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Biomedical subjects

L Needham

Publications and source records attributed to L Needham.

At least 19 recordsLinked to original sources

Fish intake and serum levels of organochlorines among Japanese women.

This study evaluates background serum levels of selected organochlorine compounds among Japanese women of reproductive age and investigates whether lifestyle factors, especially dietary factors, may be associated with these levels. A cross-sectional study was performed on 80 Japanese women, aged 26-43 years, who complained of infertility and were confirmed not to have endometriosis. The serum levels of total toxic equivalency (TEQ), 18 polychlorinated dibenzo-p-dioxins (PCDDs)/polychlorinated dibenzofurans (PCDFs), 4 coplanar polychlorinated biphenyls (cPCBs), 36 ortho-substituted polychlorinated biphenyls (PCBs), and 13 chlorinated pesticides or their metabolites were measured and data were collected on the women's age, residence, occupation, body mass index (BMI), smoking and alcohol habit and 6 dietary intakes (fish, meats, rice, vegetables, fruits and dairy products). The serum median level of total TEQ was 25.1 pg TEQ/g lipid, that of PCDDs/PCDFs/cPCBs was 11.5 pmol/g lipid, that of PCBs was 0.46 nmol/g lipid, and that of total pesticides was 1.32 nmol/g lipid. The serum levels of total TEQ, PCDDs/PCDFs/cPCBs, PCBs and pesticides were positively associated with age (P for trend=0.003, 0.01, 0.005 and 0.01, respectively) and frequent fish consumption (P for trend=0.002, 0.003, 0.0003 and 0.006, respectively). Other lifestyle factors were not associated with serum organochlorine levels. The present study suggests that Japanese women who consume fish frequently in their reproductive period tend to accumulate organochlorines in their bodies.

Adult↗

Uptake and metabolism of hydroxymatairesinol in relation to its anticarcinogenicity in DMBA-induced rat mammary carcinoma model.

The chemopreventive effects of hydroxymatairesinol (HMR), a lignan extracted from Norway spruce (Picea abies), on the development of mammary carcinoma induced by 7,12-dimethylbenz[a]anthracene (DMBA) was studied in rats. HMR administered via diet in an average daily dose of 4.7 mg/kg body wt starting before DMBA induction reduced tumor volume and tumor growth, but no significant reduction in tumor multiplicity (number of tumors/rat) was observed. The predominant histological type in the control group was type B (well-differentiated adenocarcinoma, 78%). The proportion of type B tumors decreased to 35% in the HMR group, while the type A (poorly differentiated) and type C (atrophic) tumor proportions increased. Anticarcinogenic effects of dietary HMR (4.7 mg/kg) were also evident when the administration started after DMBA induction and was seen as growth inhibition of established tumors. Dietary HMR supplementation significantly increased serum and urinary enterolactone and HMR concentrations but had no significant effect on the uterine weight, suggesting that HMR or its major metabolite enterolactone did not have an antiestrogenic effect. Further studies are warranted to further clarify and verify HMR action and the associated mechanisms in mammary tumorigenesis.

4-Butyrolactone↗

Serum hormone levels in humans with low serum concentrations of 2,3,7,8-TCDD.

We measured current serum hormone and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) concentrations in 37 men who sprayed 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) in the State of Victoria, Australia. TCDD levels were consistently significantly inversely related to prolactin levels in all analyses. In correlation analyses, TCDD levels were also inversely related to triiodothyronine (T3), thyroid-stimulating hormone (TSH), and testosterone levels, and positively associated with glucagon levels. The mean serum TCDD concentration in these sprayers was between 2.6 and 8.1 parts per trillion (ppt). Since such TCDD levels are commonly found in the general population in countries such as the US, the results could suggest that background levels of TCDD in the general population could have an effect on hormone levels. The findings are preliminary and need to be replicated in order to evaluate their full public health significance.

Adult↗

Emerging areas of research reported during the CDC National Conference on Pfiesteria: from biology to public health.

Since its identification in 1996, the marine dinoflagellate Pfiesteria piscicida Steidinger & Burkholder has been the focus of intense scientific inquiry in disciplines ranging from estuarine ecology to epidemiology and from molecular biology to public health. Despite these research efforts, the extent of human exposure and the degree of human illness directly associated with Pfiesteria is still in the process of being defined. Unfortunately, during this same time Pfiesteria has also stimulated media coverage that in some instances jumped ahead of the science to conclude that Pfiesteria presents a widespread threat to human health. Political and economic forces also came into play when the tourism and seafood industries were adversely impacted by rumors of toxin-laden water in estuaries along the east coast of the United States. Amid this climate of evolving science and public concern, Pfiesteria has emerged as a highly controversial public health issue. In October 2000 Centers for Disease Control and Prevention sponsored the National Conference on Pfiesteria: From Biology to Public Health to bring together Pfiesteria researchers from many disparate disciplines. The goal of this meeting was to describe the state of the science and identify directions for future research. In preparation for the conference an expert peer-review panel was commissioned to review the existing literature and identify research gaps; the summary of their review is published in this monograph. During the meeting primary Pfiesteria researchers presented previously unpublished results. The majority of those presentations are included as peer-reviewed articles in this monograph. The discussion portion of the conference focused upon researcher-identified research gaps. This article details the discussion segments of the conference and makes reference to the presentations as it describes emerging areas of Pfiesteria research.

Animals↗

Body burden levels of dioxin, furans, and PCBs among frequent consumers of Great Lakes sport fish. The Great Lakes Consortium.

Dioxins, furans, and polychlorinated biphenyls (PCBs) are toxic, persist in the environment, and bioaccumulate to concentrations that can be harmful to humans. Sport anglers may be exposed to these residues via consumption of contaminated Great Lakes (GL) fish. The Health Departments of five GL states, Wisconsin, Michigan, Ohio, Illinois, and Indiana, formed a consortium to study body burden levels of chemical residues in fish consumers of Lakes Michigan, Huron, and Erie. In Fall 1993, a telephone survey was administered to sport angler households to obtain fish consumption habits and demographics. A blood sample was obtained from a portion of the study subjects. One hundred serum samples were analyzed for 8 dioxin, 10 furan, and 4 coplanar PCB congeners. Multiple linear regression was conducted to assess the predictability of the following covariates: GL sport fish species, age, BMI, gender, years sport fish consumed, and lake. Of the 100 subjects, there were 58 men; 35 consumed sport fish from Lake Michigan, 29 from Lake Huron, and 36 from Lake Erie. The overall average number of GL sport fish meals consumed in the previous 12 months was 43. Lake Erie male and female consumers, on average, ate more GL sport fish, a mean of 57 and 42 meals, respectively, than men and women from the other two lake subgroups. Median total dioxin toxic equivalents (TEq), total furan TEq, and total coplanar PCB TEq were higher among all men than all women (P=0.0001). Lake trout, salmon, age, BMI, and gender were significant regression predictors of log(total coplanar PCBs). Lake trout, age, gender, and lake were significant regression predictors of log(total furans). Age was the only significant predictor of total dioxin levels.

Adult↗

Effects of prenatal and postnatal methylmercury exposure from fish consumption on neurodevelopment: outcomes at 66 months of age in the Seychelles Child Development Study.

CONTEXT: Human neurodevelopmental consequences of exposure to methyl-mercury (MeHg) from eating fish remain a question of public health concern. OBJECTIVE: To study the association between MeHg exposure and the developmental outcomes of children in the Republic of Seychelles at 66 months of age. DESIGN: A prospective longitudinal cohort study. PARTICIPANTS: A total of 711 of 779 cohort mother-child pairs initially enrolled in the Seychelles Child Development Study in 1989. SETTING: The Republic of Seychelles, an archipelago in the Indian Ocean where 85% of the population consumes ocean fish daily. MAIN OUTCOME MEASURES: Prenatal and postnatal MeHg exposure and 6 age-appropriate neurodevelopmental tests: the McCarthy Scales of Children's Abilities, the Preschool Language Scale, the Woodcock-Johnson Applied Problems and Letter and Word Recognition Tests of Achievement, the Bender Gestalt test, and the Child Behavior Checklist. RESULTS: The mean maternal hair total mercury level was 6.8 ppm and the mean child hair total mercury level at age 66 months was 6.5 ppm. No adverse outcomes at 66 months were associated with either prenatal or postnatal MeHg exposure. CONCLUSION: In the population studied, consumption of a diet high in ocean fish appears to pose no threat to developmental outcomes through 66 months of age.

Central Nervous System Diseases↗

Profiles of Great Lakes critical pollutants: a sentinel analysis of human blood and urine. The Great Lakes Consortium.

To determine the contaminants that should be studied further in the subsequent population-based study, a profile of Great Lakes (GL) sport fish contaminant residues were studied in human blood and urine specimens from 32 sport fish consumers from three Great Lakes: Lake Michigan (n = 10), Lake Huron (n = 11), and Lake Erie (n = 11). Serum was analyzed for 8 polychlorinated dioxin congeners, 10 polychlorinated furan congeners, 4 coplanar and 32 other polychlorinated biphenyl (PCB) congeners, and 11 persistent chlorinated pesticides. Whole blood was analyzed for mercury and lead. Urine samples were analyzed for 10 nonpersistent pesticides (or their metabolites) and 5 metals. One individual was excluded from statistical analysis because of an unusual exposure to selected analytes. Overall, the sample (n = 31) consumed, on average, 49 GL sport fish meals per year for a mean of 33 years. On average, the general population in the GL basin consume 6 meals of GL sport fish per year. The mean tissue levels of most persistent, bioaccumulative compounds also found in GL sport fish ranged from less than a twofold increase to that of PCB 126, which was eight times the selected background levels found in the general population. The overall mean total toxic equivalent for dioxins, furans, and coplanar PCBs were greater than selected background levels in the general population (dioxins, 1.8 times; furans, 2.4 times; and coplanar PCBs, 9.6 times). The nonpersistent pesticides and most metals were not identified in unusual concentrations. A contaminant pattern among lake subgroups was evident. Lake Erie sport fish consumers had consistently lower contaminant concentrations than consumers of sport fish from Lake Michigan and Huron. These interlake differences are consistent with contaminant patterns seen in sport fish tissue from the respective lakes; GL sport fish consumption was the most likely explanation for observed contaminant levels among this sample. Frequent consumers of sport fish proved to be effective sentinels for identifying sport fish contaminants of concern. In the larger study to follow, serum samples will be tested for PCBs (congener specific and coplanar), DDE, dioxin, and furans.

Animals↗

Immunologic findings in workers formerly exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin and its congeners.

One hundred ninety-two workers in a German pesticide factory who were exposed to polychlorinated dibenzodioxins and -furans (PCDD/PCDF) were investigated for former and present diseases and laboratory changes of the immune system. Moreover, in a subgroup of 29 highly exposed and 28 control persons, proliferation studies were performed. In addition to assays such as blood count, immunoglobulins, serum electrophoresis, monoclonal bands, surface markers, autoantibodies, and lymphocyte proliferation, two new methods, the rise of tetanus antibody concentration after vaccination and the in vitro resistance of lymphocytes to chromate, were used to diagnose the morphologic and functional state of the immune system. There was no stringent correlation of actual PCDD/PCDF concentrations with the occurrence of infections or with one of the immune parameters. In addition, outcomes of the tetanus vaccination and the chromate resistance test were not correlated with PCDD/PCDF. However, the chromate resistance of lymphocytes stimulated by phytohemagglutinin of highly exposed persons was significantly lower than that for the control group. These findings indicate that the function of lymphocytes can be stressed and possibly impaired by high exposure to PCDD/PCDF.

Adult↗

Community Health and Medical Practitioners Scheme: providers evaluate a pilot program of integration of services.

OBJECTIVE: To set up and evaluate a pilot scheme integrating salaried community health centre staff and fee-for-service medical practitioner services (CHAMPS). DESIGN: Preliminary interviews with both groups established the aims, logistics and financial arrangements of the project. The community health centre provided staff and the general practitioners provided premises and administrative services. Follow-up interviews evaluated the scheme and made recommendations. SETTING: A New South Wales country town, population 24,000, with 25 general practitioners and 23 community health centre professionals. RESULTS: Six general practitioners and 23 community health professionals determined the aims to be: improved access for patients to community health services; improved liaison between the two groups of providers; and a broadening of services offered at general practice locations. Two dietitians and three mental health workers were rostered for half a day per week in four general practices for six months. The dietitians continued after the project finished, but the mental health workers did not. The five community health staff, five of the general practitioners originally interviewed and six other general practitioner participants cited the major benefits as increased communication between providers and improved access for patients, and the major difficulties as lack of appropriate equipment and organisational logistics. CONCLUSIONS: The providers believe that the project succeeded in improving access to community health services and liaison between professionals. For future projects they recommended better communication, firmer role delineation and better planning for space and equipment.

Adolescent↗

Tryptophan contaminants associated with eosinophilia-myalgia syndrome. The Eosinophilia-Myalgia Studies of Oregon, New York and New Mexico.

Eosinophilia-myalgia syndrome (EMS) has been linked to ingestion of tryptophan contaminated with 1,1'-ethylidene-bis[L-tryptophan] (EBT), but other contaminants have received little study. The authors identified 101 lots of L-tryptophan that had been consumed either by persons with EMS or by asymptomatic tryptophan users and quantified the amounts of EBT and five other contaminants in each lot. After stratification of case and noncase lots by time of manufacture to adjust for the strong sequential pattern over time among case and noncase lots, higher EBT levels were still associated with a lot's case status, but the association lacked statistical significance (p = 0.120, odds ratio = 1.56, 95% confidence interval 0.758-3.23). While these findings do not rule out the possibility that EBT is the etiologic agent in EMS, they raise the possibility that other chemical contaminants in manufactured tryptophan modify the effects of EBT or that the causal agent of EMS is an entirely distinct compound.

Drug Contamination↗

Tumor cell adhesion to endothelial cells: endothelial leukocyte adhesion molecule-1 as an inducible adhesive receptor specific for colon carcinoma cells.

Activation of endothelial cells by the two inflammatory mediators interleukin-1 (IL-1) and tumor necrosis factor strongly increases tumor cell adhesion. We describe antibody inhibition studies showing that the endothelial leukocyte adhesion molecule-1 (ELAM-1), a cell-surface glycoprotein selectively expressed by cytokine-activated endothelial cells and responsible for neutrophil adhesion, is the major, if not the only, mediator of colon carcinoma cell adhesion to activated endothelial cells. Among the different tumor cell lines tested, seven colon carcinoma cell lines were sensitive to ELAM-1 antibodies. Adhesion of melanoma, osteosarcoma, and lung, cervix, or kidney carcinoma cell lines to IL-1-treated endothelial cells was not affected by the ELAM-1 antibody. This result suggests that ELAM-1 is selectively recognized by colon carcinoma cells and that adhesion of tumor cells to activated endothelial cells could be mediated by different and specific mechanisms.

Antibodies, Monoclonal↗

Evidence that secondary rat Schwann cells in culture maintain their differentiated phenotype.

Schwann cells, on receiving the correct signal, will encircle an axon and wrap it with a myelin sheath. To begin examining some of the mechanisms underlying the process of myelination in vitro, we isolated Schwann cells from the sciatic nerves of neonatal rats and generated large cell populations with cholera toxin. The immunological and biochemical properties of these secondary Schwann cells were characterized after five to seven passages in the absence of axonal contact. These cells continued to express antigens found in both myelinating (P0 and 2',3'-cyclic nucleotide phosphohydrolase) and nonmyelinating cells in vivo (A5E3 and glial fibrillary acidic protein) in addition to the markers common to both types of cells (Ran-1, 217c, S-100, and laminin). Biochemical analyses showed that these cells synthesize the very-long-chain fatty acids (22-26 carbon atoms) found in myelin membranes. Moreover, the enzymes required for the synthesis of myelin glycolipids (including sphingosine acyltransferase, UDP-galactose:ceramide galactosyltransferase, and cerebroside sulfotransferase) were still active, and metabolic labeling studies showed that galactocerebroside and sulfatide were synthesized even though the galactocerebroside pool was insufficient to be detected by immunostaining. Secondary Schwann cells also synthesized four species of myelin basic protein and the major structural glycoprotein in myelin, P0. The pathway necessary for glycosylation of P0 protein remained active, and an analysis of the oligosaccharide chain revealed that approximately 70% was processed to a complex form. In summary, we found that secondary Schwann cells still express most of the immunological markers of differentiated cells and continue to synthesize low levels of myelin components. Therefore, Schwann cells do not dedifferentiate in culture, as previously believed.

Animals↗

Expression of two molecular forms of the complement decay-accelerating factor in the eye and lacrimal gland.

Complement is present in ocular fluids, but the molecular mechanism(s) restricting its activation to exogenous targets and not to autologous ocular cells are currently unknown. To clarify how this control is achieved, monoclonal antibody (mAb)-based techniques were used to examine the eye, the lacrimal gland, and ocular fluids for the decay-accelerating factor (DAF), a membrane regulatory protein which protects blood cells from autologous complement activation on their surfaces. Immunohistochemical staining of tissue sections revealed DAF antigen on corneal and conjunctival epithelia, corneal endothelium, trabecular meshwork, and retina, as well as on lacrimal gland acinar cells and in adjacent lumens. By flow cytometry, cultures of conjunctival epithelium exhibited the highest DAF levels and levels on corneal epithelium greater than corneal endothelium greater than conjunctival fibroblasts. Biosynthetic labeling of corneal endothelium yielded de novo DAF protein with an apparent molecular weight (Mr) of 75 kD, approximating that of blood cell DAF protein, and digestions of conjunctival epithelium with phosphatidylinositol-specific phospholipase C (PI-PLC), an enzyme which cleaves glycoinositolphospholipid membrane anchors, released approximately 70% of the ocular surface DAF protein similar to leukocyte surface DAF protein. Quantitations of DAF by radioimmunometric assay employing mAbs against two DAF epitopes revealed 325 ng/ml (n = 12), 4.8 ng/ml (n = 10), and 22.0 ng/ml (n = 8) of soluble DAF antigen in tears, aqueous humor, and vitreous humor, respectively. Western blot analyses of the tear DAF antigen revealed two DAF forms, one with an apparent Mr of 72 kD resembling membrane DAF forms in other sites, and a second with an apparent Mr of 100 kD, which is previously undescribed. Since DAF activity is essential physiologically in protecting blood cells from autologous complement attack, the identification of DAF on the ocular surface, intraocularly, in the lacrimal gland, and in tears suggests that DAF-mediated control of complement activation is also required in these locations.

Antibodies, Monoclonal↗

Desensitization of agonist-stimulated prostacyclin release in human umbilical vein endothelial cells.

Prostacyclin (PGI2) release was studied in perfused columns of human umbilical vein endothelial cells cultured on microcarrier beads. Substantial homologous desensitization of PGI2 release occurred when cells were exposed to agonist for 2 min after a previous exposure; the extent depended on the concentration and duration of the first challenge. Recovery from exposure to ATP or bradykinin was complete in less than 80 min; recovery from thrombin was incomplete after greater than 80 min, and this was apparently related to its proteolytic activity. Experiments with ibuprofen, a reversible inhibitor of cyclo-oxygenase, demonstrated that homologous desensitization did not involve inactivation of cyclo-oxygenase. ATP and bradykinin did not induce heterologous desensitization. Thrombin and trypsin induced cross-desensitization, but neither agonist significantly reduced responses to ATP or bradykinin, suggesting that a common proteolytic mechanism is responsible for their ability to induce PGI2 synthesis. We conclude that desensitization of PGI2 release in response to physiological agonists is generally agonist-specific and involves modulation of molecular events at or close to the receptors involved, rather than inactivation of prostanoid biosynthesis.

Adenosine Triphosphate↗

Tosyl-lysyl chloromethylketone detects conformational changes in the catalytic unit of adenylate cyclase induced by receptor and G-protein stimulation.

Incubation of striatal membranes with tosyl-lysyl chloromethylketone (TLCK) led to the irreversible inactivation of adenylate cyclase. However, under conditions where an interaction between the catalytic unit of adenylate cyclase and the alpha-subunit of the stimulatory G-protein GS were promoted, then the ability of TLCK to inhibit adenylate cyclase was markedly attenuated. The potency of stimulatory ligands, functioning through GS, to attenuate the sensitivity of adenylate cyclase to inactivation by TLCK was paralleled by their potency to activate adenylate cyclase. The local anaesthetic and membrane-fluidizing agent benzyl alcohol amplified GS-mediated stimulation of adenylate cyclase activity, whilst diminishing the ability of GS-mediated coupling to attenuate inactivation of adenylate cyclase by TLCK. In the absence of GS-mediated coupling, benzyl alcohol exerted only a small stimulatory effect on adenylate cyclase activity and had little effect on the ability of TLCK to inactivate this enzyme. We suggest that TLCK modifies a reactive group at or near the active site of adenylate cyclase which causes the functional inactivation of this enzyme. The reactivity of this group appears to be markedly affected by conformational changes elicited through coupling of adenylate cyclase to GS.

Adenylyl Cyclase Inhibitors↗

Endothelial functional responses and increased vascular permeability induced by polycations.

Polycations such as poly-L-lysine powerfully stimulated cultured endothelial cells from pig aorta to release prostacyclin and cytoplasmic purines in a dose (charge)-dependent and molecular weight (size) dependent manner. Neutral or anionic polymers were inactive. Qualitatively similar findings were made in vivo where poly-L-lysine induced charge and size-dependent local edema formation after intradermal injection in the rabbit. Pretreatment of cultured endothelium with heparin or trypsin (but not neuraminidase) effectively reduced the response of the cells to subsequent exposure to poly-L-lysine suggesting an interaction of polycations with integral membrane proteins. Edema responses to poly-L-lysine were reduced in the presence of indomethacin suggesting that generation of an endogenous vasodilator prostaglandin, perhaps endothelial cell-derived, was an important component of the response. Poly-L-lysine-induced edema formation was not dependent on endogenous histamine release but was reduced by locally administered trasylol while soybean trypsin inhibitor failed to inhibit the response. Our results indicate that polycations such as poly-L-lysine can induce responses of vascular endothelium in vitro and in vivo and that the effects are not only charge-related but are also dependent on the size of the polycation. We suggest that naturally occurring polycations such as those derived from leukocytes and platelets may play an important role in various pathologic processes and that this may be closely related to their size.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗

Quinidine and melittin both decrease the fluidity of liver plasma membranes and both inhibit hormone-stimulated adenylate cyclase activity.

Increasing concentrations of either quinidine or melittin gave a dose-dependent inhibition of both the glucagon- and fluoride-stimulated activities of adenylate cyclase in the liver plasma membranes. At similar concentrations these agents increased the order of liver plasma membranes as detected by a fatty acid ESR probe, doxyl stearic acid. This increase in bilayer order (decrease in 'fluidity') is suggested to explain the inhibitory action of quinidine on adenylate cyclase activity but only in part contributes to the inhibitory action of melittin on adenylate cyclase. Arrhenius plots of fluoride-stimulated activity became non-linear in the presence of either quinidine or melittin, with a single well-defined break occurring at around 12 degrees C in each instance. Arrhenius plots of the glucagon-stimulated activity also exhibited such a novel break at around 12 degrees C when either quinidine or melittin were present as well as exhibiting a break at around 28 degrees C, as was seen in the absence of these ligands. The fatty acid spin probe inserted into liver plasma membranes detected a novel lipid phase separation occurring at around 12 degrees C when either quinidine or melittin was present and showed that the lipid phase separation occurring at around 28 degrees C in native membranes was apparently unaffected by these ligands.

Adenylyl Cyclases↗