Cocaine use and acute coronary syndromes.
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Adrenergic beta-Antagonists↗
Biomedical subjects
L Park
Publications and source records attributed to L Park.
Autosomal dominant craniometaphyseal dysplasia is caused by mutations in the transmembrane protein ANK.
Craniometaphyseal dysplasia (CMD) is a rare skeletal disorder characterized by progressive thickening and increased mineral density of craniofacial bones and abnormally developed metaphyses in long bones. Linkage studies mapped the locus for the autosomal dominant form of CMD to an approximately 5-cM interval on chromosome 5p, which is defined by recombinations between loci D5S810 and D5S1954. Mutational analysis of positional candidate genes was performed, and we describe herein three different mutations, in five different families and in isolated cases, in ANK, a multipass transmembrane protein involved in the transport of intracellular pyrophosphate into extracellular matrix. The mutations are two in-frame deletions and one in-frame insertion caused by a splicing defect. All mutations cluster within seven amino acids in one of the six possible cytosolic domains of ANK. These results suggest that the mutated protein has a dominant negative effect on the function of ANK, since reduced levels of pyrophosphate in bone matrix are known to increase mineralization.
Amino Acid Sequence↗
Phosphoramidon-sensitive endothelin-converting enzymes modulate cerebral blood flow and neural damage of hypoxic rats.
The enzymatic activity of endothelin-converting enzymes (ECE) was altered to determine the potential effect of endothelins (ET) on cerebral blood flow measured by laser Doppler flowmetry (CBF(LDF)) and the resultant neural damage of rats, made hypoxic via breathing 12% O(2) for 35 min. Intrastriatal administration of phosphoramidon (PRN, 5 microM), a dual inhibitor of ECE and neutral endopeptidase (NEP), significantly increased infarct volume to hypoxia with a significant attenuation of CBF(LDF). However, intrastriatal thiorphan (TRN, 5 microM), an inhibitor of NEP, had no effect on the CBF(LDF) responses or infarct volume induced by the hypoxic challenge. These findings showed that inhibition of ECE by PRN interfered with the vasodilator activity of ET to the hypoxic response that increased neural damage, thus suggesting that PRN-sensitive ECE is functionally active in the modulation of cerebral blood flow in rats undergoing hypoxia.
Animals↗
Dichloroacetate exerts therapeutic effects in transgenic mouse models of Huntington's disease.
Dichloroacetate (DCA) stimulates pyruvate dehydrogenase complex (PDHC) activity and lowers cerebral lactate concentrations. In the R6/2 and N171-82Q transgenic mouse models of Huntington's disease (HD), DCA significantly increased survival, improved motor function, delayed loss of body weight, attenuated the development of striatal neuron atrophy, and prevented diabetes. The percentage of PDHC in the active form was significantly reduced in R6/2 mice at 12 weeks of age, and DCA ameliorated the deficit. These results provide further evidence for a role of energy dysfunction in HD pathogenesis and suggest that DCA may exert therapeutic benefits in HD.
Animals↗
Hypoxic modulation of striatal lesions induced by administration of endothelin-1.
Levels of endothelin-1 (ET-1), a potent endogenous vasoconstrictor, are elevated in plasma and cerebrospinal fluid (CSF) following cerebral ischemia and reperfusion injury. The present study sought insight into the potential differential vasoactive effects on the cerebral vasculature and resultant neural damage of ET-1 during normoxic vs. ischemic conditions and upon reperfusion. Under normoxic conditions, intrastriatal stereotaxic injection of exogenous ET-1 (40 pmol) induced a significant (P<0.05) reduction (</=29+/-12%) in the regional (striatal) cerebral blood flow measured by Laser Doppler flowmetry (CBF(LDF)) for up to 40 min in halothane-anesthetized male Long-Evans rats. Intrastriatal injection of ET-1 10 min after the onset of hypoxia (12% O(2), balance N(2)) tended to blunt, but not significantly, the striatal CBF(LDF) responses to the 35 min period of hypoxia. ET-1 given during reoxygenation significantly (P<0.05) reduced striatal CBF(LDF), which was similar to the effect of ET-1 during normoxia. ET-1-induced infarction when administered prior to hypoxia, but not during or post-hypoxia, was significantly (P<0.05) exacerbated compared to infarction of ET-1 without hypoxia. These results suggest that exogenous ET-1 administered into the brain parenchyma can induce an infarction associated with modulation of CBF(LDF) during the normoxic or reoxygenation period, but not during the hypoxic period and that the increased release of ET-1 in any pathological phase of cerebral ischemia contributes to irreversible neural damage with associated hemodynamic disturbances.
Animals↗
Blood cocaine and metabolite concentrations, clinical findings, and outcome of patients presenting to an ED.
The purpose was to determine if blood cocaine or metabolite concentrations would accurately reflect the severity of clinical findings in patients presenting to the emergency department, identifying those requiring therapeutic intervention or those at risk for poor outcome. Blood for determination of cocaine and metabolite concentrations was drawn from patients and were determined by an extractive alkylation/mass spectrometry procedure. The mean blood concentrations (mg/L) in 111 patients were as follows: cocaine, 0.26 +/- 0.5; ecgonine 0.42 +/- 0.47; ecgonine methyl ester 0.21 +/- 0.37, norcocaine 0.03 +/- 0.17; benzoylecgonine 1.28 +/- 1.29, cocaethylene 0.02 +/- 0.06. Two patients died, 23 required hospital admission, and 88 were discharged from the ED. There was no statistical correlation between cocaine or any metabolite concentration and the severity of clinical symptoms, disposition, need for treatment or outcome. Blood cocaine and metabolite concentrations should be interpreted with caution because they vary widely and do not predict the severity of clinical findings, the incidence of adverse effects, outcome, or need for interventional therapy.
Adolescent↗
Raloxifene: designer estrogen for preventing postmenopausal osteoporosis.
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Bone Density↗
A standardized procedure for locating and documenting ECG chest electrode positions: consideration of the effect of breast tissue on ECG amplitudes in women.
Continuing uncertainty exists about standardized procedures for the placement of electrocardiographic (ECG) chest electrodes, technical variability being the largest error source for short-term variations in amplitudes and waveforms of the chest lead ECGs. To avoid presumed attenuation of ECG amplitudes by abundant breast tissue, anterolateral chest electrodes in women are often placed under the breasts and too low. There is also considerable uncertainty about locating the midclavicular line and the V4 electrode, particularly in obese persons and in women. We examined the effect of breast tissue protuberance on ECG amplitudes using ECG and anthropometric data on 6,814 women included in the Atherosclerosis Research in Communities Study (ARIC). The R wave amplitudes in anterolateral chest leads and the Sokolow-Lyon voltage decreased (P < .001 for all), and RaVL and the Cornell voltage increased significantly with increasing breast protuberance (P < .001 for all). However, these effects were small (15 microV or less for each 1-cm increment in breast protuberance), and R2 values were less than .01, indicating that breast protuberance alone explained less than 1% of ECG amplitude variations. When chest size and breast protuberance estimates were entered simultaneously into a multivariate regression model, chest size appeared to dominate, and model R2 values increased for positive associations with RaVL (R2 = .12) and the Cornell voltage (R2 = .04). Combined model R2 values remained < or =.01 for all other ECG amplitudes. A detailed step-by-step standardized electrode placement procedure was formulated. Because of the difficulties encountered in locating the left midclavicular line by visual inspection, we introduced well-defined procedures for identification and documentation of lateral chest electrode placement locations as a quality control method for clinical trials. Population data from the Third National Health and Nutrition Survey on the distributions by sex and race of chest electrode V4 and V6 locations and anthropometric data on chest size and shape are presented in order to facilitate evaluation of the comparability of electrode placement procedures in various studies and for quality control in clinical trials. It is concluded that standardized procedures to document chest electrode placement locations are feasible. Breast tissue appears to have a practically negligible effect on ECG amplitudes, and in women, the placement of chest electrodes on the breast rather than under the breast is recommended in order to facilitate the precision of electrode placement at the correct horizontal level and at the correct lateral positions.
Aged↗
Effect of an intravenous iron dextran regimen on iron stores, hemoglobin, and erythropoietin requirements in hemodialysis patients.
Iron deficiency is a common cause of delayed or diminished response to erythropoietin (EPO) in hemodialysis patients. Although oral iron is often prescribed to replete iron stores, this approach to iron supplementation may not be adequate with chronic EPO therapy. Intravenous (IV) iron dextran may be an effective alternative approach to replete iron stores and may facilitate more cost-effective use of EPO. The purpose of this study was to evaluate an IV iron dextran regimen that consisted of a loading dose phase followed by monthly maintenance doses of iron dextran. The effect of this regimen on iron stores, hemoglobin, and EPO doses was evaluated. This was an open prospective study in adult hemodialysis patients who were iron deficient as defined by a serum ferritin less than 100 ng/mL or transferrin saturation (TSAT) of less than 20%. Patients were loaded with 1 g iron dextran in five divided doses and then received monthly maintenance doses of 100 mg for the 4-month study period. Values of serum ferritin, TSAT, hemoglobin, and EPO dose were followed for the 4-month study period. Thirty hemodialysis patients receiving EPO were identified as being iron deficient and were enrolled in the study. The mean serum ferritin increased significantly from 49 ng/mL at baseline to 225 ng/mL at the end of the study period (P < 0.0001). Mean TSAT also increased significantly from 27% to 33% (P = 0.002). Values for hemoglobin did not change significantly during the study period; however, there was a significant reduction in EPO dose from a mean baseline dose of 112 U/kg/wk to 88 U/kg/wk at the end of the study period (P = 0.009). Seventeen patients experienced an increase in hemoglobin or a decrease in EPO dose. Economic analysis showed that approximately $580 (Cdn) per patient per year could be saved by use of IV iron dextran. The administration of the IV iron dextran regimen in the iron-deficient hemodialysis population was effective at repleting and maintaining iron stores and reducing EPO use.
Adult↗
A poxvirus-encoded semaphorin induces cytokine production from monocytes and binds to a novel cellular semaphorin receptor, VESPR.
The vaccinia virus A39R protein is a member of the semaphorin family. A39R.Fc protein was used to affinity purify an A39R receptor from a human B cell line. Tandem mass spectrometry of receptor peptides yielded partial amino acid sequences that allowed the identification of corresponding cDNA clones. Sequence analysis of this receptor indicated that it is a novel member of the plexin family and identified a semaphorin-like domain within this family, thus suggesting an evolutionary relationship between receptor and ligand. A39R up-regulated ICAM-1 on, and induced cytokine production from, human monocytes. These data, then, describe a receptor for an immunologically active semaphorin and suggest that it may serve as a prototype for other plexin-semaphorin binding pairs.
Amino Acid Sequence↗
Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts.
Accelerated atherosclerosis in patients with diabetes is a major cause of their morbidity and mortality, and it is unresponsive to therapy aimed at restoring relative euglycemia. In hyperglycemia, nonenzymatic glycation and oxidation of proteins and lipids results in the accumulation of irreversibly formed advanced glycation endproducts. These advanced glycation endproducts engage their receptor in cells of the blood vessel wall, thereby activating mechanisms linked to the development of vascular lesions. We report here a model of accelerated and advanced atherosclerosis in diabetic mice deficient for apolipoprotein E. Treatment of these mice with the soluble extracellular domain of the receptor for advanced glycation endproducts completely suppressed diabetic atherosclerosis in a glycemia- and lipid-independent manner. These findings indicate interaction between the advanced glycation endproducts and their receptor is involved in the development of accelerated atherosclerosis in diabetes, and identify this receptor as a new therapeutic target in diabetic macrovascular disease.
Animals↗
Do calcium channel blockers increase the risk of myocardial infarction in hypertensive patients with diabetes mellitus?
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Calcium Channel Blockers↗
Poxvirus genomes encode a secreted, soluble protein that preferentially inhibits beta chemokine activity yet lacks sequence homology to known chemokine receptors.
Poxvirus genomes encode several proteins which inhibit specific elements of the host immune response. We show the "35K" virulence gene in variola and cowpox viruses, whose vaccinia and Shope fibroma virus equivalents are strongly conserved in sequence, actually encodes a secreted soluble protein with high-affinity binding to virtually all known beta chemokines, but only weak or no affinity to the alpha and gamma classes. The viral protein completely inhibits the biological activity of monocyte chemotactic protein-1 (MCP-1) by competitive inhibition of chemokine binding to cellular receptors. As all beta chemokines are also shown to cross-compete with MCP1 binding to the viral protein, we conclude that this viral chemokine inhibitor (vCCI) not only interacts through a common binding site, but is likely a potent general inhibitor of beta chemokine activity. Unlike many poxvirus virulence genes to date, which are clearly altered forms of acquired cellular genes of the vertebrate immune system, this viral chemokine inhibitor (vCCI) shares no sequence homology with known proteins, including known cellular chemokine receptors, all of which are multiple membrane-spanning proteins. Thus, vCCI presumably has no cellular analogue and instead may be the product of unrelenting sequence variations which gave rise to a completely new protein with similar binding properties to native chemokine receptors. The proposed function of vCCI is inhibition of the proinflammatory (antiviral) activities of beta chemokines.
Amino Acid Sequence↗
LERK-7: a ligand of the Eph-related kinases is developmentally regulated in the brain.
The eph family is the largest subfamily of receptor tyrosine kinases (RTKs). Members of this subfamily display specific expression in the developing and adult brain. Recently, cDNAs encoding membrane bound ligands for these receptors have been identified which we have termed LERKs (ligand for eph-related kinases). We report here the isolation of LERK-7 from a human fetal brain cDNA library. LERK-7 encodes a protein of 228 amino acids and is anchored to the membrane by glycosyl-phosphatidylinositol (GPI) linkage. When transfected into CV1/EBNA cells, LERK-7 binds soluble forms of both hek and elk. In addition, a soluble form of LERK-7 will induce phosphorylation of eck expressed in a human duodenum adenocarcinoma cell line. LERK-7 expressed multiple transcripts (7.5-kb, 6.0-kb, and 3.5-kb) with the highest levels in human adult brain, heart, spleen, and ovary and human fetal brain, lung, and kidney. Similar to the other ligands in this family, LERK-7 is developmentally regulated in the brain. LERK-7 is identical to the recently described AL-1.
Adult↗
Experimental preretinal neovascularization by laser-induced venous thrombosis in rats.
PURPOSE: Retinal ischemia and neovascularization (NV) are important components of many retinal disorders. To facilitate further investigation of retinal ischemia and neovascularization, we sought to develop a reproducible in vivo experimental model of venous occlusion by photodynamic thrombosis in rats. METHODS: After anesthesia, 27 eyes of pigmented rats received an intraperitoneal injection of 0.2 ml of, 10% sodium fluorescein 15 minutes prior to laser treatment. With a blue-green argon laser, selected venous sites next to the optic nerve head were photocoagulated indirectly with a 78 diopter lens. Venous occlusion was accomplished using laser parameters of 1.0 second, 50 microns, and 50-100 mW. For a control group, 10 eyes were coagulated on the retina between major vessels using the same parameters after fluorescein injection. For a second control group, 1% sodium hyaluronate was injected into the subretinal space to make a long-standing retinal detachment in 5 eyes. RESULTS: With 1-8 laser impulses, each venous occlusion was obtained and was associated with extreme venous constriction and tortuousity. Retinal edema became evident 10-30 minutes after treatment in the sectors associated with the occluded veins. This edema became a bullous retinal detachment (RD) within 12 hours and intra-retinal hemorrhage was observed. The retinal edema continued for 3-10 days and the retinas reattached spontaneously. Prior to or after retinal reattachment 70% (19/27) of eyes developed retinal NV and tractional RD. Of these, 11 developed NV of the optic disc (NVD), 6 developed NV elsewhere (NVE), and 2 developed NVD and NVE. In 30% (8/27) of the eyes, retinal edema resolved without evidence of NV. In control groups no eyes showed either circulatory disorders or evidence of NV. CONCLUSIONS: This is a new model of retinal ischemia and associated neovascularization established by venous thrombosis that is easily reproducible. Many aspects of rat retinal physiology are known and this model has promise as an avenue for further investigation.
Animals↗
The salmon SmaI family of short interspersed repetitive elements (SINEs): interspecific and intraspecific variation of the insertion of SINEs in the genomes of chum and pink salmon.
The genomes of chum salmon and pink salmon contain a family of short interspersed repetitive elements (SINEs), designated the salmon SmaI family. It is restricted to these two species, a distribution that suggests that this SINE family might have been generated in their common ancestor. When insertions of the SmaI SINEs at 10 orthologous loci of these species were analyzed, however, it was found that there were no shared insertion sites between chum and pink salmon. Furthermore, at six loci where SmaI SINEs have been species-specifically inserted in chum salmon, insertions of SINEs were polymorphic among populations of chum salmon. By contrast, at four loci where SmaI SINEs had been species-specifically inserted in pink salmon, the SINEs were fixed among all populations of pink salmon. The interspecific and intraspecific variation of the SmaI SINEs cannot be explained by the assumption that the SmaI family was amplified in a common ancestor of these two species. To interpret these observations, we propose several possible models, including introgression and the horizontal transfer of SINEs from pink salmon to chum salmon during evolution.
Animals↗
Modulation of sensitivity to transforming growth factor-beta 1 (TGF-beta 1) and the level of type II TGF-beta receptor in LNCaP cells by dihydrotestosterone.
Transforming growth factor-beta 1 (TGF-beta 1) and androgen are potential physiological regulators of prostate cancer cells. In the present study, we have used LNCaP cells as a model of androgen-responsive prostate cancer to investigate the effects of dihydrotestosterone (DHT) on the sensitivity to TGF-beta 1. The ability of LNCaP cells to respond to TGF-beta has been controversial. In some studies, LNCaP cells were insensitive to TGF-beta 1 while, in others, they were sensitive to the growth inhibitory effect of TGF-beta 1. The present study was carried out to establish androgenic conditions that rendered LNCaP cells sensitive to TGF-beta 1. Cells were cultured in phenol-red-free RPMI 1640 medium supplemented with 10% charcoal-stripped fetal bovine serum. DHT was added at the following concentrations: 0, 10(-12), 10(-10), and 10(-7) M. These concentrations were selected because they represent the zero DHT control, the low-proliferative dose, the high-proliferative dose, and the growth-arrest dose, respectively. The effects of TGF-beta 1 observed on LNCaP cells included inhibition of cell proliferation, decrease in cell viability, alteration in cell morphology, and enhancement of gene transcriptional activity through activation of a TGF-beta responsive promoter. Of the various DHT concentrations investigated in this study, these effects of TGF-beta 1 on LNCaP cells were consistently demonstrated only at 10(-10) M. At other concentrations, the effects of TGF-beta 1 were either minimal or undetectable. Accompanying these effects of TGF-beta 1, a low but statistically significant level of TGF-beta 1-specific binding and an increased protein level of TGF-beta receptor type II were detected by a competitive binding assay and Western blot analysis respectively. These results indicate that LNCaP cells can be induced by DHT to respond to TGF-beta 1 and that DHT modulates the sensitivity to TGF-beta 1 and the level of TGF-beta receptor type II in these cells.
Binding, Competitive↗