bluuebunny/crossref_metadata_2025 huggingface dataset:
Contrast Enhanced Ultrasound of the Kidneys: What Is It Capable of?
Authors: Cokkinos Demosthenes D. , Antypa Eleni G. , Skilakaki Maria , Kriketou Despoina , Tavernaraki Ekaterini , Piperopoulos Ploutarchos N.
Published: December 2013

One of the many imaging uses of contrast enhanced ultrasound (CEUS) is studying a wide variety of kidney pathology, due to its ability to detect microvascular blood flow in real time without affecting renal function. CEUS enables dynamic assessment and quantification of microvascularisation up to capillary perfusion. The objective of this paper is to briefly refresh basic knowledge of ultrasound (US) contrast agents’ physical properties, to study technical details of CEUS scanning in the kidneys, and to review the commonest renal indications for CEUS, with imaging examples in comparison to baseline unenhanced US and computed tomography when performed. Safety matters and limitations of CEUS of the kidneys are also discussed.
Effect of Paracetamol, Dexketoprofen Trometamol, Lidocaine Spray, and Paracervical Block Application for Pain Relief during Suction Termination of First-Trimester Pregnancy
Authors: Açmaz Gökhan , Aksoy Hüseyin , Özoğlu Nil , Aksoy Ülkü , Albayrak Evrim
Published: December 2013

The aim of the study was to investigate the analgesic efficacy of preoperative oral dexketoprofen trometamol, intravenous paracetamol, lidocaine spray, and paracervical block with ultracaine on curettage procedure. A total of 111 subjects with the request of pregnancy termination between 5 and 7 weeks of gestation were included in the study. The first group (control group) consisted of 20 participants without medication. The second group consisted of 25 participants receiving 2 puffs of lidocaine sprays on cervical mucosa. The third group consisted of 20 participants receiving oral 25 mg dexketoprofen trometamol. The fourth group consisted of 23 participants receiving 1000 mg intravenous paracetamol and the fifth group consisted of 23 participants receiving paracervical block with ultracaine. Paracervical block reduced pain score significantly in both intraoperative and postoperative periods. All analgesic procedures were significantly effective for reducing pain in postoperative period. Paracervical block may be the best method for reducing pain scores in intraoperative and postoperative periods during curettage procedure. All analgesic procedures such as lidocaine, paracetamol, ultracaine, and paracervical block with ultracaine can be used for reducing pain score in postoperative period. This trial is registered withNCT01947205.
Alterations in Hair Follicle Dynamics in Women
Authors: Piérard-Franchimont Claudine , Piérard Gérald E.
Published: December 2013

Endocrine changes supervening after parturition and menopause participate in the control of sebum production and hair growth modulation. The ensuing conditions include some peculiar aspects of hair loss (effluvium), alopecia, and facial hirsutism. The hair cycling is of major clinical relevance because most hair growth disorders result from disturbances in this chronobiological feature. Of note, any correlation between a biologic abnormality and hair cycling disturbance does not prove a relationship of causality. The proportion of postmenopausal women is rising in the overall population. Therefore, the prevalence of these hair follicle disturbances is globally on the rise. Current therapies aim at correcting the underlying hormonal imbalances, and at improving the overall cosmetic appearance. However, in absence of pathogenic diagnosis and causality criteria, chances are low that a treatment given by the whims of fate will adequately control hair effluvium. The risk and frequency of therapeutic inertia are further increased. When the hair loss is not controlled and/or compensated by growth of new hairs, several clinical aspects of alopecia inexorably develop. Currently, there is little evidence supporting any specific treatment for these endocrine hair disorders in post-partum and postmenopausal women. Current hair treatment strategies are symptomatic and nonspecific so current researchers aim at developing new, targeted methods.
Inhibition of DNA Double-Strand Break Repair by the Dual PI3K/mTOR Inhibitor NVP-BEZ235 as a Strategy for Radiosensitization of Glioblastoma
Authors: Gil del Alcazar Carlos Rodrigo , Hardebeck Molly Catherine , Mukherjee Bipasha , Tomimatsu Nozomi , Gao Xiaohuan , Yan Jingsheng , Xie Xian-Jin , Bachoo Robert , Li Li , Habib Amyn A. , Burma Sandeep
Published: December 2013

Purpose: Inhibitors of the DNA damage response (DDR) have great potential for radiosensitization of numerous cancers, including glioblastomas, which are extremely radio- and chemoresistant brain tumors. Currently, there are no DNA double-strand break (DSB) repair inhibitors that have been successful in treating glioblastoma. Our laboratory previously demonstrated that the dual phosphoinositide 3-kinase/mTOR inhibitor NVP-BEZ235 can potently inhibit the two central DDR kinases, DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and ataxia-telangiectasia mutated (ATM), in vitro. Here, we tested whether NVP-BEZ235 could also inhibit ATM and DNA-PKcs in tumors in vivo and assessed its potential as a radio- and chemosensitizer in preclinical mouse glioblastoma models.

Experimental Design: The radiosensitizing effect of NVP-BEZ235 was tested by following tumor growth in subcutaneous and orthotopic glioblastoma models. Tumors were generated using the radioresistant U87-vIII glioma cell line and GBM9 neurospheres in nude mice. These tumors were then treated with ionizing radiation and/or NVP-BEZ235 and analyzed for DNA-PKcs and ATM activation, DSB repair inhibition, and attenuation of growth.

Results: NVP-BEZ235 potently inhibited both DNA-PKcs and ATM kinases and attenuated the repair of ionizing radiation–induced DNA damage in tumors. This resulted in striking tumor radiosensitization, which extended the survival of brain tumor–bearing mice. Notably, tumors displayed a higher DSB-load when compared with normal brain tissue. NVP-BEZ235 also sensitized a subset of subcutaneous tumors to temozolomide, a drug routinely used concurrently with ionizing radiation for the treatment of glioblastoma.

Conclusions: These results demonstrate that it may be possible to significantly improve glioblastoma therapy by combining ionizing radiation with potent and bioavailable DNA repair inhibitors such as NVP-BEZ235. Clin Cancer Res; 20(5); 1235–48. ©2013 AACR.
A Role for Peroxisome Proliferator-Activated Receptor γ Coactivator-1 in the Control of Mitochondrial Dynamics During Postnatal Cardiac Growth
Authors: Martin Ola J. , Lai Ling , Soundarapandian Mangala M. , Leone Teresa C. , Zorzano Antonio , Keller Mark P. , Attie Alan D. , Muoio Deborah M. , Kelly Daniel P.
Published: December 2013

Rationale
:

Increasing evidence has shown that proper control of mitochondrial dynamics (fusion and fission) is required for high-capacity ATP production in the heart. Transcriptional coactivators, peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) α and PGC-1β, have been shown to regulate mitochondrial biogenesis in the heart at the time of birth. The function of PGC-1 coactivators in the heart after birth has been incompletely understood.

Objective
:

Our aim was to assess the role of PGC-1 coactivators during postnatal cardiac development and in adult hearts in mice.

Methods and Results
:

Conditional gene targeting was used in mice to explore the role of PGC-1 coactivators during postnatal cardiac development and in adult hearts. Marked mitochondrial structural derangements were observed in hearts of PGC-1α/β–deficient mice during postnatal growth, including fragmentation and elongation, associated with the development of a lethal cardiomyopathy. The expression of genes involved in mitochondrial fusion (
Mfn1, Opa1
) and fission (
Drp1, Fis1
) was altered in the hearts of PGC-1α/β–deficient mice. PGC-lα was shown to directly regulate
Mfn1
gene transcription by coactivating the estrogen-related receptor α on a conserved DNA element. Surprisingly, PGC-1α/β deficiency in the adult heart did not result in evidence of abnormal mitochondrial dynamics or heart failure. However, transcriptional profiling demonstrated that PGC-1 coactivators are required for high-level expression of nuclear- and mitochondrial-encoded genes involved in mitochondrial dynamics and energy transduction in the adult heart.

Conclusions
:

These results reveal distinct developmental stage–specific programs involved in cardiac mitochondrial dynamics.
Local Effects of Pregnancy on Connexin Proteins That Mediate Ca
2+
-Associated Uterine Endothelial NO Synthesis
Authors: Morschauser Timothy J. , Ramadoss Jayanth , Koch Jill M. , Yi Fu Xian , Lopez Gladys E. , Bird Ian M. , Magness Ronald R.
Published: December 2013

Uterine artery adaptations during gestation facilitate increases in uterine blood flow and fetal growth. Hypothesis: local expression and distribution of uterine artery connexins play roles in mediating in vivo gestational eNOS activation and NO production. We established an ovine model restricting pregnancy to a single uterine horn and measured uterine blood flow, uterine artery shear stress, connexins 37/43, and P
635
eNOS protein levels in uterine artery and systemic artery (omental and renal) endothelium and connexins in vascular smooth muscle. Uterine blood flow and shear stress were locally (unilaterally) and substantially elevated by gestation. During pregnancy, uterine artery endothelial gap junction proteins connexins 37/43 were locally regulated in the gravid horn and elevated 10.3- and 25.6-fold; uterine artery endothelial P
635
eNOS and total eNOS were elevated 3.3- and 2.9-fold; whereas uterine artery vascular smooth muscle connexins 37/43 were locally elevated 12.5- and 5.9-fold, respectively. Less pronounced changes were observed in systemic vasculature except for significant pregnancy-associated increases in omental artery vascular smooth muscle connexin 43 and omental artery endothelial P
635
eNOS and total eNOS. Gap junction blockade using connexin 43, but not connexin 37–specific Gap peptides, abrogated uterine artery endothelial ATP-induced Ca
2+
-mediated NO production. Thus, uterine artery endothelial connexin 43, but not connexin 37, regulates Ca
2+
-mediated NO production required for the vasodilation to accommodate increases in uterine blood flow and shear stress during healthy pregnancies.
Deficiency of the Interleukin 17/23 Axis Accelerates Renal Injury in Mice With Deoxycorticosterone Acetate+Angiotensin II–Induced Hypertension
Authors: Krebs Christian F. , Lange Sascha , Niemann Gianina , Rosendahl Alva , Lehners Alexander , Meyer-Schwesinger Catherine , Stahl Rolf A.K. , Benndorf Ralf A. , Velden Joachim , Paust Hans-Joachim , Panzer Ulf , Ehmke Heimo , Wenzel Ulrich O.
Published: December 2013

T cells participate in angiotensin II (Ang II)–induced hypertension. However, the specific subsets of T cells that are important in the end-organ damage are unknown. T-helper 17 cells are a recently identified subset that produces interleukin 17 (IL-17) and requires interleukin 23 (IL-23) for expansion. To evaluate the role of the T-helper 17 immune response in hypertensive renal and cardiac end-organ damage, hypertension was induced with deoxycorticosterone acetate (DOCA)+Ang II in wild-type (n=39) and IL-17–deficient (n=31) mice. The injury was evaluated at day 4 and day 14. To inactivate the IL-17/IL-23 axis at a different point, DOCA+Ang II hypertension was also induced in IL-23p19–deficient mice. Renal infiltration by T-helper 17 cells was increased in hypertensive wild-type mice. Systolic blood pressure did not differ between hypertensive IL-17–deficient and wild-type mice. Three days after induction of hypertension, a significantly higher albuminuria was found in IL-17–deficient than in wild-type mice (196±64 versus 58±16 mg/mg albumin/creatinine). Histology revealed significantly more glomerular injury (1.04±0.06 versus 0.67±0.05) and renal infiltration of γδ T cells in IL-17–deficient than in wild-type mice after 14 days. Similarly, significantly higher albuminuria, glomerular injury, and γδ T cell infiltration were found in IL-23p19–deficient mice with DOCA+Ang II–induced hypertension. DOCA+Ang II also induced cardiac damage as assessed by heart weight, cardiac fibrosis, as well as expression of fetal genes and matrix components, but no significant differences were found among IL-17
–/–
, IL-23p19
–/–
, and wild-type mice. IL-17/IL-23 deficiency accelerates DOCA+Ang II–induced albuminuria and hypertensive renal but not cardiac end-organ damage.
Association of Cardiotrophin-1 With Myocardial Fibrosis in Hypertensive Patients With Heart Failure
Authors: López Begoña , González Arantxa , Querejeta Ramón , Larman Mariano , Rábago Gregorio , Díez Javier
Published: December 2013

Cardiotrophin-1 has been shown to be profibrogenic in experimental models. The aim of this study was to analyze whether cardiotrophin-1 is associated with left ventricular end-diastolic stress and myocardial fibrosis in hypertensive patients with heart failure. Endomyocardial biopsies from patients (n=31) and necropsies from 7 control subjects were studied. Myocardial cardiotrophin-1 protein and mRNA and the fraction of myocardial volume occupied by collagen were increased in patients compared with controls (
P
<0.001). Cardiotrophin-1 overexpression in patients was localized in cardiomyocytes. Cardiotrophin-1 protein was correlated with collagen type I and III mRNAs (
r
=0.653,
P
<0.001;
r
=0.541,
P
<0.01) and proteins (
r
=0.588,
P
<0.001;
r
=0.556,
P
<0.005) in all subjects and with left ventricular end-diastolic wall stress (
r
=0.450;
P
<0.05) in patients. Plasma cardiotrophin-1 and N-terminal pro-brain natriuretic peptide and serum biomarkers of myocardial fibrosis (carboxy-terminal propeptide of procollagen type I and amino-terminal propeptide of procollagen type III) were increased (
P
<0.001) in patients compared with controls. Plasma cardiotrophin-1 was correlated with N-terminal pro-brain natriuretic peptide (
r
=0.386;
P
<0.005), carboxy-terminal propeptide of procollagen type I (
r
=0.550;
P
<0.001), and amino-terminal propeptide of procollagen type III (
r
=0.267;
P
<0.05) in all subjects. In vitro, cardiotrophin-1 stimulated the differentiation of human cardiac fibroblast to myofibroblasts (
P
<0.05) and the expression of procollagen type I (
P
<0.05) and III (
P
<0.01) mRNAs. These findings show that an excess of cardiotrophin-1 is associated with increased collagen in the myocardium of hypertensive patients with heart failure. It is proposed that exaggerated cardiomyocyte production of cardiotrophin-1 in response to increased left ventricular end-diastolic stress may contribute to fibrosis through stimulation of fibroblasts in heart failure of hypertensive origin.
Introduction to the systematics and biodiversity of sharks, rays, and chimaeras (Chondrichthyes) of Taiwan
Authors: EBERT DAVID A. , HO HSUAN-CHING , WHITE WILLIAM T. , DE CARVALHO MARCELO R.
Published: December 2013

All 13 orders of chondrichthyan fishes occur in Taiwanese waters, representing 52 chondrichthyan families (31 shark, 19 batoid, 2 chimaeroid) and 98 genera (64 shark, 31 batoid, 3 chimaeroid). A total of 119 shark, 58 batoid, and 4 chimaera species may occur in the waters surrounding Taiwan, pending taxonomic resolution of some groups. Of the 34 nominally described species from Taiwan, 17 are currently considered valid. The majority of named species occurred during two peak periods in Taiwanese chondrichthyan research; the first between 1959–63, when 13 nominal species were described, of which 7 remain valid today, and a second peak period between 2003–13 when 9 nominal species were described, of which 6 remain valid. The overall species diversity of Taiwan’s chondrichthyan fauna is comparable to that of other adjacent marine zoogeographic hotspots, e.g. Japan (126 shark, 75 batoid, 11 chimaeroid species) and the Philippines (81 shark, 46 batoid, 2 chimaeroid species). The Carcharhiniformes, Squaliformes, Myliobatiformes, and Rajiformes are the most dominant orders in terms of abundance and species-richness within this region. Each of these groups may increase in relative diversity with improved taxonomic resolution resulting from the incorporation of molecular tools and renewed morphological studies. Improved identification of Taiwan’s chondrichthyan fauna will aid in developing better conservation and management practices.
Pristiophorus lanae sp. nov., a new sawshark species from the Western North Pacific, with comments on the genus Pristiophorus Müller & Henle, 1837 (Chondrichthyes: Pristiophoridae)
Authors: Ebert David A. , Wilms Hana A.
Published: December 2013

A new species of sawshark, Pristiophorus lanae sp. nov., is described from off the Philippine Islands. The new species is the second member of the genus Pristiophorus described from the western North Pacific and can be separated from its closest geographic congener, P. japonicus, by having fewer rostral teeth in front of rostral barbels (17–26 versus 25–32), mouth at corners extending forward to below the rear margin of the eye versus extending below the rear one-third of eye margin, a greater mouth width at 6.9–7.8 times into pre-oral length (versus 5.8–6.9), eye length into head length (15.6–15.9 versus 9.8–13.2), mouth width into head length 9.0–10.0 versus 7.4–8.5 times, head width at nostrils 5.2–6.1 times into pre-orbital length versus 3.9–4.9 times, shorter prebarbel length (from snout tip to barbel) of 50.7–54.5% of preoral length versus 53.6–59.2%, a snout angle of 10.6–13.0° versus 12.4°–14.6°, and lateral trunk denticles with flat crowns that are imbricated versus erect crowns that are not imbricated. The number of monospondylous vertebrae is slightly lower in P. lanae (43–48) versus P. japonicus (51–52). The genus is reviewed, with a revised key to its species presented.
Inconclusive Evidence That Age Predicts a Prolonged or Chronic Course of Acute Rhinosinusitis in Adults: A Systematic Review of the Evidence Base
Authors: Broeder Timo P. , Grooteman Karina V. , Overdijkink Sanne B. , Selhorst Christel E. , Kaper Nina M. , Grolman Wilko , van der Heijden Geert J. M. G.
Published: December 2013

Objective

To review the evidence whether the risk for a prolonged or chronic course increases with age in adult patients with acute rhinosinusitis.

Data Sources

PubMed, EMBASE, and the Cochrane Library.

Review Methods

A comprehensive literature search was performed on March 24, 2013, and articles were screened and selected using predefined inclusion and exclusion criteria. Articles reporting studies on age as a predictor for the course in patients with acute rhinosinusitis were included. For included articles, the design of reported studies was assessed for directness of evidence and risk of bias. We aimed to extract hazard ratios for age as a continuous variable.

Results

Out of 13,382 unique publications, 3 articles with moderate risk of bias were included, with a maximum follow‐up period of 30 days. The reported hazard ratios for recovery at 10, 15, and 30 days are 1.0 (95% confidence interval, 0.9‐1.1) for age as a continuous variable, 0.86 (0.66‐1.11) for age dichotomized at 38 years, and 0.58 (0.40‐0.84) for age dichotomized for an increase with 20 years, respectively.

Conclusion and Recommendation

There is no evidence that age increases the risk for chronic rhinosinusitis in adult patients with acute rhinosinusitis. The literature is inconclusive that age increases the risk for a prolonged course of acute rhinosinusitis and, therefore, does not provide grounds for different management according to age of patients. As such, patients can be managed according to clinical practice guidelines with expectant observation and symptomatic treatment.
Tracheal Reconstruction in a Canine Model
Authors: Wood Megan W. , Murphy Sean V. , Feng Xin , Wright S. Carter
Published: December 2013

Objective

Tracheal reconstruction using a stem cell–based engineered trachea has recently shown promise. Our goal is to achieve a single‐stage stem cell–based tracheal replacement.

Study Design

Prospective feasibility study.

Setting

Wake Forest Institute of Regenerative Medicine.

Subjects and Methods

Five healthy male beagles were implanted with a 2.5‐cm segment of decellularized trachea. A sixth animal, planned for the control arm, died of anesthetic complications prior to tracheal implantation. The remaining 5 beagles were divided into 2 study arms: 4 had adipose‐derived stem cells coating the lumen of the donor trachea, and a control animal had the trachea implanted cell free. The donor tracheas were obtained from previously sacrificed size‐matched canines and decellularized. The adipose tissue was harvested from a recipient animal and the trachea prepared, seeded, and then implanted, all in one operation. Adipose stem cells were labeled fluorescently.

Results

Five of 6 planned surgical procedures were completed successfully. All required sacrifice for airway distress at approximately 1 week postoperatively. All tracheal grafts were found to be malacic and compromised.

Conclusion

In a canine model using a decellularized tracheal scaffold and adipose stem cells, the postoperative inflammatory response and evidence of rejection was minimal. However, all scaffolds exhibited breakdown, compromising the animals’ airways, necessitating euthanasia earlier than planned. For future study, a similar animal model using a single‐stage approach with a more robust scaffold may allow for greater survival and stem cell differentiation.
Thrombosis: tangled up in NETs
Authors: Martinod Kimberly , Wagner Denisa D.
Published: December 2013

The contributions by blood cells to pathological venous thrombosis were only recently appreciated. Both platelets and neutrophils are now recognized as crucial for thrombus initiation and progression. Here we review the most recent findings regarding the role of neutrophil extracellular traps (NETs) in thrombosis. We describe the biological process of NET formation (NETosis) and how the extracellular release of DNA and protein components of NETs, such as histones and serine proteases, contributes to coagulation and platelet aggregation. Animal models have unveiled conditions in which NETs form and their relation to thrombogenesis. Genetically engineered mice enable further elucidation of the pathways contributing to NETosis at the molecular level. Peptidylarginine deiminase 4, an enzyme that mediates chromatin decondensation, was identified to regulate both NETosis and pathological thrombosis. A growing body of evidence reveals that NETs also form in human thrombosis and that NET biomarkers in plasma reflect disease activity. The cell biology of NETosis is still being actively characterized and may provide novel insights for the design of specific inhibitory therapeutics. After a review of the relevant literature, we propose new ways to approach thrombolysis and suggest potential prophylactic and therapeutic agents for thrombosis.
Comparative analysis of genome sequences from four strains of the Buchnera aphidicola Mp endosymbion of the green peach aphid, Myzus persicae
Authors: Jiang Zhijie , Jones Derek H , Khuri Sawsan , Tsinoremas Nicholas F , Wyss Tania , Jander Georg , Wilson Alex C C
Published: December 2013

Background

Myzus persicae, the green peach aphid, is a polyphagous herbivore that feeds from hundreds of species of mostly dicot crop plants. Like other phloem-feeding aphids, M. persicae rely on the endosymbiotic bacterium, Buchnera aphidicola (Buchnera Mp), for biosynthesis of essential amino acids and other nutrients that are not sufficiently abundant in their phloem sap diet. Tobacco-specialized M. persicae are typically red and somewhat distinct from other lineages of this species. To determine whether the endosymbiotic bacteria of M. persicae could play a role in tobacco adaptation, we sequenced the Buchnera Mp genomes from two tobacco-adapted and two non-tobacco M. persicae lineages.

Results

With a genome size of 643.5 kb and 579 predicted genes, Buchnera Mp is the largest Buchnera genome sequenced to date. No differences in gene content were found between the four sequenced Buchnera Mp strains. Compared to Buchnera APS from the well-studied pea aphid, Acyrthosiphon pisum, Buchnera Mp has 21 additional genes. These include genes encoding five enzymes required for biosynthesis of the modified nucleoside queosine, the heme pathway enzyme uroporphyrinogen III synthase, and asparaginase. Asparaginase, which is also encoded by the genome of the aphid host, may allow Buchnera Mp to synthesize essential amino acids from asparagine, a relatively abundant phloem amino acid.

Conclusions

Together our results indicate that the obligate intracellular symbiont Buchnera aphidicola does not contribute to the adaptation of Myzus persicae to feeding on tobacco.
Cost Sharing and Adherence to Tyrosine Kinase Inhibitors for Patients With Chronic Myeloid Leukemia
Authors: Dusetzina Stacie B. , Winn Aaron N. , Abel Gregory A. , Huskamp Haiden A. , Keating Nancy L.
Published: December 2013

Purpose

The introduction of imatinib, a tyrosine kinase inhibitor (TKI), has greatly increased survival for patients with chronic myeloid leukemia (CML). Conversely, nonadherence to imatinib and other TKIs undoubtedly results in disease progression and treatment resistance. We examined trends in imatinib expenditures from 2002 to 2011 and assessed the association between copayment requirements for imatinib and TKI adherence.

Patients and Methods

We used MarketScan health plan claims from 2002 to 2011 to identify adults (age 18 to 64 years) with CML who initiated imatinib therapy between January 1, 2002, and June 30, 2011, and had insurance coverage for at least 3 months before through 6 months after initiation (N = 1,541). Primary outcomes were TKI discontinuation and nonadherence. The primary independent variable was out-of-pocket cost for a 30-day supply of imatinib. By using a propensity-score weighted sample, we estimated the risk of discontinuation and nonadherence for patients with higher (top quartile) versus lower copayments.

Results

Monthly copayments for imatinib averaged $108; median copayments were $30 (range, $0 to $4,792). Mean total monthly expenditures for imatinib nearly doubled between 2002 and 2011, from $2,798 to $4,892. Approximately 17% of patients with higher copayments and 10% with lower copayments discontinued TKIs during the first 180 days following initiation (adjusted risk ratio [aRR], 1.70; 95% CI, 1.30 to 2.22). Similarly, patients with higher copayments were 42% more likely to be nonadherent (aRR, 1.42; 95% CI, 1.19 to 1.69).

Conclusion

Patients with higher copayments are more likely to discontinue or be nonadherent to TKIs. Given the importance of these therapies for patients with CML, our data suggest a critical need to reduce patient costs for these therapies.
Identification of a Novel SHP-2 Protein Tyrosine Phosphatase Inhibitor
Authors: Ju Anna , Seo Huiyun , Kim Heemun , Park Byoung Chul , Park Sung Goo , Kim Jeong Hoon , Choi Hyung-Kyoon , Min Kyung Hoon , Cho Sayeon
Published: December 2013

The Src homology 2 (SH2) domain-containing phosphatase 2 (SHP-2) is a nonreceptor protein tyrosine phosphatase (PTP) involved in extracellular-regulated kinase (ERK) activation. Recent studies have shown that gain-of-function mutations in SHP-2 are associated with several diseases, including LEOPARD syndrome, Noonan syndrome, and juvenile myelomonocytic leukemia. In this study, we identified the novel SHP-2 inhibitor 3-(1-benzimidazolylmethyl)-6-p-tolyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (MLS-001). SHP-2 activity was inhibited by MLS-001, whereas other types of PTPs, namely ACP1, CDC25A, DUSP3, DUSP14, DUSP18, DUSP22, DUSP23, DUSP26, and SSH3, were not. Furthermore, TCPTP and SHP-1 that are closely related to SHP-2 were not inhibited by the inhibitor. Kinetic studies with MLS-001 and SHP-2 revealed a competitive inhibition. The SHP-2 expressing cells treated with MLS-001 demonstrated reduced SHP-2 phosphatase activity, thereby suggesting that MLS-001 effectively passes through cell membranes. In addition, MLS-001 reduced SHP-2-mediated phosphorylation in the activation loop of ERK in cells. Therefore, MLS-001 could be a lead compound for developing a potent SHP-2 inhibitor.
The Great Equalizer: Health Care Access and Infant Mortality in Thailand
Authors: Gruber Jonathan , Hendren Nathaniel , Townsend Robert M.
Published: December 2013

This paper analyzes Thailand’s 2001 healthcare reform, “30 Baht.” The program increased funding available to hospitals to care for the poor and reduced copays to 30 Baht (~$0.75). Our estimates suggest the supply-side funding of the program increased healthcare utilization, especially among the poor. Moreover, we find significant impacts on infant mortality. Prior to 30 Baht, poorer provinces had significantly higher infant mortality rates than richer provinces. After 30 Baht, this correlation evaporates to zero. The results suggest that increased access to healthcare among the poor can significantly reduce their infant mortality rates. (JEL H51, I12, I13, I14, I18, J13, O15)
Design and Implementation of Battery Charger with Power Factor Correction using Sepic Converter and Full-bridge DC-DC Converter
Authors: Efendi Moh. Zaenal , Windarko Novie Ayub , Amir Moh. Faisal
Published: December 2013

This paper presents a design and implementation of a converter which has a high power factor for battery charger application. The converter is a combination of a SEPIC converter and a full-bridge DC-DC converter connected in two stages of series circuit. The SEPIC converter works in discontinuous conduction mode and it serves as a power factor corrector so that the shape of input current waveform follows the shape of input voltage waveform. The full-bridge DC-DC converter serves as a regulator of output voltage and operates at continuous conduction mode. The experimental results show that the power factor of this converter system can be achieved up to 0.96.
Multigenic Natural Variation UnderliesCaenorhabditis elegansOlfactory Preference for the Bacterial PathogenSerratia marcescens
Authors: Glater Elizabeth E , Rockman Matthew V , Bargmann Cornelia I
Published: December 2013

The nematode Caenorhabditis elegans can use olfaction to discriminate among different kinds of bacteria, its major food source. We asked how natural genetic variation contributes to choice behavior, focusing on differences in olfactory preference behavior between two wild-type C. elegans strains. The laboratory strain N2 strongly prefers the odor of Serratia marcescens, a soil bacterium that is pathogenic to C. elegans, to the odor of Escherichia coli, a commonly used laboratory food source. The divergent Hawaiian strain CB4856 has a weaker attraction to Serratia than the N2 strain, and this behavioral difference has a complex genetic basis. At least three quantitative trait loci (QTLs) from the CB4856 Hawaii strain (HW) with large effect sizes lead to reduced Serratia preference when introgressed into an N2 genetic background. These loci interact and have epistatic interactions with at least two antagonistic QTLs from HW that increase Serratia preference. The complex genetic architecture of this C. elegans trait is reminiscent of the architecture of mammalian metabolic and behavioral traits.
Why Breeding Values Estimated Using Familial Data Should Not Be Used for Genome-Wide Association Studies
Authors: Ekine Chinyere C , Rowe Suzanne J , Bishop Stephen C , de Koning Dirk-Jan
Published: December 2013

In animal breeding, the genetic potential of an animal is summarized as its estimated breeding value, which is derived from its own performance as well as the performance of related individuals. Here, we illustrate why estimated breeding values are not suitable as a phenotype for genome-wide association studies. We simulated human-type and pig-type pedigrees with a range of quantitative trait loci (QTL) effects (0.5–3% of phenotypic variance) and heritabilities (0.3−0.8). We analyzed 1000 replicates of each scenario with four models: (a) a full mixed model including a polygenic effect, (b) a regression analysis using the residual of a mixed model as a trait score (so called GRAMMAR approach), (c) a regression analysis using the estimated breeding value as a trait score, and (d) a regression analysis that uses the raw phenotype as a trait score. We show that using breeding values as a trait score gives very high false-positive rates (up 14% in human pedigrees and >60% in pig pedigrees). Simulations based on a real pedigree show that additional generations of pedigree increase the type I error. Including the family relationship as a random effect provides the greatest power to detect QTL while controlling for type I error at the desired level and providing the most accurate estimates of the QTL effect. Both the use of residuals and the use of breeding values result in deflated estimates of the QTL effect. We derive the contributions of QTL effects to the breeding value and residual and show how this affects the estimates.
Identification of Suppressors ofmbk-2/DYRKby Whole-Genome Sequencing
Authors: Wang Yuemeng , Wang Jennifer T , Rasoloson Dominique , Stitzel Michael L , O’ Connell Kevin F , Smith Harold E , Seydoux Geraldine
Published: December 2013

Screening for suppressor mutations is a powerful method to isolate genes that function in a common pathway or process. Because suppressor mutations often do not have phenotypes on their own, cloning of suppressor loci can be challenging. A method combining whole-genome sequencing (WGS) and single nucleotide polymorphism (SNP) mapping (WGS/SNP mapping) was developed to identify mutations with visible phenotypes in C. elegans. We show here that WGS/SNP mapping is an efficient method to map suppressor mutations without the need for previous phenotypic characterization. Using RNA-mediated interference to test candidate loci identified by WGS/SNP mapping, we identified 10 extragenic and six intragenic suppressors of mbk-2, a DYRK family kinase required for the transition from oocyte to zygote. Remarkably, seven suppressors are mutations in cell-cycle regulators that extend the timing of the oocyte-to-zygote transition.
Extensive Use of RNA-Binding Proteins inDrosophilaSensory Neuron Dendrite Morphogenesis
Authors: Olesnicky Eugenia C , Killian Darrell J , Garcia Evelyn , Morton Mary C , Rathjen Alan R , Sola Ismail E , Gavis Elizabeth R
Published: December 2013

The large number of RNA-binding proteins and translation factors encoded in the Drosophila and other metazoan genomes predicts widespread use of post-transcriptional regulation in cellular and developmental processes. Previous studies identified roles for several RNA-binding proteins in dendrite branching morphogenesis of Drosophila larval sensory neurons. To determine the larger contribution of post-transcriptional gene regulation to neuronal morphogenesis, we conducted an RNA interference screen to identify additional Drosophila proteins annotated as either RNA-binding proteins or translation factors that function in producing the complex dendritic trees of larval class IV dendritic arborization neurons. We identified 88 genes encoding such proteins whose knockdown resulted in aberrant dendritic morphology, including alterations in dendritic branch number, branch length, field size, and patterning of the dendritic tree. In particular, splicing and translation initiation factors were associated with distinct and characteristic phenotypes, suggesting that different morphogenetic events are best controlled at specific steps in post-transcriptional messenger RNA metabolism. Many of the factors identified in the screen have been implicated in controlling the subcellular distributions and translation of maternal messenger RNAs; thus, common post-transcriptional regulatory strategies may be used in neurogenesis and in the generation of asymmetry in the female germline and embryo.
Accuracy of Early DMSA Scan for VUR in Young Children With Febrile UTI
Authors: Zhang Xin , Xu Hong , Zhou Lijun , Cao Qi , Shen Qian , Sun Li , Fang Xiaoyan , Guo Wei , Zhai Yihui , Rao Jia , Pa Mier , Zhao Ruifang , Bi Yunli
Published: December 2013

OBJECTIVE:

To evaluate the accuracy of an acute 99mTc-dimercaptosuccinic acid (DMSA) scan in predicting dilating vesicoureteral reflux (VUR) among young children with a febrile urinary tract infection (UTI).

METHODS:

The medical records of children (≤2 years of age), presenting with febrile UTI between January 2000 and December 2011, were retrospectively reviewed.

RESULTS:

A total of 523 children were included in this study, of whom 397 children (75.9%) had abnormal DMSA results and 178 children (34.0%) were identified as VUR on micturating cystourethrography (MCU). Among all the patients, the number of children with dilating VUR was 151 (28.9%). The rate of abnormal results on DMSA for the dilating VUR group was significantly higher than the rates for the non-VUR and low-grade VUR groups (P < .01). In the <6 months age group and ≥6 months age group, the sensitivities of DMSA in predicting dilating VUR were 96.15% and 100.0%, respectively, the negative predictive values were 97.26% and 100.0%, respectively, and the negative likelihood ratios were 0.0911 and 0.0000, respectively.

CONCLUSION:

For children ≤2 years of age with a febrile UTI, an acute DMSA scan is valuable in the exclusion of dilating VUR. The likelihood of the presence of dilating VUR on MCU is rather low when the result of DMSA is negative. DMSA should be conducted to assess the need for an MCU.
Pneumococcal Antibody Levels in Children With PID Receiving Immunoglobulin
Authors: Tuerlinckx David , Florkin Benoit , Ferster Alina , De Schutter Iris , Chantrain Christophe , Haerynck Filomeen , Philippet Pierre , Strengers Paul , Laub Ruth
Published: December 2013

OBJECTIVES:

Clinical data are lacking on optimal levels of specific antipneumococcal antibodies (PnPsAbs) in patients with primary immunodeficiency (PID) receiving intravenous immunoglobulin (IVIG) replacement. Objectives were to conduct a prospective multicenter study providing data on total immunoglobulin G (IgG) and peak/trough levels of PnPsAbs specifically targeting the 16 most prevalent pneumococcal serotypes in IVIG-treated children with PID; to compare trough PnPsAb levels with those measured in healthy adults and the IVIG product; and to evaluate PnPsAb protection correlates with thresholds based on World Health Organization.

METHODS:

Patients received 7 consecutive IVIG infusions. Total IgG and PnPsAb levels were determined on plasma samples obtained before and after infusion.

RESULTS:

Twenty-two children with PID were treated with IVIG (mean weekly dose: 0.10 g/kg). The mean trough and peak levels of total IgG were 7.77 and 13.93 g/L, respectively. Trough and peak geometric mean concentrations and distribution curves differed between serotypes and showed wide dispersion (0.17–7.96 µg/mL). In patients (89%–100%), antibodies against most serotypes reached trough levels ≥0.2 µg/mL, a threshold considered protective against invasive pneumococcal infection. For several serotypes, trough levels reached ≥1.0 to 1.3 µg/mL, the level found in adults. Trough geometric mean concentrations correlated well with the PnPsAb contents of the IVIG product.

CONCLUSIONS:

In IVIG-treated children with PID, protective PnPsAb levels for most pathogenic serotypes were obtained. A correlation was observed between PnPsAb levels in patients and in the IVIG product. This offers the potential to improve infection prevention by adapting the IVIG product and dose according to epidemiology.
Stratification of Risk of Early-Onset Sepsis in Newborns ≥34 Weeks’ Gestation
Authors: Escobar Gabriel J. , Puopolo Karen M. , Wi Soora , Turk Benjamin J. , Kuzniewicz Michael W. , Walsh Eileen M. , Newman Thomas B. , Zupancic John , Lieberman Ellice , Draper David
Published: December 2013

OBJECTIVE:

To define a quantitative stratification algorithm for the risk of early-onset sepsis (EOS) in newborns ≥34 weeks’ gestation.

METHODS:

We conducted a retrospective nested case-control study that used split validation. Data collected on each infant included sepsis risk at birth based on objective maternal factors, demographics, specific clinical milestones, and vital signs during the first 24 hours after birth. Using a combination of recursive partitioning and logistic regression, we developed a risk classification scheme for EOS on the derivation dataset. This scheme was then applied to the validation dataset.

RESULTS:

Using a base population of 608 014 live births ≥34 weeks’ gestation at 14 hospitals between 1993 and 2007, we identified all 350 EOS cases <72 hours of age and frequency matched them by hospital and year of birth to 1063 controls. Using maternal and neonatal data, we defined a risk stratification scheme that divided the neonatal population into 3 groups: treat empirically (4.1% of all live births, 60.8% of all EOS cases, sepsis incidence of 8.4/1000 live births), observe and evaluate (11.1% of births, 23.4% of cases, 1.2/1000), and continued observation (84.8% of births, 15.7% of cases, incidence 0.11/1000).

CONCLUSIONS:

It is possible to combine objective maternal data with evolving objective neonatal clinical findings to define more efficient strategies for the evaluation and treatment of EOS in term and late preterm infants. Judicious application of our scheme could result in decreased antibiotic treatment in 80 000 to 240 000 US newborns each year.
The Role of Non-Native Interactions in the Folding of Knotted Proteins: Insights from Molecular Dynamics Simulations
Authors: Covino Roberto , Škrbić Tatjana , Beccara Silvio , Faccioli Pietro , Micheletti Cristian
Published: December 2013

For several decades, the presence of knots in naturally-occurring proteins was largely ruled out a priori for its supposed incompatibility with the efficiency and robustness of folding processes. For this very same reason, the later discovery of several unrelated families of knotted proteins motivated researchers to look into the physico-chemical mechanisms governing the concerted sequence of folding steps leading to the consistent formation of the same knot type in the same protein location. Besides experiments, computational studies are providing considerable insight into these mechanisms. Here, we revisit a number of such recent investigations within a common conceptual and methodological framework. By considering studies employing protein models with different structural resolution (coarse-grained or atomistic) and various force fields (from pure native-centric to realistic atomistic ones), we focus on the role of native and non-native interactions. For various unrelated instances of knotted proteins, non-native interactions are shown to be very important for favoring the emergence of conformations primed for successful self-knotting events.
Optimum Settings for a Compound Parabolic Concentrator with Wings Providing Increased Duration of Effective Temperature for Solar-Driven Systems: A Case Study for Tokyo
Authors: Umair Muhammad , Akisawa Atsushi , Ueda Yuki
Published: December 2013

We designed a compound parabolic concentrator (CPC) with wings angled toward the east and west. Normally, solar collectors are straight, facing south, and the effective temperature is only achieved for a short period of time at midday. In the proposed design, the collector is divided into three parts, with the ends angled and tilted at different orientations. The objective was to increase the duration of the effective temperature period by capturing the maximum solar energy in the morning and afternoon without tracking by the collector. A simulation model was developed to evaluate the performance of the proposed CPC. The tilt and bending angles of the CPC wings were optimized for year-round operation in Tokyo, Japan. A 35° tilt for the south-facing central part of the CPC and a 45° tilt for the wings with 50° angles toward the east and west were found to be optimal. Analyses were conducted at these optimum settings with temperatures of 70, 80, and 90 °C as minimum requirements. The effective duration increased by up to 2 h in the winter and up to 2.53 h in the summer using the proposed CPC. The proposed CPC will improve the efficiency of solar-driven systems by providing useful heat for longer periods of time with the same collector length and without the need for tracking.
Effectiveness of a Multi-Component Smoking Cessation Support Programme (McSCSP) for Patients with Severe Mental Disorders: Study Design
Authors: Garcia-Portilla Maria , Garcia-Alvarez Leticia , Saiz Pilar , Diaz-Mesa Eva , Galvan Gonzalo , Sarramea Fernando , Garcia-Blanco Josefa , Elizagarate Edorta , Bobes Julio
Published: December 2013

Only a few studies have examined the efficacy and safety of smoking cessation programmes in patients with mental disorders. The aim of this paper is to describe in detail the methodology used in the study as well as the Multi-component Smoking Cessation Support Programme in terms of pharmacological treatments and psychological interventions. An open-label 9-month follow-up study was conducted in Spain. A total of 82 clinically stable outpatients with schizophrenia, schizoaffective or bipolar disorder were enrolled. Treatment consisted of a programme specifically developed by the research team for individuals with severe mental disorders. The programme consisted of two phases: (1) weekly individual motivational therapy for 4–12 weeks, and (2) a 12-week active treatment phase. During this phase, at each study visit patients received a one- or two-week supply of medication (transdermal nicotine patches, varenicline or bupropion) with instructions on how to take it, in addition to group psychotherapy for smoking cessation. Evaluations were performed: (1) at the time of enrolment in the study, (2) during the 12-week active treatment phase of the study (weekly for the first 4 weeks and then biweekly), and (3) after the end of this phase (two follow-up assessments at weeks 12 and 24). Evaluations included: (1) smoking history, (2) substance use, (3) psychopathology, (4) adverse events, and (5) laboratory tests. The importance of this study lies in addressing a topical issue often ignored by psychiatrists: the unacceptably high rates of tobacco use in patients with severe mental disorders.
The Effect of 5'-Adenylic Acid on Hepatic Proteome of Mice Radiated by 60Co γ-ray
Authors: Cheng Cuilin , Zhao Haitian , Wang Zhenyu , Lu Weihong , Wang Lu , Wang Rongchun , Yao Lei
Published: December 2013

Understanding the protection mechanism of 5'-AMP requires comprehensive knowledge of the proteins expressed during the period that the body is exposed to irradiation. Proteomics provides the tools for such analyses. Here, the experimental ICR mice were divided into three groups (normal group, model group and 5'-AMP + irradiation group). After different treatment, the hepatic total protein of each animal in three groups was separated by two-dimensional gel electrophoresis (2-DE). 2-DE analysis revealed fifty-eight protein spots were differentially expressed in comparison to three groups. From 58 protein spots, we selected nine spots to identify by MALDI-TOF-MS and received credible results. They were determined to be type I arginase, annexin A5, regucalcin, catalase, Tpm3 protein, Pdia4 protein, 14-3-3 protein epsilon, NAD-Malate dehydrogenase and heat shock protein 90. Considering the characteristic of these proteins, we proposed a possible protection pathway.