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Biomedical subjects

M Schaaf

Publications and source records attributed to M Schaaf.

At least 19 recordsLinked to original sources
PubMed2002

Glucocorticoid receptor variants: clinical implications.

Following exposure to stress, cortisol is secreted from the adrenal cortex under the control of the hypothalamic-pituitary-adrenal axis (HPA-axis). Central in the regulation of the HPA-axis is a two tied corticosteroid-receptor system, comprised of high and low affinity receptors, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), respectively. In addition, these corticosteroid receptors mediate the effects of cortisol during stress on both central and peripheral targets. Cortisol modulates gene-expression of corticosteroid-responsive genes, with the effect lasting from hours to days. Mutations in the GR-gene are being associated with corticosteroid resistance and haematological malignancies, although these mutations are relatively rare and probably not a common cause of these diseases. However, several GR-gene variants and single nucleotide polymorphisms (SNP) in the GR-gene have been identified which are relatively common in the human population. The GRbeta-variant, for example, has been proposed to influence corticosteroid-sensitivity and most evidence has been derived from the immune system and in particular asthma. With respect to polymorphisms, a BclI restriction fragment polymorphism and a Asp363Ser have been described, which not only influence the regulation of the HPA-axis, but are also associated with changes in metabolism and cardiovascular control. These associations of a GR-gene polymorphism with metabolism and cardivascular control, and also with the regulation of the HPA-axis, indicates an important underlying role of cortisol in the etiology of these complex disorders. Therefore, we propose that a common underlying defect in these complex disorders is a disregulation of the HPA-axis, especially during stress. The clinical implication is that the regulation of the HPA-axis should be envisioned as a primary target of new drugs for the treatment of stress-related disorders.

Humans↗
PubMed2001

Genetic dissection of corticosterone receptor function in the rat hippocampus.

The hippocampus, a brain structure with a crucial role in learning and memory and an involvement in stress-related neurological or psychiatric disorders, is extremely sensitive to aberrant levels of corticosteroid stress hormones (CORT). We hypothesized that CORT-affected brain disorders are the result of aberrant expression of specific CORT-responsive genes. In order to identify such genes, we have applied several gene expression profiling techniques such as differential display, DNA micro-arrays and in particular the highly sensitive serial analysis of gene expression (SAGE). Using SAGE, a total of 76,790 hippocampal tags were generated which together represent 28,748 unique mRNAs of which 4626 gave a hit with rat sequences in Genbank. By comparing SAGE profiles derived from rat hippocampi treated with different concentrations of corticosteroids, we have identified over 200 CORT-responsive genes with significant differential expression in hippocampus. The identified products include genes that are important for the plasticity of hippocampal neurones such as neural cell adhesion molecules, growth-promoting proteins, genes involved in axogenesis, synaptogenesis and signal-transduction. One novel corticosteroid-responsive gene, classified as Ca2+/calmodulin-dependent protein kinase (CaMK)-VI, exhibited structural resemblance with the family of CaMKs, in particular with that of CaMK-IV. We also identified an alternatively spliced mRNA of this gene encoding a peptide (CaMK-kinase related peptide or CARP) which may function in an autoregulatory feedback loop. These findings suggest a novel mode of operation of the CaMK pathway in control of Ca2+ homeostasis relevant for CORT-related brain disorders.

Animals↗
PubMed1999

Peptidylarginine deiminase activity in postmortem white matter of patients with multiple sclerosis.

The myelin sheath in multiple sclerosis (MS) appears to contain a higher proportion of the citrullinated isoform of myelin basic protein MBP-C8. In vitro, MBP-associated arginine is deiminated to citrulline by the enzyme peptidylarginine deiminase (PAD). We investigated PAD activity in white matter from postmortem human brain samples by measuring the formation of citrulline from benzoylarginine ethyl esther. PAD activity in MS white matter was not different from that in controls. In neonates, in whom MBP is exclusively of the C8 type, white matter PAD activity was not different from that in adults. Our results suggest that in human brain either PAD plays no role in the formation of MBP-C8, or there may be a better accessibility of MBP in myelin in neonates and MS to the enzyme.

Aged↗
PubMed1999

Kainate-elicited seizures induce mRNA encoding a CaMK-related peptide: a putative modulator of kinase activity in rat hippocampus.

By means of differential display techniques, we have previously identified an mRNA transcript whose expression is highly induced in the rat hippocampus by kainate-elicited seizures. Here, we report the cloning of a corresponding cDNA encoding a 55-amino-acid, serine-rich peptide which contains four predicted phosphorylation sites. The peptide was designated CaMK-related peptide (CARP) as it shares significant amino acid sequence identity with part of a novel putative calcium/calmodulin-dependent kinase (CaMK-VI) that was also cloned in this study. It appears that CARP and CaMK-VI are derived from the same gene through differential splicing. Intriguingly, CARP also exhibits 64% amino acid sequence identity with the C-terminal part of human doublecortin, encoded by a recently identified gene which is mutated in patients with X-linked lissencephaly and the double-cortex syndrome. In addition, the structure of CARP resembles the autoinhibitory, serine-rich N-terminal domain of CaMK-IV, suggesting a possible modulatory role of CARP with respect to CaMK activity. Northern blot analysis and in situ hybridization experiments showed that CARP mRNA is specifically induced by kainate-elicited seizures in the dentate gyrus and in the pyramidal layers CA1 and CA2, but not in CA3. In contrast, kainate-induced seizures did not change the level of expression of the CaMK-VI gene. We propose that CARP induction leads to the modulation of kinase activity in specific subregions of the rat hippocampus, providing a negative feedback mechanism for seizure-induced kinases.

Amino Acid Sequence↗
PubMed1998

Insulin-like growth factor system in serum and cerebrospinal fluid in patients with multiple sclerosis.

The insulin-like growth factor (IGF) system influences oligodendrocyte survival, myelination, and immune functions. We examined whether alterations in the circulating IGF system occur in multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system. We measured concentrations of IGF-I, IGF-II, and insulin-like growth factor binding proteins -1, -2, and -3 in both serum and cerebrospinal fluid from MS patients and age- and sex-matched controls. IGFBP-1 was not detectable in cerebrospinal fluid. We found no significant differences in any of the other components between patients with MS and controls.

Adult↗
PubMed1994

Psychologic symptoms before and after parathyroid surgery.

PURPOSE: To identify in an outpatient setting the type and number of psychologic symptoms of patients with primary hyperparathyroidism before and after surgery. PATIENTS AND METHODS: A convenience sample of 18 patients with primary hyperparathyroidism and a comparison sample of 20 patients with benign thyroid disease were scheduled by their primary care physician to have surgery. Assessments of psychologic symptoms, using the Symptom Checklist-90-Revised, and measurements of serum total calcium, ionized calcium, parathyroid hormone, albumin, alkaline phosphatase, urea nitrogen, creatinine, protein, and phosphate were obtained preoperatively. and at 1, 3, and 6 months postoperatively. RESULTS: The hyperparathyroid group had significantly higher (p < 0.01) levels of total and ionized serum calcium and parathyroid hormone preoperatively, with biochemical normalization 1 month postoperatively. These patients showed multidimensional psychologic symptom distress preoperatively in the areas of obsession-compulsion, interpersonal sensitivity, depression, anxiety, hostility, and psychoticism; they also had a greater number and intensity of distressful symptoms. Paranoid ideation was significantly higher in the hyperparathyroid group than in the comparison group, but it did not quite reach the clinical range. The greatest improvement in symptoms occurred by 1 month after surgery, with the hyperparathyroid group approaching the normative mean. There were no group differences before or after surgery for the areas of somatization and phobic anxiety. CONCLUSIONS: The Symptom Checklist-90-Revised is a simple, quick, and cost-effective way to quantitatively assess the psychologic symptoms of patients with primary hyperparathyroidism. We found that psychologic symptom distress is multidimensional, that symptoms had profoundly improved by 1 month after parathyroidectomy, and that somatization and anxiety did not differ between our groups.

Adult↗
PubMed1993

Recurrent hyperparathyroidism from benign neoplastic seeding: a review with recommendations for management.

Benign neoplastic seeding represents a rare cause of hyperparathyroidism found at parathyroid reoperations. It consists of pathologically benign neoplastic parathyroid tissue scattered throughout a previous parathyroid surgical site. We describe a case of recurrent and then persistent hyperparathyroidism occurring in a patient during an 18-year period. The patient's third operation showed nonmalignant parathyroid tissue throughout the right neck bed, which necessitated extensive parathyroid and fibrofatty tissue dissection and a thyroidectomy. This unexpected finding of extensive parathyroid seeding has only been described in detail in ten other patients in the past. A review of these 11 patients shows several features: initial operations were for large parathyroid tumors or cysts in six patients; rupture and spillage of contents occurred in six; and initial hypercalcemia was severe in several patients, perhaps indicating inherently more aggressive tumors. The appearance of benign neoplastic seeding resembled parathyroid carcinoma in its local invasiveness. Therefore the presence of anaplasia, mitoses, capsular invasion, and cellular spindling must be relied on as distinguishing factors. When confronted with this presentation, we recommend removal of all nodal bearing, thyroid, and fibrofatty tissue from the level of the thyroid cartilage to the superior mediastinum and a thyroidectomy if necessary.

Female↗
PubMed1989

Ectopic adrenocorticotropic hormone syndrome: localization studies in 28 patients.

A variety of imaging procedures were performed in 28 patients with ectopic adrenocorticotropic hormone (ACTH) syndrome in an attempt to localize the ACTH-producing tumor. Diagnosis was made on the basis of removal of an ACTH-producing tumor or biopsy of metastases in the 19 patients with a proved source and the absence of ACTH gradients in bilateral samples of the inferior petrosal sinuses in the nine patients in whom an ACTH-secreting tumor had not been localized. Eleven bronchial carcinoids, two thymic carcinoids, three pheochromocytomas, and three islet-cell tumors constituted the proved sources. The condition has been cured in eight patients, six are alive with residual tumor, and five have died. Of the nine patients with undetected sites of ACTH production, one has died of pneumocystis pneumonia and eight are being treated medically or with bilateral adrenalectomy. Computed tomography (CT) of the chest and abdomen was the most helpful study in the detection of these tumors. Selective arteriography (bronchial and visceral), systemic and portal venous sampling, and iodine-131 meta-iodobenzylguanidine scintigraphy failed to demonstrate tumors when findings at CT were negative. Bronchial carcinoids constituted most of the ACTH-secreting tumors in this study (58%) and in a review of four large series (47%). To assure early detection of these potentially malignant tumors, pulmonary CT should be performed every 6 months, even after hypercortisolism has been medically or surgically controlled.

ACTH Syndrome, Ectopic↗
PubMed1987

Graves' disease with thyrotoxicosis following subacute thyroiditis.

Two patients are described who manifested the sequential occurrence of Graves' disease and subacute thyroiditis. The literature on this very unusual event is reviewed and speculation is offered on a possible mechanism linking thyroiditis to activation of Graves' disease in susceptible persons.

Adult↗
PubMed1985

Parathymic parathyroid: CT, US, and angiographic findings.

Six patients with primary hyperparathyroidism caused by an undescended parathymic adenoma are described. All glands were anterior to the common carotid artery at the level of the hyoid bone. Blood supply was from the superior thyroid artery, and venous drainage was into the superior thyroid vein. Ultrasound (one of five) and computed tomography (two of six) were rarely positive, but glands can be detected with both modalities if the examination is carried high enough. Glands within the carotid sheath are generally lower in the neck and have a blood supply from the inferior thyroid artery with drainage into the vertebral veins.

Adenoma↗
PubMed1984

Petrosal sinus sampling for Cushing syndrome: anatomical and technical considerations. Work in progress.

ACTH-producing microadenomas of the pituitary gland drain unilaterally into the adjacent cavernous sinus; therefore, petrosal sinus sampling to distinguish pituitary from ectopic-ACTH syndromes must always be performed bilaterally. A negative finding from a unilateral petrosal sinus sample does not exclude the presence of a contralateral ACTH-producing microadenoma. Hemiresection of the pituitary gland based on results of bilateral sampling can be performed if the adenoma is too small to be recognized at surgery. Large pituitary adenomas produce elevated ACTH levels in the petrosal sinuses bilaterally. However, if plain radiographs or CT scans provide unequivocally positive findings in Cushing syndrome (less than 20%), inferior petrosal sinus sampling is not indicated.

Adenoma↗
PubMed1984

Circadian rhythm of serum cortisol in Cushing's disease.

Two women with typical clinical and biochemical features of pituitary-dependent Cushing's disease each underwent hourly blood sampling for 24 h on two separate occasions for measurement of serum cortisol. The 24-h mean serum cortisol concentrations (17.7 and 15.4 micrograms/dl in patient 1; 19.0 and 15.8 micrograms/dl in patient 2) were elevated (normal level, less than 12.5 micrograms/dl), as expected. Cosinor analysis of the patients' serum cortisol patterns revealed statistically significant circadian rhythms on all four profiles. The amplitude of the rhythm on both occasions in patient 1 (5.8 and 6.6 micrograms/dl) and on one of two occasions in patient 2 (7.2 and 10.5 micrograms/dl) fell in the range for the amplitude of the cortisol circadian rhythm in normal subjects (2.2-8.6 micrograms/dl). In contrast to commonly held belief, some patients with Cushing's disease may exhibit circadian variation of serum cortisol.

Adult↗
PubMed1984

Hyperfunctioning cystic parathyroid glands: CT and sonographic findings.

Four functioning cystic parathyroid glands were evaluated with computed tomography (CT) and sonography in four patients, only one of whom had prior surgery. Sonography demonstrated solid lesions of decreased echogenicity with fluid-filled cavities near the lower thyroid poles or in the posterosuperior mediastinum. On CT the cystic parts of the lesions were of low attenuation (1-44 H), often with a well defined wall that was better demonstrated after intravenous contrast administration. Fine-needle aspiration biopsy of two of the cystic parathyroids revealed elevated parathyroid hormone levels. These lesions probably represent degenerating adenomas rather than true parathyroid cysts. While the CT and sonographic findings are nonspecific, the diagnosis of a cystic parathyroid should be entertained when a fluid-filled lesion is encountered in the neck of a patient with or without hypercalcemia. The diagnosis may be confirmed by assay of parathyroid hormone from the fluid aspirate.

Adenoma↗
PubMed1984

Detection of mediastinal parathyroid glands by nonselective digital arteriography.

Six patients with failed previous operations and anterior mediastinal parathyroid glands were evaluated with selective angiography and nonselective arterial digital arteriography. Selective angiography depicted two of nine mediastinal glands; nonselective arterial digital arteriography depicted only one of nine mediastinal glands and missed a sizable (4.5 cm) gland demonstrated by routine arteriography. Nonselective arterial digital arteriography did not demonstrate any additional mediastinal glands. From this preliminary experience, it was concluded that nonselective arterial digital arteriography is not a sensitive method for detecting mediastinal glands.

Adult↗
PubMed1983

Aspiration of enlarged parathyroid glands for parathyroid hormone assay.

Enlarged parathyroid glands were percutaneously aspirated under computed tomographic (CT) control in 7 patients, and levels of parathyroid hormone (PTH) and human thyroglobulin (HTg) were measured. All 7 patients had high levels of PTH in at least 1 specimen. It is concluded that the measurement of high concentrations of PTH in the aspirate from a cervical or mediastinal mass, with CT documentation of needle position, provides absolute localization of parathyroid masses.

Adenoma↗
PubMed1981

Hypocalcemia with osteoblastic metastases in patient with prostate carcinoma. A cause of secondary hyperparathyroidism.

A 68 year old man with prostatic carcinoma and extensive painful osteoblastic metastases was discovered to have hypocalcemia (serum calcium 7.1 mg/dl) without evidence of hypoalbuminemia, renal failure or malabsorption. Baseline studies revealed hypocalciuria (24 hour urine calcium less than 5 mg/day), normal serum phosphate (3.4 mg/dl), low tubular reabsorption of phosphate (68 percent), undetectable serum calcitonin, normal serum 25-hydroxyvitamin D, slightly elevated serum parathyroid hormone level and increased urinary cyclic AMP (8.87 mumol/g creatinine). These studies were compatible with secondary hyperparathyroidism. The intravenous administration of parathyroid extract produced no further change in urinary phosphate but a 25-fold increase in nephrogenous cyclic AMP. Three days administration of intramuscular parathyroid extract slowly and temporarily restored serum calcium to normal levels while increasing urinary cyclic AMP and phosphate. Chemotherapy with cyclophosphamide and 5-fluorouracil rendered the patient free of pain while reducing serum acid and alkaline phosphatase levels and restoring serum total and ionized calcium and urinary cyclic AMP excretion to normal.

Adenocarcinoma↗