bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of multiple ACVRL1 mutations in patients with pulmonary arterial hypertension by targeted exome capture
Authors: Piao Chunmei , Zhu Yan , Zhang Chen , Xi Xin , Liu Xuxia , Zheng Shuai , Li Xiaoyan , Guo Jun , Jia Lixin , Nakanishi Toshio , Cai Tao , Gu Hong , Du Jie
Published: June 2016

Pulmonary artery hypertension (PAH) is characterized as sustained elevation of pressure in the pulmonary vascular system that is attributable to a variety of causes. More than a dozen genes have previously been proposed as being associated with PAH. To examine potential mutations of these genes in patients with PAH, we developed a targeted exome kit containing 22 PAH-associated genes for genetic screens of 80 unrelated patients with PAH. As a result, we identified 16 different mutations in the BMPR2 gene and four different mutations in ACVRL1, the gene for activin receptor-like kinase-1 (ACVRL1). However, no deleterious mutations were found in the remaining 20 genes. In the present study, we provided detailed characterization of the ACVRL1 mutations in four pedigrees, including two novel missense mutations (c.676G>A, p.V226M; c.955G>C, p.G319R) and two recurrent mutations (c.1231C>T, p.R411W; c.1450C>T, p.R484W). Furthermore, we showed that markedly reduced Smad1/5 phosphorylation levels and reduced activities of luciferase reporters in each of the four ACVRL1 mutant-transfected NIH-3T3 cells. Therefore, our findings demonstrated that missense mutations of ACVRL1 identified in the present study significantly affected the bone morphogenetic protein 9 (BMP-9) pathway, implicating PAH pathogenesis. Detailed genotype–phenotype correlation analysis revealed initial symptoms of hereditary haemorrhagic telangiectasia (HHT) in some of the patients, suggesting the importance of sequencing molecular markers for early identification and intervention of individuals at risk for PAH and potential HHT. We developed a customized exome sequencing system to identify mutations in these PAH-associated genes, and found two novel missense mutations and two recurrent mutations in the ACVRL1 gene in four unrelated Chinese families; we also determined hypomorphic alleles using functional studies.
Das Leberfasten nach Dr. Worm
Authors: Walle Hardy
Published: June 2016

Das Leberfasten nach Dr. Worm fördert die Entfettung der Leber. Davon profitieren insbesondere
übergewichtige und adipöse Patienten mit diabetischer Stoffwechsellage und erhöhtem Fatty Liver Index.
Der Beitrag zeigt die Entwicklung des Konzepts und wie Leberfasten praktisch umgesetzt wird.
Textual dynamism as a heuristic for a delicate semantic description of ellipsis patterns
Authors: Clarke Ben
Published: June 2016

This paper puts the case that viewing text dynamically can be valuable in the practice of semantic description. Using, as its case study, the statistically significant occurrence of Subject ellipsis across consecutive clauses in a corpus of newspaper football reports, the paper demonstrates a systematic difference between the lexicogrammatical characteristics of clauses containing such patterned use of ellipsis and the clauses of their surrounding co-text. The lexicogrammatical features in question, which are analysed in detail in the paper, are: clause length in words, number of clause elements, amount of syntactic embedding, and patterns in Hallidayan transitivity process-types. Given the nature of these lexicogrammatical features, the argument is made that Subject ellipsis across consecutive clauses can iconically express an increase in pace – something only observable when the text is viewed dynamically.
Dynamicity in the construal of complex events in Irish English and Modern Irish
Authors: Nolan Brian
Published: June 2016

In this study we take an ‘above the clause’ perspective on the conceptualisation of complex events of Irish English and Modern Irish within a functional Role and Reference Grammar perspective, using corpus based data. Functional models of language generally assume some layered structure of the clause, the noun phrase and the word. (Nolan 2012a, 2012b; Van Valin 2005). While excellent work has heretofore been achieved at clause level, the description of important linguistic phenomena above the clause has often been somewhat neglected. In this regard, a central part of the grammar of every human language is the encoding of events and their participants in a clause. This motivates an ‘above the clause’ perspective to characterise the balance between uniformity of encoding and variability in encoding within and across languages. In the functional-cognitive paradigm, form and meaning are not separated into self-contained components. Instead, syntactic structures of varying degrees of complexity and abstraction are paired with their corresponding semantic structures. We argue that the interaction of semantic relations with the hierarchy of clausal linkage is at the strongest pole with the semantic relations covering phase and modifying subevents. We also argue that light verb constructions are formed pre-syntactically in the lexicon using and defend this by applying certain criteria as a diagnostic. The function of light verbs in these constructions is to modulate the realisation of event and sub-event semantics into syntax. We provide evidence of the dynamicity in conceptualising a complex event, considered as complex predication across constructions, in Irish English and Modern Irish.
Making sense of immigration processes
Authors: Vall Berta , Botella Lluís
Published: June 2016

This article analyses the narrative disruption processes and quality of life of adolescent immigrants in Spain. Furthermore, it
also provides a new methodological approach to assess meta-subjective and narrative quality of life. Participants were 30
adolescents (15 immigrant and 15 autochthons) selected form a sample of 884 adolescents (from which 204 were immigrants). Data
regarding quality of life was collected applying the Friendship Quality Scale and the Vancouver Index of Acculturation to all the
participants (n = 884). According to the punctuation of the questionnaires a subsample was chosen, the Biographical Grid was
applied to 30 participants; the immigrants group was also asked to write a text. Results indicate that both perceived quality of
life and self-esteem of immigrant’s group are lower than the autochthons’ while narrative disruption is higher. A deeply
explanation about some of the causes of these results is provided by the narratives’ analysis.
Autobiographical narrative
Authors: Nadeem Nahla
Published: June 2016

Autobiographical narrative is “a selective reconstruction of the ruminative past” and an account that serves to explain, for the self and others, how the person came to be whom s/he is at present (McAdams, 2011) and thus can provide a rich source of data for sociolinguistic analysis and a speculation in the studies of identity construction processes and narrative combined. The present paper aims to investigate how narrators — through the subtle exploitation of tense patterns manage to reflect an integrated vision of their identity and evaluate these identity construction processes. To do this, I will a) develop a model of identity construction and evaluation processes in autobiographical narrative that is based upon the writings of McAdams (1985 & 2011) and Luyckx et al. (2011)’s identity model; b) closely examine how narrators subtly use tense patterns to combine the acts of narrative with moments of reflection and finally, c) relate these linguistic features of autobiographical narrative to the process of identity construction and evaluation. For this purpose, I use as data two speeches by two females each representing a different socio-cultural background: an ex-female slave from pre-civil war America and a Lebanese author in which both reflect upon their ruminative past and how they became who they are at present. The model and the analysis give empirical evidence that a close investigation of tense patterns in autobiographical narratives is an effective analytical and explanatory tool that shows how narrators reflect their evolving self, display, and evaluate identity on its individual, relational and collective levels and make a stance on social constructs such as race and gender.
Chirality in metals: An asymmetrical journey among advanced functional materials
Authors: Riva S.
Published: June 2016

Chirality is a property of matter which manifests at any length scale and can equally appear as quantum phenomena and in three-dimensional macroscopic structures. However, while chirality can be easily achieved by removing the inversion symmetry operation in hexagonal or tetragonal metal structures, chirality in metals is an unusual and barely developed phenomenon. Nevertheless, chirality can greatly alter mechanical and functional features of materials, making them suitable for catalysis, optics, electromagnetism, thermoelectricity and superconductivity; properties strictly dependent on the anisotropy of the crystal and on the direction of the applied force. This review aims to extend the definition of chirality to describe nanoclusters, metal surfaces and crystals and to provide an interdisciplinary overview on how symmetry can affect their properties.

This review was submitted as part of the 2016 Materials Literature Review Prize of the Institute of Materials, Minerals and Mining run by the Editorial Board of MST. Sponsorship of the prize by TWI Ltd is gratefully acknowledged.
A noncatalytic function of the topoisomerase II CTD in Aurora B recruitment to inner centromeres during mitosis
Authors: Edgerton Heather , Johansson Marnie , Keifenheim Daniel , Mukherjee Soumya , Chacón Jeremy M. , Bachant Jeff , Gardner Melissa K. , Clarke Duncan J.
Published: June 2016

Faithful chromosome segregation depends on the precise timing of chromatid separation, which is enforced by checkpoint signals generated at kinetochores. Here, we provide evidence that the C-terminal domain (CTD) of DNA topoisomerase IIα (Topo II) provides a novel function at inner centromeres of kinetochores in mitosis. We find that the yeast CTD is required for recruitment of the tension checkpoint kinase Ipl1/Aurora B to inner centromeres in metaphase but is not required in interphase. Conserved CTD SUMOylation sites are required for Ipl1 recruitment. This inner-centromere CTD function is distinct from the catalytic activity of Topo II. Genetic and biochemical evidence suggests that Topo II recruits Ipl1 via the Haspin–histone H3 threonine 3 phosphorylation pathway. Finally, Topo II and Sgo1 are equally important for Ipl1 recruitment to inner centromeres. This indicates H3 T3-Phos/H2A T120-Phos is a universal epigenetic signature that defines the eukaryotic inner centromere and provides the binding site for Ipl1/Aurora B.
A Rab3a-dependent complex essential for lysosome positioning and plasma membrane repair
Authors: Encarnação Marisa , Espada Lília , Escrevente Cristina , Mateus Denisa , Ramalho José , Michelet Xavier , Santarino Inês , Hsu Victor W. , Brenner Michael B. , Barral Duarte C. , Vieira Otília V.
Published: June 2016

Lysosome exocytosis plays a major role in resealing plasma membrane (PM) disruptions. This process involves two sequential steps. First, lysosomes are recruited to the periphery of the cell and then fuse with the damaged PM. However, the trafficking molecular machinery involved in lysosome exocytosis and PM repair (PMR) is poorly understood. We performed a systematic screen of the human Rab family to identify Rabs required for lysosome exocytosis and PMR. Rab3a, which partially localizes to peripheral lysosomes, was one of the most robust hits. Silencing of Rab3a or its effector, synaptotagmin-like protein 4a (Slp4-a), leads to the collapse of lysosomes to the perinuclear region and inhibition of PMR. Importantly, we have also identified a new Rab3 effector, nonmuscle myosin heavy chain IIA, as part of the complex formed by Rab3a and Slp4-a that is responsible for lysosome positioning at the cell periphery and lysosome exocytosis.
Limited ER quality control for GPI-anchored proteins
Authors: Sikorska Natalia , Lemus Leticia , Aguilera-Romero Auxiliadora , Manzano-Lopez Javier , Riezman Howard , Muñiz Manuel , Goder Veit
Published: June 2016

Endoplasmic reticulum (ER) quality control mechanisms target terminally misfolded proteins for ER-associated degradation (ERAD). Misfolded glycophosphatidylinositol-anchored proteins (GPI-APs) are, however, generally poor ERAD substrates and are targeted mainly to the vacuole/lysosome for degradation, leading to predictions that a GPI anchor sterically obstructs ERAD. Here we analyzed the degradation of the misfolded GPI-AP Gas1* in yeast. We could efficiently route Gas1* to Hrd1-dependent ERAD and provide evidence that it contains a GPI anchor, ruling out that a GPI anchor obstructs ERAD. Instead, we show that the normally decreased susceptibility of Gas1* to ERAD is caused by canonical remodeling of its GPI anchor, which occurs in all GPI-APs and provides a protein-independent ER export signal. Thus, GPI anchor remodeling is independent of protein folding and leads to efficient ER export of even misfolded species. Our data imply that ER quality control is limited for the entire class of GPI-APs, many of them being clinically relevant.
Positioning the cleavage furrow: All you need is Rho
Authors: Liu Zairan , Weiner Orion D.
Published: June 2016

RhoA controls cleavage furrow formation during cell division, but whether RhoA suffices to orchestrate spatiotemporal dynamics of furrow formation is unknown. In this issue, Wagner and Glotzer (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201603025) show that RhoA activity can induce furrow formation in all cell cortex positions and cell cycle phases.
Claudine Kraft: A hunger for understanding
Authors: Jordan Shawn
Published: June 2016

Kraft’s work focuses on the mechanisms that regulate autophagy in response to nutrient availability.
Gut microbiota translocation to the pancreatic lymph nodes triggers NOD2 activation and contributes to T1D onset
Authors: Costa Frederico R.C. , Françozo Marcela C.S. , de Oliveira Gabriela G. , Ignacio Aline , Castoldi Angela , Zamboni Dario S. , Ramos Simone G. , Câmara Niels O. , de Zoete Marcel R. , Palm Noah W. , Flavell Richard A. , Silva João S. , Carlos Daniela
Published: June 2016

Type 1 diabetes (T1D) is an autoimmune disease that is triggered by both genetic and environmental factors, resulting in the destruction of pancreatic β cells. The disruption of the intestinal epithelial barrier and consequent escape of microbial products may be one of these environmental triggers. However, the immune receptors that are activated in this context remain elusive. We show here that during streptozotocin (STZ)-induced T1D, the nucleotide-binding oligomerization domain containing 2 (NOD2), but not NOD1, participates in the pathogenesis of the disease by inducing T helper 1 (Th1) and Th17 cells in the pancreatic LNs (PLNs) and pancreas. Additionally, STZ-injected wild-type (WT) diabetic mice displayed an altered gut microbiota compared with vehicle-injected WT mice, together with the translocation of bacteria to the PLNs. Interestingly, WT mice treated with broad-spectrum antibiotics (Abx) were fully protected from STZ-induced T1D, which correlated with the abrogation of bacterial translocation to the PLNs. Notably, when Abx-treated STZ-injected WT mice received the NOD2 ligand muramyl dipeptide, both hyperglycemia and the proinflammatory immune response were restored. Our results demonstrate that the recognition of bacterial products by NOD2 inside the PLNs contributes to T1D development, establishing a new putative target for intervention during the early stages of the disease.
Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome
Authors: Meuwissen Marije E.C. , Schot Rachel , Buta Sofija , Oudesluijs Grétel , Tinschert Sigrid , Speer Scott D. , Li Zhi , van Unen Leontine , Heijsman Daphne , Goldmann Tobias , Lequin Maarten H. , Kros Johan M. , Stam Wendy , Hermann Mark , Willemsen Rob , Brouwer Rutger W.W. , Van IJcken Wilfred F.J. , Martin-Fernandez Marta , de Coo Irenaeus , Dudink Jeroen , de Vries Femke A.T. , Bertoli Avella Aida , Prinz Marco , Crow Yanick J. , Verheijen Frans W. , Pellegrini Sandra , Bogunovic Dusan , Mancini Grazia M.S.
Published: June 2016

Pseudo-TORCH syndrome (PTS) is characterized by microcephaly, enlarged ventricles, cerebral calcification, and, occasionally, by systemic features at birth resembling the sequelae of congenital infection but in the absence of an infectious agent. Genetic defects resulting in activation of type 1 interferon (IFN) responses have been documented to cause Aicardi-Goutières syndrome, which is a cause of PTS. Ubiquitin-specific peptidase 18 (USP18) is a key negative regulator of type I IFN signaling. In this study, we identified loss-of-function recessive mutations of USP18 in five PTS patients from two unrelated families. Ex vivo brain autopsy material demonstrated innate immune inflammation with calcification and polymicrogyria. In vitro, patient fibroblasts displayed severely enhanced IFN-induced inflammation, which was completely rescued by lentiviral transduction of USP18. These findings add USP18 deficiency to the list of genetic disorders collectively termed type I interferonopathies. Moreover, USP18 deficiency represents the first genetic disorder of PTS caused by dysregulation of the response to type I IFNs. Therapeutically, this places USP18 as a promising target not only for genetic but also acquired IFN-mediated CNS disorders.
Targeting MTHFD2 in acute myeloid leukemia
Authors: Pikman Yana , Puissant Alexandre , Alexe Gabriela , Furman Andrew , Chen Liying M. , Frumm Stacey M. , Ross Linda , Fenouille Nina , Bassil Christopher F. , Lewis Caroline A. , Ramos Azucena , Gould Joshua , Stone Richard M. , DeAngelo Daniel J. , Galinsky Ilene , Clish Clary B. , Kung Andrew L. , Hemann Michael T. , Vander Heiden Matthew G. , Banerji Versha , Stegmaier Kimberly
Published: June 2016

Drugs targeting metabolism have formed the backbone of therapy for some cancers. We sought to identify new such targets in acute myeloid leukemia (AML). The one-carbon folate pathway, specifically methylenetetrahydrofolate dehydrogenase-cyclohydrolase 2 (MTHFD2), emerged as a top candidate in our analyses. MTHFD2 is the most differentially expressed metabolic enzyme in cancer versus normal cells. Knockdown of MTHFD2 in AML cells decreased growth, induced differentiation, and impaired colony formation in primary AML blasts. In human xenograft and MLL-AF9 mouse leukemia models, MTHFD2 suppression decreased leukemia burden and prolonged survival. Based upon primary patient AML data and functional genomic screening, we determined that FLT3-ITD is a biomarker of response to MTHFD2 suppression. Mechanistically, MYC regulates the expression of MTHFD2, and MTHFD2 knockdown suppresses the TCA cycle. This study supports the therapeutic targeting of MTHFD2 in AML.
Developmental regression of hyaloid vasculature is triggered by neurons
Authors: Yoshikawa Yusuke , Yamada Toru , Tai-Nagara Ikue , Okabe Keisuke , Kitagawa Yuko , Ema Masatsugu , Kubota Yoshiaki
Published: June 2016

Vascular development involves not only vascular growth, but also regression of transient or unnecessary vessels. Hyaloid vasculature is the temporary circulatory system in fetal eyes, which spontaneously degenerates when the retinal blood vessels start to grow. Failure of the hyaloid vessels to regress leads to disease in humans, persistent hyperplastic primary vitreous, which causes severe intraocular hemorrhage and impairs visual function. However, the mechanism underlying the endogenous program that mediates spontaneous regression of the hyaloid vessels is not well understood. In this study, we identify a robust switch triggering this program directed by neurons in mice. Marked up-regulation of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) occurs in retinal neurons just after birth via distal-multipotent-mesodermal enhancer, a hemangioblast-specific enhancer of VEGFR2. Genetic deletion of neuronal VEGFR2 interrupts this program, resulting in massive hyaloid vessels that persist even during late postnatal days. This abnormality is caused by excessive VEGF proteins in the vitreous cavity as a result of impairment in the neuronal sequestration of VEGF. Collectively, our data indicate that neurons trigger transition from the fetal to the postnatal circulatory systems in the retina.
Identification and treatment of the Staphylococcus aureus reservoir in vivo
Authors: Surewaard Bas G.J. , Deniset Justin F. , Zemp Franz J. , Amrein Matthias , Otto Michael , Conly John , Omri Abdelwahab , Yates Robin M. , Kubes Paul
Published: June 2016

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is reaching epidemic proportions causing morbidity, mortality, and chronic disease due to relapses, suggesting an intracellular reservoir. Using spinning-disk confocal intravital microscopy to track MRSA-GFP in vivo, we identified that within minutes after intravenous infection MRSA is primarily sequestered and killed by intravascular Kupffer cells (KCs) in the liver. However, a minority of the Staphylococci overcome the KC’s antimicrobial defenses. These bacteria survive and proliferate for many days within this intracellular niche, where they remain undetected by recruited neutrophils. Over time, the KCs lyse, releasing bacteria into the circulation, enabling dissemination to other organs such as the kidneys. Vancomycin, the antibiotic of choice to treat MRSA bacteremia, could not penetrate the KCs to eradicate intracellular MRSA. However, based on the intravascular location of these specific macrophages, we designed a liposomal formulation of vancomycin that is efficiently taken up by KCs and diminished the intracellular MRSA. Targeting the source of the reservoir dramatically protected the liver but also dissemination to other organs, and prevented mortality. This vancomycin formulation strategy could help treat patients with Staphylococcal bacteremia without a need for novel antibiotics by targeting the previously inaccessible intracellular reservoir in KCs.
Widespread Pain Among Youth With Sickle Cell Disease Hospitalized With Vasoocclusive Pain
Authors: Zempsky William T. , Wakefield Emily O. , Santanelli James P. , New Tamara , Smith-Whitley Kimberly , Casella James F. , Palermo Tonya M.
Published: June 2016

Objectives:

The purpose of this study was to describe the clinical phenotype of widespread pain (WSP) among youth with sickle cell disease (SCD) hospitalized with vasoocclusive pain.

Materials and Methods:

One hundred fifty-six youth with SCD, between 7 and 21 years of age hospitalized at 4 children’s hospitals for a vasoocclusive episode were evaluated. Data were collected during 1 day of the hospitalization.

Results:

Using the 2010 American College of Rheumatology guidelines, 21.8% of patients were identified as having WSP (pain in 7 or more unique body locations). Patients classified as having WSP had higher pain intensity (6.5 vs. 5.6; t=2.19, P=0.03) higher pain burden (13.0 vs. 9.8; t=3.09, P=0.002), higher acute functional disability (22.1 vs. 16.5; t=2.43, P=0.016), higher chronic functional disability (30.4 vs. 22.2; t=2.31, P=0.02), lower positive affect (22.9 vs. 27.6; t=2.23, P=0.027), and lower quality of life (56.2 vs. 62.9; t=1.99, P=0.049) than those youth with SCD without WSP.

Discussion:

Assessment of WSP may identify a unique clinical phenotype of youth with SCD with differing treatment needs.
Perianesthetic Management of Patients With Thyroid-Stimulating Hormone–Secreting Pituitary Adenomas
Authors: Dyer Matthew W. , Gnagey Amy , Jones Bryan T. , Pula Roger D. , Lanier William L. , Atkinson John L.D. , Pasternak Jeffrey J.
Published: June 2016

Background:

Thyroid-stimulating hormone (TSH)–secreting pituitary adenomas are a rare cause of secondary hyperthyroidism. Anesthetic management of these patients has not been formally described in the literature.

Materials and Methods:

Patients who underwent resection of a TSH-secreting pituitary adenoma during 1987 to 2012 at a single institution were identified. Preoperative thyroid hormone state, anesthetic management, and outcome were recorded. Hemodynamic associations with intraoperative events were compared between those who were hyperthyroid and euthyroid at the time of surgery.

Results:

Of 2268 patients having transsphenoidal resection of a pituitary tumor, 19 (0.84%) had resection of a TSH-secreting adenoma. At the time of surgery, 6 (32%) were hyperthyroid, 11 (58%) were euthyroid, and 2 (10%) were hypothyroid based on serum thyroxine concentration. General anesthesia was maintained with a potent inhaled anesthetic in all patients, and included nitrous oxide in 18 of 19 (95%). Seventeen (90%) had an arterial catheter placed for surgery. Only 1 patient (5%) required an intraoperative blood transfusion. There were no significant differences in heart rate or blood pressure at induction of anesthesia, upon intranasal injection of local anesthetic containing epinephrine, or upon emergence from anesthesia, between patients who were chemically hyperthyroid or euthyroid. Twelve of 19 (63%) had tumor extension beyond the sella turcica. Common complications were nausea and vomiting (42%), diabetes insipidus (32%), and temporary or permanent hypopituitarism (42%).

Conclusions:

Patients having resection of TSH-secreting pituitary adenomas can present in any thyroid state. An awareness of risks and potential complications in patients with TSH-secreting adenomas can help tailor perioperative care.
Implant Complications After Magnetically Controlled Growing Rods for Early Onset Scoliosis: A Multicenter Retrospective Review
Authors: Choi Edmund , Yaszay Burt , Mundis Gregory , Hosseini Pooria , Pawelek Jeff , Alanay Ahmet , Berk Haluk , Cheung Kenneth , Demirkiran Gokhan , Ferguson John , Greggi Tiziana , Helenius Ilkka , La Rosa Guido , Senkoylu Alpaslan , Akbarnia Behrooz A.
Published: June 2016

Background:

Traditional growing rods have a reported wound and implant complication rate as high as 58%. It is unclear whether the use of magnetically controlled growing rods (MCGR) will affect this rate. This study was performed to characterize surgical complications following MCGR in early onset scoliosis.

Methods:

A multicenter retrospective review of MCGR cases was performed. Inclusion criteria were: (1) diagnosis of early onset scoliosis of any etiology; (2) 10 years and younger at time of index surgery; (3) preoperative major curve size >30 degrees; (4) preoperative thoracic spine height <22 cm. Complications were categorized as wound related and instrumentation related. Complications were also classified as early (<6 mo from index surgery) versus late (>6 mo). Distraction technique and interval of distraction was surgeon preference without standardization across sites.

Results:

Fifty-four MCGR patients met inclusion criteria. There were 30 primary and 24 conversion procedures. Mean age at initial surgery was 7.3 years (range, 2.4 to 11 y), and mean duration of follow-up 19.4 months. Twenty-one (38.8%) of 54 patients had at least 1 complication. Fifteen (27.8%) had at least 1 revision surgery. Six (11.1%) had broken rods (2 to 4.5 and 4 to 5.5 mm rods); two 5.5 mm rods failed early (4 mo) and 4 late (mean=14.5 mo). Six (11.1%) patients experienced 1 episode of lack or loss of lengthening, of which 4 patients subsequently lengthened. Seven patients (13.0%) had either proximal or distal fixation-related complication at average of 8.4 months. Two patients (3.7%) had infections requiring incision and drainage; 1 early (2 wk) with wound drainage and 1 late (8 mo). The late case required removal of one of the dual rods.

Conclusions:

This study shows that compared with traditional growing rods, MCGR has a lower infection rate (3.7% vs. 11.1%). MCGR does not appear to prevent common implant-related complications such as rod or foundation failure. The long-term implication remains to be determined.

Level of Evidence:

Level IV.
Knee Deformities in Children With Down Syndrome: A Focus on Knee Malalignment
Authors: Duque Orozco Maria del Pilar , Abousamra Oussama , Chen Brian Po-Jung , Rogers Kenneth J. , Sees Julieanne P. , Miller Freeman
Published: June 2016

Background:

Patellofemoral instability (PFI) has been the most reported knee abnormality in people with Down syndrome. Other reported knee abnormalities have been associated with PFI and different management approaches have been described with variable outcomes. The aim of this study was to describe the anatomic variations of the knee in children with Down syndrome. A comparison between knees with and without PFI was performed and our experience in treating knee abnormalities in Down syndrome was also reported.

Methods:

Records of all children with Down syndrome were reviewed. Two groups were identified (knees with and without PFI). Radiographic measurements included the mechanical and anatomic lateral distal femoral angles, medial proximal tibial angle, angle of depression of medial tibial plateau, lateral tibial translation, and distal femoral physis-joint angle. On the lateral view, Insall-Salvati and Blackburne-Peel ratios were measured. The sulcus angle was measured on the tangential view. Measurements were compared between the 2 groups (with and without PFI).

Knees with PFI were divided into 3 subgroups based on their treatment (group A: surgical valgus correction, group B: surgical soft tissue procedures for PFI, and group C: conservative treatment). Preoperative radiographs were used for the surgical group and last available radiographs were used for the conservative group. Clinical and radiographic data were compared between the groups. For groups A and B, clinical and radiographic data were also compared between preoperative and last visits.

Results:

Of the 581 children with Down syndrome, 5% (31 children: 22 females, 9 males) had PFI in 56 knees. Mean age at diagnosis was 11.5±3.5 years. Of the remaining 550 children, 75 children had radiographs for 130 knees. Knees with PFI had significantly more valgus and a larger distal femoral physis-joint angle. Depression of the medial tibial plateau and lateral tibial translation were noted in knees with PFI. Insall-Salvati ratio was higher and the sulcus angle was larger in the PFI group.

Of the 56 knees with PFI; 10 knees were in group A, 11 knees in group B, 33 knees in group C, and the remaining 2 knees had combined procedures. Preoperative mechanical and anatomic lateral distal femoral angles were smaller in group A than in group B or C. Grades of PFI improved in group B after surgery. This improvement was not noted in group A.

Conclusions:

In children with Down syndrome, different variations of the knee anatomy can be found. Although PFI might be the most evident knee abnormality, other underlying deformities are common. Treatment of the PFI should be planned through a comprehensive anatomic approach that addresses all aspects of knee deformity.

Level of Evidence:

Level IV—prognostic and therapeutic study.
The Fibrin-Derived Peptide Bβ15–42 (FX06) Ameliorates Vascular Leakage and Improves Survival and Neurocognitive Recovery: Implications From Two Animal Models of Cardiopulmonary Resuscitation*
Authors: Bergt Stefan , Gruenewald Matthias , Beltschany Claudia , Grub Andrea , Neumann Tobias , Albrecht Martin , Vollmar Brigitte , Zacharowski Kai , Roesner Jan P. , Meybohm Patrick
Published: June 2016

Objectives:

The fibrin-derived peptide Bβ15–42 (FX06) has been proven to attenuate ischemia/reperfusion injury. We tested the hypothesis that Bβ15–42 improves survival rate and neurocognitive recovery after cardiopulmonary resuscitation.

Design:

Pig and mouse model of cardiopulmonary resuscitation.

Setting:

Two university hospitals.

Subjects:

Pigs and mice.

Interventions:

Pigs (n = 16) were subjected to 8-minute cardiac arrest. Successful resuscitated pigs (n = 12) were randomized either to 3 mg/kg Bβ15–42 followed by a continuous infusion of 1 mg/kg/hr for 5 hours (pFX06; n = 6) or the control group (pCONTROL; n = 6). Cardiac damage, function, and hemodynamics were recorded up to 8 hours. Mice (n = 52) were subjected to 4-minute cardiac arrest followed by cardiopulmonary resuscitation, and randomized either to two boli of 2.4 mg/kg Bβ15–42 (mFX06; n = 26) or the control group (mCONTROL; n = 26). Fourteen-day survival rate, neurocognitive function, and endothelial integrity (additional experiment with n = 26 mice) were evaluated.

Measurements and Main Results:

Bβ15–42 reduced cumulative fluid intake (3,500 [2,600–4,200] vs 6,800 [5,700–7,400] mL; p = 0.004) within 8 hours in pigs. In mice, Bβ15–42 improved 14-day survival rate (mFX06 vs mCONTROL; 11/26 vs 6/26; p < 0.05) and fastened neurocognitive recovery in the Water-Maze test (15/26 vs 9/26 mice with competence to perform test; p < 0.05). Bβ15–42-treated mice showed a significant higher length of intact pulmonary endothelium and reduced pulmonary leukocyte infiltration.

Conclusions:

This study confirms the new concept of an important role of fibrin derivatives in global ischemia/reperfusion injury, which can be attenuated by the fibrin-derived peptide Bβ15–42.
Comparison of Demographics, Tumor Characteristics, and Survival Between Pancreatic Adenocarcinomas and Pancreatic Neuroendocrine Tumors
Authors: Yadav Siddhartha , Sharma Prabin , Zakalik Dana
Published: June 2016

Objective:

The objective of this study is to compare the incidence, demographics, tumor characteristics, and survival between patients with pancreatic neuroendocrine tumors (PNETs) and pancreatic adenocarcinomas.

Materials and Methods:

Between 2004 and 2012, all cases of pancreatic adenocarcinomas and PNETs were extracted from the population-based cancer registries of the Surveillance Epidemiology and End Results program. To identify the cases, a combination of topographical and histology codes based on ICD-O-3 were used. Incidence, demographics, tumor characteristics, and survival was then compared between these 2 histologic subtypes of pancreatic cancer.

Results:

A total of 57,688 patients with pancreatic cancer were identified, of which 53,753 (93%) had pancreatic adenocarcinoma and 3935 (7%) had PNET. The overall age-adjusted incidence of PNETs between 2004 and 2012 was 0.52 per 100,000 per year, whereas that for pancreatic adenocarcinomas during the same period was 7.34 per 100,000 per year. PNETs had a significantly younger median age at diagnosis (61 vs. 69 y). A significant proportion of PNETs were diagnosed at stage I (20.5% vs. 6.0%) and were well differentiated (32.8% vs. 4.5%) compared with adenocarcinomas. Five-year cause-specific survival was 51.3% and 5.0% for PNETs and pancreatic adenocarcinomas, respectively. In multivariate analysis, pancreatic adenocarcinomas had a hazard ratio for death of 4.02 (95% confidence interval, 3.79-4.28) when compared with PNETs.

Conclusions:

PNETs present with favorable features such as higher proportion of early-stage tumor, higher proportion of well differentiated tumors, and younger age at diagnosis. PNETs have a significantly better survival than pancreatic adenocarcinomas even after adjusting for age, sex, race, site, grade, and stage.
Utilization of Postoperative Chemoradiotherapy Among Women in the United States With High-risk Cervical Cancer
Authors: Trifiletti Daniel M. , Swisher-McClure Samuel , Showalter Timothy N. , Cantrell Leigh A. , Grover Surbhi
Published: June 2016

Objective:

Prospective randomized data demonstrates that chemoradiotherapy (CRT) improves overall survival in women with high-risk pathologic features following radical hysterectomy. Despite this, not all high-risk patients receive adjuvant CRT and the patterns of care in this patient population are unknown. We sought to investigate the rates of adjuvant therapy utilization through analysis of the National Cancer Database.

Materials and Methods:

The National Cancer Database was queried for women with cervical cancer treated initially with hysterectomy from 2002 to 2012. Patients without high-risk pathologic features were excluded: pN+, positive surgical margins, and parametrial invasion (Peters’ criteria). Among the 5947 evaluable patients, univariable analysis and multivariable analysis were performed to investigate potential factors associated with CRT utilization and overall survival following diagnosis.

Results:

Adjuvant CRT was performed in 41.8% of women and adjuvant radiotherapy, chemotherapy, and no adjuvant therapy was utilized in 9.8%, 23.6%, and 24.8% of women, respectively. On multivariable analysis, CRT utilization was associated with younger age, race, lower facility volume, pN+, parametrial invasion, and a negative surgical margin. Residence distance to treating facility, year of diagnosis, household income, insurance status, and facility type did not predict for CRT utilization.

Conclusions:

Despite level I evidence supporting its use, less than half of women in this large US cohort with high-risk cervical cancer received adjuvant CRT. Use of adjuvant CRT for women did not significantly increase between 2002 and 2012. Patient age, race, and pathologic risk factors were associated with use of adjuvant CRT.
A Pooled Analysis of Biochemical Failure in Intermediate-risk Prostate Cancer Following Definitive Stereotactic Body Radiotherapy (SBRT) or High-Dose-Rate Brachytherapy (HDR-B) Monotherapy
Authors: Hegde John V. , Collins Sean P. , Fuller Donald B. , King Christopher R. , Demanes D. Jeffrey , Wang Pin-Chieh , Kupelian Patrick A. , Steinberg Michael L. , Kamrava Mitchell
Published: June 2016

Objectives:

To investigate biochemical relapse-free survival (BRFS) in men with National Comprehensive Cancer Network-defined intermediate-risk prostate cancer (PC) treated with either stereotactic body radiotherapy (SBRT) or high-dose-rate brachytherapy (HDR-B) monotherapy.

Materials and Methods:

A retrospective, multi-institutional analysis of 437 patients with intermediate-risk PC treated with SBRT (N=300) or HDR-B (N=137) was performed. Men who underwent SBRT were treated to 35 to 40 Gy in 4 to 5 fractions. A total of 95.6% who underwent HDR-B were treated to 42 Gy in 6 fractions. Baseline patient characteristics were compared using a T test for continuous variables and the Mantel-Haenszel χ2 metric or Fisher exact test for categorical variables. Kaplan-Meier curves were generated to estimate 5-year actuarial BRFS. Multivariate analysis using a Cox proportional-hazards model was used to evaluate factors associated with biochemical failure.

Results:

The mean age at diagnosis was 68.4 (SD±7.8) years. T-category was T1 in 63.6% and T2 in 36.4%. Mean initial prostate-specific antigen was 7.4 (SD±3.4) ng/mL. Biopsy Gleason score was ≤3+4 in 82.8% and 4+3 in 17.2%. At a median of 4.1 years of follow-up, the BRFS rate (Phoenix definition) was 96.3%, with no difference when stratifying by treatment modality or biologically equivalent dose (BED1.5). On multivariate analysis, age (hazard ratio 1.08, P=0.04) and biopsy Gleason score (hazard ratio 2.48, P=0.03) were significant predictors of BRFS.

Conclusions:

With a median follow-up period of 4 years, SBRT and HDR-B monotherapy provide excellent BRFS in intermediate-risk PC. Longer-term follow-up is necessary to determine the ultimate efficacy of these hypofractionated approaches, but they appear promising relative to standard fractionation outcomes.
Patient-reported Adherence to Adjuvant Aromatase Inhibitor Therapy Using the Morisky Medication Adherence Scale
Authors: Kesmodel Susan B. , Goloubeva Olga G. , Rosenblatt Paula Y. , Heiss Brian , Bellavance Emily C. , Chumsri Saranya , Bao Ting , Thompson Jennifer , Nightingale Ginah , Tait Nancy S. , Nichols Elizabeth M. , Feigenberg Steve J. , Tkaczuk Katherine H.
Published: June 2016

Objectives:

Endocrine therapy is part of standard adjuvant therapy for patients with hormone receptor-positive breast cancer and has been shown to improve recurrence-free and overall survival. However, adherence to endocrine therapy is suboptimal and is difficult to measure. In this study we evaluate the feasibility of using the Morisky Medication Adherence Scale (MMAS) to assess patient adherence to aromatase inhibitor (AI) therapy.

Methods:

Patients with stage 1 to 3, hormone receptor-positive breast cancer receiving adjuvant AI therapy were prospectively enrolled on an Institutional Review Board approved protocol. The MMAS questionnaire was administered to each patient and adherence was measured. Information on duration of AI therapy, patient and tumor characteristics, and treatment was collected. A multivariable logit model approach was utilized to evaluate potential barriers to adherence.

Results:

Between 2011 and 2014, 100 patients were enrolled. The distribution of adherence levels was 13% low, 37% medium, and 50% high. High adherence was reported more frequently in white women (58%), patients with stage 2 and 3 disease (54%), and patients who did not receive chemotherapy (62%). Multivariable analysis demonstrated that higher adherence was more likely in white women compared with African American women (estimated odds ratio=2.8).

Conclusions:

Using the MMAS, only 50% of women with stage 1 to 3 breast cancer reported high adherence to AI therapy, consistent with other reports showing suboptimal adherence to adjuvant endocrine therapy. The MMAS allows for the rapid assessment of adherence to oral adjuvant endocrine therapy and is valuable in a busy clinical setting.
Impact of Staging With Positron-emission Tomography (PET) and Comorbidities on Management and Survival of American Veterans With Stage I-III Non–Small Cell Lung Cancer
Authors: Raghunathan Radhika , Cease Kemp , Troeschel Sandra , Zhao Lili , Gross Milton , Chen Guoan , Chopra Vineet , Ramnath Nithya
Published: June 2016

Objectives:

The extent of whether staging by fluorodeoxyglucose positron-emission tomography (PET) impacts outcomes in American Veterans with stage I-III non–small-cell lung cancer (NSCLC) is unknown. We investigated impact of fluorodeoxyglucose PET staging and age-adjusted comorbidities (AACs) on management and survival of NSCLC in this group.

Materials and Methods:

We performed a retrospective review to identify with NSCLC who underwent initial PET scan and received care at the Ann Arbor Veterans Hospital between 2005 and 2010. Survival outcomes were estimated by Kaplan-Meier methods, quantile regressions, and Cox proportional hazards models, after accounting for age at diagnosis, sex, AAC, and initial treatment.

Results:

The number of PET scans increased from 0 in 2005 to 66 in 2010. There were 170 men, 4 women, median age 64 years. Median AAC score was 4. In CS I (n=54), initial PET upstaged 5 patients. Median survival for no change in PET stage was 27.43 versus 67 months for upstaged patients (P=0.034). For CS II (n=15), initial PET scan upstaged 1 patient. Median survival for no change in PET stage was 16.53 versus 2.8 months for upstaged patient (P=0.335). For CS III (n=104), PET scan upstaged 20 patients. Median survival for no change in PET stage was 13.3 versus 3.8 months for upstaged patients (P=0.016).

Conclusions:

PET scans resulted in upstaging in 15% in CS I-III NSCLC. AAC scores dictated therapy decisions and outcomes more than PET staging. Veterans had lower 5-year survival rates (26.3%, 15.8%/13.4%) compared with 53% and 27% in age/sex/time-period matched SEER data for stage I-II/III NSCLC.
Bifurcated Superficial Temporal Artery Island Flap for the Reconstruction of a Periorbital Burn: An Innovation
Authors: Elbanoby Tarek M. , Elbatawy Amr , Aly Gaber M. , Ayad Wael , Helmy Yasser , Helmy Emad , Sholkamy Khallad , Dahshan Hazem , Al-Hady Abdallah
Published: June 2016

Background:

Facial burns represent between one-fourth and one-third of all burns. The long-term sequelae of periorbital burns include significant ectropion and lagophthalmos as a result of secondary burn contractures in the lower and upper eyelids, in addition to complete or incomplete alopecia of the eyebrows.

Methods:

A retrospective study of 14 reconstructive procedures for 12 postburn faces was conducted with all procedures performed since 2010 at the Department of Plastic Surgery, Al-Hussein University Hospital, and at the Craniofacial Unit, Nasser Institute Hospital. Four patients experienced chemical burns, and 8 patients experienced thermal burns. All patients underwent periorbital reconstruction using a bifurcated superficial temporal artery island flap to reconstruct the eyebrows, correct the lagophthalmos, and release the ectropion in both the upper and the lower eyelids. Two patients underwent bilateral periorbital flap reconstruction. The mean age of patients was 29 years, and the study was conducted on 8 males and 4 females. Patient satisfaction was assessed using a questionnaire completed by all patients postoperatively.

Results:

The complete release of both the upper and the lower eyelids was achieved in all cases, together with ideal replacement of brow hair; no complications were noted, apart from one case in which a loss of hair density in the new eyebrow was observed, combined with the partial loss of the flap in the lower eyelid. Patient satisfaction results were collected and assembled in a table.

Conclusion:

A bifurcated superficial temporal artery island flap is an innovative flap for reconstructing both burned eyebrows and eyelids.
Physical Activity and the Risk of Gallstone Disease
Authors: Zhang Yan-Peng , Zhao Ya-Lei , Sun Yu-Ling , Zhu Rong-Tao , Wang Wei-Jie , Li Jian
Published: June 2016

Background:

The role of physical activity in preventing gallstone disease independent of its effect on the body weight has not been well established. We performed a systematic review and meta-analysis of cohort and case-control studies to analyze this potential association.

Methods:

We searched PubMed and EMBASE to identify all published studies in English through April 2016. We pooled the relative risks (RRs) or odds ratios (ORs) and corresponding 95% confidence intervals (CIs) from individual studies using a random-effects model to investigate associations between physical activity and the risk of gallstone disease.

Results:

A total of 16 studies comprising 19 independent reports of approximately 260,000 participants met the inclusion criteria, including 6 case-control studies and 13 cohort studies. In a pooled analysis of cohort studies, physical activity (in a comparison of the highest-level and the lowest-level groups) was associated with a reduced risk of gallstone disease (RR=0.85; 95% CI, 0.78-0.92;I2=79.5%). For men, the RR was 0.76 (95% CI, 0.60-0.97), and for women, the RR was similar (RR=0.77; 95% CI, 0.66-0.91). In a dose-response analysis, the RR of gallstone disease was 0.87 (95% CI, 0.83-0.92;I2=1.0%) per 20 metabolic equivalent-hours of recreational physical per week. In comparison, case-control studies yielded a stronger significant risk reduction for gallstone disease (OR=0.64; 95% CI, 0.46-0.90;I2=76.6%).

Conclusions:

This study suggests an inverse association between physical activity and gallstone disease in both men and women; however, these findings should be interpreted cautiously because of study heterogeneity.