Antimicrobial susceptibility of Escherichia coli in uncomplicated cystitis in the emergency department: is the hospital antibiogram an effective treatment guide?

OBJECTIVES: The objective was to compare the rates of antimicrobial susceptibility in strains of Escherichia coli isolated from uncomplicated cystitis cases presenting to the emergency department (ED) of a tertiary care center to those reported on that institution's hospital-wide antibiogram. The hypothesis was that cases of uncomplicated cystitis presenting to the ED will exhibit higher antimicrobial susceptibility than is reported by the hospital-wide antibiogram. METHODS: A retrospective chart review of patients who were diagnosed with uncomplicated cystitis in the ED of a large, academic tertiary care center was conducted. Due to an error in the implementation of a new electronic medical record system at this institution in 2009, all urine samples with any abnormality were reflexively sent for culture. The authors were then able to review and record the antibiotic susceptibility patterns of all cultures that grew E. coli. Exclusion criteria included fever, subsequent hospital admission, treatment of suspected pyelonephritis, receiving current cystitis treatment, male sex, indwelling catheters, recent surgery or hospitalization, or asymptomatic for cystitis. Culture isolate antimicrobial susceptibility was then compared with the hospital-wide antibiogram of the same period. Empiric treatment regimens were also recorded as secondary data. RESULTS: Greater susceptibility to trimethoprim-sulfamethoxazole (TMP-SMX; 80% vs. 71%), cefazolin (97% vs. 87%), and ciprofloxacin (89% vs. 73%) was found in our population than was published in the hospital antibiogram. These differences were shown to be statistically significant using Fisher's exact test (p < 0.05). A very high sensitivity to nitrofurantoin (99%), similar to the hospital antibiogram (98%), was also found. Also noted was a high rate of antimicrobial susceptibility when specific empiric treatment was initiated with TMP-SMX or ciprofloxacin: 92 and 89%, respectively. CONCLUSIONS: The greater susceptibility of E. coli to TMP-SMX, cefazolin, and ciprofloxacin observed in this population supports the hypothesis that antimicrobial susceptibility rates in uncomplicated cystitis presenting to the ED are greater than those reported in the hospital-wide antibiogram. This could affect treatment guidelines by confirming that antimicrobials currently recommended for use in uncomplicated cystitis are more effective in this setting than currently reported by the hospital-wide antibiogram.

Estrogen receptor ß isoform 5 confers sensitivity of breast cancer cell lines to chemotherapeutic agent-induced apoptosis through interaction with Bcl2L12.

Alternative splicing of estrogen receptor ß (ERß) yields five isoforms, but their functions remain elusive. ERß isoform 5 (ERß5) has been positively correlated with better prognosis and longer survival of patients with breast cancer (BCa) in various clinical studies. In this study, we investigated the inhibitory role of ERß5 in BCa cells. Although ERß5 does not reduce proliferation of BCa cell lines MCF-7 and MDA-MB-231, its ectopic expression significantly decreases their survival by sensitizing them to doxorubicin- or cisplatin-induced apoptosis through the intrinsic apoptotic pathway. Moreover, we discovered Bcl2L12, which belongs to the Bcl-2 family regulating apoptosis, to be a specific interacting partner of ERß5, but not ERß1 or ERα, in an estradiol-independent manner. Knockdown of Bcl2L12 enhanced doxorubicin- or cisplatin-induced apoptosis, and this process was further promoted by ectopic expression of ERß5. Whereas Bcl2L12 was previously shown to inhibit apoptosis through binding to caspase 7, such interaction is reduced in the presence of ERß5, suggesting a mechanism by which ERß5 sensitizes cells to apoptosis. In conclusion, ERß5 interacts with Bcl2L12 and functions in a novel estrogen-independent molecular pathway that promotes chemotherapeutic Agent-Induced in vitro apoptosis of BCa cell lines.

Estrogen receptor ß (ERß1) transactivation is differentially modulated by the transcriptional coregulator Tip60 in a cis-acting element-dependent manner.

Estrogen receptor (ER) ß1 and ERα have overlapping and distinct functions despite their common use of estradiol as the physiological ligand. These attributes are explained in part by their differential utilization of coregulators and ligands. Although Tip60 has been shown to interact with both receptors, its regulatory role in ERß1 transactivation has not been defined. In this study, we found that Tip60 enhances transactivation of ERß1 at the AP-1 site but suppresses its transcriptional activity at the estrogen-response element (ERE) site in an estradiol-independent manner. However, different estrogenic compounds can modify the Tip60 action. The corepressor activity of Tip60 at the ERE site is abolished by diarylpropionitrile, genistein, equol, and bisphenol A, whereas its coactivation at the AP-1 site is augmented by fulvestrant (ICI 182,780). GRIP1 is an important tethering mediator for ERs at the AP-1 site. We found that coexpression of GRIP1 synergizes the action of Tip60. Although Tip60 is a known acetyltransferase, it is unable to acetylate ERß1, and its coregulatory functions are independent of its acetylation activity. In addition, we showed the co-occupancy of ERß1 and Tip60 at ERE and AP-1 sites of ERß1 target genes. Tip60 differentially regulates the endogenous expression of the target genes by modulating the binding of ERß1 to the cis-regulatory regions. Thus, we have identified Tip60 as the first dual-function coregulator of ERß1.

Estrogens and antiestrogens as etiological factors and therapeutics for prostate cancer.

Mounting evidence supports a key role played by estrogen or estrogen in synergy with an androgen, in the pathogenesis of prostate cancer (PCa). New experimental data suggest that this process could begin as early as prenatal life. During adulthood, estrogen carcinogenicity is believed to be mediated by the combined effects of hormone-induced, unscheduled cell proliferation and bioactivation of estrogens to genotoxic carcinogens. Increased bioavailability of estrogen through age-dependent increases in conversion from androgen could also be a contributing factor. Individual variations and race-/ethnic-based differences in circulating or locally formed estrogens or in tissue estrogen responsiveness may explain differential PCa risk among individuals or different populations. Estrogen receptor (ER)-alpha and ER-beta are the main mediators of estrogen action in the prostate. However, ER-beta is the first ER subtype expressed in the fetal prostate. During cancer development, ER-beta expression is first lost as tumors progress into high grade in the primary site. Yet, its reexpression occurs in all metastatic cases of PCa. A change in cytosine methylation in a regulatory CpG island located in the proximal promoter of ER-beta may constitute an "on/off" switch for reversible regulation of ER-beta expression. A variety of estrogenic/antiestrogenic/selective estrogen receptor modulator (SERM)-like compounds have been shown to use non-ERE pathways, such as tethering of ER-beta to NF-kappaB binding proteins, Sp2, or Ap1 for gene transactivation. These findings open new avenues for drug design that now focuses on developing a new generation of estrogen-based PCa therapies with maximal proapoptotic action but few or no side effects.