Pivotal advance: CTLA-4+ T cells exhibit normal antiviral functions during acute viral infection

Previous studies have shown that T cells, which are genetically deficient in CTLA-4/CD152 expression, will proliferate uncontrollably, resulting in lethal autoimmune disease. This and other evidence indicate that CTLA-4 plays a critical role in the negative regulation of effector T cell function. In contrast to expectations, BrdU incorporation experiments demonstrated that CTLA-4 expression was associated with normal or even enhanced in vivo proliferation of virus-specific CD4+ and CD8+ T cells following acute lymphocytic choriomeningitis virus or vaccinia virus infection. When compared with CTLA-4- T cells directly ex vivo, CTLA-4+ T cells also exhibited normal antiviral effector functions following stimulation with peptide-coated cells, virus-infected cells, plate-bound anti-CD3/anti-CTLA-4, or the cytokines IL-12 and IL-18. Together, this indicates that CTLA-4 does not directly inhibit antiviral T cell expansion or T cell effector functions, at least not under the normal physiological conditions associated with either of these two acute viral infections.     

Five-year evaluation of the influence of keratinized mucosa on peri-implant soft-tissue health and stability around implants supporting full-arch mandibular fixed prostheses

Background: The question of the importance of keratinized mucosa around dental implants for the prevention of peri-implant disease could not be answered in the relevant literature so far.
Objective: To investigate the influence of peri-implant keratinized mucosa on long-term peri-implant soft-tissue health and stability over a period of 5 years.
Material and methods: A total of 386 mandibular dental implants were placed in 73 completely edentulous patients, and subsequently restored with fixed full-arch prostheses. At prosthesis delivery (baseline) and after 3, 6, 12, 18, 24, 36, 48 and 60 months, modified plaque index (mPlI), modified sulcus bleeding index (mBI), distance between implant shoulder and mucosal margin (DIM) and width of peri-implant keratinized mucosa (KM) were recorded. Statistical analysis included multivariate logistic regression, multivariate ordinal logistic regression, generalized estimating equations and Bonferroni's correction.
Results: Fifty-eight patients with 307 implants completed the 5-year study. Statistically significantly higher plaque accumulation on lingual sites (mean mPlI 0.67, SD 0.85), bleeding tendencies on lingual sites (mean mBI 0.22, SD 0.53) and larger soft-tissue recession on buccal sites (mean DIM −0.69 mm, SD 1.11 mm) were found when the width of KM was <2 mm, compared to sites with≥2 mm of KM (mean mPlI 0.40, SD 0.68, P =0.001; mean mBI 0.13, SD 0.41, P <0.01; mean DIM −0.08 mm, SD 0.86 mm, P <0.001). The width of keratinized mucosa had no effect on bleeding tendency or plaque accumulation on buccal sites ( P >0.05).
Conclusion: In patients exercising good oral hygiene and receiving regular implant maintenance therapy, implants with a reduced width of <2 mm of peri-implant keratinized mucosa were more prone to lingual plaque accumulation and bleeding as well as buccal soft-tissue recession over a period of 5 years.     

Pattern of serum autoantibodies allows accurate distinction between a tumor and pathologies of the same organ

PURPOSE: Recent studies impressively showed the diagnostic potential of seroreactivity patterns for different tumor types, offering the prospect for low-cost screening of numerous tumor types simultaneously. One of the major challenges toward this goal is to prove that seroreactivity profiles do not only allow for identifying a tumor but also allow for distinguishing tumors from other pathologies of the same organ. EXPERIMENTAL DESIGN: We chose glioma as a model system and tested 325 sera (88 glioma, 95 intracranial tumors, 60 other brain pathologies, and 82 healthy controls) for seroreactivity on a panel of 35 antigens. RESULTS: We were able to discriminate between glioma and all other sera with cross-validated specificity of 86.1%, sensitivity of 85.2%, and accuracy of 85.8%. We obtained comparably good results for the separation of glioma versus nontumor brain pathologies and glioma versus other intracranial tumors. CONCLUSION: Our study provides first evidence that seroreactivity patterns allow for an accurate discrimination between a tumor and pathologies of the same organ even between different tumor types of the same organ.     

Radiobiological determination of growth kinetics and radiosensitivity of pulmonary micrometastases of the R1H tumour

The aim of the study was to determine the radiosensitivity and the growth kinetics of pulmonary micrometastases of the R1H tumour of the rat. Lung metastases were induced by intravenous injection of viable tumour cells. At different time intervals (3–32 days) after injection, lungs were locally irradiated with 200 kVp X-rays, using 1.5 Gy/fraction. Total doses of 6–33 Gy were administered within 11 days. Endpoints used were survival time, local control rate, and number of metastases in the lungs at autopsy. The data were evaluated using the multi-target model. Beginning in the fifth week after tumour cell inoculation the animals started to exhibit a pronounced dyspnoea and were sacrificed. Sections revealed an extensive metastatic infiltration of the lungs. With increasing total dose a prolongation of survival time as well as an increase in cure rate was observed. The number of metastases found in the lungs decreased with increasing total dose. It is concluded that metastatic growth does not start earlier than 3 days after tumour cell inoculation and accelerates continuously. The doubling time of the tumour cells in the micrometastases decreases continuously and from 5.2 to 1.2 days between day 3 and 40, whereas larger metastases containing more than 10⁶ cells show gompertzian growth kinetics. The cell doubling time in this stage of metastatic growth is longer than 5 days. During the first 4 weeks of metastatic growth the radiosensitivity of metastatic R1H cells in the lungs is the same as in vitro.     

Endophenazines A-D,new phenazine antibiotics from the athropod associated endosymbiont Streptomyces anulatus II. Structure elucidation

A detailed screening of the secondary metabolite pattern produced by different athropod associated strains of the species Streptomyces anulatus resulted in the isolation and structure elucidation of the endophenazines A-D (2, 4-6). The structures were assigned by spectroscopic methods and chemical transformations. 4 represents a chromophoric system based on a phenazin-7-one, 5 and 6 are new 5,10-dihydrophenazine derivatives.     

Arylomycins A and B,new biaryl-bridged lipopeptide antibiotics produced by Streptomyces sp. Tü 6075. I. Taxonomy,fermentation, isolation and biological activities

New lipopeptide antibiotics, colourless arylomycins A series and yellow arylomycins B series were detected in the culture filtrate and mycelium extracts of Streptomyces sp. Tü 6075 by HPLC-diode-array and HPLC-electrospray-mass-spectrometry screening. Arylomycins are a family of lipohexapeptide antibiotics, which represent the first examples of biaryl-bridged lipopeptides. They show antibiotic activities against Gram-positive bacteria.     

Autosomal dominant inherited neuropathies with prominent sensory loss and mutilations: a review

Hereditary sensory neuropathies (HSNs) are rare disorders characterized by progressive distal sensory loss, predominantly affecting the lower limbs. Foot ulcers, severe skin and bone infections, arthropathy, and amputations are frequent and feared complications. Occasionally, patients complain of spontaneous shooting or lancinating pain. Autonomic fibers can be affected to a variable degree. Patients with HSN can also have severe distal weakness, and some HSN variants have therefore been classified among the hereditary motor and sensory neuropathies (HMSNs). Molecular genetic studies of autosomal dominant inherited neuropathies with prominent sensory loss and ulceromutilating features have assigned the genetic loci for HMSN type 2B (Charcot-Marie-Tooth syndrome type 2B) and HSN type 1 to chromosomes 3q13-22 and 9q22.1-22.3, respectively. However, some families with HSN have been excluded for linkage to these loci, suggesting further genetic heterogeneity. Recently, disease-causing mutations in the SPTLC1 gene have been identified in patients with HSN type 1. In this review, we discuss the hallmark features associated with the distinct genetic subtypes of autosomal dominant inherited HSN and provide genotype-phenotype correlations.     

Supplemental fructooligosaccharides and mannanoligosaccharides influence immune function, ileal and total tract nutrient digestibilities, microbial populations and concentrations of protein catabolites in the large bowel of dogs

The goal of this study was to examine whether supplemental fructooligosaccharides (FOS) and (or) mannanoligosaccharides (MOS) influenced indices of gut health of dogs. Adult female dogs (n = 4) surgically fitted with ileal cannulas were fed a dry, extruded, kibble diet twice daily. At each feeding, the following treatments were administered: 1) Control (no FOS or MOS); 2) 1 g FOS; 3) 1 g MOS; or 4) 1 g FOS + 1 g MOS. Fecal, ileal and blood samples were collected during the last 4 d of each 14-d period to measure protein catabolite concentrations, microbial populations, immune characteristics and nutrient digestibilities. Treatment means were compared using preplanned orthogonal contrasts. Dogs supplemented with MOS had lower (P = 0.05) fecal total aerobes and tended to have greater (P = 0.13) Lactobacillus populations. Ileal immunoglobulin (Ig) A concentrations were greater (P = 0.05) in dogs supplemented with FOS + MOS vs. control. Lymphocytes (% of total white blood cells) were greater (P < 0.05) in dogs supplemented with MOS. Serum IgA concentrations also tended (P = 0.13) to be greater in dogs supplemented with MOS. Dogs supplemented with FOS and FOS + MOS had lower (P < 0.05) fecal total indole and phenol concentrations. Dogs supplemented with MOS tended to have lower ileal DM (P = 0.149) and OM (P = 0.146) digestibilities vs. control. Results of this study suggest that dietary supplementation of FOS and MOS may have beneficial effects on colonic health and immune status of dogs.     

Savoxepine versus haloperidol

Savoxepine, an atypical neuroleptic compound developed in the 1980s, was believed to act via selective limbic dopamine D₂-receptor blockade. The results of the presented double-blind, randomised, controlled clinical trial comparing savoxepine (n = 58) with haloperidol (n = 29) did not confirm the preclinical data suggesting that savoxepine would produce fewer extrapyramidal symptoms than the comparator. Animal data and PET-results obtained a posteriori suggested that this unfavourable outcome may have been due to the conventional, step-wise dose increase strategy used in the study leading to a high dopamine D₂-receptor occupancy in the striatum thus eliciting EPS. Using either a slower dose-titration or a high, single loading dose followed by a low maintenance dosing may have offered the possibility to obtain a good antipsychotic effect together with low incidence of EPS. In future clinical trials with new neuroleptics, the preclinical data should be carefully evaluated, and drug brain kinetic parameters taken into consideration. Received: 4 December 2001 / Accepted: 5 April 2002