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D Seger

Publications and source records attributed to D Seger.

At least 19 recordsLinked to original sources
PubMed2001

Cost comparison of mastectomy versus breast-conserving therapy for early-stage breast cancer.

BACKGROUND: Choice of treatment for early-stage breast cancer depends on many factors, including the size and stage of the cancer, the woman's age, comorbid conditions, and perhaps the costs of treatment. We compared the costs of all medical care for women with early-stage breast cancer cases treated by breast-conserving therapy (BCT) or mastectomy. METHODS: A total of 1675 women 35 years old or older with incident early-stage breast cancer were identified in a large regional nonprofit health maintenance organization in the period 1990 through 1997. The women were treated with mastectomy only (n = 183), mastectomy with adjuvant hormonal therapy or chemotherapy (n = 417), BCT with radiation therapy (n = 405), or BCT with radiation therapy and adjuvant hormonal therapy or chemotherapy (n = 670). The costs of all medical care for the period 1990 through 1998 were computed for each woman, and monthly costs were analyzed by treatment, adjusting for age and cancer stage. All statistical tests were two-sided. RESULTS: At 6 months after diagnosis, the mean total medical care costs for the four groups differed statistically significantly (P:<.001), with BCT being more expensive than mastectomy. The adjusted mean costs were $12 987, $14 309, $14 963, and $15 779 for mastectomy alone, mastectomy with adjuvant therapy, BCT plus radiation therapy, and BCT plus radiation therapy with adjuvant therapy, respectively. At 1 year, the difference in costs was still statistically significant (P:<.001), but costs were influenced more by the use of adjuvant therapy than by type of surgery. The 1-year adjusted mean costs were $16 704, $18 856, $17 344, and $19 081, respectively, for the four groups. By 5 years, BCT was less expensive than mastectomy (P:<.001), with 5-year adjusted mean costs of $41 930, $45 670, $35 787, and $39 926, respectively. Costs also varied by age, with women under 65 years having higher treatment costs than older women. CONCLUSIONS: BCT may have higher short-term costs but lower long-term costs than mastectomy.

Adult↗
PubMed2001

The CK2 phosphorylation of vitronectin. Promotion of cell adhesion via the alpha(v)beta 3-phosphatidylinositol 3-kinase pathway.

Phosphorylation of vitronectin (Vn) by casein kinase II was previously shown to occur at Thr50 and Thr57 and to augment a major physiological function of vitronectin-cell adhesion and spreading. Here we show that this phosphorylation increases cell adhesion via the alpha(v)beta3 (not via the alpha(v)beta5 integrin), suggesting that alpha(v)beta3 differs from alpha(v)beta5 in its biorecognition profile. Although both the phospho (CK2-PVn) and non-phospho (Vn) analogs of vitronectin (simulated by mutants Vn(T50E,T57E), and Vn(T50A,T57A), respectively) trigger the alpha(v)beta3 as well as the alpha(v)beta5 integrins, and equally activate the ERK pathway, these two forms are different in their activation of the focal adhesion kinase/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) pathway. Specifically, we show (i) that, upon exposure of cells to Vn/CK2-PVn, their PKB activation depends on the availability of the alpha(v)beta3 integrin on their surface; (ii) that upon adhesion of the beta3-transfected cells onto the CK2-PVn, the extent of PKB activation coincides with the enhanced adhesion of these cells, and (iii) that both the PKB activation and the elevation in the adhesion of these cells is PI3K-dependent. The occurrence of a cell surface receptor that specifically distinguishes between a phosphorylated and a non-phosphorylated analog of Vn, together with the fact that it preferentially activates a distinct intra-cellular signaling pathway, suggest that extra-cellular CK2 phosphorylation may play an important role in the regulation of cell adhesion and migration.

Amino Acid Substitution↗
PubMed2000

Evidence showing that the two-chain form of vitronectin is produced in the liver by a selective furin cleavage.

The adhesive protein vitronectin (75 kDa) occurs in human blood fluid in a one-chain (Vn75) or a two-chain form (Vn65-10), and is produced by a specific cleavage (at Arg379-Ala380), by a proteinase not identified hitherto. These two forms were shown to be functionally different and therefore, this cleavage may have a regulatory significance in vivo. Here, we report the use of a tailored one-chain recombinant Vn, a specific protein kinase A phosphorylation at Ser378, and sequence analysis to show: (1) that none of the proteinases originating from blood, previously thought to be the endogenous proteinase (plasmin, thrombin, tPA, and uPA), is indeed the in vivo convertase; and (2) that furin, a serine endoproteinase residing in the secretory pathway of hepatocytes, where Vn is synthesized, specifically cleaves Vn at the endogenous cleavage site. Consequently, we propose that the Vn75 to Vn65-10 conversion takes place in the liver (not in blood) and is carried out by furin.

Alanine↗
PubMed2000

Testing reminder and motivational telephone calls to increase screening mammography: a randomized study.

BACKGROUND: Prospective randomized trials have demonstrated that motivational telephone calls increase adherence to screening mammography. To better understand the effects of motivational calls and to maximize adherence, we conducted a randomized trial among women aged 50-79 years. METHODS: We created a stratified random sample of 5062 women due for mammograms within the Group Health Cooperative of Puget Sound, including 4099 women with prior mammography and 963 without it. We recruited and surveyed 3743 (74%) of the women before mailing a recommendation. After 2 months, 1765 (47%) of the 3743 women had not scheduled a mammogram and were randomly assigned to one of three intervention groups: a reminder post-card group (n = 590), a reminder telephone call group (n = 585), and a motivational telephone call addressing barriers group (n = 590). The telephone callers could schedule mammography. We used Cox proportional hazards models to estimate the hazard ratio (HR) and 95% confidence interval (CI) for documented mammography use by 1 year. RESULTS: Women who received reminder calls were more likely to get mammograms (HR = 1.9; 95% CI = 1.6-2.4) than women who were mailed postcards. The motivational and reminder calls (average length, 8.5 and 3.1 minutes, respectively) had equivalent effects (HR = 0.97; 95% CI = 0.8-1.2). After we controlled for the intervention effect, women with prior mammography (n = 1277) were much more likely to get a mammogram (HR = 3.4; 95% CI = 2.7-4.3) than women without prior use (n = 488). Higher income, but not race or more education, was associated with higher adherence. CONCLUSIONS: Reminding women to schedule an appointment was as efficacious as addressing barriers. Simple intervention groups should be included as comparison groups in randomized trials so that we better understand more complex intervention effects.

Affect↗
PubMed2000

Mercury exposure and cutaneous disease.

Human contact with mercury has been ongoing for centuries and was previously considered a legitimate means of treating different cutaneous and systemic conditions. Toxicity from this heavy metal may occur from exposure to elemental, inorganic, and organic forms of mercury. This article outlines the signs and symptoms of mercury poisoning and the different clinical conditions with assorted cutaneous findings.

Acrodynia↗
PubMed2000

Accuracy of screening mammography using single versus independent double interpretation.

OBJECTIVE: We conducted an analysis among 31 community radiologists to identify the average change in screening mammography interpretive accuracy afforded by independent double interpretation. MATERIALS AND METHODS: We assessed interpretive accuracy using a stratified random sample of test mammograms that included 30 women with cancer and 83 without. Radiologists were unaware of clinical information and of each other's assessments. We describe accuracy for individual radiologists and for double interpretation, including average sensitivity, specificity, diagnostic likelihood ratios positive and negative, and area under the receiver operating characteristic (ROC) curve. We also assessed weighted and nonweighted kappa statistics among all 465 pairs of radiologists and 31,465 pairs of unique pairs. The assessment for double interpretations used the "highest" (i.e., most abnormal) assessment of the two radiologists. We calculated the difference between each radiologist's individual accuracy and the average accuracy across that radiologist's 30 double interpretations. RESULTS: We found the following average accuracy statistics for individual radiologists: sensitivity, 79%; specificity, 81%; diagnostic likelihood ratio positive, 5.53; diagnostic likelihood ratio negative, 0.26; and area under the ROC curve, 0.85. The mean kappa statistic among radiologists for cancer cases increased with double interpretation from 0.59 to 0.70, and for noncancer cases from 0.30 to 0.34. Double interpretation resulted in an average increase in sensitivity of 7%, an average decrease in specificity of 11%, a decrease in diagnostic likelihood ratio positive of 2.35, a decrease in diagnostic likelihood ratio negative of 0.06, and an increase in area under the ROC curve of 0.02. CONCLUSION: Independent double interpretation does not increase accuracy as measured by the area under the ROC curve.

Adult↗
PubMed1999

Vitronectin.

Vitronectin is a multifunctional glycoprotein present in blood and in the extracellular matrix. It binds glycosaminoglycans, collagen, plasminogen and the urokinase-receptor, and also stabilizes the inhibitory conformation of plasminogen activation inhibitor-1. By its localization in the extracellular matrix and its binding to plasminogen activation inhibitor-1, vitronectin can potentially regulate the proteolytic degradation of this matrix. In addition, vitronectin binds to complement, to heparin and to thrombin-antithrombin III complexes, implicating its participation in the immune response and in the regulation of clot formation. The biological functions of vitronectin can be modulated by proteolytic enzymes, and by exo- and ecto-protein kinases present in blood. Vitronectin contains an RGD sequence, through which it binds to the integrin receptor alpha v beta 3, and is involved in the cell attachment, spreading and migration. Antibodies against alpha v beta 3 or synthetic peptides containing an RGD sequence are now being tested as therapeutic agents in the treatment of human cancers, bone diseases (e.g. osteoporosis) and in pathological disorders which involve angiogenesis.

Animals↗
PubMed1999

Fatal multi-organ failure after suicidal overdose with MDMA, 'ecstasy': case report and review of the literature.

A 53-year-old prisoner died of multiorgan failure after a suicidal overdose with 3,4-methylenedeoxymethamphetamine (MDMA, 'Ecstasy'). Twelve hours after ingestion of MDMA, the patient became severely hyperthermic (107.2 degrees F) with evidence of rhabdomyolysis. He subsequently developed acute respiratory distress syndrome (ARDS), disseminated intravascular coagulopathy (DIC) and acute renal failure. At autopsy, plasma concentration of MDMA was 3.05 mg/L. This case shows that MDMA is still abused in our community and clinicians should know the symptoms of MDMA intoxication. In particular, MDMA should be considered when patients have symptoms or signs of increased sympathetic activity. The pathophysiology and treatment of MDMA-induced hyperthermia are discussed.

Disseminated Intravascular Coagulation↗
PubMed1998

Phosphorylation of vitronectin by casein kinase II. Identification of the sites and their promotion of cell adhesion and spreading.

The cell adhesion protein vitronectin (Vn) was previously shown to be the major target in human blood for an extracellular protein kinase A, which is released from platelets upon their physiological stimulation with thrombin and also prevails as an ectoenzyme in several other types of blood cells. Because plasma Vn was shown to have only one protein kinase A phosphorylation site (Ser378) but to contain approximately 3 mol of covalently bound phosphate, and because human serum and blood cells were shown to contain also a casein kinase II (CKII) on their surface, we studied the phosphorylation of Vn by CKII attempting to find out whether such phosphorylation modulates Vn function, an acid test for its having a physiological relevance. Here we show (i) that the CKII phosphorylation of Vn has a Km of 0.5-2 microM (lower than the Vn concentration in blood, 3-6 microM), (ii) that it is targeted to Thr50 and Thr57, which are vicinal to the RGD site of Vn, and (iii) that the phosphorylation of Thr57 facilitates the phosphorylation of Thr50. The maximal stoichiometry of the CKII phosphorylation of plasma Vn was found to be low, which, in principle, could be due to its partial prephosphorylation in vivo. However, for the detection of a functional modulation, we needed a comparison between a fully phosphorylated Vn (at Thr57 and Thr50) and a nonphosphorylated Vn. Therefore, we expressed Vn in a baculovirus system and show (i) that the CKII phosphorylation of wt-Vn enhances the adhesion of bovine aorta endothelial cells; (ii) that the double mutant T50E/T57E (in which the neutral Thr residues are replaced by the negatively charged Glu residues considered analogs of Thr-P) has a significantly enhanced capacity to promote cell adhesion and to accelerate cell spreading when compared with either wild-type Vn or to the neutral T50A/T57A mutant; and (iii) that, at least in the case of bovine aorta endothelial cells, the T50E/T57E mutant exhibits an enhanced adhesion, which seems to be due to an increased affinity toward the alphav beta3 Vn receptors.

Amino Acid Sequence↗
PubMed1997

Clinical presentation and outcome of brown recluse spider bite.

STUDY OBJECTIVE: To examine the clinical presentation and outcome of patients treated in the ED or toxicology clinic for suspected brown recluse spider bites. METHODS: We assembled a retrospective case of patients at a southeastern US university hospital. Our study group comprised 111 patients with suspected brown recluse spider bites treated during a 30-month period. Our main outcome measures were the need for skin grafting and the development of other complications. RESULTS: The mean age of our subjects was 34 +/- 17 years. Thirteen patients (12%) brought the spider to the hospital, 22 (20%) saw a spider at the time of the bite, and an exclusively clinical diagnosis was made in the remaining 76 (68%). Most wounds (59%) involved the leg. At the time of presentation, 81% had central discoloration and 37% necrosis. Sixteen patients (14%) were systemically ill, and 6 (5%) were admitted to the hospital. Most (86%) were treated with antibiotics. Dapsone was infrequently used (9%) and had usually been prescribed before the patient's presentation to our ED. Only three patients (3%; 95% confidence interval, 1% to 8%) required grafting. Mild hemolytic anemia developed in one patient, and another had mild hemolysis and a mild coagulopathy; neither patient was taking dapsone. No deaths or serious complications occurred in our study group. CONCLUSION: In our series, long-term outcome after brown recluse spider bite was good. Serious complications were rare, as was the need for skin grafting. Because the vast majority of bites heal with supportive care alone, aggressive medical therapy does not appear warranted.

Adolescent↗
PubMed1997

Position statement: single-dose activated charcoal. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists.

In preparing this Position Statement, all relevant scientific literature was identified and reviewed critically by acknowledged experts using agreed criteria. Well-conducted clinical and experimental studies were given precedence over anecdotal case reports and abstracts were not usually considered. A draft Position Statement was then produced and subjected to detailed peer review by an international group of clinical toxicologists chosen by the American Academy of Clinical Toxicology and the European Association of Poisons Centres and Clinical Toxicologists. The Position Statement went through multiple drafts before being approved by the boards of the two societies and being endorsed by other societies. The Position Statement includes a summary statement for ease of use and is supported by detailed documentation which describes the scientific evidence on which the Statement is based. Single-dose activated charcoal should not be administered routinely in the management of poisoned patients. Based on volunteer studies, the effectiveness of activated charcoal decreases with time; the greatest benefit is within 1 hour of ingestion. The administration of activated charcoal may be considered if a patient has ingested a potentially toxic amount of a poison (which is known to be adsorbed to charcoal) up to 1 hour previously; there are insufficient data to support or exclude its use after 1 hour of ingestion. There is no evidence that the administration of activated charcoal improves clinical outcome. Unless a patient has an intact or protected airway, the administration of charcoal is contraindicated.

Administration, Oral↗
PubMed1995

Identification of inhibitory and calmodulin-binding domains of the PDE1A1 and PDE1A2 calmodulin-stimulated cyclic nucleotide phosphodiesterases.

Using a bovine 61-kDa (PDE1A2) calmodulin-stimulated phosphodiesterase (CaM-PDE) cDNA and a bovine lung 59-kDa (PDE1A1) CaM-PDE cDNA reported here, we have identified two new regions within the primary structure of these two related isozymes that are important for regulation by Ca2+/CaM. PDE1A1 is identical to the PDE1A2 isozyme except for the amino-terminal 18 residues. In agreement with earlier studies, the CaM concentration required for half-maximal activation (KCaM) of recombinant PDE1A1 (0.3 nM) was approximately 10-fold less than the KCaM for recombinant PDE1A2 (4 nM). A series of deletion mutations of the PDE1A2 cDNA removing nucleotide sequence encoding the first 46-106 aminoterminal residues were constructed and expressed using the baculovirus system. Deletion of the amino acids encompassing a previously identified, putative CaM-binding domain (residues 4-46) produced a polypeptide that was still activated 3-fold by CaM (KCaM approximately 3 nM). However, complete CaM-independent activation occurred when residues 4-98 were deleted. To determine the location of the additional CaM-binding domain(s), the inhibitory potency of seven overlapping, synthetic peptides spanning amino acids 76-149 of PDE1A2 was tested using the CaM-activated enzyme. One peptide spanning amino acids 114-137 of PDE1A2 appeared to be the most potent inhibitor of CaM-stimulated activity. These results reveal the existence of a CaM-binding domain located approximately 90 residues carboxyl-terminal to the putative CaM-binding domains previously identified within the PDE1A1 and PDE1A2 isozymes. Moreover, a discrete segment important for holding these CaM-PDEs in a less active state at low Ca2+ concentrations is located between the two CaM-binding domains.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

An essential aspartic acid at each of two allosteric cGMP-binding sites of a cGMP-specific phosphodiesterase.

The amino acid sequences of all known cGMP-binding phosphodiesterases (PDEs) contain internally homologous repeats (a and b) that are 80-90 residues in length and are arranged in tandem within the putative cGMP-binding domains. In the bovine lung cGMP-binding, cGMP-specific PDE (cGB-PDE or PDE5A), these repeats span residues 228-311 (a) and 410-500 (b). An aspartic acid (residue 289 or 478) that is invariant in repeats a and b of all known cGMP-binding PDEs was changed to alanine by site-directed mutagenesis of cGB-PDE, and wild type (WT) and mutant cGB-PDEs were expressed in COS-7 cells. Purified bovine lung cGB-PDE (native) and WT cGB-PDE displayed identical cGMP-binding kinetics, with approximately 1.8 microM cGMP required for half-maximal saturation. The D289A mutant showed decreased affinity for cGMP (Kd > 10 microM) and the D478A mutant showed increased affinity for cGMP (Kd approximately 0.5 microM) as compared to WT and native cGB-PDE. WT and native cGB-PDE displayed an identical curvilinear profile of cGMP dissociation which was consistent with the presence of distinct slowly dissociating (koff = 0.26 h-1) and rapidly dissociating (koff = 1.00 h-1) sites of cGMP binding. In contrast, the D289A mutant displayed a single koff = 1.24 h-1, which was similar to the calculated koff for the fast site of WT and native cGB-PDE, and the D478A mutant displayed a single koff = 0.29 h-1, which was similar to that calculated for the slow site of WT and native cGB-PDE. These results were consistent with the loss of a slow cGMP-binding site in repeat a of the D289A mutant cGB-PDE, and the loss of a fast site in repeat b of the D478A mutant, suggesting that cGB-PDE possesses two distinct cGMP-binding sites located at repeats a and b, with the invariant aspartic acid being crucial for interaction with cGMP at each site.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1994

Overexpression of mitogen-activated protein kinase kinase (MAPKK) and its mutants in NIH 3T3 cells. Evidence that MAPKK involvement in cellular proliferation is regulated by phosphorylation of serine residues in its kinase subdomains VII and VIII.

Mitogen-activated protein kinase kinase (MAPKK) is a dual specificity protein kinase that exhibits a high degree of specificity toward its downstream target, mitogen-activated protein kinase (MAPK). In this study, we used stable overexpression of MAPKK and its mutants in NIH 3T3 cells to study effects on downstream components of the MAPK signaling cascade and to correlate them to physiological responses. We have mutated the potential regulatory serine residue 222 to alanine (S222A) or to glutamate (S222E) and serines 212 and 218 together to alanine residues (S212A,S218A). Lysine 97 was mutated to alanine (K97A) to provide an inactive enzyme. Overexpression of the wild type MAPKK had no effect on any of the parameters examined. The K97A and S222A mutants served as dominant negatives by suppressing MAPKK, MAPK, and p90rsk activation in vivo. S222E enhanced all of these activities, and S212A,S218A had a small inhibitory effect. A similar trend was observed when cellular proliferation was examined and the different effects were accompanied by altered cellular shape. Taken together, our results demonstrate a direct linkage between the MAPK signaling pathway and the control of cellular proliferation and morphology and also establish that phosphorylation of serine 222 is essential for MAPKK activation together with the phosphorylation of an additional serine(s) (probably serine 218).

3T3 Cells↗
PubMed1994

Carbon monoxide controversies: neuropsychologic testing, mechanism of toxicity, and hyperbaric oxygen.

Recent animal and clinical data require a reevaluation of the traditional approach to the patient exposed to carbon monoxide. Unfortunately, these new data are inconclusive and generate controversies regarding the indications and value of neuropsychologic testing, cause of carbon monoxide toxicity, and indications (if any) for hyperbaric oxygen therapy. These controversies and their implications for the emergency physician are discussed.

Animals↗
PubMed1994

Chloral hydrate: a dangerous sedative for overdose patients?

A child ingested a stimulant and was sedated with chloral hydrate for agitation. An arrhythmia occurred following the chloral hydrate sedation. Chloral hydrate may be contraindicated when sedating children with stimulant ingestions.

Akathisia, Drug-Induced↗