Evidence of benefit from centralised treatment of ovarian cancer: a nationwide population-based survival analysis in Finland

To assess the effect of different hospital types or surgical volume on the survival of ovarian cancer patients, a nationwide and population-based analysis was carried out in Finland. The study included all 3,851 ovarian cancer patients operated from 1983-94. The patients were classified according to the hospital of the first surgery. The hospitals were categorized by type (university, central or other hospital) and, separately, into quartiles by the number of operated patients (surgical volume). The patients operated at university hospitals had better survival than those operated in central hospitals, the 5-year relative survival rates (RSR) being 45% (95% CI = 42-48%) and 37% (34-40%), respectively. RSR in the 'other hospital' category was 45% (42-48%). The RSR for the patients operated in the highest volume hospitals was 47% (43-50%), and by decreasing volume (quartile) the RSR was 40% (36-43%), 40% (36-43%) and 42% (38-45%), respectively. After controlling for potential confounding by stage and age using regression models, the results remained practically the same. The results indicate that further centralizing of operative treatment of ovarian cancer may still improve survival rates on a population level in Finland.     

Overnight urinary isoflavone excretion in a population of women living in the United States, and its relationship to isoflavone intake.

Dietary isoflavones are biologically active in humans, but few observational data exist on the relationship between isoflavone intake and excretion in Western populations. We examined associations between self-reported soy intakes and overnight urinary isoflavone excretion in a population-based sample of western Washington State women, and we investigated the usefulness of one versus two overnight urine samples, collected 48 h apart, as a biomarker of intake. Isoflavones (genistein, daidzein, O-desmethylangolensin, and equol) were measured in two overnight urine collections from 363 women recruited from a health maintenance organization. Soy food intakes were assessed using two 1-day diet records completed on each day prior to the urine collections and a food frequency questionnaire (FFQ) that had been completed by 312 of the women with regard to their dietary habits 3.5 years (range, 2-5 years) before the urine collections. Twenty-one percent of the women consumed soy on either day of the diet recall, and 13% and 34% of the women consumed soy at least once a week or at least once a month, respectively, according to the FFQ. Women who consumed soy at either of the two diet recalls or at the FFQ (at least once a week or at least once a month) had a significantly higher urinary excretion of isoflavones than women who did not consume soy (P < 0.01). Among women who consumed soy at either of the two diet recalls or at the FFQ (soy consumed at least once a month), isoflavone intake and excretion correlated significantly (P < 0.01). Excretion of the individual isoflavones correlated significantly between the two urine samples collected 48 h apart (genistein, r = 0.41 and P < 0.001; daidzein, r = 0.30 and P < 0.001; O-desmethylangolensin, r = 0.46 and P < 0.001; equol, r = 0.60 and P < 0.001). Differences between soy consumers and nonconsumers and associations between intakes and excretion remained significant whether one or both urine collections were considered. Measuring isoflavone excretion in one overnight urine collection serves as a biomarker of recent or past isoflavone intake, even in populations whose intake of soy foods is relatively low.     

High concordance of daidzein-metabolizing phenotypes in individuals measured 1 to 3 years apart

Particular intestinal bacteria are capable of metabolizing the soya isoflavone daidzein to equol and/or O-desmethylangolensin (O-DMA), and the presence of these metabolites in urine after soya consumption are markers of particular intestinal bacteria profiles. Prevalences of equol producers and O-DMA producers are approximately 30-50 % and 80-90 %, respectively, and limited observations have suggested that these daidzein-metabolizing phenotypes are stable within individuals over time. Characterizing stability of these phenotypes is important to understand their potential as markers of long-term exposure to particular intestinal bacteria and their associations with disease risk. We evaluated concordance within an individual for the equol-producer and O-DMA-producer phenotypes measured at two time points (T1, T2), 1-3 years apart. Phenotypes were ascertained by analysing equol and O-DMA using GC-MS in a spot urine sample collected after 3 d soya (source of daidzein) supplementation. In ninety-two individuals without recent (within 3 months before phenotyping) or current antibiotics use, 41 % were equol producers at T1 and 45 % were equol producers at T2, and 90 % were O-DMA producers at T1 and 95 % were O-DMA producers at T2. The percentage agreement for the equol-producer phenotype was 82 and for the O-DMA-producer phenotype was 89. These results indicate that these phenotypes are stable in most individuals over time, suggesting that they provide a useful biomarker for evaluating disease risk associated with harbouring particular intestinal bacteria responsible for, or associated with, the metabolism of the soya isoflavone daidzein.     

Sequence variation in the ATP8B1 gene and intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic condition that may affect women during the third trimester of pregnancy. Symptoms experienced by these women generally resolve spontaneously following delivery, but prior to delivery the fetus is at increased risk of intrauterine distress and sudden intrauterine death. The genetic etiology of most cases of ICP is unknown, although heterozygous carriers of mutations causing progressive familial intrahepatic cholestasis (PFIC) diseases may experience ICP. When examining linkage to known cholestasis genes, affected members of four Finnish ICP families shared haplotypes around ATP8B1, the gene responsible for PFIC1. This gene was subsequently screened in 176 familial and sporadic ICP patients. A total of 17 sequence changes were detected, five exonic and 12 intronic. No intronic change was associated with ICP in sporadic cases. Four intronic changes segregated with ICP in three families, a different change in each of two families and three changes in another family, although the significance of this is currently unknown. Three exonic changes were nonsynonymous, one (in exon 23) is probably a polymorphism while two predict novel amino-acid replacements (N45T and K203R). These changes, in exons 2 and 7, were detected in one individual each, and may have predisposed these individuals to ICP. In conclusion, although the exon 2 and 7 changes may have functioned as risk alleles, ATP8B1 is probably not a major gene contributing to the occurrence of ICP.     

Distinct properties of functional KCC2 expression in immature mouse hippocampal neurons in culture and in acute slices

A hallmark in the development of GABAergic neurotransmission is the switch in GABA(A)-mediated responses from depolarizing to hyperpolarizing. This occurs due to a gradual decrease in the intracellular concentration of chloride caused by the functional expression of the neuron-specific K-Cl cotransporter KCC2. Whether a mere increase in the amount of KCC2 protein is the rate-limiting step in vivo, or a further activation of the otherwise nonfunctional cotransporter is required, is not clear. Imposing a fixed Cl(-) load via patch pipette we measured the resultant somato-dendritic gradients in reversal potential of GABAergic currents to determine the time course of functional maturation of KCC2-mediated Cl(-) extrusion in two preparations: cultured mouse hippocampal neurons plated at embryonic day 17 and CA1 pyramidal cells in acute slices. We found that in immature neurons in both preparations the gradient is initially small or not detectable. It undergoes an abrupt increase at around days 13-14 in culture, while a more gradual increase occurs between postnatal days 5-14 in slices. Consistent with the presence of a nonfunctional form of KCC2 in immature hippocampal neurons grown in culture, application of the broad-spectrum kinase inhibitor staurosporine produces a rapid and potent up-regulation of KCC2 function in these cultured neurons, but not in neonatal slices. Taken together with our previously published data, these results indicate that the functional activity of KCC2 in vivo parallels the developmental expression of the protein, whereas cultured neurons require an additional activation step (mimicked by staurosporine) for KCC2 to become functional.     

Biphasic ATP depletion caused by transient oxidative exposure is associated with apoptotic cell death in rat embryonal cortical neurons

Hypoxia-ischemia leads to an acute depletion of high-energy phosphates in neonatal brain. After reperfusion, energy status is restored, but may show progressive secondary failure, associated with neuronal loss, brain damage, or death. Oxidants are produced on reperfusion. We investigated whether a biphasic energy failure develops in cultured neurons after oxidant exposure, and whether the degree of primary disturbance correlates with later ATP synthesis and mode of cell death. Embryonic rat cortical neurons were exposed to varying doses of hydrogen peroxide for 60 min and incubated for 12, 24, or 48 h. Adenine nucleotides and the incorporation of [(14)C]adenine into adenine nucleotides were quantified. Apoptosis was evaluated by DNA electrophoresis and in situ end-labeling. A mild insult (10-50 microM) caused no ATP depletion or change in subsequent growth or energy metabolism, whereas an intermediate insult (100 microM) caused acute ATP depletion (49 +/- 12% of control). This recovered to 91 +/- 28% by 12 h, but then declined to 61 +/- 18% at 24 h. A severe insult (1 mM) depleted ATP to 15 +/- 3% of control, with no recovery. Moderate ATP depletion was associated with apoptotic cell death, whereas a severe insult caused acute necrosis. Transient oxidant exposure of embryonal cortical neurons causes a biphasic energy depletion followed by apoptosis in analogy with asphyxiated brains. This model may prove useful for the study of pathogenesis and treatment of hypoxic-ischemic encephalopathy.     

Cancer incidence among 10,211 airline pilots: a Nordic study

BACKGROUND: Commercial airline pilots are exposed to cosmic radiation and other potentially carcinogenic elements during work and leisure activities. HYPOTHESIS: Work-related factors affect cancer pattern of the pilots. METHODS: A cohort of 10,051 male and 160 female airline pilots from Denmark, Finland, Iceland, Norway, and Sweden was followed for cancer incidence through the national cancer registries. There were 177,000 person-years at follow-up, 51,000 of them accumulated after 20 yr since the time of first employment. Standardized incidence ratios (SIRs) were defined as ratios of observed over expected numbers of cases based on national cancer incidence rates. Dose-response analyses were done with Poisson regression method. RESULTS: Among male pilots, there were 466 cases of cancer diagnosed vs. 456 expected. The only significantly increased SIRs concerned skin cancer: melanoma 2.3 (95% CI 1.7-3.0), squamous cell cancer 2.1 (1.7-2.8), and basal cell carcinoma 2.5 (1.9-3.2). The relative risk of skin cancers increased with the time since first employment, the number of flight hours, and the estimated radiation dose. There was an increase in the relative risk of prostate cancer with increasing number of flight hours in long-distance aircraft (p trend 0.01). No increased incidence was found for acute myeloid leukemia or brain cancer which were of interest a priori based on earlier studies. CONCLUSIONS: This large study, based on reliable cancer incidence data, showed an increased incidence of skin cancer. It did not indicate a marked increase in cancer risk attributable to cosmic radiation although some influence of cosmic radiation on skin cancer cannot be entirely excluded.     

Effects of carriers and storage of formulation on the lung deposition of a hydrophobic and hydrophilic drug from a DPI

The effects of carriers, the drug:carrier ratio and a 1 month storage period of a formulation in permeable polystyrene tube at 40 degrees C/75% RH on the in vitro pulmonary deposition of model drugs from dry powder inhaler (DPI) were evaluated. Budesonide (hydrophobic) and salbutamol sulphate (hydrophilic) were used as model drugs. Mannitol and glucose were used as the carriers. In addition, lactose 110M was used as the carrier for budesonide. The novel multiple dose Taifun was used as a DPI; Taifun is a breath-actuated inhaler that contains the powder formulation in a reservoir chamber. The respirable fractions (RF%) values of the drugs were determined by the "Andersen" sampler. The RF% values of salbutamol sulphate increased with an increase in the drug:carrier ratio before storage, whereas the drug:carrier ratio did not affect the RF% values after storage. In the case of budesonide, the drug:carrier ratio did not affect the RF% values before storage, instead the RF% values of budesonide increased with an increase in the drug:carrier ratio after storage. The RF% values of salbutamol sulphate decreased after storage of the formulation, this was not dependent on the carrier and the drug:carrier ratio. However, with budesonide the effect of the storage on its RF% values was dependent on which carrier was used and also the drug:carrier ratio. Overall, storage had less effect on the RF% values of budesonide than those of salbutamol sulphate. The highest RF% values of budesonide were obtained when mannitol was used as the carrier. Furthermore, the RF% values of salbutamol sulphate tended to be higher when mannitol was used as the carrier instead of glucose.