Cytotoxic T-cell responses show more restricted specificity for self than for non-self H-2D-coded antigens

The specificity of recognition of H-2 antigens by various subsets of Tc cells was investigated with respect to the two separate molecules known to be coded in the H-2D(d) region (a) D which carries the private specificity H-2.4 and (b) D’which carries the public specificity H-2.28. BALB/c.H-2(db) mutant mice express D but not D’ on their cell surfaces, whereas wild-type BALB/c mice express both D and D’. H-2 restricted Tc cells specific for viral-plus- H-2D(d)-coded antigens on infected self cells, or minor H-plus-H-2D(d)-coded antigens on H-2-compatible cells apparently recognize D, but do not detectably recognize D. In contrast, BALB/c-H-2(db) anti-BALB/c Tc cell responses do recognize D’ (the only known antigen which is not shared by mutant and wild-type); furthermore, D’ is also detectably recognized by a significant proportion of the Tc cells that respond in MLR to H-2D(d)-coded antigens. In these latter responses, D’ was recognized separately from D, i.e., the response was not “H-2 restricted”. These results indicate that H-2 restricted Tc cell responses to modified-self cells are more specific for self H-2D(d)-coded antigens then are allogeneic Tc cell responses directed at the same antigens, in that haplotype-unique (private) specificity recognition (of the D molecule) exclusively occurs only in the former, not the latter case. The implications of this specificity of H-2 restricted responses for possible processes of somatic selection of anti-self recognition structures on progenitor Tc cells are briefly discussed.     

Circulating glycosaminoglycan anticoagulants associated with suramin treatment

A complex coagulopathy appeared in three women receiving suramin as treatment for metastatic adrenocortical carcinoma. Although hepatocellular dysfunction accounted for some of the abnormality, a unique feature of the coagulopathy was the presence of an inhibitor of the thrombin clotting time. The potency of this circulating anticoagulant increased markedly during exacerbations of hepatic injury. The anticoagulant was removed from plasma samples from two of the patients by passage over a column of diethylaminoethyl (DEAE)- Sephacel. It eluted from the DEAE at salt concentrations that removed "high-charge" glycosaminoglycans. Elimination of the purified anticoagulant activity in vitro required a combination of heparitinase and chondroitinase ABC, suggesting that the activity was mediated by both heparan sulfate and dermatan sulfate. Suramin is hypothesized to inhibit enzymes that normally degrade glycosaminoglycans, resulting in accumulation of these substances, which are released from the liver into the circulation during periods of hepatic injury.     

Eliminating right ventricular pacing may not be best for patients requiring implantable cardioverter-defibrillators

BACKGROUND: Excessive right ventricular (RV) pacing has been associated with adverse clinical outcomes in patients receiving pacemakers or implantable cardioverter-defibrillators (ICDs). It remains uncertain how much RV pacing is clinically deleterious. OBJECTIVE: This retrospective analysis assessed the relationship between the amount of RV pacing and the composite of all-cause mortality and heart failure hospitalization in all patients programmed DDDR in the Inhibition of Unnecessary RV Pacing with AV Search Hysteresis in ICDs (INTRINSIC RV) study. METHODS: Seven hundred fifteen patients consistently programmed to DDDR mode throughout follow-up (mean 11.6 months) were examined. The relationship between RV pacing tier and death and heart failure hospitalization was determined and compared with patient characteristics. RESULTS: Across the six RV pacing tiers, patients differed significantly with respect to age, clinical history of ventricular tachycardia, atrial fibrillation, and atrial flutter, and amiodarone use. When controlling for these baseline differences, the best outcome was seen in the group with RV pacing between 10% and 19% (2.8% event rate; n = 106). Increasing levels of RV pacing were generally predictive of higher event rates (death or heart failure hospitalization; P = 0.003), except for the group (n = 344) with the least amount of RV pacing (0-9%). This group exhibited poorer outcomes than otherwise expected (P = 0.016), with 8.1% of these patients experiencing an event. CONCLUSIONS: High levels of RV pacing are associated with heart failure hospitalization and mortality in a large ICD population. However, ICD patients with some RV pacing (10%-19%) exhibit lower event rates compared with those with very low levels (0-9%), possibly due to the physiologically appropriate nature of that RV pacing.     

Antisense oligodeoxynucleotide combination therapy of primary chronic myelogenous leukemia blast crisis in SCID mice

The proliferation of chronic myelogenous leukemia (CML) cells and the transformation of normal hematopoietic cells by BCR-ABL appear to require the expression of a functional MYC protein, suggesting an approach to treatment of Philadelphia leukemias based on simultaneous targeting of BCR-ABL and c-MYC. To test this hypothesis, CML-blast crisis (CML-BC) primary cells were treated in vitro with bcr-abl and c- myc antisense phosphorothioate oligodeoxynucleotides ([S]ODNs), individually or in combination. Compared with antisense ODNs targeting of individual oncogenes, downregulation of both BCR-ABL and c-MYC by specific antisense [S]ODNs resulted in a synergistic antiproliferative effect. Colony formation of normal bone marrow cells was not affected by either treatment. To assess the therapeutic potential of multiple oncogene downregulation, SCID mice injected with CML-BC primary cells were treated systematically with equal doses of bcr-abl or c-myc antisense [S]ODNs or with a combination of both antisense [S]ODNs. Compared with mice treated with individual compounds, the disease process was significantly retarded in the group treated with both [S]ODNs as revealed by flow cytometry, clonogenic assay, and RT-PCR analysis to detect leukemic cells in mouse tissue cell suspensions. These effects correlated with a markedly increased survival of leukemic mice treated with both antisense [S]ODNs. Leukemic cells harvested from antisense [S]ODN-treated mice were sensitive to the effects of antisense [S]ODNs in vitro, suggesting that the treatment can be successfully repeated. These data demonstrate the therapeutic potential of targeting multiple cooperating oncogenes.     

Expression,localization and alternative function of cytoplasmic asparaginyl-tRNA synthetase in Brugia malayi

Aminoacyl-tRNA synthetases (AARS) are a family of enzymes that exhibit primary and various secondary functions in different species. In Brugia malayi, the gene for asparaginyl-tRNA synthetase (AsnRS), a class II AARS, previously has been identified as a multicopy gene encoding an immunodominant antigen in the serum of humans with lymphatic filariasis. However, the relative level of expression and alternative functions of AARS in nematode parasites is not well understood. We searched the Filarial Genome Project database to identify the number and amino acid specificity of B. malayi AARS cDNAs to gain insight into the role of different AARS in filaria. These data showed that cytoplasmic AsnRS was present in five gene clusters, and is the most frequently represented member of the aminoacyl-tRNA synthetase family in adult B. malayi. The relative level of AsnRS transcribed in adult female B. malayi was compared to the levels of a low abundance and medium abundance AARS by quantitative real-time RT-PCR. By this method, AsnRS cDNA was 11 times greater than arginyl-tRNA synthetase and methionyl-tRNA synthetase cDNA. In situ hybridization using a B. malayi AsnRS-specific oligonucleotide probe identified abundant cytoplasmic mRNA, particularly in the hypodermis of adult B. malayi. In the absence of tRNA, AsnRS synthesizes diadenosine triphosphate, a potent regulator of cell growth in other eukaryotes. These data support the hypothesis that all AARS are not equally expressed in B. malayi and that these enzymes may demonstrate important alternative functions in filaria.     

Traumatic carotid cavernous fistula: Anatomical variations and their treatment by detachable balloons

Endovascular balloon occlusion has become a standard mode of therapy in carotid cavernous fistulas. Many angio-architectural variations are, however, encountered in individual cases, some of which influence the therapeutic mode and outcome. We report on three patients with carotid cavernous fistulas treated by endovascular techniques.     

Add-on quetiapine for bipolar depression: a 12-month open-label trial.

OBJECTIVES: Bipolar disorder (BD) is a disabling and often chronic condition. Patients with BD suffer from depression at least one-third of the time, but they do not always respond well to conventional mood stabilizers. Attempts to treat them with antidepressants can provoke a switch to mania or increased cycling. Our open-label trial aimed to assess the long-term response of patients with bipolar depression to the addition of quetiapine to their usual treatment. Our study also sought to assess the safety and tolerability of quetiapine in patients with BD. METHOD: To meet inclusion criteria for the study, patients had a DSM-IV diagnosis of type I or II BD, were aged 18 years and older, currently suffered from depression with a score of > 18 on the Hamilton Depression Rating Scale (HDRS), and had no change in antidepressant use for at least 3 weeks prior to the study. We added quetiapine to patients' medication and attempted to increase the dosage to at least 400 mg daily. Outcome was measured at baseline and once monthly for 12 months on the HDRS, the Young Mania Rating Scale, the Clinical Global Impression Scale (CGI), and the Abnormal Involuntary Movement Scale. RESULTS: There were 19 patients enrolled in the study (6 men and 13 women), 2 of whom dropped out because they could not tolerate the drug. Seventeen completed at least 2 assessments, and 7 patients completed the full 12-month trial. Data for the 17 patients (that is, last observation carried forward) at 12 months shows HDRS scores reduced from 27.2 to 12.1 and CGI scores reduced from 4.7 to 2.6. CONCLUSIONS: Quetiapine seems to be helpful to and relatively well tolerated by patients with bipolar depression when it is added to their usual treatment. There is, however, a need for controlled trials.     

Nontuberculous mycobacterial infection in AIDS: clinical, pathologic, and radiographic features

The medical records, radiographs, and pathologic specimens of ten patients with the diagnoses of nontuberculous mycobacterial infection and acquired immunodeficiency syndrome (AIDS) were examined. The radiographic findings of alveolar or nodular infiltrates and adenopathy were relatively nonspecific but in most cases led to bronchoscopic study or open-lung biopsy, which established the diagnosis. Bronchoscopic washings or sputum cultures, which frequently provided the first confirmation of infection, were always followed by positive blood or tissue cultures. In contrast to nontuberculous infection in immunocompetent hosts, disseminated infection was common, with evidence of extrapulmonary involvement in nine patients. On the basis of these findings, we recommend that any AIDS patient with sputum or bronchoscopic washings demonstrating nontuberculous mycobacterial organisms be tentatively classified as having disseminated infection while being evaluated with blood, bone-marrow, stool, and urine cultures, even if the chest radiograph shows no disease.