Biomedical subjects
D Fry
Publications and source records attributed to D Fry.
Decreased urinary excretion of beta-glucuronidase in sickle cell anemia in Nigeria.
The activities of five lysosomal hydrolases--namely beta-glucuronidase, beta-hexosaminidase, beta-galactosidase, alpha-galactosidase, and alpha-mannosidase--were measured in the plasma and urine of children (ages, 7 to 15 years) with sickle cell anemia (n = 11) and controls (n = 11) from Jos, Nigeria. The presence of SS hemoglobin was confirmed by electrophoresis of red cell hemolysates. Albuminuria was absent in all of the patients with sickle cell anemia. The creatinine-indexed urinary activity level (units of enzyme activity/milligrams creatinine) and the fractional enzyme excretion (FEE) value, which is defined as the ratio of enzyme clearance to creatinine clearance, were determined for each of the five lysosomal enzymes and compared between the two groups. The mean FEE values for beta-glucuronidase and alpha-galactosidase in the sickle cell patients were 10- and 3.5-fold lower, respectively, than the corresponding control values, and these differences were statistically significant (p < .03) for both enzymes; however, beta-hexosaminidase, beta-galactosidase, and alpha-mannosidase levels in urine were not different between the two groups. When indexed to creatinine, a comparison of the urinary enzyme levels of control and sickle cell patients showed significant differences for beta-glucuronidase (p < .01) and alpha-galactosidase (p < .05) but not for the other three enzymes. Differences in level of plasma enzyme activity between control and sickle cell patients were not significant, except for alpha-galactosidase (p < .05), which was increased slightly (25%) in the sickle cell group. These data indicate that there may be abnormalities in the metabolism of lysosomal enzymes in the kidneys of patients with sickle cell anemia.(ABSTRACT TRUNCATED AT 250 WORDS)
Characterizing the mu-conotoxin binding site on voltage-sensitive sodium channels with toxin analogs and channel mutations.
The three-dimensional organization of the domains of the rat skeletal muscle sodium channel subtype 1 (rSkM1) and the toxin-channel interaction surface have been explored by a complementary mutagenesis approach. This method involves probing mutant channels with analogs of the peptide toxin, mu-conotoxin (mu-CTX), for which the tertiary structure has been determined. mu-CTX has an overall net charge of +5. The blocking of Na+ currents of rSkM1 expressed in Xenopus oocytes by mu-CTX analogs in which negative charge had been removed by Asn substitution for Asp or positive charge had been decreased by Gln substitution for Arg or Lys was studied; the mu-CTX analogs exhibited decreased blocking potencies of up to 228-fold compared with an IC50 = 51.4 +/- 2.2 nM for native mu-CTX on wild-type rSkM1. Mutations at Arg 13 of mu-CTX were the most critical in decreasing potency and at Lys9 were the least critical. Charge alone, however, was not the essential factor in some toxin substitutions: the IC50 value for Asp12Asn showed little change while that for Asp12Glu was increased approximately 100-fold due to a change in conformation (revealed by NMR measurements of the toxin in solution). Focusing on the sites in the channel which might be involved in toxin binding, mutations were introduced involving substitutions at more than a dozen mostly anionic sites in putative extracellular residues of rSkM1. The toxin binding results indicate: firstly, many channel mutations at anionic sidechains on the putative extracellular surface of mu-CTX-sensitive channels, thought to be possible sites of interaction with toxin, have been shown to have no effect on toxin binding. Secondly, one channel mutation, rSkM1/Tyr401Cys, (in the loop between S5 and S6 of Domain 1), affected mu-CTX potency causing a 3.7-fold increase in IC50 value. The ratio of toxin blocking potencies was not significantly different when wild-type and the mutant (Tyr401Cys) rSkM1 channels were studied with two toxin analogs, Arg19Gln and Arg13Gln, in contrast to all other toxin derivatives examined. Since Tyr401 is known to be in the channel pore, these results suggest that either or both of the Arg residues at positions 13 and 19 of mu-CTX interact(s) with residue Tyr401 of rSkM1 and, therefore, indicate that mu-CTX extends into the pore region of the channel.
Biochemical analysis of the transducin-phosphodiesterase interaction.
In vertebrate rod cells, the activated alpha-subunit of rod transducin interacts with the gamma (regulatory) subunits of phosphodiesterase to disinhibit the catalytic subunits. A 22-amino acid long region of rod transducin involved in phosphodiesterase activation has recently been identified. We have used peptides from this region of rod transducin and from several other G protein alpha-subunits to study the nature and specificity of the G protein alpha-effector interaction. Although peptides derived from rod transducin, cone transducin and gustducin are similar, only the rod peptide is capable of activating rod phosphodiesterase. Using substituted peptides we have identified five residues on one exposed face of rod transducin as important to phosphodiesterase activation. These results disagree with previous models which propose that loop regions of rod transducin interact with phosphodiesterase gamma.
Child abuse--continuing problems.
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Analogs of CCK incorporating conformationally constrained replacements for Asp32.
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An evaluation of several adjuvant emulsion regimens for the production of polyclonal antisera in rabbits.
Emulsion adjuvants have been used for production of polyclonal antisera in rabbits (Oryctolagus cunniculi) for decades. Complete Freund's adjuvant has a reputation as a very effective immunoenhancer, but adverse physiological effects, including fever, inflammation and sterile abscess formation, have prompted a search for alternatives to complete Freund's. In this study, we quantitatively compared five adjuvant regimens: (a) a primary inoculation with complete Freund's followed by three boosts with incomplete Freund's; (b) four serial inoculations of incomplete Freund's adjuvant augmented with 6-bromoguanisine; (c) four serial inoculations with RIBI's MPL + TDM + CWS adjuvant emulsion; (d) four serial inoculations with Montanide ISA 50 emulsion; and (e) four serial inoculations with Montanide ISA 70 emulsion. We chose a small (12 amino acid) chain polypeptide coupled to bovine serum albumin as our test antigen. When compared, no system could be seen to be significantly better than a regimen of a primary immunization with complete Freund's adjuvant followed by serial reimmunization with incomplete Freund's adjuvant. The commercially available RIBI adjuvant produced significantly lower antibody levels, while other systems produced essentially equivalent levels. With all five adjuvants, antibody quantities plateaued after the second injection and further immunization did not increase titers significantly. Boost injections did yield greater intradermal tissue reaction than primary inoculations, and intramuscular inoculum volumes of 0.4 cc caused chronic lesions still detectable by the gross necropsy 2 weeks after the final injection.
Systems of standards for community health services in Australia.
This paper describes how the Australian Community Health Association (ACHA) has facilitated the development of quality assurance systems for community health services in Australia. The systems are based on the standards and review process produced by the Community Health Accreditation and Standards Project, known by its acronym "CHASP'. The paper outlines principles and organisation of community health services in Australia and some background to their development. It then considers what kind of standards and quality assurance methods are appropriate for community health services. The CHASP model of standards and its associated review process is explained. The paper discusses how the ACHA has worked with various states in Australia to establish systems of standards based on the CHASP work. It concludes by looking at some constraints and opportunities in developing CHASP, and some future directions.
A transgenic mouse model for studying the induction of fetal hemoglobin in the adult.
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The benzodiazepines as substances of abuse.
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Multiple-organ-failure syndrome.
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Standards for community health: the National Community Health Accreditation and Standards Project.
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A herpesvirus antigen in human premalignant and malignant cervical biopsies and explants.
Cervical biopsies and explant cultures from patients with squamous metaplasia, various grades of dysplasia, carcinoma in situ (CIS), and invasive squamous cell carcinoma were screened for VP143, an early nonstructural polypeptide of herpes simplex virus type 2 (HSV-2), VP143 was identified in 31% of biopsies exhibiting severe dysplasia, 29% with CIS, and 41% with invasive squamous cell carcinoma. Similar results were obtained when explants derived from these biopsies were examined for VP143. The expression of the protein persisted in passaged subcultures in four of five invasive carcinomas which originally contained VP143. Staining for VP157, the major capsid protein of HSV-2, was absent. Furthermore, virus structures were not seen by electron microscopy and infectious virus was not isolated from cell cultures inoculated with biopsy extracts. These results suggest that VP143 was expressed in the premalignant and malignant cervical cells in the absence of productive viral infection. Thus, a fragment of the HSV-2 genome was retained within the cells, the expression of which resulted in the production of VP143.
First steps towards community health accreditation.
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Expression of herpes simplex virus type 2 antigens in premalignant and malignant human vulvar cells.
Vulvar biopsies and explants from patients with vulvitis, hyperkeratosis, condyloma acuminatum, severe dysplasia, and squamous cell carcinoma were screened for herpes simplex virus type 2 (HSV-2) antigens. Immunoperoxidase staining for VP143, an early nonstructural polypeptide of HSV-2, was identified within three biopsies exhibiting severe dysplasia, three of seven with carcinoma in situ, and one of three with invasive squamous cell carcinoma. Similar staining for VP143 was observed in derived explants. Staining for VP119, the major envelope glycoproteins of HSV-2, was identified within tissues which were positive for VP143. Both proteins were expressed in the absence of staining for virus capsid proteins, detection of virus structures by electron microscopy, and isolation of infectious virus by co-cultivation, indicating that only a fragment of the virus genome was expressed. Neither VP143 nor VP119 was identified in biopsies exhibiting vulvitis, hyperkeratosis, or condyloma acuminatum. These data indicate a close relationship between HSV-2 and vulvar neoplasia.
Aorticoduodenal fistula secondary to a toothpick.
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Dissemination and causes of infection.
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Detection of cannabis products in urine by radioimmunoassay.
A radioimmunoassay specific for the closed, three-ringed cannabinoid nucleus was used to detect and measure caname from hospital inpatients not suspected of taking drugs. None of these contained tetrahydro-cannabinol cross-reacting cannabinoids (THC-CRC). The other 393 specimens were from patients known or suspected to be taking various drugs. Of these 51 out of 162 from one hospital treatment clinic and 19 out of 50 from another were positive for THC-CRC. Out of 107 urine specimens from an independent drug treatment clinic 71 were positive for THC-CRC, as were 13 out of 74 specimens from patients in whom drug misuse was suspected or thought possible.