Citations

Abstract Expression of neuropilin-1 (NRP-1) has been shown in many cancer cells, but its molecular effect on tumorigenesis is largely unknown. In this report, we show that in aggressive types of renal cell carcinoma (RCC), NRP-1 is expressed at a high level. We show that after knockdown of NRP-1 by short hairpin RNA, RCC cells express significantly lower levels of MDM-2 and p63 proteins but higher levels of p53, and exhibit reduced migration and invasion. When implanted in mice, RCC cells with a reduced NRP-1 level have a statistically significant smaller tumor-forming ability than control cells. Also, NRP-1 knockdown RCC cells exhibit a more differentiated phenotype, as evidenced by the expression of epithelial-specific and kidney-specific cadherins, and the inhibition of sonic hedgehog expression participated in this effect. Inhibition of sonic hedgehog expression can be reversed by ΔNp63α overexpression. Our study reveals that NRP-1 helps maintain an undifferentiated phenotype in cancer cells. [Cancer Res 2008;68(21):8667–72]

Objectives:This guideline provides evidence‐based recommendations on managing benign paroxysmal positional vertigo (BPPV), which is the most common vestibular disorder in adults, with a lifetime prevalence of 2.4 percent. The guideline targets patients aged 18 years or older with a potential diagnosis of BPPV, evaluated in any setting in which an adult with BPPV would be identified, monitored, or managed. This guideline is intended for all clinicians who are likely to diagnose and manage adults with BPPV.Purpose:The primary purposes of this guideline are to improve quality of care and outcomes for BPPV by improving the accurate and efficient diagnosis of BPPV, reducing the inappropriate use of vestibular suppressant medications, decreasing the inappropriate use of ancillary tests such as radiographic imaging and vestibular testing, and to promote the use of effective repositioning maneuvers for treatment. In creating this guideline, the American Academy of Otolaryngology—Head and Neck Surgery Foundation selected a panel representing the fields of audiology, chiropractic medicine, emergency medicine, family medicine, geriatric medicine, internal medicine, neurology, nursing, otolaryngology–head and neck surgery, physical therapy, and physical medicine and rehabilitation.ResultsThe panel made strong recommendations that 1) clinicians should diagnose posterior semicircular canal BPPV when vertigo associated with nystagmus is provoked by the Dix‐Hallpike maneuver.The panel made recommendations against 1) radiographic imaging, vestibular testing, or both in patients diagnosed with BPPV, unless the diagnosis is uncertain or there are additional symptoms or signs unrelated to BPPV that warrant testing; and 2) routinely treating BPPV with vestibular suppressant medications such as antihistamines or benzodiazepines.The panel made recommendations that 1) if the patient has a history compatible with BPPV and the Dix‐Hallpike test is negative, clinicians should perform a supine roll test to assess for lateral semicircular canal BPPV; 2) clinicians should differentiate BPPV from other causes of imbalance, dizziness, and vertigo; 3) clinicians should question patients with BPPV for factors that modify management including impaired mobility or balance, CNS disorders, lack of home support, and increased risk for falling; 4) clinicians should treat patients with posterior canal BPPV with a particle repositioning maneuver (PRM); 5) clinicians should reassess patients within 1 month after an initial period of observation or treatment to confirm symptom resolution; 6) clinicians should evaluate patients with BPPV who are initial treatment failures for persistent BPPV or underlying peripheral vestibular or CNS disorders; and 7) clinicians should counsel patients regarding the impact of BPPV on their safety, the potential for disease recurrence, and the importance of follow‐up.The panel offered as options that 1) clinicians may offer vestibular rehabilitation, either self‐administered or with a clinician, for the initial treatment of BPPV and 2) clinicians may offer observation as initial management for patients with BPPV and with assurance of follow‐up.The panel made no recommendation concerning audiometric testing in patients diagnosed with BPPV.Disclaimer:This clinical practice guideline is not intended as a sole source of guidance in managing benign paroxysmal positional vertigo. Rather, it is designed to assist clinicians by providing an evidence‐based framework for decision‐making strategies. The guideline is not intended to replace clinical judgement or establish a protocol for all individuals with this condition, and may not provide the only appropriate approach to diagnosing and managing this problem. ® 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.

Background Different rehabilitation protocols have been used after repair of distal biceps ruptures. Purpose This study investigates the safety of immediate active range of motion protocol after modified 2-incision distal biceps tendon repair in acute ruptures. Study Design Case series; Level of evidence, 4. Materials and Methods Twenty-one patients with a minimum follow-up of 2 years were participants in this study. After repair, the upper extremities were placed in a sling for 1 to 2 days and then immediate active range of motion was started. For the first 6 weeks, the elbow was allowed activities of daily living as tolerated by the patient with a 1-lb weight-lifting restriction. Elbow range of motion, isometric and dynamic flexion, and supination strengths were recorded and Disabilities of the Arm, Shoulder and Hand (DASH) scores were obtained. Results Mean follow-up extension was 0° and mean follow-up flexion was 141° on the operated side, with supination of 74° and pronation of 75°. The mean DASH score for 21 patients was 3.6 ± 3.6 (range, 0-11.4). The mean follow-up isometric flexion strength was found to be 5% (P = .411), and the power (dynamic strength) of flexion was 12% greater on the operated side (P = .046). However, follow-up isometric supination strength was 9% less on the involved side than on the noninvolved side (P = .030), and the power of supination was 11% less on the operated side (P = .007). There were no tendon reruptures at follow-up, determined by physical examination. Conclusion A modified 2-incision distal biceps repair allows a safe immediate active range of motion protocol with early return of nearly full range of motion and strength, without any clinically significant disability.

TDP-43 (also known as TARDBP) regulates different processes of gene expression, including transcription and splicing, through RNA and DNA binding. Moreover, recent reports have shown that the protein interacts with the 3′UTRs of specific mRNAs. The aberrant cellular distribution and aggregation of TDP-43 were recently reported in neurodegenerative diseases, namely frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). A detailed description of the determinants for cellular localization has yet to emerge, including information on how the known functions of TDP-43 and cellular targeting affect each other. We provide the first experimental evidence that TDP-43 continuously shuttles between nucleus and cytoplasm in a transcription-dependent manner. Furthermore, we investigate the role of the functional TDP-43 domains in determining cellular targeting through a combination of immunofluorescence and biochemical fractionation methods. Our analyses indicate that the C-terminus is essential for solubility and cellular localization, because its deletion results in the formation of large nuclear and cytoplasmic aggregates. Disruption of the RNA-recognition domain required for RNA and DNA binding, however, alters nuclear distribution by decreasing TDP-43 presence in the nucleoplasm. Our findings suggest that TDP-43 solubility and localization are particularly sensitive to disruptions that extend beyond the newly found nuclear localization signal and depend on a combination of factors that are closely connected to the functional properties of this protein.

The Sonic Hedgehog (Shh) pathway plays important roles in embryogenesis, stem cell maintenance, tissue repair, and tumorigenesis. Haploinsufficiency of Patched-1, a gene that encodes a repressor of the Shh pathway, dysregulates the Shh pathway and increases genomic instability and the development of spontaneous and ionizing radiation (IR)–induced tumors by an unknown mechanism. Here we show that Ptc1+/− mice have a defect in the IR-induced activation of the ATR–Chk1 checkpoint signaling pathway. Likewise, transient expression of Gli1, a downstream target of Shh signaling, disrupts Chk1 activation in human cells by preventing the interaction of Chk1 with Claspin, a Chk1 adaptor protein that is required for Chk1 activation. These results suggest that inappropriate Shh pathway activation promotes tumorigenesis by disabling a key signaling pathway that helps maintain genomic stability and inhibits tumorigenesis.

ABSTRACT The activity of electrical current against planktonic bacteria has previously been demonstrated. The short-term exposure of the bacteria in biofilms to electrical current in the absence of antimicrobials has been shown to have no substantial effect; however, longer-term exposure has not been studied. A previously described in vitro model was used to determine the effect of prolonged exposure (i.e., up to 7 days) to low-intensity (i.e., 20-, 200-, and 2,000-microampere) electrical direct currents on Pseudomonas aeruginosa , Staphylococcus aureus , and Staphylococcus epidermidis biofilms. Dose- and time-dependent killing was observed. A maximum of a 6-log 10 -CFU/cm 2 reduction was observed when S. epidermidis biofilms were exposed to 2,000 microamperes for at least 2 days. A 4- to 5-log 10 -CFU/cm 2 reduction was observed when S. aureus biofilms were exposed to 2,000 microamperes for at least 2 days. Finally, a 3.5- to 5-log 10 -CFU/cm 2 reduction was observed when P. aeruginosa biofilms were exposed to electrical current for 7 days. A higher electrical current intensity correlated with greater decreases in viable bacteria at all time points studied. In conclusion, low-intensity electrical current substantially reduced the numbers of viable bacteria in staphylococcal or Pseudomonas biofilms, a phenomenon we have labeled the “electricidal effect.”