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Biomedical subjects

D M Cook

Publications and source records attributed to D M Cook.

At least 37 records · Page 2Linked to original sources
PubMed1997

Intraoperative adrenocorticotropin levels during transsphenoidal surgery for Cushing's disease do not predict cure.

Recently, intraoperative rapid immunochemiluminometric assay (ICMA) ACTH measurements have been used to evaluate the completeness of resection of ectopic ACTH-secreting tumors. This study evaluates whether this method can be applied to patients undergoing transsphenoidal surgery (TSS) for Cushing's disease to predict complete pituitary tumor resection. Eighteen patients with Cushing's disease undergoing TSS had plasma ACTH concentrations measured by a standard ICMA every 10 min for 1 h immediately after pituitary tumor removal. Patients were evaluated postoperatively for cure by standard criteria. ACTH levels were evaluated for percentage decrease from baseline at each time point. Patients who were cured (n = 11) had statistically greater decreases in ACTH levels (mean decrease 54%) than patients who were not (n = 7; 26% mean decrease, P < 0.04). By Receiver-Operator Characteristic (ROC) analysis, a reduction of at least 40% best predicted which patients were cured and which were not cured. This level of reduction was observed in 82% of cured patients, and a reduction of less than 40% was observed in 71% of those not cured. The analysis misclassified 4 of the 18 patients, resulting in a diagnostic accuracy of 78%. Although the mean maximal decrease in ACTH concentrations after tumor removal was significantly different between cured and not cured patients with Cushing's disease, it was less dramatic than results in the previous ectopic ACTH study. This may relate to incomplete suppression and/or surgical manipulation of normal pituitary corticotrophs in patients with pituitary disease. In summary, in contrast to the ectopic ACTH syndrome, decline of plasma ACTH during TSS does not accurately predict complete tumor resection.

Adrenocorticotropic Hormone↗
PubMed1997

Hypothalamic-pituitary-insulin-like growth factor-I axis dysfunction in patients with fibromyalgia.

OBJECTIVE: To investigate the serum levels of insulin-like growth factor-I (IGF-I) in patients with fibromyalgia (FM) compared to healthy controls and patients with other rheumatic diseases, and to explore possible etiologic mechanisms of low IGF-I levels in patients with FM. METHODS: Five hundred patients with FM and 152 controls (74 healthy blood donors, 26 myofascial pain patients and 52 patients with other rheumatic diseases) were studied. All had measurements of acid extracted serum IGF-I. A subset of 90 patients with FM were evaluated for clinical features that might explain low IGF-I levels. Twenty-five patients with FM underwent growth hormone (GH) provocation testing with l-dopa and clonidine. RESULTS: The mean serum IGF-I level in patients with FM was 138 +/- 56 ng/ml and in controls 215 +/- 86 ng/ml (p = 0.00000000001). Low levels of IGF-I were not due to depression, tricyclic medications, nonsteroidal antiinflammatory drugs, poor aerobic conditioning, obesity, or pain level. Patients with focal myofascial pain syndromes had normal IGF-I levels (236 +/- 68), as did most patients with other rheumatic disorders, unless they had concomitant FM. Patients with FM with initially normal levels often had a rapid decline of IGF-I over 1 to 2 years. Most patients with FM with low IGF-I levels failed to secrete GH after stimulation with clonidine and l-dopa. CONCLUSION: Many, but not all, patients with FM have low levels of IGF-I that cannot be explained by clinical associations. These results suggest that low IGF-I levels in patients with FM are a secondary phenomenon due to hypothalamic-pituitary-GH axis dysfunction.

Adult↗
PubMed1996

Transcriptional activation of the syndecan-1 promoter by the Wilms' tumor protein WT1.

The Wilms' tumor suppressor gene (wt1) encodes a zinc finger DNA binding protein (WT1) which functions as a transcriptional regulator and is essential for normal urogenital development. WTI has previously been shown to repress the transcription of a variety of target genes whose products stimulate growth, such as growth factors, growth factor receptors and other transcription factors. In this study, we identify syndecan-1 as a target gene for WT1-mediated activation. Syndecan-1 is a cell surface proteoglycan whose induction is coincident with epithelial differentiation during kidney development and whose loss of expression is correlated with the loss of the epithelial phenotype and malignant transformation. The murine syndecan-1 promoter contains several potential binding sites for WT1. We demonstrate that both WT1 (-KTS) and WT1 (+KTS) isoforms bind to multiple sites in this highly G + C-rich region, as detected by gel-shift analyses. These WT1 isoforms function as transcriptional activators of syndecan-1 expression in transient transfection assays. Activation of syndecan-1 by WT1 is dependent on an intact zinc-finger region as well as a 179 amino acid proline-rich region in the amino terminus of the protein. Moreover, the endogenous syndecan-1 gene is activated by WT1 in a novel inducible cell line based upon the sheep metallothionein promoter. These results highlight an emerging role for WT1 as an activator of genes like syndecan-1 which may potentiate epithelial differentiation and maintenance in the developing kidney.

3T3 Cells↗
PubMed1996

Streptococcal meningitis as a complication of diagnostic myelography: medicolegal aspects.

Bacterial meningitis is a rare complication of myelography. Most reported cases of bacterial meningitis are caused by a wide variety of streptococcal species, but the source of these organisms is uncertain. We recently participated in the defense of two legal cases arising from this complication. We discuss the medicolegal aspects of streptococcal meningitis that is a complication of myelography.

Adult↗
PubMed1996

The tra region of the nopaline-type Ti plasmid is a chimera with elements related to the transfer systems of RSF1010, RP4, and F.

The Ti plasmids of Agrobacterium tumefaciens encode two transfer systems. One mediates the translocation of the T-DNA from the bacterium to a plant cell, while the other is responsible for the conjugal transfer of the entire Ti plasmid from one bacterium to another. The determinants responsible for conjugal transfer map to two regions, tra and trb, of the nopaline-type Ti plasmid pTiC58. By using transposon mutagenesis with Tn3HoHo1, we localized the tra determinants to an 8.5-kb region that also contains the oriT region. Fusions to lacZ formed by transposon insertions indicated that this region is expressed as two divergently transcribed units. We determined the complete nucleotide sequence of an 8,755-bp region of the Ti plasmid encompassing the transposon insertions defining tra. The region contains six identifiable genes organized as two units divergently transcribable from a 258-bp inter-genic region that contains the oriT site. One unit encodes traA, traF, and traB, while the second encodes traC, traD, and traG. Reporter insertions located downstream of both sets of genes did not affect conjugation but were expressed, suggesting that the two units encode additional genes that are not involved in transfer under the conditions tested. Proteins of the predicted sizes were expressible from traA, traC, traD, and traG. The products of several Ti plasmid tra genes are related to those of other conjugation systems. The 127-kDa protein expressed from traA contains domains related to MobA of RSF1O1O and to the helicase domain of TraI of plasmid F. The translation product of traF is related to TraF of RP4, and that of traG is related to TraG of RP4 and to VirD4 of the Ti plasmid T-DNA transfer system. Genetic analysis indicated that at least traG and traF are essential for conjugal transfer, while sequence analysis predicts that traA also encodes an essential function. traB, while not essential, is required for maximum frequency of transfer. Patterns of sequence relatedness indicate that the oriT and the predicted cognate site-specific endonuclease encoded by traA share lineage with those of the transfer systems of RSF1010 and plasmid F, while genes of the Ti plasmid encoding other essential tra functions share common ancestry with genes of the RP4 conjugation system.

Agrobacterium tumefaciens↗
PubMed1995

A new regulatory element modulates homoserine lactone-mediated autoinduction of Ti plasmid conjugal transfer.

Conjugal transfer of the Agrobacterium tumefaciens nopaline-type Ti plasmid pTiC58 is induced by agrocinopines A and B, opines secreted by crown gall tumors induced by the bacterium. This regulation functions through the transcriptional repressor, AccR. However, actual transcription of the tra genes is regulated by autoinduction through the activator TraR and the substituted homoserine lactone second messenger, Agrobacterium autoinducer (AAI). We have identified a new regulatory element that modulates the response of TraR to AAI. The gene, called traM, suppresses TraR-AAI activation of transcription of tra genes carried on recombinant clones. The suppression could be relieved by increasing the expression of TraR but not by increasing AAI levels. traM is located between traR and traAF on pTiC58 and is transcribed in the clockwise direction. The 306-bp gene encodes an 11.2-kDa protein showing no significant relatedness to other proteins in the databases. Mutations in traM in pTiC58 conferred a transfer-constitutive phenotype, and strains harboring the Ti plasmid produced easily detectable amounts of AAI. These same mutations engineered into the transfer-constitutive Ti plasmid pTiC58 delta accR conferred a hyperconjugal phenotype and very high levels of AAI production. Expression of traM required TraR, indicating that transcription of the gene is regulated by the autoinduction system. TraM had no effect on the expression of traR, demonstrating that the suppressive effect is not due to repression of the gene encoding the activator. These results suggest that TraM is not a direct transcriptional regulator. Since the suppressive effect is demonstrable only when traM is overexpressed with respect to traR, we suggest that TraM functions to sequester TraR from the very small amounts of AAI produced under conditions when the agrocinopines are not present.

4-Butyrolactone↗
PubMed1994

TraI, a LuxI homologue, is responsible for production of conjugation factor, the Ti plasmid N-acylhomoserine lactone autoinducer.

Conjugal transfer of the nopaline-type Agrobacterium Ti plasmid pTiC58 is regulated by a transcriptional activator, TraR, and a diffusible signal molecule, conjugation factor (CF). CF is a member of a family of substituted homoserine lactones (HSLs) that act as coinducers for regulating gene expression in diverse Gram-negative bacteria by a mechanism called autoinduction. In Vibrio fischeri HSL production is conferred by the luxI gene. Homologues of this gene are responsible for HSL production by other Gram-negative bacteria. A gene that we call traI, conferring production of material with CF activity, was localized to a 1-kb region at the upstream end of tra3 of pTiC58. Spectroscopy showed that the activity was authentic CF. Sequence analysis showed that traI could encode a protein of 211 amino acids, TraI, that is related to the proteins responsible for HSL production by other bacteria. A second, partial open reading frame immediately downstream of traI could encode a protein related to TrbB of plasmid RP4, which is required for conjugal transfer. Transcription of traI and of the downstream tra3 genes requires TraR and CF and initiates from the traI promoter. The results show that traI is responsible for CF production, that it is the first gene of the tra3 operon, and that expression of this operon is regulated by autoinduction.

Amino Acid Sequence↗
PubMed1994

Cushing's syndrome.

Explore the source record for details and available documents.

ACTH Syndrome, Ectopic↗
PubMed1994

Detection of occult gastrinomas with iodine 125-labeled lanreotide and intraoperative gamma detection.

BACKGROUND: Surgical exploration for gastrinoma has a high failure rate because of small primary tumors and occult metastasis. Despite extensive preoperative and intraoperative tumor localization, only 30% to 40% of patients with gastrinoma are cured by surgery. Two patients with unlocalized gastrinomas were studied with intraoperative gamma detection of an iodine 125-labeled somatostatin analog, lanreotide, to localize their tumors. METHODS: Both patients were challenged before operation with 100 micrograms of octreotide acetate, and both had circulating gastrin levels suppressed by greater than 50%. Iodine 125-labeled lanreotide (100 to 150 muCi) was injected during exploration, and an intraoperative gamma detector was used to detect tumor binding of the analog. RESULTS: In patient 1 a single source of increased counts was discovered in a retroduodenal lymph node, which was excised; no other tissue was removed. Histologic study of this node failed to demonstrate tumor; however, the patient's gastrin level was normal (63 pg/ml) 4 months after operation. In patient 2 five areas of increased counts were discovered and excised. Three of these five areas had visible tumor on microscopic examination. Three months after operation the patient's fasting gastrin level was 103 pg/ml. CONCLUSIONS: Intraoperative gamma detection of radiolabeled peptides may allow the localization of occult tumors that contain specific peptide receptors.

Adult↗
PubMed1993

Hypothalamic pituitary adrenal function in the extremely low birth weight infant.

Extremely premature infants manifest clinical features suggestive of adrenal insufficiency. Yet, serum cortisol levels are similar in ill and well preterm infants in a setting where one would expect high stress levels in the ill infants. We investigated the hypothalamic-pituitary-adrenal axis in 17 extremely low birth weight stressed premature infants, mean birth weight 739 g, gestational age, 26.1 weeks, using ovine CRH (oCRH) and ACTH stimulation. oCRH (1 microgram/kg) was administered at 2-7 days of life (mean = 4.1). ACTH rose from a basal value 6.0 +/- 0.8 pmol/L (mean +/- SEM) to 9.6 +/- 1.8 pmol/L (P < 0.01) at 15 min and 9.5 +/- 1.7 pmol/L (P < 0.01) at 60 min. Basal cortisol rose from 349.3 +/- 58.1 nmol/L to 422.3 +/- 57.9 nmol/L (P < 0.01) at 15 min and 568.7 +/- 60.2 nmol/L (P < 0.01) at 60 min. Cortisol values remained significantly (P < 0.05) elevated 24 h after oCRH. An ACTH stimulation test performed 24 h after the oCRH test demonstrated a significant cortisol rise from 603.5 +/- 130.5 nmol/L to 882.7 +/- 136.6 nmol/L (P < 0.05) at 60 min. Plasma CRH immunoactivity was also measured before oCRH testing and was detectable in 10 of 15 infants. The mean CRH immunoactivity was 21.8 +/- 4.4 pmol/L in the infants, significantly higher than 8 adult male controls (P < 0.04). Our results show a normal pituitary response to ovine CRH and a normal adrenal response to ACTH. We hypothesize that cortisol levels are inappropriately low in some ill preterm infants because of the inability of the extremely premature brain to recognize the stress of the illness or because of inadequate hypothalamic secretion of CRH. The significance of the measurable plasma CRH in the first week of life is unknown.

Adrenal Glands↗
PubMed1993

A structure-function analysis of transcriptional repression mediated by the WT1, Wilms' tumor suppressor protein.

The chromosome 11p13 Wilms' tumor locus (wt1) encodes a zinc finger-containing transcription factor (WT1). WT1 binds to the consensus sequence (5'-GCGGGGGCG-3') and represses transcription when bound to this site in vivo. The mechanism of repression is not yet defined. To investigate the mechanisms of transcriptional repression and map the domains of WT1 responsible, we constructed hybrid proteins between the yeast GAL4 1-147 DNA binding domain and WT1. Fusion of a 298 amino acid glutamine-proline-rich N-terminal segment of WT1 to the GAL4 DNA binding domain created a potent transcriptional repressor. The use of N- and C-terminal truncations of this segment demonstrated that as few as 96 amino acids were required for active repression by GAL4-WT1 hybrid proteins in NIH3T3 fibroblasts. However, the truncated GAL4-WT1 fusion proteins functioned poorly as repressors in embryonic kidney-derived 293 cells, suggesting cell type-specific requirements for transcriptional repression. Site-directed mutagenesis of the WT1 repression domain revealed that deletion of homopolymeric proline and glycine regions, as well as single amino acid changes, partially inactivated the repression function. Single repressor binding sites placed upstream of the transcription start site conferred WT1-mediated repression to a heterologous promoter, whereas multiple sites resulted in additive (non-synergistic) increases in transcriptional repression. Significant repression of transcription was observed when binding sites were placed 760 base pairs upstream or 1000 base pairs downstream relative to the site of transcription initiation. We conclude that the transcriptional repression function of WT1 is contained in the N-terminal, non-DNA binding domain of the protein and that repression can be functionally transferred to a heterologous DNA binding domain.

3T3 Cells↗
PubMed1992

Octreotide treatment of acromegaly. A randomized, multicenter study.

OBJECTIVE: To determine the effects of the somatostatin analog, octreotide acetate, in patients with acromegaly. DESIGN: Double-blind, randomized trial. SETTING: Fourteen university-affiliated medical centers. PATIENTS: One hundred fifteen acromegalic patients, 70% of whom had persistent disease after pituitary surgery or radiotherapy. INTERVENTION: Subcutaneous octreotide, 100 micrograms, or placebo every 8 hours for 4 weeks. Four weeks after the end of treatment, patients were randomized to receive 100 or 250 micrograms octreotide subcutaneously every 8 hours for 6 months. RESULTS: After 2 weeks of treatment, a single 100-micrograms injection reduced mean serum growth hormone (GH) to 30% of the pretreatment concentration within 2 hours. The integrated mean GH level was reduced over 8 hours from 39 +/- 11 micrograms/L to 9 +/- 2 micrograms/L (P less than 0.001). Mean plasma insulin-like growth factor-1 (IGF-1) was reduced from 5100 +/- 400 U/L to 2400 +/- 400 U/L (P less than 0.001). After 6 months, the mean GH was reduced from 39 +/- 13 to 15 +/- 4 micrograms/L by 300 micrograms of octreotide and from 29 +/- 5 micrograms/L to 9 +/- 2 micrograms/L by 750 micrograms of octreotide daily. The mean IGF-1 concentration was suppressed to 2100 +/- 300 and 2500 +/- 400 U/L after 300 and 750 micrograms octreotide, respectively. Integrated mean GH levels were reduced to < 5 micrograms/L in 53% (95% CI, 39% to 67%) and 49% (CI, 35% to 63%), and IGF-1 levels were normal in 68% (CI, 54% to 82%) and 55% (CI, 40% to 70%) of patients receiving low- and high-dose octreotide, respectively. A substantial decrease in headache, amount of perspiration, joint pain, and finger circumference occurred in two thirds of the patients. The pituitary size was reduced in 19% (CI, 5% to 33%) and 37% (CI, 22% to 52%) of patients receiving 6 months of low- and high-dose octreotide, respectively. Ten percent and 13% of patients in each treatment group developed transient diarrhea; 10% and 14%, biliary sludge; and 6% and 18%, cholelithiasis, respectively. CONCLUSION: Octreotide effectively decreased GH and IGF-1 concentrations in 53% and 68% of patients, respectively. The higher dose resulted in increased frequency of tumor shrinkage but added no biochemical or clinical benefit.

Acromegaly↗
PubMed1992

Safe use of glucocorticoids. How to monitor patients taking these potent agents.

Glucocorticoids reduce inflammation and combat stress. However, they are very powerful, and guidelines for their use must be followed to avoid such adverse effects as Cushing's syndrome and adrenal insufficiency. Whenever possible, physicians should consider alternative treatment strategies, because the consequences of steroid therapy may be worse than those of the disease being treated.

Glucocorticoids↗
PubMed1992

The oriT region of the Agrobacterium tumefaciens Ti plasmid pTiC58 shares DNA sequence identity with the transfer origins of RSF1010 and RK2/RP4 and with T-region borders.

Ti plasmids of Agrobacterium tumefaciens are conjugal elements whose transfer is induced by certain opines secreted from crown galls. On transmissible plasmids, DNA transfer initiates within a cis-acting site, the origin of conjugal transfer, or oriT. We have localized an oriT on the A. tumefaciens plasmid pTiC58 to a region containing the conjugal transfer loci traI and traII and acc, which is the locus encoding catabolism of the two conjugal opines, agrocinopines A and B. The smallest functional oriT clone, a 65-bp BamHI-ApaI fragment in the recombinant plasmid pDCBA60-11, mapped within the traII locus. The nucleotide sequence for a 665-bp KpnI-EcoRI fragment with oriT activity was determined. DNA sequence alignments showed identities between the pTiC58 oriT and the transfer origins of RSF1010, pTF1, and RK2/RP4 and with the pTiC58 T-region borders. The RSF1010-like sequence on pTiC58 is located in the smallest active oriT clone of pTiC58, while the sequence showing identities with the oriT regions of RK2/RP4 and with T-region borders maps outside this region. Despite their sequence similarities, pTiC58 oriT clones were not mobilized by RP4; nor could vectors containing the RK2/RP4 oriT region or the oriT-mob region from RSF1010 be mobilized by pTiC58. In contrast, other Ti plasmids and a conjugally active Agrobacterium opine catabolic plasmid, pAtK84b, efficiently mobilized pTiC58 oriT clones. In addition, the RSF1010 derivative, pDSK519, was mobilized at moderate frequencies by an Agrobacterium strain harboring only the cryptic plasmid pAtC58 and at very low frequencies by an Agrobacterium host that does not contain any detectable plasmids.

Agrobacterium tumefaciens↗