Triple A syndrome: genotype-phenotype assessment

The triple A or Allgrove syndrome is an autosomal-recessive disease (MIM*231550) characterized by the triad of achalasia, alacrima and adrenocorticotropic hormone (ACTH)-resistant adrenal insufficiency. Associated features of the syndrome are neurological and dermatological abnormalities. Until the discovery of the AAAS gene as the responsible gene in triple A syndrome, the diagnosis was based on characteristic clinical features. Here we present the clinical and molecular genetic data which demonstrated the marked phenotypic variability in three unrelated patients with triple A syndrome. The final diagnosis of triple A syndrome was confirmed by molecular analysis. In one patient with isolated achalasia, the diagnosis of triple A syndrome could only be made on the basis of the molecular genetic analysis of the AAAS gene. We therefore suggest that the diagnosis of triple A syndrome should be considered in patients who exhibit only one or two of the main symptoms (i.e. alacrima, achalasia or adrenal insufficiency). These patients require careful neurological investigation, and mutation analysis of the AAAS gene should be performed.     

The pathogenesis of Yersinia enterocolitica infection in gnotobiotic piglets

Yersinia enterocolitica is an important cause of enteritis and mesenteric adenitis in many countries. However the pathogenesis of the disease caused by this organism has not been fully elucidated. Most isolates from clinical material possess two independent properties associated with virulence whose relative contribution to the development of disease is not known. These are the ability to penetrate the intestinal wall, which is thought to be controlled by a plasmid gene, and the production of heat-stable enterotoxin, which is controlled by a chromosomal gene. In this study, we infected neonatal gnotobiotic piglets with strains of Y. enterocolitica expressing these two properties in various combinations. The suitability of the piglet model was shown in experiments in which piglets fed virulent Y. enterocolitica serogroup O3 developed a clinical illness related to the size of the inoculum, which was accompanied by intestinal lesions similar to those reported in naturally and experimentally infected people and animals. The results confirmed the key role of a 47 X 10(6)-mol. wt plasmid in the pathogenicity of Y. enterocolitica, but suggested that penetration of the intestinal wall may be governed by chromosomal rather than plasmid-borne genes. No role for enterotoxin in the pathogenesis of yersiniosis was shown, although there was evidence that enterotoxin may promote intra-intestinal proliferation of Y. enterocolitica, thus favouring increased shedding of bacteria and encouraging their spread between hosts.     

Effects of iron and desferrioxamine on infections with Yersinia enterocolitica.

The effects of iron-dextran and the iron chelator desferrioxamine B mesylate (Desferal) on the course and outcome of experimental yersiniosis were investigated. Yersinia enterocolitica strains representing the three leading serogroups pathogenic for humans, O3, O8 and O9, were studied. In mice, iron-dextran reduced the median lethal dose of intraperitoneally administered Y. enterocolitica O3 and O9 ca. 10-fold, whereas Desferal reduced this value more than 100,000-fold. Experiments in which Y. enterocolitica was given orally to mice and intraconjunctivally to guinea pigs confirmed that Desferal markedly increased the susceptibility of animals to yersiniosis. Although serogroup O8 yersiniae were inherently more virulent for laboratory animals, they were less affected by Desferal than were O3 or O9 strains. In vitro experiments indicated that Desferal promoted growth of Y. enterocolitica under iron-limiting conditions and suggested that the enhanced virulence of O8 yersiniae may be due to their comparatively low requirement for iron. The adverse effect of Desferal on the course of experimental infection with Y. enterocolitica may partly explain the heightened susceptibility of iron-overloaded patients to systemic yersiniosis.     

In vitro assessment of virulence in Yersinia enterocolitica and related species.

We have examined 136 isolates of Yersinia species, comprising 112 strains of Yersinia enterocolitica, 12 of Y. frederiksenii, 8 of Y. intermedia, and 5 of Y. kristensenii, for the presence of 40- to 50-megadalton virulence-associated plasmids and expression of the following plasmid-associated characteristics: Congo red pigmentation (CR), calcium dependence, autoagglutination, hydrophobicity, resistance to normal human serum, and pathogenicity in mice. All 136 strains yielded both pigmented (CR+) and nonpigmented (CR-) variants. Only CR+ variants, however, were virulent for iron-overloaded, desferrioxamine B-treated mice (R. M. Robins-Browne and J. K. Prpic, Infect. Immun. 47:744-779, 1985). Although the in vitro virulence-associated characteristics generally occurred together, each one could be expressed independently. Strains of Y. frederiksenii, Y. intermedia, and Y. kristensenii also expressed individual virulence-associated properties. Of 53 Y. enterocolitica strains which were virulent for iron-overloaded, desferrioxamine-treated mice, all but one expressed every virulence-associated characteristic. Several strains which were avirulent for mice, however, demonstrated these characteristics in various combinations. Because many Yersinia strains, particularly environmental isolates, carried plasmids of 40 to 50 megadaltons, detection of plasmids provided little information about bacterial pathogenicity unless virulence-associated properties were also sought. The best in vitro predictor of virulence was autoagglutination, followed by calcium dependence. Because only CR+ variants expressed virulence-associated determinants, Congo red pigmentation is useful for selecting potentially virulent strains.     

Applying Kane’s validity framework to a simulation based assessment of clinical competence

Assessment of clinical competence is complex and inference based. Trustworthy and defensible assessment processes must have favourable evidence of validity, particularly where decisions are considered high stakes. We aimed to organize, collect and interpret validity evidence for a high stakes simulation based assessment strategy for certifying paramedics, using Kane’s validity framework, which some report as challenging to implement. We describe our experience using the framework, identifying challenges, decisions points, interpretations and lessons learned. We considered data related to four inferences (scoring, generalization, extrapolation, implications) occurring during assessment and treated validity as a series of assumptions we must evaluate, resulting in several hypotheses and proposed analyses. We then interpreted our findings across the four inferences, judging if the evidence supported or refuted our proposed uses of the assessment data. Data evaluating “Scoring” included: (a) desirable tool characteristics, with acceptable inter-item correlations (b) strong item-total correlations (c) low error variance for items and raters, and (d) strong inter-rater reliability. Data evaluating “Generalizability” included: (a) a robust sampling strategy capturing the majority of relevant medical directives, skills and national competencies, and good overall and inter-station reliability. Data evaluating “Extrapolation” included: low correlations between assessment scores by dimension and clinical errors in practice. Data evaluating “Implications” included low error rates in practice. Interpreting our findings according to Kane’s framework, we suggest the evidence for scoring, generalization and implications supports use of our simulation-based paramedic assessment strategy as a certifying exam; however, the extrapolation evidence was weak, suggesting exam scores did not predict clinical error rates. Our analysis represents a worked example others can follow when using Kane’s validity framework to evaluate, and iteratively develop and refine assessment strategies.     

Seroepidemiology of hepatitis E in patients on haemodialysis in Croatia

International Urology and Nephrology - Data on the seroprevalence of hepatitis E virus (HEV) in heamodialysis (HD) patients are conflicting, ranging from 0 to 44%. The aim of this study was to...     

New ��L value�� parameter simplifies and enhances hip ultrasound interpretation in the detection of developmental dysplasia of the hip

Purpose  

The purpose of this study was to simplify and enhance the ultrasound (US) analysis of the infant’s hip by introducing a novel parameter named “L value” into the widely used Graf method.     

Cutting balloon angioplasty for the prevention of restenosis: results of the Cutting Balloon Global Randomized Trial

The cutting balloon (CB) is a specialized device designed to create discrete longitudinal incisions in the atherosclerotic target coronary segment during balloon inflation. Such controlled dilatation theoretically reduces the force needed to dilate an obstructive lesion compared with standard percutaneous transluminal coronary angioplasty (PTCA). We report a multicenter, randomized trial comparing the incidence of restenosis after CB angioplasty versus conventional balloon angioplasty in 1,238 patients. Six hundred seventeen patients were randomized to CB treatment, and 621 to PTCA. The mean reference vessel diameter was 2.86 +/- 0.49 mm, mean lesion length 8.9 +/- 4.3 mm, and prevalence of diabetes mellitus in patients was 13%. The primary end point, the 6-month binary angiographic restenosis rate, was 31.4% for CB and 30.4% for PTCA (p = 0.75). Acute procedural success, defined as the attainment of <50% diameter stenosis without in-hospital major adverse cardiac events, was 92.9% for CB and 94.7% for PTCA (p = 0.24). Freedom from target vessel revascularization was slightly higher in the CB arm (88.5% vs 84.6%, log-rank p = 0.04). Five coronary perforations occurred in the CB arm only (0.8% vs 0%, p = 0.03). At 270 days, rates of myocardial infarction, death, and total major adverse cardiac events for CB and PTCA were 4.7% versus 2.4% (p = 0.03), 1.3% versus 0.3% (p = 0.06), and 13.6% versus 15.1% (p = 0.34), respectively. In summary, the proposed mechanism of controlled dilatation did not reduce the rate of angiographic restenosis for the CB compared with conventional balloon angioplasty. CB angioplasty should be reserved for difficult lesions in which controlled dilatation is believed to provide a better acute result compared with balloon angioplasty alone.