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T R Jones

Publications and source records attributed to T R Jones.

At least 19 recordsLinked to original sources
PubMed2004

Effect on antibody and T-cell responses of mixing five GMP-produced DNA plasmids and administration with plasmid expressing GM-CSF.

One potential benefit of DNA vaccines is the capacity to elicit antibody and T-cell responses against multiple antigens at the same time by mixing plasmids expressing different proteins. A possible negative effect of such mixing is interference among plasmids regarding immunogenicity. In preparation for a clinical trial, we assessed the immunogenicity of GMP-produced plasmids encoding five Plasmodium falciparum proteins, PfCSP, PfSSP2, PfEXP1, PfLSA1, and PfLSA3, given as a mixture, or alone. The mixture induced higher levels of antibodies against whole parasites than did the individual plasmids, but was associated with a decrease in antibodies to individual P. falciparum proteins. T-cell responses were in general decreased by administration of the mixture. Immune responses to individual plasmids and mixtures were generally higher in inbred mice than in outbreds. In inbred BALB/c and C57BL/6 mice, coadministration of a plasmid expressing murine granulocyte-macrophage colony-stimulating factor (mGM-CSF), increased antibody and T-cell responses, but in outbred CD-1 mice, coadministration of mGM-CSF was associated with a decrease in antibody responses. Such variability in data from studies in different strains of mice underscores the importance of genetic background on immune response and carefully considering the goals of any preclinical studies of vaccine mixtures planned for human trials.

Animals↗
PubMed2004

Safety, tolerability and pharmacokinetics of subcutaneous A6, an 8-amino acid peptide with anti-angiogenic properties, in healthy men.

AIMS: To assess the safety, tolerability and pharmacokinetics of subcutaneous A6, an 8-amino acid peptide with anti-angiogenic properties, in healthy men. METHODS: Double-blind, placebo-controlled, parallel-group, dose-rising, phase I study of single and repeated doses. In the single dose phase, successive groups of 5 subjects received A6 15, 35, 75, 150, 300 mg, or placebo, as subcutaneous injections in the upper thigh. In the repeat dose phase, 2 groups of 6 subjects received repeat doses of A6 35 mg and 75 mg, or placebo, and 1 group of 5 subjects received 150 mg, or placebo, 12-hourly for 6 days (11 doses in total). In each group, 4 subjects received active treatment, the remainder placebo. Pharmacokinetics of A6 were assessed up to 24 h after single doses, for 12 h after the first of the repeated doses, and up to 24 h after the last of the repeated doses. MATERIALS: A6 for subcutaneous injection in phosphate buffer, pH 5.6-6.0. Phosphate-buffered saline was used as placebo. RESULTS: All dose regimens of A6 were safe and well-tolerated, both systemically and locally. Time to peak plasma concentration was similar (0.5-2.1 h) in all dosage groups. Cmax and AUC(0-inf) were linearly proportional to dose. Mean Cmax ranged from 454-10,333 ng/ml and mean AUC(0-inf) from 1,690-43,371 ng x h/ml after the 15 and 300 mg single doses, respectively. Terminal t(1/2) was 1.4-1.8 h, and there was no evidence of unexpected drug accumulation. Urinary excretion of unchanged A6 was 94.6% (SD 20.7) after the 300 mg single dose (0-24 h collection), and 78.4% (SD 13.0) after the 150 mg repeated dose (0-12 h collection). A6 did not trigger production of anti-A6 IgG antibodies within 14 days of the first dose. CONCLUSION: Single doses of A6 up to 300 mg, and repeated doses up to 150 mg, were well-tolerated and safe in healthy young men. A6 was rapidly absorbed; it was eliminated, mainly unchanged, in urine. Plasma concentrations were dose-proportional. A6 did not trigger an early immunogenic response.

Adolescent↗
PubMed2003

The infectivity of Plasmodium yoelii in different strains of mice.

We evaluated the effect of using Medium 199 alone and Medium 199 supplemented with 5% normal mouse serum, 5% fetal calf serum, 5% bovine serum albumin or 5% Albumax on Plasmodium yoelii sporozoite yield from infected mosquitoes and infectivity in BALB/c mice. The sporozoites yield, as well as their infectivity, was statistically lower (P = 0.0031) when unsupplemented Medium 199 was used to separate sporozoites from infected mosquitoes. Although Medium 199 supplemented with Albumax led to lower sporozoite yield (P < 0.0009), infectivity of the sporozoites was similar to those obtained with the other medium supplements. Because normal mouse serum supports good sporozoite infections and is also the supplement that can be used repeatedly in mice during multiple sporozoite injections without inducing anaphylaxis, we selected it to evaluate the infectivity of P. yoelii sporozoites in different strains of mice. After injecting mice with serial dilutions of sporozoites and detecting patent infections, we determined that the infective dose 50 (ID50) for BALB/c, C57Bl/6, A/J, and B10BR mice ranged between 4.9 and 10.6 sporozoites. The ID50 obtained for CD-1 mice (147 sporozoites) was significantly higher.

Animals↗
PubMed2001

Randomized, parallel placebo-controlled trial of primaquine for malaria prophylaxis in Papua, Indonesia.

Malaria causes illness or death in unprotected travelers. Primaquine prevents malaria by attacking liver-stage parasites, a property distinguishing it from most chemoprophylactics and obviating 4-week postexposure dosing. A daily adult regimen of 30 mg primaquine prevented malaria caused by Plasmodium falciparum and P. vivax for 20 weeks in 95 of 97 glucose-6-phosphate dehydrogenase (G6PD)-normal Javanese transmigrants in Papua, Indonesia. In comparison, 37 of 149 subjects taking placebo in a parallel trial became parasitemic. The protective efficacy of primaquine against malaria was 93% (95% confidence interval [CI] 71%-98%); against P. falciparum it was 88% (95% CI 48%-97%), and >92% for P. vivax (95% CI >37%-99%). Primaquine was as well tolerated as placebo. Mild methemoglobinemia (mean of 3.4%) returned to normal within 2 weeks. Blood chemistry and hematological parameters revealed no evidence of toxicity. Good safety, tolerance, and efficacy, along with key advantages in dosing requirements, make primaquine an excellent drug for preventing malaria in nonpregnant, G6PD-normal travelers.

Adolescent↗
PubMed2001

Induction of CD4(+) T cell-dependent CD8(+) type 1 responses in humans by a malaria DNA vaccine.

We assessed immunogenicity of a malaria DNA vaccine administered by needle i.m. or needleless jet injection [i.m. or i.m./intradermally (i.d.)] in 14 volunteers. Antigen-specific IFN-gamma responses were detected by enzyme-linked immunospot (ELISPOT) assays in all subjects to multiple 9- to 23-aa peptides containing class I and/or class II restricted epitopes, and were dependent on both CD8(+) and CD4(+) T cells. Overall, frequency of response was significantly greater after i.m. jet injection. CD8(+)-dependent cytotoxic T lymphocytes (CTL) were detected in 8/14 volunteers. Demonstration in humans of elicitation of the class I restricted IFN-gamma responses we believe necessary for protection against the liver stage of malaria parasites brings us closer to an effective malaria vaccine.

Adolescent↗
PubMed2001

A three-dimensional and temporo-spatial model to study invasiveness of cancer cells by heregulin and prostaglandin E2.

To study the temporal expression of motile structures and protease activity during colon cancer cell invasion by heregulin-beta1 (HRG) and prostaglandin E2 (PGE2), we have developed a three-dimensional spatial model system. HRG and PGE2 each induced the formation of well-organized, three-dimensional structures with empty spaces in the center and stimulated the expression of urokinase plasminogen activator (uPA) with differential localization of membrane-bound uPA at the focal adhesion points and leading edges of the motile cells. A specific cyclooxygenase-2 inhibitor blocked the formation of three-dimensional luminal glandular structures induced by HRG but did not block those induced by PGE2. A specific antagonist of uPA receptor completely blocked the formation of these luminal glandular structures induced by PGE2 and HRG. These findings suggest that HRG-mediated increased invasiveness of colon cancer cells is augmented at least in part by induction of PGE2 and uPA, and this augmentation may involve the formation of three-dimensional invasive structures via the uPA pathway. In addition, the three-dimensional model system presented here may have a wider application to screen the effects of therapeutic compounds and biomolecules on different spatial aspects of colonic biology, including cell growth, motility, invasion, survival, and apoptosis.

Cell Movement↗
PubMed2001

Cine MRI using steady state free precession in the radial long axis orientation is a fast accurate method for obtaining volumetric data of the left ventricle.

In this study we assessed the use of a steady state free precession (SSFP) cine sequence in a series of radially orientated long axis slices for the measurement of left ventricular volumes and mass. We validated the radial long axis approach in phantoms and ex vivo porcine hearts and applied it to normal volunteers and patients using the SSFP and turbo gradient-echo (TGE) sequences. High quality images were obtained for analysis, and the measured volumes with radial long axis SSFP sequence correlated well with short axis TGE and SSFP volumes (r > 0.98). The best interobserver agreement for left ventricular volumes was obtained using SSFP in the long axis radial orientation (variability < 2.3%). We conclude that this combination of sequence and scan orientation has intrinsic advantages for image analysis due to the improved contrast and the avoidance of errors associated with the basal slice in the short axis orientation.

Animals↗
PubMed2001

Steady-state free precession magnetic resonance imaging of the heart: comparison with segmented k-space gradient-echo imaging.

Steady-state free precession imaging is a promising technique for cardiac magnetic resonance imaging (MRI), as it provides improved blood/myocardial contrast in shorter acquisition times compared with conventional gradient-echo acquisition. The better contrast could improve observer agreement and automatic detection of cardiac contours for volumetric assessment of the ventricles, but measurements might differ from those obtained using conventional methods. We compared volumetric measurements, observer variabilities, and automatic contour detection between a steady-state free precession imaging sequence (BFFE = balanced fast field echo) and segmented k-space gradient-echo acquisition (TFE = turbo field echo) in 41 subjects. With BFFE, significantly higher end-diastolic and end-systolic volumes and lower wall thickness, ventricular mass, ejection fraction, and wall motion were observed (P < 0.0001), while interobserver variabilities were lower and automatic contour detection of endocardial contours was more successful. We conclude that the improved image quality of BFFE reduces the observer-dependence of volumetric measurements of the left ventricle (LV) but results in significantly different values in comparison to TFE measurements.

Adult↗
PubMed2001

Life-threatening upper airway edema caused by a distal rattlesnake bite.

A 36-year-old man captured a timber rattlesnake and was accidentally envenomated in the thumb by the severed head. At a local emergency department, hypotension and confusion developed. Facial and glossal edema were also observed. Oxygen was delivered by face mask, and crystalloids and dopamine were administered. Respiratory distress developed with progressive hypoxemia. Intubation was unsuccessful because of massive glossal and epiglottic (laryngeal) edema, and an emergency cricothyrotomy was performed. High-dose antivenom therapy was administered, and mechanical ventilation was started. Recovery was rapid, and the patient was discharged from the hospital a week later. This is the first report of life-threatening upper airway edema caused by snake envenomation not in the vicinity of the head or neck.

Adult↗
PubMed2001

Lymphoscintigraphy in the diagnosis of lymphatic leak after surgical repair of femoral artery injury.

PURPOSE: Technetium-99m-labeled sulfur colloid lymphoscintigraphy is useful to evaluate lower extremity lymphatic circulation in cases of possible lymphedema and to reveal abnormal lymphatic collections. Groin lymphatic fistulas and lymphoceles are known complications of peripheral vascular surgical procedures. The authors describe a patient with ascites that developed into right lower extremity swelling after surgical repair of a femoral artery injury. Even after surgical ligation of multiple lymphatic channels, the patient continued to have lymphorrhea. It was unclear whether this was attributable to a persistent lymphatic leak or an ascitic leak from a postsurgical defect resulting in an abnormal connection with the peritoneal cavity. METHODS: Lymphoscintigraphy of the lower extremities was performed using Tc-99m sulfur colloid. Images were obtained at several intervals after injection of the radiotracer. Images were also acquired after the wound packing was removed. RESULTS: The images revealed an accumulation of radiotracer in the right groin, confirming the lower extremity lymphatic origin of the collection. CONCLUSIONS: Lymphoscintigraphy is useful to evaluate the origin of serous collections in the groin, a region in which lymphatic complications of vascular surgery are not uncommon.

Femoral Artery↗
PubMed2001

Immunogenicity and protective efficacy of a Plasmodium yoelii Hsp60 DNA vaccine in BALB/c mice.

The gene encoding the 60-kDa heat shock protein of Plasmodium yoelii (PyHsp60) was cloned into the VR1012 and VR1020 mammalian expression vectors. Groups of 10 BALB/c mice were immunized intramuscularly at 0, 3, and 9 weeks with 100 microg of PyHsp60 DNA vaccine alone or in combination with 30 microg of pmurGMCSF. Sera from immunized mice but not from vector control groups recognized P. yoelii sporozoites, liver stages, and infected erythrocytes in an indirect fluorescent antibody test. Two weeks after the last immunization, mice were challenged with 50 P. yoelii sporozoites. In one experiment the vaccine pPyHsp60-VR1012 used in combination with pmurGMCSF gave 40% protection (Fisher's exact test; P = 0.03, vaccinated versus control groups). In a second experiment this vaccine did not protect any of the immunized mice but induced a delay in the onset of parasitemia. In neither experiment was there any evidence of a protective effect against the asexual erythrocytic stage of the life cycle. In a third experiment mice were primed with PyHsp60 DNA, were boosted 2 weeks later with 2 x 10(3) irradiated P. yoelii sporozoites, and were challenged several weeks later. The presence of PyHsp60 in the immunization regimen did not lead to reduced blood-stage infection or development of parasites in hepatocytes. PyHsp60 DNA vaccines were immunogenic in BALB/c mice but did not consistently, completely protect against sporozoite challenge. The observation that in some of the PyHsp60 DNA vaccine-immunized mice there was protection against infection or a delay in the onset of parasitemia after sporozoite challenge deserves further evaluation.

Animals↗
PubMed2001

Single- versus multi-detector row CT of the brain: quality assessment.

PURPOSE: To assess the quality of brain computed tomographic (CT) studies obtained with a four-channel multi-detector row CT scanner compared with those obtained with a single-detector row CT scanner. MATERIALS AND METHODS: Forty-seven patients referred for brain CT were imaged with both single- and multi-detector row scanners. Single-detector row CT images were acquired by using a 5-mm-collimated beam in the transverse mode. Multi-detector row CT images were acquired in four simultaneous 2.5-mm-thick sections, which were combined in projection space to create two contiguous 5-mm-thick sections. Two neuroradiologists blinded to the acquisition technique independently evaluated the CT image pairs, which were presented in a stacked mode on two adjacent monitors. Each study was graded by using a five-point scale for posterior fossa artifact, overall image quality, and overall preference. RESULTS: Multi-detector row CT studies were acquired 1.8 times faster than single-detector row CT studies (0.92 vs 0.52 section per second). Multi-detector row CT posterior fossa artifact was less than single-detector row CT posterior fossa artifact in 87 (93%) of 94 studies. Overall preference was expressed for multi-detector row CT in 84 (89%) of 94 studies. The differences in mean posterior fossa artifact scores (P <.001) and mean overall image quality scores (P =.001) were significant. CONCLUSION: Brain CT images obtained with multi-detector row CT resulted in significantly less posterior fossa artifact and were preferred to single-detector row CT images.

Artifacts↗
PubMed2001

Expression of the cysteinyl leukotriene 1 receptor in normal human lung and peripheral blood leukocytes.

The cysteinyl leukotrienes (CysLTs) are important mediators of human asthma. Pharmacologic and clinical studies show that the CysLTs exert most of their bronchoconstrictive and proinflammatory effects through activation of a putative, 7-transmembrane domain, G-protein-coupled receptor, the CysLT1 receptor. The initial molecular characterization of the CysLT1 receptor showed by in situ hybridization, the presence of CysLT1 receptor messenger RNA (mRNA) in human lung smooth-muscle cells and lung macrophages. We confirmed the results of these in situ hybridization analyses for the CysLT1 receptor, and produced the first immunohistochemical characterization of the CysLT1 receptor protein in human lung. The identification of the CysLT1 receptor in the lung is consistent with the antibronchoconstrictive and antiinflammatory actions of CysLT1 receptor antagonists. We also report the expression of CysLT1 receptor mRNA and protein in most peripheral blood eosinophils and pregranulocytic CD34+ cells, and in subsets of monocytes and B lymphocytes.

Blood↗
PubMed2001

Open Galeazzi fracture with concomitant radial head dislocation.

Galeazzi fractures are uncommon, but a combination of open Galeazzi fracture and radial head dislocation has not been described. This article reports on a variant of an open Galeazzi fracture in which concomitant radial head dislocation and coronoid process fracture occurred. Thorough understanding of the mechanisms and influences of pronation injuries of the forearm is essential in order to properly treat this fracture-dislocation. Our evaluation of the individual elements of this composite injury has allowed us to propose a mechanism of injury.

Fractures, Open↗
PubMed2000

Protection of Aotus monkeys by Plasmodium falciparum EBA-175 region II DNA prime-protein boost immunization regimen.

Aotus monkeys received 4 doses of Plasmodium falciparum EBA-175 region II vaccine as plasmid DNA (Dv-Dv) or recombinant protein in adjuvant (Pv-Pv) or as 3 doses of DNA and 1 dose of protein (Dv-Pv). After 3 doses, antibody titers were approximately 10(4) in DNA-immunized monkeys and 10(6) in protein-immunized monkeys. A fourth dose did not significantly boost antibody responses in the Dv-Dv only or Pv-Pv only groups, but titers were boosted to approximately 10(6) in monkeys in the Dv-Pv group. Four weeks after the last immunization, the animals were challenged with 10(4) P. falciparum-parasitized erythrocytes. Peak levels of parasitemia were lower in the 16 monkeys that received region II-containing plasmids or proteins than in the 16 controls (geometric mean: 194,178 and 410,110 parasites/microL, respectively; P=.013, Student's t test). Three of 4 monkeys in the Dv-Pv group did not require treatment. These data demonstrate that immunization with EBA-175 region II induces a significant antiparasite effect in vivo.

Adjuvants, Immunologic↗
PubMed2000

A peptide derived from the non-receptor-binding region of urokinase plasminogen activator inhibits glioblastoma growth and angiogenesis in vivo in combination with cisplatin.

The urokinase plasminogen activator system is involved in angiogenesis and tumor growth of malignant gliomas, which are highly neovascularized and so may be amenable to antiangiogenic therapy. In this paper, we describe the activity of A6, an octamer capped peptide derived from the non-receptor-binding region of urokinase plasminogen activator. A6 inhibited human microvascular endothelial cell migration but had no effect on the proliferation of human microvascular endothelial cells or U87MG glioma cells in vitro. In contrast, A6 or cisplatin (CDDP) alone suppressed subcutaneous tumor growth in vivo by 48% and 53%, respectively, and, more strikingly, the combination of A6 plus CDDP inhibited tumor growth by 92%. Such combination treatment also greatly reduced the volume of intracranial tumor xenografts and increased survival of tumor-bearing animals when compared with CDDP or A6 alone. Tumors from the combination treatment group had significantly reduced neovascularization, suggesting a mechanism involving A6-mediated inhibition of endothelial cell motility, thereby eliciting vascular sensitivity to CDDP-mediated toxicity. These data suggest that the combination of an angiogenesis inhibitor that targets endothelial cells with a cytotoxic agent may be a useful therapeutic approach.

Animals↗