NORGESTOMET AND ESTRADIOL VALERATE INDUCED LUTEOLYSIS IS DEPENDENT UPON THE UTERUS C. A. Peterson, J. C. Huhn, and D. J. Kesler SUMMARY Beef heifers were assigned to three groups: 1) untreated controls (n= 4), 2) Syncro-Mate B® (SMB) treated (n= 5), and 3) hysterectomized and SMB treated (n= 4). SMB was administered eight or nine days after estrus, approximately 30 days after hysterectomy. This study was conducted to determine if the uterus was necessary for SMB to induce luteolysis. SMB induced premature luteolysis as only 20% of the intact SMB treated heifers had ≥ .75 ng/mL of progesterone seven days after the time of SMB treatment compared to all (100%) of the untreated heifers (P <.05). By nine days after the time of SMB treatment, 25% of the untreated heifers and none (0%) of the intact SMB treated heifers had ≥ .75 ng/mL of progesterone; however, all (100%) of the hysterectomized SMB treated heifers had ≥ .75 ng/mL of progesterone (P <.05). Therefore, SMB-induced luteolysis required the involvement of the uterus. The luteolysin, prostaglandin F2α, is probably the secretion from the uterus that mediates the SMB-induced luteolysis. SMB treatment, however, required 7-8 days to induce luteolysis. INTRODUCTION Syncro-Mate B® (SMB) is a commercially available procedure to synchronize estrus in beef and dairy cattle. The procedure consists of a norgestomet implant and an intramuscular injection containing norgestomet and estradiol valerate administered at the time of implantation. SMB has three known mechanisms of action. First, an estrus suppression dosage of norgestomet diffuses from the implant during the nine days in situ (Kesler and Favero, 1995). Secondly, the injection causes atresia of antral follicles and recruitment of a new cohort of follicles four to five days after administration (Vasconcelos et al., 1997). Thirdly, the injection causes regression of corpora lutea (Kesler and Favero, 1995). Since the implant is left in place for nine days, the injection is needed to induce regression of corpora lutea in cows during the first half of the estrous cycle. Estradiol-17β, the active metabolite of the estradiol valerate contained within the SMB injection, has been demonstrated to hasten corpus luteum regression (Thatcher et al., 1986). Thatcher et al. (1986) reported spikes of 15-keto- 13, 14-dihydro-prostaglandin F2α (PGFM) in the peripheral blood before luteolysis ensued and concluded that estradiol-17β induced luteolysis by provoking a release of PGF2α from the uterus; however, Thatcher et al. (1986) administered estradiol-17β during the second half of the estrous cycle. Progesterone treatment during metestrus has also been reported to shorten the estrous cycle, but only by four days (Woody et al., 1967; Harms and Malven, 1969; Ginther, 1970; Battista et al., 1984; Garrett et al., 1988). The objective of this study was to determine if the hypothesis that SMB induced luteolysis is dependent upon uterine involvement was correct. MATERIALS AND METHODS Three groups of purebred Angus beef heifers from the University of Illinois beef research unit (Urbana, IL) were included in this study. The control group (n=4) was selected from a larger group of estrus-cycling females administered prostaglandin F2α (25 mg Lutalyse®; Pharmica and Upjohn, Kalamazoo, MI, USA) due to their similar timing of estrus (detectable estrus within 48 hours of each
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Microsoft powerpoint - evaluations.ppt [compatibility mode]IARC Monographs on the Evaluation of Carcinogenic IARC Monograph Evaluations experimental animals other relevant data Sufficient evidence Sufficient evidence • Mechanistic data "weak," Limited evidence Limited evidence "moderate," or "strong"? Inadequate evidence Inadequate evidence Evidence suggesting lack of Evidence suggesting lack of • Mechanism likely to be operative in humans? Overall evaluation Carcinogenic to humans Probably carcinogenic to humans Possibly carcinogenic to humans Not classifiable as to its carcinogenicity to humans Probably not carcinogenic to humans Evaluating human data experimental animals other relevant data — Preamble Part B, Section 6(a) Causal relationship has been established Sufficient evidence Chance, bias, and confounding could be ruled out with reasonable confidence Causal interpretation is credible Limited evidence Chance, bias, or confounding could not be ruled out Inadequate evidence Studies permit no conclusion about a causal association Several adequate studies covering the full range of Evidence suggesting exposure levels are mutually consistent in not showing a lack of carcinogenicity positive association at any observed level of exposure Conclusion is limited to cancer sites and conditions studied Identifying human tumour sites Sufficient evidence There is sufficient evidence in humans for the carcinogenicity of tobacco smoking. Tobacco smoking causes cancer of the lung, oral cavity, naso-, oro- and hypopharynx,.
Sufficient evidence and ESLC There is sufficient evidence in humans for the carcinogenicity of tamoxifen. Tamoxifen causes cancer of the endometrium. An inverse relationship has been established between exposure to tamoxifen and cancer of the female breast.
There is limited evidence in humans for the carcinogenicity of Ethylene Oxide. A positive association has been observed between exposure to Ethylene Oxide and cancers of the breast and lymphatic and haematopoietic malignancies.
Evaluating experimental animal data experimental animals other relevant data — Preamble Part B, Section 6(b) Causal relationship has been established through either: Sufficient evidence - Multiple positive results (2 species, studies, sexes of GLP)- Single unusual result (incidence, site/type, age, multi-site) Data suggest a carcinogenic effect but: (e.g.) single study, Limited evidence benign tumours only, promoting activity only Inadequate evidence Studies permit no conclusion about a carcinogenic effect Adequate studies in at least two species show that the Evidence suggesting agent is not carcinogenic lack of carcinogenicity Conclusion is limited to the species, tumour sites, age at exposure, and conditions and levels of exposure studied Identifying animal tumour sites The Working Group considers that a causal relationship has been established between the agent and an increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms originating from the same organ in (a) two or more species of animals or (b) two or more independent studies in one species carried out at different times or in different laboratories or under different protocols.
An increased incidence of tumours originating from the same organ in both sexes of a single species in a well-conducted study, ideally conducted under Good Laboratory Practices, can also provide A single study in one species and sex might be considered to provide sufficient evidence of carcinogenicity to identify tumour sites when malignant neoplasms occur to an unusual degree with regard to incidence, site, type of tumour or age at onset, or when there are strong findings of tumours at multiple sites.
Applying these criteria for the evaluation of carcinogenicity to a species and target site-specific level, the WG identifies sites established as causally related.
Evaluating mechanistic and other data experimental animals other relevant data — Preamble Part B, Section 6(c) Have the mechanistic events been established? Are there • Are the mechanistic consistent results in different experimental systems? Is the overall database coherent? Has each mechanism been challenged experimentally? Do studies demonstrate that suppression of key mechanistic processes leads to suppression of tumour development? Are there alternative explanations? Could different • Is the mechanism mechanisms operate in different dose ranges, in humans likely to be operative and experimental animals, or in a susceptible group? Note: an uneven level of support for different mechanisms may reflect only the resources focused on each one experimental animals other relevant data Sufficient evidence Sufficient evidence • Mechanistic data "weak," Limited evidence Limited evidence "moderate," or "strong"? Inadequate evidence Inadequate evidence Evidence suggesting lack of Evidence suggesting lack of • Mechanism likely to be operative in humans? Overall evaluation Carcinogenic to humans Probably carcinogenic to humans Possibly carcinogenic to humans Not classifiable as to its carcinogenicity to humans Probably not carcinogenic to humans The plenary sessions will combine the human and experimental evaluations EVIDENCE IN EXPERIMENTAL ANIMALS Group 1 (carcinogenic to humans) Group 2B (possibly carcinogenic) (exceptionally, Group 2A) Group 3 (not classifiable) Mechanistic data can be pivotal when the human data are not conclusive EVIDENCE IN EXPERIMENTAL ANIMALS 1 strong evidence in 2A belongs to a mechanistic class where other members are classified in Groups 1 or 2A Group 2B (exceptionally, Group 2A) 1 strong evidence in 2A belongs to a 2A belongs to a mechanistic class mechanistic class 2A strong evidence 2B with supporting 2B with strong … mechanism also operates in humans other relevant data other relevant data 4 consistently and 3 strong evidence … strongly supported by a broad range of other relevant data Diesel engine exhaust (V 105)
The Working Group concluded that there was "sufficient evidence" in humans for the carcinogenicity of diesel-engine exhaust. "sufficient evidence" in experimental animals for the carcinogenicity of whole diesel-engine exhaust, of diesel- engine exhaust particles and of extracts of diesel-engine exhaust particles.
"strong evidence" for the ability of whole diesel-engine exhaust to induce cancer in humans through genotoxicity.
Diesel engine exhaust is carcinogenic to humans (Group 1) Polychlorinated biphenyls (V 107)
The Working Group concluded that there was "sufficient evidence" in humans for the carcinogenicity of polychlorinated biphenyls. "sufficient evidence" in experimental animals for the carcinogenicity of PCB126, PCB118, Aroclor 1260, Aroclor 1254, and Kanechlor 500.
Strong evidence of an AhR-mediated mechanism of carcinogenesis identical to that of 2,3,7,8-TCDD.
Polychlorinated biphenyls are carcinogenic to humans (Group 1) Dioxin-like polychlorinated biphenyls are carcinogenic to humans Shift-work, Overall Evaluation Vol. 98
6.1 Cancer in humans
There is limited evidence in humans for the
carcinogenicity of shiftwork that involves night 6.2 Cancer in experimental animals
There is sufficient evidence in experimental animals
for the carcinogenicity of light during the daily dark period (biological night).
6.3 Overall evaluation
Shiftwork that involves circadian disruption is
probably carcinogenic to humans (Group 2A) Arsenic, Vol 84, Section 3
There is limited evidence in experimental animals for the carcinogenicity of sodium arsenite, calcium arsenate and arsenic trioxide.
There is inadequate evidence in experimental animals for the carcinogenicity of sodium arsenate and arsenic trisulfide.
Taken together, the studies on inorganic arsenic provide limited evidence for carcinogenicity in Lead, Vol. 97, Section 3
There is sufficient evidence in experimental animals for the carcinogenicity of lead acetate, lead subacetate, lead chromate, and lead There is inadequate evidence in experimental animals for the carcinogenicity of lead oxide and There is sufficient evidence in experimental animals for the carcinogenicity of inorganic lead "The categorization of an agent is a matter of scientific judgement . ." "It is recognized that the criteria for these evaluations cannot encompass all of the factors that may be relevant to an evaluation of carcinogenicity. In considering all of the relevant scientific data, the Working Group may assign the agent to a higher or lower category than a strict interpretation of these criteria would indicate." "These categories refer only to the strength of the evidence that an exposure is carcinogenic and not to the extent of its carcinogenic activity (potency)." Preamble Part B, Section 6 "The distinction between hazard and risk is important, and the Monographs identify cancer hazards even when risks are very low at current exposure levels, because new uses or unforeseen exposures could engender risks that are significantly higher." Preamble Part A, Section 2 You may apply an evaluation to a broad grouping of agents or to one specific agent "When the agents evaluated are considered by the Working Group to be sufficiently closely related, they may be grouped together for the purpose of a single evaluation of degree of evidence." Preamble Part B, Section 6 "In addition, when supporting data indicate that other related agents, for which there is no direct evidence of their capacity to induce cancer in humans or in animals, may also be carcinogenic, a statement describing the rationale for this conclusion is added to the evaluation narrative; an additional evaluation may be made for this broader group of agents . ." Preamble Part B, Section 6(d) "When the available epidemiological studies pertain to a mixture, process, occupation or industry, the Working Group seeks to identify the specific agent considered most likely to be responsible for any excess risk. The evaluation is focused as narrowly as the available data on exposure and other aspects permit." Preamble Part B, Section 6(a) Guidance can be found in the Preamble "The Preamble to the IARC Monographs describes the objective and scope of the programme, the scientific principles and procedures used in developing a Monograph, the types of evidence considered, and the scientific criteria that guide the evaluations." A. GENERAL PRINCIPLES AND PROCEDURES WORLD HEALTH ORGANIZATION
INTERNATIONAL AGENCY FOR RESEARCH ON CANCER
2. Objective and scope 3. Selection of agents for review IARC Monographs on the Evaluation of
Carcinogenic Risks to Humans
4. Data for the Monographs 5. Meeting participants 6. Working procedures B. SCIENTIFIC REVIEW AND EVALUATION P R E A M B L E
2. Studies of cancer in humans 3. Studies of cancer in experimental animals LYON, FRANCE
4. Mechanistic and other relevant data 6. Evaluation and rationale The text should present the Working Group's reasoning Concise statements of the principal line(s) of argument that emerge Conclusions of the Working Group on the strength of the evidence for each group of studies Citations to indicate which studies were pivotal to these conclusions Explanation of the reasoning of the Working Group in weighing data and making evaluations — Preamble Part B, Section 6(e) experimental animals other relevant data Sufficient evidence Sufficient evidence • Mechanistic data "weak," Limited evidence Limited evidence "moderate," or "strong"? Inadequate evidence Inadequate evidence Evidence suggesting lack of Evidence suggesting lack of • Mechanism likely to be operative in humans? Overall evaluation Carcinogenic to humans Probably carcinogenic to humans Possibly carcinogenic to humans Not classifiable as to its carcinogenicity to humans Probably not carcinogenic to humans
AP® STATISTICS 2011 SCORING GUIDELINES (Form B) Question 2 Intent of Question The primary goals of this question were to assess students' ability to (1) distinguish an experiment from an observational study; (2) critique statistical information, in particular whether or not researchers are justified in making a specific conclusion based on the given information; (3) recognize and describe a potential problem with a study that lacks random assignment or blinding. Solution Part (a):