4, 13.6 and 7.4% of records, respectively.

The human visual threshold depends on direction and strength of a weak magnetic field.

Completing our investigations concerning influences of weak magnetic fields on the visual discrimination threshold, we have investigated 30 subjects (20 female, 10 male) under rotation of the geomagnetic field without change in field strength. We related the thresholds to the values measured in the unchanged field. Comparison with a control experiment shows that correspondence between viewing and field direction results in a significant decrease of the threshold. The significance is lost if the angle between the directions is set to 20 degrees. On the basis of these and our earlier results an attempt is made to give a very simple description of the connection between field direction, field strength, and the change in the visual discrimination threshold.

Oceanic lidar: radiative transfer in the atmosphere at operating altitudes from 100 m to 100 km.

The feasibility of measuring water-column parameters of the sea with a fluorescence lidar under daylight conditions and at flight altitudes between 100 m and 100 km is studied by modeling the atmospheric radiative transfer. Parameters to be measured are fluorescence of gelbstoff and chlorophyll and Raman scattering of water molecules. A cloudless and stratified atmosphere with various conditions of near-surface visibility and ozone concentration is taken into consideration. Solar zenith angles are varied between 0° and 60°. Lidar specifications are set to 1 J output energy, 10 ns pulse duration, 0.1 mrad beam divergence, 0.1 mrad detection angle, and 400 cm(-1) detection bandwidth. Signal recovery is carried out over the effective pulse length of the returned signal, which is roughly 20-30 ns. Sensor zenith angles are set between 0° and 60°. As a result of the study the recommended range of excitation wavelengths for high altitudes should be chosen between 350 and 400 nm. Under these circumstances, and with the iven laser and sensor specifications, oceanic lidar measurements should also be possible at flight altitudes of up to 100 km under clear visibility conditions, even at noon.

The light sensitivity of the human visual system depends on the direction of view.

The near-stable North-South orientation of the natural geomagnetic field provides an ideal basis for navigation. Sailors have used it since ancient times, animals for much longer. Various mechanisms have developed for this purpose. Experiments have pointed to a connection between orientation in the geomagnetic field and light perception. Such observations are supported by theoretical considerations. The underlying interaction should also modulate the light sensitivity of the visual system. Recently we demonstrated the effect of an oscillating field. Here we report the existence of a weak influence of the static field on visual sensitivity in man. By comparison with control experiments, if the directions of view line and field vector coincide the perception threshold of a light stimulus is slightly but significantly increased. This significance is lost if the view line deviates by 10 degrees from the field direction.

Periodic inversion of the vertical component of the earth's magnetic field influences fluctuations of visual sensitivity in humans.

According to theoretical considerations, the magnetic field of the earth could influence the first steps of light-induced changes in ocular photopigment, an effect that is thought to underlie the magnetic orientation of some animals. To find out whether man could be influenced in this way, we have tested the effect of an artificial fluctuation in the direction of the earth's magnetic field on oscillations of the visual sensitivity in 27 healthy subjects. The resultant spectra show a significant influence of the field fluctuations, indicating that man is sensitive to changes in the direction of the earth's magnetic field.

The magnetic field sensitivity of the human visual system shows resonance and compass characteristic.

Orientation in the geomagnetic field is essential for many animal species. As yet, the interaction mechanisms of this weak field with the organisms are understood only incompletely. One mechanism in question is the interaction with the photochemical reaction in the retina. We show that the visual sensitivity of man is influenced by periodic sinusoidal inversion of the vertical component of the geomagnetic field. This effect indicates visual fixation in north-south direction and shows a pronounced resonance at a period duration of 110 s. These findings should be helpful in identifying in detail the mechanisms which are influenced by the geomagnetic field.

[Risk of invasive diagnosis with retrograde catheterization of the left ventricle in patients with acquired aortic valve stenosis]. / Risiko der invasiven Diagnostik mit retrograder Sondierung des linken Ventrikels bei Patienten mit erworbener Aortenklappenstenose.

In patients with aortic valve stenosis, the determination of the transstenotic pressure gradient is usually performed by cardiac catheterization with retrograde passage of the aortic valve. The aim of this study was to determine retrospectively the risk of the invasive examination with retrograde catheterization of the left ventricle and predictors for an increased risk. From 1984 to 1995, 457 patients (63 +/- 11 years) with aortic stenosis were investigated in the Medizinische Klinik Tübingen. In 435 patients (95.2%), the retrograde catheterization of the left ventricle was successful; in 19 cases a transseptal left heart catheterization was performed, and in 3 patients an invasive determination of the pressure gradient was not assessed. Complications occurred in 39 patients (8.5%). 5 patients died due to the catherization procedure (mortality rate 1.1%), 2 of them as a consequence of perforation of the left ventricle, one patient of heart failure, one of myocardial infarction, and another of fulminant pulmonary embolism. Four procedures (0.9%) were complicated by cerebral embolism, in 3 patients a pericard tamponade occurred, and in one case caused by transseptal punction of the interatrial septum. The most complications were peripheral vascular problems in 19 patients (4.2%). Predictors for increased risk dur to retrograde catheterization were age > 70 years (p = 0.008) and aortic valve area < or = 0.7 cm2 (p = 0.02). patients with a doppler echocardiographic instantaneous pressure gradient > or = 70 mm Hg were more likely to sustain a complication (p = 0.04). The retrograde catheterization of a stenotic aortic valve was successful in most cases. In approximately 2% of patients, complications occurred which can be attributed directly to retrograde catheterization and with significant higher frequency in patients over 70 years and with severe stenosis. Especially in these cases, invasive determination of the gradient should not be performed if reliable doppler echocardiographic information is available.