Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 54
Filter
1.
Mol Psychiatry ; 19(8): 872-9, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24126926

ABSTRACT

Schizophrenia (SZ) and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders that may share an underlying pathology suggested by shared genetic risk variants. We sequenced the exonic regions of 215 genes in 147 ASD cases, 273 SZ cases and 287 controls, to identify rare risk mutations. Genes were primarily selected for their function in the synapse and were categorized as: (1) Neurexin and Neuroligin Interacting Proteins, (2) Post-synaptic Glutamate Receptor Complexes, (3) Neural Cell Adhesion Molecules, (4) DISC1 and Interactors and (5) Functional and Positional Candidates. Thirty-one novel loss-of-function (LoF) variants that are predicted to severely disrupt protein-coding sequence were detected among 2 861 rare variants. We found an excess of LoF variants in the combined cases compared with controls (P=0.02). This effect was stronger when analysis was limited to singleton LoF variants (P=0.0007) and the excess was present in both SZ (P=0.002) and ASD (P=0.001). As an individual gene category, Neurexin and Neuroligin Interacting Proteins carried an excess of LoF variants in cases compared with controls (P=0.05). A de novo nonsense variant in GRIN2B was identified in an ASD case adding to the growing evidence that this is an important risk gene for the disorder. These data support synapse formation and maintenance as key molecular mechanisms for SZ and ASD.


Subject(s)
Child Development Disorders, Pervasive/genetics , Genetic Predisposition to Disease/genetics , Mutation/genetics , Nerve Tissue Proteins/genetics , Schizophrenia/genetics , Case-Control Studies , Female , Humans , Male , Middle Aged , White People/genetics
2.
Clin Pharmacol Ther ; 83(2): 368-71, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18091762

ABSTRACT

A framework for developing evidentiary standards for qualification of biomarkers is a key need identified in the Food and Drug Administration's Critical Path Initiative. This article describes a systematic framework that was developed by Pharmaceutical Research and Manufacturers of America (PhRMA) committees and tested at a workshop in collaboration with the Food and Drug Administration and academia. With some necessary refinements, this could be applied to create an appropriately individualized evidentiary standard for any biomarker purpose.


Subject(s)
Biomarkers, Pharmacological/analysis , Biomarkers/analysis , Clinical Trials as Topic/standards , Diagnostic Tests, Routine/standards , Drug Evaluation, Preclinical/standards , Animals , Cooperative Behavior , Drug Industry , Humans , Program Development , Quality Control , Reproducibility of Results , Risk Assessment , United States , United States Food and Drug Administration
3.
Mol Psychiatry ; 10(11): 1017-25, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16044173

ABSTRACT

Genetic studies implicating the region of human chromosome 18p11.2 in susceptibility to bipolar disorder and schizophrenia have observed parent-of-origin effects that may be explained by genomic imprinting. We have identified a transcriptional variant of the GNAL gene in this region, employing an alternative first exon that is 5' to the originally identified start site. This alternative GNAL transcript encodes a longer functional variant of the stimulatory G-protein alpha subunit, Golf. The isoforms of Golf display different expression patterns in the CNS and functionally couple to the dopamine D1 receptor when heterologously expressed in Sf9 cells. In addition, there are CpG islands in the vicinity of both first exons that are differentially methylated, a hallmark of genomic imprinting. These results suggest that GNAL, and possibly other genes in the region, is subject to epigenetic regulation and strengthen the case for a susceptibility gene in this region.


Subject(s)
Alternative Splicing , Bipolar Disorder/genetics , Chromosomes, Human, Pair 18/genetics , GTP-Binding Protein alpha Subunits/genetics , Genomic Imprinting , Schizophrenia/genetics , Amino Acid Sequence , Animals , Base Sequence , Cell Line , Central Nervous System/metabolism , CpG Islands , DNA Methylation , DNA, Complementary/genetics , Epigenesis, Genetic , Exons , Female , Humans , Male , Molecular Sequence Data , Recombinant Proteins/genetics , Sequence Homology, Amino Acid , Spodoptera , Transcription, Genetic
4.
Bioorg Med Chem Lett ; 10(20): 2291-4, 2000 Oct 16.
Article in English | MEDLINE | ID: mdl-11055341

ABSTRACT

A method for the solid-phase synthesis of P1 arginine containing peptides via attachment of the arginine side-chain guanidine group is described. This procedure is applied to the preparation of a tetrapeptide, P1 arginine aminocoumarin PS-SCL. This library was validated by using it to determine the P4-P2 specificity for thrombin and comparing the results to the known thrombin subsite specificity. This is the first reported example of a PS-SCL library containing a P1 arginine.


Subject(s)
Arginine , Coumarins , Oligopeptides/chemical synthesis , Peptide Library , Serine Endopeptidases/metabolism , Thrombin/metabolism , Trypsin/metabolism , Humans , Oligopeptides/chemistry , Oligopeptides/metabolism , Protein Conformation , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Structure-Activity Relationship , Substrate Specificity
5.
Immunopharmacology ; 48(2): 199-212, 2000 Jul 20.
Article in English | MEDLINE | ID: mdl-10936517

ABSTRACT

C3 convertase is a key enzyme in the complement cascade and is an attractive therapeutic target for drug design. Recent studies have demonstrated that this enzyme is inhibited by compstatin (Morikis, D. , Assa-Munt, N., Sahu, A., Lambris, J.D., 1998. Solution structure of Compstatin, a potent complement inhibitor. Protein Sci. (7) 619-627; Sahu, A., Kay, B.K., Lambris, J.D., 1996. Inhibition of human complement by a C3-binding peptide isolated from a phage-displayed random peptide library. J. Immunol. (157) 884-891), a 13 amino acid cyclic peptide that binds to C3. Since the enzyme exhibits some homology to serine proteases, substrate-based design could be another avenue for drug design. In this study, we confirm the activity of compstatin using different sources of enzyme and different assay systems. We also tested the activity of substituted compstatin analogs and compared the selectivity and toxicity of these compounds to peptidyl alpha-ketoheterocyclic compounds. Our work confirms the activity of compstatin in both alternative and classical complement pathways, describes 11 new active analogs of this cyclic peptide, and provides evidence for key segments of the peptide for activity. Compstatin and related active analogs showed little or no inhibition of clotting or key enzymes in the clotting cascade nor did they appear to have significant cytotoxicity. The characteristics of compstatin suggest that this peptide and its analogs could be attractive candidates for further clinical development. By contrast, known serine protease inhibitors, including peptidyl alpha-ketoheterocycles, did not inhibit C3 convertase illustrating the atypical nature of this enzyme.


Subject(s)
Complement Activation/drug effects , Complement C3/antagonists & inhibitors , Complement Inactivator Proteins/pharmacology , Peptides, Cyclic/pharmacology , Serine Proteinase Inhibitors/pharmacology , Complement C3/metabolism , Complement C3-C5 Convertases/antagonists & inhibitors , Complement Factor B/analysis , Complement Factor B/antagonists & inhibitors , Hemolysis/drug effects , Humans , Immunoenzyme Techniques , Peptides, Cyclic/chemical synthesis
6.
J Immunol ; 162(1): 366-71, 1999 Jan 01.
Article in English | MEDLINE | ID: mdl-9886408

ABSTRACT

It is generally accepted that TCR alphabeta+ CD8+ T cells recognize immunogenic peptides bound to MHC-encoded class I molecules. This recognition is a major component of the cellular response mediating immune protection and recovery from viral infections and from certain intracellular bacterial infections. Here, we report two human CD8+ TCR alphabeta+ T cell lines specific for Mycobacterium tuberculosis Ags presented in the context of CD1a or CD1c Ag-presenting molecules. These T cells recognize lipid Ags and display cytotoxicity as well as strong Th cell type I cytokine responses. By extending presentation by the CD1 system to the major TCR alphabeta+ CD8+ T cell pool, this system gains wider applicability beyond the double negative subset of T cells previously shown to have this reactivity. This implies that previous assumptions about the role of CD8+ T cells in microbial immunity may require revision as the relative proportions of CD1-restricted and MHC class I-restricted CD8+ T cells are further defined.


Subject(s)
Antigens, Bacterial/immunology , Antigens, CD1/physiology , CD8-Positive T-Lymphocytes/metabolism , Epitopes, T-Lymphocyte/immunology , Lipids/immunology , Receptors, Antigen, T-Cell, alpha-beta/immunology , T-Lymphocyte Subsets/metabolism , Antibodies, Blocking/pharmacology , Antibodies, Monoclonal/pharmacology , CD8-Positive T-Lymphocytes/immunology , Cell Line , Chromatography, Gel , Cytokines/biosynthesis , Cytotoxicity Tests, Immunologic , Glycolipids/immunology , Glycolipids/isolation & purification , Humans , Lipids/isolation & purification , Lymphocyte Activation , Mycobacterium tuberculosis/immunology , Phospholipids/immunology , Phospholipids/isolation & purification , T-Lymphocyte Subsets/immunology
7.
Nurs Times ; 94(37): 54-5, 1998.
Article in English | MEDLINE | ID: mdl-9832790

ABSTRACT

There has been a rapid increase in the number of so-called new roles in nursing. These have tended to develop in a random way. Consequently, titles are not a good indicator of what the role entails. The qualifications required to undertake a particular role are not clear and tend to be locally defined. This paper discusses the implications of this situation. Two subsequent articles will examine issues around patient consent, care provided by nurses in new roles and legality and accountability.


Subject(s)
Job Description , Nurse Clinicians/organization & administration , Nurse Practitioners/organization & administration , Humans , Nurse Clinicians/education , Nurse Practitioners/education
8.
Nurs Times ; 94(38): 52-3, 1998.
Article in English | MEDLINE | ID: mdl-9832816

ABSTRACT

The development of new nursing roles is set to continue. Patients may not always be aware that the person giving them care is a nurse. This paper explores some of the issues of ethics, equity and consent as nursing becomes involved in more invasive and independent areas of practice.


Subject(s)
Ethics, Nursing , Informed Consent , Job Description , Nurse-Patient Relations , Patient Advocacy , Humans
9.
Nurs Times ; 94(39): 61-2, 1998.
Article in English | MEDLINE | ID: mdl-9832847

ABSTRACT

The accountability of health care professionals is determined by what can reasonably be expected from an appropriately qualified practitioner. The recent proliferation of new roles raises the issue of what can be expected from postholders when their practice is questioned. This paper discusses the legal implications of roles that blur the boundaries between established professional groups.


Subject(s)
Job Description , Nursing Care/standards , Professional Autonomy , Professional Competence/legislation & jurisprudence , Humans , United Kingdom
10.
Nurs Times ; 93(39): 20, 1997.
Article in English | MEDLINE | ID: mdl-9355543
11.
Science ; 278(5336): 283-6, 1997 Oct 10.
Article in English | MEDLINE | ID: mdl-9323206

ABSTRACT

The human CD1b protein presents lipid antigens to T cells, but the molecular mechanism is unknown. Identification of mycobacterial glucose monomycolate (GMM) as a CD1b-presented glycolipid allowed determination of the structural requirements for its recognition by T cells. Presentation of GMM to CD1b-restricted T cells was not affected by substantial variations in its lipid tails, but was extremely sensitive to chemical alterations in its carbohydrate or other polar substituents. These findings support the view that the recently demonstrated hydrophobic CD1 groove binds the acyl chains of lipid antigens relatively nonspecifically, thereby positioning the hydrophilic components for highly specific interactions with T cell antigen receptors.


Subject(s)
Antigen Presentation , Antigens, CD1/immunology , Glycolipids/immunology , T-Lymphocyte Subsets/immunology , Antigens, Bacterial/immunology , Antigens, CD1/chemistry , Antigens, CD1/metabolism , Epitopes/immunology , Glycolipids/chemistry , Glycolipids/metabolism , Glycosylation , Humans , Ligands , Mass Spectrometry , Mycobacterium/immunology , Mycolic Acids/chemistry , Mycolic Acids/immunology , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism
12.
Biochemistry ; 36(19): 5685-94, 1997 May 13.
Article in English | MEDLINE | ID: mdl-9153408

ABSTRACT

The multidrug resistant cell line CEM/VBL300 and the parental CEM T-lymphoblastic cell line from which it was derived were used to study the accumulation of fluorescent phospholipid analogs of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS). The fluorescent analogs NBD-PC, NBD-PE, and NBD-PS and [3H]PC were delivered in liposomes prepared by ethanol injection. Fluorescence microscopy demonstrated decreased accumulation of the NBD-PC analog in the multidrug resistant cell line compared to the parental cell line. Verapamil enhanced NBD-PC accumulation in the resistant cells. Similar results were obtained with insect cells expressing high levels of recombinant human MDR1. Elimination of NBD fluorescence on the outer leaflet of the plasma membrane with dithionite permitted quantification of the internal cellular fluorescence by FACS analysis. The drug resistant CEM/VBL300 cells accumulated approximately 10% the amount of NBD-PE and 20% the amount of NBD-PC compared to CEM drug sensitive cells. No difference in internal accumulation of NBD-PS was found between the drug resistant and drug sensitive cell lines. The internal accumulation of NBD-PE and NBD-PC was enhanced by the MDR reversal agents verapamil, cyclosporin A, and SDZ PSC 833 in the CEM/VBL300 cells but not in the CEM cells. The increased accumulation was dose dependent, and the relative potency of the reversal agents paralleled their ability to circumvent multidrug resistance. In addition, the monoclonal antibody UIC2 directed against the P-glycoprotein produced similar results. The evidence presented here suggests that PC and PE but not PS behave as substrates for human MDR1 P-glycoprotein.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Drug Resistance, Multiple , Phosphatidylcholines/metabolism , Phosphatidylethanolamines/metabolism , 4-Chloro-7-nitrobenzofurazan/analogs & derivatives , 4-Chloro-7-nitrobenzofurazan/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/biosynthesis , Fluorescent Dyes , Humans , Leukemia, T-Cell/metabolism , Microscopy, Fluorescence , Phospholipids/metabolism , Substrate Specificity , Tumor Cells, Cultured
13.
J Infect Dis ; 175(3): 661-8, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9041339

ABSTRACT

Pneumocystis carinii lipids are similar to host lipids, but it is not known if some of these lipids are acquired from host cells. The ability of P. carinii to incorporate a fluorescent fatty acid analogue (Bodipy-C12) was analyzed, the metabolism of the incorporated lipid by P. carinii was characterized, and lipid transfer from human alveolar epithelial cells (A549) to P. carinii was investigated. Both P. carinii and A549 cells incorporated exogenous Bodipy-C12 in a concentration-dependent manner. Biochemical analysis of labeled P. carinii revealed incorporation of Bodipy-C12 into complex lipid classes. Incubation of unlabeled P. carinii with Bodipy-C12-labeled A549 cells demonstrated lipid transfer to P. carinii, a process facilitated by attachment. These data suggest that P. carinii can incorporate and modify an exogenous fluorescent lipid. The observed transfer of lipid from A549 cells to P. carinii provides important insight into the interaction of this organism with alveolar epithelial cells.


Subject(s)
Membrane Lipids/metabolism , Pneumocystis/metabolism , Animals , Boron Compounds , Cells, Cultured , Epithelium/parasitology , Fatty Acids/metabolism , Humans , Pulmonary Alveoli/parasitology , Rats
14.
Nurs Stand ; 11(25): 33-8, 1997 Mar 12.
Article in English | MEDLINE | ID: mdl-9115870

ABSTRACT

An assessment tool was developed to measure patient dependency and staff skill mix in a child psychiatry inpatient unit. The authors discuss the results of a three-month pilot implementation. The implications for practice include adjustments in staff duty rotas, allocation of skill mix and the systematic assessment of patient dependency before inpatient admission.


Subject(s)
Activities of Daily Living , Clinical Competence , Inpatients/classification , Nursing Assessment , Nursing Staff, Hospital/supply & distribution , Personnel Staffing and Scheduling , Child Psychiatry , Humans , Nursing Administration Research , Pilot Projects
15.
J Immunol ; 157(7): 2795-803, 1996 Oct 01.
Article in English | MEDLINE | ID: mdl-8816382

ABSTRACT

Previous studies suggest that CD1 is a family of Ag-presenting molecules distantly related to those encoded by the MHC. However, of the four known human CD1 proteins, only CD1b has been shown to restrict Ag-specific T cell responses. In this study, we have shown that a second member of the human CD1 family, CD1c, could also mediate Ag presentation to T cells. Three T cell lines recognizing mycobacterial Ags in a CD1c-restricted manner were isolated from normal donor blood. These T cells were MHC unrestricted, and their recognition of Ag was independent of the products of the transporter associated with Ag presentation-1/2 and DMA/B genes that are generally required for Ag presentation by MHC-encoded Ag-presenting molecules. Furthermore, unlike MHC-restricted responses to peptides, the CD1c-restricted T cell lines recognized protease-resistant mycobacterial lipid Ags. These T cell lines also showed significant cytotoxicity toward CD1c-expressing target cells even in the absence of mycobacterial Ags, which was shown by clonal analysis to be mediated by a subpopulation of T cells directly reactive to CD1c molecules. Our findings establish the ability of a second member of the CD1 family to restrict responses of Ag-specific T cells, and thus support the general hypothesis that the CD1 family comprises a third lineage of Ag-presenting molecules that presents a novel class of foreign and self Ags to MHC-unrestricted T cells.


Subject(s)
Antigen Presentation , Antigens, CD1/immunology , Mycobacterium tuberculosis/immunology , T-Lymphocyte Subsets/immunology , Antigens, Bacterial/immunology , Antigens, CD1/classification , Cell Line , Humans , Lipopolysaccharides/immunology , Mannosides/immunology , Membrane Glycoproteins/immunology , Phosphatidylinositols/immunology
16.
Headache ; 36(9): 542-6, 1996 Oct.
Article in English | MEDLINE | ID: mdl-8916562

ABSTRACT

To assess the impact of sumatriptan in clinical practice, we undertook a retrospective analysis of the government of Newfoundland and Labrador's prescription drug program data base for 35 consecutive patients prescribed sumatriptan. The number of doses of all drugs prescribed ranged from 121 to 18,874 on from 4 to 357 prescriptions per patient over 1 to 19 months. The mean number of doses of analgesic drugs prescribed before sumatriptan therapy was 56 per month and after initiation of sumatriptan was 46 per month. The prescribing of multiple analgesics was common; 79% received three or more different analgesics. Twenty-two (63%) patients were prescribed medications indicated for the prophylaxis of migraine concomitantly with drugs indicated for symptomatic treatment. Twenty-four (69%) patients were prescribed medication capable of inducing migraine. We conclude that sumatriptan did not have a major impact on the outcomes of these patients judged by their use of analgesics. The simplest explanation is that many of the patients were suffering from analgesic-induced headache rather than migraine. In addition, we conclude that there were deficiencies in prescribing practices including numbers, quantities, and choice of analgesics; the use of analgesics concomitantly with drugs indicated for migraine prophylaxis; and the use of drugs capable of inducing migraine. Further research is required to validate these findings.


Subject(s)
Analgesics/therapeutic use , Drug Prescriptions/statistics & numerical data , Headache/drug therapy , Migraine Disorders/drug therapy , Practice Patterns, Physicians' , Serotonin Receptor Agonists/therapeutic use , Sumatriptan/therapeutic use , Analgesics/adverse effects , Cohort Studies , Headache/chemically induced , Humans , Migraine Disorders/prevention & control , Newfoundland and Labrador , Retrospective Studies , Treatment Outcome
17.
J Adv Nurs ; 23(6): 1254-62, 1996 Jun.
Article in English | MEDLINE | ID: mdl-8796476

ABSTRACT

Self-administration of medicine (SAM) programmes for hospital in-patients have become increasingly popular. Such programmes are considered to facilitate education and learning. A quasi-experimental, longitudinal study was carried out to examine and compare knowledge acquisition, drug compliance, and satisfaction between patients who self-administered their medications and those who did not. Improvements in knowledge and compliance with medication regimes could not be linked directly with a SAM programme. All patients had a high level of knowledge of their medications and appeared to be compliant with prescribed drug regimes. Study findings support the hypothesis that knowledge improves with time, regardless of how medications are administered, but do not support the hypothesis that patients who self-administrate are more knowledgeable about their medications than those who do not. Therefore, SAM programmes may improve patient knowledge but opportunities to obtain knowledge may not be unique to such programmes. The ward or unit philosophy may be such that other patients, who are less willing or able to participate directly in their own care, also have the opportunity to improve their knowledge.


Subject(s)
Health Knowledge, Attitudes, Practice , Patient Compliance , Patient Satisfaction , Self Administration/psychology , Humans , Longitudinal Studies , Nurse-Patient Relations , Program Evaluation , Statistics, Nonparametric
18.
J Clin Nurs ; 5(2): 85-90, 1996 Mar.
Article in English | MEDLINE | ID: mdl-8696602

ABSTRACT

The purposes of this study were twofold. The first was to determine the rationale behind the adoption of a self-care approach to nursing. The second, to determine how a self-care philosophy is applied in practice. The study was carried out from a phenomenological perspective, as it facilitated an understanding of nursing practice from the practitioners' perspective. The adoption of a self-care philosophy and approach to caring, appears to have evolved through patients need. This finding has implications for all practitioners.


Subject(s)
Chronic Disease/nursing , Philosophy, Nursing , Practice Patterns, Physicians' , Self-Care Units/organization & administration , Holistic Nursing , Humans , Nursing Methodology Research , Patient Care Planning
19.
Br J Nurs ; 5(6): 349-52, 1996.
Article in English | MEDLINE | ID: mdl-8704462

ABSTRACT

This article describes how a nursing development unit (NDU), through the evolution of a self-care philosophy, responded to the changing needs and demands of patients. Patients in the NDU appeared to want to be more informed and involved in their health care. In addition, decreased length of stay as a result of increased sophistication of medical techniques and the need to have a faster throughput of patients has meant that a philosophy is required which is focused around empowering patients to take ownership for their own health care. The application of this philosophy is demonstrated through a case study which describes the experience of a gentleman who was cared for within the NDU.


Subject(s)
Clinical Nursing Research/organization & administration , Patient Participation , Self-Care Units/organization & administration , Humans , Length of Stay , Male , Middle Aged , Organizational Policy , Patient Care Planning , Philosophy, Nursing
20.
Prof Nurse ; 11(5): 309-11, 1996 Feb.
Article in English | MEDLINE | ID: mdl-8604425

ABSTRACT

The key characteristic of primary nursing is a flattening of the traditional nursing hierarchy. Therefore, it is essential that each practitioner of primary nursing fully understands both his/her own role and that of his/her co-workers. Few studies have examined how practitioners of primary nursing view their role and the roles of others.


Subject(s)
Attitude of Health Personnel , Nursing Staff, Hospital/psychology , Humans , Job Description , Nursing Methodology Research , Primary Nursing/organization & administration , Surveys and Questionnaires
SELECTION OF CITATIONS
SEARCH DETAIL
...