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Biomedical subjects

M Williams

Publications and source records attributed to M Williams.

At least 271 records · Page 15Linked to original sources
PubMed1998

Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA.

Huntington disease (HD) is an adult-onset, autosomal dominant inherited human neurodegenerative disorder characterized by hyperkinetic involuntary movements, including motor restlessness and chorea, slowing of voluntary movements and cognitive impairment. Selective regional neuron loss and gliosis in striatum, cerebral cortex, thalamus, subthalamus and hippocampus are well recognized as neuropathological correlates for the clinical manifestations of HD. The underlying genetic mutation is the expansion of CAG trinucleotide repeats (coding for polyglutamines) to 36-121 copies in exon 1 of the HD gene. The HD mRNA and protein product (huntingtin) show widespread distribution, and thus much remains to be understood about the selective and progressive neurodegeneration in HD. To create an experimental animal model for HD, transgenic mice were generated showing widespread expression of full-length human HD cDNA with either 16, 48 or 89 CAG repeats. Only mice with 48 or 89 CAG repeats manifested progressive behavioural and motor dysfunction with neuron loss and gliosis in striatum, cerebral cortex, thalamus and hippocampus. These animals represent clinically relevant models for HD pathogenesis, and may provide insights into the underlying pathophysiological mechanisms of other triplet repeat disorders.

Animals↗
PubMed1998

Treating alcohol problems: a study of programme effectiveness and cost effectiveness according to length and delivery of treatment.

AIMS: To compare effectiveness and cost-effectiveness of a 5-week inpatient and a two week in- and day-patient regime. DESIGN: Pre-post assessment of consecutive treatment referrals with follow-up at 6 and 12 months. In a sequential study design, 112 patients underwent a 5-week residential programme while a subsequent 100 patients underwent a 2-week in- and day-patient programme. To investigate the effect of changing programme delivery, patient groups from before and after the programme changes were compared. SETTING: Addiction treatment unit in an independent hospital. PARTICIPANTS: One hundred and thirty-six males and 76 female patients with an ICD-10 diagnosis of Alcohol Dependence Syndrome. MEASUREMENTS: Self-report (Comprehensive Drinkers Profile: Follow-Up Drinkers Profile: SADQ), collateral report (Collateral Interview Form) and blood test (MCV & GGT) data were used to categorize patients into abstinent, non-problem drinker, drinking but improved and unimproved groups. Percentage of days abstinent, intensity of drinking, length of time in treatment, treatment cost and use of aftercare were also measured. FINDINGS: Abstinence or non-problem drinking was achieved by 55.6% of all patients at 1 year. Change in programme delivery did not affect outcome but treatment costs and mean length of stay for the revised programme were significantly reduced. CONCLUSIONS: A two week in- and day-patient treatment was more cost effective than a 5-week inpatient treatment. Design limitations make these conclusions tentative pending a randomized controlled trial.

Alcoholism↗
PubMed1998

The effect of therapeutic touch on pain and anxiety in burn patients.

The purpose of this single-blinded randomized clinical trial was to determine whether therapeutic touch (TT) versus sham TT could produce greater pain relief as an adjunct to narcotic analgesia, a greater reduction in anxiety, and alterations in plasma T-lymphocyte concentrations among burn patients. Therapeutic touch is an intervention in which human energies are therapeutically manipulated, a practice conceptually supported by Rogers' (1970) theory of unitary human beings. Data were collected at a university burn centre in the south-eastern United States. The subjects were 99 men and women between the ages of 15 and 68 hospitalized for severe burns, and they received either TT or sham TT once a day for 5 days. Baseline data were collected on day 1, data were collected before and after treatment on day 3, and post-intervention data were collected on day 6. Instruments included the McGill Pain Questionnaire, Visual Analogue Scales for Pain, Anxiety and Satisfaction with Therapy, and an Effectiveness of Therapy Form. Blood was drawn on days 1 and 6 for lymphocyte subset analysis. Medication usage for pain in mean morphine equivalents, and mean doses per day of sleep, anxiety and antidepressant medications were recorded. Subjects who received TT reported significantly greater reduction in pain on the McGill Pain Questionnaire Pain Rating Index and Number of Words Chosen and greater reduction in anxiety on the Visual Analogue Scale for Anxiety than did those who received sham TT. Lymphocyte subset analyses on blood from 11 subjects showed a decreasing total CD8 + lymphocyte concentration for the TT group. There was no statistically significant difference between groups on medication usage.

Adolescent↗
PubMed1998

Efficient expression of naked plasmid DNA in mucosal epithelium: prospective for the treatment of skin lesions.

Mucocutaneous gene therapy offers exciting new treatment modalities for skin lesions. Transient expression of naked plasmid DNA could be used as a local treatment of various skin lesions where the corresponding gene product (protein) has therapeutic or immunization potential. We analyzed the time course, magnitude, and histologic expression of the indicator plasmid DNA (pCMV:beta-Gal) in mucosal epithelium and papilloma lesions. Upon direct injection of naked plasmid DNA (20 microg) into oral mucosa, expression occurred at high local concentrations, up to 35-fold higher than in comparable injections into the epidermis. Due to the accelerated turnover of mucosal epithelium beta-galactosidase positive epithelial cells were detected in the basal and suprabasal layers as early as 3 h after injection, whereas only the most superficial mucosal layers demonstrated beta-galactosidase staining at 24 h post-injection. These biologic characteristics need to be taken into consideration when clinical applications of expressing naked plasmid DNA in epithelial tissues are considered.

Animals↗
PubMed1998

A prolonged outbreak of Shigella sonnei infections in traditionally observant Jewish communities in North America caused by a molecularly distinct bacterial subtype.

During 1994-1996, Shigella sonnei outbreaks occurred in 8 North American traditionally observant Jewish communities. These communities remain relatively separate from neighboring populations while maintaining close contact by travel with coreligionists in other cities. Epidemiologic investigations suggested community-to-community transmission via travel. Outbreak-related and control isolates of S. sonnei from each city were subtyped by pulsed-field gel electrophoresis (PFGE) to confirm an epidemiologic linkage between outbreaks. Forty-three (94%) of 46 outbreak-related isolates had closely related PFGE patterns, constituting a single subtype; 33 (94%) of 35 control isolates demonstrated unrelated PFGE patterns. Several patterns differing by < or = 3 bands were identified within the outbreak subtype; one of these accounted for 65% of outbreak isolates. Hence, a single subtype of S. sonnei caused an international outbreak involving 8 traditionally observant Jewish communities, but not neighboring populations, over a 2-year period, suggesting sustained propagation of the epidemic strain between communities.

DNA, Bacterial↗
PubMed1998

Double-blind and placebo-controlled study of lithium for adolescent bipolar disorders with secondary substance dependency.

OBJECTIVE: To perform a double-blind, placebo-controlled, random assignment, parallel group, pharmacokinetically dosed study of lithium for adolescents with bipolar disorders (BP) and temporally secondary substance dependency disorders (SDD). METHOD: Subjects were 16.3 +/- 1.2 years old and were comprehensively assessed during a 6-week outpatient protocol that included random weekly urine collection for drug assays and random and weekly serum collection for lithium levels. RESULTS: Using both intent-to-treat (N = 25) and completer (n = 21) analyses, there were significant differences on continuous and categorical measures between the active and placebo groups for both psychopathology measures and weekly random urine drug assays. The mean scheduled weekly serum lithium level of active responders was 0.9 mEq/L. Addiction to both alcohol and marijuana was the most frequent category of SDD. Mean age at onset of BP was 9.6 +/- 3.9 years and of SDD was 15.3 +/- 1.3 years. There were multigenerational mood disorders in 96% and multigenerational SDD in 56% of families. CONCLUSIONS: Lithium treatment of BP with secondary SDD in adolescents was an efficacious treatment for both disorders. These results warrant replication with a long-term maintenance phase. The mean 6-year interval between the onset of BP and onset of SDD strongly argues for earliest recognition of BP.

Adolescent↗
PubMed1998

Methods for providing probe position and temperature information on MR images during interventional procedures.

Interventional magnetic resonance imaging (MRI) can be defined as the use of MR images for guiding and monitoring interventional procedures (e.g., biopsy, drainage) or minimally invasive therapy (e.g., thermal ablation). This work describes the development of a prototype graphical user interface and the appropriate software methods to accurately overlay a representation of a rigid interventional device [e.g., biopsy needle, radio-frequency (RF) probe] onto an MR image given only the probe's spatial position and orientation as determined from a three-dimensional (3-D) localizer used for interactive scan plane definition. This permits 1) "virtual tip tracking," where the probe tip location is displayed on the image without the use of separate receiver coils or a "road map" image data set, and, 2) "extending" the probe to predict its path if it were directly moved forward toward the target tissue. Further, this paper describes the design and implementation of a method to facilitate the monitoring of thermal ablation procedures by displaying and overlaying temperature maps from temperature sensitive MR acquisitions. These methods provide rapid graphical updates of probe position and temperature changes to aid the physician during the actual interventional MRI procedures without altering the usual operation of the MR imager.

Animals↗
PubMed1998

Identification of GS 4104 as an orally bioavailable prodrug of the influenza virus neuraminidase inhibitor GS 4071.

GS 4071 is a potent carbocyclic transition-state analog inhibitor of influenza virus neuraminidase with activity against both influenza A and B viruses in vitro. GS 4116, the guanidino analog of GS 4071, is a 10-fold more potent inhibitor of influenza virus replication in tissue culture than GS 4071. In this study we determined the oral bioavailabilities of GS 4071, GS 4116, and their respective ethyl ester prodrugs in rats. Both parent compounds and the prodrug of the guanidino analog exhibited poor oral bioavailability (2 to 4%) and low peak concentrations in plasma (Cmaxs; Cmax <0.06 microg/ml). In contrast, GS 4104, the ethyl ester prodrug of GS 4071, exhibited good oral bioavailability (35%) as GS 4071 and high Cmaxs of GS 4071 (Cmax = 0.47 microg/ml) which are 150 times the concentration necessary to inhibit influenza virus neuraminidase activity by 90%. The bioavailability of GS 4104 as GS 4071 was also determined in mice (30%), ferrets (11%), and dogs (73%). The plasma of all four species exhibited high, sustained concentrations of GS 4071 such that at 12 h postdosing the concentrations of GS 4071 in plasma exceeded those necessary to inhibit influenza virus neuraminidase activity by 90%. These results demonstrate that GS 4104 is an orally bioavailable prodrug of GS 4071 in animals and that it has the potential to be an oral agent for the prevention and treatment of influenza A and B virus infections in humans.

Acetamides↗
PubMed1998

Public health implications of environmental exposures.

The Agency for Toxic Substances and Disease Registry (ATSDR) is a public health agency with responsibility for assessing the public health implications associated with uncontrolled releases of hazardous substances into the environment. The biological effects of low-level exposures are a primary concern in these assessments. One of the tools used by the agency for this purpose is the risk assessment paradigm originally outlined and described by the National Academy of Science in 1983. Because of its design and inherent concepts, risk assessment has been variously employed by a number of environmental and public health agencies and programs as a means to organize information, as a decision support tool, and as a working hypothesis for biologically based inference and extrapolation. Risk assessment has also been the subject of significant critical review. The ATSDR recognizes the utility of both the qualitative and quantitative conclusions provided by traditional risk assessment, but the agency uses such estimates only in the broader context of professional judgment, internal and external peer review, and extensive public review and comment. This multifaceted approach is consistent with the Council on Environmental Quality's description and use of risk analysis as an organizing construct based on sound biomedical and other scientific judgment in concert with risk assessment to define plausible exposure ranges of concern rather than a single numerical estimate that may convey an artificial sense of precision. In this approach biomedical opinion, host factors, mechanistic interpretation, molecular epidemiology, and actual exposure conditions are all critically important in evaluating the significance of environmental exposure to hazardous substances. As such, the ATSDR risk analysis approach is a multidimensional endeavor encompassing not only the components of risk assessment but also the principles of biomedical judgment, risk management, and risk communication. Within this framework of risk analysis, the ATSDR may rely on one or more of a number of interrelated principles and approaches to screen, organize information, set priorities, make decisions, and define future research needs and directions.

Adaptation, Physiological↗
PubMed1998

HIV risk behaviors associated with the injection process: multiperson use of drug injection equipment and paraphernalia in injection drug user networks.

This study examines drug acquisition and multiperson use of paraphernalia, drugs, and needles/syringes. Ethnographers observed 54 injection episodes in which IDUs were linked by HIV risk behaviors, and developed a typology of higher-risk, lower-risk, and nonsharing-risk networks. Multiperson use of injection paraphernalia or drug solution occurred in most injection events (94%). Serial use of syringes/needles occurred infrequently (14%) relative to "backloading" (37%) and reuse of paraphernalia (cookers 84%, cotton 77%, water 77%). Higher-risk injection networks were characterized by larger size and pooling of resources for drugs. Prevention messages must include avoiding reuse of injection paraphernalia and transfer of drug solution.

Anthropology, Cultural↗
PubMed1998

Time for a change? The process of lengthening booking intervals in general practice.

Longer booking intervals between appointments in general practice are generally seen as 'a good thing', and have a strong 'evidence base' to support them. Changing to longer booking intervals is regarded as a pipe dream by many general practitioners (GPs). This paper reports the process and outcomes of a change to longer booking intervals in one practice, identifies the key elements of the change, and examines lessons learned for the practice, to help other practices to do similarly. The most important factor in bringing about change was the influence of facilitation by outside parties; first, by management consultants who identified solutions to the practice's problems, and secondly, by recruitment to a research study. Other outside influences were an awareness of the success of other practices in changing to 10-minute booking intervals, and the increasing 'evidence base' to support such change. Internal influences on the process were a desire to change as a result a perception that the practice was under-performing, and the stress associated with this. As a result of the change, the number of doctor consultations fell and the number of nurse consultations rose, fewer patients reconsulted, and marginal improvements were reported on doctor and patient satisfaction. Other practices may benefit from such change; the use of management consultants as facilitators may instigate such change.

Appointments and Schedules↗
PubMed1998

ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective analgesic acting via neuronal nicotinic acetylcholine receptors: I. In vitro characterization.

The discovery of (+/-)-epibatidine, a naturally occurring neuronal nicotinic acetylcholine receptor (nAChR) agonist with antinociceptive activity 200-fold more potent than that of morphine, has renewed interest in the potential role of nAChRs in pain processing. However, (+/-)-epibatidine has significant side-effect liabilities associated with potent activity at the ganglionic and neuromuscular junction nAChR subtypes which limit its potential as a clinical entity. ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine] is a novel, potent cholinergic nAChR ligand with analgesic properties (see accompanying paper by Bannon et al., 1998b) that shows preferential selectivity for neuronal nAChRs and a consequently improved in vivo side-effect profile compared with (+/-)-epibatidine. ABT-594 is a potent inhibitor of the binding of [3H](-)-cytisine to alpha 4 beta 2 neuronal nAChRs (Ki = 37 pM, rat brain; Ki = 55 pM, transfected human receptor). At the alpha 1 beta 1 delta gamma neuromuscular nAChR labeled by [125I] alpha-bungarotoxin (alpha-Btx), ABT-594 has a Ki value of 10,000 nM resulting in a greater than 180,000-fold selectivity of the compound for the neuronal alpha 4 beta 2 nAChR. In contrast, (+/-)-epibatidine has Ki values of 70 pM and 2.7 nM at the alpha 4 beta 2 and alpha 1 beta 1 delta gamma nAChRs, respectively, giving a selectivity of only 38-fold. The S-enantiomer of ABT-594, A-98593 has activity at the neuronal alpha 4 beta 2 nAChR identical with ABT-594 (Ki = 34-39 pM), which demonstrates a lack of stereospecific binding similar to that reported previously for (+/-)-epibatidine. A similar lack of stereoselectivity is seen at the human alpha 7 receptor. However, A-98593 is 3-fold more potent at the neuromuscular nAChR (Ki = 3420 nM) and the brain alpha-Btx-sensitive nAChR (Ki = 4620 nM) than ABT-594. ABT-594 has weak affinity in binding assays for adrenoreceptor subtypes alpha-1B (Ki = 890 nM), alpha-2B (Ki = 597 nM) and alpha-2C (Ki = 342 nM), and it has negligible affinity (Ki > 1000 nM) for approximately 70 other receptors, enzyme and transporter binding sites. Functionally, ABT-594 is an agonist. At the transfected human alpha 4 beta 2 neuronal nAChR (K177 cells), with increased 86Rb+ efflux as a measure of cation efflux, ABT-594 had an EC50 value of 140 nM with an intrinsic activity (IA) compared with (-)-nicotine of 130%; at the nAChR subtype expressed in IMR-32 cells (sympathetic ganglion-like), an EC50 of 340 nM (IA = 126%); at the F11 dorsal root ganglion cell line (sensory ganglion-like), an EC50 of 1220 nM (IA = 71%); and via direct measurement of ion currents, an EC50 value of 56,000 nM (IA = 83%) at the human alpha 7 homooligimeric nAChR produced in oocytes. A-98593 is 2- to 3-fold more potent and displays approximately 50% greater intrinsic activity than ABT-594 in all four functional assays. In terms of potency, ABT-594 is 8- to 64-fold less active than (+/-)-epibatidine and also has less IA in these functional assays. ABT-594 (30 microM) inhibits the release of calcitonin gene-related peptide from C-fibers terminating in the dorsal horn of the spinal cord, an effect mediated via nAChRs. Pharmacologically, ABT-594 has an in vitro profile distinct from that of the prototypic nicotinic analgesic (+/-)-epibatidine, with the potential for substantially reduced side-effect liability and, as such, represents a potentially novel therapeutic approach to pain management.

Administration, Oral↗
PubMed1998

ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective antinociceptive agent acting via neuronal nicotinic acetylcholine receptors: II. In vivo characterization.

The antinociceptive effects of ABT-594, a novel nicotinic acetylcholine receptor (nAChR) ligand, were examined in rats in models of acute thermal (hot box) and persistent chemical (formalin test) pain. Also, the effects of ABT-594 treatment on motor function and electroencephalogram (EEG) were determined. In the hot box and formalin test (i.e., phase 1 and 2), acute treatment with ABT-594 (0.03, 0.1 and 0.3 mumol/kg i.p.) produced significant dose-dependent antinociceptive effects. In the hot box, the efficacy of ABT-594 was maintained after a repeated dosing paradigm (5 days b.i.d.i.p.). ABT-594 was fully efficacious in the formalin test when administered before formalin, and also retained significant efficacy (0.3 mumol/kg i.p.) when administered after formalin injection. The antinociceptive effects of ABT-594 in the hot box and formalin tests were attenuated by pretreatment with the nAChR antagonist, mecamylamine, and in animals treated with the nAChR antagonist chlorisondamine, given centrally (10 micrograms/rat i.c.v. 5 days before), but not in animals pretreated with the opioid receptor antagonist, naltrexone. Acute treatment with ABT-594 produced an initial decrease in open-field locomotor activity, which was absent in animals dosed repeatedly (5 days b.i.d.) with ABT-594. Also, acute treatment with ABT-594 decreased body temperature and decreased the amount of time the animals could maintain balance in an edge-balance test. These effects were no longer present in animals dosed repeatedly with ABT-594. At antinociceptive doses, ABT-594 produced activation of free running EEG in contrast to the sedative-like effects of morphine. Full antinociceptive efficacy was maintained in both the hot box and formalin tests after oral administration, whereas the effects on motoric performance were attenuated. In conclusion, these data demonstrate that ABT-594 is a potent antinociceptive agent with full efficacy in models of acute and persistent pain and that these effects are mediated predominately by an action at central neuronal nAChRs. In addition, antinociceptive effects were maintained after repeated dosing, whereas effects of ABT-594 on motor and temperature measures were attenuated in animals treated repeatedly with ABT-594. Thus, compounds acting at nAChRs may represent a novel approach for the treatment of a variety of pain states.

Administration, Oral↗