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PubMed2005

Blockade of arachidonic acid incorporation into phospholipids induces apoptosis in U937 promonocytic cells.

Arachidonic acid (AA) participates in a reacylation/deacylation cycle of membrane phospholipids, the so-called Lands cycle, that serves to keep the concentration of this free fatty acid in cells at a very low level. To manipulate the intracellular AA level in U937 phagocytes, we have used several pharmacological strategies to interfere with the Lands cycle. We used inhibitors of the AA reacylation pathway, namely thimerosal and triacsin C, which block the conversion of AA into arachidonoyl-CoA, and a CoA-independent transacylase inhibitor that blocks the movement of AA within phospholipids. In addition, we used cells overexpressing group VIA phospholipase A(2), an enzyme with key roles in controlling basal fatty acid deacylation reactions in phagocytic cells. All of these different strategies resulted in the expected increase of cellular free AA but also in the induction of cell death by apoptosis. Moreover, when used in combination with any of the aforementioned drugs, AA itself was able to induce apoptosis at doses as low as 10 muM. Blocking cyclooxygenase or lipoxygenases had no effect on the induction of apoptosis by AA. Collectively, these results indicate that free AA levels within the cells may provide an important cellular signal for the onset of apoptosis and that perturbations of the mechanisms controlling AA reacylation, and hence free AA availability, may decisively affect cell survival.

Acyl Coenzyme A↗
PubMed1994

Spatiotemporal dynamics of intracellular [Ca2+]i oscillations during the growth and meiotic maturation of mouse oocytes.

Calcium oscillations occur during meiotic maturation of mouse oocytes. They also trigger activation at fertilization. We have monitored [Ca2+]i in oocytes at different stages of growth and maturation to examine how the calcium release mechanisms alter during oogenesis. Spontaneous calcium oscillations occur every 2-3 minutes in the majority of fully grown (but immature) mouse oocytes released from antral follicles and resuming meiosis. The oscillations last for 2-4 hours after release from the follicle and take the form of global synchronous [Ca2+]i increases throughout the cell. Rapid image acquisition or cooling the bath temperature from 28 degrees C to 16 degrees C did not reveal any wave-like spatial heterogeneity in the [Ca2+]i signal. Calcium appears to reach highest levels in the germinal vesicle but this apparent difference of [Ca2+] in nucleus and cytoplasm is an artifact of dye loading. Smaller, growing immature oocytes are less competent: about 40% are able to resume meiosis and a similar proportion of these oocytes show spontaneous calcium oscillations. [Ca2+]i transients are not seen in oocytes that do not resume meiosis spontaneously in vitro. Nonetheless, these oocytes are capable of [Ca2+]i oscillations since they show them in response to the addition of carbachol or thimerosal. To examine how the properties of calcium release change during meiotic maturation, a calcium-releasing factor from sperm was microinjected into fully grown immature and mature oocytes. The sperm-factor-induced oscillations were about two-fold larger and longer in mature oocytes compared to immature oocytes. Calcium waves travelling at 40-60 microns/second were generated in mature oocytes, but not in immature oocytes. In some mature oocytes, successive calcium waves had different sites of origin. The modifications in the size and spatial organization of calcium transients during oocyte maturation may be a necessary prerequisite for normal fertilization.

Animals↗
PubMed1995

Repetitive sperm-induced Ca2+ transients in mouse oocytes are cell cycle dependent.

Mature mouse oocytes are arrested at metaphase of the second meiotic division. Completion of meiosis and a block to polyspermy is caused by a series of repetitive Ca2+ transients triggered by the sperm at fertilization. These Ca2+ transients have been widely reported to last for a number of hours but when, or why, they cease is not known. Here we show that Ca2+ transients cease during entry into interphase, at the time when pronuclei are forming. In fertilized oocytes arrested at metaphase using colcemid, Ca2+ transients continued for as long as measurements were made, up to 18 hours after fertilization. Therefore sperm is able to induce Ca2+ transients during metaphase but not during interphase. In addition metaphase II oocytes, but not pronuclear stage 1-cell embryos showed highly repetitive Ca2+ oscillations in response to microinjection of inositol trisphosphate. This was explored further by treating in vitro maturing oocytes at metaphase I for 4-5 hours with cycloheximide, which induced nuclear progression to interphase (nucleus formation) and subsequent re-entry to metaphase (nuclear envelope breakdown). Fertilization of cycloheximide-treated oocytes revealed that continuous Ca2+ oscillations in response to sperm were observed after nuclear envelope breakdown but not during interphase. However interphase oocytes were able to generate Ca2+ transients in response to thimerosal. This data suggests that the ability of the sperm to trigger repetitive Ca2+ transients in oocytes is modulated in a cell cycle-dependent manner.

Animals↗
PubMed1996

Transient release of calcium from inositol 1,4,5-trisphosphate-specific stores regulates mouse preimplantation development.

Inositol 1,4,5-trisphosphate can regulate growth and differentiation by modulating the release of intracellular Ca2+ in a variety of cellular systems, and it is involved in oocyte activation. Recent studies suggest that mammalian preimplantation development may also be regulated by the release of Ca2+ from intracellular stores. The rate of cavitation and cell division was accelerated after a transient elevation of intracellular Ca2+ levels was induced in morulae by exposure to ethanol or ionomycin. Embryos exposed to BAPTA-AM, a chelator of intracellular Ca2+, exhibited a brief dose-dependent reduction in basal Ca2+ levels, a temporal inhibition of ionophore-induced Ca2+ signalling and a subsequent delay in blastocoel formation. BAPTA-AM at 0.5 microM did not significantly alter the basal intracellular calcium level, but chelated Ca2+ that was released after ethanol exposure and thereby attenuated the ethanol-induced acceleration of cavitation. BAPTA-AM also inhibited cell division to the 16-cell stage in a dose-dependent manner, which correlated with the inhibition of cavitation. Thimerosal and inositol 1,4,5-trisphosphate significantly elevated the intracellular Ca2+ concentration in mouse morula-stage embryos, providing evidence for the existence of inositol 1,4,5-trisphosphate-sensitive Ca2+ stores. Although caffeine failed to release intracellular Ca2+, ryanodine induced a small biphasic release of Ca2+, suggesting that ryanodine-sensitive Ca2+ stores may also exist in mouse embryos. Morulae exposed to the calmodulin inhibitor W-7 exhibited a dose-dependent delay in blastocoel formation. A 4 hour exposure to 10 microM W-7 did not significantly alter cavitation, but attenuated the ionophore-induced stimulation of blastocoel formation. This finding suggests that the developmental effects produced through Ca2+ signalling are mediated by calmodulin. Our results demonstrate that Ca2+ release in mouse morulae occurs predominantly through the inositol 1,4,5-trisphosphate receptor, and that alteration of intracellular Ca2+ levels can accelerate or delay embryonic growth and differentiation, providing a mechanistic link between the regulation of oocyte and embryonic development.

Animals↗
PubMed1993

Development of screening tests for aneuploidy induction by environmental pollutants.

When legally required mutagenicity testing of chemicals is undertaken, the important genetic end point of aneuploidy is not included because validated test methods are lacking. Therefore, the Commission of the European Communities (CEC) has funded a research program to develop and validate tests for aneuploidy induction. Ten chemicals, selected on the basis of their ability to interact with cell organelles relevant for aneuploidy induction, were tested in 11 laboratories. The assays ranged from in vitro tubulin assembly studies to in vivo germ-cell tests. The results allow several conclusions: a) Fungal aneuploidy tests are not capable of detecting inhibitors of mammalian tubulin polymerization such as colchicine and vinblastine. Therefore, they will not play a role in screening for aneuploidy but are of value for studying the relationship between induced aneuploidy and recombination. b) Chemicals that induce aneuploidy in mammalian germ cells are readily detected in the in vitro mammalian cell systems. Some chemicals such as thiabendazole and thimerosal induce aneuploidy in vitro but do not appear to be very effective in vivo. c) Cell division aberrations induced in mammalian cells in vitro seem to be predictive for aneuploidy induction in the same cell type. Likewise, c-mitotic effects and cell cycle delay in vivo in mitotic and meiotic cells correlate with aneuploidy induction in the respective tissue. A second CEC Aneuploidy Program has started recently to refine the most promising test protocols, to provide understanding of variety of mechanisms by which chemicals induce aneuploidy, and to establish a data base for aneugens among environmental pollutants.

Aneuploidy↗
PubMedDate not supplied

Further investigations on the p-nitrophenylphosphatase activity of intact Ehrlich ascites tumor cells.

The substrate specificity and the effects of nucleotides and SH-blocking agents on the p-nitrophenylphosphatase activity of intact Ehrlich ascites tumor cells (EAT) cells were studied. DL-beta-Glycerophosphate, o-phosphoethanolamine, cholinephosphate, glucose-6-phosphate, o-carboxyphenylphosphate,, phosphoenolpyruvate and AMP were not attacked by intact cells. ATP is greater than GTP is greater than UPT is greater than PPi is greater than pNPP were cleaved with decreasing velocity. A stimulation of the cleavage of p-NPP by the following nucleotides was observed with decreasing effectivity: ATP is greater than ADP is greater than GTP is greater than UTP; AMP was ineffective. The phosphatase activity was not affected by malate, tartrate and glutathion disulfide. The SH blocking agents diamide and thimerosal were more effective inhibitors of the pNPPase than of the ATPase activity, whereas the hydrolysis of ATP is more affected by the ATP analog adenylylimidodiphosphate. The present data are best compatible with a double headed enzyme: Both active sites interact with ATP, only one is active against p-NPP and sensitive against SH-blocking agents.

4-Nitrophenylphosphatase↗
PubMed2003

A review of hepatitis B vaccination.

Hepatitis B is one of the most important infectious causes of acute and chronic liver disease both in the US and worldwide. In order to combat the life-threatening effects of hepatitis B infection, recombinant hepatitis B vaccines have been developed. The medical and scientific communities have generally accepted that recombinant hepatitis B vaccine - a highly purified, genetically engineered, single antigen vaccine - is a safe vaccine. Information is presented showing that hepatitis B vaccine contains yeast, aluminium, thimerosal and hepatitis B surface antigen epitopes, which may result in hepatitis B vaccine being associated with autoimmune diseases among susceptible adult vaccine recipients. There is little doubt that the benefits of this vaccine overall far outweigh its risks. Physicians and patients should evaluate the risks and benefits of hepatitis B vaccination and, together, make an informed consent decision as to whether to undergo vaccination. Individuals who experience an adverse reaction to hepatitis B vaccination should report it to the Vaccine Adverse Event Reporting System database and be advised that they may be eligible for compensation from the no-fault National Vaccine Injury Compensation Program, administered by the US Court of Claims. The authors strongly urge that additional research be conducted into the molecular basis of adverse events following hepatitis B vaccine administration, so that further recommendations may be made on how to improve their safety profiles.

Adult↗
PubMed2004

Epidermal growth factor activates cytosolic [Ca2+] elevations and subsequent membrane permeabilization in mouse cumulus-oocyte complexes.

The role of epidermal growth factor (EGF) in the maturation of mammalian oocytes is well known but not well characterized. It is known that EGF enhances oocyte maturation in vitro and that EGF stimulation of cumulus-oocyte complexes (COCs) induces pulsatile Ca(2+) efflux from the cell complex. By use of quantitative Fura-2 imaging, EGF-stimulated changes in intracellular [Ca(2+)] in germinal vesicle stage murine COCs are shown to occur in a subpopulation of cumulus cells that interact cooperatively within individual COCs. Oocytes fail to respond to EGF stimulus. In many of the cumulus cells responding with a rise in intracellular [Ca(2+)], a concomitant permeabilization of the plasma membrane is found. Neither cumulus cells of control COCs nor those that show a rise in intracellular [Ca(2+)] in response to calcium ionophore treatment display a similar membrane permeabilization, although those cells responding with a prolonged [Ca(2+)] increase in response to thimerosal or thapsigargin do display plasma membrane permeabilization. Thus, EGF stimulation of mammalian COCs activates release of Ca(2+) from intracellular stores of cumulus cells, the depletion of which activates permeabilization of the plasma membrane. This membrane permeabilization leads to loss of cell contents and presumptive cumulus cell death. This catastrophic EGF-induced plasma membrane permeabilization of individual cumulus cells within a COC leads to pulsatile Ca(2+) efflux as previously seen, and may lead to improved cumulus cell expansion during COC maturation.

Animals↗
PubMed2005

Intracellular calcium and protein tyrosine phosphorylation during the release of bovine sperm adhering to the fallopian tube epithelium in vitro.

In mammals, sperm adhesion to the epithelial cells lining the oviductal isthmus plays a key role in the maintenance of motility and in the selection of superior quality subpopulations. In the bovine species, heparin and other sulfated glycoconjugates powerfully induce the synchronous release of sperm adhering to tubal epithelium in vitro and may represent the signal which triggers release at ovulation in vivo. Sperm detachment may be due either to surface remodeling or to hyperactivation brought about by capacitation. In this paper, the dynamics of intracellular free Ca2+concentration ([Ca2+]i) and protein tyrosine phosphorylation in sperm during and after heparin-induced release from in vitro cultured oviductal monolayers were assessed to determine whether this event is due to capacitation. Moreover, Ca2+-ionophore A23187, thapsigargin, thimerosal and caffeine were used to determine whether [Ca2+]i increase and/or hyperactivation can induce sperm release. Results showed that: 1. heparin-released sperm have significantly higher [Ca2+]i than adhering sperm; 2. heparin induces a [Ca2+]i elevation in the sperm head followed by detachment from the monolayers; 3. external Ca2+is not required for heparin-induced release; 4. [Ca2+]i increase and/or hyperactivation are unable to release sperm; and 5. heparin-released sperm have an increased level of tyrosine phosphorylated proteins compared with adhering sperm. In conclusion, although heparin is considered a long-lasting capacitation agent, it quickly modulates the capacitation of bovine sperm adhering to the fallopian epithelium, probably leading to surface remodeling and therefore to the release of sperm selected and stored within the oviduct through adhesion.

Animals↗
PubMed2000

Does sensitization to contact allergens begin in infancy?

OBJECTIVE: Because previous studies have found allergic contact sensitization common in children by 5 years of age, our aim was to determine the prevalence of positive epicutaneous test results in children <5 years of age and to determine whether sensitization to contact allergens was as common in infancy. METHODS: We recruited 95 asymptomatic children 6 months to 5 years of age from well-child visits at Denver area pediatric practices for epicutaneous patch testing using the T.R.U.E. Test system. Allergens were placed on the skin for 48 hours, and at a later follow-up visit, positive reactions were evaluated. RESULTS: A total of 85 patients completed the study. Of these, 20 (24.5%) had 1 or more positive reactions to the tested allergens. Positive reactors ranged from 6 to 65.5 months of age, with an average of 30.4 months of age. Of the children, 16 reacted to 1 allergen, and 4 reacted to 2. Eleven positive reactions were observed to nickel, followed by 8 to thimerosal. Other positive reactions were to neomycin, cobalt, and kathon CG. CONCLUSIONS: Children as young as 6 months of age may be sensitized to contact allergens. Within this pediatric population, the prevalence of sensitization is 24.5%. Sensitization to contact allergens may occur in infants.

Age of Onset↗
PubMed2002

Newborn hepatitis B vaccination policy in hospital nurseries.

OBJECTIVE: Hepatitis B vaccination (HBV) is unlike any other immunization series because it can be initiated in the hospital nursery. The objective of this study was to describe how hospital nurseries develop HBV policies and to describe the sources of information used for learning about national HBV recommendations. METHODS: A cross-sectional telephone survey was conducted on a national random sample of nursery medical directors of 290 hospital nurseries representing all 50 states. The outcomes measured were methods used by hospital nurseries to develop HBV policy and sources of information used by nursery directors to learn about national HBV recommendations. RESULTS: Directors at 207 (71%) of 290 eligible nurseries responded. Of the 184 nurseries that have considered developing an HBV policy, the most common method was through a formal committee (43%). In 104 (57%) of these nurseries a nurse was involved in policy development, and in 15 (8%) the nurse manager initiated the process. The most common source of initial information about the July 1999 announcement to suspend the nursery dose of HBV was the American Academy of Pediatrics. The most common initial source of information about the availability of thimerosal-free HBV was pharmaceutical companies. Physician, nurse, and pharmacist colleagues were cited as sources of information with similar frequency (12, 11, and 20 cases, respectively). CONCLUSIONS: Physicians are not the sole initiators and developers of HBV policy in the newborn nursery. Although almost all nurseries designate a physician as a nursery director, in many cases (55% of cases) the position is "rotating" or as part of another administrative position (63% of cases). Many hospital nurseries involve nurses and pharmacists in key roles to stay current with HBV recommendations and to develop subsequent policy. Using nonphysician national organizations as additional channels of information might expedite dissemination about changes in HBV recommendations and, as a result, improve nursery awareness and adoption of national HBV guidelines.

Cross-Sectional Studies↗
PubMed2003

Addressing parents' concerns: do vaccines contain harmful preservatives, adjuvants, additives, or residuals?

Vaccines often contain preservatives, adjuvants, additives, or manufacturing residuals in addition to pathogen-specific immunogens. Some parents, alerted by stories in the news media or information contained on the World Wide Web, are concerned that some of the substances contained in vaccines might harm their children. We reviewed data on thimerosal, aluminum, gelatin, human serum albumin, formaldehyde, antibiotics, egg proteins, and yeast proteins. Both gelatin and egg proteins are contained in vaccines in quantities sufficient to induce rare instances of severe, immediate-type hypersensitivity reactions. However, quantities of mercury, aluminum, formaldehyde, human serum albumin, antibiotics, and yeast proteins in vaccines have not been found to be harmful in humans or experimental animals.

Adjuvants, Pharmaceutic↗
PubMed2006

Vaccine adverse event reporting system reporting source: a possible source of bias in longitudinal studies.

OBJECTIVE: The US Vaccine Adverse Event Reporting System (VAERS) is a passive reporting system to which anyone can report an event. Publicity related to potential adverse events may change reporting patterns. The objective of this paper is to show how litigation-related reports have influenced the trends in possible adverse event reports to VAERS. METHODS: The VAERS public-use data files were downloaded in July 2004 and translated into identical SAS data sets for analysis. Cases that were related to litigation were identified using a word search algorithm. All cases for the most frequently reported symptoms in litigation (overdose, neuropathy, autism, "mental retardation," arthralgia, and "speech disorder") were reviewed. RESULTS: In recent years, most case reports to VAERS that were related to overdose, neuropathy, and thimerosal were related to litigation. Many cases that were related to autism and mental retardation were as well. CONCLUSIONS: This review shows a previously undisclosed rise in the number of reports to the VAERS related to pending litigation for vaccine injury. The implications of this for understanding longitudinal reporting patterns are discussed.

Adverse Drug Reaction Reporting Systems↗
PubMed2006

An unusual local reaction after microsclerotherapy with chromated glycerin.

A case of papular itching lesions after microsclerotherapy with chromated glycerin (CG) at a 72% concentration for telangiectases of the thighs is reported. Patch-test results were strongly positive for nickel sulfate (+++/+++) and thimerosal (++/++) whereas results were negative for the sclerosing agent CG 72% and glycerol (control). Intradermal injection of CG 72% in the thigh and intravascular injection of CG 72% into telangiectases of the knee produced erythematous papular itching lesions in about 5 to 6 hours. As a negative control, glycerol and sodium chloride 0.9% injected intradermically on the thigh did not cause any reaction. CG can elicit allergic reactions in patients who are sensitive to chromium and can cause new sensitizations to chromium. In our case, no positivity to potassium dichromate was observed.

Alum Compounds↗
PubMed1990

Long-term culture of neonatal rat pancreatic endocrine cells as model for insulin-secretion and ion-channel studies.

So far, only freshly isolated cells or short-term cultures have been used to study ion-channel activity in pancreatic nontumor beta-cells. We report a procedure for the long-term cultivation of pancreatic endocrine cells to study the relationship between ion channels and insulin secretion. Using thimerosal to suppress fibroblastoid cell proliferation and a preliminary 2-day cell exposure to alternating normal (5.6 mM) and high (16.7 mM) glucose levels, we observed a significant secretory responsiveness of the cells to a glucose challenge for at least 4 wk in culture. Cells also responded to glucose or other secretagogues, such as quinine and the sulfonylurea glyburide, with membrane voltage oscillations. In the cell-attached configuration of the patch-clamp technique, a 65-pS-conductance K+ channel was observed, which was inhibited by glucose, quinine, and glyburide. In the inside-out configuration, the activity of this channel was suppressed by ATP applied to the cytoplasmic side of the membrane. A K+ channel with a conductance of 200 pS was also observed, which was activated by intracellular Ca2+. A 13-pS-conductance glucose-insensitive K+ channel was present in both cell-attached and inside-out patch recordings. Even after 3 wk, the characteristics of these currents and channels were comparable to those reported by other investigators with freshly dissociated or short-term-cultured beta-cells from neonatal and adult rats and adult mice. Therefore, the neonatal rat endocrine cell culture characterized herein provides an improved model for long-term investigations combining secretion and electrophysiological studies.

Animals↗
PubMed2002

Self-reported changes in subjective health and anthrax vaccination as reported by over 900 Persian Gulf War era veterans.

A 1999 study of United Kingdom servicemembers by Unwin, et al. recently found significant relationships between anthrax and other vaccinations, reactions to those vaccines, and later health problems for male current or former active military Gulf War veterans. Likewise, in 2000 Steele and in 1998 Gilroy found possible adverse effects of vaccinations on Gulf War veterans. However, the role of such vaccinations remains controversial; more recent government reports continue to dispute the existence of any data that might reflect adversely on the role of vaccinations on the health of Gulf War veterans. To address this controversy, the current study assessed similar relationships for over 900 Reserve Component Gulf War Era veterans from Ohio and nearby states. Gulf War veterans were more likely to report poorer health than non-Gulf veterans. Female veterans were more likely to report mild or severe reactions to vaccines than male veterans. Those veterans who received anthrax vaccine reported more reactions to vaccines than those who did not receive anthrax vaccine. Declines in long-term subjective health were associated with receipt of anthrax vaccine by Gulf War veterans but not for those who did not deploy to the Gulf, although few of the latter received anthrax vaccine. Regardless of deployment status, veterans who reported more severe reactions to vaccines were more likely to report declines in subjective health. Female veterans reported poorer health during the Gulf War than did male veterans, but sex was not related to veterans' reports of subjective health at subsequent times. It is recommended that servicemembers who experience severe reactions to anthrax vaccine be medically reevaluated before receiving further anthrax vaccine and that careful follow-ups be conducted of those receiving the vaccine currently, in accordance with Nass's 1999 recommendations. We also recommend that safer alternatives to thimerosal (a mercury sodium salt, 50% mercury) be used to preserve all vaccines.

Adult↗
PubMedDate not supplied

Contact allergy to various components of topical preparations for treatment of external otitis.

Patients suffering from chronic external otitis had developed contact allergies to one or more compounds of topical preparations in 40% of 142 tested patients. Neomycin and framycetin caused most of the allergic reactions (16.2%) followed by chinoform (7.0%), chloramphenicol and polymyxin (4.2%). Preservatives of the topical otic preparations such as benzethonium chloride (8.5%), benzalkonium chloride (6.3%) and thimerosal (merthiolate) (5.6%) were also common causes of allergic reactions. An epicutaneous test (patch test) using compounds in topical preparations should be done in cases of prolonged, treatment resistant external otitis.

Anti-Infective Agents, Local↗
PubMed1984

Vaccine against human hepatitis B virus prepared from antigen derived from human hepatoma cells in culture.

Vaccine against human hepatitis B was prepared using antigen derived from hepatitis B carrier hepatoma cells grown in the interstices of a Diaflo hollow filter unit. Hepatitis B surface antigen (HBsAg) produced by these cells was purified by immune affinity chromatography, digestion with DNase and pepsin, and Sephadex G-150 separation. The Formalin-treated antigen was formulated in 20-micrograms dose on alum adjuvant with thimerosal added as a preservative. This cell culture vaccine was as potent as human plasma-derived vaccine as measured in a mouse potency assay. The vaccine proved safe in tests in chimpanzees and in human subjects who were in late stages of cancer of the central nervous system and who were receiving therapy for their condition. None of five subjects who received the vaccine developed untoward clinical reactions. Two of the subjects who received all three doses of vaccine developed antibody against HBsAg. Three persons, two given only the primary doses and one who was given all three doses but was lost to follow-up, demonstrated no response. The slow and relatively low antibody responses to the vaccine were similar to those in other immunosuppressed persons who were given vaccine of human plasma origin.

Animals↗