Interleukin-10 promotes activation-induced cell death of SLE lymphocytes mediated by Fas ligand.

Immune function in SLE is paradoxically characterized by active T cell help for autoantibody production, along with impaired T cell proliferative and cytokine responses in vitro. To reconcile these observations, we investigated the possibility that the accelerated spontaneous cell death of SLE lymphocytes in vitro is caused by an activation-induced cell death process initiated in vivo. 27 SLE patients, three patients with systemic vasculitis, seven patients with arthritis, and 14 healthy subjects were studied. Patients with clinically active SLE or systemic vasculitis had accelerated spontaneous death of PBMC with features of apoptosis at day 5 of culture. A prominent role for IL-10 in the induction of apoptosis was observed, as neutralizing anti-IL-10 mAb markedly reduced cell death in the active SLE patients by 50%, from 22.3 +/- 5.2% to 11.2 +/- 2.8%, and the addition of IL-10 decreased viability in the active SLE group, but not in the control group, by 38%. In addition, apoptosis was shown to be actively induced through the Fas pathway. The potential clinical relevance of T cell apoptosis in active SLE is supported by the correlation of increased apoptosis and IL-10 levels in vitro with low lymphocyte counts in vivo. We conclude that the spontaneous cell death observed in vitro in lymphocytes from patients with SLE and other systemic autoimmune disorders results from in vivo T cell activation, is actively induced by IL-10 and Fas ligand, and reflects pathophysiologically important events in vivo. Activation-induced cell death in vivo provides a pathogenic link between the aberrant T helper cell activation and impaired T cell function that are characteristic features of the immune system of patients with SLE.     

Abstracts from other journals

The aim of the present study was to clinically evaluate fissure sealants on the occlusal fissures and buccal pits of permanent first and second molars after 20 and 15 years, respectively. The population consisted of 72 children, each of whom had had their four first molars sealed between 1977 and 1980. At the annual examinations, all caries-free, newly erupted second molars were sealed. When sealant was applied to the second molars, the first molars were checked and sealant was reapplied to those that had deficient sealants. At the follow-up, when the subjects were 26–27 years of age, 27 in the original group had moved from the community. Thus, the present result is based on 45 subjects. One hundred and fifty-three sealed first molars and 161 sealed second molars were available for inspection. At the follow-up examination of the first molars 20 years after sealant had been applied, 65% showed complete retention, 22% partial retention without caries, and 1306 caries or restoration in the occlusal fissures or buccal pits. At the 15-year follow-up of the second molars, the corresponding figures were 65%, 30% and 5%, respectively. Of the restored or carious molars, significantly more were found in the mandible than in the maxilla ( P  < 0.001). This longitudinal study showed that pit and fissure sealants, applied during childhood, have a long-lasting, caries-preventive effect.     

Effect of recombinant human interleukin-6 (rhIL-6) and rhIL-3 on hematopoietic regeneration as demonstrated in a nonhuman primate chemotherapy model

Using a recently developed hepsulfam-induced pancytopenia model in rhesus macaques, we have studied the effects of recombinant human interleukin-6 (rhIL-6) and rhIL-3 on marrow regeneration. Control animals were given hepsulfam (1.5 g/m2 by a single 30-minute intravenous [i.v.] injection, n = 4), while study animals received hepsulfam followed by rhIL-6, rhIL-3, or a combination of rhIL-6 and rhIL-3 (n = 3 per study group). Each cytokine was administered by once- daily subcutaneous (SC) injection (15 micrograms/kg/d) for 3 weeks beginning the day after chemotherapy (days 2 through 22). Mean platelet counts in control animals were < 100,000/microL on days 15 through 24, with 50% of the counts < 50,000/microL and two of four animals requiring platelet transfusion. In the rhIL-6- and rhIL-6/rhIL-3- treated groups, the nadir mean platelet counts were 164,000 +/- 58,700/microL and 162,300 +/- 23,800/microL, respectively, and occurred on day 15. Platelet counts in the rhIL-3-treated group were similar to those in controls. Mean absolute neutrophil counts (ANCs) < 1,000/microL occurred on days 10 through 29 in control animals, days 8 through 15 in rhIL-6-treated animals, and days 6 through 8 and 13 in rhIL-6/rhIL-3-treated animals. The frequency of ANCs < 500/microL was significantly less in the rhIL-6- and rhIL-6/rhIL-3-treated groups versus control groups (2.7 +/- 0.6 and 2.0 +/- 1.0 vs 7.0 +/- 1.4 occurrences, respectively; P < .05). rhIL-3-treated animals had ANCs similar to those in controls; one animal died with septicemia on day 21. Monkeys receiving rhIL-6 were significantly more anemic during the cytokine administration period; however, the anemia resolved by day 24. Coadministration of rhIL-3 and rhIL-6 partially corrected the anemia. The data indicate that rhIL-6 prevents significant thrombocytopenia and shortens the neutropenic period in this chemotherapy model.     

单克隆抗体BDI－I导向的阿霉素白蛋白毫微球对人膀胱癌细胞的特异杀伤活性

用化学偶联法将抗人膀胱癌单克隆抗体分子偶联到阿霉素白蛋白毫微球上，构建了一个有靶向杀伤性的免疫毫微球，即：阿霉素白蛋白载单克隆抗体毫微球（ＡＤＲ－ＮＰ－Ａｂ）。改变阿霉素毫微球和单克隆抗体的反应分子比，确定了制备该免疫毫微球的最佳条件。经免疫荧光检测及显微照像分析证明，免疫毫微球可有效地和人膀胱癌细胞结合。体外杀伤试验表明，此免疫毫微球对靶细胞ＥＪ有高度特异杀伤活性，而对无关的人直肠癌Ｌｏｖｏ细胞则无明显作用。     

Rapid typing of the human Fc gamma receptor IIA polymorphism by polymerase chain reaction amplification with allele-specific primers

BACKGROUND: The human Fc gamma receptor IIa (Fc gamma RIIa) is expressed in two polymorphic forms, Fc gamma RIIa-H131 and Fc gamma RIIa-R131, that differ by the replacement of histidine by arginine at position 131. This replacement is caused by a single-nucleotide exchange of A–>G. The resulting receptor forms differ in their binding to human IgG2 and mouse IgG1, which may lead to a different immunologic defense to bacterial polysaccharides and encapsulated bacteria. STUDY DESIGN AND METHODS: A rapid and easy polymerase chain reaction(PCR) method of genotyping the Fc gamma RIIa was developed. Allele-specific primers discriminate between the Fc gamma RIIa-H131 and the Fc gamma RIIa-R131 forms of the receptor. The results were compared with those obtained by another DNA-based genotyping method, in which PCR-amplified DNA was hybridized with allele-specific oligonucleotides, and with a functional phagocytosis assay using mouse IgG1-coated red cells as target antigens. RESULTS: The genotypes deduced from the PCR with allele-specific primers were in complete accordance with those obtained by the data from the hybridization of PCR-amplified DNA with allele- specific oligonucleotides. Furthermore, the Fc gamma RIIa genotypes of 28 individuals in all cases corresponded to the functional phenotypes. CONCLUSION: The use of PCR with allele-specific primers provides a rapid and easily performed method for the determination the Fc gamma RIIa polymorphism.     

Diagnostic error due to vicarious excretion of rectal iodinated contrast

Introduction of iodinated contrast into the intact colon is not expected to result in imaging‐visible renal excretion of this contrast and is a phenomenon that has only rarely been described. We present a case in which such vicarious renal excretion was misinterpreted as a recto‐vesical fistula which resulted in unnecessary delay in the patient’s management.     

Polymorphisms in the 13q33.2 gene G72/G30 are associated with childhood-onset schizophrenia and psychosis not otherwise specified.

BACKGROUND: Childhood-onset schizophrenia (COS), defined as onset of psychotic symptoms by age 12 years, is a rare and severe form of the disorder that seems to be clinically and neurobiologically continuous with the adult disorder. METHODS: We studied a rare cohort consisting of 98 probands; 71 of these probands received a DSM-defined diagnosis of schizophrenia, and the remaining 27 were diagnosed as psychosis not otherwise specified (NOS) (upon 2-6 year follow-up, 13 have subsequently developed bipolar disorder). Two overlapping genes, G72 and G30 on 13q33.2, were identified through linkage-disequilibrium-based positional cloning. Single nucleotide polymorphisms (SNPs) at the G72/G30 locus were independently associated with both bipolar illness and schizophrenia. We analyzed SNPs at this locus with a family-based transmission disequilibrium test (TDT) and haplotype analyses for the discrete trait, as well as quantitative TDT for intermediate phenotypes, using the 88 probands (including COS and psychosis-NOS) with parental participation. RESULTS: We observed significant pairwise and haplotype associations between SNPs at the G72/G30 locus and psychotic illness. Furthermore, these markers showed associations with scores on a premorbid phenotype measured by the Autism Screening Questionnaire, and with age of onset. CONCLUSIONS: These findings, although limited by potential referral bias, confirm and strengthen previous reports that G72/G30 is a susceptibility locus both for schizophrenia and bipolar disorder.     

Evaluation of dexmedetomidine therapy for sedation in patients with toxicological events at an academic medical center

Introduction. Although clinical use of dexmedetomidine (DEX), an alpha₂-adrenergic receptor agonist, has increased, its role in patients admitted to intensive care units secondary to toxicological sequelae has not been well established. Objectives. The primary objective of this study was to describe clinical and adverse effects observed in poisoned patients receiving DEX for sedation. Methods. This was an observational case series with retrospective chart review of poisoned patients who received DEX for sedation at an academic medical center. The primary endpoint was incidence of adverse effects of DEX therapy including bradycardia, hypotension, seizures, and arrhythmias. For comparison, vital signs were collected hourly for the 5 h preceding the DEX therapy and every hour during DEX therapy until the therapy ended. Additional endpoints included therapy duration; time within target Richmond Agitation Sedation Score (RASS); and concomitant sedation, analgesia, and vasopressor requirements. Results. Twenty-two patients were included. Median initial and median DEX infusion rates were similar to the commonly used rates for sedation. Median heart rate was lower during the therapy (82 vs. 93 beats/minute, p < 0.05). Median systolic blood pressure before and during therapy was similar (111 vs. 109 mmHg, p = 0.745). Five patients experienced an adverse effect per study definitions during therapy. No additional adverse effects were noted. Median time within target RASS and duration of therapy was 6.5 and 44.5 h, respectively. Seventeen patients (77%) had concomitant use of other sedation and/or analgesia with four (23%) of these patients requiring additional agents after DEX initiation. Seven patients (32%) had concomitant vasopressor support with four (57%) of these patients requiring vasopressor support after DEX initiation. Conclusion. Common adverse effects of DEX were noted in this study. The requirement for vasopressor support during therapy warrants further investigation into the safety of DEX in poisoned patients. Larger, comparative studies need to be performed before the use of DEX can be routinely recommended in poisoned patients.