The relationship between performance on the Infectious Diseases In-Training and Certification Examinations.

BACKGROUND: The Infectious Diseases Society of America In-Training Examination (IDSA ITE) is a feedback tool used to help fellows track their knowledge acquisition during fellowship training. We determined whether the scores on the IDSA ITE and from other major medical knowledge assessments predict performance on the American Board of Internal Medicine (ABIM) Infectious Disease Certification Examination. METHODS: The sample was 1021 second-year fellows who took the IDSA ITE and ABIM Infectious Disease Certification Examination from 2008 to 2012. Multiple regression analysis was used to determine if ABIM Infectious Disease Certification Examination scores were predicted by IDSA ITE scores, prior United States Medical Licensing Examination (USMLE) scores, ABIM Internal Medicine Certification Examination scores, fellowship director ratings of medical knowledge, and demographic variables. Logistic regression was used to evaluate if these same assessments predicted a passing outcome on the certification examination. RESULTS: IDSA ITE scores were the strongest predictor of ABIM Infectious Disease Certification Examination scores (ß = .319), followed by prior ABIM Internal Medicine Certification Examination scores (ß = .258), USMLE Step 1 scores (ß = .202), USMLE Step 3 scores (ß = .130), and fellowship directors' medical knowledge ratings (ß = .063). IDSA ITE scores were also a significant predictor of passing the Infectious Disease Certification Examination (odds ratio, 1.017 [95% confidence interval, 1.013-1.021]). CONCLUSIONS: The significant relationship between the IDSA ITE score and performance on the ABIM Infectious Disease Certification Examination supports the use of the ITE as a valid feedback tool in fellowship training.

Murine colitis is mediated by vimentin.

Vimentin, an abundant intermediate filament protein, presumably has an important role in stabilizing intracellular architecture, but its function is otherwise poorly understood. In a vimentin knockout (Vim KO) mouse model, we note that Vim KO mice challenged with intraperitoneal Escherichia coli control bacterial infection better than do wild-type (WT) mice. In vitro, Vim KO phagocytes show significantly increased capacity to mediate bacterial killing by abundant production of reactive oxygen species (ROS) and nitric oxides, likely due to interactions with the p47phox active subunit of NADPH oxidase. In acute colitis induced by dextran sodium sulfate (DSS), Vim KO mice develop significantly less gut inflammation than do WT mice. Further, Vim KO mice have markedly decreased bacterial extravasation in the setting of DSS-induced acute colitis, consistent with decreased intestinal disease. Our results suggest that vimentin impedes bacterial killing and production of ROS, thereby contributing to the pathogenesis of acute colitis.

Therapies for necrotising fasciitis.

Necrotising fasciitis is a rare but life-threatening infectious disease emergency. Delays in diagnosis and treatment are common, and mortality rates often exceed 30%. Successful management of this disease requires high clinical suspicion and aggressive action. The mainstays of therapy include early and wide surgical debridement, antibiotics and supportive care, with prompt surgical intervention. Adjunctive modalities, such as protein synthesis inhibitors, hyperbaric oxygen and intravenous immunoglobulin, may have a role, but their effectiveness remains unproven. New rapid diagnostic tools are emerging that promise to revolutionize early detection of necrotising fasciitis. Research into the molecular microbiology, especially regarding group A streptococcus, are providing novel insights into the pathogenesis of necrotising soft tissue infections and identifying future targets for rationally designed interventions.

Role of hyaluronidase in subcutaneous spread and growth of group A streptococcus.

Group A streptococcus (GAS) depends on a hyaluronic acid (HA) capsule to evade phagocytosis and to interact with epithelial cells. Paradoxically, GAS also produces hyaluronidase (Hyl), an enzyme that cleaves HA. A common assumption is that Hyl digests structurally identical HA in human tissue to promote bacterial spread. We inactivated the gene encoding extracellular hyaluronidase, hylA, in a clinical Hyl(+) isolate. Hyl(+) and an isogenic Hyl(-) mutant were injected subcutaneously into mice with or without high-molecular-weight dextran blue. The Hyl(-) strain produced small lesions with dye concentrated in close proximity. The Hyl(+) strain produced identical lesions, but the dye diffused subcutaneously. However, Hyl(+) bacteria were not isolated from unaffected skin stained by dye diffusion. Thus, Hyl digests tissue HA and facilitates spread of large molecules but is not sufficient to cause subcutaneous diffusion of bacteria or to affect lesion size. GAS capsule expression was assayed periodically during broth culture and was reduced in Hyl(+) strains relative to Hyl(-) strains at the onset and the end of active capsule synthesis but not during peak synthesis in mid-exponential phase. Thus, Hyl is not sufficiently active to remove capsule during peak synthesis. To demonstrate a possible nutritional role for Hyl, GAS was shown to grow with N-acetylglucosamine but not d-glucuronic acid (both components of HA) as a sole carbon source. However, only Hyl(+) strains could grow utilizing HA as a sole carbon source, suggesting that Hyl may permit the organism to utilize host HA or its own capsule as an energy source.

Necrotizing fasciitis: pathogenesis and treatment.

Necrotizing fasciitis is a rapidly progressive, life-threatening infection and a true infectious disease emergency. Despite much clinical experience, the management of this disease remains suboptimal, with mortality rates remaining approximately 30%. Necrotizing fasciitis rarely presents with obvious signs and symptoms and delays in diagnosis enhance mortality. Therefore, successful patient care depends on the physician's acumen and index of suspicion. Prompt surgical debridement, intravenous antibiotics, fluid and electrolyte management, and analgesia are mainstays of therapy. Adjunctive clindamycin, hyperbaric oxygen therapy and intravenous immunoglobulin are frequently employed in the treatment of necrotizing fasciitis, but their efficacy has not been rigorously established. Improved understanding of the pathogenesis of necrotizing fasciitis has revealed new targets for rationally designed therapies to improve morbidity and mortality.

Plasminogen is a critical host pathogenicity factor for group A streptococcal infection.

Group A streptococci, a common human pathogen, secrete streptokinase, which activates the host's blood clot-dissolving protein, plasminogen. Streptokinase is highly specific for human plasminogen, exhibiting little or no activity against other mammalian species, including mouse. Here, a transgene expressing human plasminogen markedly increased mortality in mice infected with streptococci, and this susceptibility was dependent on bacterial streptokinase expression. Thus, streptokinase is a key pathogenicity factor and the primary determinant of host species specificity for group A streptococcal infection. In addition, local fibrin clot formation may be implicated in host defense against microbial pathogens.

Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome.

The objective of this study was to evaluate and compare the basal circadian and pulsatile architecture of the HPA axis in groups of patients with FMS, CFS, or both syndromes with individually matched control groups. Forty patients with either FMS (n = 13), FMS and CFS (n = 12), or CFS (n = 15) were matched by age (18-65), sex, and menstrual status to healthy controls. Subjects were excluded if they met criteria for major Axis I psychiatric disorders by structured clinical interview (SCID). Subjects were admitted to the General Clinical Research Center where meals and activities were standardized. Blood was collected from an intravenous line every 10 min over 24 h for analysis of ACTH and cortisol. Samples were evaluable for ACTH in 36 subject pairs and for cortisol in 37 subject pairs. There was a significant delay in the rate of decline from acrophase to nadir for cortisol levels in patients with FMS (P <.01). Elevation of cortisol in the late evening quiescent period was evident in half of the FMS patients compared with their control group, while cortisol levels were numerically, but not significantly, lower in the overnight period in patients with CFS compared with their control group. Pulsatility analyses did not reveal statistically significant differences between patient and control groups. We conclude that the pattern of differences for basal circadian architecture of HPA axis hormones differs between patients with FMS and CFS compared to their matched control groups. The abnormalities in FMS patients are consistent with loss of HPA axis resiliency.

Contribution of CsrR-regulated virulence factors to the progress and outcome of murine skin infections by Streptococcus pyogenes.

Streptococcus pyogenes with null mutations in the csrRS regulatory locus are highly virulent in mice due to derepression of hyaluronic acid capsule synthesis and exotoxins, e.g., streptolysin S (SLS) and pyrogenic exotoxin B (SpeB). We generated derivatives of a DeltacsrRS strain that also carry deletions in hasAB (leading to an acapsular phenotype) or in sagA (phenotypically SLS-) or an interruption of speB (SpeB-) to test the relative contributions of these factors to the development of necrotic skin lesions. Inoculation of 2 x 10(6) to 4 x 10(6) CFU of either acapsular or SLS- strains into hairless mice resulted in lesions approximately 70% smaller than those of the DeltacsrRS parent strain. Elimination of SLS also reduced lethality from 100% to 0% at this inoculum (P < 10(-7); Fisher exact test). In contrast, SLS+ SpeB- mutants yielded lesions that were only 41% smaller than the parent strain (t = 2.2; P = 0.04), but only 3 the 17 lesions had dermal sloughing (P = 10(-5)). The nonulcerative lesions associated with SpeB- strains appeared pale with surrounding erythema. We conclude that capsule and SLS contribute to the subcutaneous spread of S. pyogenes and to a fatal outcome of infection. SpeB facilitates early dermal ulceration but has minor influence on lesion size and mortality. Large ulcerative lesions are observed only when both toxins are present.

Use of actigraphy for monitoring sleep and activity levels in patients with fibromyalgia and depression.

OBJECTIVE: The hallmark symptom of fibromyalgia (FM) is widespread chronic pain, but most patients are also impaired due to fatigue and sleep disturbance, and there is a strong association with depression. We compared levels of activity and sleep patterns in FM patients, with and without comorbid depression, to those of normal healthy controls and depressed patients. METHODS: Actigraphy was carried out on 16 patients with uncomplicated FM, 6 FM patients with comorbid depression, 9 patients with recurrent major depression, and 28 healthy controls over a period of 5-7 days. The means of daytime activity levels, nighttime activity levels, and percentage time spent asleep during the daytime and nighttime were calculated and compared. RESULTS: Controls showed high levels of activity during the day and uninterrupted periods of sleep at night. Patients with FM alone showed similar levels of daytime activity, but disturbed sleep with significantly increased levels of activity at night compared to normal controls. Patients with depression alone also showed disturbed sleep compared to normal controls. However, patients with FM and comorbid depression showed the most impairment, with significantly reduced daytime activity and significantly increased daytime sleeping compared to controls, as well as more sleep interruption and movement during the night. CONCLUSION: Actigraphy is a useful means of studying activity levels and sleep patterns and demonstrated significant differences between FM patients with and without comorbid depression.