Molecular genetic analysis of 675 group A streptococcus isolates collected in a carrier study at Lackland Air Force Base,San Antonio,Texas

Contemporary molecular genetic analysis methods have not been used to study large samples of carriage isolates of group A Streptococcus. To determine the emm types causing asymptomatic carriage and pharyngitis in a closed population, we analyzed 675 isolates recovered from a population-based surveillance study of 10,634 recruits at Lackland Air Force Base, Texas, during 4 months in 1993-1994. Strains with emm1 and emm6 alleles accounted for only 22% of the isolates recovered from asymptomatic recruits at entrance to training. However, these 2 emm types caused 69% of the pharyngitis cases identified during training and represented 51% of the isolates recovered from the throat on exit from training. Sequence analysis of the hypervariable sic gene documented that distinct emm1 subclones disseminated in specific training groups called flights. The preferential increase in the prevalence of emm1 and emm6 isolates during the 6-week training period indicates an enhanced ability of these strains to disseminate and cause disease in this population.     

Health status of patients with juvenile rheumatoid arthritis at 1 and 5 years after diagnosis

OBJECTIVE: To describe the health and functional status of children with juvenile rheumatoid arthritis (JRA) diagnosed in the early 1990s. METHODS: Patients were obtained from the Pediatric Rheumatology Disease Registry, a database of patients seen in pediatric rheumatology centers across the United States. Questionnaires designed to be filled out after retrospective chart review were sent to pediatric rheumatologists caring for children diagnosed with JRA between 1992 and 1997. RESULTS: We studied 703 patients -- 376 with pauciarticular onset (pauci), 232 with polyarticular onset (poly), and 95 with systemic onset JRA (systemic). At 1 year after diagnosis, half of the pauci and systemic patients no longer required medication, compared to 78% of the poly patients; 98% of the patients functioned in Steinbrocker classes I and II. Six percent of pauci, 27% of poly, and 11% of systemic patients had limitations in school function. Nearly 1/3 of poly patients already had joint space narrowing on radiograph. By 5 years after diagnosis, all pauci, 88% of poly, and 70% of systemic patients were in Steinbrocker classes I and II; but 6% of pauci, 28% of poly, and 44% of systemic patients had limitations in school function. Nearly 2/3 of poly and systemic patients had joint space narrowing. CONCLUSION: In these children treated prior to the era of biologic therapy, at 5 years after onset, > 25% of poly and nearly half of systemic patients had functional limitations that required modifications in their school schedule. Radiographically evident joint space damage was seen within a year of onset in poly patients, and by 5 years 2/3 of poly and systemic patients had damage.     

CO2 retention in lung disease; could there be a pre-existing difference in respiratory physiology

Some patients with lung disease retain CO(2), while others with similar lung function do not. This could be explained if CO(2) retainers had a pre-existing low hypercapnic ventilatory response (HCVR) and, from this, a tendency to retain CO(2). To test if such a phenomenon exists in healthy people, we determined the change in end-tidal P(CO(2)) (deltaPET(CO(2))) produced by the addition of a dead-space (DS), during wakefulness and sleep, and related this to the HCVR measured awake. The group mean (n=14) HCVR slope was 2.2+/-1.1 (S.D.) L min(-1) mmHg(-1). The deltaPET(CO(2)) with the application of DS was 1.6+/-1.6 mmHg awake and 2.6+/-2.2 mmHg asleep. During wakefulness the deltaPET(CO(2)) with DS did not correlate with the HCVR slope. However, during sleep, four subjects had a marked increase in the deltaPET(CO(2)) (3.7, 4.3, 6.2, 8.0 mmHg) and a relatively low HCVR (slope 1.5, 1.7, 1.5, 1.7 L min(-1) mmHg(-1), respectively). We speculate that such individuals, should they develop lung disease, may be predisposed to retain CO(2).     

Patterns of cartilage structural protein loss in human tracheal stenosis

OBJECTIVES: The study sought to identify which of the major structural proteins in tracheal cartilage are lost in the inflammatory process, and to determine whether damaged cartilage shows signs of regeneration and whether this is an age-dependent phenomenon. STUDY DESIGN: Immunohistochemical analysis. METHODS: Archival human tracheal and subglottic stenosis segments removed for the treatment of airway compromise were investigated by means of immunohistochemical analysis for differential loss of collagen type I or type II or aggrecan. RESULTS: Specimens were found to have preferentially lost collagen I and aggrecan in areas of severe disruption of the cartilage ring. Collagen II was preserved. In addition, areas of apparent cartilage regeneration were identified based on increased collagen II and aggrecan relative to baseline levels in uninjured sections of the rings. Regenerative capacity was present in most of the specimens investigated and was not age specific. CONCLUSIONS: Collagen I and aggrecan are lost in areas of severe ring compromise, indicating that at least one of these two molecules is responsible for structural integrity. The remaining cartilage has some regenerative capacity, but it is small relative to the degree of cartilage damage. No new collagen I was identified in the cartilage ring, indicating that, although an intense inflammatory reaction occurred, fibroblasts did not deposit new collagen I as seen in other scar tissues.     

Malignant mesothelioma: PAS-diastase positivity and inversion of polarity in intravascular tumour

AIMS: Periodic acid-Schiff (PAS)-diastase-positive material was identified within pseudoglandular structures within the small intravascular component of two pleural malignant mesotheliomas. The aim of this study was to ascertain the nature of this material and to asses the polarity of the cells forming the pseudoglandular structure. METHODS AND RESULTS: Immunohistochemistry was performed using antibodies to laminin and type IV collagen and the antibody HBME-1. These demonstrated the material to be basement membrane rather than mucin. The apical polarity marker HBME-1 was not related to the internal pseudoglandular structure but stained the periphery of intravascular tumour clumps. CONCLUSIONS: Pseudoluminal PAS-diastase-positive material in malignant mesothelioma may easily be mistaken for epithelial mucin, leading to an erroneous diagnosis of adenocarcinoma. The presence of basement membrane material in pseudolumina, as defined by the presence of laminin and type IV collagen, surrounded by tumour cells whose external surface expresses the apical polarity marker HBME-1 implies inversion of polarity of tumour cells within vascular spaces.     

Systematic review of randomized controlled trials of nonpharmacological interventions for fibromyalgia

OBJECTIVE: Little is known of the effectiveness of nonpharmacological interventions for fibromyalgia syndrome (FMS). The authors therefore carried out a systematic review from 1980 to May 2000 of randomized controlled trials (RCTs) of nonpharmacological interventions for FMS. METHOD: A search of computerized databases was supplemented by hand searching of bibliographies of key publications. The methodological quality of studies included in the review was evaluated independently by two researchers according to a set of formal criteria. Discrepancies in scoring were resolved through discussion. RESULTS: The review yielded 25 RCTs, and the main categories of interventions tested in the studies were exercise therapy, educational intervention, relaxation therapy, cognitive-behavioral therapy, acupuncture, and forms of hydrotherapy. Methodological quality of studies was fairly low (mean score = 49.5/100). Most studies had small samples (median for individual treatment groups after randomization = 20), and the mean power of the studies to detect a medium effect ( > or = 0.5) was 0.36. Sixteen studies had blinded outcome assessment, but patients were blinded in only 6 studies. The median longest follow-up was 16 weeks. Statistically significant between-group differences on at least one outcome variable were reported in 17 of the 24 studies. CONCLUSIONS: The varying combinations of interventions studied in the RCTs and the wide range of outcome measures used make it hard to form conclusions across studies. Strong evidence did not emerge in respect to any single intervention, though preliminary support of moderate strength existed for aerobic exercise. There is a need for larger, more methodologically rigorous RCTs in this area.     

PS-341, a novel proteasome inhibitor,induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis

Treatment with the proteasome inhibitor, PS-341 resulted in concentration- and time-dependent effects on Bcl-2 phosphorylation and cleavage in H460 cells that coincided with the PS-341-induced G2-M phase arrest. The observed Bcl-2 cleavage paralleled the degree of PS-341-induced apoptosis but was detected to a similar extent with comparable concentrations of two other proteasome inhibitors (MG-132 and PSI). Calpain inhibitors, ALLM and ALLN, and the caspase inhibitors, Z-VAD and AC-YVAD did not induce BcI-2 phosphorylation and cleavage. Exposure to PS-341 resulted in an additional Mr 25,000 cleavage fragment of Bcl-2, whereas only a Mr 23,000 fragment was observed with other anticancer agents. The formation of the Mr 25,000 fragment was not prevented by caspase inhibitors unlike the Mr 23,000 fragment, which suggests mediation by a caspase-independent pathway. Cell fractionation studies revealed that the Bcl-2 cleaved fragments localize within membrane structures and was an early event (at approximately 12 h, posttreatment), and before the observed cleavage of poly(ADP-ribose) polymerase (PARP), beta-catenin, and DNA fragmentation (at approximately 36 h posttreatment). The Mr 23,000 Bcl-2 cleavage product was inhibited by the pan-caspase inhibitor and the inhibitors of capase-3, -8, -9; but the PARP cleavage was prevented only by the pan-caspase and caspase-3 inhibitors, which suggests that the Mr 23,000 Bcl-2 cleavage occurred at both the initiation and execution stages of apoptosis. The inhibition of the ubiquitin/proteasome pathway by PS-341 leads, at an early stage of apoptosis, to Bcl-2 phosphorylation and a unique proteolytic cleavage product, which are associated with G2-M phase arrest and the induction of apoptosis.