Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cellular nature of the giant eosinophilic cells of tuber and of the cells comprising subependymal giant cell astrocytoma (SEGA) in tuberous sclerosis (TS) remains unclear. To assess the characteristics of these lesions, 13 tubers and 6 SEGA were immunohistochemically studied with glial and neuron-associated antigens. In addition to conventional ultrastructure, 6 tubers and 8 SEGA were subjected to immunoelectron microscopic study for glial fibrillary acidic protein (GFAP) and somatostatin. Eosinophilic giant cells of tubers were positive for vimentin (100%), GFAP (77%) and S-100 protein (92%); such cells were also found to a various extent to be reactive for neuron-associated antigens, including neurofilament (NF) proteins (38%) or class III beta-tubulin (77%). SEGA also showed variable immunoreactivity for GFAP (50%) or for S-100 protein (100%); NF epitopes, class III beta-tubulin, and calbindin 28-kD were expressed in 2 (33%), 5 (83%) and 4 (67%) cases, respectively. Cytoplasmic staining for somatostatin (50%), met-enkephalin (50%), 5-hydroxytryptamine (33%), beta-endorphin (33%) and neuropeptide Y (17%) was noted in SEGA, but not in tubers. Ultrastructurally, the giant cells of tubers and the cells of SEGA contained numerous intermediate filaments, frequent lysosomes and occasional rectangular or rhomboid membrane-bound crystalloids exhibiting lamellar periodicity and structural transition to lysosomes. Some SEGA cells showed features suggestive of neuronal differentiation, including stacks of rough endoplasmic reticulum, occasional microtubules and a few dense-core granules. Furthermore, in one case of tuber, a process of a single large cell was seen to be engaged in synapse formation. Intermediate filaments within a few cells of both lesions were decorated by gold particle-labeled GFAP antiserum. Within the tumor cells of SEGA, irregular, non-membrane-bound, electron-lucent areas often contained somatostatin-immunoreactive particles, whereas the latter could not be detected in tuber. The present study provides further evidence of divergent glioneuronal differentiation, both in the giant cells of tubers and the cells of SEGA. The findings of similar cells at different sites, including the subependymal zone, white matter ("heterotopias"), and cortex indirectly supports the idea that these lesions of TS result from a migration abnormality.
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PMID:Tuber and subependymal giant cell astrocytoma associated with tuberous sclerosis: an immunohistochemical, ultrastructural, and immunoelectron and microscopic study. 854 29

Subependymal giant cell astrocytoma (SEGA) is the most common neoplastic process involving the brain in patients with tuberous sclerosis complex (TSC). Morphologically, these tumors exhibit a wide range of cytoarchitecture with spindle and epithelioid cells resembling astrocytes, and also large, occasionally giant cells, some of which have a distinctly ganglion-like appearance. Unresolved questions regarding SEGAs center on: (a) their cytogenesis, i.e., whether they are derived from single or multiple precursors; and (b) their differentiating capacity along glial or neuronal lines. We sought to determine whether SEGAs represent truly mixed tumors or whether they consist of a single population of cells with a capacity for divergent differentiation. Twenty SEGAs were assessed for immunophenotypic features of either neuronal or glial differentiation or both. Only tumors from patients with a clinically confirmed diagnosis of TSC were included. Immunoreactivity for glial fibrillary acidic protein (GFAP) and/or S-100 protein was considered indicative of a glial phenotype, whereas the presence of neuronal differentiation was assessed by staining for cytoskeletal proteins [neurofilament epitopes, class III Beta-tubulin, microtubule-associated protein 2 (MAP2), synaptophysin], neurosecretory substances [serotonin, cholecystokinin, Beta-endorphin, substance P, somatostatin, metenkephalin, neuropeptide Y, vasoactive intestinal polypeptide (VIP), and for the 28-kDa neuron-associated calcium binding protein calbindin. Of the tumors examined, 18 exhibited both glial and neuronal epitopes, the staining pattern being variable. In 19 tumors, the constituent spindle, polygonal and giant or ganglion-like cells showed variable immunoreactivity for GFAP and S-100 proteins both within the cell body and processes. Neuron-associated cytoskeletal proteins were present in 18 cases. Class III Beta-tubulin immunoreactivity was demonstrated in 17 tumors, both within the bodies of all three cell types and to varying degrees within their processes. Neurofilament protein and calbindin staining was present in 8 tumors, with reactivity for the former being distributed in a phosphorylation-dependent manner. MAP2 was detected in a few cells of two tumors. Immunoreactivity for neuropeptides was observed in 17 lesions. Somatostatin and metenkephalin staining was noted in 10 tumors (50%) being present particularly within polygonal cells. Neuropeptide Y, serotonin and Beta-endorphin reactivity was found in 6 (30%), 5 (25%), and 4 tumors (20%), respectively; Beta-endorphin was lacking in giant cells, whereas neuropeptide Y and serotonin were seen within their cell bodies. Substance P and VIP were evident in only occasional polygonal cells of 2 (10%) and 1 tumor (5%), respectively. Stains for cholecystokinin were negative. The observation of immunoreactivity for both glial- and neuron-associated epitopes within tumor cells of the same morphology suggests that SEGAs represent proliferations of cell lineages with the capacity to undergo divergent glioneuronal as well as neuroendocrine differentiation to a greater extent than do other mixed glial-neuronal neoplasms.
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PMID:Immunohistochemical characterization of subependymal giant cell astrocytomas. 892 13

The case of a 5-month-old boy with tuberous sclerosis and West syndrome is reported. Tonic spasms were noted from the age of 4 months. High-dose pyridoxal phosphate could not control the seizures completely. Very short and low-dose adrenocorticotropic hormone (ACTH) therapy (i.e. 0.011 mg/kg per dose, 12 times in 20 days) controlled the seizures, while pyridoxal phosphate was on. Early tapering of ACTH was successfully done while abnormal electroencephalogram (EEG) findings remained. Although side effects such as hypertension and brain shrinkage were transiently observed, both the cognitive and seizure prognoses were excellent at the age of 3 years and 2 months. The good response to a small dosage of ACTH might be due to some responsiveness of the high-dose pyridoxal phosphate and the underlying cause of tuberous sclerosis with normal development before onset. The present case illustrates that the duration and dosage of ACTH therapy in West syndrome should be modified according to the individual's requirements.
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PMID:A case of West syndrome well controlled by very short and low-dose ACTH therapy. 1020 Dec 87

Infantile spasms are a devastating epileptic encephalopathy of the young child. The continuing spasms and hypsarrhythmia have a deleterious effect on brain maturation and further cognitive development. Corticotropin (adrenocorticotropic hormone) or corticosteroids have been the gold standard treatment for the last 40 years, but there is little agreement on the best agent to use, or the dosage and duration of the treatment. Despite this empirical approach, corticotropin or corticosteroids are effective in controlling spasms and normalising electroencephalograms in about 60% of cases. The major concern with this treatment is the occurrence of frequent and severe adverse effects. The introduction of vigabatrin in the 1990s improved the outcome of infantile spasms. Vigabatrin shows an efficacy at least equal to that of corticosteroids, and even higher in specific groups such as those with tuberous sclerosis. The major advantages of vigabatrin are the ability to initiate treatment at the full dosage. rapid efficacy, suitability for outpatient treatment and particularly good tolerability with only minor adverse effects. Recently, however, the safety of vigabatrin has caused concern since a specific visual field loss has been reported in treated adults. The current problem is determining the risk-benefit ratio of vigabatrin and corticosteroids/corticotropin in children with infantile spasms, and to specify the groups where their use could be optimal. Visual field loss is usually asymptomatic and can be detected only by perimetric visual field studies. In children, especially in the young or disabled, it is difficult if not impossible to detect the visual field loss and it is not yet known if children are at higher or lower risk for this adverse effect. Until a clear answer about the occurrence of this adverse effect in children has been established through randomised study, vigabatrin may still be considered first-line therapy in infantile spasms. Children who do not achieve a good response to vigabatrin should be switched to corticotropin/corticosteroid therapy. Despite the efficacy of corticosteroids and vigabatrin, the use of the conventional antiepileptic drugs, the newly developed antiepileptic drugs and some promising results with ketogenic diet, 25 to 30% of patients with infantile spasms continue to have spasms and experience psychomotor regression. These drug-resistant patients could be candidates for surgery.
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PMID:A risk-benefit assessment of treatments for infantile spasms. 1166 69

To provide up-to-date information on adrenocorticotropic hormone (ACTH) therapy in the treatment of West syndrome, a review of the Finnish studies was made in answer to the questions: what are (1) its efficacy: doses and comparison with vigabatrin (VGB), (2) its tolerability, (3) its mechanism of action? Why do some patients respond, but others do not? No other drugs have been shown to be more effective than ACTH. High doses were not more effective than low doses. Synthetic derivatives were associated with more frequent side effects. Individualized therapy was developed on the basis of etiology and response. With therapy consisting of ACTH 3-6IU/kg/day, all the cryptogenic and half of the symptomatic spasms could be controlled within over 2-3 weeks therapy and with minimal risk of side effects. In a Finnish study, 26% of the patients responded to VGB as the first-line drug. Some of the non-responders responded to ACTH. In tuberous sclerosis, the initial response rate to ACTH was high (73%) and did not differ from the response rate to VGB in other series. Both drugs have severe side effects. The visual field defects caused by VGB occur even in children (in 18/91 Finnish children). The patients with cryptogenic spasms, who responded well to ACTH, differed in their biochemical parameters from the patients with symptomatic spasms. The therapeutic action of ACTH may be mediated by potentiation of nerve growth promoting activity. Neurodegeneration may be due to imbalance between nerve growth factors and nitrate/nitrite in the brain. ACTH should be used as the first choice for treatment of West syndrome (at the minimal effective dose and for shortest effective time). The side effects of steroids, unlike VGB, are well known, treatable, and reversible.
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PMID:ACTH therapy of West syndrome: Finnish views. 1170 Dec 69

Infantile spasms are the main feature in West syndrome, an age-related epilepsy syndrome that affects 1 in every 2,000-4,000 infants. The authors provide a comprehensive review of the literature about infantile spasms and their therapy. In the United States, the drug of choice for infantile spasms, at least the cryptogenic cases, has been adrenocorticotropic hormone (ACTH). It is generally considered to be more effective than corticosteroids. Adrenocorticotropic hormone appears to alter long-term prognosis of cryptogenic infantile spasms, and helps in some cases of symptomatic infantile spasm. Vigabatrin has been considered the drug of choice for infantile spasms secondary to tuberous sclerosis, and possibly, according to many neurologists, for all cases of infantile spasm. Recent concerns regarding retinopathy associated with vigabatrin therapy are, however, limiting the use of this drug. Valproic acid benefits 40%-70% of patients who failed a trial of ACTH. Nitrazepam is as effective as ACTH in acutely controlling infantile spasms; however, its long-term effects on prognosis have not been studied. Pyridoxine, lamotrigine, topiramate, zonisamide, ketogenic diet, immunoglobulin therapy, felbamate, and thyrotropin-releasing hormone have all been used for the treatment of infantile spasms, but are usually reserved for cases refractory to vigabatrin and/or ACTH.
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PMID:Medical treatment of patients with infantile spasms. 1198 Dec 30

Up-to date information about corticotropin (ACTH) in the treatment of infantile spasms and evaluation of the long-term outcome was provided to answer questions about (1) the efficacy of doses of ACTH in comparison with other drugs, especially with vigabatrin, and the efficacy in patients with tuberous sclerosis; (2) tolerability; and (3) long-term outcome. In two studies, high doses were not more effective than low doses but were more effective in another study. In the follow-up of the studies, there was no difference. In an open, randomized, prospective study, the efficacy and relapse rates of ACTH and vigabatrin treatment did not differ significantly. The high response rates in tuberous sclerosis complex were similar. Both drugs had severe side effects. In the long-term follow-up of 20 to 35 years, one third of the patients died, the intellectual outcome of the remaining patients was normal or slightly subnormal, and one quarter and one third of the patients were seizure free. ACTH should be the first choice for treatment of infantile spasms. The side effects of ACTH, unlike those of vigabatrin, are well known, treatable, and reversible. However, an open, prospective study to compare the efficacy, relapse rate, and long-term outcome of treatment with ACTH and vigabatrin is urgently needed. The frequency of visual field defects after vigabatrin therapy should be evaluated.
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PMID:Infantile spasms: therapy and outcome. 1544 86

Infantile spasms are an epilepsy syndrome with distinctive features, including age onset during infancy, characteristic epileptic spasms, and specific electroencephalographic patterns (interictal hypsarrhythmia and ictal voltage suppression). Adrenocorticotropic hormone (ACTH) was first employed to treat infantile spasms in 1958, and since then it has been tried in prospective and retrospective studies for infantile spasms. Oral corticosteroids were also used in a few studies for infantile spasms. Variable success in cessation of infantile spasms and normalization of electroencephalograms was demonstrated. However, frequent significant adverse effects are associated with ACTH and oral corticosteroids. Vigabatrin has been used since the 1990s, and shown to be successful in resolution of infantile spasms, especially for infantile spasms associated with tuberous sclerosis. It is associated with visual field constriction, which is often asymptomatic and requires perimetric visual field study to identify. When ACTH, oral corticosteroids, and vigabatrin fail to induce cessation of infantile spasms, other alternative treatments include valproic acid, nitrazepam, pyridoxine, topiramate, zonisamide, lamotrigine, levetiracetam, felbamate, ganaxolone, liposteroid, thyrotropin-releasing hormone, intravenous immunoglobulin and a ketogenic diet. Rarely, infantile spasms in association with biotinidase deficiency, phenylketonuria, and pyridoxine-dependent seizures are successfully treated with biotin, a low phenylalanine diet, and pyridoxine, respectively. For medically intractable infantile spasms, some properly selected patients may have complete cessation of infantile spasms with appropriate surgical treatments.
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PMID:Current trends in the treatment of infantile spasms. 1955 23

Infantile spasms are seizures manifesting within a spectrum of epileptic encephalopathies of infancy that often lead to cognitive impairment. Their current therapies, including adrenocorticotropic hormone (ACTH), high dose steroids, or vigabatrin, are not always effective and may be associated with serious side effects. Overactivation of the TORC1 complex of the mTOR pathway is implicated in the pathogenesis of certain genetic and acquired disorders that are linked with infantile spasms, like tuberous sclerosis. Here, we tested the therapeutic potential of rapamycin, a TORC1 inhibitor, as a potential treatment for infantile spasms in the multiple-hit rat model of ACTH-refractory symptomatic infantile spasms, which is not linked to tuberous sclerosis. Rapamycin or vehicle was given after spasms appeared. Their effects on spasms, other seizures, performance in Barnes maze, and expression of the phosphorylated S6 ribosomal protein (pS6: a TORC1 target) in the cortex, using immunofluorescence, were compared. Rapamycin suppressed spasms dose-dependently and improved visuospatial learning, although it did not reduce the frequency of other emerging seizures. High-dose pulse rapamycin effected acute and sustained suppression of spasms and improved cognitive outcome, without significant side effects. Therapeutically effective rapamycin doses normalized the pS6 expression, which was increased in perilesional cortical regions of pups with spasms. These findings support that pathological overactivation of TORC1 may be implicated in the pathogenesis of infantile spasms, including those that are not linked to tuberous sclerosis. Furthermore, a high-dose, pulse rapamycin treatment is a promising, well tolerated and disease-modifying new therapy for infantile spasms, including those refractory to ACTH.
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PMID:A pulse rapamycin therapy for infantile spasms and associated cognitive decline. 2150 92

Infantile spasms syndrome (IS) (also known as West syndrome) is an epileptic encephalopathy with a heterogeneous etiology. One of the most common specific causes is tuberous sclerosis, diagnosed in almost 10% of the affected infants. Adrenocorticotropic hormone or steroids have been the preferred treatments for IS for several decades. Clinical studies have shown that vigabatrin is superior to placebo in decreasing the frequency of infantile spasms. In tuberous sclerosis, vigabatrin may be considered the first-line treatment for IS. The mode of action is increasing concentrations of the inhibitory neurotransmitter GABA in the brain. The use of vigabatrin is limited by a serious adverse effect, permanent visual field constriction, which may affect 6-7% of exposed infants. Treatment choices are based on balancing the potential adverse effects against the risk of catastrophic cognitive and behavioral outcomes caused by uncontrolled spasms.
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PMID:Vigabatrin monotherapy for infantile spasms. 2236 26


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