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PubMed2002

Interactions between pesticides and components of pesticide formulations in an in vitro neurotoxicity test.

Organophosphate (OP) pesticides are often used in combination with one another and with the components of formulations. Evidence already exists for interactions in the neurotoxic effects of OPs through interference with metabolism, but there is also potential for interactions related directly to cell damage. The purpose of this work was to investigate this possibility for OPs and the components of one of their common formulations in vitro. NB2a neuroblastoma cells were induced to differentiate in the presence of the OPs diazinon and chlorpyrifos, in combination with a commercial formulation (identified as Commercial Formulation 1) of the compounds and, independently, the components of that formulation. The compounds were tested in pairs in various proportions and the resulting inhibition of neurite outgrowth was measured by light microscopy and quantitative image analysis. Interactions were determined in terms of enhanced or reduced effects of the paired compounds in comparison with the expected additive effects estimated from the effects of each compound on its own. Synergism was detected between combinations of: 10 microM chlorpyrifos and 500 nM pyrethrum; chlorpyrifos and one of the solvents (regular spirit) found in Commercial Formulation 1. All other combinations of OPs and products were additive in their neurotoxicity. The data suggest that exposure to multiple OP-containing pesticide formulations may lead to synergistic neurotoxicity by a direct mechanism at the cellular level.

Animals↗
PubMed2003

Stable preference for high ethanol concentrations after ethanol deprivation in Sardinian alcohol-preferring (sP) rats.

Results of a recent study have demonstrated that exposure to multiple ethanol concentrations and repeated ethanol deprivation periods in Indiana ethanol-preferring (P) rats resulted in the development of an alcohol deprivation effect (ADE; the temporary increase in voluntary ethanol intake after a period of deprivation from ethanol) characterized by consumption of intoxicating amounts of ethanol. The current study was designed to possibly extend these results to Sardinian alcohol-preferring (sP) rats, generated with the same selective program previously used for P rats. To this aim, ethanol-naive sP rats were exposed initially to the home cage four-bottle choice [10%, 20%, and 30% (vol./vol.) ethanol solutions and water] for eight consecutive weeks. Subsequently, rats were divided into two groups: The first group had continuous access to the four-bottle regimen (nondeprived rats), and the second group was exposed to five cycles of 14-day periods of deprivation from ethanol and 14-day periods of reexposure to the four-bottle regimen. An ADE developed after each deprivation period. However, the extra intake of ethanol was limited to the first hour of each reaccess period. Magnitude of ADE did not change with repeated periods of deprivation. However, a shift in preference toward the two highest concentrations of ethanol solutions was evident from the first reexposure to ethanol and was maintained throughout the study. These results provide further evidence on the heterogeneity of ethanol-drinking behavior among rat lines selectively bred for high ethanol preference and consumption.

Alcohol Drinking↗
PubMed1999

Vascular occlusion using focused ultrasound surgery for use in fetal medicine.

OBJECTIVE: Focused ultrasound surgery (FUS) is being developed clinically for the non-invasive treatment of soft tissue tumours of the prostate, bladder, liver, kidney, muscle and breast. In the work described in this paper, the application of FUS is extended to investigate the potential to induce vascular occlusion, with the aim of applying the technique to problems in fetal medicine and oncology. METHODS: In this feasibility study the occlusion of femoral blood flow in vivo is demonstrated using an array of multiple single exposures of 1.7 MHz focused ultrasound. These were placed in two rows of four lesions at a focal depth of 5 mm. The 4660-W cm-2 (free field spatial peak intensity) 2-s exposures were placed 2 mm apart. Vascular patency was assessed using a Siemens Vision (1.5T) magnetic resonance (MR) imaging scanner with an extremity coil, and intravenous gadolinium contrast agent. FLASH and FISP MR sequences were used to obtain full 3D data sets providing information on soft tissue damage and perfusion. RESULTS AND CONCLUSION: Total vascular occlusion was achieved in four of nine cases and significant vascular disruption in five of nine cases. Refinement of the FUS technique and long-term studies are now indicated prior to initial clinical application in fetal medicine.

Animals↗
PubMed2002

Inactivation of mammalian 8-oxoguanine-DNA glycosylase by cadmium(II): implications for cadmium genotoxicity.

Cadmium(II) is a toxic, mutagenic and carcinogenic metal (IARC Class 1 human carcinogen). It causes damage to eukaryotic cells both in acute and chronic modes of exposure via multiple biochemical mechanisms. In particular, Cd diminishes the capacity of cells to repair oxidative DNA damage. Oxidative DNA lesions are important precursors to mutations and ultimately may lead to neoplastic transformation of human cells. We investigated interactions of Cd with murine Ogg1 (mOgg1), an enzyme that removes 8-oxoguanine (8-oxoG), an abundant oxidative lesion, from DNA. Cd(2+) and Zn(2+), but not other divalent cations tested, suppressed mOgg1-catalyzed reactions. The apparent inhibition by Cd consisted of at least two independent processes: irreversible, DNA-independent first-order inactivation of mOgg1 and DNA-dependent inhibition. Irreversibly inactivated mOgg1 has nearly normal affinity for damaged DNA and a normal catalytic rate constant but is defective in formation of the covalent reaction intermediate. When both modes of inhibition are in effect, the catalytic rate constant is dramatically lowered, while affinity to damaged DNA is decreased moderately. Potential sites for Cd binding in mOgg1 and mOgg1-DNA complex are identified. Inactivation of Ogg1 may play a role in the mutagenic and carcinogenic action of Cd.

Animals↗
PubMed2005

Explicit memory performance in infants of diabetic mothers at 1 year of age.

The aim of the present research was to investigate the impact of abnormal fetal environment on explicit memory performance. Based on animal models, it was hypothesized that infants of diabetic mothers (IDMs) experience perturbations in memory performance due to exposure to multiple neurologic risk factors including: chronic hypoxia, hyperglycemia/reactive hypoglycemia, and iron deficiency. Memory performance, as measured by the elicited/deferred imitation paradigm, was compared between 13 IDMs (seven females, six males; mean age 365 days, SD 11) and 16 typically developing children (seven females, nine males; mean age 379 days, SD 9). The IDM group was characterized by shorter gestational age (mean 38w, SD 2), greater standardized birthweight scores (mean 3797g, SD 947), and lower iron stores (mean ferritin concentration 87C microg/L, SD 68) in comparison with the control group (mean gestational age: 40w, SD 1; mean birthweight: 3639g, SD 348; mean newborn ferritin concentration 140 microg/L, SD 46). After statistically controlling for both gestational age and global cognitive abilities, IDMs demonstrated a deficit in the ability to recall multi-step event sequences after a delay was imposed. These findings highlight the importance of the prenatal environment on subsequent mnemonic behavior and suggest a connection between metabolic abnormalities during the prenatal period, development of memory, circuitry, and behavioral mnemonic performance.

Adult↗
PubMed1998

Risk factors for typhoid fever in an endemic setting, Karachi, Pakistan.

We conducted a study to evaluate risk factors for developing typhoid fever in a setting where the disease is endemic in Karachi, Pakistan. We enrolled 100 cases with blood culture-confirmed Salmonella typhi between July and October 1994 and 200 age-matched neighbourhood controls. Cases had a median age of 5.8 years. In a conditional logistic regression model, eating ice cream (Odds ratio [OR] = 2.3; 95% confidence interval [CI] 1.2-4.2, attributable risk [AR] = 36%), eating food from a roadside cabin during the summer months (OR = 4.6, 95% CI 1.6-13.0; AR = 18%), taking antimicrobials in the 2 weeks preceding the onset of symptoms (OR = 5.7, 95% CI 2.3-13.9, AR = 21%), and drinking water at the work-site (OR = 44.0, 95% CI 2.8-680, AR = 8%) were all independently associated with typhoid fever. There was no difference in the microbiological water quality of home drinking water between cases and controls. Typhoid fever in Karachi resulted from high-dose exposures from multiple sources with individual susceptibility increased by young age and prior antimicrobial use. Improving commercial food hygiene and decreasing unnecessary antimicrobial use would be expected to decrease the burden of typhoid fever.

Adolescent↗
PubMed2006

Titanium dioxide (P25) produces reactive oxygen species in immortalized brain microglia (BV2): implications for nanoparticle neurotoxicity.

Concerns with the environmental and health risk of widely distributed, commonly used nanoparticles are increasing. Nanosize titanium dioxide (TiO2) is used in air and water remediation and in numerous products designed for direct human use and consumption. Its effectiveness in deactivating pollutants and killing microorganisms relates to photoactivation and the resulting free radical activity. This property, coupled with its multiple potential exposure routes, indicates that nanosize TiO2 could pose a risk to biological targets that are sensitive to oxidative stress damage (e.g., brain). In this study, brain microglia (BV2) were exposed to a physicochemically characterized (i.e., dispersion stability, particle size distribution, and zeta potential) nanomaterial, Degussa P25, and cellular expressions of reactive oxygen species were measured with fluorescent probes. P25's zeta potentials, measured in cell culture media and physiological buffer were -11.6 +/- 1.2 mV and -9.25 +/- 0.73 mV, respectively. P25 aggregation was rapid in both media and buffer with the hydrodynamic diameter of stable P25 aggregates ranging from 826 nm to 2368 nm depending on the concentration. The biological response of BV2 microglia to noncytotoxic (2.5-120 ppm) concentrations of P25 was a rapid (<5 min) and sustained (120 min) release of reactive oxygen species. The time course of this release suggested that P25 not only stimulated the immediate "oxidative burst" response in microglia but also interfered with mitochondrial energy production. Transmission electron microscopy indicated that small groups of nanosized particles and micron-sized aggregates were engulfed bythe microglia and sequestered as intracytoplasmic aggregates after 6 and 18 h exposure to P25 (2.5 ppm). Cell viability was maintained at all test concentrations (2.5-120 ppm) over the 18 h exposure period. These data indicate that mouse microglia respond to Degussa P25 with cellular and morphological expressions of free radical formation.

Animals↗
PubMed1998

Dynamic systems theory as a paradigm for the study of change in psychotherapy: an application to cognitive therapy for depression.

Dynamic systems theory provides a conceptual framework for the study of change in psychotherapy that is consistent with that used in other sciences. A dynamic systems model of change was proposed and evaluated in the context of cognitive therapy for depression. Consistent with this model, less client protection and more destabilization of depressive patterns predicted more improvement at the end of treatment. Less protection was associated with more therapist support/stabilization. More destabilization was associated with more affective intensity in the session and with more of a therapist focus on the historical antecedents of current problems, exposure to multiple sources of corrective information, and repeated practice of new skills. Although preliminary, this pattern of findings is consistent with the model proposed and with principles of dynamic systems from other sciences.

Adolescent↗
PubMed2005

Mothers' and fathers' behaviors toward their 3- to 4-month-old infants in lower, middle, and upper socioeconomic African American families.

African American mothers' and fathers' availability, caregiving, and social behaviors toward their infants in and around their homes were examined. Twenty lower, 21 middle, and 21 upper socioeconomic families and their 3- to 4-month-old infants were observed for 4 3-hr blocks between 8:00 a.m. and 8:00 p.m. on 4 different weekdays. With increasing economic resources, children's exposure to multiple caregivers and nonresident fathers declined. Mothers were more available to infants than fathers were, regardless of socioeconomic status. Mothers fed infants more than fathers did, whereas fathers vocalized more and displayed more affection to infants than mothers did when they were examined in proportion to caregiver presence. Mothers and fathers interacted with male and female infants quite similarly, although, in the upper socioeconomic families, fathers of daughters were more available than fathers of sons. Fathers and mothers in the different socioeconomic groups held, displayed affection to, and soothed their infants differently.

Adult↗
PubMed2006

Children's use of frequency information for trait categorization and behavioral prediction.

Two experiments examined young children's use of behavioral frequency information to make behavioral predictions and global personality attributions. In Experiment 1, participants heard about an actor who behaved positively or negatively toward 1 or several recipients. Generally, children did not differentiate their judgments of the actor on the basis of the amount of information provided. In Experiment 2, the actor behaved positively or negatively toward a single recipient once or repeatedly. Participants were more likely to make appropriate predictions and attributions after exposure to multiple target behaviors and with increasing age. Overall, children's performance was influenced by age-related positivity and negativity biases. These findings indicate that frequency information is important for personality judgments but that its use is affected by contextual complexity and information-processing biases.

Child↗
PubMed1983

Allergies and agricultural exposure as risk factors for multiple myeloma.

In a case-control study of 84 multiple myeloma patients and 168 age- and sex-matched controls with tumours at other sites, reported prior allergies were associated with an elevated risk of myeloma (RR = 3.1, P less than 0.001). In addition, more myeloma patients than controls reported prior myxoedema (RR = 5.0, P = 0.04). History of agricultural work was associated with an elevated risk of myeloma (RR = 2.2, P = 0.01), although no detailed information was available on the type of farming in which the subjects were engaged. More detailed studies are required to confirm and further delineate these findings.

Adult↗
PubMed1996

Interleukin-13 inhibits inducible nitric oxide synthase expression in human mesangial cells.

The synthesis of nitric oxide in inflammatory situations requires the expression of an inducible isoform of nitric oxide synthase (iNOS). Human mesangial cells (HMC) express an iNOS enzyme after exposure to multiple co-stimuli. In this study we have observed that while tumour necrosis factor-alpha, interleukin (IL)-1 beta, interferon-gamma and bacterial lipopolysaccharide (LPS) were unable to significantly induce NO synthesis when used alone, they induced an evident stimulation of NO synthesis when used in various combinations. A mixture of the three cytokines (CM) and LPS resulted in a 10-15-fold stimulation of NO synthesis over control values which started to be significant after 16 h. The addition of IL-13, a cytokine with anti-inflammatory properties, inhibited CM/LPS-induced NO synthesis in a concentration-dependent manner. A marked inhibitory effect (60-65%) could be observed when HMC were treated with IL-13 (10 ng/ml) 24 h before, at the same time as, or even 4 h after the addition of CM/LPS. This inhibitory effect was still significant (25%) when IL-13 was added 16 h after CM/LPS. Northern analysis showed that IL-13-mediated iNOS inhibition was closely correlated with the suppression of iNOS mRNA expression. These results identify IL-13 as a powerful regulatory tool for the inhibition of NO synthesis in human cells, a property which may be pathophysiologically relevant in NO-related inflammatory processes.

Cells, Cultured↗
PubMed2004

Assessment of young children's social-emotional development and psychopathology: recent advances and recommendations for practice.

In this paper we have tried to document some of the recent advances in the conceptualization and assessment of early-emerging social-emotional and behavior problems, competencies, and psychopathology. Considerable evidence documents that young children evidence significant psychopathology (cf., Del Carmen & Carter, in press; Emde, 1999; Zeanah, 2001; Zeanah et al., 1997). Given the range of new assessment measures that have become available over the past 10 years, the field of young child mental health is poised for dramatic gains in knowledge. It is critical to conduct large-scale, longitudinal, epidemiological studies to inform our understanding of the course of psychopathological conditions within the context of a normative developmental framework. Multi-method, multi-informant assessment approaches are more essential in early childhood due to young children's inability to provide self-reports and the embedded nature of children's development in their caregiving contexts. Screening large representative samples affords the opportunity to ascertain unbiased clinically informative sub-samples for methodologically intensive sub-studies. These sub-studies can address the child's cognitive and linguistic developmental capacities as well as utilize observational methods to examine the relational context. This approach provides an opportunity to merge dimensional and diagnostic assessments and will yield critical information for disentangling continuities and discontinuities in normative and atypical development. The assessment methodology currently exists to routinely screen very young children for social-emotional and behavior problems as well as delays in the acquisition of competencies in pediatric settings as well as in early intervention programs. Yet, despite the likely long-term benefits and cost-saving potential of early identification and intervention services, short-term cost and knowledge barriers currently limit widespread implementation. Discussions with pediatricians suggest that one of the greatest barriers to screening is the limited availability of mental health referral sources. Indeed, very few children who are rated by parents as having elevated social-emotional and behavior problems are receiving any behavioral health services (Horwitz et al., in press). Unmet mental health needs exist among non-referred children in the community as well as among children receiving early intervention services for developmental concerns. Documenting the mental health needs of young children may promote training of professionals who have the competence to treat young children and their families. Moreover, the availability of social-emotional and behavior problem assessment tools should increase studies that focus on the clinical efficacy and effectiveness of prevention and early intervention programs designed to promote positive mental health. Finally, although significant progress is occurring in the arena of young child diagnosis, a strong case can be made for intervening when young children are exhibiting elevations in problem behaviors or delays in the acquisition of competence. This is particularly true when children are also experiencing exposure to multiple contextual risk factors. It is therefore important to advocate for changes to systems that require child diagnosis as a gateway to intervention. As we learn more about the precursors or prodromal manifestations of clinical psychopathology we will be able to examine the efficacy of earlier targeted preventive intervention approaches.

Affect↗
PubMed2003

Antidepressant-induced mania: an overview of current controversies.

OBJECTIVE: The prevalence, characteristics, and possible risk factors associated with antidepressant-induced mania remain poorly described. The present review sought to identify published rates of antidepressant-induced mania and describe risk factors for its emergence. METHODS: A MedLine search was conducted of journals that focused on mania or hypomania associated with recent antidepressant use. Data from published reports were augmented with relevant findings from recent clinical trials presented at scientific conferences. RESULTS: Antidepressant-induced manias have been reported with all major antidepressant classes in a subgroup of about 20-40% of bipolar patients. Lithium may confer better protection against this outcome when compared with other standard mood stabilizers, although switch rates have been reported with comparable frequencies on or off mood stabilizers. Evidence across studies most consistently supports an elevated risk in patients with (i) previous antidepressant-induced manias, (ii) a bipolar family history, and (iii) exposure to multiple antidepressant trials. CONCLUSION: About one-quarter to one-third of bipolar patients may be inherently susceptible to antidepressant-induced manias. Bipolar patients with a strong genetic loading for bipolar illness whose initial illness begins in adolescence or young adulthood may be especially at risk. Further efforts are needed to better identify high-vulnerability subgroups and differentiate illness-specific from medication-specific factors in mood destabilization.

Affect↗
PubMed2001

Carnitine levels and the ketogenic diet.

PURPOSE: To determine the long-term effect of the ketogenic diet (KD) on carnitine levels and whether carnitine depletion is a significant cause of clinical complications during KD initiation or treatment. METHODS: Carnitine levels at 0, 1, 6, 12, and 24 months of diet treatment, carnitine antiepileptic drug (AED) history, lowest blood glucose and time to achieve ketosis during diet initiation, and diet complications were analyzed for 38 consecutive patients who initiated the KD from May 1997 to March 2000. Carnitine levels at follow-up were analyzed for eight patients started on the diet before to May 1997. RESULTS: Total carnitine (TC) at diet initiation correlated negatively with the number of AEDs at diet initiation but not with number of past AEDs, lowest blood glucose, or time to ketosis. TC decreased in the first months of diet treatment and then stabilized or increased slightly with long term treatment. Only 19% of patients were supplemented with carnitine for low TC. No patient showed clinical signs of carnitine deficiency. CONCLUSIONS: Multiple AED exposure lowers TC, but actual TC deficiency in patients initiating the KD is not common, and TC levels do not appear to predict hypoglycemia or problems achieving ketosis. Mild carnitine depletion may occur early in KD treatment and occasionally TC decreases out of the normal range, without clinical symptoms. TC stabilizes or increases back toward baseline with long-term treatment, and most patients do not require carnitine supplementation.

Adolescent↗
PubMed1996

Transfusion and cytomegalovirus-associated AIDS-defining disease in hemophiliacs. Hemophilia Malignancy Study.

BACKGROUND: Whether transfusion increases the risk of AIDS-defining cytomegalovirus (CMV) infection (CMV AIDS) in immunosuppressed patients is not known. Because of concerns about the risk of transfusion transmission of CMV and potential exposure to multiple strains of CMV through transfusion, the National Hemophilia Foundation recently recommended that CMV-negative blood be used in human immunodeficiency virus-positive hemophiliacs, regardless of their CMV serologic status. Although the multiple strains of CMV cause different CMV disease manifestations in transplant recipients, there are no data on CMV disease in human immunodeficiency virus-positive hemophiliacs. STUDY DESIGN AND METHODS: It was hypothesized that if the transmission of CMV through transfusion causes CMV disease in human immunodeficiency virus-positive hemophiliacs, then hemophiliacs with CMV AIDS would be more likely to have received transfusions than those with AIDS-defining disease not caused by CMV (non-CMV AIDS). The number and type of transfusions were evaluated in 334 hemophiliacs with AIDS (35 with CMV AIDS and 299 with non-CMV AIDS) enrolled in the multicenter Hemophilia Malignancy Study. RESULTS: There were no differences between hemophiliacs with CMV AIDS and those with non-CMV AIDS in age, type, and severity of hemophilia; the proportion receiving transfusions; or the mean number of units transfused. These findings persisted after correction for transfusion practice, (i.e., CMV-unscreened blood vs. CMV-negative and/or white cell-reduced blood). There was no difference between the groups in CMV lgG titers or in the proportion who were CMV seropositive, and there was no difference between these parameters in those who had received transfusion(s) and those who had not. CONCLUSION: Transfusion appears to have little, if any, effect on the development of CMV AIDS or CMV lgG seroprevalence in patients with hemophilia.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Systemic and local inflammation in patients with unstable atherosclerotic plaques.

The response to injury in the vasculature and the heart is inflammation. Atherosclerosis is often the result of injury followed by inflammation and atherosclerosis. Vascular and myocardial infections from various pathogens, including viruses, bacteria, chlamydia, and other infections result in vascular inflammation and almost certainly play a role in the development of atherosclerosis and acute coronary heart disease syndromes in at least some patients. Current evidence favors prior exposure to multiple pathogens as most likely playing a role in initiating inflammation and contributing to atherosclerosis. Genetic predisposition is almost certainly an important factor in the development of inflammation, impaired endothelial vascular repair, vascular infection, thrombosis, and atherosclerosis. The aging process itself is most likely associated with altered vascular and myocardial defense mechanisms predisposing to inflammation. The oxidation of cholesterol and low-density lipoprotein (LDL) leads to the production of oxidized radicals that promote vascular inflammation. Interventional injury, including angioplasty and stenting, causes endothelial inflammation, thrombosis, and fibroproliferation. Systemic evidence of inflammation identifies patients at high risk of future coronary events, including those who appear to be healthy initially as well as those with stable and unstable coronary heart disease syndromes. Increases in serum C-reactive protein (CRP) identify individuals at risk for future vascular events, including unstable angina, acute myocardial infarction, acute cerebrovascular accident, and sudden death. Similarly, systemic elevations in serum troponin 1, serum amyloid-like protein, fibrinogen, and interleukins-1, 2, 6, 8, and 18 identify patients with unstable angina and non-Q-wave myocardial infarction at increased risk for future coronary events. The presence of vascular inflammation may be detected by identifying temperature heterogeneity within plaques that demonstrate inflammation. In the future, the local evaluation of atherosclerotic plaques to detect the presence of inflammation coupled to measurements of systemic markers of inflammation, such as C-reactive protein, may help identify patients at increased risk and allow both local and systemic therapies that reduce their risk and prevent the development of acute coronary syndromes in at least some patients.

Arteriosclerosis↗
PubMed2003

Modified iliofemoral approach for major isolated acetabular revision arthroplasty.

Multiple specialized exposures have been described for revision total hip arthroplasty. In this article, we report on a series of 7 patients who underwent major isolated acetabular revision surgery through a modified iliofemoral approach. The use of this approach was deemed desirable because of the individual pathology present in each case, particularly major acetabular bone loss (Paprosky 2C/3B). However, successful reconstruction was achieved in all cases with the most frequent complication being meralgia paresthetica.

Acetabulum↗