bluuebunny/crossref_metadata_2025 huggingface dataset:
Potent organo-osmium compound shifts metabolism in epithelial ovarian cancer cells
Authors: Hearn Jessica M. , Romero-Canelón Isolda , Munro Alison F. , Fu Ying , Pizarro Ana M. , Garnett Mathew J. , McDermott Ultan , Carragher Neil O. , Sadler Peter J.
Published: July 2015

Significance

Platinum-based metallodrugs are the most widely used anticancer agents. Their reduced effectiveness after repeat dosing (resistance) constitutes a major clinical problem. We study a potent organo-osmium compound with improved activity over cisplatin and no cross-resistance in platinum-resistant cancers. This compound disrupts metabolism in A2780 human ovarian cancer cells, generating reactive oxygen species and damaging DNA. We identified mutations in complex I of the electron transport chain in A2780 cells and suggest that the osmium compound may exploit these mutations to exert a potent mechanism of action. Such activity increases selectivity toward cancer cells, given that normal-functioning cells can better adapt to drug-induced metabolic perturbations. Therefore, this report highlights a promising strategy to drive the future development of organometallic anticancer compounds.
Primer retention owing to the absence of RNase H1 is catastrophic for mitochondrial DNA replication
Authors: Holmes J. Bradley , Akman Gokhan , Wood Stuart R. , Sakhuja Kiran , Cerritelli Susana M. , Moss Chloe , Bowmaker Mark R. , Jacobs Howard T. , Crouch Robert J. , Holt Ian J.
Published: July 2015

Significance

Cellular energy production is a function of the abundance of the small circular DNA molecules in mitochondria. Mitochondrial DNA is replicated in both dividing and nondividing cells, and encoding ribonuclease H1 (RNase H1) is essential to this process. Here, we define its mechanistic role: the removal of the RNA primers used for mitochondrial DNA replication. In the absence of RNase H1, primers are fixed in both template strands of mitochondrial DNA. The retained primers are a major impediment to mitochondrial DNA polymerase γ, leading to the formation of persistent DNA gaps that are catastrophic for subsequent rounds of replication. Moreover, primer retention provides unambiguous identification of RNA-DNA transition sites in the control region of mitochondrial DNA, thereby defining two major origins of replication.
Association of Post-Saline Load Plasma Aldosterone Levels With Left
Ventricular Hypertrophy in Primary Hypertension
Authors: Catena Cristiana , Verheyen Nicolas D. , Url-Michitsch Marion , Kraigher-Krainer Elisabeth , Colussi GianLuca , Pilz Stefan , Tomaschitz Andreas , Pieske Burkert , Sechi Leonardo A.
Published: July 2015

BACKGROUND

Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular morbidity in hypertension. Current evidence suggests a contribution to LVH of plasma aldosterone levels that are inappropriately elevated for the salt status. The aim of this study was to investigate whether inappropriate modulation of aldosterone production by a saline load is associated with left ventricular (LV) mass in hypertensive patients.

METHODS

In 90 hypertensive patients free of clinically relevant cardiovascular complications in whom secondary forms of hypertension were ruled out, we performed a standard intravenous saline load (0.9% NaCl, 2 l in 4 hours) with measurement of plasma aldosterone and active renin at baseline and end of infusion. Bi-dimensional echocardiography was performed for the assessment of cardiac morphology and function.

RESULTS

LVH was present in 19% of patients who had significantly worse renal function and higher body mass, blood pressure, and plasma aldosterone levels measured both at baseline and after the saline load than patients without LVH. LV mass was directly related to age, body mass, systolic blood pressure, duration of hypertension, baseline, and post-saline load plasma aldosterone levels and inversely to glomerular filtration. Multivariate regression analysis showed independent correlation of LV mass with body mass, systolic blood pressure, and plasma aldosterone levels measured after intravenous saline load, but not at baseline.

CONCLUSIONS

In patients with hypertension, aldosterone levels measured after intravenous saline load are related to LV mass independent of age, body mass, and blood pressure, suggesting that limited ability of salt to modulate aldosterone production could contribute to LVH.
TiMEx: a waiting time model for mutually exclusive cancer alterations
Authors: Constantinescu Simona , Szczurek Ewa , Mohammadi Pejman , Rahnenführer Jörg , Beerenwinkel Niko
Published: July 2015

Motivation: Despite recent technological advances in genomic sciences, our understanding of cancer progression and its driving genetic alterations remains incomplete.

Results: We introduce TiMEx, a generative probabilistic model for detecting patterns of various degrees of mutual exclusivity across genetic alterations, which can indicate pathways involved in cancer progression. TiMEx explicitly accounts for the temporal interplay between the waiting times to alterations and the observation time. In simulation studies, we show that our model outperforms previous methods for detecting mutual exclusivity. On large-scale biological datasets, TiMEx identifies gene groups with strong functional biological relevance, while also proposing new candidates for biological validation. TiMEx possesses several advantages over previous methods, including a novel generative probabilistic model of tumorigenesis, direct estimation of the probability of mutual exclusivity interaction, computational efficiency and high sensitivity in detecting gene groups involving low-frequency alterations.

Availability and implementation: TiMEx is available as a Bioconductor R package at www.bsse.ethz.ch/cbg/software/TiMEx .

Contact:  niko.beerenwinkel@bsse.ethz.ch

Supplementary information : Supplementary data are available at Bioinformatics online.
Trophic levels of marine consumers from nitrogen stable isotope analysis: estimation and uncertainty
Authors: Jennings Simon , van der Molen Johan
Published: July 2015

Estimates of trophic levels (TLs) are used to calibrate, parameterize, and validate foodweb models and to calculate metrics and indicators of foodweb structure and human impacts. We develop a method to estimate TL from nitrogen stable isotope data (δ15N) and apply it to 5535 individuals from 62 species of marine fish and squids sampled from the Celtic Sea, English Channel, Irish Sea, and North Sea. With this method, uncertainties in δ15N at the base of the foodweb (from a marine isoscape generated with environmental data) and in trophic fractionation (from existing fixed and scaled fractionation models) are propagated through the analysis to quantify uncertainty in TL. Higher values of base and consumer δ15N lead to greater uncertainty in TL estimates for individual consumers. Base and consumer δ15N are higher in coastal regions with lower salinity, such as the Irish Sea and Channel coasts, so uncertainty in individual TL estimates is relatively high in these regions. Conversely, when base and consumer δ15N are low, as in the high salinity waters of the northern North Sea, uncertainty is relatively low. Uncertainty intervals for species' predicted TL at a reference mass (based on ≥10 individuals spanning a range of body sizes) are small compared with estimates for individual consumers, as are estimates of slope of the TL body mass relationship. For ∼50% of region and species combinations showing trends in TL with body mass, there are eight times more positive relationships than negative ones. Our approach can be applied at large spatial scales. It generates estimates of uncertainty that support more rigorous and informed comparisons of the trophic ecology of size classes, species, and species-groups. A data file that includes estimates of TL and associated uncertainty for all sampled individuals accompanies this study.
Systemic lupus erythematosus: molecular cloning and analysis of recombinant monoclonal kappa light chain NGTA2-Me-pro-ChTr possessing two different activities—trypsin-like and metalloprotease
Authors: Timofeeva Anna M. , Ivanisenko Nikita V. , Buneva Valentina N. , Nevinsky Georgy A.
Published: July 2015

Polyclonal antibodies hydrolyzing myelin basic protein (MBP) can play an important role in the pathogenesis of multiple sclerosis and systemic lupus erythematosus (SLE). An immunoglobulin light chain phagemid library derived from peripheral blood lymphocytes of patients with SLE was used. The small pools of phage particles displaying light chains with different affinity for MBP were isolated by affinity chromatography on MBP-Sepharose. The fraction eluted with 0.5M NaCl was used for preparation of individual monoclonal light chains (MLChs, 26–27kDa). The clones were expressed in Escherichia coli in a soluble form; MLChs were purified by metal-chelating chromatography followed by gel filtration. In mammalians, there are serine proteases and metalloproteases. These and many other enzymes usually have only one active site and catalyze only one chemical reaction. In contrast to canonical proteases, one MLCh (NGTA2-Me-pro-ChTr) efficiently hydrolyzed MBP (but not other proteins) and four different oligopeptides corresponding to four immunodominant sequences containing cleavage sites of MBP. The proteolytic activity of MLCh was efficiently inhibited only by specific inhibitors of serine-like (phenylmethanesulfonylfluoride, PMSF) and metalloproteases (EDTA). It was shown that MLCh possess independent serine-like and metal-dependent activities. The principal existence of monoclonal antibodies with two different proteolytic activities is unexpected but very important for the further understanding of at present unknown biological functions of human antibodies.
Exploring the Determinants of Network Effectiveness: The Case of Neighborhood Governance Networks in Beijing
Authors: Wang Weijie
Published: July 2015

Based on the models proposed by Provan and Milward and Provan and Kenis, this article employed a mixed-methods approach to study the determinants of the effectiveness of governance networks. The article is based on 22 neighborhood governance networks in Beijing with each network consisting of public, business, and civic organizations. Linear regression was used to identify independent variables that exert statistically significant influence over network effectiveness, and the fuzzy set Qualitative Comparative Analysis was used to investigate the complex interactions between explanatory variables. The analysis revealed different but functionally equivalent configurations of causal conditions that led to network effectiveness and showed that configurations of factors leading to network effectiveness were different from those leading to network ineffectiveness. The results also suggested that network structural characteristics such as network centralization and density are neither sufficient nor necessary conditions for network effectiveness. In contrast to Provan and Milward’s findings, the results suggest that network density is more important than network centralization in affecting effectiveness in small networks. Resource munificence was identified as an “almost always” necessary condition for network effectiveness.
Revisiting the dynamical case for a massive black hole in IC10 X-1
Authors: Laycock Silas G. T. , Maccarone Thomas J. , Christodoulou Dimitris M.
Published: July 2015

The relative phasing of the X-ray eclipse ephemeris and optical radial velocity (RV) curve for the X-ray binary IC10 X-1 suggests that the He [λ4686] emission line originates in a shadowed sector of the stellar wind that avoids ionization by X-rays from the compact object. The line attains maximum blueshift when the wind is directly towards us at mid X-ray eclipse, as is also seen in Cygnus X-3. If the RV curve is unrelated to stellar motion, evidence for a massive black hole (BH) evaporates because the mass function of the binary is unknown. The reported X-ray luminosity, spectrum, slow QPO and broad eclipses caused by absorption/scattering in the Wolf–Rayet (WR) wind are all consistent with either a low-stellar-mass BH or a neutron star (NS). For an NS, the centre of mass lies inside the WR envelope whose motion is then far below the observed 370 km s−1 RV amplitude, while the velocity of the compact object is as high as 600 km s−1. The resulting 0.4 per cent Doppler variation of X-ray spectral lines could be confirmed by missions in development. These arguments also apply to other putative BH binaries whose RV and eclipse curves are not yet phase-connected. Theories of BH formation and predicted rates of gravitational wave sources may need revision.
Fatal Granulomatous Amoebic Encephalitis Caused by Acanthamoeba in a Patient With Kidney Transplant: A Case Report
Authors: Salameh Ahmad , Bello Nancy , Becker Jennifer , Zangeneh Tirdad
Published: July 2015

Granulomatous amoebic encephalitis (GAE) due to Acanthamoeba is almost a uniformly fatal infection in immune-compromised hosts despite multidrug combination therapy. We report a case of GAE in a female who received a deceased donor kidney graft. She was treated with a combination of miltefosine, pentamidine, sulfadiazine, fluconazole, flucytosine, and azithromycin.
Xenon Does Not Increase Heart Rate–corrected Cardiac QT Interval in Volunteers and in Patients Free of Cardiovascular Disease
Authors: Neukirchen Martin , Schaefer Maximilian S. , Kern Carolin , Brett Sarah , Werdehausen Robert , Rellecke Philipp , Reyle-Hahn Matthias , Kienbaum Peter
Published: July 2015

AbstractAbstract

No prolongation of heart rate–corrected cardiac QT intervals was observed in volunteers during xenon monoanesthesia or in patients without preexisting long QT syndrome during xenon-based anesthesia.

Background:

Impaired cardiac repolarization, indicated by prolonged QT interval, may cause critical ventricular arrhythmias. Many anesthetics increase the QT interval by blockade of rapidly acting potassium rectifier channels. Although xenon does not affect these channels in isolated cardiomyocytes, the authors hypothesized that xenon increases the QT interval by direct and/or indirect sympathomimetic effects. Thus, the authors tested the hypothesis that xenon alters the heart rate–corrected cardiac QT (QTc) interval in anesthetic concentrations.

Methods:

The effect of xenon on the QTc interval was evaluated in eight healthy volunteers and in 35 patients undergoing abdominal or trauma surgery. The QTc interval was recorded on subjects in awake state, after their denitrogenation, and during xenon monoanesthesia (FetXe > 0.65). In patients, the QTc interval was recorded while awake, after anesthesia induction with propofol and remifentanil, and during steady state of xenon/remifentanil anesthesia (FetXe > 0.65). The QTc interval was determined from three consecutive cardiac intervals on electrocardiogram printouts in a blinded manner and corrected with Bazett formula.

Results:

In healthy volunteers, xenon did not alter the QTc interval (mean difference: +0.11 ms [95% CI, −22.4 to 22.7]). In patients, after anesthesia induction with propofol/remifentanil, no alteration of QTc interval was noted. After propofol was replaced with xenon, the QTc interval remained unaffected (417 ± 32 ms vs. awake: 414 ± 25 ms) with a mean difference of 4.4 ms (95% CI, −4.6 to 13.5).

Conclusion:

Xenon monoanesthesia in healthy volunteers and xenon/remifentanil anesthesia in patients without clinically relevant cardiovascular disease do not increase QTc interval.
Silencing the α2 Subunit of γ-aminobutyric Acid Type A Receptors in Rat Dorsal Root Ganglia Reveals Its Major Role in Antinociception Posttraumatic Nerve Injury
Authors: Obradovic´ Aleksandar L. , Scarpa Joseph , Osuru Hari P. , Weaver Janelle L. , Park Ji-Yong , Pathirathna Sriyani , Peterkin Alexander , Lim Yunhee , Jagodic Miljenko M. , Todorovic Slobodan M. , Jevtovic-Todorovic Vesna
Published: July 2015

AbstractAbstract

Nerve injury reduced the γ-aminobutyric acid (GABA) receptor type A α2 subunit expression in dorsal root ganglia (DRG). In vivo knockdown of the α2 subunit in the DRG enhanced nociception whereas pharmacologic prevention of GABA uptake reduced pain behavior. The results are consistent with the notion that modulation of GABAergic tone in the DRG may offer a novel therapeutic option for the treatment of neuropathic pain.

Background:

Neuropathic pain (NPP) is likely the result of repetitive high-frequency bursts of peripheral afferent activity leading to long-lasting changes in synaptic plasticity in the spinal dorsal horn. Drugs that promote γ-aminobutyric acid (GABA) activity in the dorsal horn provide partial relief of neuropathic symptoms. The authors examined how in vivo silencing of the GABA receptor type A (GABAA) α2 gene in dorsal root ganglia (DRG) controls NPP.

Methods:

After crush injury to the right sciatic nerve of female rats, the α2 GABAA antisense and mismatch oligodeoxynucleotides or NO-711 (a GABA uptake inhibitor) were applied to the L5 DRG. In vivo behavioral assessment of nociception was conducted before the injury and ensuing 10 days (n = 4 to 10). In vitro quantification of α2 GABAA protein and electrophysiological studies of GABAA currents were performed on acutely dissociated L5 DRG neurons at relevant time points (n = 6 to 14).

Results:

NPP postcrush injury of a sciatic nerve in adult female rats coincides with significant down-regulation of the α2 subunit expression in the ipsilateral DRG (approximately 30%). Selective down-regulation of α2 expression in DRGs significantly worsens mechanical (2.55 ± 0.75 to 5.16 ± 1.16) and thermal (7.97 ± 0.96 to 5.51 ± 0.75) hypersensitivity in crush-injured animals and causes development of significant mechanical (2.33 ± 0.40 to 5.00 ± 0.33) and thermal (10.80 ± 0.29 to 7.34 ± 0.81) hypersensitivity in sham animals (data shown as mean ± SD). Conversely, up-regulation of endogenous GABA via blockade of its uptake in DRG alleviates NPP.

Conclusion:

The GABAA receptor in the DRG plays an important role in pathophysiology of NPP caused by sciatic nerve injury and represents promising target for novel pain therapies.
Glenoid Bone Loss in Traumatic Glenohumeral Instability in the Adolescent Population
Authors: Ellis Henry Bone , Seiter Max , Wise Kelsey , Wilson Philip
Published: July 2015

Background:

Glenoid bone loss can affect the outcome and treatment for posttraumatic recurrent anterior glenohumeral instability. Clinical presentation in the adolescent age group with shoulder instability and glenoid bone loss is largely unknown. On the basis of this information, we believe there will be a high incidence of glenoid bone loss in adolescent patients with recurrent glenohumeral instability. We hypothesize that high-impact injuries, sports injuries, and reductions requiring sedation will be factors associated with glenoid bone loss.

Methods:

We performed a retrospective cross-sectional cohort study reviewing consecutive adolescent patients (n=114) with recurrent traumatic glenohumeral instability between 2004 and 2012. Chart analysis included demographic, presenting, and radiographic data. Glenoid bone loss was interpreted from plain radiographs, computed tomography (2D and/or 3D), magnetic resonance imaging, and/or arthroscopy. We compared possible risk factors between subjects with and without glenoid bone defects using the χ2 test or 2 sample t tests.

Results:

Glenoid bone loss was seen in 55 patients (48.2%) with 15 of these patients (27%) having critical bone loss. Forty-five percent of appreciated glenoid bone loss was not visualized on plain radiographs. The average age was 15.1 years (range, 6.5 to 18.1) with male to female ratio 3.7:1. Male sex, older age, and taller stature were all statistically associated with glenoid bone loss (P=0.02, 0.01, and 0.02, respectively). Primary dislocations that occurred during sports were more likely to have glenoid bone loss (55.9% vs. 78.2%, P=0.01). The presence of an apprehension sign on physical examination was positively correlated with bone loss (P=0.008).

Conclusions:

The presence of glenoid bone loss in primary traumatic glenohumeral instability in the adolescent population is high, however, not as high as previously reported. Factors associated with glenoid bone loss include male sex, older age, taller stature, sports injuries, and the presence of apprehension on physical examination.

Level of Evidence:

This study establishes patients who may be at high risk for glenoid bone loss based on mechanism of injury and physical examination findings. This prognostic study is a level II retrospective study.
Pediatric T-Condylar Humerus Fractures: A Systematic Review
Authors: Anari Jason B. , Neuwirth Alexander L. , Carducci Nicholas M. , Donegan Derek J. , Baldwin Keith D.
Published: July 2015

Background:

The pediatric T-condylar humerus fracture is different from its adult counterpart, and its rarity makes general consensus for treatment algorithms difficult to define. Pediatric orthopaedic surgeons tend to think of this fracture as a supracondylar humerus fracture with intra-articular extension. The transition age at which this injury resembles the adult distal humerus fracture and less so the pediatric supracondylar humerus fracture with intra-articular extension is unclear. The goal of this study is to synthesize the literature and identify factors associated with good and poor outcomes of these problematic injuries in children and adolescents.

Methods:

We searched EMBASE, COCHRANE, and Medline computerized literature databases from the earliest date available in the database to 2014 using the following search term including variants and pleural counterparts: pediatric T-condylar humerus fracture. A final database of individual patients was assembled from the literature. Outcomes were rated using the method described by Jarvis and colleagues. Where possible the Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association classification was used to stratify outcomes. Univariate and multivariate statistical tests were applied to the assembled database to assess differences in outcomes.

Results:

Patients with a triceps-splitting approach had improved Jarvis outcome scores compared with the other operative approaches as well as the best arc of motion at follow-up. In addition, 6/25 triceps split patients were 10 years old or younger compared with 3/38 Bryan-Morrey patients and 0/23 osteotomy patients. No patients with Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association C3 fractures were treated with a triceps-splitting approach. When an articular approach was used, the Morrey Slide led to similar range of motion and functional outcomes as an olecranon osteotomy (P=0.616). However, the olecranon osteotomy resulted in more approach-related complications (P<0.001). An approach-related complication was associated with a poor outcome in 42% of cases.

Conclusions:

Pediatric T-condylar humerus fractures requiring an open approach may benefit from less invasive approaches such as the triceps split approach where the fracture pattern allows. Younger children are more amenable to less invasive means of fracture reduction and fixation. If an articular reduction is required, the aggregated literature suggests that the Morrey slide offers equivalent results to the olecranon osteotomy but with fewer approach-related complications. An olecranon osteotomy can be considered in cases of articular comminution.

Level of Evidence:

Level IV—therapeutic.
Plantar Pressures After Nonoperative Treatment for Clubfoot: Intermediate Follow-up at Age 5 Years
Authors: Jeans Kelly A. , Erdman Ashley L. , Karol Lori A.
Published: July 2015

Introduction:

Worldwide, a nonoperative approach in the treatment of idiopathic clubfoot has been taken in an attempt to reduce the incidence of surgical outcomes. Although both the Ponseti casting (Ponseti) and the French physiotherapy (PT) methods have shown gait and pedobarograph differences at age 2 years, improved gait results have been reported by age 5 years. The purpose of this study was to assess plantar pressures in feet treated with the Ponseti versus the PT methods at this intermediate stage.

Methods:

Clubfoot patients treated nonoperatively (Ponseti or PT) underwent pedobarograph data collection at age 5 years. The foot was subdivided into the medial/lateral hindfoot, midfoot, and forefoot regions. Variables included Peak Pressure, Maximum Force, Contact Area%, Contact Time%, Pressure Time Integral, the hindfoot-forefoot angle, and displacement of the center of pressure (COP) line. Twenty controls were used for comparison.

Results:

Pedobarograph data from 164 patients (238 feet; 122 Ponseti and 116 PT) showed no significant differences between the Ponseti and the PT feet, except the PT feet had a significantly less medial movement of the COP than the Ponseti feet (P=0.0379). Compared with controls, both groups had decreased plantar pressures in the hindfoot and first metatarsal regions, whereas the midfoot and lateral forefoot experienced significant increases compared with controls. This lateralization was also reflected in the hindfoot-forefoot angle and the COP.

Conclusions:

Feet that remain nonoperative and avoid surgical intervention are considered a good clinical result. However, pedobarograph results indicate mild residual deformity in these feet despite clinically successful outcomes.

Level of Evidence:

Level II—therapeutic.
A 10-year Retrospective Review of Functional Outcomes of Adolescent Anterior Cruciate Ligament Reconstruction
Authors: Reid Duncan , Leigh Warren , Wilkins Stephanie , Willis Royce , Twaddle Bruce , Walsh Stewart
Published: July 2015

Background:

Rupture of the anterior cruciate ligament (ACL) is an increasingly prevalent sporting injury in adolescents. Surgical reconstruction of the ACL in adolescents has been controversial and there has been little reported on functional outcomes after surgery.

The aim of this study was to undertake a retrospective notes review and questionnaire survey of a group of adolescents who had their ACL surgically reconstructed over the previous 10 years, assessing delay to surgery, levels of meniscal damage, reoperation rates, and functional outcomes.

Methods:

A retrospective chart review was performed on 100 adolescent patients who underwent arthroscopic ACL reconstruction using a transphyseal technique. These patients were also contacted and completed the Knee Osteoarthritis Outcome Score (KOOS).

Results:

One hundred patients had their records reviewed. The average age at follow-up was 20.5 (SD, 2.4) years. There were 49 females and 51 males. Meniscal tears were present in 76% of patients at the time of surgery. The rate of medial meniscal tears increased with delay to surgical intervention beyond 3 months. Reoperation rate for these patients was 24%.

Eighty patients completed the KOOS questionnaire. Patients were a mean of 4 (SD, 2.2) years postsurgery. The main findings indicate that in the 5 key KOOS domains patients scored a mean of 60 (SD, 13) for symptoms, 65 (SD, 10) for pain, 70 (SD, 6.4) for activities of daily living, 54 (SD, 17.6) for sport and recreation, and 47.2 (SD, 20.1) for quality of life.

Conclusions

This study demonstrates that young people with ACL injuries have a very high associated incidence of meniscal pathology at the time of surgery. There is a high reoperation rate for meniscal surgery and graft failure. Four years post-ACL reconstruction many have not yet returned to a fully functional state.

Further research to understand why functional outcomes are modest is required.

Level of Evidence:

Level IV—retrospective case series.
Prevalence of Femoroacetabular Impingement Morphology in Asymptomatic Adolescents
Authors: Li Ying , Helvie Peter , Mead Matthew , Gagnier Joel , Hammer Matthew R. , Jong Nahbee
Published: July 2015

Background:

Femoroacetabular impingement (FAI) can lead to acetabular chondrolabral damage and has been theorized as a causative factor in the development of osteoarthritis. The pathogenesis of FAI is unknown. The purpose of this study was to determine the prevalence of FAI morphology in asymptomatic adolescents.

Methods:

We identified children 10 to 18 years of age who had undergone a pelvic CT between 2007 and 2012. Exclusion criteria included hip pain, any hip pathology, bone tumor, long-term steroid use, history of chemotherapy or radiation therapy, nonambulatory status, neuromuscular disorder, chromosomal abnormality, and metabolic bone disease. Multiplanar reformatted images were created from axial images to calculate α angles and lateral center-edge angles (LCEA). Cam morphology was defined as an α-angle ≥55 degrees and pincer morphology as a LCEA≥40 degrees.

Results:

We analyzed 558 patients (1116 hips). There were 276 males and 282 females. The average age was 14.4 years (range, 10.0 to 18.2 y). The mean α-angle was 47.9 degrees (range, 25.7 to 78 degrees) and the mean LCEA was 34.4 degrees (range, 3.9 to 58.6 degrees). Males had a significantly higher mean α-angle (49.7 vs. 46.0 degrees) (P<0.0005) and females had a significantly higher mean LCEA (35.7 vs. 33.0 degrees) (P<0.0005). Ninety-four adolescents (16.8%) had an α-angle ≥55 degrees. Cam morphology was significantly more common in males (23.9% vs. 9.9%) (P<0.001). A total of 181 adolescents (32.4%) had a LCEA≥40 degrees. Pincer morphology was equally common in males and females (29.7% vs. 35.1%) (P=0.17). Thirty-four adolescents (6.1%) had mixed morphologies. Mixed morphologies were found in 21 males (7.6%) and 13 females (4.6%) (P=0.19). The prevalence of pincer morphology increased significantly with increased age in males (P<0.001).

Conclusions:

The prevalence of cam-type FAI morphology in asymptomatic adolescents is similar to the reported prevalence in asymptomatic adults. Pincer morphology may be more common than cam morphology in adolescents. Cam morphology is more prevalent in males, whereas pincer and mixed morphologies are equally prevalent in both sexes.

Level of Evidence:

Level III—diagnostic.
Treatment of Axis Body Fractures
Authors: Kepler Christopher K. , Vaccaro Alexander R. , Fleischman Andrew N. , Traynelis Vincent C. , Patel Alpesh A. , Dekutoski Mark B. , Harrop James , Wood Kirkham B. , Schroeder Gregory D. , Bransford Richard , Aarabi Bizhan , Okonkwo David O. , Arnold Paul M. , Fehlings Michael G. , Nassr Ahmad , Shaffrey Christopher , Yoon S. Tim , Kwon Brian
Published: July 2015

Study Design:

Evidence-based systematic review.

Objectives:

To define the optimal treatment of fractures involving the C2 body, including those with concomitant injuries, based upon a systematic review of the literature.

Summary of Background Data:

Axis body fractures have customarily been treated nonoperatively, but there are some injuries that may require operative intervention. High-quality literature is sparse and there are few class I or class II studies to guide treatment decisions.

Materials and Methods:

A literature search was conducted using PubMed (MEDLINE), Cochrane Central Register of Controlled Trials, and Scopus (EMBASE, MEDLINE, COMPENDEX). The quality of literature was rated according to a grading tool developed by the Center for Evidence-based Medicine. Operative and nonoperative treatment of axis body fractures were compared using fracture bony union as the primary outcome measure. As risk factors for nonunion were not consistently reported, cases were analyzed individually.

Results:

The literature search identified 62 studies, of which 10 were case reports which were excluded from the analysis. A total of 920 patients from 52 studies were included. The overall bony union rate for all axis body fractures was 91%. Although the majority of fractures were treated nonoperatively, there has been an increasing trend toward operative intervention for Benzel type III (transverse) axis body fractures. Nearly 76% of axis body fractures were classified as type III fractures, of which 88% united successfully. Nearly all Benzel type I and type II axis body fractures were successfully treated nonoperatively. The risk factors for nonunion included: a higher degree of subluxation, fracture displacement, comminution, concurrent injuries, delay in treatment, and older age.

Conclusions:

High rates for fracture union are reported in the literature for axis body fractures with nonoperative treatment. High-quality prospective studies are required to develop consensus as to which C2 body fractures require operative fixation.
Definitive Chemoradiation With Full-dose Gemcitabine for Unresectable Pancreatic Cancer
Authors: Zhou Jessica , Fang Charles X. , Shen Jincheng , Schipper Matthew J. , Zalupski Mark M. , Minter Rebecca M. , Simeone Diane M. , Hart Deanna , Eagle Taylor , Kimmel Grace W. , Vainshtein Jeffrey , Lawrence Theodore S. , Feng Mary
Published: July 2015

Objectives:

Definitive chemoradiotherapy for unresectable pancreatic cancer has traditionally involved 5-fluorouracil-based chemotherapy. Our institution has a long history of combining gemcitabine and radiotherapy (RT), and performed a retrospective review of all patients treated in this manner.

Materials and Methods:

We reviewed the records of 180 patients treated from 1999 to 2012. Mean RT dose was 40.9 Gy in 2.2-Gy fractions, and targeted only radiographically apparent disease. Ninety-six percent of patients received full-dose gemcitabine-based chemotherapy with RT. Kaplan-Meier was used to analyze time-to-event endpoints, and Cox regression models were used to assess significant prognostic variables.

Results:

Eighty-nine percent of patients completed RT without a toxicity-related treatment break. Median follow-up was 10.2 months. Twenty-nine percent of patients had a radiographic decrease in primary tumor size following treatment. Median overall survival was 11.8 months, time to distant metastasis (TDM) was 6.7 months, and time to local recurrence (TLR) was 8.3 months. On multivariate analysis, male sex, lower performance status, and higher posttreatment CA 19-9 level predicted for worse overall survival. Posttreatment, CA 19-9 was also associated with TDM and TLR, and radiographic tumor response was associated with better TLR.

Conclusion:

Definitive chemoradiation using full-dose gemcitabine is well tolerated and achieves survival outcomes comparable to reported trials in the literature.
Defining Eligibility of FOLFIRINOX for First-Line Metastatic Pancreatic Adenocarcinoma (MPC) in the Province of British Columbia
Authors: Ho Maria Yi , Kennecke Hagen F. , Renouf Daniel J. , Cheung Winson Y. , Lim Howard J. , Gill Sharlene
Published: July 2015

Background:

FOLFIRINOX is a first-line treatment option for patients with metastatic pancreatic cancer (MPC) and is associated with improved survival yet significantly more toxicities than standard gemcitabine. Our aim was to determine the proportion of patients with MPC who would be eligible for FOLFIRINOX based upon the pivotal ACCORD study criteria.

Methods:

Patients with confirmed MPC at the time of referral to the BC Cancer Agency between 2004 and 2007 were identified from the Gastrointestinal Cancers Outcomes Unit Database (GICOU). Proportion of patients that met the ACCORD study eligibility criteria was determined by chart review. Criteria for FOLFIRINOX exclusion were assessed using descriptive statistics.

Results:

A total of 100 consecutive patients with complete chart records and MPC were identified. Fifty-two (52%) were male and the median age was 68 years (range, 42 to 98 y). The most common sites of metastases were liver (63%) and peritoneum (22%). Only 26 patients fulfilled the ACCORD study eligibility criteria. The most common reasons for FOLIFIRINOX exclusion per ACCORD were poor Eastern Cooperative Oncology Group score of ≥2 (64%), age of 76 years or greater (22%), elevated bilirubin (22%), and inadequate renal function (6%).

Conclusions:

Despite the proven survival benefit of FOLFIRINOX, only approximately one quarter of patients in the real-world setting with MPC would have been considered eligible for such therapy based upon the ACCORD eligibility criteria. Careful patient selection and more tolerable therapies are required.
Effects of Chemotherapy Regimen and Radiation Modality on Hematologic Toxicities in Patients Receiving Definitive Platinum-based Doublet Chemoradiation for Non–Small Cell Lung Cancer
Authors: Tang Chad , Lee Michael S. , Gomez Daniel , Levy Larry B. , Zhuang Yan , Lu Charles , Liao Zhongxing , Komaki Ritsuko
Published: July 2015

Objectives:

Predictors of acute hematologic toxicities during definitive chemoradiation for non–small cell lung cancer (NSCLC) are incompletely defined.

Materials and Methods:

We retrospectively analyzed 604 patients treated with definitive platinum-based doublet chemoradiation therapy for stage III NSCLC. The outcome of interest was grade ≥3 acute hematologic toxicities, specifically white blood cell, hemoglobin, platelet, neutrophil, and lymphocyte decrease during chemoradiation therapy. We assessed the association between any grade ≥3 acute hematologic toxicity with patient demographic, disease, radiation factors (specifically modality and dose), and chemotherapy agents via stepwise multivariate logistic regression. Survival was compared via log-rank and univariate Cox regression analyses.

Results:

There was no significant association between radiation modality and any hematologic toxicity on multivariate analysis. However, use of etoposide was found to be significantly associated with white blood cell, platelet, and neutrophil decrease compared with paclitaxel and docetaxel (all P<0.05). No differences were found between platinum agents. Overall survival (OS) and event-free survival (EFS) were significantly worse in patients who experienced grade ≥3 hemoglobin (OS: hazard ratio [HR]=1.5; 95% confidence interval [CI], 1.05-2.26; P=0.03, EFS: HR=1.7; 95% CI, 1.2-2.4; P=0.0032) and lymphocyte (OS: HR=1.5; 95% CI, 1.1-2.1; P=0.01, EFS: HR=1.4; 95% CI, 1.1-1.9; P=0.02) decreases.

Conclusions:

Chemotherapy identity, specifically the nonplatinum agent, was significantly associated with grade ≥3 hematologic toxicities, whereas radiation modality was not.
Long-term Outcome of Prostate Cancer Patients Who Exhibit Biochemical Failure Despite Salvage Radiation Therapy After Radical Prostatectomy
Authors: Ying James , Wang Chiachien J. , Yan Jingsheng , Liauw Stanley L. , Straka Christopher , Pistenmaa David , Xie Xian-Jin , Lotan Yair , Roehrborn Claus , Kim D. Nathan
Published: July 2015

Objectives:

Salvage radiation therapy (SRT) is an effective treatment for recurrent prostate cancer (PCa) after radical prostatectomy. We report the long-term outcome of men who developed biochemical recurrence (BCR) after SRT and were treated >14 years ago.

Methods:

In total, 61 patients treated with SRT from 1992 to 2000 at our institution were identified. Survival was calculated by Kaplan-Meier method. Log-rank test and Cox regression were used to determine significance of clinical parameters.

Results:

The median follow-up was 126 months (interquartile range, 66-167 mo). Thirty-four (56%) had prostate-specific antigen (PSA) failure after SRT. At 10 years, overall survival (OS) was 67%, freedom from PSA failure (FFPF) was 33%, prostate cancer-specific survival (PCSS) was 84%, and distant metastases-free survival (DMFS) was 84%. Pathologic T-stage, Gleason score, seminal vesicle involvement, and pre-SRT PSA were associated with FFPF. For patients who failed SRT, the median time to BCR after SRT was 30 mo. A total of 19 (68%) received androgen deprivation therapy. The median OS was 13.6 years. At 10 years from time of BCR, OS was 59%, PCSS was 73%, DMFS was 75%, and castration-resistant-free survival was 70%. Early SRT failure correlated with significantly decreased DMFS and PCSS. Ten-year DMFS from SRT was 43% (BCR≤1 y) versus 91% (BCR>1 y).

Conclusions:

Extended follow-up demonstrates that despite SRT failure, PCSS remains high in select patients. Early failure (≤1 y after SRT) predicted for significantly worse outcome and may represent a subgroup with more aggressive disease that may be considered for further prospective clinical studies.
Diagnostic Value of Ganglion Cell-Inner Plexiform Layer Thickness in Glaucoma With Superior or Inferior Visual Hemifield Defects
Authors: Kim Ho Soong , Yang Heon , Lee Tae Heon , Lee Kyung Heon
Published: July 2015

Purpose:

To determine the diagnostic value of the ganglion cell-inner plexiform layer (GCIPL) thickness in glaucomatous eyes with superior or inferior visual hemifield defects.

Patients and Methods:

Eighty-five patients with glaucoma (42 isolated superior hemifield defects and 43 isolated inferior hemifield defects) and 46 normal subjects were enrolled. All patients underwent Cirrus high-definition optical coherence tomography and standard automated perimetry. The area under the receiver operating characteristic curve (AUC) was calculated to determine the diagnostic ability of the GCIPL and peripapillary retinal nerve fiber layer (pRNFL).

Results:

In the superior hemifield defect glaucoma group, the best parameters for discriminating normal eyes from glaucomatous eyes were the inferotemporal GCIPL thickness (0.942), inferior quadrant RNFL thickness (0.974), and 7 o’clock sector RNFL thickness (0.999). For diagnosing inferior hemifield defect glaucoma, the AUCs of all GCIPL parameters (0.331 to 0.702) were significantly lower than that of the superior quadrant RNFL thickness (0.866, P<0.05).

Conclusions:

The diagnostic ability of GCIPL parameters was similar to that of the pRNFL parameters in superior hemifield defect glaucoma. However, the diagnostic performance of the GCIPL parameters was significantly inferior to those of the pRNFL parameters in eyes with inferior hemifield defect glaucoma.
Pediatric Idiopathic Orbital Inflammation: Clinical Features of 30 Cases
Authors: Spindle Jordan , Tang Sunny X. , Davies Brett , Wladis Edward J. , Piozzi Elena , Pellegrini Marco , Lally Sara E. , Shields Carol , Shinder Roman
Published: July 2015

Purpose:

Pediatric idiopathic orbital inflammation (IOI) is a rare entity with little known about the clinical presentation and natural history. The authors report the demographics, clinical presentations, radiographic and histopathologic characteristics, and treatment outcome of 30 children with IOI.

Method s:

Retrospective chart review of 30 patients 18 years and younger diagnosed with IOI and statistical analysis using analysis of variance and Fisher’s exact test. This study was reviewed and approved by the Institutional Review Board of SUNY Downstate Medical Center.

Results:

There were 9 males (30%) and 21 females (70%) with pediatric IOI who presented at a median age of 11 years (range 2–18 years). Primary IOI was found in 19 patients (63%) and recurrent IOI in 11 patients (37%). Overall, 26 patients (87%) had unilateral IOI while 4 patients (13%) had bilateral disease at presentation. There were 12 patients (40%) with systemic constitutional signs. The most common ophthalmic findings included periorbital edema (n = 20, 67%) and blepharoptosis (n = 17, 57%). All patients had orbital radiography with common findings of dacryoadenitis (n = 12, 40%), orbital mass (n = 12, 40%), or myositis (n=10, 33%). The presence of a radiographic orbital mass was significantly related to the clinical presence of blepharoptosis (p = 0.03). The most common treatment was oral glucocorticoids in 24 patients (80%). Over mean follow up of 19 months (range 6–64 months), females were more likely to display recurrent disease (p = 0.01).

Conclusions:

Idiopathic orbital inflammation is an uncommon but important cause of acute orbital syndrome in children, manifesting as a bilateral condition in 13% and with constitutional symptoms in 40%. Posttreatment recurrence is found in 37% of cases.
Infarcted Tarsal Pyogenic Granuloma Simulating Malignant Melanoma
Authors: Charles Norman C. , Kahn Jonathan B.
Published: July 2015

The authors describe a rapidly enlarging, pedunculated brown tarsal lesion in a 34-year-old man with a history of chalazia. Following excision, histopathologic analysis showed the features of a necrotic pyogenic granuloma. This unique case expands the differential diagnosis of conjunctival malignant melanoma.
Histopathology, Immunohistochemistry, and Electron Microscopic features of a Dacryocystorhinostomy Ostium Cicatrix
Authors: Ali Mohammad Javed , Mishra Dilip Kumar , Baig Farhana , Naik Milind N.
Published: July 2015

Purpose:

The aim of this study is to report the histopathological, Immunohistochemical, and ultrastructural features of a dacryocystorhinostomy ostium cicatrix.

Methods:

A prospective histopathological study was performed in a tertiary eye care setting. Scarred nasal mucosal tissues obtained during endoscopic revisions of 10 previously failed dacryocystorhinostomies secondary to complete cicatricial closure of the ostia were studied. The tissue specimens were analyzed using hematoxylin and eosin, periodic acid-Schiff staining. Special stains used include Masson’s trichrome and Alizarin red. Immunohistochemistry was performed using vimentin, smooth muscle actin, CD3, CD5, and CD20. Specimens were processed for ultrastructural analysis as per standard protocols for transmission electron microscopy.

Results:

The respiratory epithelial regeneration was noted to be complete. Irregular laying of deeply eosinophilic and hyalinized collagen with intervening fibroblasts was noted. Focal areas of new bone formation were seen within the cicatricial tissue with osteocytes and ongoing osteoblastic rimming. The infiltrates were mixture of both T and B lymphocytes and were positive for CD3, CD5, and CD20 immunostaining. Electron microscopy showed disorganized collagen fibrils with numerous fibroblasts and mononuclear inflammatory infiltrate. Amorphous bony osteoid within a fibrillar background with metabolically active osteoblasts showed a vesicular cytoplasm, hyperplastic proliferating mitochondria, large Golgi apparatus, and dense endoplasmic reticulum.

Conclusion:

There is new bone formation within the dense connective tissues of a dacryocystorhinostomy cicatrix. This study may provide useful inputs for further basic science studies aimed at better understanding of wound healing in failed dacryocystorhinostomy.
Diagnostic Accuracy of Cognitive Screening Instruments in Heart Failure
Authors: Cameron Jan , Kure Christina E. , Pressler Susan J. , Ski Chantal F. , Clark Alexander M. , Thompson David R.
Published: July 2015

Background:

Cognitive impairment is prevalent in heart failure (HF) with severe consequences, including increased risk of mortality and reduced ability to self-manage HF symptoms. Identifying cognitive impairment through screening would assist clinicians in managing HF and comorbid cognitive impairment. However, the accuracy of cognitive screening instruments for HF has not been adequately determined.

Objective:

The aim of this study was to determine the diagnostic accuracy of cognitive screening instruments in screening for mild cognitive impairment (MCI) in HF patients.

Methods:

A systematic review of major electronic bibliographic databases was searched from January 1999 to June 2013. Inclusion criteria were as follows: primary studies examining cognitive impairment in HF, administration of a cognitive screening instrument and neuropsychological test battery, and cognitive impairment indicated by performance on neuropsychological tests 1.5 SDs less than that of normative data. Methodological rigor of included publications was evaluated using 2 bias risk instruments: QUality Assessment of Diagnostic Accuracy Studies and STAndards for the Reporting of Diagnostic accuracy studies. The precision, accuracy, and receiver operating characteristic curves of the Mini Mental State Examination were computed.

Results:

From 593 citations identified, 8 publications met inclusion criteria. Risk of bias included selective HF patient samples, and no study examined the diagnostic test accuracy of the cognitive screening instruments. The Mini Mental State Examination had low sensitivity (26%) and high specificity (95%) with a score of 28 or less as the optimal threshold for MCI screening.

Conclusions:

Screening for cognitive impairment in HF is recommended; however, future studies need to establish the diagnostic accuracy of screening instruments of MCI in this population.