Intravital Multiphoton Microscopy with Fluorescent Bile Salts in Rats as an In Vivo Biomarker for Hepatobiliary Transport Inhibition

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it mediates the elimination of monovalent bile salts into the bile. Inhibition of BSEP is considered a susceptibility factor for drug-induced liver injury that often goes undetected during nonclinical testing. Although in vitro assays exist for screening BSEP inhibition, a reliable and specific method for confirming Bsep inhibition in vivo would be a valuable follow up to a BSEP screening strategy, helping to put a translatable context around in vitro inhibition data, incorporating processes such as metabolism, protein binding, and other exposure properties that are lacking in most in vitro BSEP models. Here, we describe studies in which methods of quantitative intravital microscopy were used to identify dose-dependent effects of two known BSEP/Bsep inhibitors, 2-[4-[4-(butylcarbamoyl)-2-[(2,4-dichlorophenyl)sulfonylamino]phenoxy]-3-methoxyphenyl]acetic acid (AMG-009) and bosentan, on hepatocellular transport of the fluorescent bile salts cholylglycyl amidofluorescein and cholyl-lysyl-fluorescein in rats. Results of these studies demonstrate that the intravital microscopy approach is capable of detecting Bsep inhibition at drug doses well below those found to increase serum bile acid levels, and also indicate that basolateral efflux transporters play a significant role in preventing cytosolic accumulation of bile acids under conditions of Bsep inhibition in rats. Studies of this kind can both improve our understanding of exposures needed to inhibit Bsep in vivo and provide unique insights into drug effects in ways that can improve our ability interpret animal studies for the prediction of human drug hepatotoxicity

Syntheses of Functionalized Benzylic Compounds: Development of Palladium-Catalyzed Decarboxylative Benzylation Reactions

Carbon-carbon bond formation between the benzyl carbon and a functional group is important in organic synthesis because majority of the compounds in the chemical literature contain aromatic cores appended with different functionalities in the benzyl carbon. These compounds are utilized in pharmaceuticals and medicinal chemistry. While current literature in Pd-catalyzed benzylations is increasingly becoming recognized, conventional methodologies require the use of toxic benzyl halides, stoichiometric bases and/or performed organometallics which not only generate benzyl compounds but also give side products and toxic metal wastes. Our research group has a long-standing interest using decarboxylation as a tool in constructing diverse compounds without the need of base and preformed organometallics. Previously applied in the synthesis of functionalized allylic compounds from allyl esters, we envisioned to utilize this tool towards the synthesis of functionalized benzylic compounds from benzyl esters. We thought that it would be feasible and ideal to perform decarboxylative benzylation (DcB) based from well-explored decarboxylative allylation (DcA) methodology. Indeed, we were able to show that Pd-catalyzed DcB was an indispensable tool in synthesizing functionalized benzylic compounds in good to high yields. This was shown in the syntheses of benzyl ketones and benzyl alkynes. In the DcB of ketones, simple and benzo-fused β-ketoesters underwent decarboxylation affording benzyl ketones in good to high yields. DcB was also regiospecific, the kinetically preformed enolate did not undergo thermodynamic isomerization resulting to direct functionalization to the carbon next to the carboxylate group where it was once located. In addition to naphthyl and simple benzyls, heteroaromatics were also used as coupling partners with enolate. The nature of substituents in the ring and its position from the benzyl moiety affected benzylation. Depending on the nature of heterocycle, regioselective benzylation occurred resulting in formation of C-benzylation ketone, C-arylation ketone, or O-benzylation enol ether. The utility of DcB methodology was also used towards the synthesis of Nabumetone. In the DcB of alkynes, simple and benzo-fused propiolates underwent decarboxylation to generate benzyl alkynes in good to high yields. The use of biphenyl derived ligand was crucial in the synthesis of simple benzyl alkynes. The benzylic carbon in diaryls and heterocycles can also be used as coupling partners with alkynes

The Implications of Obesity on Total Hip Arthroplasty: A Literature Review

Introduction: Obesity is a global pandemic and public health crisis associated with a wide range of comorbidities, including osteoarthritis, leading to a significantly younger age at the time of primary total hip arthroplasty (THA) and an increased rate of complications when compared to nonobese individuals. This has led to concerns regarding the implications of obesity on the need for THA itself and the associated complications, especially for arthroplasty surgeons. This literature review aims to provide a comprehensive review of the implications obesity has on total hip arthroplasties, its associated complications, and how we can potentially modify these risks. Methods: Articles were identified by searching the databases of PubMed, Google Scholar, National Center for Biotechnology Information (NCBI), and UpToDate. Results: Obese patients undergo primary THA at an earlier age and experience an increased duration of surgery, higher rates of infection, dislocation, periprosthetic fractures, and venous thromboembolism compared to nonobese patients. The role of pre-operative bariatric surgery before total hip arthroplasty has failed to show reductions in complication rates. Harris Hip Scores are lower in obese patients both pre-operatively and post-operatively, but the degree of improvement following THA is similar compared to nonobese patients. Long-term survival of total hip prostheses is similar when compared to nonobese patients. Conclusion: Current literature strongly suggests increased complication rates in obese patients who undergo THA. This phenomenon is not solely due to biomechanical forces and is multifactorial, including inflammatory and genetic predispositions, which need further study. The decision to perform THA on obese patients should not solely be based on BMI. Other factors such as management of comorbidities, surgical exposure, and nursing care should be considered when deciding on surgical candidacy

Hard x-ray polarimetry with the Ramaty High Energy Solar Spectroscopic Imager (RHESSI)

Although designed primarily as a hard X-ray imager and spectrometer, the Ramaty High Energy Solar Spectroscopic Imager (RHESSI) is also capable of measuring the polarization of hard X-rays (20-100 keV) from solar flares. This capability arises from the inclusion of a small unobstructed Be scattering element that is strategically located within the cryostat that houses the array of nine germanium detectors. The Ge detectors are segmented, with both a front and rear active volume. Low energy photons (below about 100 keV) can reach a rear segment of a Ge detector only indirectly, by scattering. Low energy photons from the Sun have a direct path to the Be and have a high probability of Compton scattering into a rear segment of a Ge detector. The azimuthal distribution of these scattered photons carries with it a signature of the linear polarization of the incident flux. Sensitivity estimates, based on simulations and in-flight background measurements, indicate that a 20-100 keV polarization sensitivity of less than a few percent can be achieved for X-class flares