Novel isoxazoles which interact with brain cholinergic channel receptors have intrinsic cognitive enhancing and anxiolytic activities.
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Alkaloids↗
Biomedical subjects
M Williams
Publications and source records attributed to M Williams.
The pro- and antioxidant properties of protoporphyrin IX.
The effect of protoporphyrin on lipid peroxidation in rat liver microsomes was investigated in the presence and absence of light. Protoporphyrin and light stimulated Fe(3+)-ADP/ascorbate-induced lipid peroxidation, whereas Fe(3+)-ADP/NADPH-mediated lipid peroxidation was inhibited. In the dark, on the other hand, protoporphyrin inhibited lipid peroxidation in both systems in a concentration-dependent manner. Protoporphyrin did not affect the reduction of the Fe(3+)-ADP complex by ascorbate, nor did it affect the activity of the NADPH-cytochrome P-450 reductase under these conditions. Uroporphyrin, a hydrophilic porphyrin and not localized in the membrane, did not inhibit lipid peroxidation in the dark in these systems, whereas bilirubin, a well-known radical scavenger and degradation product of protoporphyrin, inhibited lipid peroxidation in both systems. When peroxyl radicals were generated in solution by the azocompound 2,2'-azobis (2-amidino-propane)dihydrochloride lipid peroxidation was inhibited by both porphyrins and bilirubin. Reaction of bilirubin or protoporphyrin, in the presence of microsomes or human serum albumin, with these peroxyl radicals resulted in degradation of both compounds, which could be determined by a decrease in their absorbance at 460 or 407 nm, respectively. These results indicate that the inhibition of lipid peroxidation is most likely caused by scavenging of peroxyl radicals by protoporphyrin. Massive accumulation of protoporphyrin occurs in livers of erythropoietic protoporphyria patients. The fact that protoporphyrin was able to inhibit lipid peroxidation completely at micromolar concentrations also indicates that the deleterious effects of protoporphyrin, observed in these patients, are most likely not mediated by oxidation of lipids.
Adenosine Diphosphate↗
A lambda 1 transgene under the control of a heavy chain promoter and enhancer does not undergo somatic hypermutation.
To identify cis-acting elements responsible for targeting somatic hypermutation to immunoglobulin variable regions, we generated transgenic mice which carry a rearranged lambda 1 gene regulated by the heavy chain intron enhancer, E mu, and the heavy chain promoter PH186.2 from the VH186.2 variable region. C57BL/6 x SJL founders were bred with C57BL/6 mice to establish a line carrying a single copy of the transgene. Somatic hypermutation was studied by generating hybridoma cell lines from mice immunized with the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP) coupled to chicken gamma globulin. The immune response in this transgenic line was dominated by the endogenous VH186.2 heavy chain variable region and the transgenic lambda 1 light chain, and the transgene was actively expressed in all hybridomas analyzed. In this work we show that the transgenic V lambda 1 regions do not undergo hypermutation, despite high levels of expression, while the expressed heavy chain V regions accumulate mutations at a rate typical of the NP response in C57BL/6 mice. Thus, within the same B cell, the PH186.2 promoter in connection with E mu drives efficient expression of both a VH and a V lambda region, but only the VH is a target for somatic hypermutation. Our observations show that cis-acting sequences that activate immunoglobulin gene transcription are not sufficient to target somatic hypermutation.
Animals↗
Evaluation of the effects of radiotherapy on macroprolactinomas using the decline rate of serum prolactin levels as a dynamic parameter.
The effect of radiotherapy (24- > 50 Gy) on serum prolactin levels was studied in 28 patients with macroprolactinomas. All had been treated with surgery and 21 had also received bromocriptine interim therapy. Serum prolactin levels decreased in a log-linear fashion with time, both in the patients who never received bromocriptine and those who were treated with this drug. The decline rate of serum prolactin, which thus represented the effect of radiotherapy, was independent of intercurrent bromocriptine therapy, radiation dose and variables such as pre-radiation prolactin levels, tumour grade and tumour extension. During the course of follow-up (3-24 years) serum prolactin normalized in eight patients (28.6%). It is proposed to use the decline rates as a dynamic parameter to predict normalization time and time required for continuance of dopaminergic drug therapy.
Adult↗
Cerebral ventricle dimensions as risk factors for schizophrenia and affective psychosis: an epidemiological approach to analysis.
A case-control study was undertaken of volumetric computerized tomographic scan measures in 216 consecutive admissions for functional psychosis and 67 healthy community controls. Odds ratio analysis demonstrated significant linear trends in the association between increasing lateral and third ventricle volumes, and both RDC schizophrenia (N = 121) and schizo-affective disorder (N = 41); cases were consistently associated with larger volumes than controls. There was an association between larger third, but not lateral, ventricle size in affective psychoses (N = 54). These associations were statistically independent of intracranial volume, sex, social class and ethnicity, factors which were significantly associated with ventricular measures in the controls. There was no evidence of a threshold corresponding to the notion of normal versus enlarged ventricles. Within the schizophrenia group, there were no large or significant associations between ventricle dimensions and age at onset, duration of illness or pre-morbid social functioning. Neither obstetric complications nor a family history of schizophrenia or other psychiatric illness was associated with large ventricles in these cases.
Adolescent↗
Expression of non-NMDA glutamate receptor channel genes by clonal human neurons.
Treatment of the human teratocarcinoma line NTera2/c1.D1 (NT2) with retinoic acid induces terminal neuronal differentiation. In a previous study, we found that the neurons obtained in this way express functional N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptor channels. We now show by reverse transcriptase-polymerase chain reaction and Southern blotting that these neurons transcribe each of the nine known non-NMDA glutamate receptor genes (GluR1-7, Ka-1, and Ka-2) and that four of these genes (GluR2, GluR6, GluR7, and Ka-1) are also transcribed by undifferentiated NT2 cells. Patch clamp studies demonstrate that individual non-NMDA glutamate receptor channels are readily isolated from NT2-derived neurons and that these channels are potently modulated by the desensitization blocker cyclothiazide. NT2-derived neurons are susceptible to kainate excitotoxicity but are not injured by prolonged exposure to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate. We expect that the NT2-derived human neuronal culture system will facilitate studies of human neuronal non-NMDA glutamate receptor channels and of the pathophysiology of neuronal excitotoxicity.
6-Cyano-7-nitroquinoxaline-2,3-dione↗
Malignant vestibular schwannoma.
A 61-year-old woman underwent a translabyrinthine resection of a right intracanulicular acoustic neuroma, which had been detected in the work-up of sudden hearing loss. At the time of surgery, the tumor was roughly twice as large as indicated by the magnetic resonance scan taken only 2 months previously. The tumor eroded the vertical and transverse crests and extended well into the cerebellopontine angle. It was impossible to distinguish the facial nerve proximal to the geniculate ganglion. All visible tumor was resected, along with the facial nerve. Histological evaluation showed a highly cellular tumor, with many mitoses and areas of necrosis, meeting the criteria for malignant schwannoma. The patient has no stigmata of neurofibromatosis, and has no known relatives with that condition. This case is only the fourth reported of a malignant vestibular schwannoma. The relationships between vestibular schwannoma, neurofibromatosis, and malignancy are discussed.
Case Reports↗
The natural physical alternative to cognitive theories of motor behaviour: an invitation for interdisciplinary research in sports science?
This review examines the viability of the natural physical alternative to traditional cognitive modelling of the sport performer. It is concluded that the natural physical perspective offers an attractive framework for the study of movement control and co-ordination in sport, but, at present, does not seem capable of superseding cognitive explanations. As a consequence of the nature of the questions they are asking, natural physical theorists offer a significant avenue for interdisciplinary research in sports science. Significant differences in the philosophy underpinning both theoretical views are acknowledged, but growing support for an integrated approach to motor control is highlighted. A major task for sports scientists may be to verify empirically the nature of an integrated model of the sport performer.
Humans↗
Avascular necrosis of bone following intensified steroid therapy for acute lymphoblastic leukaemia and high-grade malignant lymphoma.
Five out of nine adults (55%) with lymphoblastic disease developed severe avascular necrosis of bone (AVN) when treated with a Berlin-Frankfurt-Munster (BFM) ALL protocol similar to the current joint MRC-ECOG ALL trial (UKALL XII). The principal purpose of these intensified regimens is to improve long-term disease-free survival without necessarily increasing toxicity and secondary morbidity. The presentation of all five was non-specific bone pain occurring after the re-intensification block of chemotherapy containing high doses of dexamethasone. Three types of diagnostic imaging were performed and magnetic resonance imaging (MRI) proved superior in demonstrating AVN and showed it at an earlier stage than plain radiographs or isotopic scans. We believe that the dose of corticosteroids was the major factor in the development of AVN. The five men in our series all remain in first remission with a median disease-free survival of 3.5 years (range 2-8 years) but with varying degrees of disability due to AVN. Clinicians involved in UKALL XII and similar trials should be aware of this debilitating and potentially crippling complication when using high-dose steroid-containing regimens, perform MRI scan early and modify treatment if necessary.
Adolescent↗
Anti-myeloperoxidase antibodies in patients with rheumatoid arthritis: prevalence, clinical correlates, and IgG subclass.
OBJECTIVES: To determine the prevalence and clinical associations of autoantibodies to myeloperoxidase (MPO) in an unselected series of well-characterised outpatients with rheumatoid arthritis (RA) and to compare the distribution of IgG subclasses of anti-MPO antibodies in these patients with that in patients with systemic vasculitis. PATIENTS AND METHODS: A study was made of 97 patients with RA, who have been seen regularly in this department for up to 20 years, and 29 patients with anti-neutrophil cytoplasmic antibody (ANCA) positive systemic vasculitis. Anti-MPO antibodies were detected using a direct-binding enzyme-linked immunosorbent assay (ELISA) with MPO from human granulocytes as antigen. The IgG subclass of anti-MPO antibodies was determined by ELISA using isotype specific monoclonal antibodies. RESULTS: Anti-MPO antibodies were detected in 12% of patients with RA. Six sera contained IgG anti-MPO antibodies only, 1 IgM only and 5 antibodies of both classes. In the patients with RA the predominant subclasses were IgG1 and IgG3: only 2 sera contained detectable IgG4 antibodies. This was in contrast to patients with vasculitis, in whom most sera contained IgG1, IgG3 and IgG4 anti-MPO antibodies. Anti-MPO antibodies in sera from both patient groups bound only to the native protein. None of the patients studied with RA had evidence of vasculitis affecting the nerves or kidney: three patients (1 positive for anti-MPO antibodies and 2 negative) had cutaneous vasculitis. In the patients with RA, positivity for anti-MPO antibodies was associated with nodules and number of active joints. Three patients with anti-MPO antibodies, and none without, had pulmonary fibrosis. CONCLUSIONS: Twelve per cent of a group of unselected outpatients with RA, but without evidence of major systemic vasculitis, had anti-MPO antibodies in their serum. Positivity for anti-MPO antibodies was more common in patients with nodular disease and lung involvement but not in patients with cutaneous vasculitis. IgG4 sub-class anti-MPO antibodies were present in 90% of sera from patients with ANCA-positive vasculitis and only 2/11 (18%) of anti-MPO antibody containing sera from patients with RA.
Adult↗
Mesenteric arterial rupture following blunt abdominal trauma: demonstration by computed tomography.
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Abdominal Injuries↗
An evaluation of drug injection behaviors and HIV infection. National AIDS Research Consortium.
This paper investigates domains of drug injection behavior and the association of derived factors to HIV serostatus. Two sets of data were randomly selected and matched from a national data set of over 40,000 drug injectors. One set was HIV seropositive and the other HIV seronegative heterosexual injectors. Samples were matched to control for the effects of race/ethnicity, gender, and age on serostatus. Factor analysis was used to investigate relationships among drug injection behaviors. Four independent factors were found. Two factors were found to be statistically related to HIV serostatus in high seroprevalence areas. None of the needle use factors was found to be significantly associated with serostatus in low seroprevalence areas.
Adult↗
Capital acquisition planning in a managed-care environment.
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California↗
The trouble with 'quality'.
Much like that elusive but sought-after commodity, beauty, quality lies to a great extent in the eye and mind of its beholder. Whilst some are content with second-hand goods, others insist that only the best will do, the judgement of what is the best being a very individual phenomenon. The mechanical aspects of quality are those things which are visible or tactile: cleanliness, completeness, adequate numbers, smiling faces, quickly answered phones. All of these may be visible and present in a unit which offers a poor quality service. Behind the smiling faces, the efficiently answered phone, may lie a philosophy of total self-centredness, a value system based on clock watching and working strictly within a job description. This person may never give that important small sacrifice which puts another's needs ahead of their own.
Efficiency, Organizational↗
Athletic injury and self diminution.
A review of the literature examining the effects of athletic injury on persons have suggested a deleterious effect. Specifically, results indicated that following traumatic injury, athletes suffer a diminution of affect and feelings of self-worth. Because studies published in this area have been post-injury in design, the present study was fashioned to examine changes from baseline values in the self-concept of university varsity football players following a disabling injury. There were 29 athletes in the subject pool. Sixteen subjects were severely injured during the season. Measures were taken on the first day of fall practice and at the end of the season. Injured athletes were assessed each week while they were unable to participate in practice. Analysis revealed a significant decrease in generalized self-concept following athletic injury (p < 0.001) which persisted through the course of treatment. Suggestions for continued research and treatment are proffered.
Adolescent↗
Efficacy of urgent thoracotomy for trauma in patients attended by a helicopter emergency medical service.
Over a 12-month period the Helicopter Emergency Medical Service underwent 1084 missions attending casualties in the London area. Sixteen patients required an emergency thoracotomy for resuscitation, nine of which were performed at the scene and seven in the emergency department. The median injury severity score of these patients was 29.9 (SIR 11.8) of which 11 had suffered blunt injuries. Medical attention at scene was administered 16.2 min (SIR 4.0) following the London ambulance service receiving the emergency call. Significantly longer time was spent attending patients who had a scene thoracotomy (35.1 min SIR 16.4) compared with those in whom the thoracotomy was performed in the casualty department. No patient in this series survived resuscitative thoracotomy. It is suggested that scene thoracotomy be abandoned and emphasis placed upon the rapid transport of patients to an emergency facility. This enables other resuscitative measures in addition to thoracotomy to be applied effectively and concentrated over a brief period by a multidisciplinary team.
Adolescent↗
Expression of activated RAF accelerates cell differentiation and RB protein down-regulation but not hypophosphorylation.
Expression of an activated raf transgene accelerated the terminal myeloid differentiation of HL-60 human promyelocytic leukemia cells induced by retinoic acid. A similar result was obtained when 1,25-dihydroxyvitamin D3 was used to induce monocytic differentiation. The stable transfectants were derived by transfecting HL-60 cells with DNA encoding an N-terminal truncated raf-1 protein. In normal HL-60 cells retinoic acid is known to induce a colony-stimulating factor-1 (CSF-1)-dependent metabolic cascade culminating in G0 arrest and phenotypic conversion. Early in this cascade, expression of the RB tumor suppressor gene product is down-regulated. A progressive redistribution of the form of the protein from largely hyperphosphorylated protein to the hypophosphorylated form begins later with G0 arrest and differentiation. In the activated raf-transfected cells, RB down regulation occurred more rapidly, consistent with accelerated differentiation. But the conversion to the hypophosphorylated form was not accelerated and occurred after G0 arrest and phenotypic conversion to myeloid differentiated cells. Thus raf activation appears to be a component of the induced metabolic cascade culminating in terminal differentiation. In this cascade raf activation promotes RB down-regulation. The data are consistent with a model in which raf is an effector of the CSF-1-dependent metabolic cascade which culminates in terminal cell differentiation, and RB downregulation is one of the downstream consequences of RAF action. Furthermore, they indicate that RB down-regulation may be an essential component of the cellular processes causing G0 arrest and differentiation, but RB hypophosphorylation is more likely a consequence thereof and not a cause.
Cell Differentiation↗
Nomenclature and classification of purinoceptors.
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Amino Acid Sequence↗