Make room at the table. Building and sustaining a strong birth community.
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Burnout, Professional↗
Biomedical subjects
L Wilson
Publications and source records attributed to L Wilson.
Rapid treadmilling of brain microtubules free of microtubule-associated proteins in vitro and its suppression by tau.
We have determined the treadmilling rate of brain microtubules (MTs) free of MT-associated proteins (MAPs) at polymer mass steady state in vitro by using [(3)H]GTP-exchange. We developed buffer conditions that suppressed dynamic instability behavior by approximately 10-fold to minimize the contribution of dynamic instability to total tubulin-GTP exchange. The MTs treadmilled rapidly under the suppressed dynamic instability conditions, at a minimum rate of 0.2 micrometer/min. Thus, rapid treadmilling is an intrinsic property of MAP-free MTs. Further, we show that tau, an axonal stabilizing MAP involved in Alzheimer's disease, strongly suppresses the treadmilling rate. These results indicate that tau's function in axons might involve suppression of axonal MT treadmilling. We describe mathematically how treadmilling and dynamic instability are mechanistically distinct MT behaviors. Finally, we present a model that explains how small changes in the critical tubulin subunit concentration at MT minus ends, caused by intrinsic differences in rate constants or regulatory proteins, could produce large changes in the treadmilling rate.
Brain↗
G protein alpha subunits activate tubulin GTPase and modulate microtubule polymerization dynamics.
G proteins serve many functions involving the transfer of signals from cell surface receptors to intracellular effector molecules. Considerable evidence suggests that there is an interaction between G proteins and the cytoskeleton. In this report, G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics. Gialpha inhibited polymerization of tubulin-GTP into microtubules by 80-90% in the absence of exogenous GTP. Addition of exogenous GTP, but not guanylylimidodiphosphate, which is resistant to hydrolysis, overcame the inhibition. Analysis of the dynamics of individual microtubules by video microscopy demonstrated that Gi1alpha increases the catastrophe frequency, the frequency of transition from growth to shortening. Thus, Galpha may play a role in modulating microtubule dynamic instability, providing a mechanism for the modification of the cytoskeleton by extracellular signals.
Animals↗
Intertester reliability of a low back pain classification system.
STUDY DESIGN: This prospective study of intertester reliability examined pairs of therapists' ability to agree independently on a patient's low back pain diagnosis. OBJECTIVE: To determine the intertester reliability of a low back pain classification system among experienced and novice clinicians. BACKGROUND: Many of the disparate categorization schemes for patients with low back pain are purely nominal, assigning designations based on the presumptive source of the problem without providing any practical guide for rehabilitation. A useful classification scheme reliably groups patients into treatment-directing categories. METHODS: The study included 204 patients with low back pain referred to 10 clinics across Canada. Paired physiotherapists performed separate physical examinations on each patient. Both examiners then completed a simple ballot choosing one of five pain patterns. RESULTS: Agreement on patient classification by independent examiners was 78.9% (kappa = 0.61). CONCLUSION: This clinically relevant and clearly defined pain pattern system uses key elements of the history and examination to classify patients with low back pain. The pattern provides a framework for initiating active rehabilitation strategy. Using this approach, clinicians agreed on the categorization of 78.9% of mechanical low back pain cases.
Adolescent↗
Diurnal changes in plasma prolactin during the last one third of pregnancy in the baboon.
Previous studies in our laboratory revealed that daily plasma prolactin (Prl) levels were higher in the evening than in the morning in the pregnant baboon suggesting a diurnal variation. The goal of this study was to examine in more detail the diurnal alterations in plasma Prl levels. A tethered pregnant baboon model was utilized for these studies. Hourly venous blood samples were taken from 0700 to 2400 hr (n=10) or until 0700 hr the following day (n=5). The studies were performed at various days of pregnancy from day 135 until delivery. Plasma samples were analyzed for Prl by radioimmunoassay. A surge in plasma Prl was detected, starting around 1500 to 1600 hr and lasting for 3 to 5 hr. The surge occurred before the lights went off in the colony (1800 hr). Baseline Prl levels were higher in animals < 15 days before delivery compared to those > 15 days before delivery (P < 0.05). In contrast, no differences were found in the average peak Prl values between these two groups of animals. In summary, in the pregnant baboon during the last one-third of pregnancy plasma Prl surges, beginning around 1500 to 1600 hr and lasting for 3 to 5 hr. Less than 15 days before delivery the mean baseline Prl levels are higher compared to animals greater than 15 days before delivery.
Animals↗
In vitro pharmacology of cryptophycin 52 (LY355703) in human tumor cell lines.
PURPOSE: Cryptophycin 52 (LY355703) is a new member of the cryptophycin family of antitumor agents that is currently undergoing clinical evaluation for cancer chemotherapy. The mechanism of action of the cryptophycin class of compounds is associated with an action on microtubules. This report details the pharmacological profile of this new clinical compound in a panel of human tumor cell lines. METHODS: Antiproliferative effects of cryptophycin 52 were measured indirectly by detection of the metabolic reduction of alamarBlue. Cytoxicity was assessed by enzymatic dye activation (calcein AM) combined with dye exclusion (ethidium homodimer) and by clonogenicity assay. Cell cycle effects were evaluated using flow cytometry and fluorescence microscopy. RESULTS: Both antiproliferative and cytotoxic effects of cryptophycin 52 were concentration- and time-dependent. IC50 values for antiproliferative activity in both solid and hematologic tumor cell lines were in the low picomolar range, and without exception, were significantly below values for the antimitotic agents paclitaxel and vinblastine. Flow cytometry and microscopic examination of tumor cells treated with cryptophycin 52 indicated that they accumulated in the mitotic phase of the cell cycle. Cryptophycin 52 was tested for its sensitivity to multidrug-resistance in several paired cell lines in which a sensitive parental line was matched with a multidrug-resistant derivative line. The resistant lines have been shown to over express Pgp and/or MRP multidrug-resistance transport factors. Compared to other antimitotic agents (paclitaxel, vinblastine, vincristine), the potency of cryptophycin 52 was shown to be minimally affected in multidrug-resistant cells compared to their sensitive parental lines. CONCLUSION: Cryptophycin 52 has potent antimitotic, antiproliferative and cytotoxic activity in in vitro human tumor cell models. It is significantly more potent and less sensitive to multidrug resistance mechanisms than other antimitotic antitumor agents currently used in cancer therapy. These characteristics may translate into therapeutic advantages for the clinical use of cryptophycin 52 in cancer chemotherapy.
Antineoplastic Agents↗
Protein kinase C-dependent activation of NF-kappaB in enterocytes is independent of IkappaB degradation.
BACKGROUND & AIMS: Nuclear translocation of the NF-kappaB family of transcription factors is a proximal step in the signal transduction of a pleiotropic group of proinflammatory genes. Activation of RelA is under the negative control of IkappaB, a family of proteins degraded in response to immunologic and oxidant stimuli. The aim of this study was to examine this mechanism of NF-kappaB activation in intestinal epithelial cells. METHODS: DLD-1 cell monolayers stimulated by interleukin (IL)-1beta or phorbol myristate acetate (PMA) were assayed for the nuclear translocation of NF-kappaB and immunoreactivity of various IkappaB isoforms that regulate NF-kappaB1/RelA activation. RESULTS: NF-kappaB activation triggered by PMA was not associated with the disappearance of immunoreactive IkappaBalpha, IkappaBbeta, IkappaBgamma, or IkappaBepsilon or with the dissociation of intact IkappaB from RelA. NF-kappaB activation induced by PMA was blocked by the protein kinase C inhibitor staurosporine but not by the proteasomal inhibitor N-acetyl-leucine leucine norleucinal (ALLN). In contrast, IL-1beta-induced NF-kappaB activation was associated with the disappearance of IkappaBalpha and was inhibited by ALLN but not staurosporine. CONCLUSIONS: Our data imply the existence of a novel pathway of NF-kappaB activation mediated by protein kinase C that does not require proteosomal degradation or the loss of IkappaB.
Biological Transport↗
Pattern span: a tool for unwelding visuo-spatial memory.
Evidence showing that non-verbal short-term memory has distinct visual and spatial/sequential components is reviewed. A new test, The Visual Patterns Test (VPT), which was designed to measure short-term visual memory largely shorn of its spatio-sequential component, is described. Correlational studies of the VPT and the Corsi Blocks Test with healthy subjects and brain-damaged patients indicate a separation between visual and sequential abilities. This separation of function is supported by double dissociations shown by patients. Moreover, in a selective interference experiment, the VPT and the Corsi tests were found to show a double dissociation pattern of interference from visual and spatio sequential subsidiary tasks, respectively. The present results are discussed in relation to other findings in the literature, and it is concluded that non-verbal short-term memory can indeed be viewed as comprising distinct visual and spatio-sequential components. The VPT will be a useful neuropsychological instrument for measuring the visual component.
Adolescent↗
The use and action of drugs in analyzing mitosis.
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Animals↗
Cognitive asymmetry patterns in schizophrenia: retest reliability and modification with recovery.
In schizophrenia syndrome-related recognition memory impairments have been demonstrated to be dependent on hemispheric specialisation--word deficits (left hemisphere) in a Withdrawn syndrome and face deficits (right hemisphere) in an Active syndrome. Deficits were largely absent in recovered patients. Here the in state/trait nature was examined through longitudinal investigation of 33 patients. In 19 patients who were tested when psychotic and when symptoms remitted (with order randomised) memory improved with recovery, particularly word memory in Withdrawn patients and face memory in Active patients. In patients who presented with different syndromes on separate admissions there was evidence that cognitive asymmetry patterns reversed with syndrome changes. In nine patients in whom the retest reliability of syndrome-asymmetry relations was examined across repeat admissions or periods or recovery, the asymmetries were stable. In sum, further evidence was disclosed of reliable associations between left vs. right preferential hemispheric impairment and syndromes based on activity vs. withdrawal. Acknowledgement of the importance of this individual difference may assist in elucidating heterogeneity of cognitive function in schizophrenia. Reversals of asymmetry support a functional component to recognition memory deficits in schizophrenia with possible relevance to the recovery process.
Adult↗
Benzyl alcohol as an alternative local anesthetic.
STUDY OBJECTIVES: Benzyl alcohol has been used as a local anesthetic for brief superficial skin procedures; however, its efficacy for long-term cutaneous anesthesia has not been established. We sought to compare the cutaneous anesthetic effects of benzyl alcohol with epinephrine with the effects of lidocaine with epinephrine and with placebo. METHODS: This study was a prospective, randomized, double-blind, placebo-controlled clinical trial of 30 healthy paid adult volunteers. Subjects received 1-mL intradermal injections of benzyl alcohol.9% with 1:100,000 epinephrine, lidocaine 1% with 1:100,000 epinephrine, and physiologic saline solution without benzyl alcohol as placebo in a randomized, double-blind fashion. Pain on injection and degree of anesthesia at 5, 15, 30, and 45 minutes was assessed with a 10-cm graded visual analog scale (VAS). Statistical significance was determined by repeated measures ANOVA between groups with a Neuman-Keuls test for post hoc comparison of means and Student's t test for paired means. RESULTS: Benzyl alcohol was 48% less painful on injection than placebo (P <.008) and 42% less painful on injection than lidocaine with epinephrine (P <.05). Lidocaine with epinephrine and placebo were equally painful on injection. After the 5-minute measurement, benzyl alcohol provided significantly better anesthesia than placebo during the remaining observation period (VAS score 48%, 49%, and 51% decreased from baseline at 15, 30, and 45 minutes, respectively, all P <.02 versus placebo). However, benzyl alcohol provided less effective anesthesia than lidocaine with epinephrine (VAS score 72%, 76%, 84%, and 88% decreased from baseline at 5, 15, 30, and 45 minutes, respectively, all P <.001 versus placebo) throughout most of the observation period. CONCLUSION: Benzyl alcohol with epinephrine provides prolonged cutaneous anesthesia, although it is not as effective as lidocaine with epinephrine. However, benzyl alcohol is significantly less painful on injection than lidocaine with epinephrine, and it may offer an alternative for local anesthesia.
Adult↗
Relations with news media: perceptions of healthcare executives.
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Attitude of Health Personnel↗
Cognitive asymmetry patterns in schizophrenia: active and withdrawn syndromes and sex differences as moderators.
Recognition memory for words and faces was examined in male and female schizophrenia patients for evidence of associations between putative left-right hemisphere asymmetry patterns and active (positive) versus withdrawn (negative) syndromes. Ninety-five normal controls and 104 schizophrenia patients with active, withdrawn, and mixed syndromes or in symptom remission were examined, including an unmedicated subgroup. Memory was poorer in patients than controls, while the remitted group had superior memory to psychotic patients. Active and withdrawn patients showed the hypothesized syndrome-dependent cognitive asymmetries: active (word > faces); withdrawn (faces > words), except active females who showed a word deficit. The results support selective lateralized temporoparietal impairment of either hemisphere in schizophrenia, with laterality related to active (face memory/right-sided impairment) and withdrawn (word memory/left-sided impairment) syndromes, except active syndrome females. These syndrome-related asymmetries moderated the sexually dimorphic asymmetries found in normal subjects. Consideration of individual differences both in sex and syndromes based on activity and withdrawal, and of left and right hemisphere memory modality, may assist in unraveling heterogeneity in schizophrenic cognition. The superior memory of recovered patients indicates that some memory impairment in schizophrenia is functional.
Adult↗
Repetitive transcranial magnetic stimulation in the treatment of medication-resistant depression: preliminary data.
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Adult↗
Effects of immunomodulation with interferon-gamma on hepatic ischemia-reperfusion injury.
The development of an inflammatory response after injury depends on the participation of a variety of cell populations and endogenous mediators. Interferon-gamma (IFN-gamma) is a potent cellular immunomodulating cytokine that contributes to acute and chronic inflammation. In this study, the effects of immunomodulation on ischemia-reperfusion injury were examined using increasing doses of recombinant, rabbit-specific IFN-gamma in an in situ model of hepatic ischemia-reperfusion. Pretreatment with low dose IFN-gamma augmented injury as measured by histology, aminotransferase concentrations, and myeloperoxidase activity. By contrast, high dose IFN-gamma pretreatment, equivalent to IFN-gamma supplements used in clinical trials, resulted in a lack of neutrophil infiltration and minimal progression of late phase, neutrophil-mediated reperfusion injury. These results suggest that immunomodulating mediators such as IFN-gamma may play a regulating role in the evolution of ischemia-reperfusion, contributing to the development and resolution of acute hepatic injury.
Adjuvants, Immunologic↗
Mechanisms of self-tolerance and autoimmunity: from whole-animal phenotypes to molecular pathways.
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Animals↗
Multiplex PCR for detection and typing of porcine circoviruses.
Sets of oligonucleotide primers were designed according to the sequences of the open reading frames (ORFs) ORF1 and ORF2 of the prototype nonpathogenic PK-15 strain of porcine circovirus (PCV) type 1 (PCV-1). By the PCR performed with the various primer sets, genomic DNA or RNA from other bacterial or viral pathogens of the respiratory tracts of pigs could not be amplified. A positive amplification reaction could be visualized with DNA extracted from a viral suspension containing as few as 10 viral particles per ml. No DNA fragment could be amplified from lysates of continuous porcine cell lines (PT, ST, and PFT cells) known to be negative for PCV. When tested with clinical samples from pigs, the results of the single PCR method showed nearly 93% (13 of 14 samples) correlation with histopathological and immunohistochemical findings. Interestingly, subclinical PCV infections could be detected by single PCR with clinical samples that have been submitted from animals with irrelevant cases of respiratory and/or enteric problems. On the basis of the nucleotide sequences of PCV strains (PCV-2) recently associated with outbreaks of postweaning multisystemic wasting syndrome (PWMS) in Quebec, Canada, pig farms, other primers were designed from the PCV-1 genome, and these primers failed to amplify genomic fragments specific to the ORF1 or ORF2 genes of clinical isolates associated with PWMS but amplified DNA from the PCV-1 strain. Two rapid multiplex PCR (mPCR) methods have been developed to distinguish between both genotypes of PCV. By those two mPCR methods, (i) species-specific primer pairs were used to amplify a DNA fragment of 488 bp specific for the ORF2 genes of both genotypes, whereas a 375-bp fragment was amplified from the ORF1 gene of the PCV-1 strain only, or (ii) species-specific primer pairs were used to amplify a DNA fragment of 646 bp specific for the ORF1 genes of both genotypes, whereas a 425-bp fragment was amplified from the ORF2 gene of the PCV-1 strain only. By both mPCR methods, a PCV-2 infection was demonstrated in tissues of 94.2% (33 of 35) of the sick pigs tested, in agreement with previous findings showing the close association of this new genotype of PCV with outbreaks of PMWS in Europe and North America. On the other hand, a PCV-1 infection was confirmed in only 5.7% (2 of 35) of the pigs, and confirmation of a mixed infection with PCV-2 was obtained by a single PCR with PCV-2-specific primers.
Animals↗
Modulation of microtubule dynamics by drugs: a paradigm for the actions of cellular regulators.
Microtubules are intrinsically dynamic polymers. Two kinds of dynamic behaviors, dynamic instability and treadmilling, are important for microtubule function in cells. Both dynamic behaviors appear to be tightly regulated, but the cellular molecules and the mechanisms responsible for the regulation remain largely unexplored. While microtubule dynamics can be modulated transiently by the interaction of regulatory molecules with soluble tubulin, the microtubule itself is likely to be the primary target of cellular molecules that regulate microtubule dynamics. The antimitotic drugs that modulate microtubule dynamics serve as excellent models for such cellular molecules. Our laboratory has been investigating the interactions of small drug molecules and stabilizing microtubule-associated proteins (MAPs) with microtubule surfaces and ends. We find that drugs such as colchicine, vinblastine, and taxol, and stabilizing MAPs such as tau, strongly modulate microtubule dynamics at extremely low concentrations under conditions in which the microtubule polymer mass is minimally affected. The powerful modulation of the dynamics is brought about by the binding of only a few drug or MAP molecules to distinct binding sites at the microtubule surface or end. Based upon our understanding of the well-studied drugs and stabilizing MAPs, it is clear that molecules that regulate dynamics such as Kin 1 and stathmin could bind to a large number of distinct tubulin sites on microtubules and employ an array of mechanisms to selectively and powerfully regulate microtubule dynamics and dynamics-dependent cellular functions.
Animals↗