bluuebunny/crossref_metadata_2025 huggingface dataset:
Drug Resistance, Up Close and Personal
Authors: Kiberstis Paula A.
Published: December 2014

Secondary chemotherapies can be developed by screening drug-resistant cells from individual cancer patients.
Immune Regulatory Functions of Mutant p53
Authors: Gough Nancy R.
Published: December 2014

Cells with hotspot mutations in p53 exhibit an altered response to TNF-α, which increases metastatic potential, reduces apoptosis, and recruits immune cells.
The MSPDBL2 Codon 591 Polymorphism Is Associated with Lumefantrine
In Vitro
Drug Responses in Plasmodium falciparum Isolates from Kilifi, Kenya
Authors: Ochola-Oyier Lynette Isabella , Okombo John , Mwai Leah , Kiara Steven M. , Pole Lewa , Tetteh Kevin K. A. , Nzila Alexis , Marsh Kevin
Published: December 2014

The mechanisms of drug resistance development in the
Plasmodium falciparum
parasite to lumefantrine (LUM), commonly used in combination with artemisinin, are still unclear. We assessed the polymorphisms of
Pfmspdbl2
for associations with LUM activity in a Kenyan population. MSPDBL2 codon 591S was associated with reduced susceptibility to LUM (
P
= 0.04). The high frequency of
Pfmspdbl2
codon 591S in Kenya may be driven by the widespread use of lumefantrine in artemisinin combination therapy (Coartem).
Posaconazole Prophylaxis in Experimental Azole-Resistant Invasive Pulmonary Aspergillosis
Authors: Seyedmousavi Seyedmojtaba , Mouton Johan W. , Melchers Willem J. G. , Verweij Paul E.
Published: December 2014

We investigated the efficacy of posaconazole prophylaxis in preventing invasive aspergillosis due to azole-resistant
Aspergillus fumigatus
isolates. Using a neutropenic murine model of pulmonary infection, posaconazole prophylaxis was evaluated using three isogenic clinical isolates, with posaconazole MICs of 0.063 mg/liter (wild type), 0.5 mg/liter (F219I mutation), and 16 mg/liter. A fourth isolate harboring TR
34
/L98H (MIC of 0.5 mg/liter) was also tested. Posaconazole prophylaxis was effective in
A. fumigatus
with posaconazole MICs of ≤0.5 mg/liter, where 100% survival was reached. However, breakthrough infection was observed in mice infected with the isolate for which the posaconazole MIC was >16 mg/liter.
A High-Affinity Native Human Antibody Neutralizes Human Cytomegalovirus Infection of Diverse Cell Types
Authors: Kauvar Lawrence M. , Liu Keyi , Park Minha , DeChene Neal , Stephenson Robert , Tenorio Edgar , Ellsworth Stote L. , Tabata Takako , Petitt Matthew , Tsuge Mitsuru , Fang-Hoover June , Adler Stuart P. , Cui Xiaohong , McVoy Michael A. , Pereira Lenore
Published: December 2014

Human cytomegalovirus (HCMV) is the most common infection causing poor outcomes among transplant recipients. Maternal infection and transplacental transmission are major causes of permanent birth defects. Although no active vaccines to prevent HCMV infection have been approved, passive immunization with HCMV-specific immunoglobulin has shown promise in the treatment of both transplant and congenital indications. Antibodies targeting the viral glycoprotein B (gB) surface protein are known to neutralize HCMV infectivity, with high-affinity binding being a desirable trait, both to compete with low-affinity antibodies that promote the transmission of virus across the placenta and to displace nonneutralizing antibodies binding nearby epitopes. Using a miniaturized screening technology to characterize secreted IgG from single human B lymphocytes, 30 antibodies directed against gB were previously cloned. The most potent clone, TRL345, is described here. Its measured affinity was 1 pM for the highly conserved site I of the AD-2 epitope of gB. Strain-independent neutralization was confirmed for 15 primary HCMV clinical isolates. TRL345 prevented HCMV infection of placental fibroblasts, smooth muscle cells, endothelial cells, and epithelial cells, and it inhibited postinfection HCMV spread in epithelial cells. The potential utility for preventing congenital transmission is supported by the blockage of HCMV infection of placental cell types central to virus transmission to the fetus, including differentiating cytotrophoblasts, trophoblast progenitor cells, and placental fibroblasts. Further, TRL345 was effective at controlling an
ex vivo
infection of human placental anchoring villi. TRL345 has been utilized on a commercial scale and is a candidate for clinical evaluation.
Photoheterotrophic Fluxome in Synechocystis sp. Strain PCC 6803 and Its Implications for Cyanobacterial Bioenergetics
Authors: You Le , He Lian , Tang Yinjie J.
Published: December 2014

This study investigated metabolic responses in
Synechocystis
sp. strain PCC 6803 to photosynthetic impairment. We used 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU; a photosystem II inhibitor) to block O
2
evolution and ATP/NADPH generation by linear electron flow. Based on
13
C-metabolic flux analysis (
13
C-MFA) and RNA sequencing, we have found that
Synechocystis
sp. PCC 6803 employs a unique photoheterotrophic metabolism. First, glucose catabolism forms a cyclic route that includes the oxidative pentose phosphate (OPP) pathway and the glucose-6-phosphate isomerase (PGI) reaction. Glucose-6-phosphate is extensively degraded by the OPP pathway for NADPH production and is replenished by the reversed PGI reaction. Second, the Calvin cycle is not fully functional, but RubisCO continues to fix CO
2
and synthesize 3-phosphoglycerate. Third, the relative flux through the complete tricarboxylic acid (TCA) cycle and succinate dehydrogenase is small under heterotrophic conditions, indicating that the newly discovered cyanobacterial TCA cycle (via the γ-aminobutyric acid pathway or α-ketoglutarate decarboxylase/succinic semialdehyde dehydrogenase) plays a minimal role in energy metabolism. Fourth, NAD(P)H oxidation and the cyclic electron flow (CEF) around photosystem I are the two main ATP sources, and the CEF accounts for at least 40% of total ATP generation from photoheterotrophic metabolism (without considering maintenance loss). This study not only demonstrates a new topology for carbohydrate oxidation but also provides quantitative insights into metabolic bioenergetics in cyanobacteria.
A
prl
Mutation in SecY Suppresses Secretion and Virulence Defects of Listeria monocytogenes secA2 Mutants
Authors: Durack Juliana , Burke Thomas P. , Portnoy Daniel A.
Published: December 2014

The bulk of bacterial protein secretion occurs through the conserved SecY translocation channel that is powered by SecA-dependent ATP hydrolysis. Many Gram-positive bacteria, including the human pathogen
Listeria monocytogenes
, possess an additional nonessential specialized ATPase, SecA2. SecA2-dependent secretion is required for normal cell morphology and virulence in
L. monocytogenes
; however, the mechanism of export via this pathway is poorly understood.
L. monocytogenes
secA2
mutants form rough colonies, have septation defects, are impaired for swarming motility, and form small plaques in tissue culture cells. In this study, 70 spontaneous mutants were isolated that restored swarming motility to
L. monocytogenes
secA2
mutants. Most of the mutants had smooth colony morphology and septated normally, but all were lysozyme sensitive. Five representative mutants were subjected to whole-genome sequencing. Four of the five had mutations in proteins encoded by the
lmo2769
operon that conferred lysozyme sensitivity and increased swarming but did not rescue virulence defects. A point mutation in
secY
was identified that conferred smooth colony morphology to
secA2
mutants, restored wild-type plaque formation, and increased virulence in mice. This
secY
mutation resembled a
prl
suppressor known to expand the repertoire of proteins secreted through the SecY translocation complex. Accordingly, the Δ
secA2prlA1
mutant showed wild-type secretion levels of P60, an established SecA2-dependent secreted autolysin. Although the
prl
mutation largely suppressed almost all of the measurable SecA2-dependent traits, the Δ
secA2prlA1
mutant was still less virulent
in vivo
than the wild-type strain, suggesting that SecA2 function was still required for pathogenesis.
Adrenal tumours: how to establish malignancy
Authors: Toogood Vanita , Milliken Sam , Morey Adrienne , Samaras Katherine
Published: December 2014

Adrenal masses are commonly found in the course of abdominal investigations and present diagnostic challenges. The foremost issue is whether the mass is the cause of the symptoms being investigated. Additional important clinical questions are: (1) is the adrenal mass benign or malignant and (2) whether the adrenal mass is functional or non-functional? We present a case of a 48-year-old man with severe abdominal pain. Imaging revealed a very large adrenal mass. Differential diagnostic procedures were performed and a diagnosis of primary adrenal lymphoma, an extremely rare cause of adrenal malignancy, was made. He proceeded to chemotherapy with cyclical cyclophosphamide, doxorubicin, etoposide and prednisolone, in addition to rituximab. This case illustrates the importance of establishing the nature of adrenal masses, to rapidly facilitate appropriate treatment.
Sclerosing osteomyelitis of Garré: management of femoral pain by intramedullary nailing
Authors: Vannet Nicola Bader , Williams Huw L M , Healy Brendan , Morgan-Jones Rhidian
Published: December 2014

We describe a case of chronic sclerosing osteomyelitis of Garré in a 50-year-old woman occurring in her right femur and presenting with uncontrolled pain. The patient was initially treated with intramedullary reaming of the femur, but 3 years later re-presented with similar symptoms. This required further reaming and intramedullary nailing, achieving good clinical outcomes and lasting pain relief at 8-year follow-up.
Compartment syndrome resulting from undetected ulnar artery injury in the absence of a forearm fracture
Authors: Chadha Priyanka , Lloyd-Hughes Hawys , Halsey Timothy
Published: December 2014

A 6-year-old boy presented following a transient crush injury to his forearm. He displayed mild abrasions but no laceration or associated fractures. The injury resulted in traumatic rupture of the ulnar artery, which caused a large forearm haematoma and an acute forearm compartment syndrome. Prompt clinical diagnosis and operative intervention were required to prevent disastrous consequences.
Internal hernia in late pregnancy after laparoscopic Roux-en-Y gastric bypass
Authors: Gruetter Florian , Kraljević Marko , Nebiker Christian A , Delko Tarik
Published: December 2014

A 27-year-old patient in late pregnancy presented to the department of obstetrics with crampy abdominal pain located in the right flank, 3 years after a laparoscopic Roux-en-Y gastric bypass. Clinical investigation showed tenderness on palpation in the upper abdomen without signs of peritonitis. The cardiotocogram and blood tests were normal. The ultrasound showed a hydronephrosis on the right side, and a pigtail catheter was inserted. The abdominal symptoms did not abate and the abdominal surgeon was consulted 36 hours after admission. Diagnostic laparoscopy was performed promptly because of high suspicion of internal hernia (IH). Laparoscopy showed IH at the mesojejunal intermesenteric defect with a herniated common channel and volvulus of the anastomosis. Conversion to open reduction and complete closure with non-absorbable interrupted sutures was performed. Small bowel resection was avoided. The patient was discharged 10 days after the operation and a healthy boy was born 4 weeks later.
Granulocytic sarcoma in a patient with chronic myeloid leukaemia in complete haematological, cytogenetic and molecular remission
Authors: Kittai Adam , Yu Eun-Mi , Tabbara Imad
Published: December 2014

Granulocytic sarcoma, also known as myeloid sarcoma, is an extramedullary tumour composed of immature myeloid cells. Granulocytic sarcoma is typically found in patients with acute myeloid leukaemia, accelerated phase or blast crisis of chronic myeloid leukaemia, myelodysplastic syndrome, or as an isolated event without bone marrow involvement. We present a case of granulocytic sarcoma in a patient with chronic myeloid leukaemia in the setting of complete haematological, molecular and cytogenetic remission. Our patient was first treated with imatinib for chronic-phase chronic myeloid leukaemia. After maintaining remission for 42 months, he developed a granulocytic sarcoma in his spine. In this case report, we describe our case, along with the three other cases reported in the literature. In addition to being a rare diagnosis, this case demonstrates the importance of being vigilant in diagnosing the cause of back pain and atypical symptoms in patients with a history of leukaemia.
Pulmonary tuberculosis among migrants in Shandong, China: factors associated with treatment delay
Authors: Zhou Chengchao , Chu Jie , Geng Hong , Wang Xingzhou , Xu Lingzhong
Published: December 2014

Objective

A timely initiation of treatment is crucial to better control tuberculosis (TB). The aim of this study is to describe treatment delay among migrant patients with TB and to identify factors associated with treatment delay, so as to provide evidence for strategy development and improvement of TB control among migrants in China.

Design

A cross-sectional study was conducted in Shandong province of China. A total of 314 confirmed smear positive migrant patients with pulmonary TB were included. Univariate logistic regression was used to analyse the association of variables with treatment delay among migrant patients with TB. A multilogistic regression model was developed to further assess the effect of variables on treatment delay.

Results

Of 314 migrant patients with TB, 65.6% experienced treatment delay (>1 day). Household income level, diagnosis symptom severity, understanding of whether TB is curable or not and knowledge about the free TB treatment policy are factors significantly associated with treatment delay.

Conclusions

Economic status and knowledge about TB are key barriers to accessing TB treatment. An integrated policy of carrying out TB-related health education and publicising the free TB treatment policy among migrants is needed. Health insurance schemes for migrants should be modified to make them transferrable and pro-poor.
Historical cancer incidence and mortality assessment in an Illinois community proximal to a former manufactured gas plant
Authors: Alexander Dominik D , Jiang Xiaohui , Bylsma Lauren C , Garabrant David H , Irvin Sarah R , Fryzek Jon P
Published: December 2014

Objectives

Concern has been raised that the occurrence of cancer may be increased in neighbourhoods around a former manufactured gas plant in Champaign, Illinois, USA. Thus, we compared historical rates of cancer in this area to comparison communities as well as with nationally standardised rates.

Design

Retrospective population-based community cancer assessment during 1990–2010.

Setting

Champaign County, Illinois, USA, and zip codes encompassing the location of the former manufactured gas plant to counties that were similar demographically.

Participants

Residents of the counties and zip codes studied between 1990 and 2010.

Main outcome measures

The relative risk (RR) and 95% CI were used to compare cancer incidence and mortality in the areas near the gas compression site to the comparison counties. Standardised incidence ratios (SIRs) were calculated to compare rates in the areas near the gas compression site to expected rates based on overall US cancer rates.

Results

Total cancer mortality (RR=0.91, 95% CI 0.88 to 0.94) and incidence (RR=0.95, 95% CI 0.94 to 0.97) were reduced significantly in Champaign County versus the comparison counties. Similarly, a reduced rate of total cancer was observed in analyses by zip code (proximal to the former gas plant) when compared with either similar counties (RR=0.89, 95% CI 0.86 to 0.93) or national standardised rates of cancer (SIR=0.88, 95% CI 0.85 to 0.91).

Conclusions

This historical cancer assessment did not find an increased risk of total cancer or specific cancer types in communities near a former manufactured gas plant site.
Can child injury prevention include healthy risk promotion?
Authors: Brussoni Mariana , Brunelle Sara , Pike Ian , Sandseter Ellen Beate Hansen , Herrington Susan , Turner Heather , Belair Scott , Logan Louise , Fuselli Pamela , Ball David J
Published: December 2014

To reflect on the role of risk-taking and risky play in child development and consider recommendations for the injury prevention field, a symposium was held prior to the November 2013 Canadian Injury Prevention and Safety Promotion Conference. Delegates heard from Canadian and international researchers, practitioners and play safety experts on child development, play space design and playground safety, provision of recreation, and legal and societal perceptions of risk and hazard. The presenters provided multidisciplinary evidence and perspectives indicating the potential negative effect on children's development of approaches to injury prevention that prioritise safety and limit children's opportunities for risky play. Delegates considered the state of the field of injury prevention and whether alternative approaches were warranted. Each presenter prepared a discussion paper to provide the opportunity for dialogue beyond attendees at the symposium. The resulting discussion papers provide a unique opportunity to consider and learn from multiple perspectives in order to develop a path forward.
Histological Features of the Gastrointestinal Tract of Wild Indonesian Shortfin Eel,Anguilla bicolor bicolor(McClelland, 1844), Captured in Peninsular Malaysia
Authors: Nasruddin Nurrul Shaqinah , Azmai Mohammad Noor Amal , Ismail Ahmad , Saad Mohd Zamri , Daud Hassan Mohd , Zulkifli Syaizwan Zahmir
Published: December 2014

This study was conducted to record the histological features of the gastrointestinal tract of wild Indonesian shortfin eel,Anguilla bicolor bicolor(McClelland, 1844), captured in Peninsular Malaysia. The gastrointestinal tract was segmented into the oesophagus, stomach, and intestine. Then, the oesophagus was divided into five (first to fifth), the stomach into two (cardiac and pyloric), and the intestine into four segments (anterior, intermediate, posterior, and rectum) for histological examinations. The stomach had significantly taller villi and thicker inner circular muscles compared to the intestine and oesophagus. The lamina propria was thickest in stomach, significantly when compared with oesophagus, but not with the intestine. However, the intestine showed significantly thicker outer longitudinal muscle while gastric glands were observed only in the stomach. The histological features were closely associated with the functions of the different segments of the gastrointestinal tract. In conclusion, the histological features of the gastrointestinal tract ofA. b. bicolorare consistent with the feeding habit of a carnivorous fish.
Directing Parthenogenetic Stem Cells Differentiate into Adipocytes for Engineering Injectable Adipose Tissue
Authors: Liu Wei , Yang Xingyuan , Yan Xingrong , Cui Jihong , Liu Wenguang , Sun Mei , Rao Yang , Chen Fulin
Published: December 2014

The selection of appropriate seed cells is crucial for adipose tissue engineering. Here, we reported the stepwise induction of parthenogenetic embryonic stem cells (pESCs) to differentiate into adipogenic cells and its application in engineering injectable adipose tissue with Pluronic F-127. pESCs had pluripotent differentiation capacity and could form teratomas that include the three primary germ layers. Cells that migrated from the embryoid bodies (EBs) were selectively separated and expanded to obtain embryonic mesenchymal stem cells (eMSCs). The eMSCs exhibited similar cell surface marker expression profiles with bone morrow mesenchymal stem cells (BMSCs) and had multipotent differentiation capacity. Under the induction of dexamethasone, indomethacin, and insulin, eMSCs could differentiate into adipogenic cells with increased expression of adipose-specific genes and oil droplet depositions within the cytoplasm. To evaluate their suitability as seed cells for adipose tissue engineering, the CM-Dil labelled adipogenic cells derived from eMSCs were seeded into Pluronic F-127 hydrogel and injected subcutaneously into nude mice. Four weeks after injection, glistering and semitransparent constructs formed in the subcutaneous site. Histological observations demonstrated that new adipose tissue was successfully fabricated in the specimen by the labelled cells. The results of the current study indicated that pESCs have great potential in the fabrication of injectable adipose tissue.
Adult T-Cell Lymphoma/Leukemia Presenting as Isolated Central Nervous System T-Cell Lymphoma
Authors: Ma Wei-Li , Li Chi-Cheng , Yu Shan-Chi , Tien Hwei-Fang
Published: December 2014

Adult T-cell leukemia/lymphoma (ATLL) is a T-cell neoplasm, associated with infection by the retrovirus human T-lymphotropic virus type 1 (HTLV-1). Central nervous system (CNS) involved by ATLL is often occurred in advanced disease, such as acute and lymphomatous variants. On the other hand, isolated CNS lymphoma is rare. We repot a 50-year-old woman who presented with multiple infiltrative brain lesions on the magnetic resonance (MR) imaging. Results of initial biopsy of brain tumor indicated CNS vasculitis. The patient received one course of high-dose methotrexate and MR imaging of brain revealed remission of infiltrative lesions. Two years later, new brain lesions were detected. Histopathologic examination of specimens via craniotomy revealed T-cell lymphoma. The patient responded poorly to subsequent chemotherapy, and salvage whole-brain irradiation was performed. Six months later, the patient had hepatosplenomegaly, hypercalcemia, and multiple lymphocytes with a cloverleaf appearance in circulation. Results of flow cytometry analysis of peripheral blood indicated ATLL and antibodies to human T-lymphotropic virus type 1 (HTLV-1) were detected. Clinicians should screen HTLV-1 infection when patients are diagnosed with peripheral T-cell lymphoma. Combined antiviral therapy and intensive chemotherapy may improve the outcomes of ATLL.
Cross-Sectional Evaluation of Kidney Function in Hospitalized Patients: Estimated GFR Versus Renal Scintigraphy
Authors: Santoro Domenico , Zappulla Zaira , Alibrandi Angela , Andulajevic Milos Tomasello , Licari Maria , Baldari Sergio , Buemi Michele , Cernaro Valeria , Campennὶ Alfredo
Published: December 2014

Background/Aims: Accurate staging of chronic kidney disease (CKD) is very important. We tried to identify difference in GFR evaluation between CKD-EPI and Gates method with renal scintigraphy and which variables are associated with these differences. Methods: We retrospectively reviewed the records of 341 patients who underwent dynamic renal scintigraphy in the last 5 years. Patients were categorized according to KDIGO staging I to V, using the eGFR calculated with the CKD-EPI equation. Secondarily, we stratified patients according to treatment with renin-angiotensin system (RAS) inhibitors. Results: Gates method tends to underestimate GFR especially in CKD stage I (mean -22.2 ml/min) and II (mean -12.5 ml/min). The division in quartiles of ages showed an underestimation of GFR only in the first quartile of age (< 50 years old). Gates method underestimation of GFR was more pronounced in stage I patients treated with RAS inhibitors (mean -34.6 ml/min). The same occurs in stage II, even though to a lesser extent. Conclusion: The assessment of GFR by the Gates method must be carefully considered in the early stages of CKD, especially in younger patients. Moreover, the difference is more pronounced in patients treated with RAS inhibitors. Longitudinal studies will prove which method better predicts cardiovascular or renal events.
Genetic Variants in Renalase and Blood Pressure Responses to Dietary Salt and Potassium Interventions: A Family-Based Association Study
Authors: Wang Yang , Chu Chao , Ren Jie , Mu Jian-Jun , Wang Dan , Liu Fu-Qiang , Ren Ke-Yu , Guo Tong-Shuai , Yuan Zu-Yi
Published: December 2014

Background/Aims: Renalase (gene name RNLS), a recently discovered enzyme with monoamine oxidase activity, is implicated in the degradation of catecholamines. Recent studies indicate that common variations in the gene with RNLS are associated with hypertension. The aim of this study was to examine the association between genetic variants in RNLS and blood pressure (BP) responses to strict dietary interventions of salt and potassium intake. Methods: A total of 334 subjects from 124 families were selected and sequentially maintained on a low-salt diet for 7 days (3.0 g/day, NaCl), then a high-salt diet for 7 days (18.0 g/day, NaCl), high-salt diet with potassium supplementation for another 7 days (4.5 g/day, KCl). Results: SNPs rs919115 and rs792205 of the RNLS gene were significantly associated with diastolic BP (DBP) and mean arterial pressure (MAP) responses to high-salt intervention. In addition, rs12356177 was significantly associated with systolic BP (SBP) and DBP responses to low-salt diet, and SBP, DBP or MAP during the high-salt intervention. Unfortunately, no associations for the 7 RNLS SNPs with BP response to high-salt diet with potassium supplementation reached nominal statistical significance. Conclusions: This family-based study indicates that genetic variants in the RNLS gene are significantly associated with BP responses to dietary salt intake.
Upregulation of the Creatine Transporter Slc6A8 by Klotho
Authors: Almilaji Ahmad , Sopjani Mentor , Elvira Bernat , Borras José , Dërmaku-Sopjani Miribane , Munoz Carlos , Warsi Jamshed , Lang Undine E. , Lang Florian
Published: December 2014

Background/Aims: The transmembrane Klotho protein contributes to inhibition of 1,25(OH)2D3 formation. The extracellular domain of Klotho protein could function as an enzyme with e.g. β-glucuronidase activity, be cleaved off and be released into blood and cerebrospinal fluid. Klotho regulates several cellular transporters. Klotho protein deficiency accelerates the appearance of age related disorders including neurodegeneration and muscle wasting and eventually leads to premature death. The main site of Klotho protein expression is the kidney. Klotho protein is also appreciably expressed in other tissues including chorioid plexus. The present study explored the effect of Klotho protein on the creatine transporter CreaT (Slc6A8), which participates in the maintenance of neuronal function and survival. Methods: To this end cRNA encoding Slc6A8 was injected into Xenopus oocytes with and without additional injection of cRNA encoding Klotho protein. Creatine transporter CreaT (Slc6A8) activity was estimated from creatine induced current determined by two-electrode voltage-clamp. Results: Coexpression of Klotho protein significantly increased creatine-induced current in Slc6A8 expressing Xenopus oocytes. Coexpression of Klotho protein delayed the decline of creatine induced current following inhibition of carrier insertion into the cell membrane by brefeldin A (5 µM). The increase of creatine induced current by coexpression of Klotho protein in Slc6A8 expressing Xenopus oocytes was reversed by β-glucuronidase inhibitor (DSAL). Similarly, treatment of Slc6A8 expressing Xenopus oocytes with recombinant human alpha Klotho protein significantly increased creatine induced current. Conclusion: Klotho protein up-regulates the activity of creatine transporter CreaT (Slc6A8) by stabilizing the carrier protein in the cell membrane, an effect requiring β-glucuronidase activity of Klotho protein.
Negative Regulation of the Creatine Transporter SLC6A8 by SPAK and OSR1
Authors: Fezai Myriam , Elvira Bernat , Borras Jose , Ben-Attia Mossadok , Hoseinzadeh Zohreh , Lang Florian
Published: December 2014

Background/Aims: Transport regulation involves several kinases including SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1), which are under control of WNK (with-no-K[Lys]) kinases. The present study explored whether SPAK and/or OSR1 participate in the regulation of the creatine transporter CreaT (SLC6A8), which accomplishes Na+ coupled cellular uptake of creatine in several tissues including kidney, intestine, heart, skeletal muscle and brain. Methods: cRNA encoding SLC6A8 was injected into Xenopus laevis oocytes with or without additional injection of cRNA encoding wild-type SPAK, constitutively active T233ESPAK, WNK insensitive T233ASPAK, catalytically inactive D212ASPAK, wild-type OSR1, constitutively active T185EOSR1, WNK insensitive T185AOSR1 and catalytically inactive D164AOSR1. Transporter activity was determined from creatine (1 mM) induced current utilizing dual electrode voltage clamp. Results: Coexpression of wild-type SPAK and of T233ESPAK, but not of T233ASPAK or of D212ASPAK was followed by a significant decrease of creatine induced current in SLC6A8 expressing oocytes. Coexpression of SPAK significantly decreased maximal transport rate. Coexpression of wild-type OSR1, T185EOSR1 and T185AOSR1 but not of D164AOSR1 significantly negatively regulated SLC6A8 activity. OSR1 again decreased significantly maximal transport rate. Conclusions: Both, SPAK and OSR1, are negative regulators of the creatine transporter SLC6A8.
Diagnostic and Prognostic Utility of Neutrophil Gelatinase-Associated Lipocalin (NGAL) in Patients with Cardiovascular Diseases - Review
Authors: Helanova Katerina , Spinar Jindrich , Parenica Jiri
Published: December 2014

NGAL (neutrophil gelatinase-associated lipocalin) is an acute phase protein, participating in antibacterial immunity. NGAL forms a complex with metalloproteinase 9 (MMP-9), thereby increasing its activity and preventing its degradation. NGAL is freely filtered through the glomerular membrane and reabsorbed by endocytosis in the proximal tubule. NGAL detected in urine is produced mainly in the distal nephron. Elevated serum and urine NGAL allows diagnosis of acute kidney injury approximately 24 hours earlier than plasma creatinine concentration. Increased levels of NGAL were detected in patients with acute myocardial infarction, heart failure or stroke and were demonstrated to be strong predictors of adverse prognosis.
Nicotinamide Adenine Dinucleotide Phosphate Oxidase-4–Dependent Upregulation of Nuclear Factor Erythroid–Derived 2-Like 2 Protects the Heart During Chronic Pressure Overload
Authors: Smyrnias Ioannis , Zhang Xiaohong , Zhang Min , Murray Thomas V.A. , Brandes Ralf P. , Schröder Katrin , Brewer Alison C. , Shah Ajay M.
Published: December 2014

The transcription factor nuclear factor erythroid–derived 2-like 2 (Nrf2) controls a network of cytoprotective genes. Neither how Nrf2 is activated in the heart under hemodynamic overload nor its role and mechanism of action are known. This study aimed to investigate the activation and role of Nrf2 during chronic cardiac pressure overload. We first compared the responses of Nrf2
−/−
mice and wild-type littermates to chronic pressure overload. Hearts of Nrf2
−/−
mice showed impaired antioxidant gene expression, increased hypertrophy, and worse function compared with those of wild-type littermates after overload. Hearts of Nrf2
−/−
mice had increased mitochondrial DNA damage, a caspase 8/BH3-interacting domain death agonist–related cleavage of mitochondrial apoptosis–inducing factor, nuclear DNA damage, and cell death. Nrf2 activation was under the control of the endogenous reactive oxygen species–generating enzyme nicotinamide adenine dinucleotide phosphate oxidase-4, both in vivo and in vitro. In mice with cardiac-specific overexpression of nicotinamide adenine dinucleotide phosphate oxidase-4, Nrf2 deletion significantly attenuated their protective phenotype during chronic pressure overload. This study identifies nicotinamide adenine dinucleotide phosphate oxidase-4–dependent upregulation of Nrf2 as an important endogenous protective pathway that limits mitochondrial damage and apoptosis-inducing factor–related cell death in the heart under hemodynamic overload.
Elevated Blood Pressure in Preterm-Born Offspring Associates With a Distinct Antiangiogenic State and Microvascular Abnormalities in Adult Life
Authors: Lewandowski Adam J. , Davis Esther F. , Yu Grace , Digby Janet E. , Boardman Henry , Whitworth Polly , Singhal Atul , Lucas Alan , McCormick Kenny , Shore Angela C. , Leeson Paul
Published: December 2014

Preterm-born individuals have elevated blood pressure. We tested the hypothesis that this associates with an enhanced antiangiogenic circulating profile and that this association is mediated by variations in capillary density. We studied 204 adults aged 25 years (range, 20–30 years), of which 102 had been followed up prospectively since very preterm birth (mean gestational age, 30.3±2.5 weeks) and 102 were born term to uncomplicated pregnancies. A panel of circulating biomarkers, including soluble endoglin and soluble fms-like tyrosine kinase-1, were compared between groups and related to perinatal history and adult cardiovascular risk. Associations with cardiovascular phenotype were studied in 90 individuals who had undergone detailed assessment of microvascular, macrovascular, and cardiac structure and function. Preterm-born individuals had elevations in soluble endoglin (5.64±1.03 versus 4.06±0.85 ng/mL;
P
<0.001) and soluble fms-like tyrosine kinase-1 (88.1±19.0 versus 73.0±15.3 pg/mL;
P
<0.001) compared with term-born individuals, proportional to elevations in resting and ambulatory blood pressure, as well as degree of prematurity (
P
<0.05). Maternal hypertensive pregnancy disorder was associated with additional increases in soluble fms-like tyrosine kinase-1 (
P
=0.002). Other circulating biomarkers, including those of inflammation and endothelial activation, were not related to blood pressure. There was a specific graded association between soluble endoglin and degree of functional and structural capillary rarefaction (
P
=0.002 and
P
<0.001), and in multivariable analysis, there were capillary density–mediated associations between soluble endoglin and blood pressure. Preterm-born individuals exhibit an enhanced antiangiogenic state in adult life that is specifically related to elevations in blood pressure. The association seems to be mediated through capillary rarefaction and is independent of other cardiovascular structural and functional differences in the offspring.
Reappraisal of the Javanese Bullfrog complex, Kaloula baleata (Müller, 1836) (Amphibia: Anura: Microhylidae), reveals a new species from Peninsular Malaysia
Authors: CHAN KIN ONN , GRISMER L. LEE , BROWN RAFE M.
Published: December 2014

A new species of Narrow-mouthed frog of the genus Kaloula is described from northern Peninsular Malaysia. Kaloula latidisca sp. nov. is genetically and morphologically most similar to K. baleata and K. indochinensis but differs from those and other congeners by the unique combination of the following characters: (1) adult males SVL 49.2–56.2 mm (x̅=53.5 ± 3.0; N=4); (2) finger tips expanded into large, transversely expanded discs (disc width 2.8–3.1 mm, x̅=3.0 ± 0.1); (3) inner metatarsal tubercle large, oval, distinctly raised, slightly shorter than first toe; (4) three subarticular tubercles on fourth toe; (5) toe webbing formula: I 1–2 II 1–3 III 2–3.5 IV 4–2 V; and (6) yellow to orange irregularly shaped patch on the axillary, inguinal and posterior region of thigh.
A supplement to the revision of the Scirtes flavoguttatus species-group (Coleoptera: Scirtidae: Scirtinae)
Authors: RUTA RAFAŁ , KIAŁKA AGATA , YOSHITOMI HIROYUKI
Published: December 2014

New species of the Scirtes flavoguttatus species-group are described from SE Asia. Altogether 34 species are newly described, including Scirtes beccus sp. nov. (Malaysia), S. bocakorum sp. nov. (Indonesia), S. crockerensis sp. nov. (Malaysia), S. decorus sp. nov. (Malaysia), S. dumogensis sp. nov. (Indonesia), S. gunongmulensis sp. nov. (Malaysia), S. ishikawai sp. nov. (Vietnam), S. kinabalensis sp. nov. (Malaysia), S. kundasangensis sp. nov. (Malaysia), S. lambriensis sp. nov. (Indonesia), S. leuserensis sp. nov. (Indonesia), S. luteus sp. nov. (Malaysia), S. malaisei sp. nov. (Myanmar), S. melinauensis sp. nov. (Malaysia), S. noonadan sp. nov. (Philippines), S. pallicolor sp. nov. (Malaysia), S. penampangensis sp. nov. (Malaysia), S. phoupanensis sp. nov. (Laos), S. prodigiosus sp. nov. (Malaysia), S. punctatus sp. nov. (Philippines), S. quasibalehensis sp. nov. (Malaysia), S. ranauensis sp. nov. (Malaysia), S. sarawakensis sp. nov. (Malaysia), S. seblatensis sp. nov. (Indonesia), S. sibayensis sp. nov. (Indonesia), S. sibolangitensis sp. nov. (Indonesia), S. sulawesicus sp. nov. (Indonesia), S. sulcigeroides sp. nov. (Malaysia), S. talinisensis sp. nov. (Philippines), S. ulukimanisensis sp. nov. (Malaysia), S. velutinus sp. nov. (Malaysia), S. vietnamicus sp. nov. (Vietnam), S. wallacei sp. nov. (Indonesia), S. yangsinensis sp. nov. (Vietnam). New localities of six species are provided. An updated identification key, checklist and a summary of distributional data are included. Probability of the occurrence of the Scirtes flavoguttatus species-group was evaluated with an analysis in MaxEnt software. It is highly plausible that members of the group occur in most mountainous rainforests of SE Asia.
A Matter of Fat
Authors: Calder Philip C.
Published: December 2014

Acute respiratory disease syndrome (ARDS) is a common complication of critical illness, associated with significant morbidity, prolonged intensive care unit (ICU) and hospital stay, and increased mortality. Inflammation plays a central role in ARDS, with inflammatory eicosanoid mediators produced from the ω‐6 fatty acid arachidonic acid, such as leukotriene B4, being involved. The ω‐3 fatty acids found in fish oil exert anti‐inflammatory effects, including decreasing production of inflammatory eicosanoids from arachidonic acid. The ω‐3 fatty acids are effective in models relevant to ARDS. Several randomized controlled trials of enteral formulas rich in ω‐3 fatty acids, often in combination with other bioactive substances, have been conducted in patients with ARDS. Four of these trials reported marked clinical benefits, 2 reported no effect, and 1 reported a negative impact. A systematic review and meta‐analysis of these 7 trials identified no overall effect on ventilator‐free days or on ICU‐free days. There was a small reduction in ICU length of stay and no overall effect on mortality. However, the authors formally identified that trials that used high fat in both treatment and control groups showed a significant reduction in mortality, while trials that used a high, or higher, fat treatment and a low‐fat control group showed a trend toward an increase in mortality. It is concluded that differences in outcome reported among these studies largely relate to the relative fat contents of the treatment and control formulas. Further, it is concluded that high‐fat enteral formulas should not be used in this patient group.
MicroRNA-486-5p is an erythroid oncomiR of the myeloid leukemias of Down syndrome
Authors: Shaham Lital , Vendramini Elena , Ge Yubin , Goren Yaron , Birger Yehudit , Tijssen Marloes R. , McNulty Maureen , Geron Ifat , Schwartzman Omer , Goldberg Liat , Chou Stella T. , Pitman Holly , Weiss Mitchell J. , Michaeli Shulamit , Sredni Benjamin , Göttgens Berthold , Crispino John D. , Taub Jeffrey W. , Izraeli Shai
Published: December 2014

Key Points

miR-486-5p, a GATA1 regulated miR, is expressed in ML-DS and enhances their aberrant erythroid phenotype. miR-486-5p cooperates with GATA1s to promote the survival of pre-leukemic and leukemic cells.
Durable remissions in a pivotal phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma
Authors: Gopal Ajay K. , Chen Robert , Smith Scott E. , Ansell Stephen M. , Rosenblatt Joseph D. , Savage Kerry J. , Connors Joseph M. , Engert Andreas , Larsen Emily K. , Chi Xuedong , Sievers Eric L. , Younes Anas
Published: December 2014

Key Points

A total of 47% of patients who achieved CR on brentuximab vedotin remain progression-free after being followed a median of 53 months. Younger age, less functional impairment, and lower disease burden at baseline were associated with CR and prognostic for longer survival.
BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease
Authors: Vassar Robert
Published: December 2014

β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the β-secretase enzyme required for the production of the neurotoxic β-amyloid (Aβ) peptide that is widely considered to have a crucial early role in the etiology of Alzheimer’s disease (AD). As a result, BACE1 has emerged as a prime drug target for reducing the levels of Aβ in the AD brain, and the development of BACE1 inhibitors as therapeutic agents is being vigorously pursued. It has proven difficult for the pharmaceutical industry to design BACE1 inhibitor drugs that pass the blood–brain barrier, however this challenge has recently been met and BACE1 inhibitors are now in human clinical trials to test for safety and efficacy in AD patients and individuals with pre-symptomatic AD. Initial results suggest that some of these BACE1 inhibitor drugs are well tolerated, although others have dropped out because of toxicity and it is still too early to know whether any will be effective for the prevention or treatment of AD. Additionally, based on newly identified BACE1 substrates and phenotypes of mice that lack BACE1, concerns have emerged about potential mechanism-based side effects of BACE1 inhibitor drugs with chronic administration. It is hoped that a therapeutic window can be achieved that balances safety and efficacy. This review summarizes the current state of progress in the development of BACE1 inhibitor drugs and the evaluation of their therapeutic potential for AD.
Duration of Androgen Suppression Before Radiotherapy for Localized Prostate Cancer: Radiation Therapy Oncology Group Randomized Clinical Trial 9910
Authors: Pisansky Thomas M. , Hunt Daniel , Gomella Leonard G. , Amin Mahul B. , Balogh Alexander G. , Chinn Daniel M. , Seider Michael J. , Duclos Marie , Rosenthal Seth A. , Bauman Glenn S. , Gore Elizabeth M. , Rotman Marvin Z. , Lukka Himanshu R. , Shipley William U. , Dignam James J. , Sandler Howard M.
Published: December 2014

Purpose

To determine whether prolonged androgen suppression (AS) duration before radiotherapy improves survival and disease control in prostate cancer.

Patients and Methods

One thousand five hundred seventy-nine men with intermediate-risk prostate cancer were randomly assigned to 8 weeks of AS followed by radiotherapy with an additional 8 weeks of concurrent AS (16 weeks total) or to 28 weeks of AS followed by radiotherapy with an additional 8 weeks of AS (36 weeks total). The trial sought primarily to detect a 33% reduction in the hazard of prostate cancer death in the 28-week assignment. Time-to-event end points are reported for up to 10 years of follow-up.

Results

There were no between-group differences in baseline characteristics of 1,489 eligible patients with follow-up. For the 8- and 28-week assignments, 10-year disease-specific survival rates were 95% (95% CI, 93.3% to 97.0%) and 96% (95% CI, 94.6% to 98.0%; hazard ratio [HR], 0.81; P = .45), respectively, and 10-year overall survival rates were 66% (95% CI, 62.0% to 69.9%) and 67% (95% CI, 63.0% to 70.8%; HR, 0.95; P = .62), respectively. For the 8- and 28-week assignments, 10-year cumulative incidences of locoregional progression were 6% (95% CI, 4.3% to 8.0%) and 4% (95% CI, 2.5% to 5.7%; HR, 0.65; P = .07), respectively; 10-year distant metastasis cumulative incidences were 6% (95% CI, 4.0% to 7.7%) and 6% (95% CI, 4.0% to 7.6%; HR, 1.07; P = .80), respectively; and 10-year prostate-specific antigen–based recurrence cumulative incidences were 27% (95% CI, 23.1% to 29.8%) and 27% (95% CI, 23.4% to 30.3%; HR, 0.97; P = .77), respectively.

Conclusion

Extending AS duration from 8 weeks to 28 weeks before radiotherapy did not improve outcomes. A lower than expected prostate cancer death rate reduced ability to detect a between-group difference in disease-specific survival. The schedule of 8 weeks of AS before radiotherapy plus 8 weeks of AS during radiotherapy remains a standard of care in intermediate-risk prostate cancer.
Social Media in Conflict
Authors: Gray Chris Hables , Gordo Ángel J.
Published: December 2014

There are important differences in how information technology is used in military and social-movement cultures. Militaries use social media in the Human Terrain model and security-police mode for quantifying and controlling social space, in order to meet low-intensity, counterinsurgency, and regime-maintenance goals (or for recruitment and public relations). For social-movement cultures, such as secular Egyptian revolutionaries, 15M (Los Indignados), and Idle No More, social media is an integral part of life; it is context. Unlike these horizontalist movements, military institutions are based on a hierarchical structure that precludes social media from becoming part of their organizational and decision-making culture. For them, social media constitute part of civil society, a commons both virtual and physical. The synergy between computer networks and decentralized social movements is clear when military, social-movement, and network theories and practices are compared. These differences are manifested in asymmetrical relationships to “veillance,” alternative modes of producing social technologies (especially protocols), contrasting theories of power, and opposing conceptions of morality and efficacy. The differences are more than a matter of how the affordances of information technologies match with the different technocultures. Horizontalist social movements incorporate new information technologies into their praxis as self-control, while militaries seek to subsume them into the existing hierarchical control paradigms.
Art After Auschwitz
Authors: Nosthoff Anna-Verena
Published: December 2014

This essay explores the works of German artist Gustav Metzger as a potential response to Theodor W. Adorno’s dictum “Nach Auschwitz ein Gedicht zu schreiben, ist barbarisch” (“To write poetry after Auschwitz is barbaric”). It argues that culture, as understood in the Adornian sense, is inextricably barbaric as a result of simply being after Auschwitz. Culture must acknowledge the finitude in its own ability to live up to an ethical demand in response to justice, whose arrival is infinitely deferred. In spite of this, culture, and art in particular, must not refrain from the very act of writing. Metzger’s works are discussed as aesthetic responses to the “new categorical imperative” of Adorno, who addresses art’s failure in light of Auschwitz by pointing to aporias that constitute the inescapable condition of “barbarism.” This essay suggests that Metzger’s aesthetic articulations are nonbarbaric ruptures, in that they challenge our living on irresponsibly within the condition of barbarism via a constant confrontation with complicity.