Reproductive risk factors and oestrogen/progesterone receptor-negative breast cancer in the Breast Cancer Family Registry.

BACKGROUND: Oestrogen receptor (ER)- and progesterone receptor (PR)-negative (ER-PR-) breast cancer is associated with poorer prognosis compared with other breast cancer subtypes. High parity has been associated with an increased risk of ER-PR- cancer, but emerging evidence suggests that breastfeeding may reduce this risk. Whether this potential breastfeeding benefit extends to women at high risk of breast cancer remains critical to understand for prevention. METHODS: Using population-based ascertained cases (n=4011) and controls (2997) from the Breast Cancer Family Registry, we examined reproductive risk factors in relation to ER and PR status. RESULTS: High parity (≥3 live births) without breastfeeding was positively associated only with ER-PR- tumours (odds ratio (OR)=1.57, 95% confidence interval (CI), 1.10-2.24); there was no association with parity in women who breastfed (OR=0.93, 95% CI 0.71-1.22). Across all race/ethnicities, associations for ER-PR- cancer were higher among women who did not breastfeed than among women who did. Oral contraceptive (OC) use before 1975 was associated with an increased risk of ER-PR- cancer only (OR=1.32, 95% CI 1.04-1.67). For women who began OC use in 1975 or later there was no increased risk. CONCLUSIONS: Our findings support that there are modifiable factors for ER-PR- breast cancer and that breastfeeding in particular may mitigate the increased risk of ER-PR- cancers seen from multiparity.

Prospective validation of the breast cancer risk prediction model BOADICEA and a batch-mode version BOADICEACentre.

BACKGROUND: Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is a risk prediction algorithm that can be used to compute estimates of age-specific risk of breast cancer. It is uncertain whether BOADICEA performs adequately for populations outside the United Kingdom. METHODS: Using a batch mode version of BOADICEA that we developed (BOADICEACentre), we calculated the cumulative 10-year invasive breast cancer risk for 4176 Australian women of European ancestry unaffected at baseline from 1601 case and control families in the Australian Breast Cancer Family Registry. Based on 115 incident breast cancers, we investigated calibration, discrimination (using receiver-operating characteristic (ROC) curves) and accuracy at the individual level. RESULTS: The ratio of expected to observed number of breast cancers was 0.92 (95% confidence interval (CI) 0.76-1.10). The E/O ratios by subgroups of the participant's relationship to the index case and by the reported number of affected relatives ranged between 0.83 and 0.98 and all 95% CIs included 1.00. The area under the ROC curve was 0.70 (95% CI 0.66-0.75) and there was no evidence of systematic under- or over-dispersion (P=0.2). CONCLUSION: BOADICEA is well calibrated for Australian women, and had good discrimination and accuracy at the individual level.

Tumour morphology predicts PALB2 germline mutation status.

BACKGROUND: Population-based studies of breast cancer have estimated that at least some PALB2 mutations are associated with high breast cancer risk. For women carrying PALB2 mutations, knowing their carrier status could be useful in directing them towards effective cancer risk management and therapeutic strategies. We sought to determine whether morphological features of breast tumours can predict PALB2 germline mutation status. METHODS: Systematic pathology review was conducted on breast tumours from 28 female carriers of PALB2 mutations (non-carriers of other known high-risk mutations, recruited through various resources with varying ascertainment) and on breast tumours from a population-based sample of 828 Australian women diagnosed before the age of 60 years (which included 40 BRCA1 and 18 BRCA2 mutation carriers). Tumour morphological features of the 28 PALB2 mutation carriers were compared with those of 770 women without high-risk mutations. RESULTS: Tumours arising in PALB2 mutation carriers were associated with minimal sclerosis (odds ratio (OR)=19.7; 95% confidence interval (CI)=6.0-64.6; P=5 × 10(-7)). Minimal sclerosis was also a feature that distinguished PALB2 mutation carriers from BRCA1 (P=0.05) and BRCA2 (P=0.04) mutation carriers. CONCLUSION: This study identified minimal sclerosis to be a predictor of germline PALB2 mutation status. Morphological review can therefore facilitate the identification of women most likely to carry mutations in PALB2.

Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk.

BACKGROUND: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. METHODS: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). RESULTS: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139). CONCLUSION: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.

Measuring, and identifying predictors of women's perceptions of three types of breast cancer risk: population risk, absolute risk and comparative risk.

Although a key function of cancer genetics services is to provide risk information, to date there has been little consistency in the way in which breast cancer risk perception has been measured. The aims of the study were to measure estimates of (i) population risk, (ii) absolute risk and (iii) comparative risk of developing breast cancer for Ashkenazi Jewish women, and to determine predictors of breast cancer risk perception. Of 152 women, 107 (70%) completed all questions. The mean (s.d.) estimates for population risk, absolute risk and comparative risk were 22.7% (15.9), 31.8% (20.6) and 1.9-fold (1.9), respectively. Most women overestimated population risk. Women at population risk generally overestimated the population risk and their own absolute risk, yet understood they are at the same risk as the population. Those with a family history understood that they are at increased risk, but underestimated the extent to which their familial risk is increased. Anxiety, high estimation of population risk and lesser family history predicted overestimation of absolute risk, whereas high estimation of population risk and a strong family history predicted underestimation of comparative risk.

MALDI-TOF MS analysis of labile Lolium perenne major allergens in mixes.

BACKGROUND: It is well known that allergen extracts used for specific therapy of allergic disorders are commonly stored as mixtures, causing an alteration of its stability. OBJECTIVE: The aim of this report is to identify pollen allergens susceptible to degradation during storage of mixtures containing different sources of proteases in the absence of glycerol as a preserving agent. METHODS: Mixes containing Lolium perenne (Lol p) pollen extract with either Aspergillus fumigatus or Periplaneta americana extracts were prepared and co-incubated for 90 days at 4 degrees C. Samples were taken off at fixed times and comparatively tested by in vitro and in vivo assays with atopic patients. Selected pollinic allergens were subjected to MALDI-TOF MS analysis. RESULTS: ELISA inhibition evidenced the loss of potency from ryegrass extract, and immunoblotting assays showed the degradation of specific pollinic allergens during storage of mixtures containing protease-rich sources. An in vivo intradermal skin assay confirmed the gradual loss of the biological activity of L. perenne pollen extract co-incubated with non-related protease-rich extracts in comparison with that of the control pollen extract. MALDI-TOF MS analysis allowed us to determine that Lol p 1 and Lol p 5 are susceptible to proteolysis whereas Lol p 4 was found to be resistant to degradation during storage. CONCLUSIONS: Lol p 1 and Lol p 5 degradation is responsible for the loss of the biological activity of L. perenne pollen extract when co-incubated with protease-rich fungal and cockroach extracts in the same vial for months in the absence of glycerol as a preserving agent. The integrity of these major allergens must be preserved to increase the vaccine stability and to assure efficacy when mixes are used for immunotherapy.

Effect of 1 year of lisinopril treatment on cardiac autonomic control in hypertensive patients with left ventricular hypertrophy.

In this study we evaluated in hypertensive patients the effects of drug-induced left ventricular hypertrophy regression on cardiac autonomic control, as assessed by means of heart period variability analysis. Power spectral analysis of 24-hour electrocardiographic monitoring was performed in 30 hypertensive patients with left ventricular hypertrophy at baseline, after 1 year of lisinopril treatment, and after 1 month of drug withdrawal. At the same times, patients underwent 24-hour blood pressure monitoring, echocardiographic study, and plasma renin activity assessment. Lisinopril treatment increased plasma renin activity and reduced 24-hour systolic and diastolic pressures (from 159 +/- 14 to 121 +/- 8 and from 103 +/- 7 to 80 +/- 3 mm Hg, respectively) and left ventricular mass index (from 159 +/- 33 to 134 +/- 26 g/m2); moreover, in 12 of 30 patients, left ventricular mass normalization was achieved. Drug withdrawal was followed by an increase in blood pressure without left ventricular mass modification. In the total study population, only high-frequency power was higher after lisinopril treatment. In the subgroup of patients with left ventricular mass normalization, daytime and nighttime high-frequency powers as well as nighttime total and very-low-frequency powers were higher after 1 year of treatment than at baseline. In the remaining 18 patients, power spectral measures after treatment were slightly lower than at baseline and were even lower after drug withdrawal. Thus, in hypertensive hypertrophic patients, lisinopril treatment improves sympathovagal imbalance when left ventricular mass normalization is achieved. In patients without left ventricular mass normalization, drug withdrawal is followed by a worsening of neural cardiac control.

Incremental prognostic value of thallium reinjection after stress-redistribution imaging in patients with previous myocardial infarction and left ventricular dysfunction.

UNLABELLED: This study evaluated the incremental prognostic value of 201TI reinjection imaging over clinical, exercise and thallium stress-redistribution data in patients with previous myocardial infarction and left ventricular dysfunction. METHODS: Thallium-201 reinjection after stress-redistribution SPECT was performed in 104 consecutive patients with a first Q-wave myocardial infarction (> 8 wk) and left ventricular ejection fraction < or = 40%. Follow-up data (mean 22 mo) were available for 98 patients; 16 patients underwent early revascularization procedures within 3 mo after exercise testing and were not considered for the analysis. RESULTS: During follow-up there were 13 hard events (cardiac death and myocardial infarction) and 11 soft events (coronary revascularization procedures > 3 mo after thallium imaging). With multivariate Cox regression analysis, the sum of defects at stress-redistribution imaging that were reversible or moderate irreversible after reinjection was a powerful predictor of subsequent events. The addition of thallium reinjection imaging data significantly improved the prognostic power of clinical, exercise and stress-redistribution data for the occurrence of hard events (p < 0.01). CONCLUSION: In patients with previous myocardial infarction and left ventricular dysfunction, thallium reinjection imaging provides incremental prognostic information over those obtained from conventional stress-redistribution imaging.

Comparison of verapamil versus felodipine on heart rate variability after acute myocardial infarction.

A depressed heart rate variability (HRV) is a powerful predictor of poor outcome in myocardial infarction patients. The beneficial effect of specific interventions on its recovery has been reported, but data concerning calcium antagonists are scarce. We evaluated the effect of a phenylalkylamine derivative, verapamil, and a dihydropyridine derivative, felodipine, on time- and frequency-domain measurements of HRV by 24-hour Holter monitoring in 60 patients with acute myocardial infarction (AMI). After a first Holter recording (65 +/- 8 hours from the onset of symptoms), patients were randomly assigned to continue standard treatment or to also receive verapamil retard (120 mg 3 times daily) or felodipine extended-release (10 mg/day). Holter recording was repeated after 7 days. After verapamil, mean RR interval increased from 823 +/- 92 to 907 +/- 95 ms and the SD of all normal RR (NN) intervals (SDNN) from 99 +/- 24 to 120 +/- 30 ms (p < 0.01); the root mean square successive difference (r-MSSD) and the percent of differences between adjacent NN intervals > 50 ms (pNN50) also increased (p < 0.01). After felodipine, only SDNN increased (p < 0.01). Regarding frequency-domain measurements, after receiving verapamil, very low frequency, low- and high-frequency powers increased (p < 0.01), whereas the low- to high-frequency ratio decreased (p < 0.01). After receiving felodipine, very low-frequency power increased (p < 0.01), whereas low- and high-frequency powers and the low- to high-frequency ratio remained unchanged. This study demonstrates that verapamil, but not felodipine, improves HRV in the early phase after AMI.

Inflammatory molecule release by beta-amyloid-treated T98G astrocytoma cells: role of prostaglandins and modulation by paracetamol.

Deposition of beta-amyloid in the brain triggers an inflammatory response which accompanies the neuropathologic events of Alzheimer's disease and contributes to the destruction of brain tissue. The present study shows that beta-amyloid can stimulate human astrocytoma cells (T98G) to secrete the proinflammatory factors interleukin-6 and prostaglandins. Furthermore, prostaglandins can stimulate T98G to secrete interleukin-6, which in turn triggers the formation of additional prostaglandins. Prostaglandins are, therefore, a key element in the induction and maintenance of a state of chronic inflammation in the brain which may exacerbate the fundamental pathology in Alzheimer patients. Paracetamol (0.01-1000 microM), an unusual analgesic/antipyretic drug which acts preferentially by reducing prostaglandin production within the central nervous system, and indomethacin (0.001-10 microM) caused a clear dose-dependent reduction of prostaglandin E2 production by stimulated T98G cells whereas interleukin-6 release was not affected. These data provide further evidence of the involvement of non-steroidal anti-inflammatory drugs in the inflammatory processes that can be generated by glial cells in intact brain.

Intensive training and cardiac autonomic control in high level athletes.

PURPOSE: We aimed to evaluate in a longitudinal study the effect of intensive training on cardiac autonomic control in athletes using 24-h heart rate variability analysis. METHODS: Time and frequency domain measures of heart rate variability were calculated from 24-h Holter monitoring in 15 high level bicyclists (mean age 21 +/- 4 yr) after 1 month of detraining and after 5 months of vigorous training. At the same times echocardiographic left ventricular mass and dimensions and maximal oxygen consumption (VO2max) were assessed. RESULTS: In detrained athletes, VO2max values, left ventricular mass and dimensions, and time and frequency domain measures of vagal modulation of heart rate were higher than in a group of untrained subjects of similar age while heart rate and the low-to-high frequency ratio were lower, indicating an enhanced vagal modulation of heart rate in athletes as compared with that in control subjects. After 5 months of vigorous training, left ventricular mass and dimensions and VO2max increased in athletes, while heart rate decreased further. In contrast, no changes were detectable in time and frequency domain measures of heart rate variability over the entire 24-h and in both waking and sleeping hours. CONCLUSIONS: This study demonstrates that an increased cardiac vagal control is detectable in detrained athletes; however, after intensive training, despite a significant decrease in heart rate, time and frequency domain measures of heart rate variability reflecting cardiac vagal control remain unchanged. Thus, other mechanisms than changes in cardiac autonomic control could be involved in determining the profound bradycardia of athletes.

Classical light scattering quantitation of protein aggregates: off-line spectroscopy versus HPLC detection.

This paper describes the development and validation of a new off-line approach to quantitate both covalent and noncovalent, in-solution aggregates present in protein formulations and compares the new assay to established HPLC methods. This off-line analysis is well suited for use in QC release testing, formulation development and stability indicating applications. An inexpensive, continuous source HPLC fluorometer has been adapted with the addition of second order filters for use as a sensitive right-angle scatterometer which can determine the molecular weight of protein aggregates in solution. When used as an HPLC detector, right-angle light scattering is a sensitive method which can determine the molecular weight of peaks separable by HPLC, thus discriminating between monomers of different conformations and aggregates. The weight-averaged molecular weight of aggregate peaks can be calculated with system calibration, yielding the average number of monomers per aggregate. If the protein concentration is high enough for an adequate signal, the off-line technique of right-angle light scattering of protein formulations has advantages of convenience and speed over the HPLC approach. Samples are placed in standard fluorometer cuvettes and toluene is used as a calibrator. Data are presented which show the off-line (static) method to be extremely rapid, rugged and precise. The accuracy of this approach is demonstrated through cross-validation to traditional GPC analysis of protein aggregate distributions. This non-invasive light scattering approach is particularly useful when non-covalent protein aggregation is reversible and readily altered by chromatographic separations typically used for characterizing aggregates.

[The hematuria symptom. Behavior of the pediatrician]. / Il sintoma "ematuria." Comportamento del pediatra.

The authors have reviewed the symptom hematuria in childhood, suggesting a simple flow chart for ambulatorial pediatricians.

[Symptomatic Kimmerle anomaly. Clinical case]. / Anomalia di Kimmerle sintomatica. Caso clinico.

After mentioning the most common forms of vertigo in childhood, the Authors quote a case come into their observation showing anomalies of the Kimmerle symptomatic.

A partnership in success.

Computers are an integral part of the administrative, financial, and clinical facets of long-term health care. Many home care agencies have automated their entire operations; others are considering acquisitions to automate one or more functions within their agency. Why automate? What functions can be automated? How can the process of vendor selection, implementation, and continuing support be assured a high success ratio? AIMS, Inc., a ten-year veteran in supplying software and support services to long-term health care facilities, and Group Health Cooperative of Puget Sound, an AIMS client, have joined together to discuss these questions.

Using tumour pathology to identify people at high genetic risk of breast and colorectal cancers.

Genes have been identified for which germline mutations are associated with high lifetime risks of breast, colorectal and other cancers. Identification of mutation carriers through genetic testing is important as it could help lower cancer incidence and mortality. The translation of genetic information into better health outcomes is expensive because of the costs of genetic counselling as well as laboratory testing. Approaches to triage for mutation screening of known genes which rely on cancer family history are not necessarily sensitive and specific or the most cost-effective. Recent population-based research has shown that the cancers and precancerous lesions arising in mutation carriers have specific molecular and morphological characteristics. People with colorectal cancer, especially those diagnosed at a young age, whose tumours exhibit microsatellite instability and some specific pathology and immunohistochemically-defined features are more likely to carry a germline mutation in one of four mismatch repair genes. Some morphological and immunohistochemically-defined features are associated with breast cancers arising in women who carry BRCA1 or BRCA2 germline mutations, especially if at a young age. Screening paradigms based on molecular and morphological features that predict mutation status, especially if focused on early-onset disease, have the potential to identify mutation carriers with greater sensitivity and specificity, and in a more cost-effective way, than those based on family history alone. Genetic testing results could help inform treatment if those affected are tested soon after diagnosis using pathology-led selection strategies to identify cases most likely to carry germline mutations. We propose how this new approach could be undertaken by having genetic testing and counselling prioritised to those with the greatest probability of carrying a germline mutation in these known cancer predisposition genes.

Voice pitch predicts reproductive success in male hunter-gatherers.

The validity of evolutionary explanations of vocal sexual dimorphism hinges upon whether or not individuals with more sexually dimorphic voices have higher reproductive success than individuals with less dimorphic voices. However, due to modern birth control methods, these data are rarely described, and mating success is often used as a second-rate proxy. Here, we test whether voice pitch predicts reproductive success, number of children born and child mortality in an evolutionarily relevant population of hunter-gatherers. While we find that voice pitch is not related to reproductive outcomes in women, we find that men with low voice pitch have higher reproductive success and more children born to them. However, voice pitch in men does not predict child mortality. These findings suggest that the association between voice pitch and reproductive success in men is mediated by differential access to fecund women. Furthermore, they show that there is currently selection pressure for low-pitch voices in men.

Validation study of the LAMBDA model for predicting the BRCA1 or BRCA2 mutation carrier status of North American Ashkenazi Jewish women.

LAMBDA is a model that estimates the probability an Ashkenazi Jewish (AJ) woman carries an ancestral BRCA1 or BRCA2 mutation from her personal and family cancer history. LAMBDA is relevant to clinical practice, and its implementation does not require a computer. It was developed principally from Australian and UK data. We conducted a validation study using 1286 North American AJ women tested for the mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. Most had a personal or family history of breast cancer. We observed 197 carriers. The area under the receiver operator characteristic (ROC) curve (a measure of ranking) was 0.79 [95% confidence interval (CI) = 0.77-0.81], similar to that for the model-generating data (0.78; 95% CI = 0.75-0.82). LAMBDA predicted 232 carriers (18% more than observed; p = 0.002) and was overdispersed (p = 0.009). The Bayesian computer program BRCAPRO gave a similar area under the ROC curve (0.78; 95% CI = 0.76-0.80), but predicted 367 carriers (86% more than observed; p < 0.0001), and was substantially overdispersed (p < 0.0001). Therefore, LAMBDA is comparable to BRCAPRO for ranking AJ women according to their probability of being a BRCA1 or BRCA2 mutation carrier and is more accurate than brcapro which substantially overpredicts carriers in this population.

A discrete choice experiment of preferences for genetic counselling among Jewish women seeking cancer genetics services.

To determine which aspects of breast cancer genetic counselling are important to Ashkenazi Jewish women, a discrete choice experiment was conducted. Participants consisted of 339 Australian Ashkenazi Jewish women who provided a blood sample for research used to test for Ashkenazi Jewish ancestral mutations in the genes BRCA1 and BRCA2, and were offered their genetic test result through a cancer genetics service. Main outcome measures were women's preferences for, and trade-offs between, the genetic counselling aspects of providing cancer, gene, and risk information (information); giving advice about cancer surveillance (surveillance); preparing for genetic testing (preparation); and, assistance with decision-making (direction). Respondents most valued information, about twice as much as advice about surveillance, four times as much as preparation for testing, and nine times as much as assistance with decision-making, which was least valued. Women's preferences were consistent with the major goals of genetic counselling, which include providing information and surveillance advice, and avoiding direction by facilitating autonomous decision-making. There were differences between the women in which aspects they most favoured, suggesting that counselling that elicits and responds to clients' preferences is more likely to meet clients' needs.