ECNP position paper on social phobia proceedings from an ECNP workshop in Jerusalem, October 1994.
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Benzodiazepines↗
Biomedical subjects
C Freeman
Publications and source records attributed to C Freeman.
The chief scientist reports.... Prevalence of psychiatric disorder, cognitive impairment and functional disability among homeless people resident in hostels.
This cross-sectional survey was performed to estimate the prevalence of psychiatric disorder among homeless residents of hostels in Edinburgh and to relate it to functional impairment. Full diagnostic assessments were completed on 136/198 (69%) of the subjects. Thirty-one per cent of subjects (95% CI 25, 42) had significant functional impairment and this was most strongly associated with the presence of functional psychosis and cognitive impairment. Few of the cognitively impaired subjects were in contact with health or social services.
Adult↗
Qualitative investigation of uptake of fine particle size microcrystalline cellulose following oral administration in rats.
A subchronic toxicity study was conducted to evaluate the potential toxicological effects associated with intestinal translocation of a special fine particle size (median particle size 6 microns) microcrystalline cellulose (MCC). Four groups of Sprague-Dawley rats (20/sex/group) received either 0 (control), 500, 2500 or 5000 mg/kg/day MCC (25% w/v in tap water) daily by oral gavage for 90 d. At study termination, organs and tissues from high-dose and control animals, including multiple sections of intestine with gut-associated lymphoid tissue, were processed for light microscopy with subsequent examination under polarised light for the presence of birefringent MCC particles. None were observed in any tissue examined. No toxicologically significant effects or lesions were found in any other parameter or organ evaluated. The 'no observed adverse effect level' (NOAEL) for toxicological effects was greater than 5000 mg/kg/day MCC, which was the highest dosage tested. These results further verify the safety of commercial MCC products for use in food and pharmaceutical applications.
Administration, Oral↗
In vitro antimicrobial susceptibility of glycopeptide-resistant enterococci.
The results of susceptibility testing of 48 phenotyped strains of glycopeptide antibiotic-resistant enterococci are reported. Minimum inhibitory and bactericidal concentrations (MICs and MBCs) were determined for 27 vanA, 17 vanB, and 4 vanC strains. Antibiotics exhibiting the greatest activity included novobiocin (MIC90 = 8 micrograms/ml and MBC90 = 32 micrograms/ml), ramoplanin (MIC90 = 2 micrograms/ml and MBC90 = 4 micrograms/ml), and the streptogramin RP59500 (MIC90 = 4 micrograms/ml and MBC90 = 32 micrograms/ml). These antibiotics warrant further investigation as potentially useful agents, either alone or in combination, for treating enterococcal infections.
Anti-Bacterial Agents↗
The families of anorexia nervosa and cystic fibrosis patients.
The objective of the study was to determine whether the families of anorexia nervosa (AN) patients were more dysfunctional than those of cystic fibrosis (CF) patients and well controls. Data were collected from self-report questionnaires, from an interview rated for Expressed Emotion (EE) and from direct observation of a family problem solving task which was rated for evidence of Minuchin's 'psychosomatic family' dimensions. A total of 87 families participated. Most self-report measures of family functioning did not distinguish between groups. There were no differences in levels of EE criticism. AN and CF households showed more EE emotional over-involvement than did the well households. Over-involvement correlated with illness severity. More households in the AN group were enmeshed, over-protective and poor at problem solving than in the CF and well groups. Minuchin's conceptualization of the anorexia nervosa family was partly supported.
Adolescent↗
Cloning of the sulphamidase gene and identification of mutations in Sanfilippo A syndrome.
Sanfilippo A syndrome is one of four recognised Sanfilippo sub-types (A, B, C and D) that result from deficiencies of different enzymes involved in the lysosomal degradation of heparan sulphate; patients suffer from severe neurological disorders. The Sanfilippo syndrome sub-types are also known as mucopolysaccharidosis (MPS) type III (MPS-IIIA, B, C and D), and are part of the large group of lysosomal storage disorders. Each of the MPS-III types is inherited as an autosomal recessive disorder with considerable variation in severity of clinical phenotype. The incidence of Sanfilippo syndrome has been estimated at 1:24,000 in The Netherlands with MPS IIIA (MIM #252900) the most common. MPS-IIIA is the predominant MPS-III in the United Kingdom, and has a similar high incidence to that found in The Netherlands (E. Wraith, personal communication). There is a particularly high incidence of a clinically severe form of MPS-IIIA in the Cayman Islands with a carrier frequency of 0.1 (ref. 4). Due to the mild somatic disease compared to other MPS disorders there is difficulty in diagnosing mild cases of MPS-III, hence Sanfilippo syndrome may be underdiagnosed, especially in patients with mild mental retardation. Here, we report the isolation, sequence and expression of cDNA clones encoding the enzyme sulphamidase (EC 3.10.1.1). In addition, we report the chromosomal localisation of the sulphamidase gene as being 17q25.3. An 11-bp deletion, present in sulphamidase cDNA from two unrelated Sanfilippo A patients, is described.
Amino Acid Sequence↗
Schizophrenia among residents of hostels for homeless people.
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Ill-Housed Persons↗
Comparison of prevalence of schizophrenia among residents of hostels for homeless people in 1966 and 1992.
OBJECTIVE: To determine whether the prevalence of schizophrenia among the homeless population of Edinburgh resident in hostels has changed between 1966 and 1992. DESIGN: Comparison of two cross sectional surveys. SETTINGS: Hostels for homeless people in Edinburgh. SUBJECTS: In 1966 a random sample of 98 residents of three common lodging houses. In 1992 a random sample of 198 residents of nine hostels. MAIN OUTCOME MEASURE: Prevalence of schizophrenia. RESULTS: The prevalence of schizophrenia in 1992 was 12/136 (9%) compared with 20/79 (25%) in 1966 (odds ratio 0.29; 95% confidence interval 0.13 to 0.62; P = 0.001). Adjustment for confounding by age, current hostel, and duration of unemployment by means of logistic regression produced an adjusted odds ratio of 0.22 (0.08 to 0.58). CONCLUSIONS: The prevalence of schizophrenia was lower in 1992 even after other changes in the population resident in hostels occurring between 1966 and 1992 were taken into account. The findings are not consistent with an increase in the prevalence of schizophrenia among homeless people despite a 66% reduction in adult psychiatric beds in the region during 1966-92.
Adolescent↗
Use of magnetic resonance imaging in diagnosing eosinophilic fasciitis. Report of two cases.
OBJECTIVE: To determine the role of magnetic resonance imaging (MRI) in the diagnosis of eosinophilic fasciitis (EF), selection of appropriate biopsy site, and followup of treatment. METHODS: MRI was used to examine 2 patients with EF at the time of their initial clinical presentation and after several months of treatment. T2-weighted axial, T2-weighted axial with fat saturation, and T1-weighted axial post-gadolinium with fat saturation scans at 1.5T were obtained. RESULTS: MRI demonstrated hyperintensity within the fascia. This defect resolved with treatment and clinical improvement. CONCLUSION: MRI is a useful noninvasive tool for diagnosing EF and for monitoring the effectiveness of therapy.
Adult↗
The effects of Arthritis Society fellowships on career choice.
OBJECTIVE: To find out if The Arthritis Society (TAS) fellowship grants influenced career choice or career development. METHODS: Two hundred former TAS training fellowship recipients (1975-1990 inclusive) were sent a questionnaire to evaluate the effects of TAS clinical or research fellowship support on their subsequent career development. RESULTS: One hundred and forty (70%) completed questionnaires were returned by 88 clinical and 37 research fellowship recipients--a further 17 had received both a clinical and a research fellowship. Fifty-one percent of the respondents are now academic rheumatologists, 40% in community practice and 9% still in training. Seventy-three percent of the research fellowship recipients currently receive research grant support, compared to 16% of the former clinical fellowship recipients. Seventy-one percent agreed that their TAS fellowship support had "directly or indirectly influenced or facilitated their chosen career path"--this included 100% of the research fellowship recipients, compared to 55% of the clinical fellowship recipients. The majority decided on an academic or a community based career path during their postgraduate training. Fourteen percent who trained for an academic career are now in community practice and 9% who planned on a community based career later became academic rheumatologists. Eighty-nine respondents (64%) enclosed a CV. This subset was further analyzed using career markers such as academic rank, number and size of research grants and number of publications. In this subset those who had received both a clinical and a research fellowship had the most advanced academic rank (22% full professor), largest number of publications (n = 39) and largest number of grants (5.3/year; average $40,446), compared to former research fellowship recipients: 4.0% full professor, 22 publications, 3.2 grants/year; average $25,164. Recipients of clinical fellowships in this subset had lower levels of all the academic career markers. CONCLUSION: Of 200 consecutive TAS fellowship recipients 71% of those responding (n = 140) to a career tracking study agreed that the fellowship support "directly or indirectly" influenced or facilitated their career choice. An apparent synergistic effect of providing both clinical and research fellowships on subsequent development of an academic career deserves further study.
Career Choice↗
A cDNA clone for human glucosamine-6-sulphatase reveals differences between arylsulphatases and non-arylsulphatases.
Glucosamine-6-sulphatase is an exo-hydrolase required for the lysosomal degradation of heparan sulphate and keratan sulphate. Deficiency of glucosamine-6-sulphatase activity leads to the lysosomal storage of the glycosaminoglycan, heparan sulphate and the monosaccharide sulphate N-acetylglucosamine 6-sulphate and the autosomal recessive genetic disorder mucopolysaccharidosis type IIID. Glucosamine-6-sulphatase can be classified as a non-arylsulphatase since, relative to arylsulphatase B, it shows negligible activity toward 4-methylumbelliferyl sulphate. We have isolated human cDNA clones and derived amino acid sequence coding for the entire glucosamine-6-sulphatase protein. The predicted sequence has 552 amino acids with a leader peptide of 36 amino acids and contains 13 potential N-glycosylation sites, of which it is likely that 10 are used. Glucosamine-6-sulphatase shows strong sequence similarity to other sulphatases such as the family of arylsulphatases, although the degree of similarity is not as high as that between members of the arylsulphatase family. This pattern of inter- and intra-family similarity delineates regions and amino acid residues that may be critical for sulphatase function and substrate specificity.
Amino Acid Sequence↗
Human alpha-L-iduronidase. Catalytic properties and an integrated role in the lysosomal degradation of heparan sulphate.
The kinetic parameters (Km and kcat) of human liver alpha-L-iduronidase were determined with a variety of heparin-derived disaccharide and tetrasaccharide substrates. More structurally complex substrates, in which several aspects of the aglycone structure of the natural substrates heparin and heparan sulphate were maintained, were hydrolysed with catalytic efficiencies up to 255 times that observed for the simplest disaccharide substrate to be hydrolysed. The major aglycone structure that influenced both substrate binding and enzyme activity was the presence of a C-6 sulphate ester on the residue adjacent to the iduronic acid residue being hydrolysed. Sulphate ions and a number of substrate and product analogues were potent inhibitors of enzyme activity. Human liver alpha-L-iduronidase activity towards 4-methylumbelliferyl alpha-L-iduronide at pH 4.8 had two Km values of 37 microM and 1.92 mM with corresponding kcat. values of 299 and 650 mol of product formed/min per mol of enzyme respectively, which may explain the wide range of Km values previously reported for alpha-L-iduronidase activity toward its substrate. Skin fibroblast alpha-L-iduronidase activity towards the heparin-derived oligosaccharides was influenced by the same substrate aglycone structural features as was observed for the human liver enzyme. A comparison was made of the effect of substrate aglycone structure upon catalytic activities of the enzymes which act to degrade the highly sulphated regions of heparan sulphate. A model was proposed whereby the substrate is directed from alpha-L-iduronidase to subsequent enzyme activities to ensure the efficient degradation of heparan sulphate.
Carbohydrate Sequence↗
Human glucosamine-6-sulphatase deficiency. Diagnostic enzymology towards heparin-derived trisaccharide substrates.
Glucosamine-6-sulphatase (6S) activity towards a series of radiolabelled heparin-derived trisaccharide substrates was determined in cultured human skin fibroblast and leucocyte homogenates, and in urine supernatants of normal individuals and patients affected with 6S deficiency [Sanfilippo D syndrome; mucopolysaccharidosis (MPS) type IIID]. The N-sulphated and N-acetylated derivatives of the trisaccharide substrate O-(alpha-glucosamine 6-sulphate)-(1----4)-L-O-(alpha-iduronic acid 2-sulphate)-(1----4)-D-O-2,5-anhydro[1-3H]mannitol 6-sulphate (GlcNH6S-IdoA2S-anM6S) were prepared by enzymic digestion of a pentasulphated tetrasaccharide isolated following the HNO2 deamination of heparin. Purified lysosomal enzymes and MPS-patient skin fibroblasts were used along with chemical degradation to confirm the structure of each of the substrates that were utilized to study the interaction of the enzyme activities required to degrade the highly sulphated regions of heparan sulphate. Human liver, skin fibroblast and urine 6S activities were separated by chromatofocusing into at least four and possibly up to six individual activities. 6S activities present in each of the tissues generally had similar catalytic properties, including Km values, pH optima and inhibition with NaCl, Na2SO4 and NaH2PO4. Leucocyte and skin fibroblast 6S activities towards GlcNAc6S-IdoA2S-anM6S were maximal at pH 4.1 and 3.9 respectively, with Km values of 2.8 microM and 0.9-1.7 microM respectively. Urine 6S activity towards GlcNAc6S-IdoA2S-anM6S was stimulated 30-fold by BSA at pH 3.9, which shifted the pH optimum from 5.1 to 4.2 and decreased the Km value at pH 4.2 from 4.0 microM to 0.5 microM. Residual 6S activity present in the skin fibroblast homogenates from MPS IIID patients was characterized for activity towards GlcNAc6S-IdoA2S-anM6S and observed to have similar pH optima and Km values to normal skin fibroblast 6S activities, although the residual 6S activity was less than 1% of the normal control range.
Chromatography, Gel↗
Lysosomal degradation of heparin and heparan sulphate.
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Animals↗
Hurler syndrome: a patient with abnormally high levels of alpha-L-iduronidase protein.
Mucopolysaccharidosis type I (MPS I: McKusick 25280) is a clinically heterogenous lysosomal storage disorder which is caused by a variable deficiency in alpha-L-iduronidase activity (alpha-L-iduronide iduronohydrolase, EC 3.2.1.76). Cultured fibroblasts from an MPS I patient (cell line 2827) with a severe clinical phenotype (Hurler syndrome) have been characterized using immunochemical and biochemical techniques. Using a specific immunoquantification assay, we have demonstrated that cell line 2827 had an alpha-L-iduronidase protein content (189 ng/mg of extracted cell protein) at least six times greater than the mean level found in normal control fibroblasts (30 ng/mg of extracted cell protein). This was the only MPS I cell line, from a group of 23 MPS I patients, that contained greater than 7% of the mean level of alpha-L-iduronidase protein detected in normal controls. Cell line 2827 had very low alpha-L-iduronidase activity toward the fluorogenic substrate 4-methylumbelliferyl-alpha-L-iduronide, and a radiolabeled disaccharide substrate derived from heparin. Maturation studies of alpha-L-iduronidase in cell line 2827 showed apparently normal levels of alpha-L-iduronidase synthesis with delayed processing to the mature form. Subcellular fractionation experiments demonstrated alpha-L-iduronidase protein in lysosomal-enriched fractions isolated from cell line 2827, suggesting a normal cell distribution and supporting the proposed delayed processing. It is proposed that the MPS I patient described has an alpha-L-iduronidase gene mutation which affects both the active site and post-translational processing of the enzyme. This mutation must be structurally conservative because it does not result in instability either during maturation or in the lysosome.
Cells, Cultured↗
Medical response to catastrophic events: California's planning and the Loma Prieta earthquake.
The threat of a great earthquake has compelled California to develop a disaster plan for catastrophic medical events that calls for local response with state-coordinated mutual aid and casualty evacuation, if necessary. During the 1989 Loma Prieta earthquake that killed 63 people and injured 3,700, local emergency medical services systems were busy but not stressed excessively. The medical mutual aid system delivered medical personnel, supplies, and blood. One hospital suffered severe nonstructural damage, but it was able to treat large numbers of casualties. Our system performed admirably in this limited response, but was hampered by difficulties with disaster intelligence, communications, emergency medical services dispatch, patient care records, hospital damage, and inadequate disaster training. We describe our state's mutual aid system, the Loma Prieta response, and lessons and recommendations for the future.
California↗
Sleep disturbances in men with asymptomatic human immunodeficiency (HIV) infection.
During the clinical latency phase of human immunodeficiency virus (HIV) disease the central nervous system may be infected and begin to manifest subtle dysfunction. Our early investigations demonstrated persistent alterations in the sleep architecture of HIV-infected asymptomatic men. The major aims of this study were to delineate alterations of sleep architecture in asymptomatic HIV-infected men, to identify and describe sleep behavior complaints and to seek a correlation between objective sleep parameters and subjective complaints of sleep behavior. The study sample consisted of 24 men, 14 HIV-infected and 10 HIV-negative, age-matched controls. The protocol included a comprehensive history and physical, two polysomnograms, urine toxicity, detailed written sleep questionnaire, the Pittsburgh Sleep Quality Index, the Spielberger State-Trait Anxiety Test and the Beck Depression Inventory. Our results indicated that sleep architecture differed from controls in that wakefulness, slow-wave sleep [SWS-stage 3 and 4 nonrapid eye movement (NREM) sleep] and stage rapid eye movement (REM) sleep were more evenly dispersed throughout the night. In particular, SWS was prevalent during the second half of recorded sleep. The observed changes in the NREM/REM cycle could not be explained on the basis of underlying psychopathology. Just as the course of individuals with HIV infection varies, it is expected that sleep abnormalities will vary. Considering the known relationships between NREM stage 3 and 4 and immune system function, it is possible that the observed alterations in the NREM/REM cycle are related to coincident changes in immunologic function. Quantitative measures of NREM sleep, especially SWS and REM sleep, are perhaps of greater significance than relative measures of sleep stages.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Radiation therapy of testicular seminoma: a 15-year survey.
A retrospective review of 69 patients with testicular seminoma, stage I and II, treated by orchiectomy and adjuvant irradiation at McGill University Hospitals from 1972 to 1987 was performed. All patients underwent either lymphangiogram or computed axial tomography scan for evaluation of retroperitoneal disease. There were 52 stage I (75%), 13 stage IIA (11%), 2 stage IIB (3%), and 2 stage IIC (Royal Marsden Hospital staging criteria). Median follow-up time was 6.2 years. The 10-year actuarial survivals were 94% and 93% for stages I and II, respectively. Only two stage I patients failed treatment, and both died from metastatic disease. Interestingly, both developed biopsy-proven metastatic brain disease and had no evidence of intra-abdominal recurrence. In stage II disease, only one patient failed the treatment. There was no serious acute toxicity and no late complications have been encountered. Radiation therapy following orchiectomy is the treatment of choice for stage I and for most stage II patients with testicular seminoma. The controversial aspects of radiographic retroperitoneal staging, the use of prophylactic mediastinal irradiation for stage II patients, and the role of surveillance only for stage I patients are discussed.
Adolescent↗