Citations

Germline mutations in the DNA base excision repair gene MUTYH are known to increase a carrier's risk of colorectal cancer. However, the risks of other (extracolonic) cancers for MUTYH mutation carriers are not well defined. We identified 266 probands (91% Caucasians) with a MUTYH mutation (41 biallelic and 225 monoallelic) from the Colon Cancer Family Registry. Mutation status, sex, age and histories of cancer from their 1,903 first‐ and 3,255 second‐degree relatives were analyzed using modified segregation analysis conditioned on the ascertainment criteria. Compared with incidences for the general population, hazard ratios (HRs) (95% confidence intervals [CIs]) for biallelic MUTYH mutation carriers were: urinary bladder cancer 19 (3.7–97) and ovarian cancer 17 (2.4–115). The HRs (95% CI) for monoallelic MUTYH mutation carriers were: gastric cancer 9.3 (6.7–13); hepatobiliary cancer 4.5 (2.7–7.5); endometrial cancer 2.1 (1.1–3.9) and breast cancer 1.4 (1.0–2.0). There was no evidence for an increased risk of cancers at the other sites examined (brain, pancreas, kidney or prostate). Based on the USA population incidences, the estimated cumulative risks (95% CI) to age 70 years for biallelic mutation carriers were: bladder cancer 25% (5–77%) for males and 8% (2–33%) for females and ovarian cancer 14% (2–65%). The cumulative risks (95% CI) for monoallelic mutation carriers were: gastric cancer 5% (4–7%) for males and 2.3% (1.7–3.3%) for females; hepatobiliary cancer 3% (2–5%) for males and 1.4% (0.8–2.3%) for females; endometrial cancer 3% (2%–6%) and breast cancer 11% (8–16%). These unbiased estimates of both relative and absolute risks of extracolonic cancers for people, mostly Caucasians, with MUTYH mutations will be important for their clinical management.

Purpose: To describe a bailout technique for use during branched/fenestrated thoracoabdominal aortic aneurysm (TAAA) repair to address celiac artery (CA) dissection. Technique: The technique is demonstrated in a 69-year-old man who underwent fenestrated stent-graft repair of a 6-cm type III TAAA. The main fenestrated stent-graft was positioned without difficulty, and the renal and superior mesenteric arteries were stented. A stent-graft was placed in the CA, but angiography showed the vessel to be occluded by dissection beyond the stent-graft. Wire manipulations to regain access to the true lumen culminated in perforation. At this point, the gastroduodenal artery was catheterized with a 0.035-inch guidewire, which was advanced in retrograde fashion into the CA true lumen and then snared back to the left brachial artery forming a loop. After exchange for a 0.014-inch system, self-expanding stents were deployed into the hepatic artery. Postoperative recovery was uneventful, and the patient was discharged on day 6. At 1-year follow-up, the patient was doing very well. Imaging demonstrated no endoleak, no graft migration, and sac shrinkage to a diameter of 5.1 cm. Conclusion: The “loop technique” can be a very useful and effective bailout maneuver in regaining access to the true lumen of a dissected CA in patients undergoing branched/fenestrated thoracoabdominal aortic aneurysm repair.

Significance Ubiquitin-specific protease 6 (USP6) is a deubiquitylase that is overexpressed by chromosome translocation in two human neoplasms, aneurysmal bone cyst and nodular fasciitis. The relevant substrates of this ubiquitin-specific protease are not clear. Here, we identify the Wnt receptor Frizzled (Fzd) as a key target of the USP6 oncogene. Increased expression of USP6 increases the membrane abundance of Fzd, and hence increases cellular sensitivity to Wnts. USP6 opposes the activity of the ubiquitin ligase and tumor suppressor ring finger protein 43 (RNF43). This study identifies a new mechanism for pathological Wnt pathway activation in human disease and suggests a new approach to regulate Wnt activity therapeutically.

Background: Subclinical hypothyroidism (SCH) has been associated with increased risk of adverse pregnancy outcomes in some, but not all, studies. Uncertainty remains regarding the impact of levothyroxine (LT4) therapy on improving health outcomes in pregnant women with SCH. The objective of this study was to assess the potential benefits of LT4 therapy in pregnant women with SCH. Methods: The medical records were reviewed of pregnant women with SCH, defined as an elevated serum thyrotropin (TSH) of >2.5 mIU/L for the 1st trimester or >3 mIU/L for the 2nd and 3rd trimesters, but ≤10 mIU/L. Pregnant women were divided into two groups depending on whether they received LT4 (group A) or not (group B). Pregnancy loss and other pre-specified adverse outcomes were evaluated during follow-up. Results: There were 82 women in group A and 284 in group B. Group A had a higher body mass index ( p = 0.04) and a higher serum TSH level ( p < 0.0001) compared with group B. Group A had fewer pregnancies lost ( n = 5 [6.1%] vs. n = 25 [8.8%]; p = 0.12), low birth weight (LBW) offspring (1.3% vs. 10%; p < 0.001), and no neonates with a five-minute Apgar score ≤7 (0% vs. 7%; p < 0.001) compared with group B. Other pregnancy-related adverse outcomes were similar between the two groups. Inferences remained unchanged after considering different models to adjust for potential predictors of outcome. Conclusions: LT4 therapy is associated with a decreased risk of LBW and a low Apgar score among women with SCH. This association awaits confirmation in randomized trials before the widespread use of LT4 therapy in pregnant women with SCH.

AbstractAimsTo estimate the sex‐stratified prevalence and clustering of 14 behavioural and metabolic health risk factors in emerging adulthood.BackgroundThe high prevalence and the clustering of risk factors multiply health consequences and increase the threat to the future health and quality of life of young adults.DesignDescriptive cross‐sectional study.MethodsDuring November‐December 2012, we assessed 14 lifestyle characteristics of 1058 1st year university students’ that were classified as: healthy (score = 0), unhealthy (score = 1) and high‐risk unhealthy (score = 2). We subsequently created a Multiple Health Risk Behaviours Index by summing the score of each behaviour adjusted to 0‐100.ResultsOnly 0·3% of the students had one risk behaviour and 21·3% (male: 31·5%; female: 12·6%) had ≥10 of 14. Male students had higher risk index score. In adjusted regression analyses, female students had higher odds of reporting healthier behaviours in oral hygiene (tooth brushing), red meat and junk food consumption, binge drinking, cannabis/hashish/marijuana use and lower number of sexual partners and Body Mass Index. Male students reported higher physical activity. No statistically significant gender differences were noted for screen time/sedentary behaviours, condom use, smoking, sunburns, breakfast and fruit and vegetable consumption.ConclusionAlthough health‐compromising behaviours are highly prevalent in both men and women, they are gender‐related, with males engaging in more health risk behaviours than females. Preventive interventions may need to focus on gender‐informed approaches when targeting multiple health risk behaviours.

Findings from genetic, animal model, and human studies support the observation that accumulation of the β-amyloid (Aβ) peptide in the brain plays a central role in the pathogenic cascade of Alzheimer’s disease (AD). Human studies suggest that one key factor leading to accumulation is a defect in brain Aβ clearance. We have developed a novel microimmunoelectrode (MIE) to study the kinetics of Aβ clearance using an electrochemical approach. This is the first study using MIEs in vivo to measure rapid changes in Aβ levels in the brains of living mice. Extracellular, interstitial fluid (ISF) Aβ levels were measured in the hippocampus of APP/PS1 mice. Baseline levels of Aβ40 in the ISF are relatively stable and begin to decline within minutes of blocking Aβ production with a γ-secretase inhibitor. Pretreatment with a P-glycoprotein inhibitor, which blocks blood–brain barrier transport of Aβ, resulted in significant prolongation of Aβ40 half-life, but only in the latter phase of Aβ clearance from the ISF.