Biomedical subjects
Publications and source records attributed to L Thomas.
Managers are challenged to provide for employees' needs and increased expectations in a way that will benefit both them and the organization without significant increases in human resource costs. This article suggests another look at motivation, employee involvement, and the value of work itself as a means of meeting these challenges.
In order to determine the contribution of alcohol intake to the severity of hepatic fibrosis in patients with chronic hepatitis C, we studied associations between various levels of alcohol intake, other demographic variables and semiquantitative liver histology in 434 cases of chronic hepatitis C. Clinical, demographic and disease-related data were entered into a relational database. Liver histology was scored according to Scheuer. The average daily alcohol intake for the year preceding liver biopsy (recent exposure) and for earlier periods (past exposure) was categorized into five levels of intake. One-third of patients gave a history of alcohol intake that had exceeded 40 g/day for at least 5 years. By univariate analysis, age, but not recent or past alcohol intake or other baseline variables, was associated with portal score (r = 0.14, P = 0.004), fibrosis score (r = 0.46, P < 0.001), total Scheuer score (r = 0.35, P < 0.001). However, by multivariate analysis, age (P < 0.001), past (but not present) alcohol intake (P < 0.001) and birth in Egypt (P = 0.006) were independently associated with fibrosis score. Age, past alcohol and birth place in Egypt contributed 27% to total variance of the hepatic fibrosis score, while age alone accounted for 23%. Age also independently predicted portal activity (P = 0.02) and total Scheuer score (P < 0.001), whereas past alcohol intake correlated with total Scheuer score (P = 0.002) but not with other histological indices. A separate multivariate analysis was performed on a more homogeneous subgroup of 196 patients who acquired hepatitis C by injection drug use. In this subgroup, age (P < 0.05) and past alcohol (P < 0.05) were independently associated with fibrosis score. In both the overall and subgroup analyses, there was a threshold level of past alcohol intake (>80 g/day) beyond which the risk of fibrosis increased significantly. It is concluded that toxic levels of alcohol exposure for at least 5 years accentuate hepatic fibrosis in hepatitis C but the influence of alcohol appears to be minor compared with age and other variables and is exerted only at toxic levels of intake.
A 4.1-kb fragment of chromosomal DNA from the lignocellulose-decomposing actinomycete Streptomyces viridosporus T7A was previously found to encode a lignin peroxidase gene. However, when cloned into Escherichia coli in pBSKS+, peroxidase activity was not expressed. When cloned in pIJ702 in Streptomyces lividans, the gene was expressed in a peroxidase positive background, owing to the production by S. lividans of its own extracellular peroxidase. To circumvent these problems, the DNA was cloned into the commercial expression vector pIC9 for extracellular expression in the yeast Pichia pastoris. Yeast transformants, however, expressed two activities, extracellular peroxidase and an extracellular endoglucanase. The enzymes were not expressed by the yeast cells alone or by yeast cells with pIC9 without the insert. Expression of the enzymes by only those transformants expressing the 4.1-kb DNA was confirmed by Western blot analyses, by nondenaturing activity gel staining, and by spectrophotometric enzyme assays of extracellular culture filtrates. Activity gel staining showed that the two activities resided in different proteins and the peroxidase expressed was similar to ALip-P3, one of the isoenzymes of lignin peroxidase of the S. viridosporus T7A wildtype. Other evidence indicated that in the transformants, the peroxidase and endoglucanase genes in the 4.1-kb insert were controlled by the methanol-inducible AOX1 yeast promoter in pIC9, since their expression was induced by methanol. In the best transformants, extracellular production of peroxidase by recombinant P. pastoris cultures was significantly higher than typically observed in S. viridosporus. The results also indicate that lignocellulose catabolism genes may be clustered on the S. viridosporus chromosome.
OBJECTIVE: The aim of this study was to evaluate the semiological value of the so-called ABCDE criteria in the differential diagnosis of pigmented tumours. Aside from the classical ABCD criteria, an E criterion for 'enlargement' is studied. MATERIAL AND METHODS: Records from melanoma patients were obtained from a melanoma database prospectively including patients treated for melanoma in our department since 1992; 460 files were found informative for this study. A prospective control group was established including 680 cases of benign pigmented tumors. All cases included in the study were histopathologically controlled in our dermatopathology unit. Records of ABCDE, i.e. corresponding to asymmetry, irregular borders, irregular coloration, diameter > or = 6 mm and enlargement, were codified as present or absent in every case. Data were statistically compared for every individual criterion with the chi 2 test and for the number of criteria present in melanoma versus other pigmented tumors with Student's t test. RESULTS: Significant differences were observed for all individual criteria (p < 0.001) between melanomas and common nevi. Significant differences were also observed for B, C and E criteria between melanomas and atypical nevi. The sensitivity of the individual criteria for the diagnosis of melanoma was 57, 57, 65, 90 and 84% for ABCDE, respectively. The specificity of the individual criteria for the diagnosis of melanoma versus other pigmented tumors was 72, 71, 59, 63 and 90% for ABCDE, respectively. The number of criteria present was significatively different between common nevi (1.24 +/- 1.26) and melanomas (3.53 +/- 1.53; p < 0.001) and between common nevi and atypical nevi (3.62 +/- 0.83, p < 0.001), but no significant difference was found between melanomas and atypical nevi. Sensitivity and specificity of diagnosis of melanoma are 89.3 and 65.3% if 2 criteria are present. Sensitivity and specificity of diagnosis of melanoma are 65.5 and 81% if 3 criteria are present. CONCLUSION: The so-called ABCD criteria have a good semiological value in the differential diagnosis of pigmented tumors. Addition of an E criterion for enlargement optimizes sensitivity and specificity of diagnosis.
Melatonin, an indole amine, primarily derived from the pineal gland is secreted during the hours of darkness. Melatonin acts as a hormonal transduction of photoperiod influencing the timing of seasonal and daily (circadian) physiological rhythms. Maternal melatonin crosses the placenta and enters the fetal circulation providing photoperiodic information to the fetus influencing the subsequent circadian and seasonal rhythms of the offspring. The function of melatonin in humans is more obscure. However, melatonin has attained prominence as a treatment for disturbed circadian rhythms and sleep patterns which occur as a result of transmeridian travel, shift work or blindness. The biological clock, the hypothalamic suprachiasmatic nuclei (SCN), possesses melatonin receptors, in both the adult and fetal human. This concurs with the reported influence of melatonin on human circadian rhythmicity and indicates that this influence may begin in utero. Melatonin receptors are widespread in the human fetus and occur in both central and peripheral tissue from early in fetal development. Thus, the influence of melatonin on the developing human fetus may not be limited to entraining circadian rhythmicity. Considering the transplacental availability of melatonin to the fetus the ingestion of melatonin by pregnant women may be inadvisable.
Fibreoptic bronchoscopy is an established diagnostic procedure for HIV-associated pulmonary infections. We retrospectively evaluated the diagnostic effectivity and safety of fibreoptic bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsy (TBB) in 153 patients with late-stage HIV infection and clinical signs of pulmonary infection or abnormal chest radiograph. Bronchoscopy leads to diagnosis in 82.4% and changed therapy in 54%. 45 patients (30%) were found to have pneumocystis carinii pneumonia (PCP), the most common bronchoscopic finding, followed by bacterial lung disease (29.3%). BAL had a sensitivity of 78% for PCP. Diagnostic yield of BAL for PCP was higher in patients without previous treatment (positive results in 82%) with regard to PCP independend of the prior treatment. Serious complication occurred in 22 cases (pneumothorax: 6 (3.9%), bleeding: 12 (7.8%), hypoxaemia: 4 (2.6%)). High serum levels of lactate dehydrogenase (LDH) correlated with pulmonary complications like pneumothorax. Age, sex and kind of pulmonary infection did not influence complication rates. 6 (3.9%) episodes of spontaneous pneumothorax occurred in the further course, 3 of them concurrently with PCP or prior history of PCP. We conclude that fibreoptic bronchoscopy is of great value for diagnosing pulmonary infection in HIV-seropositive patients. TBB provides incremental diagnostic information not available from BAL, especially in patients pretreated with cotrimoxazol or pentamidin. For that reason we believe that TBB should be performed in these patients.
INTRODUCTION: Membranous lipodystrophy represents a peculiar dermatopathologic type of cystic forming adipose tissue necrosis. In skin pathology two distinct entities are currently known: a primary idiopathic type and a secondary type found in association with various cutaneous or systemic diseases (lupus erythematosus, scleroderma, dermatomyositis, venous disorders, trauma, diabetes mellitus...). This secondary type is more common. CASE REPORT: We report the case of a female patient treated with cytostatic regimen for metastatic adenocarcinoma of the breast. She was seen with cyclic painful attacks of hypodermitis of lower limbs following drug infusions. Attacks finally vanished after treatment withdrawal. Membranous lipodystrophy was observed microscopically. DISCUSSION: This is, to the best of our knowledge, the first case of membranous lipodystrophy occurring during cytostatic treatment. The origin of such a phenomenon remains nuclear but cystic formation occurs after adipocyte necrosis and membranes are thought to be formed from dead cells plasma membrane remnants. Primary cell injury could be due to ischemia to which adipose tissue is especially susceptible. In our case, role of circulatory troubles or cytostatic chemotherapy could be equally discussed. However cyclic attack of painful hypodermatitis following drug administration was strongly in favour of treatment responsibility. Moreover clearing of lesions after treatment discontinuation brought more arguments for this last hypothesis.
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Furin catalyzes the proteolytic maturation of many proproteins within the trans-Golgi network (TGN)/endosomal system. Furin's cytosolic domain (cd) directs both the compartmentalization to and transit between its manifold processing compartments (i.e., TGN/biosynthetic pathway, cell surface, and endosomes). Here we report the identification of the first furin cd sorting protein, ABP-280 (nonmuscle filamin), an actin gelation protein. The furin cd was used as bait in a yeast two-hybrid screen to identify ABP-280 as a furin-binding protein. Binding analyses in vitro and coimmunoprecipitation studies in vivo showed that furin and ABP-280 interact directly and that ABP-280 tethers furin molecules to the cell surface. Quantitative analysis of both ABP-280-deficient and genetically replete cells showed that ABP-280 modulates the rate of internalization of furin but not of the transferrin receptor, a cycling receptor. However, although ABP-280 directs the rate of furin internalization, the efficiency of sorting of the endoprotease from the cell surface to early endosomes is independent of expression of ABP-280. By contrast, efficient sorting of furin from early endosomes to the TGN requires expression of ABP-280. In addition, ABP-280 is also required for the correct localization of late endosomes (dextran bead uptake) and lysosomes (LAMP-1 staining), demonstrating a pleiotropic role for this actin binding protein in the organization of cellular compartments and directing protein traffic. Finally, and consistent with the trafficking studies on furin, we showed that ABP-280 modulates the processing of furin substrates in the endocytic but not the biosynthetic pathways. The novel roles of ABP-280 and the cytoskeleton in the sorting of furin in the TGN/ endosomal system and the formation of proprotein processing compartments are discussed.
BACKGROUND: kappa-PVIIA is a 27-residue polypeptide isolated from the venom of Conus purpurascens and is the first member of a new class of conotoxins that block potassium channels. By comparison to other ion channels of eukaryotic cell membranes, voltage-sensitive potassium channels are relatively simple and methodology has been developed for mapping their interactions with small-peptide toxins. PVIIA, therefore, is a valuable new probe of potassium channel structure. This study of the solution structure and mode of channel binding of PVIIA forms the basis for mapping the interacting residues at the conotoxin-ion channel interface. RESULTS: The three-dimensional structure of PVIIA resembles the triple-stranded beta sheet/cystine-knot motif formed by a number of toxic and inhibitory peptides. Subtle structural differences, predominantly in loops 2 and 4, are observed between PVIIA and other conotoxins with similar structural frameworks, however. Electrophysiological binding data suggest that PVIIA blocks channel currents by binding in a voltage-sensitive manner to the external vestibule and occluding the pore. Comparison of the electrostatic surface of PVIIA with that of the well-characterised potassium channel blocker charybdotoxin suggests a likely binding orientation for PVIIA. CONCLUSIONS: Although the structure of PVIIA is considerably different to that of the alphaK scorpion toxins, it has a similar mechanism of channel blockade. On the basis of a comparison of the structures of PVIIA and charybdotoxin, we suggest that Lys19 of PVIIA is the residue which is responsible for physically occluding the pore of the potassium channel.
The pharmacokinetics of docetaxel as investigated in Phase I and Phase II trials are discussed. Phase I trials have shown that docetaxel exhibits linear pharmacokinetics consistent with a three-compartment model. Population pharmacokinetic and pharmacodynamic analysis of the results of 22 nonrandomized Phase II trials with nonlinear mixed-effects modeling showed that the interpatient variability of docetaxel pharmacokinetics is mainly related to body surface area and hepatic function. The effect of body surface area on clearance does not present a problem, since the dose of docetaxel is adjusted for body size. However, patients with impaired liver function are at increased risk of serious adverse effects (febrile neutropenia, severe infections, severe stomatitis, and toxic death) during treatment with docetaxel 100 mg/ m2. Patients with impaired liver function should receive a reduced dose (75 mg/m2). The presence of liver metastases without impaired liver function had no effect on docetaxel's clearance or safety, suggesting that a dose of 100 mg/m2 is well tolerated in such patients. Docetaxel pharmacokinetics and pharmacodynamics determined in Phase I and Phase II trials indicate a need to adjust the dosage for body surface area and liver function.
The composition of secretory granules in neuroendocrine and endocrine cells is determined by two sorting events; the first in the trans-Golgi complex (TGN), the second in the immature secretory granule (ISG). Sorting from the ISG, which may be mediated by the AP-1 type adaptor complex and clathrin-coated vesicles, occurs during ISG maturation. Here we show that furin, a ubiquitously expressed, TGN/endosomal membrane endoprotease, is present in the regulated pathway of neuroendocrine cells where it is found in ISGs. By contrast, TGN38, a membrane protein that is also routed through the TGN/endosomal system does not enter ISGs. Furin, however, is excluded from mature secretory granules, suggesting that the endoprotease is retrieved from the clathrin-coated ISGs. Consistent with this, we show that the furin cytoplasmic domain interacts with AP-1, a component of the TGN/ISG-localized clathrin sorting machinery. Interaction between AP-1 and furin is dependent on phosphorylation of the enzyme's cytoplasmic domain by casein kinase II. Finally, in support of a requirement for the phosphorylation-dependent association of furin with AP-1, expression of furin mutants that mimic either the phosphorylated or unphosphorylated forms of the endoprotease in AtT-20 cells demonstrates that the integrity of the CKII sites is necessary for removal of furin from the regulated pathway.
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OBJECTIVE: To assess knowledge, views, and behaviour of researchers on criteria for authorship and causes and control of gift authorship. DESIGN: Interview survey of stratified sample of researchers. SETTING: University medical faculty. SUBJECTS: 66 staff (94% response rate) comprising several levels of university academic and research appointments. MAIN OUTCOME MEASURES: Awareness and use of criteria for authorship, views on which contributions to research merit authorship, perceptions about gift authorship and strategies for reducing it, and experiences of authorship problems. RESULTS: 50 (76%) respondents supported criteria for authorship, but few knew about or used available criteria. Of the five people who could specify all three criteria of the International Committee of Medical Journal Editors, only one knew that all criteria had to be met. Forty one respondents (62%) disagreed with this stipulation. A range of practical and academic contributions were seen as sufficient for authorship. Gift authorship was perceived as common, promoted by pressure to publish, to motivate research teams, and to maintain working relationships. A signed statement justifying authorship and a published statement of the contribution of each author were perceived as practical ways of tackling gift authorship. Most researchers had experienced problems with authorship, most commonly the perception that authorship had been deserved but not awarded (49%). CONCLUSION: There seems to be a gap between editors' criteria for authorship and researchers' practice. Lack of awareness of criteria is only a partial explanation. Researchers give more weight than editors to practical research contributions. Future criteria should be agreed by researchers and not be imposed by editors.
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PURPOSE: To evaluate magnetic resonance imaging (MRI) in the planning of radiation therapy for patients with carcinoma of the cervix treated with a four-field technique. METHODS AND MATERIALS: Between May 1994 and February 1995, 18 patients with carcinoma of the cervix were entered in the study (1 T1 N-; 2 T2a N-; 1 T2b NO; 10 T2b N-; 2 T2b N+; 2 T3b N+). Node status was assessed by a laparoscopic pelvic lymphadenectomy. During the first step, all the patients were simulated with an isocentric four-field pelvic technique. In one group (11 patients) simulation was done based on clinical examination, computed tomography (CT), and standard guidelines. In the second group (seven patients) simulation was based on clinical examination, CT, and with the help of diagnostic MRI, which was available at that time. During the second step, MRI in treatment position with skin markings of the isocenter of the radiation fields was then performed in every patient. During the third step, in each patient, the simulated radiation fields were correlated with the MRI defined target volume by superimposing them on midsagittal and midcoronal MR images. The adequacy of the margins was arbitrarly defined as 1 cm around the MRI defined target volume (tumor of the cervix and its extension, and uterus). RESULTS: In the first group (11 patients), MRI in treatment position led to a change in 7 patients: six inadequate margins in the lateral fields and one in the anterior and lateral field. In almost all the cases, the adjustments were of an increase of 10 mm, equally matched between the anterior and posterior borders of the lateral fields. In the second group (seven patients), MRI in treatment position has led to a change in lateral fields in five patients. The mean adjustment was 10 mm: four increases (two anterior border, one posterior border, one anterior and posterior border), and one decrease of the posterior border. In the two groups, modifications of the anterior border of the lateral fields have allowed adequate margins around the uterine fundus and modifications of the posterior border have allowed adequate coverage of the cervical tumor. CONCLUSION: When treating carcinoma of the cervix with a four-field radiation technique, standard portals do not exist. The design of lateral fields has to be based on individual morbid anatomy, which is given accurately by diagnostic MRI. Magnetic resonance imaging in treatment position assesses the design of simulated lateral fields.
CGP 51901 is a non-anaphylactogenic mouse/human chimeric anti-human IgE antibody that binds to free IgE and surface IgE of IgE-expressing B cells but not to IgE bound to high affinity IgE receptors (Fc epsilonR1) on mast cells and basophils or low affinity IgE receptors (Fc epsilonR2) on other cells. A phase 1 double-blind, placebo-controlled, single dose study with doses of 3, 10, 30, and 100 mg of CGP 51901 was conducted in 33 pollen-sensitive subjects who had raised levels of serum IgE and received either intravenous CGP 51901 or placebo. The administration of CGP 51901 was well tolerated and resulted in a decrease of serum free IgE levels in a dose-dependent manner, with suppression after 100 mg of CGP 51901 reaching > 96%. Time of recovery to 50% of baseline IgE correlated with the dose of administered antibody and ranged from a mean of 1.3 d for the 3 mg to 39 d for the 100 mg dose. Total IgE, comprised of free and complexed IgE, increased as stored and newly synthesized IgE bound to CGP 51901. Complexed IgE was eliminated at a rate comparable with the terminal half-life of free CGP 51901 (11-13 d at all doses). Only one subject showed a weak antibody response against CGP 51901. We conclude that the use of anti-human IgE antibody is safe and effective in reducing serum IgE levels in atopic individuals and provides a potential therapeutic approach to the treatment of atopic diseases.
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