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Biomedical subjects

R Dickson

Publications and source records attributed to R Dickson.

At least 55 records · Page 3Linked to original sources
PubMed1996

Potentiation of diethylstilbestrol-induced alterations in the female mouse reproductive tract by transforming growth factor-alpha transgene expression.

Neonatal estrogen exposure causes numerous abnormalities in the female reproductive tract, including carcinogenesis. One mechanism by which neonatal estrogen elicits teratogenic and carcinogenic effects is epigenetic and involves the modulation of a number of estrogen-regulated genes including epidermal growth factor (EGF). Because of the evidence that there is an integral relationship between the EGF family, estrogen action, and the regulation of the growth and differentiation of the reproductive tract, we used transforming growth factor-alpha (TGF alpha) transgenic mice to investigate the interaction of constitutive TGF alpha expression with the potent estrogen diethylstilbestrol (DES) in the induction of reproductive-tract alterations. Our study was designed to determine whether TGF alpha expression could modulate DES-induced carcinogenesis of the female mouse reproductive tract. The animals were homozygous TGF alpha transgenic female mice from the MT42 line and the parental CD-1 outbred mice. The presence of the TGF alpha transgene significantly increased the incidence of DES-induced vaginal adenosis, uterine endometrial hyperplasia, uterine polyps, hypospadia, benign ovarian cysts, and pituitary adenomas. However, constitutive TGF alpha expression did not promote reproductive-tract neoplasia. This study demonstrates that TGF alpha participates in the regulation of developmental and morphogenic events in the Müllerian duct and urogenital sinus, suggesting a role for TGF alpha in the pathogenesis of reproductive-tract diseases. Furthermore, we showed that although constitutive expression of the TGF alpha transgene did have an effect on the reproductive tract, TGF alpha overexpression alone could not substitute for DES as a reproductive-tract carcinogen or as a promoter of uterine neoplasia, indicating that DES-induced carcinogenesis requires events in addition to the overexpression of this single peptide growth factor.

Animals↗
PubMed1996

Phase I trial of a novel matrix metalloproteinase inhibitor batimastat (BB-94) in patients with advanced cancer.

Degradation of basement membrane and extracellular matrix by matrix metalloproteinases (MMPs) is believed to be required for tumor invasion, tumor-induced angiogenesis and vascular invasion. A synthetic hydroxamate, batimastat (also known as BB-94), inhibits MMPs by binding the zinc ion in the active site of the MMP. Batimastat inhibits at least 50% of MMP activity at concentrations less than or equal to 10 ng/ml in vitro. Batimastat retarded ascites accumulation and increased survival in mice with human ovarian tumor xenografts. Acute and long-term toxicological studies revealed no major toxicity in animals. Batimastat is poorly soluble and was administered intraperitoneally (i.p.) as a suspension. Previous studies in patients with malignant ascites have shown no major toxicities at doses as high as 1350 mg/m2.

Adult↗
PubMed1995

Functional characterization of the higher plant chloroplast chaperonins.

The higher plant chloroplast chaperonins (ch-cpn60 and ch-cpn10) have been purified and their structural/functional properties examined. In all plants surveyed, both proteins were constitutively expressed, and only modest increases in their levels were detected upon heat shock. Like GroEL and GroES of Escherichia coli, the chloroplast chaperonins can physically interact with each other. The asymmetric complexes that form in the presence of ADP are "bullet-shaped" particles that likely consist of 1 mol each of ch-cpn60 and ch-cpn10. The purified ch-cpn60 is a functional molecular chaperone. Under "nonpermissive" conditions, where spontaneous folding was not observed, it was able to assist in the refolding of two different target proteins. In both cases, successful partitioning to the native state also required ATP hydrolysis and chaperonin 10. Surprisingly, however, the "double-domain" ch-cpn10, comprised of unique 21-kDa subunits, was not an obligatory co-chaperonin. Both GroES and a mammalian mitochondrial homolog were equally compatible with the ch-cpn60. Finally, the assisted-folding reaction mediated by the chloroplast chaperonins does not require K+ ions. Thus, the K(+)-dependent ATPase activity that is observed with other known groEL homologs is not a universal property of all chaperonin 60s.

Adenosine Diphosphate↗
PubMed1995

Case management quality assessment in rural areas of Papua New Guinea.

A study was carried out to assess the quality of case management of malaria, malnutrition, diarrhoea and acute respiratory tract infections in children in rural primary health services in Papua New Guinea. In particular, the study focused on the knowledge and skills of different categories of rural health workers (HW) in history taking, examination, diagnosis, treatment and patient education. Quality criteria were defined and health centre (HCW) and aidpost workers' (APWs) knowledge and practices were assessed. Primary health workers' (PHW) knowledge of case management was weak, but in all cases better than their actual practice. History taking and examination practices were rudimentary. HWs tended not to make or record diagnoses. Treatment knowledge was often incorrect, with inappropriate or insufficient drugs prescribed, being worst at aidpost level. These findings raise serious questions about the effectiveness of providing health services through small, isolated health units. Far greater attention must now be directed to focus on the institutionalization of problem-based training, continuous supportive supervision and maintenance of clinical skills and provision of essential drugs, supplies and equipment to ensure that rural health workers (RHW) can provide sound care.

Child↗
PubMed1995

The clinical diagnosis and treatment of important childhood diseases in rural Papua New Guinea.

This study used multiple standardized instruments to evaluate the quality of the clinical management of the common childhood diseases in rural Papua New Guinea. The findings indicate major inadequacies in the quality of history taking, examination, record keeping, diagnosis and treatment of the common causes of childhood morbidity and mortality. To improve case management by health workers in rural clinical situations everything possible must be done to make good clinical management easy and practical. This should involve provision of practical reinforcing tools, training and supervision which target rural health workers as valuable human resources, and community education which maximizes the contribution that community members can make to early diagnosis and good management.

Case Management↗
PubMed1994

Cloning, expression, and purification of a functional nonacetylated mammalian mitochondrial chaperonin 10.

An intact mouse mitochondrial chaperonin 10 has been cloned, sequenced, and overexpressed in Escherichia coli as a fusion protein harboring an oligohistidine tail at its COOH terminus. The latter was added to simplify protein purification. The purified protein is free of contaminating groES from the bacterial host cells. Edman degradation reveals that the initiator Met residue of the recombinant protein is removed in vivo, similar to the authentic chaperonin 10 purified from rat liver mitochondria. However, in contrast to the latter, the amino-terminal Ala residue of the recombinant protein is not acetylated; the molecular mass determined by electrospray ionization mass spectrometry is 12,350.9 +/- 2.6 daltons, in agreement with that predicted for the nonacetylated protein (12,351.2 daltons). Facilitated protein folding experiments with ribulose-biphosphate carboxylase, under "nonpermissive" in vitro conditions, demonstrate that the recombinant protein is fully functional with groEL. Thus, both the initial rates of protein folding and final yields observed with this heterologous combination are virtually identical to those obtained with groEL and groES. More important, like the authentic protein purified from mitochondria, the recombinant mitochondrial chaperonin 10, but not groES, is functionally compatible with the heptameric chaperonin 60 of mammalian mitochondria.

Acetylation↗
PubMed1993

Solid organ transplantation: results and implications of acyclovir use in liver transplants.

CMV infection is a major cause of morbidity and mortality following liver transplantation (LT). A prospective study of 218 LT recipients showed that 55% of patients developed CMV infection during the 1st year post-transplantation. Symptomatic CMV infection developed in 25% of all patients, being a major cause of death (21% of all deaths). Of 62 episodes of documented organ invasion, liver was the major site (38 episodes), followed by lung (20), gastrointestinal (4), and retina (4). The main patient group at risk (according to CMV serology of the recipient [(R)/donor(D)]) was the R-/D+: 77% of patients developed CMV infection, all of them with symptoms. The lowest group at risk was the R-/D-: 13% of patients developed CMV infection, half of whom developed symptoms. Time-dependent multivariate statistical analysis of risk factors indicated that the R-/D+ group was the main risk factor for CMV infection (P < .02) and symptomatic infection (P < .0001). To decrease the incidence and severity of CMV infection following LT, a randomized study is ongoing to evaluate the efficacy of ganciclovir (5 mg/kg/IV/q 12 hours for the first 14 days post-LT) followed by acyclovir (800 mg/po/qid for 14 weeks) GCV + ACV (group I), versus acyclovir (same dose for 16 weeks, starting immediately post-LT) ACV (group II). These treatment groups are compared to matched historical controls (C). Preliminary analysis of 83 LT recipients indicates that in group I the median date for the first evidence of CMV infection is delayed (82 days) as compared to group II and C (41 and 33 days, respectively) (P = .004).(ABSTRACT TRUNCATED AT 250 WORDS)

Acyclovir↗
PubMed1992

Use of designer recombinant mitochondrial antigens in the diagnosis of primary biliary cirrhosis.

The appearance of autoantibodies against mitochondria in patients with primary biliary cirrhosis has been known for more than 25 yr. In the past, based on the biochemical complexity of the mitochondrion and the use of crude extracts for immunodiagnosis, a degree of nonspecificity in assaying for antibodies to mitochondria has been present. This problem has been largely circumvented by the cloning of the mitochondrial antigens and the identification of the E2 subunits of the pyruvate dehydrogenase complex and the branched chain 2-oxo-acid dehydrogenase complex as the major and immunodominant autoantigens of primary biliary cirrhosis. More than 90% of patients with primary biliary cirrhosis have been shown to react with one or both of these enzymes using either recombinant antigen or purified native protein. Approximately 10% of patients recognize only E2 subunits of branched chain 2-oxo-acid dehydrogenase complex and not pyruvate dehydrogenase complex. Such patients would be missed by diagnostic assay that has a low sensitivity to antibodies against E2 subunits of branched chain 2-oxo-acid dehydrogenase complex. The use of recombinant and biochemically pure antigens has permitted structural and conformational analysis of epitope mapping. We have taken advantage of the antigenic mapping studies of both primary biliary cirrhosis and branched chain 2-oxo-acid dehydrogenase complex E2 subunits and designed a molecule that expresses the immunodominant epitopes of both. Using this dual-headed molecule that coexpresses the epitope of two different antigens, we report herein a sensitive and reproducible assay for antibodies to mitochondria in patients with primary biliary cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1991

Specific reactivity of recombinant human PDC-E1 alpha in primary biliary cirrhosis.

The mitochondrial autoantigens recognized by autoantibodies in patients with primary biliary cirrhosis have been identified as components of related multi-enzyme complexes, including acyltransferases of the pyruvate dehydrogenase complex (PDC), the branched-chain alpha-keto acid dehydrogenase complex (BCODH), the alpha-ketoglutarate dehydrogenase complex (OGDC), protein X and pyruvate dehydrogenase (PDC) E1 alpha and E1 beta. The major autoantigens, PDC-E2, BCODH-E2 and OGDC-E2, share some sequence homology; the epitopes on these antigens appear to be close to, or identical with, the lipoic acid binding site. Furthermore, all three antigens share some structural homology. In contrast, antibodies to PDC-E1 alpha are present in lower titers, and have been more difficult to detect. PDC-E1 alpha also differs from the three major autoantigens in that it lacks any covalently bound lipoic acid. PDC-E1 alpha cannot be purified in large quantities and becomes unstable in the absence of PDC-E1 beta. To address these problems, we have subcloned recombinant human PDC-E1 alpha to pGEX, pGEX is a vector which produces a recombinant polypeptide fused to glutathione S-transferase. The resultant E1 alpha fusion protein is stable and has a low background in immunoassays. Using the recombinant protein, we have developed an ELISA that allows rapid and reproducible quantification of antibodies to human PDC-E1 alpha. Finally, we demonstrate that a major epitope on PDC-E1 alpha is within a 300 amino acid region that contains the enzyme functional sites, namely the phosphorylation site and the TPP binding site.

Autoantibodies↗
PubMed1989

Detection of autoantibodies to recombinant mitochondrial proteins in patients with primary biliary cirrhosis.

Primary biliary cirrhosis is characterized by the presence of autoantibodies to mitochondria with specific reactivity to proteins of 74 and 52 kilodaltons (kd). The 74-kd mitochondrial protein is the E2 component--dihydrolipoamide acetyltransferase--of the pyruvate dehydrogenase complex, and the 52-kd protein is the equivalent E2 component--dihydrolipoamide acyltransferase--of the branched-chain alpha-keto acid dehydrogenase complex. Current methods for the detection of antibodies to these proteins lack specificity or sensitivity, or they are time-consuming and not readily available. We therefore developed an enzyme-linked immunoassay to quantify specific antimitochondrial antibodies in patients with primary biliary cirrhosis. Recombinant polypeptides coding for both the 74-kd and the 52-kd mitochondrial autoantigens were used to analyze 217 coded serum samples, including samples from 93 patients with primary biliary cirrhosis and 124 controls, for reactivity by our immunoassay, immunoblotting, and immunofluorescence testing. Serum samples from 89 of the 93 patients with primary biliary cirrhosis reacted with either the pyruvate dehydrogenase-E2 or the branched-chain alpha-keto acid dehydrogenase protein. None of the 124 control samples from healthy volunteers (n = 86) or patients with primary sclerosing cholangitis (n = 38) had significant reactivity. Our results indicate that the use of recombinant, cloned autoantigens provides a simple, accurate, and rapid method of quantifying and monitoring the levels of specific mitochondrial autoantibodies in the serum of patients with primary biliary cirrhosis.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗