Endothelial-Derived miR-17∼92 Promotes Angiogenesis to Protect against Renal Ischemia-Reperfusion Injury

BackgroundDamage to the renal microvasculature is a hallmark of renal ischemia-reperfusion injury (IRI)–mediated AKI. The miR-17∼92 miRNA cluster (encoding miR-17, -18a, -19a, -20a, -19b-1, and -92a-1) regulates angiogenesis in multiple settings, but no definitive role in renal endothelium during AKI pathogenesis has been established.MethodsAntibodies bound to magnetic beads were utilized to selectively enrich for renal endothelial cells from mice. Endothelial-specific miR-17∼92 knockout (miR-17∼92^endo−/−) mice were generated and given renal IRI. Mice were monitored for the development of AKI using serum chemistries and histology and for renal blood flow using magnetic resonance imaging (MRI) and laser Doppler imaging. Mice were treated with miRNA mimics during renal IRI, and therapeutic efficacies were evaluated.ResultsmiR-17, -18a, -20a, -19b, and pri–miR-17∼92 are dynamically regulated in renal endothelial cells after renal IRI. miR-17∼92^endo−/− exacerbates renal IRI in male and female mice. Specifically, miR-17∼92^endo−/− promotes renal tubular injury, reduces renal blood flow, promotes microvascular rarefaction, increases renal oxidative stress, and promotes macrophage infiltration to injured kidneys. The potent antiangiogenic factor thrombospondin 1 (TSP1) is highly expressed in renal endothelium in miR-17∼92^endo−/− after renal IRI and is a target of miR-18a and miR-19a/b. miR-17∼92 is critical in the angiogenic response after renal IRI, which treatment with miR-18a and miR-19b mimics can mitigate.ConclusionsThese data suggest that endothelial-derived miR-17∼92 stimulates a reparative response in damaged renal vasculature during renal IRI by regulating angiogenic pathways.     

Imipenem resistance inEnterobacter

Blood cultures obtained on two separate occasions from a 37-year-old male who received multiple antibiotics (including imipenem) for treatment of repeated episodes of intraabdominal abscesses and bacteremia yielded two isolates ofEnterobacter with reduced susceptibility to imipenem, extended-spectrum cephalosporins, penicillins and aztreonam. Both isolates were unstable, giving rise to different colony types, each of which produced a single, non-inducible Bush group 1 -lactamase (pI=9.6) that hydrolyzed imipenem. Outer membrane proteins were analyzed but no differences were detected between strains with different levels of imipenem resistance. Three-dimensional tests performed in conjunction with disk diffusion susceptibility tests provided a rapid and convenient means of detecting the production of imipenem-hydrolyzing enzymes by theEnterobacter strains. These isolates provided additional evidence that overproduction of the group 1 cephalosporinase ofEnterobacter can contribute to resistance to imipenem.     

The Pharmacokinetics of Recombinant Human Relaxin in Nonpregnant Women After Intravenous,Intravaginal, and Intracervical Administration

The pharmacokinetics of recombinant human relaxin (rhRlx) after intravenous (iv) bolus administration and the absorption of rhRlx after intracervical or intravaginal administration were determined in nonpregnant women. The study was conducted in two parts. In part I, 25 women received 0.01 mg/kg rhRlx iv. After a minimum 7-day washout period, these women were dosed intracervically (n = 10) or intravaginally (n = 15) with 0.75 or 1.5 mg rhRlx, respectively, in 3% methylcellulose gel. Part II was a double-blind, randomized, three-way crossover study in 26 women. At 1-month intervals, each woman received one of three intravaginal treatments consisting of 0 (placebo), 1, or 6 mg rhRlx in 3% methylcellulose gel. The serum concentrations of relaxin following iv administration were described as the sum of three exponentials. The mean (±SD) initial, intermediate, and terminal half-lives were 0.09 ± 0.04, 0.72 ± 0.11, and 4.6 ± 1.2 hr, respectively. Most of the area under the curve was associated with the intermediate half-life. The weight-normalized clearance was 170 ± 50 mL/hr/kg. The observed peak concentration was 98 ± 29 ng/mL, and the weight-normalized initial volume of distribution was 78 ± 40 mL/kg, which is approximately equivalent to the serum volume. If central compartment elimination was assumed, the volume of distribution at steady state (V _ss/W) was 280 ± 100 mL/kg, which is approximately equivalent to extracellular fluid volume. V _ss/W could be as large as 1300 ± 400 mL/kg without this assumption. After intravaginal administration of the placebo gel, endogenous relaxin concentrations were evident (i.e., 20 pg/mL) in 9 of the 26 women (maximum concentrations, 23–234 pg/mL). A similar proportion of women (approximately 35–40%) exhibited measurable serum concentrations of relaxin following intravaginal rhRlx treatment; this proportion increased to 90% following intracervical rhRlx treatment. For both routes of administration, the maximum serum concentrations of relaxin were usually within the range of values observed for endogenous relaxin, suggesting that the absorption of rhRlx was minimal.     

Transoesophageal echocardiography detects residual ductal flow during video-assisted thoracoscopic patent ductus arteriosus interruption

This report describes transoesophageal echocardiographic (TEE) monitoring in a one-year-old boy undergoing patent ductus arteriosus (PDA) interruption. After application of a first vascular clip, echocardiographic monitoring detected incomplete interruption of ductal flow, prompting the surgeon to add a second clip to the ductus. The procedure was performed via a new surgical technique: video-assisted thoracoscopic surgery (VATS). This innovative approach offers many advantages to patient care including reduced postoperative pain and better preservation of pulmonary function. We conclude that the use of TEE monitoring during PDA interruption via the VATS procedure may improve the surgical result, and eliminate reintervention and the complications associated with residual ductal flow.     

Increasing PAs' awareness and understanding of self-help groups. An educational model

A model for inclusion of information about self-help groups into a PA training program is provided based on the results of a study of 26 PA students enrolled in a patient-counseling class. Interactions with self-help groups yield more positive beliefs and greater intentions to collaborate with self-help groups than training programs that do not address self-help groups. The experiential component is also useful for increasing understanding of appropriate roles for professionals interacting with self-help groups.     

Swollen great toe following trauma

The following case is presented to illustrate the roentgenographic and clinical findings of a condition of interest to the orthopedic surgeon. Initial history, physical findings, and roentgenographic examinations are found on this page. The final clinical and roentgenographic differential diagnoses are presented on the following pages.     

The thermodynamics of xanthine oxidoreductase catalysis

Xanthine oxidoreductase is a complex enzyme found in a wide range of organisms. Recent interest in this enzyme stems from its ability to produce reactive oxygen species under a range of conditions. It is found as a homodimer, each unit containing a molybdopterin cofactor, two iron sulfur centers, and FAD. The enzyme can exist in two forms that differ primarily in their oxidizing substrate specificity. The dehydrogenase form preferentially utilizes NAD+ as an electron acceptor but is able to donate electrons to molecular oxygen. Xanthine dehydrogenase from mammalian sources can be converted to an oxidase form that readily donates electrons to molecular oxygen, but does not reduce NAD+. The catalytic mechanism of both forms of the enzyme can be described in terms of a rapid equilibrium model in which reducing equivalents are distributed rapidly between the different redox centers of the enzyme on the basis of their midpoint potentials. The present commentary gives a brief overview of the literature concerning the rapid equilibrium model and the differences between the two enzyme forms. NADH is also discussed in terms of an alternative to xanthine or hypoxanthine as an electron donor.     

An atypical presentation of Paget's disease in an immunocompromised individual. A case report

Paget's disease of bone is a localized disorder of bony resorption. The mechanism underlying the development of the disease remains controversial. There is substantial evidence suggesting a genetic basis for Paget's disease in some patients. A viral etiology of Paget's disease has been advocated. A further hypothesis implicating an immunological mechanism for this disease is based on growing evidence reviewed in the text. The presented case showed clinical and X-ray features typical of a very aggressive form of Paget's disease. We hypothesize that the extreme local aggressiveness of this case was secondary to the patient's concomitant immunosuppression due to an extended therapy following renal transplant.