Human neutrophil peptides 1-3 protect the murine urinary tract from uropathogenic Escherichia coli challenge.

Antimicrobial peptides (AMPs) are critical to the protection of the urinary tract of humans and other animals from pathogenic microbial invasion. AMPs rapidly destroy pathogens by disrupting microbial membranes and/or augmenting or inhibiting the host immune system through a variety of signaling pathways. We have previously demonstrated that alpha-defensins 1-3 (DEFA1A3) are AMPs expressed in the epithelial cells of the human kidney collecting duct in response to uropathogens. We also demonstrated that DNA copy number variations in the DEFA1A3 locus are associated with UTI and pyelonephritis risk. Because DEFA1A3 is not expressed in mice, we utilized human DEFA1A3 gene transgenic mice (DEFA4/4) to further elucidate the biological relevance of this locus in the murine urinary tract. We demonstrate that the kidney transcriptional and translational expression pattern is similar in humans and the human gene transgenic mouse upon uropathogenic Escherichia coli (UPEC) stimulus in vitro and in vivo. We also demonstrate transgenic human DEFA4/4 gene mice are protected from UTI and pyelonephritis under various UPEC challenges. This study serves as the foundation to start the exploration of manipulating the DEFA1A3 locus and alpha-defensins 1-3 expression as a potential therapeutic target for UTIs and other infectious diseases.

Acute kidney injury in hypoplastic left heart syndrome patients following the comprehensive stage two palliation.

BACKGROUND: An alternative surgical approach for hypoplastic left heart syndrome is the Hybrid pathway, which delays the risk of acute kidney injury outside of the newborn period. We sought to determine the incidence, and associated morbidity, of acute kidney injury after the comprehensive stage 2 and the cumulative incidence after the first two operations in the Hybrid pathway. DESIGN: A single centre, retrospective study was conducted of hypoplastic left heart patients completing the second-stage palliation in the Hybrid pathway from 2009 to 2018. Acute kidney injury was defined utilising Kidney Diseases Improving Global Outcomes criteria. Perioperative and post-operative characteristics were analysed. RESULTS: Sixty-one patients were included in the study cohort. The incidence of acute kidney injury was 63.9%, with 36.1% developing severe injury. Cumulatively after the Hybrid Stage 1 and comprehensive stage 2 procedures, 69% developed acute kidney injury with 36% developing severe injury. The presence of post-operative acute kidney injury was not associated with an increase in 30-day mortality (acute kidney injury 7.7% versus none 9.1%; p = > 0.9). There was a significantly longer median duration of intubation among those with acute kidney injury (acute kidney injury 32 (8, 155) hours vs. no injury 9 (0, 94) hours; p = 0.018). CONCLUSIONS: Acute kidney injury after the comprehensive stage two procedure is common and accounts for most of the kidney injury in the first two operations of the Hybrid pathway. No difference in mortality was detected between those with acute kidney injury and those without, although there may be an increase in morbidity.

Positive fluid balance and diuretic therapy are associated with mechanical ventilation and mortality in preterm neonates in the first fourteen postnatal days.

BACKGROUND: Fluid overload leads to poor neonatal outcomes. Diuretics may lower the rates of mechanical ventilation (MV) and mortality in neonates with fluid overload. METHODS: This is a retrospective study of preterm neonates ≤ 36 weeks of gestational age (GA) in the first 14 postnatal days in a level IV NICU in 2014-2020. We evaluated the epidemiology of fluid balance in the first 14 postnatal days and its association with MV and mortality and studied the association of diuretics with fluid balance, MV, and mortality. RESULTS: In 1383 included neonates, the overall median lowest and peak fluid balances were - 7.8% (IQR: - 11.7, - 4.6) and 8% (3, 16) on days 3 (2, 5) and 13 (5, 14), respectively. Fluid balance distribution varied significantly by GA. Peak fluid balance of ≥ 10% was associated with increased odds of MV on days 7 and 14 with highest odds ratios (OR) of MV in neonates with fluid balance ≥ 15%. Peak fluid balance of ≥ 15% was associated with the greatest odds of mortality. Diuretics were used more frequently in neonates with younger GA, smaller birthweight, positive fluid balance, and those on MV. CONCLUSIONS: Positive fluid balance negatively impacts pulmonary status. The odds of MV and death increase significantly as peak fluid balance percentage increases in all GA groups. The impact of diuretics on MV and death in preterm neonates needs further evaluation. A higher resolution version of the Graphical abstract is available as Supplementary information.

Novel urine biomarkers to distinguish UTI from culture-negative pyuria.

BACKGROUND: Emergency departments (EDs) often rely on urinalysis (UA) to rapidly identify urinary tract infections (UTIs) in children. However, the suboptimal test characteristics of UA can lead to false-positive results. Novel urinary biomarkers may increase the diagnostic precision of UA. In this study, we compared the concentrations of 6 pre-selected proteins: BH3 interacting domain death agonist (BID), B-cell lymphoma 6 protein, ras GTPase-activating protein 1, cathepsin S (CTSS), 3-hydroxyanthranilate 3,4-dioxygenase, and transgelin-2. METHODS: In a pediatric ED, we prospectively enrolled 167 children with UA and urine culture collected. Pyuria was defined as either ≥ 5 white blood cells per high-power field on microscopy or positive leukocyte esterase (LE). The urine culture was considered positive if it yielded ≥ 50,000 colony-forming units per milliliter of any single urinary pathogen. Urine protein levels were measured by enzyme-linked immunosorbent assay and normalized to urine creatinine. RESULTS: BID was significantly higher in the UTI group compared to the culture-negative pyuria group with a mean ratio of 1.42 (95% confidence interval (CI), 1.15, 1.76) when uncorrected for creatinine concentration. When corrected for creatinine concentration, CTSS was significantly elevated in the UTI group compared to the culture-negative pyuria group with a mean ratio of 2.11 (95% CI, 1.39, 3.21). CONCLUSIONS: BID and CTSS concentrations were elevated in the urine of children with UTI compared to those with culture-negative pyuria. These proteins deserve further research into their utility to serve as novel biomarkers for UTI.

Synergism between Rifampicin and Cationic Polyurethanes Overcomes Intrinsic Resistance of Escherichia coli.

Antibiotic-resistant Gram-negative bacteria are emergent pathogens, causing millions of infections worldwide. While there are several classes of antibiotics that are effective against Gram-positive bacteria, the outer membrane (OM) of Gram-negative bacteria excludes high-molecular-weight hydrophobic antibiotics, making these species intrinsically resistant to several classes of antibiotics, including polyketides, aminocoumarins, and macrolides. The overuse of antibiotics such as ß-lactams has also promoted the spread of resistance genes throughout Gram-negative bacteria, including the production of extended spectrum ß-lactamases (ESBLs). The combination of innate and acquired resistance makes it extremely challenging to identify antibiotics that are effective against Gram-negative bacteria. In this study, we have demonstrated the synergistic effect of outer membrane-permeable cationic polyurethanes with rifampicin, a polyketide that would otherwise be excluded by the OM, on different strains of E. coli, including a clinically isolated uropathogenic multidrug-resistant (MDR) E. coli. Rifampicin combined with a low-dose treatment of a cationic polyurethane reduced the MIC in E. coli of rifampicin by up to 64-fold. The compositions of cationic polyurethanes were designed to have low hemolysis and low cell cytotoxicity while maintaining high antibacterial activity. Our results demonstrate the potential to rescue the large number of available OM-excluded antibiotics to target normally resistant Gram-negative bacteria via synergistic action with these cationic polyurethanes, acting as a novel antibiotic adjuvant class.

The pressure's on: understanding neurocognitive and psychological associations with pediatric hypertension to inform comprehensive care.

The prevalence of hypertension is increasing in pediatric populations. While clinical data and practice guidelines identify the impact of hypertension on organ dysfunction and emphasize the importance for end-organ damage screening, the bidirectional effects of pediatric hypertension on neurocognitive and psychological outcomes are understudied. The objective of this review is to highlight the association between hypertension and cognition, attention, learning, and mental health in children and adolescents. In doing so, this review provides a framework and toolkit to integrate neuropsychology and psychology into the screening and management stages of pediatric hypertension. By recognizing the effects of hypertension on cognition, behavior, and mental health, screenings and interventions can be implemented to proactively and comprehensively improve the health outcomes for children with blood pressure concerns.

Diuretic therapy and acute kidney injury in preterm neonates and infants.

BACKGROUND: Acute kidney injury (AKI) in preterm infants is associated with prolonged hospitalization and high mortality. Diuretic therapy has been used to enhance urine output in preterm infants with AKI. Treatment with diuretics, prescription patterns, and relationship with length of stay (LOS), mechanical ventilation (MV), and mortality in preterm infants who also had AKI have not been fully evaluated. METHODS: This multicenter retrospective study used the Pediatric Hospital Information System database. We included 2121 preterm infants with AKI diagnosis from 46 hospital Neonatal Intensive Care Units (NICUs) born <37 weeks gestational age (GA). Treatment with diuretics, practice patterns across 46 NICUs in the USA, and associated outcomes including LOS, MV, and mortality were evaluated. RESULTS: Seventy-six percent of infants received at least one dose of diuretics (median treatment 18 days). Diuretic prescription varied significantly across hospitals and ranged from 42 to 96%. Diuretics were used more frequently in infants with younger GA and smaller birth weight. Infants with older GA who received diuretics at or before 28 days postnatally had worse survival even after adjusting for known confounders. CONCLUSIONS: Preterm infants with AKI diagnosis were frequently treated with diuretics. Moreover, infants with younger GA and smaller birth weight were more likely to receive diuretics. Worse survival in infants with older GA who received diuretics could be the result of more underlying severe illness in these infants and not the cause of more severe illness. Prospective studies are needed to best determine patient safety and outcomes with diuretic treatment in preterm infants with AKI. A higher resolution version of the Graphical abstract is available as Supplementary information.

Incidence and impact of acute kidney injury in patients with hypoplastic left heart syndrome following the hybrid stage 1 palliation.

OBJECTIVE: Acute kidney injury leads to worse outcomes following paediatric cardiac surgery. There is a lack of literature focusing on acute kidney injury after the Hybrid stage 1 palliation for single ventricle physiology. Patients undergoing the Hybrid Stage 1, as a primary option, may have a lower incidence of kidney injury than previously reported. When present, kidney injury may increase the risk of post-operative morbidity and mortality. METHODS: A retrospective, single centre review was conducted in patients with hypoplastic left heart syndrome who underwent Hybrid Stage 1 from 2008 to 2018. Acute kidney injury was defined as a dichotomous yes (meeting any injury criteria) or no (no injury) utilising two different criteria utilised in paediatrics. The impact of kidney injury on perioperative characteristics and 30-day mortality was analysed. RESULTS: The incidence of acute kidney injury is 13.4-20.7%, with a severe injury rate of 2.4%. Patients without a prenatal diagnosis of hypoplastic left heart syndrome have a higher incidence of kidney injury than those prenatally diagnosed, (40% versus 14.5%, p = 0.024). Patients with acute kidney injury have a significantly higher incidence of 30-day mortality, 27.3%, compared to without, 5.6% (p = 0.047). DISCUSSION: The incidence of severe acute kidney injury after the Hybrid Stage 1 palliation is low. A prenatal diagnosis may be associated with a lower incidence of kidney injury following the Hybrid Stage 1. Though uncommon, severe acute kidney injury following Hybrid Stage 1 may be associated with higher 30-day mortality.

A novel SAMD9 variant identified in patient with MIRAGE syndrome: Further defining syndromic phenotype and review of previous cases.

We present here a case of MIRAGE syndrome due to novel variant (c.2318T>C) in the sterile α motif domain-containing protein 9 (SAMD9) gene. Previous reports have described the clinical phenotype, which includes myelodysplasia, recurrent infections, restriction of growth and development, adrenal insufficiency, genitourinary abnormalities, and enteropathies, often resulting in fatality within the first few years of life. This report illustrates the variability in phenotype by describing an 11-year-old male, diagnosed with MIRAGE at age 9 years when his novel variant was identified through whole exome sequencing. A brief review of previously published cases of MIRAGE syndrome and the genotypic and phenotypic spectrum are presented.

Do Larger Acetabular Chondral Defects Portend Inferior Outcomes in Patients Undergoing Arthroscopic Acetabular Microfracture? A Matched-Controlled Study.

PURPOSE: To elucidate the effect, if any, of acetabular chondral defect size on surgical outcomes after arthroscopic microfracture was performed with concomitant treatment for labral tears and femoroacetabular impingement (FAI) syndrome. METHODS: The study period was between February 2008 and November 2014. Data were collected on patients who underwent hip arthroscopy. The inclusion criteria were acetabular microfracture; concomitant treatment for labral tears and FAI syndrome; and preoperative modified Harris Hip Score, Nonarthritic Hip Score, Hip Outcome Score-Sports Specific Subscale, and visual analog scale. Exclusion criteria were Workers' Compensation, preoperative Tönnis grade >1, or previous ipsilateral hip surgeries or conditions. Patients were grouped based on smaller chondral defects (SCDs) or larger chondral defects (LCDs), then matched 1:1 by age at surgery ±10 years, sex, body mass index ±5, labral treatment, capsular treatment, acetabuloplasty, and femoroplasty. Outcomes, secondary arthroscopies, and conversions to total hip arthroplasty (THA) were documented. RESULTS: Of 131 eligible cases, 107 (81.7%) had minimum 2-year follow-up. Before matching, the conversion rate to THA was higher for LCDs (24.6%) than for SCDs (12.0%). Thirty-five patients were matched for each group. Mean follow-up time was 47.9 months (range, 24.0, 84.1) for the matched LCD group and 46.1 months (range, 24.0, 88.1) for the matched SCD group. Ligamentum teres debridement (P = .03) was performed more frequently in the LCD group. No other differences were found regarding demographics, intraoperative findings, procedures, traction time, preoperative scores, or follow-up scores. Both groups demonstrated significant improvements in all scores. Rates of revision or conversion to THA were similar between groups. The relative risk for conversion to THA was 2.33 for patients with defects ≥300 mm2 compared with patients with defects ≤250 mm2 (P = .13). Deep vein thrombosis occurred in 3 (5.3%) patients with LCDs. CONCLUSIONS: Matched patients with either SCDs or LCDs undergoing arthroscopic acetabular microfracture with concomitant treatment for labral tears and FAI syndrome demonstrated similar improvements at minimum 2-year follow-up. Patients with chondral defects approaching 300 mm2 or greater may have a higher propensity toward conversion to THA. LEVEL OF EVIDENCE: Level III, retrospective comparative therapeutic trial.

Cell-specific qRT-PCR of renal epithelial cells reveals a novel innate immune signature in murine collecting duct.

The urinary tract is usually culture negative despite its close proximity to microbial flora. The precise mechanism by which the kidneys and urinary tract defends against infection is not well understood. The initial kidney cells to encounter ascending pathogens are the collecting tubule cells that consist of principal cells (PCs) that express aquaporin 2 (AQP2) and intercalated cells (ICs) that express vacuolar H+-ATPase (V-ATPase, B1 subunit). We have previously shown that ICs are involved with the human renal innate immune defense. Here we generated two reporter mice, VATPase B1-cre+tdT+ mice to fluorescently label ICs and AQP2-cre+tdT+ mice to fluorescently label PCs, and then performed flow sorting to enrich PCs and ICs for analysis. Isolated ICs and PCs along with proximal tubular cells were used to measure antimicrobial peptide (AMP) mRNA expression. ICs and PCs were significantly enriched for AMPs. Isolated ICs responded to uropathogenic Escherichia coli (UPEC) challenge in vitro and had higher RNase4 gene expression than control while both ICs and PCs responded to UPEC challenge in vivo by upregulating Defb1 mRNA expression. To our knowledge, this is the first report of isolating murine collecting tubule cells and performing targeted analysis for multiple classes of AMPs.

Polymorphisms in α-Defensin-Encoding DEFA1A3 Associate with Urinary Tract Infection Risk in Children with Vesicoureteral Reflux.

The contribution of genetic variation to urinary tract infection (UTI) risk in children with vesicoureteral reflux is largely unknown. The innate immune system, which includes antimicrobial peptides, such as the α-defensins, encoded by DEFA1A3, is important in preventing UTIs but has not been investigated in the vesicoureteral reflux population. We used quantitative real-time PCR to determine DEFA1A3 DNA copy numbers in 298 individuals with confirmed UTIs and vesicoureteral reflux from the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) Study and 295 controls, and we correlated copy numbers with outcomes. Outcomes studied included reflux grade, UTIs during the study on placebo or antibiotics, bowel and bladder dysfunction, and renal scarring. Overall, 29% of patients and 16% of controls had less than or equal to five copies of DEFA1A3 (odds ratio, 2.09; 95% confidence interval, 1.40 to 3.11; P<0.001). For each additional copy of DEFA1A3, the odds of recurrent UTI in patients receiving antibiotic prophylaxis decreased by 47% when adjusting for vesicoureteral reflux grade and bowel and bladder dysfunction. In patients receiving placebo, DEFA1A3 copy number did not associate with risk of recurrent UTI. Notably, we found that DEFA1A3 is expressed in renal epithelium and not restricted to myeloid-derived cells, such as neutrophils. In conclusion, low DEFA1A3 copy number associated with recurrent UTIs in subjects in the RIVUR Study randomized to prophylactic antibiotics, providing evidence that copy number polymorphisms in an antimicrobial peptide associate with UTI risk.

Ribonucleases 6 and 7 have antimicrobial function in the human and murine urinary tract.

Recent evidence suggests antimicrobial peptides protect the urinary tract from infection. Ribonuclease 7 (RNase 7), a member of the RNase A superfamily, is a potent epithelial-derived protein that maintains human urinary tract sterility. RNase 7 expression is restricted to primates, limiting evaluation of its antimicrobial activity in vivo. Here we identified ribonuclease 6 (RNase 6) as the RNase A superfamily member present in humans and mice that is most conserved at the amino acid level relative to RNase 7. Like RNase 7, recombinant human and murine RNase 6 has potent antimicrobial activity against uropathogens. Quantitative real-time PCR and immunoblot analysis indicate that RNase 6 mRNA and protein are upregulated in the human and murine urinary tract during infection. Immunostaining located RNase 6 to resident and infiltrating monocytes, macrophages, and neutrophils. Uropathogenic E. coli induces RNase 6 peptide expression in human CD14(+) monocytes and murine bone marrow-derived macrophages. Thus, RNase 6 is an inducible, myeloid-derived protein with markedly different expression from the epithelial-derived RNase 7 but with equally potent antimicrobial activity. Our studies suggest RNase 6 serves as an evolutionarily conserved antimicrobial peptide that participates in the maintenance of urinary tract sterility.

An endogenous ribonuclease inhibitor regulates the antimicrobial activity of ribonuclease 7 in the human urinary tract.

Recent studies stress the importance of antimicrobial peptides in protecting the urinary tract from infection. Previously, we have shown that ribonuclease 7 (RNase 7) is a potent antimicrobial peptide that has a broad-spectrum antimicrobial activity against uropathogenic bacteria. The urothelium of the lower urinary tract and intercalated cells of the kidney produce RNase 7, but regulation of its antimicrobial activity has not been well defined. Here, we characterize the expression of an endogenous inhibitor, ribonuclease inhibitor (RI), in the urinary tract and evaluate its effect on the antimicrobial activity of RNase 7. Using RNA isolated from non-infected human bladder and kidney tissue, quantitative real-time polymerase chain reaction showed that RNH1, the gene encoding RI, is constitutively expressed throughout the urinary tract. With pyelonephritis, RNH1 expression and RI peptide production significantly decrease. Immunostaining localized RI production to the umbrella cells of the bladder and intercalated cells of the renal collecting tubule. In vitro assays showed that RI bound to RNase 7 and suppressed its antimicrobial activity by blocking its ability to bind the cell wall of uropathogenic bacteria. Thus, these results demonstrate a new immunomodulatory role for RI and identified a unique regulatory pathway that may affect how RNase 7 maintains urinary tract sterility.

Transcervical intubation for massive self-inflicted neck wound transecting the epiglottis.

Background: Penetrating trauma to the larynx is a rare phenomenon with a high risk of mortality and morbidity due to the density of vital structures in the area (Demetriades et al., 1996). Most commonly, this type of injury is due to a gunshot wound or knife injury (Snow and Ballenger, 2003). In cases of suicidal cutthroat injury, it is relatively rare to penetrate the airway (Symbas et al., 1976). Case report: We present a case of self-penetrating trauma to the anterior neck allowing access for direct laryngeal visualization and transcervical intubation in the field. We describe the immediate workup, surgical intervention, and postoperative management. We focus on managing postoperative cough, secretion management, decannulation, and resultant dysphagia. Conclusion: Penetrating laryngeal trauma resulting in airway transection is a rare but potentially fatal phenomenon in which airway management and aggressive post-operative care for severe coughing and dysphagia should be performed to help improve patient outcomes.

Ribonuclease 7 is a potent antimicrobial peptide within the human urinary tract.

Although the urinary tract is constantly challenged by microbial invasion, it remains free from colonization. Although little is known about how the urinary tract maintains sterility, the presence of antimicrobial peptides (AMPs) in the urine suggests that they may play a role in its protection from infection. Ribonuclease 7 (RNase 7) is a potent AMP that was first identified in the skin. Here, we characterize the expression and relevance of RNase 7 in the human kidney and urinary tract. Using RNA isolated from healthy human tissue, we performed quantitative real-time PCR and found basal RNASE7 expression in kidney and bladder tissue. Immunohistochemical and immunofluorescent analysis localized RNase 7 to the urothelium of the bladder, ureter, and the intercalated cells of the collecting tubules. In control urine samples from healthy individuals, the concentration of RNase 7 was found to be in the low micromolar range; very abundant for an AMP. Antibacterial neutralization assays showed that urinary RNase 7 has potent antimicrobial properties against Gram-negative and Gram-positive uropathogenic bacteria. Thus, RNase 7 is expressed in the human kidney and urinary tract and it may have an important antimicrobial role in maintaining tract sterility.

Ribonuclease 7 polymorphism rs1263872 reduces antimicrobial activity and associates with pediatric urinary tract infections.

Ribonuclease 7 (RNase 7) is an antimicrobial peptide that prevents urinary tract infections (UTI); however, it is yet unknown how RNASE7 genetic variations affect its antimicrobial activity and its mitigation of UTI risk. This study determined whether the RNASE7 SNP rs1263872 is more prevalent in children with UTI and defined how rs1263872 affects RNase 7's antimicrobial activity against uropathogenic E. coli (UPEC). We performed genotyping for rs1263872 in 2 national UTI cohorts, including children enrolled in the Randomized Intervention for Children with Vesicoureteral Reflux trial or the Careful Urinary Tract Infection Evaluation study. Genotypes from these cohorts were compared with those of female controls with no UTI. To assess whether rs1263872 affects RNase 7's antimicrobial activity, we generated RNase 7 peptides and genetically modified urothelial cultures encoding wild-type RNase 7 and its variant. Compared with controls, girls in both UTI cohorts had an increased prevalence of the RNASE7 variant. Compared with the missense variant, wild-type RNase 7 peptide showed greater bactericidal activity against UPEC. Wild-type RNase 7 overexpression in human urothelial cultures reduced UPEC invasive infection compared with mutant overexpression. These results show that children with UTI have an increased prevalence of RNASE7 rs1263872, which may increase UTI susceptibility by suppressing RNase 7's antibacterial activity.

Publisher Correction: Whole Transcriptome Analysis of Renal Intercalated Cells Predicts Lipopolysaccharide Mediated Inhibition of Retinoid X Receptor alpha Function.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Sellar Metastasis of Cervical Adenocarcinoma.

BACKGROUND: Pituitary metastasis of cervical adenocarcinoma is an exceedingly rare phenomenon. CASE DESCRIPTION: The authors present a case of a 66-year-old female with cervical adenocarcinoma who was discovered to have a rapidly growing intrasellar mass in the work-up of adrenal insufficiency and hypothyroidism. The patient underwent subsequent endoscopic endonasal subtotal resection of the mass. Histopathological analysis of the resected lesion demonstrated features consistent with metastatic mucinous adenocarcinoma of the cervix. While initially neurologically asymptomatic following surgery, the patient developed an oculomotor nerve palsy several weeks following surgical debulking, at which time neuroimaging revealed marked regrowth and suprasellar extension of the metastatic lesion. CONCLUSIONS: While metastatic cervical adenocarcinoma to the sella is rare, it should be considered in the differential based on the history of the patient.

Identification and characterization of OmpT-like proteases in uropathogenic Escherichia coli clinical isolates.

Bacterial colonization of the urogenital tract is limited by innate defenses, including the production of antimicrobial peptides (AMPs). Uropathogenic Escherichia coli (UPEC) resist AMP-killing to cause a range of urinary tract infections (UTIs) including asymptomatic bacteriuria, cystitis, pyelonephritis, and sepsis. UPEC strains have high genomic diversity and encode numerous virulence factors that differentiate them from non-UTI-causing strains, including ompT. As OmpT homologs cleave and inactivate AMPs, we hypothesized that UPEC strains from patients with symptomatic UTIs have high OmpT protease activity. Therefore, we measured OmpT activity in 58 clinical E. coli isolates. While heterogeneous OmpT activities were observed, OmpT activity was significantly greater in UPEC strains isolated from patients with symptomatic infections. Unexpectedly, UPEC strains exhibiting the greatest protease activities harbored an additional ompT-like gene called arlC (ompTp). The presence of two OmpT-like proteases in some UPEC isolates led us to compare the substrate specificities of OmpT-like proteases found in E. coli. While all three cleaved AMPs, cleavage efficiency varied on the basis of AMP size and secondary structure. Our findings suggest the presence of ArlC and OmpT in the same UPEC isolate may confer a fitness advantage by expanding the range of target substrates.