Penetrance analysis of the PALB2 c.1592delT founder mutation

PURPOSE: PALB2 is a recently identified breast cancer susceptibility gene. We have previously identified in the Finnish population a PALB2 c.1592delT founder truncation mutation that is associated with an increased risk of breast cancer. In the present study, we wanted to assess in more detail the increased risk (hazard ratio, HR) and the age-specific cumulative risk (penetrance) of c.1592delT with regard to susceptibility to breast and other forms of cancer. EXPERIMENTAL DESIGN: Modified segregation analyses fitted under maximum likelihood theory were used to estimate age-specific cumulative risks and HRs using the families of mutation carriers identified from a consecutive series of breast cancer cases unselected for age at onset or family history. RESULTS: We found a substantially increased risk of breast cancer [HR, 6.1; 95% confidence interval (95% CI), 2.2-17.2; P = 0.01] equivalent to a 40% (95% CI, 17-77) breast cancer risk by age 70 years, comparable to that for carriers of mutations in BRCA2. We found marginal evidence (P = 0.06) that the HR for breast cancer decreased with age by 4.2% per year (95% CI, 0.2-8.1), from 7.5-fold at age 30 years to 2.0-fold at age 60 years. CONCLUSIONS: Our results suggest that it may be appropriate to offer PALB2 c.1592delT mutation testing to Finnish women with breast cancer, especially those with an early age at onset or a family history of breast or related cancers, and to offer carriers the option of participation in extended disease surveillance programs.     

Do changes in oral health-related quality-of-life,facial pain and temporomandibular disorders correlate after treatment of severe malocclusion?

Introduction. The aim was to evaluate the relationships of changes in facial pain, temporomandibular disorders (TMDs) and oral health-related quality-of-life (OHRQoL) in adults who underwent orthodontic or orthodontic/surgical treatment. Methods. Sixty-four patients (46 women, 18 men, range 18–64 years) with severe malocclusion and functional problems were treated in Oulu University Hospital. Of these, 44 underwent orthodontic-surgical and 20 orthodontic treatment. Data were collected with questionnaires and clinical stomatognathic examinations before and on average 3 years after treatment. The OHRQoL was measured with OHIP-14 (The Oral Health Impact Profile), the intensity of facial pain with the Visual Analogue Scale (VAS) and the severity of TMD with the Helkimo’s anamnestic (Ai) and clinical (Di) dysfunction indices. Results. A significant improvement was found in facial pain, signs and symptoms of TMD and OHRQoL after the treatment (p < 0.05). The decrease in VAS was associated with improvement in OHIP-14 severity (r = 0.296, p = 0.019). The correlations between changes in OHIP-14 severity and Ai and Di were not statistically significant. Conclusion. Treatment of severe malocclusion seemed to improve OHRQoL via decreased facial pain. Decreased facial pain was associated especially with improved OHRQoL dimensions of physical pain, physical disability and social disability.     

Functional Inducible Nitric Oxide Synthase Gene Variants Associate With Hypertension: A Case–Control Study in a Finnish Population—The TAMRISK Study

Increased inducible nitric oxide synthase (iNOS) activity and expression has been associated with hypertension, but less is known whether the 2 known functional polymorphic sites in the iNOS gene (g.–1026 C/A (rs2779249), g.2087 G/A (rs2297518)) affect susceptibility to hypertension. The objective of this study was to investigate the association between the genetic variants of iNOS and diagnosed hypertension in a Finnish cohort.This study included 320 hypertensive cases and 439 healthy controls. All participants were 50-year-old men and women and the data were collected from the Tampere adult population cardiovascular risk study (TAMRISK). DNA was extracted from buccal swabs and iNOS single nucleotide polymorphisms (SNPs) were analyzed using KASP genotyping PCR. Data analysis was done by logistic regression.At the age of 50 years, the SNP rs2779249 (C/A) associated significantly with hypertension (P = 0.009); specifically, subjects carrying the A-allele had higher risk of hypertension compared to those carrying the CC genotype (OR = 1.47; CI = 1.08–2.01; P = 0.015). In addition, a 15-year follow-up period (35, 40, and 45 years) of the same individuals showed that carriers of the A-allele had more often hypertension in all of the studied age-groups. The highest risk for developing hypertension was obtained among 35-year-old subjects (odds ratio [OR] 3.83; confidence interval [CI] = 1.20–12.27; P = 0.024). Those carrying variant A had also significantly higher readings of both systolic (P = 0.047) and diastolic (P = 0.048) blood pressure during the follow-up. No significant associations between rs2297518 (G/A) variants alone and hypertension were found. However, haplotype analysis of rs2779249 and rs2297518 revealed that individuals having haplotype H3 which combines both A alleles (CA–GA, 19.7% of individuals) was more commonly found in the hypertensive group than in the normotensive group (OR = 2.01; CI = 1.29–3.12; P = 0.002).In conclusion, there was a significant association between iNOS genetic variant (rs2779249) and hypertension in the genetically homogenous Finnish population. Those who carried the rare A-allele of the gene had higher risk for hypertension already at the age of 35 years.     

Reliability and validity of the Finnish version of the prosthesis evaluation questionnaire

Background: Thus far there have been no specific patient-reported outcome instrument in Finnish for health-related quality of life (HRQoL) assessment after major lower extremity amputation and successful prosthesis fitting.

Methods: The prosthesis evaluation questionnaire (PEQ) was translated and cross-culturally adapted into Finnish. Participants completed a questionnaire package including the Finnish version of the PEQ and the 15?D HRQoL instrument. Scales (n?=?10) were tested for internal consistency, floor-ceiling effect, and reproducibility for which participants completed the PEQ twice within a 2-week interval. Validity was tested by estimating the correlation between the 15?D index and the scales. The authors included 122 participants who had completed the questionnaire on two separate occasions in the final analysis.

Results: Mean scale scores of the 10 scales varied from 52 to 83. Cronbach’s alphas ranged from 0.67 to 0.96. The total score showed no floor-ceiling effect. Reproducibility of the scales was good (intraclass correlation coefficient, 0.78–0.87; coefficient of repeatability, 19–36). Significant correlations were observed between the 15?D index and the scales for ambulation, social burden, usefulness, and well-being.

Conclusions: This study provided evidence of the reliability and validity of the Finnish version of the PEQ in assessing the HRQoL among major lower extremity amputated patients who have been fitted with prosthesis.

• Implications for rehabilitation

• Measurement of quality of life during rehabilitation can provide important information on patients’ well-being.

• The prosthesis evaluation questionnaire (PEQ) is a valid instrument for assessing health-related quality of life (HRQoL) after major lower extremity amputation.

• This study provided evidence of the reliability and validity of the Finnish version of the PEQ for assessing HRQoL among patient who have undergone major lower extremity amputation.

     

Exposure to ethanol and nicotine induces stress responses in human placental BeWo cells

Human placental trophoblastic cancer BeWo cells can be used as a model of placental trophoblasts. We found that combined exposure to relevant exposure concentrations of ethanol (2‰) and nicotine (15 μM) induces an increase in the amount of reactive oxygen species (ROS). Neither ethanol or nicotine alone, nor their combination affected cell viability. However, nicotine decreased cell proliferation, both alone and combined with ethanol. Nicotine increased the expression of the endoplasmic reticulum (ER)-stress related protein GRP78/BiP, but not another marker of ER-stress, IRE1α. We also studied the effects of nicotine and/or ethanol on phosphorylation and expression of three mitogen-activated protein kinases (MAPKs), i.e. JNK, p38 and ERK1/2. Nicotine decreased the phosphorylation of JNK and also had similar effect on total amount of this protein. Phosphorylation and expression of p38 were increased 1.7- and 1.6-fold, respectively, by nicotine alone, and 1.9- and 2.1-fold by the combined treatment. Some increase (1.8-fold) was also seen in the phosphorylation of ERK2 at 48 h, in cells exposed to both ethanol and nicotine. This study shows that ethanol and nicotine, which harm the development of fetus may induce both oxidative and ER stress responses in human placental trophoblastic cells, implicating these mechanisms in their fetotoxic effects.