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PubMed1996

Identification and characterization of glima 38, a glycosylated islet cell membrane antigen, which together with GAD65 and IA2 marks the early phases of autoimmune response in type 1 diabetes.

Immunoprecipitating IgG autoantibodies to glutamic acid decarboxylase, GAD65, and/or a tyrosine phosphatase, IA2, are present in the majority of individuals experiencing pancreatic beta cell destruction and development of type 1 diabetes. Here we identify a third islet cell autoantigen, a novel 38-kD protein, which is specifically immunoprecipitated with sera from a subset of prediabetic individuals and newly diagnosed type 1 diabetic patients. The 38-kD autoantigen, named glima 38, is an amphiphilic membrane glycoprotein, specifically expressed in islet and neuronal cell lines, and thus shares the neuroendocrine expression patterns of GAD65 and IA2. Removal of N-linked carbohydrates results in a protein of 22,000 Mr. Glima 38 autoantibodies were detected in 16/86 (19%) of newly diagnosed patients, including three very young children, who had a rapid onset of disease, and in 6/44 (14%) of prediabetic individuals up to several years before clinical onset. The cumulative incidence of GAD65 and glima 38 antibodies in these two groups was 83 and 80%, respectively, and the cumulative incidence of GAD65, glima 38, and IA2 antibodies in the same groups was 91 and 84%, respectively. GAD65, IA2, and glima 38 represent three distinct targets of immunoprecipitating IgG autoantibodies associated with beta cell destruction and type 1 diabetes.

Adolescent↗
PubMed2000

Islet autoimmunity in infants with a Type I diabetic relative is common but is frequently restricted to one autoantibody.

AIMS/HYPOTHESIS: To determine the sequence of development of islet autoantibodies and their relation to HLA genes in infants at risk for Type I diabetes followed from birth. METHODS: We followed 357 (189 male, 168 female) infants, with a first degree relative with Type I diabetes for a mean of 3 years from birth. Human leukocyte antigen typing and assays for insulin autoantibodies (IAA), glutamic acid decarboxylase antibodies (GADAb) and tyrosine phosphatase IA2 (IA2Ab) antibodies were done on cord blood, and venous blood was sampled every 6 months for IAA, GADAb and IA2Ab. RESULTS: We did not find any antibodies in 263 (73%) infants; 50 (14%) were positive for a single antibody once, 19 (5%) for a single antibody more than once and 25 (7%) for two or more antibodies. Of the latter, 10 (2.8% overall) were persistently positive; they had higher frequencies of HLA DR4 (p < 0.01) and HLA DR3, 4 (p < 0.05). Of the group persistently positive for two or more antibodies four infants developed diabetes. Insulin autoantibodies were the first ones to develop in 64% of infants with two or more antibodies. CONCLUSION/INTERPRETATION: Infants with high risk HLA-DR alleles and multiple antibodies at high risk for diabetes were identified. A much larger group of infants had transient low level increases usually of a single antibody. Whereas transient low level positivity could be attributed to difficulties with assay technique and cut off levels for normality, the results overall support the phenomenon of transient 'self limited' islet autoimmunity in at risk infants.

Aging↗
PubMed1979

Coenzyme--substrate adducts as inhibitors of mouse liver 3,4-dihydroxyphenylalanine decarboxylase.

N-(5'-Phosphopyridoxyl) derivatives of several aromatic amino acids have been prepared by conventional methods and tested as inhibitors of mouse liver L-3,4-dihydroxyphenylalanine (Dopa) decarboxylase (EC 4.1.1.26; L-aromatic-amino-acid decarboxylase). The L-tyrosine, L-phenylalanine, and DL-2-hydroxyphenylalanine derivatives were effective inhibitors at concentrations of 10(-5) M. Because of the spontaneous formation of a tetrahydroisoquinoline cyclic condensation product with pyridoxal phosphate (Pictet--Spengler reaction), the Dopa derivative could not be prepared by the usual procedures. The synthesis of the desired N-(5'-phosphopyridoxyl)-Dopa was accomplished using selective blocking--deblocking methods; its properties are described. This proved to be the most effective inhibitor of those tested. Neither the tetrahydroisoquinoline of L-Dopa and pyridoxal phosphate nor the N-(5'-deoxypyridoxyl)-Dopa was an effective inhibitor of Dopa decarboxylase. These coenzyme amino acid adducts are suggested to act as stage inhibitors of the enzyme.

Amino Acids↗
PubMed1987

Studies on biomodulators of glucocorticoid actions; the nature and the modes of actions of glucocorticoid potency amplifiers.

We have found many compounds that amplify the action of glucocorticoid without themselves having any glucocorticoid-like action and have proposed the concept of 'Glucocorticoid Action Biomodulators'. These biomodulators consist of 'Glucorticoid Sensitivity Amplifiers', which greatly amplify the action of glucocorticoid at doses of glucocorticoid that alone have minimal effects, and 'Glucocorticoid Potency Amplifiers', which markedly enhance the effect of glucocorticoid at doses that have maximal effects. Potent activators of protein kinase C, such as 1,2-racemic dioctanoylglycerol, 12-o-tetradecanoyl-phorbol-13-acetate, and epidermal growth factor (EGF), markedly enhanced the induction of tyrosine aminotransferase and ornithine decarboxylase by dexamethasone in adrenalectomized rats in vivo and in primary cultures of adult rat hepatocytes in vitro. They amplified enzyme induction by even a large amount of dexamethasone that had a maximal effect, but had no effect in the absence of glucocorticoid. These modes of amplification show that these compounds are 'Glucocorticoid Potency Amplifiers'. They amplified not only enzyme induction in liver but also growth inhibition by glucocorticoid of solid tumor L5178Y lymphoblasts. They specifically amplified the actions of glucocorticoids and did not amplify the actions of other steroids, such as 17-beta estradiol, glucagon and insulin. The induction of tyrosine aminotransferase by glucocorticoid and its amplification by EGF were both inhibited by 1-(5-iso-quinoline-sulfonyl)-2-methylpiperazine, an inhibitor of protein kinase C, and not by N-[2-(methylamino)-ethyl]-5-isoquinoline-sulfonamide, an inhibitor of cyclic nucleotide dependent protein kinases, suggesting that the induction and the amplification are mediated by protein kinase C.

Animals↗
PubMed2006

Dietary risk factors for the emergence of type 1 diabetes-related autoantibodies in 21/2 year-old Swedish children.

We studied dietary risk factors by analysing a questionnaire administered at birth, 1 year and 2(1/2) years of age, as well as the level of glutamic acid decarboxylase autoantibodies (GADA) and tyrosine phosphatase autoantibodies (IA-2A), in 7208 2(1/2)-year-old children from the All Babies in Southeast Sweden cohort, using the 95th percentile cut-off for autoantibodies to identify children at risk of type 1 diabetes. A total of 657 children had either IA-2A (n 360) or GADA (n 335), and thirty-eight children had both GADA and IA-2A. In univariate analysis, male gender and maternal coeliac disease implied a risk of possessing IA-2A. Maternal type 2 diabetes, a high consumption of fresh cows milk at the age of 1 year and a late introduction of gluten were associated with a risk of GADA. Early cessation of breast-feeding (< 2 months of age) was associated with a risk of the simultaneous occurrence of both IA-2A and GADA. In logistic regression analysis, a high consumption of milk at the age of I year (odds ratio 2.6)represented a risk for GADA, and maternal coeliac disease (odds ratio 2.9) represented a risk for IA-2A. The combination of an early introduction of cows milk formula and a late introduction of gluten-containing food gave an odds ratio of 6.0 for positivity for at least one autoantibody at 1 and 21 years of age. The induction of autoantibodies by the age of 2(1/2) years has a male preponderance and is more common in children with maternal type 2 diabetes or maternal coeliac disease. Dietary risk factors for the induction of beta-cell autoantibodies in 21-year-old children are a short duration of breast-feeding, an early introduction of cows milk formula and a late introduction of gluten, as well as a high consumption of milk at the age of I year.

Age Factors↗
PubMed1998

Motifs and structural fold of the cofactor binding site of human glutamate decarboxylase.

The pyridoxal-P binding sites of the two isoforms of human glutamate decarboxylase (GAD65 and GAD67) were modeled by using PROBE (a recently developed algorithm for multiple sequence alignment and database searching) to align the primary sequence of GAD with pyridoxal-P binding proteins of known structure. GAD's cofactor binding site is particularly interesting because GAD activity in the brain is controlled in part by a regulated interconversion of the apo- and holoenzymes. PROBE identified six motifs shared by the two GADs and four proteins of known structure: bacterial ornithine decarboxylase, dialkylglycine decarboxylase, aspartate aminotransferase, and tyrosine phenol-lyase. Five of the motifs corresponded to the alpha/beta elements and loops that form most of the conserved fold of the pyridoxal-P binding cleft of the four enzymes of known structure; the sixth motif corresponded to a helical element of the small domain that closes when the substrate binds. Eight residues that interact with pyridoxal-P and a ninth residue that lies at the interface of the large and small domains were also identified. Eleven additional conserved residues were identified and their functions were evaluated by examining the proteins of known structure. The key residues that interact directly with pyridoxal-P were identical in ornithine decarboxylase and the two GADs, thus allowing us to make a specific structural prediction of the cofactor binding site of GAD. The strong conservation of the cofactor binding site in GAD indicates that the highly regulated transition between apo- and holoGAD is accomplished by modifications in this basic fold rather than through a novel folding pattern.

Amino Acid Sequence↗
PubMed1991

Morphofunctional evidence for the involvement of hypothalamic dopaminergic and GABAergic neurons in the mechanisms of photoperiod-dependent prolactin release in the mink.

This study was designed to examine possible relationships between the photoperiodic regulation of prolactin secretion and the activity of dopaminergic and GABAergic neurons projecting to the external layer of the median eminence. The study was carried out on the mink whose remarkable photosensitivity has been clearly demonstrated. The animals were reared in short (4L:20D) or long (20L:4D) photoperiods. The experiment began in November when day length is short (9.5 h). Dopaminergic and GABAergic neurons were studied using immunocytochemical methods allowing evaluation of the immunoreactivities of tyrosine hydroxylase (TH) and glutamate decarboxylase (GAD), which are respective markers of these neurons. The results were quantified by image analysis. The plasma prolactin level of animals maintained in 4L:20D decreased after 60 days and TH and GAD immunoreactivity were strongly stimulated. After 110 days, the prolactin concentration and TH and GAD immunoreactivity recovered their starting levels. In animals maintained in 20L:4D, the prolactin level was 3 times higher than at the beginning of the photoperiodic treatment but only dopaminergic neurons showed a change, i.e. a decrease in immunoreactivity. At the end of the experiment, prolactin secretion was no longer affected by the stimulatory effect of long-day treatment, and TH immunoreactivity remained low. These results confirm the generally accepted concept that dopaminergic neurons are potent PIF-producing components. GABAergic hypothalamic system appears to be implicated in photoperiodic PRL regulation, but this remains to be clearly demonstrated.

Animals↗
PubMedDate not supplied

Non-dopaminergic neurons expressing dopamine synthesis enzymes: differentiation and functional significance.

The development and functional significance of neurons in the arcuate nucleus expressing tyrosine hydroxylase and/or aromatic L-amino acid decarboxylase were studied in rat fetuses, neonates, and adults using immunocytochemical (single and double immunolabeling of tyrosine hydroxylase and aromatic L-amino acid decarboxylase) methods with a confocal microscope and computerized image analysis, HPLC with electrochemical detection, and radioimmunological analysis. Single-enzyme neurons containing tyrosine hydroxylase were first seen on day 18 of embryonic development in the ventrolateral part of the arcuate nucleus. Neurons expressing only aromatic L-amino acid decarboxylase or both enzymes of the dopamine synthesis pathway were first seen on day 20 of embryonic development, in the dorsomedial part of the nucleus. On days 20-21 of embryonic development, dopaminergic (containing both enzymes) neurons amounted to less than 1% of all neurons expressing tyrosine hydroxylase and/or aromatic L-amino acid decarboxylase. Nonetheless, in the ex vivo arcuate nucleus and in primary neuron cultures from this structure, there were relatively high leveLs of dopamine and L-dihydroxyphenylalanine (L-DOPA), and these substances were secreted spontaneously and in response to stimulation. In addition. dopamine levels in the arcuate nucleus in fetuses were sufficient to support the inhibitory regulation of prolactin secretion by the hypophysis, which is typical of adult animals. During development, the proportion of dopaminergic neurons increased, reaching 38% in adult rats. Specialized contacts between single-enzyme tyrosine hydroxylase-containing and aromatic L-amino acid decarboxylase-containing neurons were present by day 21 of embryonic development; these were probably involved in transporting L-DOPA from the former neurons to the latter. It was also demonstrated that the axons of single-enzyme decarboxylase-containing neurons projected into the median eminence, supporting the secretion of dopamine into the hypophyseal portal circulation. Thus, dopamine is probably synthesized in the arcuate nucleus not only by dopaminergic neurons, but also by neurons expressing only tyrosine hydroxylase or aromatic L-amino acid decarboxylase.

Animals↗
PubMedDate not supplied

Glutamic acid decarboxylase antibodies (GADA) is the most important factor for prediction of insulin therapy within 3 years in young adult diabetic patients not classified as Type 1 diabetes on clinical grounds.

BACKGROUND: Differentiation between Type 1 and Type 2 diabetes in adults is difficult at diagnosis. In this study we tested the hypothesis that autoantibodies at diagnosis are predictive for insulin treatment within 3 years in patients initially not classified as Type 1 diabetes. METHODS: In a nationwide population-based study, blood samples were obtained from 764 patients, all diagnosed with diabetes during a 2-year period. At diagnosis, 583 (76%) were classified as Type 1, 110 (14%) as Type 2 and 71 (9.3%) could not be classified. RESULTS: Among patients not classified as Type 1 diabetes, 52 (47%) of Type 2 and 42 (59%) of unclassified patients were positive for islet cell antibodies (ICA), glutamic acid decarboxylase antibodies (GADA) or tyrosine phosphatase antibodies (IA-2A). These patients (n=94) had lower body mass index (BMI) (p<0.001) and lower C-peptide (p<0.001) compared to the autoantibody negative patients (n=87). Compared to clinically classified Type 1 diabetes patients positive for autoantibodies (n=477), they have higher BMI (p<0.001), higher C-peptide (p<0.001) and the same levels of ICA, GADA and IA-2A. After 3 years, 93% of autoantibody positive patients initially not classified as Type 1 were on insulin. When ICA, GADA, IA-2A, BMI and C-peptide were tested in a multiple logistic regression, only GADA was significant for insulin treatment within 3 years (OR=18.8; 95% CI 1.8-191) in patients treated with diet or oral drugs at diagnosis. CONCLUSIONS: A correct classification is difficult in adult diabetic patients. The presence of pancreatic autoantibodies, especially GADA, at diagnosis of diabetes are highly predictive for insulin therapy within 3 years from diagnosis.

Adolescent↗
PubMed2002

Diabetes-related autoantibodies in cord blood from children of healthy mothers have disappeared by the time the child is one year old.

Autoantibodies found in cord blood in children who later develop diabetes might be produced by the fetus. If so, continuous autoantibody production would still be expected in these children at one year of age. We decided to determine autoantibodies in cord blood and to see whether they persisted in these children at one year. Autoantibodies against GAD65 (glutamic acid decarboxylase) and IA-2 (tyrosine phosphatase) in cord blood were determined in 2,518 randomly selected children. Forty-nine (1.95%) were positive for GAD65 antibodies, 14 (0.56%) were positive for IA-2 antibodies, and 3 of them were positive for both GAD and IA-2. Four of the mothers of children with GAD65 autoantibodies in cord blood (8.2%) had type 1 diabetes as did 5 mothers of children with IA-2 antibodies (35.7 %), but only 0.4% of the mothers had type 1 diabetes in the autoantibody-negative group (P < 0.001). Information on infections during pregnancy was available in 2,169 pregnancies. In the autoantibody-positive group, 31.5% had an infection during pregnancy, which was more common than in the autoantibody-negative group of 500 children with the lowest values (20.1%; P < 0.04). At one year follow-up nobody of those with positive cord blood had GAD65 or IA-2 autoantibodies. We conclude that most autoantibodies found in cord blood samples of children are probably passively transferred from mother to child. Antibody screening of cord blood cannot be used to predict diabetes in the general population. Infections during pregnancy may initiate an immune process related to diabetes development.

Adolescent↗
PubMed1983

Regulation of enzymes responsible for neurotransmitter synthesis and degradation in cultured rat sympathetic neurons. I. Effects of muscle-conditioned medium.

The enzymatic machinery for neurotransmitter synthesis and breakdown have been compared in sister cultures of newborn rat sympathetic neurons grown for 12-28 days either in the presence (CM+ cultures) or in the absence (CM- cultures) of a culture medium conditioned by rat skeletal muscle cells. Neuron numbers, total protein, and lactate dehydrogenase activities were identical in CM+ and CM- cultures. Choline acetyltransferase activity was 27- to 100-fold higher in homogenates of CM+ than CM- cultures, whereas acetylcholinesterase activity was 2.5-fold lower. The activities of tyrosine hydroxylase (TOH), DOPA decarboxylase, and dopamine beta-hydroxylase were all about twofold lower in homogenates from CM+ cultures. All these effects were also observed in homogenates of sympathetic neuron cultures grown with and without a macromolecular factor partially purified from CM (Weber, J. (1981). Biol. Chem. 256, 3447-3453.). Experiments of mixing homogenates from CM+ and CM- cultures suggested that the differences in each of the enzyme activities did not result from differences in the concentrations of hypothetical reversible enzyme activators and/or inhibitors. In addition, the deficit in TOH activity in CM+ cultures resulted from a decrease in the enzymatic Vmax with no significant variation in the apparent Km's for the substrate and the cofactor. An identical decrease in the Vmax was observed if TOH was assayed under phosphorylating or nonphosphorylating conditions, suggesting that this decrease did not result from differences in the state of enzyme phosphorylation. Immunoprecipitation curves of TOH activity by an anti-TOH antiserum were parallel when performed on homogenates from CM+ and CM- cultures, suggesting a difference in the number of enzyme molecules without detectable alteration of their kinetic properties.

Acetylcholinesterase↗
PubMedDate not supplied

Developments in the prediction of type 1 diabetes mellitus, with special reference to insulin autoantibodies.

The prodromal phase of type 1 diabetes is characterised by the appearance of multiple islet-cell related autoantibodies (Aab). The major target antigens are islet-cell antigen, glutamic acid decarboxylase (GAD), protein-tyrosine phosphatase-2 (IA-2) and insulin. Insulin autoantibodies (IAA), in contrast to the other autoimmune markers, are the only beta-cell specific antibodies. There is general consensus that the presence of multiple Aab (> or = 3) is associated with a high risk of developing diabetes, where the presence of a single islet-cell-related Aab has usually a low predictive value. The most commonly used assay format for the detection of Aab to GAD, IA-2 and insulin is the fluid-phase radiobinding assay. The RBA does not identify or measure Aab, but merely detects its presence. However, on the basis of molecular studies, disease-specific constructs of GAD and IA-2 have been employed leading to somewhat improved sensitivity and specificity of the RBA. Serological studies have shown epitope restriction of IAA that can differentiate diabetes-related from unrelated IAA, but current assays do not distinguish between disease-predictive and non-predictive IAA or between IAA and insulin antibodies (IA). More recently, phage display technology has been successful in identifying disease-specific anti-idiotopes of insulin. In addition, phage display has facilitated the in vitro production of antibodies with high affinity. Identification of disease-specific anti-idiotopes of insulin should enable the production of a high affinity reagent against the same anti-idiotope. Such a development would form the basis of a disease-specific radioimmunoassay able to identify and measure particular idiotypes, rather than merely detect and titrate IAA.

Aging↗
PubMed1980

Enzymes related to monoamine transmitter metabolism in brain microvessels.

The activities of tyrosine hydroxylase, aromatic L-aminoacid decarboxylase, monoamine oxidase, and catechol-O-methyltransferase were measured in microvessel (capillaries and venules), parenchymal arterioles, and pial vessels from rat brains, and the decarboxylase activity was compared in brain microvessels from rabbit, cat, dog, pig, cow, baboon, and man. Cranial sympathectomy was performed to estimate the neuronal contribution to the enzyme activities. All vascular regions had substantial activities of the various enzymes studied. The activity of aromatic L-aminoacid decarboxylase in cerebral microvessels was high in rat, dog, pig, cow, and man; intermediate in rabbit and cat; and low in baboon. In addition to this enzyme, cerebral microvessels also contained tyrosine hydroxylase and monoamine oxidase. Aromatic aminoacid decarboxylase and monoamine oxidase serve an enzymatic barrier function at the microvascular level, whereas the main function of tyrosine hydroxylase is probably to synthesize monoamines within nerve terminals that remain in close association with microvessels under the conditions used for preparation of the microvascular fraction. In larger intracerebral and pial vessels monoamine oxidase was present both in the wall itself and in perivascular sympathetic nerves; the remaining two enzymes had a primarily neuronal localization. The latter types of vessels also contained catechol-O-methyltransferase in their walls.

Animals↗
PubMed2005

Expression of the neuronal calcium sensor protein NCS-1 in the developing mouse olfactory pathway.

Neuron specific calcium sensor 1 (NCS-1) is widely expressed in the developing and adult nervous system. Like calmodulin, NCS-1 is a member of a family of calcium binding proteins that contain EF-hand motifs, which bind calcium and induce conformational changes in the protein. Their binding varies with calcium concentration, allowing them to act as true calcium sensors rather than just calcium binding proteins. This family of proteins has been implicated in important synaptic events including neurotransmitter release and synapse formation. We examined the expression of NCS-1 in the developing and mature olfactory system to determine whether this molecule may be playing a role in establishing and/or maintaining olfactory circuitry. During development, expression of NCS-1 in the olfactory epithelium was localized in the dendritic knobs and axons of olfactory sensory neurons. Axonal expression was down-regulated after synapse formation. In the developing olfactory bulb, NCS-1 was expressed in the processes of mitral/tufted and granule cells. However, in the adult olfactory bulb, strongest expression was found in a subset of periglomerular cells (PGCs). This subset of PGCs did not express other known markers of PGCs including tyrosine hydroxylase, glutamic acid decarboxylase, calbindin, or calretinin, and only partially overlapped with the subpopulation of PGCs that express parvalbumin. Together, these data suggest multiple and overlapping roles of NCS-1 in the developing and mature olfactory system.

Animals↗
PubMed1986

Retinal neurochemistry of three elasmobranch species: an immunohistochemical approach.

We surveyed retinas of Raja erinacea, Mustelus canis, and Squalus acanthias for neurotransmitter substances by using antisera directed against the substances themselves or against their synthesizing enzymes. Both the peroxidase-antiperoxidase (PAP) and indirect fluorescent techniques were employed to visualize the primary antisera. In all three species positive results were obtained with antisera directed against tyrosine hydroxylase (TOH), glutamic acid decarboxylase (GAD), serotonin (5-HT), and leucine enkephalin (Lenk). Antisera directed against glucagon, neurotensin, beta-endorphin, vasoactive intestinal peptide, or bombesin failed to show any specific staining. Immunoreactivity was located in amacrine, interplexiform, and horizontal cells as well as in axons of the optic fiber layer. The four antisera labelled different amacrine cell classes, distinguished on the bases of perikaryal morphology and the distribution of cell processes in the inner plexiform layer (IPL). Amacrine cells that labelled with the same marker were seen to have different morphologies in the species studied. Thus, TOH-like immunoreactivity was distributed in layers 1, 3, and 5 of the IPL in Mustelus but only in layers 1 and 3 in Raja retina. GAD-like immunoreactivity was found diffusely over all layers of the IPL in Raja, but in Mustelus it was confined primarily to layers 1, 3, and 5 of the IPL. Lenk- and 5-HT-like immunoreactivities showed similar species variations. Two neurochemical classes of interplexiform cell were identified in this study. In Mustelus GAD-like and Lenk-like immunoreactive interplexiform cells were seen whereas in Raja only GAD-positive interplexiform cells were detected. In squalus no unequivocal demonstration of any interplexiform cell was made with these antisera. The GAD antiserum also labelled a subset of the horizontal cells in the dorsal retina of Raja. TOH and 5-HT-antisera labelled axons in the optic fiber layer of all three species but reactive ganglion cell perikarya were not identified.

Animals↗
PubMedDate not supplied

Genetic and perinatal factors as risk for childhood type 1 diabetes.

The mechanisms by which gestational infections, blood incompatibility, birth weight, mother's age and other prenatal or neonatal events increase the risk for type 1 diabetes are not understood. Studies so far have been retrospective, and there is a lack of population-based prospective studies. The possibility of identifying children at type 1 diabetes risk among first-degree relatives has resulted in prospective studies aimed at identifying postnatal events associated with the appearance of autoantibody markers for type 1 diabetes and a possible later onset of diabetes. However, the majority (85%) of new onset type 1 diabetes children do not have a first-degree relative with the disease. Population-based studies are therefore designed to prospectively analyse pregnant mothers and their offspring. One such study is DiPiS (Diabetes Prediction in Skåne), which is examining a total of about 10,000 pregnancies expected every year in the Skåne (Scania) region of Sweden that has 1.1 million inhabitants. Blood samples from all mothers in this region are obtained during pregnancy and at the time of delivery. Cord blood is analysed for HLA high-risk alleles and for autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GADA), the protein tyrosine phosphatase-related IA-2 antigen (IA-2A) and insulin (IAA) as a measure of prenatal autoimmune exposure. Identifying high-risk children by genetic, autoimmune and gestational risk factors followed by prospective analyses will make it possible to test the hypothesis that gestational events may trigger beta cell autoimmunity as a prerequisite for childhood type 1 diabetes.

Autoimmunity↗
PubMed1991

Cellular replacement therapy for neurologic disorders: potential of genetically engineered cells.

Neural transplantation, a mode of cellular replacement, has been used as a therapeutic trial for Parkinson's disease. Studies indicate that tonic release of the metabolites from the graft that can be utilized by the host brain, is likely to be the major mechanism responsible for the therapeutic effect. The use of fetal tissue is complicated by ethical controversy and immunological incompatibility. Autografting adult tissue has not been successful mainly due to poor survival. Genetically engineered cells are promising alternative sources of donor cells. We have investigated the potential of primary skin fibroblasts as donor cells for intracerebral grafting. Primary skin fibroblasts survive in the brain and remain in situ. A number of genes (nerve growth factor, tyrosine hydroxylase, glutamic acid decarboxylase, and choline acetyltransferase) have been successfully introduced and expressed in the primary fibroblasts. The L-dopa-secreting primary fibroblasts exhibited a behavioral effect in a rat model of Parkinson's disease up to 8 weeks after being grafted into denervated striatum. Factors that can maximize gene transfer, transgene expression, and fibroblast survival in the brain make up the future direction of investigation.

Animals↗
PubMed1982

Behavioural and biochemical effects of chronic amphetamine treatment in the vervet monkey.

Five vervet monkeys were administered increasing doses (4--12 mg/kg/day) of d-amphetamine over a period of 35 days. Three phases od behavioural change were discerned: phase 1 during which animals exhibited repetitive stereotyped action sequences with rapid head movements, occasional abnormal grooming, picking at the cage, hand-staring and snatching; phase 2 in which behaviour became progressively more restricted and animals became markedly unresponsive to auditory, visual and tactile stimuli; phase 3 was characterised by the abrupt development of gross over-responsiveness to environmental stimuli, ataxia and tremor. At post-mortem, by comparison with controls, amphetamine-treated monkeys showed marked depletions of the monoamines dopamine (DA), noradrenaline (NA) and serotonin (5-HT) in corpus striatum and cerebral cortex and reductions in the activities of tyrosine hydroxylase and dopa decarboxylase in striatum. Turnover of these monoamines, assessed by high-performance liquid chromatography determinations of their respective metabolites, was also reduced. These findings are interpreted as evidence of monoamine neurone destruction, most severely in the case of DA neurones. Though there was a non-significant reduction in 3H-spiperone binding (reaching almost 50% in nucleus accumbens), numbers of receptors for the monoamines nA and 5-HT were not significantly changed, and the activities of the enzymes choline acetyltransferase and glutamine decarboxylase were similar in experimental and control animals. The contrast of these findings with those seen in post-mortem brains in schizophrenia is discussed.

Animals↗