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PubMed2005

Clinical and immunological characteristics of type 1 diabetes mellitus in a northwestern Colombian population.

We underwent a project aimed to define the clinical and immunological characteristics of type 1 diabetes (T1D) in a Colombian population. This was a multicenter and cross-sectional study. Patients were systematically interviewed and their medical records reviewed, using a questionnaire that sought information about demographic, clinical and immunological characteristics. Glutamic acid decarboxylase antibodies (GADA), tyrosine phosphatase antibodies (IA-2A) and insulin antibodies (IAA) were examined by radioimmunoassay. There were 107 patients with T1D. Male:female ratio was 1:1. Half of the patients developed diabetes ketoacidosis at onset. GADA, IA-2A, and IAA were detected in 45%, 40%, and 69% of the cases, respectively. GADA positive patients were older and had a less duration of disease than patients without these autoantibodies (p<0.01). Association between breast feeding with the presence of antibodies or clinical characteristics was not observed. The results highlight some differences of T1D expression according to geographic location and ethnicity. Differences in age at onset and clinical variables may point to an environmental factor or deficient access to health care system. Genetic studies underway will provide important information in this population. These results might help to define public health policies in our population to improve T1D diagnosis, patients' quality of life and their outcome.

Adult↗

PubMed1979

Adrenergic innervation of the human uterus. Disappearance of the transmitter and transmitter-forming enzymes during pregnancy.

The uterine adrenergic transmitter is in many animal species dramatically reduced during pregnancy, probably leading to a functional denervation near term. In order to clarify whether similar changes also occur in the human uterus, the adrenergic innervation of the isthmic myometrium during nonpregnant and pregnant conditions was analyzed by fluorescence histochemistry for demonstration of adrenergic nerves, and by quantitative measurements of norepinephrine and its synthesizing enzymes, tyrosine hydroxylase and dopa decarboxylase. At term pregnancy all fluorescent adrenergic nerves in the myometrium had disappeared, and the norepinephrine concentration had been reduced to almost zero. Parallel to this the activities of tyrosine hydroxylase and dopa decarboxylase were markedly reduced. By contrast, the activity of the acetylcholine-synthesizing enzyme, choline acetyltransferase, was unchanged, indicating that the adrenergic system was selectively affected. The results confirm that the adrenergic nerves in the human uterus, like those in uterine horns of laboratory animals, undergo fundamental changes in the course of pregnancy. This probably reflects entirely different conditions for a sympathetic influence on the myometrium during the last two trimesters of pregnancy compared to the non-pregnant situation.

Adult↗

PubMed1992

Differential sensitivity of cholinergic and GABAergic neurons in chick embryos treated intracerebrally with ethanol at 8 days of embryonic age.

We have shown that in embryos treated with ethanol in ovo during days 1-3, a critical period of neuroembryogenesis, cholinergic neuronal phenotypic expression is decreased whereas GABAergic and catecholaminergic neuronal populations are increased as assessed by neuronal markers choline acetyltransferase (ChAT), glutamic acid decarboxylase (GAD) and tyrosine hydroxylase (TH) respectively. In this study, ethanol was administered intracerebrally to embryos at embryonic day 8, embryos were sacrificed at day 9 and ChAT and GAD activities assayed separately in cerebral hemispheres and remaining brain (diencephalon-midbrain and optic lobes). We found that ChAT activity was enhanced in the cerebral hemispheres only, whereas GAD activity was decreased in both cerebral hemispheres and remaining brain. We have concluded that the differential responses of neuronal phenotypes to ethanol may reflect compensatory mechanisms to ethanol insult. Moreover, these findings emphasize the vulnerability of the GABAergic neuronal phenotypes to ethanol neurotoxicity during early brain development in the chick.

Animals↗

PubMed1998

Behavioral recovery in 6-hydroxydopamine-lesioned rats by cotransduction of striatum with tyrosine hydroxylase and aromatic L-amino acid decarboxylase genes using two separate adeno-associated virus vectors.

Parkinson's disease (PD) is characterized by the progressive loss of the dopaminergic neurons in the substantia nigra and a severe decrease in dopamine in the striatum. A promising approach to the gene therapy of PD is intrastriatal expression of enzymes in the biosynthetic pathway for dopamine. Tyrosine hydroxylase (TH) catalyzes the synthesis of L-dopa, which must be converted to dopamine by aromatic L-amino acid decarboxylase (AADC). Since the endogenous AADC activity in the striatum is considered to be low, coexpression of both TH and AADC in the same striatal cells would increase the dopamine production and thereby augment the therapeutic effects. In the present study, the TH gene and also the AADC gene were simultaneously transduced into rat striatal cells, using two separate adeno-associated virus (AAV) vectors, AAV-TH and AAV-AADC. Immunostaining showed that TH and AADC were coexpressed efficiently in the same striatal cells in vitro and in vivo. Moreover, cotransduction with these two AAV vectors resulted in more effective dopamine production and more remarkable behavioral recovery in 6-hydroxydopamine (6-OHDA)-lesioned rats, compared with rats receiving AAV-TH alone (p < 0.01). These findings suggest an alternative strategy for gene therapy of PD and indicate that the simultaneous transduction with two AAV vectors can extend their utility for potential gene therapy applications.

Animals↗

PubMed1994

Temporal and spatial development of serotonin and dopamine neurons in the Drosophila CNS.

We present a high-resolution profile of the temporal and spatial immunoreactivity for dopamine and serotonin in the Drosophila embryonic CNS and the expression pattern of two enzymes important in their biosynthesis, DOPA decarboxylase (DDC) and tyrosine hydroxylase (TH). DDC performs the final catalytic step in the synthesis of both biogenic amines and TH is the rate-limiting enzymatic step in the synthesis of dopamine. We show that the DDC-expressing neurons synthesize either serotonin or dopamine, but not both, and that the two neuronal subtypes follow similar axonal pathways. In addition, we describe two DDC-expressing cell types that do not synthesize detectable levels of serotonin or dopamine. We also describe a novel set of TH-expressing neurons that are detected only during embryogenesis. The initial appearance of both enzymes and their metabolites during embryogenesis shows unexpected diversity. The onset of Ddc expression is heterogeneous, such that certain classes of cells express high levels of DDC several hours before others. High levels of TH immunoreactivity are observed at a time when DDC immunoreactivity is barely detectable. Despite low levels of DDC, both dopamine and serotonin are first detected at the earliest stages of DDC expression. We discuss the implications of these observations in the differentiation of dopamine and serotonin neurons.

Animals↗

PubMed2001

Combined measurement of diabetes mellitus immunological markers: an assessment of its benefits in adult-onset patients.

The convenience of combining the measurement of antibodies to glutamic acid decarboxylase (GADA), protein tyrosine phosphatase (IA-2A), and autoantibodies to insulin (IAA) in diabetic patients was assessed. We analysed 71 type 1 and 115 adult-onset diabetic patients. The latter were grouped into three categories according to the time of evolution to insulin dependence. The main findings were as follows: (i) in type 1 diabetes, the combined analysis of GADA and IA-2A showed a sensitivity of 87.4% and was not appreciably improved by adding IAA; (ii) out of 31 adults who required insulin immediately or within the first two years of diagnosis, 41.9, 29.0, and 6.5% were positive for at least one, two or all three, and all three markers, respectively; GADA was the most prevalent (35.5%) and IA-2A the least represented (16.1%); (iii) 34 adult patients with slow evolution to insulin dependence showed a completely different profile: 5.9% were GADA positive and 23.5% were IAA positive and no double or triple positivity was observed as all patients were IA-2A negative; and (iv) 50 type 2 patients who had not required insulin treatment showed a low incidence of GADA (4%) as the only marker present. We conclude that a combined double-antigen test for GADA and IA-2A is a useful strategy for prospective screening of type 1 diabetes. However, in adults, the profile of individual markers discloses the course to insulin dependence. Therefore, it seems advisable to measure the markers separately, to allow a better classification of these patients, and help define their treatment.

Adolescent↗

PubMed1985

Effects of intermittent feeding on neurochemical markers in aging rat brain.

Male Wistar rats were fed a diet of 24% protein either ad lib (AL) or every other day (EOD) beginning shortly after weaning. Rats were killed at 6 or 24-months of age. The corpus striatum, cerebral cortex, hippocampus, and cerebellum were assayed for muscarinic cholinergic receptor binding and the activities of choline acetyltransferase (ChAT), L-glutamic acid decarboxylase (GAD) and tyrosine hydroxylase (TH). Sensecent rats maintained on EOD feeding schedules from weaning showed a markedly higher density of striatal muscarinic binding sites and higher activities of cerebellar, hippocampal, and striatal ChAT, as compared with values in AL-fed rats. Regional GAD and TH activities were relatively unaffected by EOD feeding; however, at 6 months, EOD-fed rats had higher cortical GAD and lower cortical TH activities than corresponding AL-fed rats. EOD feeding for only 2 weeks produced no significant effects on neurochemical parameters examined in 24-month-old rats. We conclude that EOD feeding from weaning can alter neurochemical markers of senescence in rat brain; that cholinergic systems are affected in particular; and that the observed alterations produced by EOD feeding represent chronic rather than acute effects.

Aging↗

PubMed1984

Selective cholinergic neurotoxin: AF64A's effects in rat striatum.

The selective neurotoxic effects of the aziridinium ion of ethylcholine (AF64A) have been examined after stereotaxic injection into the rat striatum. In a dose-response study (2-26 nmol), 8 nmol caused a 46% decrease in striatal choline acetyltransferase (CAT) activity with minimal effects on the activities of glutamate decarboxylase (GAD) and tyrosine hydroxylase (TH) at 7 days. Maximal CAT reductions of 78-82% occurred with doses of 16-26 nmol which also caused dose-related decreases in GAD and TH activities that paralleled the progressive decrements in CAT. A time course study with 8 nmol indicated a rapid 20% reduction of CAT activity by 12 h and an additional gradual fall of 20% over the next week; TH and GAD activities were not significantly reduced. The selective inhibition of CAT activity persisted for at least 3 months. Histological examination of Nissl stained sections revealed an area of nonspecific damage at the injection site with an abrupt border surrounded by apparently normal striatal neuropil; however; neuronal perikarya staining intensely for acetylcholinesterase were not reduced. These preliminary findings strongly suggest that AF64A has selective neurotoxic effects against striatal cholinergic neurons while relatively sparing striatal GABAergic intrinsic neurons or dopaminergic afferents.

Animals↗

PubMed2002

Prevalence of latent autoimmune diabetes of adults (LADA) in Southern Spain.

OBJECTIVE: To study the prevalence of diabetes mellitus and islet autoantibodies in an adult population from Southern Spain. RESEARCH AND METHODS: A cross-sectional study in Southern Spain of 1226 people, age 18-65 years. Clinical data were obtained and a blood sample taken to measure autoantibodies (glutamic acid decarboxylase antibodies (GADAb), tyrosine phosphatase antibodies (IA2Ab), and insulin antibodies (IAA)). An oral glucose tolerance test (OGTT) was also given to 982 of the subjects. RESULTS: The overall prevalence of diabetes mellitus according to the WHO 1979 criteria was 10.9% and according to the ADA 1997 criteria it was 14.7% (8.8% were unaware of their diabetes). The prevalence of impaired fasting glucose (IFG) was 12.4% and of impaired glucose tolerance (IGT) 11.5%. The prevalence of GADAb+ in the general population was 0.9% and in the diabetic population 3.7%. There were no significant differences between groups in the prevalence of IA2Ab or IAA (both were 0.8% in the general population). Of the three autoantibodies studied, only GADAb were significantly different in the diabetic population (P=0.0006). CONCLUSIONS: The prevalence of Type 2 diabetes and LADA are high in the south of Spain.

Adolescent↗

PubMed1981

Age and neurochemical correlates of radial maze performance in rats.

Young adult (8 months) and aged (26 months) female Wister rats were tested in a 12-arm radial maze in which the optimal strategy was to enter all arms without a repetition. In order to determine if possible age-associated alterations in behavior were correlated with defects in cholinergic. GABAergic and adrenergic neurons in the hippocampus and cerebral cortex, the activities of choline acetyltransferase (CAT), glutamic acid decarboxylase (GAD) and tyrosine hydroxylase (TH) were assayed in these regions of all animals after testing in the radial maze. In the maze, the aged rats continued to perform at the chance level after 15 trials, whereas the young rats had virtually mastered the task. The only significant neurochemical age effect was an increase in hippocampal TH. However, analysis of individual differences among rats revealed positive correlations between maze performance and hippocampal CAT in the aged group and cortical GAD in both the young and aged groups.

Aging↗

PubMed2004

Prevalence of diabetes-associated autoantibodies in schoolchildren: the Karlsburg Type 1 Diabetes Risk Study.

This study attempts to assess the prevalence of diabetes-associated autoantibodies in a general population in the northeastern part of Germany, with emphasis on autoantibodies against glutamic acid decarboxylase (GADA), protein tyrosine phosphatase (IA-2A), and insulin (IAA) by radioassays >/= 98th percentile, and AAbs binding on pancreatic sections (ICA) by immunofluorescence >/= 10 Juvenile Diabetes Foundation units. From a total of 11,840 schoolchildren tested for all four AAbs, 821 (6.9%) children were positive for single AAbs, whereas 83 (0.7%) had multiple AAbs. If the primary screening were performed by testing GADA/IA-2A/IAA, 94% of probands with single AAbs and all with multiple AAbs would be identified. The combinations of GADA/IA-2A, GADA/IAA, and IA-2A/IAA would identify 97.6, 98.8, and 85.5% of probands with multiple AAbs, respectively. Thus, combined AAb screening in the general population identifies those probands at risk for diabetes.

Adolescent↗

PubMed1998

Metabolic and immune parameters at clinical onset of insulin-dependent diabetes: a population-based study. IMDIAB Study Group. Immunotherapy Diabetes.

The age at diagnosis of insulin-dependent diabetes mellitus (type I DM) varies between childhood and adulthood. The aim of this study was to define the immunologic and metabolic characteristics of the disease according to the age at which it is diagnosed. We evaluated the residual beta-cell function (basal and stimulated C-peptide) and frequency of two major islet cell-related autoantibodies, glutamic acid decarboxylase (GAD) and tyrosine phosphatase-like molecule (IA-2ic), at the onset of type I DM. A population-based study was performed with 235 consecutive cases of recent-onset (<4 weeks) type I DM (ages 5 to 45 years) diagnosed in the Lazio region of central Italy. Five age groups were considered: patients diagnosed between ages 5 and 7 years (n = 10), 7 and 10 years (n = 38), 10 and 17 years (n = 94), 17 and 20 years (n = 17), and 20 and 45 years (n = 76). Patients diagnosed before puberty had significantly reduced C-peptide secretion compared with patients diagnosed at a later age (P < .02). Glycosylated hemoglobin (HbA1c) did not differ at diagnosis between the different age groups. Patients diagnosed at puberty or after required significantly less insulin compared with younger patients (P < .04). GAD antibodies were found in 65% and IA-2ic antibodies in 59% of patients. GAD antibodies tended to be more frequent in patients diagnosed after age 17 compared with younger patients (P = .05), while IA-2ic antibodies were not age-related. These data suggest that (1) the extent of beta-cell damage differs between patients diagnosed before and after puberty, the process being more destructive in children less than 7 years of age, when C-peptide levels are the lowest; and (2) residual beta-cell function at diagnosis is not influenced by the presence or absence of islet cell-related antibodies. These findings have implications for trials in type I DM diagnosis aimed at protecting beta cells from end-stage destruction and in attempts to prevent the disease in susceptible individuals.

Adult↗

PubMed1999

Tyrosine hydroxylase and aromatic L-amino acid decarboxylase do not coexist in neurons in the human anterior cingulate cortex.

Immunoreactivity for aromatic L-amino acid decarboxylase (AADC), the second step dopamine-synthesizing enzyme, was found immunohistochemically in neurons of the human anterior cingulate cortex (ACC). Most of these neurons were located in layers V and VI and subcortical white matter; a small number were occasionally found in layer III. Double immunohistochemistry for tyrosine hydroxylase (TH: the first step dopamine-synthesizing enzyme) and AADC revealed that no neuronal cell bodies in the ACC were doubly immunostained for TH and AADC, suggesting that these TH-only- or AADC-only-immunoreactive neurons were not dopaminergic. AADC neurons in the human ACC might transform L-DOPA to dopamine, droxidopa to noradrenaline, and/or 5-hydroxytryptophan to serotonin.

Adult↗

PubMed1987

Interspecific comparisons of immunohistochemical localization of retinal neurotransmitters in four species of bats.

Four ecologically distinctive Neotropical bat species of the family Phyllostomidae were collected and their retinae surveyed immunohistochemically for the presence of neurotransmitter candidates: glucagon, somatostatin, vasoactive intestinal peptide, substance P (SP), methionine enkephalin, serotonin (5-HT) and two enzymes, glutamic acid decarboxylase (GAD) and tyrosine hydroxylase (TOH). In all four species immunoreactivity (IR) to GAD, TOH and SP was found. GAD-IR and SP-IR showed little interspecies variation whereas TOH-IR differed interspecifically in a pattern that matched the systematic relationships and the ecological characteristics of the bats. 5-HT-IR, which has not previously been reported from mammalian retinae, was found in fibers in the inner nuclear layer and in the outer and inner plexiform layers of Macrotus waterhousii, which is a relatively underived insectivorous phyllostomid bat, but was not found in the retinae from frugivorous or nectarivorous species.

Animals↗

PubMed1990

Unilateral, neonatal olfactory deprivation alters tyrosine hydroxylase expression but not aromatic amino acid decarboxylase or GABA immunoreactivity.

Recent publications have demonstrated an important role for olfactory afferent innervation in maintenance of the dopamine phenotype of olfactory bulb target neurons. The mechanisms underlying the control of phenotypic expression in this system are not known. These studies employed the model of unilateral neonatal olfactory deprivation to investigate the effects of lack of odorant stimulation on dopamine expression in the rat. Immunoreactivity of tyrosine hydroxylase, the first and rate-limiting enzyme in dopamine biosynthesis, used as a marker of the dopamine system, exhibited a large decrease both 40 and 70 days following olfactory deprivation. The losses were region specific suggesting that the deprivation was not complete. The number of immunoreactive GABAergic neurons was not reduced. The number of neurons containing aromatic L-amino acid decarboxylase (the second enzyme in the dopamine biosynthetic pathway) was also not decreased. Olfactory marker protein immunoreactivity in the glomeruli, a marker for afferent innervation, was not significantly altered indicating that the olfactory bulb was not denervated. These data demonstrate that neonatal deprivation, and the resulting lack of odorant stimulation, produces a transneuronal alteration in dopamine expression without neuronal loss. The studies also suggest that neuronal activity or the activity-dependent release of a trophic factor is necessary for the expression of the dopamine phenotype.

Animals↗

PubMed2003

[Expression and assessment of double genes of tyrosine hydroxylase gene and aromatic L-amino acid decarboxylase gene in vitro].

The characteristic pathological changes of Parkinson s disease (PD) include a severe loss of dopamine neurons in the substantia nigra and a severe decrease in dopamine in the striatum. Since the expression of tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC) in the biosynthetic pathway for dopamine are low, a promising approach to the gene therapy of PD is to augment the gene expression of the enzymes in the biosynthetic pathway for dopamine. In the present study, human TH and AADC genes were reconstructed into retrovirous vectors pLHCX and pLNCX(2) respectively. Then pLHCX/TH and pLNCX(2)/AADC were transfected into packaging cell line PA317 with liposome. PA317/TH and PA317/AADC were selected by different antibiotics. Gene expression was examined by methods of immunohistochemistry and in situ hybridization. The catalytic activity of two cloned gene enzymes was assessed in vitro by HPLC-EC. Immunocytochemical staining showed that TH and AADC were expressed efficiently in vitro. Both TH and AADC mRNA were transcripted in PA317 cell lines by using in situ hybridazation. HPLC-EC experiments revealed that the transfected cells produced a significantly higher level of dopamine and L-dopa than the untransfected cells. The two genetically modified cells could improve the production of L-dopa and dopamine in response to suitable substrate. The present results suggest that not only recombinant TH and AADC genes are successfully expressed in vitro, but also the enzymes have respective functional activities. These results have set up a way for in vivo gene therapy of PD with TH and AADC genes.

Aromatic-L-Amino-Acid Decarboxylases↗

PubMedDate not supplied

Humoral and cellular immune responses to proinsulin in adults with newly diagnosed type 1 diabetes.

BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease characterized by immunity against pancreatic islet-derived proteins. The object of this study was to measure antibody and T-cell responses against proinsulin (PI), an islet-derived protein, and to map its dominant T-cell epitopes. METHODS: Antibody responses to proinsulin, insulin, glutamic acid decarboxylase (GAD), protein tyrosine phosphatase IA-2 and islet-cell antigen were measured in 116 newly diagnosed diabetic subjects aged 16 to 40 years. T-cell proliferative responses to proinsulin and proinsulin peptides were measured in 33 of these diabetic subjects and in 21 healthy control subjects. RESULTS: 22% of diabetic subjects but no control subjects expressed antibodies to proinsulin. A strong correlation existed between antibody levels to proinsulin and insulin within diabetic subjects. Similar proportions of diabetic (12%) and healthy (9.5%) subjects displayed T-cell responses to proinsulin. There was no correlation between antibody and T-cell responses to proinsulin within subjects. Amino acid region 56 to 72 was identified as the major T-cell epitope of proinsulin, though significant responses to region 14 to 37 were also present. CONCLUSION: Elevated proinsulin autoantibodies in diabetic subjects confirm proinsulin is an important autoantigen in type 1 diabetes. Though elevated cellular immunity to proinsulin protein was not detected, two dominant T-cell epitopes of proinsulin were identified that span the C-peptide and insulin junctions. Immunity to proinsulin was lower than that reported for childhood-onset type 1 diabetes and we propose that, like insulin, proinsulin may be targeted less frequently in adulthood.

Adolescent↗

PubMed1988

Neurochemical development of the striatum in a precocial (guinea pig) and an altricial (rat) species.

In this study, the developmental patterns of key neurotransmitter marker enzymes, namely choline acetyltransferase (ChAT), glutamate decarboxylase (GAD), and tyrosine hydroxylase (TH) in the corpus striatum were compared between the guinea pig and rat. In an attempt to assess cell acquisition and differentiation, striatal DNA and protein content were also determined during development in the two species. The most outstanding feature apparent from these investigations was a sequential maturation of the three neurotransmitter-synthesizing enzymes: TH and GAD first, followed by ChAT in striata of both species. The developmental increase in DNA content suggests that cell acquisition in the rat striatum is approximately 50% at birth, whereas in the guinea pig, the total population is present before birth, and thereafter cell numbers decline. The accretion of protein, reflecting the increase in region size, continued into adulthood in both species. With emphasis on cholinergic neurons, the neurochemical findings are assessed in relation to the morphological descriptions of cellular changes during pre- and postnatal development of the striatum.

Animals↗