Genetic counselling and the intention to undergo prophylactic mastectomy: effects of a breast cancer risk assessment.

Scientific reports suggest that women at risk for familial breast cancer may benefit from prophylactic mastectomy. However, few data are available about how women decide upon this clinical option, and in particular, what role an objective risk assessment plays in this. The purpose of the present study is to assess whether this objective risk information provided in genetic counselling affects the intention for prophylactic mastectomy. Additionally, the (mediating) effects of breast cancer worry and perceived risk are investigated. A total of 241 women completed a questionnaire before and after receiving information about their familial lifetime breast cancer risk in a genetic counselling session. Path analysis showed that the objective risk information had a corrective effect on perceived risk (beta=0.38; P=0.0001), whereas the amount of breast cancer worry was not influenced by the counselling session. The objective risk information did not directly affect the intention for prophylactic mastectomy. The intention was influenced by perceived risk after counselling (beta=0.23; P=0.002), and by the precounselling levels of perceived risk (beta=0.27; P=0.00025) and breast cancer worry (beta=0.32; P=0.0001), that is, higher levels of perceived risk and breast cancer worry imply a stronger intention for prophylactic mastectomy. A personal history of breast cancer did not directly influence the intention for prophylactic mastectomy, but affected women who had undergone a mastectomy as surgical treatment were more positively inclined to have a prophylactic mastectomy than women who had had breast-conserving therapy. The impact of objective risk information on the intention for prophylactic mastectomy is limited and is mediated by perceived risk. Important determinants of the intention for prophylactic mastectomy were precounselling levels of breast cancer worry and perceived risk, suggesting that genetic counselling is only one event in the entire process of decision making. Therefore, interventions aimed at improving decision making on prophylactic mastectomy should explicitly address precounselling factors, such as personal beliefs and the psychological impact of the family medical history.

Quasi-two-dimensional turbulence in shallow fluid layers: the role of bottom friction and fluid layer depth.

The role of bottom friction and the fluid layer depth in numerical simulations and experiments of freely decaying quasi-two-dimensional turbulence in shallow fluid layers has been investigated. In particular, the power-law behavior of the compensated kinetic energy E0(t)=E(t)e(2lambda t), with E(t) the total kinetic energy of the flow and lambda the bottom-drag coefficient, and the compensated enstrophy Omega(0)(t)=Omega(t)e(2lambda t), with Omega(t) the total enstrophy of the flow, have been studied. We also report on the scaling exponents of the ratio Omega(t)/E(t), which is considered as a measure of the characteristic length scale in the flow, for different values of lambda. The numerical simulations on square bounded domains with no-slip boundaries revealed bottom-friction independent power-law exponents for E0(t), Omega(0)(t), and Omega(t)/E(t). By applying a discrete wavelet packet transform technique to the numerical data, we have been able to compute the power-law exponents of the average number density of vortices rho(t), the average vortex radius a(t), the mean vortex separation r(t), and the averaged normalized vorticity extremum omega(ext)(t)/square root E(t). These decay exponents proved to be independent of the bottom friction as well. In the experiments we have varied the fluid layer depth, and it was found that the decay exponents of E0(t), Omega(0)(t), Omega(t)/E(t), and omega(ext)(t)/square root E(t) are virtually independent of the fluid layer depth. The experimental data for rho(t) and a(t) are less conclusive; power-law exponents obtained for small fluid layer depths agree with those from previously reported experiments, but significantly larger power-law exponents are found for experiments with larger fluid layer depths.

Paradox of a better test for Huntington's disease.

OBJECTIVES: To describe the consequences of the identification of the Huntington's disease (HD) mutation on predictive and prenatal testing. METHODS: A retrospective study was performed considering the test applicants, procedures, and results before and after the identification of the mutation. 1032 people at risk for Huntington's disease in The Netherlands were included, of whom 741 applied for the predictive test in the period 1987 to 1997 in Leiden at the Department of Clinical Genetics, and after 1994, also in the other seven clinical genetics departments in The Netherlands. Uptake, sociodemographic variables, and test results, taken before and after the mutation was identified, are described. RESULTS: The uptake of the predictive test in the period studied was 24% and for the prenatal test 2%. No differences were noted in numbers and sociodemographic data between the period before and after the mutation was identified. After an initial increase in test applicants, a decrease was seen after 1995. After 1993 a significant increase of 25% at risk test applicants and a significant decrease of prenatal exclusion tests was noticed. Only 7% asked for reassessment by mutation analysis. New problems arose after the identification of the mutation, such as the option of reassessing the risk obtained by linkage analysis, direct mutation testing of 25% at risk persons with a parent who does not wish to know, new choices regarding reproduction, and new uncertainties for carriers of intermediate and reduced penetrance alleles and for their offspring and relatives. CONCLUSIONS: Although predictive testing has become reliable and available for every person at risk since the mutation has been identified, the uptake of predictive and prenatal tests fell short of expectation, no change in sociodemographic variables was seen, and a decrease in number of applicants was noted. Furthermore, new uncertainties, psychological problems, and questions arose.

Predictive testing of 25 percent at-risk individuals for Huntington disease (1987-1997).

Before the mutation causing Huntington disease was identified, predictive testing of 25% at-risk persons with a 50% at-risk parent who did not wish to know his/her genetic status, was only possible by exclusion testing. The exclusion test, using linked markers, ensures the parent's wish not to know because the parent's risk is not changed. When mutation analysis became available in 1993, new testing options for 25% at-risk persons emerged: viz., the exclusion-definitive test and direct mutation analysis. These new tests not only disclose the risk of the test candidate, but may also change the risk of the at-risk parent and siblings. The testing options for 25% at-risk test applicants and their consequences are discussed and the testing procedures and results of testing 64 25% at-risk persons in the period 1987 to 1997 are described. Relatives received unsought information in 56% of the test procedures before and 34% after the mutation was identified. A decision tree and guidelines for predictive testing of 25% at-risk test applicants are proposed. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:662-668, 1999.

Experience in prenatal testing for Huntington's disease in The Netherlands: procedures, results and guidelines (1987-1997).

We have performed 31 exclusion tests (43 per cent) and 41 direct tests (57 per cent) in 43 couples at risk, in the period 1987 to 1997 in Leiden, The Netherlands. This resulted in termination of 28 pregnancies (39 per cent), with an increased risk. In 28 couples (65 per cent), the woman was at risk. Prenatal testing in consecutive pregnancies (mean number: 3) was performed in 15 couples (35 per cent), with a mean time interval of 15 months. Parents should make an independent choice for (every) pregnancy, although most (86 per cent) did not change their initial choice. It is important that the position of children in the same family, of whom some know their status as a result of prenatal testing, whereas others remain at risk, is taken into consideration in counselling. The relative number of exclusion tests when compared with direct tests has diminished since the mutation was identified. The prenatal exclusion-definitive test (Fig. 1) was rarely used (2/72, 3 per cent). Nowadays, direct mutation testing of the fetus only is simpler and faster and the risk of disclosure of the genetic status of the at-risk parent is only 25 per cent. This test should therefore be offered as another option and included in the international guidelines. The uptake for prenatal testing is low: for 2 per cent of the at-risk persons, 11 per cent of the tested carriers and a small group of at-risk persons wishing not to be tested themselves, prenatal testing seems an acceptable choice regarding reproduction.

Psychological distress in applicants for predictive DNA testing for autosomal dominant, heritable, late onset disorders. The Rotterdam/Leiden Genetics Workgroup.

In a comparative study on the effects of predictive DNA testing for late onset disorders, pre-test psychological distress was assessed in people at risk for Huntington's disease (HD, n = 41), cerebral haemorrhage (HCHWA-D, n = 9), breast and ovarian cancer (HBOC, n = 24), and polyposis coli (FAP, n = 45). Partners, if available, also participated in the study. Distress was measured with the subscales Intrusion and Avoidance of the Impact of Event Scale. People at risk for the neurodegenerative disorders reported more avoidance than those at risk for the cancer syndromes. People at risk for FAP and partners of those at risk for HBOC reported less intrusion than the others at risk and the other partners. Subjects who were more distressed reported more experiences with the disease in close relatives, the disease having a great impact on their lives, having considerations against predictive testing, expecting that being identified as a gene carrier would have adverse effects, and expecting relief after being identified as a non-carrier. Test candidates who expected an increase of personal problems showed higher avoidance, whereas those who could better anticipate future life as a carrier had higher intrusion levels. Generally, subjects with high distress levels are of more concern to the healthcare professional than those with low distress levels. However, high distress may reflect worrying as a mental preparation for the test result, whereas low distress may indicate denial-avoidance behaviour and poor anticipation of the test outcome. In pre-test counselling sessions, this should be acknowledged and addressed.

First experiences with genetic counselling based on predictive DNA diagnosis in hereditary glomus tumours (paragangliomas).

Hereditary glomus tumour (MIM 168,000) or paraganglioma (PGL) is a slowly progressive disorder causing benign tumour growth predominantly in the head and neck region. Though benign in nature the tumours can lead to severe morbidity. Inheritance of PGL is autosomal dominant and is strongly modified by genomic imprinting; only a paternally transmitted PGL gene leads to symptoms. A gene for PGL has recently been mapped to 11q22.3-q23. Genetic counselling on the basis of DNA linkage diagnosis was offered in an extended Dutch pedigree. Thirty-two subjects opted for further counselling, of whom 20 applied for DNA testing and participated in a standardised protocol. Sixteen cases had presymptomatic testing (paternal allele); four of these appeared to have the at risk haplotype and in two of them a glomus tumour was subsequently detected on MRI. In one case linkage results were inconclusive (recombination) and one person did not want to learn his test result. Four cases had testing for carrier status (maternal allele) of which one appeared to be a carrier. Our data show that genetic counselling gains significant accuracy when based on parent of origin, sex of the counsellee, and DNA linkage diagnosis. Moreover, a normal DNA result may prevent unnecessary worry and investigations, while an established presymptomatic diagnosis will guide adequate clinical management. The psychological impact of counselling and predictive DNA testing is unclear as yet. Further investigations into the natural history of PGL in gene carriers and into the psychological impact of DNA testing is desirable.

White matter lesions and cognitive deterioration in presymptomatic carriers of the amyloid precursor protein gene codon 693 mutation.

OBJECTIVE: To determine early manifestations of hereditary cerebral hemorrhage with amyloidosis (Dutch). DESIGN: Survey. SETTING: Neurologic outpatient department of the University Hospital Leiden in the Netherlands. PARTICIPANTS: Ten presymptomatic carriers of the amyloid precursor protein gene codon 693 mutation. MAIN OUTCOME MEASUREMENTS: Extensive neuropsychological examination and cerebral magnetic resonance imaging. RESULTS: Six subjects older than 40 years showed white matter hyperintensities on magnetic resonance imaging. Three of these six individuals had signs of cognitive deterioration. The four younger subjects (age, < 31 years) showed no abnormalities on magnetic resonance imaging or on neuropsychological examination. CONCLUSIONS: We suggest that white matter hyperintensities in hereditary cerebral hemorrhage with amyloidosis (Dutch) are probably caused by chronic ischemia due to stenosis of the meningocortical arterioles, which becomes visible on magnetic resonance imaging scans in individuals who are between the ages of 30 and 40 years. The finding of cognitive deterioration in three of 10 presymptomatic mutation carriers supports the finding that in hereditary cerebral hemorrhage with amyloidosis (Dutch), deterioration can occur without stroke. A direct relation between cognitive deterioration and white matter hyperintensities is unlikely, because only half of the individuals with white matter hyperintensities showed signs of deterioration.

Work resumption and leisure activities after cardiac rehabilitation: the development of criteria to measure social recovery.

In a multicentered trial, the authors investigated 280 cardiac patients to determine the level of recovery of their social life after they had completed a physical training program. Data on work and leisure activities (sports, hobbies, social contacts, and odd jobs) were obtained immediately before and after rehabilitation and again 12 months later by means of semistructured interviews and an inventory of leisure activities. For the analysis of leisure variables, they developed a classification procedure to assign patients to one of five categories indicating an unchanged good outcome, significant recovery, nonparticipation, significant deterioration, or an unchanged poor outcome. The results after rehabilitation showed that some patients had benefited more than others. In addition, improvement or deterioration in one aspect of social recovery appeared to be independent from other aspects. Further systematic research is needed to determine which factors influence the amount of benefit derived from rehabilitation.

Medical, social and psychological recovery after cardiac rehabilitation.

A multidisciplinary study was undertaken to determine the number of patients that recovered, deteriorated or remained unchanged during a cardiac rehabilitation programme, as assessed in medical, social and psychological terms. In addition, the relationship between the medical, social and psychological aspects of recovery were investigated. Criteria for improvement, deterioration and an unchanged condition had been developed for the different aspects of recovery. These criteria were based on the degree of change during the rehabilitation programme (expressed in an effect size index) and the outcome at completion of the programme (expressed in terms of good, moderate or poor according to external standards). Although more patients improved than deteriorated, quite a few patients remained unchanged in medical, social or psychological condition. We conclude that cardiac rehabilitation might not be necessary for some patients and is not sufficient for others. Further, the relationship between the several aspects of recovery investigated was found to be weak.