Citations

Abstract Introduction: The metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A) functions to enhance local insulin-like growth factor (IGF)-I bioavailability through cleavage of inhibitory IGF binding proteins. Because IGF-I is an important regulator of skeletal growth and remodeling and PAPP-A is highly expressed by osteoblastic cells, we hypothesized that, in the absence of PAPP-A, bone physiology would be compromised because of a blunting of local IGF-I action even in the presence of normal circulating IGF-I levels. Materials and Methods: pQCT, μCT, histomorphometry, and mechanical strength testing were performed on bones from PAPP-A knockout (KO) mice and wildtype (WT) littermates at 2–12 mo of age. IGF-I levels and bone formation and resorption markers were determined in sera from these animals. Results: Volumetric BMD in PAPP-A KO mice measured by pQCT at the femoral midshaft, which is primarily cortical bone, was 10% less than WT at 2 mo. This difference was maintained at 4, 6, and 12 mo. Cortical thickness at this site was similarly decreased. On the other hand, trabecular bone at the distal femur (pQCT) and in the tibia (μCT) showed age-progressive decreases in bone volume fraction in PAPP-A KO compared with WT mice. Tibial μCT indicated a 46% relative decrease in trabecular bone volume/total volume (BV/TV) and a 28% relative decrease in trabecular thickness in PAPP-A KO compared with WT mice at 6 mo. These trabecular deficiencies in PAPP-A KO mice corresponded to a weakening of the bone. Serum markers and bone histomorphometry indicated that the primary impact of PAPP-A is on skeletal remodeling resulting in a state of low-turnover osteopenia in adult PAPP-A KO mice. Circulating IGF-I levels were not altered in PAPP-A KO mice. Conclusions: PAPP-A is a bone growth regulatory factor in vivo and, in its absence, mice show skeletal insufficiency in mass, density, architecture, and strength. The data suggest a primary role for PAPP-A in modulating local IGF bioavailability for trabecular bone remodeling.

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 < 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 < 0.001), and linked with both BRAF and K-ras mutations (P < 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)

Object Enhancement of pathological entities in the central nervous system is a common finding when the blood–brain barrier has been compromised. In the brain, the presence or absence of gadolinium enhancement is often an indicator of tumor invasiveness and/or grade. In the spinal cord, however, contrast enhancement has been shown in all tumor types, regardless of grade. In this study the authors explore the incidence of nonenhancing tumors of the spinal cord and the clinical course of patients with these lesions. Methods A retrospective analysis was conducted in which investigators examined the patterns of enhancement of histologically proven intramedullary spinal cord tumors that had been evaluated at the Mayo Clinic between 1998 and 2002. The tumors that did not enhance were the subject of this report. Results A total of 130 patients with intramedullary tumors were evaluated. Of those, 11 patients (9%) had tumors that did not enhance. Histologically, a majority of tumors were astrocytomas (eight low-grade and two high-grade lesions); one tumor was a subependymoma. Morphologically, most of the tumors were diffuse and none had associated cysts. Tumors spanned from two to seven levels and were located throughout the spinal cord (four cervical, three cervicothoracic, one thoracic, and three thoracolumbar). Biopsy procedures were performed in eight patients, subtotal resection was performed in two, and gross-total resection in one. After a mean follow-up period of 19 months, tumors remained stable in eight patients but progressed in three, two of whom died. Conclusions A number of intramedullary spinal cord tumors will not enhance after addition of contrast agents. The absence of enhancement does not imply the absence of tumor.

Abstract MUC1 (MUC1 in humans and Muc1 in nonhuman species) is a transmembrane mucin-like glycoprotein expressed in epithelial cells lining various mucosal surfaces as well as hematopoietic cells. Recently, we showed that Muc1−/− mice exhibited greater inflammatory responses to Pseudomonas aeruginosa or its flagellin compared with their wild-type littermates, and our studies with cultured cells revealed that MUC1/Muc1 suppressed the Toll-like receptor (TLR) 5 signaling pathway, suggesting its anti-inflammatory role. Here we demonstrate that other TLR signaling (TLR2, 3, 4, 7, and 9) is also suppressed by MUC1/Muc1. The results from this study suggest that MUC1/Muc1 may play a crucial role during airway infection and inflammation by various pathogenic bacteria and viruses.

✓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.

Object The suprascapular nerve may become entrapped as it travels deep to the suprascapular ligament, necessitating decompression. The present study was performed to verify the feasibility of a minimally invasive, endoscopically assisted technique for decompressing the suprascapular nerve in the supraspinous fossa. Methods The authors performed dissection and decompression of the suprascapular ligament using an endoscopically assisted technique via a 3-cm skin incision in 10 adult cadavers (20 sides). Measurements were also made of the depth from the skin to the suprascapular ligament. Results A mean depth of 4 cm was necessary to reach the suprascapular ligament from the skin surface. With the authors' approach, no obvious injury occurred to the suprascapular or other vicinal neurovascular structures (such as the spinal accessory nerve and suprascapular vessels). Conclusions The results of this cadaveric study demonstrate that access to the suprascapular nerve can be obtained endoscopically via a small suprascapular incision. This approach obviates a large incision, entry into the glenohumeral joint, and reduces the risk of spinal accessory nerve injury in the posterior cervical triangle, or atrophy of the trapezius or supraspinatus muscles from a standard larger dissection. To the authors' knowledge an endoscopically assisted approach to decompressing the suprascapular nerve as it courses deep to the suprascapular ligament has not been reported previously.