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)

We have cloned a bovine adrenal cortical (bKv1.4) K(+) channel cDNA whose expression is rapidly inhibited by adrenocorticotropic hormone (ACTH). The 4386-nucleotide cDNA is homologous to other voltage-gated, rapidly inactivating Kv1.4 channels, and includes a 1986-nucleotide coding region and large 5'- and 3'-untranslated regions. Bovine Kv1.4-specific mRNA from adrenal zona fasciculata (AZF) cells was rapidly and potently reduced by ACTH, with a t(12) of approximately 1 h and an IC(50) of 1.2 pm. The membrane-permeable cAMP analog 8-pcpt-cAMP also reduced bKv1.4 mRNA expression with kinetics similar to that observed with ACTH. Reduction of bKv1.4 mRNA expression by ACTH and 8-pcpt-cAMP was only partially inhibited by the selective protein kinase A antagonist H-89. Consistent with their effect on bKv1.4 mRNA, ACTH and 8-pcpt-cAMP both dramatically reduced the expression of bKv1.4-associated A-type current measured over 72 h. These results demonstrate that bovine AZF cells synthesize a Kv1.4-type channel whose expression is inhibited at the pretranslational level by ACTH and 8-pcpt-cAMP by a mechanism that is partially dependent on the activation of protein kinase A. The rapid, potent reduction of bKv1.4 mRNA produced by ACTH and 8-pcpt-cAMP indicates that the expression of this K(+) channel is under tonic inhibitory control of the hypothalamic-pituitary-adrenal axis. The basic electrical properties of AZF cells might be tightly regulated at the transcriptional level by the normal diurnal pattern of ACTH secretion, and altered during bouts of stress by the enhanced release of this pituitary peptide. Under conditions of prolonged stress or adrenal insufficiency, persistent ACTH-induced changes in the electrical properties of AZF cells could be coupled to parallel changes in cortisol secretion.
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PMID:A bovine adrenocortical Kv1.4 K(+) channel whose expression is potently inhibited by ACTH. 1091 43

Many vital organs, including the endocrine glands, are affected by iron deposition in thalassemic (Thal.) patients. Involvement of the adrenal gland, although not uncommon, is usually not clinically evident, especially in non-stressful situations. Although the pituitary-adrenal axis (PAA) has been evaluated by several investigators, the impact of surgical stress has not yet been assessed. Do Thal. patients have an adequate adrenocorticotropic hormone (ACTH) cortisol response upon surgical insult? The PAA of 27 (8 female, 19 male) Thal. patients aged 4-15 years (mean 8.96) admitted during 1996-1997 for splenectomy was evaluated before and after surgical stress. Blood samples for measurement of ACTH and cortisol were taken 1 day before and about 2 h after the surgical insult. For comparison, 22 (9 female, 13 male) non-thalassemic (N. Thal.) patients aged 3.5-14 years (mean 7.95) admitted for elective laparotomy who had no evidence of chronic disease or malnutrition served as controls. Timing of blood sampling was similar to that of the study group. The cortisol response after surgical stress was significantly higher than baseline for both the Thal. (17.4 +/- 6.3 vs 30.81 +/- 11.49 microg/dl; P < 0.001) and N. Thal. groups (20.65 +/- 9.1 vs 36.87 +/- 11.08 microg/dl; P < 0.001). N. Thal. patients showed significant elevation of ACTH upon surgical stress (72.5 +/- 39.5 vs 129.09 +/- 67.9 pg/ml; P < 0.001), while the difference between pre- and post-stress was not statistically remarkable in Thal. patients (104.15 +/- 60.74 vs 186.8 +/- 246.24 pg/ml; P = 0.123). However, ACTH before operation in Thal. was significantly higher than that of N. Thal. patients (104.15 +/- 60.74 vs 72.5 +/- 39.5 pg/ml; P < 0.042), with no remarkable difference after surgical stress between both groups (186.8 +/- 246.24 vs 129.09 +/- 67.9; P = 0.261). The serum ferritin in 8 of 13 young Thal. patients (4-8 years old) was < 2,000 ng/ml and 2,000-3,000 in the remaining 5, while in the 14 older patients (9-15 years) it was < 2,000 in 5, 2,000-3,000 in 7, and more than 3,000 ng/ml in the oldest 2 (13 and 15 years). The PAA is usually intact and responsive in Thal. patients. However, the underlying cause of the significantly increased preoperative ACTH concentrations may be a decreased adrenal reserve, presumably related to age and iron load. For this reason, the possibility of primary partial or early adrenal insufficiency in spite of adequate but probably less than expected cortisol synthesis before and after surgical stress should be considered in every prepubertal or older Thal. patient.
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PMID:Cortisol and adrenocorticotropic hormone response to surgical stress (splenectomy) in thalassemic patients. 1095 73

The short ACTH test is widely used in clinical practice for the diagnosis of adrenal insufficiency. It is classically performed administering 250.0 microg ACTH(1-24) although 1.0 microg ACTH dose has been reported having maximal stimulatory effect on cortisol levels in normal subjects. We aimed to define the maximal and the minimal stimulatory ACTH dose on cortisol, aldosterone, and dehydroepiandrosterone (DHEA) in humans. To this goal, in 12 normal volunteers (6 males and 6 females; age, 22-34 yr; body mass index 20-25 kg/m2; body surface 1.6-1.9 m2), we studied the dose-response effect of eight ACTH doses (0.01, 0.03, 0.06, 0.125, 0.5, 1.0, 25.0, and 250.0 microg) on cortisol, aldosterone, and DHEA levels. Each ACTH dose administered at 0 min was followed by a second ACTH dose of 250.0 microg at +60 min. The cortisol delta areas under response curve (deltaAUCs) after all ACTH doses, apart from 0.01 microg, were significantly higher (P < 0.02) than that after placebo, showing a clear dose-response relationship (P < 0.001). The doses of 0.03 and 1.0 microg ACTH were the minimal and maximal effective doses, respectively. The cortisol response to 250.0 microg ACTH was not modified by pretreatment with 0.01, 0.03, and 0.06 microg ACTH doses, whereas it was progressively reduced by increasing the dose of ACTH pretreatment (P < 0.001). The aldosterone deltaAUCs to all but 0.01 microg ACTH doses were significantly higher (P < 0.02) than that after placebo, showing a clear dose-response relationship (P < 0.001). The dose of 0.03 microg was the minimal effective stimulating dose, whereas 25.0 microg showed the same aldosterone-releasing effect of 250.0 microg. The aldosterone response to 250.0 microg ACTH, preceeded by placebo, was not modified by pretreatment with 0.01 and 0.03 microg ACTH doses, whereas it was reduced by increasing the dose of ACTH pretreatment (P < 0.05-0.02). The DHEA deltaAUCs to all ACTH doses were significantly higher (P < 0.01) than that after placebo, showing a clear dose-response relationship (P < 0.001). The doses of 0.01 and 1.0 microg ACTH were the minimal and maximal effective dose, respectively. The DHEA response to 250.0 microg ACTH was not modified by pretreatment with 0.01, 0.03, 0.06, and 0.125 microg ACTH doses, whereas it was progressively reduced by pretreatment with 0.5, 1.0, and 25.0 microg ACTH doses (P < 0.01). In conclusion, these results show that an extremely low ACTH dose is needed to stimulate adrenal steroids and, among them, DHEA seems the most sensitive to corticotropin stimulation.
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PMID:Stimulatory effect of adrenocorticotropin on cortisol, aldosterone, and dehydroepiandrosterone secretion in normal humans: dose-response study. 1099 99

Triple-A syndrome (MIM 231550; also known as Allgrove syndrome) is an autosomal recessive disorder characterized by adrenocorticotropin hormone (ACTH)-resistant adrenal insufficiency, achalasia of the oesophageal cardia and alacrima. Whereas several lines of evidence indicate that triple-A syndrome results from the abnormal development of the autonomic nervous system, late-onset progressive neurological symptoms (including cerebellar ataxia, peripheral neuropathy and mild dementia) suggest that the central nervous system may be involved in the disease as well. Using fine-mapping based on linkage disequilibrium in North African inbred families, we identified a short ancestral haplotype on chromosome 12q13 (<1 cM), sequenced a BAC contig encompassing the triple-A minimal region and identified a novel gene (AAAS) encoding a protein of 547 amino acids that is mutant in affected individuals. We found five homozygous truncating mutations in unrelated patients and ascribed the founder effect in North African families to a single splice-donor site mutation that occurred more than 2,400 years ago. The predicted product of AAAS, ALADIN (for alacrima-achalasia-adrenal insufficiency neurologic disorder), belongs to the WD-repeat family of regulatory proteins, indicating a new disease mechanism involved in triple-A syndrome. The expression of the gene in both neuroendocrine and cerebral structures points to a role in the normal development of the peripheral and central nervous systems.
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PMID:Mutant WD-repeat protein in triple-A syndrome. 1106 74

The triple A syndrome or Allgrove syndrome (MIM*231550) is characterized by adrenocorticotropic hormone (ACTH) resistant Adrenal insufficiency, Achalasia of the cardia and Alacrima. In addition to the main features, patients frequently suffer from neurological disturbances. Dermatological abnormalities such as palmoplantar hyperkeratosis as well as other signs like short stature, microcephaly and osteoporosis point to the multisystemic character of the disorder. The molecular defect of the autosomal recessively inherited triple A syndrome is not known. We initially performed a systematic genome linkage scan in eight triple A families and were able to map the syndrome to a 6 cM interval on human chromosome 12q13 near the type II keratin gene cluster. A refinement of the triple A critical region was achieved by detailed haplotype analysis in a further 37 families from different ethnic backgrounds. There was no indication of genetic heterogeneity. The achalasia-alacrima (AA) syndrome which has been defined as a distinct clinical entity (MIM 200440) is most likely a variant of the triple A syndrome as shown by haplotype analysis in three AA families. We constructed a high-resolution BAC/PAC-based transcript map of the region which will greatly facilitate the identification of the triple A syndrome gene. The considerable intra- and interfamilial variability of the severity of the disorder implies a variable expression of an impaired pleiotropically acting gene.
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PMID:Triple A syndrome--clinical aspects and molecular genetics. 1119 51

Adrenal insufficiency is known to be a complication of HIV infection, although estimates of its prevalence and severity vary. Adrenal insufficiency is the most serious endocrine complication that occurs in persons with HIV infection. Patients with acquired immune deficiency syndrome (AIDS) are considered to be at high risk for primary or secondary adrenal insufficiency. We describe 3 patients with AIDS who had clinical features suggestive of adrenal insufficiency, but their corticotropin (ACTH) stimulation tests were normal. Repeat testing confirmed the diagnosis in one patient, and further testing with the overnight metyrapone test revealed evidence of secondary adrenal insufficiency in the other patients. Persistent clinical improvement was evident on subsequent glucocorticoid therapy. A normal response to the ACTH stimulation test can be dangerously misleading. Patients with AIDS and suspected adrenal insufficiency who have normal screening by the ACTH stimulation test should undergo further testing for secondary adrenal disease.
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PMID:Adrenal insufficiency in HIV infection: a review and recommendations. 1121 16

Adrenal insufficiency is a common and underdiagnosed disorder that develops in critically ill patients. Most forms are acquired and will resolve with treatment of the underlying disease. Hypotension that is refractory to fluids and requires vasopressors is the most common presentation of adrenal insufficiency in the ICU. It is important to make the diagnosis of adrenal insufficiency, because current data suggest that treatment with glucocorticoids improves outcome. Diagnosis usually can be made on the basis of a stress cortisol level. Occasionally, when the level of stress is uncertain, the low-dose corticotropin stimulation test will be required for definitive diagnosis. A therapeutic trial with hydrocortisone should be started in patients with suspected adrenal insufficiency pending results of diagnostic testing.
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PMID:Hypothalamic-pituitary-adrenal insufficiency. 1121 33

A 63-year-old man received high-dose cyclophosphamide for peripheral blood stem-cell (PBSC) harvest. He received 200 mg fluconazole. On day 3, atrial fibrillation developed with blood pressure declining to 78 mmHg. The rapid adrenocorticotropin (ACTH) test showed blunted adrenal responses. He was suspected as having adrenal failure, and fluconazole was discontinued. The rapid ACTH test became normal on Day 14, and PBSCs were successfully harvested. To clarify the association between adrenal failure and fluconazole, we resumed 400 mg fluconazole on Day 16 and repeated the test on Day 21, which showed blunted adrenal responses. This case demonstrates that prophylactic use of fluconazole can cause adrenal insufficiency.
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PMID:Acute adrenal failure associated with fluconazole after administration of high-dose cyclophosphamide. 1127 45

The metabolic response to critical illness promotes catabolism, which mobilizes substrates for energy. Initially the hypothalamic-pituitary-adrenal axis is stimulated, but later there appears to be anterior pituitary depression. Despite this, the early increase in plasma cortisol levels is usually maintained by means independent of (falling) corticotropin levels. Some patients, however, develop acute adrenal insufficiency and appear to benefit from replacement exogenous glucocorticoid. However, identifying such patients is often difficult. The replacement of other deficiencies may not be in the patients' interests. For example, leptin, a stress-related hormone, has multiple effects, some seemingly advantageous and others detrimental in critical illness. Its overall influence and significance remains unclear.The health of gut mucosa and the inflammatory response might be improved or influenced to the (presumed) benefit of the patient by agents such as glutamine, arginine, some eicosanoids, and exogenous nucleic acids. Such "immunonutrition" appears to improve mortality and other measures of outcome in surgical intensive care unit patients and those with sepsis.
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PMID:The metabolic and nutritional response to critical illness. 1132 6

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to measure 6 metabolic compounds of the adrenocorticosteroid pathway simultaneously on residual specimens from patients who had previously been previously diagnosed, on the basis of immunoassays, as having congenital adrenal hyperplasia (CAH), 11 beta-hydroxylase deficiency, 21-hydroxylase deficiency, or Addison disease (adrenal insufficiency). Two subjects with normal adrenal function had serum cortisol values of 13.6 and 8.9 micrograms/dL and serum cortisone values of 2.1 and 0.6 microgram/dL, but the rest of the compounds were undetectable. Two patients with 11 beta-hydroxylase deficiency had serum 11 beta-deoxycortisol values of 14.9 and 10.0 micrograms/dL and serum 11-deoxycorticosterone values of 3.9 and 1.0 microgram/dL, but their serum levels of cortisol and cortisone were diminished. A patient with 21-hydroxylase deficiency had a highly increased serum 17-hydroxyprogesterone concentration of 28.5 micrograms/dL (or 28,500 ng/dL, the traditional unit to report this assay) and a serum 21-deoxycortisol concentration of 6.9 ug/dL (this is a pathologic marker of 21-hydroxylase deficiency that is nondetectable in sera of healthy subjects). This patient also had diminished concentrations of serum cortisol and cortisone (0.9 and 0.3 microgram/dL, respectively). At 30 and 60 min after corticotropin (ACTH) stimulation, serum cortisol was the only compound that showed a dramatic increase in the normal subjects; the patient with 21-hydroxylase deficiency showed an increase of serum 17-hydroxyprogesterone level, but no increase of serum cortisol level; the patient with Addison disease showed no increase in the levels of serum cortisol or other compounds. Metyprapone, which blocks 11 beta-hydroxylase activity, increased the serum 11-deoxycorticosteroid levels and decreased the serum cortisol level. This pilot study demonstrates that it is feasible to use LC-MS/MS for the laboratory diagnosis of adrenal cortical dysfunction. The authors envision that LC-MS/MS may soon become an ideal analytical technique for the diagnosis of such endocrine diseases.
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PMID:Diagnosis of adrenal cortical dysfunction by liquid chromatography-tandem mass spectrometry. 1133 10


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