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PubMed1994

The continuing important role of radionuclide generator systems for nuclear medicine.

In this review, the continuing importance and status of development of radionuclide generator systems for nuclear medicine are discussed. Radioisotope costs and availability are two important factors, and both nuclear reactors and accelerator facilities are required for production of the parent radioisotopes. Radionuclide generator research is currently focused on the development of generators which provide radioisotopes for positron emission tomography (PET) applications and daughter radioisotopes for various therapeutic applications which decay primarily by particle emission. Generator research continues to be influenced by developments and requirements of complementary technologies, such as the increasing availability of PET. In addition, the availability of a wide spectrum of tumor-specific antibodies, fragments, and peptides for radioimmunodiagnosis and radioimmunotherapy has stimulated the need for generator-derived radioisotopes. The advantages of treatment of arthritis of the synovial joints with radioactive particles (radiation synovectomy) may be expected to be of increasing importance as the elderly population increases, and many of these agents are prepared using generator-derived radioisotopes such as yttrium-90 and rhenium-188. Therapeutic use of the "in vivo generator" is a new approach, where the less radiotoxic parent radioisotope is used to prepare tissue-specific therapeutic agents. Following in vivo site localization, decay of the parent provides the daughter for therapy at the target site. The principal foundation of most diagnostic agents will continue to require technetium-99m from the molybdenum-99/technetium-99m ("Moly") generator. With the limited availability of nuclear reactors and facilities necessary for production and processing of fission 99mTc and the significant issues and problems associated with radioactive waste processing, however, the possibility of utilizing lower specific activity 99Mo produced from neutron activation of enriched 98Mo may become practical in the future.

Costs and Cost Analysis↗

PubMed2025

Generative AI Models in Time-Varying Biomedical Data: Scoping Review.

BACKGROUND: Trajectory modeling is a long-standing challenge in the application of computational methods to health care. In the age of big data, traditional statistical and machine learning methods do not achieve satisfactory results as they often fail to capture the complex underlying distributions of multimodal health data and long-term dependencies throughout medical histories. Recent advances in generative artificial intelligence (AI) have provided powerful tools to represent complex distributions and patterns with minimal underlying assumptions, with major impact in fields such as finance and environmental sciences, prompting researchers to apply these methods for disease modeling in health care. OBJECTIVE: While AI methods have proven powerful, their application in clinical practice remains limited due to their highly complex nature. The proliferation of AI algorithms also poses a significant challenge for nondevelopers to track and incorporate these advances into clinical research and application. In this paper, we introduce basic concepts in generative AI and discuss current algorithms and how they can be applied to health care for practitioners with little background in computer science. METHODS: We surveyed peer-reviewed papers on generative AI models with specific applications to time-series health data. Our search included single- and multimodal generative AI models that operated over structured and unstructured data, physiological waveforms, medical imaging, and multi-omics data. We introduce current generative AI methods, review their applications, and discuss their limitations and future directions in each data modality. RESULTS: We followed the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines and reviewed 155 articles on generative AI applications to time-series health care data across modalities. Furthermore, we offer a systematic framework for clinicians to easily identify suitable AI methods for their data and task at hand. CONCLUSIONS: We reviewed and critiqued existing applications of generative AI to time-series health data with the aim of bridging the gap between computational methods and clinical application. We also identified the shortcomings of existing approaches and highlighted recent advances in generative AI that represent promising directions for health care modeling.

Artificial Intelligence↗

PubMed2000

Simple new method for effective concentration of 188Re solutions from alumina-based 188W-188Re generator.

UNLABELLED: (188)Re is a useful generator-produced radioisotope currently under evaluation for a variety of therapeutic applications, including bone pain palliation and intravascular radiation therapy. Because the (188)W parent is available only in a relatively low specific activity (<0.15-0.19 GBq/mg) from reactor irradiation of enriched (186)W, relatively large volumes of 0.9% saline (>15 mL) are required for elution of the (188)Re daughter from traditional alumina-based (188)W-(188)Re generators. Because these large bolus volumes result in solutions with a relatively low specific volume activity of (188)Re (<1 GBq/mL for the 18.5-GBq generator), the availability of effective methods for eluent concentration is important. Our new approach is based on the use of 0.3 mol/L ammonium acetate as a representative salt of a weak acid instead of saline for generator elution. METHODS: After generator elution, the ammonium acetate generator eluent (15-20 mL) is passed through a tandem IC-H Plus cation (Dowex-H)-anion (QMA Light) column system. Exchange of ammonium cations with hydrogen ions on the cation column forms an acetic acid solution containing perrhenate anions from which the macroscopic levels of the acetate anion of the eluent have been effectively removed. Because perrhenic acid is fully dissociated at this pH, the QMA Light column specifically traps the (188)Re-perrhenate, which is subsequently eluted with a low volume (<1 mL) of saline. Concentration ratios greater than 20:1 are readily achieved with this method. RESULTS: A typical clinical-scale generator loaded with 19.2 GBq (188)W was used to validate the approach. Saline elution provided (188)Re in a 75%-80% yield. Although elution with 0.15 mol/L NH4OAc gave lower yields (55%-60%), use of 0.3 mol/L NH4OAc provided yields comparable with those of saline (70%-75%). (188)W parent breakthrough was not detected after passage of the bolus through the tandem concentration system. Bolus volumes of 15-20 mL, which initially contained as much as 11.1-14.8 GBq (188)Re, were readily concentrated to less than 1 mL saline using QMA Light cartridges. The generator was evaluated for more than 3 mo with no decrease in performance. CONCLUSION: This approach represents a simple, rapid, and effective method using inexpensive disposable components of concentrating solutions of (188)Re for preparation of therapeutic agents.

Aluminum Oxide↗

PubMed2000

Characterization of MHC class II-presented peptides generated from an antigen targeted to different endocytic compartments.

We evaluated the capacity of the secretory pathway or of different endocytic compartments in B cell lines to generate MHC class II-presented peptides from the antigen ovalbumin (OVA). Sorting signals from the transferrin receptor (TFR), targeted a chimeric OVA fusion protein to early endosomes and led to the generation of 8 of 12 presented peptides. Sorting signals from the lysosome-associated membrane protein 1 (LAMP-1), targeted an OVA fusion protein to lysosomes, and led to the generation of 9 of 12 peptides. In contrast, OVA with only a signal sequence led to the generation of only 2 presented peptides. There were both qualitative and quantitative differences in the generation of peptides from the different fusion proteins, suggesting that multiple distinct compartments are involved in generating different epitopes. One peptide was presented better from the TFR fusion protein, while all others were presented better from the LAMP-1 construct. Twelve peptides were generated from exogenously supplied OVA, including 3 peptides that were not generated from any of the fusion proteins. Since most endogenously synthesized foreign antigens are rarely presented on class II molecules, these studies further suggest a strategy whereby antigens in DNA-based vaccines could be targeted to endocytic compartments to enhance immunogenicity.

Antigen Presentation↗

PubMed1977

The pacemaker-twiddler's syndrome: another disadvantage of abdominal implantation of pulse generators.

Breakage of a pacer lead due to the pacemaker-twiddler's syndrome (PTS) occurred in 4 of 62 survivors following epicardial-intramural pacer lead implantation with the pulse generator placed in each case in a subcostal left upper quadrant subcutaneous pocket. The abdominal pulse generator pocket appears to invite spontaneously occurring PTS, more so in a pregnant woman. The important predisposing factor to the development of PTS is an excessively spacious pulse generator pocket containing a pool of fluid. Addition of a few simple modifications to the technique of cardiac pacing would prevent the complication; these include implantation of the pulse generator in a plane deeper to the pectoral muscles, suspending the pulse generator from the clavicle and application of vacuum-suction drainage to the generator pocket in the initial phase of wound healing. In the presence of an optimally fitting pulse generator pocket, PTS should be rare with subclavicular subpectoral pulse generator implantation without active patient participation. The syndrome may not be as rare a cause of pacer lead malfunction as may appear from the relative paucity of reports in the literature.

Abdomen↗

PubMed1979

The generation of neurons involved in an early reflex pathway of embryonic mouse spinal cord.

The generation of lateral motor neurons (LMNs), interneurons and dorsal root ganglion (DRG) neurons of the cervical mouse spinal cord has been investigated by [3H]thymidine autoradiographic techniques. This investigation has two main objectives: (a) to determine on which embryonic days these three neuronal populations are born, and (b) to investigate the possibility that the neurons comprising early reflex circuits might be formed by a retrograde temporal sequencing of generation. LMNs are the first neurons generated in the cervical spinal cord. They arise between E8.8 and E11.5, and approximately 90% of these cells are born within a 36-hour period between E9 and E10.5. The earliest time of origin for interneurons is on E9.5, and those cells which are generated between E9.5 and E10.5 cluster in two distinct regions of the adult spinal cord. One of these regions is the lateral portions of laminae IV through VI; this appears to be the location of many ipsilateral association neurons. DRG neurons begin to arise on E9.5 and their generation is completed by E14. There is a trend within the DRG population for large neurons to be born before small neurons. Those cells with diameters of 40 micron or greater reach their generation peak on E10.5, while those smaller than 40 micron arise in the greatest numbers on E12. The findings of other investigations have provided evidence for a retrograde sequence of synaptic closure in the formation of the early disynaptic forelimb reflex pathway. The temporal difference in synapse formation in the terminal fields of DRG and association neurons is discussed in terms of our observation that both of these populations appear to have similar generation times. We suggest that factors responsible for the delayed synaptic closure of DRG afferents include the greater distances and the degree of collateralization which these afferents must undergo in order to establish their terminal fields. Finally, we discuss the possibility that the temporal sequence of neuronal generation and factors involved with the growth of neurites combine to produce a retrograde sequence of synaptic closure in the early disynaptic forelimb reflex pathway of mouse spinal cord.

Animals↗

PubMed2006

Thrombin generation in patients with cirrhosis: the role of platelets.

Coagulation factor defects, thrombocytopenia, and thrombocytopathy are associated with cirrhosis. However, bleeding in patients who have cirrhosis does not entirely correlate with abnormal coagulation tests. Recently, it was shown that because of the concomitant abnormalities of the procoagulant and anticoagulant drives, thrombin generation in plasma patients with cirrhosis is normal when assessed with assays that include thrombomodulin (the main protein C activator). However, thrombin is also generated in vivo as a function of platelets, suggesting that thrombocytopenia and thrombocytopathy might affect thrombin generation in patients with cirrhosis. We addressed this issue using an assay that accounts for the contribution of plasma and platelets. The study showed that platelet-rich plasma with platelets adjusted by dilution of autologous platelet-rich into autologous platelet-poor plasma to a standard count (100 x 10(9)/L) generates as much thrombin in patients with cirrhosis as in controls (1,063 nmol/L vs. 1,167 nmol/L; P value not significant). When platelets were adjusted to correspond to whole-blood counts, patients with cirrhosis generated significantly less thrombin than controls (949 nmol/L vs. 1,239 nmol/L; P < .001). Furthermore, thrombin generation correlated with platelet numbers (rho = 0.50; P < .001). In addition, the amount of thrombin generated as a function of the whole-blood patients' platelet counts increased significantly when the numbers were adjusted to 100 x 10(9)/L (953 nmol/L vs.1,063 nmol/L; P < .001). In conclusion, severe thrombocytopenia may limit thrombin generation in patients with cirrhosis. These findings might justify platelet transfusion in patients with low platelet counts when they bleed spontaneously or before undergoing surgery or liver biopsy. Controlled clinical trials supporting this indication are warranted.

Adult↗

PubMed1991

Effect of tumor necrosis factor on the generation of chlorinated oxidants by adherent human neutrophils.

Human neutrophils adherent to simulated biologic surfaces undergo significant activation of the respiratory burst over prolonged periods of time in response to stimulation with the cytokines tumor necrosis factor-alpha (TNF alpha) or tumor necrosis factor-beta (TNF beta) or with the chemotactic peptide N-formyl-methionylleucylphenylalanine (FMLP). In this study, neutrophils were examined for their ability to generate the highly reactive and powerful oxidant hypochlorous acid (HOCl) and the longer-lived, less reactive endogenous nitrogen-chlorine (N-Cl) derivatives in response to these stimuli either alone or when exposed to recombinant human TNF alpha (rTNF alpha) or beta (rTNF beta) prior to addition of FMLP. Neutrophils adherent to fetal bovine serum-coated polystyrene tissue culture wells were able to generate only small quantities of HOCl when incubated with rTNF alpha, rTNF beta, or FMLP individually. However, when neutrophils were first incubated with either rTNF alpha or rTNF beta prior to addition of FMLP, there was a marked increase in HOCl generation. Neutrophils stimulated in such a manner consumed approximately 18% of the HOCl generated in the formation of N-Cl derivatives. Further scrutiny of the response to the combination of rTNF alpha and FMLP revealed that HOCl release was rapid, with 80% of total HOCl accumulation occurring within 15 min after FMLP addition. The amount of HOCl generated was dependent on the number of cells added and on the concentration of both rTNF alpha and FMLP. Comparison of HOCl generation with superoxide anion and myeloperoxidase release showed that the amount of HOCl generated was limited primarily by the amount of myeloperoxidase released rather than by the degree of respiratory burst activation. These results demonstrate that human neutrophils stimulated with FMLP after a brief incubation with rTNF alpha or rTNF beta can generate cytotoxic and microbicidal concentrations of chlorinated oxidants.

Cell Adhesion↗

PubMed1992

C-reactive protein selectively enhances the intracellular generation of reactive oxygen products by IgG-stimulated monocytes and neutrophils.

The acute phase protein, C-reactive protein (CRP), when heat-aggregated (Agg-CRP), potentiates immunoglobulin G (IgG) Fc receptor-mediated luminol-enhanced chemiluminescence (CL) in human monocytes and neutrophils. Luminol-CL is a sensitive measure of phagocyte respiratory burst activity; however, the nature of oxidative products contributing to the light emission and their site of generation remain incompletely defined. To more precisely describe the oxidative burst of monocytes and neutrophils to Agg-CRP, superoxide anion release was measured by cytochrome c reduction. In addition, the extracellular release of hydrogen peroxide was distinguished from hydrogen peroxide generation using a phenol red oxidation assay. Finally, a flow cytometric determination of dichlorofluorescein (DCFH) oxidation was employed as an index of intracellular peroxide production. Although Agg-CRP alone did not stimulate hydrogen peroxide generation by either monocytes or neutrophils, it significantly enhanced hydrogen peroxide generation in response to heat-aggregated IgG (Agg-IgG). In contrast, Agg-CRP did not enhance the extracellular release of either hydrogen peroxide or superoxide anion from Agg-IgG-stimulated cells. The capacity of Agg-CRP to enhance selectively intracellular oxidative product generation was confirmed when measuring DCFH oxidation in Agg-IgG-stimulated cells. To evaluate whether this selective enhancement of intracellular oxidative events could be attributed, at least in part, to a scavenging effect of Agg-CRP, a cell-free oxygen radical-generating system was employed. Agg-CRP did not significantly diminish the lucigenin-amplified CL response induced by the xanthine/xanthine oxidase reaction. These results indicate that although Agg-CRP enhances the intracellular generation of reactive oxygen intermediates by monocytes and neutrophils, extracellular release of those products is not influenced by cell interaction with Agg-CRP. It is tempting to speculate that CRP can selectively boost the microbicidal activities of monocytes and neutrophils within an inflammatory site by amplifying the intracellular generation of reactive oxygen products without increasing damage to surrounding normal tissues.

Acridines↗

PubMed2003

Temperature controlled burn generation system based on a CO2 laser and a silver halide fiber optic radiometer.

BACKGROUND AND OBJECTIVES: Experimental animal study of burns is dependent on a reliable burn generation system. Most of the experimental systems used today are unable to produce precise partial thickness burns. This limits the ability to study minor changes associated with burn care. The aim of the study was to develop a method for generating burns with a fixed depth using a CO2 laser burn generation system. MATERIALS AND METHODS: The burn generation system was composed of two components: a burn generation device and a temperature sensing and control system. These components were designed to operate together in order to keep a constant, predetermined skin surface temperature during prolonged burn generation. One hundred thirty-eight spot burns were generated on the back of five shaved 450 g male Wistar rats. The rat skin was exposed to a 70 degrees C for 5-60 seconds. The burned areas were excised and underwent evaluation by hematoxylin-eosin-stained slide microscopy. RESULTS: A linear correlation was found between the duration of exposure and the average burn depth (r = 0.93). This correlation is represented by the equation: burn depth in millimeters = 0.012x (duration in seconds of skin exposure at 70 degrees C). CONCLUSIONS: The fiber-optic-controlled laser burn generation system studied is a reliable tool for creating partial thickness as well as full thickness skin burns in rats.

Animals↗

PubMed1980

Investigation of burst generation by the electrically coupled cyberchron network in the snail Helisoma using a single-electrode voltage clamp.

This paper describes the results of investigating burst generation by the cyberchron network in the snail Helisoma. The cyberchron network is composed of aproximately 20 electrically coupled neurons and controls the feeding behavior of the snail. The electrical coupling between network members has made it particularly difficult to distinguish between the importance and involvement of single-cell and network properties in burst generation by this system. The present investigations utilized the new single-electrode voltage clamp to examine the membrane properties and network interactions of the cyberchron neurons: (1) A slow outward current is activated by moderately large depolarizing commands (-40 to 0 mV) and does not undergo inactivation decay (i.e., decline in magnitude) during a command potential step maintained for 10 sec or more. The lack of inactivation of the outward current in cyberchron neurons appears to be due to the dominating role of a Ca-dependent K current. (2) There are two functionally distinct classes of cyberchrons--current generator cyberchrons and follower cyberchrons. (3) Primary current generator cyberchrons have membrane properties similar to endogenous bursting neurons (e.g., persistent inward Ca current and negative resistance region in I-V plot) and appear to provide the main driving and timing current for the rest of the network. (4) The vast majority of cyberchrons are secondary current generator cyberchrons with membrane properties which exhibit inward-going rectification and appear to burst as a result of regenerative excitation with one another and the primary current generator cyberchrons. (5) The second class of cyberchrons are driven by the electrical synaptic input from the current generator cyberchrons, do not exhibit inward-going rectification, and are called follower cyberchrons. (6) Burst termination is due to activation of a slow outward tail current in most cyberchrons during the burst (probably Ca-activated K current) which causes a hyperpolarization in individual cyberchrons, terminating the burst. (7) Decay of the outward tail current causes the cyberchrons to depolarize, which activates the persistent inward Ca current in the primary current generator cyberchrons, starting the burst cycle anew.

Action Potentials↗

PubMed1993

Vanadate-mediated hydroxyl radical generation from superoxide radical in the presence of NADH: Haber-Weiss vs Fenton mechanism.

The mechanism of hydroxyl (.OH) radical generation from O2- and H2O2 by vanadate [V(V)] and the role of NADH in this reaction have been investigated using electron spin resonance (ESR) and spin trapping techniques. The results show that the reaction of V(V) with O2- (generated via xanthine/xanthine oxidase) does not generate any ESR detectable V(IV) ion or .OH radical and the addition of H2O2 has little effect on the radical yield. In the presence of NADH, however, the xanthine/xanthine oxidase/V(V) system generates .OH as well as V(IV), the formation of both of which could be suppressed by superoxide dismutase. Catalase inhibits the .OH formation but enhances V(IV) generation. Reaction of V(V) with NADH alone in the presence of phosphate buffer also causes .OH radical generation albeit at a much reduced rate, and superoxide dismutase reduces the .OH yield. These observations indicate, in contrast to earlier reports, that O2- does not reduce V(V) to V(IV) in the absence of NADH. It is concluded that vanadate generates the .OH radical via not a Haber-Weiss but a Fenton-like reaction [V(IV) + H2O2-->V(V) + .OH+OH-], the V(IV) and H2O2 being generated by V(V)-stimulated, O(2-)-dependent NADH oxidation.

Cyclic N-Oxides↗

PubMed1997

One-electron reduction of chromium(VI) by alpha-lipoic acid and related hydroxyl radical generation, dG hydroxylation and nuclear transcription factor-kappaB activation.

Reaction of chromium(VI) with alpha-lipoic acid (reduced form, also called 1,2-dithiolane-3-pentanoic acid) generated Cr(V) and hydroxyl radical (*OH) as measured by electron spin resonance and ESR spin trapping. 5,5-Dimethyl-1-pyrroline was used as a spin trapping agent. Catalase inhibited the *OH generation and enhanced the Cr(V) formation. Superoxide dismutase had an opposite effect. H2O2 enhanced the *OH generation and decreased the Cr(V) formation in a dose-dependent manner. Metal chelators, EDTA, diethylenetriaminepentaacetic acid, deferoxamine, and 1, 10-phenanthroline inhibited *OH radical generation in the order of EDTA > 1,10-phenanthroline > DTPA > deferoxamine. Oxygen consumption measurements indicated that molecular oxygen was used to generate *OH radical in the mixture of Cr(VI) and alpha-lipoic acid. H2O2 and superoxide radical (O2-) were involved as reactive intermediates. The *OH radical was generated via Cr(V)-mediated Fenton-like reaction (Cr(V) + H2O2 --> Cr(VI) + OH- + *OH). HPLC measurements show that the *OH radical generated by this reaction is capable of generating 8-hydroxyl-2'-deoxyguanosine from 2-deoxyguanosine. Incubation of Cr(VI) with cultured Jurkat cells resulted in an activation of DNA binding activity of the nuclear factor (NF)-kappaB. Addition of alpha-lipoic acid enhanced the NF-kappaB activation, while the *OH radical scavenger, sodium formate, inhibited it, showing that alpha-lipoic acid enhanced Cr(VI)-induced NF-kappaB activation via free radical reactions. The results indicate that while alpha-lipoic acid is considered to be an antioxidant, it may be a cellular one-electron Cr(VI) reductant and could be involved in the mechanism of Cr(VI)-induced carcinogenesis.

Antioxidants↗

PubMed2001

Effect of six compounds isolated from rhizome of Anemone raddeana on the superoxide generation in human neutrophil.

The effect of six compounds isolated from rhizome of Anemone raddeana on the superoxide generation in human neutrophils was investigated. The six compounds examined were 3-acetyloleanolic acid (AOA), oleanolic acid (OA), eleutheroside K (EK), oleanolic acid-3-O-alpha-L-rhamnopyranosyl-(1 --> 2)-[beta-D-glucopyranosyl-(1 --> 4)]-alpha-L-arabinopyranoside (Rd10), raddeanoside 12 (Rd12) and raddeanoside 13 (Rd13). AOA, OA, Rd12 and Rd13 suppressed the superoxide generation induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) in a concentration-dependent manner. EK and Rd10 significantly enhanced the fMLP-induced superoxide generation in a specific narrow range of low concentration (0.5-0.75 microM), while these compounds more efficiently suppressed the superoxide generation than the other four compounds in other concentrations. In the case of superoxide generation induced by phorbol 12-myristate 13-acetate (PMA), Rd12, OA, EK and Rd10 dose-dependently suppressed the superoxide generation but AOA and Rd13 gave no effect. Arachidonic acid-induced superoxide generation was suppressed by EK, Rd10, Rd12 and Rd13, but was weakly enhanced by AOA and OA. Rd12 dose-dependently inhibited fMLP-induced tyrosyl phosphorylation of 123.0, 79.4, 60.3, 56.2 and 50.1 kDa proteins in human neutrophil. On the other hand, RD10 and EK enhanced the tyrosyl phosphorylation of these proteins in a low concentration range. These phenomena were parallel to the suppression of the fMLP-induced superoxide generations.

Drugs, Chinese Herbal↗

PubMed1999

Verb generation priming involves conceptual implicit memory.

Brain activation patterns differ and generation latencies are reduced when generating verbs to repeated nouns (Raichle et al., 1994). Amnesic participants show normal magnitude of priming (Seger et al., 1997). Despite its importance in neuropsychology, verb generation priming is not well characterized psychologically. Six behavioral studies found that verb generation priming was specific to the verb rather than to the noun or the noun-verb pair, was equivalent after overt or covert generation and after reading verbs or generating verbs, was affected by levels of processing, and transferred completely across languages in bilinguals. These results indicate that verb generation priming involves priming of particular responses and happens at a conceptual level. These findings provide new insights about the significance of brain imaging and neuropsychological studies involving verb generation priming.

Analysis of Variance↗

PubMed2000

Interferon-gamma and interleukin 4 inhibit interleukin 1beta-induced delayed prostaglandin E(2)generation through suppression of cyclooxygenase-2 expression in human fibroblasts.

Interleukin (IL-)1 stimulates prostaglandin E(2)(PGE(2)) generation in fibroblasts, and preferential couplings between particular phospholipase A(2)(PLA(2)) and cyclooxygenase (COX) isozymes are implicated with IL-1-induced delayed PGE(2)generation. The regulatory effects of interferon (IFN)-gamma and IL-4 on IL-1beta-induced COX, PLA(2)isoforms expression and terminal delayed PGE(2)generation were examined in three types of human fibroblasts. These human fibroblasts constitutively expressed cytosolic PLA(2)(cPLA(2)) and COX-1 enzymes, and exhibited delayed PGE(2)generation in response to IL-1beta. IL-1beta also stimulated expression of cPLA(2)and COX-2 only, while constitutive and IL-1beta-induced type IIA and type V secretory PLA(2)s (sPLA(2)s) expression could not be detected. A COX-2 inhibitor and cPLA(2)inhibitor markedly suppressed the IL-1beta-induced delayed PGE(2)generation, while a type IIA sPLA(2)inhibitor failed to affect it. IFN-gamma and IL-4 dramatically inhibited the IL-1beta-induced delayed PGE(2)generation; these cytokines apparently suppressed IL-1beta-stimulated COX-2 expression and only weakly suppressed cPLA(2)expression in response to IL-1beta. These results indicate that IL-1beta-induced delayed PGE(2)generation in these human fibroblasts mainly depends on de novo induction of COX-2 and cPLA(2), irrespective of the constitutive presence of COX-1, and that IFN-gamma and IL-4 inhibit IL-1beta-induced delayed PGE(2)generation by suppressing, predominantly, COX-2 expression.

Adult↗

PubMed1996

The effect of dimethoate on bone marrow cell chromosomes of rats in subchronic four-generation experiments.

The effect of the insecticide dimethoate (O,O-dimethyl S-/N-methylcarbamoylmethyl phosphorodithioate) on bone marrow cells of four generations of rats was investigated. Male and female Wistar rats were treated for 6 weeks with 5 treatments per week via gavage at doses of 7.0, 9.33, and 14.0 mg/kg (1/ 100, 1/75, and 1/50 of the LD50). Chromosomes of 10 of the treated males were prepared. Other males (6-8 males per dose) were paired with females (11-16 females per dose). This represented the first (P) generation. During pregnancy and lactation females were treated with adequate doses of dimethoate. In F1 (70 males and 56 females), F2 (71 males and 62 females), and F3 generations (62 males and 44 females) treatment with dimethoate and the preparation of chromosomes (40 males per generation) were the same as those in the P generation. Following treatment with dimethoate in P and F1 generations, the number of numerical chromosome aberrations increased significantly. No significant changes in chromosome aberrations were found in F2 and F3 generations compared to the control groups. The frequency of numerical chromosome aberrations decreased considerably compared to the P generation at the dose of 14.0 mg/kg (1/50 of LD50).

Animals↗

PubMed1997

Cellular mechanisms of reactive oxygen metabolite generation from human polymorphonuclear leukocytes induced by crocidolite asbestos.

In our previous study, we demonstrated that reactive oxygen metabolites (ROM) generation from phagocytic cells may be involved in the carcinogenic mechanism of crocidolite asbestos. In the present study, the mechanism of human polymorphonuclear leukocytes (PMN) to generate ROM by crocidolite was investigated using verapamil, a calcium channel inhibitor; staurosporine, a NADPH oxidase inhibitor; and cytochalasin B (CB), an inhibitor of phagocytosis. The results indicate that whereas verapamil and staurosporine inhibited the crocidolite-induced ROM generation from PMN dose-dependently, CB caused an enhancement. We conclude that crocidolite-induced ROM generation involves a cell surface reaction due to influx of extracellular calcium through calcium channels and the activation of NADPH oxidase on the PMN cell membrane. This hypothesis was indirectly supported by dose-dependent enhancement of the ROM generation by CB, as CB increases calcium ion permeability in PMN. However, as in our previous studies, the time course of the ROM generation and the cell type difference suggested that ROM were also generated intracellularly from PMN due to phagocytosis of crocidolite. In conclusion, our evidence indicates that ROM generation from PMN by crocidolite involves cellular mechanisms related both to direct cell surface membrane interactions, together with an apparent phagocytic-dependent process.

Asbestos, Crocidolite↗