The patient-physician relationship: is three a crowd?
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Physician-Patient Relations↗
Biomedical subjects
J H Lin
Publications and source records attributed to J H Lin.
CLAP, a novel caspase recruitment domain-containing protein in the tumor necrosis factor receptor pathway, regulates NF-kappaB activation and apoptosis.
Molecules that regulate NF-kappaB activation play critical roles in apoptosis and inflammation. We describe the cloning of the cellular homolog of the equine herpesvirus-2 protein E10 and show that both proteins regulate apoptosis and NF-kappaB activation. These proteins were found to contain N-terminal caspase-recruitment domains (CARDs) and novel C-terminal domains (CTDs) and were therefore named CLAPs (CARD-like apoptotic proteins). The cellular and viral CLAPs induce apoptosis downstream of caspase-8 by activating the Apaf-1-caspase-9 pathway and activate NF-kappaB by acting upstream of the NF-kappaB-inducing kinase, NIK, and the IkB kinase, IKKalpha. Deletion of either the CARD or the CTD domain inhibits both activities. The CARD domain was found to be important for homo- and heterodimerization of CLAPs. Substitution of the CARD domain with an inducible FKBP12 oligomerization domain produced a molecule that can induce NF-kappaB activation, suggesting that the CARD domain functions as an oligomerization domain, whereas the CTD domain functions as the effector domain in the NF-kappaB activation pathway. Expression of the CARD domain of human CLAP abrogates tumor necrosis factor-alpha-induced NF-kappaB activation, suggesting that cellular CLAP plays an essential role in this pathway of NF-kappaB activation.
Adaptor Proteins, Signal Transducing↗
Different spatial distributions of sodium channels in the slowly and rapidly adapting stretch receptor neuron of the crayfish.
Inward Na+ currents were studied, using a two-microelectrode intracellular voltage-clamp technique, in the slowly adapting (SA) and rapidly adapting (RA) stretch receptor neurons of the crayfish after the axons were cut at different distances from the soma. In the SA neuron, inward Na+ currents were recorded in the soma even when the axon was cut as close as 100 microm from the center of the soma, indicating the presence of Na+ channels in these parts. Also, two populations of Na+ channels seem to exist in the SA neuron. In the RA neuron, only minute Na+ currents were observed if the axon was shorter than 250 microm. The results strongly indicate that the voltage-gated Na+ channels in the SA and RA neurons have different distributions and that the difference in the spatial distribution of Na+ channel types may be important for the difference in firing properties in the two types of neurons.
Adaptation, Physiological↗
The ankyrin repeat-containing adaptor protein Tvl-1 is a novel substrate and regulator of Raf-1.
Tvl-1 is a 269-amino acid ankyrin repeat protein expressed primarily in thymus, lung, and testes that was identified by screening a murine T-cell two-hybrid cDNA library for proteins that associate with the serine-threonine kinase Raf-1. The interaction of Tvl-1 with Raf-1 was confirmed by co-immunoprecipitation of the two proteins from COS-1 cells transiently transfected with Tvl-1 and Raf-1 expression constructs as well as by co-immunoprecipitation of the endogenous proteins from CV-1 and NB2 cells. Tvl-1 interacts with Raf-1 via its carboxyl-terminal ankyrin repeat domain. The same domain also mediates Tvl-1 homodimerization. Tvl-1 was detected by immunofluorescence in both the cytoplasm and the nucleus suggesting that in addition to Raf-1 it may also interact with nuclear proteins. Activated Raf-1 phosphorylates Tvl-1 both in vitro and in vivo. In baculovirus-infected Sf9 insect cells, Tvl-1 potentiates the activation of Raf-1 by Src and Ras while in COS-1 cells it potentiates the activation of Raf-1 by EGF. These data suggest that Tvl-1 is both a target as well as a regulator of Raf-1. The human homologue of Tvl-1 maps to chromosome 19p12, upstream of MEF2B with the two genes in a head to head arrangement.
Adaptor Proteins, Signal Transducing↗
Direct gap junction communication between malignant glioma cells and astrocytes.
Gap junctions are intercellular channels that connect the interiors of coupled cells. We sought to determine the extent to which malignant glioma cells form gap junction channels with astrocytes from either adult human brain or rat forebrain. The astrocytic gap junction protein, connexin 43 (Cx43), was identified in immunoreactive plaques at areas of cell-to-cell contact between cocultured glioma cells and astrocytes. These gap junction plaques were composed of functional channels, because extensive dye coupling was evident between the glioma cells and astrocytes from both human and rat brain. Calcium signaling was also readily transmitted from glioma cells to astrocytes and vice versa. In live rat brain, injection of glioma cells prelabeled with the gap junction tracer, dicarboxy-dichlorofluorescein, revealed extensive dye transfer to host cells, demonstrating that malignant glioma cells directly couple with normal brain cells. These observations suggest that intercellular communication via gap junctions may play a role in regulating cellular interactions during tumor invasion. In fact, the presence of gap junctions between astrocytes and glioma cells was sufficient to induce a transformation of astrocytic phenotype. Astrocytes cocultured with C6 glioma cells overexpressing Cx43 were significantly smaller and expressed a lower level of glial fibrillary acidic protein than astrocytes cocultured with otherwise identical mock-transfected, gap junction-deficient C6 cells. Thus, direct cellular coupling with glioma cells result in a phenotypic transformation of astrocytes that may contribute to the susceptibility of surrounding tissue to glioma invasion.
Adult↗
Characterization of hydroxyapatite and titanium coatings sputtered on Ti-6Al-4V substrate.
A series of thin (<10 microm), single-layered HA/Ti coatings were deposited on Ti-6Al-4V substrate using a radio frequency magnetron-assisted sputtering system. The adhesion strength, microstructure, and chemistry of the coatings were characterized. Experimental results showed that higher Ti contents in targets or coatings resulted in higher deposition rates. When Ti was added the highly crystalline structure of monolithic HA coating was largely disrupted and the coating became amorphous-like. The highly crystalline structure of the monolithic Ti coating was also disrupted by introducing small amounts of Ca, P, and O into the coating. The HA/Ti coatings had quite uniform thicknesses and appeared smooth, dense, and well bonded to the substrate. A scanning electron microscope with an energy dispersive spectroscopy system showed that monolithic HA, 95HA/5Ti, 25HA/75Ti, and 50HA/50Ti coatings had the lowest Ca/P ratios while the 75HA/25Ti coating had the highest. The adhesion strengths of all coatings were between 60 and 80 MPa.
Alloys↗
Molecular cloning and characterization of porcine cDNA encoding a 90-kDa heat shock protein and its expression following hyperthermia.
We have isolated and sequenced cDNA clones encoding a 90-kDa heat shock protein (HSP90) from a porcine brain cDNA library. The sequence of the 2202-nucleotide coding region showed 88.6% homology with that of the human homologue. Moreover, the deduced amino acid sequence of the porcine hsp90 cDNA was 99.7% identical to that of the human counterpart, with a difference of only three amino acids in a total of 733 residues. Expression of the gene was greatly increased in cultured cells during recovery from heat shock treatment at 45 degrees C for 60 min. Three major transcripts 2.2, 3.0, and 4.1kb in size were detected by Northern blot hybridization. These transcripts were further identified in a whole-pig hyperthermia experiment. These three hsp90 transcripts were constitutively expressed in porcine tissues including kidney, liver, brain, and heart, and their levels were markedly enhanced during recovery from 30-min hyperthermia treatment at 43 degrees C. Furthermore, we found that HSP90 was preferentially expressed in pituitary gland, brain, adrenal gland, and testis, in comparison to the other tissues.
Amino Acid Sequence↗
Renal handling of biphosphonate alendronate in rats.
Alendronate is a bisphosphonate that is secreted via a saturable pathway in rat kidney. This study is designed to discover if the rate-determining step in its net renal secretion is uptake into the renal tubule. The tissue uptake clearance of alendronate by the kidney, estimated from an integration plot analysis and normalized with respect to plasma protein binding, was 4.2 times higher at a tracer dose than that of inulin, indicating uptake of alendronate by the renal tubules. The uptake clearance is comparable with the net secretion clearance obtained from an infusion study, indicating that the rate-determining step in the net secretion is uptake under the tracer conditions. When the dose was increased, however, there was no reduction in uptake clearance while the net secretion clearance fell to almost zero. The urinary excretion clearance defined with respect to the steady state concentration in the kidney also fell to almost zero. This result suggests that saturation of the net secretion of alendronate is caused by saturation of membrane transport through the brush-border membrane. Thus, it would seem that there is a transport mechanism for alendronate on the brush-border membrane of kidney epithelial cells.
Alendronate↗
Low-density lipoprotein augments interleukin-1-induced vascular adhesion molecule expression in human endothelial cells.
In this study, the effect of low density lipoproteins (LDL) on the ability of the vascular endothelium to respond to vascular cell adhesion molecule 1 (VCAM-1) activation by a cytokine was investigated. After a 4-day pre-exposure to 240 mg/dl of LDL, human umbilical vein endothelial cells (HUVECs) were hyperresponsive to minute amounts of interleukin 1 alpha (IL-1 alpha) as demonstrated by an augmentation of VCAM-1 gene expression. Furthermore, in response to LDL exposure, endothelial recruitment of monocytes induced by minute amounts of IL-1 alpha was increased. This enhancing effect was blocked by an anti-VCAM antibody. The increased response appears not to be due to changes in IL-1 binding affinity or induction of endogenous IL-1 alpha. Transient transfection of HUVECs with a reporter driven by the VCAM promoter showed that LDL increased cellular response to IL-1 alpha by 46%. LDL itself does not increase NF-kappa B binding in endothelial cells (ECs). However, after a 2-day LDL incubation, NF-kappa B binding could be induced by over 63% with a very low dose of IL-1 alpha. IL-1 alpha at this dose (which activates NF-kappa B, but not AP-1) also enhanced LDL-activated AP-1 binding. This cross-enhanced effect may be an important intracellular signaling mechanism for EC activation. The results from this study provide new clues to understanding the mechanisms governing combined risk factors for atherosclerosis.
Cells, Cultured↗
3-D power Doppler cerebral angiography in neonates and young infants: comparison with 2-D power Doppler angiography.
The aims of this study were to evaluate the ability of 3-dimensional (3-D) power Doppler angiography (3DPDA) to depict the intracranial vasculature in infants, to compare with 2-D power Doppler ultrasonography (2DPDU), and to explore the potential clinical applications of this procedure in young infants with brain disorders. We performed 3DPDA in 27 infants. 2DPDU were completed in both sagittal and coronal directions in 12 of these patients. In the other 15, only right sagittal plane images were available for comparison. Using a grading system and with only vessels with more than half of the length demonstrated included for comparison, we compared the Doppler signals of major vessels. 3DPDA could have good visualization in more than 60% of the internal carotid artery, ophthalmic artery, pericallosal artery, callosomarginal artery, internal cerebral vein, vein of Galen, and straight sinus in the sagittal plane. 3DPDA also could have good demonstration in about 50% of basilar artery in coronal plane, and posterior communicating artery, posterior cerebral artery, and lenticulostriate artery in sagittal plane. 3DPDA was better than 2DPDU in demonstrating all the major intracranial vessels in different planes, except the anterior communicating artery. In the anterior communicating artery, neither can demonstrate more than 30%.
Brain Diseases↗
Dose-dependent plasma clearance of MK-826, a carbapenem antibiotic, arising from concentration-dependent plasma protein binding in rats and monkeys.
After intravenous administration of MK-826, a new carbapenem antibiotic, the compound exhibited nonlinear pharmacokinetics in rats and monkeys. In both species, time-averaged plasma clearance (based on total concentrations) increased about 5-fold over the 10- to 180-mg/kg dose range. MK-826 was extensively plasma protein bound in rat and monkey plasma, and the extent of binding was concentration dependent at plasma concentrations achieved after administration of these doses. Rosenthal analysis of the plasma protein binding indicated that there were two classes of binding sites. The binding capacity of the primary site was comparable to the plasma albumin concentration, which suggested that this primary site consisted of a single site on albumin. The extent of binding of MK-826 to rat albumin was similar to that in whole plasma. Clearance values based on unbound concentrations appeared independent of dose from 10 to 180 mg/kg, which is consistent with saturation of protein binding as the primary cause of the nonlinear pharmacokinetic behavior.
Animals↗
Central control of blood pressure by nitrergic mechanisms in organum vasculosum laminae terminalis of rat brain.
Experiments were carried out to explore the possible role played by the nitric oxide (NO) system in the organum vasculosum laminae terminalis (OVLT) of rat brain in arterial pressure regulation. Intracerebroventricular (ICV) or intra-OVLT administration of NO donors such as hydroxylamine, sodium nitro-prusside or s-nitro-acetylpenicillamine caused an up to 55 mmHg decrease in blood pressure (BP) but an increase in NO release (measured by porphyrin/nafion coated carbon fibre electrodes in combination with voltammetry) in the OVLT. In contrast, ICV or intra-OVLT administration of N(G)-nitro-L-arginine methyl ester (L-NAME; a constitutive NO synthase inhibitor) caused an up to 45 mmHg increase in BP but a fall in NO release in the OVLT. Compared with the BP responses induced by ICV injection of NO donors or NO synthase inhibitors, the OVLT route of injection required a much lower dose of NO donors or NO synthase inhibitors to produce a similar BP effect. The depressor effects induced by ICV or intra-OVLT administration of NO donors were attenuated by pretreatment with intra-OVLT injection of methylene blue (an inhibitor of guanylate cyclase), haemoglobin (a NO scavenger), L-NAME or spinal transection. On the other hand, the L-NAME-induced pressor effects were attenuated by pretreatment with intra-OVLT injection of L-arginine or spinal transection. The data suggest that activation of cyclic GMP-dependent NO synthase in the OVLT of rat brain causes cyclic GMP-dependent decreases in arterial pressure via inhibiting the sympathetic efferent activity.
Animals↗
The mechanotransduction of the crayfish stretch receptor neurone can be differentially activated or inactivated by local anaesthetics.
The effect of the local anaesthetics lidocaine, its meta-isomer, LL33, bupivacaine, tetracaine and procaine on the transducer properties of the stretch receptor neurone of the crayfish Pacifastacus leniusculus was investigated using a two microelectrode voltage clamp. Lidocaine increased the receptor current whereas LL33, bupivacaine and tetracaine reduced the receptor current in a reversible dose-dependent way. Procaine did not affect the receptor responses. The onset of the effect was generally slow in the order of minutes. Lidocaine increased the conductance of the mechanotransducer 50 +/- 7% (mean +/- SD, n = 4) and changed the reversal potential -8 +/- 1 mV (mean +/- SEM, n = 8), which indicates a major K+ conductance increase through the mechanosensitive channels. The other local anaesthetics increase the K+ conductance of the mechanotransducer without increasing the total conductance, which suggests that only P(Na)/P(K) is changed. These substances seem to have a Ca2+ dependent effect on the gating properties of the mechanosensitive channels in addition to their effect on the permeability through the channels as compared with lidocaine. All local anaesthetics investigated decreased the leak conductance of the receptor neurone. The effects of local anaesthetics on the mechanosensitive channels whether activating or blocking is correlated to the oil:water distribution coefficients and their relative hydrophobicity/hydrophilicity ratio. The results are consistent with the hypothesis that the local anaesthetic effect is mediated by changes in the lipid phase of the membrane.
Anesthetics, Local↗
Metabolic interactions between mibefradil and HMG-CoA reductase inhibitors: an in vitro investigation with human liver preparations.
AIMS: To determine the effects of mibefradil on the nletabolism in human liver microsomal preparations of the HMG-CoA reductase inhibitors simvastatin, lovastatin, atorvastatin, cerivastatin and fluvastatin. METHODS: Metabolism of the above five statins (0.5, 5 or 10 microM), as well as of specific CYP3A4/5 and CYP2C8/9 marker substrates, was examined in human liver microsomal preparations in the presence and absence of mibefradil (0.1-50 microM). RESULTS: Mibefradil inhibited, in a concentration-dependent fashion, the metabolism of the four statins (simvastatin, lovastatin, atorvastatin and cerivastatin) known to be substrates for CYP3A. The potency of inhibition was such that the IC50 values (<1 microM) for inhibition of all of the CYP3A substrates fell within the therapeutic plasma concentrations of mibefradil, and was comparable with that of ketoconazole. However, the inhibition by mibefradil, unlike that of ketoconazole, was at least in part mechanism-based. Based on the kinetics of its inhibition of hepatic testosterone 6beta-hydroxylase activity, mibefradil was judged to be a powerful mechanism-based inhibitor of CYP3A4/5, with values for Kinactivation, Ki and partition ratio (moles of mibefradil metabolized per moles of enzyme inactivated) of 0.4 min(-1), 2.3 microM and 1.7, respectively. In contrast to the results with substrates of CYP3A, metabolism of fluvastatin, a substrate of CYP2C8/9, and the hydroxylation of tolbutamide, a functional probe for CYP2C8/9, were not inhibited by mibefradil. CONCLUSION: Mibefradil, at therapeutically relevant concentrations, strongly suppressed the metabolism in human liver microsomes of simvastatin, lovastatin, atorvastatin and cerivastatin through its inhibitory effects on CYP3A4/5, while the effects of mibefradil on fluvastatin, a substrate for CYP2C8/9, were minimal in this system. Since mibefradil is a potent mechanism-based inhibitor of CYP3A4/5, it is anticipated that clinically significant drug-drug interactions will likely ensue when mibefradil is coadministered with agents which are cleared primarily by CYP3A-mediated pathways.
Aryl Hydrocarbon Hydroxylases↗
Microcalcifications of non-palpable breast lesions detected by ultrasonography: correlation with mammography and histopathology.
OBJECTIVES: Microcalcifications are generally not demonstrated well on ultrasonography. In this study, we attempted to demonstrate the usefulness of high-resolution ultrasonography in the detection of microcalcifications associated with non-palpable breast cancers. DESIGN: Fourteen patients with non-palpable breast lesions in whom microcalcifications were detected or suspected by ultrasonography and one patient in whom microcalcifications were detected on mammography only were included in the study. Mammography and analysis of biopsy specimens were performed in each patient and the findings were correlated with the ultrasonographic findings. Ultrasonography and mammography were performed independently by different physicians at different times. RESULTS: In three patients < or = 30 years of age, who were not at high risk of breast cancer and who had no evidence of cancer on palpation, high-resolution ultrasonography clearly showed microcalcifications but no mass. Two of these patients had ductal carcinoma in situ and one had small invasive carcinoma with extensive comedocarcinoma. Among the other 12 patients with non-palpable breast lesions, ultrasonography detected microcalcifications accurately in six and suggested possible microcalcifications in a further four. Microcalcifications in all of these ten patients were confirmed by mammography thereafter. Four of these ten patients had ductal carcinoma in situ, with or without invasive carcinoma. Of the remaining two patients, one demonstrated false-positive findings and one false-negative findings on ultrasound. On high-resolution ultrasonography, microcalcifications produced the appearance of twinkling stars (bright dots in different planes) in a dark sky (contrasted against ill-defined hypoechoic patches), corresponding on histopathology to groups of expanded ducts with increased cell density with or without necrosis. CONCLUSION: High-resolution ultrasonography may be used for detection of microcalcifications in non-palpable breast lesions. Ultrasonography is helpful in screening for early breast cancers, especially in young patients who are at risk for breast cancer and in whom mammography is not usually carried out.
Adult↗
p50(cdc37) acting in concert with Hsp90 is required for Raf-1 function.
Genetic screens in Drosophila have identified p50(cdc37) to be an essential component of the sevenless receptor/mitogen-activated kinase protein (MAPK) signaling pathway, but neither the function nor the target of p50(cdc37) in this pathway has been defined. In this study, we examined the role of p50(cdc37) and its Hsp90 chaperone partner in Raf/Mek/MAPK signaling biochemically. We found that coexpression of wild-type p50(cdc37) with Raf-1 resulted in robust and dose-dependent activation of Raf-1 in Sf9 cells. In addition, p50(cdc37) greatly potentiated v-Src-mediated Raf-1 activation. Moreover, we found that p50(cdc37) is the primary determinant of Hsp90 recruitment to Raf-1. Overexpression of a p50(cdc37) mutant which is unable to recruit Hsp90 into the Raf-1 complex inhibited Raf-1 and MAPK activation by growth factors. Similarly, pretreatment with geldanamycin (GA), an Hsp90-specific inhibitor, prevented both the association of Raf-1 with the p50(cdc37)-Hsp90 heterodimer and Raf-1 kinase activation by serum. Activation of Raf-1 via baculovirus coexpression with oncogenic Src or Ras in Sf9 cells was also strongly inhibited by dominant negative p50(cdc37) or by GA. Thus, formation of a ternary Raf-1-p50(cdc37)-Hsp90 complex is crucial for Raf-1 activity and MAPK pathway signaling. These results provide the first biochemical evidence for the requirement of the p50(cdc37)-Hsp90 complex in protein kinase regulation and for Raf-1 function in particular.
Animals↗
Is the role of the small intestine in first-pass metabolism overemphasized?
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Animals↗
The influence of rehabilitation therapy on the prognosis for stroke patients--a preliminary study.
The purpose of this prospective study was to investigate the influence of rehabilitation therapy on the prognosis for stroke patients. Sociodemographic and clinical factors were collected in a sample of 147 stroke patients (81 men and 66 women) admitted to the inpatient rehabilitation department at our university hospital over 10 days between January 1, 1997 and December 31, 1997. Functional Independence Measure (FIM) scores at discharge and gains during rehabilitation period were used as the prognosis index. Statistical techniques with univariate and multiple regression analyses indicated that significant predictors of discharge FIM scores include age, previous attacks twice or over, medical comorbidities, sensory and orientation impairments, and dementia. In addition, previous stroke attacks twice or over and sensory impairment were significant predictors of FIM gains during rehabilitation period. We concluded that: 1) age is a critical factor to determine the rehabilitation outcome, but may not be an important factor to predict the ability for the improvement through rehabilitation therapy; 2) the delay of rehabilitation therapy may not affect the potential for further improvement; 3) patients with low initial functional level may have poor final outcome, they may still have good rehabilitation potential to improve the functional level; 4) complications of stroke may affect the rehabilitation outcome and should be prevented; and 5) patients with impaired mental status should not routinely be excluded from rehabilitation programs.
Adult↗