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D C Martin

Publications and source records attributed to D C Martin.

At least 37 records · Page 2Linked to original sources
PubMed1999

Insulin-like growth factor II signaling in neoplastic proliferation is blocked by transgenic expression of the metalloproteinase inhibitor TIMP-1.

Insulin-like growth factor (IGF) II is overexpressed in many human cancers and is reactivated by, and crucial for viral oncogene (SV40 T antigen, [TAg])-induced tumorigenesis in several tumor models. Using a double transgenic murine hepatic tumor model, we demonstrate that tissue inhibitor of metalloproteinase 1 (TIMP-1) blocks liver hyperplasia during tumor development, despite TAg-mediated reactivation of IGF-II. Because the activity of IGFs is controlled by IGF-binding proteins (IGFBPs), we investigated whether TIMP-1 overexpression altered the IGFBP status in the transgenic liver. Ligand blotting showed that IGFBP-3 protein levels were increased in TIMP-1-overexpressing double transgenic littermates, whereas IGFBP-3 mRNA levels were not different, suggesting that TIMP-1 affects IGFBP-3 at a posttranscriptional level. IGFBP-3 proteolysis assays demonstrated that IGFBP-3 degradation was lower in TIMP-1-overexpressing livers, and zymography showed that matrix metalloproteinases (MMPs) were present in the liver homogenates and were capable of degrading IGFBP-3. As a consequence of reduced IGFBP-3 proteolysis and elevated IGFBP-3 protein levels, dissociable IGF-II levels were significantly lower in TIMP-1-overexpressing animals. This decrease in bioavailable IGF-II ultimately resulted in diminished IGF-I receptor signaling in vivo as evidenced by diminished receptor kinase activity and decreased tyrosine phosphorylation of the IGF-I receptor downstream effectors, insulin receptor substrate 1 (IRS-1), extracellular signal regulatory kinase (Erk)-1, and Erk-2. Together, these results provide evidence that TIMP-1 inhibits liver hyperplasia, an early event in TAg-mediated tumorigenesis, by reducing the activity of the tumor-inducing mitogen, IGF-II. These data implicate the control of MMP-mediated degradation of IGFBPs as a novel therapy for controlling IGF bioavailability in cancer.

Animals↗
PubMed1999

Timp-1 is important for epithelial proliferation and branching morphogenesis during mouse mammary development.

The dynamic process of mammary ductal morphogenesis depends on regulated epithelial proliferation and extracellular matrix (ECM) turnover. Epithelial cell-matrix contact closely dictates epithelial proliferation, differentiation, and survival. Despite the fact that tissue inhibitors of metalloproteinases (Timps) regulate ECM turnover, their function in mammary morphogenesis is unknown. We have delineated the spatiotemporal expression of all Timps (Timp-1 to Timp-4) during discrete phases of murine mammary development. Timp mRNAs were abundant in mammary tissue, each displaying differential expression patterns with predominant localization in luminal epithelial cells. Timp-1 mRNA was unique in that its expression was limited to the stage at which epithelial proliferation was high. To assess whether Timp-1 promotes or inhibits epithelial cell proliferation we manipulated mammary Timp-1 levels, genetically and biochemically. Down-regulation of epithelial-derived Timp-1 in transgenic mice, by mouse mammary tumor virus promoter-directed Timp-1 antisense RNA expression, led to augmented ductal expansion and increased number of ducts (P < 0.004). In these transgenics the integrity of basement membrane surrounding epithelial ducts, as visualized by laminin-specific immunostaining, was breached. In contrast to these mice, ductal expansion was markedly attenuated in the proximity of implanted recombinant Timp-1-releasing pellets (rTIMP-1), without an increase in basement membrane deposition around migrating terminal end buds. Epithelial proliferation and apoptosis were measured to determine the basis of altered ductal expansion. Luminal epithelial proliferation was increased by 55% (P < 0.02) in Timp-1-reduced transgenic mammary tissue and, conversely, decreased by 38% (P < 0.02) in terminal end buds by implanted rTIMP-1. Epithelial apoptosis was minimal and remained unaffected by Timp-1 manipulations. We conclude that Timps have an integral function in mammary morphogenesis and that Timp-1 regulates mammary epithelial proliferation in vivo, at least in part by maintaining basement membrane integrity.

Animals↗
PubMed1999

Rate-determining step of Escherichia coli alkaline phosphatase altered by the removal of a positive charge at the active center.

Escherichia coli alkaline phosphatase catalyzes both the nonspecific hydrolysis of phosphomonoesters and a transphosphorylation reaction in which phosphate is transferred to an alcohol via a phosphoseryl intermediate. The rate-determining step for the wild-type enzyme is pH dependent. At alkaline pH, release of the product phosphate from the noncovalent enzyme-phosphate complex determines the reaction rate, whereas at acidic pH hydrolysis of the covalent enzyme-phosphate complex controls the reaction rate. When the lysine at position 328 was substituted with a cysteine (K328C), the rate-determining step at pH 8.0 of the mutant enzyme was altered so that hydrolysis of the covalent intermediate became limiting rather than phosphate release. The transphosphorylation activity of the K328C enzyme was selectively enhanced, while the hydrolysis activity was reduced compared to that of the wild-type enzyme. The ratio of the transphosphorylation to the hydrolysis activities increased 28-fold for the K328C enzyme in comparison with the wild-type enzyme. Several other mutant enzymes for which a positive charge at the active center is removed by site-specific mutagenesis share this characteristic of the K328C enzyme. These results suggest that the positive charge at position 328 is at least partially responsible for maintaining the balance between the hydrolysis and transphosphorylation activities and plays an important role in determining the rate-limiting step of E. coli alkaline phosphatase.

Alanine↗
PubMed1999

Association between percutaneous transluminal coronary angioplasty volumes and outcomes in the Healthcare Cost and Utilization Project 1993-1994.

Studies from a variety of settings have indicated that outcomes for coronary angioplasty are improved when performed in institutions with high caseloads (> 400/year). The purpose of this investigation was to examine the volume outcome hypothesis for coronary angioplasty in a 20% stratified sample of acute care, non-federal hospitals in 17 states. Data were derived from the Nationwide Inpatient Sample from the Health Care Cost and Utilization Project releases 2 and 3. From these records, 163,527 angioplasties from 214 hospitals were selected. Outcomes included hospital mortality, same-admission coronary artery bypass surgery, and a combined end point of either death or same-admission surgery, or both. Hospital volumes were defined as low (< or = 200 cases/year), medium (201 to 400), and high (> 400). Analyses were conducted separately for patients with and without a principal discharge diagnosis of acute myocardial infarction (AMI). For both AMI and no-AMI groups, the rates of adverse outcomes were generally lower in high-volume institutions, and this finding was true in both univariate and multivariate analyses. Although 27% of hospitals were in the low-volume category, only 5% of all procedures were performed in these institutions. Projecting to all United States hospitals for the 2 years, if all procedures performed in low-volume centers had been done in high-volume institutions, 137 deaths could have been averted (90 AMIs, 47 no-AMIs) as well as 404 (46 AMIs, 358 no-AMIs) same-admission surgeries. The results of this study support the hypothesis that better results are obtained in higher volume institutions, but also show that in 1993 and 1994, relatively few patients had their procedures performed in low-volume institutions.

Angioplasty, Balloon, Coronary↗
PubMed1999

Resolution of subdiaphragmatic gas.

A woman experienced dehydration, nausea, and vomiting after laparoscopic ovarian cystectomy. Symptoms resolved with hydration and observation. Daily abdominal radiographs revealed persistence of subdiaphragmatic gas for 7 days. There were no signs of peritonitis at any time during the evaluation. When patients experience abdominal complaints after laparoscopy, a major concern is perforated bowel. Since subdiaphragmatic air can persist for up to 24 days, clinical decisions are generally made on the basis of other findings.

Adult↗
PubMed1999

Air embolus associated with tubal insufflation.

A patient underwent laparoscopy for a rectovaginal mass, dysmenorrhea, and infertility. After CO(2) pneumoperitoneum was established the laparoscope was placed without difficulty. Before the procedure was completed, the tubes were insufflated with air through a 20-ml syringe attached to a Cohen cannula. Tubes were patent. No other intraabdominal manipulation was performed at that time. During tubal insufflation the patient's end-tidal CO(2) decreased to 18%, partial pressure of oxygen decreased to 83%, and pulse increased to 130/minute. The CO(2) pneumoperitoneum was released, and the woman stabilized spontaneously. The CO(2) pneumoperitoneum was again established, with no further difficulty. The time relationship with tubal insufflation and lack of recurrence on reestablishing pneumoperitoneum suggest that air embolization during tubal insufflation occurred.

Adult↗
PubMed1999

Endometriosis and pain.

Endometriosis generally causes pain that is cyclic and generally responds to medication and/or surgery. When endometriosis is found coincidentally, it may need no treatment because many women have endometriosis as a self-limited disease. In other women, the biologic behavior is much more unpredictable. Severe dysmenorrhea, focal pelvic tenderness, and deep dyspareunia are suggestive of endometriosis. Diagnosis at laparoscopy includes concerns about subtle appearance, endometriosis hidden within adhesions, retroperitoneal disease, and intra-ovarian lesions. Negative laparoscopy results do not mean that patients have no endometriosis. In contrast, a response to GnRH agonists can occur in patients with no endometriosis because conditions other than endometriosis are estrogen sensitive. Coexistent disease can confuse the picture at the time of surgery. Some coexistent diseases also can cause pain that is similar to that of endometriosis. Distinguishing those patients who need no treatment from those who need intermediate or extensive treatment can be very difficult. Care is needed to ensure that patients are neither overtreated or undertreated. An integrated approach involving a multidisciplinary team is needed in some. Other patients respond to primary care techniques.

Acupuncture Therapy↗
PubMed1999

Comparison of topical and oral treatments for tinea gladiatorum.

OBJECTIVE: Little has been published regarding treatment guidelines for tinea gladiatorum in the competitive wresting population, where outbreaks are commonplace. This study compares the efficacy of a first-line topical treatment regimen and an oral treatment regimen. DESIGN: A randomized, prospective, open-label pilot study was conducted during the 1997 to 1998 interscholastic wrestling season. SETTING: Training rooms at two suburban high schools. PARTICIPANTS: Male high school wrestlers with culture-proven tinea corporis were included in the study. There were 22 wrestlers enrolled; 17 finished the study. INTERVENTIONS: Wrestlers were randomized to receive either clotrimazole 1% cream applied twice daily or fluconazole 200 mg once weekly for a total treatment duration of 3 weeks. MAIN OUTCOME MEASURES: Symptom scores, lesion measurements, and fungal cultures were followed to assess treatment efficacy. RESULTS: Eleven wrestlers received clotrimazole and six wrestlers finished the full course of fluconazole. The extrapolated time to 50% improvement in symptom scores was 11.9 days in the clotrimazole group and 10.1 days in the fluconazole group. The extrapolated time to 50% lesion reduction was 18.7 days in the clotrimazole group and 17.2 days in the fluconazole group. The extrapolated time to 50% culture eradication was 22.7 days in the clotrimazole group and 11.1 days in the fluconazole group. CONCLUSION: Both clotrimazole and fluconazole produce similar improvement in clinical parameters. Fluconazole showed arithmetically, but not statistically, superior culture eradication. Fluconazole in a weekly dosing schedule should be considered in the first-line treatment of tinea gladiatorum.

Administration, Oral↗
PubMed1999

Amino acid substitutions at the subunit interface of dimeric Escherichia coli alkaline phosphatase cause reduced structural stability.

The consequences of amino acid substitutions at the dimer interface for the strength of the interactions between the monomers and for the catalytic function of the dimeric enzyme alkaline phosphatase from Escherichia coli have been investigated. The altered enzymes R10A, R10K, R24A, R24K, T59A, and R10A/R24A, which have amino acid substitutions at the dimer interface, were characterized using kinetic assays, ultracentrifugation, and transverse urea gradient gel electrophoresis. The kinetic data for the wild-type and altered alkaline phosphatases show comparable catalytic behavior with k(cat) values between 51.3 and 69.5 s(-1) and Km values between 14.8 and 26.3 microM. The ultracentrifugation profiles indicate that the wild-type enzyme is more stable than all the interface-modified enzymes. The wild-type enzyme is dimeric in the pH range of pH 4.0 and above, and disassembled at pH 3.5 and below. All the interface-modified enzymes, however, are apparently monomeric at pH 4.0, begin assembly at pH 5.0, and are not fully assembled into the dimeric form until pH 6.0. The results from transverse urea gradient gel electrophoresis show clear and reproducible differences both in the position and the shape of the unfolding patterns; all these modified enzymes are more sensitive to the denaturant and begin to unfold at urea concentrations between 1.0 and 1.5 M; the wild-type enzyme remains in the folded high mobility form beyond 2.5 M urea. Alkaline phosphatase H370A, modified at the active site and not at the dimer interface, resembles the wild-type enzyme both in ultracentrifugation and electrophoresis studies. The results obtained suggest that substitution of a single amino acid at the interface sacrifices not only the integrity of the assembled dimer, but also the stability of the monomer fold, even though the activity of the enzyme at optimal pH remains unaffected and does not appear to depend on interface stability.

Alkaline Phosphatase↗
PubMed1999

Transgenic TIMP-1 inhibits simian virus 40 T antigen-induced hepatocarcinogenesis by impairment of hepatocellular proliferation and tumor angiogenesis.

Tissue inhibitors of metalloproteinases (TIMP) block proteolytic degradation of extracellular matrix and consequently impede tumor invasion and metastasis. In addition, we have previously reported that hepatic TIMP-1 modulation alters the susceptibility of the liver to oncogene (simian virus 40 T-antigen; TAg)-induced tumorigenesis in a double-transgenic mouse model. To identify the cellular processes by which TIMP-1 inhibits hepatocarcinogenesis, we examined the effects of TIMP-1 on four specific events that are important during tumorigenesis: hepatocellular proliferation, apoptosis, the stromal characteristics of the liver, and tumor vascularization. Transgenic mice with elevated or reduced hepatic TIMP-1 expression were bred independently with TAg transgenics. Liver tissue from littermates were analyzed by in situ hybridization with TIMP-1 cDNA probes; gelatin enzymography; immunohistochemistry for proliferating cell nuclear antigen, von Willebrand factor, and collagen type IV; reticulin histochemistry; and collagens type III and IV, laminin, fibronectin, and CD31 immunoblotting. We demonstrate that TIMP-1 overexpression significantly inhibited the proliferation of hepatocytes in TAg mice but did not affect their apoptotic index, the hepatic parenchymal architecture, or extracellular matrix composition, including collagens type III and IV, laminin, and fibronectin. Moreover, the hepatocellular carcinomas formed in TIMP-1-overexpressing mice had significantly reduced tumor vascularization; conversely, tumor vascularization was significantly increased in TIMP-1-reduced livers. These data indicate that TIMP-1 inhibits TAg-induced hepatocarcinogenesis by altering hepatocellular proliferation and tumor vascularization, without any effect on hepatocyte apoptosis and stromal composition. To our knowledge, this is the first in vivo demonstration that genetic modulation of TIMP-1 inhibits cellular proliferation and angiogenesis during hepatocarcinogenesis. This potentially extends the use of matrix metalloproteinase inhibitors in cancer beyond control of invasion and metastasis.

Animals↗
PubMed1998

Sodium lactate and hypertonic sodium chloride induce equivalent panic incidence, panic symptoms, and hypernatremia in panic disorder.

BACKGROUND: Although experimental induction of panic by infusion of 0.5 mol/L sodium lactate in persons with panic disorder was described three decades ago, the mechanism underlying this observation remains unclear. Here we asked if the rapid administration of the large sodium load contained in the 0.5-mol/L sodium lactate infusion might be involved in panic induction. METHODS: We compared in panic disorder and healthy subjects behavioral, electrolyte, endocrine, and acid-base responses to three double-blind randomly ordered equal volume 20-min infusions: 0.5 mol/L sodium lactate, hypertonic saline (3% sodium chloride), and normal saline placebo. RESULTS: Sodium lactate (0.5 mol/L) and hypertonic saline produced the same high incidence of panic and equivalent increases in panic symptoms, serum sodium, and plasma vasopressin in the panic disorder subjects. Neither hypertonic infusion increased cortisol or adrenocorticotropin. No normal subject experienced panic in any condition. The 0.5-mol/L sodium lactate infusion induced alkalosis, whereas hypertonic saline and normal saline induced a mild acidosis. CONCLUSIONS: Hypertonic sodium solution containing either chloride or lactate anion induces panic in panic disorder. The large sodium loads delivered by hypertonic saline and 0.5 mol/L sodium lactate may be involved in the mechanism of panic induction.

Acidosis↗
PubMed1998

Host TIMP-1 overexpression confers resistance to experimental brain metastasis of a fibrosarcoma cell line.

Within the tumor-stromal microenvironment a disrupted balance between matrix metalloproteinases (MMPs) and their inhibitors compromises the integrity of the extracellular matrix and promotes malignancy. Tissue inhibitors of metalloproteinases (TIMPs) have been linked to tumor suppression in studies of genetically altered tissue culture cells and in analyses of clinical specimens in situ. We generated transgenic mice as a model system to test the relationship between TIMP-1 levels in a host organ and susceptibility to experimentally targeted metastasis. Ectopically overexpressed TIMP-1 in the brain resulted in a tissue microenvironment with elevated protein levels of this natural MMP inhibitor. Metastatic challenge provided by lacZ-tagged fibrosarcoma cells permitted high-resolution analysis of metastatic load and pattern. We found that elevated host TIMP-1 imposed resistance to experimental metastasis of fibrosarcoma: In TIMP-1 overexpressing mice, brain metastases were significantly reduced by 75% compared to wild-type littermates. Our findings demonstrate that ectopic TIMP-1 expression efficiently exerts a suppressive effect on metastasizing tumor cells.

Animals↗
PubMed1998

A comparison of percutaneous transluminal coronary angioplasty in the Department of Veterans Affairs and in the private sector in the State of Washington.

Coronary angioplasty is performed > 1,000 times daily in a variety of health care settings in the public and private sectors in the USA. How outcomes for this procedure differ in the Department of Veterans Affairs and the private sector is unknown. The purpose of this study was to compare outcomes of coronary angioplasty performed in hospitals in the Department of Veterans Affairs and the State of Washington. This study used administrative data from the Department of Veterans Affairs patient treatment file (n = 8,326) and the State of Washington episode of illness file (n = 6,666) and included men who underwent coronary angioplasty in 1993 and 1994. Outcomes included (1) in-hospital mortality and mortality at 10 and 30 days after hospital admission, and (2) the use of coronary artery bypass surgery at similar intervals. Patients with a principal diagnosis of acute myocardial infarction were analyzed separately. Men in the Department of Veterans Affairs had more comorbid conditions than their counterparts in Washington State, and the length of hospital stay was longer in the former group. After using logistic regression to adjust for patient differences, mortality rates for the 2 groups of patients with acute myocardial infarction were similar, although bypass surgery was used more frequently in patients in Washington State. For patients without myocardial infarction, hospital and 10-day mortality did not differ with respect to health care system, and the use of bypass surgery subsequent to angioplasty was similar. In the Department of Veterans Affairs, most hospitals had low institutional caseloads (< 150 procedures per year), whereas > 40% of Washington State hospitals performed > or = 300 procedures per year. Although there were greatly differing institutional caseloads, mortality and the need for early bypass surgery were similar in the 2 systems.

Adult↗
PubMed1998

Coronary angioplasty outcomes in the Healthcare Cost and Utilization Project, 1993-1994.

It is estimated that >400,000 percutaneous transluminal coronary angioplasty (PTCA) procedures are performed in the Unites States annually. This study reports patient characteristics and outcomes for 163,527 PTCAs performed in 214 hospitals in 17 states from 1993 to 1994. These hospitals were a 20% random sample of hospitals in the Healthcare Cost and Utilization Project, which was designed to reflect hospitalization in the United States, generally. Cases with International Classification of Diseases, 9th Revision, Clinical Modification procedure codes 36.01, 36.02, and 36.05 were defined as PTCA and were categorized as to whether acute myocardial infarction (AMI) was the principal discharge diagnosis. The average age of 44,270 AMI discharges (27%) was 62 +/- 12 years and that of 119,257 no-AMI cases (73%) was 64 +/- 11 years; 1/3 of both groups were women, 88% were white, and almost 90% had Medicare or private insurance as the primary payer. The states contributing the most cases were Florida (26%), California (12%), and Wisconsin (10%). Hospital mortality was 1.7% overall and was 3.8% for AMI and 0.8% for no-AMI cases. Bypass surgery performed during the same admission was 3.4% overall and was 4.5% and 3.0% for AMI and no-AMI cases, respectively. Multivariate analysis showed that advanced age, diabetes, female gender, and Medicaid payer status were associated with increased risk of mortality. National estimates from this 20% sample indicate that >850,000 PTCAs were performed in the 2 years, with 452,319 cases estimated for 1994. In 1994 there were an estimated 2,789 deaths and 9,903 bypass surgeries in the no-AMI subset of 327,856 procedures. For the AMI group of 124,463 procedures, there were 4,486 deaths and 5,799 bypass surgeries in 1994. This study of PTCA outcomes contains the largest number of cases as well as the most representative sample reported to date.

Angioplasty, Balloon, Coronary↗
PubMed1998

Perceived efficacy of pain clinics in the rehabilitation of injured workers.

OBJECTIVE: To assess the perceived efficacy of pain clinics in the rehabilitation of injured workers among four groups of professionals. DESIGN: A questionnaire was given to 351 subjects representing four professional groups: physicians, vocational rehabilitation counselors, staff at pain clinics, and employees of a workers compensation program. Subjects rated the effectiveness of pain clinics in eight specific functions, estimated the percentage of workers who return to work after pain clinic treatment, and indicated how soon after injury a worker should be referred to a pain clinic. RESULTS: Pain clinic staff consistently gave the most favorable ratings and workers compensation employees the least favorable ones. There was good agreement across professional groups regarding the need for early referral of injured workers to pain clinics and the specific functions that pain clinics carry out relatively well. Clinics were ranked as most effective in reducing workers' use of opiates, and as least effective in reducing workers' pain. Return-to-work estimates varied significantly across professional groups. Within professional groups, subjects with high estimates gave more favorable overall ratings to pain clinics. CONCLUSIONS: The results provide a profile of the perceived effectiveness of pain clinics in various functions and highlight the importance of getting accurate information about return to work rates following pain clinic treatment. They suggest that workers are not referred to pain clinics early enough.

Accidents, Occupational↗
PubMed1997

Association of positive Chlamydia trachomatis and Chlamydia pneumoniae immunoglobulin-gamma titers with increasing age.

STUDY OBJECTIVES: To use Chlamydia trachomatis immunoglobulin-gamma (IgG) titers to investigate the possibility of their association with ovarian cancer, and to evaluate the effectiveness of this titer in algorithmic protocols in infertility. DESIGN: Prospective, age-matched, pilot study (Canadian Task Force classification II-2). SETTING: University and university-affiliated office practice. PATIENTS: The original 30 patients were seen for follow-up of ovarian cancer (19) and at yearly examination for nonmalignant disease (10). An additional group of 21 women seen for pelvic pain and infertility was added to clarify questions that arose during the study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Chlamydia trachomatis IgG titers were positive in 15 (79%) of 19 of women with ovarian cancer, 9 (90%) of 10 age-matched controls, and 14 (67%) of 21 patients with infertility and pain. When analyzed by age, 4 (40%) of 10 patients under 30 years and 34 (85%) of 40 patients 30 years of age or older had positive titers (p = 0.007). Of 21 women with positive Chlamydia pneumoniae titers, 17 (81 %) had positive C. trachomatis titers, and 17 (85%) of 20 with positive C. trachomatis titers had positive C. pneumoniae titers. CONCLUSION: The test kit used in this study may not be adequate in older patients due to cross-reaction with C. pneumoniae titers. Further evaluation of C. trachomatis IgG titers as a marker in the study of ovarian cancer will require titers that are more specific than those we used. Although these titers may be useful as an immunologic screening marker in infertile patients, results should be interpreted with caution. A positive test may not be evidence of C. trachomatis infection and is not an indication for specific therapy. Successful use of some currently available C. trachomatis IgG titers in algorithms for infertility may be related to a patient's age.

Adolescent↗
PubMed1997

Cancer and endometriosis: do we need to be concerned?

The absolute risk of endometrioid carcinoma of the ovary is very small. When endometriosis is left behind at the time of hysterectomy, there may be increased risk and difficulties in hormone replacement management.

Antineoplastic Agents, Hormonal↗