bluuebunny/crossref_metadata_2025 huggingface dataset:
Significance of Semiquantitative Assessment of Preformed Donor-Specific Antibody Using Luminex Single Bead Assay in Living Related Liver Transplantation
Authors: Yoshizawa Atsushi , Egawa Hiroto , Yurugi Kimiko , Hishida Rie , Tsuji Hiroaki , Ashihara Eiji , Miyagawa-Hayashino Aya , Teramukai Satoshi , Maekawa Taira , Haga Hironori , Uemoto Sinji
Published: May 2013

Aim. To analyze the risks of preoperatively produced donor-specific antibody (DSA) in liver transplantation.Methods. DSA was assessed using direct complement-dependent cytotoxicity (CDC) and anti-human globulin- (AHG-) CDC tests, as well as the Luminex Single Antigen assay. Among 616 patients undergoing blood type identical or compatible living donor liver transplantation (LDLT), 21 patients were positive for CDC or AHG-CDC tests, and the preserved serum from 18 patients was examined to determine targeted Class I and II antigens. The relationships between the mean fluorescence intensity (MFI) of DSA and the clinical outcomes were analyzed.Results. Patients were divided into 3 groups according to the MFI of anti-Class I DSA: high (11 patients with MFI > 10,000), low (2 patients with MFI < 10,000), and negative (5 patients) MFI groups. Six of 11 patients with high Class-I DSA showed positive Class-II DSA. Hospital death occurred in 7 patients of the high MFI group. High MFI was a significant risk factor for mortality (). Univariate analysis showed a significant correlation between MFI strength and C4d deposition ().Conclusions. HLA Class I DSA with MFI > 10,000 had a significant negative effect on the clinical outcome of patients with preformed DSA in LDLT.
Tumor Promotion by Intratumoral Plasmacytoid Dendritic Cells Is Reversed by TLR7 Ligand Treatment
Authors: Le Mercier Isabelle , Poujol Dominique , Sanlaville Amélien , Sisirak Vanja , Gobert Michael , Durand Isabelle , Dubois Bertrand , Treilleux Isabelle , Marvel Jacqueline , Vlach Jaromir , Blay Jean-Yves , Bendriss-Vermare Nathalie , Caux Christophe , Puisieux Isabelle , Goutagny Nadège
Published: May 2013

Plasmacytoid dendritic cells (pDC) are key regulators of antiviral immunity. In previous studies, we reported that pDC-infiltrating human primary breast tumors represent an independent prognostic factor associated with poor outcome. To understand this negative impact of tumor-associated pDC (TApDC), we developed an orthotopic murine mammary tumor model that closely mimics the human pathology, including pDC and regulatory T cell (Treg) infiltration. We showed that TApDC are mostly immature and maintain their ability to internalize antigens in vivo and to activate CD4+ T cells. Most importantly, TApDC were specifically altered for cytokine production in response to Toll-like receptor (TLR)–9 ligands in vitro while preserving unaltered response to TLR7 ligands (TLR7L). In vivo pDC depletion delayed tumor growth, showing that TApDC provide an immune-subversive environment, most likely through Treg activation, thus favoring tumor progression. However, in vivo intratumoral administration of TLR7L led to TApDC activation and displayed a potent curative effect. Depletion of pDC and type I IFN neutralization prevented TLR7L antitumoral effect. Our results establish a direct contribution of TApDC to primary breast tumor progression and rationalize the application of TLR7 ligands to restore TApDC activation in breast cancer. Cancer Res; 73(15); 4629–40. ©2013 AACR.
Evaluation of LDH-A and Glutaminase Inhibition In Vivo by Hyperpolarized 13C-Pyruvate Magnetic Resonance Spectroscopy of Tumors
Authors: Dutta Prasanta , Le Anne , Vander Jagt David L. , Tsukamoto Takashi , Martinez Gary V. , Dang Chi V. , Gillies Robert J.
Published: May 2013

Hyperpolarized 13C magnetic resonance spectroscopy provides a unique opportunity to detect real-time metabolic fluxes as a means to measure metabolic treatment responses in vivo. Here, we show that pharmacologic inhibition of lactate dehydrogenase-A suppressed the conversion of hyperpolarized 13C-pyruvate to lactate in murine xenografts of P493 human lymphoma. In contrast, a glutaminase inhibitor reduced conversion of 13C-pyruvate to alanine without affecting conversion of pyruvate to lactate. These results illustrate the ability to monitor biomarkers for responses to antimetabolic therapy in real-time, paving the way for clinical development of imaging biomarkers to monitor metabolic pharmacodynamics. Cancer Res; 73(14); 4190–5. ©2013 AACR.
Therapeutic Potential of HSP90 Inhibition for Neurofibromatosis Type 2
Authors: Tanaka Karo , Eskin Ascia , Chareyre Fabrice , Jessen Walter J. , Manent Jan , Niwa-Kawakita Michiko , Chen Ruihong , White Cory H. , Vitte Jeremie , Jaffer Zahara M. , Nelson Stanley F. , Rubenstein Allan E. , Giovannini Marco
Published: May 2013

Purpose: The growth and survival of neurofibromatosis type 2 (NF2)–deficient cells are enhanced by the activation of multiple signaling pathways including ErbBs/IGF-1R/Met, PI3K/Akt, and Ras/Raf/Mek/Erk1/2. The chaperone protein HSP90 is essential for the stabilization of these signaling molecules. The aim of the study was to characterize the effect of HSP90 inhibition in various NF2-deficient models.

Experimental Design: We tested efficacy of the small-molecule NXD30001, which has been shown to be a potent HSP90 inhibitor. The antiproliferative activity of NXD30001 was tested in NF2-deficient cell lines and in human primary schwannoma and meningioma cultures in vitro. The antitumor efficacy of HSP90 inhibition in vivo was verified in two allograft models and in one NF2 transgenic model. The underlying molecular alteration was further characterized by a global transcriptome approach.

Results: NXD30001 induced degradation of client proteins in and suppressed proliferation of NF2-deficient cells. Differential expression analysis identified subsets of genes implicated in cell proliferation, cell survival, vascularization, and Schwann cell differentiation whose expression was altered by NXD30001 treatment. The results showed that NXD30001 in NF2-deficient schwannoma suppressed multiple pathways necessary for tumorigenesis.

Conclusions: HSP90 inhibition showing significant antitumor activity against NF2-related tumor cells in vitro and in vivo represents a promising option for novel NF2 therapies. Clin Cancer Res; 19(14); 3856–70. ©2013 AACR.
Leukemia Cell-Rhabdovirus Vaccine: Personalized Immunotherapy for Acute Lymphoblastic Leukemia
Authors: Conrad David P. , Tsang Jovian , Maclean Meaghan , Diallo Jean-Simon , Le Boeuf Fabrice , Lemay Chantal G. , Falls Theresa J. , Parato Kelley A. , Bell John C. , Atkins Harold L.
Published: May 2013

Purpose: Acute lymphoblastic leukemia (ALL) remains incurable in most adults. It has been difficult to provide effective immunotherapy to improve outcomes for the majority of patients. Rhabdoviruses induce strong antiviral immune responses. We hypothesized that mice administered ex vivo rhabdovirus-infected ALL cells [immunotherapy by leukemia-oncotropic virus (iLOV)] would develop robust antileukemic immune responses capable of controlling ALL.

Experimental Design: Viral protein production, replication, and cytopathy were measured in human and murine ALL cells exposed to attenuated rhabdovirus. Survival following injection of graded amounts of ALL cells was compared between cohorts of mice administered γ-irradiated rhabdovirus-infected ALL cells (iLOV) or multiple control vaccines to determine key immunotherapeutic components and characteristics. Host immune requirements were assessed in immunodeficient and bone marrow–transplanted mice or by adoptive splenocyte transfer from immunized donors. Antileukemic immune memory was ascertained by second leukemic challenge in long-term survivors.

Results: Human and murine ALL cells were infected and killed by rhabdovirus; this produced a potent antileukemia vaccine. iLOV protected mice from otherwise lethal ALL by developing durable leukemia-specific immune-mediated responses (P < 0.0001), which required an intact CTL compartment. Preexisting antiviral immunity augmented iLOV potency. Splenocytes from iLOV-vaccinated donors protected 60% of naïve recipients from ALL challenge (P = 0.0001). Injecting leukemia cells activated by, or concurrent with, multiple Toll-like receptor agonists could not reproduce the protective effect of iLOV. Similarly, injecting uninfected irradiated viable, apoptotic, or necrotic leukemia cells with/without concurrent rhabdovirus administration was ineffective.

Conclusion: Rhabdovirus-infected leukemia cells can be used to produce a vaccine that induces robust specific immunity against aggressive leukemia. Clin Cancer Res; 19(14); 3832–43. ©2013 AACR.
Functional Profiling of Receptor Tyrosine Kinases and Downstream Signaling in Human Chondrosarcomas Identifies Pathways for Rational Targeted Therapy
Authors: Zhang Yi-Xiang , van Oosterwijk Jolieke G. , Sicinska Ewa , Moss Samuel , Remillard Stephen P. , van Wezel Tom , Bühnemann Claudia , Hassan Andrew B. , Demetri George D. , Bovée Judith V.M.G. , Wagner Andrew J.
Published: May 2013

Purpose: Chondrosarcomas are notoriously resistant to cytotoxic chemotherapeutic agents. We sought to identify critical signaling pathways that contribute to their survival and proliferation, and which may provide potential targets for rational therapeutic interventions.

Experimental Design: Activation of receptor tyrosine kinases (RTK) was surveyed using phospho-RTK arrays. S6 phosphorylation and NRAS mutational status were examined in chondrosarcoma primary tumor tissues. siRNA or small-molecule inhibitors against RTKs or downstream signaling proteins were applied to chondrosarcoma cells and changes in biochemical signaling, cell cycle, and cell viability were determined. In vivo antitumor activity of BEZ235, a phosphoinositide 3-kinase (PI3K)/mTOR inhibitor, was evaluated in a chondrosarcoma xenograft model.

Results: Several RTKs were identified as critical mediators of cell growth, but the RTK dependencies varied among cell lines. In exploration of downstream signaling pathways, strong S6 phosphorylation was found in 69% of conventional chondrosarcomas and 44% of dedifferentiated chondrosarcomas. Treatment with BEZ235 resulted in dramatic reduction in the growth of all chondrosarcoma cell lines. Tumor growth was similarly inhibited in a xenograft model of chondrosarcoma. In addition, chondrosarcoma cells with an NRAS mutation were sensitive to treatment with a mitogen-activated protein kinase/extracellular signal–regulated kinase kinase (MEK) inhibitor. Functional NRAS mutations were found in 12% of conventional central chondrosarcomas.

Conclusions: RTKs are commonly activated in chondrosarcoma, but because of their considerable heterogeneity, targeted inhibition of the PI3K/mTOR pathway represents a rational therapeutic strategy. Chondrosarcomas with NRAS mutations may benefit from treatment with MEK inhibitors. Clin Cancer Res; 19(14); 3796–807. ©2013 AACR.
Cyclin D1 Downregulation Contributes to Anticancer Effect of Isorhapontigenin on Human Bladder Cancer Cells
Authors: Fang Yong , Cao Zipeng , Hou Qi , Ma Chen , Yao Chunsuo , Li Jingxia , Wu Xue-Ru , Huang Chuanshu
Published: May 2013

Isorhapontigenin (ISO) is a new derivative of stilbene compound that was isolated from the Chinese herb Gnetum Cleistostachyum and has been used for treatment of bladder cancers for centuries. In our current studies, we have explored the potential inhibitory effect and molecular mechanisms underlying isorhapontigenin anticancer effects on anchorage-independent growth of human bladder cancer cell lines. We found that isorhapontigenin showed a significant inhibitory effect on human bladder cancer cell growth and was accompanied with related cell cycle G0–G1 arrest as well as downregulation of cyclin D1 expression at the transcriptional level in UMUC3 and RT112 cells. Further studies identified that isorhapontigenin downregulated cyclin D1 gene transcription via inhibition of specific protein 1 (SP1) transactivation. Moreover, ectopic expression of GFP-cyclin D1 rendered UMUC3 cells resistant to induction of cell-cycle G0–G1 arrest and inhibition of cancer cell anchorage-independent growth by isorhapontigenin treatment. Together, our studies show that isorhapontigenin is an active compound that mediates Gnetum Cleistostachyum's induction of cell-cycle G0–G1 arrest and inhibition of cancer cell anchorage-independent growth through downregulating SP1/cyclin D1 axis in bladder cancer cells. Our studies provide a novel insight into understanding the anticancer activity of the Chinese herb Gnetum Cleistostachyum and its isolate isorhapontigenin. Mol Cancer Ther; 12(8); 1492–503. ©2013 AACR.
Tumor Suppressor Functions of miR-133a in Colorectal Cancer
Authors: Dong Yujuan , Zhao Junhong , Wu Chung-Wah , Zhang Lijing , Liu Xiaodong , Kang Wei , Leung Wing-Wah , Zhang Ning , Chan Francis K.L. , Sung Joseph J.Y. , Ng Simon S.M. , Yu Jun
Published: May 2013

Dysregulated microRNA (miRNA) expression was profiled through a miRNA array comparison between human colorectal cancer tumors and their adjacent normal tissues. Specifically, using laser capture micro-dissection, miR-133a was shown to be significantly downregulated in primary colorectal cancer specimens compared with matched adjacent normal tissue. Ectopic expression of miR-133a significantly suppressed colorectal cancer cell growth in vitro and in vivo. Cell-cycle analysis revealed that miR-133a induced a G0/G1-phase arrest, concomitant with the upregulation of the key G1-phase regulator p21Cip1. We further revealed that miR-133a markedly increased p53 protein and induced p21Cip1 transcription. Studies in silico revealed that the 3′UTR of the ring finger and FYVE-like domain containing E3-ubiquitin protein ligase (RFFL), which regulates p53 protein, contains an evolutionarily conserved miR-133a binding site. miR-133a repressed RFFL-3′UTR reporter activity and reduced RFFL protein levels, indicating that miR-133a directly bound to RFFL mRNA and inhibited RFFL translation. Moreover, miR-133a sensitized colon cancer cells to doxorubicin and oxaliplatin by enhancing apoptosis and inhibiting cell proliferation. These data add weight to the significance of miR-133a in the development of CRC.

Implications: miR-133a serves as a potential tumor suppressor upstream of p53 in colorectal cancer and may sensitize cells to therapeutics. Mol Cancer Res; 11(9); 1051–60. ©2013 AACR.
Quantitative Profiling and Identification of Plasma Proteins of Spinocerebellar Ataxia Type 2 Patients
Authors: Swarup Vishnu , Srivastava Achal K. , Padma Madakasira V. , Moganty Rajeswari R.
Published: May 2013

Background: Spinocerebellar ataxia type 2 (SCA2) is an autosomal-dominant hereditary ataxia characterized by progressive gait and limb ataxia, dysarthria, slow saccades, neuropathy and dementia. The expansion of trinucleotide CAG repeats in the coding region of the ATXN-2 gene leads to expanded polyglutamine stretch in the mutated protein which causes neuronal death. Objective: In this study, we investigated the blood plasma of SCA2 patients to find protein biomarkers. Methods: Thirty-two ataxia patients clinically suspected for SCA2 were evaluated by the International Co-operative Ataxia Rating Scale followed by genetic analysis using PCR. Plasma proteomics of SCA2 patients and age- and gender-matched healthy controls was done using 2D-difference in-gel electrophoresis, LC-MS/MS and Western blot. Results: Genetic analysis confirmed 10 of 32 suspected SCA2 patients. Proteomic data revealed nine differentially expressed proteins in SCA2. These proteins find good association with oxidative stress, calcium-dependent apoptosis, neuropathy, and cognitive impairment in SCA2 patients. Interestingly, the elevated levels of the voltage-dependent calcium channel γ-3 subunit showed a direct correlation with calcium-generated apoptosis of Purkinje cells. The cognitive deficit, a common symptom in SCA2 patients, seems to correlate with decreased levels of transthyretin and retinol-binding protein-4. Conclusions: Some of these identified proteins in SCA2 can be useful for therapeutic, diagnostic and prognostic purposes.
New Generation Synthetic Surfactants
Authors: Curstedt Tore , Calkovska Andrea , Johansson Jan
Published: May 2013

The treatment of preterm newborn rabbits with synthetic surfactants containing simple phospholipid mixtures and peptides gives similar tidal volumes to treatment with poractant alfa (Curosurf®). The addition of both surfactant protein B and C analogs to the phospholipid mixture will stabilize the alveoli, measured as lung gas volumes at end expiration, even if no positive end-expiratory pressure is applied. The effect on lung gas volumes seems to depend on the structure of the peptides as well as the phospholipid composition. It seems that synthetic surfactants containing two peptides and a more complex phospholipid composition will be able to replace natural surfactants within the near future, but more experiments need to be performed before any conclusion can be drawn about the ideal composition of this new generation of synthetic surfactants.
Factors Affecting the Complications of Pneumatic Lithotripsy for the Treatment of Ureteral Stones with Different Localizations: A Multivariate Analysis of Complications
Authors: Gunlusoy Bulent , Degirmenci Tansu , Kozacioglu Zafer , Arslan Murat , Ceylan Yasin , Nergiz Nihat , Minareci Suleyman
Published: May 2013

Objective: To evaluate the complications of ureterorenoscopy (URS) using the modified Clavien classification system for ureteral stones with different localizations. Patients and Methods: From February 2001 to January 2010, a total of 1,926 patients underwent URS for the treatment of ureteral stones with different localizations. The complications were evaluated according to the modified Clavien system. Univariate and multivariate analyses were conducted to identify risk factors affecting the complication rates. Results: The patient cohort included 1,212 males and 714 females with a mean age of 47.8 ± 14.3 years (range 15-86). The success rate was 95.7%. The overall complication rate was 9.3%. Univariate analysis revealed that solitary kidney, stone burden, bilaterality, stone localization (proximal to the iliac crest) and stone impaction significantly affected the complication rates. Multivariate analysis revealed that preoperative shock wave lithotripsy treatment, stone impaction, multiplicity, proximal localization and stone burden were significant parameters affecting the occurrence of complications (relative risks of 6.5, 4.3, 3.3, 2.4 and 2.0, respectively). Conclusions: URS is a safe and minimally invasive procedure with a high success rate and low-grade, self-limiting complications. Preoperative shock wave lithotripsy treatment, stone impaction, multiplicity, proximal localization and stone burden were independent risk factors for the development of complications.
Reducing Anastomotic Leakage by Reinforcement of Colorectal Anastomosis with Cyanoacrylate Glue
Authors: Wu Z. , Vakalopoulos K.A. , Kroese L.F. , Boersema G.S.A. , Kleinrensink G.J. , Jeekel J. , Lange J.F.
Published: May 2013

Introduction: Technical failure of sutured or stapled anastomoses may lead to anastomotic leakage, which is one of the most important complications after colorectal surgery. Cyanoacrylate glue (CA) provides strong mechanical attachment, making it a good candidate for suture reinforcement. This study aimed to demonstrate that CA is the most important factor in the strength of a sealed colorectal anastomosis, in both normal and insufficient anastomoses. Methods: Ex vivo porcine colorectal segments were resected. A 1-layer continuous anastomosis or an insufficient 6-interrupted-suture anastomosis was created, and the baseline anastomotic bursting pressure (ABP) was measured. The primary anastomosis was then reinforced either by CA or with 4 additional interrupted sutures, further inverting the anastomosis. After reinforcement a second ABP test was performed. Results: Thirty-two segments were used. Reinforcing the anastomosis by CA significantly increased ABP in both normal and insufficient anastomoses when compared to the primary anastomosis (p < 0.05 for all groups); no significant difference in ABP was found between normal and insufficient anastomosis groups after CA reinforcement. Anastomotic reinforcement with CA was not inferior to the reinforcement with sutures in both normal and insufficient anastomoses, and had significantly fewer ABP variances in normal anastomosis groups (p = 0.042). Conclusion: Reinforcing a colorectal anastomosis with CA increases its mechanical strength in both normal and technically insufficient situations, which may contribute to the reduction of anastomotic leakage. CA is promising for anastomotic reinforcement based on mechanical improvement of the anastomosis, and in vivo studies are needed to evaluate its biological effects.
Feasibility Study of the Pharmacology of Local Application of Amifostine (WR-2721) to the Buccal Mucosa in Guinea Pigs
Authors: Li Changjiang , Wang Shengzi , Huang Taomin , Chen Nianzu , Ou Meixian
Published: May 2013

Background/Aims: We have undertaken this study to investigate the feasibility of topical application of the radioprotective compound WR-2721 to the buccal mucosa. Methods: Saliva samples were collected from 5 volunteers and were reconstituted in 3 amifostine solutions. Measurements of amifostine and WR-1065 contents were performed at 6 different time points. Young-adult guinea pigs were topically administered amifostine 50 and 100 mg to each buccal mucosa. At 0, 15 and 30 min after application, the blood samples obtained from the heart and the buccal tissues were prepared for the analysis of amifostine and WR-1065. Results: There was no significant difference between the 3 concentrations of amifostine in saliva in vitro at any of the 6 study time points (p > 0.05). No WR-1065 was detected in saliva. In the guinea pigs from groups A and B, there were significant differences in concentrations of amifostine and WR-1065 in the tissues between the 0-min and 15-min subgroups and between the 0-min and 30-min subgroups (p < 0.05). The concentrations of amifostine and WR-1065 from the 15-min and 30-min subgroups did not differ statistically (p > 0.05). Conclusions: It is feasible to administer topical amifostine (WR-2721) to mucosa to prevent radiation-induced oral mucositis, and systemic absorption is negligible. Relatively high concentrations of amifostine in human saliva in vitro were maintained, although some inconsistent changes are observed.
Paricalcitol and Cardiorenal Outcome: From the IMPACT Study to Clinical Practice
Authors: Bellasi Antonio , Galassi Andrea , Salvi Paolo , Cozzolino Mario
Published: May 2013

Chronic kidney disease mineral bone disorders (CKD-MBD) encompass laboratory, vascular and bone abnormalities that might portend a poor prognosis in CKD. In spite of a great effort in elucidating the CKD-MBD natural history and pathogenesis, the underlying mechanisms are still largely unknown. However, a deficit in vitamin D is commonly reported as one of the first steps in CKD-MBD, and numerous epidemiological studies have associated serum vitamin D levels with different markers of cardiovascular disease and the risk of death in different populations. We herein summarize current evidence that links vitamin D deficiency to an adverse outcome and the results of the most recent clinical trials that have investigated the impact of paricalcitol supplementation on hard outcome in CKD patients.
Personal Daily Dialysis: The Evolution of the Artificial Kidney
Authors: Kim Jeong Chul , Ronco Claudio
Published: May 2013

To improve hemodialysis (HD) patients' clinical tolerance and quality of life, a new paradigm of technological evolution of the artificial kidney needs to be addressed at this point. Compared to the second law of thermodynamics, if HD is a barrier against entropy increase, personal daily dialysis (PDD), taking account of multidimensional treatment parameters specific to the patient, can be a new treatment option. Here, we review currently used HD equipment and competing technologies of the wearable artificial kidney (WAK) for future application to PDD. Biofeedback control during HD personalizes treatment parameters such as blood volume changes, thermal energy balance and biochemical variables in well-defined ranges and tries to deliver the targeted treatment dose without intradialytic hypotension. Miniaturized devices such as WAK could also meet the needs of patients by providing mobility, the possibility of normal social activities and flexibility of treatment schedule. So far, many studies have shown the future direction of renal replacement therapy for chronic patients: personalization and daily treatment. PDD might require a new index including a biological plan for recovery of homeostasis and a strategy toward long-term rehabilitation of the patient. The concept of entropy includes these multidimensional factors, and the artificial kidney should be evolved to minimize the increase in entropy of the patient.
On Which Abilities Are Category Fluency and Letter Fluency Grounded A Confirmatory Factor Analysis of 53 Alzheimer's Dementia Patients
Authors: Bizzozero Ilaria , Scotti Stefania , Clerici Francesca , Pomati Simone , Laiacona Marcella , Capitani Erminio
Published: May 2013

Background/Aims: In Alzheimer's dementia (AD), letter fluency is less impaired than category fluency. To check whether category fluency and letter fluency depend differently on semantics and attention, 53 mild AD patients were given animal and letter fluency tasks, two semantic tests (the Verbal Semantic Questionnaire and the BORB Association Match test), and two attentional tests (the Stroop Colour-Word Interference test and the Digit Cancellation test). Methods: We conducted a LISREL confirmatory factor analysis to check the extent to which category fluency and letter fluency tasks were related to semantics and attention, viewed as latent variables. Results: Both types of fluency tasks were related to the latent variable Semantics but not to the latent variable Attention. Conclusions: Our findings warn against interpreting the disproportionate impairment of AD patients on category and letter fluency as a contrast between semantics and attention.
Elevated Serum Aminotransferases Secondary to Rippling Muscle Disease
Authors: Nalankilli Kumanan , Lubel John
Published: May 2013

A 43-year-old man was referred by his general practitioner to the hepatology clinic with deranged serum aminotransferases, discovered as part of routine blood tests. The objective was to identify the cause of elevated serum aminotransferases in this patient in a systematic manner. Thorough history and physical examination revealed a background history of rippling muscle disease secondary to caveolin-3 protein deficiency, with typical clinical signs. There was a positive family history of musculoskeletal disease in the patient's father and brother. Previous diagnostic tests performed to investigate the patient's musculoskeletal symptoms, including muscle biopsies, were revisited. Subsequent systematic investigations such as blood tests, liver ultrasound scan and Fibroscan® were performed to exclude potential causes of the deranged serum aminotransferases. Liver biopsy was not performed. A consistent pattern of chronic low-grade elevations of serum aminotransferases, less than three times the upper limit of the normal range, was found. This was associated with a consistently elevated serum creatine kinase and normal renal function tests. Previous muscle biopsies had revealed chronic degenerative and regenerative changes suggestive of a focal necrotizing myopathy. Liver ultrasound scan and Fibroscan® were normal. With exclusion of other liver diseases and identification of profoundly elevated serum creatine kinase concentration, the deranged aminotransferases were attributed to rippling muscle disease.
Observation of Lymphangioma of the Duodenum by a Magnifying Endoscope with a Narrow-Band Imaging System
Authors: Iwamuro Masaya , Kawai Yoshinari , Takata Katsuyoshi , Okada Hiroyuki , Yamamoto Kazuhide
Published: May 2013

Among duodenal tumors, lymphangioma is relatively infrequent. In this case report, we describe the case of a 65-year-old Japanese man with duodenal lymphangioma diagnosed by esophagogastroduodenoscopy. Endoscopically, the tumor appeared as a soft submucosal tumor with white spots. When the white spots were grasped by biopsy forceps, milky liquid exuded from the tumor. Additionally, observation by a magnifying endoscope with narrow-band imaging revealed elongated microvessels on the surface. We speculated that this feature was formed because the duodenal villi were dilated and the microvessels were stretched due to the retention of chyle. These endoscopic findings are key features in the diagnosis of duodenal lymphangioma.
Voltage-Gated Potassium Channel Antibody Paraneoplastic Limbic Encephalitis Associated with Acute Myeloid Leukemia
Authors: Alcantara Marion , Bennani Omar , Verdure Pierre , Leprêtre Stéphane , Tilly Hervé , Jardin Fabrice
Published: May 2013

Among paraneoplastic syndromes (PNS) associated with malignant hemopathies, there are few reports of PNS of the central nervous system and most of them are associated with lymphomas. Limbic encephalitis is a rare neurological syndrome classically diagnosed in the context of PNS. We report the case of a 81-year-old man who presented with a relapsed acute myeloid leukemia (AML) with minimal maturation. He was admitted for confusion with unfavorable evolution as he presented a rapidly progressive dementia resulting in death. A brain magnetic resonance imaging, performed 2 months after the onset, was considered normal. An electroencephalogram showed non-specific bilateral slow waves. We received the results of the blood screening of neuronal autoantibodies after the patient's death and detected the presence of anti-voltage-gated potassium channel (VGKC) antibodies at 102 pmol/l (normal at <30 pmol/l). Other etiologic studies, including the screening for another cause of rapidly progressive dementia, were negative. To our knowledge, this is the first case of anti-VGKC paraneoplastic limbic encephalitis related to AML.
A Novel
APOB
Mutation Identified by Exome Sequencing Cosegregates With Steatosis, Liver Cancer, and Hypocholesterolemia
Authors: Cefalù Angelo B. , Pirruccello James P. , Noto Davide , Gabriel Stacey , Valenti Vincenza , Gupta Namrata , Spina Rossella , Tarugi Patrizia , Kathiresan Sekar , Averna Maurizio R.
Published: May 2013

Objective—

In familial hypobetalipoproteinemia, fatty liver is a characteristic feature, and there are several reports of associated cirrhosis and hepatocarcinoma. We investigated a large kindred in which low-density lipoprotein cholesterol, fatty liver, and hepatocarcinoma displayed an autosomal dominant pattern of inheritance.

Approach and Results—

The proband was a 25-year-old female with low plasma cholesterol and hepatic steatosis. Low plasma levels of total cholesterol and fatty liver were observed in 10 more family members; 1 member was affected by liver cirrhosis, and 4 more subjects died of either hepatocarcinoma or carcinoma on cirrhosis. To identify the causal mutation in this family, we performed exome sequencing in 2 participants with hypocholesterolemia and fatty liver. Approximately 22 400 single nucleotide variants were identified in each sample. After variant filtering, 300 novel shared variants remained. A nonsense variant, p.K2240X, attributable to an A>T mutation in exon 26 of
APOB
(c.6718A>T) was identified, and this variant was confirmed by Sanger sequencing. The gentotypic analysis of 16 family members in total showed that this mutation segregated with the low cholesterol trait. In addition, genotyping of the
PNPLA3
p.I148M did not show significant frequency differences between carriers and noncarriers of the c.6718A>T
APOB
gene mutation.

Conclusions—

We used exome sequencing to discover a novel nonsense mutation in exon 26 of
APOB
(p.K2240X) responsible for low cholesterol and fatty liver in a large kindred. This mutation may also be responsible for cirrhosis and liver cancer in this family.
Beneficial Effect of Mechanical Stimulation on the Regenerative Potential of Muscle-Derived Stem Cells Is Lost by Inhibiting Vascular Endothelial Growth Factor
Authors: Beckman Sarah A. , Chen William C.W. , Tang Ying , Proto Jonathan D. , Mlakar Logan , Wang Bing , Huard Johnny
Published: May 2013

Objective—

We previously reported that mechanical stimulation increased the effectiveness of muscle-derived stem cells (MDSCs) for tissue repair. The objective of this study was to determine the importance of vascular endothelial growth factor (VEGF) on mechanically stimulated MDSCs in a murine model of muscle regeneration.

Approach and Results—

MDSCs were transduced with retroviral vectors encoding the
LacZ
reporter gene (lacZ-MDSCs), the soluble VEGF receptor
Flt1
(sFlt1-MDSCs), or a short hairpin RNA (shRNA) targeting messenger RNA of VEGF (shRNA_VEGF MDSCs). Cells were subjected to 24 hours of mechanical cyclic strain and immediately transplanted into the gastrocnemius muscles of
mdx/scid
mice. Two weeks after transplantation, angiogenesis, fibrosis, and regeneration were analyzed. There was an increase in angiogenesis in the muscles transplanted with mechanically stimulated lacZ-MDSCs compared with nonstimulated lacZ-MDSCs, sFlt1-MDSCs, and shRNA _VEGF MDSCs. Dystrophin-positive myofiber regeneration was significantly lower in the shRNA_VEGF-MDSC group compared with the lacZ-MDSC and sFlt1-MDSC groups. In vitro proliferation of MDSCs was not decreased by inhibition of VEGF; however, differentiation into myotubes and adhesion to collagen were significantly lower in the shRNA_VEGF-MDSC group compared with the lacZ-MDSC and sFlt1-MDSC groups.

Conclusions—

The beneficial effects of mechanical stimulation on MDSC-mediated muscle repair are lost by inhibiting VEGF.
Elevated Prothrombin Promotes Venous, but Not Arterial, Thrombosis in Mice
Authors: Aleman Maria M. , Walton Bethany L. , Byrnes James R. , Wang Jian-Guo , Heisler Matthew J. , Machlus Kellie R. , Cooley Brian C. , Wolberg Alisa S.
Published: May 2013

Objective—

Individuals with elevated prothrombin, including those with the prothrombin G20210A mutation, have increased risk of venous thrombosis. Although these individuals do not have increased circulating prothrombotic biomarkers, their plasma demonstrates increased tissue factor–dependent thrombin generation in vitro. The objectives of this study were to determine the pathological role of elevated prothrombin in venous and arterial thrombosis in vivo, and distinguish thrombogenic mechanisms in these vessels.

Approach and Results—

Prothrombin was infused into mice to raise circulating levels. Venous thrombosis was induced by electrolytic stimulus to the femoral vein or inferior vena cava ligation. Arterial thrombosis was induced by electrolytic stimulus or ferric chloride application to the carotid artery. Mice infused with prothrombin demonstrated increased tissue factor–triggered thrombin generation measured ex vivo, but did not have increased circulating prothrombotic biomarkers in the absence of vessel injury. After venous injury, elevated prothrombin increased thrombin generation and the fibrin accumulation rate and total amount of fibrin ≈3-fold, producing extended thrombi with increased mass. However, elevated prothrombin did not accelerate platelet accumulation, increase the fibrin accumulation rate, or shorten the vessel occlusion time after arterial injury.

Conclusions—

These findings reconcile previously discordant findings on thrombin generation in hyperprothrombinemic individuals measured ex vivo and in vitro, and show elevated prothrombin promotes venous, but not arterial, thrombosis in vivo.
Androgen Receptor Promotes Sex-Independent Angiogenesis in Response to Ischemia and Is Required for Activation of Vascular Endothelial Growth Factor Receptor Signaling
Authors: Yoshida Sumiko , Aihara Ken-ichi , Ikeda Yasumasa , Sumitomo-Ueda Yuka , Uemoto Ryoko , Ishikawa Kazue , Ise Takayuki , Yagi Shusuke , Iwase Takashi , Mouri Yasuhiro , Sakari Matomo , Matsumoto Takahiro , Takeyama Ken-ichi , Akaike Masashi , Matsumoto Mitsuru , Sata Masataka , Walsh Kenneth , Kato Shigeaki , Matsumoto Toshio
Published: May 2013

Background—

Hypoandrogenemia is associated with an increased risk of ischemic diseases. Because actions of androgens are exerted through androgen receptor (AR) activation, we studied hind-limb ischemia in
AR
knockout mice to elucidate the role of AR in response to ischemia.

Methods and Results—

Both male and female
AR
knockout mice exhibited impaired blood flow recovery, more cellular apoptosis, and a higher incidence of autoamputation after ischemia. In ex vivo and in vivo angiogenesis studies, AR-deficient vascular endothelial cells showed reduced angiogenic capability. In ischemic limbs of
AR
knockout mice, reductions in the phosphorylation of the Akt protein kinase and endothelial nitric oxide synthase were observed despite a robust increase in hypoxia-inducible factor 1α and vascular endothelial cell growth factor (
VEGF
) gene expression. In in vitro studies, siRNA-mediated ablation of AR in vascular endothelial cells blunted VEGF-stimulated phosphorylation of Akt and endothelial nitric oxide synthase. Immunoprecipitation experiments documented an association between AR and kinase insert domain protein receptor that promoted the recruitment of downstream signaling components.

Conclusions—

These results document a physiological role of AR in sex-independent angiogenic potency and provide evidence of novel cross-talk between the androgen/AR signaling and VEGF/kinase insert domain protein receptor signaling pathways.
Silent Information Regulator 1 Protects the Brain Against Cerebral Ischemic Damage
Authors: Hernández-Jiménez Macarena , Hurtado Olivia , Cuartero María I. , Ballesteros Iván , Moraga Ana , Pradillo Jesús M. , McBurney Michael W. , Lizasoain Ignacio , Moro María A.
Published: May 2013

Background and Purpose—

Sirtuin 1 (SIRT1) is a member of NAD
+
-dependent protein deacetylases implicated in a wide range of cellular functions and has beneficial properties in pathologies including ischemia/reperfusion processes and neurodegeneration. However, no direct evidence has been reported on the direct implication of SIRT1 in ischemic stroke. The aim of this study was to establish the role of SIRT1 in stroke using an experimental model in mice.

Methods—

Wild-type and
Sirt1
−/−
mice were subjected to permanent focal ischemia by permanent ligature. In another set of experiments, wild-type mice were treated intraperitoneally with vehicle, activator 3 (SIRT1 activator, 10 mg/kg), or sirtinol (SIRT1 inhibitor, 10 mg/kg) for 10 minutes, 24 hours, and 40 hours after ischemia. Brains were removed 48 hours after ischemia for determining the infarct volume. Neurological outcome was evaluated using the modified neurological severity score.

Results—

Exposure to middle cerebral artery occlusion increased SIRT1 expression in neurons of the ipsilesional mouse brain cortex. Treatment of mice with activator 3 reduced infarct volume, whereas sirtinol increased ischemic injury.
Sirt1
−/−
mice displayed larger infarct volumes after ischemia than their wild-type counterparts. In addition, SIRT1 inhibition/deletion was concomitant with increased acetylation of p53 and nuclear factor κB (p65).

Conclusions—

These results support the idea that SIRT1 plays an important role in neuroprotection against brain ischemia by deacetylation and subsequent inhibition of p53-induced and nuclear factor κB-induced inflammatory and apoptotic pathways.
Owners as a secure base for their dogs
Authors: Mariti Chiara , Ricci Eva , Zilocchi Marcella , Gazzano Angelo
Published: May 2013

A modified version of the Ainsworth Strange Situation Test was used to analyse 40 dog–owner pairs in order to assess whether owners can represent a secure base for their dogs. The Wilcoxon test revealed significant differences between owner and stranger for protest at separation (whining), contact maintenance effect (proximity, attention seeking and physical contact) and secure base effect (exploration, individual play and social play). The results suggest that dogs behave similarly to children towards the mothers and to chimpanzees towards human caretakers in the Ainsworth Strange Situation Test: owners are the preferred recipient of affiliative behaviours and, in their absence, dogs show behaviours indicative of distress. After reunion with the owner, dogs show an increase in social behaviours towards him/her. Dogs did not show fear of the stranger, and it was regarded as a normal behaviour for adult well-socialized dogs. Until now whether owners represented a secure base for their dogs was debated, due to controversial results. This study found that dogs play and explore more when owners were present, suggesting that owners can represent a secure base for their dogs. Therefore, according to Bowlby’s definition, dogs are linked to their owners by an attachment bond.
The Use of Printed Images for Instrument-Making  at the Arsenius Workshop
Authors: Gessner Samuel
Published: May 2013

Mathematical instruments in the early-modern period lay at the intersection of various knowledge traditions, both practical and scholarly. Scholars treated instrument-related questions in their works, while instrument makers and mathematical practitioners also put much energy into producing instrument books. Assessing the role of that literature in the exchange of knowledge between the different traditions is a complex task. Did it directly influence workshop practice? Here, I will examine instruments from a famous Louvain workshop ca. 1570, focussing on the role of printed images. I will suggest that woodcuts did indeed inspire instrument makers; that images were sometimes more important than the text; and that the viewer’s appreciation of the images depended upon his familiarity with an instrument’s mathematical structure.
Reconstructing Vernacular Mathematics
Authors: Taylor Katie
Published: May 2013

This article presents an account of my attempt to follow Thomas Hood’s instructions for the inscription of two scales on the sector, as laid out in his The Making and Use of the Geometricall Instrument, Called a Sector (1598). This will allow us to identify those aspects of the work that he expected readers to infer for themselves. I will then piece together the ways in which readers might have inscribed the scales and build up a picture of the kind of background knowledge that the author expected of his readers. It was this knowledge that made it possible to communicate the tacit skills involved in instrument making through a book. We will find that much of the background knowledge required involved experience of manual techniques, rather than abstract principles. Thus, we will develop an understanding of the thoroughly practical nature of vernacular mathematics.
The Use of Private Force by the United Nations to Coercively Prevent or Halt Gross Violations of the ‘Responsibility to Protect’ Doctrine
Authors: Riley Morgan
Published: May 2013

The United Nations’ ability to coercively intervene to prevent or stop gross violations of the Responsibility to Protect doctrine is weakened by its reliance on ad hoc mechanisms to secure troops. Although controversial, the deployment of private force to intervene in such circumstances is not prohibited by extant international law and may provide a pragmatic solution. Developing international legal norms can be interpreted to allow the United Nations to employ Private Military and Security Companies to protect vulnerable populations. Existing standards and guidelines for more conventional operations could be used to construct a robust framework of accountability for the United Nations, the corporations and their personnel. In turn, this could lead to the de facto international regulation of much of the global private military and security industry.
Book Reviews
Authors: Galis K.W. , Röder Josef , Graaf H.J. , Tarling Nicholas , Graaf H.J. , Northcote Parkinson C. , Hulsewé A.F.P. , Williams Lea E.
Published: May 2013

- K.W. Galis, Josef Röder, Felsbilder und Vorgeschichte des MacCluer-Golfes. West-Neuguinea. L.C. Wittich Verlag. Darmstadt. 1959. 162 pp. geïll. - H.J. de Graaf, Nicholas Tarling, British policy in the Malay Peninsula and Archipelago 1824-1871. Journal of the Malayan Branch of the Royal Asiatic Society. Vol. XXX, Pt. 3 (no. 179). - H.J. de Graaf, C. Northcote Parkinson, British intervention in Malaya, 1867-1877. University of Malaya Press, Singapore, 1960. 375 pp. text, 1 ill., 10 maps. - A.F.P. Hulsewé, Lea E. Williams, Overseas Chinese Nationalism - The genesis of the Pan-Chinese movement in Indonesia, 1900-1916. The center for International Studies, Massachusets Institute of Technology (The Free Press, Glencoe, Ill.; 1960). xiv + 235 pp.
Book Reviews
Authors: Jassin H.B. , Winstedt Richard , Teeuw A. , Anwar Chairil , Teeuw A. , Teeuw A. , Echols John M. , Winstedt Richard , Teeuw A. , Winstedt Richard , Teeuw A. , Niel R. , Palmier Leslie H. , Thomas jr. William L. , Buschkens W.F.L. , Teeuw A.
Published: May 2013

- Leslie H. Palmier, R. van Niel, The emergence of the modern Indonesian elite. The Hague and Bandung, W. van Hoeve Ltd., 1960.- A. Teeuw, Richard Winstedt, Kamus Bahasa Melayu. Marican & Sons, Singapore & Kuala Lumpur. 1960. 338 pp.- A. Teeuw, Richard Winstedt, An unabridged English-Malay Dictionary. Marican & Sons, Singapore. 398 pp. 2nd ed. with two appendices. id. 1960. 431 pp.- A. Teeuw, Richard Winstedt, An unabridged Malay-English dictionary. Kelly & Walsh Limited, Singapore. [+/- 1955]. 359 pp. 3rd ed. enlarged. Marican & Sons, Singapore & Kuala Lumpur. 1959.- A. Teeuw, John M. Echols, An Indonesian-English Dictionary. Cornell University Press, Ithaca, N.Y. 1961. XVI + 384 pp., Hassan Shadily (eds.)- A. Teeuw, Chairil Anwar, Sharp Gravel, Indonesian Poems by Chairil Anwar. Translated by Donna M. Dickinson. [Reproduced and distributed by: Center for Southeast Asia Studies, University of California, Berkeley 4, California. 1960.] 91 pages.- A. Teeuw, H.B. Jassin, Chairil Anwar. Pelopor Angkatan 45. Satu pembitjaraan. Disertai kumpulan hasil-hasil tulisannja. Tjet. ke-2. Gunung Agung - Djakarta 1959. 161 pp.- W.F.L. Buschkens, William L. Thomas jr., Man, Time, and Space in Southern California. A Suplement “Annals of the Association of American Geographers”, Washington 6, D.C., Allen Press, Lawrence, Kansas; 120 blz.
Book Reviews
Authors: Nieuwenhuys R. , Bouman H.
Published: May 2013

- R. Nieuwenhuys, H. Bouman, Meer licht over Kartini, met steun van de Van Deventer-Maasstichting uitgegeven bij H.J. Paris te Amsterdam (1954).
Book Reviews
Authors: Bader P. Hermann , Keuning J.
Published: May 2013

- J. Keuning, P. Hermann Bader, Die reifefeiern bei den Ngada (Mittelflores, Indonesien) St. Gabrieler Studien, XIV band.
Book Reviews
Authors: KITLV Redactie
Published: May 2013

- A. Teeuw, R.B. Slametmuljana, Bimbingan Seni-Sastra, tjetakan kedua; J.B. Wolters, Djakarta, Groningen 1953, 232 pgg. - ,
Book Reviews
Authors: KITLV Redactie
Published: May 2013

- G.J. Held, P.E. de Josselin de Jong, Minangkabau and Negri Sembilan; Socio-political structure in Indonesia, 1951, PhD thesis, Leiden, viii + 208 pp. H.Th. Fischer, C. Nooteboom, Trois problèmes d'ethnologie maritime, 1952, Rotterdam: Museum van Land- en Volkenkunde, 25 figuren.