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Biomedical subjects

T R Jones

Publications and source records attributed to T R Jones.

At least 109 records · Page 6Linked to original sources
PubMed1993

Significant changes in gastrointestinal tract parasitic infections in children of St. Kitts over the 9-year period 1982-1991.

When 239 (1982) and 361 (1991) five- and nine-year-old children in St. Kitts were assessed for the presence of parasitic infections, there were significant reductions in the prevalence of trichuriasis from 83% to 58%, of ascariasis from 24% to 8.6% and of giardiasis from 15% to 9.4%. Anthelminthic use, which appeared to be the most important responsible intervention tool, remained roughly at the same level at 59-51%. However, the types of anthelminthics used changed over the period. Piperazine citrate, which was used by 66% in 1982, only had 35% usage in 1991. Albendazole which was not used at all in 1982 was taken by 32% of the children in 1991 and at the same time use of laevo-tetramisole increased by 20% from 14%. Suggestions are made for an island-wide mass intervention programme to manage parasitic infections.

Anthelmintics↗
PubMed1992

Development of a novel series of styrylquinoline compounds as high-affinity leukotriene D4 receptor antagonists: synthetic and structure-activity studies leading to the discovery of (+-)-3-[[[3-[2-(7-chloro-2-quinolinyl)-(E)-ethenyl]phenyl][[3- (dimethylamino)-3-oxopropyl]thio]methyl]thio]propionic acid.

Based on LTD4 receptor antagonist activity of 3-(2-quinolinyl-(E)-ethenyl)pyridine (2) found in broad screening, structure-activity studies were carried out which led to the identification of 3-[[[3-[2-(7-chloro-2-quinolinyl)-(E)-ethenyl]phenyl][[3- (dimethylamino)-3-oxopropyl]thio]methyl]thio]propionic acid (1, MK-571) as a potent and orally active LTD4 receptor antagonist. These studies demonstrated that a phenyl ring could replace the pyridine in 2 without loss of activity, that 7-halogen substitution in the quinoline group was optimal for binding, that the (E)-ethenyl linkage was optimal, that binding was enhanced by incorporation of a polar acidic group or groups in the 3-position of the aryl ring, and that two acidic groups could be incorporated via a dithioacetal formed from thiopropionic acid and the corresponding styrylquinoline 3-aldehyde to yield compounds such as 20 (IC50 = 3 nM vs [3H]LTD4 binding to the guinea pig lung membrane). It was found that one of the acidic groups could be transformed into a variety of the amides without loss of potency and that the dimethylamide 1 embodied the optimal properties of intrinsic potency (IC50 = 0.8 nM on guinea pig lung LTD4 receptor) and oral in vivo potency in the guinea pig, hyperreactive rat, and squirrel monkey. The evolution of 2 to 1 involves the increase of > 6000-fold in competition for [3H]LTD4 binding to guinea pig lung membrane and a > 40-fold increase in oral activity as measured by inhibition of antigen-induced dyspnea in hyperreactive rats.

Animals↗
PubMed1992

A monoclonal antibody directed against the sporozoite stage of Plasmodium vivax binds to liver parenchymal cells.

The circumsporozoite (CS) protein of malaria parasites is a major surface protein of the sporozoite stage. In the process of investigating the immunogenicity of this protein in the Plasmodium vivax complex, we found that a monoclonal antibody (mAb) directed against the CS protein of isolates of P. vivax recognizes New World monkey hepatocytes and human hepatoma cells HepG2A16 in Western blot and by immunoelectron microscopy. The mAb NVS3 binds to the amino acid sequence AGDR, which is also shared with the alpha 3 domain of the human and primate major histocompatibility complex class I. In addition, in vitro experiments suggest that the binding of the mAb NVS3 to hepatocytes from Saimiri monkey enhances the invasion or development of malaria sporozoites. These results form the basis for investigating the relationships between parasite surface proteins and host-cell receptors.

Amino Acid Sequence↗
PubMed1992

A cluster of dispensable genes within the human cytomegalovirus genome short component: IRS1, US1 through US5, and the US6 family.

By insertional mutagenesis, human cytomegalovirus recombinants deleted of each of the US6 glycoprotein family genes were isolated. A recombinant lacking IRS1, US1 through US5, and most of the US6 family was also isolated. The growth kinetics of these mutants were similar to that of the wild type. A dispensable cluster of genes was identified.

Cells, Cultured↗
PubMed1992

Low immunogenicity of a Plasmodium vivax circumsporozoite protein epitope bound by a protective monoclonal antibody.

The repeat region of the Plasmodium vivax circumsporozoite (CS) protein contains 20 copies of the nine-amino acid sequence DRA A/D GQPAG. A monoclonal antibody that passively protects monkeys against sporozoite challenge recognizes a four-amino acid linear sequence AGDR included within this nonamer, but when monkeys were immunized with a vaccine, NS1(81)V20, which contains 20 copies of the nonamer, they failed to produce antibodies to AGDR. To determine if natural exposure to sporozoites induces antibodies to AGDR, we tested sera from 176 individuals from a malaria-endemic area in Flores, Indonesia. Seventy-one percent of the adults had antibodies to the P. vivax repeat region; only 18% had detectable antibodies to AGDR. None of the subjects had antibodies to the P. vivax variant repeat ANGAGNQPG. We next tested sera from six human volunteers immunized with NS1(81)V20 and found that the vaccine, despite inducing antibodies against the nonamer, as it did in the monkeys, did not induce antibodies against AGDR. To further test our ability to raise anti-AGDR antibodies using synthetic peptides, we immunized Aotus monkeys and BALB/c mice with AGDR. Sera from the mice reacted strongly with both AGDR and a recombinant protein containing the 20 copies of the nonamer. Sera from the monkeys reacted only minimally with a protein (VIVAX-1) that contains monomeric AGDR within its sequence. Sera from the mice also bound air-dried P. vivax sporozoites, while sera from the monkeys did not.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Inability of malaria vaccine to induce antibodies to a protective epitope within its sequence.

Saimiri monkeys immunized with a recombinant protein containing 20 copies of the nine amino acid repeat of the Plasmodium vivax circumsporozoite (CS) protein developed high concentrations of antibodies to the repeat sequence and to sporozoites, but were not protected against challenge. After intravenous injection of an immunoglobulin G3 monoclonal antibody (NVS3) against irradiated P. vivax sporozoites, four of six monkeys were protected against sporozoite-induced malaria, and the remaining two animals took significantly longer to become parasitemic. Epitope mapping demonstrated that NVS3 recognizes only four (AGDR) of the nine amino acids within the repeat region of the P. vivax CS protein. The monkeys immunized with (DRAADGQPAG)20 did not produce antibodies to the protective epitope AGDR. Thus, determination of the fine specificity of protective immune responses may be critical to the construction of successful subunit vaccines.

Amino Acid Sequence↗
PubMed1991

Quinazoline antifolates inhibiting thymidylate synthase: 4-thio-substituted analogues.

We report the synthesis of four new 4-thio-5,8-dideazafolic acid analogues and a 4-(methylthio) analogue structurally related to the thymidylate synthase (TS) inhibitor N10-propargyl-5,8-dideazafolic acid. Three N10-propargyl-4-thio-5,8-dideazafolic acid analogues had C2 amino, hydrogen, and methyl substituents. A 4-thio and a 4-(methylthio) compound each with hydrogen at C2 and ethyl at N10 were also synthesized. In general, the synthetic route involved thionation of the appropriate 4-oxoquinazoline; the sulfur thus introduced was then protected by methylation. Further protection with a pivaloyl group was required for the quinazoline bearing a 2-amino substituent. The protected quinazolines were treated with N-bromosuccinimide and the resulting 6-(bromomethyl) compounds were then coupled to the appropriate N-monoalkylated diethyl N-(4-aminobenzoyl)-L-glutamate in N,N-dimethylacetamide with calcium carbonate as base. The 4-thio-5,8-dideazafolic acids were obtained by removal of the methylthio group with sodium hydrosulfide, followed by deprotection of the carboxyl groups with cold dilute alkali. For the compound containing a pivaloyl protecting group, hot dilute alkali was used. To obtain the 5,8-dideazafolic acid containing a 4-(methylthio) substituent, the corresponding diester was treated with lithium hydroxide which selectively deprotected the carboxyl groups. The five compounds were tested as inhibitors of L1210 TS. It was found that replacement of the 4-oxygen of the quinazoline moiety by sulfur did not alter the TS inhibition. However, the introduction of a methylthio substituent at position 4 severely impaired TS inhibition. All 4-thio compounds were less cytotoxic to L1210 cells in culture than their 4-oxo counterparts.

Animals↗
PubMed1991

Replacement mutagenesis of the human cytomegalovirus genome: US10 and US11 gene products are nonessential.

The US6 gene family, located within the unique short region (US) of the human cytomegalovirus (HCMV) genome, contains six open reading frames (US6 through US11) which may encode glycoproteins, such as gcII (D. Gretch, B. Kari, R. Gehrz, and M. Stinski, J. Virol. 62:1956-1962, 1988). By homologous recombination, several different recombinant HCMV were created which contain a marker gene, beta-glucuronidase, inserted within this gene family. It was demonstrated that beta-glucuronidase has utility as a marker gene for the identification of recombinants in this herpesvirus system, without the occurrence of deletions in other regions of the viral genome. DNA and RNA blot analyses attested to the fidelity of the recombination. Immunoprecipitation experiments using monospecific polyclonal antisera indicated that the US10 and/or US11 gene products were not expressed in the recombinants, as predicted. These results, along with single-cycle growth analyses, indicated that the US10 and US11 gene products are nonessential for virus replication and growth in tissue culture. HCMV recombinants expressing beta-glucuronidase seemed to be genetically stable.

Cell Cycle↗
PubMed1991

Fine mapping of transcripts expressed from the US6 gene family of human cytomegalovirus strain AD169.

By sequence analysis (K. Weston and B. G. Barrell, J. Mol. Biol. 192:177-208, 1986), the human cytomegalovirus (HCMV) strain AD169 HindIII X DNA fragment contains six open reading frames (US6 through US11; called the US6 family) which may encode glycoproteins. Sense transcripts from the US6 family were mapped. The kinetics of appearance of steady-state cytoplasmic RNA was different for each transcription unit. The 1.5-kb US11-US10 and the 1.7-kb US9-US8 transcripts belonged to the early kinetic class. The former reached peak abundance by 8 h postinfection, while the latter peaked at 24 h postinfection. These RNAs greatly decreased in abundance by 48 to 72 h after infection, unlike transcripts from other HCMV early transcription units reported previously. US6 and US7 messages were most abundant at late times postinfection. US6 transcripts utilized different initiation sites at early or late times postinfection. There was evidence for both spliced and unspliced messages from this family. In a transient expression assay, chimeric plasmids containing the regions upstream of the mapped transcription initiation sites were active in promoting indicator gene expression in HCMV-infected, but not uninfected, human foreskin fibroblast cells.

Base Sequence↗
PubMed1991

Pharmacology of the leukotriene antagonist verlukast: the (R)-enantiomer of MK-571.

Verlukast (MK-679) (3-[(3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl)[3-(dimethylamino)- 3- oxopropyl)thio)methyl)-thio)propionic acid) is a potent and selective inhibitor of [3H]leukotriene D4 binding in guinea-pig (IC50 = 3.1 +/- 0.5 nM) and human (IC50 = 8.0 +/- 3.0 nM) lung homogenates and dimethyl sulfoxide differentiated U937 cell membrane preparations (IC50 = 10.7 +/- 1.6 nM) but is essentially inactive versus [3H]leukotriene C4 binding in guinea-pig lung homogenates (IC50 values of 19 and 33 microM). Functionally, when tested at 60 nM, it antagonized contractions of guinea-pig trachea (GPT) induced by leukotriene C4, leukotriene D4, and leukotriene E4 (respective-log KB values of 8.6, 8.8, and 8.9) and contractions of human trachea (HT) induced by leukotriene D4 (-log KB value 8.3 +/- 0.2). In contrast, verlukast (20-200 nM) failed to antagonize contractions of GPT induced by leukotriene C4 in the presence of 45 mM L-serine borate. Intravenous (i.v.) and aerosol verlukast antagonized bronchoconstriction (BC) induced in anaesthetized guinea pigs by i.v. leukotriene D4 but did not block BC to arachidonic acid or histamine. Intraduodenal verlukast (0.25 mg/kg) antagonized leukotriene D4 (0.2 micrograms/kg) induced BC in guinea pigs. Oral and aerosol administration blocked leukotriene D4-induced BC in conscious squirrel monkeys. Orally administered compound also blocked ovalbumin-induced BC in conscious sensitized rats treated with methysergide (3 micrograms/kg). The pharmacological profile for verlukast is similar to that of the racemic compound, MK-571. Verlukast is currently in clinical development for the treatment of asthma and related diseases.

Animals↗
PubMed1991

Evidence for specific suppression of gametocytemia by Plasmodium falciparum in residents of hyperendemic Irian Jaya.

An epidemiologic study of hyperendemic malaria in Arso PIR, a village in northeastern Irian Jaya (Indonesian New Guinea), revealed evidence suggesting suppression of gametocytemia independent of immune control of the asexual parasitemia. A total of 240 people, representing ages between 2 and 60 years, were followed by biweekly blood film examination for 16 weeks beginning in November 1987. Two distinct subpopulations were represented--1) life-long residents of Irian Jaya, and 2) transmigrants from Java who arrived in Irian Jaya 20 months before the surveillance effort began. Twenty-five percent of blood films from natives and 31% from Javanese were positive for falciparum malaria; of these, the rate of gametocytemia was 21% for natives, and 42% for the Javanese transmigrants (P less than 0.001). This difference could not be explained by differences in the frequency or grade of parasitemia, illness, or by known patterns of antimalarial consumption. Similarly, in Wor, a village near Arso PIR, the gametocyte rate for P. falciparum diminished from 83% to 25% in transmigrants from Java between their eleventh and twenty-fifth month of residence in Irian Jaya, a period during which the falciparum malaria rate remained stable between 30% and 50%. An immunofluorescent antibody test using whole, acetone-fixed gametocytes as substrate revealed correlation between antibody titer and protection from gametocytemia among the semi-immune natives of Arso PIR, but not among the Javanese. Specific immune suppression of gametocytes, independent of immune control of asexual parasites, can explain all of these observations.

Adolescent↗
PubMed1991

Acridine orange detection of Plasmodium falciparum malaria: relationship between sensitivity and optical configuration.

Blood samples collected from five volunteers participating in a P. falciparum infectivity trial were examined to determine the efficacy of the acridine orange technique. Several lens configurations were tested for efficiency in the diagnosis of malaria using this system. There was no significant difference in the sensitivity for detecting positive specimens or number of parasites among three lens configurations: a 50x long working distance objective (0.34 mm) with either a 10x ocular (total magnification 500x) or a 12.5x ocular (625x) and a 750x configuration using a 50x objective with a shorter working distance (0.24 mm). All three lens configurations were significantly better than the 1,000x configuration using a commonly available 100x oil immersion objective. The results achieved using this lens still exceeded the sensitivity of the thick blood film.

Acridine Orange↗
PubMed1991

Resistance to antimalarials by Plasmodium falciparum in Arso PIR, Irian Jaya, Indonesia.

Between 1987 and 1990, susceptibility of Plasmodium falciparum to chloroquine and to Fansidar was measured in vivo in 151 volunteers using the standard 7-day test. All volunteers lived in Arso PIR, Irian Jaya. A 25 mg/kg dose of chloroquine base was administered over a three-day period to 92 volunteers positive for P. falciparum rings (greater than 10 rings/200 white blood cells). Fifty volunteers (54%) showed results consistent with resistance. Twenty-nine were classified RII, and 21 RIII. In November 1989, a single curative dose of Fansidar was administered to 59 volunteers divided among three groups with 18 months, four years, and life-long exposure to endemic malaria. The proportion of volunteers in each group still positive for P. falciparum on day 7 of followup was 54%, 0%, and 14%, respectively. Thus, immune status profoundly effected clinically response to Fansidar. Standard in vitro microtests were also performed on parasites from 11 volunteers against chloroquine, amodiaquine, quinine, pyrimethamine/sulfadoxine, and and mefloquine. Nine of ten isolates showed in vitro growth consistent with resistance to chloroquine. Tests with other drugs showed few isolates with results considered indicative of susceptibility. Arso PIR has a severe drug resistance problem.

Amodiaquine↗
PubMed1991

Age-dependent acquired protection against Plasmodium falciparum in people having two years exposure to hyperendemic malaria.

An epidemiologic study of susceptibility to frequent and high-grade parasitemia by Plasmodium falciparum revealed that age-dependent acquired protection developed within a two-year period of exposure to hyperendemic infection pressure. The study was conducted in a single village in northeastern Irian Jaya, Indonesia, where half the residents were native to the province and the other half were transmigrants from areas of Java, where there is little or no malaria transmission. Five separate measures of susceptibility to the asexual parasitemia of falciparum malaria were derived from results of four months of biweekly surveillance of 240 volunteers. Increasing protection as a function of age among the Javanese was a consistent pattern among the five estimates of susceptibility. These age-dependent functions of protection were quantitatively parallel to those among life-long residents of Irian Jaya. When humoral immune responsiveness to ring-infected erythrocyte surface antigen (RESA) was measured by ELISA, a similar pattern emerged; the relative level of antibody to RESA increased as parallel functions of age among the two subpopulations. Acquired protective immunity against P. falciparum was not the cumulative product of many years of heavy exposure to antigen. Instead, the full benefit of protection appeared to develop quickly. The degree of protection was governed by recent exposure and age, independent of history of chronic heavy exposure.

Adolescent↗
PubMed1991

Chronic femoral arteriovenous fistula masquerading as the postphlebitic syndrome.

A patient with a traumatic femoral arteriovenous fistula was misdiagnosed for 11 years as having "postphlebitic syndrome." Angiography revealed diffuse dilatation of the veins and arteries of the right lower extremity with the iliac vein measuring 16.0 cm in diameter and the cava 6.0 cm in diameter. Operative repair of the fistula has resulted in marked clinical improvement and return of the patient to fulltime employment. A history of trauma should be sought when a patient presents with unilateral chronic venous insufficiency.

Aneurysm↗