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PubMed1987

Glutamic acid decarboxylase-like immunoreactivity in brainstem auditory nuclei of the rat.

The distribution of GABA-producing neurons in the brainstem auditory nuclei of the rat was investigated immunohistochemically by using an antibody to glutamic acid decarboxylase (GAD). In the cochlear nuclei, GAD immunoreactive neurons are present only in the superficial granular and molecular layers, whereas terminals are found in all subdivisions of the nuclei and are particularly dense surrounding large spherical cells and one type of stellate cell. In the superior olivary complex, GAD immunoreactive neurons are located in the lateral olivary nucleus and throughout the periolivary region. Immunoreactive terminals are distributed along dendrites of principal cells of the medial and lateral olivary nuclei and are clustered around somata of globular neurons of the nucleus of the trapezoid body. An extremely dense band of immunoreactive somata and terminals is present along the ventral edge of the olivary complex. The ventral, intermediate, and dorsal nuclei of the lateral lemniscus contain small fusiform GAD-immunoreactive neurons and a moderately dense plexus of immunoreactive terminals. The inferior colliculus contains a large population of GAD-immunoreactive perikarya and an extremely dense accumulation of immunoreactive terminals in the central, dorsomedial, and external nuclei. These observations indicate that GABA systems are involved in function at all levels of the brainstem auditory pathway.

Animals↗
PubMed1996

Efficacy of lodoxamide 0.1% versus N-acetyl aspartyl glutamic acid 6% ophthalmic solutions in patients with vernal keratoconjunctivitis.

In a double-masked, randomized and controlled clinical trial, the effectiveness and safety of lodoxamide 0.1% eye drops were compared with N-acetyl aspartyl glutamic acid 6% (NAAGA) drops in the treatment of 120 patients with vernal keratoconjunctivitis. There were 60 patients in each of the two study groups. The drugs were instilled 4 times daily for 60 days. Follow-up examinations were made on days 7, 30 and 60. Of the 120 patients, 98 (50 in lodoxamide and 48 in NAAGA groups) were still available for follow-up on day 7, 89 (45 in lodoxamide and 44 in NAAGA groups) on day 30 and 75 (38 in lodoxamide and 37 in NAAGA groups) on day 60. Lodoxamide was clinically more effective than NAAGA. Statistically significant trends toward improvement were noted in the lodoxamide group in resolving papillae on day 30, decreasing corneal staining on days 30 and 60, relieving photophobia on day 60, tearing on days 7, 30 and 60 and itching on days 30 and 60. Lodoxamide 0.1% was more effective in lowering the mean scores for corneal staining on days 30 and 60 (p < 0.05). The composite scores for clinical signs and symptoms calculated by averaging the mean scores for signs and symptoms showed clinically significant differences in favor of the lodoxamide group. More frequent follow-up visits might have resulted in better statistical correlations. Treatment-related adverse events were reported in both groups with similar frequency but none were permanent or serious.

Adolescent↗
PubMedDate not supplied

Paclitaxel and water-soluble poly (L-glutamic acid)-paclitaxel, induce direct chromosomal abnormalities and cell death in a murine metastatic melanoma cell line.

The purpose of this study was to demonstrate the effects of paclitaxel and water-soluble poly (L-glutamic acid)-paclitaxel (PG-TXL), on chromosome morphology, telomeric associations, and induction of cell death in a murine melanoma cell line (K-1735 clone X-21). Murine melanoma cells were treated with various concentrations (0.1 microgram, 1.0 microgram, 4.0 micrograms, and 8.0 micrograms/ml) of paclitaxel alone, PG alone, or PG-TXL for 2 hr and 4 hr and harvested immediately without recovery. We found that: (1) the frequency of metaphases with telomeric associations increased, (2) metaphases had clumped and distorted chromosome morphology, (3) cells accumulated in metaphase (mitotic arrest), and (4) cell death had been induced. Cells treated with PG-TXL showed more such abnormalities than did cells treated with either paclitaxel or PG alone. Our preliminary results indicate that PG-TXL may be superior to paclitaxel alone in inducing cytotoxic effects, and these effects could be mediated by various chromosomal abnormalities in cancer cells.

Animals↗
PubMed1998

Complete regression of well-established tumors using a novel water-soluble poly(L-glutamic acid)-paclitaxel conjugate.

Despite an intensive search, few water-soluble paclitaxel derivatives have been shown to have a therapeutic index superior to paclitaxel itself. We now report a water-soluble poly(L-glutamic acid)-paclitaxel conjugate (PG-TXL) that produces striking antitumor effects with diminished toxicity. A single i.v. injection of PG-TXL at its maximum tolerated dose (defined as that dose that produces a maximum 12-15% body weight loss within 2 weeks after a single i.v. injection) equivalent to 60 mg of paclitaxel/kg and at even a lower dose equivalent to 40 mg of paclitaxel/kg resulted in the disappearance of an established implanted 13762F mammary adenocarcinoma (mean size, 2000 mm3) in rats. (An equivalent dose of PG-TXL is the amount of conjugate that contains the stated amount of paclitaxel.) Similarly, mice bearing syngeneic OCA-1 ovarian carcinoma (mean size, 500 mm3) were tumor-free within 2 weeks after a single i.v. injection of the conjugate at a dose equivalent to 160 mg of paclitaxel/kg. The conjugate has little if any intrinsic tubulin polymerization activity in vitro and is >20 times less potent in supporting the growth of a paclitaxel-dependent CHO mutant cell line. PG-TXL has a prolonged half-life in plasma and greater uptake in tumor as compared with paclitaxel. Furthermore, only a small amount of total radioactivity from PG-[3H]TXL was recovered as free [3H]paclitaxel in either the plasma or the tumor tissue within 144 h after drug injection. Histological studies of tumor tissues obtained from mice treated with PG-TXL show fewer apoptotic cells but more extensive tumor necrosis as compared with paclitaxel treatment. These data suggest that in addition to its role as a carrier for selective delivery of paclitaxel to the tumor, PG-TXL exerts distinct pharmacological actions of its own that may contribute to its remarkable antitumor efficacy.

Animals↗
PubMed1999

Clinical characteristics, and time course of pancreatic beta-cell function and glutamic acid decarboxylase antibodies in Thai patients with adult-onset Type 1 diabetes: distinction between patients of rapid- and slow-onset.

In order to study the clinical characteristics, time course of beta cell function and glutamic acid decarboxylase antibodies (GAD65Ab) in Thai patients with adult-onset Type 1 diabetes and to examine the distinctive features between patients with rapid-and slow-onset, 61 Thai patients with Type 1 diabetes who had age of disease onset at or after 20 years were studied. All patients were treated with insulin at the time of study and had fasting C-peptide levels +/-0.33 nmol/l. Twenty-six (42.6%) were in rapid-onset and 35 (57.4%) were in slow-onset groups. Fourty-four of 61 (70.5%) were male. About three-fourths had body mass index (BMI) < 19 kg/m2 at the time of insulin therapy. Only 7 of 61 (11.5%) patients had ketoacidosis at first presentation. Five patients had associated autoimmune thyroid disease and 10 (16.7%) patients had family history of diabetes in first-degree relatives. GAD65Ab was positive in 31 patients (50.8%); 10 (38.5%) were in rapid-onset and 21 (60.0%) were in slow-onset groups. GAD65Ab particularly of high levels were persistently elevated during 3-4 years follow-up period. The persistence of GAD65Ab were not associated with changes in fasting C-peptide levels. At the time of insulin dependency, there were no distinctive clinical features between rapid- and slow-onset patients except higher fasting C-peptide (0.08+/-0.08 vs. 0.14+/-0.10 nmol/l; p = 0.023) and GAD65Ab levels (19.6+/-17.4 vs. 46.1+/-49.7 U/ml; p = 0.036) in slow-onset patients. Fasting C-peptide levels of patients in the latter group were also demonstrated to be higher after 3-4 years of follow-up. In conclusion, most Thai patients with adult-onset Type 1 diabetes in this study were male and had significant degree of weight loss and lean BMI prior to insulin therapy. The presence of GAD65Ab did not predict clinical features or rate of beta cell loss. Patients in rapid-onset group had lower fasting C-peptide and GAD65Ab levels than those of slow-onset group which confirms the slower process of beta cell failure in the latter.

Adult↗
PubMed1996

Consequence of nigrostriatal denervation and L-dopa therapy on the expression of glutamic acid decarboxylase messenger RNA in the pallidum.

To examine the consequences of nigrostriatal denervation and L-dopa treatment on the basal ganglia output system, we analyzed, by quantitative in situ hybridization, the messenger RNA coding for glutamic acid decarboxylase (Mr 67,000) (GAD67 mRNA) in pallidal cells from patients with Parkinson's disease (PD), monkeys rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) receiving or not receiving L-dopa, and their respective control subjects. In MPTP-treated monkeys, the expression of GAD67 mRNA was increased in cells from the internal pallidum, and this effect was abolished by L-dopa treatment. There were no differences in the levels of GAD67 mRNA between patients with PD, who were all treated with L-dopa, and control subjects. These results indicate that the level of GAD67 mRNA is increased in the cells of the internal pallidum after nigrostriatal dopaminergic denervation and that this increase can be reversed by L-dopa therapy.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Islet cell antibodies and glutamic acid decarboxylase antibodies in patients with insulin-dependent diabetes mellitus undergoing kidney and islet-after-kidney transplantation.

The humoral immune response to islet autoantigens, here defined by the presence of islet cell antibodies (ICA) and glutamic acid decarboxylase (GAD 65) antibodies, was studied in patients with long-term insulin-dependent diabetes mellitus (IDDM) receiving immunosuppressive therapy following kidney and islet-after-kidney transplantation. In a cross-sectional study of 30 kidney-grafted, long-term IDDM patients and 30 matched, nontransplanted IDDM controls, we observed a significant (P<0.05) decrease in ICA positivity by standard immunosuppressive therapy, but not in frequency or index levels of GAD 65 antibodies. Because of this intriguing finding, we investigated, in a pilot study on seven islet-after-kidney transplant recipients, the time course of frequency and levels of ICAs and GAD 65 antibodies relative to islet graft function. Stable islet graft function was seen in the patients with low GAD 65 antibody index levels, whereas rapid islet graft failure occurred in a patient with high GAD 65 antibody index levels prior to transplantation. In addition, GAD 65 autoimmunity reoccurred in one pretransplant antibody-negative patient 2 months after graft failure was noted. In conclusion, these observations suggest that beta-cell autoimmunity directed to GAD 65 can persist despite immunosuppressive therapy and may adversely affect islet graft function, possibly indicating disease recurrence as a major threat to successful clinical islet transplantation.

Adult↗
PubMed1994

Do glutamic acid decarboxylase antibodies improve the prediction of IDDM in first-degree relatives at risk for IDDM?

To determine whether the predictive value of islet cell antibodies (ICA) and insulin autoantibodies (IAA) is increased by measurement of glutamic acid decarboxylase antibodies (GADAb) in first-degree relatives of patients with insulin-dependent diabetes mellitus (IDDM), we measured GADAb in those developing IDDM and in relatives found to be ICA- or IAA-positive in our family screening study. First-degree relatives (n = 2904) were followed for 2.4 (median, range 0.04-5.8) years. Of the subjects developing IDDM, 11/14 (78%) had ICA > or = 20JDF units, 1/14 (7%) had IAA > or = 100 nU/ml and 6/14 (43%) had GADAb (> or = 460 nU/ml, measured by precipitation of enzymatic activity). Of the four subjects with ICA < 20 and IAA < 100 nU/ml who developed IDDM, one had elevated GADAb. Significant inhibition of GAD enzymatic activity by serum immunoglobulins, a potential cause of false-negative results in our immunoprecipitation assay, was not detected in seven subjects who developed IDDM in the absence of GADAb. Sixty-nine of the 2904 subjects with ICA > or = 20 or IAA > or = 100 were followed for 3.1 (median range 0.1-5.4) years. Survival analysis showed that diabetes-free survival in this group was not influenced significantly by GADAb positivity. In conclusion, GADAb in the absence of ICA and IAA are uncommon in first-degree relatives who progress to IDDM and the presence of GADAb does not increase the risk for IDDM in ICA- or IAA-positive relatives.

Adolescent↗
PubMed1986

Phylogenesis of brain glutamic acid decarboxylase from vertebrates: immunochemical studies.

Brain high-speed supernatants from various lower and higher vertebrates were subjected to sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis, electroblot on nitrocellulose membranes, and immunolabelling using an anti-glutamic acid decarboxylase (anti-GAD) antiserum prepared from rat antigen. Rat brain extracts showed two distinct immunolabelled bands (MW 59,000 and 62,000 daltons). The molecular weight of the native enzyme was 120,000 daltons. The immunoblot pattern was not affected by a 3-h incubation of the homogenate. In the substantia nigra, the decrease in the immunolabelling of both bands corresponded very closely to the decrease of GAD activity following lesioning of the striato-nigral pathway. Moreover, experiments with preadsorbed antiserum showed that both subunits have common antigenic determinants. The immunolabelling was consistently more intense over the lightest band. The autoradiography of immunoprecipitated rat brain GAD, iodinated prior to electrophoresis, revealed two radiolabelled bands corresponding to the two immunolabelled ones. Their radioactivity was found in a one-to-five ratio which closely paralleled their respective immunolabelling intensity. Thus, the two subunits recognized by the antiserum are not present in stoichiometric proportions in the rat brain high-speed supernatant. These findings suggest the existence of two homodimeric GAD with common antigenic determinants which are present in different amounts. Immunoprecipitation curves of brain GAD from rat, mouse, rabbit, monkey, human, quail, frog, and trout were similar, with a less than 10-fold maximum shift in affinity for GAD. GAD immunoblots from the various higher vertebrates showed a pattern similar to that obtained in rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Glutamic acid decarboxylase 65 autoantibody levels discriminate two subtypes of latent autoimmune diabetes in adults.

OBJECTIVE: To compare the clinical characteristics between type 2 diabetes mellitus (T2DM) and latent autoimmune diabetes in adults (LADA) with different titers of glutamic acid decarboxylase autoantibody (GADA) and to define the two distinct subtypes of LADA. METHODS: Sera of 750 patients with an initial diagnosis of T2DM from central south of China were screened for GADA using a radioligand assay. The distribution and frequency of GADA levels were described. Two hundred and ninety-five patients were divided into the T2DM group (n = 233) and the LADA group (n = 62) to compare the age of onset, body mass index, HbA(1c), C-peptide, hypertension, dyslipidemia and chronic diabetic complications. Furthermore, LADA patients with different GADA titers were subdivided to analyze the same indexes as the above. RESULTS: The prevalence of LADA (defined as GADA > or = 0.05, namely GADA positive) was 9.7% in the 750 initially diagnosed type 2 diabetic patients. Compared with T2DM, LADA patients were younger at their ages of onset, had lower C-peptide and body mass index, and also had less cases with hypertension and with dyslipidemia. However, only patients with high titer of GADA had poorer beta cell functions and less diabetic complications compared to T2DM and low GADA titer of LADA patients. Patients with low GADA titer were similar to T2DM patients, except that they were prone to develop ketosis more frequently. CONCLUSIONS: Two clinically distinct subtypes of LADA can be identified by GADA levels in patients initially-diagnosed as type 2 diabetes. Patients with high titer of GADA (GADA > or = 0.5) subsequently develop more insulin dependency, which are classified as LADA-type 1; while those with lower GADA titer (0.05 < or = GADA < 0.5) and having clinical and metabolic phenotypes of type 2 diabetes are classified as LADA-type 2.

Adult↗

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