Identification of highly selective SIK1/2 inhibitors that modulate innate immune activation and suppress intestinal inflammation.

The salt-inducible kinases (SIK) 1-3 are key regulators of pro- versus anti-inflammatory cytokine responses during innate immune activation. The lack of highly SIK-family or SIK isoform-selective inhibitors suitable for repeat, oral dosing has limited the study of the optimal SIK isoform selectivity profile for suppressing inflammation in vivo. To overcome this challenge, we devised a structure-based design strategy for developing potent SIK inhibitors that are highly selective against other kinases by engaging two differentiating features of the SIK catalytic site. This effort resulted in SIK1/2-selective probes that inhibit key intracellular proximal signaling events including reducing phosphorylation of the SIK substrate cAMP response element binding protein (CREB) regulated transcription coactivator 3 (CRTC3) as detected with an internally generated phospho-Ser329-CRTC3-specific antibody. These inhibitors also suppress production of pro-inflammatory cytokines while inducing anti-inflammatory interleukin-10 in activated human and murine myeloid cells and in mice following a lipopolysaccharide challenge. Oral dosing of these compounds ameliorates disease in a murine colitis model. These findings define an approach to generate highly selective SIK1/2 inhibitors and establish that targeting these isoforms may be a useful strategy to suppress pathological inflammation.

Percutaneous mitral annuloplasty with the Carillon device: Outcomes in proportionate and disproportionate functional mitral regurgitation.

BACKGROUND: It has been suggested that the disparity of outcomes between the studies of transcutaneous edge-to-edge repair (TEER) for functional mitral regurgitation (FMR) in heart failure with reduced ejection fraction (HFrEF) could be due to systematic differences in the populations studied. One proposal is that there are 2 broad groups: those with proportional FMR who respond less favorably, and those in whom the FMR is greater than expected (disproportionate) FMR where edge-to-edge TEER seems to be more effective. Whether this grouping is relevant for other percutaneous interventions for FMR is unknown. OBJECTIVES: We sought to compare clinical and echocardiographic outcomes of patients with HFrEF and proportionate and disproportionate FMR treated with indirect annuloplasty using the Carillon device. METHODS: This is a pooled analysis from 3 trials of patients with FMR. Key patient eligibility in these trials specified persistent grade 2+ to 4+ FMR with >5.5 cm left ventricular (LV) end-diastolic diameter (LVEDD) and reduced ejection fraction. Patients with an effective regurgitant orifice area/LV end-diastolic volume (EROA/LVEDV) ratio under 0.15 were assigned to the proportionate FMR group (n = 74;65%) and those with a ratio above 0.15 were classed as having disproportionate FMR (n = 39;35%). RESULTS: At 12 months following treatment, both groups showed improvements in all MR variables including regurgitation volume, EROA and vena contracta. Moreover, in patients with proportionate MR there were clinically relevant and statistically significant improvements in LV volumes and diameters. There was no independent relationship between the degree of proportionality as a continuous variable and the remodeling response to Carillon therapy (change in LVEDV r = 0.17; change in LVESV r = 0.14). CONCLUSION: Percutaneous mitral annuloplasty with the Carillon device reduces MR in patients with both proportionate and disproportionate FMR, and also results in LV reverse remodeling in those with proportionate FMR. The effect on remodeling remains to be verified in a large-scale trial.

The Effects of Botulinum Toxin A on Pain in Ischemic Vasospasm.

PURPOSE: The purpose was to describe the impact of botulinum toxin A (BTX-A) administration in patients with ischemic vasospasm on the magnitude and timing of pain relief and subsequent effect on opioid use. The secondary purposes were to determine the role of photoplethysomgraph (PPG) testing on treatment decisions, effect on patient-reported outcomes, and additional procedures. METHODS: A retrospective analysis of patients who received BTX-A injections was performed. Botulinum toxin type A was injected subcutaneously in symptom-specific 2-level patterns. Pain, shortened version of the Disabilities of the Arm, Shoulder, and Hand (QuickDASH), and opioid use (quantified by median morphine equivalents) were recorded and the need for repeat injections or unplanned surgeries was assessed. RESULTS: All patients (n = 20 patients; 31 hands) had ischemic pain from vasospasm and failed multiple pharmacological options. Average follow-up was 10.5 months. All patients had abnormal PPG amplitude (mean, 6.43 mm) at room temperature and increased amplitude (mean, 19.55 mm) after immersion in warm water. All patients (n = 12) with a PPG amplitude increase of 4 mm or greater had clinical success. Eleven of 13 patients had a clinically relevant decrease in pain at 20 minutes after injection. Clinically significant pain relief was sustained for 3 months (visual analog scale decreased by a mean of 4). Median morphine equivalent usage view decreased from 82.5 to 0 after injection. Patient-reported disability (QuickDASH) improved from 49 before treatment to 29 and 26 at 6 weeks and 6 months after BTX-A injection, respectively. Three patients were retreated for recurrent symptoms. Four patients required unplanned secondary procedures. CONCLUSIONS: Botulinum toxin type A administration can result in rapid (within 20 minutes) and sustained pain relief for several months with a reduction in opioid prescriptions. Botulinum toxin type A administration also improved patient-reported disability for 6 months. Use of PPG testing to determine baseline perfusion deficit and capacity to improve after warm water immersion was helpful in consideration of BTX-A use. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

The Ability of Upper Extremity Surgeons to Assess Patient's Functional Status.

PURPOSE: To compare surgeon and patient assessment of upper extremity functional status at the time of initial consultation. We hypothesized that surgeons and patients demonstrate low levels of agreement with respect to assessing pain scores, functional status, and self-efficacy. METHODS: One hundred forty-three consecutive new patients were evaluated by 1 of 5 fellowship-trained upper extremity surgeons. Patients completed a Numeric Pain Rating Scale as well as the Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extremity (UE), Pain Interference (PI), and Self-Efficacy (SE) instruments. Surgeons provided their own estimates of patient function on each questionnaire at the conclusion of the visit and were blinded to the results of the patient-reported outcome measures (PROMs) for the duration of the study. Estimation errors, which represent the absolute value of the difference between the patient's actual score and the surgeon's estimated score on each questionnaire, were calculated for each questionnaire. RESULTS: As a group, surgeons assumed that the PROMIS UE and SE scores were higher than the patients' actual scores and assumed that patients had lower PROMIS PI scores than were actually reported. Mean estimation errors for all PROMIS instruments were greater than 10 points and larger than the SD for these instruments in the general population. CONCLUSIONS: Upper extremity surgeons demonstrate difficulty assessing their patient's self-reported functional status, pain interference, and level of self-efficacy during initial consultations. CLINICAL RELEVANCE: Although formalized PROMs are infrequently administered in orthopedic clinics, increased utilization of these questionnaires would allow for a more accurate baseline functional assessment. When evaluating new patients in the outpatient clinic, surgeons should recognize the potential limitations of their assessments of patient-reported function.

Anatomic total shoulder arthroplasty using a stem-free ellipsoid humeral implant in patients of all ages.

BACKGROUND: Stem-free shoulder arthroplasty has recently been shown to have comparable results to stemmed arthroplasty, though stemless designs are typically used in a younger patient population. Additionally, although the native humeral head is elliptical in shape, clinical results with ellipsoid implants in shoulder arthroplasty have not been reported on previously. This case series reports on the outcomes of a recently introduced anatomic total shoulder arthroplasty with an ellipsoid-shaped articular surface and unique multiplanar platform type of stemless fixation. METHODS: This retrospective case series examines the initial cohort of patients who received an anatomic total shoulder arthroplasty using an ellipsoid stem-free humeral prosthesis and an all-polyethylene glenoid component from the Catalyst CSR Total Shoulder System (Catalyst OrthoScience) over a 1-year period. Inclusion criteria were patients with a diagnosis of advanced glenohumeral joint arthritis with an intact rotator cuff, regardless of patient age. Clinical outcomes including shoulder range of motion and patient-reported outcome measures, as well as radiographs, were evaluated at multiple time points postoperatively, with minimum 2-year follow-up. RESULTS: Sixty-three shoulders in 57 patients with a mean age of 73.0 years (range 60-85 years) were included in the study with a mean follow-up period of 30.5 months (range 24-41 months). Forward elevation improved from 121° to 150° (P < .0001), external rotation improved from 28° to 48° (P < .0001), and internal rotation improved from L3 to L1 (P < .001). There were statistically significant improvements exceeding the minimal clinically important difference (MCID) in the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) score (37 to 94, P < .001), Single Assessment Numeric Evaluation (SANE) (40 to 93, P < .001), visual analog scale (6.3 to 0.4, P < .001), and Patient-Reported Outcomes Measurement Information System physical domain T score (44 to 57, P < .001). The improvement in the ASES score also exceeded the threshold for the substantial clinical benefit. Age, sex, and preoperative glenoid morphology did not appear to have an effect on the clinical outcome scores. There were no implant failures or evidence of radiographic loosening of the humerus component in any patients. CONCLUSION: At 2-year minimum follow-up, this stem-free ellipsoid humerus total shoulder arthroplasty provides very good results with high patient satisfaction, clinical improvement in all outcome measures studied, and no signs of loosening.

Optimization and biological evaluation of thiazole-bis-amide inverse agonists of RORγt.

The nuclear receptor retinoic acid receptor-related orphan receptor gamma t (RORγt) is a transcription factor that drives Th17 cell differentiation and IL-17 production in both innate and adaptive immune cells. The IL-23/IL-17 pathway is implicated in major autoimmune and inflammatory diseases. RORγt lies at the core of this pathway and represents an attractive opportunity for intervention with small molecule therapeutics. Despite diverse chemical series having been reported, combining high potency and nuclear receptor selectivity with good physicochemical properties remains a challenging endeavor in the field of RORγt drug discovery. We recently described the discovery and evaluation of a new class of potent and selective RORγt inverse agonists based on a thiazole scaffold. Herein we describe the successful optimization of this class by incorporation of an additional amide moiety at the 4-position of the thiazole core. In several optimization cycles, we have reduced human PXR activation, improved solubility, and increased potency while maintaining nuclear receptor selectivity. X-ray crystallographic analysis of compound 1g bound in the sterol binding site of the ligand binding domain of RORγt was largely consistent with an earlier structure, guiding further insight into the molecular mechanism for RORγt inhibition with this series. Compound 1g is orally bioavailable, potent in a human whole blood assay and proved to be efficacious in an ex-vivo IL-17A assay, and was selected for preclinical evaluation.

Discovery and optimization of new oxadiazole substituted thiazole RORγt inverse agonists through a bioisosteric amide replacement approach.

Starting from previously identified thiazole-2-carboxamides exemplified by compound 1/6, two new series of RORγt inverse agonists with significantly improved aqueous solubility, ADME parameters and oral PK properties were discovered. These scaffolds were identified from a bioisosteric amide replacement approach. Amongst the variety of heterocycles explored, a 1,3,4-oxadiazole led to compounds with the best overall profile for SAR development and in vivo exploration. In an ex vivo mouse PD model, concentration dependent efficacy was demonstrated and compounds 3/5 and 6/3 were profiled in a 5-day rat tolerability study.

Identification and biological evaluation of thiazole-based inverse agonists of RORγt.

The nuclear receptor retinoic acid receptor-related orphan receptor gamma t (RORγt) is a transcription factor that drives Th17 cell differentiation and IL-17 production in both innate and adaptive immune cells. The IL-23/IL-17 pathway is implicated in major autoimmune and inflammatory diseases. RORγt lies at the core of this pathway and represents an attractive opportunity for intervention with a small molecule. Despite diverse chemical series having been reported, combining high potency and nuclear receptor selectivity with good physicochemical properties remains a challenging endeavor in the field of RORγt drug discovery. We describe the discovery and evaluation of a new class of potent and selective RORγt inverse agonists based on a thiazole core. Acid analog 1j demonstrated oral bioavailability in rats and was potent in a human whole blood assay, suggesting potential utility in treating autoimmune and inflammatory diseases such as psoriasis. X-ray crystallographic data helped to elucidate the molecular mechanism for RORγt inhibition with this series.

A randomized double-blind trial of an interventional device treatment of functional mitral regurgitation in patients with symptomatic congestive heart failure-Trial design of the REDUCE FMR study.

The Carillon Mitral Contour System has been studied in 3 nonrandomized trials in patients with symptomatic congestive heart failure and functional mitral regurgitation. The REDUCE FMR study is a uniquely designed, double-blind trial evaluating the impact of the Carillon device on reducing regurgitant volume, as well as assessing the safety and clinical efficacy of this device. Carillon is a coronary sinus-based indirect annuloplasty device. Eligible patients undergo an invasive venogram to assess coronary sinus vein suitability for the Carillon device. If the venous dimensions are suitable, they are randomized on a 3:1 basis to receive a device or not. Patients and assessors are blinded to the treatment assignment. The primary end point is the difference in regurgitant volume at 1 year between the implanted and nonimplanted groups. Other comparisons include clinical parameters such as heart failure hospitalizations, 6-minute walk test, Kansas City Cardiomyopathy Questionnaire (KCCQ), and other echocardiographic parameters. An exercise echo substudy will also be included.

Attenuation of Cocaine-Induced Conditioned Place Preference and Motor Activity via Cannabinoid CB2 Receptor Agonism and CB1 Receptor Antagonism in Rats.

Background: Studies have shown the involvement of cannabinoid (CB) receptors in the behavioral and neurobiological effects of psychostimulants. Most of these studies have focused on the role of CB1 receptors in the psychostimulant effects of cocaine, while very few have investigated the respective role of CB2 receptors. Further studies are warranted to elucidate the extent of CB receptor involvement in the expression of cocaine-induced effects. Methods: The role of CB1 and CB2 receptors in the rewarding and motor properties of cocaine was assessed in conditioned place preference, conditioned motor activity, and open field activity in rats. Results: The CB1 receptor antagonist rimonabant (3 mg/kg) decreased the acquisition and the expression of conditioned place preference induced by cocaine (20 mg/kg). Rimonabant inhibited cocaine-elicited conditioned motor activity when administered during the expression of cocaine-induced conditioned place preference. Rimonabant decreased ambulatory and vertical activity induced by cocaine. The CB2 receptor agonist JWH-133 (10 mg/kg) decreased the acquisition and the expression of cocaine-induced conditioned place preference. JWH-133 inhibited cocaine-elicited conditioned motor activity when administered during the acquisition and the expression of cocaine-induced conditioned place preference. JWH-133 decreased ambulatory activity and abolished vertical activity induced by cocaine. The effects of JWH-133 on cocaine conditioned and stimulated responses were abolished when the CB2 receptor antagonist/inverse agonist AM630 (5 mg/kg) was preadministered. Conclusions: Cannabinoid CB1 and CB2 receptors modulate cocaine-induced rewarding behavior and appear to have opposite roles in the regulation of cocaine's reinforcing and psychomotor effects.

Biotechnology Based Process for Production of a Disulfide-Bridged Peptide.

A disulfide-bridged peptide drug development candidate contained two oligopeptide chains with 11 and 12 natural amino acids joined by a disulfide bond at the N-terminal end. An efficient biotechnology based process for the production of the disulfide-bridged peptide was developed. Initially, the two individual oligopeptide chains were prepared separately by designing different fusion proteins and expressing them in recombinant E. coli. Enzymatic or chemical cleavage of the two fusion proteins provided the two individual oligopeptide chains which could be conjugated via disulfide bond by conventional chemical reaction to the disulfide-bridged peptide. A novel heterodimeric system to bring the two oligopeptide chains closer and induce disulfide bond formation was designed by taking advantage of the self-assembly of a leucine zipper system. The heterodimeric approach involved designing fusion proteins with the acidic and basic components of the leucine zipper, additional amino acids to optimize interaction between the individual chains, specific cleavage sites, specific tag to ensure separation, and two individual oligopeptide chains. Computer modeling was used to identify the nature and number of amino acid residue to be inserted between the leucine zipper and oligopeptides for optimum interaction. Cloning and expression in rec E. coli, fermentation, followed by cell disruption resulted in the formation of heterodimeric protein with the interchain disulfide bond. Separation of the desired heterodimeric protein, followed by specific cleavage at methionine by cyanogen bromide provided the disulfide-bridged peptide.

Differential effects of presynaptic versus postsynaptic adenosine A2A receptor blockade on Δ9-tetrahydrocannabinol (THC) self-administration in squirrel monkeys.

Different doses of an adenosine A2A receptor antagonist MSX-3 [3,7-dihydro-8-[(1E)-2-(3-ethoxyphenyl)ethenyl]-7 methyl-3-[3-(phosphooxy)propyl-1-(2 propynil)-1H-purine-2,6-dione] were found previously to either decrease or increase self-administration of cannabinoids delta-9-tetrahydrocannabinol (THC) or anandamide in squirrel monkeys. It was hypothesized that the decrease observed with a relatively low dose of MSX-3 was related to blockade of striatal presynaptic A2A receptors that modulate glutamatergic neurotransmission, whereas the increase observed with a higher dose was related to blockade of postsynaptic A2A receptors localized in striatopallidal neurons. This hypothesis was confirmed in the present study by testing the effects of the preferential presynaptic and postsynaptic A2A receptor antagonists SCH-442416 [2-(2-furanyl)-7-[3-(4-methoxyphenyl)propyl]-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] and KW-6002 [(E)-1, 3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione], respectively, in squirrel monkeys trained to intravenously self-administer THC. SCH-442416 produced a significant shift to the right of the THC self-administration dose-response curves, consistent with antagonism of the reinforcing effects of THC. Conversely, KW-6002 produced a significant shift to the left, consistent with potentiation of the reinforcing effects of THC. These results show that selectively blocking presynaptic A2A receptors could provide a new pharmacological approach to the treatment of marijuana dependence and underscore corticostriatal glutamatergic neurotransmission as a possible main mechanism involved in the rewarding effects of THC.

Synbiotics-supplemented amino acid-based formula supports adequate growth in cow's milk allergic infants.

BACKGROUND: Children with cow's milk allergy (CMA) are at risk for inadequate nutritional intake and growth. Dietary management of CMA, therefore, requires diets that are not only hypoallergenic but also support adequate growth in this population. This study assessed growth of CMA infants when using a new amino acid-based formula (AAF) with prebiotics and probiotics (synbiotics) and evaluated its safety in the intended population. METHODS: In a prospective, randomized, double-blind controlled study, full-term infants with diagnosed CMA received either an AAF (control; n = 56) or AAF with synbiotics (oligofructose, long-chain inulin, acidic oligosaccharides, Bifidobacterium breve M-16V) (test; n = 54) for 16 wk. Primary outcome was growth, measured as weight, length and head circumference. Secondary outcomes included allergic symptoms and stool characteristics. RESULTS: Average age (±SD) of infants at inclusion was 4.5 ± 2.4 months. Both formulas equally supported growth according to WHO 2006 growth charts and resulted in similar increases of weight, length and head circumference. At week 16, differences (90% CI) in Z-scores (test-control) were as follows: weight 0.147 (-0.10; 0.39, p = 0.32), length -0.299 (-0.69; 0.09, p = 0.21) and head circumference 0.152 (-0.15; 0.45, p = 0.40). Weight-for-age and length-for-age Z-scores were not significantly different between the test and control groups. Both formulas were well tolerated and reduced allergic symptoms; the number of adverse events was not different between the groups. CONCLUSIONS: This is the first study that shows that an AAF with a specific synbiotic blend, suitable for CMA infants, supports normal growth and growth similar to the AAF without synbiotics. This clinical trial is registered as NCT00664768.

Role of three-dimensional echocardiography in management of acquired intracardiac shunts.

Gerbode defect and sinus of Valsalva aneurysm fistula are congenital and acquired forms of intracardiac shunt. The increasing prevalence of invasive, recurrent cardiovascular procedures cause tissue damage and has led to more iatrogenic and acquired cases of predominantly congenital shunt over time. We report 2 cases of acquired intracardiac fistula precisely defined by Real time three-dimensional transesophageal echocardiography (3DTEE). The first case is a 70-year-old male with Gerbode defect after second aortic valve replacement surgery due to prosthetic valve endocarditis and the other case is a 41-year-old male with sinus of Valsalva aneurysm fistula between aorta and right atrium post subclinical infective endocarditis. Advanced cardiac imaging techniques such as cardiac computerized tomography, MRI and Real time three-dimensional (3D) echocardiography help to precisely detect intracardiac fistula and provide detailed anatomic and physiologic information. The relatively low cost, lack of radiation exposure, portability and guiding characteristic make real time 3DTEE an imaging technique with arguably the most advantages. Surgical repair is the usual treatment for intracardiac shunt, and percutaneous catheter-based closure is a less invasive alternative.

The CINCH-FMR postmarket registry: Real-world long-term outcomes with percutaneous mitral valve repair with the Carillon Mitral Contour System®.

BACKGROUND: The Carillon® Mitral Contour System® has been studied in 4 prospective controlled studies in the treatment of functional mitral regurgitation (FMR) where it has been found to reduce mitral regurgitation, reduce left ventricular and atrial volumes, and be associated with improvements in clinical parameters. AIMS: The CINCH post-market registry is designed to evaluate immediate, mid-term and long-term outcomes from a post-approval study of the Carillon® device evaluated in real-world practice. METHODS: The CINCH post-market registry is a single-arm study of percutaneous mitral annuloplasty with the Carillon device in patients with functional (secondary) mitral regurgitation and symptomatic congestive heart failure when utilized in real-world conditions. Patient selection, echocardiographic hemodynamic measurements, and patient follow-up requirements were performed per standard of care at each institution. RESULTS: A total of 101 patients treated with the Carillon device at 13 sites in Germany were enrolled in the CINCH registry. The mean age was 75 ± 9 years, 57 % were male, and patient presentation included primarily NYHA class III (69 %) with MR grade 3 (68 %). Over 5 years of follow-up, all-cause mortality was 40.1 %, the incidence of HFH was 53.9 %, and the composite outcome of HFH or death was 66.4 %. At each follow-up interval through 5 years, statistically significant reductions in NYHA class (p < 0.05) and MR grade (p < 0.01) were reported. CONCLUSIONS: In this "real world" registry of the Carillon Mitral Contour System, procedural safety and medium-term follow-up outcomes is similar to the outcomes seen in the prospective, controlled clinical trials, despite being used in populations of patients that extend outside of those studied in the trials. The use of this therapy in patients with atrial functional mitral regurgitation, and heart failure with preserved ejection fraction, was notable, since these types of patients were excluded from the prospective, controlled trials. This supports possible additional patient populations who might benefit from this type of mechanical therapy. The safety profile of this therapy in this registry and in the earlier trials may support a potential role in earlier forms of secondary mitral regurgitation.

CREB phosphorylation regulates striatal transcriptional responses in the self-administration model of methamphetamine addiction in the rat.

Neuroplastic changes in the dorsal striatum participate in the transition from casual to habitual drug use and might play a critical role in the development of methamphetamine (METH) addiction. We examined the influence of METH self-administration on gene and protein expression that may form substrates for METH-induced neuronal plasticity in the dorsal striatum. Male Sprague-Dawley rats self-administered METH (0.1mg/kg/injection, i.v.) or received yoked saline infusions during eight 15-h sessions and were euthanized 2h, 24h, or 1month after cessation of METH exposure. Changes in gene and protein expression were assessed using microarray analysis, RT-PCR and Western blots. Chromatin immunoprecipitation (ChIP) followed by PCR was used to examine epigenetic regulation of METH-induced transcription. METH self-administration caused increases in mRNA expression of the transcription factors, c-fos and fosb, the neurotrophic factor, Bdnf, and the synaptic protein, synaptophysin (Syp) in the dorsal striatum. METH also caused changes in ΔFosB, BDNF and TrkB protein levels, with increases after 2 and 24h, but decreases after 1month of drug abstinence. Importantly, ChIP-PCR showed that METH self-administration caused enrichment of phosphorylated CREB (pCREB), but not of histone H3 trimethylated at lysine 4 (H3K4me3), on promoters of c-fos, fosb, Bdnf and Syp at 2h after cessation of drug intake. These findings show that METH-induced changes in gene expression are mediated, in part, by pCREB-dependent epigenetic phenomena. Thus, METH self-administration might trigger epigenetic changes that mediate alterations in expression of genes and proteins serving as substrates for addiction-related synaptic plasticity.

Modification of pharmacokinetic and abuse-related effects of cocaine by human-derived cocaine hydrolase in monkeys.

Although substantial research effort has focused on developing pharmacological treatments for cocaine abuse, no effective medications have been developed. Recent studies show that enzymes that metabolize cocaine in the periphery, forestalling its entry into the brain, can prevent cocaine toxicity and its behavioral effects in rodents. Here we report on effects of one such enzyme (Albu-CocH) on the pharmacokinetic and behavioral effects of cocaine in squirrel monkeys. Albu-CocH was developed from successive mutations of human butyrylcholinesterase (BChE) and has 1000-fold greater catalytic activity against cocaine than naturally occurring BChE. Pharmacokinetic studies showed that Albu-CocH (5 mg/kg) had a half-life of 56.6 hours in squirrel monkeys. In these studies, plasma levels of cocaine following i.v. 1 mg/kg cocaine were reduced 2 hours after administration of Albu-CocH, whereas plasma levels of the cocaine metabolite ecgonine methyl ester were increased. These effects were still evident 72 hours following Albu-CocH administration. In behavioral experiments in monkeys, pre-treatment with 5 mg/kg Albu-CocH dramatically decreased self-administration of a reinforcing dose of i.v. cocaine (30 µg/kg/injection) for over 24 hours. Pre-treatment with 5 mg/kg Albu-CocH also attenuated the reinstatement of extinguished cocaine self-administration by an i.v. priming injection of cocaine (0.1 or 0.3 mg/kg) and, in separate studies, attenuated the discriminative-stimulus effects of cocaine. The ability of Albu-CocH to attenuate the abuse-related effects of cocaine in squirrel monkeys indicates that further investigation of BChE mutants as potential treatment for cocaine abuse and toxicity is warranted.

Improving teamwork, confidence, and collaboration among members of a pediatric cardiovascular intensive care unit multidisciplinary team using simulation-based team training.

Findings show that simulation-based team training (SBTT) is effective at increasing teamwork skills. Postpediatric cardiac surgery cardiac arrest (PPCS-CA) is a high-risk clinical situation with high morbidity and mortality. Whereas adult guidelines managing cardiac arrest after cardiac surgery are available, little exists for pediatric cardiac surgery. The authors developed a post-PPCS-CA algorithm and used SBTT to improve identification and management of PPCS-CA in the pediatric cardiovascular intensive care unit. Their goal was to determine whether participation aids in improving teamwork, confidence, and communication during these events. The authors developed a simulation-based training course using common postcardiac surgical emergency scenarios with specific learning objectives. Simulated scenarios are followed by structured debriefings. Participants were evaluated based on critical performance criteria, key elements in the PPCS-CA algorithm, and Team Strategies and Tools to Enhance Performance and Patient Safety (Team STEPPS) principles. Surveys performed before, immediately after, and 3 months after participation evaluated perception of skill, knowledge, and confidence. The study had 37 participants (23 nurses, 5 cardiology/critical care trainees, 5 respiratory therapists, and 4 noncategorized subjects). Confidence and skill in the roles of team leader, advanced airway management, and cardioversion/defibrillation were increased significantly (p < 0.05) immediately after training and 3 months later. A significant increase (p < 0.05) also was observed in the use of Team STEPPS concepts immediately after training and 3 months later. This study showed SBTT to be effective in improving communication and increasing confidence among members of a multidisciplinary team during crisis scenarios. Thus, SBTT provides an excellent tool for teaching and implementing new processes.

Chemistry and containing: the analyst's use of unavoidable failures.

Certain patients overwhelm the analyst's capacity to contain both the patient and the analyst's own unbearable feelings. Though some such failures of containing may lead fairly quickly to self-correction and others to clinical impasse, our focus is on an in-between state in which the analyst's ability to tolerate his inevitable failures and gradually to (re)establish his containing capacities through difficult self-analytic work can lead to significant change that might not otherwise be possible. The authors argue that this internal psychological work on the analyst's part, which may require considerable time, effort, and suffering, is an important aspect of "good enough" containing. The unique chemistry generated between patient and analyst plays an important role in both establishing and maintaining this kind of productive analytic process.