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PubMed2002

The Fawn-Hooded (FH/Wjd) rat: a genetic animal model of comorbid depression and alcoholism.

The Fawn-Hooded (FH/Wjd) rat is an inbred strain of rat that has been reported to exhibit both high immobility in the forced swim test and high voluntary ethanol intake, measures that have been periodically linked with depression and alcoholism in humans. The present paper will first present a survey of the literature and previously unpublished findings that bear on the question of whether FH/Wjd rats should be considered genetic animal models of depression and alcoholism. Subsequently, behavioral studies of the FH/Wjd rats, the non-drinking ACI/N strain, and their F1 and F2 intercrosses will be described. Under free choice conditions, the FH/Wjd rat drinks up to 6 g/kg 10% ethanol per day. This intake was sufficient to render the rats tolerant to the hypothermic effects of injected ethanol (2.5 g/kg). Rats that had been voluntarily drinking for at least 6 weeks also exhibited withdrawal-induced anxiety in the social interaction, elevated plus maze, and ultrasonic vocalization tasks. The FH/Wjd rat exhibits a 25-30% increase in alcohol intake when the alcohol is returned after a 24-h period of deprivation. It responds to drugs that are effective in humans with a reduction in alcohol intake. Therefore, the FH/Wjd rat meets most of the criteria for an animal model of alcoholism. Chronic antidepressant treatments correct several of the abnormalities exhibited by the FH/Wjd rats, including the exaggerated immobility in the forced swim test. Therefore, the FH/Wjd rats also fulfill some of the criteria for an animal model of depression. On the contrary, inbred ACI/N rats do not drink much alcohol voluntarily and are quite active in the forced swim test. The FH/Wjd and ACI/N rats were intercrossed to obtain the F1 and F2 progenies, which were then tested for alcohol intake and immobility. Alcohol intake and immobility were distributed in different patterns in the F1 and F2 progenies. Alcohol intake was intermediate in the F1 progeny, while immobility was closer to the FH/Wjd parents. In the F2 progeny, chi-square analyses indicated that the distributions were significantly different. In addition, there were no significant litter effects, indicating that maternal effects did not appear to occur. There were also no significant differences among rats with different coat colors, suggesting that the Fawn-Hooded phenotype can be separated from the measures of alcohol intake and immobility. We conclude that the FH/Wjd rat is a genetic animal model of depression and alcoholism, but that the two measures reflective of these states are under separate genetic controls.

Alcoholism↗
PubMed1992

Genetic animal models of depression and ethanol preference provide support for cholinergic and serotonergic involvement in depression and alcoholism.

The present article summarizes some comparative studies of the Fawn-Hooded (FH) rat, a potential animal model of ethanol preference, and the Flinders Sensitive Line (FSL) rat, a potential animal model of depression. Both FH and FSL rats exhibit high degrees of immobility in the forced swim test and have difficulty learning a two-way active avoidance task. However, there were no differences between the FH and FSL rats in the elevated plus maze. Studies of ethanol preference indicated high rates of ethanol intake (greater than 4 g/kg) and preference (greater than 50%) in the FH rats, but low rates of ethanol intake (less than 1.1 g/kg) and preference (less than 20%) in FSL rats. It is concluded that the FSL rats exhibit behaviors consistent with their being an animal model of depression, whereas the FH rats exhibit features consistent with their being an animal model of both depression and alcoholism. Psychopharmacological challenges indicated that both FSL and FH rats were more sensitive to the hypothermic effects of oxotremorine, a muscarinic agonist. However, FSL rats were also more sensitive to serotonergic agonists, and some of the present results and other investigators have reported serotonergic subsensitivity in the FH rats. Thus, FSL rats exhibit both cholinergic and serotonergic supersensitivity, whereas FH rats exhibit cholinergic supersensitivity but normal or reduced serotonergic sensitivity. Progeny from a genetic cross between FH and FSL rats exhibit cholinergic supersensitivity and have high ethanol preference scores. These data are consistent with genetic models suggesting that ethanol preference may be influenced by dominant genes, whereas cholinergic sensitivity may be influenced by recessive genes.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

Genetic family history assessment.

The purpose of this article is to familiarize nurses with why, how, when, and where a genetic family history assessment should be used in clinical practice. Pedigrees are diagrams that display the relationship among family members by using a combination of symbols and lines. They are used to record concisely a complete family history to identify the risk of transmitting inherited condition, to identify people at risk for development of adult-onset conditions, to aid in clinical diagnosis, and to serve as a reference for social and biologic relationships. A detailed explanation of the standardized pedigree nomenclature that was recommended by the Pedigree Standardization Task Force in 1995 is included. Step-by-step guidelines on taking a genetic family history and drawing pedigrees are provided. A case study is also included to illustrate pedigree construction.

Adult↗
PubMed1991

The WHO Task Force on Vaccines for Fertility Regulation. Its formation, objectives and research activities.

Over the past 18 years, the WHO Task Force on Vaccines for Fertility Regulation has been supporting basic and clinical research on the development of birth control vaccines directed against the gametes or the preimplantation embryo. These studies have involved the use of advanced procedures in peptide chemistry, hybridoma technology and molecular genetics as well as the evaluation of a number of novel approaches in general vaccinology. As a result of this international, collaborative effort, a prototype anti-HCG vaccine is now undergoing clinical testing, raising the prospect that a totally new family planning method may be available before the end of the current decade.

Animals↗
PubMed1990

Mouth asymmetry during speech of epileptic patients who have undergone carotid amytal testing.

Asymmetry in the opening of the two sides of the mouth during speech has been suggested as an observable correlate of lateralization of cerebral speech motor control. For 24 epileptic patients who suffered speech disturbance only during left hemisphere carotid amytal anesthetization, 22 showed the expected greater opening of the right side of the mouth during a repetition task. However, all four of the patients who suffered speech disturbance following only right hemisphere anesthetization, and 8 of the 11 "bilateral speech" patients, also showed greater opening of the right side of the mouth. The speech dominant patients may, however, have genetic left speech dominance but a pathology-forced shift of some components of language to the right hemisphere. Basic mouth asymmetry, as measured here, may primarily reflect lateralization of a component of the motor/speech/language control system that may not be shifted by pathology in epileptic patients sustaining early brain insult. Relative change in mouth asymmetry as the speech task becomes more demanding may, however, be a more sensitive indicator or cerebral asymmetries for language in pathological cases.

Adolescent↗
PubMed1997

Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium.

OBJECTIVE: To provide recommendations for cancer surveillance and risk reduction for individuals carrying mutations associated with hereditary nonpolyposis colon cancer (HNPCC). PARTICIPANTS: A task force with expertise in medical genetics, oncology, primary care, gastroenterology, and epidemiology convened by the Cancer Genetics Studies Consortium (CGSC), organized by the National Human Genome Research Institute (previously the National Center for Human Genome Research). EVIDENCE: Studies evaluating cancer risk, surveillance, and risk reduction in individuals genetically susceptible to colon cancer were identified using MEDLINE and bibliographies of articles thus identified. Indexing terms used were "genetics" in combination with "colon cancer," and "screening" in combination with "cancer family" and "HNPCC." For studies evaluating specific interventions, quality of evidence was assessed using criteria of the US Preventive Services Task Force. CONSENSUS PROCESS: The task force developed recommendations through discussions over a 14-month period. CONCLUSIONS: Efficacy of cancer surveillance or other measures to reduce risk in individuals who carry cancer-predisposing mutations is unknown. Based on observational studies, colonoscopy every 1 to 3 years starting at age 25 years is recommended for individuals known to have HNPCC-associated mutations. Endometrial cancer screening is also recommended, based on expert opinion concerning presumptive benefit. No recommendation is made for or against prophylactic surgery (ie, colectomy, hysterectomy); these surgeries are an option for mutation carriers, but evidence of benefit is lacking. It is recommended that individuals considering genetic testing be counseled regarding the unknown efficacy of measures to reduce risk and that care for individuals with cancer-predisposing mutations be provided whenever possible within the context of research protocols designed to evaluate clinical outcomes.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Aneuploidy: a report of an ECETOC task force.

Aneuploidy plays a significant role in adverse human health conditions including birth defects, pregnancy wastage and cancer. Although there is clear evidence of chemically induced aneuploidy in experimental systems, to date there are insufficient data to determine with certainty if chemically induced aneuploidy contributes to human disease. However, since there is no reason to assume that chemically induced aneuploidy will not occur in human beings, it is prudent to address the aneugenic potential of chemicals in the safety assessment process. A wide range of methods has been described for the detection of chemically induced aneuploidy including subcellular systems, tests with fungi, plants and Drosophila as well as in vitro mammalian systems and in vivo mammalian somatic and germ cell assays. However, none of these methods is sufficiently validated or widely used in routine screening. Underlying the efforts to develop aneuploidy-specific assays is the presumption that current genetic toxicology tests do not detected chemicals that have aneuploidy-inducing potential. To address this, we have critically evaluated data from standard genetic toxicology assays for 16 known or suspected aneugens. The conclusions from the review are listed below. 1. At present there are only nine chemicals that can be classified as definitive aneugens, as determined by positive results in in vivo rodent assays. 2. As expected, the majority of definitive and suspected aneugens are negative in the bacterial mutation assay. 3. The majority of definitive aneugens evaluated induce polyploidy in vitro. With few exception, they also induced structural chromosome aberrations in vitro. 4. All of the definitive aneugens that have been sufficiently tested induce micronuclei in rodent bone marrow cells in vivo. A number of these chemicals also induced structural chromosome aberrations in vivo. 5. There is no evidence for a unique germ cell aneugen, that is a chemical that induces aneuploidy in germ cells and not in somatic cells. Furthermore, an analysis of several databases indicates the proportion of chemicals which induce polyploidy and not chromosome aberrations in vitro is low. Based on these conclusions, the following recommendations are made: for screening purposes, a standard genotoxicity test battery (including an in vitro cytogenetic assay with an assessment of polyploidy and clastogenicity at the same harvest time) should be performed; in the absence of polyploidy induction in vitro no further evaluation of aneuploidy-inducing potential is needed; if polyploidy is observed, in vitro follow-up testing to investigate further the aneuploidy-inducing potential should be conducted; such follow-up testing will generally start with the conduct of a standard in vivo somatic cell micronucleus assay; if the in vivo somatic cell micronucleus assay is negative, with adequate evidence of exposure of the bone marrow to the test compound, no further testing of aneuploidy-inducing potential is needed; if the in vivo somatic cell micronucleus assay is positive, further information on mechanisms of micronucleus induction can be obtained by using kinetochore/centromeric staining in vitro and/or in vivo; an assessment of potential germ cell aneuploidy activity may then be considered; aneuploidy induction which does not involve the direct interaction of a chemical or its metabolite(s) with DNA is expected to have a threshold. This must be considered in the risk assessment of such chemicals; this is not addressed by current risk assessment guidelines.

Abnormalities, Drug-Induced↗
PubMed1997

Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium.

OBJECTIVE: To provide recommendations for cancer surveillance and risk reduction for individuals carrying mutations in the BRCA1 or BRCA2 genes. PARTICIPANTS: A task force with expertise in medical genetics, oncology, primary care, gastroenterology, and epidemiology convened by the Cancer Genetics Studies Consortium (CGSC), organized by National Human Genome Research Institute (previously the National Center for Human Genome Research). EVIDENCE: Studies evaluating cancer risk, surveillance, and risk reduction in individuals genetically susceptible to breast and ovarian cancer were identified using MEDLINE (National Library of Medicine) and from bibliographies of articles thus identified. Indexing terms used were "genetics" in combination with "breast cancer," "ovarian cancer," and "screening," or "surveillance" in combination with "cancer family" and "BRCA1" and "BRCA2." For studies evaluating specific interventions, quality of evidence was assessed using criteria of the US Preventive Services Task Force. CONSENSUS PROCESS: The task force developed recommendations through discussions over a 14-month period. CONCLUSIONS: Efficacy of cancer surveillance or other measures to reduce risk in individuals who carry cancer-predisposing mutations is unknown. Based on expert opinion concerning presumptive benefit, early breast cancer and ovarian cancer screening are recommended for individuals with BRCA1 mutations and early breast cancer screening for those with BRCA2 mutations. No recommendation is made for or against prophylactic surgery (eg, mastectomy, oophorectomy); these surgeries are an option for mutation carriers, but evidence of benefit is lacking, and case reports have documented the occurrence of cancer following prophylactic surgery. It is recommended that individuals considering genetic testing be counseled regarding the unknown efficacy of measures to reduce risk and that care for individuals with cancer-predisposing mutations be provided whenever possible within the context of research protocols designed to evaluate clinical outcomes.

Antineoplastic Agents, Hormonal↗
PubMed1993

Genetic information and health insurance. Report of the Task Force on Genetic Information and Insurance. NIH/DOE Working Group on Ethical, Legal, and Social Implications of Human Genome Research.

One of the ironies in the current health care coverage crisis is that developing more accurate biomedical information could make things worse rather than better. In the current American health care system, information about an individual's risk of disease plays a crucial role for many people in determining access to health care coverage. This link between the likelihood of needing health care and the ability to obtain coverage for that care has the unfortunate result that those most in need may have the greatest difficulty finding affordable health care coverage. New advances in human genetics are transforming medicine by making available increasing amounts of such information about risk. Biomedical science and the delivery of health care are being reshaped by advances in our understanding of human genetics. New insights into health and disease, new diagnostic and prognostic tests and the possibility of new therapies reflect significant investments by the public and by private business and are no longer limited to the uncommon disorders traditionally labeled as "genetic diseases." Among the first products of genetic research is information useful in predicting the likelihood that an individual will develop particular diseases, opening the door both to preventive strategies that we would welcome, such as changes in diet and exercise patterns, and to the unwelcome possibility of genetic discrimination. Injecting information about genetic risks into the current health care system could result in ever more refined risk rating by insurers and ever greater difficulty in finding affordable health care coverage for large numbers of people. At a minimum, people could be discouraged from obtaining genetic information that might be useful in disease prevention and early treatment or for case planning and management because that same information could jeopardize their access to health care coverage in general, or to treatment for a condition excluded from coverage because it was "pre-existing." Under other circumstances people might be compelled to provide genetic information as a condition of obtaining affordable health care coverage. Genetic risk information carries an additional, wider burden because information about an individual's genetic health risks may also be information about the risks of children, parents, brothers, sisters, and other relatives. One suggested approach--providing special protection for genetic information--is unlikely to succeed. This special protection has been suggested because of the relevance of genetic information to family members and its implications for reproductive choices, potential discrimination and stigmatization.(ABSTRACT TRUNCATED AT 400 WORDS)

Discrimination, Psychological↗
PubMedDate not supplied

U.S. newborn screening policy dilemmas for the twenty-first century.

Newborn screening has traditionally referred to biochemical testing for inherited disorders, generally metabolic in origin, that are usually correctable by dietary or drug interventions. As new tests have been developed, state public health newborn screening systems have slowly evolved without the benefit of national policies. Thus, newborn screening program changes, when viewed nationally, have been uncoordinated. The net result has been unequally applied mandated screening and, consequently, unequal availability of related public health disease prevention services. Technological advances in laboratory testing over the past 10 years have resulted in limited program changes in some state newborn screening systems, and even greater program disparities. A recent Newborn Screening Task Force identified numerous issues of concern and proposed elements for a plan of action involving public health programs, healthcare providers, and consumers. This minireview details past policy history in newborn screening and identifies some of the current issues confronting programs as they seek to move ahead with the technologies and medical treatments for the twenty-first century.

Genetic Privacy↗
PubMed2001

The ACVD task force on canine atopic dermatitis (IV): environmental allergens.

Numerous environmental allergens have been incriminated in the pathogenesis of canine atopic dermatitis (AD). These include dust and storage mite antigens, house dust, pollens from grasses, trees and weeds, mould spores, epidermal antigens, insect antigens, and miscellaneous antigens such as kapok. In this paper, we review the literature concerning the allergens that have been reported to contribute to canine AD. We conclude that attempts to identify the relevant canine antigens in the past have been plagued by a lack of standardisation of extracts and techniques, and the presence of false-positive and -negative reactions in allergy tests. Until these problems are rectified, it is unlikely that we will be able to provide a list of major and minor antigens for dogs. Hence, we recommend that future studies should be aimed at determining the major patterns of reactivity and cross-reactivity to specific protein allergens within antigenic extracts using electrophoresis and immunoblotting techniques. Once this information becomes available, it may be possible to use a selection of genetically engineered, highly pure antigens for both diagnostic and therapeutic purposes in canine allergy investigations. The use of such antigens will allow standardisation of canine allergy testing and immunotherapy so that the reliability and efficacy of these procedures can be objectively assessed.

Air Pollutants↗
PubMed1996

Colorectal cancer screening.

The decision whether to launch a screening program in asymptomatic patients of average risk for colorectal cancer and the selection of the appropriate protocol for screening are complex issues. There are still many unanswered questions. Many organizations such as the American Cancer Society, the World Health Organization Collaborating Center for the Prevention of Colorectal Cancer, and the U.S. National Cancer Institute advocate screening with annual Hemoccult tests and screening with flexible sigmoidoscopy every 3 to 5 years in patients more than 50 years of age. The U.S. Preventive Services Task Force, the Canadian Task Force on Periodic Health Examination, and the International Union Against Cancer have not recommended screening asymptomatic average-risk patients for colorectal cancer. One study showed a small but significant benefit (3 per 1000) of the rehydrated annual Hemoccult test in reducing mortality from colorectal cancer. To embark on a mass screening strategy as recommended, however, would require significant costs, increases in physician training, improved access to the requisite technology, and enhancements in patient and physician compliance. Furthermore, the high false-positive rates of the rehydrated Hemoccult tests would lead to many unnecessary tests, causing greater expense as well as patient discomfort and anxiety. It is, therefore, premature to recommend mass screening for colorectal cancer in asymptomatic individuals at this time. Further research is needed to identify risk factors (such as genetic markers) better and to develop and evaluate screening strategies targeted at those with high risk for colorectal cancer. In the meantime, efforts at primary prevention for the general population should be increased (through nutrition and exercise). Patients over the age of 50 who desire screening should be given information of the benefits and risks of screening and together with their physicians decide on a screening strategy that suits their needs and values.

Colonoscopy↗
PubMed1976

Efforts in cancer diagnosis: national task forces--large bowel cancer.

Current information from the National Large Bowel Cancer Project and other sources is given concerning new leads and avenues of research that may be used in early diagnosis or possibly in monitoring therapy. The search for biological markers has developed in two general directions: (1) to identify by genetic studies patients with a high probability of developing cancer who will provide insight into biochemical changes as premalignant lesions develop into frankly developed cancer, and (2) to fine differences between tissue and body fluid constituents in normal subjects and patients with cancer. Screening for colon cancer is discussed with a selective diagnostic approach and with emphasis on this approach in early diagnosis of asymptomatic high risk patients.

Adult↗
PubMed2001

Strain and gender differences in the behavior of mouse lines commonly used in transgenic studies.

The present study was aimed at establishing behavioral differences between three inbred mouse strains (129S2/SvHsd, C57BL/6JOlaHsd, FVB/NHsd) and two F1 hybrid lines derived from them (129 x C57BL/6 and 129 x FVB). The choice of the given strains was based on the frequent use of these mice in transgenic research. For the behavioral phenotyping, we employed a test battery consisting of the following models: elevated plus-maze (EPM), open field (OF), light-dark exploration, spontaneous locomotor activity, rota-rod (RR), Porsolt's forced-swimming test (FST), and Morris water task. Significant variations between the strains were established in all tests. Anxiety-like behavior was more pronounced in the 129S2/Sv and 129 x C57BL/6 mice, the FVB/N mice were spontaneously hyperactive, the best coordination ability was demonstrated by the C57BL/6 and 129 x C57BL/6 groups. A good performance in the learning test was established in both hybrid lines and the 129S2/Sv mice, whereas the well-known visual impairment of the FVB strain was confirmed by low performance in spatial and non-spatial tasks. Differences related to the gender were revealed occasionally; most importantly, 129 x C57BL/6 males had a higher anxiety level than their female counterparts in the EPM. Several other gender dissociations suggest the strain and task specificity. In conclusion, we would like to highlight the importance of the genetic background and gender of mice for the molecular biological and pharmacological studies and also the need for well-established testing protocols to obtain wide information at the first stage of behavioral screening of genetically modified mice.

Animals↗
PubMed2001

Mastering the value chain. An interview with Mark Levin of Millennium Pharmaceuticals. Interview by David Champion.

As today's business leaders are all too aware, a new scientific or technological break-through can quickly transform an industry's competitive landscape. The upheaval is often traumatic for the companies involved, forcing them to rethink their strategies and redefine their boundaries. But an industry in flux also creates vast opportunities. To seize them, companies must see how the current upheavals will affect the future distribution of profits--and then reinvent themselves to capitalize on the new sources of value. In this interview with HBR senior editor David Champion, Mark Levin, the founder and CEO of Millennium Pharmaceuticals, describes his vision of the future of the pharmaceutical industry in the wake of the genetics revolution and new technologies that have altered the economics of drug development. No company, he argues, will create serious long-term value by staying in just one or two stages of the value of chain. That's why Millennium, which started out doing basis research into genes and proteins and selling its findings to pharmaceutical giants, has moved downstream - toward the patients who actually use and pay for the drugs. He explains why the research end has become less lucrative than the more mechanical tasks of identifying, testing, and manufacturing molecules. Levin talks about the changes Millennium has undergone since its inception in 1993-from 30 workers to more than 1,000, and from one end of the value chain to the other. He discusses the company's cultural transformations as well as the partnerships and acquisitions that have helped millennium become involved in every stage of the chain-from gene to patient. Levin's vigorous approach to balancing long-term strategy with short-term tactics offers important lessons to any executive facing an industry upheaval.

Drug Design↗
PubMed1997

Reduced Mg2+ inhibition of Ca2+ release in muscle fibers of pigs susceptible to malignant hyperthermia.

The inhibitory effect of myoplasmic Mg2+ on Ca2+ release from the sarcoplasmic reticulum (SR) was examined in mechanically skinned skeletal muscle fibers from pigs of different ryanodine-receptor (RyR) genotypes. In fibers from pigs homozygous for the normal RyR allele, the free Mg2+ concentration ([Mg2+]) had to be lowered from the normal resting level of 1 to approximately 0.1 mM to induce Ca2+ release and a force response. Fibers from pigs heterozygous or homozygous for the RyR allele associated with malignant hyperthermia (MH) needed only a smaller reduction in free [Mg2+] to induce Ca2+ release (reduction to 0.1-0.2 and > or = 0.2 mM, respectively). Dantrolene (20 microM) counteracted the effect of this reduced Mg2+ inhibition in MH muscle. The response of muscle fiber bundles to the caffeine-halothane contracture test in the three genotypes correlated well with the responsiveness of single fibers to reduced [Mg2+]. Thus the abnormal responsiveness of MH muscle to various stimuli may largely result from the reduced ability of myoplasmic Mg2+ to inhibit Ca2+ release from the SR.

Animals↗
PubMed1998

Genetic effects on task performance, but not on age polyethism, in a swarm-founding eusocial wasp

Division of labour among workers in insect societies often includes two major components: age-related changes in behaviour (age polyethism) and specialization in task performance. The aim of this study was to test whether similarity in inside-nest task performance and in rate of age polyethism correspond to genetic similarity among nestmates in the polygynous eusocial wasp Polybia aequatorialis.Behavioural data were collected on marked, known-age workers from three source colonies introduced into two observation colonies in the field. Genetic similarity among workers was assessed by quantifying sharing of random amplified polymorphic DNA (RAPD) marker alleles. Workers were categorized by whether they engaged in nest cleaning as an indicator of individual differences in inside-nest task performance. Within source colonies, workers that performed nest-cleaning tasks were more genetically similar to each other than they were to workers not performing these tasks. Workers also differed in their rates of passage through the age-related task sequence, but no association was found between sharing of RAPD marker alleles and rate of age polyethism. These results accord with earlier studies demonstrating flexibility in age polyethism in swarm-founding wasps, and with findings that worker genotypic variability corresponds to specialization in task performance in P. aequatorialis. Polybia spp. workers rarely switch among tasks, even in response to changes in colony conditions, and workers' genotypes may constrain flexibility in task performance at the individual level. Conversely, colonies may accrue benefits from having genotypically diverse worker forces, which could favour the maintenance of polygyny in swarm-founding wasps.Copyright 1998 The Association for the Study of Animal Behaviour.

Journal Article↗