INDICATIONS OF TISSUE SPECIFICITY IN A TRANSPLANTABLE SARCOMA

1. A sarcoma of the mouse which has proved to be transplantable to a great variety of strains of mice does not furnish an exception to the theory that transplantability is controlled by genetic factors, since this tumor possesses some characteristics that are more than probably genetic. 2. The phenomenon of the assumption of tissue specificity on the part of the host may possibly be of genetic origin. 3. The evidence suggests that the gonads have some influence on the assumption of tissue specificity on the part of the host. 4. The growth rate of the transplanted tumor may possibly be correlated with the genetic constitution of the host.     

Genetic consultations in primary care: GPs' responses to three scenarios

OBJECTIVE: This study investigated general practitioners' responses to three scenarios in which patients consulted regarding genetic conditions. DESIGN: Self-completed postal study. Setting. Primary care in Northern Ireland. SUBJECTS: Questionnaire were distributed to all the GPs in Northern Ireland (n = 1079). A total of 541 GPs participated (50%). MAIN OUTCOME MEASURES: Responses to three scenarios in which patients consulted regarding their family history and risk of bowel cancer, breast cancer, and cystic fibrosis. RESULTS: Most GPs correctly identified the patients' risk of bowel cancer, recommended regular colonoscopy, advised lifestyle changes, and did not refer to the genetic clinic. GPs who were qualified for longer were more likely to recommend colonoscopy and less likely to advise lifestyle changes. With the breast cancer patient GPs adopted a cautious approach; most would refer to the genetic and mammography clinics. With the cystic fibrosis example, most correctly identified the patient's risk of carrying the gene, would refer to the genetic clinic, and would encourage the patient to discuss the risk with his partner. In general, doctors were unsure, but would pass on genetic information to insurance companies if requested. CONCLUSION: The study suggests that, in most cases, general practitioners correctly identify at-risk individuals but there may still be some uncertainty regarding referrals. The results suggest that ways of educating GPs should be explored. Educational interventions should be linked to a greater understanding of factors involved in referral (including the influence of gender and experience). The guidelines provided to GPs in relation to the provision of genetic information to insurance companies may need to be reviewed in some countries.     

Genetic information in the workplace. Implications for occupational health surveillance.

Rapid progress in understanding the human genome has made individual genetic information accessible through genetic testing. Different types of genetic testing may be encountered in the workplace. Genetic screening examines individuals for specific inherited characteristics. Genetic monitoring evaluates individuals for acquired modifications to their genetic material. A recent survey provides evidence that some employers are conducting genetic testing of their employees and using the genetic information they obtain to make employment related decisions. Occupational and environmental health nurses must be prepared to meet the challenges presented by the complex issues related to genetic information in the workplace.     

Narcolepsy and disorders of excessive somnolence

Recent studies provide valid criteria that help differentiate idiopathic narcolepsy from other disorders of excessive daytime somnolence [3]. Research to date suggests that idiopathic narcolepsy might properly be considered a disorder of excessive sleepiness with dysfunctional REM-sleep mechanisms, clinically evidenced as cataplexy and electrophysiologically recognized as SOREMPs. Given these criteria, a diagnosis can generally be made using a combination of history, PSG, and MSLT. Traditionally, the medical treatment of idiopathic narcolepsy has centered on a two-drug regimen (stimulants for sleepiness and TCAs for cataplexy and auxiliary symptoms). Some newer medications are proving efficacious for sleepiness with minimal adverse effects, whereas others may provide a single-drug regimen that simultaneously addresses sleepiness and cataplexy [18]. New research has allowed some experts to hypothesize that idiopathic narcolepsy may be the result of a genetic predisposition to autoimmune disease [176]. It is possible that aberrant genetic coding of elements in the hypocretin/orexin systems allows a sensitivity to inducible and possibly virally mediated changes, which leave cells in the lateral hypothalamus susceptible to autoimmune attack [96]. As such, genetic screening of high-risk individuals might eventually rationalize the prophylactic use of immunosuppressants in some instances. In the future, for atypical cases(poorly responsive to therapy), genetic, CSF, and brain imaging studies, and possibly even neuronal transplantation may prove beneficial in the assessment and treatment of idiopathic narcolepsy.     

Cancer genetics: consultants' perceptions of their roles, confidence and satisfaction with knowledge

RATIONALE, AIMS AND OBJECTIVES: Genetic testing for susceptibility for common cancers is widely available. Cancer specialists and specialists in other areas may have a role in identifying and referring patients who would benefit from a consultation with a specialist in genetics. This study aimed to find out which consultants believed that genetic testing was relevant to their practice. We also wanted to determine their views of their roles in relation to genetic testing, their confidence in these roles, and the value of different educational tools. METHODS: This was a self-completed, cross-sectional, postal survey of all the consultants in Northern Ireland (n=520, response rate=59.3%) identified from the Central Services Agency list. RESULTS: Three hundred and ninety questionnaires were returned (44%). A total of 28.6% did not complete the questionnaire stating that genetics was not relevant to their practice. Few consultants reported having consultations related to genetic disease, receiving training in genetics and referring to genetics services. There was some dissatisfaction with their current knowledge of genetics and they believed that guidelines and educational tools may be useful. The respondents lacked confidence in undertaking some of their roles. Through their responses to the cancer scenarios, these consultants showed that they would offer appropriate advice and referrals. Many consultants did not know if family history information should be provided to insurance companies. CONCLUSIONS: Some consultants may require further training to enable them to fulfil their roles in relation to genetics. Tools or guidelines to assist with referral decisions may also be useful. Consultants may need clearer guidance regarding the provision of family history information to insurance companies.     

Do allelic variants of SLC6A14 predispose to obesity?

Obesity is arguably the world's most prevalent nutritional disorder and is a substantial contributor to morbidity and early mortality. Obesity is known to have a strong genetic component, but the specific influential genes in humans are largely unknown. A new paper describes a genetic variant that appears as though it may cause some people to be fatter or thinner than others (see the related article beginning on page 1762). This commentary considers the strength of the evidence in support of this finding and discusses additional research questions that should be addressed in further evaluations of this genetic variant as a putative contributor to human obesity.     

Molecular diagnostics of genetic eye diseases

Eye diseases can be simple or complex, and mostly of heterogeneous molecular genetics. Some eye diseases are caused by mutations in a single gene, but some diseases, such as primary open angle glaucoma, can be due to sequence variations in multiple genes. In some diseases, both genetic and epigenetic mechanisms are involved, as was recently revealed in the mechanism of retinoblastoma. Disease causative mutations and phenotypes may vary by ethnicity and geography. To date, more than a hundred candidate genes for eye diseases are known, although less than 20 have definite disease-causing mutations. The three common genetic eye diseases, primary open angle glaucoma, age-related macular degeneration, and retinitis pigmentosa, all have known gene mutations, but these account for only a portion of the patients. While the search for eye disease genes and mutations still goes on, known mutations have been utilized for diagnosis. Genetic markers for pre-symptomatic and pre-natal diagnosis are available for specific diseases such as primary open angle glaucoma and retinoblastoma. This paper reviews the molecular basis of common genetic eye diseases and the available genetic markers for clinical diagnosis. Difficulties and challenges in molecular investigation of some eye diseases are discussed. Establishment of ethnic-specific disease databases that contain both clinical and genetic information for identification of genetic markers with diagnostic, prognostic, or pharmacological value is strongly advocated.     

Statistical considerations for analysis of microarray experiments

Microarray technologies enable the simultaneous interrogation of expressions from thousands of genes from a biospecimen sample taken from a patient. This large set of expressions generates a genetic profile of the patient that may be used to identify potential prognostic or predictive genes or genetic models for clinical outcomes. The aim of this article is to provide a broad overview of some of the major statistical considerations for the design and analysis of microarrays experiments conducted as correlative science studies to clinical trials. An emphasis will be placed on how the lack of understanding and improper use of statistical concepts and methods will lead to noise discovery and misinterpretation of experimental results.     

Genetic consultations in primary care: GPs’ responses to three scenarios

Objective This study investigated general practitioners’ responses to three scenarios in which patients consulted regarding genetic conditions. Design. Self-completed postal study. Setting. Primary care in Northern Ireland. Subjects Questionnaire were distributed to all the GPs in Northern Ireland (n=1079). A total of 541 GPs participated (50%). Main outcome measures Responses to three scenarios in which patients consulted regarding their family history and risk of bowel cancer, breast cancer, and cystic fibrosis. Results. Most GPs correctly identified the patients’ risk of bowel cancer, recommended regular colonoscopy, advised lifestyle changes, and did not refer to the genetic clinic. GPs who were qualified for longer were more likely to recommend colonoscopy and less likely to advise lifestyle changes. With the breast cancer patient GPs adopted a cautious approach; most would refer to the genetic and mammography clinics. With the cystic fibrosis example, most correctly identified the patient's risk of carrying the gene, would refer to the genetic clinic, and would encourage the patient to discuss the risk with his partner. In general, doctors were unsure, but would pass on genetic information to insurance companies if requested. Conclusion The study suggests that, in most cases, general practitioners correctly identify at-risk individuals but there may still be some uncertainty regarding referrals. The results suggest that ways of educating GPs should be explored. Educational interventions should be linked to a greater understanding of factors involved in referral (including the influence of gender and experience). The guidelines provided to GPs in relation to the provision of genetic information to insurance companies may need to be reviewed in some countries.     

Genetic and Genomic Testing in Clinical Practice: What You Need to Know

The clinical applications of genetic testing are growing rapidly and they now account for a significant percentage of total laboratory testing procedures. Many clinicians are uncomfortable with the types and applications of genetic tests and the dependable resources that are available for self‐education. Furthermore, Direct to Consumer genetic testing has presented several challenges to healthcare providers as consumers now have an access to tests that they may not fully understand and results they may act upon inappropriately. This article presents some of the issues and resources to help nurses navigate this changing landscape.     

Mitochondrial dysfunction and migraine: evidence and hypotheses

The molecular basis of migraine is still not completely understood. An impairment of mitochondrial oxidative metabolism might play a role in the pathophysiology of this disease, by influencing neuronal information processing. Biochemical assays of platelets and muscle biopsies performed in migraine sufferers have shown a decreased activity of the respiratory chain enzymes. Studies with phosphorus magnetic resonance spectroscopy ((31)P-MRS) have demonstrated an impairment of the brain oxidative energy metabolism both during and between migraine attacks. However, molecular genetic studies have not detected specific mitochondrial DNA (mtDNA) mutations in patients with migraine, although other studies suggest that particular genetic markers (i.e. neutral polymorphisms or secondary mtDNA mutations) might be present in some migraine sufferers. Further studies are still needed to clarify if migraine is associated with unidentified mutations on the mtDNA or on nuclear genes that code mitochondrial proteins. In this paper, we review morphological, biochemical, imaging and genetic studies which bear on the hypothesis that migraine may be related to mitochondrial dysfunction at least in some individuals.     

Possibility of gene-specific treatment for hereditary arrhythmic diseases]

Recent genetic and molecular technology have shown that genetic abnormalities related to the cardiac ion channels can be a cause of some hereditary arrhythmic diseases. Until now, advanced analysis has proceeded especially in congenital long QT syndrome, and six different subtypes have been identified in Romano-Ward syndrome and 2 subtypes in Jervell & Lange-Nielsen syndrome. Since the mechanism of QT interval prolongation in each subtype is based on the malfunction of different cardiac ion channels, the same pharmacological treatment may show different antiarrhythmic effects for each subtype. In this paper, we review some of the hereditary arrhythmic diseases and discuss the possibility of gene-specific treatment in such diseases.     

Microalbuminuria: A Genetic Link Between Diabetes and Cardiovascular Disease?

Non-insulin-dependent diabetes is associated with a 2–3 fold increased risk of cardiovascular disease. The poor relationship between this risk and either glycaemic control or diabetes duration suggests that some other aspect of the diabetic state, and not hyperglycaemia per se, mediates this risk. This other aspect of diabetes does not comprise alterations in recognized cardiovascular risk factors such as blood pressure or lipids, as the major component of the excess risk is in those diabetics with low levels of the other risk factors. It thus appears that there may be some factors that predispose both to diabetes and to cardiovascular disease. In insulin-dependent diabetics most of the excess risk of cardiovascular disease occurs in subjects with proteinuria, and microalbuminuria or proteinuria in non-insulin-dependent diabetics also substantially increases cardiovascular risk. Although changes in recognized risk factors in diabetics with nephropathy may partly explain these observations, we and others have shown that microalbuminuric non-diabetics also have a markedly increased prevalence of cardiovascular disease and substantially increased cardiovascular mortality. The observations that in insulin-dependent diabetics nephropathy shows family clustering and that these patients have elevated sodium lithium counter-transport rate, a possible genetic marker for the vascular complications of hypertension, have led to the suggestion that microalbuminuria may be a marker of a genetic predisposition to vascular disease. However, in a recent population study, we have found that microalbuminuric men are substantially shorter than normoalbuminuric men, raising instead the possibility that early environmental influences, in utero or in early neonatal life, may predispose to microalbuminuria in similar fashion to recent work which has associated low fetal and neonatal growth rate with both diabetes and other cardiovascular risk factors. Future work may determine the respective genetic and environmental contributions to microalbuminuria and to cardiovascular risk.     

Regulation of serum paraoxonase activity by genetic,nutritional, and lifestyle factors in the general population

BACKGROUND: Paraoxonase may protect lipoproteins and cell membranes from peroxidation, and alterations in the activity of this enzyme have been associated with some chronic diseases. Serum paraoxonase appears to be mainly under genetic control, but some studies suggest that environmental factors may also modulate its activity. The aim of the present study was to investigate whether diet and lifestyle affect serum paraoxonase activity. METHODS: We studied a population-based sample of 388 individuals (194 women and 194 men; age range, 18-75 years) and assessed their daily dietary intake using a 3-day estimated food record. The variables studied included serum paraoxonase activity, paraoxonase polymorphisms at positions 55 and 192, age, gender, smoking status, physical exercise, body mass index, energy consumption, nutrient intake (total lipids, saturated fatty acids, beta-carotenes, vitamins C and E), and serum lipid concentrations. RESULTS: Multiple linear regression analysis showed that only genetic polymorphisms, serum cholesterol, HDL-cholesterol concentrations, and cigarette smoking were significant predictors of serum paraoxonase activity. HDL-cholesterol concentrations were also related to body mass index, daily energy consumption, and saturated fatty acid intake. CONCLUSIONS: The between-individual variability of serum paraoxonase activity is regulated mainly by genetic determinants. Although HDL-cholesterol and tobacco smoking may contribute to the modulation of this enzyme, the other nutritional and lifestyle factors do not seem to play a significant role.     

Microalbuminuria: a genetic link between diabetes and cardiovascular disease?

Non-insulin-dependent diabetes is associated with a 2-3 fold increased risk of cardiovascular disease. The poor relationship between this risk and either glycaemic control or diabetes duration suggests that some other aspect of the diabetic state, and not hyperglycaemia per se, mediates this risk. This other aspect of diabetes does not comprise alterations in recognized cardiovascular risk factors such as blood pressure or lipids, as the major component of the excess risk is in those diabetics with low levels of the other risk factors. It thus appears that there may be some factors that predispose both to diabetes and to cardiovascular disease. In insulin-dependent diabetics most of the excess risk of cardiovascular disease occurs in subjects with proteinuria, and microalbuminuria or proteinuria in non-insulin-dependent diabetics also substantially increases cardiovascular risk. Although changes in recognized risk factors in diabetics with nephropathy may partly explain these observations, we and others have shown that microalbuminuric non-diabetics also have a markedly increased prevalence of cardiovascular disease and substantially increased cardiovascular mortality. The observations that in insulin-dependent diabetics nephropathy shows family clustering and that these patients have elevated sodium lithium counter-transport rate, a possible genetic marker for the vascular complications of hypertension, have led to the suggestion that microalbuminuria may be a marker of a genetic predisposition to vascular disease.(ABSTRACT TRUNCATED AT 250 WORDS)     

Racial differences in venous thromboembolism

Summary. The incidence of venous thrombosis (VTE) varies by race, with African‐Americans having over 5‐fold greater incidence than Asian‐ancestry populations, and an intermediate risk for European and Hispanic populations. Known racial differences in genetic polymorphisms associated with thrombosis do not account for this gradient of risk, nor do known racial variations in environmental risk factors. Data on the incidence of and risk factors for VTE outside of Europe and North America and in non‐European ancestry populations are sparse. Common genetic polymorphisms in European‐Ancestry populations, such as factor V Leiden and prothrombin G20210A, and environmental risk factors, such as obesity, may account for some of the increased risk in European populations, and high factor VIII, high von Willebrand factor and low protein C levels and increased prevalence of obesity may explain some of the increased risk in African‐Americans. The low rates in Asian populations may be partially explained by low clinical suspicion in a perceived low‐risk population and lack of access to healthcare in other populations. As risk factors for thrombosis, such as surgery and treatment for cancer, are applicable to more people, as obesity increases in prevalence in the developing world, and as surveillance systems for VTE improve, VTE may increase in previously low‐risk populations. While differences in VTE by race due to genetic predisposition will probably always be present, understanding the reasons for racial differences in VTE will help providers develop strategies to minimize VTE in all populations.     

In utero stem cell transplantation: two steps forward but one step back?

The concept of in utero stem cell transplantation has provided hope that at least some of the genetic disorders which can be diagnosed prenatally can be treated before the pathological sequelae become manifested. Our increasing knowledge of haematopoietic stem cell biology has provided further possibilities for optimising this transplant procedure. However, the relatively poor success rate achieved using this procedure has prompted some to suggest that there may be fetal rejection of donor cells via an immune mechanism. However, the prevailing evidence from both animal models and from human cases, suggest that there may be other mechanisms which are preventing successful engraftment in some disorders and these must be addressed if the procedure is to receive further attention. The ability to achieve sustained engraftment after in utero transplantation will have relevance for those seeking to use gene therapy as an alternative therapeutic stratagem.     

The Abuse of Rest as a Therapeutic Agent

Abstract

Sudden cardiac death (SCD) due to ventricular tachyarrhythmias is an important cause of mortality in the United States, 4% of which occurs in patients with structurally normal hearts. At least some arrhythmias are caused by ≥ 1 mutation in 1 of the genes that control electrical conduction through the heart by altering calcium homeostasis or depolarization or repolarization gradients in the ventricle. Although SCD may be the first presentation, patients may often present with symptoms of palpitations or hemodynamic compromise, such as dizziness, seizure, or syncope, particularly following exertion. They may also be made aware of possibly having the condition due to symptoms in other family members. The primary care physician is ideally placed to investigate these symptoms, including detailed clinical and family histories and examining the baseline electrocardiogram. In all inherited cardiac death syndromes, first-degree relatives should be referred to a cardiologist, and should undergo testing appropriate for the condition. While management of patients at risk of SCD largely centers on risk stratification and, if necessary, insertion of an implantable cardioverter-defibrillator, there are a number of other treatments being developed. β-Blockers are often very effective in preventing arrhythmic episodes associated with catecholaminergic polymorphic ventricular tachycardia and some subtypes of long QT syndrome. In certain situations, calcium channel blockers may also be used. Quinidine and isoproterenol can be useful in treating Brugada syndrome. Left cervicothoracic stellectomy may occasionally be used in the treatment of long QT syndrome. As the genetic basis of these diseases becomes known, genetic testing is forming an increasingly important part of diagnosis, and gene-specific therapy is an area under investigation.     

Recent developments in the management of patients at risk for sudden cardiac death

Sudden cardiac death (SCD) due to ventricular tachyarrhythmias is an important cause of mortality in the United States, 4% of which occurs in patients with structurally normal hearts. At least some arrhythmias are caused by ≥ 1 mutation in 1 of the genes that control electrical conduction through the heart by altering calcium homeostasis or depolarization or repolarization gradients in the ventricle. Although SCD may be the first presentation, patients may often present with symptoms of palpitations or hemodynamic compromise, such as dizziness, seizure, or syncope, particularly following exertion. They may also be made aware of possibly having the condition due to symptoms in other family members. The primary care physician is ideally placed to investigate these symptoms, including detailed clinical and family histories and examining the baseline electrocardiogram. In all inherited cardiac death syndromes, first-degree relatives should be referred to a cardiologist, and should undergo testing appropriate for the condition. While management of patients at risk of SCD largely centers on risk stratification and, if necessary, insertion of an implantable cardioverter-defibrillator, there are a number of other treatments being developed. β-Blockers are often very effective in preventing arrhythmic episodes associated with catecholaminergic polymorphic ventricular tachycardia and some subtypes of long QT syndrome. In certain situations, calcium channel blockers may also be used. Quinidine and isoproterenol can be useful in treating Brugada syndrome. Left cervicothoracic stellectomy may occasionally be used in the treatment of long QT syndrome. As the genetic basis of these diseases becomes known, genetic testing is forming an increasingly important part of diagnosis, and gene-specific therapy is an area under investigation.