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Biomedical subjects

D L Brown

Publications and source records attributed to D L Brown.

At least 37 records · Page 2Linked to original sources
PubMed2001

Meta-analysis of effectiveness and safety of abciximab versus eptifibatide or tirofiban in percutaneous coronary intervention.

Three platelet glycoprotein (GP) IIb/IIIa receptor antagonists have been evaluated in patients undergoing percutaneous coronary intervention (PCI). One of these agents, abciximab, is structurally and pharmacologically quite different from the other 2, eptifibatide and tirofiban. We conducted a meta-analysis to determine whether different antagonist types achieved different clinical outcomes, possibly related to their structural differences. Odds ratios (OR) were calculated and a random effects model was used to combine the outcomes of 14,644 patients enrolled in 8 prospective, randomized, placebo-controlled clinical trials assessing treatment with a GP IIb/IIIa inhibitor to prevent ischemic complications of PCI. Neither abciximab (OR 0.69; 95% confidence interval [CI] 0.4 to 1.9) nor eptifibatide or tirofiban treatment (OR 0.74; 95% CI 0.4 to 1.28) resulted in reductions in mortality. Only the abciximab-treated patients had reductions in myocardial infarction (4.3% vs 8.5%, OR 0.49; 95% CI 0.40 to 0.59). There was no effect of eptifibatide or tirofiban on myocardial infarction (OR 0.85; 95% CI 0.69 to 1.04). Urgent revascularization was reduced in both abciximab-treated (2.7% vs 6.2%, OR 0.42; 95% CI 0.34 to 0.53) and eptifibatide- and tirofiban-treated (4.2% vs 5.5%, OR 0.76; 95% CI 0.60 to 0.96) groups. Only abciximab-treated patients had increased major bleeding (5.8% vs 3.8%; OR 1.53; 95% CI 1.24 to 1.90). There was no effect of eptifibatide or tirofiban on major bleeding (5.0% vs 4.3%; OR 1.19; 95% CI 0.94 to 1.52). Thus, significant differences exist between clinical outcomes achieved by abciximab and those achieved by eptifibatide or tirofiban following PCl procedures.

Abciximab↗
PubMed2001

Congenital insensitivity to pain with anhidrosis (CIPA): novel mutations of the TRKA (NTRK1) gene, a putative uniparental disomy, and a linkage of the mutant TRKA and PKLR genes in a family with CIPA and pyruvate kinase deficiency.

Congenital insensitivity to pain with anhidrosis is an autosomal recessive hereditary disorder characterized by recurrent episodic fever, anhidrosis (inability to sweat), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. The human TRKA gene (NTRK1), located on chromosome 1q21-q22 encodes the receptor tyrosine kinase for nerve growth factor. We reported that TRKA is the gene responsible for CIPA and we developed a comprehensive strategy to screen for TRKA mutations and polymorphisms, as based on the gene's structure and organization. Here we report eight novel mutations detected as either a homozygous or heterozygous state in nine CIPA families from five countries. Mendelian inheritance of the mutations was confirmed in seven families for which samples from either parent were available. However, non-mendelian inheritance seems likely for the family when only samples from the mother and siblings, (but not from the father) were available. A paternal uniparental disomy for chromosome 1 is likely to be the cause of reduction to homozygosity of the TRKA gene mutation in this family. Interestingly, a Hispanic patient from the USA has two autosomal genetic disorders, CIPA and pyruvate kinase deficiency, whose genetic loci are both mapped to a closely linked chromosomal region. A splice mutation and a missense mutation were detected in the TRKA and PKLR genes from the homozygous proband, respectively. Thus, concomitant occurrence of two disorders is ascribed to a combination of two separate mutant genes, not a contiguous gene syndrome. This finding suggests a mechanism responsible for two autosomal genetic disorders in one patient. All these data further support findings that TRKA defects can cause CIPA in various ethnic groups. This will aid in diagnosis and genetic counseling of this painless but severe genetic disorder.

Adolescent↗
PubMed2001

Gynecologic ultrasound.

For most women, pelvic sonography using a transvaginal probe is the imaging modality of choice for evaluating the uterus and adnexae. It is reliable for detecting ovarian cysts and other adnexal masses, and it can often determine if a lesion can be observed on serial examinations or if it requires more urgent attention. Uterine ultrasound is reliable for evaluating both the normal and abnormal endometrium and myometrium. In cases that are technically limited, or in those that are difficult to interpret, a tailored MR imaging examination often can be helpful.

Female↗
PubMed2001

The GRIP domain is a specific targeting sequence for a population of trans-Golgi network derived tubulo-vesicular carriers.

Vesicular carriers for intracellular transport associate with unique sets of accessory molecules that dictate budding and docking on specific membrane domains. Although many of these accessory molecules are peripheral membrane proteins, in most cases the targeting sequences responsible for their membrane recruitment have yet to be identified. We have previously defined a novel Golgi targeting domain (GRIP) shared by a family of coiled-coil peripheral membrane Golgi proteins implicated in membrane trafficking. We show here that the docking site for the GRIP motif of p230 is a specific domain of Golgi membranes. By immuno-electron microscopy of HeLa cells stably expressing a green fluorescent protein (GFP)-p230GRIP fusion protein, we show binding specifically to a subset of membranes of the trans-Golgi network (TGN). Real-time imaging of live HeLa cells revealed that the GFP-p230GRIP was associated with highly dynamic tubular extensions of the TGN, which have the appearance and behaviour of transport carriers. To further define the nature of the GRIP membrane binding site, in vitro budding assays were performed using purified rat liver Golgi membranes and cytosol from GFP-p230GRIP-transfected cells. Analysis of Golgi-derived vesicles by sucrose gradient fractionation demonstrated that GFP-p230GRIP binds to a specific population of vesicles distinct from those labelled for beta-COP or gamma-adaptin. The GFP-p230GRIP fusion protein is recruited to the same vesicle population as full-length p230, demonstrating that the GRIP domain is solely proficient as a targeting signal for membrane binding of the native molecule. Therefore, p230 GRIP is a targeting signal for recruitment to a highly selective membrane attachment site on a specific population of trans-Golgi network tubulo-vesicular carriers.

Animals↗
PubMed2001

Use of routine functional testing after percutaneous transluminal coronary angioplasty: results from the ROSETTA Registry.

BACKGROUND: The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for exercise testing suggest that only selected groups of high-risk patients should undergo routine functional testing after percutaneous transluminal coronary angioplasty (PTCA) for the detection of restenosis. OBJECTIVES: Our purpose was (1) to document the patterns of use of post-PTCA functional testing and (2) to determine whether the choice of functional testing strategy is related to clinical characteristics of patients or whether physicians use a similar strategy for all their patients. METHODS: The Routine Versus Selective Exercise Treadmill Testing After Angioplasty (ROSETTA) Registry is a prospective study examining the use of functional testing among 788 patients at 13 centers in 5 countries. RESULTS: During the 6-month period after a successful PTCA, 49% of patients underwent functional testing (range among centers 10%-81%). Among patients who underwent functional testing, 39% had a clinical indication and 61% had functional testing as a routine follow-up. The first functional test was performed a median of 7 weeks after PTCA, with 13% of patients having second tests at a median of 14 weeks and 4% having additional tests at a median of 20 weeks. Univariate and multivariate analyses demonstrated that the chief determinant of the use of routine functional testing was clinical center. Aside from age (P <.0001), no baseline clinical or procedural characteristics were consistently associated with the use of routine functional testing after PTCA. CONCLUSIONS: Physicians do not appear to be adhering to the ACC/AHA guidelines for exercise testing regarding the routine use of post-PTCA functional testing. None of the clinical characteristics identified by the ACC/AHA guidelines were associated with the routine use of post-PTCA functional testing, and the primary determinant of functional testing was the location of the center at which the patient had the PTCA.

Angioplasty, Balloon, Coronary↗
PubMed2001

A randomized trial of stenting with or without balloon predilation for the treatment of coronary artery disease.

BACKGROUND: Stent placement has historically been preceded by predilation of the target lesion with percutaneous transluminal coronary angioplasty. Direct stent implantation, without predilation, has the potential to have a favorable impact on procedure cost by reducing the number of devices used, contrast administered, and procedure time. METHODS AND RESULTS: We conducted a prospective randomized trial to compare the economic outcome of stenting with or without predilation. Inclusion criteria included intention to treat a single lesion with a coronary stent in a vessel with a reference diameter >2.4 mm. Exclusion criteria included total occlusions, culprit lesion within a saphenous vein graft, lesion length >25 mm, patients within 48 hours of an acute myocardial infarction, and patients unable to be treated with aspirin and clopidogrel. From September 1999 to March 2000, 77 patients were randomized to direct stent implantation (n = 37) or balloon-facilitated stenting (n = 40). Stent placement was successful in all patients. Crossover to predilation was required in 2 patients in the direct stent group because of inability to deliver the stent. Compared with balloon-facilitated stenting, direct stenting used fewer catheter devices (1.4 +/- 0.7 vs 2.5 +/- 0.8, P <.001), less contrast (92.7 +/- 43.1 mL vs 117.4 +/- 61.0 mL, P =.04), and less fluoroscopy time (7.5 +/- 3.9 minutes vs 11.6 +/- 8.3 minutes, P =.006). No difference in procedural complications or predischarge outcome was found. No difference in major adverse cardiovascular events was found at 6-month follow-up. CONCLUSION: Direct stenting is a safe and successful procedure that reduces the number of devices used, fluoroscopy time, and contrast administration.

Angioplasty, Balloon, Coronary↗
PubMed2001

Coronary stenting in diabetic patients: Results from the ROSETTA registry.

OBJECTIVE: Diabetes mellitus is associated with high rates of restenosis and adverse outcomes after percutaneous transluminal coronary angioplasty (PTCA). It is unclear whether coronary stenting reduces adverse events in diabetic patients after PTCA. Our purpose was to determine whether coronary stenting improves clinical event rates in diabetic patients after PTCA. METHODS: The Routine Versus Selective Exercise Treadmill Testing After Angioplasty (ROSETTA) registry was a prospective multicenter observational study examining functional testing and adverse outcomes after successful PTCA. RESULTS: Among the 791 patients enrolled, 180 were diabetic. A total of 90 diabetics received stents while the remaining 90 patients did not. Baseline clinical characteristics were similar between the 2 groups of patients. However, patients with stents were more likely to have complex lesions, whereas those without stents were more likely to undergo atherectomy and have greater residual coronary stenosis. At 6-month follow-up, the composite end point defined as cardiac death, unstable angina, myocardial infarction, need for repeat PTCA, or coronary artery bypass graft surgery (CABG) occurred in 25.0% of stented and 22.2% of nonstented diabetic patients (P not significant [NS]). A multivariate logistic regression analysis showed that coronary stenting was not associated with a reduced incidence of the composite end point among diabetic patients (odds ratio 0.97, 95% CI 0.46-2.05, P NS). CONCLUSION: Coronary stenting does not improve clinical event rates in diabetic patients after PTCA.

Angioplasty, Balloon, Coronary↗
PubMed2001

Primary versus secondary ovarian malignancy: imaging findings of adnexal masses in the Radiology Diagnostic Oncology Group Study.

PURPOSE: To analyze ultrasonographic (US), computed tomographic (CT), and magnetic resonance (MR) imaging features of primary and secondary ovarian malignant neoplasms to determine if there is any significant difference in their appearance. MATERIALS AND METHODS: Analysis of the multi-institutional Radiology Diagnostic Oncology Group data revealed 86 patients with primary ovarian carcinoma and 24 patients with a secondary ovarian neoplasm. Numerous imaging features that had been recorded for the adnexal masses with each imaging modality were reviewed and compared between primary and secondary malignant ovarian neoplasms. RESULTS: Of the imaging features assessed with all three modalities, multilocularity as determined at US (P =.02) or MR imaging (P: =.01) was the only significant feature. At US, 30 (37%) of 81 primary ovarian cancers were multilocular, whereas only three (12%) of 24 metastatic neoplasms were multilocular. At MR imaging, 40 (74%) of 54 primary ovarian cancers were multilocular, whereas only five (36%) of 14 metastatic neoplasms were multilocular. Neither a predominately solid appearance nor bilaterality was significantly different between primary and secondary neoplasms. CONCLUSION: For malignant ovarian masses, multilocularity at MR imaging or US favors the diagnosis of primary ovarian malignancy rather than secondary neoplasm, but it is difficult to accurately distinguish between primary and secondary ovarian malignancies.

Adult↗
PubMed2001

Dual trafficking of Slit3 to mitochondria and cell surface demonstrates novel localization for Slit protein.

Drosophila slit is a secreted protein involved in midline patterning. Three vertebrate orthologs of the fly slit gene, Slit1, 2, and 3, have been isolated. Each displays overlapping, but distinct, patterns of expression in the developing vertebrate central nervous system, implying conservation of function. However, vertebrate Slit genes are also expressed in nonneuronal tissues where their cellular locations and functions are unknown. In this study, we characterized the cellular distribution and processing of mammalian Slit3 gene product, the least evolutionarily conserved of the vertebrate Slit genes, in kidney epithelial cells, using both cellular fractionation and immunolabeling. Slit3, but not Slit2, was predominantly localized within the mitochondria. This localization was confirmed using immunoelectron microscopy in cell lines and in mouse kidney proximal tubule cells. In confluent epithelial monolayers, Slit3 was also transported to the cell surface. However, we found no evidence of Slit3 proteolytic processing similar to that seen for Slit2. We demonstrated that Slit3 contains an NH(2)-terminal mitochondrial localization signal that can direct a reporter green fluorescent protein to the mitochondria. The equivalent region from Slit1 cannot elicit mitochondrial targeting. We conclude that Slit3 protein is targeted to and localized at two distinct sites within epithelial cells: the mitochondria, and then, in more confluent cells, the cell surface. Targeting to both locations is driven by specific NH(2)-terminal sequences. This is the first examination of Slit protein localization in nonneuronal cells, and this study implies that Slit3 has potentially unique functions not shared by other Slit proteins.

Amino Acid Sequence↗
PubMed2001

Sonographic and Doppler characteristics of the corpus luteum: can they predict pregnancy outcome?

OBJECTIVE: To determine whether there is a relationship between gray scale or Doppler characteristics of the corpus luteum and first-trimester pregnancy outcome. METHODS: We conducted a prospective study of patients with spontaneous singleton pregnancies between 5 and 8 weeks' gestation. The corpus luteum size, sonographic appearance, resistive index, and peak systolic velocity were measured on transvaginal sonography. Maternal use of exogeneous progesterone was recorded. Only patients with known first-trimester outcome were included. RESULTS: There were 201 study patients. The corpus luteum could be visualized in 197 (98%) and had a mean +/- SD size of 1.9 +/- 0.6 cm, a mean resistive index of 0.50 +/- 0.08, and a peak systolic velocity of 20.5 +/- 11.2 cm/s. There were 151 first-trimester survivors (75.1 %) and 50 spontaneous losses (24.9%). In a comparison of the survivors and losses, there was no significant difference in mean corpus luteum size (1.9 versus 1.7 cm; P = .10, t test), mean resistive index (0.50 versus 0.50; P = .71, t test), peak systolic velocity (21 versus 19 cm/s; P = .29, t test), or sonographic appearance (P = .78, chi2 test). The lack of association between corpus luteum characteristics and outcome persisted when cases were stratified by progesterone use and the presence or absence of a heartbeat on the study sonogram. CONCLUSION: There is no apparent relationship between the characteristics of the corpus luteum and first-trimester pregnancy outcome.

Corpus Luteum↗
PubMed2000

Relation between coronary atherosclerotic plaque burden and cardiac enzyme elevation following percutaneous coronary intervention.

Several studies have reported that elevation of cardiac creatine kinase (CK) enzymes after percutaneous coronary intervention (PCI) is associated with an increase in cardiac morbidity and mortality during follow-up. However, it remains unclear if enzyme elevation contributes to the adverse outcomes or is simply a marker for adverse events. We conducted a case-control study to determine if angiographically determined atherosclerotic plaque burden correlated with CK elevation. Patients (cases, n = 23) with CK elevation after PCI were identified along with 46 age- and gender-matched controls without CK elevation. Detailed angiographic analysis quantified the percentage of coronary artery length with any luminal irregularity, a surrogate for plaque burden. The CK elevation group was characterized by a greater number of smokers (65% vs 33%, p = 0.02), more thrombus-containing lesions (22% vs 2.2%, p = 0.014), and more frequent abrupt closure (13% vs 0%, p = 0.03). In addition, the case group had a 50% increase in atherosclerotic plaque burden compared with controls (30 +/- 14% vs 20 +/- 14%, p = 0.006). These data suggest that CK elevation after PCI is a marker for more extensive atherosclerosis, which may explain the worse prognosis of these patients.

Angioplasty, Balloon, Coronary↗
PubMed2000

Effects of microtubule-associated protein (MAP) expression on methylmercury-induced microtubule disassembly.

The sensitivity of microtubules (MTs) to methylmercury- (MeHg) induced disassembly was compared in undifferentiated, MAP1A- and MAP2C-transfected, and neuronally differentiated P19 Embyronal Carcinoma (EC) cells. The extent of MT disassembly was examined qualitatively by immunofluorescence microscopy and Western blotting and quantitatively by dot blotting of polymer and soluble proteins extracts. Immunofluorescence microscopy showed that MeHg disassembled MTs in a time- and dose-dependent manner and that MTs in both MAP2C-transfected and neuronally differentiated cells, but not those in MAP1A-transfected cells, were significantly more resistant to MeHg-induced MT depolymerization than those in undifferentiated cells. These results suggest that MAP2C has a greater ability to stabilize MTs against MeHg-induced disassembly than MAP1A. Surprisingly, however, when the extent of MT disassembly was assessed by Western blotting and by quantitative dot blotting, no change was observed in the amounts of tubulin, MAP2, or MAP1A, in the polymer and soluble fractions in MeHg-treated samples, compared to the control cells that were not treated. These data show that, although MeHg treatment resulted in the disassembly of MTs, they were not depolymerized as detergent-soluble subunits, but rather appeared to form insoluble tubulin-MAP oligomers or aggregates.

Animals↗
PubMed2000

Effect of early revascularization on mortality from cardiogenic shock complicating acute myocardial infarction in California.

Recent retrospective analyses of treatment of cardiogenic shock suggest that early revascularization reduces mortality. All nonfederal hospital admissions in California for 1994 with a diagnosis of acute myocardial infarction (AMI) were identified. From that cohort, patients who developed cardiogenic shock were selected to determine demographic features, procedure utilization, and outcomes of their admission compared with patients with AMI without cardiogenic shock. Multivariate logistic regression analysis was performed to assess the effect of early revascularization on survival of patients in cardiogenic shock. Cardiogenic shock was identified in 1,122 patients. Mean age was 70.4 years, 45% of patients were women, and 28% had diabetes mellitus. Shock patients were more likely to be older, diabetic, women, and having an anterior Q-wave AMI. Overall in-hospital mortality for patients with shock was 56%. Patients referred for early revascularization had more favorable risk profiles, but after multivariate analysis early revascularization remained a powerful, independent predictor of improved survival, reducing the odds of death by 80%. This population-based study suggests that early revascularization may improve in-hospital survival of patients with cardiogenic shock complicating AMI, even after adjustment for baseline differences between patients who underwent early revascularization and those who did not.

Aged↗
PubMed2000

A naturally occurring mutation near the amino terminus of alphaIIb defines a new region involved in ligand binding to alphaIIbbeta3.

Decreased expression of functional alphaIIbbeta3 complexes on the platelet surface produces Glanzmann thrombasthenia. We have identified mutations of alphaIIb(P145) in 3 ethnically distinct families affected by Glanzmann thrombasthenia. Affected Mennonite and Dutch patients were homozygous and doubly heterozygous, respectively, for a P(145)A substitution, whereas a Chinese patient was doubly heterozygous for a P(145)L substitution. The mutations affect expression levels of surface alphaIIbbeta3 receptors on their platelets, which was confirmed by co-transfection of alphaIIb(P145A) and beta3 cDNA constructs in COS-1 cells. Each mutation also impaired the ability of alphaIIbbeta3 on affected platelets to interact with ligands. Moreover, when alphaIIb(P145A) and beta3 were stably coexpressed in Chinese hamster ovary cells, alphaIIbbeta3 was readily detected on the cell surface, but the cells were unable to adhere to immobilized fibrinogen or to bind soluble fluorescein isothiocyanate-fibrinogen after alphaIIbbeta3 activation by the activating monoclonal antibody PT25-2. Nonetheless, incubating affected platelets with the peptide LSARLAF, which binds to alphaIIb, induced PF4 secretion, indicating that the mutant alphaIIbbeta3 retained the ability to mediate outside-in signaling. These studies indicate that mutations involving alphaIIb(P145 )impair surface expression of alphaIIbbeta3 and that the alphaIIb(P145A) mutation abrogates ligand binding to the activated integrin. A comparative analysis of other alphaIIb mutations with a similar phenotype suggests that these mutations may cluster into a single region on the surface of the alphaIIb and may define a domain influencing ligand binding. (Blood. 2000;95:180188)

Adolescent↗