bluuebunny/crossref_metadata_2025 huggingface dataset:
Cauliflower mosaic virus, a Compatible Pathogen of Arabidopsis, Engages Three Distinct Defense-Signaling Pathways and Activates Rapid Systemic Generation of Reactive Oxygen Species
Authors: Love Andrew J. , Yun Byung Wook , Laval Valérie , Loake Gary J. , Milner Joel J.
Published: September 2005

We analyzed expression of marker genes for three defense pathways during infection by Cauliflower mosaic virus (CaMV), a compatible pathogen of Arabidopsis (Arabidopsis thaliana), using luciferase reporter transgenes and directly by measuring transcript abundance. Expression of PR-1, a marker for salicylic acid signaling, was very low until 8 d postinoculation and then rose sharply, coinciding with the rise in virus levels. In contrast, as early as 2 h postinoculation, transcriptional up-regulation of GST1—a marker for reactive oxygen species—and PDF1.2—a marker for jasmonic acid/ethylene defense signaling—was detectable in the virus-inoculated leaf and systemically. In parallel with the activation of GST1, H2O2 accumulated locally and systemically in virus- but not mock-inoculated plants. However, in plants inoculated with infectious CaMV DNA rather than virus particles, the onset of systemic luciferase activity was delayed by 24 to 48 h, suggesting that virion structural proteins act as the elicitor. This phenomenon, which we term the rapid systemic response, preceded virus movement from the inoculated leaf; therefore, the systemic signal is not viral. Systemic, but not local, H2O2 accumulation was abolished in rbohDF double mutants and in etr1-1 and ein2-1 mutants, implicating NADPH oxidase and ethylene signaling in the generation and transduction of the response. Ethylene, but not rbohDF mutants, also showed reduced susceptibility to CaMV, whereas in NahG transgenics, virus levels were similar to wild type. These findings implicate reactive oxygen species and ethylene in signaling in response to CaMV infection, but suggest that salicylic acid does not play an effective role.
Involvement of protein kinase C in crystalline silica-induced activation of the MAP kinase and AP-1 pathway
Authors: Ding Min , Huang Chuanshu , Lu Yongju , Bowman Linda , Castranova Vince , Vallyathan Val
Published: September 2005

Crystalline silica has long been well established as a fibrogenic agent, and recent evidence has implicated it as a potential human carcinogen. However, the mechanisms of silica-induced disease development and progression are not well understood. Our previous studies demonstrated that crystalline silica is able to activate activator protein-1 (AP-1) through mitogen-activated protein kinase (MAPK) pathways. The present study investigates the possible involvement of protein kinase C (PKC) in silica-induced activation of the MAPK/AP-1 signal transduction pathway. Treatment of mouse epidermal cells (JB6 cell line) with freshly fractured silica stimulated translocation of PKCα and PKCε from the cytosol to the membrane and activated AP-1 transcription activity. Pretreatment of cells with PKC inhibitors, including RO-32-0432, calphostin C, and bisindolylmaleimide I, inhibited silica-induced AP-1 activation and phosphorylation of ERKs and p38 kinase. These inhibitory effects by PKC inhibitors were dose dependent. Furthermore, overexpression of dominant negative mutant (DNM) of PKCα or PKCε markedly blocked AP-1 activation as well as phosphorylation of ERKs and p38 kinase induced by freshly fractured silica. These results demonstrate that PKCα and PKCε are essential in silica-induced AP-1 activation through the MAP kinase (ERKs and p38 kinases) pathway.
Alveolar type II cells inhibit fibroblast proliferation: role of IL-1α
Authors: Portnoy Joshua , Pan Tianli , Dinarello Charles A. , Shannon John M. , Westcott Jay Y. , Zhang Lening , Mason Robert J.
Published: September 2005

Alveolar type II (ATII) cells inhibit fibroblast proliferation in coculture by releasing or secreting a factor(s) that stimulates fibroblast production of prostaglandin E2(PGE2). In the present study, we sought to determine the factors released from ATII cells that stimulate PGE2production in fibroblasts. Exogenous addition of rat IL-1α to cultured lung fibroblasts induced PGE2secretion in a dose-response manner. When fibroblasts were cocultured with rat ATII cells, IL-1α protein was detectable in ATII cells and in the coculture medium between days 8 and 12 of culture, correlating with the highest levels of PGE2. Furthermore, under coculture conditions, IL-1α gene expression increased in ATII cells (but not fibroblasts) compared with either cell cultured alone. In both mixed species (human fibroblasts-rat ATII cells) and same species cocultures (rat fibroblasts and ATII cells), PGE2secretion was inhibited by the presence of IL-1 receptor antagonist (IL-1Ra) or selective neutralizing antibody directed against rat IL-1α (but not IL-1β). Conditioned media from cocultures inhibited fibroblast proliferation, and this effect was abrogated by the addition of IL-1Ra. Addition of keratinocyte growth factor (KGF) resulted in an earlier increase in PGE2secretion and fibroblast inhibition ( day 8 of coculture). This effect was inhibited by indomethacin but was not altered by IL-1Ra. We conclude that in this coculture system, IL-1α secretion by ATII cells is one factor that stimulates PGE2production by lung fibroblasts, thereby inhibiting fibroblast proliferation. In addition, these studies demonstrate that KGF enhances ATII cell PGE2production through an IL-1α-independent pathway.
Integrins β1, α6, and α3contribute to mechanical strain-induced differentiation of fetal lung type II epithelial cells via distinct mechanisms
Authors: Sanchez-Esteban Juan , Wang Yulian , Filardo Edward J. , Rubin Lewis P. , Ingber Donald E.
Published: September 2005

Mechanical forces regulate lung maturation in the fetus by promoting type II epithelial differentiation. However, the cell surface receptors that transduce these mechanical cues into cellular responses remain largely unknown. When distal lung type II epithelial cells isolated from embryonic day 19 rat fetuses were cultured on flexible plates coated with laminin, fibronectin, vitronectin, collagen, or elastin and exposed to a level of mechanical strain (5%) similar to that observed in utero, transmembrane signaling responses were induced under all conditions, as measured by ERK activation. However, mechanical stress maximally increased expression of the type II cell differentiation marker surfactant protein C when cells were cultured on laminin substrates. Strain-induced alveolar epithelial differentiation was inhibited by interfering with cell binding to laminin using soluble laminin peptides (IKVIV or YIGSR) or blocking antibodies against integrin β1, α3, or α6. Additional studies were carried out with substrates coated directly with different nonactivating anti-integrin antibodies. Blocking integrin β1and α6binding sites inhibited both cell adhesion and differentiation, whereas inhibition of α3prevented differentiation without altering cell attachment. These data demonstrate that various integrins contribute to mechanical control of type II lung epithelial cell differentiation on laminin substrates. However, they may act via distinct mechanisms, including some that are independent of their cell anchoring role.
Endocytic pathway for surfactant protein A in human macrophages: binding, clathrin-mediated uptake, and trafficking through the endolysosomal pathway
Authors: Crowther Joy E. , Schlesinger Larry S.
Published: September 2005

In the noninflamed lung, surfactant protein A (SP-A) acts as an anti-inflammatory molecule through its effects on macrophage (MΦ) function, modulating cytokine and reactive oxygen and nitrogen intermediate production. The receptors responsible for these effects of SP-A on human MΦ are not clear, although SP-A binding to several proteins has been described. In this study, we demonstrate high-affinity specific binding of SP-A to primary human MΦ. SP-A binding was inhibited by EGTA, indicating calcium dependence. However, mannan did not inhibit SP-A binding, suggesting that binding is mediated by a direct protein-protein interaction that does not involve carbohydrate recognition. Our laboratory has previously shown that SP-A is rapidly endocytosed by human MΦ into discrete vesicles. Although previous work indicates that SP-A is ultimately degraded by murine MΦ over time, the trafficking pathway of SP-A through MΦ after uptake has not been reported and is of potential biological importance. We examined trafficking of SP-A in human MΦ by electron and confocal microscopy and show for the first time that SP-A is endocytosed by primary human MΦ through clathrin-coated pits and colocalizes sequentially over time with the early endosome marker EEA1, late endosome marker lamp-1, and lysosome marker cathepsin D. We conclude that SP-A binds to receptor(s) on human MΦ, is endocytosed by a receptor-mediated, clathrin-dependent process, and trafficks through the endolysosomal pathway. These studies provide further insight into the interactions of SP-A with the MΦ cell surface and intracellular compartments that play important roles in SP-A modulation of lung MΦ biology.
Selective Attention Modulates Neural Substrates of Repetition Priming and “Implicit” Visual Memory: Suppressions and Enhancements Revealed by fMRI
Authors: Vuilleumier Patrik , Schwartz Sophie , Duhoux Stéphanie , Dolan Raymond J. , Driver Jon
Published: September 2005

Attention can enhance processing for relevant information and suppress this for ignored stimuli. However, some residual processing may still arise without attention. Here we presented overlapping outline objects at study, with subjects attending to those in one color but not the other. Attended objects were subsequently recognized on a surprise memory test, whereas there was complete amnesia for ignored items on such direct explicit testing; yet reliable behavioral priming effects were found on indirect testing. Event-related fMRI examined neural responses to previously attended or ignored objects, now shown alone in the same or mirror-reversed orientation as before, intermixed with new items. Repetition-related decreases in fMRI responses for objects previously attended and repeated in the same orientation were found in the right posterior fusiform, lateral occipital, and left inferior frontal cortex. More anterior fusiform regions also showed some repetition decreases for ignored objects, irrespective of orientation. View-specific repetition decreases were found in the striate cortex, particularly for previously attended items. In addition, previously ignored objects produced some fMRI response increases in the bilateral lingual gyri, relative to new objects. Selective attention at exposure can thus produce several distinct long-term effects on processing of stimuli repeated later, with neural response suppression stronger for previously attended objects, and some response enhancement for previously ignored objects, with these effects arising in different brain areas. Although repetition decreases may relate to positive priming phenomena, the repetition increases for ignored objects shown here for the first time might relate to processes that can produce “negative priming” in some behavioral studies. These results reveal quantitative and qualitative differences between neural substrates of long-term repetition effects for attended versus unattended objects.
Tracing Problem Solving in Real Time: fMRI Analysis of the Subject-paced Tower of Hanoi
Authors: Anderson John R. , Albert Mark V. , Fincham Jon M.
Published: September 2005

Previous research has found three brain regions for tracking components of the ACT-R cognitive architecture: a posterior parietal region that tracks changes in problem representation, a prefrontal region that tracks retrieval of task-relevant information, and a motor region that tracks the programming of manual responses. This prior research has used relatively simple tasks to incorporate a slow event-related procedure, allowing the blood oxygen level-dependent (BOLD) response to go back to baseline after each trial. The research described here attempts to extend these methods to tracking problem solving in a complex task, the Tower of Hanoi, which involves many complex steps of cognition and motor actions in rapid succession. By tracking the activation patterns in these regions, it is possible to predict with intermediate accuracy when participants are planning a future sequence of moves. The article describes a cognitive model in the ACT-R architecture that is capable of explaining both the latency data in move generation and the BOLD responses in these three regions.
An ERP Study of Second Language Learning after Childhood: Effects of Proficiency
Authors: Ojima Shiro , Nakata Hiroki , Kakigi Ryusuke
Published: September 2005

Whether there is an absolute critical period for acquiring language is a matter of continuous debate. One approach to address this issue is to compare the processes of second language (L2) learning after childhood and those of first language (L1) learning during childhood. To study the cortical process of postchildhood L2 learning, we compared event-related brain potentials recorded from two groups of adult Japanese speakers who attained either high or intermediate proficiency in English after childhood (J-High and J-Low), and adult native English speakers (ENG). Semantic anomalies embedded in English sentences evoked a clear N400 component in all three groups, with only the time course of the brain activation varying among the groups. Syntactic violations elicited a left-lateralized negativity similar to the left anterior negativity in ENG and J-High, but not in J-Low. In ENG, a P600 component was additionally found. These results suggest that semantic processing is robust from early on in L2 learning, whereas the development of syntactic processing is more dependent on proficiency as evidenced by the lack of the left-lateralized negativity in J-Low. Because early maturation and stability of semantic processing as opposed to syntactic processing are also a feature of L1 processing, postchildhood L2 learning may be governed by the same brain properties as those which govern childhood L1 learning. We argue that these processes are qualitatively similar in many respects, with only restricted domains of language processing being subject to absolute critical period effects.
Automatic Versus Contingent Mechanisms of Sensory-Driven Neural Biasing and Reflexive Attention
Authors: Hopfinger Joseph B. , Ries Anthony J.
Published: September 2005

Recent studies have generated debate regarding whether reflexive attention mechanisms are triggered in a purely automatic stimulus-driven manner. Behavioral studies have found that a nonpredictive “cue” stimulus will speed manual responses to subsequent targets at the same location, but only if that cue is congruent with actively maintained top-down settings for target detection. When a cue is incongruent with top-down settings, response times are unaffected, and this has been taken as evidence that reflexive attention mechanisms were never engaged in those conditions. However, manual response times may mask effects on earlier stages of processing. Here, we used event-related potentials to investigate the interaction of bottom-up sensory-driven mechanisms and top-down control settings at multiple stages of processing in the brain. Our results dissociate sensory-driven mechanisms that automatically bias early stages of visual processing from later mechanisms that are contingent on top-down control. An early enhancement of target processing in the extrastriate visual cortex (i.e., the P1 component) was triggered by the appearance of a unique bright cue, regardless of top-down settings. The enhancement of visual processing was prolonged, however, when the cue was congruent with top-down settings. Later processing in posterior temporal-parietal regions (i.e., the ipsilateral invalid negativity) was triggered automatically when the cue consisted of the abrupt appearance of a single new object. However, in cases where more than a single object appeared during the cue display, this stage of processing was contingent on top-down control. These findings provide evidence that visual information processing is biased at multiple levels in the brain, and the results distinguish automatically triggered sensory-driven mechanisms from those that are contingent on top-down control settings.
Biases in Attentional Orientation and Magnitude Estimation Explain Crossover: Neglect is a Disorder of Both
Authors: Mennemeier Mark , Pierce Christopher A. , Chatterjee Anjan , Anderson Britt , Jewell George , Dowler Rachael , Woods Adam J. , Glenn Tannahill , Mark Victor W.
Published: September 2005

Crossover refers to a pattern of performance on the line bisection test in which short lines are bisected on the side opposite the true center of long lines. Although most patients with spatial neglect demonstrate crossover, contemporary theories of neglect cannot explain it. In contrast, we show that blending the psychophysical construct of magnitude estimation with neglect theory not only explains crossover, but also addresses a quantitative feature of neglect that is independent of spatial deficits. We report a prospective validation study of the orientation/estimation hypothesis of crossover. Forty subjects (17 patients with and without neglect following unilateral brain injury and 23 normal controls) completed four experiments that examined crossover using line bisection, line bisection with cueing, and reproducing line lengths from both memory and a standard. Replicating earlier findings, all except one subject group exhibited crossover on the standard line bisection test, all groups showed a spontaneous preference to orient attention to one end of the lines, and all groups overestimated the length of short lines and underestimated long lines. Biases in attentional orientation and magnitude estimation are exaggerated in patients with neglect. The truly novel finding of this study occurred when, after removing the line from the bisection task, the direction of crossover was completely reversed in all subject groups depending on where attention was oriented. These findings are consistent with our hypothesis of crossover: (1) crossover is a normal component of performance on line bisection; (2) crossover results from the interplay of biases in attentional orientation and magnitude estimation; and (3) attentional orientation predicts the direction of crossover, whereas a disorder of magnitude estimation, not previously emphasized in neglect, accounts for the quantitative changes in length estimation that make crossover more obvious in neglect subjects. Paradoxically, we observed that the traditional line bisection test is suboptimal for exploring crossover because lines elicit spontaneous orientation responses from subjects that confound experimental manipulations of attention. We conclude that attentional orientation and magnitude estimation are necessary and sufficient to explain crossover and that bias in magnitude estimation is a core component of neglect.
Structural Encoding of Body and Face in Human Infants and Adults
Authors: Gliga Teodora , Dehaene-Lambertz Ghislaine
Published: September 2005

Most studies on visual perception of human beings have focused on perception of faces. However, bodies are another important visual element, which help us to identify a member of our species in the visual scene. In order to study whether similar configural information processing is used in body and face perception, we recorded high-density even-related potentials (ERPs) to normal and distorted faces and bodies in adults and 3-month-old infants. In adults, the N1 responses evoked by bodies and faces were similar in amplitude but differed slightly in latency. The voltage topography of N1 also differed in concordance with fMRI data showing that two distinct areas are involved in face and body perception. Distortion affected ERPs to faces and bodies similarly from N1 on, although the effect was significant earlier for bodies than for faces. These results suggest that fast processing of configural information is not specific to faces but it also occurs for bodies. In 3-month-old infants, distortion decreased the amplitude of P400 around 450 msec, showing no interaction with image category. This result demonstrates that infants are not only able to recognize the normal configuration of faces, but also that of bodies. This could either be related to an innate knowledge of this particular type of biological object, or to fast learning through intense exposure during the first months of life.
Naming the Same Entities from Visual or from Auditory Stimulation Engages Similar Regions of Left Inferotemporal Cortices
Authors: Tranel Daniel , Grabowski Thomas J. , Lyon Jill , Damasio Hanna
Published: September 2005

We have proposed that the left inferotemporal (IT) region contains structures that mediate between conceptual knowledge retrieval and word-form retrieval, and we have hypothesized that these structures are utilized for word retrieval irrespective of the sensory modality through which an entity is apprehended, thus being “modality neutral.” We tested this idea in two sensory modalities, visual and auditory, and for two categories of concrete entities, tools and animals. In a PET experiment, 10 normal participants named tools and animals either from pictures or from characteristic sounds (e.g., “scissors” from a picture of a scissors or from the sound of a scissors cutting; “rooster” from a picture of a rooster or from the sound of a rooster crowing). Visual and auditory naming of tools activated the left posterior/lateral IT; visual and auditory naming of animals activated the left anterior/ ventral IT. For both tools and animals, the left IT activations were similar in location and magnitude regardless of whether participants were naming entities from pictures or from sounds. The results provide novel evidence to support the notion that left IT structures contain “modality-neutral” systems for mediating between conceptual knowledge and word retrieval.
Electrophysiological Dissociation of Picture Versus Word Encoding: The Distinctiveness Heuristic as a Retrieval Orientation
Authors: Budson Andrew E. , Droller Daniel B. J. , Dodson Chad S. , Schacter Daniel L. , Rugg Michael D. , Holcomb Philip J. , Daffner Kirk R.
Published: September 2005

Event-related potentials (ERPs) were used to investigate the neural processes underlying the distinctiveness heuristic— a response mode in which participants expect to remember vivid details of an experience and make recognition decisions based on this metacognitive expectation. One group of participants studied pictures and auditory words; another group studied visual and auditory words. Studied and novel items were presented at test as words only, with all novel items repeating after varying lags. ERP differences were seen between the word and picture groups for both studied and novel items. For the novel items, ERP differences were largest in frontal and central midline electrodes. In separate analyses, the picture group showed the greatest ERP differences between item types in a parietally based component from 550 to 1000 msec, whereas the word group showed the greatest differences in a frontally based component from 1000 to 2000 msec. The authors suggest that the distinctiveness heuristic is a retrieval orientation that facilitates reliance upon recollection to differentiate between item types. Although the picture group can use this heuristic and its retrieval orientation on the basis of recollection, the word group must engage additional postretrieval processes to distinguish between item types, reflecting the use of a different retrieval orientation.
Imru' al-Qays and Byzantium
Authors: Mumayiz Ibrahim
Published: September 2005

This article presents four reasons that were instrumental in bringing Imru' al-Qays to the Byzantine emperor Justinian's notice. The poet, seeking vengeance for his father's homicide, approached the poet al-Samawa'al who contacted Arethas the Ghassinid who, in turn, interceded for the poet with Justinian, Arethas' overlord and close ally. Second, the article traces the poet's trip to Constantinople to meet Justinian and refutes assorted legendary and fictitious accounts that have been associated with the trip, viz., the poisoned robe, the affair with Justinian's daughter, the poet's appointment as Phylarch of Palestine, and the Caliph al-Ma'mūn's seeing a statue of the poet. The poet, it is shown, died of the plague on his way back from Constantinople in 542.
The Transverse Humeral Ligament
Authors: Gleason Paul D. , Beall Douglas P. , Sanders Timothy G. , Bond James L. , Ly Justin Q. , Holland Lorne L. , Pasque Charles B.
Published: September 2005

Background

No study to date has isolated the anatomical nature of the transverse humeral ligament and its relationship to the biceps tendon and the anterosuperior portion of the rotator cuff.

Hypothesis

There is no separate identifiable transverse humeral ligament, but rather the fibers covering the intertubercular groove are composed of a sling formed by fibers from the subscapularis and supraspinatus tendons.

Study Design

Descriptive laboratory study.

Methods

A total of 14 shoulder examinations were performed on 7 matched pairs of fresh-frozen cadaveric shoulders. Magnetic resonance imaging scans were performed, followed by gross and microscopic anatomical dissection.

Results

In the location of the transverse humeral ligament, magnetic resonance imaging and gross dissection revealed the continuation of superficial fibers of the subscapularis tendon from the tendon body across the intertubercular groove to attach to the greater tuberosity, whereas deeper fibers of the subscapularis tendon inserted on the lesser tuberosity. Longitudinal fibers of the supraspinatus tendon and the coracohumeral ligament were also noted to travel the length of the groove, deep to the other interdigitating fibers but superficial to the biceps tendon. Histologic studies confirmed these gross dissection patterns of fiber attachment and also revealed the absence of elastin fibers, which are more commonly seen in ligamentous structures and are typically absent from tendinous structures.

Conclusion

There is no identifiable transverse humeral ligament, but rather the fibers covering the intertubercular groove are composed of a sling formed mainly by the fibers of the subscapularis tendon, with contributions from the supraspinatus tendon and the coracohumeral ligament.

Clinical Relevance

According to our findings, dislocations of the long head of the biceps must disrupt at least the deep fibers of the annular sling created mainly by the subscapularis tendon insertion. This finding provides anatomical support for the findings of a positive biceps tendon subluxation or dislocation and subscapularis tear during glenohumeral arthroscopy with a normal-appearing subscapularis during open surgery or subacromial arthroscopy.
Predictors of Stress Fracture Susceptibility in Young Female Recruits
Authors: Shaffer Richard A. , Rauh Mitchell J. , Brodine Stephanie K. , Trone Daniel W. , Macera Caroline A.
Published: September 2005

Background

Stress fractures account for substantial morbidity for young women undergoing U.S. Marine Corps basic training.

Hypothesis

Certain pretraining characteristics identify women at increased risk of stress fractures during boot camp.

Study Design

Cohort study; Level of evidence, 2.

Methods

Data collected included baseline performance on a timed run (a measure of aerobic fitness), anthropometric measurements, and a baseline questionnaire highlighting exercise and menstrual status among 2962 women undergoing basic training at the Marine Corps Recruit Depot, Parris Island, in 1995 and 1996.

Results

One hundred fifty-two recruits (5.1%) had 181 confirmed lower extremity stress fractures, with the most common sites being the tibia (25%), metatarsals (22%), pelvis (22%), and femur (20%). Logistic regression models revealed that having low aerobic fitness (a slower time on the timed run) and no menses during the past year were significantly associated with the occurrence of any stress fracture and with pelvic or femoral stress fracture during boot camp.

Conclusion

These findings suggest that stress fractures may be reduced if women entering Marine Corps Recruit Depot training participated in pretraining activities designed to improve aerobic fitness. Furthermore, women reporting no menses during the previous year may need additional observation during training.

Clinical Relevance

Consistent with previous studies, we found that low aerobic fitness was the only modifiable risk factor associated with stress fractures during boot camp.
Structural Properties of Lateral Collateral Ligament Reconstruction at the Fibular Head
Authors: Ciccone William J. , Bratton Derek R. , Weinstein David M. , Walden David L. , Elias John J.
Published: September 2005

Background

Anatomical reconstruction of a ruptured lateral collateral ligament using allograft tissue secured within the fibular head with an interference screw has been described.

Hypothesis

Interference fixation at the fibular head does not reproduce the strength of the intact ligament.

Study Design

Controlled laboratory study.

Methods

Ten intact lateral collateral ligaments were tested to failure. The distal fixation of 11 ligaments reconstructed with a graft including a bone plug and 11 ligaments reconstructed with a graft without a bone plug were also tested.

Results

The reconstructed ligaments consistently failed at the fibular head. The intact specimens predominately failed through ligament rupture. The mean strength and stiffness values were 460 ± 163 N and 82 ± 25 N/mm, respectively, for the intact ligaments, 113 ± 40 N and 36 ± 10 N/mm, respectively, for reconstruction with a bone plug, and 135 ± 81 N and 34 ± 14 N/mm, respectively, for reconstruction without a bone plug. The strength and stiffness were significantly (P <. 05) greater for the intact ligaments than for either reconstruction group. The variation in strength was significantly larger for reconstruction without a bone plug than for reconstruction with a bone plug.

Conclusion

Tension applied to lateral collateral ligaments reconstructed using fibular interference fixation should be limited immediately after surgery. Soft tissue fixation should be employed with care because of the inconsistency in the failure strength.

Clinical Relevance

Although fibular interference fixation is increasingly being described in the literature, the properties of reconstructed lateral collateral ligaments have not previously been quantified.
Tolerance to bronchodilation during treatment with long-acting beta-agonists, a randomised controlled trial
Authors: Haney Sarah , Hancox Robert J
Published: September 2005

Background

Regular use of beta-agonists leads to tolerance to their bronchodilator effects. This can be demonstrated by measuring the response to beta-agonist following bronchoconstriction using methacholine. However most studies have demonstrated tolerance after a period of beta-agonist withdrawal, which is not typical of their use in clinical practice. This study assessed tolerance to the bronchodilator action of salbutamol during ongoing treatment with long-acting beta-agonist.

Methods

Random-order, double-blind, placebo-controlled, crossover trial. After 1 week without beta-agonists, 13 asthmatic subjects inhaled formoterol 12 μg twice daily or matching placebo for 1 week. Eight hours after the first and last doses subjects inhaled methacholine to produce a 20% fall in FEV1. Salbutamol 100, 200 and 400 μg (cumulative dose) was then given at 5-minute intervals and FEV1 was measured 5 minutes after each dose. After a 1 week washout subjects crossed over to the other treatment. Unscheduled use of beta-agonists was not allowed during the study. The main outcome variable was the area under the salbutamol response curve.

Results

The analysis showed a significant time by treatment interaction indicating that the response to salbutamol fell during formoterol therapy compared to placebo. After 1 week of formoterol the area under the salbutamol response curve was 48% (95% confidence interval 28 to 68%) lower than placebo. This reduction in response remained significant when the analyses were adjusted for changes in the pre-challenge FEV1 and dose of methacholine given (p = 0.001).

Conclusion

The bronchodilator response to salbutamol is significantly reduced in patients taking formoterol. Clinically relevant tolerance to rescue beta-agonist treatment is likely to occur in patients treated with long-acting beta-agonists.
Bayesian designs with frequentist and Bayesian error rate considerations
Authors: Wang You-Gan , Leung Denis Heng-Yan , Li Ming , Tan Say-Beng
Published: September 2005

So far, most Phase II trials have been designed and analysed under a frequentist framework. Under this framework, a trial is designed so that the overall Type I and Type II errors of the trial are controlled at some desired levels. Recently, a number of articles have advocated the use of Bayesian designs in practice. Under a Bayesian framework, a trial is designed so that the trial stops when the posterior probability of treatment is within certain prespecified thresholds. In this article, we argue that trials under a Bayesian framework can also be designed to control frequentist error rates. We introduce a Bayesian version of Simon’s well-known two-stage design to achieve this goal. We also consider two other errors, which are called Bayesian errors in this article because of their similarities to posterior probabilities. We show that our method can also control these Bayesian-type errors. We compare our method with other recent Bayesian designs in a numerical study and discuss implications of different designs on error rates. An example of a clinical trial for patients with nasopharyngeal carcinoma is used to illustrate differences of the different designs.
The role of proxy information in missing data analysis
Authors: Huang Rong , Liang Yuanyuan , Carriere K C
Published: September 2005

This article investigates the role of proxy data in dealing with the common problem of missing data in clinical trials using repeated measures designs. In an effort to avoid the missing data situation, some proxy information can be gathered. The question is how to treat proxy information, that is, is it always better to utilize proxy information when there are missing data? A model for repeated measures data with missing values is considered and a strategy for utilizing proxy information is developed. Then, simulations are used to compare the power of a test using proxy to simply utilizing all available data. It is concluded that using proxy information can be a useful alternative when such information is available. The implications for various clinical designs are also considered and a data collection strategy for efficiently estimating parameters is suggested.
Chance-corrected measures of reliability and validity in K K tables
Authors: Andres A Martín , Marzo P Femia
Published: September 2005

When studying the degree of overall agreement between the nominal responses of two raters, it is customary to use the coefficient kappa. A more detailed analysis requires the evaluation of the degree of agreement category by category, and this is carried out in two different ways: using the value of kappa in the collapsed table for each category or using the agreement index for each category (proportion of agreements observed). Both indices have disadvantages: the former is sensitive to marginal totals; the latter is not chance corrected; and neither distinguishes the case where one of the two raters is a gold standard (an expert) from the case where neither rater is a gold standard. This article suggests five chance-corrected indices which are not sensitive to marginal totals and which differ depending on whether there is a standard rater. The article also justifies the reason for poor performance of kappa when the two marginal totals are unbalanced (especially if they are so in opposite directions) and the reason for its good performance when analysing the various 2 2 tables obtained by the collapse of a wider table.
Assessing the reliability of ordered categorical scales using kappa-type statistics
Authors: Roberts Chris , McNamee Roseanne
Published: September 2005

Methods for the analysis of reliability of ordered categorical scales are discussed, focussing on the limitation of the single summary-weighted kappa coefficients. A symmetric matrix of kappa-type coefficients is suggested as an alternative. The method is proposed as being suitable for ordinal scale where there is no underlying continuum. Their application is illustrated using two data sets from reliability studies. If, instead, distances between categories can be specified, a weighted mean of the matrix terms can be used as a summary measure. This is equal to a weighted kappa coefficient with squared weights, provided distances between adjacent categories are equal. When a study design corresponds to a one-way random effects model, estimates of precision of kappa-type coefficient, including the coefficients described here, can be obtained using the delta-method, bootstrap resampling by subjects or jack-knifing by subjects. In the case of interobserver reliability studies, where there may be systematic differences between observers, the investigator may wish to generalise to a population of observers and subjects. In this case, jack-knifing by observer and subject is suggested. Empirical comparisons are made between standard error estimates based on the delta-method, on jack-knifing by subjects and a two-way jack-knife by subjects and observers. The results suggest that standard errors based on the delta-method or jack-knifing by subject alone may be overly precise.
Outcome selection bias in meta-analysis
Authors: Williamson P R , Gamble C , Altman D G , Hutton J L
Published: September 2005

Publication bias has been previously identified as a threat to the validity of a meta-analysis. Recently, new evidence has documented an additional threat to validity, the selective reporting of trial outcomes within published studies. Several diseases have several possible measures of outcome. Some articles might report only a selection of those outcomes, perhaps those with statistically significant results. In this article, we review this problem while addressing the questions: what is within-study selective reporting? how common is it? why is it done? how can it mislead? how can it be detected?, and finally, what is the solution? We recommend that both publication bias and selective reporting should be routinely investigated in systematic reviews.
No Advantage of Dexamethasone Over Prednisolone for the Outcome of Standard- and Intermediate-Risk Childhood Acute Lymphoblastic Leukemia in the Tokyo Children's Cancer Study Group L95-14 Protocol
Authors: Igarashi Shunji , Manabe Atsushi , Ohara Akira , Kumagai Masaaki , Saito Tomohiro , Okimoto Yuri , Kamijo Takehiko , Isoyama Keiichi , Kajiwara Michiko , Sotomatsu Manabu , Sugita Ken-ichi , Sugita Kanji , Maeda Miho , Yabe Hiromasa , Kinoshita Akitoshi , Kaneko Takashi , Hayashi Yasuhide , Ikuta Kouichiro , Hanada Ryohji , Tsuchida Masahiro
Published: September 2005

Purpose

To evaluate whether dexamethasone (DEXA) yields a better outcome than prednisolone (PRED) in a prospective, randomized, controlled trial for the treatment of childhood acute lymphoblastic leukemia (ALL).

Patients and Methods

Two hundred thirty-one standard-risk (SR) patients and 128 intermediate-risk (IR) non–B-cell ALL patients were registered from March 1995 to March 1999. After random assignment in each group, the PRED arm patients received PRED 60 mg/m2 during induction followed by PRED 40 mg/m2 over four intensifications in the SR group and three intensifications in the IR group. DEXA arm patients received DEXA 8 mg/m2 during induction and DEXA 6 mg/m2 during the intensifications. The maintenance phase was continued until week 104.

Results

Event-free survival rates at 8 years in the DEXA and PRED arms were 81.1% ± 3.9% (n = 117) and 84.4% ± 5.2% (n = 114), respectively, in the SR group (P = .217) and 84.9% ± 4.6% (n = 62) and 80.4% ± 5.1% (n = 66), respectively, in the IR group (P = .625). The primary reason for treatment failure was marrow relapse. Only two extramedullary relapses occurred in the DEXA arm compared with seven relapses in the PRED arm. Although complications were more prevalent in the DEXA arm than in the PRED arm, fatal toxicity was rare both groups.

Conclusion

DEXA administered at 8 mg/m2 during induction and 6 mg/m2 during intensification showed no advantage over PRED administered at 60 mg/m2 during induction and 40 mg/m2 during intensification in both the SR and IR groups.
Dacarbazine, Cisplatin, and Interferon-Alfa-2b With or Without Interleukin-2 in Metastatic Melanoma: A Randomized Phase III Trial (18951) of the European Organisation for Research and Treatment of Cancer Melanoma Group
Authors: Keilholz Ulrich , Punt Cornelis J.A. , Gore Martin , Kruit Wim , Patel Poulam , Lienard Danielle , Thomas Jose , Proebstle Thomas M. , Schmittel Alexander , Schadendorf Dirk , Velu Thierry , Negrier Sylvie , Kleeberg Ulrich , Lehman Frederic , Suciu Stefan , Eggermont Alexander M.M.
Published: September 2005

Background

Based on phase II trial results, chemoimmunotherapy combinations have become the preferred treatment for patients with metastatic melanoma in many institutions. This study was performed to determine whether interleukin-2 (IL-2) as a component of chemoimmunotherapy influences survival of patients with metastatic melanoma.

Patients and Methods

Patients with advanced metastatic melanoma were randomly assigned to receive dacarbazine 250 mg/m2 and cisplatin 30 mg/m2 on days 1 to 3 combined with interferon-alfa-2b 10 × 106 U/m2 subcutaneously on days 1 through 5 without (arm A) or with (arm B) a high-dose intravenous decrescendo regimen of IL-2 on days 5 through 10 (18 × 106 U/m2/6 hours, 18 × 106 U/m2/12 hours, 18 × 106 U/m2/24 hours, and 4.5 × 106 U/m2 for 3 × 24 hours). Treatment cycles were repeated in the absence of disease progression every 28 days to a maximum of four cycles.

Results

Three hundred sixty-three patients with advanced metastatic melanoma were accrued. The median survival was 9 months in both arms, with a 2-year survival rate of 12.9% and 17.6% in arms A and B, respectively (P = .32; hazard ratio, 0.90; 95% CI, 0.72 to 1.11). There was also no statistically significant difference regarding progression-free survival (median, 3.0 v 3.9 months) and response rate (22.8% v 20.8%).

Conclusion

Despite its activity in melanoma as a single agent or in combination with interferon-alfa-2b, the chosen schedule of IL-2 added to the chemoimmunotherapy combination had no clinically relevant activity.
Psychoactive Medications and Risk of Delirium in Hospitalized Cancer Patients
Authors: Gaudreau Jean-David , Gagnon Pierre , Harel François , Roy Marc-André , Tremblay Annie
Published: September 2005

Purpose

Psychoactive medications are biologically plausible and potentially modifiable risk factors of delirium. To date, however, research findings are inconsistent regarding their association with delirium. The association between exposure to anticholinergics, benzodiazepines, corticosteroids, and opioids and the risk of delirium was studied.

Patients and Methods

A total of 261 hospitalized cancer patients were followed up with repeated assessments by using the Nursing Delirium Screening Scale for up to 4 weeks for incident delirium. Detailed exposure to psychoactive medications was documented daily. Strengths of association with delirium were expressed as hazard ratios (HRs) in univariate and multivariate analyses by using Cox regression models. All medication variables were coded as time-dependent covariates. Whenever possible, exposure was computed by using cumulative daily doses in equivalents; dichotomous cutoffs were determined.

Results

During follow-up (mean, 8.6 days), 43 patients became delirious (16.5%). Delirium was associated with a history of delirium and the presence of hepatic metastases at admission. Analysis of the effect of medications was performed adjusting for these factors. Patients exposed to daily doses of benzodiazepines above 2 mg (HR, 2.04; 95% CI, 1.05 to 3.97), above 15 mg of corticosteroids (HR, 2.67; 95% CI, 1.18 to 6.03), or above 90 mg of opioids (HR, 2.12; 95% CI, 1.09 to 4.13) had increases in the risks for delirium. We did not observe associations between anticholinergics and risk for delirium.

Conclusion

Exposure to opioids, corticosteroids, and benzodiazepines is independently associated with an increased risk of delirium in hospitalized cancer patients.
Quantitative Methylation-Specific Polymerase Chain Reaction Gene Patterns in Urine Sediment Distinguish Prostate Cancer Patients From Control Subjects
Authors: Hoque Mohammad Obaidul , Topaloglu Ozlem , Begum Shahnaz , Henrique Rui , Rosenbaum Eli , Van Criekinge Wim , Westra William H. , Sidransky David
Published: September 2005

Purpose

Aberrant promoter hypermethylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of prostate cancers and is a promising marker for cancer detection. We sought to develop a test for prostate cancer based on a quantitative methylation-specific polymerase chain reaction (QMSP) of multiple genes in urine sediment DNA.

Patients and Methods

We tested urine sediment DNA for aberrant methylation of nine gene promoters (p16INK4a, p14ARF, MGMT, GSTP1, RARβ2, CDH1 [E-cadherin], TIMP3, Rassf1A, and APC) from 52 patients with prostate cancer and 21 matched primary tumors by quantitative fluorogenic real-time polymerase chain reaction. We also analyzed urine sediments from 91 age-matched individuals without any history of genitourinary malignancy as controls.

Results

Promoter hypermethylation of at least one of the genes studied was detected in urine samples from all 52 prostate cancer patients. Urine samples from the 91 controls without evidence of genitourinary cancer revealed no methylation of the p16, ARF, MGMT, and GSTP1 gene promoters, whereas methylation of RARβ2, TIMP3, CDH1, Rassf1A, and APC was detected at low levels.

Conclusion

Overall, methylation found in urine samples matched the methylation status in the primary tumor. A combination of only four genes (p16, ARF, MGMT, and GSTP1) would theoretically allow us to detect 87% of prostate cancers with 100% specificity. Our data support further development of the noninvasive QMSP assay in urine DNA for early detection and surveillance of prostate cancer.