Citations

Genetic variants in the gene encoding integrin α2 ( ITGA2) have been reported to be associated with an increased risk for ischemic stroke. The purpose of this study was to investigate the association between haplotype-tagging single-nucleotide polymorphisms (tSNPs) in ITGA2 and risk of ischemic stroke in a collection of North American stroke cases and controls. The study included 484 cases and 263 controls. Thirteen tSNPs were genotyped. Association tests at and across each tSNP were performed, including haplotype association analysis. Secondary analyses considered stroke subtypes on the basis of Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. We observed significant association between tSNP rs3756541 (additive model, odds ratio (OR), 1.49; 95% confidence interval (CI), 1.11 to 2.04; P = 0.009) and disease and a trend toward association at rs2303124 (recessive model, OR, 1.56; 95% CI, 1.05 to 2.33; P = 0.03). These associations remained significant in the haplotype analyses. The associated tSNPs did not distinguish stroke etiology after application of TOAST criteria. Our results suggest that genetic variability within ITGA2 may confer risk for ischemic stroke independent of conventional risk factors. These results provide additional support for a role for platelet receptor genes in the pathogenesis of ischemic stroke of diverse subtypes.

Multiple myeloma is a radiosensitive malignancy that is currently incurable. Here, we generated a novel recombinant vesicular stomatitis virus [VSV(Δ51)-NIS] that has a deletion of methionine 51 in the matrix protein and expresses the human sodium iodide symporter (NIS) gene. VSV(Δ51)-NIS showed specific oncolytic activity against myeloma cell lines and primary myeloma cells and was able to replicate to high titers in myeloma cells in vitro. Iodide uptake assays showed accumulation of radioactive iodide in VSV(Δ51)-NIS–infected myeloma cells that was specific to the function of the NIS transgene. In bg/nd/xid mice with established subcutaneous myeloma tumors, administration of VSV(Δ51)-NIS resulted in high intratumoral virus replication and tumor regression. VSV-associated neurotoxicity was not observed. Intratumoral spread of the infection was monitored noninvasively by serial gamma camera imaging of 123I-iodide biodistribution. Dosimetry calculations based on these images pointed to the feasibility of combination radiovirotherapy with VSV(Δ51)-NIS plus 131I. Immunocompetent mice with syngeneic 5TGM1 myeloma tumors (either subcutaneous or orthotopic) showed significant enhancements of tumor regression and survival when VSV(Δ51)-NIS was combined with 131I. These results show that VSV(Δ51)-NIS is a safe oncolytic agent with significant therapeutic potential in multiple myeloma.

Facial plastic surgeons commonly see patients with submental laxity and an excess of skin and fat in the upper neck. This has colloquially been called the “turkey gobbler” deformity. In some cases, this deformity is the patient's only aesthetic concern, and full face-lift surgery is not desired. In this study, we reviewed the English-language peer-reviewed literature for descriptions of direct excisional submentoplasty techniques. Various designs for skin excision and wound closure have been used by surgeons over the past several decades. This article summarizes the surgical technique as well as the advantages and disadvantages of each method. Furthermore, we propose an approach that incorporates many of the other designs but to our knowledge has not been described previously in the peer-reviewed literature. An understanding of these numerous approaches will better enable facial plastic surgeons to appropriately address and correct patient aesthetic concerns.

Abstract The use of tyrosine kinase inhibitors (TKI) has yielded great success in treatment of lung adenocarcinomas. However, patients who develop resistance to TKI treatment often acquire a somatic resistance mutation (T790M) located in the catalytic cleft of the epidermal growth factor receptor (EGFR) enzyme. Recently, a report describing EGFR-T790M as a germ-line mutation suggested that this mutation may be associated with inherited susceptibility to lung cancer. Contrary to previous reports, our analysis indicates that the T790M mutation confers increased Y992 and Y1068 phosphorylation levels. In a human bronchial epithelial cell line, overexpression of EGFR-T790M displayed a growth advantage over wild-type (WT) EGFR. We also screened 237 lung cancer family probands, in addition to 45 bronchoalveolar tumors, and found that none of them contained the EGFR-T790M mutation. Our observations show that EGFR-T790M provides a proliferative advantage with respect to WT EGFR and suggest that the enhanced kinase activity of this mutant is the basis for rare cases of inherited susceptibility to lung cancer. [Cancer Res 2007;67(10):4665–70]

The increasing use of endonasal techniques and a new 3-dimensional CT-guided imaging system have allowed us to develop a combined, minimally invasive endonasal approach to the pituitary gland. Thus far, more than 30 patients have undergone an endonasal transsphenoidal approach to the sella using a combined endoscopic approach, with additional selective use of the Instatrak CT-guided imaging system for realtime imaging. Our current technique involves obtaining a preoperative CT using a plastic head frame with registration markers. By using this head frame intraoperatively, real-time localization with CT images in axial, coronal, and sagittal planes can be performed. Using endoscopic techniques and a Papavero-Caspar speculum, the sella is exposed. A combined approach using endoscopes, the operating microscope, and real-time localization is undertaken to expose and resect tumors. We have encountered minimal associated complications in our series, and this method has been progressively modified to improve exposure and safety. Because we are able to visualize the sella without a sublabial incision or septal resection, we have nearly eliminated the need for nasal packing, reduced the average hospital stay to 2.5 days, and improved patient satisfaction.

Patients with hypertension have a blunted sensitivity of baroreflex control of heart period. In these patients, baroreflex sensitivity is positively related to heart rate variability and inversely related to blood pressure variability. We hypothesized that this relationship would also be evident in healthy normotensive subjects and that individuals with higher baroreflex sensitivity would have lower ambulatory 24-hour blood pressure. Twenty-four-hour ambulatory blood pressure and heart rate were recorded in 50 healthy, normotensive, nonobese individuals (31 women and 19 men). The baroreflex was assessed using sequential bolus administration of sodium nitroprusside and phenylephrine, and baroreflex sensitivity was calculated as the slope of the relation between systolic blood pressure and R-R interval during the resulting blood pressure transients. Baroreflex sensitivity was inversely correlated to 24-hour average mean arterial pressure ( R =0.49; P <0.001) and positively related to daytime heart rate variability ( R =0.33; P =0.02). In contrast, no relationship was found between baroreflex sensitivity and 24-hour heart rate or blood pressure variabilities. We conclude that the relationship between baroreflex sensitivity and daytime heart rate variability was similar to that reported previously in hypertensive subjects. Furthermore, the inverse relation between baroreflex sensitivity and mean arterial pressure supports the idea that the baroreflex may exert longer-term effects on blood pressure than thought previously.

Abstract The Janus kinase 2 mutation, JAK2617V>F, is myeloid neoplasm-specific; its presence excludes secondary polycythemia, thrombocytosis, or bone marrow fibrosis from other causes. Furthermore, JAK2617V>F or a JAK2 exon 12 mutation is present in virtually all patients with polycythemia vera (PV), whereas JAK2617V>F also occurs in approximately half of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Therefore, JAK2 mutation screening holds the promise of a decisive diagnostic test in PV while being complementary to histology for the diagnosis of ET and PMF; the combination of molecular testing and histologic review should also facilitate diagnosis of ET associated with borderline thrombocytosis. Accordingly, revision of the current World Health Organization (WHO) diagnostic criteria for PV, ET, and PMF is warranted; JAK2 mutation analysis should be listed as a major criterion for PV diagnosis, and the platelet count threshold for ET diagnosis can be lowered from 600 to 450 × 109/L. The current document was prepared by an international expert panel of pathologists and clinical investigators in myeloproliferative disorders; it was subsequently presented to members of the Clinical Advisory Committee for the revision of the WHO Classification of Myeloid Neoplasms, who endorsed the document and recommended its adoption by the WHO.

Purpose This report describes the speech characteristics of individuals with a neurodegenerative syndrome called pallido-ponto-nigral degeneration (PPND) and examines the speech samples of at-risk, but asymptomatic, relatives for possible preclinical detection. Method Speech samples of 9 members of a PPND kindred were subjected to perceptual characterization. Speech deterioration patterns were reported for 2 participants followed longitudinally at 6-month intervals. Cross-sectional findings were reported for 3 participants at various stages of disease. Longitudinal and cross-sectional findings were used to guide the examination of 4 at-risk, but asymptomatic, participants. Results Results revealed a progressive mixed dysarthria with hypokinetic, spastic, and flaccid features. It was characterized primarily by vocal tremor and high-frequency vocal flutter, speaking rate abnormalities most often in the direction of slowing, and a tendency toward monopitch. Dysarthria progression was marked by exacerbation and increasing severity of early features, progressive decrease in spontaneous speech output, verbal perseverations, and eventual mutism. Results for at-risk participants revealed preclinical speech abnormalities that preceded other motor signs. Speech results were examined in light of available autopsy findings for site of lesion associations. Conclusion The dysarthria of PPND is an early harbinger of disease onset. It has a mixed presentation, with hypokinetic, spastic, and flaccid features.