Expression and function of human ribonuclease 4 in the kidney and urinary tract.

Antimicrobial peptides are essential host defense mechanisms that prevent urinary tract infections. Recent studies have demonstrated that peptides in the ribonuclease A superfamily have antimicrobial activity against uropathogens and protect the urinary tract from uropathogenic Escherichia coli (UPEC). Little is known about the antibacterial function or expression of ribonuclease 4 (RNase 4) in the human urinary tract. Here, we show that full-length recombinant RNase 4 peptide and synthetic amino-terminal RNase 4 peptide fragment have antibacterial activity against UPEC and multidrug-resistant (MDR)-UPEC. RNASE4 transcript expression was detected in human kidney and bladder tissue using quantitative real-time PCR. Immunostaining or in situ hybridization localized RNase 4 expression to proximal tubules, principal and intercalated cells in the kidney's collecting duct, and the bladder urothelium. Urinary RNase 4 concentrations were quantified in healthy controls and females with a history of urinary tract infection. Compared with controls, urinary RNase 4 concentrations were significantly lower in females with a history of urinary tract infection. When RNase 4 was neutralized in human urine or silenced in vitro using siRNA, urinary UPEC replication or attachment to and invasion of urothelial and kidney medullary cells increased. These data show that RNase 4 has antibacterial activity against UPEC, is expressed in the human urinary tract, and can contribute to host defense against urinary tract infections.NEW & NOTEWORTHY Ribonuclease 4 (RNase 4) is a newly identified host defense peptide in the human kidney and bladder. RNase 4 kills uropathogenic Escherichia coli (UPEC) and multidrug-resistant UPEC. RNase 4 prevents invasive UPEC infection and suppressed RNase 4 expression may be a risk factor for more severe or recurrent urinary tract infection.

Basal and bolus insulin requirements in children, adolescents, and young adults with type 1 diabetes mellitus on continuous subcutaneous insulin infusion (CSII): effects of age and puberty.

OBJECTIVE: Guidelines for insulin dosing, including the insulin to carbohydrate ratio (I/C), insulin sensitivity factor (ISF), and basal/bolus ratio guidelines, have been well established for adults with type 1 diabetes mellitus (T1DM). However, clinical experience suggests that these guidelines are not appropriate for children. The purpose of this study was to determine the continuous subcutaneous insulin infusion (CSII) settings in children with T1DM at different ages and stages of puberty. METHODS: A total of 154 patients data between the ages of 3 and 21 years with well-controlled T1DM according to American Diabetes Association guidelines were reviewed. Only patients on CSII who were not in the honeymoon period were included. RESULTS: Patients were divided into 8 groups according to age, gender, and/or pubertal stage. Insulin requirements increased with puberty in both sexes (0.69, 0.97, and 0.90 U/kg/day in children <7 years of age, midpubertal girls, and late-pubertal boys, respectively). Basal insulin requirement was lowest in the youngest group (34%; P<.01). The youngest group had the lowest I/C prediction factor (PF) (mean, 315.7 ± 79.4; P<.01 with all groups), and the ISF-PF was higher than that of the oldest group (mean, 2,588.3 ± 1,101.8; P<.01). CONCLUSION: CSII dose calculations vary with age and pubertal status in children with T1DM. These differences must be considered when calculating CSII dosing, especially for younger children.

A phase II study of CI-980 in previously untreated extensive small cell lung cancer: an Ohio State University phase II research consortium study.

CI-980, (ethyl (S)-(5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b] pyrazine-7-yl) carbamate 2-hydroxyethansulfonate (1:1)), is a water-soluble mitotic inhibitor. It acts by binding to the colchicine-binding site on tubulin, a site different from that of the vinca alkaloids, inhibiting tubulin polymerization. Cells exposed to CI-980 accumulate in M phase and die. In preclinical tumor models, CI-980 showed a broad spectrum of activity, including in multi-drug resistant tumor cell lines, with activity at least equal to that of vincristine. Extensive small cell lung cancer, despite its responsiveness to chemotherapy, is usually an incurable disease with survival in patients of less than one year. Due to the preclinical activity of CI-980 and its similar mechanism of action to drugs effective in small cell lung cancer, a phase II trial in extensive small cell lung cancer was initiated by The Ohio State University Phase II Research Consortium. A "window of opportunity" design was chosen where a short six-week trial of the drug was given unless there was significant objective response. Twelve patients were entered in the study and underwent a total of 16 cycles of chemotherapy. The median age of the patients was 54 years old (range 34-71) and performance status was ECOG 0 (four patients), ECOG 1 (seven patients), and ECOG 2 (one patient). The patients were treated with a 72-hr infusion at a dose of 4.5 mg/m2/day. Toxicity was predominantly myelosuppression with granulocytopenia (nine episodes), and anemia (seven episodes). There were no objective responses with 11 patients being removed from study due to progressive disease. Evaluation of leukocyte microtubule structure in peripheral blood revealed microtubule depolymerization, which was seen after treatment (t = 72 hr) and was reversible within 24 hr of stopping the drug. We conclude that despite antitumor activity demonstrated in preclinical studies, CI-980 does not have biological activity in previously untreated small cell lung cancer at this dose and infusion protocol.