Citations

Key Points A recurring mutation in NDUFB11 causes congenital sideroblastic anemia. The NDUFB11 p.93del mutation impairs erythroid proliferation, but not differentiation.

AbstractAlthough current antiplatelet therapies provide potent antithrombotic effects, their efficacy is limited by a heightened risk of bleeding and failure to affect vascular remodeling after injury. New lines of research suggest that thrombosis and hemorrhage may be uncoupled at the interface of pathways controlling thrombosis and inflammation. Here, as one remarkable example, studies using a novel and highly selective pharmacologic inhibitor of the spleen tyrosine kinase Syk [PRT060318; 2-((1R,2S)-2-aminocyclohexylamino)-4-(m-tolylamino)pyrimidine-5-carboxamide] coupled with genetic experiments, demonstrate that Syk inhibition ameliorates both the acute and chronic responses to vascular injury without affecting hemostasis. Specifically, lack of Syk (murine radiation chimeras) attenuated shear-induced thrombus formation ex vivo, and PRT060318 strongly inhibited arterial thrombosis in vivo in multiple animal species while having minimal impact on bleeding. Furthermore, leukocyte-platelet–dependent responses to vascular injury, including inflammatory cell recruitment and neointima formation, were markedly inhibited by PRT060318. Thus, Syk controls acute and long-term responses to arterial vascular injury. The therapeutic potential of Syk may be exemplary of a new class of antiatherothrombotic agents that target the interface between thrombosis and inflammation.

Background There have been few biomechanical studies to clarify which size of a glenoid defect is critical. However, those studies have assumed that the defect occurred anteroinferiorly. Recent studies have reported that the defect is located anteriorly rather than anteroinferiorly. Therefore, the effect of the anterior, not anteroinferior, glenoid defect on shoulder stability needs to be investigated. Hypothesis The anterior glenoid defect would have a similar effect on anterior shoulder stability as that of the anteroinferior glenoid defect. Study Design Controlled laboratory study. Methods Eight fresh-frozen cadaveric shoulders were used (mean age, 74 years). The specimen was attached to a shoulder-testing device with the arm in abduction and external rotation. An osseous defect was created stepwise with a 2-mm increment of the defect width. The stability ratio was used to evaluate joint stability. With a 50-N axial force, the translational force applied to the humeral head was measured by a force transducer. Results The stability ratio without a defect (32% ± 6%) significantly decreased after creating a 6-mm defect (17% ± 5%; P = .0001), which was equivalent to 20% of the glenoid length. Conclusion An osseous defect at 3 o'clock with a width that was equal to or greater than 20% of the glenoid length significantly decreased anterior stability. Clinical Relevance The results suggest that reconstruction of the glenoid concavity might be necessary in shoulders with an anterior glenoid defect of at least 20% of the glenoid length.

AbstractPurpose: Most familial cancer susceptibility genes are tumor suppressor genes that are biallelically inactivated in familial neoplasms through somatic deletion of the wild-type allele. Identifying the genomic losses that occur in pancreatic neoplasms, particularly those that occur in familial and precursor neoplasms, may help localize the genes responsible for pancreatic cancer susceptibility.Experimental Design: Normal and neoplastic tissue DNA was isolated from fresh-frozen surgically resected tissues from 20 patients with primary familial pancreatic adenocarcinoma (defined as having at least one first-degree relative with pancreatic cancer), 31 with sporadic intraductal papillary mucinous neoplasms (IPMN), and 7 with familial IPMNs using laser capture microdissection. Microdissected DNA was whole genome amplified using multiple strand displacement. Genome-wide allelotypes were determined using 391 microsatellite markers. The accuracy of microdissection and fidelity of the whole genome amplification were determined by comparing the genotypes of microdissected primary pancreatic cancers to the genotypes of xenografts derived from these cancers and by comparing the results of amplified to nonamplified specimens.Results: The concordance of genotypes between LCM whole genome amplified primary pancreatic cancers and their corresponding pancreatic cancer xenograft DNAs was 98%. Among the 20 primary familial pancreatic adenocarcinomas, we found a high prevalence of loss of heterozygosity (LOH) with an average fractional allelic loss (FAL) of 49.9% of an aggregate of 2,378 informative markers. The level of FAL in the IPMNs (10%) was significantly lower than in the pancreatic adenocarcinomas. The most common locus of LOH in the IPMNs was at 19p (LOH at 24% of markers). The regions of frequent allelic loss observed in the familial pancreatic cancers were similar to those found in sporadic pancreatic cancers.Conclusions: The allelic loss patterns of familial and sporadic pancreatic cancers and IPMNs provide clues as to the genomic locations of tumor suppressor genes inactivated in these neoplasms.