Neurofibromatosis type 1 (NF1) is one of the most common heritable autosomal dominant disorders. Alternative splicing modulates the function of neurofibromin, the NF1 gene product, by inserting the in-frame exon 23a into the region of NF1 mRNA that encodes the GTPase-activating protein-related domain. This insertion, which is predominantly skipped in neurons, reduces the ability of neurofibromin to regulate Ras by 10-fold. Here, we report that the neuron-specific Hu proteins control the production of the short protein isoform by suppressing inclusion of NF1 exon 23a, while TIA-1/TIAR proteins promote inclusion of this exon. We identify two binding sites for Hu proteins, located upstream and downstream of the regulated exon, and provide biochemical evidence that Hu proteins specifically block exon definition by preventing binding of essential splicing factors. In vitro analyses using nuclear extracts show that at the downstream site, Hu proteins prevent binding of U1 and U6 snRNPs to the 5 splice site, while TIAR increases binding. Hu proteins also decrease U2AF binding at the 3 splice site located upstream of exon 23a. In addition to providing the first mechanistic insight into tissue-specific control of NF1 splicing, these studies establish a novel strategy whereby Hu proteins regulate RNA processing.Neurofibromatosis type I (NF1), which affects 1 in 3,500 individuals (11), is one of the most common dominantly inherited autosomal disorders. Loss-of-function mutations in the NF1 gene cause several abnormalities, including development of benign peripheral and optic nerve tumors (neurofibromas and gliomas) and abnormal distribution of melanocytes (café-aulait spots). NF1 patients also have increased risk of developing malignant tumors of neuronal origin (11, 13). The tumor suppression function of NF1 was linked to a domain in its encoded protein, neurofibromin, which is structurally similar to the Ras GTPase-activating protein (GAP) family (13). In addition to its widely accepted tumor suppression function, NF1 also plays a significant role in brain development. About 30 to 60% of children with NF1 mutations develop learning disabilities, ranging from mild cognitive impairment to attention deficit disorders (15).Exon 23a is an in-frame exon encoding 21 amino acids in the NF1 GAP region. This exon is alternatively included, producing two NF1 isoforms (5). The type I isoform does not contain this exon, while the type II isoform does. The ratio of the two isoforms varies in different tissues and during development. The type I isoform is predominantly expressed in neurons of the adult central nervous system (21, 25) and shows 10-timeshigher activity in down-regulating Ras activity than the type II isoform (5, 48). In the pheochromocytoma cell line PC12, production of the NF1 type 1 isoform can be induced by nerve growth factor treatment (48). These lines of evidence suggest that a balance of the two isoforms is important during neuronal differentiation. Indeed, when exon 23a was deleted from the NF1 locus by gene targ...
Routine use of vacuum-assisted closure with open tibia fractures is safe and provides a good primary dressing over open wounds. For Gustilo grade IIIB tibia fractures, vacuum-assisted closure therapy does not allow delay of soft-tissue coverage past 7 days without a concomitant elevation in infection rates.
Randomized Clinical Trial, Level II.
To assess the validity of performance measures used in a nationwide pay-forperformance (P4P) project on hip and knee replacement, we analyzed hospital performance data from a Medicare P4P initiative and compared them to publicly available outcomes data. Overall, the ability to measure hospital quality was poor. A hospital's ranking on the composite score was primarily determined by process measures. A higher composite quality score was not associated with lower rates of complications or mortality. The current Medicare P4P quality measure has limited validity because of poor discrimination, lack of measure balance, and lack of correlation with important clinical outcomes. P ay-f o r -p e r f o r m a n c e (P4P) programs have been advocated as a method to improve the quality of health care in the United States. 1 The success of P4P programs hinges upon the development of performance measures that accurately reflect the quality of clinical care delivered. Ideally, quality measures should be easily obtainable, discriminate between high-and low-quality providers, be adjusted for the severity of casemix, and correlate with important external measures such as mortality and complication rates. 2 Although numerous P4P programs have been implemented, little is known about how well the quality measures used by these programs actually perform, especially in the resource-intensive surgical fields. 3 Rigorous assessment of performance measures should precede expansion of P4P programs.n Suitability of arthroplasty for P4P. P4P programs target total hip and knee replacement because arthroplasty is one of the few well-defined procedures in medicine where performance can be measured. The surgical procedure is relatively standardized. Existing treatment care guidelines and clinical pathways facilitate the development of clinical performance measures. 4 Outcomes after total hip and total knee arthroplasty are well studied, and the relationship between greater hospital case volume and improved outcomes has been described. Total joint replacement is 5 2 6 M a r c h /A p r i l 2 0 0 9 H e a l t h T r a c k i n g
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