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Biomedical subjects

J M Williamson

Publications and source records attributed to J M Williamson.

At least 55 records · Page 3Linked to original sources
PubMed1989

Morphological and immunohistological study of testicular lymphomas.

We have studied normal testis, seminomas and malignant lymphomas of the testis using routine stains and a panel of antibodies directed against lymphoid and basement membrane antigens. The results show that normal testis contains, at most, a minor population of T-lymphocytes: seminomas contain mixed T- and B-cell populations with a predominance of B-lymphocytes; and most primary lymphomas are B-cell tumours of large centroblastic type. Solid testicular lymphomas presenting secondarily to acute lymphoblastic leukaemias showed intact seminiferous tubular basement membranes with predominantly interstitial lymphomatous infiltrates, whereas the tubules in primary cases were over-run by lymphoma cells and basement membranes were disrupted.

Antibodies, Monoclonal↗
PubMed1989

Induction of paroxysmal discharges in the dentate gyrus: frequency dependence and relationship to afterdischarge production.

1. Electrical-stimulus trains activated hippocampal circuits in urethan-anesthetized rats. Responses were monitored with recordings of extracellular potentials and with measurements of the extracellular potassium ([K+]o). Stimulating electrodes were placed in the CA3 region contralateral to the recording electrode (cCA3) and in the ipsilateral angular bundle (AB) while recording in the CA1 pyramidal-cell layer or the granule-cell layer of the dentate gyrus. Patterns of maximal activation were identified. 2. In the CA1 region, maximal activation was indicated by the presence of 10- to 15-mV population spikes, a smooth rise in [K+]o of 5-6 mM above base-line levels of 3 mM, and a negative shift of the sustained DC potential of 2-4 mV. The dentate gyrus was considered to be maximally activated when bursts of large-amplitude (20-40 mV) population spikes were present. These population spikes were associated with a secondary rise in [K+]o to 6-8 mM above base line and an abrupt negative shift of the DC potential of 5-8 mV. 3. Maximal activation depended on the stimulus intensity, frequency, and duration. Trains of 10-Hz stimuli were used to determine the lowest stimulus intensity needed to elicit complete activation in CA1 and in the dentate gyrus. At this intensity, afterdischarges were not produced, and these responses could be elicited repeatedly. 4. By the use of this threshold stimulus intensity, cCA3 stimulation produced a rapid and progressive augmentation of CA1 responses until maximal activation was reached. In comparison, stimulation of the AB could produce the same end result, but the appearance of CA1 population spikes was delayed. Stimulation of the AB produced a steady increase in the evoked granule-cell population spike until the appearance of the paroxysmal large-amplitude population spikes. In contrast, cCA3 stimulation produced two positive evoked responses in the dentate gyrus before the paroxysms of population spikes began. 5. The frequency dependence of the responses was determined by giving stimulus trains ranging from 2 to 100 Hz. Stimulation of cCA3 produced population spikes in CA1 up to 100 Hz that were all associated with the same peak rise in [K+]o. AB stimulation only produced CA1 responses with stimulation frequencies between 15 and 25 Hz. The paroxysmal dentate population spikes were generated by stimulus frequencies between 15 and 30 Hz with both AB and cCA3 stimulation. 6. Unilateral colchicine injections caused a loss of dentate granule cells and a loss of maximal dentate activation on the side of the injection.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

A structurally unique, potent, and selective oxytocin antagonist derived from Streptomyces silvensis.

The in vitro and in vivo oxytocin/arginine vasopressin (OT/AVP) antagonist properties of two cyclic hexapeptides derived from a newly discovered natural product (L-156,373) of Streptomyces silvensis are described. In radioligand binding assays, L-156,373 [cyclo(L-Pro-D-Phe-N-OH-L-Ile-D-piperazyl-L-piperazyl-N-Me-D -Phe)] exhibited moderate affinity for rat uterine OT receptors (Ki, 150 nM), with some selectivity (approximately 20-fold) vs. liver AVP-V1 and kidney AVP-V2 receptors. Dehydroxylation of N-hydroxyisoleucine and oxidation of the piperazic acid residues of L-156-373 produced an interesting derivative, L-365,209. These structural modifications increased OT receptor affinity and selectivity by 20- and 2.5-5-fold, respectively. In the isolated rat uterus, L-365,209 was a potent (apparent dissociation constant, 1.7 nM) and competitive OT antagonist. L-365,209 also blocked the effects of AVP at both AVP-V1 (phosphatidylinositol turnover in rat hepatocytes) and AVP-V2 (adenylate cyclase in rat kidney medulla) receptors, but only at low micromolar concentrations. L-365,209, given iv to anesthetized rats, antagonized the action of exogenous OT on the uterus (ID50, 460 micrograms/kg) with a relatively long duration of action. L-365,209 represents a unique class of compounds that provides an entirely new approach for the design of antagonists for these neurohypophyseal hormones.

Animals↗
PubMed1987

Adverse reactions to sulphasalazine and 5-amino salicylic acid in the same patient.

We report a patient who developed sulphasalazine-related hepatitis with a subsequent adverse reaction to rectal 5-amino salicylic acid, in the form of pain and fever without associated liver dysfunction, suggesting reactions to both components of sulphasalazine. Included is a review of the literature. Caution should be observed when prescribing 5-amino salicylic acid to sulphasalazine-intolerant patients.

Adult↗
PubMed1987

Ploidy, proliferative activity, cluster differentiation antigen expression and clinical remission in high-grade non-Hodgkin's lymphoma.

Using a large range of monoclonal antibodies to specific cluster differentiation antigens the phenotypes of a series of high-grade non-Hodgkin's lymphomas of B- and T-cell type were investigated. Cell ploidy and proliferative fraction were assessed by fluorescent staining of DNA and flow cytometry and data on the incidence of complete clinical remission were obtained. With the exception of some lymphoblastic lymphomas, high-grade B-cell lymphomas normally expressed the pan B-cell antigens CD19 and CD22 but only immunoblastic lymphomas consistently expressed the pan B marker CD20. Variable, generally weak expression of CD21 was observed whilst CD23 expression was most prevalent in rapidly proliferative cases and in Burkitt's and centroblastic lymphomas. A rapidly proliferative, multilobated B-cell lymphoma displayed phenotypic properties intermediate between centroblastic and immunoblastic lymphomas. The T-cell lymphomas generally showed low proliferative activity and expression of CD4 prevailed over CD8. Most cases also showed CD2 and CD5 positivity with some also showing CD3 and CD7 expression. Patients with rapidly proliferative diploid or DNA aneuploid tumours obtained complete remission more readily than patients with lowly proliferative diploid tumours. An excess of early deaths occurred among T-cell cases.

Adolescent↗
PubMed1987

Major histocompatibility complex class II antigen expression in B and T cell non-Hodgkin's lymphoma.

An immunohistochemical study of 46 B and T cell non-Hodgkin's lymphomas, using monoclonal antibodies to the products of the major histocompatibility complex (MHC) class II antigen subregions, DP, DQ, and DR, showed that most B and T cell lymphomas express these antigens. Both coordinate and non-coordinate expression of MHC class II antigens was observed, but this did not correlate with immunological phenotype, morphological grade, or proliferation index as determined by flow cytometry.

B-Lymphocytes↗
PubMed1986

Cluster differentiation antigen expression, proliferative activity and clinical stage in centroblastic centrocytic lymphomas.

Using a panel of B-cell antibodies recognizing clusters of leucocyte differentiation antigens, immunostaining patterns of eight reactive lymph nodes and 28 centroblastic/centrocytic and centrocytic lymphomas have been studied. Centroblastic/centrocytic and centrocytic lymphomas retained many of the B-cell differentiation antigens and neoplastic follicles partially recapitulated the staining patterns observed in reactive follicles. Centrocytic lymphomas usually expressed a heavy chain mantle zone-like phenotype. Nearly one-half of follicular lymphomas showed extension of neoplastic cells into interfollicular areas as evidenced by positivity for CD10 (common acute lymphoblastic leukaemia) and/or CD9 (immature B-cell) and CD23 (B-blast cell) antigens. Cases showing interfollicular involvement also manifested considerable phenotypic heterogeneity. Light chain restriction could not be used to determine interfollicular involvement because of the presence of many non-neoplastic cells. Most follicular lymphomas retained a polyclonal mantle around at least some neoplastic follicles and in no case was a monoclonal mantle seen. Most lymphomas (16/21) were diploid when examined by flow cytometry. Diploid tumours exhibiting interfollicular lymphomatous involvement had high proliferation (S + G2) fractions and these lymph nodes were usually derived from patients with widespread disease. Tumours containing a high percentage of cells in the G0/G1 phases displayed fewer B-cell differentiation antigens than tumours with low G0/G1 fractions.

Antigens, Neoplasm↗
PubMed1986

DNA content and prognosis of non-Hodgkin's lymphoma.

Ninety cases of non-Hodgkin's lymphoma diagnosed prior to the use of modern therapeutic regimens (1963-67) and 88 cases treated with such chemotherapy (1980-85) were studied using conventional morphology and flow cytometry. DNA aneuploidy as determined by flow cytometry was more common among high grade (38%) than low grade (19%) tumours (P less than 0.01). Measurements of proliferative index (S + G2 phase cells) revealed significantly increased values for high grade as compared with low grade lymphomas (P less than 0.001). In the first group of cases (1963-67) the relationship between histological grade and survival just failed to reach statistical significance over the long term (20 yr) (P = 0.1) but proved significant over 3 yr (P = 0.012). Differences in ploidy and proliferative index status were not associated with survival. In the second patient group (1980-85) attainment of complete remission following chemotherapy was associated with the presence of DNA aneuploidy in high grade tumours (P less than 0.05). The limited follow up of this group precluded assessment of survival in relation to ploidy.

Adolescent↗
PubMed1986

Biosynthesis of fluorothreonine and fluoroacetic acid by the thienamycin producer, Streptomyces cattleya.

An antimetabolite, THX, was isolated from fermentation broths of the thienamycin producer, Streptomyces cattleya, when the organism was grown in the presence of a fluorine-containing substrate. THX was subsequently identified as one of the four possible stereoisomers of 4-fluorothreonine. Inorganic fluoride or any one of a number of organofluorine compounds can be used as precursors of 4-fluorothreonine. In addition, 19F NMR has provided evidence that the organism synthesizes fluoroacetate under the same fermentation conditions. The in vitro antibacterial spectrum of 4-fluorothreonine is also presented.

Animals↗
PubMed1985

Biosynthesis of the beta-lactam antibiotic, thienamycin, by Streptomyces cattleya.

Radioactive- and stable isotope-containing substrates were used to identify the biosynthetic precursors of the beta-lactam antibiotic, thienamycin, in Streptomyces cattleya. Acetate is utilized by the organism to form C(6) and C(7) of the beta-lactam ring. The two carbons of the hydroxyethyl group attached to C(6) are both derived from the methyl of methionine. The cysteaminyl side chain attached to C(2) is derived from cysteine. Selective inhibition of thienamycin and cephamycin C biosynthesis has been achieved either through the addition of metabolic inhibitors or through manipulation of the growth medium. These results suggest that the two beta-lactam antibiotics, thienamycin and cephamycin C, are formed by different biosynthetic pathways.

Magnetic Resonance Spectroscopy↗
PubMed1985

Reverse transsulfuration and its relationship to thienamycin biosynthesis in Streptomyces cattleya.

Cystathionine gamma-lyase (EC 4.4.1.1) was purified from Streptomyces cattleya, an actinomycete which produces the unusual beta-lactam antibiotic thienamycin. The enzyme displays broad substrate specificity and is similar to gamma-lyases purified from other microorganisms. That the gamma-lyase functions in vivo to provide cysteine for antibiotic synthesis was shown by two types of experiments. First, cystathionine and methionine, as well as cysteine itself, are efficiently utilized by S. cattleya for thienamycin biosynthesis. Second, propargylglycine, a mechanism-based inactivator of cystathionine gamma-lyase in vitro, inhibits the synthesis of thienamycin in vivo. This inhibition can be substantially reversed by providing the cells with another source of cysteine, such as cystine.

Alkynes↗
PubMed1985

Primary biliary cirrhosis and chronic active hepatitis: an examination of clinical, biochemical, and histopathological features in differential diagnosis.

Seventy four liver biopsies from 59 patients were reviewed by two observers and histologically graded in the absence of clinical information, firstly, to assess the level of agreement with previous diagnoses; secondly, to identify differences between primary biliary cirrhosis and chronic active hepatitis; and, thirdly, to assess the specificity of Shikata orcein staining and antimitochondrial antibody positivity and titre for primary biliary cirrhosis. Thirty six patients with adequate histology were initially selected as typical of primary biliary cirrhosis or chronic active hepatitis; agreement both between observers and with original diagnoses was reached in 26 (72%) (15 with primary biliary cirrhosis (group 1), 11 with chronic active hepatitis (group 2)). In 19 diagnostically difficult patients in whom clinical and original histological findings had been at variance, histological agreement between observers was reached in 17 (group 3) and original underdiagnosis of primary biliary cirrhosis was suggested. The main clinical and histological differences between groups 1 and 2 are discussed in this paper. Although a high grade of positivity for copper associated protein in the Shikata orcein stain was seen only in primary biliary cirrhosis, a high titre of antimitochondrial antibody positivity was not unique to this condition.

Alkaline Phosphatase↗
PubMed1982

New substrates of 5-oxo-L-prolinase.

Interaction of 5-oxo-L-prolinase (which catalyzes stoichiometric cleavage of 5-oxo-L-proline to L-glutamate coupled to that of cleavage of ATP to ADP and Pi), with a number of new 5-oxo-L-proline analogs was examined in studies in which (a) analogs were substituted for 5-oxo-L-proline and the formation of products was determined, (b) the effects of the analogs on the normal catalytic reaction were observed, and (c) the effects of the analogs on the ITPase activity exhibited by the enzyme were examined. Some of these reactions are partially coupled, i.e. the molar formation of ADP exceeds that of amino acid; others are uncoupled, i.e. cleavage of ATP, but not that of imino acid occurs. Analogs in which the 4-methylene moiety of 5-oxo-L-proline is replaced by O, S, and NH (L-2-oxooxazolidine-4-carboxylate, L-2-oxothiazolidine-4-carboxylate, and 2-imidazolidone-4-carboxylate) participate in reactions that are, partially coupled, coupled, and uncoupled respectively. Partial coupling occurs with cis- and trans-2-oxo-5-methyloxazolidine-4-carboxylate, and uncoupled reactions occur with L-2-iminothiazolidine-4-carboxylate, 2-thiazolinone-4-carboxylate, and 2-oxo-5,5-dimethylthiazolidine-4-carboxylate. These and earlier findings indicate that significant binding of the imino acid substrate requires a 5-carbonyl (or = NH), an unsubstituted N-1 and a C-2 of the L-configuration; substantial modification of 5-oxo-L-proline in the region of C-3 and C-4 is possible with retention of binding properties. Uncoupling and partial coupling may be associated with significant differences in the orientations of the analogs at the active site that facilitate (to various extents) the access of water to the nucleoside triphosphate.

Adenosine Triphosphate↗
PubMed1982

Effect of sulfhydryl group modification on the activities of 5-oxo-L-prolinase.

5-Oxo-L-prolinase was isolated from rat kidney by a new procedure; highly active and apparently homogeneous enzyme was obtained in 50% yield after 1700-fold purification. The enzyme, which couples cleavage of ATP to ADP with that of 5-oxo-L-proline to L-glutamate, is uncoupled by Ca2+, Co2+, or excess Mn2+ as well as by replacement of adenosine 5'-triphosphate or of 5-oxo-L-proline by certain analogs as previously reported. The enzyme has Mr = 325,000 and is composed of 2 apparently identical subunits. It contains 27 sulfhydryl groups/monomer, 6 of which can be titrated in the native enzyme and 2 of which are required for catalysis. One of the sulfhydryl groups that can be titrated with 5,5'-dithiobis(2-nitrobenzoic acid) and N-ethylmaleimide can be protected against modification by ATP or inosine 5'-triphosphate. The findings suggest that at least 1 sulfhydryl group is at or close to the nucleoside triphosphate binding site and is involved in cleavage of NTP. 5'-p-Fluorosulfonylbenzoyl adenosine and 5'-p-fluorosulfonylbenzoyl inosine interact with the sulfhydryl group involved in NTPase activity and also with another amino acid residue of the enzyme. The data provide additional strong evidence that (a) the enzyme can bind 5-oxo-L-proline in the absence of NTP, and that it can bind NTP in the absence of 5-oxo-L-proline, and (b) the L-glutamate synthesis and NTP-cleaving activities are catalyzed by the same protein.

Adenosine Diphosphate↗
PubMed1982

Intracellular cysteine delivery system that protects against toxicity by promoting glutathione synthesis.

Depletion of glutathione by inhibition of its synthesis by buthionine sulfoximine, an irreversible inhibitor of gamma-glutamylcysteine synthetase, leads to increased sensitivity to (i) irradiation and (ii) oxidative stress. In the present work, an intracellular cysteine delivery system was used to promote glutathione synthesis, and this was found to protect against toxicity. Thus, administration of L-2-oxothiazolidine-4-carboxylate protected against acetaminophen toxicity in mice; the thiazolidine, which is converted to L-cysteine by the enzyme 5-oxo-L-prolinase (present in many animal tissues and in plants) promotes the synthesis of glutathione, which is the actual protectant. The effect of this thiazolidine in increasing the level of glutathione is prevented by administration of buthionine sulfoximine. This thiazolidine may be useful in the treatment of other toxicities and in the treatment of certain diseases. It may also be valuable as a component of amino acid mixtures used in therapy and as a safener in agriculture.

Acetaminophen↗