Missed problems and missed opportunities for addicted doctors.
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Alcoholism↗
Biomedical subjects
J Marshall
Publications and source records attributed to J Marshall.
Leukocyte trafficking in experimental autoimmune uveitis in vivo.
Leukocyte trafficking from blood into tissue is a fundamental process in immune surveillance and the immune response to stimuli. Experimental autoimmune uveitis (EAU) is an animal model for posterior uveitis and is mediated by T lymphocytes and macrophages that infiltrate the posterior segment of the eye. To analyze leukocyte migration into retinal tissue during the course of EAU, labeled cells were identified in vivo by scanning laser ophthalmoscopy and in retinal flatmounts by confocal microscopy. Adhesion of blood leukocytes to retinal endothelial cells in vivo was significantly raised 48 h before the appearance of clinical disease, and this correlated with the increased expression of CD54 on retinal vessels. Mitogen-activated spleen cells and CD4+ T cells only entered into retinal tissue in animals with clinical disease and not naive recipients. The disease status of the donor animal had no effect on leukocyte trafficking. These results, which identify leukocyte-endothelial cell interactions in vivo, suggest that the activation of the retinal endothelium is a prerequisite to leukocyte adhesion and extravasation into ocular tissue during EAU.
Animals↗
Cationic lipid formulations for intracellular gene delivery of cystic fibrosis transmembrane conductance regulator to airway epithelia.
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Animals↗
The influence of alcoholism and cirrhosis on benzodiazepine receptor function.
In a previous study we reported that the affinity of the platelet benzodiazepine receptor was greater in alcoholic cirrhotic patients compared with normal controls and that there were detectable ligands for the neuronal benzodiazepine receptor in plasma from both alcoholic and nonalcoholic cirrhotic patients. The aim of the present study was to assess the separate contributions of alcoholism and cirrhosis to the presence of ligands in plasma for the neuronal and peripheral benzodiazepine receptors and to changes in peripheral benzodiazepine receptor binding in platelets. These parameters were measured in 10 alcoholic cirrhotics, 9 nonalcoholic cirrhotics, 7 alcoholics with a normal liver function, and 15 nonalcoholic subjects and normal liver function. Both groups of alcoholics had been abstinent for several months and the nonalcoholic groups had abstained for 24 h before the study. The concentration of ligands for the peripheral benzodiazepine receptor were significantly higher in both cirrhotic groups compared with the other two groups, suggesting that cirrhosis was responsible for this accumulation. Furthermore, the cirrhotic patients with detectable concentrations of these ligands had significantly poorer episodic memory than those without ligands. However, the presence of ligands for the peripheral benzodiazepine receptor did not correlate with the change in receptor affinity, which was increased in the alcoholic cirrhotic group compared with all other groups. Neither cirrhosis nor alcoholism altered the peripheral benzodiazepine receptor number. The cirrhotic patients with detectable ligands for the neuronal benzodiazepine receptor showed psychomotor slowing and executive dysfunction. The results suggest that the ligands for the peripheral benzodiazepine receptor may contribute to some of the cognitive deficits seen in hepatic encephalopathy, but are not responsible for the receptor affinity change seen in the alcoholic cirrhotics. This affinity change is not solely due to the effects of alcohol and could possibly serve as a marker for those at risk for developing alcoholic cirrhosis.
Adult↗
Photorefractive keratectomy. A 6-year follow-up study.
OBJECTIVE: This study aimed to assess the long-term stability and efficacy of excimer laser photorefractive keratectomy. DESIGN: Patients who participated in the first United Kingdom photorefractive keratectomy clinical trial were asked to attend a 6-year follow-up assessment. PARTICIPANTS: Eighty-three patients (68%) of the original cohort of 120 participants were observed for 6 years. A Summit Technology UV200 excimer laser with a 4-mm ablation zone had been used with patients allocated to one of six groups according to their preoperative refraction. Each group received one of the following spherical corrections: -2, -3, -4, -5, -6, or -7 diopters (D). Within each group, all patients received an identical treatment, and thus emmetropia was not the goal in all patients. INTERVENTION: The induced refractive change, objective corneal haze, glare, and halo measurements, together with possible late-phase complications, were analyzed. MAIN OUTCOME MEASURES: All groups achieved a refractive undercorrection, and the magnitude of the undercorrection was related to the size of the attempted correction. The induced refraction stabilized by 6 to 12 months and has been maintained up to the 6-year follow-up stage. RESULTS: Ninety-one percent of patients who underwent a -2.00-D correction and 76% of patients who received a -3.00-D correction were within +/- 1 D of the intended refraction at 6 years. Fifty-seven percent of the -4.00-D group and 50% of those in the -5.00-D group were within +/- 1 D, and this was reduced further to 43% in the -6.00-D group and 19% in the -7.00-D group. Six patients (7%) had evidence of residual corneal haze, which was visually significant in two patients (3%). Ten patients (12%) had significant night halos due to the small 4-mm ablation zone that was used in this early treatment trial. CONCLUSIONS: There was no further regression of the refraction after 1 year, and, more important, there was no sign of hyperopic shift or diurnal fluctuation in the patients' refraction. In addition, corneal haze appeared to reduce further with time, with no intraocular or retinal side effects being noted. Night halos remain a significant reported problem in a small number of patients who were treated with the 4-mm ablation zone.
Adult↗
A method for purification and characterisation of Mycobacterium avium subsp. paratuberculosis from the intestinal mucosa of sheep with Johne's disease.
Mycobacterium avium subsp. paratuberculosis, the cause of Johne's disease in ruminants, cannot be cultured in large quantities from affected sheep in Australia. A method is described for the purification of the organism from the intestinal mucosa of sheep with multibacillary Johne's disease in order to undertake restriction fragment length polymorphism (RFLP) analysis for epidemiological purposes. Using sucrose and potassium chloride as separation media for differential and density gradient centrifugation, yields of approximately 90 mg dry weight M. avium subsp. paratuberculosis per 5 g intestinal mucosa were obtained. The preparations of purified M. avium subsp. paratuberculosis were visually free of non-acid fast bacteria and contained 10(2)-10(3) aerobic/ facultatively anaerobic organisms per gram wet weight. DNA extracted from purified M. avium subsp. paratuberculosis was examined by hybridisation with an IS900 probe after digestion with BstEII and RFLP patterns distinct from isolates from cattle were obtained. The RFLP pattern of purified M. avium subsp. paratuberculosis from five sheep matched that obtained previously from organisms cultured from sheep in studies in New Zealand, indicating that the purification and RFLP method is robust.
Animals↗
SAP90 binds and clusters kainate receptors causing incomplete desensitization.
The mechanism of kainate receptor targeting and clustering is still unresolved. Here, we demonstrate that members of the SAP90/PSD-95 family colocalize and associate with kainate receptors. SAP90 and SAP102 coimmunoprecipitate with both KA2 and GluR6, but only SAP97 coimmunoprecipitates with GluR6. Similar to NMDA receptors, GluR6 clustering is mediated by the interaction of its C-terminal amino acid sequence, ETMA, with the PDZ1 domain of SAP90. In contrast, the KA2 C-terminal region binds to, and is clustered by, the SH3 and GK domains of SAP90. Finally, we show that SAP90 coexpressed with GluR6 or GluR6/KA2 receptors alters receptor function by reducing desensitization. These studies suggest that the organization and electrophysiological properties of synaptic kainate receptors are modified by association with members of the SAP90/PSD-95 family.
Amino Acid Sequence↗
Phonological naming therapy in jargon aphasia: positive but paradoxical effects.
This article is a single-case investigation of phonological naming therapy. The individual involved had fluent jargon speech, with neologisms, verbal paraphasias, and paragrammatisms. The jargon was underpinned by a severe anomia. Content words were rarely accessed either in spontaneous speech or naming. Single word investigations highlighted some preserved skills. Auditory comprehension, at least for concrete words, was relatively intact and although nonwords could not be repeated, words could, and at a level which was far superior to naming. The patient also had some ability to respond to phonological cues. These results suggested that phonological representations were preserved and that there were some intact semantic abilities. It seemed that the naming disorder was primarily due to an inability to access phonology from semantics. Therapy took a phonological approach. The patient was encouraged to reflect upon the syllabic structure and first phoneme of pictured targets. Subsequently, she was required to use this partial phonological knowledge as a self-cue. It was hypothesized that this therapy might equip the subject with a self-cuing naming strategy. Posttherapy investigations of naming demonstrated dramatic improvements, which generalized to untreated items. However, there was little evidence that these were due to a self cuing strategy. Performance on phonological judgment and discrimination assessments, which required conscious phonological reflection, was unchanged, and there were no signs that the patient was self-cuing during naming. Reasons for these paradoxical results are discussed.
Anomia↗
Indocyanine green angiography in inflammatory eye disease.
PURPOSE: The choroid plays an integral role in the evolution of a number of inflammatory eye diseases but only limited information is provided on the choroidal vasculature by fluorescein angiography. METHODS: This study used indocyanine green (ICG) videoangiography to assess the degree of choroidal vascular involvement in inflammatory eye diseases and the results obtained were compared with fluorescein angiography. RESULTS: A total of 34 patients were examined: 6 with retinal vasculitis and 28 with chorioretinitis of various aetiologies. Areas of active involvement of the choroid were seen as areas of hypofluorescence on ICG angiography, representing areas of inflammatory infiltrate and/or choroidal hypoperfusion. No leakage of ICG occurred from large choroidal vessels at any stage in any disease. In contrast to sodium fluorescein, there was no leakage of ICG from retinal vessels in active inflammation. An inflammatory choroidal neovascular membrane leaked fluorescein and fluoresced late with ICG. CONCLUSION: ICG videoangiography provides useful information on the degree of choroidal involvement in inflammatory eye disease and is a valuable adjunct to fluorescein angiography.
Adult↗
Keratocyte density and size in conscious humans by digital image analysis of confocal images.
PURPOSE: Confocal microscopy can give images of high magnification and resolution in undisturbed living tissue. It provides new information about the cellular structure of the cornea. Our aim was to measure the density, size and distribution of keratocytes. METHODS: Healthy cornea in four subjects was examined using tandem scanning confocal microscopy. Methods for digital analysis of images were developed. RESULTS: Keratocyte density in confocal cross-sections was greatest immediately under Bowman's membrane (maximum 800 cells/mm2) and decreased sharply towards posterior cornea (minimum 65 cells/mm2). Cross-sectional cell size ranged from 78 to 211 microns2, but did not correlate with depth in the tissue. CONCLUSIONS: Results are consistent with those of earlier work using histological and biochemical techniques in isolated tissue. The methods we have developed enable studies of ongoing processes in conscious humans and can be used to examine diseased tissue as well as the response to injury.
Adult↗
Mutations of the forkhead/winged-helix gene, FKHL7, in patients with Axenfeld-Rieger anomaly.
Genetic linkage, genome mismatch scanning, and analysis of patients with alterations of chromosome 6 have indicated that a major locus for development of the anterior segment of the eye, IRID1, is located at 6p25. Abnormalities of this locus lead to glaucoma. FKHL7 (also called "FREAC3"), a member of the forkhead/winged-helix transcription-factor family, has also been mapped to 6p25. DNA sequencing of FKHL7 in five IRID1 families and 16 sporadic patients with anterior-segment defects revealed three mutations: a 10-bp deletion predicted to cause a frameshift and premature protein truncation prior to the FKHL7 forkhead DNA-binding domain, as well as two missense mutations of conserved amino acids within the FKHL7 forkhead domain. Mf1, the murine homologue of FKHL7, is expressed in the developing brain, skeletal system, and eye, consistent with FKHL7 having a role in ocular development. However, mutational screening and genetic-linkage analyses excluded FKHL7 from underlying the anterior-segment disorders in two IRID1 families with linkage to 6p25. Our findings demonstrate that, although mutations of FKHL7 result in anterior-segment defects and glaucoma in some patients, it is probable that at least one more locus involved in the regulation of eye development is also located at 6p25.
Amino Acid Sequence↗
A Canadian survey of transfusion practices in critically ill patients. Transfusion Requirements in Critical Care Investigators and the Canadian Critical Care Trials Group.
OBJECTIVES: To characterize the contemporary red cell transfusion practice in the critically ill and to define clinical factors that influence these practices. DESIGN: Scenario-based national survey. STUDY POPULATION: Canadian critical care practitioners. MEASUREMENTS AND MAIN RESULTS: We evaluated transfusion thresholds before transfusion and the number of red cell units ordered, under the given conditions. Of 254 Canadian critical care physicians, 193 (76%) responded to the survey. The primary specialty of most respondents was internal medicine (56%). Internal medicine respondents were in practice for an average of 8.4 +/- 5.7 (SD) yrs, and worked most often in combined medical/surgical intensive care units. Baseline hemoglobin transfusion thresholds averaged from 8.3 +/- 1.0 g/dL in a scenario involving a young stable trauma victim to 9.5 +/- 1.0 g/dL for an older patient after gastrointestinal bleeding. Transfusion thresholds differed significantly (p< .0001) between all four separate scenarios. With the exception of congestive heart failure (p> .05), all clinical factors (including age, Acute Physiology and Chronic Health Evaluation II score, preoperative status, hypoxemia, shock, lactic acidosis, coronary ischemia, and chronic anemia) significantly (p< .0001) modified the transfusion thresholds. A statistically significant (p< .01) difference in baseline transfusion thresholds was noted across four major regions (with a maximum of five academic centers per region) of the country. Low physician numbers in two of the regions did not allow for further investigation of regional variations. CONCLUSIONS: There is significant variation in critical care transfusion practice, with many intensivists adhering to a 10.0-g/dL threshold, while other physicians described a much more restrictive approach to red cell transfusion. Also, many physicians opted to administer multiple units, despite published guidelines to the contrary. Additionally, the administration of red cells was strongly influenced by a number of clinical factors, many unique to intensive care unit patients. There is a need for prospective studies to define optimal practice in the critically ill.
Adult↗
The safety of laser pointers: myths and realities.
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Consumer Product Safety↗
Substance misuse and risk of aggression and offending among the severely mentally ill.
BACKGROUND: The aim of this study was to investigate whether 'dual diagnosis' (substance misuse and severe mental illness) is associated with aggression and offending. METHOD: Twenty-seven people meeting the criteria for both psychotic illness and a substance use disorder and 65 people with psychosis only were interviewed. Case notes were also examined and keyworkers asked to rate substance misuse and aggression. RESULTS: The severity of aggression and offending among this community treatment sample was low. Individuals with a dual diagnosis were significantly more likely than those with psychosis only to report any history of committing an offence (P = 0.001), or recent hostile behaviour (P = 0.001). Keyworkers were more likely to report recent aggression among the dually diagnosed (P = 0.01). Significant differences persisted when we used logistic regression to control for potentially confounding demographic and clinical variables. CONCLUSIONS: Dual diagnosis may be an important factor in aggression and offending among severely mentally ill individuals in inner-city areas. Accurate risk assessment requires examination of substance use.
Adult↗
Phase I trial of Marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer.
PURPOSE: This phase I study was performed to evaluate the safety and pharmacokinetics of escalating doses of Marimastat (British Biotech, Inc, Oxford, United Kingdom) in patients with advanced malignancies and to determine the phase II recommended dose to be used in subsequent studies. PATIENTS AND METHODS: A standard phase I design was used in this study, in which consecutive groups of three patients were treated with escalating doses of the study drug. Marimastat was administered orally at 25, 50, or 100 mg twice daily to consecutive groups of patients with advanced lung cancer. An additional three patients were added at the highest dose studied (100 mg orally twice daily) to assess whether the inflammatory polyarthitis observed at that dose level can be prevented by a concurrent administration of nonsteroidal antiinflammatory drugs (NSAIDS) and/or low-dose corticosteroids. Blood was drawn for safety monitoring, pharmacokinetic analysis, and plasma levels of metalloproteinase (MMP)-2 and MMP-9 (determined by zymography). A total of 12 patients were studied. RESULTS: The most significant toxicity at the highest dose studied (100 mg orally twice daily) was a symptomatic inflammatory polyarthritis that persisted for up to 8 weeks after discontinuation of the study drug and was dose-limiting. The estimated plasma elimination half-life of Marimastat was 4 to 5 hours. The mean maximum concentration (Cmax) at a reasonably well-tolerated dose (50 mg orally twice daily) was 196 ng/mL and was reached within 1 to 2 hours (Tmax) after administration. Areas under the curve (AUC) tended to correlate with the dose of Marimastat. Zymographic analysis of peripheral-blood ratios of activated proenzymatic forms of MMP-2 and -9 did not show any consistent patterns of change in MMP levels or in a degree of their activation during the course of treatment. CONCLUSION: Marimastat was well absorbed from the gastrointestinal tract, with high levels of the study drug detected in plasma within hours after drug administration. Plasma concentrations of Marimastat achieved at dose levels 2 and 3 (50 mg and 100 mg orally twice daily) were substantially higher than those required for MMP inhibition in vitro. The dose-limiting toxicity (DLT) was severe inflammatory polyarthritis, which seemed to be a cumulative toxicity.
Administration, Oral↗
Reliability of the non-contact corneal aesthesiometer and its comparison with the Cochet-Bonnet aesthesiometer.
AIMS: To determine the repeatability of measurement of the corneal sensation threshold using the Non-Contact Corneal Aesthesiometer (NCCA); to evaluate the effect of the air-jet diameter and stimulus duration on the threshold; and to compare the sensation thresholds found with the NCCA and with the Cochet-Bonnet Aesthesiometer (C-BA), on the same group of normal, human subjects. METHODS: For all experiments, only the central corneal sensation thresholds were measured. (1) NCCA Repeatability; 17 subjects tested at the same time on five separate days. (2) NCCA Air-Jet Diameter; 15 subjects tested using four different air-jets: 0.35, 0.5, 1 and 2 mm. (3) NCCA Stimulus Duration; 15 subjects tested using three stimulus durations: 0.5, 0.9 and 1.5 sec. (4) NCCA and C-BA; 43 subjects tested using each instrument in turn. RESULTS: (1) No significant differences in mean sensation threshold were detected across the five days of testing, or between individual days. (2) 0.5 and 1 mm air-jets produce least variability in mean sensation threshold. (3) No significant difference in mean sensation thresholds was found between the three test durations. (4) For each subject, there was no correlation between each instrument's mean sensation threshold. CONCLUSIONS: (1) The NCCA was able to assess the corneal sensation threshold in an accurate and repeatable manner. (2) The optimum test parameters were found using the 0.5 mm air-jet, over a stimulus duration of 0.9 sec. (3) The C-BA has serious deficiencies in its design which limit its ability to accurately measure corneal sensitivity at low stimulus thresholds.
Anesthesiology↗
Healthcare's professional image: an element of success.
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Clothing↗
What makes alcohol-dependent individuals early in abstinence crave for alcohol: exposure to the drink, images of drinking, or remembrance of drinks past?
Craving is a major factor in addiction, predicting poorer outcome to treatment To improve our understanding of craving for alcohol, we have compared in the laboratory the effects of inducing craving for alcohol by exposure to the sight and the smell of an alcoholic beverage, imagery of craving scripts, and recall of autobiographical memories of craving. We used subjective measures of craving, together with autonomic measures, in 14 abstinent alcohol-dependent individuals in the first month after detoxification. All subjects reported a significant increase in ratings of urges after exposure to alcoholic drinks, following the imagery of craving and after recalling autobiographical memories of craving. Physiological measures have shown that craving imagery as well as memory induction were equally effective as exposure to alcoholic drinks in modestly increasing autonomic arousal (indicated by systolic blood pressure). Our preliminary findings support the existing evidence in nicotine and opiate dependence that images and memories are as effective as in vivo exposure in eliciting craving for drugs.
Adult↗