Testing the joint health and safety committee assessment tool in the education sector.

Joint Health and Safety Committee (JHSC) effectiveness has been identified as an area of concern for Ontario's education sector. The JHSC Assessment Tool has been previously tested in hospitals with positive results. This study assessed the feasibility and usability of the JHSC Assessment Tool in the education sector. Members of multi-workplace JHSCs from Ontario school boards used the tool to assess their committees' effectiveness before, during and after a committee meeting with usability testing conducted pre and post meeting. Results suggested that the JHSC Assessment Tool was feasible to use during a regular JHSC meeting, groups were able to come to consensus on the majority of items, and usability scores were high overall. Participant feedback provided insight that informed the development of a version relevant to multi-workplace committees.

Functional limitations in workers with hand-arm vibration syndrome (HAVS).

BACKGROUND: Hand-arm vibration syndrome (HAVS) is a chronic occupational disease affecting workers exposed to hand-transmitted vibration. However, limited information exists on task-related disability experienced by workers with HAVS. AIMS: This study was conducted to characterize the impact of HAVS on task-related disability and daily life activities. METHODS: A retrospective chart review was undertaken of difficulty in carrying out activities reported by workers with HAVS who had been assessed in an Occupational Medicine clinic in 2015. Prior to their clinical assessment, the workers had been asked to complete an open-ended questionnaire regarding activities they were having difficulty performing in the domains of personal care, household activities and recreational activities or hobbies. RESULTS: Data from 107 workers diagnosed with HAVS were obtained through the retrospective chart review. The activities most affected included: getting dressed (n = 72), lawn maintenance (n = 61), fishing (including ice fishing) (n = 56), snow removal (n = 36), washing the car (n = 26) and doing the dishes (n = 25). CONCLUSIONS: These findings reported in an open-ended fashion by workers with HAVS provide a better understanding of the impact of HAVS on specific activities of daily living in comparison to highly structured questionnaires lacking any open-ended responses. Understanding the implications of HAVS on activities of daily living will contribute to the provision of patient-centred care, by enabling health care providers to effectively support HAVS patients, based on workers' actual experiences of functional limitations.

The anti-apoptotic response of the Gq/11-coupled muscarinic receptor family.

It is now clear that G-protein-coupled receptors can regulate programmed cell death (apoptosis) through a variety of mechanisms that are dependent on cell type and receptor subtype. Here we present evidence that the G(q/11)-coupled subtypes of the muscarinic receptor family (namely M(1), M(3) and M(5)-muscarinic receptor subtypes) are able to protect against apoptotic cell death. In particular we demonstrate that the C-terminal tail of the M(3)-muscarinic receptor is an essential structural element for signalling to the anti-apoptotic pathway. Removal of the distal portion of the C-terminal tail results in a receptor that is coupled normally to the G(q/11)/phospholipase C pathway and the mitogen-activated protein kinase pathway, but is unable to couple to the anti-apoptotic pathway. Furthermore, a poly-basic region conserved within the C-terminal tail of the G(q/11)-coupled muscarinic receptor subtypes appears to be the structural determinant of coupling to the anti-apoptotic pathway.

Effect of treatment on health-related quality of life in acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma: a randomized trial of pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine.

The purpose of this study was to determine whether health-related quality of life (HRQL) would be improved in patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma treated by pegylated-liposomal doxorubicin (PLD) as compared to those treated by a conventional combination of doxorubicin, bleomycin, and vincristine (ABV). One hundred thirty-three patients received PLD and 125 patients received ABV every 2 weeks with a planned total of 6 cycles. Patients completed a 30-item AIDS-related HRQL questionnaire before beginning treatment (baseline), every 2 weeks while on treatment, and about 21 days after the end of treatment. Twenty-two items, involving nine domains, were analyzable. While on treatment, PLD-treated patients with partial clinical responses achieved statistically significant greater improvement (compared to baseline) in general health than did ABV-treated patients with partial clinical responses (rho = 0.008). By the end of treatment, the overall group of patients receiving PLD showed statistically significant greater improvement in pain and energy/fatigue than did the group receiving ABV (rho = 0.01-0.002). In addition, duration of clinically significant improvement in global QL was longer in the PLD arm.

Measuring central executive functioning: what's in a reading span?

Although variations of Daneman and Carpenter's (1980) Reading Span Test (RST) have seen increasing use in both cognitive and neuropsychological research, the specific mental operations involved in performing it remain unclear. We tested 80 undergraduates to examine the extent to which speed of processing, manipulation capacity, and susceptibility to interference contributed to RST performance. The results suggest that, rather than unitary central executive or processing speed functions underlying RST performance, at least two factors, manipulation capacity and susceptibility to interference, underlie the task. Further study of RST operations may lead to a better understanding of the nature of the central executive itself.

Phosphorylation of the Gq/11-coupled m3-muscarinic receptor is involved in receptor activation of the ERK-1/2 mitogen-activated protein kinase pathway.

We investigated the role played by agonist-mediated phosphorylation of the G(q/11)-coupled M(3)-muscarinic receptor in the mechanism of activation of the mitogen-activated protein kinase pathway, ERK-1/2, in transfected Chinese hamster ovary cells. A mutant of the M(3)-muscarinic receptor, where residues Lys(370)-Ser(425) of the third intracellular loop had been deleted, showed a reduced ability to activate the ERK-1/2 pathway. This reduction was evident despite the fact that the receptor was able to couple efficiently to the phospholipase C second messenger pathway. Importantly, the ERK-1/2 responses to both the wild-type M(3)-muscarinic receptor and DeltaLys(370)-Ser(425) receptor mutant were dependent on the activity of protein kinase C. Our results, therefore, indicate the existence of two mechanistic components to the ERK-1/2 response, which appear to act in concert. First, the activation of protein kinase C through the diacylglycerol arm of the phospholipase C signaling pathway and a second component, absent in the DeltaLys(370)-Ser(425) receptor mutant, that is independent of the phospholipase C signaling pathway. The reduced ability of the DeltaLys(370)-Ser(425) receptor mutant to activate the ERK-1/2 pathway correlated with an approximately 80% decrease in the ability of the receptor to undergo agonist-mediated phosphorylation. Furthermore, we have previously shown that M(3)-muscarinic receptor phosphorylation can be inhibited by a dominant negative mutant of casein kinase 1alpha and by expression of a peptide corresponding to the third intracellular loop of the M(3)-muscarinic receptor. Expression of these inhibitors of receptor phosphorylation reduced the wild-type M(3)-muscarinic receptor ERK-1/2 response. We conclude that phosphorylation of the M(3)-muscarinic receptor on sites in the third intracellular loop by casein kinase 1alpha contributes to the mechanism of receptor activation of ERK-1/2 by working in concert with the diacylglycerol/PKC arm of the phospholipase C signaling pathway.

Phosphorylation and regulation of a Gq/11-coupled receptor by casein kinase 1alpha.

Agonist-mediated receptor phosphorylation by one or more of the members of the G-protein receptor kinase (GRK) family is an established model for G-protein-coupled receptor (GPCR) phosphorylation resulting in receptor desensitization. Our recent studies have, however, suggested that an alternative route to GPCR phosphorylation may be an operation involving casein kinase 1alpha (CK1alpha). In the current study we investigate the involvement of CK1alpha in the phosphorylation of the human m3-muscarinic receptor in intact cells. We show that expression of a catalytically inactive mutant of CK1alpha, designed to act in a dominant negative manner, inhibits agonist-mediated receptor phosphorylation by approximately 40% in COS-7 and HEK-293 cells. Furthermore, we present evidence that a peptide corresponding to the third intracellular loop of the m3-muscarinic receptor (Ser(345)-Leu(463)) is an inhibitor of CK1alpha due to its ability to both act as a pseudo-substrate for CK1alpha and form a high affinity complex with CK1alpha. Expression of this peptide was able to reduce both basal and agonist-mediated m3-muscarinic receptor phosphorylation in intact cells. These results support the notion that CK1alpha is able to mediate GPCR phosphorylation in an agonist-dependent manner and that this may provide a novel mechanism for GPCR phosphorylation. The functional role of phosphorylation was investigated using a mutant of the m3-muscarinic receptor that showed an approximately 80% reduction in agonist-mediated phosphorylation. Surprisingly, this mutant underwent agonist-mediated desensitization suggesting that, unlike many GPCRs, desensitization of the m3-muscarinic receptor is not mediated by receptor phosphorylation. The inositol (1,4, 5)-trisphosphate response did, however, appear to be dramatically potentiated in the phosphorylation-deficient mutant indicating that phosphorylation may instead control the magnitude of the initial inositol phosphate response.

The effects of hair loss in European men: a survey in four countries.

Despite the high prevalence and the accepted psychological aspects of male pattern hair loss, few have characterized the effects of hair loss in representative samples of men in different countries. A representative sample of households in 4 European countries (France, Germany, Italy and the United Kingdom) was contacted by an interviewer and resident males 18-40 years of age (n = 1,717) completed a questionnaire designed specifically to evaluate attitudes to hair loss. The questionnaire was comprised of 78 questions translated and pilot-tested using standard methodology into each local language. Questionnaires queried about self-rated hair loss, satisfaction with hair appearance, noticeability of hair loss to others, and bother, concerns and perceptions about hair loss, as well as general physical health (the SF-12 questionnaire) plus three additional questions about mental health. The self-reported degree of hair loss in men was statistically significantly associated (p < 0.001) with all hair-loss specific effects measured, except "limiting job opportunities". The impact of hair loss was generally consistent in the four countries surveyed, although less pronounced in the United Kingdom. Age was significantly correlated with hair loss (rs = 0.34, p < 0.001). Men with greater hair loss were more bothered, more concerned about looking older due to their hair loss, and less satisfied with their hair appearance. Male pattern hair loss has significant negative effects on hair-loss specific measures in men 18 to 40 years of age in France, Italy, Germany and the UK. The degree that hair loss is perceived as noticeable to others appears to be a significant contributor to these negative effects.

Cross talk between m3-muscarinic and beta(2)-adrenergic receptors at the level of receptor phosphorylation and desensitization.

In this study we investigated cross talk between m3-muscarinic and beta(2)-adrenergic receptors coexpressed in Chinese hamster ovary (CHO-m3/beta(2)) cells, focusing on two possible mechanisms of regulation. The first mechanism is based on recent in vitro studies demonstrating that G protein-coupled receptor kinase (GRK) activity, the protein kinase responsible for beta(2)-adrenergic receptor homologous phosphorylation and desensitization, may be regulated by calcium/calmodulin and membrane phosphatidylinositol 4, 5-bisphosphate. Stimulation of the phospholipase C signaling pathway via m3-muscarinic receptors in CHO-m3/beta(2) cells increased intracellular free calcium by approximately 10 fold and membrane phosphatidylinositol 4,5-bisphosphate levels decreased by approximately 74%. However, despite these changes the ability of endogenous kinases, possibly the GRKs, to phosphorylate the beta(2)-adrenergic receptor was not altered. The second mechanism investigated involves a direct heterologous phosphorylation of the beta(2)-adrenergic receptor after muscarinic receptor stimulation. Activation of m3-muscarinic receptors did mediate heterologous phosphorylation of beta(2)-adrenergic receptors in a GRK-independent fashion, via protein kinase C. Heterologous beta(2)-adrenergic receptor phosphorylation correlated with receptor desensitization as measured by a loss in guanine-nucleotide sensitive-high affinity agonist binding and reduction in maximal cAMP response. This receptor cross talk may have a profound physiological importance in a wide variety of cell types, for example smooth muscle, where these two receptors are known to be coexpressed.

Activation of the mitogen-activated protein kinase pathway by a Gq/11-coupled muscarinic receptor is independent of receptor internalization.

A number of recent studies have demonstrated an essential role for receptor endocytosis in the activation of the mitogen-activated protein (MAP) kinases, Erk-1 and Erk-2 (extracellular activated protein kinases 1 and 2), by growth factor receptors and the G-protein coupled beta2-adrenergic receptor. Because ligand-mediated receptor endocytosis and activation of the MAP kinase pathway are common phenomena among G-protein coupled receptors, it has been suggested that the essential role of endocytosis in MAP kinase activation identified for the beta2-adrenergic receptor may be universal for all G-protein coupled receptors (Daaka,Y., Luttrell, L. M., Ahn, S., Della Rocca, G. J., Ferguson, S. S. G., Caron, M. G., and Lefkowitz, R. J. (1998) J. Biol. Chem. 273, 685-688). We tested this hypothesis using the Gq/11-coupled m3-muscarinic receptor expressed in Chinese hamster ovary cells and an m3-muscarinic receptor mutant that does not undergo endocytosis. We demonstrate that inhibition of endocytosis by concanavalin A and cytochalasin D does not affect the ability of the wild type m3-muscarinic receptor to activate Erk-1/2. Furthermore, the mutant m3-muscarinic receptor that is unable to undergo endocytosis, activates the MAP kinase pathway in an identical manner to the wild type receptor. We conclude that receptor endocytosis is not universally essential for MAP kinase activation by G-protein coupled receptors. We discuss the possibility that the differential roles played by endocytosis in MAP kinase activation between various receptor subtypes may be linked to the mechanism of upstream activation of Raf-1.

Arachidonic acid potentiates the duration of the metabotropic, protein kinase C-mediated, suppression of the inhibitory adenosine A1 receptor pathway in glutamatergic nerve terminals from rat cerebral cortex.

The KCl-evoked exocytotic release of glutamate from rat cerebrocortical synaptosomes is inhibited by a presynaptic adenosine A1 receptor decreasing voltage-activated Ca2+ entry. This inhibition was transiently suppressed by (1S,3R)-1-aminocyclopenthyl-1,3-dicarboxylate (ACPD) but was restored within 1 min in the continued presence of the metabotropic agonist. In the presence of 2 microM arachidonic acid ACPD initiated a prolonged suppression of the adenosine-mediated inhibition persisting for at least 10 min. Arachidonic acid (20-40 pmol) was bound per mg synaptosomal protein. Prolonged ACPD-mediated phosphorylation of the protein kinase C (PKC) substrate myristoylated alanine-rich C-kinase substrate (MARCKS) was detected in the presence but not the absence of arachidonic acid, but arachidonic acid added 2 min after ACPD was ineffective. It is concluded that arachidonic acid synergistically prolongs the metabotropic glutamate receptor-mediated activation of presynaptic PKC, suppressing inhibitory receptor pathways.

A randomized controlled trial evaluating the use of sterile water as an irrigation fluid during transurethral electrovaporization of the prostate.

OBJECTIVE: To compare the safety of sterile water and glycine when used as bladder irrigation during transurethral electrovaporization of the prostate (TUVP) in a randomized controlled trial. PATIENTS AND METHODS: The study comprised 50 consecutive patients admitted for transurethral prostatic surgery who were randomly allocated to receive bladder irrigation with either sterile water or 1.5% glycine during TUVP. After surgery, serum electrolytes and the presence of free plasma haemoglobin (suggesting haemolysis) were determined and the patients observed for clinical evidence of the transurethral resection (TUR) syndrome. RESULTS: There was no significant difference in the level of free plasma haemoglobin between the groups and no difference in serum sodium levels. None of the patients developed any signs of the TUR syndrome. CONCLUSIONS: Water is a safe irrigant for use during TUVP and has several advantages over 1.5% glycine.

Presynaptic receptors and the control of glutamate exocytosis.

When a typical glutamate-containing neurone fires, an action potential is propagated down the branching axon through more than a thousand varicosities. At each of these release sites the probability that a synaptic vesicle will be exocytosed into the synaptic cleft is individually controlled by means of presynaptic receptors: autoreceptors responding by positive or negative feedback to previously released transmitter, or heteroreceptors under the influence of other neurotransmitters or modulators. The simplest system in which to investigate presynaptic modulation is the isolated nerve terminal or synaptosome; studies with this preparation have revealed a complex interplay of signal-transduction pathways.

Inhibition by lifarizine of intracellular Ca2+ rises and glutamate exocytosis in depolarized rat cerebrocortical synaptosomes and cultured neurones.

1. The effects of lifarizine (RS-87476) on intracellular Ca2+ rises and the release of glutamate from rat cerebrocortical synaptosomes depolarized with 30 mM KCl were investigated by use of entrapped fura 2 and exogenous glutamate dehydrogenase. 2. Prior (1 min) addition of lifarizine decreased 30 mM KCl-induced total glutamate release, with 3 microM and 10 microM causing 39% and 72% averaged decreases from controls. The calcium-dependent component of glutamate release (approx. 40% of total) was similarly decreased by 47% and 74%, whereas the calcium-independent component was decreased by only 32% and 43% respectively. 3. In parallel experiments with fura-2-loaded synaptosomes, lifarizine reduced the depolarization-induced increases in intracellular [Ca2+], suggesting that this is the means by which the decreases in glutamate release are brought about. Lifarizine inhibited both the plateau and the spike phases of the Ca2+ increases suggesting that, in addition to its known sodium channel blocking properties, it may also inhibit more than one class of calcium channel in the synaptosomes. 4. Lifarizine at 1 microM and 3 microM also inhibited the rises in intracellular [Ca2+] in rat cultured cortical neurons depolarized with 60 mM KCl. 5. These effects of lifarizine on intracellular Ca2+ and glutamate exocytosis may contribute to its neuroprotective action.

Isolation and characterization of a cDNA clone encoding a member of the Com44/Cim44 envelope components of the chloroplast protein import apparatus.

Many of the proteins in the chloroplast envelope play an important role in facilitating the biochemical and transport processes of the compartment. For the transport of proteins into the chloroplast, we have recently identified at least three different envelope proteins (Com44/Cim44, Com70, and Cim97) in close physical proximity to a partially translocated chimeric precursor protein (Wu, C., Seibert, F. S., and Ko, K. (1994) J. Biol. Chem. 269, 32264-32271). In this study we report the characterization of a cDNA clone encoding a member of the Com44/Cim44 envelope proteins. The combined data from nucleotide sequencing, and RNA and protein blot analyses indicate the existence of multiple forms of the 44-kDa envelope protein. Depending on the plant species examined, immunologically-related protein bands with molecular masses of 42 to 46 kDa were observed. Organelle subfractionation, protease treatment, and immunomicroscopic studies together provide an indication that the immunologically-related proteins may be present in both the outer and inner envelope membranes. Co-migration of the product synthesized from the cDNA insert with a 44-kDa immunoreactive band of the chloroplast envelope, and the in vitro import results, together suggest that the in vitro synthesized 44-kDa protein is targeted to the envelope membrane without any further processing.

Individual differences in working memory strategies for reading expository text.

This study investigated whether individual differences in working memory (WM) span are associated with different WM management strategies during the reading of expository text. In Experiment 1, probe questions were presented on line during reading to determine whether thematic information was maintained in WM throughout comprehension. The data indicated that readers across the range of WM span maintained thematic information in WM throughout the reading of a given passage. In Experiment 2, sentence reading times and accuracy for both topic and detail questions were measured in two conditions: when topic sentences were present and when topic sentences were absent. Subjects performed similarly across the range of WM span in the topic-present condition, but lower span subjects performed more poorly on detail questions in the topic-absent condition. In Experiment 3, the topic-present condition of the second experiment was replicated, except that subjects expected to receive questions about details only. Thematic processing and retention of topic and detail information all increased with span. Taken together, these results suggest that, for more difficult text processing tasks, high- and low-span subjects adopt different WM management strategies and these strategies influence what is learned from reading the text.

Protein kinase C-mediated suppression of the presynaptic adenosine A1 receptor by a facilitatory metabotropic glutamate receptor.

KCl-evoked glutamate exocytosis from cerebrocortical synaptosomes can be inhibited by the adenosine A1 receptor agonist cyclohexyladenosine (CHA). Inhibition is associated with a decreased KCl-evoked Ca2+ level elevation, and the effect of the agonist is occluded by prior incubation with the Agelenopsis aperta neurotoxin omega-agatoxin-IVA at 250 nM. The inhibition is suppressed in the presence of 3 nM phorbol dibutyrate (PDBu) or by activation of the protein kinase C (PKC)-coupled metabotropic glutamate receptor by 100 microM (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate [(1S,3R)ACPD]. A tonic inhibition of release by leaked exogenous adenosine can be reversed by adenosine deaminase or by PDBu addition. The CHA-induced inhibition can be enhanced by the PKC inhibitor Ro 31-8220. The mechanism for the suppression of the adenosine A1 receptor-mediated inhibition is distinct from that previously described for the (1S,3R)ACPD-evoked, PKC-mediated, facilitatory pathway, which enhances phosphorylation of the MARCKS protein, 4-aminopyridine-induced action potentials, and release of glutamate because the latter requires at least 100 nM PDBu [or the combination of (1S,3R)ACPD and arachidonic acid] and is not seen following KCl depolarization. Both PKC-mediated pathways may be involved in the presynaptic events associated with the establishment of synaptic plasticity.

Co-existence and interaction between facilitatory and inhibitory metabotropic glutamate receptors and the inhibitory adenosine A1 receptor in cerebrocortical nerve terminals.

We have investigated the interaction between facilitatory and inhibitory metabotropic glutamate receptors (mGluRs) and the inhibitory adenosine A1 receptor in cerebrocortical nerve terminals from young (3 weeks postnatal) rats. The adenosine A1 receptor agonist N6-cyclohexyladenosine (CHA) (1 microM) and the mGluR agonist L-2-amino-4-phosphonobutyrate (L-AP4) (100 microM) inhibited Ca(2+)-dependent release of glutamate evoked by depolarization of synaptosomes with 30 mM KCl to 33 +/- 6 and 30 +/- 4% of control values, respectively. The CHA and L-AP4 inhibition of release was consistent with the reduction of a component of Ca2+ entry in nerve terminals which was also sensitive to omega-Aga-IVA. When the inhibitory agonists were co-applied at optimal concentrations, no additivity of the inhibitory effects on either glutamate release or [Ca2+]c was observed. The nerve terminals from young rats also exhibit the facilitatory pathway for glutamate release that is observed during 4-aminopyridine-evoked depolarization after stimulation of mGluRs with the agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD) in the presence of arachidonic acid (AA). The addition of ACPD or AA alone did not alter the ability of CHA and L-AP4 to reduce the release, however the co-application of AA and ACPD abolished the inhibitory effect induced by CHA and L-AP4 whether alone or in combination. These results indicate the co-existence of the three modulatory pathways of glutamate release and the dominant role of the ACPD/AA activated facilitatory pathway in its interaction with the inhibitory pathways activated by L-AP4 and CHA.