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T R Jones

Publications and source records attributed to T R Jones.

At least 37 records · Page 2Linked to original sources
PubMed2000

A longitudinal study of an endemic disease in its wildlife reservoir: cowpox and wild rodents.

Cowpox is an orthopoxvirus infection endemic in European wild rodents, but with a wide host range including human beings. In this longitudinal study we examined cowpox in two wild rodent species, bank voles Clethrionomys glareolus and wood mice Apodemus sylvaticus, to investigate the dynamics of a virus in its wild reservoir host. Trapping was carried out at 4-weekly intervals over 3 years and each animal caught was uniquely identified, blood sampled and tested for antibodies to cowpox. Antibody prevalence was higher in bank voles than in wood mice and seroconversion varied seasonally, with peaks in autumn. Infection was most common in males of both species but no clear association with age was demonstrated. This study provides a model for studying other zoonotic infections that derive from wild mammals since other approaches, such as one-off samples, will fail to detect the variation in infection and thus, risk to human health, demonstrated here.

Animals↗
PubMed2000

A peptide derived from the nonreceptor binding region of urokinase plasminogen activator (uPA) inhibits tumor progression and angiogenesis and induces tumor cell death in vivo.

Urokinase plasminogen activator (uPA) plays an important role in the progression of several malignancies including breast cancer. We have identified a noncompetitive antagonist of the uPA-uPAR interaction derived from a nonreceptor binding region of uPA (amino acids 136-143). This 8-mer capped peptide (A6) inhibited breast cancer cell invasion and endothelial cell migration in a dose-dependent manner in vitro without altering cell doubling time. Intraperitoneal administration of A6 resulted in a significant inhibition of tumor growth and suppressed the development of lymph node metastases in several models of breast cancer cell growth and metastasis. Large areas of tumor necrosis and extensive positive staining by TUNEL were observed on histological and immunohistochemical analysis of experimental tumor sections from A6-treated animals. A6 treatment also resulted in a decrease in factor VIII-positive tumor microvessel hot-spots. These results identify a new epitope in uPA that is involved in the uPA-uPAR interaction and indicate that an antagonist based on this epitope is able to inhibit tumor progression by modulating the tumor microenvironment in the absence of direct cytotoxic effects in vivo.

Amino Acid Sequence↗
PubMed2000

Novel class of thiourea compounds that inhibit herpes simplex virus type 1 DNA cleavage and encapsidation: resistance maps to the UL6 gene.

In our search for novel inhibitors of herpes simplex virus type 1 (HSV-1), a new class of thiourea inhibitors was discovered. N-(4-[3-(5-Chloro-2,4-dimethoxyphenyl)-thioureido]-phenyl)-acetamide and its 2-fluoro-benzamide derivative inhibited HSV-1 replication. HSV-2, human cytomegalovirus, and varicella-zoster virus were inhibited to a lesser extent. The compounds acted late in the replication cycle by impairing both the cleavage of concatameric viral DNA into progeny genome length and the packaging of the DNA into capsids, indicative of a defect in the encapsidation process. To uncover the molecular target of the inhibition, resistant HSV-1 isolates were generated, and the mutation responsible for the resistance was mapped using marker transfer techniques. Each of three independent isolates had point mutations in the UL6 gene which resulted in independent single-amino-acid changes. One mutation was located in the N terminus of the protein (E121D), while two were located close together in the C terminus (A618V and Q621R). Each of these point mutations was sufficient to confer drug resistance when introduced into wild-type virus. The UL6 gene is one of the seven HSV-1 genes known to play a role in DNA packaging. This novel class of inhibitors has provided a new tool for dissection of HSV-1 encapsidation mechanisms and has uncovered a new viable target for the treatment of herpesviral diseases.

Animals↗
PubMed2000

Repeated infection of Aotus monkeys with Plasmodium falciparum induces protection against subsequent challenge with homologous and heterologous strains of parasite.

We evaluated repeated blood-stage infections with Plasmodium falciparum in eight Aotus lemurinus lemurinus monkeys. Over the course of seven infections with 10(4) P. falciparum (the Vietnam Oak Knoll [FVO] strain), the pre-patent period lengthened from 8.2 to 30.8 days; the peak parasitemia decreased from 4.5 x 10(5) to 0 parasites/microl (Challenges 6 and 7), and the requirement for treatment decreased from 100% to 0% (Challenges 3 to 7). Five weeks after the seventh FVO challenge, the eight immune and three naïve monkeys received 10(4) parasitized erythrocytes infected with P. falciparum (CAMP strain). The three control animals experienced uncontrolled parasitemias reaching between 4.8 and 7.7 x 10(5) parasites/microl (pre-patency = 6.3 days) and all required drug treatment; six of the eight immune monkeys became parasitemic (pre-patency = 8.8 days), but self-cured. Two of three of the monkeys having the greatest reductions in hematocrit (50-60%) also had the highest parasitemias (approximately 10(4) parasites/microl) before self-curing. Repeated homologous infections induced sterile immunity to homologous challenge; during heterologous challenge the monkeys developed clinically relevant, but not life-threatening, parasitemias and anemia.

Animals↗
PubMed1999

Substituted indoles as potent and orally active 5-lipoxygenase activating protein (FLAP) inhibitors.

This paper reports on the SAR investigation of inhibitors of 5-lipoxygenase activating protein (FLAP) based on MK-0591. Emphasis was made on modifications to the nature of the link between the indole and the quinoline moieties, to the substitution pattern around the two heterocycles and to possible replacements of the quinoline moiety. Lead optimization culminated in (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(pyridin-2-ylmethoxy)-ind ol-2-yl]-2,2-dimethylpropanoic acid (18k), as a potent inhibitor of leukotriene biosynthesis that is well absorbed and active in functional models.

5-Lipoxygenase-Activating Proteins↗
PubMed1999

Synthetic oligodeoxynucleotides containing CpG motifs enhance immunogenicity of a peptide malaria vaccine in Aotus monkeys.

Synthetic peptide and recombinant protein vaccines are optimally immunogenic when delivered with an effective adjuvant. Candidate vaccines currently insufficiently immunogenic may induce a protective immunity if they could be delivered with more effective adjuvants. For example, immunogens that induce promising responses when administered to mice with complete and incomplete Freund's adjuvants perform less well in primate animal models where complete Freund's adjuvant is not used. We report the use of synthetic oligodeoxynucleotides containing CpG motifs, the sequences of which are based on immunostimulatory bacterial DNA sequences, to enhance the immune response in Aotus monkeys to a synthetic peptide malaria vaccine. Monkeys were immunized with the synthetic peptide PADRE 45, a synthetic peptide containing amino acid sequences derived from the circumsporozoite protein (CSP) from Plasmodium falciparum, and delivered in an emulsion of saline and Montanide 720, a mannide oleate in oil solution, that also contained one of three oligodeoxynucleotides. The animals receiving oligodeoxynucleotides containing either three or four CpG motifs produced antibodies that bound a recombinant CSP as measured in ELISA, and reacted with P. falciparum sporozoites in a sporozoite immunofluorescent test. These responses were significantly greater than those seen in animals receiving the oligodeoxynucleotide without CpG motifs. These data indicate that oligodeoxynucleotides containing CpG motifs improve immunogenicity of peptide immunogens in non-human primates, and may be immunopotentiators useful in humans.

Adjuvants, Immunologic↗
PubMed1999

Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing recognition by CD4+ T cells.

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that causes life-threatening disease in patients who are immunosuppressed for bone marrow or tissue transplantation or who have AIDS (ref. 1). HCMV establishes lifelong latent infections and, after periodic reactivation from latency, uses a panel of immune evasion proteins to survive and replicate in the face of robust, fully primed host immunity. Monocyte/macrophages are important host cells for HCMV, serving as a latent reservoir and as a means of dissemination throughout the body. Macrophages and other HCMV-permissive cells, such as endothelial and glial cells, can express MHC class II proteins and present antigens to CD4+ T lymphocytes. Here, we show that the HCMV protein US2 causes degradation of two essential proteins in the MHC class II antigen presentation pathway: HLA-DR-alpha and DM-alpha. This was unexpected, as US2 has been shown to cause degradation of MHC class I (refs. 5,6), which has only limited homology with class II proteins. Expression of US2 in cells reduced or abolished their ability to present antigen to CD4+ T lymphocytes. Thus, US2 may allow HCMV-infected macrophages to remain relatively 'invisible' to CD4+ T cells, a property that would be important after virus reactivation.

Adenoviridae↗
PubMed1999

Malaria prophylaxis using azithromycin: a double-blind, placebo-controlled trial in Irian Jaya, Indonesia.

New drugs are needed for preventing drug-resistant Plasmodium falciparum malaria. The prophylactic efficacy of azithromycin against P. falciparum in malaria-immune Kenyans was 83%. We conducted a double-blind, placebo-controlled trial to determine the prophylactic efficacy of azithromycin against multidrug-resistant P. falciparum malaria and chloroquine-resistant Plasmodium vivax malaria in Indonesian adults with limited immunity. After radical cure therapy, 300 randomized subjects received azithromycin (148 subjects, 750-mg loading dose followed by 250 mg/d), placebo (77), or doxycycline (75, 100 mg/d). The end point was slide-proven parasitemia. There were 58 P. falciparum and 29 P. vivax prophylaxis failures over 20 weeks. Using incidence rates, the protective efficacy of azithromycin relative to placebo was 71.6% (95% confidence interval [CI], 50.3-83.8) against P. falciparum malaria and 98.9% (95% CI, 93.1-99.9) against P. vivax malaria. Corresponding figures for doxycycline were 96.3% (95% CI, 85.4-99.6) and 98% (95% CI, 88.0-99.9), respectively. Daily azithromycin offered excellent protection against P. vivax malaria but modest protection against P. falciparum malaria.

Adolescent↗
PubMed1999

CD4(+) T-cell- and gamma interferon-dependent protection against murine malaria by immunization with linear synthetic peptides from a Plasmodium yoelii 17-kilodalton hepatocyte erythrocyte protein.

Most work on protective immunity against the pre-erythrocytic stages of malaria has focused on induction of antibodies that prevent sporozoite invasion of hepatocytes, and CD8(+) T-cell responses that eliminate infected hepatocytes. We recently reported that immunization of A/J mice with an 18-amino-acid synthetic linear peptide from Plasmodium yoelii sporozoite surface protein 2 (SSP2) in TiterMax adjuvant induces sterile protection that is dependent on CD4(+) T cells and gamma interferon (IFN-gamma). We now report that immunization of inbred A/J mice and outbred CD1 mice with each of two linear synthetic peptides from the 17-kDa P. yoelii hepatocyte erythrocyte protein (HEP17) in the same adjuvant also induces protection against sporozoite challenge that is dependent on CD4(+) T cells and IFN-gamma. The SSP2 peptide and the two HEP17 peptides are recognized by B cells as well as T cells, and the protection induced by these peptides appears to be directed against the infected hepatocytes. In contrast to the peptide-induced protection, immunization of eight different strains of mice with radiation-attenuated sporozoites induces protection that is absolutely dependent on CD8(+) T cells. Data represented here demonstrate that CD4(+) T-cell-dependent protection can be induced by immunization with linear synthetic peptides. These studies therefore provide the foundation for an approach to pre-erythrocytic-stage malaria vaccine development, based on the induction of protective CD4(+) T-cell responses, which will complement efforts to induce protective antibody and CD8(+) T-cell responses.

Amino Acid Sequence↗
PubMed1999

Susceptibility of Panamanian Aotus lemurinus lemurinus to sporozoite-induced Plasmodium falciparum (Santa Lucia) infection.

Aotus monkeys are good models for erythrocyte-induced Plasmodium falciparum and P. vivax infections and have been extensively used in malarial drug and vaccine development. Recently, it has been shown that certain species of Aotus can be infected with sporozoites, and that the degree of susceptibility varies among species. We demonstrate here that Panamanian Aotus lemurinus lemurinus are susceptible to a sporozoite-induced infection, opening the possibility that this species of Aotus could be used as models for testing the efficacy of pre-erythrocytic P. falciparum vaccines and drug candidates directed at the pre-erythrocytic stages of P. falciparum and P. vivax malaria. In this species, we compared sporozoite infection rates. Two of four animals splenectomized prior to infection with sporozoites developed patent parasitemias. Seven of eight animals splenectomized either 7 or 35 days after infection became parasitemic. Additionally, we used a P. falciparum-specific polymerase chain reaction (PCR) method to detect the early appearance of parasitized erythrocytes in the blood prior to detection by conventional microscopy, and found that the parasitemia was detected first in five animals by the PCR method, first in three animals by blood film, with one parasitemia detected simultaneously. We also demonstrated the feasibility of infecting monkeys located in Panama with sporozoites isolated at an insectary in Atlanta, thus documenting the feasibility of similar studies where the insectary and monkey colony are not in the same location. A subsequent attempt to infect these monkeys using sporozoites was not successful, suggesting that this model of human malaria is not yet ready for routine use in vaccine or drug efficacy screening. This model merits further study because of the importance of testing pre-erythrocytic P. falciparum malaria vaccines and drugs in animals.

Animals↗
PubMed1999

The stenosis ratio: a new tool for the diagnosis of degenerative spinal stenosis.

CLINICAL RELEVANCE: Low back pain from lumbar spinal stenosis is a significant source of morbidity, especially among the elderly population. Accurate diagnosis is imperative for effective treatment to be initiated. This paper presents a quantitative method for the evaluation of spinal stenosis that, when used in conjunction with CT and MRI, may greatly aid the clinician in the diagnosis of this debilitating condition. OBJECTIVE: Precise clinical tools for the diagnosis of spinal stenosis are severely lacking. Low back pain and dysfunction derived from lumbar spinal stenosis is a significant source of morbidity, especially among the elderly. Despite its importance, there has been little progress made towards establishing valid, quantitative criteria for the diagnosis of spinal stenosis. We present a new quantitative tool for the diagnosis of lumbar stenosis, the Stenosis Ratio (SR). METHODS: CT scans and MRI scans of 43 patients presenting with clinico-radiographic evidence of lumbar stenosis were used. The patient group consisted of 13 males and 30 females between the ages 49 and 82 with average age of 67. CT and MRI/scans of 43 patients were digitized and computer analyzed. Measurements of SR, defined as the ratio of the cross-sectional dural area of the motion segment to that of the stable segment, were established for L3-L4, L4-L5 and L5-S1 stenotic levels and compared to SR values for a non-stenotic (internal control) level, L2-L3. RESULTS: The L4-L5 level had the lowest SR value of 0.71, followed by 0.74 at L3-L4, and 0.87 at L5-S1. Ninety-five percent confidence intervals of (0.66, 0.81), (0.62, 0.81), and (0.73, 1.00) were found for SR values at levels L3-L4, L4-L5 and L5-S1 respectively. The SR at L2-L3 had a mean value of 1.37 with a 95% confidence interval of (0.970, 1.78). At all levels, SRs were significantly lower for the spinal stenotic L3-S1 levels than for the L2-L3 control as confirmed by a student's t-test (p < 0.05). CONCLUSION: In a select population of patients with spinal stenosis confirmed by neuroradiological assessment, values of SRs were consistently and significantly lower than controls. We believe that measurements of SRs may provide reproducible quantitative measures for the diagnosis of spinal stenosis. SR values below the 95% confidence limit may be indicative of lumbar stenosis. Through the use of ratios, inherent differences in patient size are controlled for, thus allowing comparison of values between patients and treatment groups and effective clinical diagnosis of spinal stenosis.

Adult↗
PubMed1998

Induction of antigen-specific cytotoxic T lymphocytes in humans by a malaria DNA vaccine.

CD8+ cytotoxic T lymphocytes (CTLs) are critical for protection against intracellular pathogens but often have been difficult to induce by subunit vaccines in animals. DNA vaccines elicit protective CD8+ T cell responses. Malaria-naïve volunteers who were vaccinated with plasmid DNA encoding a malaria protein developed antigen-specific, genetically restricted, CD8+ T cell-dependent CTLs. Responses were directed against all 10 peptides tested and were restricted by six human lymphocyte antigen (HLA) class I alleles. This first demonstration in healthy naïve humans of the induction of CD8+ CTLs by DNA vaccines, including CTLs that were restricted by multiple HLA alleles in the same individual, provides a foundation for further human testing of this potentially revolutionary vaccine technology.

Adult↗
PubMed1998

Chemokine sequestration by viral chemoreceptors as a novel viral escape strategy: withdrawal of chemokines from the environment of cytomegalovirus-infected cells.

Human cytomegalovirus (HCMV), a betaherpesvirus, has developed several ways to evade the immune system, notably downregulation of cell surface expression of major histocompatibility complex class I heavy chains. Here we report that HCMV has devised another means to compromise immune surveillance mechanisms. Extracellular accumulation of both constitutively produced monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor-superinduced RANTES (regulated on activation, normal T cell expressed and secreted) was downregulated in HCMV-infected fibroblasts in the absence of transcriptional repression or the expression of polyadenylated RNA for the cellular chemokine receptors CCR-1, CCR-3, and CCR-5. Competitive binding experiments demonstrated that HCMV-infected cells bind RANTES, MCP-1, macrophage inflammatory protein (MIP)-1beta, and MCP-3, but not MCP-2, to the same receptor as does MIP-1alpha, which is not expressed in uninfected cells. HCMV encodes three proteins with homology to CC chemokine receptors: US27, US28, and UL33. Cells infected with HCMV mutants deleted of US28, or both US27 and US28 genes, failed to downregulate extracellular accumulation of either RANTES or MCP-1. In contrast, cells infected with a mutant deleted of US27 continues to bind and downregulate those chemokines. Depletion of chemokines from the culture medium was at least partially due to continuous internalization of extracellular chemokine, since exogenously added, biotinylated RANTES accumulated in HCMV-infected cells. Thus, HCMV can modify the chemokine environment of infected cells through intense sequestering of CC chemokines, mediated principally by expression of the US28-encoded chemokine receptor.

Binding Sites↗
PubMed1998

Dislocation of type I membrane proteins from the ER to the cytosol is sensitive to changes in redox potential.

The human cytomegalovirus (HCMV) gene products US2 and US11 dislocate major histocompatibility class I heavy chains from the ER and target them for proteasomal degradation in the cytosol. The dislocation reaction is inhibited by agents that affect intracellular redox potential and/or free thiol status, such as diamide and N-ethylmaleimide. Subcellular fractionation experiments indicate that this inhibition occurs at the stage of discharge from the ER into the cytosol. The T cell receptor alpha (TCR alpha) chain is also degraded by a similar set of reactions, yet in a manner independent of virally encoded gene products. Diamide and N-ethylmaleimide likewise inhibit the dislocation of the full-length TCR alpha chain from the ER, as well as a truncated, mutant version of TCR alpha chain that lacks cysteine residues. Cytosolic destruction of glycosylated, ER-resident type I membrane proteins, therefore, requires maintenance of a proper redox potential for the initial step of removal of the substrate from the ER environment.

Cell Line↗
PubMed1998

Transplantation of vascularized allogeneic skeletal muscle for scalp reconstruction in a renal transplant patient.

BACKGROUND: We report the case of a vascularized allogeneic skeletal muscle transplant (VASM) and autologous skin grafting as rescue therapy for refractory squamous cell carcinoma of the scalp. METHODS: A renal transplant recipient with recurrent squamous carcinoma of the scalp underwent an excision that resulted in a 11 x 14 cm2 scalp defect with exposed cranium. At the time of multiorgan procurement, a section of rectus abdominis and external oblique muscle and fascia with its independent vascular bundle was isolated and stored in cold University of Wisconsin solution. The patient received methylprednisolone and rabbit antithymocyte globulin intravenously during scalp preparation, before single-vessel anastomosis of the deep inferior epigastric vascular bundle from the donor muscle to the recipient neck vessels. An autologous split-thickness skin graft was secured to the surface of the allogeneic muscle. RESULTS: Immunosuppression was maintained with prednisone and cyclosporine. Serial VASM biopsies were used to evaluate acute rejection. Perivascular lymphocytic infiltrates and rare focal myonecrosis were evident on biopsy at 2 weeks postoperatively, and mycophenolate mofetil was added. Subsequent VASM biopsies showed predominately interstitial and perivascular T-cell lymphocytic infiltrates interpreted as consistent with mild rejection, but the allograft appeared intact without clinical evidence of rejection. On postoperative week 18, the mycophenolate mofetil was discontinued. There has been no evidence of recurrence or metastasis. The patient remains ambulatory with a healed scalp 12 months after the VASM. CONCLUSION: The success of this first allogeneic skeletal muscle transplant is encouraging and provides another reconstruction option for wounds in transplant patients on chronic immunosuppression.

Animals↗