Use of MACI (Autologous Cultured Chondrocytes on Porcine Collagen Membrane) in the United States: Preliminary Experience.

Background: In December 2016, MACI (autologous cultured chondrocytes on porcine collagen membrane) received approval from the US Food and Drug Administration for the treatment of symptomatic articular cartilage defects of the knee with or without bone involvement in adults.

Purpose: To describe the cartilage defects and patient characteristics for 1000 adult patients treated with MACI for knee cartilage repair in the United States.

Study Design: Case series; Level of evidence, 4.

The introduction of a safety checklist in two UK hospital emergency departments: A qualitative study of implementation and staff use.

Aims And Objectives: To explore the extent to which a checklist designed to support patient safety in hospital Emergency Departments was recognised and used by staff.

Background: Patient crowding in UK Emergency Departments makes it difficult for staff to monitor all patients for signs of clinical deterioration. An Emergency Department Safety Checklist was developed at a UK hospital to ensure patients are regularly monitored.

Red and orange flags for secondary headaches in clinical practice: SNNOOP10 list.

A minority of headache patients have a secondary headache disorder. The medical literature presents and promotes red flags to increase the likelihood of identifying a secondary etiology. In this review, we aim to discuss the incidence and prevalence of secondary headaches as well as the data on sensitivity, specificity, and predictive value of red flags for secondary headaches.

Twenty-Five Years' Experience and Beyond with Cultured Epidermal Autografts for Coverage of Large Burn Wounds in Adult and Pediatric Patients, 1989-2015.

This report summarizes the characteristics of 954 burned patients treated with cultured epidermal autografts (CEA), the largest number of patients to date. Data collected include patient demographics, survival, and final graft take. Source data were provided by the treating physician or attending burn team.

Ixmyelocel-T for patients with ischaemic heart failure: a prospective randomised double-blind trial.

Background: Ixmyelocel-T is an expanded, multicellular therapy produced from a patient's own bone marrow by selectively expanding two key types of bone marrow mononuclear cells: CD90+ mesenchymal stem cells and CD45+ CD14+ auto-fluorescent+ activated macrophages. Early phase clinical trials suggest that intramyocardial delivery of ixmyelocel-T might improve clinical, functional, symptomatic, and quality-of-life outcomes in patients with heart failure due to ischaemic dilated cardiomyopathy. We aimed to assess the safety and efficacy of catheter-based transendocardial injection of ixmyelocel-T cell therapy in patients with heart failure and reduced ejection fractions.

The ixCELL-DCM Trial: Rationale and Design.

Ixmyelocel-T is an investigational patient-specific, expanded, multicellular therapy produced from a patient's own bone marrow. It is produced by selectively expanding two key types of bone marrow mononuclear cells (BM-MNCs), CD90 mesenchymal stem cells (MSCs), and CD45CD14 autofluorescent, alternatively activated macrophages. Earlier clinical trials suggested that intramyocardial ixmyelocel-T might improve clinical, functional, symptomatic, and quality of life outcomes in patients with ischemic dilated cardiomyopathy (IDCM).

[Hypomania following the use of varenicline in two patients with bipolar disorder].

Varenicline is a drug that has been developed to help people stop smoking . Results regarding its efficacy are promising. The safety of the drug, however, is controversial when used for patients with mental illnesses because it can have neuropsychiatric side-effects.

Safety and efficacy of ixmyelocel-T: an expanded, autologous multi-cellular therapy, in dilated cardiomyopathy.

Rationale: Ixmyelocel-T is associated with a wide range of biological activities relevant to tissue repair and regeneration.

Objective: To evaluate the safety and efficacy of ixmyelocel-T in 2 prospective randomized phase 2A Trials administered via minithoracotomy or intramyocardial catheter injections in patients with dilated cardiomyopathy (DCM) stratified by ischemic or nonischemic status.

Methods And Results: In IMPACT-DCM, patients were randomized to either ixmyelocel-T or standard-of-care control in a 3:1 ratio (n=39); ixmyelocel-T was administered intramyocardially via minithoracotomy.

Ovulation-inhibiting effects of dienogest in a randomized, dose-controlled pharmacodynamic trial of healthy women.

Dienogest offers pharmacological advantages for the effective treatment of endometriosis and for use in contraception and hormone replacement therapy. This pharmacodynamic study investigated the ovulation-inhibiting effects of dienogest monotherapy in healthy women. Dienogest was administered at 0.

Modeling and simulation to support dose selection and clinical development of SC-75416, a selective COX-2 inhibitor for the treatment of acute and chronic pain.

Pharmacokinetic/pharmacodynamic (PK/PD) models were developed and clinical trial simulations were conducted to recommend a study design to test the hypothesis that a dose of SC-75416, a selective cyclooxygenase-2 inhibitor, can be identified that achieves superior pain relief (PR) compared to 400 mg ibuprofen in a post-oral surgery pain model. PK/PD models were developed for SC-75416, rofecoxib, valdecoxib, and ibuprofen relating plasma concentrations to PR scores using a nonlinear logistic-normal model. Clinical trial simulations conducted using these models suggested that 360 mg SC-75416 could achieve superior PR compared to 400 mg ibuprofen.

Quantitative imaging of cartilage morphology at 3.0 Tesla in the presence of gadopentate dimeglumine (Gd-DTPA).

MRI-based cartilage morphometry was previously validated in the absence of gadopentate dimeglumine (Gd-DTPA). However, Gd-DTPA is required for compositional (proteoglycan) imaging using delayed gadolinium-enhanced MRI of cartilage (dGEMRIC). Therefore, the effect of Gd-DTPA on cartilage morphometry was studied.

Effects of three cytochrome P450 inhibitors, ketoconazole, fluconazole, and paroxetine, on the pharmacokinetics of lasofoxifene.

Aims: Two studies were conduced to assess the effects of ketoconazole, a CYP3A4/5 inhibitor; fluconazole, a CYP2C9 inhibitor; and paroxetine, a CYP2D6 inhibitor, on lasofoxifene pharmacokinetics.

Methods: The first parallel group study was conducted in 45 healthy postmenopausal women (15 per group) to compare the pharmacokinetics of a single dose of lasofoxifene (0.25 mg) administered alone and in combination with ketoconazole (400 mg daily x 20 days) or fluconazole (400 mg daily x 20 days).

Effects of lasofoxifene on the pharmacokinetics and pharmacodynamics of single-dose warfarin.

Aim: To investigate the effect of steady-state lasofoxifene on the pharmacokinetics and pharmacodynamics of warfarin.

Methods: Twelve healthy postmenopausal women received warfarin (single 20-mg dose) alone and during lasofoxifene. R- and S-warfarin concentrations, prothrombin time (PT) and international normalized ratio (INR) were determined with each treatment.

Accuracy and precision of quantitative assessment of cartilage morphology by magnetic resonance imaging at 3.0T.

Objective: Quantitative magnetic resonance imaging (MRI) of articular cartilage represents a powerful tool in osteoarthritis (OA) research, but has so far been confined to a field strength of 1.5T. The aim of this study was to evaluate the precision of quantitative MRI assessments of human cartilage morphology at 3.

Relationship between rate and extent of G protein activation: comparison between full and partial opioid agonists.

Opioid agonists acting at their receptors alter intracellular events by initiating activation of various types of Gi/Go proteins. This can be measured by the binding of the stable GTP analog [(35)S]guanosine-5'-O-(3-thio)triphosphate ([(35)S]GTPgammaS). In this study agonist efficacy is defined by the degree to which an opioid stimulates the binding of [(35)S]GTPgammaS.

Late recurrence of lupus nephritis in a renal transplant recipient: response to mycophenolate mofetil.

Clinically significant recurrence of lupus nephritis in the renal allograft is low, with an incidence of 1 to 3%, and usually occurs within the first 6 years after transplantation. We report an unusual case of a patient with end-stage renal disease caused by lupus nephritis who received a kidney transplant from a living relative; 13 years later, the patient had a severe recurrence of diffuse proliferative lupus nephritis. The patient relapsed after receiving intravenous cyclophosphamide therapy and had a partial response to oral mycophenolate mofetil.

Activation of G protein by opioid receptors: role of receptor number and G-protein concentration.

The collision-coupling model for receptor-G-protein interaction predicts that the rate of G-protein activation is dependent on receptor density, but not G-protein levels. C6 cells expressing mu- or delta-opioid receptors, or SH-SY5Y cells, were treated with beta-funaltrexamine (mu) or naltrindole-5'-isothiocyanate (delta) to decrease receptor number. The time course of full or partial agonist-stimulated ¿35SGTPgammaS binding did not vary in C6 cell membranes containing <1-25 pmol/mg mu-opioid receptor, or 1.

Interdomain interactions regulate GDP release from heterotrimeric G proteins.

The role of interdomain contact sites in basal GDP release from heterotrimeric G proteins is unknown. G(alpha)(o) and G(alpha)(i1) display a 5-fold difference in the rate of GDP dissociation with half-times of 2.3 +/- 0.

Membrane microviscosity modulates mu-opioid receptor conformational transitions and agonist efficacy.

The influence of membrane microviscosity on mu-opioid agonist and antagonist binding, as well as agonist efficacy, was examined in membranes prepared from SH-SY5Y cells and from a C6 glioma cell line stably expressing the rat mu-opioid receptor (C6mu). Addition of cholesteryl hemisuccinate (CHS) to cell membranes increased membrane microviscosity and reduced the inhibitory effect of sodium and guanine nucleotides on the affinity of the full agonists sufentanil and [D-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAMGO) for the mu-opioid receptor. Binding of the antagonists [3H]naltrexone and [3H]diprenorphine and the partial agonist nalbuphine was unaffected by CHS.

Acute renal failure in a patient with AIDS: histoplasmosis-induced granulomatous interstitial nephritis.

Although the most frequent cause of acute renal failure (ARF) in patients with AIDS is acute tubular necrosis (ATN) secondary to ischemic renal injury from septicemia, a spectrum of causes may result in ARF in these patients. We report a patient with AIDS who developed ARF and was found to have granulomatous interstitial nephritis as a result of disseminated histoplasmosis. Histoplasma capsulatum was seen in the interstitium of the kidney on renal biopsy.

Opioid efficacy in a C6 glioma cell line stably expressing the human kappa opioid receptor.

A C6 glioma cell line stably transfected with the human kappa opioid receptor (kappaOR) was used to characterize receptor binding and G protein activation via the kappaOR by a comprehensive series of opioid ligands. The ligand-binding affinity for [3H]5alpha,7alpha, 8beta(-)-N-methyl-N-(7-Cl-pyrrolidinyl)-1-oxaspiro(4, 5)dec-8-yl)benzene acetamide (U69593) was similar to that observed in monkey brain membranes and was 10-fold lower in the presence of sodium and GDP. Both peptide and nonpeptide agonists maximally stimulated [35S]GTPgammaS binding.

Delta opioid receptor down-regulation is independent of functional G protein yet is dependent on agonist efficacy.

Chronic treatment of C6 glioma cells stably expressing the rat delta opioid receptor (C6delta) with full agonists resulted in receptor down-regulation. Chronic [D-Ser2,L-Leu5]enkephalyl-Thr treatment caused a decrease in cell surface as well as a decrease in agonist-stimulated [35S]guanosine-5'-O-(3-thio)triphosphate binding. Treatment with full agonists for 12 hr resulted in a 90% decrease in receptor number that was paralleled by a decrease in the ability of agonist to stimulate [35S]guanosine-5'-O-(3-thio)triphosphate binding and inhibit forskolin-stimulated adenylyl cyclase.

Determinants of gi1alpha and beta gamma binding. Measuring high affinity interactions in a lipid environment using flow cytometry.

G protein heterocomplex undergoes dissociation and association during its functional cycle. Quantitative measurements of alpha and betagamma subunit binding have been difficult due to a very high affinity. We used fluorescence flow cytometry to quantitate binding of fluorescein-labeled Gi1alpha (F-alpha) to picomolar concentrations of biotinylated G beta gamma.