High frequency of BRCA1/2 germline mutations in 42 Belgian families with a small number of symptomatic subjects

AIM: The initial risk assessments for BRCA1/2 mutation carriers and estimates of carrier frequencies were based on extended pedigrees with a large number of symptomatic subjects. When counselling based on BRCA gene mutation analysis was initiated, we faced requests for counselling mostly from members of small families with only two or three affected members. We report on the likelihood of finding a BRCA mutation in such small families. METHODS: In the first 100 families that came for oncogenetic counselling since September 1994, a BRCA1/2 gene mutation screen was initiated if there were two or more symptomatic first degree relatives, if one of them had ovarian cancer, or if one breast cancer was diagnosed before the age of 50 years. RESULTS: BRCA gene mutations were found and confirmed by sequencing in 14 out of 42 families (33%); 10 mutations were in the BRCA1 gene and four in the BRCA2 gene. Our findings indicate an increased probability of detecting a BRCA gene mutation when ovarian cancer occurred in the family. There is no increased probability of detecting a mutation with increasing numbers of breast cancers. Only 22% of the eligible presymptomatic family members opted for testing. The presymptomatic female carriers currently prefer breast surveillance rather than prophylactic surgery. CONCLUSION: BRCA1/2 gene mutation testing can be done with reasonable efficiency in the Belgian population when there are two symptomatic family members. The availability of testing does not lead to a high frequency of requests for testing by presymptomatic family members.     

Estimation of dynamical model parameters taking into account undetectable marker values

Background  

Mathematical models are widely used for studying the dynamic of infectious agents such as hepatitis C virus (HCV). Most often, model parameters are estimated using standard least-square procedures for each individual. Hierarchical models have been proposed in such applications. However, another issue is the left-censoring (undetectable values) of plasma viral load due to the lack of sensitivity of assays used for quantification. A method is proposed to take into account left-censored values for estimating parameters of non linear mixed models and its impact is demonstrated through a simulation study and an actual clinical trial of anti-HCV drugs.     

The muscular membrane and calcium activation of the contractile system of a lamellibranch smooth muscle (ABRM)

1. Thin bundles of fresh ABRM treated by EDTA solution or Triton x-100 0.1% can be brought like glycerol-extracted fibres through contraction-relaxation cycles by changing the free Ca2+ level of the bathing medium for 10-6 M to 10-9 M. The kinetics of isometric force development and relaxation has been studied in the two conditions i.e ionic strength 0.06 pH 6.5 and ionic strength 0.28, pH 7.0 which are known to induce the catch-state in glycerol extracted fibres. When the low Ca-2+ solution (10-9M) is substituted for the high Ca-2+ solution (10-6M) immediately after the maximal force has been developed, relaxation occurs at a higher rate at ionic strength 0928 and pH 6.5. In this last condition, no tension redevelops after a quick release applied during the slow relaxation. 2. During the plateau, in presence of Ca-2+ 10-6 M. a quick release applied at any time is followed by a large redevelopment of tension at ionic strength 0.06 and pH 6.5. At ionic strength 0.28 and pH 7.0, the tension redevelops only during the decreased from 10-6 to 10-9 M without any change in the time course of the tension maintained. 3. These results suggest that in EDTA and Triton X-100 treated fibres of Abrm, the catch-state is spontaneously induced after the activation of the contractile mechanism under the same conditions of ionic strengh and pH as in glycerol extracted fibres. However, in the EDTA and Triton treated fibres, the presence of a high free Ca-2+ level is not necessary to maintain the tension in the catch-state induced at ionic strength 0.28 and pH 7.0.     

Deficient expression of enhanced reactivation of parvovirus H-1 in ataxia telangiectasia cells irradiated with X-rays or u.v. light

Cells of patients with ataxia telangiectasia (AT), an inheriteddisease characterized by a high propensity to cancer, are hypersensitiveto ionizing radiation. We investigated whether the hyper-radiosensitivityof AT cells correlated with a defect in their constitutive and/orconditional ability to rescue a damaged exogenous virus. Forthat purpose, parvovirus H-1, a single-stranded DNA virus whoseintranuclear replication mostly relies on host cell functions,was used as a probe. The survival of u.v.-or -irradiated H-1was measured in X-, u.v.- or mock-irradiated human cells ofnormal (NB-E) or AT (AT5BIVA) origin. -irradiated H-1 survivedto similar extents in untreated normal and AT cell lines. BothX- and u.v.-irradiatlon induced normal cells to achieve an enhancedreactivation (ER) of -- or u.v.-damaged H-1. In contrast, neitherdose-effect curves nor time course revealed significant levelsof ER expression after X- or u.v.-irradiation in AT5BIVA cells.Our results suggest that the impairment of ER of damaged parvovirusesmay constitute a marker of the AT cell phenotype and be relatedto the radiosensitivity of AT cells.     

Determinants of attrition in a pediatric healthy lifestyle intervention: The CIRCUIT program experience

IntroductionAttrition in pediatric weight management programs is notoriously high. Greater understanding of its determinants is needed to inform retention strategies. We identified determinants of attrition in CIRCUIT, a healthy lifestyle intervention program for youth at risk of cardiovascular disease.MethodsA one-arm intervention study of children aged 4-18 years who initiated the CIRCUIT program in the first five years of its existence (N = 403). We defined attrition as attending the baseline visit but ceasing attendance prior to the 1-year follow-up. Potential determinants of dropout included the child’s age, sex, ethnicity, body mass index (BMI) z-score, family socio-demographic characteristics, and estimated driving time to the program, all measured at baseline. Associations were estimated bivariately, using chi-squared- and t-tests, and simultaneously in a multivariable logistic regression model.ResultsOf the 403 participants who started the program, 198 (49%) dropped out within 12 months of enrollment. Youth who dropped out were older (mean age 12.8y vs. 11.3y; p < 0.01), were less likely to live with both parents (62% vs. 71%; p = 0.05), and to have mothers who had completed high school (79% vs. 88%; p = 0.01). No group differences were observed for sex, ethnicity, baseline BMI z-score, fathers’ education, or driving time to the program. In multivariate models, only older age at initiation of the intervention (OR: 1.2; CI: 1.1,1.3) and lower maternal education (OR: 2.0; CI: 1.0,3.8) were associated with dropout.ConclusionImproved tailoring of interventions to older pediatric participants and to families of lower maternal education may help reduce attrition in CIRCUIT and similar lifestyle intervention programs.     

Rural and urban variation in psychological distress among adults: results of the 2014–2015 Eastern Townships Population Health Survey (ETPHS)

ObjectiveA growing number of people live in urban areas. Urbanization has been associated with an increased prevalence of mental disorders, but which mechanisms cause this increase is unknown. Psychological distress is a good indicator of mental health. This study sought to examine the relationship between urbanization and distress among adults in the Eastern Townships (southern region of Quebec, Canada).MethodIn the 2014–2015 Eastern Townships Population Health Survey (N = 10,687 adults living in one of the 96 Eastern Townships communities), distress was measured with the K6 distress scale (≥ 7). Urbanization was estimated by the residential density of the community treated in quintiles. Logistic regression analyses were carried out with adjustments for individual and environmental characteristics.ResultsWomen, young people aged 18–24, single parents, those without diplomas, those without a job, those with < $20,000 in income, adults with two or more chronic physical illnesses, adults with bad perceived health, or those living in disadvantaged neighbourhoods exhibited more distress. The unadjusted estimate between density and distress is only significant for the fifth quintile when compared with the first quintile (OR 1.23; 95% CI: 1.06–1.42). The relationship is practically the same after controlling for individual characteristics but decreases considerably after controlling for environmental characteristics (lack of trees, social deprivation, intersection density, vegetation index, and land use mix).ConclusionThis study was the first to examine an association between urbanization and distress by considering individual and environmental characteristics. The latter seem to explain the relationship between these concepts.     

Atrial natriuretic peptides in canine hypoxic pulmonary vasoconstriction

STUDY OBJECTIVE--The aim of the study was to investigate whether atrial natriuretic peptides have a physiological role in regulation of the pulmonary circulation. DESIGN--Plasma concentrations of immunoreactive atrial natriuretic peptide and guanosine-3',5'-cyclic monophosphate (cGMP) were measured during evaluation of pulmonary vascular tone by multipoint pulmonary arterial pressure-cardiac index (Ppa/Q) relationships. SUBJECTS--Experimental animals were 17 mongrel dogs of either sex, 21-35 kg weight, anaesthetised with pentobarbitone. MEASUREMENTS and MAIN RESULTS--Measurements of Ppa/Q relationships and atrial natriuretic peptide/cGMP were made during hyperoxia (Fio2 0.4) and hypoxia (Fio2 0.1). Hypoxic pulmonary vasoconstriction, defined as hypoxia induced increase in pulmonary artery pressure over the entire range of Q studied from 2-5 litre.min-1.m-2, was elicited in nine dogs ("responders"). In the other eight dogs, hypoxia did not change pulmonary artery pressure over the entire range of Q studied ("non-responders"). At neither the highest nor the lowest Q in hyperoxia did atrial natriuretic peptide and cGMP concentrations differ between these two groups, nor did acute reduction in Q affect the concentrations in either group. At the highest Q, plasma atrial natriuretic peptide increased in hypoxia from 11(SEM 2) to 15(3) pmol.litre-1 in the responders (p less than 0.05), and from 15(2) to 20(2) pmol.litre-1 in the non-responders (p less than 0.05). However at the lowest Q, atrial natriuretic peptide was increased in non-responders only, from 17(3) to 23(4) pmol.litre-1 (p less than 0.05). CGMP did not vary significantly in any experimental condition. CONCLUSIONS--Hypoxia slightly increased plasma atrial natriuretic peptides without any relationship with associated pulmonary haemodynamic changes. These data do not support the hypothesis that atrial natriuretic peptides play a physiological role in the regulation of the pulmonary circulation in dogs.     

Diffusion of information about genetic risk within families

Recent developments in genetics are likely to exacerbate the ethical issues in clinical practice, especially with regard to privacy and disclosure of genetic information. To evaluate the behaviour of patients with respect to transmitting carrier information, we undertook a survey of 283 families with a balanced chromosomal rearrangement as a model. In these families, 1816 relatives were considered at risk and 806 of them were karyotyped (44.4%). The percentage of karyotypes performed is significantly related to the number of living children of the index couple, the reason for referral, the nature of the anomaly, the training of the counsellor and the age of the index case. This study shows the limits of the screening of at risk individuals within families, based on the willingness of the patients, and addresses practical and ethical issues around family disclosure in medical genetics.     

Increased monocyte-dependent suppression of polyclonal activation of B lymphocytes from cystinotic children

In infantile cystinosis the amino acid cystine preferentially accumulates in phagocytic cells, polymorphonuclear leucocytes (PMN) and monocytes, rather than in lymphocytes. We previously described functional abnormalities in the oxidative metabolism and locomotion of cystinotic PMN and monocytes. The present study shows an abnormal lymphocyte polyclonal activation as evidenced by a decreased immunoglobulin (Ig) production and generation of Ig-containing cells (ICC) in cultures of peripheral blood mononuclear cells (PBMC) from cystinotic children upon stimultion with pokeweed mitogen andStaphylococcus aureus Cowan I. However, monocyte depletion from cystinotic PBMC fully reconstituted Ig production and ICC generation, indicating: (1) the presence of an increased monocyte-dependent suppression on lymphocyte polyclonal activation, and (2) that the intrinsic ability of cystinotic lymphocytes to respond to polyclonal stimulation was preserved. The increased cystinotic monocytedependent suppressive effect was not mediated by prostaglandin E₂ (PGE₂) since its production by cystinotic PBMC upon polyclonal activation was not different from that of controls. In addition, the sensitivity of cystinotic lymphocytes to the immunosuppressive effect of varying concentrations of exogenous PGE₂ was similar to that of controls. Finally, indomethacin and 2-mercaptoethanol, two agents able to scavenge hydroxyl (OH) radicals, restored Ig production by cystinotic PBMC, suggesting a role for reactive oxygen species in the increased cystinotic monocyte-dependent suppression.