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J Alexander

Publications and source records attributed to J Alexander.

At least 181 records · Page 10Linked to original sources
PubMed1998

The optimization of helper T lymphocyte (HTL) function in vaccine development.

Helper T lymphocyte (HTL) responses play an important role in the induction of both humoral and cellular immune responses. Therefore, HTL epitopes are likely to be a crucial component of prophylactic and immunotherapeutic vaccines. For this reason, Pan DR helper T cell epitopes (PADRE), engineered to bind most common HLA-DR molecules with high affinity and act as powerful immunogens, were developed. Short linear peptide constructs comprising PADRE and Plasmodium-derived B cell epitopes induced antibody responses comparable to more complex multiple antigen peptides (MAP) constructs in mice. These antibody responses were composed mostly of the IgG subclass, reactive against intact sporozoites, inhibitory of schizont formation in liver invasion assays, and protective against sporozoite challenge in vivo. The PADRE HTL epitope has also been shown to augment the potency of vaccines designed to stimulate a cellular immune response. Using a HBV transgenic murine model, it was found that CTL tolerance was broken by PADRE-CTL epitope lipopeptide, but not by a similar construct containing a conventional HTL epitope. There are a number of prophylactic vaccines that are of limited efficacy, require multiple boosts, and/or confer protection to only a fraction of the immunized population. Also, in the case of virally infected or cancerous cells, new immunotherapeutic vaccines that induce strong cellular immune responses are desirable. Therefore, optimization of HTL function by use of synthetic epitopes such as PADRE or pathogen-derived, broadly crossreactive epitopes holds promise for a new generation of highly efficacious vaccines.

Animals↗
PubMed1998

Translocation of the retina for management of subfoveal choroidal neovascularization II: a preliminary report in humans.

PURPOSE: To report a surgical method for translocation of the foveal retina in eyes with subfoveal choroidal neovascularization. METHODS: In three eyes of three patients, a crescent-shaped, partial-thickness scleral resection was performed near the equator at either the superotemporal or the inferotemporal quadrant. A near-total retinal detachment was created; then the edges of the resected sclera were sutured, causing shortening of the sclera with subsequent reattachment of the retina, resulting in translocation of the fovea to an area overlying nonfoveal retinal pigment epithelium and choroid. RESULTS: In three eyes of three patients, the fovea was surgically translocated to overlie retinal pigment epithelium that preoperatively was not underlying the fovea. In two patients, laser photocoagulation was applied to the choroidal neovascularization that, after translocation of the fovea, was no longer subfoveal, so that the photocoagulation was not associated with immediate visual loss. After a follow-up of 4 to 6 months, the visual acuity had improved in all patients (from 20/126 preoperatively to 20/70 in one patient, from 20/200 preoperatively to 20/70 in the second, and from 20/160 to 20/30 in the third). The patients noted distortion or tilting of the images, which improved over time. CONCLUSIONS: Limited foveal translocation may offer a therapeutic modality to preserve or improve vision in cases of subfoveal choroidal neovascularization. Additional follow-up is needed to assess the impact of potential complications associated with the surgical procedure, such as retinal detachment, proliferative vitreoretinopathy, and cataract, as well as the possibility of recurrent choroidal neovascularization.

Adult↗
PubMed1998

The role of IL-4 in adult acquired and congenital toxoplasmosis.

The course of Toxoplasma gondii infection was studied in IL-4-deficient mice from three genetic backgrounds and their wild-type counterparts following peroral inoculation of tissue cysts. Survival rates were significantly reduced in disease-susceptible C57 BL/6 mice and F1 (C57BL/6 x 129Sv) mice deficient in IL-4 compared with wild-type controls. In contrast, this difference was not observed in T. gondii-resistant BALB/c mice. However, brain tissue cyst burdens in IL-4-deficient mice were either equivalent to (C57BL/6 and BALB/c mice) or significantly less (B6/129 mice) than similarly infected wild-type mice. Thus strain-specific differences in the course of T. gondii were demonstrated in the absence of IL-4. The course of T. gondii infection was also compared between B6/129 IL-4-deficient mice and their wild-type counterparts following peroral challenge with 20 tissue cysts on day 12 of pregnancy. Age-matched non-pregnant IL-4-/- and IL-4+/+ mice were also infected to assess the role of IL-4 on T. gondii infection during pregnancy. Disease phenotypes, as measured by mortality, were reversed if infections were initiated during pregnancy compared with non-pregnant infection. Thus significant mortality occurred immediately post partum in IL-4+/+ mothers, while all IL-4-/- mothers survived. Cyst burdens 28 days p.i. were significantly lower in IL-4-/- mothers than IL-4+/+ mothers and both IL-4-/- and IL-4+/+ non-pregnant mice. Congenital disease transmission as measured by foetal death or vertical disease transmission was independent of the presence or absence of IL-4. These studies demonstrate a role for IL-4 in pregnancy-induced immunosuppression and the associated increased susceptibility to T. gondii infection.

Animals↗
PubMed1998

Recognition of a novel naturally processed, A2 restricted, HCV-NS4 epitope triggers IFN-gamma release in absence of detectable cytopathicity.

Using short term CTL lines derived from HLA A2/Kb transgenic mice and IFN-gamma release assays we demonstrate that the NS4.1769 epitope, is generated from natural processing of the NS4 antigen, and presented in the context of the A2/Kb molecules. Interestingly, T cell recognition of the naturally processed form of the NS4. 1769 epitope was associated with significant IFN-gamma release, but no direct cytolytic activity. Epitopes of this phenotype might be of interest, in terms of therapy of chronic HCV infection by associating the benefit of localized lymphokine release with low or absent direct cytopathicity.

Animals↗
PubMed1998

Shared learning for community based maternity care.

In order to ensure the best quality of maternity care midwives and doctors must work closely together but unfortunately the necessary interdisciplinary cooperation and respect has not always been present. This paper suggests that the benefits claimed for interprofessional education, which remain largely untested in maternity care, are being put forward as a panacea for earlier difficulties. It outlines some of the initiatives currently taking place. Material ripe for shared learning is identified and it is suggested that shared teaching in addition to shared learning for midwifery and medical students and for midwives and doctors should be the norm. Learners may then eventually provide shared care based on both their shared learning experiences and also on the role model of shared teaching. Such a major change would require considerable political will, including a shift in funding. There is some evidence that the necessary political will is developing and this may be given more emphasis by the need for teaching to follow care as the NHS becomes more primary-care led.

Community Health Nursing↗
PubMed1998

Pools of lipidated HTL-CTL constructs prime for multiple HBV and HCV CTL epitope responses.

Various peptide-based approaches to simultaneous induction of multiple cytotoxic T lymphocyte (CTL) responses were evaluated as part of ongoing efforts to develop immunotherapeutic vaccines for use in humans. To this end, HLA (human histocompatibility leukocyte antigen)-A2-restricted epitopes from several specific viral proteins were tested in an HLA-A2 transgenic mouse model system, which mimics human CTL responses to these viral proteins. Multiple CTL responses were elicited by immunization with either peptides emulsified in incomplete Freund's adjuvant (IFA), or lipidated peptides administered in phosphate buffered saline (PBS). In the case of lipidated peptides, induction of CTL responses was crucially dependent on the presence of helper T lymphocyte (HTL) epitopes, and most efficient in the case of lipidated covalently linked HTL-CTL epitope constructs. CTL could also be induced by immunization with lipidated HTL epitopes simply mixed with CTL epitopes and formulated in PBS. However, this approach was highly dependent on the particular lipidated HTL/CTL combination utilized, and was marginally effective for simultaneous priming of multiple CTL responses. By contrast, all HTL/CTL combinations were potent immunogens when delivered as lipidated, covalently linked molecules. This was the most effective of the approaches analysed in terms of multi-epitope priming, as demonstrated by the induction of simultaneous CTL responses to a pool of five different epitopes.

Adjuvants, Immunologic↗
PubMed1998

One- and two-incision anterior cruciate ligament reconstruction: a biomechanical comparison including the effect of simulated closed-chain exercise.

The purpose of this study was to evaluate the effect of simulated closed-chain exercise on anterior translation in the anterior cruciate ligament (ACL) reconstructed knee comparing patellar tendon grafts secured with endoscopic and two-incision techniques. ACL reconstructions, were performed on five matched pairs of fresh frozen cadaver lower extremities. One of each pair had endoscopic (inside-out) placement of the femoral interference screw and other had outside-in femoral screw placement. A model for closed-chain exercise was developed to simulate half squat exercises using a custom apparatus on the Material Testing machine with a 356 N (80 lb) axial load and 40 N (9 lb) static hamstring force. Knee motion from near full extension to 60 degrees flexion was achieved by varying the quadricep force. One thousand squats were performed, and KT-1000 arthometry was done before and after cycling each specimen. The femur-graft-tibia constructs were then stressed to failure. Closed-chain cycling resulted in no significant change in anterior translation in either group. The mean maximum load to failure of the femur-graft-tibia construct was 340.4N in the one-incision group and 434.2 N in the two-incision group. P=.048 was considered statistically significant. Anterior translation did not increase after 1,000 simulated half knee bends in either the one- or two-incision groups. Shallow knee bends are an important part of aggressive rehabilitation programs, and our data support the position that these closed-chain exercises do not deleteriously affect the graft. Though the maximum strength to failure differed significantly between the one- and two-incision groups, both techniques offered sufficient strength to withstand an aggressive simulated rehabilitation protocol.

Aged↗
PubMed1998

Neither interleukin-6 nor signalling via tumour necrosis factor receptor-1 contribute to the adjuvant activity of Alum and Freund's adjuvant.

The potential contribution made by the inflammatory cytokines, interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) to the adjuvant activity of aluminium hydroxide gels (Alum) or Freund's complete adjuvant (FCA) was studied by comparing the immunological responses of IL-6- or TNF receptor 1- (p55; TNFR-1) deficient mice with immunocompetent control mice. While both TNFR-1- and IL-6-deficient mice primed with ovalbumin (OVA) prepared in either Alum or FCA produced similar IgG.1 responses in comparison to control mice, the pattern of T-helper type 1- (Th1) dependent IgG2a production was significantly altered. In TNFR-1-deficient mice, IgG2a responses were greater than in control mice when FCA, but not when Alum, was used as an adjuvant. Correspondingly, spleen cells from FCA-inoculated TNFR-1-deficient mice restimulated with antigen in vitro produced higher Th1 cytokine (interferon-gamma; IFN-gamma) levels with no alteration in Th2 cytokine (IL-4; IL-5, IL-6 and IL-10) production in comparison with wild-type mice. Higher levels of IgG2a were also detected in IL-6-deficient mice compared with wild-type mice following inoculation with OVA prepared in either FCA or in Alum. Furthermore, analysis of cytokine production by spleen cells revealed that both Th1 and Th2 cytokine production was higher in IL-6-deficient mice compared with control mice. As the majority of the effects of TNF-alpha are mediated via TNFR-1, we conclude that this cytokine inhibits the adjuvant activities of FCA. Furthermore, the results also imply that immunopotentiating effects of FCA or Alum adjuvant are both inhibited by IL-6.

Adjuvants, Immunologic↗
PubMed1998

A protective role for IL-6 during early infection with Toxoplasma gondii.

IL-6 deficient mice were found to be significantly more susceptible to peroral infection with Toxoplasma gondii than their wild-type counterparts as measured by survival, brain cyst burdens and brain pathology at 28 days post infection. The physical manifestations of disease, such as weight loss, were not observed in IL-6 deficient animals until at least seven days later than such changes occurred in wildtype mice. During this early stage of infection IL-6+/+ but not IL-6-/- mice mounted a peripheral blood neutrophilia. Furthermore, between 6-8 days post-infection there was a significant increase in plasma IFN-gamma levels in wild-type but not IL-6 deficient mice. Not until days 18-23 post-infection, concurrent with the majority of deaths in IL-6-/- mice, were plasma IFN-gamma levels substantially and significantly raised in IL-6-/- mice. At this time not only were these plasma IFN-gamma levels 20-fold higher than background but eight-fold greater than peak (6-8 days post-infection) IFN-gamma levels in IL-6+/+ mice. IFN-gamma dependent parasite specific IgG2a levels were also significantly higher in IL-6-/- mice over this period and thereafter. Overall the evidence suggests that in the absence of IL-6 mice are unable to initiate a rapid proinflammatory response against T. gondii, which allows increased parasite growth. Increased mortality in IL-6-/- mice may be directly due to this increased parasite burden and the excessive inflammatory response this induces three weeks post-infection.

Animals↗
PubMed1998

Sex-determined resistance against Leishmania mexicana is associated with the preferential induction of a Th1-like response and IFN-gamma production by female but not male DBA/2 mice.

Female DBA/2 mice are relatively resistant to infection with Leishmania mexicana compared with male mice. Following subcutaneous infection with 5 x 10(6) L. mexicana, amastigotes lesion growth in male and female DBA/2 mice was measured and the developing immune responses were monitored both in vitro and in vivo. Over the 10 week duration of the experiment all male DBA/2 mice developed rapidly growing non-healing lesions while female mice either developed no lesions whatsoever or developed smaller slower growing lesions than males. Both male and female mice produced parasite specific IgG2a during the course of the disease. However, significant titres of parasite specific IgG1 antibodies could be detected only in male mice indicating a Th2-influenced response in this sex. Furthermore, female mice, unlike male mice, developed significant parasite induced cutaneous delayed-type hypersensitivity footpad responses, indicating a Th1-influenced response in female mice. Although both male and female DBA/2 mice infected with L. mexicana displayed a significant increase in the number of cells in their draining lymph nodes at week 10 post-infection, no significant differences could be observed in the numbers of CD4+, CD8 + T cells as well as B cells between male and female DBA/2 mice. However. following in vitro stimulation, the lymph node cells from female mice displayed significantly higher antigen specific proliferative responses than the males and produced significant amounts of IFN-gamma which could not be detected in the equivalent culture supernatants from male mice. There were no significant differences in the levels of Th2-associated cytokines IL-4 and IL-5, produced by the lymph node cells of both sexes. Treatment of female DBA/2 mice with IFN-gamma neutralizing antibody following L. mexicana infection resulted in lesion growth equivalent to male mice. Conversely, intralesional injections of murine recombinant IFN-gamma significantly inhibited lesion growth in male mice.

Animals↗
PubMed1998

Cost-effectiveness of acyclovir suppression to prevent recurrent genital herpes in term pregnancy.

The objective of this paper is to determine whether acyclovir suppression provides a greater cost savings over no medical therapy in the management of recurrent genital herpes (HSV) in pregnancy. Estimates of the risk of HSV recurrence and cesarean delivery rates in acyclovir-treated and -untreated patients and frequency of neonatal acyclovir treatment were derived from literature reviews, prospective surveillance, and practices at our institution. Estimates of costs were derived from average hospital and outpatient clinic charges at our institution. Calculations were run separately for four different groups of patients: women whose first diagnosis of genital herpes occurred during the pregnancy, women whose diagnosis antedated pregnancy and who had infrequent recurrences, women whose diagnosis antedated pregnancy and had frequent recurrences, and all women with a history of genital herpes regardless of timing of diagnosis or frequency of recurrences. Suppressive acyclovir treatment of all term pregnant women with a history of genital herpes resulted in an estimated savings of $183.00 per patient or $36,600,000 per year. Women with their first episode of herpes diagnosed during pregnancy or with frequent recurrences benefitted even more, achieving a savings of $455.00 and $391.00 per patient, respectively. Assuming that prenatal acyclovir treatment is safe for the fetus, utilizing this management for all patients with recurrent HSV in pregnancy could immediately save $183 per patient. On a national level, this translates to $36,600,000 per year just in reduced obstetrical costs. If indirect costs associated with cesarean deliveries had been included in these calculations, the estimated savings would be even more substantial.

Acyclovir↗
PubMed1998

Amorphous silicon, flat-panel, x-ray detector versus screen-film radiography: effect of dose reduction on the detectability of cortical bone defects and fractures.

RATIONALE AND OBJECTIVES: The purpose of this phantom study was to assess the diagnostic performance of a self-scanning, solid-state amorphous silicon (a-Si) detector in skeletal radiography using different exposure parameters. METHODS: A flat-panel detector (15 cm x 15 cm), based on a-Si technology with 143 microm x 143 microm pixel size, 1k x 1k matrix, and 12 bit digital output was used. State-of-the-art screen-film radiography (SFR; speed 400, detector dose 2.5 microGy) was compared with a-Si images taken at doses that were equivalent to a speed of 400, 800, 1,250, and 1,600, respectively. A total of 232 segments of long tubular deer-bones (femur, tibia, humerus, radius) had 110 artificial fractures and 112 cortical defects simulating osteolytic lesions. Receiver operating characteristic analysis was performed for 9,280 observations made by four independent observers. Two-tailed Student's paired t test was used for statistical analysis (95% confidence level). RESULTS: Receiver operating characteristic analysis yielded equivalent results of the a-Si and SFR system. Even at the lowest dose there were no statistically significant differences between both imaging modalities with respect to the detectability of fractures and cortical defects. CONCLUSIONS: The results of this study indicate that a-Si detector technology holds promise in terms of dose reduction in skeletal radiography without loss of diagnostic accuracy.

Animals↗
PubMed1998

A fish oil-derived concentrate enriched in eicosapentaenoic and docosahexaenoic acid as ethyl esters inhibits the formation and growth of aberrant crypt foci in rat colon.

It was examined whether the fish oil derived n-3 fatty acid concentrate K85 (51.0% of eicosapentaenoic acid, 35.3% of docosahexaenoic acid and 7.7% of other n-3 fatty acids, all as ethyl esters) could inhibit the initial formation of aberrant crypt foci and the later growth of pre-existing aberrant crypt foci in the colon of male F344 rats treated with the carcinogens dimethylhydrazine or azoxymethane, the proximate metabolite of dimethylhydrazine. Given intragastrically 5 times a week, K85 caused a dose-dependent reduction of the initial (week 0-6) formation of aberrant crypt foci induced by azoxymethane (2 x 15 mg/kg body weight/injection the first two weeks). The number of aberrant crypt foci was reduced by 36% (P < 0.001) with 3.0 g K85/kg body weight/dose, the largest dose tested. The reduction was most pronounced (46%, P = 0.009) among the fastest growing aberrant crypt foci (foci with 3 or more aberrant crypts). When given in a later phase of the carcinogenesis (week 17-23) a similar intragastric treatment with K85 caused a dose-dependent reduction of the growth of pre-existing aberrant crypt foci induced by dimethylhydrazine (3 x 20 mg/kg body weight/injection the first week). The crypt multiplicity (aberrant crypt/focus) was reduced by 22% (P = 0.016) with 2.24 g K85/kg body weight/dose, the largest dose tested. This was sufficient to completely block the growth of the pre-existing aberrant crypt foci in the treatment period. The arrest of crypt multiplication was further documented by the 63% reduction (P = 0.03) of the large aberrant crypt foci (foci with 9 or more aberrant crypts). The total number of aberrant crypt foci was not affected.

Animals↗
PubMed1998

A new method to measure regional myocardial time-varying elastance using minute vibration.

We developed a new technique to evaluate regional myocardial elastance using minute vibration. In 13 isolated cross-circulated canine hearts, we applied small sinusoidal vibrations of displacement to the left ventricular surface at various frequencies (50-100 Hz). Using the measured displacement and force between the vibrator head and myocardium, we derived myocardial elastance on the basis of the equation of motion for a given moment of the cardiac cycle. Simultaneous solution of the equations of motion at different frequencies yielded a unique value of elastance. Time-varying myocardial elastance increased from diastole (0.028 +/- 0.211 x 10(6) dyn/cm) to systole (0.833 +/- 0.391 x 10(6) dyn/cm). The end-systolic elastance (ees) linearly correlated with end-systolic left ventricular elastance (r = 0.717, P < 0.001) and also with the end-systolic Young's modulus (r = 0.874, P < 0.0001). We also measured ees at both ischemic and nonischemic regions during coronary occlusion. Young's modulus, estimated by normalizing ees by the wall thickness and by the estimated mass, did not change significantly at the nonischemic regions, whereas it decreased significantly from 2.303 +/- 0.556 to 1.173 +/- 0.370 x 10(6) dyn/cm2 at the ischemic region after coronary occlusion (P < 0.005). We conclude that this technique is useful for the quantitative assessment of regional myocardial elastance.

Animals↗
PubMed1998

Dynamic sympathetic regulation of left ventricular contractility studied in the isolated canine heart.

We investigated the dynamic sympathetic regulation of left ventricular end-systolic elastance (Ees) using an isolated canine ventricular preparation with functioning sympathetic nerves intact. We estimated the transfer function from both stellate ganglion stimulation to Ees and ganglion stimulation to heart rate (HR) for both left and right ganglia by means of the white noise approach and transformed those transfer functions into corresponding step responses. The HR response was much larger with right sympathetic stimulation than with left sympathetic stimulation (4.3 +/- 1.4 vs. 0.7 +/- 0.6 beats . min-1 . Hz-1, P < 0.01). In contrast, the Ees responses without pacing were not significantly different between left and right sympathetic stimulation (0.72 +/- 0.34 vs. 0.76 +/- 0. 42 mmHg . ml-1 . Hz-1). Fixed-rate pacing significantly decreased the Ees response to right sympathetic stimulation (0.53 +/- 0.43 mmHg . ml-1 . Hz-1, P < 0.01), but not to left sympathetic stimulation (0.67 +/- 0.32 mmHg . ml-1 . Hz-1, not significant). Although the mechanism by which the sympathetic nervous system regulates cardiac contractility is different depending on whether the left or right sympathetic nerves are activated, this difference does not affect the apparent response of Ees to dynamic sympathetic stimulation.

Animals↗
PubMed1998

Accumulation of cAMP augments dynamic vagal control of heart rate.

Recent investigations in our laboratory using a Gaussian white noise perturbation technique have shown that simultaneous sympathetic stimulation augmented the gain of the transfer function from vagal stimulation frequency to heart rate response. However, the mechanism of that augmentation remains to be elucidated. In this study, we examined in anesthetized rabbits how three pharmacological interventions known to cause intracellular accumulation of cAMP affected the transfer function. Isoproterenol (0.3 microg . kg-1 . min-1 iv) increased the dynamic gain of transfer function from 7.12 +/- 0.67 to 12.4 +/- 1.21 beats . min-1 . Hz-1 (P < 0.05) without changing the corner frequency or the lag time. Similar augmentations were observed when forskolin (5 microg . kg-1 . min-1 iv) or theophylline (20 mg/kg iv) was administered under conditions of beta-adrenergic blockade. These results suggest that the accumulation of cAMP at postjunctional effector sites contributes, at least in part, to the sympathetic augmentation of the dynamic vagal control of heart rate.

Animals↗