Publications

Recent studies have suggested that mycophenolate mofetil (MMF) may offer advantages over intravenous cyclophosphamide (IVC) for the treatment of lupus nephritis, but these therapies have not been compared in an international randomized, controlled trial. Here, we report the comparison of MMF and IVC as induction treatment for active lupus nephritis in a multinational, two-phase (induction and maintenance) study. We randomly assigned 370 patients with classes III through V lupus nephritis to open-label MMF (target dosage 3 g/d) or IVC (0.5 to 1.0 g/m(2) in monthly pulses) in a 24-wk induction study. Both groups received prednisone, tapered from a maximum starting dosage of 60 mg/d. The primary end point was a prespecified decrease in urine protein/creatinine ratio and stabilization or improvement in serum creatinine. Secondary end points included complete renal remission, systemic disease activity and damage, and safety. Overall, we did not detect a significantly different response rate between the two groups: 104 (56.2%) of 185 patients responded to MMF compared with 98 (53.0%) of 185 to IVC. Secondary end points were also similar between treatment groups. There were nine deaths in the MMF group and five in the IVC group. We did not detect significant differences between the MMF and IVC groups with regard to rates of adverse events, serious adverse events, or infections. Although most patients in both treatment groups experienced clinical improvement, the study did not meet its primary objective of showing that MMF was superior to IVC as induction treatment for lupus nephritis.

The significance of elevated plasma levels of bacterial lipopolysaccharide (LPS) in persons with chronic HIV infection remains undefined. We measured LPS levels by use of limulus lysate assay, and DNA sequences encoding bacterial ribosomal 16S RNA (16S rDNA) were assessed by quantitative polymerase chain reactions in plasma samples obtained from 242 donors. Plasma levels of 16S rDNA were significantly higher in human immunodeficiency virus (HIV)-infected subjects than in uninfected subjects, and they correlated with LPS levels. Higher levels of 16S rDNA were associated with higher levels of T cell activation and with lower levels of CD4 T cell restoration during antiretroviral therapy. Antiretroviral therapy reduces but does not fully normalize plasma levels of bacterial 16S rDNA, an index of microbial translocation from the gastrointestinal tract. High levels of 16S rDNA during therapy are strongly associated with reduced increases in the CD4(+) T lymphocyte count, irrespective of plasma HIV RNA levels. These findings are consistent with the importance of microbial translocation in immunodeficiency and T cell homeostasis in chronic HIV infection.

BACKGROUND

Small intensive pharmacokinetic (PK) studies of medications in early-phase trials cannot identify the range of factors that influence drug exposure in heterogenous populations. We performed PK studies in large numbers of HIV-infected women on nonnucleoside reverse transcriptase inhibitors (NNRTIs) under conditions of actual use to assess patient characteristics that influence exposure and evaluated the relationship between exposure and response.

METHODS

Two hundred twenty-five women on NNRTI-based antiretroviral regimens from the Women's Interagency HIV Study were enrolled into 12-hour or 24-hour PK studies. Extensive demographic, laboratory, and medication covariate data were collected before and during the visit to be used in multivariate models. Total NNRTI drug exposure was estimated by area under the concentration-time curves.

RESULTS

Hepatic inflammation and renal insufficiency were independently associated with increased nevirapine exposure in multivariate analysis: crack cocaine, high fat diets, and amenorrhea were associated with decreased levels (n = 106). Higher efavirenz exposure was seen with increased transaminase, albumin levels, and orange juice consumption; tenofovir use, increased weight, being African American, and amenorrhea were associated with decreased exposure (n = 119). With every 10-fold increase in nevirapine or efavirenz exposure, participants were 3.3 and 3.6 times likely to exhibit virologic suppression, respectively. Patients with higher drug exposure were also more likely to report side effects on therapy.

CONCLUSIONS

Our study identifies and quantitates previously unrecognized factors modifying NNRTI exposure in the "real-world" setting. Comprehensive PK studies in representative populations are feasible and may ultimately lead to dose optimization strategies in patients at risk for failure or adverse events.

BACKGROUND

The current study was performed to determine whether neuropsychologic functioning differs in breast cancer survivors 6 months after the completion of adjuvant treatment compared with women without cancer.

METHODS

Participants were 187 women who were diagnosed with ductal carcinoma in situ or stage I or stage II breast cancer and 187 age-matched and geographically matched women without cancer. Of the survivors, 97 had been treated after surgery with chemotherapy only or chemotherapy plus radiotherapy and 90 had been treated after surgery with radiotherapy only (grading determined according to the American Joint Committee on Cancer grading system).

RESULTS

Small but statistically significant differences in cognitive functioning and cognitive impairment were observed in those survivors who were treated with chemotherapy and their matched controls, as well as in survivors treated with radiotherapy only and their matched controls. No group differences were observed with regard to cognitive symptoms.

CONCLUSIONS

Data from the current study suggest that cognitive deficits are subtle and likely the result of the general effects of cancer diagnosis and treatment rather than systemic treatment.

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.