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Biomedical subjects

R Chang

Publications and source records attributed to R Chang.

At least 19 recordsLinked to original sources
PubMed2006

Laparoscopic combined rectal anterior resection and total hysterectomy with bilateral salpingo-oophorectomy.

Pelvic conditions involving both the colorectum and gynaecological organs are traditionally treated by laparotomy. We report two cases of colorectal cancer and one of endometriosis treated by laparoscopic anterior resection and total hysterectomy bilateral salpingooophorectomy (LapAR & THBSO), at the same session. There have been no previously reported cases of the feasibility of such combined procedures, safely performed. Our results confirm that LapAR & THBSO is feasible and offers the advantages of a laparoscopic procedure in the hands of a well trained laparoscopic colorectal surgeon and gynaecologist working together.

Adult↗
PubMed2006

Blockade of mGluR1 receptor results in analgesia and disruption of motor and cognitive performances: effects of A-841720, a novel non-competitive mGluR1 receptor antagonist.

BACKGROUND AND PURPOSE: To further assess the clinical potential of the blockade of metabotropic glutamate receptors (mGluR1) for the treatment of pain. EXPERIMENTAL APPROACH: We characterized the effects of A-841720, a novel, potent and non-competitive mGluR1 antagonist in models of pain and of motor and cognitive function. KEY RESULTS: At recombinant human and native rat mGluR1 receptors, A-841720 inhibited agonist-induced calcium mobilization, with IC50 values of 10.7+/-3.9 and 1.0 +/- 0.2 nM, respectively, while showing selectivity over other mGluR receptors, in addition to other neurotransmitter receptors, ion channels, and transporters. Intraperitoneal injection of A-841720 potently reduced complete Freund's adjuvant-induced inflammatory pain (ED50 = 23 micromol kg(-1)) and monoiodoacetate-induced joint pain (ED50 = 43 micromol kg(-1)). A-841720 also decreased mechanical allodynia observed in both the sciatic nerve chronic constriction injury and L5-L6 spinal nerve ligation (SNL) models of neuropathic pain (ED50 = 28 and 27 micromol kg(-1), respectively). Electrophysiological studies demonstrated that systemic administration of A-841720 in SNL animals significantly reduced evoked firing in spinal wide dynamic range neurons. Significant motor side effects were observed at analgesic doses and A-841720 also impaired cognitive function in the Y-maze and the Water Maze tests. CONCLUSIONS AND IMPLICATIONS: The analgesic effects of a selective mGluR1 receptor antagonist are associated with motor and cognitive side effects. The lack of separation between efficacy and side effects in pre-clinical models indicates that mGluR1 antagonism may not provide an adequate therapeutic window for the development of such antagonists as novel analgesic agents in humans.

Analgesia↗
PubMed2005

Evidence for a multivalent interaction of symmetrical, N-linked, lidocaine dimers with voltage-gated Na+ channels.

The interaction of symmetrical lidocaine dimers with voltage-gated Na+ channels (VGSCs) was examined using a FLIPR membrane potential assay and voltage-clamp. The dimers, in which the tertiary amines of the lidocaine moieties are linked by an alkylene chain (two to six methylene units), inhibited VGSC activator-evoked depolarization of cells heterologously-expressing rat (r) Na(v)1.2a, human (h) Na(v)1.5, and rNa(v)1.8, with potencies 10- to 100-fold higher than lidocaine (compound 1). The rank order of potency (C4 (compound 4) > C3 (compound 3) > or = C2 (compound 2) = C5 (compound 5) = C6 (compound 6) >> compound 1) was similar at each VGSC. Compound 4 exhibited strong use-dependent inhibition of hNa(v)1.5 with pIC50 values < 4.5 and 6.0 for tonic and phasic block, respectively. Coincubation with local anesthetics but not tetrodotoxin attenuated compound 4-mediated inhibition of hNa(v)1.5. These data suggest that the compound 4 binding site(s) is identical, or allosterically coupled, to the local anesthetic receptor. The dissociation rate of the dimers from hNa(v)1.5 was dependent upon the linker length, with a rank order of compound 1 > compound 5 = compound 6 > compound 2 >> compound 3. The observation that both the potency and dissociation rate of the dimers was dependent upon linker length is consistent with a multivalent interaction at VGSCs. hNa(v)1.5 VGSCs did not recover from inhibition by compound 4. However, "chase" with free local anesthetic site inhibitors increased the rate of dissociation of compound 4. Together, these data support the hypothesis that compound 4 simultaneously occupies two binding sites on VGSCs, both of which can be bound by known local anesthetic site inhibitors.

Anesthetics, Local↗
PubMed2005

Aberrant methylation of the Human Hedgehog interacting protein (HHIP) gene in pancreatic neoplasms.

Hedgehog pathway overactivity has been implicated in the development of a variety of human cancers. The Human Hedgehog interacting protein (HHIP), a negative regulator of hedgehog signaling, has been shown to be underexpressed in pancreatic cancers. In this study we determined if the HHIP gene is a target for genetic and epigenetic alterations. While no mutations of HHIP were identified, we found complete methylation of the HHIP promoter CpG island in three pancreatic cancer cell lines, and partial hypermethylation in 13/17 (80%) pancreatic cancer cell lines, 35/75 (46%) primary pancreatic cancers and 14/18 (78%) pancreatic cancer xenografts, but no methylation in 13 normal pancreata. In pancreatic cancer cell lines, complete methylation was associated with absent or reduced HHIP expression by real-time RT-PCR. HHIP expression could be restored in methylated cell lines using epigenetic modifier drugs. Restoring the expression of HHIP in pancreatic cancer cells by 5-aza-2'-deoxycytidine led to a decrease in Gli reporter activity, consistent with downregulation of Hedgehog signaling. These results indicate in some pancreatic adenocarcinomas that HHIP is epigenetically inactivated by promoter methylation, and its silencing could contribute to the increased Hedgehog signaling observed in pancreatic neoplasms.

Adenocarcinoma↗
PubMed2004

Technique for incorporating the density functional Hessian into the geometry optimization of biomolecules, solvated molecules, and large floppy molecules.

Traditional geometry optimization methods require the gradient of the potential surface, together with a Hessian which is often approximated. Approximation of the Hessian causes difficulties for large, floppy molecules, increasing the number of steps required to reach the minimum. In this article, the costly evaluation of the exact Hessian is avoided by expanding the density functional to second order in both the nuclear and electronic variables, and then searching for the minimum of the quadratic functional. The quadratic search involves the simultaneous determination of both the geometry step and the associated change in the electron density matrix. Trial calculations on Taxol indicate that the cost of the quadratic search is comparable to the cost of the density functional energy plus gradient. While this procedure circumvents the bottleneck coupled-perturbed step in the evaluation of the full Hessian, the second derivatives of the electron-repulsion integrals are still required for atomic-orbital-based calculations, and they are presently more expensive than the energy plus gradient. Hence, we anticipate that the quadratic optimizer will initially find application in fields in which existing optimizers breakdown or are inefficient, particularly biochemistry and solvation chemistry.

Algorithms↗
PubMed2004

Comparison of the pharmacological properties of rat Na(V)1.8 with rat Na(V)1.2a and human Na(V)1.5 voltage-gated sodium channel subtypes using a membrane potential sensitive dye and FLIPR.

A novel, membrane potential sensitive dye and a fluorescence imaging plate reader (FLIPR) have been used to characterize the pharmacological properties of rat Na(v)1.8 voltage-gated sodium channels (VGSC) in parallel with rat Na(v)1.2a and human Na(v)1.5 VGSC subtypes, respectively. The sensitivity of recombinant Na(v)1.2a-CHO, Na(v)1.5-293-EBNA, and Na(v)1.8-F-11 cells to VGSC activators was subtype dependent. Veratridine evoked depolarization of Na(v)1.2a-CHO and Na(v)1.5-293-EBNA cells with pEC(50) values of 4.78 +/- 0.13 and 4.84 +/- 0.12, respectively (n = 3), but had negligible effect on Na(v)1.8-F-11 cells (pEC(50) < 4.5). Type I pyrethroids were without significant effect at all subtypes. In contrast, the type II pyrethroids deltamethrin and fenvalerate evoked direct depolarization of Na(v)1.8-F-11 and Na(v)1.5-293-EBNA cells. Deltamethrin potentiated the veratridine-evoked response in Na(v)1.8-F-11 cells by > or =20-fold, in contrast to a <or =3-fold potentiation of the response in Na(v)1.2a, and Na(v)1.5 cells. Tetrodotoxin (TTX) inhibited VGSC activator-evoked depolarization of Na(v)1.8-F-11 cells with a biphasic concentration-response curve. The calculated pIC(50) values were 8.05 +/- 0.25 (n = 4) and 4.32 +/- 0.21 (n = 4), corresponding to TTX inhibition of endogenous TTX-sensitive (TTX-S), and recombinant Na(v)1.8 TTX-resistant (TTX-R) VGSCs, respectively. With the exception of TTX, the potencies of a number of ion channel blockers for the Na(v)1.8, Na(v)1.2a, and Na(v)1.5 VGSC subtypes were similar. In summary, these high-throughput FLIPR assays represent a valuable tool for the determination of the relative potencies of compounds at different VGSC subtypes and may prove useful for the identification of novel subtype-selective inhibitors.

Animals↗
PubMed2002

Activation of soluble guanylate cyclase causes relaxation of corpus cavernosum tissue: synergism of nitric oxide and YC-1.

Nitric oxide (NO) activates corpus cavernosum smooth muscle soluble guanylate cyclase (sGC) and increases the synthesis of cGMP that results in smooth muscle relaxation and ultimately, penile erection. To characterize sGC and define the potential synergy between NO and the allosteric activator YC-1 in corpus cavernosum, rat sGC was activated by either sodium nitroprusside (SNP) or YC-1, and YC-1 potentiated the effects of SNP with a 200-fold activation of sGC. Both SNP and YC-1 decreased the Km and increased the Vmax. ODQ significantly inhibited sGC activated by SNP with IC50 of 0.5 nM, but did not affect the sGC activated by YC-1 as well as basal sGC activity. SNP and YC-1 synergistically increased intracellular cGMP levels in rabbit corpus cavernosum smooth muscle cell cultures. YC-1 significantly relaxed rabbit cavernosum tissue strips in organ baths with an EC50 of 8.4 microM. In the presence of L-nitroarginine methyl ester to block endogenous NO production, co-administration of SNP shifted the dose response of YC-1 to the left, showing the synergism of SNP and YC-1 in tissue strips. In view of the clinical efficacy of phosphodiesterase-5 inhibitors, activation of sGC may provide an alternative means for enhancing the activity of neurally derived NO during sexual stimulation in the corpus cavernosum, representing a novel approach for the treatment of erectile dysfunction.

Animals↗
PubMed2002

Transferrin regulates transcription of the MBP gene and its action synergizes with IGF-1 to enhance myelinogenesis in the md rat.

Myelin-deficient (md) rats and their unaffected littermates were injected at postnatal day 4 either with a single dose of transferrin (Tf) or insulin-like growth factor one (IGF-1) singly or combined. Two weeks later, their brains were perfused and coronal sections were analyzed for MBP by in situ hybridization and for transferrin and myelin basic protein (Tf and MBP) by double immunofluorescence. Each of the factors separately had an effect on mutant animals as seen by both increased OL maturation, and MBP mRNA and protein synthesis. The combination of factors resulted in a profound enhancement of the myelinogenic properties of oligodendrocytes (OL) with a consequent increase in the number of MBP-labeled fibers. The brains of unaffected littermates also responded to growth factor(s) injection either by increasing myelination in some brain areas or by regulating the synthesis of MBP in OL. Using rat OL cultures we studied the site of transferrin action for the expression of MBP gene. We found by run off transcription that the MBP mRNA was significantly increased at the nuclear level but the PLP message was unaffected. Thus, transferrin selectively regulates MBP at the transcriptional level and together with IGF-1 synergizes to increase both the maturation and myelinogenic properties of md and normal OL.

Animals↗
PubMed2001

Circulating cardiac troponin-T in patients before and after renal transplantation.

BACKGROUND: The diagnostic and prognostic use of cardiac troponin T (cTnT) in patients with renal failure has been questioned. Raised serum concentrations of cTnT, with no apparent signs of cardiac damage using conventional methods of detection, have been reported. We aimed to relate circulating concentrations of cTnT to improved renal function following renal transplantation over a one-year period. METHOD: Plasma cTnT was analysed from patients with end stage renal disease before and after transplantation and subsequently at 1, 3, 6 and 12 months. Eight patients had diabetes, 14 had hyperlipidaemia, 8 were smokers and 4 were ex-smokers; all were hypersensitive. RESULTS: At the time of transplantation, 3 of the 32 patients (9.4%) had plasma cTnT concentrations above 0.1 microg/l. In addition to these three patients, five others showed raised cTnT over the one-year period. CONCLUSIONS: The overall trend in circulating cTnT concentrations did not seem to be affected by improved renal function. However, all of the patients that had raised cTnT concentrations at any stage of the one-year period had explainable pathologies or were exposed to multiple cardiac risk factors.

Adult↗
PubMed2001

Region-specific transcriptional response to chronic nicotine in rat brain.

Even though nicotine has been shown to modulate mRNA expression of a variety of genes, a comprehensive high-throughput study of the effects of nicotine on the tissue-specific gene expression profiles has been lacking in the literature. In this study, cDNA microarrays containing 1117 genes and ESTs were used to assess the transcriptional response to chronic nicotine treatment in rat, based on four brain regions, i.e. prefrontal cortex (PFC), nucleus accumbens (NAs), ventral tegmental area (VTA), and amygdala (AMYG). On the basis of a non-parametric resampling method, an index (called jackknifed reliability index, JRI) was proposed, and employed to determine the inherent measurement error across multiple arrays used in this study. Upon removal of the outliers, the mean correlation coefficient between duplicate measurements increased to 0.978+/-0.0035 from 0.941+/-0.045. Results from principal component analysis and pairwise correlations suggested that brain regions studied were highly similar in terms of their absolute expression levels, but exhibited divergent transcriptional responses to chronic nicotine administration. For example, PFC and NAs were significantly more similar to each other (r=0.7; P<10(-14)) than to either VTA or AMYG. Furthermore, we confirmed our microarray results for two representative genes, i.e. the weak inward rectifier K(+) channel (TWIK-1), and phosphate and tensin homolog (PTEN) by using real-time quantitative RT-PCR technique. Finally, a number of genes, involved in MAPK, phosphatidylinositol, and EGFR signaling pathways, were identified and proposed as possible targets in response to nicotine administration.

Amygdala↗
PubMed2001

Effects of sulfur impregnation temperature on the properties and mercury adsorption capacities of activated carbon fibers (ACFs).

Laboratory studies were conducted to determine the role of sulfur functional groups and micropore surface area of carbon-based adsorbents on the adsorption of Hg0 from simulated coal combustion flue gases. In this study, raw activated carbon fibers that are microporous (ACF-20) were impregnated with elemental sulfur between 250 and 650 degrees C. The resulting samples were saturated with respect to sulfur content. Total sulfur content of the sulfur impregnated ACF samples decreased with increasing impregnation temperatures from 250 and 500 degrees C and then remained constant to 650 degrees C. Results from sulfur K-edge X-ray absorption near-edge structure (S-XANES) spectroscopy showed that sulfur impregnated on the ACF samples was in both elemental and organic forms. As sulfur impregnation temperature increased, however, the relative amounts of elemental sulfur decreased with a concomitant increase in the amount of organic sulfur. Thermal analyses and mass spectrometry revealed that sulfur functional groups formed at higher impregnation temperatures were more thermally stable. In general, sulfur impregnation decreased surface area and increased equilibrium Hg0 adsorption capacity when compared to the raw ACF sample. The ACF sample treated with sulfur at 400 degrees C had a surface area of only 94 m2/g compared to the raw ACF sample's surface area of 1971 m2/g, but at least 86% of this sample's surface area existed as micropores and it had the largest equilibrium Hg0 adsorption capacities (2211-11,343 micrograms/g). Such a result indicates that 400 degrees C is potentially an optimal sulfur impregnation temperature for this ACF. Sulfur impregnated on the ACF that was treated at 400 degrees C was in both elemental and organic forms. Thermal analyses and CS2 extraction tests suggested that elemental sulfur was the main form of sulfur affecting the Hg0 adsorption capacity. These findings indicate that both the presence of elemental sulfur on the adsorbent and a microporous structure are important properties for improving the performance of carbon-based adsorbents for the removal of Hg0 from coal combustion flue gases.

Adsorption↗
PubMed2001

Production of human type I collagen in yeast reveals unexpected new insights into the molecular assembly of collagen trimers.

Substantial evidence supports the role of the procollagen C-propeptide in the initial association of procollagen polypeptides and for triple helix formation. To evaluate the role of the propeptide domains on triple helix formation, human recombinant type I procollagen, pN-collagen (procollagen without the C-propeptides), pC-collagen (procollagen without the N-propeptides), and collagen (minus both propeptide domains) heterotrimers were expressed in Saccharomyces cerevisiae. Deletion of the N- or C-propeptide, or both propeptide domains, from both proalpha-chains resulted in correctly aligned triple helical type I collagen. Protease digestion assays demonstrated folding of the triple helix in the absence of the N- and C-propeptides from both proalpha-chains. This result suggests that sequences required for folding of the triple helix are located in the helical/telopeptide domains of the collagen molecule. Using a strain that does not contain prolyl hydroxylase, the same folding mechanism was shown to be operative in the absence of prolyl hydroxylase. Normal collagen fibrils were generated showing the characteristic banding pattern using this recombinant collagen. This system offers new opportunities for the study of collagen expression and maturation.

Circular Dichroism↗
PubMed2001

Daily catheter-directed single dosing of t-PA in treatment of acute deep venous thrombosis of the lower extremity.

The strong fibrin affinity of recombinant tissue plasminogen activator (rt-PA) theoretically obviates continuous infusion or replacement of t-PA after direct intrathrombic injection. This hypothesis led the authors to evaluate single daily catheter-directed injection of rt-PA as a thrombolytic treatment for acute deep vein thrombosis of the lower extremity. Once-daily injection of rt-PA was performed in large thrombosed veins (popliteal or larger) with use of pulse-spray catheters and in small thrombosed veins in patients' calves with use of 3-4-F coaxial catheters. Patients received only full systemic anticoagulation on his/her patient care unit. This dosing regimen has been tested in 10 patients (12 legs) with a maximum dose of 50 mg per leg per day. Extensive thrombolysis was achieved in nine patients and partial thrombolysis was achieved in one patient, at an average total dose of 106 mg of rt-PA per leg. Minor bleeding was seen in three patients and no transfusions were needed. Our technique and the rationale for this pilot study is the focus of this article.

Catheterization, Peripheral↗
PubMed2001

Remyelination of the adult demyelinated mouse brain by grafted oligodendrocyte progenitors and the effect of B-104 cografts.

The 4e transgenic mouse is characterized by overexpression of the PLP gene. Heterozygous littermates containing three PLP gene copies develop and myelinate normally. However, a progressive CNS demyelination begins at 3-4 months of age. Despite focal demyelination, these animals survive for one year with hind limb paralysis. We used this CNS demyelination model to determine if grafts of CG4 oligodendrocyte progenitors would survive and myelinate the adult CNS. Either CG4 cells, or co-grafts of CG4/B 104 cells 11:1 ratio respectively) were performed. Grafted cells survived and migrated in the normal and transgenic brain. Non-treated transgenic animals revealed extensive lack of myelin. Three months post-transplant hosts with CG4 or co-transplants displayed a near normal myelin pattern. Double immunofluorescence for neurofilament and myelin basic protein revealed the presence of many naked axons in non-grafted transgenic animals. Those grafted with progenitor CG4 cells or cografts displayed a clear increase in remyelination. This data provides a new direction for the development of cell replacement therapies in demyelinating diseases.

Animals↗
PubMed2001

Caspase cleavage of vimentin disrupts intermediate filaments and promotes apoptosis.

Caspases are key mediators of apoptosis. Using a novel expression cloning strategy we recently developed to identify cDNAs encoding caspase substrates, we isolated the intermediate filament protein vimentin as a caspase substrate. Vimentin is preferentially cleaved by multiple caspases at distinct sites in vitro, including Asp85 by caspases-3 and -7 and Asp259 by caspase-6, to yield multiple proteolytic fragments. Vimentin is rapidly proteolyzed by multiple caspases into similar sized fragments during apoptosis induced by many stimuli. Caspase cleavage of vimentin disrupts its cytoplasmic network of intermediate filaments and coincides temporally with nuclear fragmentation. Moreover, caspase proteolysis of vimentin at Asp85 generates a pro-apoptotic amino-terminal fragment whose ability to induce apoptosis is dependent on caspases. Taken together, our findings suggest that caspase proteolysis of vimentin promotes apoptosis by dismantling intermediate filaments and by amplifying the cell death signal via a pro-apoptotic cleavage product.

Apoptosis↗
PubMed2001

Survival of conditionally immortalized hepatocytes in the spleen of syngeneic rats.

BACKGROUND: Hepatocyte transplantation has been shown to be effective in the treatment of liver failure; however, the shortage of donor organs limits its clinical application. Several reports have suggested that conditionally immortalized hepatocytes (CIH) could be an alternative to primary hepatocytes. However, CIH are known to undergo apoptosis in vitro at a non-permissive temperature, which is similar to body temperature. METHODS: To investigate the duration of survival and in vivo apoptosis of CIH in the syngeneic host, the L2A2 cells (a kind of CIH) that were established from hepatocytes of a Lewis rat with a gene for a temperature-sensitive Simian Virus 40 (SV40) large T antigen were transplanted into the spleen. Cells were isolated from the spleen that was removed periodically up to 6 months, and used to detect the presence of the L2A2 cells among them with the selective culture for CIH and T-antigen PCR. In situ apoptosis of L2A2 cells was also examined. In order to improve the survival of transplanted L2A2 cells in the host, a group of rats were partially hepatectomized 1 day before transplantation was performed. RESULTS: The L2A2 cells secreted albumin at a rate of 1.17 +/- 0.18 microg/24 h per 10(6) cells in vitro. After transplantation, L2A2 cell colonies and PCR amplification bands appeared up to 14 and 7 days, respectively, but this duration was not prolonged by a partial hepatectomy. The spleen showed a large number of hepatocytes that were in the process of dying on the 5th day, and only a number of ghost hepatocytes were present on the 7th day of transplantation. No tumors were found during the 6-month observation period. CONCLUSIONS: Conditionally immortalized hepatocytes can survive in the spleen for a limited period, in spite of the growth stimulation, most likely because they undergo apoptosis in vivo as well as in vitro at a non-permissive temperature. These data suggest that the use of these cells in hepatocyte transplantation be limited to temporary hepatic support.

Albumins↗