Gene-targeted inhibition of transactivation of human immunodeficiency virus type-1 (HIV-1)-LTR by antisense oligonucleotides

We have used an in vitro approach to study the efficiency of antisense oligonucleotides in inhibiting LTR-(HIV-1)-directed CAT expression catalyzed by tat protein, the functional protein of the transactivator gene. We selected the target sequence localized near the 5 end of the tat mRNA. The following conclusions can be drawn from the data presented here: a) Antisense oligonucleotides modified by conjugation of cholesterol at the 3 end have a severalfold higher inhibitory response, b) inhibitory response is dependent on the mode of introducing oligonucleotides, and c) the inhibition by antisense oligonucleotides is sequence specific and directed towards the targeted region. This approach could be useful for targeting functional regions of regulatory gene products and designing gene-targeted inhibitors of virus replication.Dedicated to Professor Klaus Ring on his 60th birthday.     

A Guide to Immunotherapy of Genital Warts

Genital warts affect at least 1% of sexually active adults. Current therapies are inadequate because they are often painful, may fail to prevent recurrence and transmission of warts, and usually require either surgery or at least application by a physician. Investigation of immunotherapy for genital warts began with interferon. It has been studied in topical, intralesional, systemic and adjuvant applications. We review the major clinical trials of interferon for genital warts, and conclude that intralesional therapy with interferon-alpha or interferon-beta, with complete response rates of 36 to 63%, is the most successful route for interferon monotherapy. In choosing patients for therapy with interferon, major considerations include immune status, pregnancy and ability to return for frequent injections. Imiquimod is a new immune response enhancer that acts through stimulating host cytokine production. Interleukins-1, -2, -6, -8 and -12, interferons alpha, beta and gamma and tumour necrosis factor alpha have all been associated with the mechanism of action of imiquimod. Recently, 3 clinical trials have reported positive results using topical imiquimod to treat genital warts. Complete response rates ranged from 37 to 54% for these controlled trials of 5% imiquimod cream. Adverse effects reported include localised pruritis, erythema, erosion, burning and pain, which were rarely severe enough to cause discontinuation of the medication. Although further trials are necessary to identify the role of imiquimod in the therapy of genital warts, it appears to be an efficacious and well tolerated patient-controlled measure for wart therapy.     

Flow-mediated cell stress induction in adherent leukocytes is accompanied by modulation of morphology and phagocytic function

Leukocytes adherent to the surfaces of both vascular biomaterials and normal blood vessels experience blood flow induced shear stress. The goal of the reported studies was to investigate the effect of fluid flow on the morphology, phagocytic function and stress response induction in adherent immune cells. Shear approximating arterial, venous and intermediate levels were applied onto glass-adherent IC21 macrophages in a temperature-controlled parallel plate flow system. The results indicate that fluid flow induces a shear-dependent physiological stress response in adherent macrophages and that significant morphological changes accompany macrophage responses to shear stress. In addition, arterial flow conditions induce not only significant cell polarisation, but also enhanced phagocytic ingestion in glass-adherent IC21 macrophages. These findings suggest that blood flow induced shear stress may not only be consequent to adherent leukocyte activation, but may also be integral to the regulation of adherent leukocyte behaviour in vivo.     

Left-ventricular pressure gradients: a computer-model simulation

Both invasive left-ventricular pressure measurements and non-invasive colour M-mode echographic measurements have shown the existence of intraventricular pressure gradients (IVPGs) during early filling. The mechanisms responsible for these IVPG cannot be completely explained by the experiments. Therefore a one-dimensional numerical model is developed and validated. The model describes filling (both velocities and pressures) along a left ventricular (LV) base-apex axis. Blood-wall interaction in the left ventricle with moving boundaries is taken into account. The computational results for a canine heart indicate that the observed IVPGs during filling are the consequence of a complex interaction between, on the one hand, pressure waves travelling in the LV and, on the other hand, LV geometry, relaxation and compliance. The computational results indicate the pressure dependency of wavespeed (0.77-1.90 m-1 s) for different mean intraventricular pressures (0.88-5.00 mmHg) and IVPGs up to 2 mmHg, independent of the ratio of end systolic volume and equilibrium volume. Increasing relaxation rate not only decreases minimum basal pressure (2.8 instead of 3.6 mmHg) but also has a strong influence on the time delay between the minimum basal and apical pressures (14 ms instead of 49 ms). The results sustain the hypothesis that pressure-wave propagation determines IVPGs and that IVPGs are no proof of elastic recoil.     

Mechanism for polarisation of cardiac tissue at a sealed boundary

If current is flowing in cardiac tissue, and if the myocardial fibres approach a sealed boundary at an angle, then the tissue within a few length constants of the boundary is polarised. This polarisation occurs when the cardiac tissue has different anisotropy ratios in the intracellular and extracellular spaces. This new mechanism of tissue polarisation is demonstrated using a simple, analytical model, and it is shown quantitatively that this polarisation can be nearly as large as that occurring near an electrode.     

Spatial and temporal variations in the magnetic fields produced by human gastrointestinal activity

Magnetoenterography (MENG) is a new, non-invasive technique that measures gastrointestinal magnetic signals near the body surface. This study was undertaken to evaluate the temporal and spatial characteristics of the magnetic signals generated by gastric and duodenal slow wave activity. The gastrointestinal magnetic fields of eight normal subjects were measured for 60 minutes in both the fasting and fed state using 36 magnetic sensors simultaneously. The results were displayed as a succession of maps over time showing the temporal evolution of the spatial distribution of the signal over the upper abdomen. In all subjects, slow wave activity of the stomach centred at 3.0 +/- 0.5 cycles min-1 in both the fasting and fed state was observed. The duodenal signal at 11.0 +/- 1.0 cycles min-1 was observed in four subjects. The spatial distribution of these two signals is distinctly different. The observed spatial and temporal variations are described in terms of a model used previously to explain the potentials observed in electrogastrography (EGG).     

Restraint-induced stress ulcer. I. Hypothalamic,urinary, and adrenal biochemical studies

The purpose of these experiments was to study the incidence of stress ulcers in restrained rats and to correlate it with hypothalamic and adrenal cortical and medullary activity, with and without vagotomy. A total of 217 adult rats were used, grouped into 56 sets, and distributed at random in 5 experimental groups. Restraint was followed by a 79% incidence of ulceration in the glandular portion of the gastric mucosa. Vagotomy made these worse (p<0.01). Hypothalamic levels of catecholamines and serotonin showed no significant changes. Urinary measurements revealed decreased excretion of 17-ketosteroids (p<0.001), increased excretion of uropepsinogen (p<0.01), and no significant changes in vanillylmandelic acid among the rats submitted to immobilization. In the adrenal glands of stressed animals, there was a decreased level of catecholamines (p<0.01) and no significant changes in corticosteroid content (17-ketosteroids). These results suggest that hypothalamic stimulation and the participation of the adrenal glands are not essential factors in the pathogenesis of restraint-induced experimental stress ulcer.     

A new method for evaluation of the acrosome reaction in viable human spermatozoa

The acrosome reaction of human spermatozoa was induced by changes of temperature. Spermatozoa were collected from fertile donors and a patient group, and selected by the "swim-up" method. The spermatozoa were treated in two different ways: Protocol I: 24 hours at room temperature followed by additional incubation at 37 degrees C for 3 hours (control), and protocol II: 24 hours at 4 degrees C followed by additional incubation at 37 degrees C for 3 hours. The acrosome reaction of the viable spermatozoa was evaluated by a new method utilizing indirect immunofluorescence with anti-outer acrosomal membrane antibodies and exposure to a hypo-osmotic medium. In fertile donors as well as in the patient group, significant induction of the acrosome reaction (20%) was evident after exposure to low temperature (4 degrees C). The spontaneous rate of acrosome reaction in the control group was below 7%.     

Hemodialysis in schizophrenia

Summary Therapeutic trials with hemodialysis have been performed in three cases of chronic schizophrenia. The severely ill patients had been hospitalized for more than ten years and had not responded to different types of conventional somatic treatment. Psychopathology was evaluated by use of the IMPS, BPRS, and NOSIE scales. No improvement could be observed as a consequence of 12 (11 in one case) hemodialysis treatments. Rather, some deterioration occurred in two of the patients. This result is not in accord with the markedly positive findings of Wagemaker and Cade (1977). However, further studies appear necessary to render final conclusions.Supported by a Stipendium of the Fritz-Thyssen-Foundation, Cologne     

Precancerous lesions of the stomach

The etiology of stomach cancer in relation to preexisting mucosal alterations is described and discussed from a review of the literature and our own previously reported experience. The incidence of cancerization or malignant change of gastric polyp, chronic gastric ulcer, and chronic gastritis varies considerably from researcher to researcher. Clinical follow-up studies in many cases of gastric polyp and chronic ulcer discovered in the mass survey examination of the stomach revealed incidences of malignant degeneration of 2.3% of the gastric polyp cases and 2.06% of the gastric ulcer cases.

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Résumé Les relations entre altérations préexistantes de la muqueuse et étiologie du cancer gastrique sont décrites et discutées, avec revue de la littérature et de notre expérience personnelle. La fréquence des cancérisations ou des dégénérescences malignes des polypes gastriques, de l'ulcère gastrique chronique et de la gastrite chronique est éminemment variable d'une étude à l'autre. Les follow-up de populations soumises à des examens systématiques de dépistage indiquent que la fréquence des dégénérescences malignes est de 2.3% pour les polypes gastriques et de 2.06% pour l'ulcère gastrique.