Modulators of cat carotid body chemotransduction.
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Acetylcholine↗
Biomedical subjects
I Chang
Publications and source records attributed to I Chang.
Effect of PK11195, a peripheral benzodiazepine receptor agonist, on insulinoma cell death and insulin secretion.
Functional role of peripheral benzodiazepine receptor on mitochondrial membrane in apoptosis and insulin secretion from insulinoma cells was studied. A prototypic peripheral benzodiazepine receptor agonist PK11195 induced insulinoma cell apoptosis, while a central benzodiazepine receptor agonist did not. Death of insulinoma cells by PK11195 was inhibited by cyclosporin A, a blocker of mitochondrial permeability transition pore. Caspase inhibitors further inhibited MIN6N8 cell death. PK11195 induced dissipation of mitochondrial potential and cytochrome c translocation to cytoplasm. PK11195 induced an increase in cytoplasmic [Ca(2+)], which was reversed by cyclosporin A. Rhod-2 staining showed decreased mitochondrial [Ca(2+)] after PK11195 treatment. PK11195 potentiated glucose-induced insulin secretion probably due to the increased cytoplasmic [Ca(2+)]. Calpain was activated following Ca(2+) release, and calpain inhibitors attenuated death of insulinoma cells by PK11195. These results suggest that PK11195 induces mitochondrial potential loss, cytochrome c translocation, increased insulin secretion in conjunction with an increase in cytoplasmic [Ca(2+)] and calpain activation, which collectively leads to apoptosis of insulinoma cells.
Animals↗
Pigment-lightening effect of N,N'-dilinoleylcystamine on human melanoma cells.
BACKGROUND: Cystamine and linoleic acid have been reported to reduce melanin synthesis in vitro and in vivo. N,N'-dilinoleylcystamine (DLC) is a compound of cystamine and linoleic acid connected by an ester bond. OBJECTIVES: To investigate the effects of DLC on melanin synthesis using cultured human melanoma cells. METHODS: Levels of total melanin, eumelanin and phaeomelanin, tyrosinase protein and tyrosinase activity in situ were measured in HM3KO melanoma cells. Changes in degree of pigmentation were quantified by image analysis and compared with absorbance values. Tyrosinase from HM3KO cells was used to measure the direct effect of DLC on DOPA and DOPAchrome production. RESULTS: At concentrations of 1.4-14 micromol L-1, DLC reduced the pigmentation of HM3KO melanoma cells but did not affect cell growth. The visual decrease in pigmentation produced by DLC was more dramatic than the decrease in total melanin content as measured by absorbance at 500 nm. DLC treatment decreased eumelanin synthesis and increased phaeomelanin synthesis in HM3KO melanoma cells. An in situ tyrosinase assay showed that DLC inhibited tyrosinase activity, as well as the level of tyrosinase protein. CONCLUSIONS: These results suggest that DLC has pigment-lightening effects on HM3KO melanoma cells, produced by reducing the level of eumelanin while increasing the level of phaeomelanin.
Blotting, Western↗
Pyruvate inhibits zinc-mediated pancreatic islet cell death and diabetes.
AIMS/HYPOTHESIS: We have shown that zinc ion (Zn2+) in secretory granules of pancreatic beta cells could act as a paracrine death effector in streptozotocin-induced diabetes. As Zn2+ has been reported to perturb glycolysis, we studied if pyruvate could inhibit Zn(2+)-mediated islet cell death in vitro and streptozotocin-induced diabetes in vivo by normalizing intracellular energy metabolism. METHODS: Cell death was measured by quantitative viable cell staining and Hoechst/propidium iodide staining. ATP was measured by bioluminescence determination. Pyruvate was infused through the tail vein 1 h before streptozotocin administration. Beta-cell volume was measured by point counting of the insulin-containing cells. RESULTS: Zn2+ induced classical necrosis on MIN6N8 insulinoma cells which was associated with a rapid decline of intracellular ATP levels. Pyruvate inhibited Zn(2+)-induced necrosis of insulinoma cells and depletion of intracellular ATP by Zn2+. Pyruvate did not inhibit other types of necrosis or apoptosis. Energy substrates such as oxaloacetate, alpha-ketoglutarate and succinic acid dimethylester also attenuated Zn(2+)-induced insulinoma cell death. Methylpyruvate that does not generate NAD+ in the cytoplasm or alpha-ketoisocaproate that stimulates ATP generation exclusively in mitochondria also protected insulinoma cells from Zn(2+)-induced necrosis. Pyruvate infusion inhibited the development of diabetes by protecting beta-cell mass after streptozotocin administration. CONCLUSION/INTERPRETATION: These results indicate that pyruvate inhibits Zn(2+)-induced necrosis of beta cells in vitro by protecting intracellular ATP levels and also streptozotocin-induced diabetes in vivo where Zn2+ has been reported to act as a paracrine death effector.
Adenosine Triphosphate↗
Identification and functional characterization of a novel mutation of hepatocyte nuclear factor-1alpha gene in a Korean family with MODY3.
AIMS/HYPOTHESIS: After screening 16 Korean families with early onset Type 2 diabetes in search for hepatocyte nuclear factor (HNF) -1alpha gene mutation, we identified a novel missense mutation (R263L) associated with MODY phenotype. We studied the biological characteristics of the mutation and the potential functional consequences based on the crystallographic structure of HNF-1alpha in complex with DNA. METHODS: DNA from subjects with a familial form of early onset diabetes was isolated and HNF-1alpha was sequenced. The R263L substitution was generated by PCR-based sited-directed mutagenesis. Functional and biochemical studies were conducted by reporter assay using glucose-transporter type 2 (GLUT2) or insulin promoters and electrophoretic mobility shift assay, respectively. RESULTS: Transfection of wild-type HNF-1alpha increased the reporter activities of GLUT2 and insulin promoters in NIH3T3 and SK-Hep1 cells, while R263L mutant was defective in transactivation of those promoters. Both wild-type HNF-1alpha and R263L mutant could not transactivate GLUT2 and insulin promoters in MIN6N8 insulinoma cells. R263L mutant had a defective cooperation with its heterodimeric partner HNF-1beta or coactivator p300. R263L mutant protein displayed greatly reduced DNA binding ability, despite its comparable protein stability to the wild-type HNF-1alpha. CONCLUSION/INTERPRETATION: These results suggest that the mutation of HNF-1alpha at codon 263 from arginine to leucine leads to the development of MODY3 through decreased insulin production and defective glucose sensing. These findings are in good agreement with the crystal structure in which R263 makes hydrogen bonds with phosphorus atoms of DNA backbone to mediate the stable binding of HNF-1alpha homeodomain to the promoter.
Amino Acid Substitution↗
IFN gamma/TNF alpha synergism in MHC class II induction: effect of nicotinamide on MHC class II expression but not on islet-cell apoptosis.
AIMS/HYPOTHESIS: Interferon-gamma (IFN gamma) and TNFalpha synergistically induce pancreatic beta-cell apoptosis. Apart from their direct effect, we studied the possible indirect immunological role of IFNgamma/TNFalpha synergism on pancreatic beta-cell death by investigating MHC class II induction by cytokines. The effect of nicotinamide on the cytokine-induced MHC class II expression and pancreatic beta-cell death was also studied. METHODS: Immunocytochemistry, flow cytometry and RNase protection assay were used to study MHC class II expression. Immunoblotting was done to study downstream signals of IFN gamma. The effects of nicotinamide on islet-cell apoptosis and diabetes mellitus were examined using MTT assay and adoptive transfer model. RESULTS: IFN gamma alone induced MHC class II expression on a small number of insulinoma cells. TNFalpha alone did not induce MHC class II expression, but enhanced IFN gamma-induced MHC class II expression. MHC class II expression by cytokine(s) was due to the induction of class II transactivator (CIITA). Nicotinamide reduced MHC class II expression by cytokine(s) but did not protect insulinoma-cell apoptosis by IFN gamma and TNFalpha in combination or protect against the development of diabetes mellitus after adoptive transfer of diabetogenic lymphocytes. CONCLUSION/INTERPRETATION: IFN gamma and TNFalpha synergistically induced MHC class II expression on insulinoma cells through the induction of CIITA; nicotinamide reduced the expression of cytokine-induced MHC class II expression on insulinoma cells through its effect on CIITA expression; and the preventive effect of nicotimamide on Type I (insulin-dependent) diabetes mellitus is probably due to its effect of MHC class II expression rather than that on islet cell apoptosis.
Animals↗
Precision test apparatus for evaluating the heating pattern of radiofrequency ablation devices.
Radiofrequency has established itself as a useful technique for managing cardiac arrhythmias and treating soft tissue tumors. However, despite its pervasive use, many of the biophysical principals needed to fully understand and optimize the radiofrequency ablation technique have not been explored. We have designed a test rig that is useful for studying the heat transfer mechanisms that affect the outcome of radiofrequency ablation devices. Using both solid and liquid phantom materials, which simulate body tissues and blood, the test rig is designed for systematic testing of the effects of predictable flow patterns on the temperature profiles generated within the solid phantom. The test rig consists of a custom built thermistor array, a linear test chamber, and a radiofrequency generator. We calibrate the flow of a liquid phantom material to demonstrate that predictable laminar flow profiles are generated. To demonstrate the performance of the ablation system, we present preliminary data attained using a commercially available cardiac ablation catheter. The advantages of this test system are its flexibility, its reproducibility, its precision, and its low cost. Thus, it is ideally suited for studying a variety of complex ablation problems involving multiple tissues types and complex blood flow geometries.
Blood Flow Velocity↗
The skin barrier state of aged hairless mice in a dry environment.
BACKGROUND: Many elderly people have chronic xerosis, and frequently experience an exacerbation during winter. OBJECTIVES: To investigate the barrier state of aged murine skin with or without barrier disruption in a dry environment. METHODS: Aged and young hairless mice were kept separately in dry and normal conditions for 9 days. Acetone treatment was used to perturb the skin barrier. Skin barrier function was measured as transepidermal water loss (TEWL), and morphological changes in the epidermis were studied by electron microscopy. RESULTS: The baseline TEWL was not higher in the dry environment. The number of stratum corneum (SC) layers and the epidermal thickness of aged mice increased in the dry environment. The recovery rate of the aged skin barrier was neither accelerated nor delayed in the dry environment. In the normal environment, aged mice recovered more slowly than young mice. After barrier perturbation in the aged mice, changes in SC layers and in epidermal thickness were similar in the two environments. The secretion and number of lamellar bodies did not differ between the two environments. CONCLUSIONS: We confirmed that a dry environment induces epidermal proliferation and scaling in both aged and young mice. However, no remarkable difference was found in the skin barrier recovery of aged hairless mice in a dry environment.
Acetone↗
Protein threading by learning.
By using techniques borrowed from statistical physics and neural networks, we determine the parameters, associated with a scoring function, that are chosen optimally to ensure complete success in threading tests in a training set of proteins. These parameters provide a quantitative measure of the propensities of amino acids to be buried or exposed and to be in a given secondary structure and are a good starting point for solving both the threading and design problems.
Amino Acid Sequence↗
Anisotropic domain growth of the axial next-nearest-neighbor Ising model at low temperatures.
We investigate the ordering kinetics for the axial next-nearest-neighbor Ising (ANNNI) model in one and two dimensions by the multispin heat bath dynamical simulation. This dynamics enables us to overcome the pinning effect and to observe the dynamical scaling law for domain growth in the ANNNI model at zero temperature. The domain growth exponent is 1/2 isotropically both in the ferromagnetic and the dry (commensurate) antiphase. In the wet (commensurate) antiphase, however, it is approximately 1/3 in the modulated direction, whereas it remains 1/2 in the nonmodulated direction. We suggest that these exponent values are dictated by 3- and 4-body diffusion-reaction processes of domain walls.
Journal Article↗
IFNalpha sensitizes ME-180 human cervical cancer cells to TNFalpha-induced apoptosis by inhibiting cytoprotective NF-kappaB activation.
Tumor necrosis factor alpha (TNFalpha) induces apoptosis of a variety of tumor cell types. The anti-tumor effect of TNFalpha is often augmented by interferon (IFN) gamma. We hypothesized that IFNalpha, which shares many biological activities with IFNgamma, might also synergize with TNFalpha for the induction of tumor cell death. We tested our hypothesis using ME-180 human cervical cancer cells exposed to either IFNalpha or TNFalpha alone or both. We analyzed the death of ME-180 cells by biochemical and cytological means, and investigated the molecular mechanism underlying cytotoxic synergism between the two cytokines. We found that (i) IFNalpha/TNFalpha synergistically induced apoptosis of ME-180 cells, which was accompanied by activation of caspases-3 and -8; (ii) IFNalpha induced signal transducer and activator of transcription (STAT) 1 phosphorylation, and transfection of phosphorylation-defective STAT1 dominant-negative mutant inhibited IFNalpha/TNFalpha-induced apoptosis; (iii) inhibition of nuclear factor kappaB (NF-kappaB) by proteasome inhibitor MG-132 sensitized ME-180 cells to TNFalpha alone; (iv) IFNalpha treatment attenuated TNFalpha-induced NF-kappaB reporter activity, while it did not inhibit DNA binding of NF-kappaB. Taken collectively, our results indicate that IFNalpha sensitizes ME-180 cells to TNFalpha-induced apoptosis by inhibiting TNFalpha-mediated cytoprotective NF-kappaB activation, and this sensitizing effect of IFNalpha is mediated through a STAT1-dependent pathway.
Apoptosis↗
IFN-gamma/TNF-alpha synergism as the final effector in autoimmune diabetes: a key role for STAT1/IFN regulatory factor-1 pathway in pancreatic beta cell death.
Fas ligand (FasL), perforin, TNF-alpha, IL-1, and NO have been considered as effector molecule(s) leading to beta cell death in autoimmune diabetes. However, the real culprit(s) in beta cell destruction have long been elusive, despite intense investigation. We and others have demonstrated that FasL is not a major effector molecule in autoimmune diabetes, and previous inability to transfer diabetes to Fas-deficient nonobese diabetic (NOD)-lpr mice was due to constitutive FasL expression on lymphocytes from these mice. Here, we identified IFN-gamma/TNF-alpha synergism as the final effector molecules in autoimmune diabetes of NOD mice. A combination of IFN-gamma and TNF-alpha, but neither cytokine alone, induced classical caspase-dependent apoptosis in insulinoma and pancreatic islet cells. IFN-gamma treatment conferred susceptibility to TNF-alpha-induced apoptosis on otherwise resistant insulinoma cells by STAT1 activation followed by IFN regulatory factor (IRF)-1 induction. IRF-1 played a central role in IFN-gamma/TNF-alpha-induced cytotoxicity because inhibition of IRF-1 induction by antisense oligonucleotides blocked IFN-gamma/TNF-alpha-induced cytotoxicity, and transfection of IRF-1 rendered insulinoma cells susceptible to TNF-alpha-induced cytotoxicity. STAT1 and IRF-1 were expressed in pancreatic islets of diabetic NOD mice and colocalized with apoptotic cells. Moreover, anti-TNF-alpha Ab inhibited the development of diabetes after adoptive transfer. Taken together, our results indicate that IFN-gamma/TNF-alpha synergism is responsible for autoimmune diabetes in vivo as well as beta cell apoptosis in vitro and suggest a novel signal transduction in IFN-gamma/TNF-alpha synergism that may have relevance in other autoimmune diseases and synergistic anti-tumor effects of the two cytokines.
Animals↗
Interferon gamma (IFNgamma ) and tumor necrosis factor alpha synergism in ME-180 cervical cancer cell apoptosis and necrosis. IFNgamma inhibits cytoprotective NF-kappa B through STAT1/IRF-1 pathways.
We investigated the molecular mechanism of the synergism between interferon gamma (IFNgamma) and tumor necrosis factor alpha (TNFalpha) documented in a variety of biological occasions such as tumor cell death and inflammatory responses. IFNgamma/TNFalpha synergistically induced apoptosis of ME-180 cervical cancer cells. IFNgamma induced STAT1 phosphorylation and interferon regulatory factor 1 (IRF-1) expression. Transfection of phosphorylation-defective STAT1 inhibited IFNgamma/TNFalpha-induced apoptosis, whereas IRF-1 transfection induced susceptibility to TNFalpha. Dominant-negative IkappaBalpha transfection sensitized ME-180 cells to TNFalpha. IFNgamma pretreatment attenuated TNFalpha- or p65-induced NF-kappaB reporter activity, whereas it did not inhibit p65 translocation or DNA binding of NF-kappaB. IRF-1 transfection alone inhibited TNFalpha-induced NF-kappaB activity, which was reversed by coactivator p300 overexpression. Caspases were activated by IFNgamma/TNFalpha combination; however, caspase inhibition did not abrogate IFNgamma/TNFalpha-induced cell death. Instead, caspase inhibitors directed IFNgamma/TNFalpha-treated ME-180 cells to undergo necrosis, as demonstrated by Hoechst 33258/propidium iodide staining and electron microscopy. Taken together, our results indicate that IFNgamma and TNFalpha synergistically act to destroy ME-180 tumor cells by either apoptosis or necrosis, depending on caspase activation, and STAT1/IRF-1 pathways initiated by IFNgamma play a critical role in IFNgamma/TNFalpha synergism by inhibiting cytoprotective NF-kappaB. IFNgamma/TNFalpha synergism appears to activate cell death machinery independently of caspase activation, and caspase activation seems to merely determine the mode of cell death.
Apoptosis↗
Prevalence of psychiatric disorders among persons convicted of driving while impaired.
BACKGROUND: Large numbers of convicted drunk drivers are entering alcohol treatment programs, yet little information is available about their need for psychiatric treatment. This study of convicted drunk drivers estimates lifetime and 12-month prevalence of DSM-III-R psychiatric disorders (alcohol and drug abuse and dependence, major depressive disorder, dysthymic disorder, generalized anxiety disorder, posttraumatic stress disorder, and antisocial personality disorder) and compares rates with estimates from a US population-based survey. METHODS: Six hundred twelve women and 493 men, aged 23 to 54 years, convicted of driving while impaired, who had been referred to a screening program in Bernalillo County, New Mexico, were located and interviewed using the Diagnostic Interview Schedule between January 25, 1994, and June 30, 1997. Psychiatric diagnoses were compared with findings from the National Comorbidity Survey for the western region of the United States, conducted between September 14, 1990, and February 6, 1992. RESULTS: Eighty-five percent of female and 91% of male offenders reported a lifetime alcohol-use disorder, compared with 22% and 44%, respectively, in the National Comorbidity Survey sample. Thirty-two percent of female and 38% of male offenders had a drug-use disorder, compared with 16% and 21%, respectively, in the National Comorbidity Survey sample. For offenders with alcohol-use disorders, 50% of women and 33% of men had at least 1 additional psychiatric disorder other than drug abuse or dependence, mainly posttraumatic stress disorder or major depression. CONCLUSION: Drunk-driving offenders need assessment and treatment services not only for alcohol problems but also for drug use and the other psychiatric disorders that commonly accompany alcohol-related problems.
Adult↗
Design of a group-randomized Streptococcus pneumoniae vaccine trial.
A group-randomized, double-masked, phase III trial of a Streptococcus pneumoniae conjugate vaccine is being conducted in American Indian populations in the southwestern United States. Approximately 9000 infants will be enrolled in the primary efficacy cohort with vaccine allocation determined by community of residence. The trial is designed to continue until 48 cases of invasive pneumococcal disease due to vaccine serotypes have accumulated. Thirty-eight geographically and socially distinct areas were randomized within blocks formed by population size and geographic location. This design affords the opportunity to capture the effects of herd immunity (indirect effects) by estimating the impact of the vaccine intervention on nonimmunized infants. Group-randomized trials have challenging design and analysis features, many of which are discussed here in the context of the first such trial designed to lead to licensure of a drug or biologic in the United States.
Arizona↗
Safety and immunogenicity of four doses of Neisseria meningitidis group C vaccine conjugated to CRM197 in United States infants.
BACKGROUND: Following widespread use of conjugate pneumococcal vaccine, Neisseria meningitidis likely will become the leading cause of bacterial sepsis and meningitis in US children. This report describes the safety and immunogenicity in US children of four consecutive doses of a meningococcal group C vaccine conjugated to CRM197 via reductive amination (MnCC). METHODS: One hundred six healthy 2-month-old infants received MnCC at 2, 4 and 6 months of age in a randomized, controlled double blind study; children in the other treatment arm were given a 7-valent conjugate pneumococcal vaccine. Parents reenrolled 64 of these children at 12 to 15 months to receive a fourth dose of MnCC. Routine childhood vaccines, including DTP, were coadministered. Temperatures and symptoms were recorded for 3 days after each immunization. Serum enzyme-linked immunosorbent assay IgG and bactericidal antibodies were measured prevaccination and before and 1 month after Doses 3 and 4. RESULTS: Moderate to severe local reactions, defined as erythema or induration > or =2.4 cm or pain that interfered with limb movement was reported after 0 to 3.2% of MnCC injections, depending on the reaction and dose. Fever occurred in 23 to 37% of children, but the contribution of MnCC to the febrile reactions is unknown. Geometric mean concentrations of IgG antibody to group C meningococcal polysaccharide were 3.72 microg/ml after Dose 3 and 8.03 microg/ml after the booster. Geometric mean functional serum bactericidal antibody titers after Doses 3 and 4 were 1:463 and 1:2341, respectively. One hundred percent of children had a serum bactericidal antibody titer of > or =1:64 after three doses and > or = 1:128 after the booster. CONCLUSIONS: The MnCC vaccine had an acceptable safety profile and generated high titers of bactericidal antibody in immunized US infants and toddlers. It appears to be an attractive candidate vaccine for the prevention of serogroup C meningococcal disease in young children.
Antibodies, Bacterial↗
Noxious hot and cold stimulation produce common patterns of brain activation in humans: a functional magnetic resonance imaging study.
We used functional magnetic resonance imaging (fMRI) to determine whether similar brain regions activate during noxious hot and cold stimulation. Six male subjects underwent whole brain fMRI during phasic delivery of noxious hot (46 degrees C) and noxious cold (5 degrees C) stimulation to the dorsum of the left hand. Mid-brain regions activated included thalamus, basal ganglia and insula. Cortical areas activated included cingulate, somatosensory, premotor and motor cortices, as well as prefrontal and inferior parietal cortex. Most regions activated bilaterally but with stronger activation contralateral to the stimulus. Noxious cold stimulation produced significantly increased volumes of activation compared to noxious heat in prefrontal areas only. Our results suggest a similar network of regions activate common to the perception of pain produced by either noxious hot or cold stimulation.
Adult↗
Substance abuse intervention for health care workers: a preliminary report.
The Workplace Managed Care Cooperative Agreement project targets 3,300 health care professionals in hospital, specialty clinic, and primary care settings located in metropolitan New Mexico communities. This project will evaluate whether enhancements to existing substance abuse prevention/early intervention programs can prevent the onset of risky drinking, reduce prevalence of risky drinking, better identify employees who abuse alcohol and drugs, and improve employee wellness. This article describes one such enhancement (Project WISE [Workplace Initiative in Substance Education]), implemented at Lovelace Health Systems. Project WISE includes relatively low-cost elements such as substance abuse awareness training, information on how to reduce drinking, and brief motivational counseling. Evaluation will consist of baseline comparisons of the intervention and comparison sites, a process evaluation, a qualitative analysis using focus groups, and an outcome evaluation using health and work records. Methodological challenges, solutions, and implications for researchers undertaking similar projects are presented.
Counseling↗