Effect of Genetic Variants, Especially CYP2C9 and VKORC1, on the Pharmacology of Warfarin

The genes encoding the cytochrome P450 2C9 enzyme (CYP2C9) and vitamin K-epoxide reductase complex unit 1 (VKORC1) are major determinants of anticoagulant response to warfarin. Together with patient demographics and clinical information, they account for approximately one-half of the warfarin dose variance in individuals of European descent. Recent prospective and randomized controlled trial data support pharmacogenetic guidance with their use in warfarin dose initiation and titration. Benefits from pharmacogenetics-guided warfarin dosing have been reported to extend beyond the period of initial dosing, with supportive data indicating benefits to at least 3 months. The genetic effects of VKORC1 and CYP2C9 in African and Asian populations are concordant with those in individuals of European ancestry; however, frequency distribution of allelic variants can vary considerably between major populations. Future randomized controlled trials in multiethnic settings using population-specific dosing algorithms will allow us to further ascertain the generalizability and cost-effectiveness of pharmacogenetics-guided warfarin therapy. Additional genome-wide association studies may help us to improve and refine dosing algorithms and potentially identify novel biological pathways

Reconstruction of recent sea-level change using testate amoebae

Reproduced with permission of the publisher. Copyright © 2009 University of Washington Published by Elsevier Inc.Proxy-based sea-level reconstructions place the instrumentally observed rates of recent sea-level rise in a longer term context by providing data that extend the instrumental sea-level record into past centuries. This paper presents the first sea-level reconstructions based on analyses of testate amoebae, to test their ability to produce high-precision reconstructions of past sea level. We present two reconstructions for the past 100 yr from sites in Maine (USA) and Nova Scotia (Canada) based on short cores from salt marshes, and modern training data from North America and the United Kingdom. These are compared with tide-gauge records and reconstructions based on foraminifera from the same cores. The reconstructions show good agreement with both the tide-gauge data and the foraminifera-based reconstructions. The UK data perform well in predicting known elevations of North American surface samples and produce sea-level reconstructions very similar to those based on the North American data, suggesting the methodology is robust across large geographical areas. We conclude that testate amoebae have the potential to provide robust, higher precision sea-level reconstructions for the past few centuries if modern transfer functions are improved and core sites are located within the main zone of testate amoebae occurrence on the salt marsh

The effect of hypothermia on influx of leukocytes in the digital lamellae of horses with oligofructose-induced laminitis

Sepsis-related laminitis (SRL) is a common complication in the septic/endotoxemic critically-ill equine patient, in which lamellar injury and failure commonly lead to crippling distal displacement of the distal phalanx. Similar to organ injury in human sepsis, lamellar injury in SRL has been associated with inflammatory events, including the influx of leukocytes into the lamellar tissue and markedly increased expression of a wide array of inflammatory mediators at the onset of Obel grade 1 (OG1) laminitis. The only treatment reported both clinically and experimentally to protect the lamellae in SRL, local hypothermia (“cryotherapy”), has been demonstrated to effectively inhibit lamellar expression of multiple inflammatory mediators when initiated at the time of administration of a carbohydrate overload in experimental models of SRL. However, the effect of hypothermia on leukocyte influx into affected tissue has not been assessed. We hypothesized that cryotherapy inhibits leukocyte emigration into the digital lamellae in SRL. Immunohistochemical staining using leukocyte markers MAC387 (marker of neutrophils, activated monocytes) and CD163 (monocyte/macrophage-specific marker) was performed on archived lamellar tissue samples from an experimental model of SRL in which one forelimb was maintained at ambient temperature (AMB) and one forelimb was immersed in ice water (ICE) immediately following enteral oligofructose administration (10\ua0g/kg, n\ua0=\ua014 horses). Lamellae were harvested at 24\ua0h post-oligofructose administration (DEV, n\ua0=\ua07) or at the onset of OG1 laminitis (OG1, n\ua0=\ua07). Both MAC387-positive and CD163-positive cells were counted by a single blinded investigator on images [n\ua0=\ua010 (40× fields/digit for MAC387 and 20\ua0x fields/digit for CD163)] obtained using Aperio microscopy imaging analysis software. Data were assessed for normality and analyzed with a paired t-test and one-way ANOVA with significance set at p\ua

Police Criminal Charging Decisions: An Examination of Post-Arrest Decision-Making

Scholars have encouraged studies of police decision-making to move beyond the arrest decision into research that broadens the understanding of police behavior. The criminal charge placed by officers against offenders is largely an untouched area of study. Examining criminal charging decisions goes beyond simple dichotomous decisions, such as arrest, but instead explores the area of police leniency or punitiveness. Randomly constructed vignettes describing a domestic violence incident were given to officers from four agencies. Officers indicated the criminal charges they would likely list against an offender if they were to make an arrest. Serious criminal charges were often supported by additional, but less serious, charges. Victim injury and an uncooperative offender were related to the decision to charge a misdemeanor offense. There was a significant negative relationship between the number of charges listed and more experienced officers and officers working in smaller agencies. The implications of this study and directions for future research are discussed

Eradication of multidrug-resistant Acinetobacter baumannii in a female patient with total hip arthroplasty, with debridement and retention: a case report

<p>Abstract</p> <p>Introduction</p> <p>Multidrug-resistant <it>Acinetobacter baumannii </it>has become a significant cause of healthcare-associated infections, but few reports have addressed <it>Acinetobacter baumannii </it>infections associated with orthopedic devices. The current recommended treatment for complicated infections due to orthopedic devices, including resistant gram-negative rods, consists of antimicrobial therapy with debridement and removal of implants.</p> <p>Case presentation</p> <p>The patient, a 47-year-old woman, had previously had a prior total hip arthroplasty at 16 years of age for a complex femoral neck fracture, and multiple subsequent revisions. This time, she underwent a fifth revision secondary to pain. Surgery was complicated by hypotension resulting in transfer to the intensive care unit and prolonged respiratory failure. She received peri-operative cefazolin but postoperatively developed surgical wound drainage requiring debridement of a hematoma. Cultures of this grew ampicillin-sensitive <it>Enterococcus </it>and <it>Acinetobacter baumannii </it>(sensitive only to amikacin and imipenem). The patient was started on imipenem. Removal of the total hip arthroplasty was not recommended because of the recent surgical complications, and the patient was eventually discharged home. She was seen weekly for laboratory tests and examinations and, after 4 months of therapy, the imipenem was discontinued. She did well clinically for 7 months before recurrent pain led to removal of the total hip arthroplasty. Intra-operative cultures grew ampicillin-sensitive <it>Enterococcus </it>and coagulase-negative <it>Staphylococcus </it>but no multidrug-resistant <it>Acinetobacter baumannii</it>. The patient received ampicillin for 8 weeks and had not had recurrent infection at the time of writing, 37 months after discontinuing imipenem.</p> <p>Conclusion</p> <p>We describe the successful treatment of an acute infection from multidrug-resistant <it>Acinetobacter baumannii </it>with debridement and retention of the total hip arthroplasty, using monotherapy with imipenem. This case challenges the general assumption that all orthopedic-device infections due to multidrug-resistant gram-negative organisms will require hardware removal. Further studies are needed to determine if organisms such as multidrug-resistant <it>Acinetobacter baumannii </it>are amenable to treatment with hardware retention.</p

Eradication of multidrug-resistant Acinetobacter baumannii in a female patient with total hip arthroplasty, with debridement and retention: a case report

<p>Abstract</p> <p>Introduction</p> <p>Multidrug-resistant <it>Acinetobacter baumannii </it>has become a significant cause of healthcare-associated infections, but few reports have addressed <it>Acinetobacter baumannii </it>infections associated with orthopedic devices. The current recommended treatment for complicated infections due to orthopedic devices, including resistant gram-negative rods, consists of antimicrobial therapy with debridement and removal of implants.</p> <p>Case presentation</p> <p>The patient, a 47-year-old woman, had previously had a prior total hip arthroplasty at 16 years of age for a complex femoral neck fracture, and multiple subsequent revisions. This time, she underwent a fifth revision secondary to pain. Surgery was complicated by hypotension resulting in transfer to the intensive care unit and prolonged respiratory failure. She received peri-operative cefazolin but postoperatively developed surgical wound drainage requiring debridement of a hematoma. Cultures of this grew ampicillin-sensitive <it>Enterococcus </it>and <it>Acinetobacter baumannii </it>(sensitive only to amikacin and imipenem). The patient was started on imipenem. Removal of the total hip arthroplasty was not recommended because of the recent surgical complications, and the patient was eventually discharged home. She was seen weekly for laboratory tests and examinations and, after 4 months of therapy, the imipenem was discontinued. She did well clinically for 7 months before recurrent pain led to removal of the total hip arthroplasty. Intra-operative cultures grew ampicillin-sensitive <it>Enterococcus </it>and coagulase-negative <it>Staphylococcus </it>but no multidrug-resistant <it>Acinetobacter baumannii</it>. The patient received ampicillin for 8 weeks and had not had recurrent infection at the time of writing, 37 months after discontinuing imipenem.</p> <p>Conclusion</p> <p>We describe the successful treatment of an acute infection from multidrug-resistant <it>Acinetobacter baumannii </it>with debridement and retention of the total hip arthroplasty, using monotherapy with imipenem. This case challenges the general assumption that all orthopedic-device infections due to multidrug-resistant gram-negative organisms will require hardware removal. Further studies are needed to determine if organisms such as multidrug-resistant <it>Acinetobacter baumannii </it>are amenable to treatment with hardware retention.</p

A novel model to assess lamellar signaling relevant to preferential weight bearing in the horse

Supporting limb laminitis (SLL) is a devastating sequela to severe unilateral lameness in equine patients. The manifestation of SLL, which usually only affects one limb, is unpredictable and the etiology is unknown. A novel, non-painful preferential weight bearing model designed to mimic the effects of severe unilateral forelimb lameness was developed to assess lamellar signaling events in the supporting limb (SL). A custom v-shaped insert was attached to the shoe of one forelimb to prevent normal weight bearing and redistribute weight onto the SL. Testing of the insert using a custom scale platform built into the floor of stocks confirmed increased distribution of weight on the SL compared with the unloaded forelimb (UL) and the contralateral (CH) and ipsilateral (IH) hind limbs in six Standardbred horses. In a second part of the study, eight healthy Standardbred horses were fitted with the insert and tied with consistent monitoring and free access to hay and water for 48 h, after which the lamellae were harvested. Real-time qPCR was performed to assess lamellar mRNA concentrations of inflammatory genes and immunoblotting and immunofluorescence were performed to assess lamellar protein concentration and cellular localization of hypoxia-related proteins, respectively. Lamellar mRNA concentrations of inflammatory signaling proteins did not differ between SL and either CH or IH samples. HIF-1α concentrations were greater (P

Early-Onset Progressive Retinal Atrophy Associated with an IQCB1 Variant in African Black-Footed Cats (Felis nigripes)

African black-footed cats (Felis nigripes) are endangered wild felids. One male and full-sibling female African black-footed cat developed vision deficits and mydriasis as early as 3 months of age. The diagnosis of early-onset progressive retinal atrophy (PRA) was supported by reduced direct and consensual pupillary light reflexes, phenotypic presence of retinal degeneration, and a non-recordable electroretinogram with negligible amplitudes in both eyes. Whole genome sequencing, conducted on two unaffected parents and one affected offspring was compared to a variant database from 51 domestic cats and a Pallas cat, revealed 50 candidate variants that segregated concordantly with the PRA phenotype. Testing in additional affected cats confirmed that cats homozygous for a 2 base pair (bp) deletion within IQ calmodulin-binding motif-containing protein-1 (IQCB1), the gene that encodes for nephrocystin-5 (NPHP5), had vision loss. The variant segregated concordantly in other related individuals within the pedigree supporting the identification of a recessively inherited early-onset feline PRA. Analysis of the black-footed cat studbook suggests additional captive cats are at risk. Genetic testing for IQCB1 and avoidance of matings between carriers should be added to the species survival plan for captive management