FK 506-based immunosuppression in clinical pancreas transplantation.
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Antilymphocyte Serum↗
Biomedical subjects
M Rubin
Publications and source records attributed to M Rubin.
9-Cis retinoic acid inhibits growth of breast cancer cells and down-regulates estrogen receptor RNA and protein.
All-trans retinoic acid (tRA) inhibits growth of estrogen receptor-positive (ER+) breast cancer cells in vitro, and a variety of retinoids inhibit development of breast cancer in animal models. 9-cis retinoic acid (9-cis RA) is a naturally occurring high affinity ligand for the retinoid X receptors, as well as the retinoic acid receptors (RARs). Whether 9-cis RA has a different spectrum of biological activity from tRA, which only binds RARs with high affinity, is largely unknown. We studied the effects of 9-cis RA on growth and gene expression in ER+ and ER- human breast cancer cells. 9-cis RA inhibited the growth in monolayer culture of several ER+, but not ER-, cell lines in a dose-dependent manner. Growth inhibition and morphological changes by 9-cis RA were similar to those of tRA, suggesting that the ability to bind both RAR and retinoid X receptors did not significantly augment growth inhibition or confer sensitivity to tRA-resistant lines. MCF-7 cells exposed to 9-cis RA showed a dose-dependent accumulation in G1. Northern analyses showed that RAR-alpha and RAR-beta were not significantly regulated, while RAR-gamma was up-regulated and retinoid X receptor alpha was down-regulated by 9-cis RA. Since interactions between tRA and ER-dependent transcription have recently been reported, we investigated whether these retinoids regulate expression of ER itself or estrogen-responsive genes. Both 9-cis RA and tRA induce down-regulation of ER mRNA and protein in MCF-7 cells. 9-cis RA down-regulates expression of the estrogen-responsive genes PR and pS2 in MCF-7 cells as reported previously for tRA. In several ER-positive subclones, we found that the degree of ER expression and regulation, but not always estrogen-sensitivity, correlates with the growth-inhibitory effects of 9-cis RA. Further, in an ER-, retinoid-unresponsive breast cancer cell line, induced ER expression confers responsiveness to retinoid growth inhibition. These data, combined with reports of additive growth inhibition of tRA and tamoxifen in vitro, suggest that 9-cis RA might augment the ability of tamoxifen to inhibit growth of ER+ breast cancer cells in vivo.
Breast Neoplasms↗
Insight into the mechanism of TCR-V beta 8+/CD8+ T cell-mediated MOPC-315 tumor eradication.
We have previously shown that depletion of TCR-V beta 8+ T cells by treatment with mAb reduces the curative effectiveness of low dose melphalan (L-phenylalanine mustard; L-PAM) for mice bearing a large MOPC-315 tumor and extensive metastases. Here we show that V beta 8+/CD8+ T cell lines derived from mice that are in the process of immune-mediated eradication of a large MOPC-315 tumor as a consequence of low dose L-PAM therapy (L-PAM TuB mice) are capable of mediating tumor eradication in vivo upon adoptive transfer. Analysis of the possible mechanisms through which these cell lines bring about tumor eradication revealed that the V beta 8+/CD8+ cells can exert in vitro a potent lytic activity and secrete large amounts of IFN-gamma. Both of these activities can be triggered by the MOPC-315 but not the MOPC-104E plasmacytoma and are restricted by the MHC class I H-2Kd molecule. In vivo neutralization of IFN-gamma by treatment with mAb was found to cause a noticeable delay in tumor rejection in mice subjected to adoptive chemoimmunotherapy with low dose L-PAM and V beta 8+/CD8+ cells; however, all tumors did regress after initial growth. Thus, the V beta 8+/CD8+ cells use an IFN-gamma-dependent mechanism for the realization of their in vivo tumor-eradicating immunity. However, an IFN-gamma-independent mechanism, most likely involving direct V beta 8+/CD8+ CTL activity, is apparently also used.
Animals↗
Cooperation between staphylococcal enterotoxin B and low dose melphalan in the cure of mice bearing a large MOPC-315 tumor and extensive metastases.
We have recently demonstrated the importance of V beta 8+/CD8+ cells for the curative effectiveness of a suboptimal low dose (0.75 mg/kg) of melphalan (L-phenylalanine mustard; L-PAM) for mice bearing a large s.c. MOPC-315 tumor and extensive metastases. Here we show that staphylococcal enterotoxin B (SEB), which is known to selectively stimulate T cells expressing members of the TCR-V beta 8 gene family, substantially improved the curative effectiveness of the suboptimal dose of L-PAM for mice bearing a large MOPC-315 tumor. Moreover, treatment of mice with mAb F23.1 (anti-V beta 8) abrogated the in vivo therapeutic effect of SEB for low dose L-PAM-treated MOPC-315 tumor bearers (L-PAM TuB mice). Analysis of the effect of SEB on the tumor-infiltrating lymphocytes (TILs) demonstrated that the SEB-mediated therapeutic effect was associated with a significant increase in: 1) the percentage of V beta 8+ cells among the CD8+ T cells that accumulated in the s.c. tumor nodules, 2) the total number of V beta 8+/CD8+ cells present per tumor on day 4 after low dose L-PAM therapy, and 3) the ability of the TILs to lyse MOPC-315 tumor cells in vitro in a short term assay. Furthermore, treatment of mice with mAb F23.1 abolished the ability of SEB to render the TIL population of L-PAM TuB mice more cytotoxic in vitro for MOPC-315 tumor cells. Thus, the SEB-mediated improvement in the therapeutic outcome of low dose L-PAM therapy for mice bearing a large MOPC-315 tumor may be due in part to SEB-mediated increase in the contribution of the V beta 8+ T cells to tumor eradication through enhancement in the magnitude of the anti-MOPC-315 lytic activity exhibited by the TIL population.
Animals↗
Direct visualization of lipid aggregates in native human bile by light- and cryo-transmission electron-microscopy.
The evolution of microstructures present in human gallbladder and hepatic bile was observed simultaneously by video-enhanced light microscopy (VELM) and transmission electron microscopy of vitrified specimens (cryo-TEM), as a function of time after withdrawal from patients. Fresh centrifuged gallbladder bile samples contained small (6 nm) spherical micelles in coexistence with vesicles (40 nm). Out of the seven bile samples investigated four contained, in addition, two types of elongated aggregates that have not been previously described. Uncentrifuged gallbladder bile also contained a mixture of ribbon- and plate-like crystals seen by VELM, but not by cryo-TEM. In aged (3-6-week-old) gallbladder bile samples VELM also revealed spiral and helical crystal structures. No such crystals were present in hepatic bile samples, although microcrystals, not observable by VELM were seen by cryo-TEM in addition to micelles and vesicles. The similarity of these observations to those observed in bile models lends strong support for the validity of the model systems. Furthermore, the presence of microcrystals in hepatic bile samples, apparently devoid of crystals by light microscopy, indicates that under certain conditions the common criterion of 'nucleation time' (NT), based on light microscopy, does not represent the real time of nucleation. In the human bile samples investigated in this study the dissociation between NT and the time of observation of microcrystals was seen in hepatic but not in gallbladder bile samples. Hence, crystal growth may be rate limiting only in dilute biles.
Bile↗
Effect of three intravenously administered fat emulsions containing different concentrations of fatty acids on the plasma fatty acid composition of premature infants.
The effects of an intravenously administered lipid emulsion supplemented with gamma-linolenic acid on the fatty acid profile of premature infants were compared with those of two conventional lipid emulsions. Fifty-nine premature neonates receiving total parenteral nutrition were randomly assigned to receive either fat emulsion containing gamma-linolenic acid and long-chain triglycerides (LCT), an LCT emulsion, or a 50% (wt/wt) mixture of medium-chain triglycerides and LCT emulsion. Forty-nine infants completed the study. During the 6-day study there was a significant tenfold increase in the plasma levels of gamma-linoleic acid in the supplemented group versus the other two groups. A significant threefold to fivefold increase in the omega 6 long-chain polyunsaturated fatty acids was observed in all groups. These changes seemed to be attributable mostly to linoleic acid from the lipid emulsion, despite the 50% lower dose in the medium- and long-chain triglycerides group. The increase in the omega 3 long-chain polyunsaturated fatty acids also was mainly caused by a similar increase in the level of alpha-linolenic acid. No differences were recorded in the linoleic/alpha-linolenic acid ratio among the groups. Plasma levels of some of the semiessential fatty acids were significantly higher in the medium- and long-chain triglycerides group than in the LCT group. This may be related to slower elimination of LCT, to the difference between emulsions, or to less substrate inhibition on delta-6-desaturase, which seems to be less of a rate-limiting enzyme than previously considered. Further intravenous feeding trials are needed to identify the optimal balance of fatty acids for nutrition of these premature infants.
Double-Blind Method↗
Strength training increases resting metabolic rate and norepinephrine levels in healthy 50- to 65-yr-old men.
Resting metabolic rate (RMR) decreases with age, largely because of an age-related decline in fat-free mass (FFM). We hypothesized that a strength-training program capable of eliciting increases in FFM would also increase RMR in older individuals. To test this hypothesis, RMR, body composition, and plasma concentrations of certain hormones known to affect RMR were measured before and after a 16-wk heavy-resistance strength-training program in 13 healthy men 50-65 yr of age. Average strength levels, assessed by the three-repetition maximum test, increased 40% with training (P < 0.001). Body weight did not change, but body fat decreased (25.6 +/- 1.5 vs. 23.7 +/- 1.7%; P < 0.001) and FFM increased (60.6 +/- 2.2 vs. 62.2 +/- 2.1 kg; P < 0.01). RMR, measured by indirect calorimetry, increased 7.7% with strength training (6,449 +/- 217 vs. 6,998 +/- 226 kJ/24 h; P < 0.01). This increase remained significant even when RMR was expressed per kilogram of FFM. Strength training increased arterialized plasma norepinephrine levels 36% (1.1 +/- 0.1 vs. 1.5 +/- 0.1 nmol/l; P < 0.01) but did not change fasting glucose, insulin, or thyroid hormone levels. These results indicate that a heavy-resistance strength-training program increases RMR in healthy older men, perhaps by increasing FFM and sympathetic nervous system activity.
Aged↗
Strength training increases insulin action in healthy 50- to 65-yr-old men.
The insulin resistance associated with aging may be due, in part, to reduced levels of physical activity in the elderly. We hypothesized that strength training increases insulin action in older individuals. To test this hypothesis, 11 healthy men 50-63 yr old [mean 58 +/- 1 (SE) yr] underwent a two-step hyperinsulinemic-euglycemic glucose clamp with concurrent indirect calorimetry and an oral glucose tolerance test (OGTT) before and after 16 wk of strength training. The training program increased overall strength by 47% (P < 0.001). Fat-free mass (FFM; measured by hydrodensitometry) increased (62.4 +/- 2.1 vs. 63.6 +/- 2.1 kg; P < 0.05) and body fat decreased (27.2 +/- 1.8 vs. 25.6 +/- 1.9%; P < 0.001) with training. Fasting plasma glucose levels and glucose levels during the OGTT were not significantly lower after training. In contrast, fasting plasma insulin levels decreased (85 +/- 25 vs. 55 +/- 10 pmol/l; P < 0.05) and insulin levels decreased (P < 0.05, analysis of variance) during the OGTT. Glucose infusion rates during the hyperinsulinemic-euglycemic glucose clamp increased 24% (13.5 +/- 1.7 vs. 16.7 +/- 2.2 mumol.kg FFM-1.min-1; P < 0.05) during the low (20 mU.m-2.min-1) insulin infusion and increased 22% (55.7 +/- 3.3 vs. 67.7 +/- 3.9 mumol.kg FFM-1.min-1; P < 0.05) during the high (100 mU.m-2.min-1) insulin infusion. These increases were accompanied by a 40% increase (n = 7; P < 0.08) in nonoxidative glucose metabolism during the high insulin infusion. These results demonstrate that strength training increases insulin action and lowers plasma insulin levels in middle-aged and older men.
Aged↗
Proximal median neuropathy and cervical radiculopathy: double crush revisited.
"Double crush" refers to the hypothesis that a single lesion along the course of a nerve predisposes that nerve to a second lesion further along its course. The reason for this is uncertain and indeed the existence of the double crush syndrome is itself debated. We present two cases of proximal median neuropathy (PMN) associated with cervical radiculopathy which we diagnosed in our EMG laboratory over a short period of time. Seeing these cases in relative rapid succession and considering the extreme rarity of PMN, its association in both cases with cervical root disease supports the notion that the cervical radiculopathy may have predisposed the nerve to a second lesion along its course, resulting in the so called double crush syndrome, and that this syndrome may therefore be a true entity.
Aged↗
Involvement of TCR-V beta 8.3+ cells in the cure of mice bearing a large MOPC-315 tumor by low dose melphalan.
We have previously shown that the curative efficacy of low dose melphalan (L-phenylalanine mustard; L-PAM) for mice bearing a large s.c. MOPC-315 tumor requires the participation of CD8+ (but not CD4+) T cell-dependent antitumor immunity. Here we show that CD8+ T cells obtained from regressing tumors on day 4 or 5 after low dose L-PAM therapy of MOPC-315 tumor bearers (L-PAM TuB mice) display a preferential enhancement in the utilization of the TCR-V beta 8.3 gene segment as compared to CD8+ T cells from normal lymph nodes. Treatment of L-PAM TuB mice with mAb F23.1, which leads to the depletion of V beta 8.3+ cells, as well as V beta 8.1 and 8.2+ cells, led to a significant reduction in the ability of their tumor-infiltrating lymphocytes as well as their spleen cells to lyse MOPC-315 tumor cells in vitro in a short term assay. In addition, the mAb F23.1 treatment almost completely abrogated the lytic activity of the tumor-infiltrating lymphocytes against another syngeneic, antigenically related plasmacytoma (the MOPC-104E). Moreover, the mAb F23.1 treatment significantly reduced the curative effectiveness of low dose L-PAM for mice bearing a large MOPC-315 tumor. In contrast, mAb KJ16 treatment, which leads to the depletion of V beta 8.1 and 8.2+ cells (but not V beta 8.3+ cells), did not reduce significantly the curative effectiveness of low dose L-PAM for such MOPC-315 tumor bearers. Thus, V beta 8.3+ T cells are important for the curative effectiveness of low dose L-PAM therapy for MOPC-315 tumor bearers, and it is conceivable that the V beta 8.3+ cells mediate their effect (at least in part) by contributing to the acquisition of CTL activity against plasmacytoma-shared Ag.
Animals↗
[Malignant peritoneal mesothelioma].
Public attention has recently been devoted worldwide to malignant mesotheliomas and their relation to exposure to industrial materials, especially asbestos and its products. The more common form of the disease is the pleural type, while the peritoneal variant is rare, with an estimated incidence of less than 1:1,000,000 new cases per year. In contrast to the pleural type, the relationship of malignant peritoneal mesothelioma to exposure to asbestos is unclear. The differential diagnosis, based on clinical appearance and imaging techniques, is broad and the diagnosis is inconclusive, so that the diagnosis must be confirmed by histologic examination. Treatment is a combination of surgery, chemotherapy and irradiation. Contrary to occasional reports, the malignancy is fatal, death occurring within a few months of diagnosis. We present a 65-year-old man in whom malignant peritoneal mesothelioma was diagnosed. The presenting symptoms were a large abdominal mass involving the colon, and ascites. He died 5 months after the diagnosis was made.
Aged↗
The utility of F wave chronodispersion in lumbosacral radiculopathy.
The sensitivity of F wave chronodispersion (Fc) in evaluating nerve root pathology is unknown. We compared Fc in 91 patients with clinical and EMG evidence of L5 or S1 radiculopathy with Fc in 81 controls in order to evaluate its sensitivity in lumbosacral radiculopathy. F waves were obtained by stimulating the peroneal and tibial nerves behind the knee and recording from the extensor digitorum brevis (L5 predominant) and flexor hallucis brevis (S1 predominant) muscles, respectively. Fc was calculated by subtracting the shortest F wave latency from the longest and, in controls, ranged from 0.2 to 23.4 ms in the peroneal nerve, and from 1.2 to 13.4 ms in the tibial nerve (95th percentile = 13 ms for the peroneal nerve and 9.2 ms for the tibial nerve). In the patient group, Fc also ranged from 0.2 to 23.4 ms in the peroneal nerve, and from 0.4 to 18.2 ms in the tibial nerve. Only 5 (5.5%) and 8 (11.3%) patients for the peroneal and tibial nerves, respectively, had Fc values which fell beyond the 95th percentile, a percentage far below the sensitivity of F wave latency measurement and not substantially different from chance. Thus we conclude that Fc has no substantial additional value in evaluating lumbosacral radiculopathy over that of F wave latency.
Adult↗
Characterization of the exogenous interleukin-2 requirements for the generation of enhanced antitumor cytotoxicity by thymocytes from low-dose melphalan-treated MOPC-315 tumor bearers.
We have shown previously that thymocytes from MOPC-315-tumor-bearing mice treated with low-dose melphalan (L-phenylalanine mustard) (L-PAM TuB mice) are superior to thymocytes from untreated MOPC-315-tumor-bearing mice or thymocytes from untreated normal mice or normal mice treated with low-dose melphalan in their ability to generate an antitumor cytotoxic response following 5-day in vitro stimulation with MOPC-315 tumor cells in the presence of a low concentration of recombinant interleukin-2 (rIL-2) [Mokyr MB, Bartik MM, Ahn M-C (1989) Cancer Res 49; 870]. Here we characterize the rIL-2 requirements for the generation of enhanced antitumor cytotoxicity by L-PAM TuB thymocytes relative to normal thymocytes upon in vitro stimulation with MOPC-315 tumor cells. Specifically, we show that delaying the addition of a low concentration of rIL-2 to 5-day in vitro stimulation cultures of thymocytes resulted in a progressive decline in the generation of antitumor cytotoxicity by both normal and L-PAM TuB thymocytes. However, even when rIL-2 was added on day 2 after culture initiation, thymocytes from L-PAM TuB mice generated a more potent antitumor cytotoxicity than did thymocytes from normal mice. In addition, when rIL-2 was added at the time of culture initiation, replacement of the conditioned medium with fresh medium lacking rIL-2 on day 3 of the 5-day in vitro stimulation culture period eliminated the ability of normal thymocytes, and reduced (but did not eliminate) the ability of L-PAM TuB thymocytes, to generate a significant level of antitumor cytotoxicity. A low concentration of fresh rIL-2 was sufficient to restore completely the generation of antitumor cytotoxicity by normal or L-PAM TuB thymocytes when added to the stimulation cultures immediately after the removal of the rIL-2-containing conditioned medium. The same low concentration of rIL-2 was also sufficient for restoring the generation of antitumor cytotoxicity by cultures of L-PAM TuB thymocytes, but not normal thymocytes, from which the rIL-2-containing medium was removed 1 day earlier. At the same time, conditioned medium from stimulation cultures of L-PAM TuB thymocytes was not superior to conditioned medium from stimulation cultures of normal thymocytes in supporting the generation of antitumor cytotoxicity by either normal or L-PAM TuB thymocytes.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine.
PURPOSE: To investigate the efficacy and safety of midodrine for treatment of patients with orthostatic hypotension due to autonomic failure. PATIENTS: Ninety-seven patients with orthostatic hypotension were randomized in a 4-week, double-blinded, placebo-controlled study with a 1-week placebo run-in period. Patients ranged in age from 22 to 86 years (mean: 61 years). METHODS: After a 1-week run-in phase, either placebo or midodrine at a dose of 2.5 mg, 5 mg, or 10 mg was administered three times a day for 4 weeks. Both the placebo group and the 2.5-mg midodrine group received constant doses throughout the double-blind phase. The patients receiving 5 mg or 10 mg of midodrine were given doses that were increased at weekly intervals by 2.5-mg increments until the designated dose was reached. Efficacy evaluations were based on an improvement at 1-hour postdose in standing systolic blood pressure and in symptoms of orthostatic hypotension (syncope, dizziness/lightheadedness, weakness/fatigue, and low energy level). RESULTS: Midodrine (10 mg) increased standing systolic blood pressure by 22 mm Hg (28%, p < 0.001 versus placebo). Midodrine improved (p < 0.05) the following symptoms of orthostatic hypotension compared to placebo: dizziness/lightheadedness, weakness/fatigue, syncope, low energy level, impaired ability to stand, and feelings of depression. The overall side effects were mainly mild to moderate. One or more side effects were reported by 22% of the placebo group compared with 27% of the midodrine-treated group. Scalp pruritus/tingling, which was reported by 10 of 74 (13.5%) of the midodrine-treated patients, was most frequent. Other reported side effects included supine hypertension (8%) and feelings of urinary urgency (4%). CONCLUSION: We conclude that midodrine is an effective and well-tolerated treatment for moderate-to-severe orthostatic hypotension associated with autonomic failure.
Adult↗
Laparoscopic cholecystectomy in childhood.
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Activities of Daily Living↗
Stability of renal allograft glomerular filtration rate associated with long-term use of cyclosporine A.
Renal allograft glomerular filtration rate (GFR) was measured at 4-month intervals for up to 1 year in 43 CsA-treated patients using x-ray fluorescence determination of plasma iohexol clearance. Study patients were divided into cohorts based on time (years) after transplantation at study entry (0-1; 1-2; 2-3; and > 3 years) and entry GFR levels (20-29; 30-39; 40-49; and > or = 50 ml/min/1.73 m2). GFR at study entry was 42 +/- 2 and was comparable in CAD (n = 31) versus LRD (n = 12) allografts (42 +/- 2 and 44 +/- 4 ml/min/1.73 m2, respectively). Range of entry GFR levels was similar in each of the "time at entry" cohorts defined above. Serum creatinine concentrations of 1.5-2.5 mg% were associated with GFR levels of 20-60 ml/min/1.73 m2. Serial GFR levels obtained at 4-month intervals for 1 year (n = 34 patients) were not consistent with a pattern of progressively declining GFR occurring as a function of either time after transplantation or absolute GFR level at study entry (intraindividual coefficient of variation 10.3 +/- 1.0%). Patients in the lower quartile of "entry GFR" levels (< 34 ml/min/1.73 m2) were more likely than their counterparts to have had a history of acute rejection. Results are consistent with retrospective population studies of aggregate serum creatinine levels, indicating that long-term CsA use is not uniformly associated with accelerated loss of renal allograft function consequent to a progressive, toxic nephropathy. The data also suggest that neither absolute GFR level nor time after transplantation represent indications for routine dose reduction or conversion to AZA.
Adult↗
Bile and plasma lipid composition in non-obese normolipidemic subjects with and without cholesterol gallstones.
A two-stage study was carried out to characterize the bile and plasma lipid composition in normolipidemic non-obese patients with and without cholesterol gallstones. The first stage involved 11 patients with cholesterol gallstones admitted for elective cholecystectomy and a control group of 16 patients without cholesterol gallstones undergoing elective laparotomy. Bile samples were obtained intraoperatively by aspiration from the gallbladder. The bile of all the gallstone patients was supersaturated with cholesterol and its nucleation time was much shorter than that of bile in the control group (2.5 days vs 22.5 days, respectively, P < 0.001). The biliary fatty acid profile of phosphatidylcholine (PC) and free fatty acids (FFA) of gallstone patients was similar to that of the control group. C-22 fatty acids were found in a higher concentration in the FFA than in the PC fatty acids (P < 0.05) in both groups of patients. Plasma triglyceride levels in the gallstone patients were significantly higher than those in the control group and the biliary cholesterol level correlated with that of plasma triglycerides. In the second stage of the study, plasma lipid profiles were obtained in two additional groups of patients, 20 patients with and 24 patients without cholesterol gallstones, for an in-depth characterization of the differences in plasma lipid profiles. The gallstone patients were found to have not only significantly higher concentrations of plasma triglycerides but increased cholesterol and phospholipid level as well. These differences were essentially due to a higher lipid content of the plasma VLDL fraction, similar to the pattern of patients with type IV hyperlipoproteinemia.
Bile↗
A novel antineuronal antibody in stiff-man syndrome.
Two-thirds of stiff-man syndrome (SMS) patients harbor an autoantibody specific for a 64-kD species of glutamic acid decarboxylase (GAD), the rate-limiting enzyme in GABA synthesis. We assayed SMS antisera from two patients with SMS for the presence of anti-GAD antibodies using Western blot, immunohistochemical, and enzymatic analyses. Both SMS antisera recognized an 80-kD antigen present in human and rat neuronal extracts, and failed to recognize the 64-kD GAD species. Immunohistochemistry demonstrated neuronal binding identical to that reported with anti-GAD antibodies. Both sera depleted GAD activity from brain extracts. Our analysis indicates that these SMS antisera differ from previously reported SMS antisera by recognizing a novel 80-kD antigen, and suggests that they contain antibodies directed against either a species of GAD different in size from the 64-kD enzyme, or a protein that co-immunoprecipitates with GAD.
Adult↗