Patients with long-standing inflammatory bowel disease (IBD) involving at least 1/3 of the colon are at increased risk for colorectal cancer (CRC). Advancements in CRC screening and surveillance and improved treatment of IBD has reduced CRC incidence in patients with ulcerative colitis and Crohn’s colitis. Most cases of CRC are thought to arise from dysplasia, and recent evidence suggests that the majority of dysplastic lesions in patients with IBD are visible, in part thanks to advancements in high definition colonoscopy and chromoendoscopy. Recent practice guidelines have supported the use of chromoendoscopy with targeted biopsies of visible lesions rather than traditional random biopsies. Endoscopists are encouraged to endoscopically resect visible dysplasia and only recommend surgery when a complete resection is not possible. New technologies such as virtual chromoendoscopy are emerging as potential tools in CRC screening. Patients with IBD at increased risk for developing CRC should undergo surveillance colonoscopy using new approaches and techniques.

We examined the relationship between physician adherence with a smoking cessation guideline and organizational structures, policies, leadership support, and physician knowledge and attitudes. A random sample of 844 physicians practicing in 127 VHA hospitals was surveyed. Survey results were aggregated to the hospital level and linked with data on organizational characteristics from the 1998 annual survey of hospitals by the American Hospital Association. Significant predictors of adherence included organizational policies related to nicotine replacement prescriptions, the timing and effectiveness of guideline implementation, physicians' knowledge of VHA clinical guidelines generally, and physicians' beliefs about the receptiveness of patients to smoking cessation.

We previously described the Trypanin family of cytoskeleton-associated proteins that have been implicated in dynein regulation [Hill et al., J Biol Chem2000; 275(50):39369-39378; Hutchings et al., J Cell Biol2002;156(5):867-877; Rupp and Porter, J Cell Biol2003;162(1):47-57]. Trypanin from T. brucei is part of an evolutionarily conserved dynein regulatory system that is required for regulation of flagellar beat. In C. reinhardtii, the trypanin homologue (PF2) is part of an axonemal 'dynein regulatory complex' (DRC) that functions as a reversible inhibitor of axonemal dynein [Piperno et al., J Cell Biol1992;118(6):1455-1463; Gardner et al., J Cell Biol1994;127(5):1311-1325]. The DRC consists of an estimated seven polypeptides that are tightly associated with axonemal microtubules. Association with the axoneme is critical for DRC function, but the mechanism by which it attaches to the microtubule lattice is completely unknown. We demonstrate that Gas11, the mammalian trypanin/PF2 homologue, associates with microtubules in vitro and in vivo. Deletion analyses identified a novel microtubule-binding domain (GMAD) and a distinct region (IMAD) that attenuates Gas11-microtubule interactions. Using single-particle binding assays, we demonstrate that Gas11 directly binds microtubules and that the IMAD attenuates the interaction between GMAD and the microtubule. IMAD is able to function in either a cis- or trans-orientation with GMAD. The discovery that Gas11 provides a direct linkage to microtubules provides new mechanistic insight into the structural features of the dynein-regulatory complex.

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The median free fraction of valproic acid was significantly higher in inpatients than in outpatients. Low albumin concentration was a predictor of discordance between free and total valproic acid concentrations.

This prospective observational study including consecutive patients with inflammatory bowel disease treated with either infliximab or adalimumab showed that although the correlation between the ELISA and the homogeneous mobility shift assay was good for both drugs, the agreement was poor.

SummarySyncoilin is an atypical type III intermediate filament (IF) protein, which is expressed in muscle and is associated with the dystrophinassociated protein complex. Here, we show that syncoilin is expressed in both the central and peripheral nervous systems. Isoform Sync1 is dominant in the brain, but isoform Sync2 is dominant in the spinal cord and sciatic nerve. Peripherin is a type III IF protein that has been shown to colocalise and interact with syncoilin. Our analyses suggest that syncoilin might function to modulate formation of peripherin filament networks through binding to peripherin isoforms. Peripherin is associated with the disease amyotrophic lateral sclerosis (ALS), thus establishing a link between syncoilin and ALS. A neuronal analysis of the syncoilin-null mouse (Sync -/-) revealed a reduced ability in accelerating treadmill and rotarod tests. This phenotype might be attributable to the impaired function of extensor digitorum longus muscle and type IIb fibres caused by a shift from large-to small-calibre motor axons in the ventral root.

over days 2-3), and intrathecal methotrexate (15 mg/day on day 1). Although initially successful, the patient later relapsed with an increase in the size and number of the cerebral lesions. Oral dasatinib (70 mg twice per day) was started and led to a complete regression of lesions visible on MRI and neurologic disease. The patient is currently in remission (Ͼ 12 months) with no measurable monoclonal lymphocyte population in blood and bone marrow on continuous therapy.Pitini et al 2 and others 3 initially reported responses to dasatinib in patients with CLL, although subsequent phase 2 clinical trials in relapsed CLL demonstrated only moderate activity. 5 This is the first report of dasatinib treatment in central nervous system B-CLL and might serve as a proof of concept for future cases. In vitro data suggest that del(17p) mutated CLL and those with unmutated immunoglobulin heavy chains (IgVHs) might be especially sensitive to dasatinib. 2,5,6 Unfortunately, IgVH mutational analysis was not initially performed. Dasatinib CSF concentration is reported to reach only 5% to 28% of plasma concentrations in humans. 4 Still, the effect in this case was clinically meaningful and lasting. Further clinical investigation of dasatinib treatment in B-CLL with CNS involvement is warranted. Georg Russwurm To the editor:Gemtuzumab ozogamicin: is there room for salvage?On May 17, 2000, gemtuzumab ozogamicin received marketing approval from the US Food and Drug Administration (FDA) under accelerated approval regulations for the treatment of patients with CD33-positive acute myeloid leukemia (AML) in first relapse who are 60 years of age or older and who are not considered candidates for cytotoxic chemotherapy. 1 The data supporting this application included 3 open-label studies that enrolled 157 patients at least 60 years of age in whom an overall response rate of 24% (12% CR ϩ 12% CRp) was observed. On June 21, 2010, the FDA and Pfizer announced that this drug would be voluntarily withdrawn from the market due to failure of 2 confirmatory clinical trials to demonstrate clinical benefit. Of note, the confirmatory trials examined gemtuzumab as an addition to standard induction chemotherapy in newly diagnosed patients up to 70 years of age, rather than in a relapsed or refractory older population. To those familiar with other attempts at improving outcomes in patients with newly diagnosed AML and with the hepatic toxicity of the approved dosing regimen of gemtuzumab, the failure of gemtuzumab to provide survival benefit when combined with anthracycline and cytarabine was not surprising. [2][3][4] It is, therefore, appropriate for the drug to be withdrawn from the market at this time given the accelerated regulatory pathway agreed upon previously. However, questions remain. Is there a role for this agent in a certain population of patients? Is there a safer method for administering the drug?Data from uncontrolled studies clearly indicate that the drug has single-agent activity in the setting of relapsed or refractory AML in a...