The prevalence of obesity in the United States continues to grow and is estimated to affect over a quarter of the working-age population. Some studies have identified obesity as a risk factor for ...flap failure and complications in free flap-based breast reconstruction, but its clinical significance is less clear in nonbreast reconstruction. The role of obesity as a risk factor for failure and complications following lower extremity reconstruction has not been well described, and the limited existing literature demonstrates conflicting results.
The American College of Surgeons National Surgical Quality Improvement Program database was reviewed to identify patients undergoing local- or free-flap reconstruction of the lower extremity between 2010 and 2015. Preoperative variables and outcomes were compared between obese (body mass index ≥ 30) and nonobese patients. Chi-square analysis and Fisher's exact test were used for categorical variables and
-tests for continuous variables. Multivariate regression was performed to control for confounders.
Univariate analysis of medical and surgical outcomes revealed that obese patients undergoing local flaps of the lower extremity required a significantly longer operative time (187.7 ± 123.2 vs. 166.2 ± 111.7 minutes;
= 0.003) and had significantly higher rates of superficial surgical site infection (SSI; 7.2% vs. 4.5%;
= 0.04). On univariate analysis, there were no significant differences in any postoperative outcomes between obese and nonobese patients undergoing microvascular free flaps of the lower extremity.On multivariate regression analysis, obesity was not an independent risk factor for superficial SSI (odds ratio = 1.01,
= 0.98) or increased operative time (
= 16.01,
= 0.14) for local flaps of the lower extremity.
Evaluation of a large, multicenter, validated and risk-adjusted nationwide cohort demonstrated that obesity is not an independent risk factor for early complications following lower extremity reconstruction, suggesting that these procedures may be performed safely in the obese patient population.
BACKGROUND AND PURPOSE—Higher low-density lipoprotein cholesterol is associated with more rapid chronic kidney disease progression; reduction in cholesterol with statins, in conjunction with statins’ ...pleiotropic effects, such as decreasing inflammation, may be renoprotective. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial assessed the effect of statin treatment on the risk of nonfatal and fatal stroke in subjects with a noncardioembolic stroke or transient ischemic attack, no known coronary heart disease, and low-density lipoprotein cholesterol between 2.6 and 4.9 mmol/L (100–190 mg/dL).
METHODS—We explored the effect of randomization to atorvastatin 80 mg/d or placebo on the change in estimated glomerular filtration rate (eGFR; using the 4-component Modification of Diet in Renal Disease Study equation) in SPARCL subjects (n=4731) with (eGFR, <60 mL/min per 1.73 m; n=3119) and without (eGFR, ≥60 mL/min per 1.73 m; n=1600) chronic kidney disease overall and by glycemic status at baseline.
RESULTS—Mean baseline eGFR was similar between treatment groups (65.5±0.26 versus 65.6±0.26 mL/min per 1.73 m atorvastatin versus placebo; 33% versus 34% had chronic kidney disease, respectively; P=0.55). After 60 months, eGFR increased 3.46±0.33 mL/min per 1.73 m in those randomized to atorvastatin versus 1.42±0.34 mL/min per 1.73 m in those randomized to placebo (P<0.001) independent of baseline renal function. In the subgroup with diabetes mellitus at randomization, eGFR increased 1.12±0.92 mL/min per 1.73 m in the atorvastatin group and decreased 1.69±0.92 mL/min per 1.73 m in placebo group during a period of 60 months (P=0.016).
CONCLUSIONS—This post hoc analysis suggests that atorvastatin treatment may improve renal function in patients with prior stroke or transient ischemic attack with and without chronic kidney disease, and that atorvastatin treatment may prevent eGFR decline in patients with stroke and diabetes mellitus.
CLINICAL TRIAL REGISTRATION—URLhttp://www.clinicaltrials.gov. Unique identifierNCT00147602.
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GlaxoSmithKline and Astex Pharmaceuticals recently disclosed the discovery of the potent H-PGDS inhibitor GSK2894631A 1a (IC50 = 9.9 nM) as part of a fragment-based drug discovery ...collaboration with Astex Pharmaceuticals. This molecule exhibited good murine pharmacokinetics, allowing it to be utilized to explore H-PGDS pharmacology in vivo. Yet, with prolonged dosing at higher concentrations, 1a induced CNS toxicity. Looking to attenuate brain penetration in this series, aza-quinolines, were prepared with the intent of increasing polar surface area. Nitrogen substitutions at the 6- and 8-positions of the quinoline were discovered to be tolerated by the enzyme. Subsequent structure activity studies in these aza-quinoline scaffolds led to the identification of 1,8-naphthyridine 1y (IC50 = 9.4 nM) as a potent peripherally restricted H-PGDS inhibitor. Compound 1y is efficacious in four in vivo inflammatory models and exhibits no CNS toxicity.
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With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin ...D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC50 = 220,000 nM, LE = 0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC50 = 3,100 nM, LE = 0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC50 = 9.9 nM, LE = 0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD2 production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.
Background:Intravenous (IV) loop diuretics are recommended to relieve vascular congestion in patients with acute decompensated heart failure (ADHF); however, initial dosing is often empirical. Strong ...evidence supporting individualized diuretic dosing in the emergency department (ED) is lacking. Objective: The purpose of this study was to compare the efficacy and safety of aggressive (≥2 daily home doses) and conservative (<2 daily home doses) initial doses of loop diuretic. Methods: This was a retrospective cohort study in adult patients presenting to the ED with ADHF at an academic medical center from Apri 2015 to September 2015. The primary outcome was time to transition from IV to oral diuretics. Results: A total of 91 patients were included (aggressive dosing, n = 44; conservative dosing, n = 47). Mean time to transition from IV to oral diuretics was 67.9 hours in the aggressive group compared with 88.1 hours in the conservative group (P = 0.049). Mean hospital length of stay (LOS) was 119.5 hours in the aggressive group versus 123.0 hours in the conservative group (P = 0.799). No differences were observed between the mean urine output (P = 0.829), change in body weight (P = 0.528), or serum creatinine (P = 0.135). Conclusion: Patients who received an aggressive initial diuretic dose in the ED had a significantly faster time to oral diuretic therapy without any significant differences in hospital LOS, urine output, change in body weight, and renal function when compared with conservative dosing.
Abstract
Bacteria use siderophores to mediate the transport of essential Fe(III) into the cell. In
Campylobacter jejuni
the periplasmic binding protein CeuE, an integral part of the Fe(III) transport ...system, has adapted to bind tetradentate siderophores using a His and a Tyr side chain to complete the Fe(III) coordination. A series of tetradentate siderophore mimics was synthesized in which the length of the linker between the two iron-binding catecholamide units was increased from four carbon atoms (4-LICAM
4−
) to five, six and eight (5-, 6-, 8-LICAM
4−
, respectively). Co-crystal structures with CeuE showed that the inter-planar angles between the iron-binding catecholamide units in the 5-, 6- and 8-LICAM
4−
structures are very similar (111°, 110° and 110°) and allow for an optimum fit into the binding pocket of CeuE, the inter-planar angle in the structure of 4-LICAM
4−
is significantly smaller (97°) due to restrictions imposed by the shorter linker. Accordingly, the protein-binding affinity was found to be slightly higher for 5- compared to 4-LICAM
4−
but decreases for 6- and 8-LICAM
4−
. The optimum linker length of five matches that present in natural siderophores such as enterobactin and azotochelin. Site-directed mutagenesis was used to investigate the relative importance of the Fe(III)-coordinating residues H227 and Y288.
Inhibition of siderophore biosynthetic pathways in pathogenic bacteria represents a promising strategy for antibacterial drug development. Escherichia coli synthesize and secrete the small molecule ...iron chelator siderophore, enterobactin, in response to intracellular iron depletion. Here we describe a detailed kinetic analysis of EntE, one of six enzymes in the enterobactin synthetase gene cluster. EntE catalyzes the ATP-dependent condensation of 2,3-dihydroxybenzoic acid (DHB) and phosphopantetheinylated EntB (holo-EntB) to form covalently arylated EntB, a product that is vital for the final assembly of enterobactin. Initial velocity studies show that EntE proceeds via a bi-uni-uni-bi ping-pong kinetic mechanism with a k cat equal to 2.8 s−1 and K m values of 2.5, 430, and 2.9 μM for DHB, ATP, and holo-EntB-ArCP, respectively. Inhibition and direct binding experiments suggest that, during the first half-reaction (adenylation), DHB binds first to the free enzyme, followed by ATP and the release of pyrophosphate to form the adenylate intermediate. During the second half-reaction (ligation), phosphopantetheinylated EntB binds to the enzyme followed by the release of products, AMP and arylated EntB. Two hydrolytically stable adenylate analogues, 5′-O-N-(salicyl)sulfamoyladenosine (Sal-AMS) and 5′-O-N-(2,3-dihydroxybenzoyl)sulfamoyladenosine (DHB-AMS), are shown to act as slow-onset tight-binding inhibitors of the enzyme with app K i values of 0.9 and 3.8 nM, respectively. Direct binding experiments, via isothermal titration calorimetry, reveal low picomolar dissociation constants for both analogues with respect to EntE. The tight binding of Sal-AMS and DHB-AMS to EntE suggests that these compounds may be developed further as effective antibiotics targeted to this enzyme.
Paper wicks fluids autonomously due to capillary action. By patterning paper with hydrophobic barriers, the transport of fluids can be controlled and directed within a layer of paper. Moreover, ...stacking multiple layers of patterned paper creates sophisticated three-dimensional microfluidic networks that can support the development of analytical and bioanalytical assays. Paper-based microfluidic devices are inexpensive, portable, easy to use, and require no external equipment to operate. As a result, they hold great promise as a platform for point-of-care diagnostics. In order to properly evaluate the utility and analytical performance of paper-based devices, suitable methods must be developed to ensure their manufacture is reproducible and at a scale that is appropriate for laboratory settings. In this manuscript, a method to fabricate a general device architecture that can be used for paper-based immunoassays is described. We use a form of additive manufacturing (multi-layer lamination) to prepare devices that comprise multiple layers of patterned paper and patterned adhesive. In addition to demonstrating the proper use of these three-dimensional paper-based microfluidic devices with an immunoassay for human chorionic gonadotropin (hCG), errors in the manufacturing process that may result in device failures are discussed. We expect this approach to manufacturing paper-based devices will find broad utility in the development of analytical applications designed specifically for limited-resource settings.
Intermolecular interactions between charged membranes and biological polyelectrolytes, tuned by physical parameters, which include the membrane charge density and bending rigidity, the membrane ...spontaneous curvature, the biopolymer curvature, and the overall charge of the complex, lead to distinct structures and morphologies. The self-assembly of cationic liposome-microtubule (MT) complexes was studied, using synchrotron x-ray scattering and electron microscopy. Vesicles were found to either adsorb onto MTs, forming a "beads on a rod" structure, or undergo a wetting transition and coating the MT. Tubulin oligomers then coat the external lipid layer, forming a tunable lipid-protein nanotube. The beads on a rod structure is a kinetically trapped state. The energy barrier between the states depends on the membrane bending rigidity and charge density. By controlling the cationic lipid/tubulin stoichiometry it is possible to switch between two states of nanotubes with either open ends or closed ends with lipid caps, a process that forms the basis for controlled chemical and drug encapsulation and release.
Radiation therapy is an effective treatment strategy for many types of cancer but is limited by its side effects on normal tissues, particularly the skin, where persistent and progressive fibrotic ...changes occur and can impair wound healing. In this study, we attempted to mitigate the effects of irradiation on skin using a novel transcutaneous topical delivery system to locally inhibit p53 up-regulated modulator of apoptosis (PUMA) gene expression with small interfering RNA (siRNA). In an isolated skin irradiation model, the dorsal skin of C57 wild-type mice was irradiated. Prior to irradiation, PUMA and nonsense siRNA were applied via a novel hydrogel formulation to dorsal skin and reapplied weekly. Skin was harvested at multiple time points to evaluate dermal siRNA penetration, mRNA expression, protein expression, dermal thickness, subcutaneous fat, stiffness, vascular hypertrophy, SCAR index, and reactive oxygen species (ROS) generation. Murine skin treated with topical PUMA siRNA via optimized hydrogel formulation demonstrated effective PUMA inhibition in irradiated tissue at 3-4 days. Tissue stiffness, dermal thickness, vascular hypertrophy, SCAR index, ROS levels, and mRNA levels of MnSOD and TGF-β were all significantly reduced with siPUMA treatment compared to nonsense controls. Subcutaneous fat area was significantly increased, and levels of SMAD3 and Phospho-SMAD3 expression were unchanged. These results show that PUMA expression can be effectively silenced in vivo using a novel hydrogel lipoplex topical delivery system. Moreover, cutaneous PUMA inhibition mitigates radiation induced changes in tissue character, restoring a near-normal phenotype independent of SMAD3 signaling.
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