Effects of intestine-specific deletion of FGF15 on the development of fatty liver disease with vertical sleeve gastrectomy.

BACKGROUND: Vertical sleeve gastrectomy (SGx) is a type of bariatric surgery to treat morbid obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular mechanisms of SGx to improve MASLD are unclear, but increased bile acids (BAs) and FGF19 (mouse FGF15) were observed. FGF15/19 is expressed in the ileum in response to BAs and is critical in not only suppressing BA synthesis in the liver but also promoting energy expenditure. We hypothesized the reduction of obesity and resolution of MASLD by SGx may be mediated by FGF15/19. METHODS: First, we conducted hepatic gene expression analysis in obese patients undergoing SGx, with the results showing increased expression of FGF19 in obese patients' livers. Next, we used wild-type and intestine-specific Fgf15 knockout mice (Fgf15ile-/-) to determine the effects of FGF15 deficiency on improving the metabolic effects. RESULTS: SGx improved metabolic endpoints in both genotypes, evidenced by decreased obesity, improved glucose tolerance, and reduced MASLD progression. However, Fgf15ile-/- mice showed better improvement compared to wild-type mice after SGx, suggesting that other mediators than FGF15 are also responsible for the beneficial effects of FGF15 deficiency. Further gene expression analysis in brown adipose tissue suggests increased thermogenesis. CONCLUSIONS: FGF15 deficiency, the larger BA pool and higher levels of secondary BAs may increase energy expenditure in extrahepatic tissues, which may be responsible for improved metabolic functions following SGx.

Pharmacokinetics and Pharmacodynamics of Anthocyanins after Administration of Tart Cherry Juice to Individuals with Gout.

SCOPE: Tart cherries (TCs) contain high levels of anthocyanins that exert potent antioxidant and antiinflammatory effects and potentially benefit individuals with gout. METHODS AND RESULTS: This study aims to quantitate the major anthocyanins in TC Juice Concentrate (TCJC) and identify the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of the major anthocyanin cyanidin-3-glucosylrutinoside (C3GR). A PK-PD study enrolling human subjects with a history of gout is performed. Subjects are randomized to receive either 60 or 120 mL of TCJC. Anthocyanins are quantitated using liquid chromatography-mass spectroscopy (LCMS). Antioxidant and antiinflammatory mRNA expression is measured using real-time qPCR before and after the administration of TCJC. A population PK model (popPK) is fit to the experimental data, and an indirect PD model (IDR) is constructed in Monolix. CONCLUSION: Of the bioavailable anthocyanins, C3GR achieves the highest plasma concentration in a dose-dependent manner. A popPK predicts anthocyanin exposure, and an IDR produces reasonable approximations of PD effects.

A validated LC-MS/MS method for the quantitation of cefazolin in human adipose tissue: Application of EMR-Lipid sorbent as an efficient sample clean-up before mass spectrometric analyses.

A novel, simple, rapid, and sensitive high-performance liquid chromatography-tandem mass spectrometry method was developed to determine cefazolin concentrations in human adipose tissue. Sample preparation was performed by protein precipitation followed by using Captiva EMR-Lipid plates. The mobile phase consisted of 5 mM ammonium formate and 0.1% formic acid in water and 0.1% formic acid in ACN, and was pumped through a Synergi Fusion-RP column with a gradient elution program at a flow rate of 0.3 mL/min. The mass spectrometer was operated in a positive ion mode. Cloxacillin was used as an internal standard due to the observed cross-signal contribution between cefazolin and 13C2,15N-cefazolin. The method was validated according to the FDA and EMA guidelines and passed all the acceptance criteria. The calibration range was 0.05-50 µg/mL in adipose tissue homogenate (0.15-150 µg/g in adipose tissue), precision CV < 4.5%, accuracy within 93.1-100.4%. The carry-over was negligible, recovery of the method was high, and no significant matrix effect was present. Rat subcutaneous adipose tissue was demonstrated to be a suitable surrogate matrix for human adipose tissue. The validated method was successfully applied in a pilot pharmacokinetic study and will further be used in a large cohort of non-obese and obese patients dosed prophylactically with cefazolin before surgeries.

Difficult Revision Total Hip Arthroplasty Cases Treated with an Offset Head Center Acetabular Shell.

Acetabular bone loss is common during revision total hip arthroplasty (THA). A new acetabular shell was developed with a goal of maintaining native hip center-of-rotation (COR) while achieving good fixation with standard instrumentation and technique. Previous radiographic studies have demonstrated the efficacy of this shell in lowering hip COR. In this case series, we demonstrate the use of this shell in patients undergoing difficult revision THAs. Based on these cases, we have presented how this offset COR acetabular shell may help bring down the hip COR in patients who undergo revision total hip arthroplasty with severe bone loss.

Use of an offset head center acetabular shell in difficult primary total hip arthroplasties.

Several conditions may predispose patients to development of antero-lateral acetabular bone deficiency, including developmental dysplasia of the hip, osteonecrosis, or septic arthritis, among others. This may compromise the ability to gain acetabular component stability and impair reliable fixation. Large acetabular shells have often been used to achieve adequate fixation in scenarios of severe bone loss, however, these techniques have been shown to elevate the center of rotation (COR) of the hip and alter hip biomechanics. Recently, a new acetabular shell was developed with a goal of maintaining the native hip COR while achieving good fixation with standard instrumentation and technique. Previous radiographic studies have demonstrated the efficacy of this shell in lowering hip COR. In this case series, we demonstrate the use of this shell in patients with difficult hip pathologies. We have demonstrated how this offset COR acetabular shell may help bring down the COR of the hip in these quite challenging cases utilizing conventional techniques.

Pharmacokinetics, Pharmacodynamics, and PKPD Modeling of Curcumin in Regulating Antioxidant and Epigenetic Gene Expression in Healthy Human Volunteers.

Curcumin is a major component of the spice turmeric ( Curcuma longa), often used in food or as a dietary supplement. Many preclinical studies on curcumin suggest health benefits in many diseases due to its antioxidant/anti-inflammatory and epigenetic effects. The few human studies and curcumin's unfavorable pharmacokinetics (PK) have limited its potential, leading researchers to study and develop formulations to improve its PK. The purpose of this clinical study is to describe the acute pharmacokinetics and pharmacodynamics (PK/PD) of commercially marketed curcumin in normal, healthy human volunteers. Twelve volunteers received a 4 g dose of curcumin capsules with a standard breakfast. Plasma samples were collected at specified time points and analyzed for curcumin and its glucuronide levels. RNA was extracted from leukocytes and analyzed for expression of select antioxidant and epigenetic histone deacetylase (HDAC) genes. Plasma levels of parent curcumin were below the detection limit by HPLC-ITMS/MS/MS. However, curcumin-O-glucuronide (COG), a major metabolite of curcumin, was detected as soon as 30 min. These observations of little to no curcumin and some levels of metabolite are in line with previous studies. PD marker antioxidant genes NRF2, HO-1, and NQO1 and epigenetic genes HDAC1, HDAC2, HDAC3, and HDAC4 were quantified by qPCR. COG PK is well-described by a one-compartment model, and the PK/PD of COG and its effect on antioxidant and epigenetic gene expression are captured by an indirect response model (IDR). A structural population PK model was sequentially established using a nonlinear mixed-effect model program (Monolix Lixoft, Orsay, France). Physiologically based pharmacokinetic modeling (PBPK) and simulation using Simcyp correlated well with the observed data. Taken together, these results show that the bioavailability of the parent curcumin compound is low, and oral administration of curcumin can still deliver detectable levels of curcumin glucuronide metabolite. But most importantly, it elicits antioxidant and epigenetic effects which could contribute to the overall health beneficial effects of curcumin.

Anticoagulant activity of enoxaparin and unfractionated heparin for venous thromboembolism prophylaxis in obese patients undergoing sleeve gastrectomy.

BACKGROUND: One risk of bariatric surgery is venous thromboembolism and the optimal strategy to reduce risk requires further clarification. OBJECTIVES: The objectives of this study were to identify antiXa goal attainment with the institutional standard chemoprophylaxis, analyze discordance between antiXa and thrombin generation assay (TGA) in terms of adequacy of anticoagulation, and to identify correlations between patient characteristics or covariates and markers of coagulation status. SETTING: Large academic medical center in Northeastern United States. METHODS: A total of 60 sleeve gastrectomy patients were enrolled in this institutional review board-approved, prospective cohort study. Patients received the institutional standard prophylactic therapy (subcutaneous enoxaparin 40 mg twice daily or unfractionated heparin [UFH]). The UFH dose was weight based, 5000 units (<120 kg) or 7500 units (≥120 kg) every 8 hours. Various measures of coagulation status were measured at or near steady state. RESULTS: Patients receiving enoxaparin achieved goal antiXa more frequently compared with the UFH group, and statistical significance was demonstrated (93.8 % versus 4.5%, respectively; P < .0001). Target endogenous thrombin potential reduction from baseline was more frequently obtained in the enoxaparin group versus UFH (50% versus 27.7%, respectively; P = .12). AntiXa was below the limit of detection for the majority of UFH patients; while TGA suggested patients did experience anticoagulation at some level of effectiveness. Endogenous thrombin potential change in the enoxaparin group was correlated to several measures of body composition. CONCLUSIONS: Patients receiving enoxaparin achieved goal antiXa more often versus UFH. There was discordance between antiXa and TGA-based assessment of coagulation status. TGA may provide a more robust assessment of the adequacy of chemoprophylaxis.

Indications, complications and outcomes of inferior vena cava filters: A retrospective study.

INTRODUCTION: Inferior vena cava filters are used to prevent embolization of a lower extremity deep vein thrombosis when the risk of pulmonary embolism is thought to be high. However, evidence is lacking for their benefit and guidelines differ on the recommended indications for filter insertion. The study aim was to determine the reasons for inferior vena cava filter placement and subsequent complication rate. MATERIALS AND METHODS: A retrospective cohort of patients receiving inferior vena cava filters in Edmonton, Alberta, Canada from 2007 to 2011. Main outcome was the indication of inferior vena cava filter insertion. Other measures include baseline demographic and medical history of patients, clinical outcomes and filter retrieval rates. RESULTS: 464 patients received inferior vena cava filters. An acute deep vein thrombosis with a contraindication to anticoagulation was the indication for 206 (44.4%) filter insertions. No contraindication to anticoagulation could be identified in 20.7% of filter placements. 30.6% were placed in those with active cancer, in which mortality was significantly higher. Only 38.9% of retrievable filters were successfully retrieved. CONCLUSIONS: Inferior vena cava filters were placed frequently in patients with weak or no guideline-supported indications for filter placement and in up to 20% of patients with no contraindication to anticoagulation. The high rates of cancer and the high mortality rate of the cohort raise the possibility that some filters are placed inappropriately in end of life settings.

Late-onset radial nerve palsy associated with conservatively managed humeral fracture. A case report and suggested classification system.

Radial nerve palsy can occur with humerus fracture, either at the time of injury (primary) or during reduction (secondary). Late-onset radial nerve palsy (not immediately related to injury or reduction) has been very seldom reported in the English literature. We describe a case of late-onset radial nerve palsy, which developed 9 weeks after an attempted closed management of a midshaft humerus fracture. Exploration of the nerve was performed. The radial nerve was found to be stretched over the ends of the fracture. Open reduction and external fixation of the fracture with mobilization of the nerve from the fracture site lead to complete return of radial nerve function occurring by 3 months. We recommend exploration of cases of late-onset radial nerve palsy in contrast to primary or secondary radial nerve palsy, which can be treated conservatively. Our experience suggests that the cause of the palsy is a continuous ongoing pathology and not a single time event as in primary or secondary cases. Radial nerve palsies associated with humeral fracture should be classified as either primary (at the time of injury), secondary (at the time of reduction), or late onset (not related to either injury or reduction).