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Biomedical subjects

R Day

Publications and source records attributed to R Day.

At least 19 recordsLinked to original sources
PubMed1992

The clinical application of the interferons: a review. NSW Therapeutic Assessment Group.

OBJECTIVES: To review the clinical information on the use of alpha, beta and gamma interferons and to classify the use of alpha interferons in Australia according to approved indications, indications for which there is good supporting evidence and indications where therapy is under investigation; and to estimate the cost of therapy with alpha interferons in New South Wales in 1991. DATA SOURCES: Data were obtained from computerised literature searches. DATA EXTRACTION: A position paper was drafted on behalf of the NSW Therapeutic Assessment Group (NSWTAG). This was circulated to clinicians identified as having a particular interest in the use of the interferons in major NSW teaching hospitals, for comment and amendment where necessary. CONCLUSIONS: Two forms of alpha interferon, interferon alfa-2b and interferon alfa-2a have been approved for use in Australia, interferon alfa-2b for use in the management of hairy cell leukaemia and condylomata acuminata and interferon alfa-2a for use in the management of hairy cell leukaemia and human immunodeficiency virus (HIV) related Kaposi's sarcoma. Applications have been lodged for the use of interferon alfa-2b in HIV related Kaposi's sarcoma, cutaneous basal cell carcinoma and hepatitis B and C and for the use of interferon alfa-2a in the management of hepatitis B, cutaneous T-cell lymphoma and metastatic renal cancer. Interferon alfa-n1 is not available in Australia except for use in a clinical trial in patients who are HIV seropositive. The use of the alpha interferons is currently under investigation in a wide variety of other diseases, with the likelihood that other indications will soon be established. However, the alpha interferons are generally not regarded as first line agents. Beta and gamma interferons have been studied less intensively than the alpha interferons, but it is likely that selected applications for their use will also be defined with the passage of time.

Australia↗
PubMed1992

Immunological effects of treatment with sequential administration of recombinant interferon gamma and alpha in patients with metastatic renal cell carcinoma during a phase I trial.

Many anticancer mechanisms of the interferons have been proposed but none have been associated with clinical response to date. The biological activities of the interferons in vivo have included effects upon the natural killer cell, T- and B-lymphocytes, and macrophages. This report details a prospective study of the immunological effects on peripheral blood mononuclear cells of sequentially administered recombinant (r) interferon (IFN) gamma and rIFN alpha in 28 patients with metastatic renal cell carcinoma. Natural killer cell activity, T-cell phenotype (CD4, CD8, CD56, CD16, CD4/HLA-DR, CD8/HLA-DR, CD56/HLA-DR) and 2',5'-oligoadenylate synthetase were measured prior to therapy, during therapy, and following completion of treatment. Statistical analysis of all parameters was performed for the entire group, by individual patient, by dosage, by time, and by clinical response. An overall significant depression in natural killer cell activity and in the percentage of circulating CD56, CD16, and CD8+ cells were noted. Significant increases in 2',5'-oligoadenylate synthetase and in the percentage of circulating CD4 cells were also noted. Although an association between the magnitude of change in percentage of CD16+ cells and 2',5'-oligoadenylate synthetase and dosage of rIFN gamma and rIFN alpha, respectively, was observed, optimal biological dose of this sequence of rIFNs could not be determined due to the limited number of patients. A decrease in the percentage of circulating CD8+ cells was observed among patients with objective clinical response (partial and complete). Sequentially administered rIFN gamma and rIFN alpha can modulate immunological parameters in vivo in patients with metastatic renal cell carcinoma. A fall in percentage of circulating CD8+ cell is associated with response and suggests that this sequence of rIFN alpha and rIFN gamma might influence T-cell mediated antitumor activity.

2',5'-Oligoadenylate Synthetase↗
PubMed1992

Calculation of lytic units for the expression of cell-mediated cytotoxicity.

Over the past 10 years, the lytic unit has become the most common means by which activity is expressed in cell-mediated cytotoxicity assays. The strengths and weaknesses of the lytic unit as a summary of cytotoxicity are discussed, and computational methods reviewed. The fundamental "assumption of proportional effect" which is implicit in the interpretation of lytic units is described and empirically tested. Based on extensive data from the assay of human natural killer (NK) activity against K562 targets, simplified computational methods are recommended. The proposed methods are easily explained, may be made robust to occasional erratic data, and permit a reasonable interpretation of lytic units even when the assumption of proportional effect breaks down.

Cytotoxicity Tests, Immunologic↗
PubMed1992

A comparative ecological study of selected cancers in Kanawha County, West Virginia.

This study compares mortality rates for selected causes of death in Kanawha County, West Virginia, to rates reported in a number of geographically defined populations for 1950-1984. Specific conditions selected for study included cancers of the biliary passages and liver, the bladder and other urinary organs, and the central nervous system (CNS), as well as leukemia and aleukemia, lymphosarcoma and reticulosarcoma, Hodgkin's disease, and cancer of all other lymphopoietic tissue. The analysis made use of several techniques for the investigation of ecological data, including the modeling of rates using Poission regression. The primary findings of this study concern two subgroups of cancers of the lymphatic and hematopoietic tissue: (1) leukemia and aleukemia, and (2) lymphosarcoma and reticulosarcoma. For both subgroups of cancers, white male residents of Kanawha County show evidence of significantly elevated mortality rates over the 35-year period of this study.

Adult↗
PubMed1992

The cDNA sequence of the human pro-hormone and pro-protein convertase PC1.

Using a probe consisting of the full-length cDNA sequence of the mouse pro-hormone convertase PC1 (mPC1), we isolated from a lambda gt10 human pituitary cDNA library a number of contiguous clones, of which composite sequence of 3.3-kb defined the complete coding sequence of human PC1 (hPC1). The cDNA sequence of hPC1 encodes a protein containing 753 amino acids and potentially two N-glycosylation sites, one carboxy-terminal amidation site, a cAMP-dependent protein kinase Ser phosphorylation site, a tyrosine kinase phosphorylation site, and an ArgGlyAsp (RGD) sequence. Like mPC1, the carboxy-terminal sequence of hPC1 exhibits an amphipathic domain potentially involved in membrane association. The coding region of hPC1 exhibits an overall 92.6% protein sequence identity to the mouse mPC1 sequence, with the highest homology (98%) found in the catalytic segment of the molecule (residues 84-399). Whereas Northern blot analysis of tissues obtained from mouse, rat and porcine demonstrated the presence of two mRNAs of 3 kb and 5 kb, Northern blots of human tissues and cells demonstrated the presence of a dominant transcript of 6.2 kb and the presence of smaller transcripts in some tissues. The major site of production of hPC1 seems to be the pituitary and brain, although detection was also possible in pancreas and heart.

Amino Acid Sequence↗
PubMed1992

Testicular expression of PC4 in the rat: molecular diversity of a novel germ cell-specific Kex2/subtilisin-like proprotein convertase.

The rat cDNA sequence of PC4 (rPC4), representing a new member of the Kex2/subtilisin-like proprotein convertases, demonstrated the presence of at least three rPC4 mRNAs resulting in the production of rPC4-A (654 amino acids), rPC4-B (619 amino acids), and rPC4-C (609 amino acids) with different C-terminal sequences. Analogous to rat PC4, three cDNAs were also found for the mouse PC4. The observed molecular diversity of PC4 mRNA possibly results from the differential splicing and/or exon skipping of the parent gene. PC4 mRNA, with a major form at 2.8 kilobases, was highly abundant in the rat testis but could not be detected by Northern analysis in any other tissues including the central nervous system and peripheral tissues. Testicular cell separation studies combined with Northern analysis indicate the high expression levels of PC4 in germ cells but not in Leydig, Sertoli, or peritubular cells. In situ hybridization histochemistry confirms the site of PC4 gene expression as the pachytene spermatocytes and the round spermatids but not in the elongating spermatids. We also demonstrate the colocalization of PC4 with proenkephalin in testicular germ cells by in situ hybridization. A study of the ontogeny of PC4 indicated that PC4 mRNA was first expressed postnatally between days 19 and 22, coinciding with the first stages of spermiogenesis. The stage-specific expression of PC4 in testis indicates its potential role in the developmental maturation of germ cells and that this convertase may play a specific physiological function in reproduction.

Amino Acid Sequence↗
PubMed1992

Distribution and regulation of the prohormone convertases PC1 and PC2 in the rat pituitary.

PC1 and PC2 are enzymes involved in the activation of prohormones via the cleavage of pairs of basic amino acids. The expression levels of each of these enzymes were evaluated in the rat anterior and neurointermediate pituitary lobes by in situ hybridization and Northern gel analysis and after various pharmacological manipulations. All intermediate lobe melanotrophs expressed high levels of PC2 mRNA and lower levels of PC1 mRNA. PC1 mRNA was highly expressed throughout the anterior lobe; however, appreciable PC2 mRNA levels were also found. Based on colocalization studies, anterior lobe corticotrophs were found to express PC1 mRNA, but very little PC2 mRNA. Neurointermediate lobe levels of PC1, PC2, and POMC mRNA increased 2- to 6-fold in rats treated with haloperidol, while they decreased to 10-25% of their control values after bromocriptine treatment. These results indicate that in the intermediate lobe, dopamine is involved in the regulation of PC1 and PC2. In the anterior lobe, haloperidol had a strong effect on PC2 mRNA, increasing its levels by 8- to 12-fold compared to the control value, while PC1 mRNA was unaffected. Both PC1 and PC2 mRNA levels were increased 5- to 9-fold in animals made hypothyroid by treatment with 6-n-propyl-2-thiouracil. Adrenalectomy had no significant effect on anterior lobe PC1 mRNA levels. However, both PC1 and PC2 mRNA levels were responsive to dexamethasone treatment in the AtT-20 cell lines. Our results indicate that dopamine, thyroid hormones, and corticosteroids are involved in PC1 and/or PC2 gene expression. These data are also consistent with the role of PC1 and PC2 as prohormone-processing enzymes.

Amino Acid Sequence↗
PubMed1992

Leprosy control in 7 districts of south Sulawesi, Indonesia, 1986-91.

This paper describes the leprosy control programme in 7 districts of the South Sulawesi Province in Indonesia. This province is reported to have the highest prevalence of leprosy in the country. The programme started in 1986 with re-registration of all patients on the cumulative registers. Strict criteria for admission of patients to MDT were initially applied. In 1990 it appeared that these criteria had been too strict, thus necessitating a second re-registration of patients still on DDS monotherapy. More flexible criteria for admission to MDT led to an increase in MDT coverage from 45% to 78% within 6 months. By April 1991, 5 years after the start of the programme, the registered prevalence had decreased from 4.4 per 1000 in 1986 to 1.6 per 1000; the coverage with MDT had increased from 6% in 1986 to 78%, and the case detection rate remained stable around 4 per 10,000 after an initial increase at the start of the programme.

Humans↗
PubMed1991

Quinolinic acid elevates striatal and pallidal Met-enkephalin levels: the role of enkephalin synthesis and release.

Huntington's chorea (HC) is characterized, in part, by a substantial deficit in the striatal and pallidal enkephalin levels. Recently, an attempt was made to replicate this deficit by focally injecting quinolinic acid (QUIN), an excitotoxin, into the rat striatum. However, at 7 days post-injection, QUIN produced a dose-related and bilateral increase in the striatal and pallidal levels of met-enkephalin-like immunoreactivity (ME-i.r.), an effect which was attenuated in the presence of excitatory amino acid (EAA) receptor antagonists. In the present study, the action of QUIN was investigated further. To determine whether the QUIN (72 nmol)-induced elevations in ME-i.r. reflected the enhanced synthesis of the peptide, the striatal levels of proenkephalin mRNA were assayed 7 days following a unilateral injection of QUIN into the rat striatum. QUIN significantly depleted (50%) of the proenkephalin mRNA level in the injected, but not the contralateral striatum when compared to that in the saline-injected animals. To determine whether the QUIN-induced increases in ME-i.r. were due to an impaired release of the peptide, the release of ME-i.r. from the striatal or pallidal slices obtained from animals 7 days after a saline- or QUIN-injection, was measured. The 30 mM K(+)-stimulated ME-i.r. release from the saline-injected and contralateral striatum represented an 8-fold increase above the spontaneous release level, while this stimulus induced a 6-fold increase in the ME-i.r. release from both the QUIN-injected and contralateral striatum.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

PC1 and PC2 are proprotein convertases capable of cleaving proopiomelanocortin at distinct pairs of basic residues.

A recombinant vaccinia virus vector was used to coexpress the two candidate mouse prohormone convertases, PC1 and PC2, together with mouse proopiomelanocortin (POMC) in the constitutively secreting cell line BSC-40 and in the endocrine tissue-derived cell lines PC12 and AtT-20, which exhibit regulated secretion. Monitoring of POMC processing demonstrated the distinct cleavage specificities of PC1 and PC2, since in the cell lines analyzed (i) PC1 cleaves POMC into corticotropin and beta-lipotropin, (ii) PC2 cleaves POMC into beta-endorphin, an N-terminally extended corticotropin containing the joining peptide, and either alpha MSH or desacetyl-alpha MSH, and (iii) PC2 cleaves POMC at the five pairs of basic residues analyzed, whereas PC1 cleaves two of them preferentially, suggesting that PC2 has a broader spectrum of activity than PC1. These data are consistent with our hypothesis on the physiological role of PC1 and PC2 as distinct proprotein convertases acting alone or together to produce a set of tissue-specific maturation products in the brain and in peripheral tissues.

Amino Acid Sequence↗
PubMed1991

Atypical prodynorphin gene expression in corticosteroid-producing cells of the rat adrenal gland.

Prodynorphin (proDyn) gene expression was examined in the rat adrenal gland. In situ hybridization revealed a heterogenous proDyn mRNA distribution limited almost exclusively to the adrenal cortex; the inner cortical layers contained the highest amounts. In the adrenal medulla, only scattered single cells were seen. By Northern (RNA) blot analysis, adrenocortical proDyn mRNA levels were highly abundant but of smaller size than proDyn transcripts found in the brain. Low levels of the brain-size proDyn mRNA transcript were detected but restricted to the medulla. A discrepancy was suggested when comparing the high abundance of proDyn mRNA levels with the low levels of proDyn-derived peptide in the adrenal. A hypothesis of nontranslation of the shorter proDyn mRNA by adrenocortical cells was rejected because polysomal loading analysis suggests that the mRNA is translated. We propose that adrenocortical proDyn-derived peptides are not targeted for storage but are released shortly after synthesis, thus accounting for low peptide levels. We also measured proDyn mRNA levels in response to stimuli known to affect adrenocortical cells and their most important function--steroidogenesis. Adrenals from hypophysectomized rats had less proDyn mRNA by a factor of 5 than adrenals from normal sham-operated rats. Normal levels were restored by adrenocorticotrophic hormone administration, indicating a potential importance of adrenal proDyn in the hypothalamic-adrenal-pituitary axis.

Adrenal Cortex↗
PubMed1991

Gene amplification and gene dosage in cell lines derived from squamous cell carcinoma of the head and neck.

Gene amplification and related alterations in gene dosage were analyzed in a series of 34 cell lines derived from different human head and neck squamous cell carcinomas (SCCHN). INT2 gene amplification was observed in 62%, MYC gene amplification in 24%, and EGFR gene amplification in 21% of the cell lines. There was a strong correlation between EGFR gene amplification and increased copies of the ERBB2 gene on chromosome 17, suggesting a synergistic selection for these two genes either during cancer progression or in culture. Two abnormalities showed a significant correlation with clinical course: MYC gene amplification showed an inverse correlation with tumor recurrence (r = -0.44, p = 0.01), and a small increase in MYCL gene copies on chromosome I correlated with the presence of metastases (r = 0.61, p = 0.001). This altered MYCL gene dosage might represent a chromosome translocation rather than true gene amplification. In addition to gene amplification, 79% of the cell lines had increased copies of chromosome 8. Comparison of the cell lines with several of the corresponding primary tumors demonstrated that most gene amplifications were already present in the primary tumors, although some appeared de novo in cell culture. These studies indicate that gene amplification, especially of INT2, is a prominent abnormality in head and neck squamous cell cancer. Aneuploidy and chromosomal lesions other than gene amplification were also found to alter the dosage of several oncogenes specifically.

Carcinoma, Squamous Cell↗
PubMed1991

Effect of cold ischemia time on the early outcome of human hepatic allografts preserved with UW solution.

Five hundred ninety-three cadaveric livers were used for primary liver transplantation between October 24, 1987, and May 19, 1989. The grafts were procured with a combined method, using in situ cooling with cold electrolyte solution and backtable flushing with UW solution. The mean cold-ischemia time was 12.8 (range 2.4-34.7) hr. The cases were divided into 5 groups according to the cold-ischemia time: group 1: less than 10 hr (n = 223); group 2: 10-14 hr (n = 188); group 3: 15-19 hr (n = 101); group 4: 20-24 hr (n = 52); and group 5: greater than or equal to 25 hr (n = 29). There was no difference between the 5 groups in 1-year patient survival, highest SGOT in first week after operation, and SGOT and total bilirubin during the first month after operation. However, with a logistic regression model, the retransplantation rate (P = 0.001) and primary nonfunction rate (P = 0.006) significantly rose as cold-ischemia time increased, meaning that the equivalency of patient survival was increasingly dependent on aggressive retransplantation.

Adenosine↗
PubMed1991

The treatment of patients with newly diagnosed poor prognosis acute myelogenous leukaemia: response to treatment and treatment failure.

The failure of poor prognosis patients with newly diagnosed AML to enter remission is usually due to two phenomena: a high mortality rate and resistance of the leukaemia to chemotherapy. We conducted a pilot study of a regimen designed to overcome these two types of treatment failure. Patients were carefully selected for therapy on the basis of their likelihood of surviving. Chemotherapy consisted of high dose cytosine arabinoside (HDaraC) with the doses modified on the basis of patient age so as to reduce the risk of toxicity. Finally, daunorubicin was administered only to those patients for whom HDaraC was not likely to produce sufficient antileukaemia effects to produce a remission. The median patient age was 67 years and 69/88 (78%) patients had a history of preleukaemia and/or toxic exposure. Only 11/84 (13%) patients died during remission induction therapy and 40/84 (48%) entered CR. Patients with only one risk factor had a higher CR rate than those with more than one risk factor (56% v. 30%, P = 0.02) and also had longer durations (222 d v. 113.5 d, P = 0.035). Two types of resistance to chemotherapy were observed: 'classical resistance' (the failure of chemotherapy to produce substantial killing of leukaemia cells) and the rapid regrowth of leukaemia cells subsequent to a level of cytoreduction which otherwise would have been sufficient to produce a CR.

Aged↗