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Biomedical subjects

S A Gruber

Publications and source records attributed to S A Gruber.

At least 19 recordsLinked to original sources
PubMed2006

Short-term experience with early steroid withdrawal in African-American renal transplant recipients.

There are limited data on the results of early steroid withdrawal (ESW) in African-American (AA) renal allograft recipients. We examined short-term transplant outcomes in a retrospective, non-concurrent cohort study of 40 AAs who did not (ESW group), and 33 who did [steroid maintenance (SM) group] receive maintenance steroids after day 4 post-transplant. Patients received thymoglobulin (ATG) induction, mycophenolate mofetil, and tacrolimus or sirolimus. Data were analyzed using survival analysis methods and regression models. Patients in the ESW group were older, had lower current panel reactive antibody and fewer re-transplants, and received fewer doses of ATG. One-year graft survival and acute rejection (AR) rates were 100% and 13% in the ESW group and 97% and 15% in the SM group. After controlling for confounders, at 1 year, ESW was not associated with higher risk of graft loss, AR, or worse graft function, but was associated with less weight gain. The SM group had higher cholesterol levels at 3 months and higher risk of post-transplant diabetes mellitus. We did not observe any cases of subclinical rejection. This study suggests that ESW under modern immunosuppression is safe over the short term in at least a subset of AA recipients with risk profiles similar to those studied herein, and could be associated with improved outcomes.

Adult↗
PubMed2002

Chronic citicoline increases phosphodiesters in the brains of healthy older subjects: an in vivo phosphorus magnetic resonance spectroscopy study.

RATIONALE: Phosphatidylcholine (PtdCho) in brain cell membranes decreases with age. Evidence from both animal and in vitro studies indicates that CDP-choline (citicoline) administration may increase phosphatidylcholine (PtdCho) synthesis and might reverse PtdCho loss. OBJECTIVES: We investigated whether oral citicoline can increase PtdCho synthesis in the brains of older subjects by measuring levels of phosphorus-containing metabolites using proton-decoupled phosphorus magnetic resonance spectroscopy ((31)P-MRS) before and after citicoline treatment. METHODS: All subjects took 500 mg citicoline once orally each day for 6 weeks, then took either citicoline or placebo once orally per day for a second 6-week period. Subjects underwent a (31)P-MRS scan at baseline and following 6 and 12 weeks of treatment. RESULTS: Treatment with citicoline for 6 weeks was associated with a 7.3% increase from baseline levels in brain phosphodiesters ( P=0.008), including an 11.6% increase in glycerophosphoethanolamine ( P=0.002) and a 5.1% increase in glycerophosphocholine ( P=0.137). Subjects who continued to take citicoline for the second 6-week period did not show significant additional increases in the levels of these metabolites. No changes were seen in other phosphorus-containing metabolites. There was a correlation between improvement on the California Verbal Learning Test and increase in phosphodiesters. CONCLUSIONS: The increases in phosphodiesters seen in this study indicate that phospholipid synthesis and turnover were stimulated by 6 weeks of oral citicoline. These results in humans support previous in vitro and animal studies and suggest that the administration of oral citicoline may be of use in reversing age-related changes in the brain.

Administration, Oral↗
PubMed2000

Successful hand transplantation. One-year follow-up. Louisville Hand Transplant Team.

BACKGROUND: On the basis of positive results in studies of the transplantation of pig extremities and the information exchanged at an international symposium on composite tissue transplantation, we developed a protocol for human hand transplantation. METHODS: After a comprehensive pretransplantation evaluation and informed-consent process, the left hand of a 58-year-old cadaveric donor, matched for size, sex, and skin tone, was transplanted to a 37-year-old man who had lost his dominant left hand 13 years earlier. Immunosuppression consisted of basiliximab for induction therapy and tacrolimus, mycophenolate mofetil, and prednisone for maintenance therapy. RESULTS: The cold-ischemia time of the donor hand was 310 minutes. There were no intraoperative or early postoperative complications. Moderate acute cellular rejection of the skin of the graft developed 6, 20, and 27 weeks after transplantation. All three episodes resolved completely after treatment with intravenous methylprednisolone and topical tacrolimus and clobetasol. Temperature, pain, and pressure sensation had developed in the hand and fingers by one year. At one year, the patient had regained the ability to perform many functional activities with his left hand that he had not been able to perform with his prosthesis, such as throwing a baseball, turning the pages of a newspaper, writing, and tying his shoelaces. CONCLUSIONS: Early success has been achieved in hand transplantation with the use of currently available immunosuppressive drugs.

Adult↗
PubMed2000

Initial results of solitary pancreas transplants performed without regard to donor/recipient HLA mismatching.

BACKGROUND: We hypothesized that solitary pancreas transplants could be performed successfully even in the presence of poor HLA matching if an aggressive approach were taken with regard to immunosuppressive protocol and the performance of allograft biopsy. METHODS: Seven pancreas-after-kidney transplants and seven pancreas transplants alone were performed without consideration given to the degree of HLA mismatching (MM) using tacrolimus (FK506)/mycophenolate mofetil (MMF)/prednisone maintenance therapy. Mean (+/-SD) total HLA MM was 4.8+/-1.2. All patients were followed for at least 6 months. The first four cases were induced with ATGAM for 7 to 10 days. In the remaining 10 cases, an ultrasound-guided percutaneous needle biopsy was attempted on a protocol basis 10 days after completing induction with OKT3 for 7 (n=2) or 14 (n=8) days. RESULTS: Overall patient survival, graft survival, and incidence of acute rejection requiring treatment were 86, 79, and 50%, respectively. Two patients receiving ATGAM developed grade III-IV rejection at 3 weeks. Both patients receiving OKT3 for 7 days developed early grade III rejection. However, only three of eight patients receiving OKT3 for 14 days developed rejection requiring treatment. Protocol biopsy was successfully performed in six of seven patients and uncovered three cases of otherwise undetectable grade III-IV rejection. CONCLUSIONS: Although based on a small number of cases, our results suggest that solitary pancreas transplants with a poor HLA match can be performed with an acceptable rejection incidence and graft survival rate using an OKT3/FK506/MMF/prednisone regimen with protocol biopsy.

Adolescent↗
PubMed2000

Choline, myo-inositol and mood in bipolar disorder: a proton magnetic resonance spectroscopic imaging study of the anterior cingulate cortex.

OBJECTIVES: Alterations in choline and myo-inositol metabolism have been noted in bipolar disorder, and the therapeutic efficacy of lithium in mania may be related to these effects. We wished to determine the relationship between anterior cingulate cortex choline and myo-inositol levels, assessed using proton magnetic resonance spectroscopic imaging (MRSI), and mood state in subjects with bipolar disorder. METHODS: Serial assessments of anterior cingulate cortex choline and myo-inositol metabolism were performed in nine subjects with bipolar disorder, taking either lithium or valproate, and 14 controls. Each bipolar subject was examined between one and four times (3.1 +/- 1.3). On the occasion of each examination, standardized ratings of both depression and mania were recorded. RESULTS: In the left cingulate cortex, the bipolar subjects' depression ratings correlated positively with MRSI measures of Cho/Cr-PCr. In the right cingulate cortex, the Cho/Cr-PCr ratio was significantly higher in subjects with bipolar disorder compared with control subjects. In addition, bipolar subjects not taking antidepressants had a significantly higher right cingulate cortex Cho/Cr-PCr ratio compared with patients taking antidepressants or controls. No clinical or drug-related changes were observed for the Ino/Cr-PCr ratio. CONCLUSIONS: The results of this study suggest that bipolar disorder is associated with alterations in the metabolism of cytosolic, choline-containing compounds in the anterior cingulate cortex. As this resonance arises primarily from phosphocholine and glycerophosphocholine, both of which are metabolites of phosphatidylcholine, these results are consistent with impaired intraneuronal signaling mechanisms.

Adult↗
PubMed2000

fMRI during affect discrimination in bipolar affective disorder.

OBJECTIVE: It has been hypothesized that disturbances in affect may represent distinct etiologic factors for bipolar affective disorder. The neural mechanisms mediating affective processes and their relationship to brain development and the pathophysiology of bipolar affective disorder remain to be clarified. Recent advances in neuroimaging techniques have made possible the non-invasive examination of specific brain regions during cortical challenge paradigms. This study reports findings based on fMRI data acquired during fearful and happy affect recognition paradigms in patients with bipolar affective disorder and in healthy adult subjects. METHODS: Prior to the scan, subjects were instructed to view the stimuli and to identify the type of facial expression presented. Echo planar scanning was performed on a 1.5 Tesla scanner which had been retrofitted with a whole body echo planar coil, using a head coil. RESULTS: The data indicate that in adult subjects with bipolar affective disorder, there is a reduction in dorsolateral prefrontal cortex activation and an increase in amygdalar activation in response to fearful facial affect. In a healthy comparison group, signal intensity changes were not found in these regions. In addition, although the patients with bipolar affective disorder completed the task demands, they demonstrated an impaired ability to correctly identify fearful facial affect but not the happy facial affect displayed. CONCLUSION: These findings are consistent with the hypothesis that in some patients with bipolar affective disorder, there may be a reduction of frontal cortical function which may be associated with affective as well as attentional processing deficits.

Adult↗
PubMed1999

Flow cytometry-detected IgG is not a contraindication to renal transplantation: IgM may be beneficial to outcome.

BACKGROUND: At our transplant center, primary recipients of either a haplo-identical (haplo-ID) living related (LRD) or a cadaveric (CAD) donor renal allograft are transplanted after a negative donor-specific IgG anti-human globulin (AHG) cross-match (XM). Testing included the historically highest panel-reactive antibody and the immediate (0-7 days) pretransplant sera. A positive donor specific IgM-AHG XM has not been a contraindication to transplant. Reports suggest that donor-specific flow cytometry cross-matches (FCXM) may be more clinically informative than the AHG-XM. METHODS: We therefore evaluated the impact of a positive FCXM (IgG or IgM) on the rejection frequency (0-12 months after transplant) and 1-year graft survival for cyclosporine-prednisone-treated primary (haplo-ID and CAD) renal allograft recipients. All transplants were performed after a negative donor-specific IgG AHG-XM regardless of the IgM-AHG XM status. RESULTS: Rejection frequencies (26% vs. 31%, P = NS) and 1-year graft survivals (92% vs. 89%, P = NS) were comparable for haplo-ID LRD FCXM-negative and IgG-FCXM-positive recipients. However, IgM-FCXM-positive LRD recipients experienced significantly fewer rejections (13% vs. 26% P<0.02) and an improved 1-year graft survival (100% vs. 92%, P<0.02) than FCXM-negative LRD recipients. Similar results were observed for primary CAD recipients. Rejection frequencies (40% vs. 44%, P = NS) and 1-year graft survivals (83% vs. 81%, P = NS) were comparable for primary CAD FCXM-negative and IgG-FCXM-positive recipients. Again, IgM-FCXM-positive primary CAD recipients experienced significantly fewer rejections (22% vs. 40%, P<0.02) and improved 1-year graft survivals (89% vs. 83%, P<0.05) than FCXM-negative recipients. CONCLUSION: These data suggest that, after a negative donor-specific IgG-AHG XM, an IgG-positive FCXM is not a contraindication to transplantation. The presence of IgM may be beneficial in reducing the occurrence of rejection episodes and improving graft survivals.

Contraindications↗
PubMed1999

Measurement of human brain dexfenfluramine concentration by 19F magnetic resonance spectroscopy.

OBJECTIVE: The goals of this study were to quantitate the brain concentration of the anorectic drug dexfenfluramine (DF) in human subjects receiving clinical doses of DF and to determine whether human brain DF concentrations approach those reported to cause irreversible neurochemical changes in animals. Each subject's brain DF concentration was measured several times over an extended period of DF treatment to determine whether drug accumulation in the brain would plateau or continue to increase throughout the treatment period. DESIGN: Fluorine magnetic resonance spectroscopy (19F-MRS) was used to directly detect and quantitate brain levels of the fluorinated drug dexfenfluramine and its active metabolite dex-norfenfluramine (dNF). Patients received 15 mg dexfenfluramine BID for 90 days. 19F-MRS measurements were performed at baseline and at three times during the treatment period. PARTICIPANTS: Twelve women (age 38-54 years) who were obese, with body mass indices of 28. 4-37.4, but otherwise healthy. RESULTS: The combined concentration of DF and nDF reached steady-state in the human brain after approximately 10 days of treatment. The steady-state brain concentration averaged approximately 4 microM and did not tend to increase significantly during the 90 day treatment period. CONCLUSIONS: These results demonstrate that fluorinated drugs can be quantified using 19F MRS at concentrations below 10 microM in the human brain. The time-course data suggest that brain DF concentrations parallel DF plasma pharmacokinetics in humans. Measured brain dexfenfluramine/nor-dexfenfluramine concentrations were well below levels previously found to cause irreversible brain alterations in animals.

Adult↗
PubMed1999

Scoring of skin rejection in a swine composite tissue allograft model.

BACKGROUND: For the first time, we define and correlate visual and histologic grading systems of composite tissue allograft (CTA) skin rejection in a large-animal model and determine the utility of these grading systems for early diagnosis and monitoring of rejection. MATERIALS AND METHODS: Sixteen pairs of outbred swine underwent transplant of a forelimb osteomyocutaneous free flap. Group I (n = 6) did not receive immunosuppressive therapy. Group II (n = 10) received oral cyclosporin A, mycophenolate mofetil, and prednisone. The flap was visually inspected and protocol skin biopsies were taken at frequent intervals over a 90-day period. Visual Grades 0 (no rejection) to 4 (severe rejection) were assigned based on skin color, bleeding from biopsy site, and blister formation. Histologic Grades 0 to 4 were assigned based on the degree of vasculitis, folliculitis, dermal inflammation, and epidermal degeneration present. RESULTS: All Group I animals progressively rejected their graft by Day 7. Group II grafts survived from 19 and 90 days; 93% of 115 biopsy specimens were read to be within +/-1 histologic score of their assigned flap visual grade. Visual assessment carried an 8% false positive and 39% false negative rate with regard to biopsy-proven rejection. However, 81% of missed rejection specimens were histologic Grade 1. Biopsy, when visually indicated, would detect all rejection episodes when histologically Grade 1 or 2 and still potentially reversible. CONCLUSIONS: Visual scoring of CTA skin serves as a useful tool for initially detecting rejection, but repeated histologic evaluation is necessary for monitoring the subsequent course of the graft.

Animals↗
PubMed1999

Functional magnetic resonance imaging of facial affect recognition in children and adolescents.

OBJECTIVE: To examine further the role of the amygdala in the recognition of facial expression in adolescents. METHOD: Twelve healthy adolescents were studied using functional magnetic resonance imaging technology during a task of facial affect recognition and a visual control task. RESULTS: All subjects demonstrated a significant increase in signal intensity in the amygdala for the facial expression recognition task. CONCLUSIONS: The data are consistent with previous work in healthy adult subjects implicating the amygdala as essential for the recognition of fearful facial expression.

Adolescent↗
PubMed1999

Pharmacokinetic advantage of intra-arterial cyclosporin A delivery to vascularly isolated rabbit forelimb. I. Model development.

Effective antirejection therapy with minimal systemic morbidity is required if limb transplantation is to become a clinical reality. We investigated whether i.a. infusion of cyclosporin A (CSA) into the vascularly isolated rabbit forelimb will distribute drug homogeneously to the tissues and produce higher local drug levels than same-dose i.v. treatment, thereby improving the therapeutic index. CSA 4.0 mg/kg/day was infused continuously via osmotic minipump into either the right brachial artery (i.a. group) or jugular vein (i.v. group) of New Zealand rabbits. Ligation of all muscles at the right mid-arm level was performed in the i.a. group to eliminate collateral circulation and simulate allografting, while leaving bone and neurovasculature intact. On day 6, CSA concentrations were measured in skin, muscle, bone, and bone marrow samples taken from different compartments of the right and left forearms in the i.a. group and right forearm only in the i.v. group. There were no significant differences between compartmental CSA levels in all tissues examined on the locally treated, right side during i.a. infusion, indicating that drug streaming from the catheter tip is not occurring in our model. During i.a. infusion, mean CSA concentrations were 4- to 7-fold higher in the right limb than in the left limb in all four tissues examined. Tissue CSA levels in the left limb were equivalent to those achieved during i.v. infusion, but CSA concentrations in blood, kidney, and liver were higher during i.a. infusion. These favorable, preliminary, single-dose pharmacokinetic results warrant further investigation in our novel rabbit model.

Animals↗
PubMed1999

Pharmacokinetic advantage of intra-arterial cyclosporin A delivery to vascularly isolated rabbit forelimb. II. Dose dependence.

A vascularly isolated rabbit forelimb model simulating conditions of composite tissue allografting was used to determine the regional pharmacokinetic advantage achievable in extremity tissue components during i.a. cyclosporin A (CSA) administration. CSA was infused continuously via osmotic minipump into the right brachial artery of New Zealand rabbits at multiple doses ranging from 1.0 to 8.0 mg/kg/day. On day 6, CSA concentrations were measured in aortic whole blood, as well as in skin, muscle, bone, and bone marrow samples from both right and left forelimbs. The variation of right-sided mean CSA concentrations with dose was tissue dependent and saturable in the case of skin and bone, whereas left-sided tissue concentrations correlated significantly with systemic blood levels. At 1.0 mg/kg/day, there were no significant differences between right and left mean CSA concentrations for all four tissues examined. However, with a doubling of the i.a. dose, huge increases in local tissue CSA concentrations were produced with only very modest increases in systemic whole-blood and tissue drug levels, resulting in a 4-fold regional advantage (right/left ratio of CSA concentrations) in bone and bone marrow, 7-fold in muscle, and 14-fold in skin. With further dose increases to 8.0 mg/kg/day, the regional advantage decreased to 4-fold in skin, increased to 9-fold in bone marrow, remained relatively constant in bone, and initially decreased and then increased to 9-fold in muscle. These favorable pharmacokinetic results suggest that reduced, local doses of CSA might be useful in preventing extremity composite tissue allograft rejection with decreased systemic drug exposure.

Animals↗
PubMed1999

Pharmacokinetics of intra-arterial delivery of tacrolimus to vascularly isolated rabbit forelimb.

A vascularly isolated rabbit forelimb model simulating conditions of composite tissue allografting was used to determine the regional pharmacokinetic advantage achievable in extremity tissue components during i.a. tacrolimus (FK506) administration. FK506 was infused continuously via osmotic minipump into the right brachial artery of New Zealand rabbits at 0.05, 0.1, and 0.2 mg/kg/day. On day 6, FK506 concentrations were measured in aortic whole blood, heart, lung, liver, kidney, spleen, and fat, as well as in skin, muscle, bone, and bone marrow samples from both right and left forelimbs. The relative tissue concentrations of FK506 in descending order were [spleen approximately lung approximately kidney] > [heart approximately skin approximately muscle] > [fat approximately bone marrow] > [liver approximately bone approximately blood]. In marked contrast to previous results with i.a. cyclosporin A infusion, only a minimal regional advantage of local FK506 delivery (mean right/left concentration ratios 1.0-1.4) was obtained in all forearm tissues over the dose range studied. For each limb tissue, left-sided FK506 concentrations significantly correlated with systemic blood levels, and the left-sided tissue-to-whole-blood concentration ratio did not vary significantly with dose. We conclude that FK506 is pharmacokinetically inferior to cyclosporin A for continuous i.a. administration to the vascularly isolated rabbit forelimb, and hypothesize that this difference is the result of differences in the distribution of each drug within whole blood. Our findings suggest that, despite its demonstrated efficacy in experimental and clinical transplantation, FK506 would not be an appropriate immunosuppressant to deliver via the i.a. route for prevention of limb allograft rejection.

Animals↗
PubMed1999

Long-term survival of an extremity composite tissue allograft with FK506-mycophenolate mofetil therapy.

BACKGROUND: High-dose tacrolimus (FK506) monotherapy has significantly prolonged rat hindlimb allograft survival. With an eye toward direct clinical application, we used a large-animal extremity composite tissue allograft model to assess the antirejection efficacy and systemic toxicity of combination FK506-mycophenolate mofetil (MMF) treatment. METHODS: Radial forelimb osteomyocutaneous flap transplants were performed between size-matched outbred pigs assigned to one of two groups: 5 control pigs received no immunosuppression and 9 animals received a once-daily oral FK506-MMF-prednisone regimen. Rejection was assessed by visual inspection of flap skin and was correlated with serial histopathologic examination of skin biopsy specimens. RESULTS: In all control pigs the flap was completely rejected on day 7. Of the 9 pigs receiving treatment, 3 died from pneumonia on days 29, 30, and 83 without signs of rejection and another died from gastric rupture on day 42 with persistent mild rejection. The remaining 5 animals were free of rejection at the end of the 90-day follow-up period (P < 0.005 vs controls). Overall, 5 pigs had pneumonia, 4 septic arthritis, 3 toe abscesses, and 5 diarrhea and decreased weight gain. CONCLUSIONS: Combination oral FK506-MMF treatment provided a superior antirejection effect but more produced more toxicity than that previously demonstrated with cyclosporin A-MMF therapy in our model. Our results suggest that reduction of FK506 or MMF doses might decrease both infectious and drug-specific side effects while still providing adequate prophylaxis against rejection.

Animals↗