Response of human HT-29 colorectal tumor cells to extended exposure to bromodeoxyuridine

Effects of the extended exposure of a human colorectal tumor-cell line (HT-29) to bromodeoxyuridine (BrdUrd) were studied in anticipation of the clinical use of that agent to treat colorectal cancer, particularly as a regionally delivered radiosensitizer. We found that 72-h exposure to a concentration of BrdUrd that is estimated to be locally maintained in the liver (100 μ M ) was significantly cytotoxic with a 3-log reduction in survival. As measured by GC/MS-SIM method, incorporation of BrdUrd into DNA followed an unexpected time course in that continuous exposure to 10 μ M BrdUrd resulted in maximal incorporation at 3 days, after which the extent of incorporated analog fell significantly (despite daily changes of the medium). This finding was apparently due to a greater rate of loss of BrdUrd from the medium at later time points. Flow cytometric analysis using an anti-BrdUrd antibody (IU-4) revealed that antibody binding also peaked and fell off with time. However, at exposure times of >24 h, the timing and extent of this decline were significantly different than had been indicated by the GC/MS method. These results indicate that the quantitative relationship between antibody staining and BrdUrd incorporation changes as drug-exposure time increases and that quantitative studies of anti-BrdUrd antibody binding must be interpreted with caution, especially when extended drug-treatment protocols have been used.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46921/1/280_2004_Article_BF00694337.pd

Asymmetric recurrent laryngeal nerve conduction velocities and dorsal cricoarytenoid muscle electromyographic characteristics in clinically normal horses

The dorsal cricoarytenoid (DCA) muscles, are a fundamental component of the athletic horse’s respiratory system: as the sole abductors of the airways, they maintain the size of the rima glottis which is essential for enabling maximal air intake during intense exercise. Dysfunction of the DCA muscle leads to arytenoid collapse during exercise, resulting in poor performance. An electrodiagnostic study including electromyography of the dorsal cricoarytenoid muscles and conduction velocity testing of the innervating recurrent laryngeal nerves (RLn) was conducted in horses with normal laryngeal function. We detected reduced nerve conduction velocity of the left RLn, compared to the right, and pathologic spontaneous activity (PSA) of myoelectrical activity within the left DCA muscle in half of this horse population and the horses with the slowest nerve conduction velocities. The findings in this group of horses are consistent with left sided demyelination and axonal loss, consistent with Recurrent Laryngeal Neuropathy (RLN), a highly prevalent degenerative disorder of the RLn in horses that predominantly affects the left side. The detection of electromyographic changes compatible with RLN in clinically unaffected horses is consistent with previous studies that identified “subclinical” subjects, presenting normal laryngeal function despite neuropathologic changes within nerve and muscle confirmed histologically

Melanoma Differentiation-Associated Gene 5 (MDA5) Is Involved in the Innate Immune Response to Paramyxoviridae Infection In Vivo

The early host response to pathogens is mediated by several distinct pattern recognition receptors. Cytoplasmic RNA helicases including RIG-I and MDA5 have been shown to respond to viral RNA by inducing interferon (IFN) production. Previous in vitro studies have demonstrated a direct role for MDA5 in the response to members of the Picornaviridae, Flaviviridae and Caliciviridae virus families ((+) ssRNA viruses) but not to Paramyxoviridae or Orthomyxoviridae ((−) ssRNA viruses). Contrary to these findings, we now show that MDA5 responds critically to infections caused by Paramyxoviridae in vivo. Using an established model of natural Sendai virus (SeV) infection, we demonstrate that MDA5−/− mice exhibit increased morbidity and mortality as well as severe histopathological changes in the lower airways in response to SeV. Moreover, analysis of viral propagation in the lungs of MDA5−/− mice reveals enhanced replication and a distinct distribution involving the interstitium. Though the levels of antiviral cytokines were comparable early during SeV infection, type I, II, and III IFN mRNA expression profiles were significantly decreased in MDA5−/− mice by day 5 post infection. Taken together, these findings indicate that MDA5 is indispensable for sustained expression of IFN in response to paramyxovirus infection and provide the first evidence of MDA5-dependent containment of in vivo infections caused by (−) sense RNA viruses

Detection of partial-thickness supraspinatus tendon tears: is a single direct MR arthrography series in ABER position as accurate as conventional MR arthrography?

The purpose of this study was to retrospectively evaluate sensitivity and specificity of a single magnetic resonance (MR) arthrography series in abduction external rotation (ABER) position compared with conventional MR arthrography for detection of supraspinatus tendon tears, with arthroscopy as gold standard, and to assess interobserver variability. Institutional review board approval was obtained; informed consent was waived. MR arthrograms of 250 patients (170 men and 80 women; mean age, 36 years) were retrospectively and independently evaluated by three observers. Oblique coronal T1-weighted fat-suppressed images, proton density, and T2-weighted images and axial T1-weighted images and oblique sagittal T1-weighted fat-suppressed images were analyzed to detect supraspinatus tendon tears. Separately, a single T1-weighted fat-suppressed oblique axial series in ABER position was evaluated. Both protocols were scored randomly without knowledge of patients' clinical history and arthroscopy results. Tears were subclassified, based on articular surface integrity and extension (Lee classification). Interobserver agreement was assessed by kappa statistics for all patients. Ninety-two of 250 patients underwent arthroscopy; sensitivity and specificity of ABER and conventional MR arthrography were calculated and compared using paired McNemar test. Weighted kappa values of ABER and conventional MR arthrography were 0.48-0.65 and 0.60-0.67, respectively. According to arthroscopy, 69 of 92 patients had an intact cuff, and 23 patients had a cuff tear (16 partial thickness and seven full thickness). There were no statistically significant differences between ABER and conventional MR arthrography regarding sensitivity (48-61% and 52-70%, respectively) and specificity (80-94% and 91-95%). Sensitivity and specificity of a single T1-weighted series in ABER position and conventional MR arthrography are comparable for assessment of rotator cuff tear

Viral Capsid Is a Pathogen-Associated Molecular Pattern in Adenovirus Keratitis

Human adenovirus (HAdV) infection of the human eye, in particular serotypes 8, 19 and 37, induces the formation of corneal subepithelial leukocytic infiltrates. Using a unique mouse model of adenovirus keratitis, we studied the role of various virus-associated molecular patterns in subsequent innate immune responses of resident corneal cells to HAdV-37 infection. We found that neither viral DNA, viral gene expression, or viral replication was necessary for the development of keratitis. In contrast, empty viral capsid induced keratitis and a chemokine profile similar to intact virus. Transfected viral DNA did not induce leukocyte infiltration despite CCL2 expression similar to levels in virus infected corneas. Mice without toll-like receptor 9 (Tlr9) signaling developed clinical keratitis upon HAdV-37 infection similar to wild type mice, although the absolute numbers of activated monocytes in the cornea were less in Tlr9−/− mice. Virus induced leukocytic infiltrates and chemokine expression in mouse cornea could be blocked by treatment with a peptide containing arginine glycine aspartic acid (RGD). These results demonstrate that adenovirus infection of the cornea induces chemokine expression and subsequent infiltration by leukocytes principally through RGD contact between viral capsid and the host cell, possibly through direct interaction between the viral capsid penton base and host cell integrins

Carpal Tunnel Syndrome: A Review of the Recent Literature

Carpal Tunnel Syndrome (CTS) remains a puzzling and disabling condition present in 3.8% of the general population. CTS is the most well-known and frequent form of median nerve entrapment, and accounts for 90% of all entrapment neuropathies. This review aims to provide an overview of this common condition, with an emphasis on the pathophysiology involved in CTS. The clinical presentation and risk factors associated with CTS are discussed in this paper. Also, the various methods of diagnosis are explored; including nerve conduction studies, ultrasound, and magnetic resonance imaging

Hepatic arterial chemotherapy for primary and metastatic liver cancers

Hepatic arterial chemotherapy represents a means of selectively exposing hepatic tumor to cytotoxic agents. Although 5-fluoro-2′-deoxyuridine has been shown to generate a higher response rate in the treatment of colorectal liver metastases than that achieved by intravenous infusion, responses are largely incomplete and rarely of long duration. This review describes the rationale for the use of the thymidine analogs 5-bromo-2′-deoxyuridine and 5-iodo-2′-deoxyuridine in hepatic arterial infusions and indicates how combination therapy adding radiotherapy, specifically with hepatic arterially administered yttrium-90 microspheres, might generate a new, more efficient and effective therapeutic approach.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46919/1/280_2004_Article_BF00647244.pd