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Biomedical subjects

T M Chang

Publications and source records attributed to T M Chang.

At least 55 records · Page 3Linked to original sources
PubMed1998

Allelic loss of the BRCA1 and BRCA2 genes and other regions on 17q and 13q in breast cancer among women from Taiwan (area of low incidence but early onset).

We have examined the role of the breast cancer susceptibility genes BRCA1 and BRCA2 and other loci in the vicinity of these 2 genes on the long arms of chromosomes 17 and 13 (17q and 13q) for the presence of genomic deletions in breast cancer among Taiwanese women. Breast cancer in Taiwan is particularly characterized by its low incidence rate and its early age of tumor onset. Twelve microsatellite markers spanning the region 17q12-21 and 8 microsatellite markers spanning the region 13q12-14 were analyzed for allelic loss or loss of heterozygosity (LOH) in 90 patients with primary infiltrating ductal carcinoma. Compared with the background LOH level (10-12%) estimated by LOH at 4 unrelated loci, 17 markers (11 at 17q and 6 at 13q) demonstrated a significantly increased frequency (21-42%) of allelic loss (p < 0.05). Subsequent construction of deletion maps based on LOH at these significant loci localized the 6 smallest regions of overlap, including those harboring BRCA1, BRCA2, the retinoblastoma gene and 3 novel regions (the 1st located approximately 0.5 to 1 cM telomeric to BRCA1, the 2nd centromeric to BRCA1 flanked by D17S857/D17S846 and the 3rd closely adjacent to BRCA2), suggesting sites of susceptibility genes. Allelic loss at BRCA1 and BRCA2 was specifically associated with poorly differentiated tumors.

Aged↗
PubMed1998

Partial or complete circular duodenectomy with highly selective vagotomy for severe obstructing duodenal ulcer disease: an initial experience.

OBJECTIVE: To evaluate partial and complete circular duodenectomy combined with highly selective vagotomy (HSV) for relief of gastric retention. DESIGN: A retrospective, case-comparison study. SETTING: University hospital referral center. PATIENTS: Eighteen patients with severe obstructing duodenal ulcer disease defined by failure of a saline load test and endoscopic narrowing of the gastric outlet to 5 mm or less. METHODS: In patients with severe obstructing ulcer the diseased duodenal segment was excised with electrocautery (partial excision, 10 patients; complete excision, 8 patients). An HSV was then done. Postoperative fasting gastric residuum measurement and measurement of the emptying of liquids and solids was done at 3 months and patients were weighed at 3 and 12 months. RESULTS: No patient experienced postoperative gastric retention or required reoperation in a 2-year follow up. The early emptying of liquid (20 minutes) in complete circular duodenectomy plus HSV was more rapid than in normal subjects and duodenal ulcer patients. The emptying of solids was slightly delayed in partial duodenectomy plus HSV compared with duodenal ulcer patients but not with normal controls. The emptying of solids in duodenal ulcer patients was more rapid than in normal controls. Weight gain was excellent at 3 and 12 months. CONCLUSION: Partial duodenectomy and complete circular duodenectomy plus HSV are more efficacious than alternative nonresective procedures in restoring gastric emptying to near normal and restoring weight in patients with obstructing duodenal ulcer.

Duodenal Obstruction↗
PubMed1998

Pituitary adenylate cyclase-activating peptide stimulates rat pancreatic secretion via secretin and cholecystokinin releases.

BACKGROUND & AIMS: Pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates protein and/or amylase secretion from isolated rat pancreatic acini. The effect of PACAP on pancreatic secretion in vivo and its mechanism of action were studied. METHODS: Rats were prepared with pancreatic duct cannulation, pyloric ligation, and bile diversion into duodenum, and 2.5, 5, and 10 nmol/kg PACAP-27 was administered intravenously while pancreatic juice was collected for 30 minutes. In other groups of rats, the effect of 10 nmol/kg PACAP-27 was studied under the influence of either atropine; loxiglumide, an antisecretin serum; a combination of both loxiglumide and the antiserum; or a PACAP antagonist (PACAP 6-38). Plasma secretin and cholecystokinin concentrations were measured by radioimmunoassay. RESULTS: (1) PACAP dose-dependently increased pancreatic secretion of fluid, bicarbonate, and protein; (2) the increase in pancreatic secretion paralleled that of plasma secretin and cholecystokinin; (3) a combination of loxiglumide and antisecretin serum eliminated the PACAP-stimulated pancreatic secretion, whereas loxiglumide or antisecretin serum alone partially but significantly blocked pancreatic secretion; (4) atropine failed to influence PACAP-induced pancreatic secretion; and (5) PACAP antagonist profoundly suppressed the PACAP action. CONCLUSIONS: PACAP-27 dose-dependently stimulates pancreatic secretion of fluid, bicarbonate, and protein in rats. This effect is mediated by release of both secretin and cholecystokinin and is independent of cholinergic tone.

Animals↗
PubMed1998

Comparison of polymerically stabilized PEG-grafted liposomes and physically adsorbed carboxymethylchitin and carboxymethyl/glycolchitin liposomes for biological applications.

The stabilities of two types of polymerically stabilized liposomes consisting of PEG-grafted (DSPC:CHOL:DSPE-PEG1900, 5:4:1) and physically adsorbed carboxymethylchitin (CMC) and carboxymethyl/glycolchitin (CO) are compared. The polyelectrolyte is adsorbed on positive (DSPC:CHOL:DMTAP, 5:4:1) and neutral (DSPC:CHOL, 1:1) liposomes at different molecular weights (Mw). In PBS buffer (c(s) = 154 mM, pH = 7.4) the theoretical stability ratios (W) calculated using the classical DLVO Theory, indicate that the CMC-coated vesicles and the negative liposomes (DSPC:CHOL:DMPG, 5:4:1) are highly stable (W >> 1) compared to the PEG-grafted (W = 0.9511) and CO-coated (W = 0.9550) liposomes. Meanwhile, experimentally determined values of W, prove that the PEG-grafted is the most stable suspension (W = 5.5). Computation of the theoretical values of W for liposome-red blood cell and liposome-macrophage indicates that the electrosterically stabilized suspensions and the negative liposomes are stable. Light scattering results show that the flocculation of liposomes in blood and plasma depends on polymer molecular weight, type of polyelectrolyte and surface charge of the uncoated liposome. Neutral liposomes coated with CMC of Mw = 1.01 x 10(5) and negative liposomes provide a more effective barrier to plasma macromolecular protein adsorption than the grafted PEG groups and are easy to resuspend in blood.

Adsorption↗
PubMed1998

Absence of hemoprotein-associated free radical events following oxidant challenge of crosslinked hemoglobin-superoxide dismutase catalase.

Crosslinking hemoglobin with superoxide dismutase and catalase (PolyHb-SOD-CAT) helps to limit free radical reactivity of modified hemoglobin red blood cell substitutes. In the present study, in vitro oxidant challenge experiments were performed with exogenous hydrogen peroxide (H2O2) and xanthine oxidase-derived superoxide (O2.-). PolyHb-SOD-CAT was compared to PolyHb for the presence of secondary hemoprotein-free radical events. PolyHb-SOD-CAT prevents ferrylhemoglobin formation, measured as Na2S-induced absorbance at 620 nm. Similarly, PolyHb-SOD-CAT inhibited ferrozine-detectable iron release at high oxidant-heme ratios. The formation of oxygen radicals, monitored by salicylate hydroxylation, was prevented at high oxidant-heme ratios with PolyHb-SOD-CAT. The peroxidation of liposomal membranes was also inhibited in PolyHb-SOD-CAT mixtures subject to oxidant challenge. These results show that PolyHb-SOD-CAT prevents secondary hemoprotein-associated free radical events. This new type of modified hemoglobin oxygen carrier with antioxidant activity may reduce the potential toxicity of hemoglobin-based substitutes in certain applications, especially during reperfusion of ischemic tissues.

Animals↗
PubMed1998

Pharmaceutical and therapeutic applications of artificial cells including microencapsulation.

Artificial cells for pharmaceutical and therapeutic applications started as microencapsulation on the micron scale. This has now expanded up to the higher range of macrocapsules and down to the nanometer range of nanocapsules and even to the macromolecular range of cross-linked hemoglobin as blood substitutes. This author first reported microencapsulation of biologically active material in 1957 (T.M.S. Chang, Hemoglobin corpuscles. Research Report for Honours Physiology, Medical Library, McGill University, 1957. (Also reprinted as part of 30th anniversary in Artificial Red Blood Cells Research, J. Biomater. Artif. Cells Artif. Organs 16 (1988) 1-9.) and 1964 (T.M.S. Chang, Semipermeable microcapsules, Science 146 (1964) 524-525). While pharmaceutical research has made use of these approaches for drug delivery, this author has been concentrating on the encapsulation of biotechnological products for therapeutic applications. Therefore, there was little interaction between the two approaches. In the last 10 years, pharmaceutical research, as in other areas of research, has become increasingly interested in biotechnology. Because of this interest, this article is a brief overview of developments of artificial cells for biotechnological products with emphasis on hemoglobin, enzymes, cells and genetically engineered microorganisms.

Animals↗
PubMed1998

Therapeutic uses of microencapsulated genetically engineered cells.

Microencapsulated genetically engineered cells have the potential to treat a wide range of diseases. For example, in experimental animals, implanted microencapsulated cells have been used to secrete growth hormone to treat dwarfism, neurotrophic factors for amyotrophic lateral sclerosis, beta-endorphin to decrease pain, factor XI for hemophilia B, and nerve growth factors to protect axotomized neurons. For some applications, microencapsulated cells can even be given orally. They can be engineered to remove unwanted molecules from the body as they travel through the intestine, and are finally excreted in the stool without being retained in the body. This application has enormous potential for the removal of urea in kidney failure, ammonia in liver failure and amino acids such as phenylalanine in phenylketonuria and other inborn errors of metabolism.

Animals↗
PubMed1998

Modified hemoglobin blood substitutes: present status and future perspectives.

Biotechnological techniques of cross-linking and microencapsulation of hemoglobin result in blood substitutes that can replace red blood cells. Unlike red blood cells they can be sterilized by pasteurization, ultrafiltration and chemical means. This removes microorganisms responsible for AIDS, hepatitis, etc. Since they are free of red blood cell blood group antigens, there is no need for cross-matching or typing. This saves time and facilities and allows on-the-spot transfusion such as the infusion of salt solution. Furthermore, they can be stored for a long time. Hemoglobin for modification can be extracted from human red blood cells. Other sources of hemoglobin include bovine hemoglobin and recombinant human hemoglobin. Clinical trials are ongoing testing the possible uses of cross-linked hemoglobin in cardiac, orthopedic, trauma and other types of surgery. It is also being tested for the replacement of lost blood in severe bleeding due to trauma or other causes. Cross-linked hemoglobins are first generation blood substitutes that only fulfil some of the functions of red blood cells. New generations of more complete red blood cell substitutes are being developed. These include cross-linked hemoglobin-catalase-superoxide dismutase and microencapsulated hemoglobin-enzyme systems.

Animals↗
PubMed1998

Polyhemoglobin-superoxide dismutase-catalase as a blood substitute with antioxidant properties.

Polyhemoglobin-superoxide dismutase-catalase is designed to function as an oxygen carrier with antioxidant properties. This is based on cross-linking hemoglobin with superoxide dismutase and catalase (PolyHb-SOD-CAT). This study describes the structural and antioxidant properties of this solution. Our studies show that superoxide dismutase and catalase retain their enzymatic activity following glutaraldehyde polymerization with 8:1 and 16:1 glutaraldehyde:hemoglobin ratio. We have analyzed the optimal SOD/CAT ratios to prevent oxidation of hemoglobin in the presence of oxygen free radicals. The circulation half-life of crosslinked hemoglobin, SOD, and catalase in Sprague-Dawley rats correlates with the degree of polymerization as determined by high-performance molecular weight gel filtration. PolyHb-SOD-CAT decreases the formation of oxygen radicals compared with PolyHb in a rat intestinal ischemia-reperfusion model.

Animals↗
PubMed1998

Artificial cells with emphasis on cell encapsulation of genetically engineered cells.

Artificial cells are prepared in the laboratory for medical and biotechnological applications. Encapsulated cells are being studied for the treatment of diabetes, liver failure, and other conditions. More recently, there have been extensive studies into the use of encapsulated genetically engineered cells for gene therapy. We recently found that daily orally administered artificial cells, each containing a genetically engineered microorganism, can lower the elevated urea level in uremic rats to normal levels. This may solve the final obstacle of the lack of an effective oral urea removal system for the simple and inexpensive oral treatment of uremia. This is important because 85% of the world's uremic population cannot afford standard dialysis. Other areas of artificial cell application include use in hemoperfusion. Red blood cell substitutes based on modified hemoglobin are already in Phase 3 clinical trials in patients. Artificial cells containing enzymes are being developed for clinical trial in hereditary enzyme deficiency disease and other diseases. They are also being investigated for drug delivery and for use in other applications in biotechnology, chemical engineering, and medicine.

Administration, Oral↗
PubMed1998

Modified hemoglobin-based blood substitutes: crosslinked, recombinant and encapsulated hemoglobin.

Native hemoglobin in the form of stroma-free hemoglobin cannot be used as blood substitute. Hemoglobin has to be modified either molecularly or encapsulated. First generation molecularly modified ultrapure hemoglobins are now in clinical trial--some in Phase III. There are a number of these. Polyhemoglobin is formed by crosslinking hemoglobin molecules intermolecularly and intramolecularly. A crosslinked single hemoglobin molecule is formed by crosslinking hemoglobin intramolecularly. Recombinant hemoglobin from E.coli is formed by fusion of the subunits of each hemoglobin molecule. Conjugated hemoglobin is formed by crosslinking each hemoglobin molecule to soluble polymers. A second generation system formed by crosslinking hemoglobin-superoxide dismutase-catalase is being developed. A third generation hemoglobin-based blood substitute is based on microencapsulated hemoglobin, artificial red blood cells, that more closely resemble a complete red blood cell.

Animals↗
PubMed1998

Secretin inhibits gastric acid secretion via a vagal afferent pathway in rats.

Secretin is an enterogastrone that inhibits gastric acid secretion and motility. Recently, it was reported that secretin inhibited gastric emptying via a capsaicin (Cap)-sensitive vagal afferent pathway. However, a possible role of the sensory afferent pathway in secretin-inhibited acid secretion has not been clarified. We investigated whether or not the acid secretion suppressed by secretin is modulated by a vagal and/or splanchnic afferent pathway in rats. Subdiaphragmatic perivagal (PV) or periceliac ganglionic (PCG) application of Cap (10 mg/ml) or vehicle was performed in both conscious and anesthetized rats 2 wk before experiments. Bilateral vagotomy was performed in some conscious rats 5 days before studies. Pentagastrin was administered intravenously at 0.6 microg . kg-1 . h-1. Secretin (20 pmol . kg-1 . h-1 iv) or 0.03 N HCl (4.32 ml/h id) was infused in conscious rats with gastric cannulas or anesthetized rats with ligation of the pylorus, respectively. A rabbit antisecretin serum was injected in some anesthetized rats before duodenal acidification. Secretin significantly inhibited pentagastrin-stimulated acid secretion by 63% (P < 0.01), which was abolished by both vagotomy and PV treatment of Cap in conscious rats. In anesthetized rats, duodenal infusion of 0.03 N HCl suppressed pentagastrin-induced acid secretion by 59.4% (P < 0.01), which was reversed not only by antisecretin serum but also by PV application of Cap. However, PCG treatment with Cap did not influence the inhibition by secretin or duodenal acidification in either awake or anesthetized rats. These results indicate that the inhibition by secretin of pentagastrin-stimulated acid secretion is mediated by a Cap-sensitive vagal afferent pathway but not via a splanchnic afferent pathway in rats.

Afferent Pathways↗
PubMed1998

Modulation of secretin release by neuropeptides in secretin-producing cells.

Nerve fibers containing bombesin (BB)/gastrin-releasing polypeptide (GRP), pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal polypeptide (VIP), or galanin are known to innervate the mucosa of the upper small intestine. Both BB/GRP and PACAP have been shown to elicit secretin secretion in vivo. We studied whether the above-mentioned neuropeptides can act directly on secretin-producing cells, including the murine neuroendocrine cell line STC-1 and a secretin cell-enriched preparation isolated from rat upper small intestinal mucosa. Secretin release from both cell types was stimulated by various agents known to elicit secretin release and by the neuropeptides BB, GRP, and PACAP, suggesting a comparable response between the two cell preparations. The effects of neuropeptides were further studied in STC-1 cells. BB, GRP, and PACAP stimulated secretin release time and concentration dependently. VIP also stimulated secretin release concentration dependently. Stimulation by BB/GRP or PACAP was accompanied by elevation of inositol-1,4,5-trisphosphate (IP3) or cAMP, respectively. The stimulatory effect of PACAP on secretin release was synergistically enhanced by BB without any synergistic increase in IP3 or cAMP production, suggesting cross talk between different signal transduction pathways downstream of the production of these two second messengers. The L-type Ca2+ channel blocker diltiazem (10 microM) and the Ca2+ chelator EGTA (1 mM) significantly inhibited BB-stimulated secretin release by 64% and 59%, respectively, and inhibited PACAP-stimulated release by 75% and 55%, respectively. The protein kinase A-specific inhibitor Rp-cAMPS (100 microM) also inhibited both BB- and PACAP-stimulated secretin release by 30% and 62%, respectively. Galanin inhibited BB- and PACAP-stimulated secretin release and production of second messengers in a concentration-dependent and pertussis toxin-sensitive manner. These results suggested that the neuropeptides BB/GRP, PACAP, VIP, and galanin can modulate secretin release in secretin-producing cells and that STC-1 cells can serve as a useful model for studying the cellular mechanism of secretin secretion elicited by luminal secretagogues and neuropeptides.

1-Methyl-3-isobutylxanthine↗
PubMed1998

Evidence for the existence of CCK-producing cells in rat pancreatic islets.

BACKGROUND: Although the existence of cholecystokinin-like immunoreactivity (CCK-LI) in rat pancreas had been reported previously, it was never clearly demonstrated whether CCK is produced in rat pancreatic islets. AIMS: The purpose of this study was to elucidate the source of the CCK-LI, the molecular properties of CCK, and the expression of the CCK gene in islet cells. METHODS: Immunohistochemical studies of rat pancreas were carried out with different rabbit antisera against CCK-8 and CCK-related peptide including N-terminal CCK-33 (1-22) and gastrin-17, and colocalization with known islet hormones including insulin, glucagon, somatostatin, and pancreatic polypeptide was investigated. The major molecular form of CCK in the islets was determined by HPLC. RT-PCR and in situ hybridization were performed to demonstrate the presence of the CCK transcript in the pancreas. RESULTS: CCK-LI was found in the center of the islets, colocalized with insulin in B cells. The major molecular form of CCK in the islets was CCK-8. A 350-nucleotide fragment of PCR-amplified CCK cDNA was detected in the islet as well as the duodenum by RT-PCR. In situ hybridization showed that CCK messenger RNA was located in a large portion of the islets, and this was consistent with the immunohistochemical findings. CONCLUSION: CCK messenger RNA and immunoreactivity are expressed in adult rat pancreatic islets, indicating that CCK-producing cells are present in adult rat islets.

Animals↗
PubMed1998

Growth and survival of renal failure rats that received oral microencapsulated genetically engineered E. coli DH5 cells for urea removal.

In our earlier reports we have introduced a new method for urea removal in renal failure. This is based on the oral administration of polymeric artificial cells containing nonpathogenic genetically engineered E. coli DH5 cells to renal failure rats. This resulted in the lowering of systemic uremic urea level to normal range without elevation of ammonia. The present article deals with the safety study of this approach. Microscopic study follows changes in microcapsule morphology with time are described. Two parameters, the body weight of the renal failure rats and, the survival for of the renal failure rats receiving microcapsules containing genetically engineered E. coli DH5 cells are discussed in this article. Result shows that there is no significant difference between the weight profile of uremic rats receiving oral therapy and normal control rats. Also the treated group of uremic rats survived longer than the untreated uremic rats.

Administration, Oral↗
PubMed1997

Artificial cells and bioencapsulation in bioartificial organs.

The most common use of artificial cells is for bioencapsulation of biologically active materials. Many combination of materials can be bioencapsulated. The permeability, composition and configurations of artificial cell membrane can be varied using different types of synthetic or biological materials. These possible variations in contents and membranes allow for large variations in the properties and functions of artificial cells.

Animals↗