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Biomedical subjects

J M Chen

Publications and source records attributed to J M Chen.

At least 127 records · Page 7Linked to original sources
PubMed1998

Evidence for a postnatal doubling of neuron number in the developing human cerebral cortex between 15 months and 6 years.

The generalization of the finding of no postnatal neurogenesis in non-human primates to humans may be incorrect because: (1) rhesus macaques belong to a superfamily that diverged more than 25 million years ago from the superfamily including the genus Homo; (2) the pulse thymidine labeling method, which demonstrates DNA synthesis rather than mitosis per se, is less reliable than some have assumed. This study examines changes in the number of neurons in a column underneath a cortical surface area of 1 mm2, extending through all cortical layers (mm2-column) for 35 gyri (representing about 73% of the human cerebral cortex) based on the data of J.L. Conel (1939 to 1967). We corrected these data, derived from his measures of cortical neuronal packing density, somal breadth and height, and cortical layer thickness at postnatal ages 0, 1, 3, 6, 15, 24, 48, and 72 months, for shrinkage and stereological errors. In all 35 gyri, neuron number/mm2-column: (1) initially declines (mu = 46% decline, sigma = 8%), 95% of which is due to surface area expansion (mean age of nadir value = 15.8 months); (2) then increases to age 72 months by 70% (mu = 1.7-fold increase, (mu rate = 1.1% per month). Because of a a concomitant 1.3-fold increase in cortical surface from 15 to 72 months, total cortical neuron number increases 2.2-fold. The close agreement between neuron number/mm2-column for Conel's age 72-month data to the corresponding values reported by others for adult human and primate cortex using more modern methods suggests the finding is not an artifact. Neuronal proliferative fate-determining factors provide at least four mechanisms for increasing cortical neuron number postnatally, with or without DNA synthesis.

Aging↗
PubMed1998

Alternative technique of right-sided outflow cannula insertion for right ventricular support.

Right ventricular assist devices are an important part of the armamentarium of cardiac surgeons for the treatment of right-sided circulatory failure after cardiac transplantation or insertion of a left ventricular assist device. However, right ventricular assist device insertion can be technically challenging in the setting of pulmonary hypertension because of a number of concomitant anatomic and physiologic phenomena. We present a technique for the insertion of the right ventricular assist device outflow cannula that is easier and faster to insert, and safer to explant, especially if cardiopulmonary bypass is to be avoided.

Heart-Assist Devices↗
PubMed1998

Selective anticoagulation with active site-blocked factor IXA suggests separate roles for intrinsic and extrinsic coagulation pathways in cardiopulmonary bypass.

BACKGROUND: Multiple stimuli converge in cardiopulmonary bypass to create a tremendous prothrombotic stimulus. The ideal anticoagulant for cardiopulmonary bypass should selectively target only the intravascular stimuli, thereby eliminating pathologic clotting in the bypass circuit while preserving hemostasis in the thoracic cavity. We propose the inhibition of factor IX as such a targeted anticoagulant strategy. METHODS: We prepared an inhibitor of activated factor IX and applied it to a primate model of cardiopulmonary bypass to confirm the anticoagulant efficacy of activated factor IX in this setting and to assess more subtle markers of thrombin generation, macrophage procoagulant activity, and cellular tissue factor expression. Seven baboons that received activated factor IX (460 microg/kg) and 7 that received heparin (300 IU/kg) and protamine underwent cardiopulmonary bypass for 90 minutes and were followed after the operation for 3 hours. RESULTS: Analysis of plasma factor IX activity demonstrated adequate inhibition (<20%) of factor IX throughout cardiopulmonary bypass. Activated factor IX-treated baboons demonstrated similar circuit patency to heparin-treated baboons but had significantly diminished intraoperative blood loss. Preservation of extravascular hemostasis was further demonstrated in activated factor IX-treated animals by (1) significantly increased levels of thrombin-antithrombin III complex and prothrombin activation peptide (F1+2) without intravascular thrombosis, (2) significantly greater macrophage procoagulant activity in pericardial-derived monocytes, and (3) immunohistochemical evidence of tissue factor expression in pericardial mesothelial cells and macrophages. CONCLUSIONS: Anticoagulation with activated factor IX allows for intravascular anticoagulation with maintenance of extravascular hemostasis. These findings suggest activated factor IX as an agent that not only exemplifies a targeted approach to selective anticoagulation in cardiac surgery but also further characterizes the procoagulant milieu during cardiopulmonary bypass.

Animals↗
PubMed1998

Management of vasodilatory shock after cardiac surgery: identification of predisposing factors and use of a novel pressor agent.

BACKGROUND: Cardiopulmonary bypass can be associated with vasodilatory hypotension requiring pressor support. We have previously found arginine vasopressin to be a remarkably effective pressor in a variety of vasodilatory shock states. We investigated the incidence and clinical predictors of vasodilatory shock in a general population of cardiac surgical patients and the effects of low-dose arginine vasopressin as treatment of this syndrome in patients with heart failure. METHODS: Patients undergoing cardiopulmonary bypass (n = 145) were studied prospectively. Preoperative ejection fraction, medications, and perioperative hemodynamics were recorded, and postbypass serum arginine vasopressin levels were measured. Vasodilatory shock was defined as a mean arterial pressure lower than 70 mm Hg, a cardiac index greater than 2.5 L/min/m2, and norepinephrine dependence. Predictors of vasodilatory shock were investigated by logistic regression analysis. The hemodynamic responses of patients who received arginine vasopressin infusions for vasodilatory shock after cardiopulmonary bypass for left ventricular assist device placement or heart transplantation were analyzed retrospectively. RESULTS: Eleven of 145 general cardiac surgery patients (8%) met criteria for postbypass vasodilatory shock. By multivariate analysis, an ejection fraction lower than 0.35 and angiotensin-converting enzyme inhibitor use were independent predictors of postbypass vasodilatory shock (relative risks of 9.1 and 11.9, respectively). Vasodilatory shock was associated with inappropriately low serum arginine vasopressin concentrations (12.0 +/- 6.6 pg/mL). Retrospective analysis found 40 patients with postbypass vasodilatory shock who received low-dose arginine vasopressin infusions, resulting in increased mean arterial pressure and decreased norepinephrine requirements. CONCLUSIONS: Low ejection fraction and angiotensin-converting enzyme inhibitor use are risk factors for postbypass vasodilatory shock, and this syndrome is associated with vasopressin deficiency. In patients exhibiting this syndrome after high-risk cardiac operations, replacement of arginine vasopressin increases blood pressure and reduces catecholamine pressor requirements.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Bone-conduction amplification with completely-in-the-canal hearing aids.

Recent advances in miniaturization have provided clinicians with hearing aids that can be comfortably inserted as far as the bony portion of the ear canal. It is possible to take advantage of these deeply inserted hearing aids in new ways. For example, the physical vibrations of microphone and receiver components may be used to improve hearing aid gain through bone conduction. Three cases are presented that will introduce this phenomenon for two transcranial CROS fittings and for one unilateral otosclerosis fitting. In each case, functional gain measurements under headphones were obtained with the hearing aid receivers acoustically plugged. Considerable gain was still present. Potential benefits, ramifications, and side effects are discussed.

Adult↗
PubMed1998

Acupuncture utilization in Taiwan.

BACKGROUND: The objective of this study was to examine the prevalence of acupuncture utilization in Taiwan by people over 20 years of age. METHODS: Stratified cluster sampling was used to randomly select 20 villages and neighborhoods (townships), a total of 8,280 people, from northern, central, southern and eastern Taiwan. A structured questionnaire was used to collect information during home visits. A total of 5,805 questionnaires were valid for use in the study. RESULTS: The complete rate of home visits was 70.1%; 73.2% of those interviewed recognized acupuncture as one of the common therapeutic methods used in traditional Chinese medicine, whereas only 12.4% had received acupuncture treatment. Typical interviewees who had received acupuncture treatment were generally ethnic from southern Fukien and aged from 30-39 years; 58.3% of the 716 interviewees had received acupuncture treatment from licensed practitioners, while the remainder were treated by non-licensed practitioners. CONCLUSIONS: The response rate to the questionnaire was high (70.1%). However, the percentage of people who had received acupuncture treatment was only 12.4%, while many people (73.2%) were familiar with it. Approximately 40% of those who received acupuncture treatment did so from non-licensed practitioners. This may reveal either a lack of awareness by the public or a lack of public protection of health and safety.

Acupuncture Therapy↗
PubMed1998

A study of vestibular schwannomas using positron emission tomography and monoclonal antibody Ki-67.

OBJECTIVE: This study aimed to evaluate the role of positron emission tomography (PET) as an in vivo determinant of tumor aggressiveness and growth. STUDY DESIGN: The study design was a prospective pilot study. SETTING: Positron emission tomography was performed at the Clarke Institute of Psychiatry. All patients were treated at the Sunnybrook Health Science Centre. Both institutions are affiliated with the University of Toronto, Toronto, Canada. PATIENTS: The study consisted of five consecutive patients with vestibular schwannomas with tumor size of 1 cm or larger within the cerebellopontine angle. One was a recurrent tumor and four were primary tumors. INTERVENTIONS: Preoperative PET studies were conducted using 18-fluorodeoxyglucose (FDG) as a radionuclide tracer to measure glucose metabolism within tumors. Tumors were processed and immunostained against Ki-67 nuclear antigen; their proliferative potentials were quantified based on immunoreactivity of tumor cells. MAIN OUTCOME MEASURES: Tumor metabolic activity on PET was compared with that of contralateral cerebellum to arrive at an FDG index. This number was compared with clinical parameters and Ki-67 reactivity. RESULTS: On PET, all tumors showed less metabolic activity than the cerebellum. The FDG uptake varied greatly between tumors independent of clinical parameters. All the tumors had a low proliferative index (<5%) with immunohistochemistry; there were quite a bit of intralesional variations in proliferative activities. CONCLUSION: Large tumor size and recurrent disease did not correlate well with increased FDG uptake on PET. Similarly, they did not show increased cellular activities as expressed by Ki-67 immunostaining.

Adult↗
PubMed1997

Cloning, isolation, and characterization of mammalian legumain, an asparaginyl endopeptidase.

Legumain is a cysteine endopeptidase that shows strict specificity for hydrolysis of asparaginyl bonds. The enzyme belongs to peptidase family C13, and is thus unrelated to the better known cysteine peptidases of the papain family, C1 (Rawlings, N. D., and Barrett, A. J. (1994) Methods Enzymol. 244, 461-486). To date, legumain has been described only from plants and a blood fluke, Schistosoma mansoni. We now show that legumain is present in mammals. We have cloned and sequenced human legumain and part of pig legumain. We have also purified legumain to homogeneity (2200-fold, 8% yield) from pig kidney. The mammalian sequences are clearly homologous with legumains from non-mammalian species. Pig legumain is a glycoprotein of about 34 kDa, decreasing to 31 kDa on deglycosylation. It is an asparaginyl endopeptidase, hydrolyzing Z-Ala-Ala-Asn-7-(4-methyl)coumarylamide and benzoyl-Asn-p-nitroanilide. Maximal activity is seen at pH 5.8 under normal assay conditions, and the enzyme is irreversibly denatured at pH 7 and above. Mammalian legumain is a cysteine endopeptidase, inhibited by iodoacetamide and maleimides, but unaffected by compound E64 (trans-epoxysuccinyl-L-leucylamido-(4-guanidino)butane). It is inhibited by ovocystatin (cystatin from chicken egg white) and human cystatin C with Ki values < 5 nM. We discuss the significance of the discovery of a cysteine endopeptidase of a new family and distinctive specificity in man and other mammals.

Amino Acid Sequence↗
PubMed1997

Conformation-dependent phosphorylation of p53.

Phosphorylation of the p53 tumor suppressor protein is known to modulate its functions. Using bacterially produced glutathione S-transferase (GST)-p53 fusion protein and baculovirus-expressed histidine-tagged p53 ((His)p53), we have determined human p53 phosphorylation by purified forms of jun-N-kinase (JNK), protein kinase A (PKA), and beta subunit of casein kinase II (CKIIbeta) as well as by kinases present in whole cell extracts (WCEs). We demonstrate that PKA is potent p53 kinase, albeit, in a conformation- and concentration-dependent manner, as concluded by comparing full-length with truncated forms of p53. We further demonstrate JNK interaction with GST-p53 and the ability of JNK to phosphorylate truncated forms of GST-p53 or full-length (His)p53. Dependence of phosphorylation on conformation of p53 is further supported by the finding that the wild-type form of p53 (p53wt) undergoes better phosphorylation by CKIIbeta and by WCE kinases than mutant forms of p53 at amino acid 249 (p53(249)) or 273 (p53(273)). Moreover, shifting the kinase reaction's temperature from 37 degrees C to 18 degrees C reduces the phosphorylation of mutant p53 to a greater extent than of p53wt. Comparing truncated forms of p53 revealed that the ability of CKIIbeta, PKA, or WCE kinases to phosphorylate p53 requires amino acids 97-155 within the DNA-binding domain region. Among three 20-aa peptides spanning this region we have identified residues 97-117 that increase p53 phosphorylation by CKIIbeta while inhibiting p53 phosphorylation by PKA or WCE kinases. The importance of this region is further supported by computer modeling studies, which demonstrated that mutant p53(249) exhibits significant changes to the conformation of p53 within amino acids 97-117. In summary, phosphorylation-related analysis of different p53 forms in vitro indicates that conformation of p53 is a key determinant in its availability as a substrate for different kinases, as for the phosphorylation pattern generated by the same kinase.

Adenosine Triphosphate↗
PubMed1997

The role of microvascular permeability in the mechanism for stunned myocardium in rats.

The microvascular permeability of stunned myocardium in rats in vivo was studied with FITC-labeled albumin (FITC-BSA). It was found that 15 and 20 min of myocardial ischemia followed by 1 hr of reperfusion resulted in myocardial stunning. The concentrations of FITC-BSA in myocardial tissue were 240.6 +/- 7.8 (IS15) and 267.4 +/- 7.9 (IS20) micrograms/g myocardium in ischemic groups, respectively, which were significantly higher than those in the control group (166.0 +/- 7.9 micrograms/g myocardium; P < 0.01). In stunned groups, the concentrations were 224.8 +/- 11.8 (MS15) and 241.7 +/- 6.0 (MS20) micrograms/g myocardium, decreased from those in ischemic groups but still higher than those in control group by 35.4 and 45.6%, respectively. The more significant the concentration of FITC-BSA, the more serious the myocardial stunning. Electron microscopy revealed no significant vascular injury. The results suggest that the increase in microvascular permeability resulting from transient ischemia is functional and is involved in the pathogenesis of stunned myocardium.

Animals↗
PubMed1997

A simplified schedule to integrate the hepatitis B vaccine into an expanded program of immunization in endemic countries.

OBJECTIVE: To investigate the safety, immunogenicity, and efficacy of a simplified hepatitis B vaccination schedule. METHODS: The second dose of hepatitis B vaccine and the first dose of diphtheria-tetanus-pertussis (DTP) vaccine were given simultaneously at age 6 weeks. The second dose of DTP vaccine was given at age 3.5 months. The third dose of DTP vaccine and the third dose of hepatitis B vaccine were given at age 5.5 months. One hundred three infants (group A) born to mothers without hepatitis B surface antigen (HBsAg) received DTP with whole-cell pertussis vaccine. Fifty-five infants (group B) born to mothers with HBsAg and hepatitis B e antigen received DTP with acellular pertussis vaccine. RESULTS: By age 9 months, none of group A and 4 (7%) group B infants were sero-positive for HBsAg. The protective efficacy against the hepatitis B carrier state in these infants at high risk was 92%. Antibody to hepatitis B surface antigen was 10 mlU/ml or greater in 99 (96%) of group A infants and in 50 (91%) of group B infants. Both the acellular and whole-cell DTP vaccines were immunogenic, and the incidences of adverse reactions were within an expected and acceptable range. CONCLUSIONS: The simplified vaccination schedule to integrate the hepatitis B vaccine into the Expanded Programme of Immunization was safe, Immunogenic, and effective. This schedule may improve vaccine compliance and be applied to DTP and hepatitis B combination vaccines now under investigation.

Antigens↗
PubMed1997

Reevaluating the significance of pulmonary hypertension before cardiac transplantation: determination of optimal thresholds and quantification of the effect of reversibility on perioperative mortality.

OBJECTIVES: Right-sided circulatory failure resulting from severe preoperative pulmonary hypertension is a source of mortality early after cardiac transplantation. We undertook the present study (1) to analyze the association of elevated pulmonary hemodynamic indices with 30-day mortality, (2) to define threshold ranges associated with an increase in 30-day mortality, and (3) to evaluate the effect of vasodilator reversibility on 30-day mortality. METHODS: Preoperative hemodynamic profiles were evaluated in 476 patients who ultimately underwent cardiac transplantation. From these data, receiver-operating characteristic curves and stratum-specific likelihood ratios were generated to compare the efficacy of each hemodynamic index. A subset of patients with elevated hemodynamic profiles at baseline additionally underwent graded sodium nitroprusside infusion. RESULTS: Analysis of receiver-operating characteristic curves demonstrated no statistically significant difference among the indices in their ability to predict 30-day mortality. Analysis of stratum-specific likelihood ratios demonstrated three risk strata that correlated with significant differences in 30-day mortality, with patients in the high-risk stratum having a 3.2 to 4.4 increase in odds of 30-day mortality when compared with patients in the low-risk stratum. Nitroprusside data demonstrated that although 30-day mortality was better in patients with reversible pulmonary hypertension than in those with fixed pulmonary hypertension, it was not comparable with that of patients without pulmonary hypertension at baseline. CONCLUSIONS: Candidates for cardiac transplantation may be categorized into three risk strata on the basis of their preoperative pulmonary hemodynamic profile; the association of this profile with 30-day mortality is not linear. Reversibility with nitroprusside appears to confer some improvement in the risk of 30-day mortality, but it may not eliminate the risk entirely.

Cardiac Catheterization↗
PubMed1997

Systolic ventricular interaction in normal and diseased explanted human hearts.

OBJECTIVE: The purpose of this study was to quantify the magnitude of interaction between the right and left ventricles in conditions of heart failure. METHODS: Human hearts were taken from transplant recipients diagnosed with diluted cardiomyopathy at the time of transplantation and were restored to beating condition with use of an isolated perfusion circuit. Left ventricular-right ventricular interaction was determined by ramping volume in the left ventricle while holding right ventricular volume constant. Right ventricular pressure gain was plotted against left ventricular pressure and the slope of the linear regression determined the left ventricular-right ventricular interaction. A similar procedure was used to determine right ventricular-left ventricular interaction. Two normal hearts were obtained from transplant donors not suitable for cardiac donation to serve as control hearts. RESULTS: Mean left ventricular-right ventricular interaction was 0.22 in the hearts with dilated cardiomyopathy compared with 0.06 in the control hearts. Mean right ventricular-left ventricular interaction was 0.14 in the hearts with dilated cardiomyopathy compared with 0.09 in the control hearts. A marked increase in left ventricular-right ventricular interaction was noted in the hearts with dilated cardiomyopathy compared with control hearts. Although observed values of right ventricular-left ventricular interaction also correspond to previously published results, no significant increase was observed in the dilated cardiomyopathy condition. CONCLUSIONS: These studies confirm previously published values for systolic ventricular interaction obtained with animal models and demonstrate a marked increase in the dependence of the right ventricle on left ventricular function to maintain systolic pressure generation during conditions of dilated cardiomyopathy.

Cardiomyopathy, Dilated↗
PubMed1997

Molecular dynamics on complexes of ras-p21 and its inhibitor protein, rap-1A, bound to the ras-binding domain of the raf-p74 protein: identification of effector domains in the raf protein.

We have computed the average structures for the ras-p21 protein and its strongly homologous inhibitor protein, rap-1A, bound to the ras-binding domain (RBD) of the raf protein, using molecular dynamics. Our purpose is to determine the differences in structure between these complexes that would result in no mitogenic activity of rap-1A-RBD but full activity of p21-RBD. We find that despite the similarities of the starting structures for both complexes, the average structures differ considerably, indicating that these two proteins do not interact in the same way with this vital target protein. p21 does not undergo major changes in conformation when bound to the RBD, while rap-1A undergoes significant changes in structure on binding to the RBD, especially in the critical region around residue 61. The p21 and rap-1A make substantially different contacts with the RBD. For example, the loop region from residues 55-71 of rap-1a makes extensive hydrogen-bond contacts with the RBD, while the same residues of p21 do not. Comparison of the structures of the RBD in both complexes reveals that it undergoes considerable changes in structure when its structure bond to p21 is compared with that bound to rap-1A. These changes in structure are due to displacements of regular structure (e.g., alpha-helices and beta-sheets) rather than to changes in the specific conformations of the segments themselves. Three regions of the RBD have been found to differ significantly from one another in the two complexes: the binding interface between the two proteins at residues 60 and 70, the region around residues 105-106, and 118-120. These regions may constitute effector domains of the RBD whose conformations determine whether or not mitogenic signal transduction will occur.

GTP-Binding Proteins↗
PubMed1997

Inhibition of oncogenic and activated wild-type ras-p21 protein-induced oocyte maturation by peptides from the ras-binding domain of the raf-p74 protein, identified from molecular dynamics calculations.

In the preceding paper we found from molecular dynamics calculations that the structure of the ras-binding domain (RBD) of raf changes predominantly in three regions depending upon whether it binds to ras-p21 or to its inhibitor protein, rap-1A. These three regions of the RBD involve residues from the protein-protein interaction interface, e.g., between residues 60 and 72, residues 97-110, and 111-121. Since the rap-1A-RBD complex is inactive, these three regions are implicated in ras-p21-induced activation of raf. We have therefore co-microinjected peptides corresponding to these three regions, 62-76, 97-110, and 111-121, into oocytes with oncogenic p21 and microinjected them into oocytes incubated in in insulin, which activates normal p21. All three peptides, but not a control peptide, strongly inhibit both oncogenic p21- and insulin-induced oocyte maturation. These findings corroborate our conclusions from the theoretical results that these three regions constitute raf effector domains. Since the 97-110 peptide is the strongest inhibitor of oncogenic p21, while the 111-121 peptide is the strongest inhibitor of insulin-induced oocyte maturation, the possibility exists that oncogenic and activated normal p21 proteins interact differently with the RBD of raf.

Amino Acid Sequence↗