Relationship between peptide binding and T cell epitope selection: a study with subtypes of HLA-B27

The effect of HLA-B27 polymorphism on antigen presentation was analysed by comparing the binding of three Epstein-Barr virus-derived peptide epitopes to HLA-B27 subtypes with their immunogenicity and antigenicity in the context of these subtypes. The effect of altering the major anchor residue Arg2 on binding or on recognition by peptide-specific cytotoxic T lymphocytes (CTL) was also examined. The three peptides bound significantly to all the B*2701-B*2706 subtypes. This did not correlate with the peptides being immunogenic or recognized by specific CTL in the context of only particular subtypes. In addition, of the three viral epitopes tested, those that were immunogenic in B*2702- or B*2705-restricted responses bound to these subtypes less efficiently than one peptide that was immunogenic only in the B*2704 context. Thus, among several potentially immunogenic peptides from the same virus, the antiviral response is not necessarily directed against the one that binds best to the restricting subtype. These results indicate that HLA- B27 polymorphism influences antigen presentation in ways other than simply peptide affinity. Synthetic analogues lacking the canonical Arg2 motif of HLA-B27-bound peptides, even when binding much worse to the restricting subtype, were recognized equally by CTL specific for the parental peptide. This indicates that Arg2 is not required to maintain the structure of the epitope. The implications of these results for pathogenetic models of HLA-B27-associated disease are discussed.      

GIR2 Noncompliance with Dosing Instructions and Gastrointestinal Outcomes Associated with Alendronate for Osteoporosis in a Large HMO

Gastroesophageal reflux disease(GERD) usually requires long-term therapy. Treatment strategies include proton pump inhibitor (PPI) or H2receptor-antagonists (H2RA), or prokinetic agents.
OBJECTIVE: A decision tree analytic model for comparing economic and clinical outcomes of GERD treatment strategies using continuous or intermittent therapy with PPI, H2RA, or prokinetic agents was developed.
METHODS: Two decision tree models were constructed. One compared four continuous drug therapies; the other compared four intermittent drug treatments. Base values for heal rates and relapse frequencies were determied by analysis of published clinical data. Costs were drug, physician visit, endoscopy, and surgery costs. Clinical outcomes (percent of patients asymptomatic) and economic outcomes (direct costs) were determined at 12 months.
RESULTS: The four continuous treatment strategies resulted in 99–100% asymptomatic patients at 1 year whereas the four intermittent strategies resulted in 76–80% asymptomatic patients at 1 year. At 1 year, the costs per asymptomatic patient, for continuous treatment strategies, were $1069, $1083, $1164, and $1193 for omeprazole 20 mg daily initially followed by omeprazole 10 mg, omeprazole 20 mg, or ranitidine 300 mg daily, or ranitidine 300 mg daily continously, respectively, and for intermittent strategy, were $1299, $1304, $1353, and $1455 for omeprazole 20 mg, cisapride 40 mg daily followed by omeprazole for failures, ranitidine 300 mg daily followed by omeprzole for failures, and ranitidine 300 mg daily followed by ranitidine 600 mg daily. Sensitivity analyses showed omeprazole cost and healing rate to have the greatest impact on the cost of treatment.
CONCLUSIONS: These GERD decision tree analytic models are useful tools for comparing economic and clinical outcomes of drug treatment strategies over a wide range of costs and clinical efficacies.     

O，O＇－二烷基－O－″－（取代苯乙腈肟）磷酸酯、硫代磷酸酯的合成及对氯硝柳胺的灭螺增效作用

合成了２０个Ｏ，Ｏ’－二烷基－Ｏ－”－（取代苯乙睛肟）磷酸酯、硫代磷酸酯，并分别与杀螺剂氯硝柳胺组成复方，进行室内杀螺试验，初步结果表明，化合物Ｖ４、７、１２、１８有明显杀螺增效作用，其中Ｖ１２可使氯硝柳胺的杀螺效果提高３．８ｌ倍。同时发现化合物Ｖ２、１０、１３单独使用时，也有良好的杀螺作用。     

Assessing Coronary Flow Physiology with Intracoronary Doppler Following Coronary Interventions

Although coronary angiography has been the gold standard for assessing coronary artery stenoses, it yields information primarily about the anatomical severity of coronary artery disease, which frequently does not correlate with its physiological severity. Coronary interventions (PTCA, atherectomy, laser, etc.) are performed primarily to improve coronary flow physiology. Coronary flow physiology may be a more important end point than angiography following coronary interventions that were performed to normalize coronary flow physiology. In addition, the physiological significance of angiographically intermediate stenoses should he assessed before proceeding with catheter-based revascularization. Currently, the Doppler guidewire is available for routine clinical assessment of coronary flow physiology in the Cardiac Catheterization Lab. Several Doppler measurements have been used to assess the physiological effect of a stenosis, including the diastolic-systolic velocity ratio, proximal-distal velocity ratio, coronary flow reserve, continuity equation, and the hyperemic diastolic pressure-flow relationship. The Doppler derived coronary flow reserve correlates highly with stress nuclear perfusion images. These Doppler measurements have been made following PTCA, directional atherectomy, rotational atherectomy, and excimer laser. Following coronary interventions, adverse clinical events may be predicted if there is impaired flow physiology or cyclic flow variations. Many of the Doppler measurements used for assessing the lesion severity remain abnormal following successful coronary interventions for reasons unrelated to the lesion. Conversely, normalization of coronary physiology does not guarantee an adequate anatomical result. Further clinical trials will provide a more complete definition of the exact role for coronary flow velocity assessment following coronary interventions. (J Interven Cardiol 1996;9:163–173)     

Molecular Characterization of MPT83: a Seroreactive Antigen of Mycobacterium tuberculosis with Homology to MPT70

The Mycobacterium bovis antigens MPB70 and MPB83 are homologous cross-reactive proteins. It has been reported previously that MPB83 is glycosylated and exists in two forms with apparent molecular masses of 23 kDa and 25 kDa, whereas the apparent molecular mass of MPB70 is 22 kDa. Using a monoclonal antibody, SB10, which recognizes an epitope common to both MPB70 and MPB83, we compared the expression of these proteins in M. bovis BCG, virulent M. bovis and virulent Mycobacterium tuberculosis by Western blotting of bacterial lysates. The previously described pattern of high and low producing substrains of BCG for MPB70 was also applicable for MPB83. Virulent M. bovis was found to express high levels of MPB70 and MPB83. Immunoblotting experiments using sera from Balb/c mice infected with live M. tuberculosis H37Rv revealed that although the MPB83 homologue of M. tuberculosis, MPT83, is expressed at low levels in M. tuberculosis when grown in vitro, the protein is highly immunogenic during infection with live bacteria. A clone from a mycobacterial shuttle cosmid library of M. tuberculosis H37Rv was isolated which expressed both MPT70 and MPT83. Genetic analysis of this cosmid revealed that MPT70 and MPT83 were encoded by separate genes with the gene encoding MPT83 situated 2.4 kb upstream of mpt70. Both genes are transcribed in the same direction. The gene encoding MPT83 was cloned and DNA sequencing revealed an open reading frame of 660 bp encoding a protein with a predicted molecular mass of 22 kDa. Recombinant MPT83 was expressed in Escherichia coli from the native AUG initiation codon by translational coupling. In E. coli MPT83 was expressed as a 23 kDa antigen whereas in the rapid growing mycobacterium Mycobacterium smegmatis the protein was expressed as a 25 kDa protein indicating post-translational modification of the protein by M. smegmatis. In recombinant M. smegmatis MPT83 was predominantly cell associated whereas MPT70 was secreted into the culture medium. Amino acid sequence comparison between MPT83 and MPT70 revealed a 61% identity between the proteins, although little homology was apparent at the amino terminus. In MPT83 this region contained a typical lipoprotein signal peptide cleavage motif and a putative signal motif for O glycosylation. Both these motifs were absent from the amino acid sequence of MPT70.     

Pelvic Staging of Advanced and Recurrent Gynecologic Cancers: Contribution of Endosonography

From January 1988 to December 1992, 106 patients with advanced gynecologic cancer were preoperatively explored by clinical examination (CE) and endosonography (ESG) under anesthesia and by computed tomography (CT). Sixty-one tumors were primary and 45 recurrent; the main locations were cervical (73 cases), ovarian (10 cases), and endometrial (8 cases). All the patients were operated. This prospective study compares the data from clinical and imaging examinations with the histologic findings and the surgical reports. Accuracy of the CE, ESG, cytoscopy, and CT was respectively 79, 90, 82, and 80% for vesical involvement (ESG versus CT: P < 0.05). For vesicovaginal septum extension, accuracy of ESG (92%) was statistically better than that of CE (80%) and CT (77%). Accuracy of the CE, ESG, and CT was respectively 93, 97, and 89% for rectal involvement (ESG versus CT: P < 0.02). For rectovaginal septum extension, accuracy of ESG (96%) was statistically better than that of CE (85%) and CT (85%). Endosonography is valuable in the assessment of regional staging of advanced gynecologic cancers. Since it is realized during the clinical examination under anesthesia, this low-cost procedure is easily performed and provided no discomfort to the patients.     

Gangrene of the perineum. Plea for a standardized therapeutic management apropos of 50 cases]

From 1988 to 1992, 50 cases of perineal gangrene were treated with a therapeutic protocol combining: a) repeated extensive excisions, b) hyperbaric oxygen therapy, even before surgery if this was possible, and c) intensive care. The mortality rate was 24% (12/50). It was even higher in patients admitted more than 6 hours after diagnosis. The average stay in hospital was of 20 (+/- 2) days. Four patients presented with residual signs. Twenty-eight (56%) had had colostomy for lesions originating in the rectum or threatening the anal margin; 9 of these patients died, while gastrointestinal continuity was restored in another 17 cases. There were three predictive factors of survival in this series: a) early diagnosis and treatment, b) severity index on admission, c) some associations of bacteria.     

Mycotic Aneurysm of the Aortic Arch with Aortoesophageal Fistula

An elderly man presented with an aortoesophageal fistula (AEF) and underwent resection of a mycotic aneurysm of the aortic arch. After an initial success, the patient ultimately succumbed to mediastinal sepsis. The various approaches to combined aortic and esophageal pathology are presented with the recommendation for aortic replacement along with early removal of mediastinal contamination.