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PubMed1988

Reexposure to OKT3 in renal allograft recipients.

Between 40% and 80% of patients treated with the monoclonal antibody OKT3 develop blocking antibody against its idiotypic region. Thus a major concern with the use of OKT3 as part of a baseline immunosuppressive regimen is that formation of blocking antibodies might preclude its subsequent use. Between 7/86 and 2/87, 32 patients received prophylactic OKT3 in addition to low-dose prednisone, azathioprine, and cyclosporine. Prophylactic OKT3 did not prevent rejection, as 21 of 32 patients studied developed rejection. Retreatment of 13 patients with OKT3 successfully reversed 12 rejections and lowered the number of T3-positive cells in spite of a low level of blocking antibody in two patients in this group. Of the patients analyzed, 38% developed blocking antibody on initial exposure to OKT3, but OKT3 reuse was denied only 4 patients due to the presence of these antibodies. Three of these had rejections reversed with steroids alone; the other patient lost the allograft. A high frequency of infectious complications occurred in the retreatment group, with viral infections predominating. Only one patient in the retreated group developed antibodies after the second use. Appearance of blocking antibodies after use of OKT3 as part of a base-line prophylactic immunosuppressive regimen did not significantly compromise access to OKT3 for treatment of subsequent rejection episodes, but multiple exposures to OKT3 did increase the frequency of infectious complications.

Antibodies, Anti-Idiotypic↗
PubMedDate not supplied

Hyperglycemia and retinopathy of prematurity in very low birth weight infants.

OBJECTIVE: Retinopathy of prematurity (ROP) remains a leading cause of morbidity in the very low-birth-weight (VLBW) infant. This study investigates a possible association between serum/blood glucose and the development of ROP. METHODS: A retrospective case-control study of all infants born between 1992 and 1997 at the Johns Hopkins Hospital with birth weights less than 1000 g who developed Stage 3 or 4 ROP was conducted. Controls either had Stage 1 ROP or no eye disease and were matched 2:1 with ROP patients for gestational age, birth weight and year of birth. Odds ratios (ORs) of ROP were calculated for multiple exposures over the first month after birth, including oxygen concentration (FiO(2)), blood glucose levels, vitamin E, mean airway pressure and mean blood pressure. RESULTS: In a simple logistic regression analysis, we found an increased ROP risk for: (1) each 10 mg/dl increase of mean glucose (OR 1.96; 95% CI 1.13 to 3.42), (2) each 1% increase of mean FiO(2) (OR 1.06; 95% CI 1.004 to 1.13), (3) history of dopamine infusion (OR 5.4; 95% CI 1.16 to 25.2) and (4) intraventricular hemorrhage Grade 3 or 4 (OR 7.3; 95% CI 1.53 to 34.7). Using a multiple regression model, we found an increased ROP risk for each 10 mg/dl increase of mean glucose (OR 2.7; 95% CI 1.003 to 7.27). Each IU/kg/day of vitamin E supplementation reduced ROP risk (OR 0.37; 95% CI 0.16-0.86). CONCLUSION: In this study, we could demonstrate that glucose levels in the first month of life are associated with the development of ROP. Further studies have to determine if this association is causal or if hyperglycemia is just an expression of severity of illness.

Case-Control Studies↗
PubMed1987

Early inflammatory changes in the skin of SENCAR and C57BL/6 mice following exposure to 12-O-tetradecanoylphorbol-13-acetate.

Tumor-promoting phorbol esters are potent inflammatory agents. Inflammation has long been associated with carcinogenesis, particularly the promotion phase. SENCAR mice have been bred for their sensitivity to the promotion of skin tumors by phorbol esters whereas C57BL/6 mice have been shown to be resistant. When 12-O-tetradecanoylphorbol-13 acetate (TPA) was applied to the skin of SENCAR and C57BL/6 mice, SENCAR mice had a much more intense inflammatory response than the C57BL/6 animals. There was more edema formation at the site of application and vascular permeability was also greatly enhanced in the SENCAR strain. When samples of skin were examined microscopically, a fulminant, acute inflammatory cellular infiltrate was observed in SENCAR mice. Very few inflammatory cells migrated into the skin of C57BL/6 mice. At higher doses and multiple exposures to TPA there was a hyperplastic response of the keratinocytes in C57BL/6 mice, but it was less intense than in SENCAR mice. These data demonstrate that enhanced inflammatory responses in TPA in the skin correlate with the sensitivity to the promotion of skin tumors by TPA.

Animals↗
PubMed2004

Fully three-dimensional modeling of the fabrication and behavior of photonic crystals formed by holographic lithography.

A comprehensive and fully three-dimensional model of holographic lithography is used to predict more rigorously the geometry and transmission spectra of photonic crystals formed in Epon SU-8 photoresist. It is the first effort known to the authors to incorporate physics of exposure, postexposure baking, and developing into three-dimensional models of photonic crystals. Optical absorption, reflections, standing waves, refraction, beam coherence, acid diffusion, resist shrinkage, and developing effects combine to distort lattices from their ideal geometry. These are completely neglected by intensity-threshold methods used throughout the literature to predict lattices. Numerical simulations compare remarkably well with experimental results for a face-centered-cube (FCC) photonic crystal. Absorption is shown to produce chirped lattices with broadened bandgaps. Reflections are shown to significantly alter lattice geometry and reduce image contrast. Through simulation, a diamond lattice is formed by multiple exposures, and a hybrid trigonal-FCC lattice is formed that exhibits properties of both component lattices.

Journal Article↗
PubMed1975

[Effect of the multiple administration of hydrocortisone on the ultrastructure of the lymph nodes of rabbits].

The effect of dayly multiple exposure to hydrocortison in the dose 1 mg/kg on the submicroscopic structure of the mesenteric lymphatic nodes in rabbits was studied. In contrast to a single-dose administration of the hormone, no pycnotic forms of small and middle lymphocytes were observed. Prolonged application of hydrocortison led to the appearance of atypical forms of reticular cells, an increase in the number of plasmatised lymphocytes, as well as of mature plasmatic cells. Macrophages disappear almost entirely. The number of dark lymphocytes and reticular cells with the thickened matrix of the cytoplasma and great number of ribosomes and polysomes increased considerably. Mechanisms of action of single and multiple doses of hydrocortison on the cells of lymphatic nodes was not identical.

Animals↗
PubMed2002

[Effect of exposure to tick-bites on the course of lyme borreliosis in Bialowieza residents].

UNLABELLED: The aim of the study was to evaluate relationship between clinical picture of Lyme disease and risk of Borrelia burgdorferi infection, expressed as an exposure to ticks in an endemic area of the disease. METHODS: Questionnaires regarding frequency of tick bites, symptoms of the disease in an acute phase and symptoms likely associated with previous infection were collected from 131 residents of Białowieza village, who suffered from Lyme disease in the past. RESULTS: Lower prevalence of erythema migrans and significantly higher prevalence of arthritis was demonstrated in the group of persons with the highest frequency of tick bites. Evaluation of symptoms that can be related to previous Lyme disease showed significant increase of arthralgia, myalgia, ischialgia, sleep and concentration difficulties in persons with higher frequency of tick bites. CONCLUSIONS: These results demonstrate, that multiple exposures to B. burgdorferi promote manifestation of the disease in the form of arthritis, and less frequently lead to the development of erythema migrans.

Adult↗
PubMed1987

Reaction to injectable collagen: results in animal models and clinical use.

Since its commercial release, Zyderm collagen implant has been used to treat more than 200,000 subjects in the United States for soft-tissue contour defects and more than 250,000 patients internationally (including the United States). Approximately 3 percent of subjects' skin tested with Zyderm collagen experience localized hypersensitivity reactions to collagen, whereas approximately 1 percent of treated patients demonstrate symptoms of hypersensitivity at treatment sites. Of the latter treatment responses reported since the conclusion of clinical trials with Zyderm, 56 percent occurred following the first treatment, 28 percent following the second, 10 percent following the third, and 6 percent following subsequent exposures. The data indicate that most patients receive a median of three treatments (mean = 4.4) with Zyderm collagen, but most patients who are likely to develop sensitivity to Zyderm collagen appear to respond immunologically to the test implant or first treatment exposure. Examining these treatment responses, 45 percent of the patients reported an onset of symptoms within 10 days and 22 percent at more than 30 days following the last treatment with Zyderm collagen. Erythema was the sole symptom in 24 percent of cases, whereas erythema plus induration comprised an additional 42 percent. Antibodies against Zyderm collagen were detected in the sera of 88 percent of these subjects using an ELISA, but no reactivity was observed against human collagen. Sera from patients reporting only systemic symptoms were not found to have anticollagen antibodies. These data suggest that the relative risk of a hypersensitivity reaction to Zyderm collagen does not increase with multiple exposures, since patients who are going to develop an immune response to bovine collagen react with greatest frequency to initial injections of collagen. In animal models, Zyderm collagen was shown to be less immunogenic than other medical devices which are composed of bovine collagen. Specifically, comparative studies were conducted in which Zyderm collagen and hemostatic agents were implanted in the guinea pig subcutaneum: sera from animals treated with collagen-derived hemostatic devices possessed significant levels of anti-implant antibodies (titers greater than 640), whereas animals treated with Zyderm collagen mounted minimal responses (titers less than 40). Additional studies were conducted in which implant materials were compared in a guinea pig parietal (bony defect) model and in a rabbit hemostasis model: in both, Zyderm collagen demonstrated lower immunogenicity than commercial bovine collagen hemostatic agents. Histologic results from these studies showed Zyderm

Animals↗
PubMed1997

Toxicokinetics in the National Toxicology Program.

Toxic responses to test chemicals are known to be dependent on the exposure route, the kinetic behavior of the chemical, and the dose used in the toxicology study. Therefore, knowledge of internal dose is indispensable for the interpretation of toxicology study results, for the facilitation of interspecies scaling, and for risk assessment. By monitoring the blood and/or tissue concentrations of test chemical and/or metabolites versus time after administration of study chemicals by different routes, the bioavailability and kinetic characteristic of test chemicals can be readily obtained. This data can define the so-called linear dose range using area under the plasma concentration versus time curve, clearance, or other related toxicokinetic parameters, and can also be used to predict the possible bioaccumulation under multiple dose regimes. Changes in kinetic parameters after multiple exposures indicate alteration in how the animal handles the chemical (e.g., that there was enzyme induction or inhibition). A recommended approach for conducting toxicokinetic studies generally involves three steps. Step 1 is a preliminary study, which uses a minimum number of animals to estimate the range of blood/tissue concentrations, the required quantitation limit for the analytical method, and the optimal sampling times for the definitive toxicokinetic studies. Step 2 is the definitive study and generates blood and/or tissue concentration data for calculating the toxicokinetic parameters. Step 3 is the toxicokinetic study conducted in conjunction with the toxicology study to determine the internal dose and the effects of age and continuous exposure on kinetic parameters. Examples of the application of NTP toxicokinetic evaluations were also presented in this chapter, demonstrating their use in the design and interpretation of toxicology studies.

Animals↗
PubMed2001

The effect of repeated gavage doses of fumonisin B1 on the sphinganine and sphingosine levels in vervet monkeys.

Fumonisins occur widely around the world in maize products intended for human and animal consumption posing a health hazard. Direct measurement of fumonisins in physiological fluids as a biomarker of exposure is not practicable, however fumonisins disrupt sphingoid metabolism by inhibition of sphinganine N-acyltransferase. In this study the disruption in sphinganine (Sa) and sphingosine (So) levels in plasma and urine was measured in vervet monkeys (Cercopithecus aethiops) dosed with repeated gavages of 1mg fumonisin B1 (FB1)/kg body weight three times/week continuously over a 51-day period. The plasma Sa/So ratio reached a maximum (mean of 4.3) after 30 days in the dosed monkeys with a three-fold increase above the ratio of the control monkeys and then declined slowly to double the value in controls after 51 days. The lack of a clear elevation in urinary Sa/So ratios after 51 days of multiple exposure in the dosed monkeys indicates that the plasma ratio is more sensitive than urinary changes in monkeys. This is confirmed by the plasma levels of liver function enzymes of which aspartate transaminase, glutamyl-transferase and lactate dehydrogenase were increased in the dosed monkeys, while the plasma indicators of renal function were not increased above the levels in the control monkeys. Thus repeated low doses of FB1 can cause sustained disruption of sphingoid metabolism.

Animals↗
PubMedDate not supplied

Pediatric intensive care nurses and their grief experiences: a phenomenological study.

OBJECTIVE: To describe the grief experience of pediatric intensive care nurses when their patients die. DESIGN: Heideggerian phenomenological approach; nonprobability, purposive sampling; semistructured interviews; data analyzed using Colaizzi's method of phenomenology. SETTING: Pediatric intensive care unit within a Canadian pediatric metropolitan university teaching hospital. PARTICIPANTS: Six registered nurses, currently working in the pediatric intensive care unit, who had experienced the death of at least three children for whom they had cared. Nursing experience ranged from 2 to 20 years, intensive care nursing experience from 9 months to 19 years, and tenure on the unit from 9 months to 15 years. RESULTS: Data were analyzed for recurring themes according to the procedure outlined by Colaizzi. These nurses acknowledged they suffered multiple exposures to children's death and experienced grief. The interviews revealed eight themes that included one about their grief responses--hurting; two that described the influencing contextual factors--nurse-family unit relationship and dissonance; and five that related to coping strategies used to manage their feeling of grief--self-expression, self-nurturance, termination of relationship activities, engaging in control-taking activities, and self-reflection. Further analysis revealed that managing grief effectively was an experiential learning process for the participants. CONCLUSIONS: These results demonstrate that pediatric intensive care nurses' grief is different from that of surviving family member grief. Further research is required to document in further depth the experiential learning process to coping with multiple, accumulated losses for these professional caregivers. The findings of this study also could encourage further research that examines interventions designed to enhance the type of education and support needed in relation to the grief experience of nurses.

Adaptation, Psychological↗
PubMedDate not supplied

Differential impact of naltrexone on luteinizing hormone release during single versus repetitive exposure to restraint stress.

The objective of the present study was to determine the impact of repeated exposure to the same stressor on opiate receptor-mediated inhibition of basal and stress-related alterations of pituitary LH release. Groups of intact adult male rats were exposed to 8 hr of restraint stress for either 1 or 14 consecutive days. Animals in each group were injected intravenously with the specific opioid receptor antagonist naltrexone (NALT, 2 mg/kg bodyweight) or the vehicle saline (SAL) prior to the final scheduled stress episode. Rats pretreated with SAL prior to the single exposure to stress exhibited an increase in plasma LH over the 1st hr of stress, followed by a decline in hormone levels, which reached significance between 3 and 7 hr after initiation of the stress. NALT pretreatment of rats prior to restraint significantly blunted the suppressive effect of stress on circulating LH. Rats repeatedly exposed to stress did not show any significant alteration in plasma LH levels from prestress values at any time during their final stress episode. Pretreatment of chronically stressed rats with NALT before reexposure to stress resulted in plasma hormone levels that were not different from those in animals pretreated with SAL. When the opioid antagonist was administered to animals 24 hr after termination of single or multiple exposures to restraint, NALT-induced increases in basal plasma LH were significantly attenuated in the chronically stressed rats compared to animals subjected to stress only once or not at all.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

p38 mitogen-activated protein kinase (p38MAPK) upregulates catalase levels in response to low dose H2O2 treatment through enhancement of mRNA stability.

V79 fibroblasts were repetitively stressed through multiple exposures to a low dose (30 microM) H2O2 in culture for 4 weeks. Catalase activity, protein levels and mRNA levels increased markedly (5-6-fold) during this time and these augmentations were inhibited by the simultaneous presence of SB203580, an inhibitor of p38 mitogen-activated protein kinase (p38MAPK). p38MAPK became dually phosphorylated and ATF-2, a p38MAPK substrate also became increasingly phosphorylated over the repetitive stress period. Short interfering RNA that induced effective silencing of p38MAPK, was used to silence p38MAPK in V79 fibroblasts. Silencing of p38MAPK drastically hindered the elevation in catalase (protein and mRNA) levels observed after a single low dose (50 microM) of H2O. The rise in catalase mRNA levels induced by low concentration (single and multiple dose) H2O2 treatment was established to be unconnected with transcriptional upregulation but was brought forth primarily by an enhancement in catalase mRNA stability through the action of p38MAPK. Therefore, our data strongly indicate that activation of p38MAPK is a key controlling step in the upregulation of catalase levels by low dose H2O2 treatment.

Activating Transcription Factor 2↗
PubMed1994

Effect of animal age and chronicity of interleukin-1 exposure on cartilage proteoglycan depletion in vivo.

Rheumatoid arthritis and osteoarthritis are characterized by an early depletion of cartilage proteoglycans, which leads to a decrease in cartilage compressibility and, eventually, to a loss of joint function. Interleukin-1, which is thought to have a role in mediating this loss of proteoglycans in arthritis, induces an acute depletion of proteoglycans from articular cartilage following intra-articular injection in rabbits. As the structure and metabolism of proteoglycans are known to change with age, my laboratory investigated the effect of age on depletion and recovery of proteoglycans in response to interleukin-1 in the rabbit. Loss of cartilage proteoglycans induced by interleukin-1 was less severe in immature animals, increased until the age of sexual maturity, and then remained constant. The rate of recovery and compensatory overshoot in the rate of proteoglycan synthesis following challenge with interleukin-1 was more rapid in immature animals and may have been responsible for the quicker return of the cartilage proteoglycan content to control levels in younger animals. With multiple exposures to interleukin-1 at time intervals too short for recovery to occur, smaller amounts of interleukin-1 induced loss of proteoglycans, and the proteoglycan content and the rate of synthesis remained depressed longer after treatment had stopped. The decreased ability of mature cartilage to replace proteoglycans rapidly after exposure to cytokines would increase the probability of subsequent inflammatory episodes before recovery is complete; this may result in increased susceptibility of adult cartilage to proteoglycan depletion.

Aging↗
PubMed1978

Ultraviolet light in the oncogenic transformation of cultured C3H/10T1/2 mouse embryo cells.

Skin tumors are produced in rats, mice, and humans by exposure to UV light. We developed a mouse embryo fibroblast line C3H/10T1/2, which can be transformed by chemical carcinogens, X-irradiation, UV radiation, and oncornavirus. When we irradiated these cells with 10, 25, 50, 100, 150, or 200 ergs/mm2 of UV light, neither transformation nor cytotoxicity was observed at the two lower doses. When the irradiated cells were cultured in medium containing 0.1 micrograms TPA/1 ml (a potent tumor promoter) starting from 0-120 hours after irradiation, a high frequency of transformation was always produced. When the cells were initiated with subeffective concentrations of 0.1 micrograms MCA/ml followed by UV radiation at different intervals, no transformation occurred; however, these initiated cells were transformed after TPA treatment. When we treated the cells with multiple exposures to UV light, no transformation occurred then nor when the cells were treated with TPA followed by UV irradiation at different intervals. Thus UV in our system acts as a pure initiator in the two-stage process of oncogenic transformation.

Animals↗
PubMedDate not supplied

Toxicology and immunotoxicology of mercury: a comparative review in fish and humans.

This review addresses an important area of environmental and mammalian toxicology by evaluating and comparing mercury-induced effects upon the immune responses of two evolutionarily divergent yet immunologically-related species. The mechanisms of mercury toxicology and immunotoxicology are described herein, including supporting data from the following: sources of exposure; bioavailability and biodistribution; metabolism; and laboratory and field investigations. Based upon the studies presented, the relative sensitivities of fish and human immune cells to mercury exposure are compared and contrasted with regard to mercury's ability to stimulate and/or suppress host immunocompetence. In addition, results from immune assays are compared to mercury tissue burdens, as well as to toxicological threshold level estimates. Such comparisons may help to resolve gaps in our knowledge regarding sensitivity of immunological assays, standardization of immunotoxicological techniques between species, and the extent to which the vertebrate immune system possesses functional reserve and redundancy in response to xenobiotics. A review of this type begins to provide support for the potential usefulness of fish immune cells to serve as indicators for human immunotoxicology risk assessment. Analysis of the reviewed studies supports the following conclusions in both lower and higher vertebrates: a threshold for mercury-induced immunotoxicological effects is likely; multiple exposure scenarios involving high and/or chronic exposures leading to increased body burdens are linked to increased risk of immunomodulation; and highly exposed and/or susceptible subpopulations are at greater risk of toxicological impact.

Animals↗
PubMed2003

A multicompartment model of carboxyhemoglobin and carboxymyoglobin responses to inhalation of carbon monoxide.

We have developed a model that predicts the distribution of carbon monoxide (CO) in the body resulting from acute inhalation exposures to CO. The model includes a lung compartment, arterial and venous blood compartments, and muscle and nonmuscle soft tissues with both vascular and nonvascular subcompartments. In the model, CO is allowed to diffuse between the vascular and nonvascular subcompartments of the tissues and to combine with myoglobin in the nonvascular subcompartment of muscle tissue. The oxyhemoglobin dissociation curve is represented by a modified Hill equation whose parameters are functions of the carboxyhemoglobin (HbCO) level. Values for skeletal muscle mass and cardiac output are calculated from prediction formulas based on age, weight, and height of individual subjects. We demonstrate that the model fits data from CO rebreathing studies when diffusion of CO into the muscle compartment is considered. The model also fits responses of HbCO to single or multiple exposures to CO lasting for a few minutes each. In addition, the model reproduces reported differences between arterial and venous HbCO levels and replicates predictions from the Coburn-Forster-Kane equation for CO exposures of a 1- to 83-h duration. In contrast to approaches based on the Coburn-Forster-Kane equation, the present model predicts uptake and distribution of CO in both vascular and tissue compartments during inhalation of either constant or variable levels of CO.

Adult↗
PubMed1976

Challenge of dogs with live enterotoxigenic Escherichia coli and effects of repeated challenges on fluid secretion in jejunal Thiry-Vella loops.

Dogs were evaluated as experimental models for the study of diarrheal disease produced by enterotoxigenic Escherichia coli. Although a suitable whole model for orogastric bacterial challenge could not be developed, chronic jejunal Thiry-Vella loops were used to study the secretory effects of multiple jejunal challenges with enterotoxin of either Vibrio cholerae or E. coli. The heat-stable and heat-labile E. coli enterotoxins could be differentiated clearly in this model. Sequential weekly challenges over a four-week period showed a significant decrease in loop secretory response to homologous enterotoxin, although levels of antitoxin in serum remained unchanged, a finding suggesting a local immune response. Dogs challenged with E. coli enterotoxin were markedly protected against subsequent challenge with V. cholerae enterotoxin; the converse was not true. Histologic studies of the loops showed only minimal atrophy, and results of absorption studies in the loops were normal. These studies suggest that mongrel dogs are resistant to colonization by enterotoxigenic E. coli and partially resistant to challenge with enterotoxin, perhaps on an immune basis due to prior antigenic exposure. Multiple challenges with enterotoxin effect a decreased secretory response; this finding also suggests a local immune mechanism.

Animals↗
PubMed1996

Epidemiological analysis of persistent organochlorine contaminants in cetaceans.

Information is provided to test the hypothesis that organochlorines introduced into the environment since the early 1940s could threaten the reproductive potential of baleen whales and other cetaceans. Comparisons are made using data on the role of organochlorines in a model system, the Great Lakes region of North America, and in model animals, including humans, pinnipeds, and other wildlife. DDT and PCB are used as model organochlorines with the caveat that there may be thousands of other chemicals in the environment also involved. Improved sensitivity in analytical quantification of synthetic chemicals in biological tissue has been accompanied by an increase in knowledge about biochemical processes that control development and function. The effects described in this review are the result of disrupted gene expression, not damage to the gene. The mechanisms of action of the organochlorines reveal their ability to affect developing organisms at very low concentrations during critical life stages: embryonic, fetal, and early postnatal. Exposure during early development can disrupt the organization of the endocrine, reproductive, immune and nervous systems, effecting irreversible damage that may not be expressed until the individuals reach adulthood. The recent discovery that human sperm count is declining worldwide at a rate of 1 x 10(6) sperm/(mL.yr) suggests common exposure to estrogen-like chemicals during prenatal and early postnatal development. This raises concern for other top predator species that also share the same exposure. Periods of intense feeding followed by long periods of fasting are common among species of baleen whales. This unique strategy places the embryonic and nursing calves in vulnerable positions, because under both situations maternal blood levels are elevated as a result of absorption from food intake or as a result of mobilization as fat is metabolized. Estimates of Toxic Equivalents (TEQs) based on the occurrence of four PCB congeners (118, 183, 153, 180) in sigma PCB reported in whales are highest for St. Lawrence belugas and Faroe Island long-finned pilot whales. This conservative approach reveals that some whale species are within the range of enzyme-induced TEQs at which effects have been associated with adverse health effects in other aquatic species. The epidemiological approach was used for analysis because it was developed to handle multiple exposure scenarios in which direct causal links are virtually impossible to isolate. The analysis includes the tenets of timeorder, strength of association, specificity of cause and effect, consistency, coherence, and predictive performance.

Animals↗