Publications

Activation of Ras proteins underlies functional decisions in diverse cell types. Two molecules, Ras-GRP and SOS (Ras-guanine nucleotide-releasing protein and Son of Sevenless, respectively), catalyze Ras activation in lymphocytes. Binding of active Ras to the allosteric pocket of SOS markedly increases the activity of SOS. Thus, there is a positive feedback loop regulating SOS. Combining in silico and in vitro studies, we demonstrate that "digital" signaling in lymphocytes (cells are "on" or "off") is predicated on this allosteric regulation of SOS. The SOS feedback loop leads to hysteresis in the dose-response curve, which may enable T cells to exhibit "memory" of past encounters with antigen. Ras activation by Ras-GRP alone is "analog" (a graded increase in activation in response to an increase in the amplitude of the stimulus). We describe how the complementary analog (Ras-GRP) and digital (SOS) pathways act on Ras to efficiently convert analog input to digital output and make predictions regarding the importance of digital signaling in lymphocyte function and development.

BACKGROUND

The incidence of skin and soft-tissue infections (SSTIs) has rapidly increased among children in primary care settings since the emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA). Recent treatment recommendations emphasize CA-MRSA as the primary cause, performing incision and drainage (I&D) as the primary therapy, and not prescribing antibiotics for uncomplicated cases. It is unknown how this epidemic has impacted primary care pediatricians in terms of their practice patterns and barriers they face to providing recommended therapies.

METHODS

3 Focus groups among 29 primary care pediatricians in the San Francisco Bay Area were conducted. Transcripts were reviewed and coded into major themes by two investigators using modified grounded theory.

RESULTS

Substantial changes in clinical practice have occurred since the emergence of CA-MRSA. These include increased office visits for SSTIs, patients with multiple recurrences and transmission within households. Additionally, our participants reported increased visits for mild skin problems due to media reports contributing to fears about CA-MRSA. Participants routinely prescribed antibiotics for SSTIs, however, few performed I&D. Few were aware of recent SSTI treatment recommendations. Barriers to prescribing antibiotics with CA-MRSA activity included concerns about side-effects and lack of local epidemiologic data showing that it is the primary etiology. Barriers to performing I&D included lack of training, resources and skepticism about its necessity. Important clinical challenges included increased time demands for follow-up visits and patient education along with the lack of evidence-based strategies for preventing recurrent infections and household transmission.

CONCLUSION

CA-MRSA has influenced the presentation and treatment of SSTIs especially in terms of case numbers and recurrences. Barriers to providing recommended therapies can be addressed through improved dissemination of treatment guidelines and epidemiologic data. Studies are urgently needed to improve the evidence-base for treatment and prevention strategies.

There is increasing interest in utilizing novel markers of cardiovascular disease risk, and consequently, there is a need to assess the value of their use. This scientific statement reviews current concepts of risk evaluation and proposes standards for the critical appraisal of risk assessment methods. An adequate evaluation of a novel risk marker requires a sound research design, a representative at-risk population, and an adequate number of outcome events. Studies of a novel marker should report the degree to which it adds to the prognostic information provided by standard risk markers. No single statistical measure provides all the information needed to assess a novel marker, so measures of both discrimination and accuracy should be reported. The clinical value of a marker should be assessed by its effect on patient management and outcomes. In general, a novel risk marker should be evaluated in several phases, including initial proof of concept, prospective validation in independent populations, documentation of incremental information when added to standard risk markers, assessment of effects on patient management and outcomes, and ultimately, cost-effectiveness.