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Biomedical subjects

D M Cook

Publications and source records attributed to D M Cook.

At least 55 records · Page 3Linked to original sources
PubMed1991

Transcriptional repression mediated by the WT1 Wilms tumor gene product.

The wt1 gene, a putative tumor suppressor gene located at the Wilms tumor (WT) locus on chromosome 11p13, encodes a zinc finger-containing protein that binds to the same DNA sequence as EGR-1, a mitogen-inducible immediate-early gene product that activates transcription. The transcriptional regulatory potential of WT1 has not been demonstrated. In transient transfection assays, the WT1 protein functioned as a repressor of transcription when bound to the EGR-1 site. The repression function was mapped to the glutamine- and proline-rich NH2-terminus of WT1; fusion of this domain to the zinc finger region of EGR-1 converted EGR-1 into a transcriptional repressor.

Amino Acid Sequence↗
PubMed1991

Characterization of the zinc finger protein encoded by the WT1 Wilms' tumor locus.

We analysed the biochemical properties of the transcription factor encoded by the putative tumor-suppressor gene present at the WT1 Wilms' tumor locus. A gene containing the full-length amino acid coding sequence of human wt1 was reconstructed from synthetic oligonucleotides and cloned into expression vectors for in vitro and in vivo protein synthesis. Polyclonal rabbit antibodies specific for the WT1 protein were raised to an Escherichia coli-produced 91 amino acid N-terminal segment and to a 136 amino acid C-terminal segment, which contains the zinc finger domain. WT1 produced by in vitro translation migrated as a 52 kDa protein on sodium dodecylsulfate-polyacrylamide gels and bound to the EGR consensus sequence in gel-retardation assays. Expression of the wt1 gene via transient transfection in COS-1 cells revealed a 52 kDa protein which was immunoprecipitated by both the N-terminal- and C-terminal-specific antisera. Immunofluorescence studies of wt1-transfected COS-1 cells revealed that the WT1 protein was localized to the nucleus. Metabolic labeling with [32P]orthophosphate failed to reveal significant phosphorylation of the WT1 protein in COS-1 cells. Two immunoreactive WT polypeptides of 52 and 54 kDa were observed in murine embryonic stem cells and COS-1 kidney cells and may represent previously identified splicing variants of WT1. These antisera should be useful in characterizing the structure and function of the WT1 protein in human Wilms' tumor specimens.

Amino Acid Sequence↗
PubMed1990

Binding of the Wilms' tumor locus zinc finger protein to the EGR-1 consensus sequence.

The Wilms' tumor locus (WTL) at 11p13 contains a gene that encodes a zinc finger-containing protein that has characteristics of a DNA-binding protein. However, binding of this protein to DNA in a sequence-specific manner has not been demonstrated. A synthetic gene was constructed that contained the zinc finger region, and the protein was expressed in Escherichia coli. The recombinant protein was used to identify a specific DNA binding site from a pool of degenerate oligonucleotides. The binding sites obtained were similar to the sequence recognized by the early growth response-1 (EGR-1) gene product, a zinc finger-containing protein that is induced by mitogenic stimuli. A mutation in the zinc finger region of the protein originally identified in a Wilms' tumor patient abolished its DNA-binding activity. These results suggest that the WTL protein may act at the DNA binding site of a growth factor-inducible gene and that loss of DNA-binding activity contributes to the tumorigenic process.

Amino Acid Sequence↗
PubMed1990

Diminished adrenocorticotropin response to insulin-induced hypoglycemia in nondepressed, actively drinking male alcoholics.

Although changes in hypothalamic-pituitary-adrenal axis function have frequently been reported in alcoholics, the majority of studies have used recently detoxified subjects in whom abstinence phenomena and clinical depression may contribute to observed stress axis alterations. To isolate the primary effects of alcohol dependence on the stress axis, the ACTH and cortisol responses to insulin-induced hypoglycemia were measured in seven actively drinking male alcoholics recruited from the general public through a newspaper advertisement along with eight age-matched male controls. The alcoholic subjects met current American Psychiatric Association diagnostic criteria for alcohol dependence, were stably employed, and had no concurrent psychiatric disorders, cognitive impairment, or psychometric evidence of depression. While relatively young (30.0 yr; range, 22-48 yr), they had lengthy histories of alcohol-related problems (11.9 yr; range, 5-30 yr). Insulin administration resulted in similar nadirs in blood sugar in both alcoholic and control groups. However, the plasma ACTH response was markedly blunted in the alcoholics (P = 0.040, by Mann-Whitney U test). There was a nonsignificant trend toward increased cortisol levels in the alcoholic group. The findings suggest that altered hypothalamic-pituitary-adrenal axis function in alcoholics is a primary results of chronic ethanol exposure rather than a confounding effect of clinical depression or recent detoxification.

Adrenocorticotropic Hormone↗
PubMed1989

Characterization of the promoter region and 3' end of the human insulin receptor gene.

The insulin receptor is an essential protein present on the surface of virtually all cells. Little is known about the control of the level of this protein on cellular surfaces, but it has been found that the level of insulin receptor protein correlates roughly with the level of insulin receptor (IR) gene transcripts within cells. Although the protein-encoding region is only about 4000 base pairs (bps), there are multiple species of IR mRNA ranging in size from 5400 to 9400 bps. We have found that the variation in size of these transcripts is due to multiple 3' ends, presumably reflecting alternative polyadenylation, so that the final IR exon ranges in size from 1400 to 5400 bps. The IR gene promoter is like other housekeeping promoters in that it has no TATA or CAAT boxes, is extremely GC-rich, and has multiple transcriptional initiation sites primarily within a 300-bp GC-rich region. Reporter gene analysis using IR promoter-chloramphenicol acetyltransferase (HIRcat) fusion plasmids established regions responsible for promoter activity and verified the localization of the major IR gene transcriptional initiation sites. However, transfection with HIRcat plasmids containing regions from -153 to -1818 resulted in increased utilization of the most 5' IR gene mRNA initiation sites in transfected relative to untransfected cells. Reporter gene analysis also established that a region of the IR promoter and first exon containing all of the transcriptional initiation sites is more active in HepG2 than CV1 cells. Because the steady-state level of expression of the IR gene is much higher in HepG2 than CV1 cells, the results of the reporter gene analysis may reflect tissue-specific differences in IR gene transcription. Such tissue-specific transcriptional regulation would be a novel finding in a housekeeping promoter.

Base Sequence↗
PubMed1988

Failure of hypophysectomy to correct pituitary-dependent Cushing's disease in two patients.

One woman (patient 1), aged 27 years, and one man (patient 2), aged 26 years, had pituitary surgery for pituitary-dependent Cushing's syndrome. An adenoma was identified and removed in both patients. Persistence of hypercortisolism characterized the response of patient 2 to surgery; transient hypoadrenalism, the response of patient 1. Patient 1 subsequently underwent a relapse. At the second surgery (total hypophysectomy for both patients), hyperplasia was demonstrated in patient 1, and scattered nests of adrenocorticotropic hormone (ACTH)-secreting cells were demonstrated in patient 2. Postoperatively, Cushing's syndrome persisted in both patients. Inferior petrosal sampling for ACTH during corticotropin releasing hormone stimulation verified a pituitary source of ACTH in patient 1. A decrease in cortisol secretion following hypophysectomy and subsequent cure by pituitary irradiation constitutes the evidence for pituitary origin in patient 2. Dexamethasone suppression and corticotropin releasing hormone-stimulation tests consistently suggested a pituitary cause throughout the clinical course of both patients. Computed tomographic scans after hypophysectomy revealed postoperative changes only. In both patients, panhypopituitarism, except for cortisol and ACTH, followed hypophysectomy. It may be concluded that patients with diffuse pituitary ACTH hyperplasia cannot, at present, be identified preoperatively by conventional clinical testing. Surgery for such patients may not be the therapy of choice.

Adenoma↗
PubMed1987

Diagnostic value of thyrotropin-releasing-hormone stimulation in patients with pituitary tumor.

Plasma prolactin response to thyrotropin-releasing-hormone (TRH) stimulation was diminished in 30 patients with prolactinomas and 9 patients with acromegaly who had normal serum prolactin levels. There was no overlap of prolactin responses when compared with 32 control patients. Responses of ten patients with adrenocorticotropin (ACTH)-secreting pituitary tumors were similar to those of controls. Plasma growth hormone concentrations after TRH stimulation changed significantly in 28% of normal control and 20%, 25% and 50% of patients with prolactin-, growth hormone- and ACTH-secreting pituitary tumors, respectively. Our data suggest that the blunted TRH-induced rise in plasma prolactin levels in patients with prolactinomas and those with acromegaly may be related to humoral factor(s) affecting TRH receptor or postreceptor function. Growth hormone responses to TRH are nonspecific and should not be considered a marker for active acromegaly.

Female↗
PubMed1986

Gonadotrophin-secreting pituitary adenomas masquerading as primary ovarian failure.

Three women, 20-35 years old, appeared on initial presentation to have primary ovarian failure, because each had amenorrhoea or oligomenorrhoea and markedly supranormal serum concentrations of gonadotrophins. On further evaluation, however, each had ovaries that could secrete oestradiol normally, and one had normal oestradiol secretion without any treatment. Another secreted oestradiol normally only after reduction of her gonadotrophins following partial excision of a pituitary adenoma. The third secreted oestradiol normally only after exogenous oestrogens were administered to reduce her gonadotrophins and were then withdrawn. Each had an enlarged, contrast-enhancing pituitary gland by computed tomographic scan and a markedly supranormal serum concentration of glycoprotein alpha subunit. We conclude that each of these women had a gonadotrophin-secreting pituitary adenoma that masqueraded as primary ovarian failure. Their persistently supranormal serum gonadotrophins appear to have inhibited ovarian function.

Adenoma↗
PubMed1985

Factitious Cushing's syndrome.

A woman with pituitary-dependent Cushing's disease remained hypercortisolemic after bilateral adrenalectomy. A search for an adrenal remnant by venous catheterization study suggested persistent cortisol-secreting tissue in the left adrenal bed. During ACTH stimulation, plasma corticosterone concentrations remained low and cortisol remained high, suggesting the cortisol was of exogenous origin. Cushingoid features resolved after confronting the patient with this evidence. Plasma corticosterone concentrations played a novel role in the diagnosis of factitiously induced Cushing's syndrome in this patient.

Adrenocorticotropic Hormone↗
PubMed1985

Rehabilitation of neck and low back injuries.

Sports-related mechanisms of cervical and lumbar spine injury and their clinical presentations have been discussed. The keys to treatment of these injuries in the athlete include rehabilitation of the injured area, recognition of the mechanism of injury, and correction of any technical faults that may have contributed thereto. Criteria for return to sport are a critical part of the rehabilitation of the injured athlete. Most importantly, the practitioner can anticipate potential areas of injury and can recommend prehabilitation exercises to avert many of these injuries.

Athletic Injuries↗
PubMed1983

Impaired visual flicker discrimination with hypothalamic pituitary disease.

In a group of 19 patients with pituitary dysfunction, we assessed peripheral visual fields and flicker discrimination. Two subgroups of patients were defined: (1) nonsurgical (n = 6), and (2) surgical (n = 13). For the nonsurgical group, 16.7% (2/12) of the eyes tested had impaired flicker discrimination, whereas 33% (4/12) had a deficit in visual field. For the surgical group, none of the patients had a deficit of visual field, whereas 60% (15/25) of the eyes tested had an alteration of flicker discrimination. For this latter group, abnormalities of the flicker fusion threshold were present several months to several years after surgery.

Adult↗
PubMed1980

Corticotrophin, growth hormone and prolactin deficiencies with hypoaldosteronism and corticosteroid-reversible hypothyroidism in Sheehan's syndrome. Clinical and anatomical correlations.

Deficiencies of corticotrophin (ACTH), growth hormone, and prolactin were documented in a woman with diabetes mellitus and Sheehan's syndrome. The patient's ACTH deficit appeared to be secondary to a hypothalamic abnormality since on two occasions the patient had a marked plasma ACTH response to vasopressin but not to insulin induced hypoglycaemia. It is postulated that the deficits of these three adenohypophysial hormones were instrumental in causing a severely impaired aldosterone secretory capacity in response to sodium restriction and an angiotensin infusion. In addition, the patient had an unusual form of thyroid dysfunction that was in part reversed with hydrocortisone replacement. The patient's unfortunate death during a hypoglycaemic crisis allowed correlation between her extensive antemortum endocrine testing and her pathologic anatomy.

Adrenal Glands↗
PubMed1980

Cushing syndrome: current concepts of diagnosis and therapy.

A variety of diagnostic advances including radioimmunoassay of adrenocorticotropic hormone (ACTH) have increased the number of methods for laboratory investigation of Cushing syndrome.* However, experience with these procedures has led to a recognition of their limitations. We have developed an algorithm which incorporates these newer techniques and minimizes the number of procedures required to diagnose the various causes of Cushing syndrome. At present, we recommend pituitary surgical operations for pituitary-dependent Cushing syndrome because we believe this disease is caused by the development of a pituitary ACTH-secreting tumor.

Cushing Syndrome↗
PubMed1980

Pituitary tumors--current concepts of diagnosis and therapy.

Familiarity with the concepts and methods of diagnosis and their limitations is essential to outline a plan of investigation for individual patients suspected of having pituitary tumors. Therapy depends somewhat on the extent of suprasellar extension, a factor which especially limits irradiation. The role of transsphenoidal and other forms of pituitary operations must await long-term follow-up. This is especially true because we do not know the role of the hypothalamus in the pathogenesis of pituitary tumors.

Humans↗
PubMed1979

Nelson's syndrome and spontaneous pituitary tumor infarction.

Large, adrenocorticotrophic hormone-secreting pituitary tumors (Nelson's syndrome) developed in four of 12 patients treated with a bilateral adrenalectomy for Cushing's disease. Two of the patients with Nelson's syndrome suffered spontaneous pituitary tumor infarctions. One patient improved under close observation and subsequent radiation therapy, although she ultimately died from her locally invasive tumor. The condition of the other patient-which had stabilized-appeared to be worsened by surgical intervention. The high incidence of these tumors after bilateral adrenalectomy, their large and agressive nature, and their apparent propensity to undergo spontaneous infarction supports the position that initial therapy for Cushing's disease should be directed to the pituitary gland.

Adrenalectomy↗