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Biomedical subjects

A M Prince

Publications and source records attributed to A M Prince.

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

Prevention of liver cancer and cirrhosis by vaccines.

HBV and HCV infections are the most important causes of chronic hepatitis, cirrhosis, and HCC. These occur in chronically infected individuals of whom there are more than 700 million worldwide. Prevention of chronic infection with these viruses by immunization is a high priority. Safe and effective HBV vaccines, both plasma-derived and recombinant DNA-derived are available, although not yet used universally because of cost. An HCV vaccine is not yet available and may be difficult to develop because of the high variability of the viral proteins. Nevertheless, research on such a vaccine remains a major goal. Therapeutic vaccines that induce a CTL response capable of killing infected cells offer an exciting approach to the treatment of chronic infections.

Carcinoma, Hepatocellular↗
PubMed1995

Onchocerca volvulus: a comparative study of in vitro neutrophil killing of microfilariae and humoral responses in infected and endemic normals.

In vitro neutrophil-mediated microfilarial killing, humoral responses to crude adult worm antigens (OVAg) and to four recombinant Onchocerca antigens (GST-OV7, GST-OV103, GST-OV3.6, and MBP-OV16), as well as Western blot analysis to stage-specific Onchocerca proteins were studied in individuals from Bassa County, Liberia, infected with onchocerciasis and in endemic normals, defined as individuals without microfilaridermia. Both groups exhibited high levels of specific serum-dependent killing of microfilariae but could not be differentiated on the basis of these results. However, infected individuals had a significantly higher frequency of antibody response to OVAg (P = 0.0001) except GST-OV103. Based on the pattern of response to the different antigens, 17 categories of specific recognition were observed. Nine of these categories were common to both the infected individuals and the endemic normals, 2 were unique to the infected individuals, and 6 were unique to the endemic normals. Among the endemic normals, we identified a subcategory of individuals who had nondetectable levels of total IgG to OVAg by ELISA and had significantly lower IgG4 responses to OVAg. These same individuals demonstrated evidence of past infection, based on serum antibodies detectable by Western blot analysis to male and female adult worms and skin microfilariae, and had a positive response to two or less of the recombinant antigens. We believe that this subcategory may represent individuals with a unique status of immunity.

Adolescent↗
PubMed1995

Hypericin as an inactivator of infectious viruses in blood components.

BACKGROUND: Hypericin is a potent virucidal agent with activity against a broad range of enveloped viruses and retroviruses. The effective virucidal activity emanates from a combination of photodynamic and lipophilic properties. Hypericin binds cell membranes (and, by inference, virus membranes) and crosslinks virus capsid proteins. This action results in a loss of infectivity and an inability to retrieve the reverse transcriptase enzymatic activity from the virion. STUDY DESIGN AND METHODS: Since hypericin is devoid of adverse action in most blood components and blood analyses, it is investigated as an additive with potential to inactivate infective viruses in blood components intended for transfusion. RESULTS: Complete inactivation of 10(6) tissue culture-infective doses of human immunodeficiency virus was obtained in whole blood and in diluted packed red cells after illumination with fluorescent light for 1 hour. Loss of viral infectivity to cultured CEM cells has been monitored by use of a detection assay for human immunodeficiency virus p55 in enzyme-linked immunosorbent assay and cytopathic assays. In physiologic media, hypericin interacts with albumin and lipoproteins, retaining the virucidal activity in bound form. The molecule is negatively charged and forms organic and inorganic monobasic salts (ion pairs) in physiologic pH. Various ion pairs differ in virucidal efficacy. CONCLUSION: The apparent transfusibility of hypericin, taken together with the efficacy of the virucidal activity, the broad range of enveloped viruses affected, and the absence of adverse effects on stored red cells, may render hypericin useful for inactivation of infectious viruses in red cells.

Anthracenes↗
PubMed1995

Transglutaminase-catalyzed reaction is important for molting of Onchocerca volvulus third-stage larvae.

Highly insoluble proteins, which are probably cross-linked, are common in the cuticle and epicuticle of filarial parasites and other nematode species. We have investigated the possible involvement of transglutaminase (TGase)-catalyzed reactions in the development of Onchocerca volvulus fourth-stage larvae (L4) by testing the effects of TGase inhibitors on the survival of third-stage larvae (L3) and the molting of L3 to L4 in vitro. The larvae were cultured in the presence of three specific TGase inhibitors: monodansylcadaverine, cystamine, and N-benzyloxycarbonyl-D,L-beta-(3-bromo-4,5-dihydroisoxazol-5-yl)-al anine benzylamide. None of the inhibitors reduced the viability of either L3 or L4. However, the inhibitors reduced, in a time- and dose-dependent manner, the number of L3 that molted to L4 in vitro. Molting was completely inhibited in the presence of 100 to 200 microM inhibitors. Ultrastructural examination of L3 that did not molt in the presence of monodansylcadaverine or cystamine indicated that the new L4 cuticle was synthesized, but there was an incomplete separation between the L3 cuticle and the L4 epicuticle. The product of the TGase-catalyzed reaction was localized in molting L3 to cuticle regions where the separation between the old and new cuticles occurs and in the amphids of L3 by a monoclonal antibody that reacts specifically with the isopeptide epsilon-(gamma-glutamyl)lysine. These studies suggest that molting and successful development of L4 also depends on TGase-catalyzed reactions.

Animals↗
PubMed1994

Characterization and mapping of a B-cell immunogenic domain in hepatitis C virus E2 glycoprotein using a yeast peptide library.

To identify conserved humoral antigenic determinants within the hepatitis C virus (HCV) envelope protein E2, we expressed a peptide library containing random short fragments of the HCV envelope in yeast. Clones were identified using a monospecific rabbit antibody to a region downstream of the E2 hypervariable region. The clones define the limits of two original antigenic domains: a major one (aa 493-576) and a minor one (aa 535-606). The major antigenic domain maps in a region that displays a high degree of homology within a (HCV) subtype (92-97.6% identity). Yeast-encoded determinants were characterized by Western blot analysis, N-glycosidase F digestion, and using a panel of synthetic peptides. The data suggest that the major antigenic domain contains at least two determinants, one of them mimicked by an 18-mer peptide (aa 514-531). ELISA and competitive inhibition assays demonstrated that: (1) the determinants appear subtype 1a-specific, (2) seroprevalence of antibody to the determinants is rather low (20.6%), and (3) donors show a heterologous response to the different determinants. Antibody response to the E2 determinants was studied in HCV-infected chimpanzees and post-transfusion-associated NANB hepatitis cases. The antibody response was found during chronic infection and may not be effective for virus clearance.

Amino Acid Sequence↗
PubMed1994

Identification and characterization of an Onchocerca volvulus cDNA clone encoding a highly immunogenic calponin-like protein.

The identification and characterization of a recombinant cDNA clone, designated OV9M, expressing an antigen present in Onchocerca volvulus infective larvae and adult stages is described. Clone OV9M was identified by screening a lambda gt11 cDNA expression library derived from adult O. volvulus mRNA using pooled rabbit antisera raised against the third (L3) and fourth (L4) stage larvae of the parasite. The cDNA clone encodes an open reading frame of 238 amino acids corresponding to a 27-kDa polypeptide. This polypeptide contains a series of five highly conserved repeats of 25 amino acids that are similar to repeats found in calponin, a protein previously only identified in vertebrate smooth muscle. Extension of the 5' end of the cDNA clone revealed two additional repeats extending the sequence to 378 amino acids, encoding a 41.8-kDa protein. Affinity purified antibodies, which bound specifically to the glutathione S-transferase-OV9M fusion polypeptide, recognize a series of antigens in extracts of O.volvulus microfilariae, L3, L4 and adult stages. The apparent molecular weight of the native OV9M protein in the adult is 45 kDa. Similar proteins are present in extracts of other nematodes including Caenorhabditis elegans, and antibodies from other filarial infections are cross reactive with glutathione S-transferase-OV9M fusion polypeptide. Immunoelectron microscopy revealed that the antigen encoded by this clone is present in the longitudinal muscles of the various larval stages and adult worms. Antibodies to the OV9M protein are present in 40-60% of both patently infected and non-patent individuals residing in onchocerciasis endemic areas.

Amino Acid Sequence↗
PubMed1994

Viral safety of solvent/detergent-treated blood products.

Laboratory research that began in 1982 led to the licensing in the USA of a solvent/detergent (SD)-treated factor VIII concentrate in 1985. The licence was granted on the basis of several factors. First, studies had demonstrated the inactivation of several marker viruses (vesicular stomatitis virus, Sindbis virus, Sendai virus) and other viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and non-A, non-B hepatitis virus (NANBHV; now known principally to be hepatitis C virus) added to the factor VIII concentrate just before treatment. Secondly, it had been realized that the relevant viruses in transfusion (e.g. HIV, HBV, NANBHV) all had lipid envelopes. Finally, laboratory, preclinical and clinical evidence indicated that factor VIII and other proteins present in the preparation were unaffected by SD treatment. The applicability of the SD method to a wide range of products and preparations, high process recoveries and a growing body of viral safety information linked with the failure of several other virus-inactivation methods to eliminate hepatitis transmission fostered the adoption of SD technology by more than 50 organizations worldwide. SD mixtures are now used in the preparation of a diverse array of products. Numerous laboratory and clinical studies suggest that coagulation-factor concentrates and other SD-treated products prepared from plasma pools are now safer than the individual units from which they were derived. Also, a large body of evidence indicates that hepatitis A virus (HAV) is not typically transmitted by blood and blood products.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Immunity in hepatitis C virus infection.

Immunity after HCV infection is weak, even after reinfection with the identical strain of virus. Even chronically infected chimpanzees can be reinfected. Weak immunity may reflect the fact that HCV virions are coated with lipoproteins (VLDL), preventing antibody binding. This phenomenon presents a serious challenge for development of vaccines.

Animals↗
PubMed1994

Challenges for development of hepatitis C virus vaccines.

Impediments to the development of a hepatitis C virus (HCV) vaccine are reviewed. Foremost is the perception that the limited transmissability of HCV, and reduced spread by blood-associated routes, make this a low priority target. It is argued that such a vaccine may have an important therapeutic use in the treatment of chronic HCV carriers of which an estimated 30 million exist worldwide. An HCV vaccine would also have prophylactic use in multivalent (hepatitis) vaccines, and in the developing world. An effective HCV vaccine will not be easy to develop. The high variability of the viral proteins, especially that of the envelope proteins, provide a major challenge. The association of HCV with very low density lipoproteins renders a major proportion of the virions non-neutralizable, a further challenge. It may be necessary to design an HCV vaccine which acts primarily through the generation of cytotoxic lymphocytes reactive with conserved epitopes displayed on the surface of infected cells.

Hepacivirus↗
PubMed1994

Chimpanzees in AIDS research: a biomedical and bioethical perspective.

The present article represents a consensus view of the appropriate utilization of chimpanzees in AIDS research arrived at as a result of a meeting of a group of scientists involved in AIDS research with chimpanzees and bioethicists. The paper considers which types of studies are scientifically justifiable in this species, the conditions under which such studies should be carried out, and the conditions which should be encouraged for post-experimental retirement of these animals.

AIDS Vaccines↗
PubMed1994

New phthalocyanines for photodynamic virus inactivation in red blood cell concentrates.

Cationic phthalocyanines with either aluminum or silicon as the central metal were evaluated for their ability to inactivate viruses in red blood cell concentrates (RBCC) photodynamically. In addition, the virucidal potential of a substituted anionic phthalocyanine, aluminum dibenzodisulfophthalocyanine hydroxide (A1N2SB2POH) was evaluated and compared with that of the much studied anionic aluminum tetrasulfophthalocyanine hydroxide (A1PcS4OH). Based on the rate of inactivation of the lipid-enveloped vesicular stomatitis virus (VSV), the virucidal potential of these phthalocyanines was: HOSiPcOSi(CH3)2(CH2)3N+(CH3)3I- (Pc 5) = SiPc[OSi(CH3)2-(CH2)3N+(CH3)3I-]2 (Pc 6) > A1PcOSi(CH3)2(CH2)3N+(CH3)2(CH2)11CH3I- (Pc 21) = A1N2SB2POH = A1PcS4 > HOSiPc[OSi(CH3)2(CH2)3N+(CH3)2(CH2)11CH3I-]2 (Pc 14) > A1PcOSi(CH3)2(CH2)3N+(CH3)3I- (Pc 2). Phthalocyanine ligand 14 and Pc 21 are new phthalocyanines, made by quaternizing known amino analogues. Compared to VSV, the rate of inactivation of Sindbis virus (another model lipid-enveloped virus) was identical when treated in red blood cells (RBC) with Pc 5 and slightly higher when treated with Pc 6 and A1PcS4OH. Treatment of RBCC containing cell-free human immunodeficiency virus (HIV-1) with Pc 5 or A1PcS4OH required 15 min of irradiation to inactivate (> 5 log10 reduction) the virus. The extent of HIV-1 inactivation with A1N2SB2POH was 3.7 log10 after 60 min of red light exposure. The RBC integrity after photosensitization was measured by the ability of the cells to bind to plates coated with poly-L-lysine, (which reflects the retention of the RBC surface negative charges) and hemolysis of the cells over a 7 day storage period.(ABSTRACT TRUNCATED AT 250 WORDS)

Erythrocyte Transfusion↗
PubMed1994

Onchocerca volvulus: in vitro cytotoxic effects of human neutrophils and serum on third-stage larvae.

The cytotoxic effects of neutrophils co-cultured with infective third-stage larvae (L3) and autologous serum from three groups of individuals: infected (INF), non-patent endemic normals (EN) and non-endemic controls (NEC), were compared using a MTT (3-(4,5 dimethylthiazol-2yl)-2,5 diphenyl tetrazolium bromide) reduction assay as a biochemical parameter of larval viability. The MTT assay permitted the detection of L3 which had suffered varying levels of necrosis. The observations from this study indicate that infected individuals and endemic normals are capable of mounting a specific immune response against the infective L3. This is based on our findings of i) significantly greater numbers of L3 showed necrosis in neutrophil cultures of the INF and EN compared to those from the NEC, ii) a superior ability of cultures from these individuals to inhibit the molting of L3 to fourth-stage larvae, iii) IgG antibodies reactive with the surface of L3, detected by immunofluorescence in the serum of the INF and the EN and iv) recognition of specific antigens in extracts of L3 detected by Western blot analysis. The specific immune response directed against L3 is probably a significant immunological defense mechanism used to limit infection in endemic areas.

Adolescent↗
PubMed1994

Hypotonus cyclodialysis cleft following suture fixation of a posterior chamber intraocular lens.

A 63-year-old man developed hypotony due to a cyclodialysis cleft after suture fixation of a posterior chamber intraocular lens. Since medical management and argon laser photocoagulation were unsuccessful, a direct cyclopexy was performed. The intraocular pressure returned to normal postoperatively, and gonioscopy confirmed closure of the cleft. To our knowledge, this is the first case report of cyclodialysis complicating ciliary sulcus fixation of a posterior chamber lens.

Cataract Extraction↗
PubMed1993

Experimental onchocerciasis in chimpanzees: cellular responses and antigen recognition after immunization and challenge with Onchocerca volvulus infective third-stage larvae.

Immunization of chimpanzees with radiation-attenuated infective 3rd-stage larvae (L3) of Onchocerca volvulus did not induce strong protective immunity against a subsequent challenge infection; only 1 out of 4 immunized animals remained non-patent (i.e. microfilariae-negative) after challenge, and may have been protected. However, during immunization and before challenge, a broad range of adult O. volvulus-derived antigens (OvAg) and also uterus-derived OvAg were recognized by circulating antibodies; moreover, the repertory of antigens recognized increased further in subsequently patent animals after challenge, particularly in the range of M(r) 12-42 kDa. In the immunized and non-patent chimpanzee, by contrast, serological recognition of uterus-derived OvAg with M(r) 14 kDa and 105 kDa disappeared by 19 months post-challenge (p.c.). During immunization, Acanthocheilonema viteae L3 antigens of M(r) 11-12 kDa were strongly recognized only by the non-patent animal, suggesting that recognition of these antigens may have supported resistance to the subsequent challenge infection. In immunized chimpanzees, a substantial increase in the cellular reactivity to OvAg was induced; this, however, declined by 19 months p.c. to levels similar to those seen prior to immunization. At that time, 3 out of 4 immunized animals were patently infected. The effect of exogenous cytokines on in vitro-reactivity of PBMC to OvAg was examined. Addition of exogenous IL-2 alone, IFN-gamma alone, and IFN-gamma in combination with IL-2, did not augment net cellular responses to OvAg by PBMC from infected and control chimpanzees. In the presence of IL-4 alone, IL-6 alone, IL-2 with IL-4, IL-2 with IL-4 and IFN-gamma, or IL-2 with IL-4 and IL-6, the net cellular reactivity to OvAg increased significantly in patent chimpanzees and reached levels similar to non-patent animals. Thus, non-patent chimpanzees maintain high cellular reactivity to OvAg and in vitro cellular unresponsiveness to OvAg on the part of patent chimpanzees is reversible after addition of several cytokines which act individually or synergistically.

Animals↗
PubMed1993

Phylogenetic and serological characterization of two Ugandan HIV-1 isolates.

HIV-1 isolates Ug06 and Ug23 were established in culture from peripheral blood mononuclear cells (PBMCs) of Ugandan subjects. The isolates were studied for phylogenetic and serological relationships with each other and with the laboratory strains, HTLV-IIIB and HIV-1MN. The results suggest that the Ugandan isolates are related to different subgroups of African viruses with 17.3% of genetic distance between UG06 and the U455 provirus (Uganda); and 12.6% of genetic distance between UG23 and the JY1 provirus (Zaire). Analysis of the predicted amino acid sequences for Ug06 and Ug23 showed marked sequence heterogeneity in the V3 region and CD4-binding site. A conserved amino acid sequence was identified in the C-terminal immunodominant region of the envelope glycoprotein gp120. The isolates were compared in virus-neutralization experiments with HTLV-IIIB and HIV-1MN stocks, using panels of Western blot-positive North American and Ugandan sera. The North American serum samples showed broad neutralizing activity against both of the Ugandan isolates. However, the Ugandan serum panel demonstrated strain-specific activity against either Ug06 or Ug23. Furthermore, the African serum specimens showed higher prevalence and titers of neutralizing activity against the HIV-1MN stock as compared with HTLV-IIIB.

Amino Acid Sequence↗