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Biomedical subjects

J Miller

Publications and source records attributed to J Miller.

At least 271 records · Page 15Linked to original sources
PubMed1998

Cellular immune responses of human cadaver donor bone marrow cells and their susceptibility to commonly used immunosuppressive drugs in transplantation.

BACKGROUND: The cascade of immunological effects brought about by donor bone marrow cell (DBMC) infusions in human organ transplantation, especially in the context of continuous pharmacologic immunosuppression, is not fully understood. Yet, in inbred rodents and even primates, administration of specific bone marrow cells has caused a state of acquired immunologic tolerance. METHODS: In vitro mixed lymphocyte culture (MLC) and cell-mediated lympholysis (CML) culture systems were used to compare the responding and regulatory properties of DBMC and individual bone marrow cell subsets versus spleen cells in the presence or absence of pharmacologic immunosuppression. RESULTS: In the absence of immunosuppressive drugs, the DBMC proliferated in MLC and in response to phytohemagglutinin, but to a lower magnitude than donor spleen cells. In CML assays, DBMC failed to function as cytotoxic cells. Removal of both CD3+ and CD34+ cells together (not just singly) had to occur for complete abrogation of the proliferative response of DBMC evoked in the presence of allogeneic stimulating cells. Testing several experimental variables using flow cytometric analysis led to the conclusion that when purified DBMC CD34+ cells were placed in coculture with irradiated allogeneic peripheral blood mononuclear cells, such CD34+ cells give rise both to CD3- TCRalphabeta+ as well as to dimly staining CD3+ TCRalphabeta+ cells. Low pharmacologic concentrations of tacrolimus/cyclosporine (CsA) and mycophenolic acid (MPA) singly or in combination had no effect on the spontaneous proliferation of DBMC and had significantly less inhibitory activity on MLC responses of DBMC and its purified CD3+ or CD34+ subpopulations, compared with the responses of spleen cells. Moreover, the previously described regulatory effects of DBMC on the MLC responses of peripheral blood or splenic responding cells were not inhibited by these immunosuppressive drugs. CONCLUSIONS: Taken together, these results support the notion that in vitro DBMC subpopulations, which proliferate as responding cells in co-culture with x-irradiated allogeneic cells and which cause regulatory effects when added as a third component to MLC reactions, seem to be culture-generated lymphoid cell lineage(s) progeny of CD34+ cells. This possibly includes unique CD3+ "primitive" (dimly staining) T cells, which are not as inhibited in their function by tacrolimus/CsA and MPA, as are postthymic (splenic) T cells.

Antigens, CD34↗
PubMed1998

Continuing observations on the regulatory effects of donor-specific bone marrow cell infusions and chimerism in kidney transplant recipients.

BACKGROUND: Continued follow-up of a series of donor bone marrow cell (DBMC)-infused first cadaver renal transplant recipients is described (n=58), now at a 36-month actuarial time point postoperatively. Serial polymerase chain reaction-flow cytometry (PCR-Flow) and cellular immune assays of iliac crest bone marrow aspirates and peripheral blood have begun to be compared with concomitantly transplanted recipients of living-related donor (LRD) kidneys and donor marrow infusions given the same immunosuppressive regimen (n=16). There have also been comparisons (36 months) with 188 controls transplanted concomitantly, i.e., recipients of first cadaver kidney transplants, who did not receive bone marrow. METHODS: Each group was given equivalent immunosuppressive regimens of OKT3 anti-T cell induction and maintenance tacrolimus, mycophenolate mofetil, and methylprednisolone. Actuarial patient and graft survival have been 96% and 93%, respectively, in the controls and 91% and 91%, respectively, in the DBMC-infused recipients. Trough levels of tacrolimus were significantly lower in the DBMC-infused group. RESULTS: In PCR-Flow measurements, in peripheral blood up to 6 months postoperatively, there were higher levels of chimerism, i.e., in the total number of donor cells, as well as the donor CD3+ and CD34+ subsets in the LRD recipients administered DBMC infusions, compared with cadaver DBMC recipients, supporting the notion of a positive effect of histocompatibility on chimerism levels. In PCR-Flow measurements of recipient iliac crest bone marrow aspirates as in previous studies on peripheral blood, early acute rejection episodes (<1 month) were found to be associated with a later (6-14 months) decrease in donor cell lineage chimerism. However, a trend toward recovery of chimeric levels occurred by 21-28 months in a second iliac crest marrow aspirate 1 year after the first aspirate in the DBMC-infused recipients who experienced such early rejection episodes. This was in contrast to the controls in whom there were sustained low levels of iliac crest bone marrow chimerism at both the earlier and later intervals (i.e., no chimeric recovery), with 17/183 surviving controls progressing into chronic rejection. This has not yet been seen in the DBMC-infused group (0/54). In in vitro observations on cellular immune reactivity at 1 year postoperatively, decreased peripheral blood lymphocyte proliferative reactions were seen in response to phytohemagglutinin and Staph-A mitogens, as well as to cytomegalovirus and Epstein-Barr viral protein antigens in the DBMC-infused group versus the controls. Chronic immunosuppression did not seem to effect a vigorous in vitro inhibitory (regulatory) activity of bone marrow taken from these transplant recipients 2 years postoperatively in mixed lymphocyte culture and cell-mediated lympholysis reactions, using allogeneic responding cells from "normal" laboratory volunteers. Autologous peripheral blood lymphoproliferative responses to phytohemagglutinin and Staph-A mitogens, as well as to cytomegalovirus and Epstein-Barr virus protein antigens, were also regulated by either organ donor (non-immunosuppressed) bone marrow cells or by transplant recipient (immunosuppressed) bone marrow cells. What appeared to be disparate between the DBMC-infused and control groups (both immunosuppressed) was the trend for the (autologous) bone marrow suppressive effect on antiviral lymphoproliferative responses, to be stronger in the DBMC-infused group, who also had significantly (>one order of magnitude) higher levels of chimerism (P=0.01). CONCLUSIONS: It is concluded that the establishment of a chimeric state in DBMC-infused recipients, albeit of relatively low magnitude (approximately 1% at 2 years in recipient iliac crest bone marrow), has had a definite regulatory effect on immune responses. These results, therefore, add weight to the "causal" horn of the dilemma as to whether donor cell chimerism is a cause or an effect of

Bone Marrow Cells↗
PubMed1998

Functional consequences of costimulation by ICAM-1 on IL-2 gene expression and T cell activation.

LFA-1 is a well-recognized adhesion molecule, but its role in providing costimulatory signals to T cells has remained controversial. We have compared the ability of class II-positive transfectants that do and do not coexpress ICAM-1 (ProAd and ProAd-ICAM) to activate Ag-specific Th1 clones and naive CD4-positive T cells isolated from TCR transgenic mice. Ag presentation by ProAd to Th1 clones can induce calcium-dependent signaling events after engagement of the TCR, as evidenced by the nuclear localization of the transcription factors NF-AT and NF-kappaB. Nevertheless, coexpression of ICAM-1 or B7-1 on ProAd is required to induce detectable levels of IL-2 gene expression in either Th1 clones or naive T cells. In Th1 clones, activation by ProAd-ICAM induces very transient IL-2 mRNA expression that does not result in detectable IL-2 secretion or T cell proliferation. In naive T cells, the duration of IL-2 mRNA expression is longer, allowing for a transient burst of IL-2 protein that is sufficient to drive the cells into the cell cycle. In spite of this initial response, Ag presentation by ProAd-ICAM is a tolerogenic signal to naive T cells, and responding T cells undergo apoptosis 4 to 5 days poststimulation. These data suggest that engagement of LFA-1 can provide sufficient costimulatory signals to induce T cell activation and IL-2 gene expression, but cannot protect against anergy induction or provide for T cell survival.

Animals↗
PubMed1998

Prognostic importance of emotional support for elderly patients hospitalized with heart failure.

BACKGROUND: Several studies have indicated that a variety of social relationships are important predictors of morbidity and mortality in patients with coronary artery disease, but little attention has been focused on the prognostic importance of these factors in the growing population of elderly patients with heart failure. To address this issue, we sought to determine whether emotional support is associated with fatal and nonfatal cardiovascular events in elderly patients hospitalized with heart failure. METHODS AND RESULTS: We reviewed the medical records of 292 subjects aged > or =65 years who were hospitalized with clinical heart failure and were part of the New Haven, Conn, cohort of the Established Population for the Epidemiologic Study of the Elderly, a longitudinal, community-based study of aging that included a comprehensive assessment of psychosocial support. In the unadjusted analysis, lack of emotional support was significantly associated with the 1-year risk of fatal and nonfatal cardiovascular outcomes [odds ratio, 2.4; 95% confidence interval, 1.1 to 4.9]. After adjustment for demographic factors, clinical severity, comorbidity and functional status, social ties, and instrumental support, the absence of emotional support remained associated with a significantly higher risk (odds ratio, 3.2; 95% confidence interval, 1.4 to 7.8). The test for interaction between emotional support and sex was significant (P=.01). In the fully adjusted model, the odds ratio for women was 8.2 (95% confidence interval, 2.5 to 27.2) compared with 1.0 (95% confidence interval, 0.3 to 3.3) for men. CONCLUSIONS: Among elderly patients hospitalized with clinical heart failure, the absence of emotional support, measured before admission, is a strong, independent predictor of the occurrence of fatal and nonfatal cardiovascular events in the year after admission. In this cohort, the association is restricted to women.

Aged↗
PubMed1998

Injecting behaviours and prevalence of hepatitis B, C and D markers in New Zealand injecting drug user populations.

AIM: To determine the seroprevalence of hepatitis C virus (HCV), hepatitis B virus (HBV) & hepatitis D virus (HDV) markers of infection among injecting drug user populations in New Zealand and to examine the relationship between demographic features, risk behaviours and infection. METHODS: A total of 323 current injecting drug users completed a questionnaire that explored their needle and syringe using behaviours. Information was collected on injection pattern, sharing behaviours and methods of cleaning needles and syringes. Two hundred and forty-one respondents gave blood samples which were tested for hepatitis B, C and D markers. RESULTS: Over half the respondents (59%) were male and 41% were female. Most (89%) identified as European. Sixty-four percent were anti-HCV positive. The likelihood of infection increased with age and duration of injecting. Forty-one percent (33/81) of those aged 25 or under, sixty-four percent (45/70) of those aged 26-30 and eighty-seven percent (78/90) over 30 were anti-HCV positive. Those who tested anti-HCV positive had been injecting for an average of 12.0 years compared to 6.0 years for those were anti-HCV negative. The results for hepatitis B are to be reported fully at a later date. Sharing behaviour was also a factor although this was less important as an independent factor. Comparisons with earlier surveys suggested that there has not been a significant decline in the rate of sharing needles and syringes since the initial period following introduction of the needle exchange programme. CONCLUSION: The prevalence of hepatitis C infection is common among injecting drug users of all ages. Without a significant reduction in sharing behaviour, particularly among younger injecting drug users, it is unlikely that the prevalence of hepatitis C among injecting drug users will decline in the future. Evidence suggests that the carriage of hepatitis C is higher than that of hepatitis B which would help explain the differing rates of prevalence. However, the risk of future transmission of other parenterally transmitted diseases remains high without a further significant decline in sharing behaviour.

Adolescent↗
PubMed1998

Primary immunosuppression with tacrolimus and mycophenolate mofetil for renal allograft recipients.

BACKGROUND: Studies using tacrolimus and corticosteroids or the combination of cyclosporine, mycophenolate mofetil, and corticosteroids have been shown to reduce the incidence of biopsy-proven acute rejection episodes in cadaveric kidney recipients compared with cyclosporine-based immunosuppression. The current study is a retrospective analysis of our experience with tacrolimus combined with mycophenolate mofetil and steroids as primary immunosuppression for kidney transplant recipients. METHODS: In a retrospective analysis, 72 patients who received primary therapy with tacrolimus, mycophenolate mofetil, and corticosteroids (triple therapy) were compared with a control group of 98 kidney recipients who received tacrolimus and corticosteroids (double therapy). RESULTS: There was a significant reduction in the incidence of biopsy-confirmed acute rejection in the triple therapy group (8.2%) compared with the double therapy group (21%; P=0.003). One-year patient and graft survival did not differ between groups. The incidence of posttransplant diabetes mellitus was 18% and 21% in the triple and double therapy groups, respectively. Leukopenia and gastrointestinal side effects were the most common cause for discontinuation of mycophenolate mofetil. CONCLUSIONS: The combination of tacrolimus with mycophenolate mofetil and corticosteroids is more effective at preventing early acute rejection than tacrolimus and corticosteroids alone. The use of mycophenolate mofetil was associated with a higher incidence of leukopenia and diarrhea, often leading to discontinuation of the drug.

Actuarial Analysis↗
PubMed1998

Photodynamic therapy of subfoveal choroidal neovascularization: clinical and angiographic examples.

BACKGROUND: Conventional photocoagulation of subfoveal choroidal neovascularization (CNV) is often accompanied by visual loss due to thermal damage to adjacent retinal structures. Photodynamic therapy (PDT) allows vascular occlusion by selective photochemical destruction of vascular endothelial cells only. In a pilot study we evaluated the use of PDT in CNV. METHODS: In a clinical phase I/II trial, patients with subfoveal CNV were treated with PDT. Benzoporphyrin derivative monoacid ring A (BPD) was used as sensitizer at a drug dose of 6 mg/m2 or 12 mg/m2. Irradiation was performed via a diode laser emitting at 690 nm coupled into a slit lamp. Safe and maximum tolerated light doses were defined by dose escalation from 25 to 150 J/cm2. Photodynamic effects were documented ophthalmoscopically and angiographically. RESULTS: Sixty-one patients received a single course of BPD-PDT. Preliminary results suggest no damage to retinal structures within the treated area clinically. Retinal perfusion was not altered, while CNV demonstrated immediate absence of fluorescein leakage in the majority of lesions subsequent to PDT. At optimized parameters (6 mg/m2 and 50 J/cm2) complete cessation of leakage from classic CNV occurred in 100% of cases at 1 week and in 50% at week 4. In 70-80% of classic CNV, leakage reappeared at week 12, but markedly less than before treatment. CONCLUSION: PDT allows temporary absence of leakage from CNV with preservation of visual acuity. The long-term prognosis of CNV secondary to age-related macular degeneration treated with repeated courses of PDT is being evaluated in a phase III trial.

Adult↗
PubMed1998

A randomized comparison of the methods of sperm preparation for intrauterine insemination.

OBJECTIVE: To compare the effectiveness of three methods of sperm preparation for IUI during superovulation of infertile women. DESIGN: Randomized assignment of one of three sperm preparation methods. SETTING: University infertility practice. PATIENT(S): Infertile couples undergoing superovulation and IUI. INTERVENTION(S): The method of preparation of sperm for IUI during superovulation was assigned randomly to double centrifugation, multiple-tube swim-up, or Percoll density gradient. MAIN OUTCOME MEASURE(S): Total number and percent recovery of motile sperm, percent of recovered sperm with normal morphology, and cycle fecundity. RESULT(S): No method of sperm preparation provided better cycle fecundity than the others despite differences in sperm recovery. CONCLUSION(S): Double centrifugation, multiple-tube swim-up, and Percoll density gradient sperm preparation for IUI yield similar cycle fecundity rates.

Centrifugation↗