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A projected shortage of hematopoietic cell transplantation (HCT) health professionals was identified as a major issue during the National Marrow Donor Program/Be The Match System Capacity Initiative. Work-related distress and work-life balance were noted to be potential barriers to recruitment/retention. This study examined these barriers and their association with career satisfaction across HCT disciplines. A cross-sectional, 90-item, web-based survey was administered to advanced practice providers, nurses, physicians, pharmacists, and social workers in 2015. Participants were recruited from membership lists of 6 professional groups. Burnout (measured with the Maslach Burnout Inventory subscales of emotional exhaustion and depersonalization) and moral distress (measured by Moral Distress Scale-Revised) were examined to identify work-related distress. Additional questions addressed demographics, work-life balance, and career satisfaction. Of 5759 HCT providers who received an individualized invitation to participate, 914 (16%) responded; 627 additional participants responded to an open link survey. Significant differences in demographic and practice characteristics existed across disciplines (P < .05). The prevalence of burnout differed across disciplines (P < .05) with an overall prevalence of 40%. Over one-half of pharmacists had burnout, whereas social workers had the lowest prevalence at less than one-third. Moral distress scores ranged from 0 to 336 and varied by discipline (P < .05); pharmacists had the highest mean score (62.9 ± 34.8) and social workers the lowest (42.7 ± 24.4). In multivariate and univariate analyses, variables contributing to burnout varied by discipline; however, moral distress was a significant contributing factor for all providers. Those with burnout were more likely to report inadequate work-life balance and a low level of career satisfaction; however, overall there was a high level of career satisfaction across disciplines. Burnout, moral distress, and inadequate work-life balance existed at a variable rate in all HCT disciplines, yet career satisfaction was high. These results suggest specific areas to address in the work environment for HCT health professionals, especially the need for relief of moral distress and a greater degree of personal time. As the creation of healthy work environments is increasingly emphasized to improve quality care and decrease costs, these findings should be used by HCT leadership to develop interventions that mitigate work-related distress and in turn foster recruitment and retention of HCT providers., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The NPY5 receptor binding and pharmacokinetic properties of a novel series of cis-1-oxo-heterocyclyl-4-amido-cyclohexane derivatives are described., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The effect of using small-scale, high surface area, nanoparticles to supplement polymer-conditioned wastewater sludge dewatering was investigated. Aerobically digested sludge and waste activated sludge sourced from the Hunter Valley, NSW, Australia, were tested with titanium dioxide nanoparticles. The sludge samples were dosed with the nanoparticles in an attempt to adsorb a component of the charged biopolymer surfactants present naturally in sludge. The sludge was conditioned with a cationic polymer. The dewatering characteristics were assessed by measuring the specific resistance to filtration through a modified time-to-filter testing apparatus. The solids content of the dosed samples was determined by a mass balance and compared to the original solids content in the activated sludge. Test results indicated that nanoparticle addition modified the structure of the sludge and provided benefits in terms of the dewatering rate. The samples dosed with nanoparticles exhibited faster water removal, indicating a more permeable filter cake and hence more permeable sludge. A concentration of 2-4% nanoparticles was required to achieve a noticeable benefit. As a comparison, the sludge samples were also tested with a larger particle size, powdered activated carbon (PAC). It was found that the PAC did provide some minor benefits to sludge dewatering but was outperformed by the nanoparticles. The solids content of the final sludge was increased by a maximum of up to 0.6%. The impact of the order sequence of particles and polymer was also investigated. It was found that nanoparticles added before polymer addition provided the best dewatering performance. This outcome was consistent with current theories and previous research through the literature. An economic analysis was undertaken to confirm the viability of the technology for implementation at a full-scale plant. It was found that, currently, this technology is unlikely to be favourable unless the nanoparticles can be sourced for a low cost.

1-[2-(2,4-Dimethylphenyl-sulfanyl)-phenyl]-piperazine (Lu AA21004) is a human (h) serotonin (5-HT)(3A) receptor antagonist (K(i) = 3.7 nM), h5-HT(7) receptor antagonist (K(i) = 19 nM), h5-HT(1B) receptor partial agonist (K(i) = 33 nM), h5-HT(1A) receptor agonist (K(i) = 15 nM), and a human 5-HT transporter (SERT) inhibitor (K(i) = 1.6 nM) (J Med Chem 54:3206-3221, 2011). Here, we confirm that Lu AA21004 is a partial h5-HT(1B) receptor agonist [EC(50) = 460 nM, intrinsic activity = 22%] using a whole-cell cAMP-based assay and demonstrate that Lu AA21004 is a rat (r) 5-HT(7) receptor antagonist (K(i) = 200 nM and IC(50) = 2080 nM). In vivo, Lu AA21004 occupies the r5-HT(1B) receptor and rSERT (ED(50) = 3.2 and 0.4 mg/kg, respectively) after subcutaneous administration and is a 5-HT(3) receptor antagonist in the Bezold-Jarisch reflex assay (ED(50) = 0.11 mg/kg s.c.). In rat microdialysis experiments, Lu AA21004 (2.5-10.0 mg/kg s.c.) increased extracellular 5-HT, dopamine, and noradrenaline in the medial prefrontal cortex and ventral hippocampus. Lu AA21004 (5 mg/kg per day for 3 days; minipump subcutaneously), corresponding to 41% rSERT occupancy, significantly increased extracellular 5-HT in the ventral hippocampus. Furthermore, the 5-HT(3) receptor antagonist, ondansetron, potentiated the increase in extracellular levels of 5-HT induced by citalopram. Lu AA21004 has antidepressant- and anxiolytic-like effects in the rat forced swim (Flinders Sensitive Line) and social interaction and conditioned fear tests (minimal effective doses: 7.8, 2.0, and 3.9 mg/kg). In conclusion, Lu AA21004 mediates its pharmacological effects via two pharmacological modalities: SERT inhibition and 5-HT receptor modulation. In vivo, this results in enhanced release of several neurotransmitters and antidepressant- and anxiolytic-like profiles at doses for which targets in addition to the SERT are occupied. The multimodal activity profile of Lu AA21004 is distinct from that of current antidepressants.

Subtype specific ligands are needed to evaluate the therapeutic potential of modulating the brain's neuropeptide Y system. The benzothiazepine glycinamide 1a was identified as an NPY5 antagonist lead. While having acceptable solubility, the compound was found to suffer from high clearance and poor exposure. Optimization efforts are described targeting improvements in potency, microsomal stability, and PK properties. The low microsomal stability and poor PK properties were addressed through the optimization of the sulfonyl urea and replacement of the benzothiazepinone with other N-heteroaryl glycinamides. For example, the analogous benzoxazine glycinamide 2e has improvements in both affinity (human Y5 K(i) 4 nM vs 1a 27 nM) and microsomal stability (human CL(int) 2.5 L/min vs 1a 35L/min). However the brain penetration (B/P 43/430 nM at 10 mg/kg PO) remained an unresolved issue. Further optimization by decreasing the hydrogen bond donating properties and PSA provided potent and brain penetrant NPY5 antagonists such as 5f (human Y5 K(i) 9 nM, B/P 520/840 nM 10 mg/kg PO)., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The human serotonin transporter (hSERT) has primary and allosteric binding sites for escitalopram and R-citalopram. Previous studies have established that the interaction of these two compounds at a low affinity allosteric binding site of hSERT can affect the dissociation of [(3)H]escitalopram from hSERT. The allosteric binding site involves a series of residues in the 10th, 11th, and 12th trans-membrane domains of hSERT. The low affinity allosteric activities of escitalopram and R-citalopram are essentially eliminated in a mutant hSERT with changes in some of these residues, namely A505V, L506F, I507L, S574T, I575T, as measured in dissociation binding studies. We confirm that in association binding experiments, R-citalopram at clinically relevant concentrations reduces the association rate of [(3)H]escitalopram as a ligand to wild type hSERT. We demonstrate that the ability of R-citalopram to reduce the association rate of escitalopram is also abolished in the mutant hSERT (A505V, L506F, I507L, S574T, I575T), along with the expected disruption the low affinity allosteric function on dissociation binding. This suggests that the allosteric binding site mediates both the low affinity and higher affinity interactions between R-citalopram, escitalopram, and hSERT. Our data add an additional structural basis for the different efficacies of escitalopram compared to racemic citalopram reported in animal studies and clinical trials, and substantiate the hypothesis that hSERT has complex allosteric mechanisms underlying the unexplained in vivo activities of its inhibitors.

The authors report the results of a retrospective review of patients who underwent nasal transposition of the vertical rectus muscles between 1997 and 2004. Eight patients were identified, 4 males and 4 females. There was an average age at surgery of 37 years, with a range from 8 to 79 years. The aetiologies included 6 patients with trauma to their medial rectus (4 following endoscopic sinus surgery) and 2 patients with paralytic medial rectus muscles secondary to 3rd nerve palsy. All patients underwent whole tendon transposition of the superior and inferior rectus muscles, with resection of both muscles in 7 cases, before reattachment adjacent to the upper and lower borders of the medial rectus, respectively. One patient had a reduced amount of resection and this was combined with inferior oblique disinsertion and traction sutures. All patients had a reduction in deviation in the primary position and in 5 patients there was some improvement in adduction. A consequence of surgery was a degree of limitation of abduction, elevation and depression in some patients. Overall, patients were satisfied with the improvement in their appearance.

Introduction: Four muscle surgery for congenital nystagmus was originally described in 1956 and popularized by two articles in the 1990s. A review of the literature revealed only three studies of seven, nine, and six patients published since then. We therefore reviewed our patients to determine the objective and subjective benefits of this procedure., Methods: A retrospective review was carried out on patients who underwent bilateral maximal horizontal muscle recessions for congenital nystagmus between 1997 and 2002. Improvement in visual acuity was documented. An external assessor administered an anonymized questionnaire to discover any perceived benefit. Eighteen patients were identified, 12 men and 6 women, with an average age at surgery of 32 years., Results: Preoperative visual acuity ranged from 6/9 binocularly to 6/60. All underwent bilateral medial rectus muscle recessions of 8 mm to 10 mm and bilateral lateral rectus muscle recessions of 8 mm to 12 mm. Nine patients (50%) gained one line of Snellen visual acuity. There were four complications: one scleral perforation; two developed exotropia; and one complained of asthenopic symptoms. This latter patient was the only one who experienced some deterioration of vision acuity. Fourteen of 18 (78%) questionnaires were returned. Eight patients said they were pleased; four were indifferent and two were displeased., Conclusions: We conclude that this operation delivers limited objective benefit. None of our patients were able to obtain a driving license. Fifty-seven percent of patients expressed the view that they were glad to have had the surgery, although the visual improvement was only slight.

Damage to the occipital lobe of the brain results in hemianopia when unilateral, and cerebral blindness when bilateral. However, in some cases a degree of visual function persists in the blind visual field. This aim of this study was to describe this phenomenon of 'blindsight' in a cohort of children with brain-damage and to relate the clinical features to their visual evoked potentials. We performed a retrospective analysis of 541 case records of children referred to a tertiary vision-assessment clinic in the Royal Hospital for Sick Children, Glasgow, UK from 1992 to 2002. A total of 541 patients were analyzed (243 females, 298 males; age range 2 mo to 19 y 6 mo, mean 6 y 2 mo). In 19 children with profound visual impairment and four children with hemianopia (12 females, 11 males; age range 1 to 18 y, mean age 8 y 3 mo), evidence of perception of movement in the blind visual field was found and is described. Flash visual evoked potentials varied from no response to normal and was not correlated with visual behaviour. Recognition, detection, and use of this phenomenon in children is vital to their rehabilitation and interaction with their surroundings.

The exact mechanisms of deposition and accumulation of amyloid in senile plaques and in blood vessels in Alzheimer's disease remain unknown. Heparan sulfate proteoglycans may play an important role in amyloid deposition in Alzheimer's disease. Previous investigations have demonstrated high affinity binding between heparan sulfate proteoglycans and the amyloid precursor, as well as with the A4 peptide. In the current studies, a specific vascular heparan sulfate proteoglycan found in senile plaques bound with high affinity to two amyloid protein precursors (APP695 and APP770). Vascular heparan sulfate proteoglycan also bound the Alzheimer's amyloid A4 peptide, and not other amyloid protein precursor regions studied, with high affinity. Both heparan sulfate glycosaminoglycan chains and chemically deglycosylated vascular heparan sulfate proteoglycan protein core bound to A4. High affinity interactions between vascular heparan sulfate proteoglycan and the A4 peptide may play a role in the process of amyloidogenesis in Alzheimer's disease, by localizing the site of deposition of A4, protecting A4 from further proteolysis, or by promoting aggregation and fibril formation.

A modification of a method for the detection of proteoglycans on positively charged nylon was adapted for use in a dot-blot assay and improved. Different dot-blot membranes were tested and variations in the Alcian blue staining solution (including pH, critical electrolyte concentration, and ionic strength) were explored. With modifications, we were able to eliminate interferences by other polyanions such as DNA or proteins. We were able to detect glycosaminoglycans and proteoglycans down to the 10 ng range. Furthermore, our assay is compatible with high concentration of urea (up to 7 M) used in classic proteoglycans extraction methods and is a useful tool to monitor the isolation of proteoglycans by anion exchange and gel filtration chromatography. It is technically easier, faster, more sensitive, and more specific than previously published methods and can be adaptated as a quantitative assay using a scanning densitometer with a linear range of detection from 10 to 100 ng of glycosaminoglycans.