BRCA1 mutations in women with familial or early-onset breast cancer and BRCA2 mutations in familial cancer in Estonia

Background

The aim of this study was to identify BRCA1 and BRCA2 mutations in the Estonian population. We analyzed genetic data and questionnaire from 64 early-onset (< 45 y) breast cancer patients, 47 familial cases (patients with breast or ovarian cancer and a case of these cancers in the family), and 33 predictive cases (patients without breast or ovarian cancer, with a family history of such diseases) from Estonia for mutations in the BRCA1 gene. A sub-set of familial cases and predictive cases were also analyzed for mutations in the BRCA2 gene.

Methods

For mutation detection, we used the Polymerase Chain Reaction-Single Stranded Conformation Polymorphism Heteroduplex Analysis (PCR-SSCP-HD), followed by direct DNA sequencing.

Results

We identified three clinically important mutations in the BRCA1 gene, including seven occurrences of the c.5382insC mutation, three of c.4154delA, and one instance of c.3881_3882delGA. We also detected six polymorphisms: c.2430T>C, c.3232A>G, c.4158A>G, c.4427T>C, c.4956A>G, and c.5002T>C. Four sequence alterations were detected in introns: c.560+64delT, c.560+ [36-38delCTT, 52-63del12], c.666-58delT, and c.5396+60insGTATTCCACTCC. In the BRCA2 gene, two clinically important mutations were found: c.9610C>T and c.6631delTTAAATG. Additionally, two alterations (c.7049G>T and c.7069+80delTTAG) with unknown clinical significance were detected.

Conclusions

In our dataset, the overall frequency of clinically important BRCA1 mutations in early-onset patients, familial cases, and predictive testing was 7.6% (144 cases, 11 mutation carriers). Pathogenic mutations were identified in 4 of the 64 early-onset breast cancer cases (6.3%). In familial cases, clinically important mutations in the BRCA1 gene were found in 6 of the 47 individuals analyzed (12.8%). In predictive cases, 1 clinically important mutation was detected in 33 individuals studied (3%). The occurrence of clinically important mutations in BRCA2 in familial cases of breast cancer was 2 of the 16 individuals analyzed (12.5%).     

Extracellular matrix and myofibrils during unloading and reloading of skeletal muscle

The aim of the study was to elucidate the effect of unloading and reloading on the collagen expression and synthesis rate of myofibrillar proteins in fast-twitch (FT) muscle in relation to changes in muscle strength and motor activity. Northern blot analysis was used for testing the specificity of cDNA probes and protein synthesis rate was measured according to incorporation of radioactive leucine into different protein fractions. Unloading depresses collagen type I and III (p<0.001), type IV (p<0.05) and reloading enhances collagen expression in fast-twitch skeletal muscle in comparison with unloading. Enhanced expression of matrix metalloproteinase-2 continued during the first week of reloading (p<0.01) and tissue inhibitor of metalloproteinase-2 during reloading (p<0.05). Changes in collagen expression in FT muscle are in good agreement with changes in myofibrillar protein synthesis during unloading and reloading. In conclusion alterations in extracellular matrix and myofibrillar apparatus in FT skeletal muscle are related to changes in muscle strength and motor activity, are significant in exercise training and determination of recovery periods in the training process as well as in athletes' rehabilitation.     

Health impact assessment of particulate pollution in Tallinn using fine spatial resolution and modeling techniques

Background

Higher exposure to outdoor air pollution is associated with increased cardiopulmonary deaths, but there is limited evidence about the association between outdoor air pollution and diagnosed cardiovascular disease. Our study aimed to estimate the size of the association between long term exposure to outdoor air pollution and prevalent cardiovascular disease.

Methods

We carried out a cross-sectional analysis of data on more than 19,000 white adults aged 45 and older who participated in three representative surveys of the English population in 1994, 1998 and 2003, examining the relationship between self-reported doctor-diagnosed cardiovascular disease and exposure to outdoor air pollutants using multilevel regression techniques and meta-analysis.

Results

The combined estimates suggested that an increase of 1 μg m^-3 in concentration of particulate matter less than 10 microns in diameter was associated with an increase of 2.9% (95% CI -0.6% to 6.5%) in prevalence of cardiovascular disease in men, and an increase of 1.6% (95%CI -2.1% to 5.5%) in women. The year-specific analyses showed strongly positive associations in 2003 between odds of cardiovascular disease in both men and women and exposure to particulate matter but not in 1994 or 1998. We found no consistent associations between exposure to gaseous air pollutants and doctor-diagnosed cardiovascular disease.

Conclusion

The associations of prevalent cardiovascular disease with concentration of particulate matter less than 10 microns in diameter, while only weakly positive, were consistent with the effects reported in cohort studies. The results provide evidence of the size of the association between particulate air pollution and the prevalence of cardiovascular disease but no evidence for an association with gaseous pollutants. We found strongly positive associations between particulate matter and cardiovascular disease in 2003 only, which highlights the importance of replicating findings in more than one population.     

Coronary heart disease risk factors in middle-aged former top-level athletes

A cross-sectional study was conducted to determine the impact of previous athleticism on coronary heart disease (CHD) risk factors in 168 middle-aged men and 147 middle-aged women in Estonia. Participants were divided into four groups: physically active ex-athletes (AA), sedentary ex-athletes (SA), recreational exercisers (RE), and non-exercisers (NE). The Sharkey's questionnaire was applied to determine the CHD risk factors, health habits, medical, safety, personal, psychological and women's risk factors scores. Anthropometric characteristics, resting systolic and diastolic blood pressure values (SBP, DBP), and physical working capacity (PWC₁₇₀) were measured. Concentrations of total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), triacylglycerols (TG), and glucose were determined. Low-density lipoprotein cholesterol (LDL-C) and HDL-C/CHOL ratio were computed. From the questionnaire results, significant differences in CHD risk scores in both sex groups in favour of AA and RE were found. DBP in men was significantly higher in SA, and SBP in women was significantly higher in NE in comparison with other groups. PWC₁₇₀ and PWC₁₇₀/kg was highest in AA and lowest in NE in both sex groups. There were no significant differences for blood biochemical parameters between women's groups. In men, AA had a lower CHOL level in comparison with SA and NE, and lower concentrations of TG and LDL-C than other groups. AA and RE had a higher HDL-C concentration and HDL-C/CHOL ratio in comparison with the other groups. In conclusion, differences in CHD risk factors were related to current physical activity, and were more expressed in men than in women.     

Review on aging, unloading and reloading: changes in skeletal muscle quantity and quality

Aging and muscle unloading are associated with a decline in muscle mass, structure, force and changes in the mechanical properties of skeletal muscle. There is a perception that reloading restores muscle architecture and function but differences in the regeneration capacity of intra- and extra-cellular compartments, age dependent susceptibility to muscle damage, particularly in the contractile machinery, make it difficult to attribute the main role of the above mentioned components. This review briefly summarizes studies that examine aging skeletal muscle during unloading and reloading. The article highlights changes in muscle mass, structure, extra-cellular matrix (ECM) components, strength, locomotion, adaptability to exercise, peculiarities of protein metabolism, susceptibility to glucocorticoids and recovery of muscle from injury.     

Lead-induced excessive lipid peroxidation and changes in local cerebral blood flow in rabbit brain

Lead-poisoning is a disease of environmental origin. The primary target for lead is the nervous system. Lead ions are able to accelerate lipid peroxidation (LP) and, hence, induce cellular damage. Endothelial cell alteration and cerebral microvessel dysfunction are important in lead-induced encephalopathy. It is possibile that the altered functional state of brain microvasculature cannot ensure the adequate level of local cerebral blood flow (LCBF). The purpose of the present study was to evaluate LP in brain tissue homogenates of the cerebral cortex (CTX) and hypothalamus (HYP) of 15 lead-exposed vs seven control rabbits after a short-time lead exposure (5 and 10 days, 40 mg/kg). Another aim was to compare the dynamics of changes in LP and LCBF, detected by the H₂ clearance method in another group (seven lead-exposed rabbits vs seven controls). The basal level of thiobarbituric acid reactive substances (TBARS), the Fe-stimulated part of the TBARS (Fe-TBARS) and diene conjugates (DC) were used for the evaluation of LP in the brain tissue. A tendency to the slight enhancement of TBARS and DC concentrations in brain homogenates 5 days after the 10 days lead exposure period was found (CTX p < 0.05). The enhancement of the Fe TBARS was expressed maximally on 1 day after 10 day exposure period (CTX p < 0.05, HYP p < 0.001 compared to controls). The biphasic reaction of changes in LCBF was detected: during (5th day) and in 1 day after a 10 day exposure period a decrease of LCBF in both investigated regions was found (10.5 and 9.3 ml/100g/min i.e. 28.6 and 24.1%, respectively, in CTX, p < 0.05; and 11.2 and 10.1 ml/100g/min i.e. 19.9 and 18.7%, respectively in HYP, p < 0.05); on the 5th day after exposure minimal tendency to increase was found (7.1 ml/100g/min, p < 0.01 in HYP compared with controls). In conclusion, lead induces excessive LP in brain homogenates and disturbances in LCBF. However, the causal relationship between those events remains to be proven.