Risk profiles and prognosis of treated and untreated hypertensive men and women in a population-based longitudinal study: the Reykjavik Study

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldThe aim was to examine the risk profiles and prognosis of treated and untreated hypertensive subjects and examine to what degree confounding by indication was present in a population-based cohort study with up to 30-year follow-up. The study population consisted of 9328 men and 10 062 women, aged 33-87 years at the time of attendance from 1967 to 1996. The main outcome measures were myocardial infarction (MI), cardiovascular disease (CVD) mortality and all-cause mortality. Comparing the risk profiles between treated and untreated subjects entering the study showed significantly higher values for some risk factors for treated subjects. During the first 10 years, hypertensive men without treatment, compared with those treated, had a significantly lower risk of suffering MI, CVD and all-cause mortality, hazard ratio (HR) 0.72 (95% CI; 0.57, 0.90), 0.75 (95% CI; 0.59, 0.95) and 0.81 (95% CI; 0.61, 0.98), respectively. No significant differences in outcome were seen during the following 20 years. In identically defined groups of women, no significant differences in mortality were seen between groups. Subgroup analysis, at two stages of the study 5 years apart, revealed that some cardiovascular risk factors had a higher prevalence in hypertensive men who were treated at the later stage, compared with those who remained untreated (P=0.004). In conclusion, hypertensive treated men had a worse prognosis during the first 10 years of follow-up than untreated ones, which is most likely due to worse baseline risk profile. Hypertensive men that were treated at a later stage had a worse risk profile than those not treated at a later stage

Improved Cortisol Exposure-Time Profile and Outcome in Patients with Adrenal Insufficiency: A Prospective Randomized Trial of a Novel Hydrocortisone Dual-Release Formulation.

Context:Patients with treated adrenal insufficiency (AI) have increased morbidity and mortality rate. Our goal was to improve outcome by developing a once-daily (OD) oral hydrocortisone dual-release tablet with a more physiological exposure-time cortisol profile.Objective:The aim was to compare pharmacokinetics and metabolic outcome between OD and the same daily dose of thrice-daily (TID) dose of conventional hydrocortisone tablets.Design and Setting:We conducted an open, randomized, two-period, 12-wk crossover multicenter trial with a 24-wk extension at five university hospital centers.Patients:The trial enrolled 64 adults with primary AI; 11 had concomitant diabetes mellitus (DM).Intervention:The same daily dose of hydrocortisone was administered as OD dual-release or TID.Main Outcome Measure:We evaluated cortisol pharmacokinetics.Results:Compared with conventional TID, OD provided a sustained serum cortisol profile 0-4 h after the morning intake and reduced the late afternoon and the 24-h cortisol exposure. The mean weight (difference = -0.7 kg, P = 0.005), systolic blood pressure (difference = -5.5 mm Hg, P = 0.0001) and diastolic blood pressure (difference: -2.3 mm Hg; P = 0.03), and glycated hemoglobin (absolute difference = -0.1%, P = 0.0006) were all reduced after OD compared with TID at 12 wk. Compared with TID, a reduction in glycated hemoglobin by 0.6% was observed in patients with concomitant DM during OD (P = 0.004).Conclusion:The OD dual-release tablet provided a more circadian-based serum cortisol profile. Reduced body weight, reduced blood pressure, and improved glucose metabolism were observed during OD treatment. In particular, glucose metabolism improved in patients with concomitant DM

Deaths Among Adult Patients with Hypopituitarism: Hypocortisolism During Acute Stress, and De Novo Malignant Brain Tumors Contribute to an Increased Mortality.

Context:Patients with hypopituitarism have an increased standardized mortality rate. The basis for this has not been fully clarified.Objective:To investigate in detail the cause of death in a large cohort of patients with hypopituitarism subjected to long-term follow-up.Design and Methods:All-cause and cause-specific mortality in 1286 Swedish patients with hypopituitarism prospectively monitored in KIMS (Pfizer International Metabolic Database) 1995-2009 were compared to general population data in the Swedish National Cause of Death Registry. In addition, events reported in KIMS, medical records, and postmortem reports were reviewed.Main Outcome Measures:Standardized mortality ratios (SMR) were calculated, with stratification for gender, attained age, and calendar year during follow-up.Results:An excess mortality was found, 120 deaths vs 84.3 expected, SMR 1.42 (95% confidence interval: 1.18-1.70). Infections, brain cancer, and sudden death were associated with significantly increased SMRs (6.32, 9.40, and 4.10, respectively). Fifteen patients, all ACTH-deficient, died from infections. Eight of these patients were considered to be in a state of adrenal crisis in connection with death (medical reports and post-mortem examinations). Another 8 patients died from de novo malignant brain tumors, 6 of which had had a benign pituitary lesion at baseline. Six of these 8 subjects had received prior radiation therapy.Conclusion:Two important causes of excess mortality were identified: first, adrenal crisis in response to acute stress and intercurrent illness; second, increased risk of a late appearance of de novo malignant brain tumors in patients who previously received radiotherapy. Both of these causes may be in part preventable by changes in the management of pituitary disease

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

Background: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. Methods: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. Results: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93–1.04, P=0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89–1.06, P=0.5) mutation carriers. Conclusion: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out. A Osorio1, R L Milne2, G Pita3, P Peterlongo4,5, T Heikkinen6, J Simard7, G Chenevix-Trench8, A B Spurdle8, J Beesley8, X Chen8, S Healey8, KConFab9, S L Neuhausen10, Y C Ding10, F J Couch11,12, X Wang11, N Lindor13, S Manoukian4, M Barile14, A Viel15, L Tizzoni5,16, C I Szabo17, L Foretova18, M Zikan19, K Claes20, M H Greene21, P Mai21, G Rennert22, F Lejbkowicz22, O Barnett-Griness22, I L Andrulis23,24, H Ozcelik24, N Weerasooriya23, OCGN23, A-M Gerdes25, M Thomassen25, D G Cruger26, M A Caligo27, E Friedman28,29, B Kaufman28,29, Y Laitman28, S Cohen28, T Kontorovich28, R Gershoni-Baruch30, E Dagan31,32, H Jernström33, M S Askmalm34, B Arver35, B Malmer36, SWE-BRCA37, S M Domchek38, K L Nathanson38, J Brunet39, T Ramón y Cajal40, D Yannoukakos41, U Hamann42, HEBON37, F B L Hogervorst43, S Verhoef43, EB Gómez García44,45, J T Wijnen46,47, A van den Ouweland48, EMBRACE37, D F Easton49, S Peock49, M Cook49, C T Oliver49, D Frost49, C Luccarini50, D G Evans51, F Lalloo51, R Eeles52, G Pichert53, J Cook54, S Hodgson55, P J Morrison56, F Douglas57, A K Godwin58, GEMO59,60,61, O M Sinilnikova59,60, L Barjhoux59,60, D Stoppa-Lyonnet61, V Moncoutier61, S Giraud59, C Cassini62,63, L Olivier-Faivre62,63, F Révillion64, J-P Peyrat64, D Muller65, J-P Fricker65, H T Lynch66, E M John67, S Buys68, M Daly69, J L Hopper70, M B Terry71, A Miron72, Y Yassin72, D Goldgar73, Breast Cancer Family Registry37, C F Singer74, D Gschwantler-Kaulich74, G Pfeiler74, A-C Spiess74, Thomas v O Hansen75, O T Johannsson76, T Kirchhoff77, K Offit77, K Kosarin77, M Piedmonte78, G C Rodriguez79, K Wakeley80, J F Boggess81, J Basil82, P E Schwartz83, S V Blank84, A E Toland85, M Montagna86, C Casella87, E N Imyanitov88, A Allavena89, R K Schmutzler90, B Versmold90, C Engel91, A Meindl92, N Ditsch93, N Arnold94, D Niederacher95, H Deißler96, B Fiebig97, R Varon-Mateeva98, D Schaefer99, U G Froster100, T Caldes101, M de la Hoya101, L McGuffog49, A C Antoniou49, H Nevanlinna6, P Radice4,5 and J Benítez1,3 on behalf of CIMB

iSAM2 : incremental smoothing and mapping using the Bayes tree

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Sage for personal use, not for redistribution. The definitive version was published in International Journal of Robotics Research 31 (2012): 216-235, doi:10.1177/0278364911430419.We present a novel data structure, the Bayes tree, that provides an algorithmic foundation enabling a better understanding of existing graphical model inference algorithms and their connection to sparse matrix factorization methods. Similar to a clique tree, a Bayes tree encodes a factored probability density, but unlike the clique tree it is directed and maps more naturally to the square root information matrix of the simultaneous localization and mapping (SLAM) problem. In this paper, we highlight three insights provided by our new data structure. First, the Bayes tree provides a better understanding of the matrix factorization in terms of probability densities. Second, we show how the fairly abstract updates to a matrix factorization translate to a simple editing of the Bayes tree and its conditional densities. Third, we apply the Bayes tree to obtain a completely novel algorithm for sparse nonlinear incremental optimization, named iSAM2, which achieves improvements in efficiency through incremental variable re-ordering and fluid relinearization, eliminating the need for periodic batch steps. We analyze various properties of iSAM2 in detail, and show on a range of real and simulated datasets that our algorithm compares favorably with other recent mapping algorithms in both quality and efficiency.M. Kaess, H. Johannsson and J. Leonard were partially supported by ONR grants N00014-06-1-0043 and N00014-10-1-0936. F. Dellaert and R. Roberts were partially supported by NSF, award number 0713162, “RI: Inference in Large-Scale Graphical Models”. V. Ila has been partially supported by the Spanish MICINN under the Programa Nacional de Movilidad de Recursos Humanos de Investigación

The management and survival outcomes of nasopharyngeal cancer in the Nordic countries

Peer reviewe

Broad phenotypic spectrum in familial adenomatous polyposis; from early onset and severe phenotypes to late onset of attenuated polyposis with the first manifestation at age 72

<p>Abstract</p> <p>Background</p> <p>Familial adenomatous polyposis (FAP) is typically characterized by multiple colonic polyps and frequent extracolonic features. Whereas the number of colonic polyps has been linked to the <it>APC </it>gene mutation, possible genotype-phenotype correlations largely remain to be defined for the extracolonic manifestations.</p> <p>Methods</p> <p>Full genomic sequencing combined with multiplex ligation-dependent probe amplification was used to identify <it>APC </it>gene mutations, which were correlated to the clinical presentations.</p> <p>Results</p> <p>10 novel <it>APC </it>gene mutations were identified in 11 families. A broad spectrum of extracolonic manifestations was identified in most of these individuals. Two sisters with an insertion in codon 528 (c.1582_1583insGC) both showed severe phenotypes with classical polyposis, upper gastrointestinal polyps and thyroid cancer. A woman with a 3'<it>APC </it>mutation (c.5030_5031insAA) developed colon cancer at age 72 as the first manifestation of attenuated FAP.</p> <p>Conclusion</p> <p>With an increasing number of FAP families diagnosed, a broad and variable tumor spectrum and a high frequency of extracolonic manifestations are gradually recognized. We report novel <it>APC </it>mutations and present two FAP cases that suggest familial aggregation of thyroid cancer and demonstrate the need to consider attenuated FAP also among elderly patients with colon cancer.</p

Clinical and pathological features of BRCA1 associated carcinomas in a hospital-based sample of Dutch breast cancer patients

Thus far, studies investigating the differences in tumour characteristics between breast cancer in BRCA1-carriers and other patients, have focused on highly selected groups of patients, potentially limiting the conclusions that can be drawn. Previously, we had identified 10 patients with BRCA1 germline mutations in a hospital-based series of 642 breast cancer patients not selected for age or family history. The aim of this analysis is to investigate the clinical and pathological features of these BRCA1 associated carcinomas as compared to other breast cancers in this representative sample. Tumours from patients with BRCA1 germline mutations (n= 10) were compared to an age-matched sample of other patients (n= 50) from the same cohort. The following characteristics were considered: axillary nodal status and tumour size, histologic parameters (tumour type, histologic grade, mitotic rate, tubule formation, nuclear grade, CIS and lymphangio invasion) and expression of several proteins (oestrogen and progesterone receptors, cyclin D1, p53, HER2/neu, E-cadherin). In BRCA1associated tumours receptors for oestrogen and progesterone were expressed less frequently (respectively P= 0.001 and P= 0.002) than in controls, which is in line with findings from other studies. Other differences were also in accordance with findings from other studies, although not statistically significant. We conclude that the features of BRCA1 associated tumours detected in a hospital-based series of breast cancer patients not selected for family history of age at diagnosis are similar to tumours in cases selected for family history or age at diagnosis. © 2001 Cancer Research Campaign  http://www.bjcancer.co

CpG island hypermethylation of BRCA1 and loss of pRb as co-occurring events in basal/triple-negative breast cancer

Triple-negative breast cancer (TNBC) occurs in approximately 15% of all breast cancer patients, and the incidence of TNBC is greatly increased in BRCA1 mutation carriers. This study aimed to assess the impact of BRCA1 promoter methylation with respect to breast cancer subtypes in sporadic disease. Tissue microarrays (TMAs) were constructed representing tumors from 303 patients previously screened for BRCA1 germline mutations, of which a subset of 111 sporadic tumors had previously been analyzed with respect to BRCA1 methylation. Additionally, a set of eight tumors from BRCA1 mutation carriers were included on the TMAs. Expression analysis was performed on TMAs by immunohistochemistry (IHC) for BRCA1, pRb, p16, p53, PTEN, ER, PR, HER2, CK5/6, CK8, CK18, EGFR, MUC1, and Ki-67. Data on BRCA1 aberrations and IHC expression was examined with respect to breast cancer-specific survival. The results demonstrate that CpG island hypermethylation of BRCA1 significantly associates with the basal/triple-negative subtype. Low expression of pRb, and high/intense p16, were associated with BRCA1 promoter hypermethylation, and the same effects were seen in BRCA1 mutated tumors. The expression patterns of BRCA1, pRb, p16 and PTEN were highly correlated, and define a subgroup of TNBCs characterized by BRCA1 aberrations, high Ki-67 (≥ 40%) and favorable disease outcome. In conclusion, our findings demonstrate that epigenetic inactivation of the BRCA1 gene associates with RB/p16 dysfunction in promoting TNBCs. The clinical implications relate to the potential use of targeted treatment based on PARP inhibitors in sporadic TNBCs, wherein CpG island hypermethylation of BRCA1 represents a potential marker of therapeutic response

Five recurrent BRCA1/2 mutations are responsible for cancer predisposition in the majority of Slovenian breast cancer families

<p>Abstract</p> <p>Background</p> <p>Both recurrent and population specific mutations have been found in different areas of the world and more specifically in ethnically defined or isolated populations. The population of Slovenia has over several centuries undergone limited mixing with surrounding populations.</p> <p>The current study was aimed at establishing the mutation spectrum of <it>BRCA1/2 </it>in the Slovenian breast/ovarian cancer families taking advantage of a complete cancer registration database. A second objective was to determine the cancer phenotype of these families.</p> <p>Methods</p> <p>The original population database was composed of cancer patients from the Institute of Oncology Ljubljana in Slovenia which also includes current follow-up status on these patients. The inclusion criteria for the <it>BRCA1/2 </it>screening were: (i) probands with at least two first degree relatives with breast and ovarian cancer; (ii) probands with only two first degree relatives of breast cancer where one must be diagnosed less than 50 years of age; and (iii) individual patients with breast and ovarian cancer, bilateral breast cancer, breast cancer diagnosed before the age of 40 and male breast cancer without any other cancer in the family.</p> <p>Results</p> <p>Probands from 150 different families met the inclusion criteria for mutation analysis of which 145 consented to testing. A <it>BRCA1/2 </it>mutation was found in 56 (39%). Two novel large deletions covering consecutive exons of <it>BRCA1 </it>were found. Five highly recurrent specific mutations were identified (1806C>T, 300T>G, 300T>A, 5382insC in the <it>BRCA1 </it>gene and IVS16-2A>G in the <it>BRCA2 </it>gene). The IVS16-2A>G in the <it>BRCA2 </it>gene appears to be a unique founder mutation in the Slovenian population. A practical implication is that only 4 PCR fragments can be used in a first screen and reveal the cancer predisposing mutation in 67% of the <it>BRCA1/2 </it>positive families. We also observed an exceptionally high frequency of 4 different pathogenic missense mutations, all affecting one of the cryptic cysteine residues of the <it>BRCA1 </it>Ring Finger domain.</p> <p>Conclusion</p> <p>A high mutation detection rate and the frequent occurrence of a limited array of recurring mutations facilitate <it>BRCA1/2 </it>mutation screening in Slovenian families.</p