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OBJECTIVES An isolated MPFL reconstruction (MPFLR) has been demonstrated to be an effective treatment option in the prevention of patellar instability, but there is growing support for performing a tibial tubercle osteotomy (TTO) in patients with an elevated tibial tubercle-trochlear groove distance. The purpose of this study was to evaluate the impact of adding a TTO to MPFLR on patient reported outcomes. METHODS A retrospective review of patients who underwent MPFLR with or without TTO with a minimum of 12-month follow-up was performed. Patients in both groups were matched based on age, gender, and follow-up time. Recurrent instability (including re-dislocation and subluxation), Visual Analogue Scale (VAS) score, Kujala score, and satisfaction were evaluated. RESULTS There were 59 patients who underwent MPFLR with concomitant TTO performed at our institution and met our inclusion and exclusion criteria. These patients were then matched to patients undergoing isolated MPFLR based on demographics and follow up time. The mean age was 25.0, 76.3% were female, and the mean follow up time was 49 months. There was a significant difference in mean tibial tubercle-trochlear groove distance (19.8 ± 3.9 vs. 14.1 ± 2.8) between groups. There was no significant difference in VAS (1.48 ± 2.0 vs. 1.49 ± 2.1, p = 0.972), satisfaction (86.1% ± 24.2% vs. 81.2% ± 27.9, p=0.311), or revision surgeries (10.2% vs 10.2%) between groups. CONCLUSION Matched patients undergoing MPFLR with TTO compared to isolated MPFLR demonstrate no statistically significant difference in patient reported outcomes, levels of pain and satisfaction post-operatively. Furthermore, the addition of a TTO does not increase the risk of further surgery or complications. Level of evidence III, retrospective comparative study.

LYS006 is a potent leukotriene A4 hydrolase inhibitor currently in clinical development for long-term treatment of various neutrophil-driven inflammatory conditions. Here, we present pharmacokinetics from the first-in-human study with complementary metabolism and transporter profiling data. The randomized first-in-human study included nine cohorts receiving 5-2*100 mg of LYS006 or placebo, a crossover food-effect part, and a multiple-dose part consisting of two fasted (5 mg and 15 mg once daily) and three fed cohorts (20-80 mg twice a day) of LYS006 or placebo. LYS006 and metabolites were assessed in plasma and urine, and transporters involved in LYS006 disposition were analyzed in vitro. Systemic plasma exposure increased with dose; steady-state exposure was dose proportional up to 40 mg twice a day. Steady state was achieved after ∼3 days, with mean accumulation of 2.1-fold for 5 mg once daily and ≤1.4-fold for all higher doses. Despite limited accumulation, a long terminal half-life (T

To compare satisfaction and return to play (RTP) rates between patients undergoing primary biceps tenodesis for a symptomatic SLAP tear and patients undergoing secondary biceps tenodesis following a failed SLAP repair.A retrospective review of patients who underwent subpectoral mini-open biceps tenodesis following failed SLAP repair between January 2011 and October 2019 was performed. Inclusion criteria included age older than 16 years, skeletal maturity, and a minimum follow-up of 12 months. Both athletes and nonathletes were included across all types of sport. Patients who had anterior or posterior instability or rotator cuff tears were excluded; in addition, those requiring concomitant procedures were excluded. Case-control matching was performed using age, sex, indication, follow-up, and type of sport, to generate a 3:1 control group for the primary biceps tenodesis cohort. Primary outcome measurements were collected via telephone in 2020 and included the American Shoulder and Elbow Surgeons score, visual analog scale score, Subjective Shoulder Value score, patient satisfaction, willingness to undergo surgery again, and revisions. RTP and timing of RTP were evaluated as secondary outcomes. AThe current study included 76 patients in total; 57 patients with primary biceps tenodesis, and 19 patients with secondary biceps tenodesis. The mean age was 39 years (19-48 years), 100% were male, and the mean follow-up was 54 months (16-99 months). Patient reported outcomes were obtained postoperatively via telephone survey. Overall, we found that primary biceps tenodesis patients reported greater American Shoulder and Elbow Surgeons scores (89.9 vs 76.4,In this study, patients undergoing primary biceps tenodesis had significantly better functional outcomes compared with secondary biceps tenodesis following a failed SLAP repair.III, retrospective comparative study.

Objectives: Patients with a superior labral anterior to posterior (SLAP) tear of the shoulder are often initially treated non-operatively, but many do not respond and require surgery. Identifying patients who are likely to fail non-operative management and would benefit from early surgical intervention can shorten time of disability and limit resources utilized on unsuccessful treatments. The purpose of this study is to create a clinical prediction model to determine which patients are likely to fail non-operative treatment of SLAP tears and require surgical intervention. Methods: This was a case-control study consisting of patients treated at a single institution for isolated, non-degenerative SLAP tears. Patients with concomitant rotator cuff tears were excluded from this analysis. Patients were retrospectively surveyed using the Research Electronic Data Capture (REDCap) system regarding clinical features of their shoulder injury, non-operative treatments that they received, and key functional outcomes during their post-injury period. Responders underwent additional medical record review to identify other variables related to the clinical presentation and treatment of their shoulder injury. In order to simplify the predictive model and optimize its interpretability, the lasso (least absolute shrinkage and selection operator) method of penalized logistic regression analysis was used to identify the characteristics that were most closely associated with failure of nonoperative treatment. The data was randomly split into a training set and test set. Using the training set, the value of lambda which minimized cross-validation prediction error rate was determined (Figure 1). The final lasso model was then computed. The predictive accuracy of the final model was assessed using the test data set. Results: Overall, 189 patients were contacted and included in the analysis. The mean age of included patients was 29.9 +/- 6.7 years. Thirty-eight patients (20.1%) were female. One hundred and six patients (56.1%) failed non-operative management and required surgical intervention. The final lasso model identified a total of 9 variables that were significantly associated with failure of non-operative management of SLAP tears (Table 1). These predictors included pre-injury overhead sports participation, presence of specific symptoms, severity of pain, and the type of non-operative treatment modalities used. Injury to the dominant extremity, history of prior shoulder injury, patient age, use of NSAIDs, and occupation involving manual labor or overhead work were not associated with failure of nonoperative treatment. The predictive accuracy of the model was 70.3% (95% CI 53.0%, 84.1%). Sensitivity of the model was 81.0% and specificity was 56.3%. Conclusions: A clinical prediction model consisting of variables describing patient characteristics, specific symptoms, and the type of non-operative treatment modalities utilized was found to predict failure of non-operative management of SLAP tears with moderate accuracy. Further refinements of this prediction model, including the inclusion of additional physical examination and imaging variables, will be required before future iterations are tested in clinical practice.

Objectives: Medial patellofemoral ligament reconstruction (MPFLR) using allograft tissue has several potential benefits including the absence of donor site morbidity, ability to predict graft parameters, and decreased operative time. The purpose of this study was to evaluate the outcomes of patients following MPFLR with allograft. Our hypothesis was that there would be a low rate of recurrent instability, and excellent clinical outcomes reported. Methods: A retrospective review of athletes who underwent MPFL Reconstruction, with a minimum of 12-month follow-up was performed. Recurrent instability (including re-dislocation and subluxation), Visual Analogue Scale (VAS) score, Kujala score, satisfaction, and whether they would undergo the same surgery again, were evaluated. Results: Overall, follow up was attained for 131 patients with 141 knees (73.4%). The mean patient age of 25.0 years, 67.4% females, and mean time to follow-up was 46.8 months (12-111). At final follow up, the mean VAS score was 1.4 ± 2.0, the mean Kujala score was 84.8 ± 15.6, the mean satisfaction score was 84% ± 26.0, and 117 (83.0%) would undergo the same procedure again if required. There was 17 (12.0%) patients that had recurrent instability, with 2 being re-dislocations (1.4%). A further procedure was performed in 14 patients (9.9%). There were no intra-operative complications in our series. Conclusions: There was a low rate of recurrent instability following MPFLR with allograft, with excellent patient reported outcomes, and a low complication rate.

Objective: The purpose of this study was to evaluate the efficacy of osteochondral allograft (OCA) in patients older than 45 years of age, particularly with respect to return to sport. Design: A retrospective review was performed to evaluate patients greater than 45 who underwent an OCA for a symptomatic osteochondral defect of the knee between June 2011 and January 2019. Results: Overall, there were 18 patients (76% male) that met our inclusion and exclusion criteria. Follow-up was attained in 14 of these patients (78%). The mean age of patients included was 52.6 years (48-57) with a mean of 37 months of follow-up (18-60). Visual Analogue Scale scores decreased significantly from the preoperative baseline to final follow-up (7.7 ± 1.7 vs. 2.0 ± 2.0, P < 0.01). Furthermore, the mean Visual Analogue Scale while playing sport was 3.4 ± 3.2, and the mean Knee Injury and Osteoarthritis Outcome Score was 77.5 ± 12.7 at final follow-up. Overall, 11 patients (78.6%) were able to return to their desired sport. No clinical failures were identified during the follow-up period. Conclusion: In our series of patients 45 years and older who were treated with OCA for focal osteochondral injuries of the knee, we found a significant improvement in clinical outcome scores at a midterm follow-up of 37 months with no revision OCA procedures or conversion to any form of knee arthroplasty. In addition, a high percentage of patients were able to return to their preferred level of athletic activity.

Objective The purpose of the current study is to evaluate the clinical and radiographic outcomes at early to midterm follow-up between fresh precut cores versus hemi-condylar osteochondral allograft (OCAs) in the treatment of symptomatic osteochondral lesions. Design A retrospective review of patients who underwent an OCA was performed. Patient matching between those with OCA harvested from an allograft condyle/patella or a fresh precut allograft core was performed to generate 2 comparable groups. The cartilage at the graft site was assessed with use of a modified Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scoring system and patient-reported outcomes were collected. Results Overall, 52 total patients who underwent OCA with either fresh precut OCA cores ( n = 26) and hemi-condylar OCA ( n = 26) were pair matched at a mean follow-up of 34.0 months (range 12 months to 99 months). The mean ages were 31.5 ± 10.7 for fresh precut cores and 30.9 ± 9.8 for hemi-condylar ( P = 0.673). Males accounted for 36.4% of the overall cohort, and the mean lesion size for fresh precut OCA core was 19.6 mm2 compared to 21.2 mm2 for whole condyle ( P = 0.178). There was no significant difference in patient-reported outcomes including Visual Analogue Scale, Knee Injury and Osteoarthritis Outcome Score for Joint Replacement, and Tegner ( P > 0.5 for each), or in MOCART score (69.2 vs. 68.3, P = 0.93). Conclusions This study found that there was no difference in patient-reported clinical outcomes or MOCART scores following OCA implantation using fresh precut OCA cores or size matched condylar grafts at early to midterm follow-up.

Fevipiprant, an oral, nonsteroidal, highly selective, reversible, and competitive prostaglandin D2 receptor 2 antagonist, is eliminated by glucuronidation and by direct renal excretion predominantly via organic anion transporter (OAT) 3. This study aimed to assess the effect of simultaneous UDP-glucuronosyltransferase (UGT) and OAT3 inhibition by probenecid on the pharmacokinetics of fevipiprant and its acyl glucuronide (AG) metabolite to support the dosing recommendation of fevipiprant in the presence of drugs inhibiting these pathways; however, phase III clinical trial results did not support its submission. This was a single-center, open-label, single-sequence, two-period crossover study in healthy subjects. Liquid chromatography with tandem mass spectrometry was used to measure concentrations of fevipiprant and its AG metabolite in plasma and urine. In the presence of probenecid, the mean maximum concentrations of fevipiprant increased approximately 1.7-fold, and the area under the concentration-time curve in plasma increased approximately 2.5-fold, whereas the mean apparent volume of distribution and the AG metabolite:fevipiprant ratio decreased. The apparent systemic clearance decreased by approximately 60% and the renal clearance decreased by approximately 88% in the presence of probenecid. Using these data and those from previous studies, the relative contribution of OAT and UGT inhibition to the overall effect of probenecid was estimated. Furthermore, a general disposition scheme for fevipiprant was developed, showing how a perpetrator drug such as probenecid, which interferes with two key elimination pathways of fevipiprant, causes only a moderate increase in exposure and allows estimation of the drug-drug inhibition when only one of the two pathways is inhibited. SIGNIFICANCE STATEMENT: In this drug-drug interaction (DDI) study, probenecid was used as a tool to inhibit both glucuronidation and active renal secretion of fevipiprant. The combination of plasma and urine pharmacokinetic data from this study with available data allowed the development of a quantitative scheme to describe the fate of fevipiprant in the body, illustrating why the DDI effect on fevipiprant is weak-to-moderate even if a perpetrator drug inhibits several elimination pathways.

Objectives: Injury-induced molecular changes in the intra-articular microenvironment of the knee are thought to play a role in the development of post-traumatic osteoarthritis. The purpose of this study was to evaluate the association between post-traumatic synovial fluid biomarker concentrations and intermediate-term functional outcomes. Methods: Patients undergoing primary knee arthroscopy for ACL injury, meniscus injury, and/or focal chondral lesions were prospectively enrolled. Synovial fluid aspirate, collected immediately prior to surgical incision, was processed and analyzed using a multiplex magnetic bead immunoassay to determine the concentration of 10 pre-determined cytokines and chemokines. Patients with a minimum of five years of postoperative follow-up were surveyed with Visual Analog Pain Scale (VAS), Lysholm Knee Scoring Scale, and Knee Injury and Osteoarthritis Outcome Score Physical Function Shortform (KOOS-PS). Stepwise regression was used to fit a linear regression model and model accuracy was evaluated using k-fold cross validation. Results: 39 patients (mean age: 41.56 +/- 15.98 years, mean postoperative follow-up: 6.79 +/- 0.72 years) were included in the study. Mean Lysholm, KOOS-PS, and VAS scores were 83.67 +/- 17.64, 88.37 +/- 12.79, and 11.03 +/- 19.84, respectively. 11 patients had undergone further ipsilateral knee surgery during the follow-up period. Of the remaining 28 patients, a model consisting of VEGF, TIMP-2, and MMP-3 was found to most accurately predict intermediate-term functional outcomes. Regardless of the type or extent of injury, these three biomarkers were able to explain 60.35%, 34.75%, and 39.38% of the variability in Lysholm, KOOS-PS, and VAS scores, respectively. Conclusions: By measuring the concentrations of MMP-3, TIMP-2, and VEGF at the time of surgery, functional outcomes and level of pain can be predicted at 5 years postoperatively with moderate accuracy. This suggests that these biomarkers may play an important role in the development of post-traumatic osteoarthritis and may serve as potential targets for therapeutic intervention. [Table: see text]

This drug-drug interaction (DDI) study determined the effect of cyclosporine, an inhibitor of OATP1B3 and P-gp, on the pharmacokinetics (PK) of fevipiprant, an oral, highly selective, competitive antagonist of the prostaglandin D2 receptor 2 and a substrate of the two transporters. The concomitant administration of an intravenous (IV) microdose of stable isotope-labeled fevipiprant provided the absolute bioavailability of fevipiprant, as well as mechanistic insights in its PK and sensitivity to drug interactions. Liquid chromatography-mass spectrometry/mass spectrometry was used to measure plasma and urine concentrations. Geometric mean ratios (90% CI) for oral fevipiprant with or without cyclosporine were: for Cmax, 3.02 (2.38, 3.82); for AUClast, 2.50 (2.17, 2.88); and for AUCinf, 2.35 (1.99, 2.77). The geometric mean ratios (90% CI) for fevipiprant IV microdose with or without cyclosporine were: for Cmax, 1.04 (0.86, 1.25); for AUClast, 2.04 (1.83, 2.28) and for AUCinf, 1.95 (1.76, 2.16). The absolute bioavailability for fevipiprant was approximately 0.3-0.4 in the absence and 0.5 in the presence of cyclosporine. The IV microdose allowed differentiation between systemic and pre-systemic effects of cyclosporine on fevipiprant, demonstrating a small (approximately 1.2-fold) pre-systemic effect of cyclosporine and a larger (approximately 2-fold) effect on systemic elimination of fevipiprant. Uptake by OATP1B3 appears to be the rate-limiting step in the hepatic elimination of fevipiprant while P-gp does not have a relevant effect on oral absorption. SIGNIFICANCE STATEMENT The drug interaction investigated here with cyclosporine, an inhibitor of several drug transporters, provides a refined quantitative understanding of the role of active transport processes in liver and intestine for the absorption and elimination of fevipiprant, as well as the basis to assess the need for dose adjustment in the presence of transporter inhibitors. The applied IV microdose approach presents a strategy to maximize learnings from a trial, limit the number and duration of clinical trials, and enhance mechanistic DDI understanding.

Objectives: Superior-labrum anterior-posterior (SLAP) tears are common among athletic populations and may require surgical treatment. Return to play post-operatively may be complicated by a number of factors, including psychological readiness to return. The purpose of this study was to evaluate the use of the SLAP Return to Sport Index (SLAP-RSI) score to quantify psychological readiness to return to play following operative management of SLAP tears. Methods: A retrospective review of athletes who underwent operative management of SLAP tears with a minimum of 12-month follow-up was performed. Patients were evaluated for their psychological readiness to return to sport using the SLAP-RSI score. The SLAP-RSI score was created by adapting the terms in the Anterior (ACL-RSI score) with terms related to SLAP tears. A SLAP-RSI score > 56 is considered a passing score for being psychologically ready to return to play. Results: The study included 174 athletes who underwent operative management of SLAP tears. Overall, 73.5% percent of patients were able to return to play, and the mean SLAP-RSI score in this cohort was 74.1±20.9, as compared to 46.7±27.7 in those who were unable to return (pConclusions: Following the operative management of SLAP repair, patients that are unable to return to play exhibit poor psychological readiness to return which may be due to residual pain or fear of re-injury.

Objectives: Socioeconomic factors have been shown to impact patient care in many surgical fields; however, their effects have not been thoroughly evaluated in the context of anterior cruciate ligament reconstruction (ACLR) outcomes. The purpose of this study is to investigate the effects of socioeconomic factors on time to surgery, knee function, and subjective outcomes measures following ACLR. Methods: A retrospective query of primary ACLR surgeries at a single institution performed from 2011 to 2015 with minimum two-year follow-up was conducted. Patient demographics, insurance type, worker’s compensation status, surgical variables, IKDC score, and failure were recorded from chart review. Education level and income were obtained via phone interview. Differences between functional outcome were compared between Medicaid and non-Medicaid groups. Results: 268 patients were included in the analysis (43 patients in the Medicaid group and 225 patients in the non-Medicaid group). The Medicaid group demonstrated lower annual income (pConclusions: Socioeconomic factors impacted care in the setting of ACL injury. Medicaid insurance patients were seen significantly later after initial injury when compared to non-Medicaid carriers, and had worse outcomes compared to their non-Medicaid peers. Higher annual income brackets had significantly higher clinical outcomes scores at a minimum of two years postoperatively. Education level did not affect outcomes.

Premature labor is a cause of high rates of perinatal morbidity and mortality. The use of tocolytics is one of the efforts to handle the risk of preterm labor. Tocolytics which are widely used in Indonesia is isoxsuprine and nifedipine. The purpose of this study was to identify the difference of effectiveness and safety of isoxsuprine as tocolytics in the risk of preterm labor. This was an observational study in the form of a case study that was done in detail and depth to the patients who were diagnosed as imminent preterm labor. In conclusion, there were differences in the effectiveness and safety of isoxsuprine and nifedipine as tocolytics in the risk of preterm labor.

Selective serotonin reuptake inhibitors (SSRIs) are one of the most commonly prescribed antidepressants worldwide and recent data show significant impairment of fracture healing after treatment with the SSRI fluoxetine in mice. Here, we provide evidence that the negative effects of SSRIs can be overcome by administration of the beta-blocker propranolol at the time of fracture. First, in vitro experiments established that propranolol does not affect osteogenic differentiation. We then used a murine model of intramembranous ossification to study the potential rescue effect of propranolol on SSRI-induced impaired fracture healing. Micro-CT analysis revealed that fluoxetine treatment resulted in a smaller bony regenerate and that this decrease in bone formation can be overcome by co-treatment with propranolol. We then tested this in a clinically relevant model of endochondral ossification. Fluoxetine-treated mice with a femur fracture were treated with propranolol initiated at the time of fracture, and a battery of analyses demonstrated a reversal of the detrimental effect of fluoxetine on fracture healing in response to propranolol treatment. These experiments show for the first time to our knowledge that the negative effects of SSRIs on fracture healing can be overcome by co-treatment with a beta-blocker. © 2019 American Society for Bone and Mineral Research.

Background: \ud Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial.\ud \ud Methods: \ud NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy.\ud \ud Findings: \ud Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22–1·36), and the risk was similar for those without known PFO (1·06; 0·84–1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69–4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity.\ud \ud Interpretation: \ud Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted.\ud \ud Funding: \ud Bayer and Janssen.

Fevipiprant is a novel oral prostaglandin D2 receptor 2 (DP2; also known as CRTh2) antagonist, which is currently in development for the treatment of severe asthma and atopic dermatitis. We investigated the absorption, distribution, metabolism, and excretion properties of fevipiprant in healthy subjects after a single 200-mg oral dose of [14C]-radiolabeled fevipiprant. Fevipiprant and metabolites were analyzed by liquid chromatography coupled to tandem mass spectrometry and radioactivity measurements, and mechanistic in vitro studies were performed to investigate clearance pathways and covalent plasma protein binding. Biotransformation of fevipiprant involved predominantly an inactive acyl glucuronide (AG) metabolite, which was detected in plasma and excreta, representing 28% of excreted drug-related material. The AG metabolite was found to covalently bind to human plasma proteins, likely albumin; however, in vitro covalent binding to liver protein was negligible. Excretion was predominantly as unchanged fevipiprant in urine and feces, indicating clearance by renal and possibly biliary excretion. Fevipiprant was found to be a substrate of transporters organic anion transporter 3 (OAT3; renal uptake), multidrug resistance gene 1 (MDR1; possible biliary excretion), and organic anion-transporting polypeptide 1B3 (OATP1B3; hepatic uptake). Elimination of fevipiprant occurs via glucuronidation by several uridine 5'-diphospho glucuronosyltransferase (UGT) enzymes as well as direct excretion. These parallel elimination pathways result in a low risk of major drug-drug interactions or pharmacogenetic/ethnic variability for this compound.

Objective: To compare the survival and side effects in epithelial ovarian cancer patients receiving adjuvant chemotherapy of cisplatin/ cyclophosphamide and carboplatin/paclitaxel. Method: We recruited epithelial ovarian cancer patients receiving cisplatin/cyclophosphamide (group A) or carboplatin/paclitaxel (group B) adjuvant chemotherapy after surgery. Chemotherapy was given for six cycles. Overall survival and side effects were assessed. Result: A total of 49 patients were recruited, consisting of 25 patients for group A and 24 patients for group B. In this study, the overall survival of stage IC-IV ovarian cancer patients was 37.3 months in group A (95%CI=31.86-43.46) and 35.5 months (95%CI= 13.93- 43.46) in group B (p

Background and Purpose— Strokes have especially devastating implications if they occur early in life; however, only limited information exists on the characteristics of acute cerebrovascular disease in young adults. Although risk factors and manifestation of atherosclerosis are commonly associated with stroke in the elderly, recent data suggests different causes for stroke in the young. We initiated the prospective, multinational European study Stroke in Young Fabry Patients (sifap) to characterize a cohort of young stroke patients. Methods— Overall, 5023 patients aged 18 to 55 years with the diagnosis of ischemic stroke (3396), hemorrhagic stroke (271), transient ischemic attack (1071) were enrolled in 15 European countries and 47 centers between April 2007 and January 2010 undergoing a detailed, standardized, clinical, laboratory, and radiological protocol. Results— Median age in the overall cohort was 46 years. Definite Fabry disease was diagnosed in 0.5% (95% confidence interval, 0.4%–0.8%; n=27) of all patients; and probable Fabry disease in additional 18 patients. Males dominated the study population (2962/59%) whereas females outnumbered men (65.3%) among the youngest patients (18–24 years). About 80.5% of the patients had a first stroke. Silent infarcts on magnetic resonance imaging were seen in 20% of patients with a first-ever stroke, and in 11.4% of patients with transient ischemic attack and no history of a previous cerebrovascular event. The most common causes of ischemic stroke were large artery atherosclerosis (18.6%) and dissection (9.9%). Conclusions— Definite Fabry disease occurs in 0.5% and probable Fabry disease in further 0.4% of young stroke patients. Silent infarcts, white matter intensities, and classical risk factors were highly prevalent, emphasizing the need for new early preventive strategies. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov .Unique identifier: NCT00414583

8-(N-2-hydroxy-5-chlorobenzoyl)-amino-caprylic acid (5-CNAC), a compound lacking pharmacological activity enhances the absorption of salmon calcitonin, when co-administered. Disposition and biotransformation of 5-CNAC was studied in six healthy postmenopausal women following a single oral dose of 200mg (14)C-radiolabeled 5-CNAC (as disodium monohydrate salt). Blood, plasma, urine and feces collected over 7 days were analyzed for radioactivity. Metabolite profiles were determined in plasma and excreta and metabolite structures were elucidated by LC-MS/MS, LC-(1)H NMR, enzymatic methods and by comparison with reference compounds. Oral 5-CNAC was safe and well tolerated in this study population. 5-CNAC absorption was rapid (t(max)=0.5h; C(max)=9.00 ± 2.74 μM (mean ± SD, n=6) and almost complete. The elimination half-life (t(½)) was 1.5 ± 1.1h. The radioactive dose was excreted mainly in urine (≥ 90%) in form of metabolites and 0.071% as intact 5-CNAC. Excretion of radioactivity in feces was minor and mostly as metabolites (

The adenosine A(2a) receptor belongs to the seven transmembrane helix G-protein-coupled receptor family, is abundant in striatum, vasculature and platelets and is involved in several physiological processes such as blood pressure regulation and protection of cells during anoxia. For structural and biophysical studies we have expressed the human adenosine A(2a) receptor (hA2aR) at high levels inserted into the Escherichia coli inner membrane, and established a purification scheme. Expression was in fusion with the periplasmic maltose-binding protein to levels of 10-20 nmol of receptor per L of culture, as detected with the specific antagonist ligand [(3)H]ZM241385. As the receptor C-terminus was proteolyzed upon solubilization, a protease-resistant but still functional receptor was created by truncation to Ala316. Addition of the sterol, cholesteryl hemisuccinate, allowed a stable preparation of functional hA2aR solubilized in dodecylmaltoside to be obtained, and, increased the stability of the receptor solubilized in other alkylmaltosides. Purification to homogeneity was achieved in three steps, including ligand affinity chromatography based on the antagonist xanthine amine congener. The purified hA2aR fusion protein bound [(3)H]ZM241385 with a K(d) of 0.19 nm and an average B(max) of 13.7 nmol x mg(-1) that suggests 100% functionality. Agonist affinities for the purified solubilized receptor were higher than those for the membrane-bound form. Sufficient pure, functional hA2aR can now be prepared regularly for structural studies.

Cyclosporin A reduces the mitotic activity of allosensitized lymphocytes, but fails to limit emigration of these cells into the donor organ. However, the modulation of both lymphocyte proliferation and infiltration are desirable characteristics of immunosuppressive therapy. The calcium-channel blocker, verapamil, has recently been shown to effectively prevent the transmigration of CD4+ and CD8+ T cells through allogeneic endothelium. Mibefradil (Ro 40-5967) represents a new generation of calcium antagonists with high potency and long-term activity. To evaluate the immunosuppressive potential of this drug, the influence of mibefradil on lymphocyte adhesion to, horizontal locomotion along, and penetration through allogeneic endothelium (HUVEC) was performed. When lymphocytes were prestimulated for 24 hr with mibefradil, adhesion and penetration were dose-dependently reduced. The adhesion ID50 values were 3.4 microM (CD4+ T cells) versus 9.2 microM (CD8+ T cells) and 2.1 microM (CD4+ T cells) versus 3.9 microM (CD8+ T cells) with regard to penetration. Mibefradil also effectively blocked horizontal locomotion. Specific down-regulation of T-cell binding to the P-selection receptor (ID50: CD4+ T cells, 0.8 microM: CD8+ T cells, 1.2 microM) and to the intracellular adhesion molecule-1 (ICAM-1) receptor (ID50: CD4+ T cells, 1.9 microM; CD8+ T cells, 1.5 microM) by mibefradil seems to be responsible for the decreased adhesion and penetration rates. Reduction of intracellular F-actin in T lymphocytes could diminish cell locomotion. In conclusion, the potent suppressive properties of mibefradil support its use as a co-medication in cyclosporin A-based immunosuppressive therapy.

Lymphocyte cultures grown from liver allograft biopsies were shown to exhibit alloreactivity towards donor cells as measured by primed lymphocyte testing (PLT). The PLT specificity was determined in assays using HLA typed panel cells and/or by inhibition testing with HLA specific monoclonal antibodies. Certain cultures exhibited PLT specificity towards class I HLA antigens of the donor, whereas others were specific for class II HLA antigens or recognized mixtures of class I and II antigens. These PLT specificity patterns were compared with clinical, histological and laboratory findings on the liver transplant patients at the time of the biopsy. Biopsies yielding class I specific PLT cells were taken generally during the earlier posttransplant period, whereas class II specific cells were grown from later biopsies. There was no significant correlation of the PLT specificity towards class I vs II antigens with the levels of total or direct bilirubin, serum glutamate oxaloacetic transaminase (SGOT), and serum glutamate pyruvate transaminase (SGPT), although a trend towards higher values was noted for biopsies presenting with a class II specific infiltrate. However, the levels of gamma glutamyl transpeptidase (GGTP) and alkaline phosphatase (AP) were significantly increased when biopsies yielded class II specific rather than class I specific PLT cells. Biopsy histology showed more damage to bile duct epithelium in association with class II PLT specificity whereas intense but often reversible infiltrates were found in biopsies yielding class I specific cells. The elevated GGTP and AP levels are probably related to the interaction of class II specific T cells with bile duct epithelium, which has been shown to express induced class II HLA antigens on their cell surface.

Bioartificial liver support systems have demonstrated limited efficacy in compensation of liver detoxification and substitution of liver-derived factors. However, in these devices, the biological substitution of the complex liver function has been restricted to xenogeneic or transformed hepatocytes. Therefore, we have examined the long-term effect of coculturing normal human hepatocytes (HCs) with allogeneic biliary epithelial cells (BECs). We applied functional in vitro assays to examine their metabolic potential by ammonia detoxification to urea, cytochrome P450-dependent lignocaine conversion to mono-ethyl-glycine-xylidide (MEGX), and protein expression and secretion. As the liver has a pivotal role in the synthesis of coagulation factors, we measured antithrombin III (AT III), factor VII, and albumin, comparing HCs plated on collagen or inside 3-dimensional collagen gels. Over 30 days, expression and secretion of albumin and clotting factors by human HCs were augmented by culture inside collagen gel, but were also enhanced and better maintained by coculture with BECs. Higher proportions of BECs cocultured with HCs substantially increased the protein synthesis and urea production. Remarkably, the almost absent cytochrome P450 activity of HC alone after 1 week could be reversed and maintained over 3 weeks by coculture with BECs. The pattern of these effects differed from the extent of interleukin-6 (IL-6) production and HC viability under the compared conditions. In conclusion, coculture of human HCs with BECs impressively restores the synthetic and metabolic liver function in vitro. These results suggest mechanisms of improved liver epithelial differentiation supported by coculture conditions. This technique offers new perspectives in bioartificial liver support, hepatocyte transplantation, and stem cell differentiation.

Aims To determine blood binding parameters of imatinib and its metabolite CGP74588 in humans and non-human species. Methods The blood distribution and protein binding of imatinib and CGP74588 were determined in vitro using 14C labelled compounds. Results The mean fraction of imatinib in plasma (fp) was 45% in dog, 50% in mouse, 65% in rat, 70% in healthy humans and up to 92% in acute lymphatic leukaemia (AML) patients. Similarly, fp for CGP74588 was low in dog and monkey (30%), higher in rat, mouse and humans (70%) and highest in some AML patients (90%). The unbound fraction of imatinib and CGP74588 in plasma was lower in rat, mouse, healthy humans and AML patients (2.3–6.5% at concentrations ≤ 5000 ng ml−1) compared to monkey and dog (7.6–19%). Both compounds displayed high binding to human α1-acid glycoprotein. AML patients had a reduced haematocrit and showed greatest variability in their blood binding parameters. Conclusion Imatinib and CGP74588 displayed very similar blood binding parameters within all species/groups investigated. The five species clustered into two distinct groups with rat, mouse and humans being clearly different from dog and monkey. For both compounds, higher protein binding was associated with a decreased partitioning into blood cells.

The adenosine A(2a) receptor belongs to the seven transmembrane helix G-protein-coupled receptor family, is abundant in striatum, vasculature and platelets and is involved in several physiological processes such as blood pressure regulation and protection of cells during anoxia. For structural and biophysical studies we have expressed the human adenosine A(2a) receptor (hA2aR) at high levels inserted into the Escherichia coli inner membrane, and established a purification scheme. Expression was in fusion with the periplasmic maltose-binding protein to levels of 10-20 nmol of receptor per L of culture, as detected with the specific antagonist ligand [(3)H]ZM241385. As the receptor C-terminus was proteolyzed upon solubilization, a protease-resistant but still functional receptor was created by truncation to Ala316. Addition of the sterol, cholesteryl hemisuccinate, allowed a stable preparation of functional hA2aR solubilized in dodecylmaltoside to be obtained, and, increased the stability of the receptor solubilized in other alkylmaltosides. Purification to homogeneity was achieved in three steps, including ligand affinity chromatography based on the antagonist xanthine amine congener. The purified hA2aR fusion protein bound [(3)H]ZM241385 with a K(d) of 0.19 nm and an average B(max) of 13.7 nmol x mg(-1) that suggests 100% functionality. Agonist affinities for the purified solubilized receptor were higher than those for the membrane-bound form. Sufficient pure, functional hA2aR can now be prepared regularly for structural studies.

Yeasts combine the advantages of fast and easy handling with the potential to perform eukaryotic post-translational modifications and are for this reason interesting hosts for heterologous production of G-protein-coupled receptors. The possibility to connect foreign receptors to a yeast internal MAP kinase pathway was used to establish yeast-based systems for high-throughput screening of compound libraries. In addition, yeasts have the potential for high level production of G-protein-coupled receptors. In this field, non-Saccharomyces yeasts seems to be interesting alternatives to S. cerevisiae, as well as to systems based on higher eukaryotic cells.

Sir,—Hyperhomocysteinaemia and Helicobacter pylori infection have recently been implicated in the pathogenesis of coronary heart disease and a possible link between these factors has been suggested in this journal.1 Our work has shown that chronic infection with H pylori confers a twofold risk of coronary heart disease2 and this association, like hyperhomocysteinaemia, is independent of hypertension, smoking, and hyperlipidaemia. Our studies have shown that fibrinogen concentrations and total leucocyte counts were higher in H pylori seropositive patients with cardiovascular disease.3 We therefore suggested that the mechanism is chronic infection accompanied by persistent inflammation. Sir,—Hyperhomocysteinaemia and Helicobacter pylori infection have recently been implicated in the pathogenesis of coronary heart disease and a possible …