Prognostic value of the combined assessment of proliferating cell nuclear antigen immunostaining and nuclear DNA content in invasive human mammary carcinomas

The expression of theS-phase associated, nuclear protein proliferating cell nuclear antigen (PCNA) was investigated in routinely paraffin-embedded surgical specimens from 209 breast cancer patients. Cytometric DNA assessments were performed on fine-needle aspirates, upon which the primary diagnosis of breast cancer had been based. The mean clinical follow-up was 16 years (range 13–20 years). The percentage of PCNA immunoreactive tumour cells ranged between less than 5 to 60% (mean value 13.34%). There was a direct association between PCNA expression, high histological tumour grade (p<0.01), and DNA aneuploidy (p=0.009). In a subgroup of 22 patients with near-diploid DNA distribution patterns the PCNA expression yielded additional prognostic information. Patients with tumours of near-diploid DNA histograms and more than 20% of PCNA immunoreactive neoplastic cells had a significantly worse clinical course, than patients with neardiploid tumours containing less than 20% PCNA immunoreactive cells (p=0.0001). In contrast, the PCNA immunoreactivity did not yield additional prognostic information for patients with distinctly diploid or highly aneuploid tumour variants. In a multivariate analysis comprising all 209 patients, nodal status (p<0.01), tumour size (p<0.01), and DNA ploidy (p<0.01) were found to have significant prognostic effect. The findings indicate that carcinomas characterised by high proliferative activity and near-diploid DNA distribution patterns can show rapid tumour progression. The combined assessment of the PCNA immunoreactivity and of the nuclear DNA content in routinely processed surgical specimens of breast cancer patients appears to be of prognostic value.     

Clinical genetic counselling for familial cancers requires reliable data on familial cancer risks and general action plans

Familial cancer clustering, without obvious heritability, poses a major challenge for current cancer risk assessment and management. Reliable determination of familial risks for cancer is important for clinical genetic counselling, but medically verified data on familial risks for many malignancies have been limited. However, the nationwide Swedish Family-Cancer Database allows a reliable characterisation of familial risk for all major neoplasms. Even though alert genetic counsellors and certainly clinical cancer geneticists will consider familial cancer clustering in their purview, the standard medical referral systems, which have already been shown to be poor in capturing and referring families at high risk for heritable cancers, are unlikely to ascertain familial aggregations of other cancers that are not known to belong to an inherited cancer syndrome. The data will be helpful in implementing evidence based guidelines for helping the general medical system to ascertain and refer even familial cancer clusters to cancer genetics professionals.     

Relationship between Serum 25(OH)D and Depression: Causal Evidence from a Bi-Directional Mendelian Randomization Study

The relationship between depression and vitamin D deficiency is complex, with evidence mostly from studies affected by confounding and reverse causality. We examined the causality and direction of the relationship between 25-hydroxyvitamin D (25(OH)D) and depression in bi-directional Mendelian randomization (MR) analyses using information from up to 307,618 white British participants from the UK Biobank and summary results from the SUNLIGHT (n = 79,366) and Psychiatric Genomics consortia (PGC 113,154 cases and 218,523 controls). In observational analysis, the odds of depression decreased with higher 25(OH)D concentrations (adjusted odds ratio (OR) per 50% increase 0.95, 95%CI 0.94–0.96). In MR inverse variance weighted (IVW) using the UK Biobank, there was no association between genetically determined serum 25(OH)D and depression (OR per 50% higher 0.97, 95%CI 0.90–1.05) with consistent null association across all MR approaches and in data from PGC consortium. In contrast, genetic liability to depression was associated with lower 25(OH)D concentrations (MR IVW −3.26%, −4.94%–−1.55%), with the estimates remaining generally consistent after meta-analysing with the consortia. In conclusion, we found genetic evidence for a causal effect of depression on lower 25(OH)D concentrations, however we could not confirm a beneficial effect of nutritional vitamin D status on depression risk.     

Intuitive Eating is Associated With Higher Fruit and Vegetable Intake Among Adults

ObjectiveAssess how intuitive eating relates to dietary intake.MethodsSurvey data were collected in Project Eating and Activity in Teens and Young Adults, the fourth wave of a longitudinal cohort study (weighted n = 1,830, 49% women; mean age = 31 years). Intuitive eating was assessed using a 7-item scale adapted from the Intuitive Eating Scale and Intuitive Eating Scale-2. Dietary intake was measured via a semiquantitative food frequency questionnaire. Mean servings were stratified by gender and intuitive eating quartiles and adjusted for sociodemographic characteristics and caloric intake.ResultsWomen and men in the top intuitive eating quartile consumed 0.6–0.3 servings more fruit and 0.4–0.6 servings more vegetables daily, respectively, compared with the bottom quartile, whereas men in the top quartile also consumed 0.6 servings fewer whole grains (all P < 0.05) than the bottom quartile.Conclusions and ImplicationsIntuitive eating shows promise as a healthier alternative to practices such as dieting.     

Endothelial-Derived miR-17∼92 Promotes Angiogenesis to Protect against Renal Ischemia-Reperfusion Injury

BackgroundDamage to the renal microvasculature is a hallmark of renal ischemia-reperfusion injury (IRI)–mediated AKI. The miR-17∼92 miRNA cluster (encoding miR-17, -18a, -19a, -20a, -19b-1, and -92a-1) regulates angiogenesis in multiple settings, but no definitive role in renal endothelium during AKI pathogenesis has been established.MethodsAntibodies bound to magnetic beads were utilized to selectively enrich for renal endothelial cells from mice. Endothelial-specific miR-17∼92 knockout (miR-17∼92^endo−/−) mice were generated and given renal IRI. Mice were monitored for the development of AKI using serum chemistries and histology and for renal blood flow using magnetic resonance imaging (MRI) and laser Doppler imaging. Mice were treated with miRNA mimics during renal IRI, and therapeutic efficacies were evaluated.ResultsmiR-17, -18a, -20a, -19b, and pri–miR-17∼92 are dynamically regulated in renal endothelial cells after renal IRI. miR-17∼92^endo−/− exacerbates renal IRI in male and female mice. Specifically, miR-17∼92^endo−/− promotes renal tubular injury, reduces renal blood flow, promotes microvascular rarefaction, increases renal oxidative stress, and promotes macrophage infiltration to injured kidneys. The potent antiangiogenic factor thrombospondin 1 (TSP1) is highly expressed in renal endothelium in miR-17∼92^endo−/− after renal IRI and is a target of miR-18a and miR-19a/b. miR-17∼92 is critical in the angiogenic response after renal IRI, which treatment with miR-18a and miR-19b mimics can mitigate.ConclusionsThese data suggest that endothelial-derived miR-17∼92 stimulates a reparative response in damaged renal vasculature during renal IRI by regulating angiogenic pathways.     

Biomarkers of styrene exposure in lamination workers: levels of 06-guanine DNA adducts, DNA strand breaks and mutant frequencies in the hypoxanthine guanine phosphoribosyltransferase gene in T-lymphocytes

Occupational exposure to styrene was studied in nine workersof a hand lamination plant in Bohemia. Personal dosimeters wereused to monitor the styrene workplace exposure, and the levelsof styrene in blood and mandelic acid in urine were measured.Blood samples were taken at four occasions during a 7 monthperiod to determine styrene-specific 0⁶-guanine DNA adductsin lymphocytes and granulocytes, DNA strand breaks and hypoxanthineguanine phosphoribosyltransferase (HPRT) mutant frequency inT-lymphocytes. Seven administrative employees in the same factory(factory controls) and eight persons in a research laboratory(laboratory controls) were used as referents. DNA adduct levelsdetermined by the ³²P-postlabelling method in lymphocytes oflamina-tors were remarkably constant and significantly higher(P < 0.0001) than in factory controls at all four samplingtimes. HPRT mutant frequencies (MF) measured by the T-cell cloningassay were higher in the laminators (17.5 x10^–6, groupmean) than in the factory controls (15.7x10^–6, group mean)at three of the four sampling times, but the differences werenot statistically significant. However, a statistically significant(P = 0.021) difference between MF in the laminators (18.0 x10^–6,group mean) and laboratory controls (11.8 xl0^–6, groupmean) was observed at sampling time 4 (the only sampling timewhen this latter group was studied). This result indicates thatstyrene exposure may induce gene mutation in T-cells in vivo.DNA strand breaks were studied by the ‘Comet assay’at the fourth sampling time. The laminators were found to havesignificantly higher levels of DNA strand breaks than the factorycontrols (P = 0.032 for tail length, TL; P = 0.007 for percentageof DNA in tail, T%; and P = 0.020 for tail moment, TM). A statisticallysignificant correlation was also found between the levels oflymphocyte DNA adducts and all three DNA strand break parameters(TL P = 0.046; T% P = 0.026 and TM P = 0.034). On the contrary,no significant correlations were found between DNA adduct levelsand the HPRT mutant frequencies or between the mutant frequenciesand DNA strand breaks. Taken together, these results add furthersupport to the genotoxic and possibly mutagenic effects of styreneexposure in vivo. However, no simple quantitative relationshipseems to exist between the levels of styrene-induced DNA damageand frequency of HPRT mutation in T-lymphocytes.     

Parental age and risk of sporadic and familial cancer in offspring: implications for germ cell mutagenesis.

We used the nationwide Swedish Family-Cancer Database to analyze the effect of parental age on cancer in offspring at ages 15-53 years. We studied 13 cancer sites, including 37,877 people. Data on familial and sporadic cancers were analyzed separately. We adjusted for age of spouse, year of diagnosis, and birth order. Rate ratios (RRs) were calculated by Poisson regression. Maternal age was associated with sporadic melanoma and leukemia, causing a 30% excess if mothers were more than 40 years vs. less than 20 years of age. A marginal effect of about 10% of both maternal and paternal age was observed for sporadic breast cancer. Paternal age increased the RR of sporadic nervous system cancer by about 15%. Accumulation of chromosomal aberrations and mutations during the maturation of germ cells may be a mechanism for these findings. In familial cancers of colon, melanoma, and thyroid, higher age showed an apparent protective effect, which was also noted for sporadic cervical cancer and melanoma. The results argue against major age-induced mutagenic/carcinogenic effects on germ cells as well as against age-induced adverse cancer-related hormonal effects during pregnancy. Because two or more mutations are required for adult cancers, however, these cancers may be an insensitive indicator of germ cell mutagenesis.     

Reactions of 'bay-region' and non-'bay-region' diol-epoxides of benz(a)anthracene with DNA: evidence indicating that the major products are hydrocarbon-N2-guanine adducts

The rates of reaction and the products formed when two vicinaldiol-epoxides derived from benz(a)an-thracene, anti-BA-3, 4-dioI1, 2-oxide (t-3, r-4-dihydroxy-t-1, 2-oxy-l, 2, 3, 4-tetrahydrobenz(a)anthracene)^* and anti-BA-8, 9-diol 10, 11-oxide (r-8, t-9-dihydroxy-t-10,ll-oxy-8, 9, 10, ll-tetrahydro-benz(a)anthracene) reacted withDNA were studied in vitro and the results were compared withthose obtained in similar experiments using anti-BP-7, 8-diol9, 10-oxide (r-7, t-8-dihydroxy-t-9, 10-oxy-7, 8, 9, 10-tetrahydrobenzo(a)pyrene).The reactivities appeared to decrease in the order anti-BP-7,8-diol 9, 10-oxide > anti-BA-3, 4-diol 1, 2-oxide anti-BA-8,9-diol 10, 11-oxide. The diol-epoxides reacted to a similarextent with single- and with double-stranded DNA but reactionswith dGMP, at equivalent concentrations, were much slower thanwith DNA. With the diol-epoxides of benz(a)anthracene, two principaladducts were present in DNA hydrolysates and evidence was obtained,based on pK determinations before and after nitrous acid treatment,consistent with their being N²-guanine derivatives, analogousto the known DNA-reaction products of benzo(a)-pyrene 7, 8-diol9, 10-oxide.     

Session 12 Acceptance and effectiveness of modern contraception: A comparison of Western and Central Europe

Abstract

Session 12 Acceptance and effectiveness of modern contraception: A comparison of Western and Central Europe     

Midwives as providers of prenatal care in Finland--past and present

This study analyzes the role of the midwife in prenatal care by exploring the history of the midwifery profession in Finland and by interviewing midwives. Midwifery education started in Finland in the beginning of the 19th century due to the utilitarian population policy aiming to reduce the high infant mortality rate. Because of a shortage of physicians professional midwives attained an important status in the care of births. With industrialization a state-directed welfare policy with state-subsidized health care developed. After World War II, the midwifery were legally defined as care during pregnancy, delivery, and the postpartum period. In the 1950s, the scope of work of midwifery was further altered because hospital deliveries had become routine. Some midwives provided prenatal care in ambulatory maternity health centers while others worked in hospitals managing normal childbirths. Separate midwifery education ended in 1968 and resumed 1986. Since 1972, public health nurses have increasingly provided prenatal and postnatal care in maternity centers, and specialized nurses have managed normal childbirths. In the future, public health nurses may totally replace midwives in prenatal care, and the role of midwives may return to care of normal deliveries. Midwife interviews revealed the "medicalization" of pregnancy caused both by physicians and midwives' own medical concept of pregnancy and by clients' demands for good care.