Novel fluorobenzothiazole as a dual inhibitor of gyrase B and topoisomerase IV against Gram-positive pathogens.

Aim: The development of a novel inhibitor targeting gyrase B and topoisomerase IV offers an opportunity to combat multidrug resistance. Methods: We investigated the activity of RBx 10080758 against Gram-positive bacteria in vitro and in vivo. Results: RBx 10080758 showed a potent 50% inhibitory concentration of 0.13 µM and 0.25 µM against gyrase B and topoisomerase IV, respectively, and exhibited strong whole-cell in vitro activity with MIC ranges of 0.015-0.06 and 0.015-0.03 µg/ml against Staphylococcus aureus and Streptococcus pneumoniae, respectively. In a rat thigh infection model with methicillin-resistant S. aureus, RBx 10080758 at 45 mg/kg exhibited a >3 log10 CFU reduction in thigh muscles. Conclusion: RBx 10080758 displayed potent activity against multiple multidrug-resistant Gram-positive bacteria with a dual-targeting mechanism of action.

Pharmacist-led telehealth tobacco cessation services compared with usual care in a community health center.

BACKGROUND: Previous studies regarding tobacco cessation services (TCS) concluded that pharmacist interventions lead to higher or similar quit rates compared with usual care; however, little is known about patient satisfaction with these services. OBJECTIVES: This study assessed 30-day point prevalence abstinence and patient satisfaction of TCS provided by pharmacists compared with primary care providers (PCPs) in a community health center. Secondary objectives assessed the number of encounters and time spent counseling and medications prescribed at each visit. METHODS: Patients at the age of 18 years or older with tobacco use disorder and a new quit attempt were invited to complete a 9-question survey via e-mail, phone, and mail 7 months after their initial tobacco cessation visit. The survey assessed 30-day point prevalence abstinence and patient satisfaction. Chart reviews were conducted to assess time spent counseling and prescribing patterns. RESULTS: The response rate was 38.8% (50/129) overall, 43.9% in the pharmacist group and 36.3% in the PCP group. A 30-day point prevalence abstinence was reached by 22.2% (4/18) in the pharmacist group and 9.4% (3/32) in the PCP group (P = 0.23). Patient satisfaction was significantly higher in the pharmacist group with regard to discussion around medications used to quit smoking (100% vs. 65.6%, P = 0.004), understanding how to properly use the medications (100% vs. 62.5%, P = 0.002), identifying behavioral changes to assist with quitting (94.4% vs. 65.6%, P = 0.036), and frequent follow-up visits (83.3% vs. 46.9%, P = 0.016). Pharmacists spent more time counseling patients and were more likely to prescribe dual nicotine replacement therapy and prescription medications. CONCLUSIONS: There was not a statistically significant difference in abstinence rates, and patient satisfaction with TCS provided by pharmacists and PCPs was high. Pharmacists provide a more intensive service by spending more time counseling patients and providing more follow-ups and are more likely to diversify medications prescribed to quit smoking.

PDZK1 is a novel factor in breast cancer that is indirectly regulated by estrogen through IGF-1R and promotes estrogen-mediated growth.

Although a relationship between PDZK1 expression and estrogen receptor (ER)-α stimulation has been suggested, the nature of such a connection and the function of PDZK1 in breast cancer remain unknown. Human tissue microarrays (cancer tissue: 262 cores; normal tissue: 87 cores) and breast cancer cell lines were used to conduct the study. We show that PDZK1 protein expression is tightly correlated with human breast malignancy, is negatively correlated with age and had no significant correlation with ER-α expression levels. PDZK1 exhibited an exclusive epithelial expression with mostly cytosolic subcellular localization. Additionally, 17ß-estradiol induced PDZK1 expression above its basal level more than 24 h after treatment in MCF-7 cells. PDZK1 expression was indirectly regulated by ER-α stimulation, requiring insulinlike growth factor 1 receptor (IGF-1R) expression and function. The molecular link between PDZK1 and IGF-1R was supported by a significant correlation between protein and mRNA levels (r = 0.591, p < 0.001, and r = 0.537, p < 0.001, respectively) of the two factors in two different cohorts of human breast cancer tissues. Interestingly, PDZK1 knockdown in MCF-7 cells blocked ER-dependent growth and reduced c-Myc expression, whereas ectopic expression of PDZK1 enhanced cell proliferation in the presence or absence of 17ß-estradiol potentially through an increase in c-Myc expression, suggesting that PDZK1 has oncogenic activity. PDKZ1 also appeared to interact with the Src/ER-α/epidermal growth factor receptor (EGFR) complex, but not with IGF-1R and enhanced EGFR-stimulated MEK/ERK1/2 signaling. Collectively, our results clarify the relationship between ER-α and PDZK1, propose a direct relationship between PDZK1 and IGF-1R, and identify a novel oncogenic activity for PDZK1 in breast cancer.

A paradigm shift in the treatment of advanced non-small cell lung cancer.

Lung cancer is the most common cause of cancer death for men and women worldwide. Nonsmall cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Systemic chemotherapy is a cornerstone of treatment in the management of stage IV NSCLC. First-line chemotherapy typically consists of a platinum-based treatment. The optimum approach to long-term treatment beyond 4 to 6 cycles of chemotherapy is still evolving. Second-line chemotherapy given at the time of disease progression has shown clear survival advantages when compared with best supportive care alone. With the recent increase in the number of active and more tolerable agents available to treat NSCLC, there is renewed interest in the role of continuation of antineoplastic agents (continuation maintenance) or switching to a different agent (switch maintenance) after first-line chemotherapy. This case-based review discusses the role of maintenance chemotherapy in the long-term management of advanced NSCLC.

Clinical case of the month. A rare case of Budd Chiari syndrome.

Budd Chiari syndrome is a rare disorder resulting from hepatic venous outflow tract obstruction anywhere from the small hepatic veins to the suprahepatic inferior vena cava. This patient has a hypercoagulable state secondary to heterozygous mutation of factor V and the JAK2 mutation and is being anticoagulated. We hypothesize that the low protein C and low antithrombin III levels seen in this patient resulted from decreased synthetic function of the liver and were not indicative of actual deficiencies. Indeed, reports of coexisting protein C and antithrombin III deficiencies are not existent in the literature and likely are not compatible with life. All patients with BCS warrant a hypercoagulable work up and JAK2 mutation is increasingly recognized as a contributing factor, even in those patients without obvious signs of polycythemia vera.

Morning-only one-gallon polyethylene glycol improves bowel cleansing for afternoon colonoscopies: a randomized endoscopist-blinded prospective study.

OBJECTIVES: Inadequate bowel preparation is a known factor associated with increased failure rates of afternoon colonoscopy and lower adenoma detection rates. The aim of our study was to compare the efficacy of bowel cleansing achieved by administering 1-gallon (4 l) polyethylene glycol (PEG) preparation to patients in the morning of an afternoon colonoscopy with that of the traditional evening regimen. METHODS: A prospective endoscopist-blinded study was conducted, in which patients undergoing afternoon colonoscopy were randomized to receive either 1 gallon of PEG the evening before the procedure or the morning of the colonoscopy. Bowel cleansing efficacy was scored by a blinded endoscopist using the Ottawa scale and each participant filled out a satisfaction survey. Mean scores for each bowel segment, composite mean scores, and rates of "good prep" interpreted from the Ottawa scale were compared between the two groups. RESULTS: A total of 136 patients (mean age 51.8 years, 52.2% men) evenly distributed between the two groups formed the study sample. Patients in the morning group had significantly lower Ottawa scale scores and were more likely to have a good preparation for each bowel segment and overall when compared with the evening group (P<0.01). Moreover, patients in the morning group were over 50% less likely to lose sleep or have bloating compared with the evening group (P<0.05). There was no difference in the study groups on overall polyp detection rate, adenomatous polyps, or number of patients with adenomas. CONCLUSIONS: This study shows that the bowel cleansing efficacy of morning-only 1-gallon PEG is superior and better tolerated compared with consumption of 1-gallon PEG in the evening before the day of an afternoon colonoscopy. Thus, administering 1-gallon PEG solution in the morning of an afternoon colonoscopy is a feasible option that can improve the quality of an afternoon colonoscopy.