bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of Color Duplex Sonography in the Diagnosis of Giant Cell Arteritis
Authors: Romera-Villegas Antonio , Vila-Coll Ramón , Poca-Dias Violant , Cairols-Castellote Marc A.
Published: January 2017

Objective. To determine the clinical usefulness of color duplex sonography in the diagnosis of giant cell arteritis as an alternative to temporal artery biopsy. Methods. From May 1998 to November 2002, 68 consecutive patients seen in our hospital with a clinical suggestion of active temporal arteritis were included. Forty‐eight patients were female and 20 were male, with a mean age of 77 years. Color duplex sonography with a linear array transducer (5–10 MHz) was used to assess temporal artery morphologic characteristics before a biopsy was performed. The main sonographic criterion for a positive diagnosis was visualization of a hypoechoic halo around the temporal artery. These data were compared with pathologic findings. The κ statistic was used to determine the level of agreement. Sensitivity, specificity, positive and negative predictive values, and accuracy of duplex sonography as a diagnostic test were assessed. Results. The color duplex sonographic findings were positive in 25 of 68 patients with a clinical suggestion of giant cell arteritis. The diagnosis was confirmed by biopsy in 22 patients; there were 4 false‐positive results and 1 false‐negative result by duplex sonography. The κ value was 0.84. Sensitivity, specificity, positive and negative predictive values, and accuracy for duplex sonography were 95.4%, 91.3%, 84%, 97.6%, and 92.6%, respectively. Conclusions. The use of high‐resolution color duplex sonography may replace biopsy in the diagnosis of giant cell arteritis.
Utility of the Sonographic Whirlpool Sign in Diagnosing Midgut Volvulus in Patients With Atypical Clinical Presentations
Authors: Patino Maria Olga , Munden Martha M.
Published: January 2017

Objective. To illustrate cases of midgut volvulus in 7 children, of whom only 2 were neonates, diagnosed initially by sonography using the whirlpool sign, and to emphasize the importance of considering malrotation and midgut volvulus in the differential diagnosis of acute or chronic abdominal pain in those beyond the neonatal period, the usual time of presentation for midgut volvulus. Methods. The sonography computer database of a large pediatric hospital was reviewed over a 26‐month period for sonographic reports that contained the key words midgut volvulus and whirlpool sign. From November 1999 until January 2002, 7 patients had a sonographic diagnosis of midgut volvulus on the basis of the whirlpool sign. Sonographic and surgical records of these patients were reviewed retrospectively. In addition, the department computer database of all contrast‐enhanced upper gastrointestinal examinations performed over the same period was searched using the key words midgut volvulus, and an additional 2 cases of midgut volvulus were found, neither of which had undergone a prior or subsequent sonographic study. Results. Seven patients, ranging in age from 1 day to 5½ years were found to have the whirlpool sign on sonography performed for acute abdominal symptoms, including projectile nonbilious emesis, colicky abdominal pain with suspicion of intussusception, palpable abdominal masses, right lower quadrant abdominal pain with suspected appendicitis, and chronic diarrhea. Six of the 7 cases of midgut volvulus were confirmed with upper gastrointestinal examinations. One patient was taken directly to surgery on the basis of the sonographic findings alone. One patient had subsequent computed tomography of the abdomen for continued suspicion of an abdominal mass. All 7 cases were confirmed as midgut volvulus at surgery. Conclusions. The sonographic whirlpool sign is a valid and highly sensitive sign for the diagnosis of midgut volvulus secondary to malrotation, and sonographers should be aware that it frequently occurs beyond the neonatal period with symptoms other than bilious emesis.
Sonographic Diagnosis of Urethral Anomalies in Infants
Authors: Schoellnast Helmut , Lindbichler Franz , Riccabona Michael
Published: January 2017

Objective. To assess the value of urethral sonography including a perineal approach in evaluating urethral anomalies in infants. Methods. A radiology database review identified 88 patients (mean age ± SD, 64 ± 84 days) who underwent voiding cystourethrography (VCUG) and urethral sonography as part of extended sonography of the urinary tract. Sonographic and VCUG images and reports were reviewed to assess agreement between both modalities for detection of urethral anomalies. Results. Sonography facilitated the correct diagnosis of all 3 posterior urethral valves. The only urethral diverticulum, the only ectopic ureteric insertion into the urethra, the only urogenital sinus, and the only urethrovaginal fistula were also shown on sonography. In 73 (94%) of 78 cases, sonography correctly showed the absence of anomalies. In 5 infants, sonography could not reliably assess the urethra and showed indirect signs of urethral anomalies; however, these patients had normal urethras on VCUG. Conclusions. Our data show that sonography of the urethra is a valuable tool for diagnosis of urethral anomalies. Especially, negative findings on sonography are highly suggestive of the absence of urethral anomalies. Positive or equivocal sonographic findings should indicate VCUG.
Leydig Cell Tumors of the Testis
Authors: Maizlin Zeev V. , Belenky Alexander , Kunichezky Myriam , Sandbank Judith , Strauss Simon
Published: January 2017

Objective. To determine the gray scale and color Doppler sonographic features of Leydig cell tumors of the testis in a series of patients. Methods. We retrospectively analyzed the sonographic appearance of 10 proven Leydig cell tumors in 9 patients aged 26 to 47 years. Sonographic features that were reviewed included the size and echogenicity of the tumors, presence of cystic areas or calcifications, and distribution pattern of detectable blood flow on color or power Doppler imaging. Results. The tumors ranged from 0.4 to 3.0 cm in diameter, but most were less than 1.0 cm in diameter. In 1 testis, 2 discrete Leydig cell tumors were found. Nine (90%) of the 10 tumors were homogeneously hypoechoic. Only 1 tumor was isoechoic with the testis. None of the tumors contained calcifications. Of 8 tumors with color Doppler imaging, 7 (88%) showed a characteristic pattern of increased peripheral blood flow, which was either circumferential or punctate. Only 1 tumor was found with internal hypervascularity. Conclusions. Peripheral hypervascularity in a hypoechoic testicular tumor that has little or no internal color Doppler flow should suggest the possibility of a Leydig cell tumor, and consideration should be given to testicle‐sparing surgery.
Four‐Dimensional Ultrasonography for Dynamic Bladder Shape Visualization and Analysis During Voiding
Authors: Hirahara Naoki , Ukimura Osamu , Ushijima So , Yamada Yasuhiro , Okihara Koji , Kawauchi Akihiro , Miki Tsuneharu
Published: January 2017

Objective. The purpose of this study was to describe initial applications of 4‐dimensional ultrasonography (4DUS) for visualizing dynamic change in 3‐dimensional (3D) bladder shape as well as for analyzing intravesical volume and diameters during voiding. Methods. In 15 healthy volunteers and 5 patients with lower urinary tract symptoms, 4DUS images of the bladder during voiding were obtained by transabdominal 4DUS and compared with the outcome of uroflowmetry. Changes of intravesical volume as well as diameters in axial, coronal, and sagittal planes were measured and analyzed in comparison with uroflow data. Results. Dynamic 3D visualization of the bladder shape was feasible in all 20 men. Multiplanar display of 4DUS showed dynamic 3D images of the bladder during voiding to be simultaneously visualized in the axial, coronal, and sagittal planes. The change and decrease rate in intravesical volume calculated by 4DUS data had significant correlation with the average flow rate (P = .02) and the maximum flow rate (P = .04), respectively. Among the 3 diameters, the change of coronal diameter was significantly most correlated with change of the intravesical volume (P < .0001). The change in coronal diameter, which was observed in patients with urinary disturbance, had a significant difference compared with those observed in control subjects (P = .01). Conclusions. Monitoring of voiding with 4DUS was feasible in healthy men and patients with lower urinary tract symptoms. Four‐dimensional ultrasonography has the potential to be a novel noninvasive urodynamic modality to visualize dynamically the lower urinary tract during voiding and to improve pathophysiologic understanding of voiding.
The Use of Additionally Trained Sonographers as Ultrasound Practitioners
Authors: Bude Ronald O. , Fatchett John P. , Lechtanski Tena A.
Published: January 2017

Objective. Two sonographers were trained to help manage an abrupt, permanent increase in the number of ultrasound examinations in our department. Called “ultrasound practitioners,” they functioned as physician assistants and triaged 20 to 30 cases per day, allowing the cases to be batch read at a formal reading at day's end. We report our first‐year experience with this program. Methods. Two sonographers with 10 and 30 years of experience, respectively, were trained to triage and dictate cases. Once trained, they triaged the cases of 20 to 30 patients per day. Reports were predictated with voice recognition technology. A radiologist was always readily available to provide support, and consultation with a radiologist was always obtained for the infrequent verbal reports that were requested. Reports from the practitioner were graded subjectively on a 4‐point scale for the first year, according to the modification required at formal readout (A, no change; B, minor change not affecting patient care; C, moderate change not affecting care in a dramatic way; and D, major change markedly affecting care). Results. Practitioner 1 monitored the examinations of 2858 patients. The graded report results were as follows: A, 96.2%; B, 3.5%; C, 0.3%; and D, 0.00%. Practitioner 2 monitored the examinations of 2825 patients. The graded report results were as follows: A, 96.1%; B, 3.6%; C, 0.2%; and D, 0.00%. There were no category D reports. Conclusions. The results far exceeded expectations, with a very low rate of category B and C reports and an absence of category D reports. The practitioners allowed the cases of 20 to 30 patients to be batch read by the existing radiologist staff at the end of the day.
Applications of 2‐Dimensional Matrix Array for 3‐ and 4‐Dimensional Examination of the Fetus
Authors: Gonçalves Luís F. , Espinoza Jimmy , Kusanovic Juan Pedro , Lee Wesley , Nien Jyh Kae , Santolaya-Forgas Joaquin , Mari Giancarlo , Treadwell Marjorie C. , Romero Roberto
Published: January 2017

Objectives. Two‐dimensional (2D) matrix array is a new technology for the performance of 3‐dimensional and 4‐dimensional (4D) ultrasonography. In this study, we report the use of a 2D matrix array transducer for examination of fetal structures including the fetal heart. Methods. Thirty‐four fetuses without abnormalities and 19 fetuses with congenital anomalies were examined with a 2D matrix array transducer (x3‐1, IE‐33; Philips Medical Systems, Bothell, WA). Median gestational age was 25 6/7 weeks (range, 13 0/7–40 1/7 weeks). Results. (1) A 360° rotation and examination of selected structures was possible in the second trimester. (2) Structures were examined by maintaining the transducer in a fixed position and rotating the volume using the system trackball. (3) Dorsal and ventral parts of the hands and feet were visualized in a single volume data set, in real time, without moving the transducer. (4) Real‐time en face visualization of atrioventricular valves was possible from the ventricular or atrial chambers. (5) Four‐dimensional images of bones were obtained by decreasing gain settings only, with no need for cropping. (6) Four‐dimensional reconstruction of vascular structures was possible with color Doppler imaging. Two limitations were identified: (1) lower resolution than mechanical volumetric transducers, and (2) narrow volume display. Conclusions. Real‐time direct 4D imaging with 360° rotation for examination of fetal anatomic structures is feasible. This technology allows examination of fetal structures from multiple perspectives, in real time, without the need to move the transducer in the maternal abdomen. Further technological developments may overcome the limitations identified in this study.
Sonographic Features of Female Pelvic Tuberculous Peritonitis
Authors: Tongsong Theera , Sukpan Kornkanok , Wanapirak Chanane , Sirichotiyakul Supatra , Tongprasert Fuanglada
Published: January 2017

Objectives

The purpose of this study was to evaluate the sonographic features of tuberculous peritonitis in an attempt to facilitate the recognition of this disorder preoperatively.

Methods

The sonographic findings of 16 patients who had tuberculous peritonitis were reviewed.

Results

The sonographic findings showed that 14 of the 16 patients had ascites; 10 of these had fine, complete and incomplete mobile septations. Of these 10 patients, 4 had ascites with a latticelike appearance, and 2 had ascites with a parallel violin string appearance, which to our knowledge has not been described previously; 3 had particulate ascites. Peritoneal and omental thickening or nodules were identified in 9 patients. Two patients showed bilateral complex adnexal masses with multiloculated fluid with a thick wall‐like tubo‐ovarian abscess.

Conclusions

Tuberculous peritonitis seems to have characteristic sonographic features, especially the findings of peritoneal and omental thickening and ascites with fine, mobile septations. These sonographic findings may provide valuable information to help with further investigations and may prevent unnecessary laparotomies.
Prenatal Surveillance of Bronchopulmonary Sequestration Using 3‐Dimensional Ultrasonography
Authors: Xie Hong-Ning , Li Li-Juan , He Hua , Shi Hui-Juan , Peng Ruan , Zhu Yun-Xiao
Published: January 2017

Objective. The purpose of this study was to assess the growth of fetal lung lesions using 3‐dimensional ultrasonography (3DUS) and to note the clinical outcomes of infants with congenital bronchopulmonary sequestration (BPS) diagnosed prenatally. Methods. Twenty‐two cases of intrathoracic BPS diagnosed prenatally occurred between May 2005 and September 2008. The volume of the BPS lesion (Vmass) and the volume of the fetal chest (Vchest) were measured with the 3DUS software Virtual Organ Computer‐Aided Analysis (VOCAL; GE Healthcare, Kretztechnik, Zipf, Austria). The clinical outcomes of all cases were recorded. Results. Among 22 cases with fetal BPS, 8 were terminated, and 2 were lost to follow‐up. The growth pattern of the BPS lesions was assessed in 12 live‐born cases with 2 or 3 3DUS measurements per case. There was no statistically significant difference between the Vmass (P = .859) and Vmass/Vchest (P = .078) at 19 to 24 weeks' gestational age (WGA) and greater than 24 to 30 WGA, but there was a statistically significant difference between the Vmass (P = .010) and Vmass/Vchest (P = .008) at greater than 24 to 30 WGA and greater than 30 to 39 WGA. The lung lesion resolved spontaneously before birth in 4 fetuses and postnatally in 2 infants. All 12 fetuses survived to term without any prenatal intervention, were born without any evidence of neonatal respiratory impairment, and did not undergo surgical resection of the mass. Conclusions. Our data showed that fetuses with BPS had a favorable clinical outcome, and the pulmonary mass decreased during late pregnancy and resolved spontaneously. Three‐dimensional ultrasonography with VOCAL provides a useful method for assessing the growth of pulmonary lesions.
Umbilical Cord Hernias
Authors: Haas Jigal , Achiron Reuven , Barzilay Eran , Yinon Yoav , Bilik Ron , Gilboa Yinon
Published: January 2017

Objectives

The purpose of this study was to describe the characteristics and outcomes of umbilical cord hernias diagnosed prenatally.

Methods

We conducted a retrospective study of all pregnancies with the diagnosis of a fetal umbilical cord hernia during a 5‐year period. All women received care from a multidisciplinary team and underwent complete meticulous sonography for structural malformations as well as fetal echocardiography and amniocentesis.

Results

Between 2004 and 2009, isolated fetal umbilical cord hernias were diagnosed in 8 pregnant women. The gestational ages at the time of referral ranged from 16 to 28 weeks (median, 20 weeks). In 1 case, intrauterine fetal death occurred at 35 weeks due to rupture of the umbilical cord. All remaining cases were delivered at 36 to 40 weeks, and the neonates underwent corrective surgery with good outcomes.

Conclusions

Despite 1 case complicated by intrauterine fetal death in this study, the outcome of an isolated fetal umbilical hernia seems favorable.
Brightness Mode Quality Ultrasound Imaging Examination Technique (B‐QUIET)
Authors: Bahner David P. , Adkins Eric J. , Nagel Rollin , Way David , Werman Howard A. , Royall Nelson A.
Published: January 2017

Objectives

Ultrasound image interpretation and education relies on obtaining a high‐quality ultrasound image; however, no literature exists to date attempting to define a high‐quality ultrasound image. The purpose of this study was to design and perform a pilot reliability study of the Brightness Mode Quality Ultrasound Imaging Examination Technique (B‐QUIET) method for ultrasound quality image assessment.

Methods

A single sonologist performed a Trinity hypotensive ultrasound protocol on 3 participants of varying body types. Each participant's ultrasound examination was repeated in 4 locations; static clinic location, mobile ambulance, airplane, and helicopter. Images were reviewed by a sonographer, radiologist, and emergency medicine physician using the B‐QUIET method and underwent statistical analysis using generalizability theory for reliability of the assessments using the tool.

Results

The B‐QUIET method showed high reliability of most subscale items. Approximately two‐thirds of the reviewed images had complete inter‐rater reliability on 90% of the items. There was relatively low inter‐rater reliability for the Identification/ Orientation subscale items. The inter‐rater reliability κ value was calculated as 0.676 overall for the method.

Conclusions

The need for a standardized method to evaluate the quality of an ultrasound image is well documented. The B‐QUIET method represents the first attempt to quantify the sonographer component of ultrasound images. Further reliability and validation studies of this method will be needed; however, it represents a tool for standardized ultrasound interpretation, ultrasound training, and institutional quality assessment.
Ultrasound Biosafety During Pregnancy: What Do Operators Know in the Developing World?
Authors: Akhtar Waseem , Arain Mubashir Aslam , Ali Arif , Manzar Nabeel , Sajjad Zafar , Memon Mukhtiar , Memon Wasim , Ahmad Nadeem
Published: January 2017

Objectives

The purpose of this study was to evaluate the knowledge and attitudes of ultrasound users toward safety aspects during routine obstetric examinations.

Methods

A self‐administered questionnaire was given to all registered participants of the 10th Annual International Radiological Conference in Karachi, Pakistan.

Results

A total of 306 participants completed the questionnaire (response rate, 70%), including 170 consultant radiologists (55%), 90 radiology residents (30%), 31 sonographers (10%), and 15 others (5%). The mean sonography experience of the end users ± SD was 5.1 ± 5 years. Around half of the participants (45.5%) reported that there should be limitations on the use of ultrasound during low‐risk pregnancy. Overall, safety knowledge was inadequate among the participants. However, those who were concerned about limitations on the use of ultrasound during pregnancy were 2.5 times more likely to be familiar with the mechanical index (P < .001) and 1.8 times more likely to be familiar with the thermal index (P < .001).

Conclusions

Increased training for professionals on safety issues of ultrasound procedures during pregnancy is needed. Furthermore, the concept of the absolute safety of ultrasound procedures without knowledge of safety parameters such as the mechanical and thermal indices needs to be changed, and more clarity is required when defining parameters under which the procedures can be safely performed.
Placental Thickness in the Second Trimester
Authors: Lee Anna J. , Bethune Michael , Hiscock Richard J.
Published: January 2017

Objectives

We sought to determine the normal sonographically measured placental thickness in millimeters at the second‐trimester scan (18 weeks to 22 weeks 6 days) and determine whether the measurement should be adjusted for gestational age and the placental site.

Methods

We conducted a cross‐sectional observational pilot study involving 114 consecutive patients with singleton pregnancies presenting for routine second‐trimester sonography between 18 weeks and 22 weeks 6 days.

Results

The unadjusted overall mean placental thickness was 24.6 (SD, 7.29) mm. The placental thickness was normally distributed. On multivariable analysis, the predicted mean thickness was 6.6 mm (95% confidence interval, 4.4 to 8.8 mm; P < .001) less in anterior compared to posterior or fundal placentas and increased by 0.6 mm (95% confidence interval, −0.5 to 1.7 mm; P = .27) for each week increase in gestation after 18 weeks

Conclusions

The placental position and possibly gestational age need to be considered when determining placental thickness. Anterior placentas are approximately 7 mm thinner than posterior or fundal placentas. Anterior placentas of greater than 33 mm and posterior placentas of greater than 40 mm should be considered abnormally thick.
Generation of 3‐D hydrostratigraphic zones from dense airborne electromagnetic data to assess groundwater model prediction error
Authors: Christensen N. K. , Minsley B. J. , Christensen S.
Published: January 2017

We present a new methodology to combine spatially dense high‐resolution airborne electromagnetic (AEM) data and sparse borehole information to construct multiple plausible geological structures using a stochastic approach. The method developed allows for quantification of the performance of groundwater models built from different geological realizations of structure. Multiple structural realizations are generated using geostatistical Monte Carlo simulations that treat sparse borehole lithological observations as hard data and dense geophysically derived structural probabilities as soft data. Each structural model is used to define 3‐D hydrostratigraphical zones of a groundwater model, and the hydraulic parameter values of the zones are estimated by using nonlinear regression to fit hydrological data (hydraulic head and river discharge measurements). Use of the methodology is demonstrated for a synthetic domain having structures of categorical deposits consisting of sand, silt, or clay. It is shown that using dense AEM data with the methodology can significantly improve the estimated accuracy of the sediment distribution as compared to when borehole data are used alone. It is also shown that this use of AEM data can improve the predictive capability of a calibrated groundwater model that uses the geological structures as zones. However, such structural models will always contain errors because even with dense AEM data it is not possible to perfectly resolve the structures of a groundwater system. It is shown that when using such erroneous structures in a groundwater model, they can lead to biased parameter estimates and biased model predictions, therefore impairing the model's predictive capability.
Transverse and longitudinal mixing in real emergent vegetation at low velocities
Authors: Sonnenwald F. , Hart J. R. , West P. , Stovin V. R. , Guymer I.
Published: January 2017

Understanding solute mixing within real vegetation is critical to predicting and evaluating the performance of engineered natural systems such as storm water ponds. For the first time, mixing has been quantified through simultaneous laboratory measurements of transverse and longitudinal dispersion within artificial and real emergent vegetation. Dispersion coefficients derived from a routing solution to the 2‐D Advection Dispersion Equation (ADE) are presented that compare the effects of vegetation type (artificial, Typha latifolia or Carex acutiformis) and growth season (winter or summer). The new experimental dispersion coefficients are plotted with the experimental values from other studies and used to review existing mixing models for emergent vegetation. The existing mixing models fail to predict the observed mixing within natural vegetation, particularly for transverse dispersion, reflecting the complexity of processes associated with the heterogeneous nature of real vegetation. Observed stem diameter distributions are utilized to highlight the sensitivity of existing models to this key length‐scale descriptor, leading to a recommendation that future models intended for application to real vegetation should be based on probabilistic descriptions of both stem diameters and stem spacings.
Overexpression of heparanase attenuated TGF‐β‐stimulated signaling in tumor cells
Authors: Batool Tahira , Fang Jianping , Barash Uri , Moustakas Aristidis , Vlodavsky Israel , Li Jin‐Ping
Published: January 2017

Heparan sulfate (HS) mediates the activity of various growth factors including TGF‐β. Heparanase is an endo‐glucuronidase that specifically cleaves and modifies HS structure. In this study, we examined the effect of heparanase expression on TGF‐β1‐dependent signaling activities. We found that overexpression of heparanase in human tumor cells (i.e., Fadu pharyngeal carcinoma, MCF7 breast carcinoma) attenuated TGF‐β1‐stimulated Smad phosphorylation and led to a slower cell proliferation. TGF‐β1‐stimulated Akt and Erk phosphorylation was also affected in the heparanase overexpression cells. This effect involved the enzymatic activity of heparanase, as overexpression of mutant inactive heparanase did not affect TGF‐β1 signaling activity. Analysis of HS isolated from Fadu cells revealed an increase in sulfation of the HS that had a rapid turnover in cells overexpressing heparanase. It appears that the structural alterations of HS affect the ability of TGF‐β1 to signal via its receptors and elicit a growth response. Given that heparanase expression promotes tumor growth in most cancers, this finding highlights a crosstalk between heparanase, HS, and TGF‐β1 function in tumorigenesis.
Role of Interfaces on Multi‐length Scale Wear Mechanics of TaC‐based Composites
Authors: Nisar Ambreen , Balani Kantesh
Published: January 2017

In the current work, contact‐mechanics at different length scale is utilized to correlate damage accumulation in TaC‐based composites. Upon synergistic reinforcement with silicon carbide (SiC) and carbon nanotubes (CNTs), TaC has shown to reduce the wear rate from 10.5 × 10−7 to 4.1 × 10−7 mm3 N−1 m−1 upon fretting (micro‐wear) and from 8.0 to 2.7 mm3 N−1 m−1 upon micro‐scratching (meso‐wear). Enhancement in the fracture toughness from 2.9 to 10.7 MPam1/2 with reinforcement is attributed to the processing induced defects (such as dislocation, stacking fault etc.) in SiC and strong interfacial bonding of CNTs with TaC, as revealed by transmission electron microscopy (TEM). Delineation of the synergistic contribution of SiC and CNT reinforcement in TaC establishes the wear mechanism to be abrasion (via fretting test), brittle tensile cracking, and fracture (via micro‐scratch test).
Significance of recurrence of minimal residual disease detected by multi‐parameter flow cytometry in patients with acute lymphoblastic leukemia in morphological remission
Authors: Pemmaraju Naveen , Kantarjian Hagop , Jorgensen Jeffrey L. , Jabbour Elias , Jain Nitin , Thomas Deborah , O'Brien Susan , Wang Xuemei , Huang Xuelin , Wang Sa A. , Konopleva Marina , Konoplev Sergej , Kadia Tapan , Garris Rebecca , Pierce Sherry , Garcia‐Manero Guillermo , Cortes Jorge , Ravandi Farhad
Published: January 2017

We sought to determine the significance of minimal residual disease (MRD) relapse in patients with ALL after achieving MRD negative status following induction and consolidation therapy. Between January 2003 and September 2014, 647 newly diagnosed patients were treated [HyperCVAD‐based (n = 531); Augmented BFM (n = 116)]. Six hundred and one (93%) achieved complete remission (CR), and 546 (91%) became MRD negative. Fifty‐five patients [HyperCVAD‐based (n = 49); Augmented BFM (n = 6)] developed recurrence of MRD while still in morphological CR and are the subjects of this study. MRD was assessed by 6‐color (4‐color prior to 2009) multi‐parameter flow cytometry (MFC) at CR and multiple time points thereafter. Their median age was 44 years (range, 18–72 years), median WBC at initial presentation was 7.3 K/µL−1 (range, 0.6–303.8 K/µL−1) and median bone marrow blast percentage 88% (range, 26–98%). The median time to MRD relapse was 14 months (range 3–58 months). Forty‐four (80%) patients subsequently developed morphological relapse after median of 3 months (range, <1–33 months) from detection of MRD recurrence. Treatments received after MRD positivity and prior to morphological relapse: 16 continued maintenance chemotherapy; 15 received late intensification; 9 allogeneic stem cell transplant, 9 changed chemotherapy, 6 no further therapy. Only six remain alive and in CR1 and nine are alive after morphological relapse. MRD relapse detected by MFC at any time after achieving CR is associated with a high risk for morphological relapse. SCT can result in long‐term remission in some patients. Prospective studies of long‐term MRD assessments, together with less toxic treatment strategies to eradicate MRD, are warranted.
The combination of cyclosporine and mycophenolate mofetil is less effective than cyclosporine and methotrexate in the prevention of acute graft‐versus host disease after stem‐cell transplantation from unrelated donors
Authors: Yerushalmi Ronit , Shem‐Tov Noga , Danylesko Ivetta , Shouval Roni , Nagler Arnon , Shimoni Avichai
Published: January 2017

Acute graft‐versus‐host disease (GVHD) is the major treatment‐related complication after stem‐cell transplantation (SCT) from unrelated‐donors. Several GVHD prophylaxis regimens have been explored, but no regimen has shown superiority. We analyzed transplantation outcomes in 472 consecutive unrelated‐donor SCT recipients, using cyclosporine/methotrexate (MTX, n = 314) or cyclosporine/mycophenolate‐mofetil (MMF, n = 158) for GVHD prophylaxis. Neutrophil engraftment was faster after MMF, days 11 and 14, respectively (P = .001). Acute GVHD grade II‐IV and III‐IV occurred in 47% and 28% after MMF compared to 27% and 12% after MTX, respectively (P < .001). Nonrelapse mortality (NRM) was 44% and 24%, respectively (P < .001). Death associated with GVHD occurred in 25% and 8% (P < .0001), while other NRM causes occurred in 19% and 16%, respectively (P = .39). Relapse mortality was similar. Overall survival was better after MTX, 40% and 29%, respectively (P = .006). However, this difference had only borderline significance when adjusting for differences in patient characteristics (HR, 1.3, P = .08). To minimize potential selection bias we analyzed outcomes on the basis of an intention‐to‐treat like analysis. During the years 2008‐2009, the leading GVHD prophylaxis regimen for unrelated‐donor SCT included MMF (89% of transplants). During the other periods, MTX was used predominantly (82% of transplants). The two periods were otherwise well‐matched. Acute GVHD occurred more often in 2008‐2009. Death associated with GVHD occurred more often, while other NRM causes occurred less often resulting in similar NRM and overall survival. In conclusion, cyclosporine/MMF is associated with faster engraftment and possibly with less organ toxicity than cyclosporine/MTX. However, it is associated with increased rates of acute GVHD and GVHD‐associated deaths.
IKAROS expression in distinct bone marrow cell populations as a candidate biomarker for outcome with lenalidomide‐dexamethasone therapy in multiple myeloma
Authors: Bolomsky Arnold , Hübl Wolfgang , Spada Stefano , Müldür Ercan , Schlangen Karin , Heintel Daniel , Rocci Alberto , Weißmann Adalbert , Fritz Veronique , Willheim Martin , Zojer Niklas , Palumbo Antonio , Ludwig Heinz
Published: January 2017

Immunomodulatory drugs (IMiDs) are a cornerstone in the treatment of multiple myeloma (MM), but specific markers to predict outcome are still missing. Recent work pointed to a prognostic role for IMiD target genes (e.g. CRBN). Moreover, indirect activity of IMiDs on immune cells correlated with outcome, raising the possibility that cell populations in the bone marrow (BM) microenvironment could serve as biomarkers. We therefore analysed gene expression levels of six IMiD target genes in whole BM samples of 44 myeloma patients treated with lenalidomide‐dexamethasone. Expression of CRBN (R = 0.30, P = .05), IKZF1 (R = 0.31, P = .04), IRF4 (R = 0.38, P = .01), MCT‐1 (R = 0.30, P = .05), and CD147 (R = 0.38, P = .01), but not IKZF3 (R = −0.15, P = .34), was significantly associated with response. Interestingly, IKZF1 expression was elevated in BM environmental cells and thus selected for further investigation by multicolor flow cytometry. High IKAROS protein levels in total BM mononuclear cells (median OS 83.4 vs. 32.2 months, P = .02), CD19+ B cells (median OS 71.1 vs. 32.2 months, P = .05), CD3+ CD8+ T cells (median OS 83.4 vs 19.0 months, P = .008) as well as monocytes (median OS 53.9 vs 18.0 months, P = .009) were associated with superior overall survival (OS). In contrast, IKAROS protein expression in MM cells was not predictive for OS. Our data therefore corroborate the central role of immune cells for the clinical activity of IMiDs and built the groundwork for prospective analysis of IKAROS protein levels in distinct cell populations as a potential biomarker for IMiD based therapies.
Impact of FAB classification on predicting outcome in acute myeloid leukemia, not otherwise specified, patients undergoing allogeneic stem cell transplantation in CR1: An analysis of 1690 patients from the acute leukemia working party of EBMT
Authors: Canaani Jonathan , Beohou Eric , Labopin Myriam , Socié Gerard , Huynh Anne , Volin Liisa , Cornelissen Jan , Milpied Noel , Gedde‐Dahl Tobias , Deconinck Eric , Fegueux Nathalie , Blaise Didier , Mohty Mohamad , Nagler Arnon
Published: January 2017

The French, American, and British (FAB) classification system for acute myeloid leukemia (AML) is extensively used and is incorporated into the AML, not otherwise specified (NOS) category in the 2016 WHO edition of myeloid neoplasm classification. While recent data proposes that FAB classification does not provide additional prognostic information for patients for whom NPM1 status is available, it is unknown whether FAB still retains a current prognostic role in predicting outcome of AML patients undergoing allogeneic stem cell transplantation. Using the European Society of Blood and Bone Marrow Transplantation registry we analyzed outcome of 1690 patients transplanted in CR1 to determine if FAB classification provides additional prognostic value. Multivariate analysis revealed that M6/M7 patients had decreased leukemia free survival (hazard ratio (HR) of 1.41, 95% confidence interval (CI), 1.01–1.99; P = .046) in addition to increased nonrelapse mortality (NRM) rates (HR, 1.79; 95% CI, 1.06–3.01; P = .028) compared with other FAB types. In the NPM1wt AML, NOS cohort, FAB M6/M7 was also associated with increased NRM (HR, 2.17; 95% CI, 1.14–4.16; P = .019). Finally, in FLT3‐ITD+ patients, multivariate analyses revealed that specific FAB types were tightly associated with adverse outcome. In conclusion, FAB classification may predict outcome following transplantation in AML, NOS patients.
Unexplained isolated hyperferritinemia without iron overload
Authors: Ravasi Giulia , Pelucchi Sara , Mariani Raffaella , Casati Marco , Greni Federico , Arosio Cristina , Pelloni Irene , Majore Silvia , Santambrogio Paolo , Levi Sonia , Piperno Alberto
Published: January 2017

Although hyperferritinemia may be reflective of elevated total body iron stores, there are conditions in which ferritin levels are disproportionately elevated relative to iron status. Autosomal dominant forms of hyperferritinemia due to mutations in the L−ferritin IRE or in A helix of L−ferritin gene have been described, however cases of isolated hyperferritinemia still remain unsolved. We describe 12 Italian subjects with unexplained isolated hyperferritinemia (UIH). Four probands have affected siblings, but no affected parents or offspring. Sequencing analyses did not identify casual mutations in ferritin gene or IRE regions. These patients had normal levels of intracellular ferritin protein and mRNA in peripheral blood cells excluding pathological ferritin production at transcriptional and post‐transcriptional level. In contrast with individuals with benign hyperferritinemia caused by mutations affecting the ferritin A helix, low rather than high glycosylation of serum ferritin was observed in our UIH subjects compared with controls. These findings suggest that subjects with UIH have a previously undescribed form of hyperferritinemia possibly attributable to increased cellular ferritin secretion and/or decreased serum ferritin clearance. The cause remains to be defined and we can only speculate the existence of mutations in gene/s not directly implicated in iron metabolism that could affect ferritin turnover including ferritin secretion.
CELSR2, encoding a planar cell polarity protein, is a putative gene in Joubert syndrome with cortical heterotopia, microophthalmia, and growth hormone deficiency
Authors: Vilboux Thierry , Malicdan May Christine V. , Roney Joseph C. , Cullinane Andrew R. , Stephen Joshi , Yildirimli Deniz , Bryant Joy , Fischer Roxanne , Vemulapalli Meghana , Mullikin James C. ,   NISC Comparative Sequencing Program, Steinbach Peter J. , Gahl William A. , Gunay‐Aygun Meral
Published: January 2017

Joubert syndrome is a ciliopathy characterized by a specific constellation of central nervous system malformations that result in the pathognomonic “molar tooth sign” on imaging. More than 27 genes are associated with Joubert syndrome, but some patients do not have mutations in any of these genes. Celsr1, Celsr2, and Celsr3 are the mammalian orthologues of the drosophila planar cell polarity protein, flamingo; they play important roles in neural development, including axon guidance, neuronal migration, and cilium polarity. Here, we report bi‐allelic mutations in CELSR2 in a Joubert patient with cortical heterotopia, microophthalmia, and growth hormone deficiency. © 2017 Wiley Periodicals, Inc.
0D/2D Heterojunctions of Vanadate Quantum Dots/Graphitic Carbon Nitride Nanosheets for Enhanced Visible‐Light‐Driven Photocatalysis
Authors: Ye Meng‐Yang , Zhao Zhi‐Hao , Hu Zhuo‐Feng , Liu Le‐Quan , Ji Hui‐Ming , Shen Zhu‐Rui , Ma Tian‐Yi
Published: January 2017

0D/2D heterojunctions, especially quantum dots (QDs)/nanosheets (NSs) have attracted significant attention for use of photoexcited electrons/holes due to their high charge mobility. Herein, unprecedent heterojunctions of vanadate (AgVO3, BiVO4, InVO4 and CuV2O6) QDs/graphitic carbon nitride (g‐C3N4) NSs exhibiting multiple unique advances beyond traditional 0D/2D composites have been developed. The photoactive contribution, up‐conversion absorption, and nitrogen coordinating sites of g‐C3N4 NSs, highly dispersed vanadate nanocrystals, as well as the strong coupling and band alignment between them lead to superior visible‐light‐driven photoelectrochemical (PEC) and photocatalytic performance, competing with the best reported photocatalysts. This work is expected to provide a new concept to construct multifunctional 0D/2D nanocomposites for a large variety of opto‐electronic applications, not limited in photocatalysis.
Temporal and spatial regulation of mRNA export: Single particle RNA‐imaging provides new tools and insights
Authors: Heinrich Stephanie , Derrer Carina Patrizia , Lari Azra , Weis Karsten , Montpetit Ben
Published: January 2017

The transport of messenger RNAs (mRNAs) from the nucleus to cytoplasm is an essential step in the gene expression program of all eukaryotes. Recent technological advances in the areas of RNA‐labeling, microscopy, and sequencing are leading to novel insights about mRNA biogenesis and export. This includes quantitative single molecule imaging (SMI) of RNA molecules in live cells, which is providing knowledge of the spatial and temporal dynamics of the export process. As this information becomes available, it leads to new questions, the reinterpretation of previous findings, and revised models of mRNA export. In this review, we will briefly highlight some of these recent findings and discuss how live cell SMI approaches may be used to further our current understanding of mRNA export and gene expression.
Characterization of isochlorogenic acid A metabolites in rats using high‐performance liquid chromatography/quadrupole time‐of‐flight mass spectrometry
Authors: Wang Jing , Cao Guoxiu , Wang Hong , Ye Hui , Zhong Yunxi , Wang Guangji , Hao Haiping
Published: January 2017

Isochlorogenic acid A is widely present in fruits, vegetables and herbal medicines, and is characterized by anti‐inflammatory, hepatoprotective and antiviral properties. However, little is known about its metabolic fate and pharmacokinetic properties. This study is thus designed to investigate the metabolic fate of isochlorogenic acid A. An analytical method based on high‐performance liquid chromatography/quadrupole time‐of‐flight mass spectrometry (HPLC/Q‐TOF MS) was established to characterize the metabolites of isochlorogenic acid A in the plasma, urine and feces of rats. A total of 32 metabolites were identified. The metabolic pathways mainly include hydrolyzation, dehydroxylation, hydrogenation and conjugation with methyl, glucuronic acid, glycine, sulfate, glutathione and cysteine. Moreover, the pharmacokinetic profiles of all the circulating metabolites were investigated. M11 resulting from hydrolyzation, dehydroxylation and hydrogenation was the dominant circulating metabolite after the intragastric administration of isochlorogenic acid A. The results obtained will be useful for further study of elucidating potential bioactive metabolites which can provide better explanation of the pharmacological and/or toxicological effects of this compound.
Oxygen Atom Transfer Using an Iron(IV)‐Oxo Embedded in a Tetracyclic N‐Heterocyclic Carbene System: How Does the Reactivity Compare to Cytochrome P450 Compound I?
Authors: Cantú Reinhard Fabián G. , de Visser Sam P.
Published: January 2017

N‐Heterocyclic carbenes (NHC) are commonly featured as ligands in transition metal catalysis. Recently, a cyclic system containing four NHC groups with a central iron atom was synthesized and its iron(IV)‐oxo species, [FeIV(O)(cNHC4)]2+, was characterized. This tetracyclic NHC ligand system may give the iron(IV)‐oxo species unique catalytic properties as compared to traditional non‐heme and heme iron ligand systems. Therefore, we performed a computational study on the structure and reactivity of the [FeIV(O)(cNHC4)]2+ complex in substrate hydroxylation and epoxidation reactions. The reactivity patterns are compared with cytochrome P450 Compound I and non‐heme iron(IV)‐oxo models and it is shown that the [FeIV(O)(cNHC4)]2+ system is an effective oxidant with oxidative power analogous to P450 Compound I. Unfortunately, in polar solvents, a solvent molecule will bind to the sixth ligand position and decrease the catalytic activity of the oxidant. A molecular orbital and valence bond analysis provides insight into the origin of the reactivity differences and makes predictions of how to further exploit these systems in chemical catalysis.
Isolation of a Reactive Cyclopropane Intermediate via a Unique Catalyst‐Free Spontaneous Cyclopropanation Step at 0 °C
Authors: Braunschweig Holger , Dewhurst Rian D. , Ewing William C. , Kuntze‐Fechner Maximilian W. , Schäfer Marius
Published: January 2017

A remarkably mild, catalyst‐free cyclopropanation reaction is confirmed by low‐temperature isolation of a fused bicyclic cyclopropane intermediate. This intermediate is one of two that were isolated and fully characterised in a three‐step temperature‐controllable reaction cascade.
Sprayable, Large‐Area Metal–Organic Framework Films and Membranes of Varying Thickness
Authors: Hurrle Silvana , Friebe Sebastian , Wohlgemuth Jonas , Wöll Christof , Caro Jürgen , Heinke Lars
Published: January 2017

Despite their huge potential for efficient molecular separation, the fabrication of membranes from metal–organic frameworks (MOFs) remains a major challenge. The powders obtained by the conventional solvothermal MOF syntheses are difficult to process, and as a result the fabrication of well‐performing, large‐area MOF‐based membranes is still awaiting success. The deposition of MOF thin films suited for membrane applications is demonstrated by employing a step‐by‐step spray method. This method can be scaled up to obtain industrially relevant membrane areas and a continuous process is also possible. The performance of sprayed HKUST‐1‐based membranes by the separation of a binary H2/CO2 mixture is also demonstrated. Furthermore, this approach enables the control of the MOF film thickness, and thus controlling the permeance and the selectivity of the membrane.
Innocent But Deadly: Nontoxic Organoiridium Catalysts Promote Selective Cancer Cell Death
Authors: Yang Lu , Bose Sohini , Ngo Anh H. , Do Loi H.
Published: January 2017

We demonstrate that nontoxic organoiridum complexes can selectively chemosensitize cancer cells toward platinum antiproliferative agents. Treatment of human cancer cells (breast, colon, eye/retina, head/neck, lung, ovary, and blood) with the iridium chemosensitizers led to lowering of the 50 % growth inhibition concentration (IC50) of the Pt drug carboplatin by up to ∼30–50 %. Interestingly, non‐cancer cells were mostly resistant to the chemosensitizing effects of the iridium complexes. Cell culture studies indicate that cancer cells that were administered with Ir show significantly higher reactive oxygen species concentrations as well as NAD+/NADH ratios (oxidized vs. reduced nicotinamide adenine dinucleotide) than Ir‐treated non‐cancer cells. These biochemical changes are consistent with a catalytic transfer hydrogenation cycle involving the formation of iridium‐hydride species from the reaction of the iridium catalysts with NADH and subsequent oxidation in air to generate hydrogen peroxide.