Evaluating the effects of herbicide drift on nontarget terrestrial plants: A case study with mesotrione.

Nature of exposure is a fundamental driver in nontarget terrestrial plant risk assessment for pesticides; consequently a novel study was designed to generate field-based drift exposure and evaluate corresponding biological effects of the herbicide mesotrione. The approach used a combination of US guideline drift reduction technology and vegetative vigor approaches. In each of 3 independent replicate spray application trials, 10 pots each of lettuce and tomato were placed at distances of 10, 20, 30, 40, and 50 ft (∼3, 6, 9, 12, and 15 m) from the downwind edge of the spray boom. Each application was conducted using a commercial 60-ft (18-m) boom sprayer fitted with TeeJet® Technologies TTI110025 nozzles, with a nominal application rate of 0.2 lb a.i./A (224 g a.i./ha). The environmental conditions required by the protocol (air temperature 10-30 °C and wind perpendicular to the swath (±30°) blowing toward the plants at a mean wind speed of ≥10 mph [≥4.5 m/s] measured at 2.0 m above the ground) were met for each application. Following exposure, plants were transferred to a greenhouse for the 21-d vegetative vigor phase of the study. Symptoms of phytotoxicity and plant height were assessed at 7, 14, and 21 d after treatment. On completion of the 21-d after treatment assessment, all plants were harvested and dried in an oven to determine shoot dry weight. The biological data indicated that no statistically significant effects were observed at a distance of 30 ft (∼9 m) from mesotrione drift at wind speeds of ≥10 mph (10.9-12.4 mph); this endpoint (30 ft) is defined as the no observed effects distance (NOED). Environ Toxicol Chem 2017;36:2465-2475. © 2017 SETAC.

Monitoring the effects of thiamethoxam applied as a seed treatment to winter oilseed rape on the development of bumblebee (Bombus terrestris) colonies.

BACKGROUND: The development of bumblebee (Bombus terrestris audax) colonies that had foraged for 5 weeks on flowering winter oilseed rape grown from seed treated with thiamethoxam (as Cruiser OSR) was assessed (two control, one treated field). Colony development was evaluated by monitoring the colony mass, forager activity was assessed, both at the hive and within the crop, and the contribution of oilseed rape to the pollen stored within the colony was analysed. RESULTS: Pollen collected from the treated crop contained residues of 1.0 µg thiamethoxam kg(-1) and 3.0 µg CGA322704 (metabolite likely equivalent to clothiandin) kg(-1) , and nectar contained residues of 1.8 µg thiamethoxam kg(-1) and no metabolite. No residues of thiamethoxam or CGA322704 were detected in samples from the control fields. Up to 93% of bumblebee collected pollen sampled from within the colonies originated from oilseed rape, and B. terrestris were observed actively foraging on all the fields. Colonies on all three fields showed similar rates of mass gain during the exposure phase and comparable production of gynes and drones. CONCLUSIONS: B. terrestris colonies placed adjacent to a field of flowering oilseed rape grown from thiamethoxam-treated seed developed at a comparable rate with colonies placed adjacent to oilseed rape grown from untreated seed. © 2015 Society of Chemical Industry.

Return to driving after total knee arthroplasty.

OBJECTIVE: The aim of this study was to ascertain the duration from time of surgery to resumption of driving after total knee arthroplasty (TKA) and to examine recommendations in the literature. METHODS: All patients who underwent primary unilateral TKA and were driving within 6 months preceding the arthroplasty were included. The patients' age, gender and side of the TKA were noted. The time taken to resume driving by each patient as well as the type of vehicle were noted. RESULTS: Ninety-eight patients were included in our survey. Fifty-five patients (56%) underwent TKA on their left knee and 94 (96%) were manual car drivers. Seventy-seven patients (79%) were able to resume driving within 6 weeks of TKA; 18 patients (18%) were able to do so at Week 12 postoperatively. The remaining 3 patients (3%) did not feel confident enough to drive at Week 12 postoperatively. No patient reported deterioration in driving ability, whereas 27 patients (27%) felt a subjective improvement in their driving ability. CONCLUSION: The vast majority of patient resumed driving by 6 weeks postoperatively. Only a small number did not return to regular driving. Patients are advised to resume driving after 6 weeks but should wait until they feel comfortable and confident enough to do so.

Ulnohumeral debridement arthroplasty: a retrospective study and midterm outcome results.

INTRODUCTION: Osteoarthritis of the elbow (OA) is an uncommon entity. In most cases, it can be attributed to long-standing occupational stress, previous injury, loose bodies in the joint. Patients complain of pain and stiffness at the extremes of movements. This can be caused by degenerative changes at the radio-capitellar, ulnohumeral joint or due to ulnar nerve symptoms. We perform the Outerbridge-Kashiwagi (OK) procedure at our institution for the management of problematic primary elbow osteoarthritis. OBJECTIVES: The purpose of this retrospective study was to evaluate the outcome of ulnohumeral arthroplasty in 13 elbows which was done over a period of 6 years in our institution. Range of movement (ROM) and pain were measured, and X-rays were assessed. METHODS: Thirteen patients who underwent ulnohumeral arthroplasty between 2006 and 2012 were included in the study. There were 11 males and 2 females with an average age of 54 years (35-78), with a mean follow-up of 4 years. RESULTS: The pain score improved from 8 (6-10) to 2 (0-2) using the visual analogue scale. Eleven patients were completely pain-free. There was an improvement of 27° in the flexion extension arc. There were no complications. CONCLUSIONS: Ulnohumeral arthroplasty can yield good pain relief and moderate improvement in the range of movement. It is a relatively easy and safe procedure to perform in patients with primary degenerative osteoarthritis of the elbow.

Obliteration of the medullary canal in an atypical bisphosphonate-related femoral fracture.

We present a case of a patient with a bisphosphonate-related atypical femoral fracture. Her surgical management was complicated by obliteration of the medullary canal, which prohibited the passage of an intramedullary nail. The relevant literature is discussed.

Unfolded Protein Response in Cancer: IRE1α Inhibition by Selective Kinase Ligands Does Not Impair Tumor Cell Viability.

The kinase/endonuclease inositol requiring enzyme 1 (IRE1α), one of the sensors of unfolded protein accumulation in the endoplasmic reticulum that triggers the unfolded protein response (UPR), has been investigated as an anticancer target. We identified potent allosteric inhibitors of IRE1α endonuclease activity that bound to the kinase site on the enzyme. Structure-activity relationship (SAR) studies led to 16 and 18, which were selective in kinase screens and were potent against recombinant IRE1α endonuclease as well as cellular IRE1α. The first X-ray crystal structure of a kinase inhibitor (16) bound to hIRE1α was obtained. Screening of native tumor cell lines (>300) against selective IRE1α inhibitors failed to demonstrate any effect on cellular viability. These results suggest that IRE1α activity is not essential for viability in most tumor cell lines, in vitro, and that interfering with the survival functions of the UPR may not be an effective strategy to block tumorigenesis.

Discovery of clinical candidate 1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone (AMG 579), a potent, selective, and efficacious inhibitor of phosphodiesterase 10A (PDE10A).

We report the identification of a PDE10A clinical candidate by optimizing potency and in vivo efficacy of promising keto-benzimidazole leads 1 and 2. Significant increase in biochemical potency was observed when the saturated rings on morpholine 1 and N-acetyl piperazine 2 were changed by a single atom to tetrahydropyran 3 and N-acetyl piperidine 5. A second single atom modification from pyrazines 3 and 5 to pyridines 4 and 6 improved the inhibitory activity of 4 but not 6. In the in vivo LC-MS/MS target occupancy (TO) study at 10 mg/kg, 3, 5, and 6 achieved 86-91% occupancy of PDE10A in the brain. Furthermore, both CNS TO and efficacy in PCP-LMA behavioral model were observed in a dose dependent manner. With superior in vivo TO, in vivo efficacy and in vivo PK profiles in multiple preclinical species, compound 5 (AMG 579) was advanced as our PDE10A clinical candidate.

Delayed and Prolonged Histone Hyperacetylation with a Selective HDAC1/HDAC2 Inhibitor.

The identification and in vitro and in vivo characterization of a potent SHI-1:2 are described. Kinetic analysis indicated that biaryl inhibitors exhibit slow binding kinetics in isolated HDAC1 and HDAC2 preparations. Delayed histone hyperacetylation and gene expression changes were also observed in cell culture, and histone acetylation was observed in vivo beyond disappearance of drug from plasma. In vivo studies further demonstrated that continuous target inhibition was well tolerated and efficacious in tumor-bearing mice, leading to tumor growth inhibition with either once-daily or intermittent administration.

Neonicotinoid concentrations in arable soils after seed treatment applications in preceding years.

BACKGROUND: Concentrations of the neonicotinoid insecticides clothianidin, thiamethoxam and imidacloprid were determined in arable soils from a variety of locations in England. RESULTS: In soil samples taken from the central area of fields, concentrations of clothianidin ranged from 0.02 to 13.6 µg kg(-1) . Thiamethoxam concentrations were between <0.02 and 1.50 µg kg(-1) , and imidacloprid concentrations between <0.09 and 10.7 µg kg(-1) . Concentrations of clothianidin and thiamethoxam were lower in soil samples taken from the edges of fields than from the centres of fields, but this difference was less pronounced for imidacloprid. CONCLUSION: This work gives a clear indication of the levels of neonicotinoids in arable soils after typical use of these compounds as seed dressings in the United Kingdom. There was evidence that imidacloprid was more persistent in the soils studied than clothianidin and thiamethoxam. As clothianidin and thiamethoxam have largely superseded imidacloprid in the United Kingdom, neonicotinoid levels were lower than suggested by predictions based on imidacloprid alone.

The modified Brunelli procedure for scapholunate instability: a single centre study.

Management of scapholunate (SL) instability remains controversial. The modified Brunelli procedure is a soft tissue procedure that recreates the stabilising forces of the SL ligament using a split flexor carpi radialis tendon graft passed from volar to dorsal via a tunnel in the distal pole of the scaphoid. Thirteen consecutive patients with an average age of 35 years underwent the modified Brunelli procedure. Pain improved from a mean visual analog score of eight preoperatively to 1.5. The DASH score improved from a preoperative score of 55.4 to 34.9 as did the grip strength from 40% to 75% respectively. All wrist ranges of motion were decreased post-operatively in particular wrist flexion. SL ligament reconstruction using the modified Brunelli procedure resulted in satisfactory outcomes. Post-operatively patients were relatively pain free, with improved grip strength. The range of motion was reduced postoperatively, however did not restrict return to work or premorbid activities.

Divergent kinetics differentiate the mechanism of action of two HDAC inhibitors.

Histone deacetylases (HDACs) play diverse roles in many diseases including cancer, sarcopenia, and Alzheimer's. Different isoforms of HDACs appear to play disparate roles in the cell and are associated with specific diseases; as such, a substantial effort has been made to develop isoform-selective HDAC inhibitors. Our group focused on developing HDAC1/HDAC2-specific inhibitors as a cancer therapeutic. In the course of characterizing the mechanism of inhibition of a novel HDAC1/2-selective inhibitor, it was determined that it did not exhibit classical Michaelis-Menten kinetic behavior; this result is in contrast to the seminal HDAC inhibitor SAHA. Enzymatic assays, along with a newly developed binding assay, were used to determine the rates of binding and the affinities of both the HDAC1/2-selective inhibitor and SAHA. The mechanism of action studies identified a potential conformational change required for optimal binding by the selective inhibitor. A model of this putative conformational change is proposed.

Metabolism-guided discovery of a potent and orally bioavailable urea-based calcimimetic for the treatment of secondary hyperparathyroidism.

A series of urea based calcimimetics was optimized for potency and oral bioavailability. Crucial to this process was overcoming the poor pharmacokinetic properties of lead thiazole 1. Metabolism-guided modifications, characterized by the use of metabolite identification (ID) and measurement of time dependent inhibition (TDI) of CYP3A4, were essential to finding a compound suitable for oral dosing. Calcimimetic 18 exhibited excellent in vivo potency in a 5/6 nephrectomized rat model and cross-species pharmacokinetics.

The optimization of aminooxadiazoles as orally active inhibitors of Cdc7.

A series of aminooxadiazoles was optimized for inhibition of Cdc7. Early lead isoquinoline 1 suffered from modest cell potency (cellular IC50=0.71 µM measuring pMCM2), low selectivity against structurally related kinases, and high IV clearance in rats (CL=18 L/h/kg). Extensive optimization resulted in azaindole 26 (Cdc7 IC50=1.1 nM, pMCM2 IC50=32 nM) that demonstrated robust lowering of pMCM2 in a mouse pharmacodynamic (PD) model when dosed orally. Modifications to improve the pharmacokinetic profile of this series were guided by trapping experiments with glutathione in rat hepatocytes.

Acute ulnar shortening for delayed presentation of distal radius growth arrest in an adolescent.

Distal radius physeal fractures are common in children and adolescents. However, posttraumatic growth arrest is uncommon. The management of posttraumatic growth arrest is dependent on the severity of the deformity and the remaining growth potential of the patient. Various treatment options exist. We present a 17-year-old male with distal radius growth arrest who presented four years after the initial injury. He had a symptomatic 15 mm positive ulnar variance managed with an ulnar shortening osteotomy with the use of the AO mini distractor intraoperatively. To the best of our knowledge, an acute ulnar shortening of 15 mm is the largest reported.

Functional Outcome after Simultaneous Bilateral Four-Part Proximal Humerus Fracture: A Comparison of ORIF and Hemiarthroplasty in an Individual Patient.

Simultaneous bilateral four-part proximal humeral fractures are rare. Four-part fractures of the proximal humerus are difficult for the patient and technically demanding for the surgeon. Our surgical tactic is to attempt open reduction and internal fixation where possible. We report the functional outcome in a 56-year-old female who sustained simultaneous bilateral four-part proximal humeral fractures after falling down a flight of stairs. Open reduction and internal fixation using threaded pins and tension band suture was performed on one side, and shoulder replacement hemiarthroplasty was required on the other. Functional assessment was undertaken at two years after surgery, using the Oxford Shoulder Score. Although the objective outcomes assessment revealed little difference, the patient herself expressed a preference for the side treated by internal fixation. We conclude that an attempt to retain the native humeral head and the surgical tactic that favours internal fixation where possible is appropriate in these injuries. Excellent function can be achieved following hemiarthroplasty for trauma in a fit patient.

Isoform-selective thiazolo[5,4-b]pyridine S1P1 agonists possessing acyclic amino carboxylate head-groups.

Replacement of the azetidine carboxylate of an S1P(1) agonist development candidate, AMG 369, with a range of acyclic head-groups led to the identification of a novel, S1P(3)-sparing S1P(1) agonist, (-)-2-amino-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-2-methylbutanoic acid (8c), which possessed good in vivo efficacy and pharmacokinetic properties. A 0.3mg/kg oral dose of 8c produced a statistically significant reduction in blood lymphocyte counts 24h post-dosing in female Lewis rats.

Optimization of a Potent, Orally Active S1P1 Agonist Containing a Quinolinone Core.

The optimization of a series of S1P1 agonists with limited activity against S1P3 is reported. A polar headgroup was used to improve the physicochemical and pharmacokinetic parameters of lead quinolinone 6. When dosed orally at 1 and 3 mg/kg, the azahydroxymethyl analogue 22 achieved statistically significant lowering of circulating blood lymphocytes 24 h postdose. In rats, a dose-proportional increase in exposure was measured when 22 was dosed orally at 2 and 100 mg/kg.

Quinolinone-based agonists of S1P1: use of a N-scan SAR strategy to optimize in vitro and in vivo activity.

We reveal how a N-scan SAR strategy (systematic substitution of each CH group with a N atom) was employed for quinolinone-based S1P(1) agonist 5 to modulate physicochemical properties and optimize in vitro and in vivo activity. The diaza-analog 17 displays improved potency (hS1P(1) RI; 17: EC(50)=0.020 µM, 120% efficacy; 5: EC(50)=0.070 µM, 110% efficacy) and selectivity (hS1P(3) Ca(2+) flux; 17: EC(50) >25 µM; 5: EC(50)=1.5 µM, 92% efficacy), as well as enhanced pharmacokinetics (17: CL=0.15 L/h/kg, V(dss)=5.1L/kg, T(1/2)=24h, %F=110; 5: CL=0.93L/h/kg, V(dss)=11L/kg, T(1/2)=15 h, %F=60) and pharmacodynamics (17: 1.0mg/kg po, 24h PLC POC=-67%; 5: 3mg/kg po, 24h PLC POC=-51%) in rat.

Evidence-based practice implementation strategy: the central role of the clinical nurse specialist.

The Hospital of the University of Pennsylvania Model of Excellence in Nursing Professional Practice serves to fully integrate the role of the clinical nurse specialist (CNS) in the implementation of evidence-based care and the role of organizational change agent. In this role, the CNS is responsible for the identification and remedy of system-wide challenges to optimal quality care, mentorship of clinical nurses both as clinicians and as leaders, and enhancement of interdisciplinary partnerships. Integrating the CNS role as the nursing department knowledge keepers, knowledge seekers and knowledge disseminators able to proactively develop and enhance interdisciplinary partnerships required systematic educational sessions and use of outcome measurement tools. Resources have included role development seminars, individual mentoring and standardization of role expression, across service lines. Development and implementation of an outcome measurement tool has served to further quantify the contribution of the CNS and standardized role implementation across service divisions. This dedication of resources has resulted in a significant number of unit-based and system-wide CNSs, serving as a significant support to the clinical nurse's practice and leadership development. This article will describe some of the processes used to enhance the role of the CNS implementing change and practice improvement at the Hospital of the University of Pennsylvania.