Publications

BACKGROUND

Stool DNA testing is a new approach to colorectal cancer detection. Few data are available from the screening setting.

OBJECTIVE

To compare stool DNA and fecal blood testing for detection of screen-relevant neoplasia (curable-stage cancer, high-grade dysplasia, or adenomas >1 cm).

DESIGN

Blinded, multicenter, cross-sectional study.

SETTING

Communities surrounding 22 participating academic and regional health care systems in the United States.

PARTICIPANTS

4482 average-risk adults.

MEASUREMENTS

Fecal blood and DNA markers. Participants collected 3 stools, smeared fecal blood test cards and used same-day shipment to a central facility. Fecal blood cards (Hemoccult and HemoccultSensa, Beckman Coulter, Fullerton, California) were tested on 3 stools and DNA assays on 1 stool per patient. Stool DNA test 1 (SDT-1) was a precommercial 23-marker assay, and a novel test (SDT-2) targeted 3 broadly informative markers. The criterion standard was colonoscopy.

RESULTS

Sensitivity for screen-relevant neoplasms was 20% by SDT-1, 11% by Hemoccult (P = 0.020), 21% by HemoccultSensa (P = 0.80); sensitivity for cancer plus high-grade dysplasia did not differ among tests. Specificity was 96% by SDT-1, compared with 98% by Hemoccult (P < 0.001) and 97% by HemoccultSensa (P = 0.20). Stool DNA test 2 detected 46% of screen-relevant neoplasms, compared with 16% by Hemoccult (P < 0.001) and 24% by HemoccultSensa (P < 0.001). Stool DNA test 2 detected 46% of adenomas 1 cm or larger, compared with 10% by Hemoccult (P < 0.001) and 17% by HemoccultSensa (P < 0.001). Among colonoscopically normal patients, the positivity rate was 16% with SDT-2, compared with 4% with Hemoccult (P = 0.010) and 5% with HemoccultSensa (P = 0.030).

LIMITATIONS

Stool DNA test 2 was not performed on all subsets of patients without screen-relevant neoplasms. Stools were collected without preservative, which reduced detection of some DNA markers.

CONCLUSION

Stool DNA test 1 provides no improvement over HemoccultSensa for detection of screen-relevant neoplasms. Stool DNA test 2 detects significantly more neoplasms than does Hemoccult or HemoccultSensa, but with more positive results in colonoscopically normal patients. Higher sensitivity of SDT-2 was particularly apparent for adenomas.

It has been hypothesized that stress contributes to the severity of inflammatory diseases. However, the mechanisms underlying this effect are incompletely understood. In this study we investigated the effects of sound stress on function of the polymorphonuclear neutrophil-immune cells that play key roles in both the acute and chronic inflammatory response. Specifically, we examined the effect of stress on the production of reactive oxygen species (ROS) and phagocytosis by rat neutrophils, and the role of sympathoadrenal stress axis in these effects. Since many inflammatory diseases exhibit sexual dimorphism, we also investigated the contribution of sex and gonadal hormones to the effects of stress on neutrophil function. Peripheral blood neutrophils were harvested from male and female rats exposed to intermittent sound stress (over 4 days). Stress suppressed ROS production in males (but not females) an effect that was eliminated in adrenal medullectomized males. Stress also suppressed neutrophil phagocytosis in males and females. Again, this effect was absent following adrenal medullectomy. To investigate the role of sex hormones in these sexual dimorphic responses to stress, rats were gonadectomized prepubertally and exposed to stress as adults. In gonadectomized males, stress produced an even larger decrease in ROS production, but had no effect on the stress-induced inhibition of phagocytosis. Gonadectomy prevented the stress-induced inhibition of neutrophil phagocytosis in females. These data indicate that the adrenal medulla, perhaps via release of epinephrine, suppresses neutrophil ROS production in males and phagocytosis in males and females.

OBJECTIVES

To compare tympanostomy tube insertion for children with otitis media in 2002 with the recommendations of two sets of expert guidelines.

DESIGN

Retrospective cohort study.

SETTING

New York metropolitan area practices associated with five diverse hospitals.

PARTICIPANTS

682 of 1046 children who received tympanostomy tubes in the five hospitals for whom charts from the hospital, primary care physician, and otolaryngologist could be accessed.

RESULTS

The mean age was 3.8 years. On average, children with acute otitis media had fewer than four infections in the year before surgery. Children with otitis media with effusion had less than 30 consecutive days of effusion at the time of surgery. Concordance with recommendations was very low: 30.3% (n=207) of all tympanostomies were concordant with the explicit criteria developed for this study and 7.5% (n=13) with the 1994 guideline from the American Academy of Pediatrics, American Academy of Family Medicine, and American Academy of Otolaryngology-Head and Neck Surgery. Children who had previously had tympanostomy tube surgery, who were having a concomitant procedure, or who had "at risk conditions" were more likely to be discordant.

CONCLUSIONS

A significant majority of tympanostomy tube insertions in the largest and most populous metropolitan area in the United States were inappropriate according to the explicit criteria and not recommended according to both guidelines. Regardless of whether current practice represents a substantial overuse of surgery or the guidelines are overly restrictive, the persistent discrepancy between guidelines and practice cannot be good for children or for people interested in improving their health care.

Plasmacytoid dendritic cells (PDCs) represent a unique immune cell type specialized in type I interferon (IFN) secretion in response to viral nucleic acids. The molecular control of PDC lineage specification has been poorly understood. We report that basic helix-loop-helix transcription factor (E protein) E2-2/Tcf4 is preferentially expressed in murine and human PDCs. Constitutive or inducible deletion of murine E2-2 blocked the development of PDCs but not of other lineages and abolished IFN response to unmethylated DNA. Moreover, E2-2 haploinsufficiency in mice and in human Pitt-Hopkins syndrome patients was associated with aberrant expression profile and impaired IFN response of the PDC. E2-2 directly activated multiple PDC-enriched genes, including transcription factors involved in PDC development (SpiB, Irf8) and function (Irf7). These results identify E2-2 as a specific transcriptional regulator of the PDC lineage in mice and humans and reveal a key function of E proteins in the innate immune system.

The fungus Cryptococcus neoformans is a leading cause of mortality and morbidity among HIV-infected individuals. We utilized the completed genome sequence and optimized methods for homologous DNA replacement using high-velocity particle bombardment to engineer 1201 gene knockout mutants. We screened this resource in vivo for proliferation in murine lung tissue and in vitro for three well-recognized virulence attributes-polysaccharide capsule formation, melanization, and growth at body temperature. We identified dozens of previously uncharacterized genes that affect these known attributes as well as 40 infectivity mutants without obvious defects in these traits. The latter mutants affect predicted regulatory factors, secreted proteins, and immune-related factors, and represent powerful tools for elucidating novel virulence mechanisms. In particular, we describe a GATA family transcription factor that inhibits phagocytosis by murine macrophages independently of the capsule, indicating a previously unknown mechanism of innate immune modulation.

BACKGROUND

We conducted subanalyses of the combined results of the Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and MOTIVATE 2 studies to better characterize the efficacy and safety of maraviroc in key subgroups of patients.

METHODS

We analyzed pooled data from week 48 from the two studies according to sex, race or ethnic group, clade, CC chemokine receptor 5 (CCR5) delta32 genotype, viral load at the time of screening, the use or nonuse of enfuvirtide in optimized background therapy (OBT), the baseline CD4 cell count, the number of active antiretroviral drugs coadministered, the first use of selected background agents, and tropism at baseline. Changes in viral tropism and the CD4 count at treatment failure were evaluated. Data on aminotransferase levels in patients coinfected with hepatitis B virus (HBV) or hepatitis C virus (HCV) were also analyzed.

RESULTS

A treatment benefit of maraviroc plus OBT over placebo plus OBT was shown in all subgroups, including patients with a low CD4 cell count at baseline, those with a high viral load at screening, and those who had not received active agents in OBT. Analyses of the virologic response according to the first use of selected background drugs showed the additional benefit of adding a potent new drug to maraviroc at the initiation of maraviroc therapy. More patients in whom maraviroc failed had a virus binding to the CXC chemokine receptor 4 (CXCR4) at failure, but there was no evidence of a decrease in the CD4 cell count at failure in such patients as compared with those in whom placebo failed. Subanalyses involving patients coinfected with HBV or HCV revealed no evidence of excess hepatotoxic effects as compared with baseline.

CONCLUSIONS

Subanalyses of pooled data from week 48 indicate that maraviroc provides a valuable treatment option for a wide spectrum of patients with R5 HIV-1 infection who have been treated previously. (ClinicalTrials.gov numbers, NCT00098306 and NCT00098722.)