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Concept: Urine

154

Cranberry consumption has shown prophylactic effects against urinary tract infections (UTI), although the mechanisms involved are not completely understood. In this paper, cranberry phenolic compounds and their potential microbial-derived metabolites (such as simple phenols and benzoic, phenylacetic and phenylpropionic acids) were tested for their capacity to inhibit the adherence of uropathogenic Escherichia coli (UPEC) ATCC®53503™ to T24 epithelial bladder cells. Catechol, benzoic acid, vanillic acid, phenylacetic acid and 3,4-dihydroxyphenylacetic acid showed anti-adhesive activity against UPEC in a concentration-dependent manner from 100-500 µM, whereas procyanidin A2, widely reported as an inhibitor of UPEC adherence on uroepithelium, was only statistically significant (p < 0.05) at 500 µM (51.3% inhibition). The results proved for the first time the anti-adhesive activity of some cranberry-derived phenolic metabolites against UPEC in vitro, suggesting that their presence in the urine could reduce bacterial colonization and progression of UTI.

Concepts: Kidney, Urinary tract infection, Urine, Escherichia coli, Urinary bladder, Urinary system, Catechin, Vanillin

133

Colistin is increasingly used as an antibiotic of last resort for the treatment of carbapenem-resistant Gram-negative infections. The plasmid-borne colistin resistance gene mcr-1 was initially identified in animal and clinical samples from China and subsequently reported worldwide, including in the United States. Of particular concern is the spread of mcr-1 into carbapenem-resistant bacteria, thereby creating strains that approach pan-resistance. While several reports of mcr-1 have involved carbapenem-resistant strains, no such isolates have been described in the United States. Here, we report the isolation and identification of an Escherichia coli strain harboring both mcr-1 and carbapenemase gene blaNDM-5 from a urine sample in a patient without recent travel outside the United States. The isolate exhibited resistance to both colistin and carbapenems, but was susceptible to amikacin, aztreonam, gentamicin, nitrofurantoin, tigecycline, and trimethoprim-sulfamethoxazole. The mcr-1- and blaNDM-5-harboring plasmids were completely sequenced and shown to be highly similar to plasmids previously reported from China. The strain in this report was first isolated in August 2014, highlighting an earlier presence of mcr-1 within the United States than previously recognized.

Concepts: Kidney, Bacteria, Virus, Urinary tract infection, Urine, United States, Antibiotic resistance, Escherichia coli

101

Urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7 predict the development of acute kidney injury following renal insults of varied aetiology. To aid clinical interpretation, we describe the kinetics of biomarker elevations around an exposure.

Concepts: Immune system, Renal failure, Kidney, Blood, Glucose, Urine, Apoptosis, Ureter

66

Pathogens often inhabit the body asymptomatically, emerging to cause disease in response to unknown triggers. In the bladder, latent intracellular Escherichia coli reservoirs are regarded as likely origins of recurrent urinary tract infection (rUTI), a problem affecting millions of women worldwide. However, clinically plausible triggers that activate these reservoirs are unknown. Clinical studies suggest that the composition of a woman’s vaginal microbiota influences her susceptibility to rUTI, but the mechanisms behind these associations are unclear. Several lines of evidence suggest that the urinary tract is routinely exposed to vaginal bacteria, including Gardnerella vaginalis, a dominant member of the vaginal microbiota in some women. Using a mouse model, we show that bladder exposure to G. vaginalis triggers E. coli egress from latent bladder reservoirs and enhances the potential for life-threatening outcomes of the resulting E. coli rUTI. Transient G. vaginalis exposures were sufficient to cause bladder epithelial apoptosis and exfoliation and interleukin-1-receptor-mediated kidney injury, which persisted after G. vaginalis clearance from the urinary tract. These results support a broader view of UTI pathogenesis in which disease can be driven by short-lived but powerful urinary tract exposures to vaginal bacteria that are themselves not “uropathogenic” in the classic sense. This “covert pathogenesis” paradigm may apply to other latent infections, (e.g., tuberculosis), or for diseases currently defined as noninfectious because routine culture fails to detect microbes of recognized significance.

Concepts: Kidney, Bacteria, Gut flora, Urinary tract infection, Urine, Escherichia coli, Ureter

45

Many urological studies rely on models of animals, such as rats and pigs, but their relation to the human urinary system is poorly understood. Here, we elucidate the hydrodynamics of urination across five orders of magnitude in body mass. Using high-speed videography and flow-rate measurement obtained at Zoo Atlanta, we discover that all mammals above 3 kg in weight empty their bladders over nearly constant duration of 21 ± 13 s. This feat is possible, because larger animals have longer urethras and thus, higher gravitational force and higher flow speed. Smaller mammals are challenged during urination by high viscous and capillary forces that limit their urine to single drops. Our findings reveal that the urethra is a flow-enhancing device, enabling the urinary system to be scaled up by a factor of 3,600 in volume without compromising its function. This study may help to diagnose urinary problems in animals as well as inspire the design of scalable hydrodynamic systems based on those in nature.

Concepts: Blood, Urine, Mass, Urinary bladder, Urinary system, Urethra, Urination, Fluid mechanics

40

Up to 50% of urinary tract infections (UTIs) in young children are missed in primary care. Urine culture is essential for diagnosis, but urine collection is often difficult. Our aim was to derive and internally validate a 2-step clinical rule using (1) symptoms and signs to select children for urine collection; and (2) symptoms, signs, and dipstick testing to guide antibiotic treatment.

Concepts: Kidney, Disease, Urinary tract infection, Urine, Greek loanwords, Fatigue, Fever, Urinalysis

36

Background The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. Methods We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. Results We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10(-14)). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. Conclusions We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.).

Concepts: DNA, Kidney, Gene, Genetics, Urine, Urinary bladder, Urinary system, Ureter

34

High urine flow rate (UFR) has been suggested as a target for effective prevention of contrast-induced acute kidney injury (CI-AKI). The RenalGuard therapy (saline infusion plus furosemide controlled by the RenalGuard system) facilitates the achievement of this target.

Concepts: Kidney, Urine, Acute kidney injury

32

The introduction of metagenomic sequencing to diagnostic microbiology has been hampered by slowness, cost and complexity. We explored whether MinION nanopore sequencing could accelerate diagnosis and resistance profiling, using complicated urinary tract infections as an exemplar.

Concepts: Kidney, Bacteria, Microbiology, Urinary tract infection, Urine, Escherichia coli, Pathogen, Microorganism

32

AIM: To describe and test a new technique to obtain midstream urine samples in newborns. DESIGN AND METHODS: This was a prospective feasibility and safety study conducted in the neonatal unit of University Infanta Sofía Hospital, Madrid. A new technique based on bladder and lumbar stimulation manoeuvres was tested over a period of 4 months in 80 admitted patients aged less than 30 days. The main variable was the success rate in obtaining a midstream urine sample within 5 min. Secondary variables were time to obtain the sample and complications. RESULTS: This technique was successful in 86.3% of infants. Median time to sample collection was 45 s (IQR 30). No complications other than controlled crying were observed. CONCLUSIONS: A new, quick and safe technique with a high success rate is described, whereby the discomfort and waste of time usually associated with bag collection methods can be avoided.

Concepts: Time, Infant, Urine, Median, Infant mortality, Pediatrics, Hematuria, Urinalysis