In situ characterization of cell infiltrates in human dental periapical granulomas. 1. Demonstration of receptors for the Fc region of IgG

The aims of the present study were to demonstrate FcR activity of dental periapical granulomas and to correlate the activity with the degree of lymphoreticular cell infiltration. Cryostat sections of 46 out of 51 granulomas adsorbed sheep erythrocytes(E) sensitized with rabbit IgG antibodies (A) (EA). No adsorption occurred using erythrocytes sensitized with F(ab')2 fragments of IgG. IgG and Fc fragments of human of rabbit IgG inhibited the binding of EA, whereas F(ab')2 fragments, human IgA, IgM or albumin did not, indicating the presence of receptors for the Fc region of IgG. Periodate, neutral formaldehyde and phospholipase C abolished the FcR activity whereas neuraminidase had no effect. Comparison of sections binding EA and adjacent sections stained with haematoxylin and eosin showed that EA adhered to areas infiltrated with mononuclear cells. The degree of binding of EA coincided with the density of mononuclear cell infiltration. Point attachments between the tissue sections and the adsorbed EA could be demonstrated by scanning electron microscopy. Sections with no infiltrates did not bind EA.     

Actin pools and actin microfilament organization in cultured human endothelial cells after exposure to thrombin

Human umbilical vein endothelial cells (HUVEC) in primary confluent cultures lost their normal polygonal shape and assumed a 'contracted' appearance as judged by phase contrast microscopy when exposed to highly purified bovine thrombin (2 N.I.H. u/ml). Total actin in thrombin-exposed cells did not differ from that of control cells, as measured by the deoxyribonuclease I inhibition assay. However, the monomeric actin pool (unpolymerized actin) in thrombin-treated HUVEC was c. 15% smaller (P<0.01) than in control HUVEC (in which it represented approximately 50% of total actin). Transmission electron microscopy showed that thrombin-stimulated HUVEC contained more and thicker bundles of filamentous actin than control cells. Polymerization of actin and reorganization of actin microfilaments may contribute to the shape changes of HUVEC induced by thrombin.     

Incorporation of dUMP into DNA is a major source of spontaneous DNA damage, while excision of uracil is not required for cytotoxicity of fluoropyrimidines in mouse embryonic fibroblasts

Uracil may arise in DNA as a result of deamination of cytosine or through incorporation of dUMP instead of dTMP during replication. We have studied the steady-state levels of uracil in the DNA of primary cells and mouse embryonic fibroblast (MEF) cell lines from mice deficient in the Ung uracil-DNA glycosylase. The results show that the levels of uracil in the DNA of Ung(-/-) cells strongly depend on proliferation, indicating that the uracil residues originate predominantly from misincorporation during replication. Treatment with 5-fluoro-2'-deoxyuridine (5-FdUrd) or 5-fluorouracil (5-FU) gives rise to a dose-dependent increase of uracil in Ung(-/-) MEFs (up to 1.5-fold) but not in wild-type cells. Interestingly, Ung(-/-) MEFs accumulate AP-sites as well as uracil in response to 5-FdUrd but not to 5-FU. This accumulation of repair intermediates suggests a loss of tightly co-ordinated repair in the absence of Ung, and correlates with stronger inhibition of cell proliferation in response to 5-FdUrd, but not to 5-FU, in Ung(-/-) MEFs compared with wild-type cells. However, other cytotoxic effects of these fluoropyrimidines are comparable in both wild-type and Ung-deficient cells, demonstrating that excision of uracil from DNA by the Ung uracil-DNA glycosylase is not a prerequisite for obtaining cytotoxicity.     

Specific types of activated Factor XII increase following thrombolytic therapy with tenecteplase

Background Activated Factor XII (XIIa) is believed to participate in a number of pathophysiological processes including inflammation, thrombosis and fibrinolysis. Increasing XIIa levels following thrombolytic therapy have previously been reported. In contrast to other thrombolytics, tenecteplase (TNK-tpa) does not show paradoxical thrombin activation, indicating a lower procoagulant effect of this fibrin-selective thrombolytic agent. Recent research has demonstrated that in-vivo XIIa exists in a number of different types, and the aim of this study was to investigate plasma variations of different types of XIIa following thrombolytic treatment with TNK-tpa.Methods Citrated blood samples were obtained from 34 patients admitted with acute ST-elevation myocardial infarction (STEMI) treated with TNK-tpa. Samples were taken immediately prior to treatment, 30–90 min after and 4 days post-treatment. XIIa measurements were performed using 2 ELISA assays designed to preferentially measure different types of XIIa; XIIaA and XIIaR. Both assays utilised a monoclonal antibody 2/215, which is highly specific for XIIa, as the solid phase capture antibody. The assay for XIIaA used a conjugate based on a polyclonal antibody against the entire XIIa molecule, whilst the assay for XIIaR incorporated a reagent to release otherwise unavailable XIIa and used a conjugate based on a monoclonal antibody against β-XIIa.Results Changes in plasma XIIaA concentration as a result of therapy were more evident than changes in XIIaR concentration. XIIaA showed a significant increase from 67.1 (49.0–84.4) pM to 97.8 (75.5–133.1) pM [median and 25 and 75% percentiles] in the 30–90 min sample (P < 0.001), returning to pre-intervention levels 61.5 (47.5–81.0) pM by day 4. In contrast, no significant change in XIIaR concentration was observed following thrombolytic therapy with TNK-tpa.Conclusion In patients admitted with STEMI, thrombolytic therapy with TNK-tpa resulted in a significant short-lasting increase in specific types of XIIa (namely XIIaA), whereas other types of XIIa (XIIaR) were largely unaffected by this intervention.     

Ghrelin, cholecystokinin, and peptide YY in Atlantic salmon (Salmo salar): Molecular cloning and tissue expression

Gastrointestinal (GI) peptide hormones, ghrelin (GHRL), cholecystokinin (CCK), and peptide YY (PYY) genes were identified in Atlantic salmon, Salmo salar. Full-length cDNAs encoding two isoforms of GHRL (GHRL-1 and GHRL-2), two isoforms of CCK (CCK-L and CCK-N) and peptide YY (PYY) cDNA were obtained. The GHRL-1 and GHRL-2 genes encoded proteins of 111- and 108-amino acids, respectively. Both types of GHRL were mainly expressed in the stomach, but also weakly expressed in the pyloric caeca, mid-gut, adipose tissue, and testis. The CCK-L and CCK-N genes encoded preproproteins of 132- and 140-amino acids, respectively. Both types of CCK were strongly expressed in the brain and comparatively weakly expressed in other tissues, including the digestive tract. In the digestive tract, CCK-L was mainly expressed in the pyloric caeca and hind-gut, while CCK-N was only expressed in the pyloric caeca. The PYY gene encoded for 97-amino acid residues and was mainly expressed in the brain and anterior part of the intestine, including the pyloric caeca. In an experiment, we demonstrated that 6 days starvation led to, increased GHRL-1 mRNA levels in the GI tract (stomach), while there no significant changes in expression levels for the other hormones in the GI tract. This suggests an orexigenic role for GHRL-1 in Atlantic salmon. These data contribute to elucidate the functional relationships among teleost gastrointestinal peptide hormones.     

Prevalence of antibodies against herpes simplex virus types 1 and 2 in children and young people in an urban region in Tanzania

Herpes simplex virus type 1 (HSV-1) is transmitted by close contact, both sexual and nonsexual, and infections are acquired during childhood and adolescence. Herpes simplex virus type 2 (HSV-2), however, is thought to be transmitted mainly by sexual contact. Most HSV-2 infections are consequently expected to occur after the onset of sexual activity. Recent reports indicate an increasing prevalence of HSV-2 on the African continent, but most studies have been performed on adult cohorts. In the present study, we collected sera from Tanzanian children and young persons from 1 to 20 years old, with at least 100 individuals in each age group. Antibodies against HSV-1 and HSV-2 were detected by an in-house Western blot method which was shown to perform well in comparison with a commercial Western blot assay. Type-specific antibodies were also analyzed by two noncommercial enzyme-linked immunosorbent assay methods based upon the antigenicities of branched synthetic oligopeptides corresponding to epitopes in glycoprotein G of HSV-1 or HSV-2. The prevalence of HSV-1 antibodies increased gradually from 73% for the age group of 1 to 4 years to 92% for the age group of 17 to 20 years. The prevalence of HSV-2 antibodies was unexpectedly high, as 15% of the children were infected by the age of 8 years, with the incidence increasing gradually to 40% in the age group of 17 to 20 years. The reason for this unexpectedly high frequency is not clear but could suggest that nonsexual transmission of HSV-2 is more common than previously thought. There was no statistically significant association between seropositivities for HSV-2 and human immunodeficiency virus.     

Antiepileptic effect of gap-junction blockers in a rat model of refractory focal cortical epilepsy

PURPOSE: Epilepsy is the most common serious neurologic disease, and current treatments are ineffective for or=1 h before drug infusion and for >or=3 h afterward. No ill effects were observed. RESULTS: An immediate and marked reduction in percentage of seizure time was seen in rats receiving carbenoxolone (baseline, 69.4%+/- 7.0% (SEM); maximum effect, 9.3%+/- 3.5%, p 相似文献   

Sontochin as a guide to the development of drugs against chloroquine-resistant malaria

Sontochin was the original chloroquine replacement drug, arising from research by Hans Andersag 2 years after chloroquine (known as "resochin" at the time) had been shelved due to the mistaken perception that it was too toxic for human use. We were surprised to find that sontochin, i.e., 3-methyl-chloroquine, retains significant activity against chloroquine-resistant strains of Plasmodium falciparum in vitro. We prepared derivatives of sontochin, "pharmachins," with alkyl or aryl substituents at the 3 position and with alterations to the 4-position side chain to enhance activity against drug-resistant strains. Modified with an aryl substituent in the 3 position of the 7-chloro-quinoline ring, Pharmachin 203 (PH-203) exhibits low-nanomolar 50% inhibitory concentrations (IC(50)s) against drug-sensitive and multidrug-resistant strains and in vivo efficacy against patent infections of Plasmodium yoelii in mice that is superior to chloroquine. Our findings suggest that novel 3-position aryl pharmachin derivatives have the potential for use in treating drug resistant malaria.     

Physical exercise, body mass index, and risk of chronic pain in the low back and neck/shoulders: longitudinal data from the Nord-Trondelag Health Study

Chronic musculoskeletal pain constitutes a large socioeconomic challenge, and preventive measures with documented effects are warranted. The authors' aim in this study was to prospectively investigate the association between physical exercise, body mass index (BMI), and risk of chronic pain in the low back and neck/shoulders. The study comprised data on approximately 30,000 women and men in the Nord-Tr?ndelag Health Study (Norway) who reported no pain or physical impairment at baseline in 1984-1986. Occurrence of chronic musculoskeletal pain was assessed at follow-up in 1995-1997. A generalized linear model was used to calculate adjusted risk ratios. For both females and males, hours of physical exercise per week were linearly and inversely associated with risk of chronic pain in the low back (women: P-trend = 0.02; men: P-trend < 0.001) and neck/shoulders (women: P-trend = 0.002; men: P-trend < 0.001). Obese women and men had an approximately 20% increased risk of chronic pain in both the low back and the neck/shoulders. Exercising for 1 or more hours per week compensated, to some extent, for the adverse effect of high BMI on risk of chronic pain. The authors conclude that physical inactivity and high BMI are associated with an increased risk of chronic pain in the low back and neck/shoulders in the general adult population.