Search PubMed⌕ Search

Biomedical subjects

L A Jones

Publications and source records attributed to L A Jones.

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

CD28-B7 interactions are not required for intrathymic clonal deletion.

Activation of antigen specific T cells requires more than stimulation through the TCR-CD3 complex. A second or costimulatory signal is also required, and this second signal can be delivered by interactions between CD28 and B7, ligands expressed on T cells and antigen presenting cells respectively. We have examined the role of the CD28-B7 interaction in superantigen mediated T cell activation and intrathymic negative selection by blocking B7 molecules with a high affinity soluble ligand, CTLA4lg. In vitro T cell activation mediated by both virally encoded endogenous and exogenous bacterial superantigens was significantly blocked by the addition of CTL4Alg to cultures. However, intrathymic clonal deletion in vivo and in fetal thymic organ cultures was not inhibited by blocking B7 molecules. Therefore, although the CD28-B7 costimulation pathway is necessary for T cell activation, it does not appear to play a role in intrathymic clonal deletion.

Abatacept↗
PubMed1993

In vivo induction of increased DNA ploidy of mouse cervicovaginal epithelium by neonatal estrogen treatment.

The purpose of this study was to test the hypothesis that exposure to natural estrogen early in the development of hormone-dependent tissue induces a change in nuclear DNA content. Female BALB/c mice were treated neonatally with daily s.c. injections of either 25 micrograms of 17 beta-estradiol (E2) in 0.02 ml of sesame oil (vehicle) or vehicle alone for 5 days. Treatment was begun either within 15 h of birth or 6 days after birth. One set each of 10-day-old E2-treated and control mice received s.c. pellet implants containing 15 mg of E2 and cholesterol (10% E2 and 90% cholesterol), a second set received implants containing 25 mg of cholesterol alone, and a third set did not receive implants. Cervicovaginal tracts from intact BALB/c mice were examined histologically and by flow cytometry at 21, 40, 70, 180, or 240 days of age. The results obtained include several important findings: 1) neonatal E2 treatment in BALB/c mice causes an increase in nuclear DNA content in cervicovaginal epithelium; 2) short-term administration of secondary exogenous E2 reduces the latency period for the appearance of increased nuclear DNA content in neonatally E2-treated cervicovaginal epithelium; 3) increased nuclear DNA content can indicate abnormal cervicovaginal epithelium before histological abnormalities become evident; and 4) there is a sensitive period for neonatal E2 induction of increased nuclear DNA content in the cervicovaginal epithelium. These findings support other reports of the carcinogenic potential of estrogen in vivo. Therefore, increased DNA ploidy may be an important early detectable event in estrogen-induced carcinogenesis.

Aneuploidy↗
PubMed1993

Advances in amyloidosis.

Major advances of the past year in the amyloidoses include a better understanding of the polymorphism of the acute-phase reactant serum amyloid A protein and the appearance of a new mouse model for primary amyloidosis. The list of single point mutations in transthyretin in different families with slightly varied clinical manifestations of the disease continues to grow. Gelsolin, with its asparagine 187 mutation, was found to cause amyloidosis beyond the borders of Finland, where it has been extensively evaluated. The incredible range of osteoarticular lesions due to beta 2-microglobulin in hemodialysis amyloidosis continues to expand and includes severe manifestations of spondyloarthropathy. The greatest number of papers in the amyloid literature have involved amyloid beta protein, amyloid beta protein precursor associated with Alzheimer's disease, and prion protein associated with the spongiform encephalopathies. The widespread systemic involvement of amyloidosis has led to the appearance of a host of manifestations, some common and some rare. Treatment advances focus on the use of liver transplantation in familial amyloid polyneuropathy to remove the source of mutant protein synthesis.

Amyloidosis↗
PubMed1992

Effects of tamoxifen adjuvant therapy and a low-fat diet on serum binding proteins and estradiol bioavailability in postmenopausal breast cancer patients.

Serum was collected at intervals from postmenopausal breast cancer patients to determine the effects of tamoxifen adjuvant therapy and a low-fat dietary intervention, alone and in combination, on sex hormone-binding globulin (SHBG) concentrations and circulating estradiol bioavailability. Serum corticosteroid-binding globulin and follicle-stimulating hormone were also assayed as indicators of patient compliance to tamoxifen therapy. The immunoreactive SHBG concentration was higher (P less than 0.001) in 22 patients who had been treated with tamoxifen for 6-36 weeks when first sampled, compared with 27 who were not receiving tamoxifen therapy. Tamoxifen also produced a reduction in the percentage non-protein-bound estradiol (P less than 0.001) and percentage albumin-bound estradiol (P less than 0.01), the two biologically available fractions, and a corresponding increase in the percentage SHBG-bound estradiol (P less than 0.01). A longitudinal study of 7 patients showed significant reductions in the percentage of albumin-bound estradiol and an increased percentage of SHBG-bound estradiol, after 3-6 months of tamoxifen; after 12-18 months there was also a significant decrease in the non-protein-bound estradiol fraction. We conclude that in postmenopausal breast cancer patients the redistribution of circulating estradiol, with reduced bioavailability, provides an additional mechanism to those demonstrated previously for the therapeutic activity of tamoxifen. Another 12 patients receiving tamoxifen and 8 who were not were followed for 6-12 months on a low-fat diet (fat comprised 20% of the total calories). The dietary intervention had no effect on the serum SHBG concentration or the estradiol distribution. Although tamoxifen increased the serum corticosteroid-binding globulin and partially suppressed the follicle-stimulating hormone concentrations, the responses obtained were less consistent compared with those of the SHBG levels.

Biological Availability↗
PubMed1992

Mice deprived of exogenous antigenic stimulation develop a normal repertoire of functional T cells.

The development of T cells and the selection of the TCR repertoire in the absence of exogenous antigenic stimulation were investigated. For this purpose germfree BALB/c mice fed an ultrafiltered solution of chemically defined low m.w. nutrients (GF-CD) were used. Previous studies on B cell development and differentiation in GF-CD mice have demonstrated a high reduction in the number of cells secreting Ig of the non-IgM isotypes but an Ig-VH gene usage and a B cell specificity repertoire that is substantially different from that observed in conventional adult mice and more closely resembles that of neonatal conventional mice. In contrast, the present comparison of the various lymphocyte populations in the thymus, lymph nodes, and spleen from GF-CD and conventional mice using flow cytometry analysis revealed no significant differences. Analysis of the TCR-V beta expression on both mature thymocytes and lymph node T cells showed a high degree of similarity between GF-CD and conventional mice. These findings indicate a marked difference in the influence of exogenous antigenic stimulation on the development of B and T cells. Additionally, development in an environment free of exogenous antigenic stimulation allows for full functional maturation of T cells to occur, because MLC showed that GF-CD splenic T cells could mount allogeneic responses in a way similar to T cells generated in a conventional environment. Most importantly, full Th cell function is generated, because activation of GF-CD spleen cells by cross-linking with mAb against CD3 resulted in the induction of cells secreting IFN-gamma and Ig of the non-IgM isotypes, which cannot be detected in GF-CD sera. These findings demonstrate that functional T and B cells develop in mice that have not been exposed to exogenous Ag, and that the TCR repertoire, in contrast to the B cell compartment, is predominantly shaped by endogenously expressed Ag.

Animals↗
PubMed1992

Expression and function of insulin-like growth factor receptors on anti-CD3-activated human T lymphocytes.

The pattern of expression of receptors for insulin-like growth factors (IGF-I and IGF-II) and insulin was studied on monocyte-depleted human peripheral blood T cells activated via anti-CD3. Binding assays demonstrated the sequential appearance of receptors for IGF-I, IGF-II, and insulin on activated T cells. IGF-IR appeared early, their expression reaching maximum levels at or before the peak of cellular proliferation. IGF-IIR expression generally followed that of the IGF-IR and was more transient, with increases and decreases in expression paralleling the rise and decline of cellular proliferation. Insulin receptor expression remained low throughout the activation time course. The identity of the IGFR on anti-CD3-activated T cells was confirmed in affinity cross-linking experiments. These data demonstrated a 135,000 Mr peptide that specifically binds radiolabeled IGF-I and corresponds to the alpha subunit of the type I IGF-IR, and a 260,000 Mr peptide that specifically binds radiolabeled IGF-II and corresponds to the type II IGFR. We have additionally found that IGF-I and IGF-II (in nanomolar concentrations) produce as much as a threefold enhancement of T cell proliferation early in the activation process, correlating with the early appearance of IGF-IR. The effect of both IGF appeared to be mediated through the type I receptor, since an antibody (alpha IR3), which blocks binding to the alpha subunit of this receptor, inhibited enhancement by up to 83%. Furthermore, we have found expression of IGF-IR on T cells after activation to be associated with both CD4+ and CD8+ T cell subpopulations. These observations provide a foundation for investigating the contribution of IGF in regulating T cell proliferation, differentiation, and effector function.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1992

The species concept and its application to tailed phages.

A recently proposed polythetic definition of virus species appears easily applicable to bacteriophages. Criteria for classification of tailed phages are evaluated. Morphology, DNA homology, and serology are the most important criteria for delineation of species, but no single criterion is satisfactory. Dot-blot hybridization and seroneutralization may suggest false relationships by detecting common sequences in the DNA of otherwise unrelated phages. Species of tailed phages can be defined by a combination of morphology and DNA homology or serology. A procedure for identification of novel phages is outlined. Phage names should include elements of host names.

Bacteriophages↗
PubMed1992

Sounds of swallowing following total laryngectomy.

Accelerometer transduced sounds of swallowing in total laryngectomees did not show acoustical differences for liquid vs paste swallows, as are found in normals. Compared with normal swallows, tongue propulsion of the bolus in laryngectomee swallows occurred closer in time to a distinctive spectral change associated with bolus flow into the esophagus. Interpretation stressed the lack of mechanical traction from laryngeal elevation contributing to pharyngoesophageal sphincter opening, and the increased role of tongue propulsion in laryngectomee swallows.

Adult↗
PubMed1992

A new transthyretin mutation associated with amyloidotic vitreous opacities. Asparagine for isoleucine at position 84.

An inherited type of amyloidosis was suspected in an individual of Italian descent who presented with vitreous opacities. Although no family history of amyloidosis was apparent, the patient's transthyretin gene was examined and found not to possess any of the known transthyretin mutations. Complete DNA sequencing revealed a substitution of adenine for thymine in the second base of codon 84 causing an amino acid change of asparagine for isoleucine. The mutation was confirmed by demonstrating the loss of an Sfa N1 restriction endonuclease site. Allele-specific DNA amplification by polymerase chain reaction also was used to confirm the mutation. Either of these tests can be used for diagnosis. Asparagine 84 represents the second mutation associated with amyloidosis to occur at codon 84.

Aged↗
PubMed1992

Evaluation of the Vision Theophylline assays in the emergency department setting.

STUDY OBJECTIVES: To determine whether the use of fingerstick blood samples or venipuncture blood samples affect the accuracy and the precision of the Vision Theophylline I assay and the Vision Theophylline II assay in the emergency department setting. DESIGN: Prospective clinical trial. SETTING: ED in a university teaching hospital. SUBJECTS/INTERVENTIONS: Simultaneous fingerstick and venipuncture blood samples were obtained from adult patients who required baseline theophylline levels in the ED. MEASUREMENTS: The Vision system was used in the ED to measure theophylline concentrations from fingerstick and venipuncture samples. Vision samples were drawn and analyzed by one of three pharmacists rounding within the ED between March and October 1990. These pharmacists were instructed by laboratory personnel concerning pertinent operating procedures. The vision Theophylline I and Theophylline II assays are enzyme-inhibitor immunoassays contained within a multi-chamber test packet. The high-performance liquid chromatography (HPLC) theophylline assay was used as the reference method. MAIN RESULTS: Linear regression of theophylline concentrations determined by the Vision Theophylline I assay versus HPLC revealed a significant correlation for fingerstick samples (r = .9440; P less than .05) and for venipuncture samples (r = .9750; P less than .05). The accuracy values for Vision Theophylline I assay venipuncture and fingerstick samples versus HPLC were -0.63 +/- 1.2 mg/l and 0.22 +/- 1.8 mg/L, respectively. The precision for Vision Theophylline I assay venipuncture and fingerstick samples versus HPLC were 0.27 and 0.38, respectively. Linear regression of theophylline concentrations determined by the Vision Theophylline II assay versus HPLC revealed a significant correlation for fingerstick samples (r = .9804; P less than .05) and for venipuncture samples (r = .9875; P less than .05). Accuracy values for Vision Theophylline II fingerstick and venipuncture samples versus HPLC were -0.53 +/- 1.4 mg/L and -0.65 +/- 1.3 mg/L, respectively. Precision values for Vision Theophylline II fingerstick and venipuncture samples versus HPLC were 0.34 and 0.29, respectively. CONCLUSION: There is a strong correlation between theophylline concentrations measured by Vision Theophylline assay versus HPLC, regardless of whether the Vision Theophylline assay is performed on a fingerstick or venipuncture sample. Vision fingerstick samples were more accurate than Vision venipuncture samples for both Vision Theophylline I and II assays. Theophylline concentrations measured by the Vision system using venipuncture samples were slightly more precise than those using fingerstick samples when compared with HPLC analysis. These differences in accuracy and precision were not clinically relevant.

Blood Specimen Collection↗
PubMed1992

Hospital delays and problems with thrombolytic administration in patients receiving thrombolytic therapy: a multicenter prospective assessment. Virginia Thrombolytic Study Group.

STUDY OBJECTIVES: To assess the timing of key decisions and clinical events in the treatment of acute myocardial infarction with thrombolytic therapy. DESIGN: Prospective study of emergency department patients. SETTING: EDs in 11 urban and two rural hospitals. TYPES OF PARTICIPANTS: Patients with presumed acute myocardial infarction for whom a decision was made in the ED to administer thrombolytic therapy. MEASUREMENTS AND MAIN RESULTS: Statistical analyses included determination of frequency of response, cross tabulation analysis, and Wilcoxon rank sum tests. In 210 thrombolytic-treated patients (mean age, 57 +/- 14.1 years), a median time of 155 minutes elapsed between pain onset and therapy; 67% of the delay was pre-ED arrival. The median time between ED arrival and the initial ECG was six minutes. The median time required for physicians to make a treatment decision was 20 minutes, followed by another median time of 20 minutes for staff to begin drug infusion. The median total hospital (door-to-needle) time was 50 minutes. Significantly shorter delays occurred in urban, teaching, and high-volume hospitals; when thrombolytics were stocked and/or started in the ED; and when emergency physicians treated without involving private attending physicians. Although 95% of patients received tissue plasminogen activator, six patients treated with anisoylated plasminogen-streptokinase activator complex experienced a significantly faster door-to-needle time (P less than .05). CONCLUSION: Thrombolytics should be stocked and started in the ED. Emergency physicians should generally make the decision to administer thrombolytic therapy with reference to accepted protocols without awaiting an ED consultation from either private attendings or cardiologists.

Adult↗
PubMed1992

Di- and triester prodrugs of the varicella-zoster antiviral agent 6-methoxypurine arabinoside.

6-Methoxypurine arabinoside (9-beta-D-arabinofuranosyl-6-methoxy-9H-purine, 1) has potent and selective activity against varicella-zoster virus in vitro. An unfavourable metabolic profile observed with oral dosing in the rat led to the preparation of a variety of 2',3',5'-triesters (2a-n) and several 2',3'-, 2',5'-, and 3',5'-diesters of this arabinoside (3a-n, 4a-f, and 5a-j, respectively). The compounds were evaluated as prodrugs by measuring the urinary levels of 1 in rat urine after oral dosing. With the exception of triacetate 2a, the triesters failed to significantly enhance bioavailability. Administration of compound 2a resulted in a 3-fold increase in systemic availability of 1, possibly because of its increased water solubility (1.6 times more soluble than 1) and only slightly increased relative log P value (1.93 vs 0.50 for 1). The longer chain aliphatic triesters and aromatic triesters had lower water solubilities and increased lipophilic partitioning. These factors might account for the lower systemic bioavailability of these compounds. In contrast, the diesters, especially the aliphatic diesters, showed significantly improved systemic availability. This might be a consequence of the higher aqueous solubilities and enhanced partition coefficients seen with these compounds. 2',3'-Diacetate 3a showed the best combination of high systemic availability and water solubility of all the prodrugs of 1.

Administration, Oral↗
PubMed1992

Changes in pinch force with bidirectional load forces.

The forces used to grasp an object were measured while positive (push) and negative (pull) load forces were applied to the hand under varying frictional conditions. Subjects held between the tips of their thumb and index finger a manipulandum composed of two symmetrically mounted disks. The manipulandum was connected to the stage of an electromagnetic linear motor that generated load forces under computer control. In the first experiment, subjects held the position of the manipulandum constant while the motor generated forces in first the positive and then the negative direction. The motor force at which the manipulandum slipped from the fingers was measured in the second experiment. In both experiments, friction was varied by changing the surface (sandpaper, suede, or plastic) of the manipulandum disks. The pinch forces produced by subjects were linearly related to changes in motor force in both the positive and negative directions, with the slope of this relation varying as a function of the surface properties of the manipulandum. The modulation of pinch force with motor force was influenced, however, by the direction of the load force; higher forces were produced in response to negative load forces. Slip forces varied as a function of pinch force and surface texture; higher forces were associated with materials with lower coefficients of friction. These findings suggest that the friction between the skin and an object being grasped changes as a function of the direction of force that the object applies to the skin, possibly due to the anisotropic nature of glabrous skin, and that this mechanical property contributes to variations in pinch force.

Journal Article↗
PubMed1992

Familial amyloidotic polyneuropathy: a new transthyretin position 30 mutation (alanine for valine) in a family of German descent.

Familial amyloidotic polyneuropathy (FAP) is a dominantly inherited form of amyloidosis usually associated with an abnormal transthyretin (TTR), previously known as prealbumin. Several disease-related variants of the protein, each with a different amino acid substitution and correlating DNA point mutation, have been identified. The TTR gene from a patient suffering from this disorder was asymmetrically amplified and directly sequenced, revealing a cytosine for thymine substitution in the second base of codon 30 and the creation of a novel Cfo I restriction endonuclease site in exon 2. This mutation results in a previously undescribed substitution of an alanine for valine in the final TTR protein. Analysis of the amino acid mutation reveals it to be a hydrophilic substitution at a hydrophobic core position. Alanine at position 30 represents the second FAP-associated mutation at position 30 in TTR.

Adult↗
PubMed1992

Adjunctive medications in patients receiving thrombolytic therapy: a multicenter prospective assessment. The Virginia Multicenter Thrombolytic Study Group.

OBJECTIVE: To describe the use of adjunctive therapies in patients with acute myocardial infarction receiving thrombolytic agents. DESIGN: Data were collected prospectively by the study-site investigator or the emergency department physician caring for the patient. Study participation did not influence thrombolytic regimen selection or the adjunctive therapies ordered. SETTING: Thirteen Virginia hospitals representing a cross-section of hospitals in the state. Eleven are urban medical centers; four have graduate medical education programs. PARTICIPANTS: Patients were included in the study if the decision to administer thrombolytic therapy was made in the emergency department. MAIN OUTCOME MEASURES: Concomitant medications administered during the first six hours after initiation of thrombolytic therapy. RESULTS: Two hundred ten patients (aged 57 +/- 14.1 y) were evaluated. Ninety-five percent of these patients were treated with tissue plasminogen activator, 3 percent received anisoylated plasminogen streptokinase activator complex, and 2 percent received streptokinase. Ninety-one percent of the patients also received heparin, the most commonly used adjunctive medication; 77 percent concomitantly received lidocaine; 62 percent received aspirin; and only 19 percent received a beta-blocker. CONCLUSIONS: Our data provide a reference point for future studies to determine factors that influence the selection of adjunctive agents for treating patients with acute myocardial infarction receiving thrombolytics.

Adrenergic beta-Antagonists↗
PubMed1992

Differential thresholds for limb movement measured using adaptive techniques.

Differential thresholds for limb movement were measured in 10 subjects, using the transformed up-down procedure. Subjects were required to indicate which of two random displacement perturbations delivered to their forearms had the larger standard deviation (SD). The SD of the reference signal was fixed for each experimental condition at one of seven values ranging from 0.05 to 3.2 mm. THe SD of the other signal varied depending on the subject's response. Using this procedure, the differential threshold for limb movement was calculated to be 8%, which is very similar to the thresholds estimated previously for changes in limb position (9%) and force (7%). The sensitivity of the human proprioceptive system to changes in limb displacement was much greater than anticipated, with subjects being able to resolve a 5-microns difference between two perturbations delivered to their arms.

Adult↗
PubMed1992

Amyloid and amyloidosis.

Discovery of the different proteins that constitute the multiple types of amyloid has led to an increasing variety of studies in the literature of diverse medical subspecialties. In fact, in this review, the editors have chosen to review the beta 2-microglobulin amyloid of long-term hemodialysis in the section on renal disease. The current review focuses on the rapidly advancing basic studies of familial, amyloid A protein amyloid and the relevant clinical studies, although the research on amyloid light-chain protein and other forms of amyloidosis is also noted.

Amyloid↗