Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 25 year old male with features typical of Bartter's syndrome is described. Studies were performed to evaluate the pathogenesis of this disorder. In response to oral water loading the subject excreted free water normally. Normal renal sodium conservation was documented. Autonomy of the reninangiotensin-aldosterone system was excluded by demonstrating appropriate directional changes in plasma renin activity and aldosterone excretion in response to alterations in sodium and potassium intake. During aminoglutethimide inhibition of aldosterone synthesis the subject was able to maintain potassium balance at a normal serum potassium concentration on a potassium intake of 130 mEq/day which suggests that aldosterone is the major cause of the potassium wasting. Decreased vascular responses to intra-arterial infusions of angiotensin II and norepinephrine were documented in the absence of extracellular volume depletion. These findings argue against tachyphylaxis as the explanation for the vascular insensitivity and implicate a defect at some step in the sequence between agonist-receptor interaction and the contractile response. It is proposed that the vascular defect plays a primary role in the pathogenesis of the hyperreninemia by interrupting pressure-mediated inhibition of renin secretion and/or impairing direct feedback inhibition of renin secretion by angiotensin II. A unique finding in our case was the lack of a postural influence on plasma renin activity and plasma aldosterone. An accentuated plasma aldosterone circadian rhythm was observed independent of plasma renin activity and plasma potassium concentration. Dexamethasone suppression of ACTH reduced but did not abolish the circadian rhythm. Thus some factor in addition to plasma renin activity, potassium and ACTH appears to influence aldosterone secretion in this patient.
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PMID:On the pathogenesis of Bartter's syndrome: report of studies in a patient with this disorder. 99 67

The mechanism by which cord factor (CF), a toxic glycolipid from mycobacteria, induces cachexia was studied in BALB/c mice. Body weight was markedly reduced 48 h after CF administration; the animals became severely wasted and exhibited hypertriglyceridemia, hypoglycemia, and high levels of tumor necrosis factor (TNF) in plasma. After CF administration, a transferable factor which caused cachexia and hypertriglyceridemia in recipient mice was detected in the blood. Dexamethasone partially inhibited the cachexia-inducing action of CF. Conditioned medium from adherent peritoneal cell cultures incubated with CF produced the same wasting symptoms when inoculated intravenously into mice. These studies also demonstrated that adherent peritoneal cells produced a humoral factor in response to CF which was related to CF-induced cachexia. Antiserum to recombinant TNF-alpha prevented the cachectin action in passive-transfer experiments. Our findings indicate that cachectin (TNF) plays a role as a central mediator of the wasting induced by CF.
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PMID:Tumor necrosis factor (cachectin) mediates induction of cachexia by cord factor from mycobacteria. 305 51

Dexamethasone was injected daily (2.5 and 5 micrograms/day) into pregnant mice from the 8th gestational day until delivery, and their offspring were examined in terms of body weight, organ histopathology, immunological function, and serum hormone level. Two different postnatal patterns were observed among the treated offspring: one pattern showing a wasting appearance and death within 1 week, and the other showing retardation of growth without any wasting appearance. In the latter, the offspring showed an immunologically impaired antibody-forming capacity to T-cell-dependent antigen (SRBC) and cell-mediated cytolytic T-cell activity. Histologically, the lymphoid tissues, thyroid, and adrenals of these offspring are atrophied and their serum thyroxine (T4) levels were significantly reduced. These results suggest that intrauterine exposure of the fetus to dexamethasone can disrupt the normal development and function of endocrine and immune organs which can lead to early death or retardation of growth after birth.
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PMID:Long-lasting impairment of immune and endocrine systems of offspring induced by injection of dexamethasone into pregnant mice. 622 48

We report on the prenatal diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase in 20 at-risk pregnancies (16 salt-wasting and 4 simple virilizing families). We have diagnosed 3 affected fetuses (2 males and 1 female), 3 healthy homozygotes (2 males and 1 female), and 14 healthy heterozygotes (7 females and 7 males). These data were collected over 4 years. In 16 fetuses, the diagnosis was made with measurements of 17-hydroxyprogesterone (17-OHP) and delta-4-androstenedione (delta) in amniotic fluid (AF), human leukocyte antigen (HLA) typing of amniotic cells, as well as karyotypes between the 16th and 18th weeks of gestation. In 4 fetuses, DNA analysis of amniotic cells was also performed. In 3 pregnancies in which affected fetuses were suspected (on the basis of HLA typing and measurements of 17-OHP and delta concentrations in AF), the fetuses were electively aborted between the 17th to 19th weeks of gestation by parental decision. In all aborted fetuses, diagnosis was confirmed with HLA typing, autopsy findings of hyperplastic adrenal glands, and ambiguous genitalia in female fetuses. Postnatal diagnosis was confirmed in healthy fetuses with HLA typing and serum measurements of 17-OHP concentrations, and in 4 of them with DNA analysis. In 3 of the 4 families, DNA analyses revealed the following mutations: in Family 1, the index case mutation was Intron 2, Exon 3/Exon 6, and the fetus was Normal/Exon 6; in Family 2, the index case mutation was Ex1 Int2 Ex3/ Int2, and the fetus was Ex1 Int2 Ex3/Normal; and in Family 3, the index case mutation was Ex8(356)/Ex8(356), and the fetus was Ex8(356)/ Normal. We also report one case of prenatal diagnosis and treatment. Dexamethasone 0.5 mg BID (20 micrograms/kg/d) was given starting at 6th week of gestation. Prenatal diagnosis suggested, but did not prove, that the female fetus was a heterozygote as the fetus lacked the paternal mutation Ex8(318). No mutation was found in the mother. The fetus, the mother, and the affected sib shared a haplotype, further suggesting heterozygosity. The unaffected status was confirmed postnatally.
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PMID:Prenatal diagnosis of congenital adrenal hyperplasia (21-hydroxylase deficiency) in Croatia. 933 59

The diagnostic term congenital adrenal hyperplasia (CAH) applies to a family of inherited disorders of steroidogenesis caused by an abnormality in one of the five enzymatic steps necessary in the conversion of cholesterol to cortisol. The enzyme defects are translated as autosomal recessive traits, with the enzyme deficient in more than 90% of CAH cases being 21-hydroxylase. In the classical forms of CAH (simple virilizing and salt wasting), owing to 21-hydroxylase deficiency (21-OHD), androgen excess causes external genital ambiguity in newborn females and progressive postnatal virilization in males and females. Non-classical 21-OHD (NC21OHD) refers to the condition in which partial deficiencies of 21-hydroxylation produce less extreme hyperandrogenemia and milder symptoms. Females do not demonstrate genital ambiguity at birth. The gene for adrenal 21-hydroxylase, CYP21, is located on chromosome 6p in the area of HLA genes. Specific mutations may be correlated with a given degree of enzymatic compromise and the clinical form of 21-OHD. NC21OHD patients are predicted to have mild mutations on both alleles or one severe and one mild mutation of the 21-OH locus (compound heterozygote). In most cases the mutation groups represent one diagnosis (e.g., Del/Del with SW CAH), however we have found several non-correlations of genotype to phenotype. Non-classical and classical patients were found within the same mutation group. Phenotypic variability within each mutation group has important implications for prenatal diagnosis and treatment. Prenatal treatment of 21-OHD with dexamethasone has been utilized for a decade. An algorithm has been developed for prenatal diagnosis and treatment, which, when followed closely, has been safe for both the mother and the fetus, and has been effective in preventing ambiguous genitalia in the affected female newborn. This is an instance of an inborn metabolic error successfully treated prenatally. Since 1986, prenatal diagnosis and treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OHD) has been carried out in 403 pregnancies in The New York Hospital Cornell Medical Center. In 280, diagnoses were made by amniocentesis, while 123 were diagnosed using chorionic villus sampling. Of the 403 pregnancies evaluated, 84 babies were affected with classical 21-OHD. Of these, 52 were females, 36 of whom were treated prenatally with dexamethasone. Dexamethasone administered at or before 10 weeks of gestation (23 affected female fetuses) was effective in reducing virilization. Thirteen cases had affected female sibs (Prader stages 1-4); 6 of these fetuses were born with entirely normal female genitalia, while 6 were significantly less virilized (Prader stages 1-2) than their sibs, and one was Prader stage 3. Eight newborns had male sibs: 4 were born with normal genitalia, 3 were Prader stages 1-2, and 3 were born Prader stages 3-4. No significant or enduring side effects were noted in either the mothers or the fetuses, indicating that dexamethasone treatment is safe. Prenatally treated newborns did not differ in weight, length, or head circumference from untreated, unaffected newborns. Based on our experience, proper prenatal diagnosis and treatment of 21-OHD is effective in significantly reducing or eliminating virilization in the newborn female. This spares the affected female the consequences of genital ambiguity of genital surgery, sex misassignment, and gender confusion.
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PMID:Congenital adrenal hyperplasia: update on prenatal diagnosis and treatment. 1041 77

Glucocorticoids comprise an important class of hormonal mediators of fuel and protein homeostasis in normal and pathological scenarios. In skeletal muscle, exposure to glucocorticoids is characterized by a reduction in protein synthetic rate coincident with hampered translation initiation. However, it is unclear whether this involves attenuation of anabolic stimuli or is simply due to inhibition of the basally activated translational apparatus. Therefore, this inquiry was designed to determine whether leucine, administered orally, could rescue the translational inhibition induced by glucocorticoids. Dexamethasone, injected intraperitoneally, acutely diminished protein synthetic rates to 80% of control values in skeletal muscle from rat hindlimb. The eukaryotic initiation factor (eIF)4 regulatory element was simultaneously and negatively impacted via sequestration of eIF4E by the hypophosphorylated form of the translational suppressor, eIF4E binding protein 1 (4E-BP1). The 70-kDa ribosomal protein S6 kinase (S6K1) was also dephosphorylated, notably at T389, in response to glucocorticoids. Leucine, administered orally, effectively restored each aforementioned translational parameter to control levels. Inasmuch as leucine's potency in modulation of the translational machinery, and indeed of protein turnover in general, is widely appreciated, this amino acid may prove useful in normalizing the impairment of mRNA translation associated with various muscle-wasting pathologies, such as glucocorticoid excess.
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PMID:Glucocorticoids oppose translational control by leucine in skeletal muscle. 1105 75

Congenital adrenal hyperplasia (CAH) refers to a family of monogenic inherited disorders of adrenal steroidogenesis most often caused by enzyme 21-hydroxylase deficiency (21-OHD). In the classic forms of CAH (simple virilizing and salt wasting), androgen excess causes external genital ambiguity in newborn females and progressive postnatal virilization in males and females. Prenatal treatment of CAH with dexamethasone has been successfully used for over a decade. This article serves as an update on 532 pregnancies prenatally diagnosed using amniocentesis or chorionic villus sampling between 1978 and 2001 at New York Presbyterian Hospital-Weill Medical College of Cornell University. Of the 532 pregnancies, 281 were prenatally treated for CAH due to the risk of 21-hydroxylase deficiency. Follow-up telephone interviews with mothers, genetic counselors, endocrinologists, pediatricians, and obstetricians were performed in all cases. Of the pregnancies evaluated, 116 babies were affected with classic 21-OHD. Of these, 61 were female, 49 of whom were treated prenatally with dexamethasone. Dexamethasone administered at or before 9 wk gestation (in proper doses) was effective in reducing virilization. There were no statistical differences in the symptoms during pregnancy between mothers treated with dexamethasone and those not treated with dexamethasone, except for weight gain, edema, and striae, which were greater in the treated group. No significant or enduring side-effects were noted in the fetuses, indicating that dexamethasone treatment is safe. Prenatally treated newborns did not differ in weight from untreated, unaffected newborns. Based on our experience, prenatal diagnosis and proper prenatal treatment of 21-OHD are effective in significantly reducing or eliminating virilization in the newborn female. This spares the affected female the consequences of genital ambiguity, genital surgery, and possible sex misassignment.
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PMID:Prenatal diagnosis for congenital adrenal hyperplasia in 532 pregnancies. 1173 15