| 1. |
- Hibar, Derrek P., et al.
(författare)
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Novel genetic loci associated with hippocampal volume
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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| 2. |
- Satizabal, Claudia L., et al.
(författare)
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Genetic architecture of subcortical brain structures in 38,851 individuals
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
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Tidskriftsartikel (refereegranskat)abstract
- Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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| 3. |
- Becker, Joel, et al.
(författare)
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Resource profile and user guide of the Polygenic Index Repository
- 2021
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Ingår i: Nature Human Behaviour. - : Nature Research (part of Springer Nature). - 2397-3374. ; 51:6, s. 694-695
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Tidskriftsartikel (refereegranskat)abstract
- Polygenic indexes (PGIs) are DNA-based predictors. Their value for research in many scientific disciplines is growing rapidly. As a resource for researchers, we used a consistent methodology to construct PGIs for 47 phenotypes in 11 datasets. To maximize the PGIs’ prediction accuracies, we constructed them using genome-wide association studies—some not previously published—from multiple data sources, including 23andMe and UK Biobank. We present a theoretical framework to help interpret analyses involving PGIs. A key insight is that a PGI can be understood as an unbiased but noisy measure of a latent variable we call the ‘additive SNP factor’. Regressions in which the true regressor is this factor but the PGI is used as its proxy therefore suffer from errors-in-variables bias. We derive an estimator that corrects for the bias, illustrate the correction, and make a Python tool for implementing it publicly available. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
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| 4. |
- Frisch, Morten, et al.
(författare)
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[Sexually transmitted infection as a cause of anal cancer]
- 1998
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Ingår i: Ugeskrift for læger. - 0041-5782 .- 1603-6824. ; 160:49, s. 7109-7117
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Tidskriftsartikel (refereegranskat)abstract
- Interviews were carried out with 423 women and 93 men with invasive or in situ anal cancer in Denmark and Sweden in a search for clues to the aetiology of this neoplasm. Patients with rectal adenocarcinoma (n = 534) and persons drawn from the background population (n = 554) served as controls. Multivariate logistic regression analyses confirmed previous observations of a strong association between either male homosexual experience or a history of anogenital warts and the risk for anal cancer. Moreover, hitherto unknown, but strong and consistent associations were observed between measures of high heterosexual activity and the risk for anal cancer among both sexes. Polymerase chain reaction analysis revealed human papilloma-virus DNA in the majority (88%) of anal cancer specimens but in none of 20 examined rectal adenocarcinomas. It is concluded that most anal cancers appear to be caused by sexually transmitted types of human papillomaviruses and, consequently, that anal cancer is a potentially preventable neoplasm.
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| 5. |
- Frisch, Morten, et al.
(författare)
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Sexually transmitted infection as a cause of anal cancer
- 1997
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 337:19, s. 1350-1358
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The incidence of anal cancer has increased in recent decades, particularly among women. To identify underlying risk factors, we conducted a population-based case-control study in Denmark and Sweden. METHODS: We conducted telephone interviews with 324 women and 93 men in whom invasive or in situ anal cancer was diagnosed between 1991 and 1994, 534 controls with adenocarcinoma of the rectum, and 554 population controls. The interviews covered a wide spectrum of possible risk factors for anal cancer. Odds ratios were calculated by logistic regression. Specimens of anal-cancer tissue and samples of rectal adenocarcinomas were tested for human papillomavirus (HPV) DNA with the polymerase chain reaction. RESULTS: Multivariate analysis revealed consistent and statistically significant associations between measures of sexual promiscuity and the risk of anal cancer in both men and women. There was a significant trend toward an association between higher numbers of partners of the opposite sex in women (P<0.001) and men (P<0.05) and strong associations with a variety of venereal diseases. In women, receptive anal intercourse, particularly before the age of 30 years, and venereal infections in the partner were also associated with an increased risk (odds ratios, 3.4 and 2.4, respectively). Fifteen percent of the men with anal cancer reported having had homosexual contact, as compared with none of the controls (P<0.001). High-risk types of HPV, notably HPV-16, were detected in 84 percent of the anal-cancer specimens examined, whereas all rectal-adenocarcinoma specimens tested were negative for HPV. CONCLUSIONS: Our study provides strong evidence that a sexually transmitted infection causes anal cancer. The presence of high-risk types of HPV, notably HPV-16 (which is known to cause cancer of the cervix), in the majority of anal-cancer tissue specimens suggests that most anal cancers are potentially preventable.
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| 6. |
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| 7. |
- Machado, Mikael, et al.
(författare)
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Defunctioning stoma in low anterior resection with colonic pouch for rectal cancer : A comparison between two hospitals with a different policy
- 2002
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Ingår i: Diseases of the Colon & Rectum. - : Ovid Technologies (Wolters Kluwer Health). - 0012-3706 .- 1530-0358. ; 45:7, s. 940-945
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The aim of this study was to compare surgical outcome, after low anterior resection for rectal cancer with colonic J-pouch, at two departments with a different policy regarding the use of a routine diverting stoma. METHODS: A total of 161 consecutive patients with invasive rectal carcinomas operated on between 1990 and 1997 with a total mesorectal excision and a colonic J-pouch were included in the study. Eighty patients were operated on in a surgical unit using routine defunctioning stomas (96 percent), whereas 81 were operated on in a department in which diversion was rarely used (5 percent). Recorded data with respect to surgical outcome were analyzed and compared. RESULTS: There was no difference between the two centers in postoperative mortality in connection with the primary resection and subsequent stoma reversal (3.7 vs. 3.8 percent). No significant difference could be found in the number of patients with pelvic sepsis (anastomotic leaks, 9 vs. 12 percent). Surgical outcome in patients with pelvic sepsis was also similar. The frequency of reoperations associated with the anterior resection and subsequent stoma reversal was identical (14 percent). The total hospital stay (primary operation and stoma reversal) was significantly longer with than without a routine stoma (17 (range, 2-59) vs. 12 (range, 5-55) days, respectively, P < 0.001). CONCLUSION: This study suggests that the routine use of diversion does not protect the patient from anastomotic complications or pelvic sepsis and its use requires a second admission for closure.
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| 8. |
- Machado, Mikael, et al.
(författare)
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Functional and physiologic assessment of the colonic reservoir or side-to-end anastomosis after low anterior resection for rectal cancer : a two-year follow-up
- 2005
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Ingår i: Diseases of the Colon & Rectum. - Philadelphia, USA : Lippincott Williams & Wilkins. - 0012-3706 .- 1530-0358. ; 48:1, s. 29-36
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Functional disturbances are common after anterior resection for rectal cancer. This study was designed to compare functional and physiologic outcome after low anterior resection and total mesorectal excision with a colonic J-pouch or a side-to-end anastomosis.Methods: Functional and physiologic variables were analyzed in patients randomized to a J-pouch (n = 36) or side-to-end anastomosis (n = 35). Postoperative functional outcome was investigated with questionnaires. Anorectal manometry was performed preoperatively and at six months, one year, and two years postoperatively.Results: There was no statistical difference in functional outcome between groups at two years. Maximum neorectal volume increased in both groups but was approximately 40 percent greater at two years in pouches compared with the side-to-end anastomosis. Anal sphincter pressures volumes were halved postoperatively and did not recover during follow-up of two years. Male gender, low anastomotic level, pelvic sepsis, and the postoperative decrease of sphincter pressures were independent factors for more incontinence symptoms.Conclusions: Colonic J-pouch and side-to-end anastomosis gives comparable functional results two years after low anterior resection. Neorectal volume had no detectable influence on function. There was a pronounced and sustained postoperative decrease in sphincter pressures.
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| 9. |
- Machado, Mikael, et al.
(författare)
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Similar outcome after colonic pouch and side-to-end anastomosis in low anterior resection for rectal cancer : a prospective randomized trial.
- 2003
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Ingår i: Annals of Surgery. - Philadelphia, USA : Lippincott Williams & Wilkins. - 0003-4932 .- 1528-1140. ; 238:2, s. 214-20
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To compare a colonic J-pouch or a side-to-end anastomosis after low-anterior resection for rectal cancer with regard to functional and surgical outcome.Summary beckground data: A complication after restorative rectal surgery with a straight anastomosis is low-anterior resection syndrome with a postoperatively deteriorated anorectal function. The colonic J-reservoir is sometimes used with the purpose of reducing these symptoms. An alternative method is to use a simple side-to-end anastomosis.Methods: One-hundred patients with rectal cancer undergoing total mesorectal excision and colo-anal anastomosis were randomized to receive either a colonic pouch or a side-to-end anastomosis using the descending colon. Surgical results and complications were recorded. Patients were followed with a functional evaluation at 6 and 12 months postoperatively.Results: Fifty patients were randomized to each group. Patient characteristics in both groups were very similar regarding age, gender, tumor level, and Dukes' stages. A large proportion of the patients received short-term preoperative radiotherapy (78%). There was no significant difference in surgical outcome between the 2 techniques with respect to anastomotic height (4 cm), perioperative blood loss (500 ml), hospital stay (11 days), postoperative complications, reoperations or pelvic sepsis rates. Comparing functional results in the 2 study groups, only the ability to evacuate the bowel in <15 minutes at 6 months reached a significant difference in favor of the pouch procedure.Conclusions: The data from this study show that either a colonic J-pouch or a side-to-end anastomosis performed on the descending colon in low-anterior resection with total mesorectal excision are methods that can be used with similar expected functional and surgical results.
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| 10. |
- Nilsson, Per J, et al.
(författare)
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Epidermoid anal cancer : a review of a population-based series of 308 consecutive patients treated according to prospective protocols
- 2005
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Ingår i: International Journal of Radiation Oncology, Biology, Physics. - New York, USA : Elsevier. - 0360-3016 .- 1879-355X. ; 61, s. 92-102
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Forskningsöversikt (refereegranskat)abstract
- Purpose: The primary therapy in epidermoid anal cancer is radiotherapy, generally with chemotherapy. The use of neoadjuvant chemotherapy has been infrequently reported in the literature. This study presents results from a large population-based series and provides comparisons between different treatments.Methods and materials: Between 1985 and 2000, 308 patients with invasive epidermoid anal cancer were diagnosed in the Stockholm Health Care Region. Treatment was given according to defined protocols. External beam radiotherapy alone or with concomitant bleomycin and neoadjuvant chemotherapy followed by radiotherapy alone were the primary treatments. Radical surgery was reserved for poor responders or recurrences. Data were reviewed with regard to treatment, outcome, and prognostic factors.Results: Among the 276 patients (90%) treated with curative intent, 264 (96%) received treatment in accordance with the protocols. The overall 5-year survival rate was 68%. Among the 142 patients with locally advanced tumors (T > or =4 cm or N+), patients treated with neoadjuvant platinum-based chemotherapy (n = 91) had significantly better complete response rates compared with patients treated with radiotherapy with or without bleomycin (n = 51) (92% vs. 76%, p < 0.01). A significantly increased overall 5-year survival rate was also found among patients receiving neoadjuvant therapy (63% vs. 44%, p < 0.05).Conclusion: Structured treatment protocols result in favorable outcome on a population level. The results further suggest a significant therapeutic gain from including neoadjuvant chemotherapy in the treatment of locally advanced anal cancer.
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