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J Alexander

Publications and source records attributed to J Alexander.

At least 235 records · Page 13Linked to original sources
PubMed1997

Estimation of arterial mechanical properties from aortic and tonometric arterial pressure waveforms.

Although arterial mechanical properties have been evaluated using arterial input impedance, the relative difficulty in accurate flow measurement made the value of impedance somewhat limited. To develop an alternative method to evaluate arterial mechanical properties, we analyzed the aortic pressure (AoP)-radial arterial pressure (RAP) relationship because of relative ease in obtaining peripheral pressure waveform by tonometry. In 8 patients we simultaneously recorded aortic root and radial arterial pressure waveforms. We calculated the transfer function from AoP to RAP. We then fitted the transfer function to a model of a lossless uniform elastic tube terminated with a modified Windkessel model. The fact that the model transfer function predicted AoP from RAP waveform with considerable accuracy indicated that the model represented the arterial mechanical properties well. We conclude that we can estimate the arterial mechanical properties by the pressure-pressure transfer function analysis.

Adolescent↗
PubMed1997

Cytokines and the mechanisms of action of vaccine adjuvants.

There is an increasing trend away from classical attenuated or killed whole pathogen vaccines towards developing chemically defined preparations. Paradoxically, in order to be effective, these defined vaccines require incorporation into adjuvants, of which very little is actually understood about how or why they work. It is, therefore, of little surprise that, in this context, adjuvants have been referred to as 'the immunologists' dirty little secret'. [Janeway CA, Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harbor Symp Quantit Biol (1989) 54: 1-13]. However, modern techniques in immunology have made available a number of powerful tools that will allow a more complete dissection of how traditional adjuvants work, knowledge of which will not only facilitate the rational design of new adjuvants but also further clarify our understanding of the immune system. The initial studies described in this review indicate that cytokines play an important, if not the central, role in the ability of adjuvants to influence both the quantity and quality of immune responses.

Adjuvants, Immunologic↗
PubMed1996

Analysis of cytotoxic T cell responses to dominant and subdominant epitopes during acute and chronic lymphocytic choriomeningitis virus infection.

The cytotoxic T cell response against lymphocytic choriomeningitis virus (LCMV) in BALB/c (H-2d) mice is predominantly directed against a single immunodominant Ld-restricted epitope in the viral nucleoprotein (NP118-126). Here we report that the immunodominance of this peptide can be in part attributed to its very high affinity for Ld class I molecules. By employing motif searches and sensitive MHC class I binding assays, we also identified 5 Kd-binding peptides in the viral nucleoprotein and glycoprotein among 16 Kd motif-fitting peptides. The nucleoprotein and glycoprotein sequences also contained 18 Dd motif-fitting peptides, three of which bound Dd with weak affinity. Two of the Kd-binding peptides, residues 99-108 and residues 283-291 from the viral glycoprotein, are subdominant epitopes. Although these peptides did not sensitize target cells for direct ex vivo killing by primary antiviral CTL, secondary responses against these peptides were readily detected in BALB/c mice after acute LCMV infection. BALB/c mice that had cleared a long-term LCMV infection showed more sustained CTL responses against these subdominant epitopes, suggesting that subdominant responses might play a role in clearance of chronic infections. One of the subdominant epitopes, GP283-291, conferred partial protection against persistent viral infection after peptide vaccination.

Acute Disease↗
PubMed1996

Enzymes of energy metabolism in the bradyzoites and tachyzoites of Toxoplasma gondii.

The bradyzoite and tachyzoite forms of Toxoplasma gondii, purified from infected animals, were analysed for their activities of phosphofructokinase, pyruvate kinase, lactate dehydrogenase, NAD(+)- and NADH-linked isocitrate dehydrogenases, and succinic dehydrogenase. Both developmental stages contained high activities of phosphofructokinase (specific for pyrophosphate rather than ATP), pyruvate kinase and lactate dehydrogenase, suggesting that energy metabolism in both forms may centre around a high glycolytic flux linked to lactate production. The markedly higher activity of the latter two enzymes in bradyzoites suggests that lactate production is particularly important in this developmental form. NAD(+)-specific isocitrate dehydrogenase was not detectable in either stage of the parasite (and proved useful as a measure of the purity of the bradyzoite preparation), whereas both parasite forms contained low activities of NADP(+)-linked isocitrate dehydrogenase. The results are consistent with the bradyzoites lacking a functional TCA cycle and respiratory chain and are suggestive of a lack of susceptibility of this developmental stage to atovaquone.

Animals↗
PubMed1996

Effects of phenethyl isothiocyanate on metabolism and on genotoxicity of dimethylnitrosamine and 2-amino-1-methyl-6-phenylimidazo[4, 5-beta]pyridine (PhIP).

Phenethyl isothiocyanate (PEITC), a constituent of cruciferous vegetables, inhibited the genotoxic effects of N-nitrosodimethylamine (DMN) and of 2-amino-1-methyl-6-phenylimidazo[4,5-beta]pyridine (PhIP) in differential DNA repair assays with E. coli K-12 strains in vitro and in animal mediated assays with mice. In Salmonella typhimurium, the mutagenic activities of DMN and PhIP measured after activation with S-9 homogenates from several organs of PEITC-treated mice were substantially lower than those obtained with homogenates of untreated animals as well. PEITC also reduced the formation of micronuclei by DMN in metabolically competent Hep-G-2 cells of human origin but was ineffective in combination with PhIP. Biochemical investigations showed that the prevention of genotoxic effects of DMN by PEITC results form an inhibition of its alpha-hydroxylation. The effect of oral administration of PEITC on the formation of DNA adducts of PhIP was examined in the colon and liver of mice. No inhibition of adduct formation was observed in these experiments. Biochemical experiments showed that PEITC reduces not only the metabolic activation of PhIP via 2-hydroxyamino PhIP but also inhibits a detoxification pathway (formation of 4-hydroxy PhIP). The present results can be taken as an indication that the anticarcinogenic activities of isothiocyanates towards nitrosamines are paralleled by antimutagenic effects, and that probably no such protective effects occur in combination with heterocyclic amines. Furthermore, our findings show that the effects of chemopreventive agents demonstrated in bacteria in vitro cannot always be extrapolated to reactions occurring in intact mammalian cells.

Animals↗
PubMed1996

Investigation of (Oxodioxolenyl)methyl carbamates as nonchiral bioreversible prodrug moieties for chiral amines.

The preparation of (oxodioxolenyl)methyl carbamates and their evaluation as novel nonchiral prodrug moieties for chiral primary and secondary amino functional drugs are described. 4-(Carbamoylmethyl)-2-oxo-1,3-dioxolene derivatives of 3,4-dimethoxyphenethylamine with 5-methyl, 5-phenyl, and 5-anisyl substitution (5a, 5b, and 5c) on the dioxolenone ring were prepared as model amine prodrugs by a one step process involving displacement of p-nitrophenol from appropriately substituted ring opening of these carbamates led to a cascade reaction resulting in the rapid and quantitative regeneration of the parent amine drug. Aryl substitution did not significantly alter the hydrolysis rates of these dioxolenone carbamates in buffers at pH 1 and 7.4 or in rat plasma, although the hydrolysis rates of 5-phenyl- (1b) and 5-anisyl- 4-methyl-1,3-dioxol-4-en-2-one (1c) in pH 7.4 phosphate buffer were 2-3 fold faster than that of the 5-methyl-substituted analog (1a). Application of this prodrug strategy to the chiral fibrinogen receptor antagonist L-734,217 resulted in a prodrug that gave quantitative reconversion in rat and dog plasma in vitro and oral bioavailability of 23 +/- 6% in dogs for the parent drug.

Amines↗
PubMed1996

Macular scatter ('grid') laser treatment of poorly demarcated subfoveal choroidal neovascularization in age-related macular degeneration. Results of a randomized pilot trial.

OBJECTIVES: To determine the effects of macular scatter ("grid") laser photocoagulation compared with observation on the visual function of eyes with subfoveal choroidal neovascularization (CNV) that has poorly demarcated boundaries and to provide preliminary data for the evaluation of the feasibility and design of a larger, definitive trial. DESIGN: Randomized pilot clinical trial. SETTING: Two tertiary care retinal referral practices. PATIENTS: Symptomatic individuals with subfoveal CNV secondary to age-related macular degeneration in whom fluorescein angiography showed occult CNV with poorly demarcated boundaries; classic CNV was allowed but did not need to be present for entry into the study. MAIN OUTCOME MEASURE: Change in visual acuity from baseline to specified time periods. RESULTS: Fifty-two eyes were assigned to observation. Fifty-one eyes were assigned randomly to treatment consisting of macular scatter ("grid") laser photocoagulation to the area of CNV. The treatment protocol for 8 of these eyes also included confluent laser photocoagulation to areas of classic CNV. The average visual acuity decrease from baseline was greater in the treated than in the observed group. The difference between these groups was greatest within the first year after study enrollment. At 24 months, slightly more than 40% of the eyes in each group had lost 6 or more lines of visual acuity. Similar results were noted for the subgroup of eyes initially with angiographic features of occult CNV but no classic CNV. CONCLUSIONS: These short-term study results suggest that macular scatter ("grid") laser treatment is not beneficial and is possibly harmful compared with observation for symptomatic subfoveal CNV with poorly demarcated boundaries in age-related macular degeneration. With or without treatment, a significant proportion of these patients are at risk of severe visual loss within 2 years of seeking treatment, even when the eye initially has occult CNV and no classic CNV.

Aged↗
PubMed1996

The influence of sleeping position on functional residual capacity and effective pulmonary blood flow in healthy neonates.

Variation in body position has been shown to affect respiratory function in adults and neonates with and without respiratory illness. At present it remains unclear why respiratory function should be affected by different body positions. We hypothesized that the effect of body weight on the relatively compliant chest wall of the newborn infant in the prone position would cause a reduction in functional residual capacity (FRC) and a compensatory improvement in ventilation/perfusion matching as measured by effective pulmonary blood flow. To evaluate this, a paired crossover study was performed on 12 normal newborn infants. The inert gas (argon) rebreathing method adapted for neonates was used to measure FRC. Simultaneously effective pulmonary blood flow (Qpeff) was determined using Freon 22 and a mass spectrometer with computerized analysis. The babies were studied in three different positions in random order: prone, supine and right lateral decubitus. The means (95% confidence intervals) of the three groups of FRC were 23.8 (19.2 to 28.4), 23.8 (20.2 to 27.5), and 24.3 (19.5 to 29.2) ml/kg, respectively (P = 0.59) and for Qpeff were 104 (91 to 116), 108 (95 to 122), 109 (97 to 122) ml/ kg-min, respectively (P = 0.11). Thus no significant differences were demonstrated. In nine of the babies, a repeat supine measurement was taken at the end of the study to assess repeatability of the method. In these nine babies alone the results were 22.7 (19.1 to 26.3) and 22.1 (18.6 to 25.6) ml/kg for FRC, and 102 (89 to 116) and 98 (90 to 107) ml/kg-min for Qpeff. The coefficients of repeatability were 4.7 ml/kg for FRC (21%) and 30 ml/kg-min for Qpeff (30%).

Argon↗
PubMed1996

Lipid vesicle-entrapped influenza A antigen modulates the influenza A-specific human antibody response in immune reconstituted SCID-human mice.

This study was designed to investigate the capacity of purified influenza antigen in the presence and absence of adjuvant to induce human antibody responses in human-PBL-SCID mice. Non-ionic surfactant vesicles (NISV) were used as adjuvant as they have been shown to promote the development of Th1 responses in mouse studies. Human peripheral blood lymphocyte-SCID mice were inoculated with either purified influenza antigen (A/Texas, H3N2) or influenza antigen entrapped in NISV. Both vaccinated groups produced significantly higher plasma levels of influenza-specific human IgG when individually compared with non-vaccinated controls. However, similar comparisons revealed that specific IgM levels were significantly higher only in the group challenged with purified antigen. Further analysis of IgG subclasses also demonstrated an adjuvant-dependent dichotomy in the responses of the vaccine groups when compared with non-vaccinated controls. Thus, only influenza-specific IgG1 antibodies (associated with Th1 responses in humans) were significantly increased above control levels using antigen with adjuvant, while both this subclass and antigen-specific IgG4 (Th2 associated) were significantly increased with antigen alone. These results illustrate the suitability of this model for use in human vaccination studies and demonstrates that influenza antigen applied with NISV selectively promotes only Th1 responses, unlike free antigen which also promotes Th2 responses in vivo.

Adjuvants, Immunologic↗
PubMed1996

In interleukin-4-deficient mice, alum not only generates T helper 1 responses equivalent to freund's complete adjuvant, but continues to induce T helper 2 cytokine production.

The role of interleukin (IL)-4 in the activity of two frequently used vaccine adjuvants, Freund's complete adjuvant (FCA) and the aluminum hydroxide gels (alum), was studied using the standard antigen ovalbumin (OVA) in IL-4 genedisrupted mice (IL-4 -/-). In the absence of adjuvant, there was an overall reduction in antibody production to OVA in IL-4 -/- mice and significantly greater amounts of interferon (IFN)-gamma were produced following restimulation of splenocytes with antigen in vitro compared with immunocompetent controls (IL-4 +/+). FCA and alum boosted the immune response to OVA in both IL-4 -/- and IL-4 +/+ mice. In IL-4 +/+ mice, while FCA stimulated a wide-spectrum immunoglobulin response, including both Th1-associated IgG2a and Th2-associated IgG1, alum enhanced only Th2 antibody production and no OVA-specific IgG2a could be detected. In IL-4-deficient mice, however, not only was IgG2a production increased in all adjuvant-treated groups, but alum was as potent at stimulating this antibody subclass as FCA. Similarly, increased production in vitro by splenocytes of the Th1 cytokine IFN-gamma, equivalent to that produced after inoculation with FCA/OVA, was only detected in IL-4 -/- mice inoculated with alum/OVA. There was no IgE production in IL-4 -/- mice and OVA-specific IgG1 production, although still at significant levels, was reduced compared with wild-type mice irrespective of the adjuvant used. However, although production of the Th2 cytokine IL-5 was totally inhibited in IL-4-deficient mice inoculated with FCA/OVA, there was no significant difference in IL-5 production between the two strains when alum was used as adjuvant.

Adjuvants, Immunologic↗
PubMed1996

Antigen analogs as tools to study T-cell activation function and activation.

Herein we review data relating to the molecular mechanism of T-cell receptor antagonists, their effect on thymic education, the occurrence of naturally occurring antigen analogs, and the therapeutic potential of the TCR antagonist approach. Our data suggest that MHC bound antigen analogs which antagonize the mature T-cell response, bind the T-cell receptor below a crucial affinity threshold required to stimulate the early biochemical events necessary for activation, such as phosphatidylinositol metabolism and the Ca2+ influx. The same peptides do not inhibit the formation of APC/T-cell complexes, suggesting interference with more complex equilibria such as receptor oligomerization and co-receptor interaction. Our laboratory and others have also begun to investigate how these antigen analogs may affect the processes involved in thymic education. Non-stimulatory antagonist peptides can elicit deletion of CD4+/CD8+ thymocytes suggesting a lower affinity requirement for negative selection than for activation. These data also demonstrate that these antigen analogs can, indeed, act upon immature T cells. We have also reviewed evidence that antagonists may, in fact, occur in nature. Recent data suggest that viral mutations resulting in altered immunodominant epitopes may produce antagonist determinants potentially involved in immunosuppression and viral persistence. Finally, we discuss the therapeutic potential of antigen analogs and TCR antagonism in autoimmune disease and allergy.

Animals↗
PubMed1996

Sex steroids, pregnancy-associated hormones and immunity to parasitic infection.

A wealth of evidence has accumulated that illustrates the ability of sex-associated hormones to influence directly a variety of diverse immunological functions. Thus, it is not surprising that differences have also been noted between the sexes in their relative susceptibility to parasitic infections. Furthermore, during pregnancy, much of the observed maternal immunomodulation, essential for fetal survival, has been attributed to changes in the levels of steroid hormones. These pregnancy-induced alterations in immune function can also have profound effects on the course of parasitic infection. In this article, Craig Roberts, Abhay Satoskar and James Alexander review the immunological basis for differences in the relative susceptibilities of males, non-pregnant females and pregnant females to parasitic infection, particularly leislumaniasis and toxoplasmosis. They also discuss the role of the major sex- and pregnancy-associated hormones in mediating these effects.

Journal Article↗
PubMed1996

Immune responses in mice induced by HSV-1 glycoproteins presented with ISCOMs or NISV delivery systems.

The purpose of this study was to evaluate the immunogenicity of a herpes simplex virus type I (HSV-1) antigen preparation, obtained following zwitterionic detergent treatment of virus, and incorporation of the antigens into either immunostimulating complexes (ISCOMs) or non-ionic surfactant vesicles (NISV) delivery systems. Using Balb/c mice the ISCOM and NISV HSV-1 vaccines were assayed for their capacity to induce and enhance both the humoral and cellular immune responses, and to elicit protection against both homologous and heterologous virus challenge. The serum from animals vaccinated with either the NISV or the ISCOM HSV-1 antigen preparation, were found to contain high levels of total IgG and IgG1 and IgG2a subclass antibodies. In addition, both preparations were found to induce high neutralizing (NT) antibody levels following a two immunization protocol and to provide some protection against homologous and heterologous HSV challenge infection. Lymphoproliferative responses were observed in cultures of splenocytes from mice immunized with both HSV-1 NISV vaccine and HSV-1 ISCOMs vaccine, following various antigenic stimuli in vitro. In general, these were most marked in animals immunized with the HSV-1 NISV preparation, and particularly so when the splenocytes were stimulated in vitro with live HSV-1. Both the NISV and ISCOM HSV-1 vaccines were found to have induced interleukin 2, interleukin 10 and interferon-gamma in spleen cell culture supernatants, although again, the highest responses in general were observed in supernatant fluids from spleen cell cultures from animals immunized with the HSV-1 NISV preparation. These results suggest that a wide range of immune activity can be elicited by HSV-1 antigens presented to the immune system of mice in these formulations.

Animals↗
PubMed1996

Gabapentin in generalized seizures.

The efficacy of gabapentin (Neurontin), in generalized seizures was evaluated in this 14 week, double-blind, placebo-controlled, parallel-group, add-on, multicenter study. A total of 129 patients with refractory generalized seizures were randomized to receive either placebo or 1200 mg/day gabapentin as add-on therapy. Patients received their standard regimens of antiepileptic drugs (AEDs) during a 12 week baseline period, and gabapentin or placebo was added-on in the subsequent 14 week evaluation period. Results of both an intent-to-treat (ITT) and evaluable-patient analyses showed that gabapentin provided greater reduction in the frequency of generalized tonic-clonic seizures than did placebo; however, the differences between treatments were not statistically significant. Gabapentin did not affect the frequency of absence or myoclonic seizures. Adverse events were reported by 67% of gabapentin-treated patients and by 56% of placebo-treated patients. The most frequently occurring adverse events among patients receiving gabapentin were somnolence, fatigue, and dizziness. Gabapentin is well tolerated by patients with generalized seizures. The results of this study show a trend toward an effect of gabapentin in reducing the frequency of generalized tonic-clonic seizures and suggest that further exploration of high dose gabapentin in generalized epilepsy is warranted.

Acetates↗