Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This paper presents epidemiological data on the prevalence of 26 common (i.e., having a lifetime prevalence of more than 1 per 10(4) individuals in the population) multifactorial diseases in Hungary and estimates of detriment associated with them. The detriment is expressed using 3 indicators, namely years of lost life (LL), potentially impaired life (PIL) and actually impaired life (AIL). The total prevalence of these diseases in Hungary has been estimated to be about 6500 per 10(4) individuals in the population. This estimate is in agreement with published data for other parts of the world. On the basis of clinical severity, these diseases have been split into 3 groups, namely (1) very severe (schizophrenia, multiple sclerosis, epilepsy, acute myocardial infarction and related conditions, and systemic lupus erythematosus); (2) moderately severe and/or episodal or seasonal (15 entities including Graves' disease, diabetes mellitus, gout, affective psychoses, essential hypertension, peptic ulcers, asthma, etc.); and (3) less severe than those in the first 2 groups (varicose veins, allergic rhinitis, atopic dermatitis, Scheuermann disease and adolescent idiopathic scoliosis). The essential clinical and genetic aspects of these diseases are briefly discussed. With the exception of epilepsy, none of the diseases included in our list causes mortality between ages 0 and 19. However, they are among the leading causes of death between ages 20 and 69 and thereafter. A sizeable proportion of those with essential hypertension, diabetes mellitus, rheumatoid arthritis, etc. survive to 70 years and beyond, as do those with gout, glaucoma, allergic rhinitis, psoriasis, etc. Overall, about 16% of all deaths that occur in Hungary every year (all age groups) can be attributed to these diseases. The mean number of years of PIL covers a wide range (about 20-40, 12-70 and 40-60 for groups 1, 2 and 3, respectively), the overall mean being about 24 years. However, the nature and degree of impairment and the impact on the life quality of those afflicted differ for the different diseases. Likewise, the mean number of years of AIL (for which the interval between the mean age at premature retirement and mean age at death was used as a rough index) also spans a wide range from 16 to 45, and the overall mean is about 20 years. At the population level, the diseases considered in this paper cause about 2700 years of LL, 96,000 years of PIL and about 5800 years of AIL per 10(4) individuals in the population. Relative to Mendelian diseases as a whole, these multifactorial diseases are associated with much greater detriment (LL: 1.4 X; PIL: 30 X and AIL: 3.9 X).
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PMID:The load of genetic and partially genetic diseases in man. II. Some selected common multifactorial diseases: estimates of population prevalence and of detriment in terms of years of lost and impaired life. 305 77

There are reports in the literature that suggest slightly impaired average intellectual ability, slightly increased signs of brain irritability, and possibly, a slightly increased susceptibility to late-onset schizophrenia with depressive signs, reproductive anomalies, and varicose veins in heterozygotes for phenylketonuria (PKU). The possible significance of such results for our understanding of genetic liabilities for common disease, or of genetic variability influencing mental performance in the normal range is discussed.
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PMID:Phenotypic deviations in heterozygotes of phenylketonuria (PKU). 401 7

Dopamine projections to the cerebral cortex have been implicated in normal and pathological cognitive processes, notably, Parkinson's disease and schizophrenia. To help elucidate the function of these dopamine axons, they were characterized by serial section electron microscopy in individual layers of monkey prefrontal cortex. Dopamine immunoreactivity was visualized with a silver precipitation technique that allowed clear resolution of the internal structures and cell membranes of labeled axons. Apart from the occasional large microtubule-filled axon, dopamine axons were thin and varicose with many clear synaptic vesicles and fewer dense-core vesicles. With few exceptions, dopamine synapses were symmetric and quite small, seen in only one to three serial sections. A determination of the "synaptic incidence" showed that only 39% of labeled varicosities formed identifiable synapses. However, it is certain that some small synapses could not be visualized even in serial sections, and it is possible that the vast majority if not all varicosities form synapses. Except for one soma, dendritic spines and shafts were the recipients of dopamine synapses. Many postsynaptic shafts were small and spiny, indicating that they were distal pyramidal dendrites. However, some postsynaptic shafts especially in supragranular layers had distinctly nonpyramidal features. These lacked spines, had a high density of synaptic inputs, and often had a strikingly varicose morphology. The data suggest that the majority of dopamine synapses in all layers are on pyramidal cells, but that a significant fraction are on presumed GABAergic nonpyramidal cells.
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PMID:Heterogeneous targets of dopamine synapses in monkey prefrontal cortex demonstrated by serial section electron microscopy: a laminar analysis using the silver-enhanced diaminobenzidine sulfide (SEDS) immunolabeling technique. 768 95

Recent postmortem studies have suggested that reduced gamma-aminobutyric acid (GABA)ergic activity in limbic cortex may be one component to the pathophysiology of schizophrenia. This hypothesis has underscored the importance of knowing whether midbrain dopamine afferents interact extensively enough with inhibitory interneurons to suggest a direct functional relationship. Toward this end, a double immunofluorescence approach combined with confocal laser scanning microscopy has been used to localize dopamine and GABA simultaneously in rat medial prefrontal cortex. The results confirm studies from other laboratories showing a rich network of dopamine-immunoreactive fibers forming a gradient across the cortical laminae, with deeper layers having the highest density. When viewed with oil immersion optics, dopamine-immunoreactive fibers were frequently found to be in close apposition with GABA-immunoreactive cell bodies. The percentage of GABA-containing neurons showing such contacts was highest in layer VI (65%) and progressively decreased toward layer I (9%). Varicose regions of the dopamine fibers were typically present at the point of contact with a GABA-immunoreactive cell body. Using an immunoperoxidase technique to localize dopamine fibers and cresyl violet staining to visualize neurons simultaneously, two separate statistical analyses were performed to assess whether the frequency of contacts between dopamine fibers and cell bodies in general may be due to random effects. In layer VI, a high percentage of both pyramidal and nonpyramidal neurons were found to be in contact with dopamine varicosities (71% and 76%, respectively), but these were not significantly different from that observed for GABA-containing cells (65%) in double-immunofluorescence specimens. A Chi-square statistical test was used to compare the observed and predicted number of varicosities forming cell body contacts. This analysis indicated that the percentage of dopamine varicosities (30%) that form appositions with cell bodies is much greater than would be expected if these appositions were due to random effects (15%). Moreover, using an estimate of intensity for a stationary Poisson process, it was again found that random effects can not account for these interactions (P = 0.01). Taken together with earlier electron microscopic studies from other laboratories, the present findings support the idea that GABAergic interneurons have extensive interactions with dopamine varicosities. While these interactions are not unique to GABAergic cell bodies, they suggest that inhibitory interneurons can play a direct role in mediating the effects of midbrain dopamine afferents in rat medial prefrontal cortex.
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PMID:Dopamine-immunoreactive axon varicosities form nonrandom contacts with GABA-immunoreactive neurons of rat medial prefrontal cortex. 815 76

A series of recent postmortem investigations of the anterior cingulate cortex in schizophrenic brain have suggested that there may be a loss and/or impairment of inhibitory interneurons in layer II. It has been postulated that changes of this type could secondarily result in a relative increase of dopaminergic inputs to GABAergic interneurons. To test this hypothesis, an immunoperoxidase technique was developed to extensively and reliably visualize tyrosine hydroxylase-immunoreactive (TH-IR) varicose fibers in human postmortem cortex. This method has been applied to the anterior cingulate (ACCx; Brodmann area 24) and prefrontal (PFCx: Brodmann area 10) cortices from a cohort of 15 normal control and 10 schizophrenic cases. The number of TH-IR varicosities in contact with large neurons (LN), small neurons (SN), and neuropil (NPL) was blindly analyzed using a computer-assisted microscopic technique. There was no significant difference in density of TH-IR varicosities in apposition with either LN or SN cell bodies observed in either ACCx or PFCx of schizophrenics when compared to normal controls. The density of varicosities was significantly reduced in NPL of layers V and VI in ACCx, but 2 neuroleptic-free cases did not show this change, suggesting that these decreases of TH-IR varicosities may be related to antipsychotic effects on corticostriatal projection cells in this region. When the density of TH-IR varicosities on SNs was compared to that observed on LNs, both groups showed a higher density on SNs. In ACCx, this pattern was much more pronounced for the schizophrenic group, particularly in layer II where the density on SNs was three times higher than that for LNs (P = 0.01). Unlike the changes in layer V, this latter change in layer II showed no relationship to neuroleptic exposure. There was a positive correlation between age and the density of TH-IR varicosities on SNs of layer II in ACCx; however, the patients were younger than the controls and would have been expected to show a lower density, rather than a higher one, if age considerations had accounted for the group differences. Overall, the results reported here suggest that there are no gross differences in the distribution of TH-IR varicosities in various laminae of the dorsolateral prefrontal cortex. In the anterior cingulate region, however, there may be a significant shift in the distribution of TH-IR varicosities from large neurons to small neurons that occurs selectively in layer II of schizophrenic subjects. Using size criteria, the majority of small neurons are likely nonpyramidal, while the majority of large neurons are predominantly pyramidal in nature. Taken together with other accumulating evidence of preferential abnormalities in this lamina of the cingulate region, the findings reported here are consistent with a model of schizophrenia in which a subtle "miswiring" of ventral tegmental inputs may result in a relative, though not absolute, hyperdopaminergic state with respect to an impaired population of GABAergic interneurons.
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PMID:Differential distribution of tyrosine hydroxylase fibers on small and large neurons in layer II of anterior cingulate cortex of schizophrenic brain. 898 51

Interactions between dopamine and glutamate play prominent roles in memory, addiction, and schizophrenia. Several lines of evidence have suggested that the ventral midbrain dopamine neurons that give rise to the major CNS dopaminergic projections may also be glutamatergic. To examine this possibility, we double immunostained ventral midbrain sections from rat and monkey for the dopamine-synthetic enzyme tyrosine hydroxylase and for glutamate; we found that most dopamine neurons immunostained for glutamate, both in rat and monkey. We then used postnatal cell culture to examine individual dopamine neurons. Again, most dopamine neurons immunostained for glutamate; they were also immunoreactive for phosphate-activated glutaminase, the major source of neurotransmitter glutamate. Inhibition of glutaminase reduced glutamate staining. In single-cell microculture, dopamine neurons gave rise to varicosities immunoreactive for both tyrosine hydroxylase and glutamate and others immunoreactive mainly for glutamate, which were found near the cell body. At the ultrastructural level, dopamine neurons formed occasional dopaminergic varicosities with symmetric synaptic specializations, but they more commonly formed nondopaminergic varicosities with asymmetric synaptic specializations. Stimulation of individual dopamine neurons evoked a fast glutamatergic autaptic EPSC that showed presynaptic inhibition caused by concomitant dopamine release. Thus, dopamine neurons may exert rapid synaptic actions via their glutamatergic synapses and slower modulatory actions via their dopaminergic synapses. Together with evidence for glutamate cotransmission in serotonergic raphe neurons and noradrenergic locus coeruleus neurons, the present results suggest that glutamatergic cotransmission may be the rule for central monoaminergic neurons.
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PMID:Dopamine neurons make glutamatergic synapses in vitro. 961 34

About the 'Omnipotence' of the Chelation Therapy In the eighties the 'method of treatment proven in many thousands of cases over 20 years' was transferred from the USA to Germany (enjoys a priori considerable faith) using very dubious promises. It was Clarke et al. who introduced this 'therapy' in 1955. The dubious promise was to maintain that the chelation therapy eliminates or alleviates symptoms in the case of the following illnesses: Alzheimer's disease, senility, schizophrenia, rheumatoid arthritis, osteoarthritis, gout, renal calculus, apoplectic coma, gallstones, multiple sclerosis, osteoporosis, chronic fatigue syndrome, varicose veins, hypertension, failure of memory, scleroderma, Raynaud's disease, digitalis intoxication, intermittent claudication, diabetic ulcer, disturbance of the blood supply, ulcer on the legs, snake poison, impotence, emotional difficulties, defective hearing, vision disorder. There is not the slightest proof of effectiveness for any of the listed indications. The burden of proof lies with the supplier. Even in the case of the relatively often examined peripheral atherosclerotic changes (claudicatio intermittens) there is no proof that EDTA has a greater effect than placebo. For coronary heart disease too there is no evidence for any usefulness of the chelation therapy beyond that of a placebo effect. Only controlled studies can help to improve the therapy in the sense of 'Evidence-based medicine'. Retrospective investigations on thousands of patients cannot 'prove' anything, although this is maintained again andagain.
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PMID:ber die laquo;Omnipotenz>> der Chelattherapie. 997 59

The density of TH-IR varicosities was analyzed in the hippocampus of 15 normal controls and 11 schizophrenics. The average density of varicosities in apposition with pyramidal cells and in the neuropil was 30-35% lower in CA2, but not other sectors of schizophrenics. Age was correlated with varicosity density in all sectors, particularly in CA2 where young patients showed a 50% reduction on non-pyramidal cells. Neuroleptic dose showed a negative correlation with the density of varicosities, and notably the dose of young schizophrenics was four times higher than that of older subjects. Thus, antipsychotic dose appears to be associated with a suppression of a normal age-related increase of dopamine projections to CA2 during the early phases of schizophrenia.
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PMID:Effect of age and neuroleptics on tyrosine hydroxylase-IR in sector CA2 of schizophrenic brain. 1061 38

The mesoaccumbens projection, formed by ventral tegmental area dopamine neurons synapsing on nucleus accumbens gamma-aminobutyric acid neurons, has been implicated in the pathogenesis of schizophrenia and drug addiction. Despite intensive study, the nature of the signal conveyed by dopamine neurons has not been fully resolved. In addition to several slower, dopamine-mediated, modulatory actions, several lines of evidence suggest that dopamine neurons have fast excitatory actions. To test this, we placed dopamine neurons together with accumbens neurons in microcultures. Surprisingly, most dopamine neurons made excitatory recurrent connections (autapses), which provided a basis for their identification; accumbens gamma-aminobutyric acid neurons were identified by their distinctive size. In 75% of mesoaccumbens cell pairs, stimulation of the dopamine neuron evoked a glutamate-mediated, excitatory synaptic response in the accumbens neuron. Immunostaining revealed dopamine neuron varicosities that were predominantly dopaminergic, ones that were predominantly glutamatergic, and ones that were both dopaminergic and glutamatergic. Despite close appositions of both glutamatergic and dopaminergic varicosities to the dendrites of accumbens neurons, only glutamatergic synaptic responses were seen. In the majority of cell pairs, pharmacologic activation of D2-type dopamine receptors inhibited glutamatergic responses, presumably via immunocytochemically-visualized presynaptic D2 receptors. In some cell pairs, the evoked autaptic and synaptic responses were discordant, suggesting that D2 receptors may be differentially trafficked to different presynaptic varicosities.Thus, dopamine neurons appear to mediate both slow dopaminergic and fast glutamatergic actions via separate sets of synapses. Together with evidence for glutamate cotransmission in serotonergic raphe neurons and noradrenergic locus coeruleus neurons, these results add a new dimension to monoamine neuron signaling that may have important implications for neuropsychiatric disorders.
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PMID:Mesoaccumbens dopamine neuron synapses reconstructed in vitro are glutamatergic. 1102 37

Cortical serotonin(2A) receptors are hypothesized to be involved in the pathology and treatment of schizophrenia. Light microscopic studies in the rat prefrontal cortex have localized serotonin(2A) receptors to the dendritic shafts of pyramidal and local circuit neurons. Electrophysiological studies have predicted that these receptors are also located on glutamate terminals, whereas neurochemical studies have hypothesized that they are located on dopamine terminals in this area. The present study sought to determine the ultrastructural localization of immunoperoxidase labeling for serotonin(2A) receptors in the middle layers of the prelimbic portion of the rat prefrontal cortex. Serotonin(2A) receptor immunoreactivity was observed in 325 identifiable structures. Of these, 73% were postsynaptic profiles that were composed of either dendritic shafts (58%) or dendritic spine heads and necks (42%). Twenty-four percent of the labeled profiles were presynaptic axons and varicosities; most of these had morphological features that were characteristic of monoamine axons: thin diameter, lack of myelination, occasional content of dense-cored vesicles, and infrequent formation of synapses in single sections. The remainder of the labeled profiles (4%) were glial processes. These findings suggest that serotonin(2A) receptor-mediated effects within the rat prelimbic prefrontal cortex are primarily postsynaptic in nature, affecting both the spines of pyramidal cells and the dendrites of pyramidal and local circuit neurons in this area. The results further suggest that serotonin acts presynaptically via this receptor subtype, most likely at receptors on monoamine fibers, and only rarely directly on glutamate axons.
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PMID:Ultrastructural localization of serotonin2A receptors in the middle layers of the rat prelimbic prefrontal cortex. 1253 44


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