Citations

After Alzheimer's disease, frontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in persons less than 65 years of age. Up to 40% of FTLD cases have a positive family history. Research on these families has led to the discovery of four disease-causing genes: microtubule-associated protein tau ( MAPT), progranulin ( PGRN), valosin-containing protein ( VCP), and charged multivesicular body protein 2B ( CHMP2B). MAPT and PGRN are responsible for the largest number of familial cases. Each of these genes differs by disease mechanism. Moreover mutations in both genes are associated with significant interfamilial and intrafamilial phenotypic variation. Genetic counseling needs to address the differences between the PGRN and MAPT mutations as well as the variation in clinical symptoms. The aims of this article are to describe the genetics of the FTLD spectrum and aid in the genetic counseling of individuals who may carry genetic mutations.

Abstract Context: The process of epiphyseal fusion during puberty is regulated by estrogen, even in males. Objective: Our objective was to investigate whether anastrozole, a potent aromatase inhibitor, could delay bone age acceleration and increase predicted adult height in adolescent boys with GH deficiency. Methods: Fifty-two adolescent males with GH deficiency treated with GH were randomized to cotreatment with anastrozole or placebo daily for up to 36 months. Results: Fifty subjects completed 12 months, 41 completed 24 months, and 28 completed 36 months. Linear growth was comparable between groups; however, there was a significantly slower increase in bone age advancement from baseline in the anastrozole group vs. placebo group after 2 yr (+1.8 ± 0.1 vs. +2.7 ± 0.1 yr, P < 0.0001) and after 3 yr (+2.5 ± 0.2 vs. +4.1 ± 0.1 yr, P < 0.0001). This resulted in a net increase in predicted adult height of +4.5 ± 1.2 cm in the anastrozole group at 24 months and +6.7 ± 1.4 cm at 36 months as compared with a 1-cm gain at both time points in the placebo group. Estradiol and estrone concentrations increased less in the anastrozole group compared with placebo group. All boys on the aromatase inhibitor had normal tempo of virilization. Safety data, including glucose, and plasma lipid concentrations were comparable between groups. Conclusions: Anastrozole increases adult height potential of adolescent boys on GH therapy while maintaining normal pubertal progression after 2–3 yr. This treatment offers an alternative in promoting growth in GH-deficient boys in puberty. Long-term follow up is needed to elucidate fully the safety and efficacy of this approach.

Objective— The clinical use of venous stents is increasing dramatically. Although antiplatelet agents are required for arterial stent patency, optimal thrombo-prophylaxis after venous stenting remains undefined. To address this issue, PD0348292, a direct Factor Xa inhibitor, was compared with antiplatelet therapy in a porcine venous stent model. Methods and Results— Four hours before stent deployment, pigs (n=5 to 6 per group) received oral PD0348292 at 0.4, 0.9, 4.3 mg/kg, or 0.4 mg/kg plus aspirin (325 mg). Aspirin, clopidogrel (75 mg), aspirin plus clopidogrel, or vehicle (n=10) were administered daily for 2 days before the procedure. Two hours after stent placement, thrombi were quantified by autologous 111 In-platelet content and weights. Thrombus weight and platelet deposition were significantly reduced by PD0348292 at 0.4 (49±79 mg and 110±145×10 6 /cm 2 ), 0.9 (5±6 mg and 107±128×10 6 /cm 2 ), 4.3 mg/kg (0±0 mg and 87±125×10 6 /cm 2 ), and PD348292 plus aspirin (20±40 mg and 157±70×10 6 /cm 2 ) compared with vehicle (402±226 mg; 584±454×10 6 /cm 2 ). Despite prolonging bleeding times and inhibiting platelet aggregation, neither aspirin (567±683 mg and 533±622×10 6 /cm 2 ), clopidogrel (404±349 mg and 178±101×10 6 /cm 2 ), nor aspirin plus clopidogrel (247±261 mg and 231±266×10 6 /cm 2 ) significantly decreased stent thrombosis. Conclusions— PD0348292 completely inhibited thrombosis after venous stenting. Platelet accretion in these venous thrombi appear to involve pathways distinct from arachidonate metabolism or ADP P 2 Y 12 receptor activation.

In vitro and animal studies suggest that oxidative stress is associated with endothelial dysfunction. We tested whether local oxidative stress and nitric oxide (NO) bioavailability in the coronary circulation is associated with coronary endothelial dysfunction in humans. Blood samples were obtained simultaneously from the left main coronary artery and the coronary sinus for measurement of F2-isoprostanes, myeloperoxidase, nitrotyrosine, and superoxide dismutase in 20 patients without significant coronary disease. Afterward, coronary blood flow and the vascular response to intracoronary acetylcholine and N G -monomethyl- L -arginine (L-NMMA) were assessed. The gradient of isoprostanes between the arterial levels and coronary sinus correlated with the change in coronary artery diameter in response to acetylcholine ( r =−0.79, P <0.0001). Isoprostanes net production across the left anterior descending artery territory correlated with a decrease in superoxide dismutase activity ( r =0.66, P =0.002) and decrease in coronary artery diameter in response to L-NMMA (r s =0.48, P <0.05). Myeloperoxidase and nitrotyrosine gradients were similar in patients with endothelial dysfunction and controls. The effect of L-NMMA was similar in both groups. We conclude that coronary endothelial dysfunction in humans is characterized by local enhancement of oxidative stress without a decrease in basal NO release. This study supports the hypothesis that local oxidative stress has a role in reduction of NO bioavailability in humans with coronary endothelial dysfunction.

AbstractDiscriminant markers are required for accurate cancer screening. We evaluated genes frequently methylated in colorectal neoplasia to identify the most discriminant ones. Four genes specifically methylated in colorectal cancer [bone morphogenetic protein 3 (BMP3), EYA2, aristaless-like homeobox-4 (ALX4), and vimentin] were selected from 41 candidate genes and evaluated on 74 cancers, 62 adenomas, and 70 normal epithelia. Methylation status was analyzed qualitatively and quantitatively and confirmed by bisulfite genomic sequencing. Effect of methylation on gene expression was evaluated in five colon cancer cell lines. K-ras and BRAF mutations were detected by sequencing. Methylation of BMP3, EYA2, ALX4, or vimentin was detected respectively in 66%, 66%, 68%, and 72% of cancers; 74%, 48%, 89%, and 84% of adenomas; and 7%, 5%, 11%, and 11% of normal epithelia (P &lt; 0.01, cancer or adenoma versus normal). Based on area under the curve analyses, discrimination was not significantly improved by combining markers. Comethylation was frequent (two genes or more in 72% of cancers and 84% of adenomas), associated with proximal neoplasm site (P &lt; 0.001), and linked with both BRAF and K-ras mutations (P &lt; 0.01). Cell line experiments supported silencing of expression by methylation in all four study genes. This study shows BMP3, EYA2, ALX4, and vimentin genes are methylated in most colorectal neoplasms but rarely in normal epithelia. Comethylation of these genes is common, and pursuit of complementary markers for methylation-negative neoplasms is a rational strategy to optimize screening sensitivity. (Cancer Epidemiol Biomarkers Prev 2007;16(12):2686–96)

Abstract Epidemiologic studies have shown the health risks of exposure to cigarette smoke and air pollution, with heavy metal composition implicated as contributing to both. Environmental exposure to cigarette smoke has been epidemiologically associated with pancreatic cancer, but the pathophysiologic basis for this is not yet clear. In the current work, we have used inductively coupled plasma mass spectrometry to quantify the metal composition of pancreatic juice collected in response to secretin stimulation in successive patients evaluated for abdominal pain (35 with pancreatic cancer, 30 with chronic pancreatitis, and 35 with normal pancreas). Indeed, metal composition of pancreatic juice was distinctive in patients with pancreatic cancer relative to those without such a cancer. The metal concentrations that were found to have the strongest association with pancreatic cancer were chromium, selenium, and molybdenum, with 1 SD increases in the concentrations of each associated with substantial increases in the odds of having pancreatic cancer relative to those in patients with normal pancreas (210%, 160%, and 76%, respectively). Of note, elevations in concentrations of chromium and selenium did not correlate in individuals, whereas those having a 1 SD increase in the sum of the concentrations of these two metals in their pancreatic juice had a 480% increase in the odds of having pancreatic cancer. Elevations of nickel and zinc correlated with elevated chromium in individuals, with each of these metals known to be present in cigarette smoke, whereas other recognized metal components of cigarette smoke were not elevated. An understanding of why these metals are elevated in pancreatic juice and what effects they might have on pancreatic cells may have important implications for the diagnosis, treatment, and even prevention of pancreatic cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(12):2656–63)

✓The authors report the successful staged stenting and coil embolization of a large vertebral artery–posterior inferior cerebellar artery (VA-PICA) aneurysm using the contralateral VA for access. A 67-year-old woman presented with a large ruptured VA-PICA aneurysm. Initial attempts to stent the wide-necked aneurysm from the ipsilateral side failed, so coil embolization of the dome was performed. During a second endovascular session, the aneurysm neck was successfully stented from the contralateral VA into the PICA. Six weeks later, coils were inserted into the aneurysm from the ipsilateral side. The coil result was stable at the 3-month follow-up examination.