Indoles: A joint effort of light and air We have developed a mild aerobic oxidation protocol using visible light photocatalysis to synthesize structurally diverse N-arylindoles. The procedure employs 4 mol% [Ru(bpz)3](PF6)2, 18W LED light, and is performed open to the atmosphere. Readily prepared o-stryryl anilines are converted to a variety of indoles via a cascade sequence composed of oxidation of anilines, C-N bond formation, and aromatization. A 1,2-carbon shift can be also incorporated into this cascade event to further extend the substrate scope of the method. bpz = 2, 2′-Bipyrazine
cascade; indole; photocatalysis; ruthenium; visible light
To examine the association between nursing home (NH) work environment attributes such as teams, consistent assignment and staff cohesion and the risk of pressure ulcers and incontinence.
Minimum Data Set for 46,044 residents in 162 facilities in New York State, for June 2006-July 2007, and survey responses from 7,418 workers in the same facilities.
For each individual and facility primary and secondary data were linked. Random effects logistic models were used to develop/validate outcome measures. GEE models with robust standard errors and probability weights were employed to examine the association between outcomes and work environment attributes. Key independent variables were: staff cohesion, percent staff in daily-care teams, and percent staff with consistent assignment. Other facility factors were also included.
Residents in facilities with worse staff cohesion had significantly greater odds of pressure ulcers and incontinence, compared to residents in facilities with better cohesion scores. Residents in facilities with greater penetration of self-managed teams had lower risk of pressure ulcers, but not of incontinence. Prevalence of consistent assignment was not significantly associated with the outcome measures.
NH environments and management practices influence residents' health outcomes. These findings provide important lessons for administrators and regulators interested in promoting NH quality improvement.
nursing homes; health outcomes; staff cohesion; teams; consistent assignment
Purpose of the study:
This study examines urban–rural differences in end-of-life (EOL) quality of care provided to nursing home (NH) residents.
Data and Methods:
We constructed 3 risk-adjusted EOL quality measures (QMs) for long-term decedent residents: in-hospital death, hospice referral before death, and presence of severe pain. We used CY2005-2007 100% Minimum Data Set, Medicare beneficiary file, and inpatient and hospice claims. Logistic regression models were estimated to predict the probability of each outcome conditional on decedents’ risk factors. For each facility, QMs were calculated as the difference between the actual and the expected risk-adjusted outcome rates. We fit multivariate linear regression models, with fixed state effects, for each QM to assess the association with urban–rural location.
We found urban–rural differences for in-hospital death and hospice QMs, but not for pain. Compared with NHs located in urban areas, facilities in smaller towns and in isolated rural areas have significantly (p < .001) worse EOL quality for in-hospital death and hospice use. Whereas the differences in these QMs are statistically significant between facilities located in large versus small towns, they are not statistically significant between facilities located in small towns and isolated rural areas.
This study provides empirical evidence for urban–rural differences in EOL quality of care using a national sample of NHs. Identifying differences is a necessary first step toward improving care for dying NH residents and for bridging the urban–rural gap.
Nursing homes; Quality of care; Rural & urban issues
The Centers for Medicare and Medicaid Services (CMS) publishes a web-based quality report card for nursing homes. The quality measures (QMs) do not assess quality of end-of-life (EOL) care, which affects a large proportion of residents. This study developed prototype EOL QMs that can be calculated from data sources available for all nursing homes nationally.
The study included approximately 1.5 million decedents residing in 16,000 nursing homes during 2003–2007, nationally. Minimum Data Set (MDS) data were linked to Medicare enrollment files, hospital claims, and hospice claims. Random effect logistic models were estimated to develop risk-adjustment models predicting two outcome measures (place of death [POD] and hospice enrollment), which were then used to construct two EOL QMs. The distributional properties of the QMs were investigated.
The QMs exhibited moderate stability over time. They were more stable in identifying quality outliers among the larger nursing homes and in identifying poor-quality outliers than high-quality outliers.
This study offers two QMs specialized to EOL care in nursing homes that can be calculated from data that are readily available and could be incorporated in the Nursing Home Compare (NHC) report card. Further work to validate the QMs is required.
A photocatalytic system involving [Ru(bpyrz)3](PF6)2·2H2O, visible light, and air has been developed for cleavage of the N–N bonds of hydrazines and hydrazides. This catalytic system is generally effective for N,N-disubstituted hydrazine and hydrazide derivatives, including arylhydrazides, N-alkyl-N-arylhydrazines, and N,N-diarylhydrazines. The utility of this cleavage reaction has been demonstrated by synthesizing a variety of secondary aromatic amines.
nitrogen–nitrogen bonds; visible light; cleavage; ruthenium; amines
Quantitative estimations of first-in-human (FIH) doses are critical for phase I clinical trials in drug development. Human pharmacokinetic (PK) prediction methods have been developed to project the human clearance (CL) and bioavailability with reasonable accuracy, which facilitates estimation of a safe yet efficacious FIH dose. However, the FIH dose estimation is still very challenging and complex. The aim of this article is to review the common approaches for FIH dose estimation with an emphasis on PK-guided estimation. We discuss 5 methods for FIH dose estimation, 17 approaches for the prediction of human CL, 6 methods for the prediction of bioavailability, and 3 tools for the prediction of PK profiles. This review may serve as a practical protocol for PK- or pharmacokinetic/pharmacodynamic-guided estimation of the FIH dose.
allometric scaling; FIH dose; in vitro–in vivo correlations; pharmacokinetics; prediction
This study presents an evaluation of the bidirectional correlation between attention deficit hyperactivity disorder (ADHD) and epilepsy using 2 cohorts from the same population database.
We used data from the Taiwan National Health Insurance Research Database to establish 2 separate cohort studies with participants <19 years old. We subdivided Cohort 1 in 2 groups: (1) 2468 patients initially diagnosed with epilepsy during the period 1999–2008, and (2) 9810 randomly selected sex- and age-matched non-epileptic controls. We subdivided Cohort 2 into 2 groups: (1) 3664 patients with newly diagnosed ADHD and (2) 14 522 sex- and age-matched non-ADHD patients. We evaluated the risk of subsequent ADHD in relationship to epilepsy and vice versa in the 2 cohorts at the end of 2008.
The ADHD incidence in Cohort 1 was 7.76 in patients with epilepsy and 3.22 in those without epilepsy (per 1000 person-years) after a median follow-up of 7–7.5 years. The adjusted hazard ratio (HR) for ADHD was 2.54 (95% CI 2.02–3.18) in the epilepsy group compared to the non-epilepsy group. In Cohort 2, the incidence of epilepsy was 3.24 in patients with ADHD and 0.78 in those without ADHD (per 1000 person-years) after a median follow-up of 3–3.5 years and an HR of 3.94 (95% CI 2.58–6.03).
This study shows a bidirectional association between ADHD and epilepsy in the 2 cohort studies. Causative factors may be common between these 2 disorders, leading to a cascade of transcriptional changes in the brain that alter behavior or cognition prior to seizures.
Amines have been used as sacrificial electron donors to reduce photoexcited Ru(II) or Ir(III) complexes, during which they are oxidized to nitrogen radical cations. Recently, the synthetic potential of these nitrogen radical cations have caught synthetic organic chemists’ attention. They have been exploited in various transformations yielding a number of elegant methods for amine synthesis. This article highlights recent developments on nitrogen radical cation chemistry under visible-light photocatalysis.
amines; visible light; nitrogen radical cations; ruthenium; iridium
Significant racial disparities have been reported regarding nursing home residents’ use of hospital and hospice care at the end-of-life.
To examine whether the observed racial disparities in end-of-life care are due to within- or across-facility variations.
Research Design and Subjects
Cross-sectional study of 49,048 long-term-care residents (9.23% Black and 90.77% White) in 555 New York State nursing homes who died during 2005–2007. Minimum Data Set was linked with Medicare inpatient and hospice claims.
In-hospital death determined by inpatient claims and hospice use determined by hospice claims. For each outcome, risk factors were added sequentially to examine their partial effects on the racial differences. Hierarchical models were fit to test whether racial disparities are due to within- or across-facility variations.
40.33% of Blacks and 24.07% of Whites died in hospitals; 11.55% of Blacks and 17.39% of Whites used hospice. These differences are partially due to disparate use of feeding tubes, Do-Not-Resuscitate (DNR) and Do-Not-Hospitalize (DNH) orders. We find no racial disparities in in-hospital death (OR of race=0.95, CI:0.87–1.04) or hospice use (OR of race=0.90, CI:0.79–1.02) within same facilities. Living in facilities with 10% more Blacks increases the odds of in-hospital death by 22% (OR=1.22, CI:1.17–1.26) and decreases the odds of hospice use by 15% (OR=0.85, CI:0.78–0.94).
Differential use of feeding tubes, DNR and DNH orders lead to racial differences in in-hospital death and hospice use. The remaining disparities are primarily due to overall end-of-life care practices in predominately-Black facilities, not to differential hospitalization and hospice-referral patterns within facilities.
Racial disparities; end of life care; nursing home; hospice; hospitalization
The systemic pharmacokinetics and pharmacodynamics of small molecules are determined by subcellular transport phenomena. Although approaches used to study the subcellular distribution of small molecules have gradually evolved over the past several decades, experimental analysis and prediction of cellular pharmacokinetics remains a challenge. In this article, we surveyed the progress of subcellular distribution research since the 1960s, with a focus on the advantages, disadvantages and limitations of the various experimental techniques. Critical review of the existing body of knowledge pointed to many opportunities to advance the rational design of organelle-targeted chemical agents. These opportunities include: 1) development of quantitative, nonfluorescence-based, whole cell methods and techniques to measure the subcellular distribution of chemical agents in multiple compartments; 2) exploratory experimentation with nonspecific transport probes that have not been enriched with putative, organelle-targeting features; 3) elaboration of hypothesis-driven, mechanistic and modeling-based approaches to guide experiments aimed at elucidating subcellular distribution and transport; and 4) introduction of revolutionary conceptual approaches borrowed from the field of synthetic biology combined with cutting edge experimental strategies. In our laboratory, state-of-the-art subcellular transport studies are now being aimed at understanding the formation of new intracellular membrane structures in response to drug therapy, exploring the function of drug-membrane complexes as intracellular drug depots, and synthesizing new organelles with extraordinary physical and chemical properties.
drug transport; pharmacokinetics; biodistribution; drug targeting; databases; mathematical modeling; drug delivery; drug-membrane aggregates; unnatural organelles; synthetic organelles
To explore the extent to which current knowledge about the organelle-targeting features of small molecules may be applicable towards controlling the accumulation and distribution of exogenous chemical agents inside cells, molecules with known subcellular localization properties (as reported in the scientific literature) were compiled into a single data set. This data set was compared to a reference data set of approved drug molecules derived from the DrugBank database, and to a reference data set of random organic molecules derived from the PubChem database. Cheminformatic analysis revealed that molecules with reported subcellular localizations were comparably diverse. However, the calculated physicochemical properties of molecules reported to accumulate in different organelles were markedly overlapping. In relation to the reference sets of Drug Bank and Pubchem molecules, molecules with reported subcellular localizations were biased towards larger, more complex chemical structures possessing multiple ionizable functional groups and higher lipophilicity. Stratifying molecules based on molecular weight revealed that many physicochemical properties trends associated with specific organelles were reversed in smaller vs. larger molecules. Most likely, these reversed trends are due to the different transport mechanisms determining the subcellular localization of molecules of different sizes. Molecular weight can be dramatically altered by tagging molecules with fluorophores or by incorporating organelle targeting motifs. Generally, in order to better exploit structure-localization relationships, subcellular targeting strategies would benefit from analysis of the biodistribution effects resulting from variations in the size of the molecules.
drug transport; pharmacokinetics; biodistribution; drug targeting; databases; mathematical modeling; drug delivery; cheminformatics
Conformational selection is a primary mechanism in biomolecular recognition. The conformational ensemble may determine the ability of a drug to compete with a native ligand for a receptor target. Traditional docking procedures which use one or few protein structures are limited and may not be able to represent a complex competition among closely related protein receptors in agonist and antagonist ensembles. Here, we test a protocol aimed at selecting a drug candidate based on its ability to synergistically bind to distinct conformational states. We demonstrate, for the case of estrogen receptor α (ERα) and estrogen receptor β (ERβ), that the functional outcome of ligand binding can be inferred from its ability to simultaneously bind both ERα and ERβ in agonist and antagonist conformations as calculated docking scores. Combining a conformational selection method with an experimental reporter gene system in yeast, we propose that several phytoestrogens can be novel estrogen receptor β selective agonists. Our work proposes a computational protocol to select estrogen receptor subtype selective agonists. Compared with other models, present method gives the best prediction in ligands’ function.
conformational ensemble; conformational selection; docking; phytoestrogen; SERMs; two-state theory
cycloaddition; cyclopropylamines; photochemistry; ruthenium; visible light
Modeling the local absorption and retention patterns of membrane-permeant small molecules in a cellular context could facilitate development of site-directed chemical agents for bioimaging or therapeutic applications. Here, we present an integrative approach to this problem, combining in silico computational models, in vitro cell based assays and in vivo biodistribution studies. To target small molecule probes to the epithelial cells of the upper airways, a multiscale computational model of the lung was first used as a screening tool, in silico. Following virtual screening, cell monolayers differentiated on microfabricated pore arrays and multilayer cultures of primary human bronchial epithelial cells differentiated in an air-liquid interface were used to test the local absorption and intracellular retention patterns of selected probes, in vitro. Lastly, experiments involving visualization of bioimaging probe distribution in the lungs after local and systemic administration were used to test the relevance of computational models and cell-based assays, in vivo. The results of in vivo experiments were consistent with the results of in silico simulations, indicating that mitochondrial accumulation of membrane permeant, hydrophilic cations can be used to maximize local exposure and retention, specifically in the upper airways after intratracheal administration.
We have developed an integrative, cell-based modeling approach to facilitate the design and discovery of chemical agents directed to specific sites of action within a living organism. Here, a computational, multiscale transport model of the lung was adapted to enable virtual screening of small molecules targeting the epithelial cells of the upper airways. In turn, the transport behaviors of selected candidate probes were evaluated to establish their degree of retention at a site of absorption, using computational simulations as well as two in vitro cell-based assay systems. Lastly, bioimaging experiments were performed to examine candidate molecules' distribution in the lungs of mice after local and systemic administration. Based on computational simulations, the higher mitochondrial density per unit absorption surface area is the key parameter determining the higher retention of small molecule hydrophilic cations in the upper airways, relative to lipophilic weak bases, specifically after intratracheal administration.
Neurons in the cerebellar nuclei fire at accelerated rates for prolonged periods after trains of synaptic inhibition that interrupt spontaneous firing. Both in vitro and in vivo, however, this prolonged rebound firing is favored by strong stimulation of afferents, suggesting that neurotransmitters other than GABA may contribute to the increased firing rates. Here, we tested whether metabotropic glutamate receptors modulate excitability of nuclear cells in cerebellar slices from mouse. In current clamp, the prolonged rebound firing rate after high-frequency synaptic stimulation was reduced by a variety of group I mGluR antagonists, including CPCCOEt (7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester), JNJ16259685 ((3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone)+MPEP, or 3-MATIDA (α-amino-5-carboxy-3-methyl-2-thiopheneacetic acid) +MPEP, as long as both mGluR1 and mGluR5 were blocked. This mGluR-dependent acceleration of firing was reduced but still evident when IPSPs were prevented by GABAA receptor antagonists. In voltage clamp, voltage ramps revealed a non-inactivating, low-voltage-activated, nimodipine-sensitive current that was enhanced by the selective group I mGluR agonist s-DHPG ((S)-3,5-dihydroxyphenylglycine). This putative L-type current also increased when mGluRs were activated by trains of evoked synaptic currents instead of direct application of agonist. In current clamp, blocking L-type Ca channels with the specific blocker nifedipine greatly reduced prolonged post-stimulus firing and occluded the effect of adding group I mGluR antagonists. Thus, potentiation of a low-voltage-activated L-type current by synaptically released glutamate accounted nearly fully for the mGluR-dependent acceleration of firing. Together, these data suggest that prolonged rebound firing in the cerebellar nuclei in vivo is most likely to occur when GABAA and mGluRs are simultaneously activated by concurrent excitation and inhibition.
A general method for the synthesis of 2,3-disubstituted indoles is described. The key feature of this method is amination of aromatic C-H bonds via FeCl2-catalyzed ring opening of 2H-azirines. The method tolerates a variety of functional groups such as Br, F, NO2, OMe, CF3, OTBS, alkenes, and OPiv. The method can be also extended to synthesize azaindoles.
Staff communication has been shown to influence overall nursing home (NH) performance. However, no empirical studies have focused specifically on the impact of CNA communication on end-of-life (EOL) care processes. This study examines the relationship between CNA communication and nursing home performance in EOL care processes.
Secondary data analysis of two NH surveys conducted in 2006-07.
107 nursing homes in New York State.
2,636 CNAs and 107 directors of nursing (DON).
The measures of EOL care processes—EOL assessment and care delivery (5-point Likert scale scores) - were obtained from survey responses provided by 107 Directors of Nursing (DON). The measure of CNA communication was derived from survey responses obtained from 2,636 CNAs. Other independent variables included staff education, hospice use intensity, staffing ratio, staff-resident ethnic overlap index, facility religious affiliation and ownership.
The reliability and validity of the measures of EOL care processes and CNA communication were tested in the current study sample. Multivariate linear regression models with probability weights were employed. The analysis was conducted at the facility level.
We found better CNA communication to be significantly associated with better EOL assessment (p = 0.043) and care delivery (p= 0.098). Two potentially modifiable factors—staff education and hospice use intensity—were associated with NHs' performance in EOL care processes. Facilities with greater ethnic overlap between staff and residents demonstrated better EOL assessment (p = 0.051) and care delivery scores (P = 0.029).
Better CNA communication was associated with better performance in EOL care processes. Our findings provide specific insights for NH leaders striving to improve EOL care processes and ultimately the quality of care for dying residents.
staff communication; end-of-life care; quality of care in nursing homes; care process; certified nurse aides
A biophysical, computational model of cell pharmacokinetics (1CellPK) is being developed to enable prediction of the intracellular accumulation and transcellular transport properties of small molecules using their calculated physicochemical properties as input. To test if 1CellPK can generate accurate, quantitative hypotheses and guide experimental analysis of the transcellular transport kinetics of small molecules, epithelial cells were grown on impermeable polyester membranes with cylindrical pores and chloroquine (CQ) was used as a transport probe. The effect of the number of pores and their diameter on transcellular transport of CQ was measured in apical-to-basolateral or basolateral-to-apical directions, at pH 7.4 and 6.5 in the donor compartment. Experimental and simulation results were consistent with a phospholipid bilayer-limited, passive diffusion transport mechanism. In experiments and 1CellPK simulations, intracellular CQ mass and the net rate of mass transport varied <2-fold although total pore area per cell varied >10-fold, so by normalizing the net rate of mass transport by the pore area available for transport, cell permeability on 3µm pore diameter membranes was more than an order of magnitude less than on 0.4µm pore diameter membranes. The results of simulations of transcellular transport were accurate for the first four hours of drug exposure, but those of CQ mass accumulation were accurate only for the first five minutes. Upon prolonged incubation, changes in cellular parameters such as lysosome pH rise, lysosome volume expansion, and nuclear shrinkage were associated with excess CQ accumulation. Based on the simulations, lysosome volume expansion alone can partly account for the measured, total intracellular CQ mass increase, while adding the intracellular binding of the protonated, ionized forms of CQ (as reflected in the measured partition coefficient of CQ in detergent-permeabilized cells at physiological pH) can further improve the intracellular CQ mass accumulation prediction.
Systems Biology; Epithelial Cells; Membrane Transport; Mathematical Models; Pharmacokinetics; Cell Permeability
Work environment attributes - job design, teamwork, work effectiveness - are thought to influence nursing home (NH) quality of care. However, few studies tested these relationships empirically.
We investigated the relationship between these work environment attributes and quality of care measured by facility-level regulatory deficiencies.
Data on work environment were derived from survey responses obtained (in 2006-2007) from 7,418 direct care workers in 162 NHs in NYS. Data on facility deficiencies and characteristics came from the OSCAR database.
We fit multivariate linear and logistic regressions, with random effects and probability weights, to models with the following dependent variables: presence/absence of quality of life (QL) deficiencies; number of quality of care (QC) deficiencies; and presence/absence of high severity G-L deficiencies (causing actual harm/immediate jeopardy). Key independent variables included: work effectiveness (a 5-point Likert scale score); percent staff in daily care teams and with primary assignment. The work effectiveness measure has been demonstrated to be psychometrically reliable and valid. Other variables included staffing, size, facility case-mix, and ownership.
In support of the proposed hypotheses, we found work effectiveness to be a statistically significant predictor of all three measures of deficiencies. Primary assignment of staff to residents was significantly associated with fewer QC and high severity deficiencies. Greater penetration of self-managed teams was associated with fewer QC deficiencies.
Work environment attributes impact quality of care in NHs. These findings provide important insights for NH administrators and regulators in their efforts to improve quality of care for residents.
Neurons of the cerebellar nuclei generate the non-vestibular output of the cerebellum. Like other neurons, they integrate excitatory and inhibitory synaptic inputs and filter them through their intrinsic properties to produce patterns of action potential output. The synaptic and intrinsic features of cerebellar nuclear cells are unusual in several respects, however: these neurons receive an overwhelming amount of basal and driven inhibition from Purkinje neurons, but are also spontaneously active, producing action potentials even without excitation. Moreover, not only is spiking by nuclear cells sensitive to the amount of inhibition, but the strength of inhibition is also sensitive to the amount of spiking, through multiple forms of long-term plasticity. Here, we review the properties of synaptic excitation and inhibition, their short-term plasticity, and their influence on action potential firing of cerebellar nuclear neurons, as well as the interactions among excitation, inhibition, and spiking that produce long-term changes in synaptic strength. The data provide evidence that electrical and synaptic signaling in the cerebellar circuit is both plastic and resilient: the strength of IPSPs and EPSPs readily changes as the activity of cerebellar nuclear cells is modified. Notably, however, many of the identified forms of plasticity have an apparently homeostatic effect, responding to perturbations of input by restoring cerebellar output toward pre-perturbation values. Such forms of self-regulation appear consistent with the role of cerebellar output in coordinating movements. In contrast, other forms of plasticity in nuclear cells, including a long-term potentiation of excitatory postsynaptic currents (EPSCs) and excitation-driven increases in intrinsic excitability, are non-homeostatic, and instead appear suited to bring the circuit to a new set point. Interestingly, the combinations of inhibitory and excitatory stimuli that potentiate EPSCs resemble patterns of activity predicted to occur during eyelid conditioning, suggesting that this form long-term potentiation, perhaps amplified by intrinsic plasticity, may represent a cellular mechanism that is engaged during cerebellar learning.
Purkinje; Deep cerebellar nuclei; Rebound; Delay eyeblink; Long-term potentiation (LTP); Long-term depression (LTD)
Purpose: The objectives of this study were to develop measures of end-of-life (EOL) care processes in nursing homes and to validate the instrument for measuring them. Design and Methods: A survey of directors of nursing was conducted in 608 eligible nursing homes in New York State. Responses were obtained from 313 (51.5% response rate) facilities. Secondary data on structural characteristics of the nursing homes were obtained from the Online Survey Certification and Reporting System. Exploratory factor analyses and internal consistency reliability analyses were performed. Multivariate regression models with fixed and random effects were estimated. Results: Four EOL process domains were identified—assessment, delivery, communication and coordination of care among providers, and communication with residents and families. The scales measuring these EOL process domains demonstrated acceptable to high internal consistency reliability and face, content, and construct validity. Facilities with more EOL quality assurance or monitoring mechanisms in place and greater emphasis on EOL staff education had better scores on EOL care processes of assessment, communication and coordination among providers, and care delivery. Facilities with better registered nurse and certified nurse aide staffing ratios and those with religious affiliation also scored higher on selected care process measures. Implications: This study offers a new validated tool for measuring EOL care processes in nursing homes. Our findings suggest wide variations in care processes across facilities, which in part may stem from lack of gold standards for EOL practice in nursing homes.
End of life; Assessment; Delivery; Communication; Practice
Qualitative studies of the nursing home work environment have long suggested that such attributes as leadership and communication may be related to nursing home performance, including residents' outcomes. However, empirical studies examining these relationships have been scant.
This study is designed to: develop an instrument for measuring nursing home work environment and perceived work effectiveness; test the reliability and validity of the instrument; and identify individual and facility-level factors associated with better facility performance.
Research Design and Methods
The analysis was based on survey responses provided by managers (N=308) and direct care workers (N=7,418) employed in 162 facilities throughout New York State. Exploratory factor analysis, Chronbach's alphas, analysis of variance, and regression models were used to assess instrument reliability and validity. Multivariate regression models, with fixed facility effects, were used to examine factors associated with work effectiveness.
The reliability and the validity of the survey instrument for measuring work environment and perceived work effectiveness has been demonstrated. Several individual (e.g. occupation, race) and facility characteristics (e.g. management style, workplace conditions, staffing) that are significant predictors of perceived work effectiveness were identified.
The organizational performance model used in this study recognizes the multidimensionality of the work environment in nursing homes. Our findings suggest that efforts at improving work effectiveness must also be multifaceted. Empirical findings from such a line of research may provide insights for improving the quality of the work environment and ultimately the quality of residents' care.
work environment; work effectiveness; quality; nursing homes
In neurons of the cerebellar nuclei, long-term potentiation of EPSCs is induced by high-frequency synaptic excitation by mossy fibers followed by synaptic inhibition by Purkinje cells. Induction requires activation of synaptic receptors as well as voltage-gated Ca channels. To examine how Purkinje-mediated inhibition of nuclear neurons affects Ca levels during plasticity-inducing stimuli, we have combined electrophysiology, Ca imaging, and pharmacology of cerebellar nuclear neurons in mouse cerebellar slices. We find that spontaneous firing generates tonic Ca signals in both somata and dendrites, which drop during 500-ms, 100-Hz trains of Purkinje IPSPs or hyperpolarizing steps. Although the presence of low-voltage-activated (T-type) Ca channels in nuclear neurons has fostered the inference that disinhibition activates these channels, synaptic inhibition with a physiological ECl (−75 mV) fails to hyperpolarize neurons sufficiently for T-type channels to recover substantially. Consequently, after IPSPs, Ca signals return to baseline, although firing is accelerated by ∼20 Hz for ∼300 ms. Only after hyperpolarizations beyond ECl does Ca rise gradually beyond baseline, as firing further exceeds spontaneous rates. Cd2+ (100 μM), which nearly eliminates L-type, N-type, P/Q-type, and R-type Ca currents while sparing about half the T-type current, prevents Ca changes during and after hyperpolarizations to ECl. Thus, high-frequency IPSPs in cerebellar nuclear neurons evoke little post-inhibitory current through T-type channels. Instead, inhibition regulates Ca levels simply by preventing action potentials, which usually permit Ca influx through high-voltage-activated channels. The decreases and restoration of Ca levels associated with Purkinje-mediated inhibition are likely to contribute to synaptic plasticity.
rebound; T-type; high voltage activated; Ca channel; Purkinje; interpositus; deep cerebellar nuclei; IPSP
A restricted number of studies have shown that human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic CD4+ T cells are present in HIV-1-infected individuals. However, the roles of this type of CD4+ T cell in the immune responses against an HIV-1 infection remain unclear. In this study, we identified novel Nef epitope-specific HLA-DRB1*0803-restricted cytotoxic CD4+ T cells. The CD4+ T-cell clones specific for Nef187-203 showed strong gamma interferon production after having been stimulated with autologous B-lymphoblastoid cells infected with recombinant vaccinia virus expressing Nef or pulsed with heat-inactivated virus particles, indicating the presentation of the epitope antigen through both exogenous and endogenous major histocompatibility complex class II processing pathways. Nef187-203-specific CD4+ T-cell clones exhibited strong cytotoxic activity against both HIV-1-infected macrophages and CD4+ T cells from an HLA-DRB1*0803+ donor. In addition, these Nef-specific cytotoxic CD4+ T-cell clones exhibited strong ability to suppress HIV-1 replication in both macrophages and CD4+ T cells in vitro. Nef187-203-specific cytotoxic CD4+ T cells were detected in cultures of peptide-stimulated peripheral blood mononuclear cells (PBMCs) and in ex vivo PBMCs from 40% and 20% of DRB1*0803+ donors, respectively. These results suggest that HIV-1-specific CD4+ T cells may directly control HIV-1 infection in vivo by suppressing virus replication in HIV-1 natural host cells.
The development of a new method for the assembly of unsymmetrical carbazoles is reported. The strategy involves the selective intramolecular functionalization of an arene C-H bond and the formation of a new arene C-N bond. The substitution pattern of the carbazole product can be controlled by the design of the biaryl amide substrate, and the method is compatible with a variety of functional groups. The utility of the new protocol was demonstrated by the concise synthesis of three natural products from commercially available materials.
Palladium; Catalysis; C-H Bond; C-N bond; Carbazole