bluuebunny/crossref_metadata_2025 huggingface dataset:
Ulcerating Ileocolitis in Severe Amatoxin Poisoning
Authors: Hilty Matthias Peter , Halama Marcel , Zimmermann Anne-Katrin , Maggiorini Marco , Geier Andreas
Published: August 2015

Amatoxin poisoning is still associated with a great potential for complications and a high mortality. While the occurrence of acute gastroenteritis within the first 24 hours after amatoxin ingestion is well described, only very few descriptions of late gastrointestinal complications of amatoxin poisoning exist worldwide. We present the case of a 57-year-old female patient with severe amatoxin poisoning causing fulminant but reversible hepatic failure that on day 8 after mushroom ingestion developed severe abdominal pain and watery diarrhea. Ulcerating ileocolitis was identified by computed tomography identifying a thickening of the bowel wall of the entire ileum and biopsies taken from the ileum and large bowel revealing distinct ileitis and proximally accentuated colitis. The absence of discernible alternative etiologies such as infectious agents makes a causal relationship between the ulcerating ileocolitis and the amatoxin poisoning likely. Diarrhea and varying abdominal pain persisted over several weeks and clinical follow-up after six months showed a completely symptom-free patient. The case presented highlights the importance to consider the possibility of rare complications ofAmanitaintoxication in order to be able to respond to them early and adequately.
The Application of Fluorescence Optical Imaging in Systemic Sclerosis
Authors: Pfeil Alexander , Drummer Karl F. , Böttcher Joachim , Jung Christian , Oelzner Peter , Renz Diane M. , Franz Marcus , Hansch Andreas , Wolf Gunter
Published: August 2015

Objective. The aim of this study was to visualize soft tissue inflammation using FOI on patients with Systemic Sclerosis (SSc) characterized by SSc-related Raynaud’s phenomenon and to detect the therapeutic response to treatment with iloprost or alprostadil.Methods. Twenty-one patients with SSc and Raynaud’s phenomenon and twenty-six healthy controls were prospectively included. The SSc patients were intravenously treated with iloprost or alprostadil over seven days. FOI was performed at baseline and after seven days using an intravenous application of indocyanine green (ICG). The hands were divided into nineteen segments per hand. All segments were quantitatively evaluated to determine changes in ICG.Results. The sensitivity and specificity of FOI in the detection of ICG enhancement in patients with SSc were 95% versus 96%. At baseline, 31.5% hand segments showed ICG enhancement. After seven days of either iloprost or alprostadil therapy a significant reduction in the ICG was observed which ranged from 40.9% to 24.7%.Conclusion. The study demonstrates that the FOI technique is able to visualize soft-tissue inflammation with both high sensitivity and specificity. The anti-inflammatory therapeutic effects of iloprost were slightly stronger than alprostadil. FOI offers promising benefits in the diagnosis and therapy of patients with SSc-associated Raynaud’s phenomenon.
Systems Medicine: The Application of Systems Biology Approaches for Modern Medical Research and Drug Development
Authors: Ayers Duncan , Day Philip J.
Published: August 2015

The exponential development of highly advanced scientific and medical research technologies throughout the past 30 years has arrived to the point where the high number of characterized molecular agents related to pathogenesis cannot be readily integrated or processed by conventional analytical approaches. Indeed, the realization that several moieties are signatures of disease has partly led to the increment of complex diseases being characterized. Scientists and clinicians can now investigate and analyse any individual dysregulations occurring within the genomic, transcriptomic, miRnomic, proteomic, and metabolomic levels thanks to currently available advanced technologies. However, there are drawbacks within this scientific brave new age in that only isolated molecular levels are individually investigated for their influence in affecting any particular health condition. Since their conception in 1992, systems biology/medicine focuses mainly on the perturbations of overall pathway kinetics for the consequent onset and/or deterioration of the investigated condition/s. Systems medicine approaches can therefore be employed for shedding light in multiple research scenarios, ultimately leading to the practical result of uncovering novel dynamic interaction networks that are critical for influencing the course of medical conditions. Consequently, systems medicine also serves to identify clinically important molecular targets for diagnostic and therapeutic measures against such a condition.
Thioredoxin 1 in Prostate Tissue Is Associated with Gleason Score, Erythrocyte Antioxidant Enzyme Activity, and Dietary Antioxidants
Authors: Vance Terrence M. , Azabdaftari Gissou , Pop Elena A. , Lee Sang Gil , Su L. Joseph , Fontham Elizabeth T. H. , Bensen Jeannette T. , Steck Susan E. , Arab Lenore , Mohler James L. , Chen Ming-Hui , Koo Sung I. , Chun Ock K.
Published: August 2015

Background. Prostate cancer is the most common noncutaneous cancer and second leading cause of cancer-related mortality in men in the US. Growing evidence suggests that oxidative stress is involved in prostate cancer.Methods. In this study, thioredoxin 1 (Trx 1), an enzyme and subcellular indicator of redox status, was measured in prostate biopsy tissue from 55 men from the North Carolina-Louisiana Prostate Cancer Project. A pathologist blindly scored levels of Trx 1. The association between Trx 1 and the Gleason score, erythrocyte antioxidant enzyme activity, and dietary antioxidant intake was determined using Fisher’s exact test.Results. Trx 1 levels in benign prostate tissue in men with incident prostate cancer were positively associated with the Gleason score (P=0.01) and inversely associated with dietary antioxidant intake (P=0.03). In prostate cancer tissue, Trx 1 levels were associated with erythrocyte glutathione peroxidase activity (P=0.01). No association was found for other erythrocyte enzymes. Greater Gleason score of malignant tissue corresponds to a greater difference in Trx 1 levels between malignant and benign tissue (P=0.04).Conclusion. These results suggest that the redox status of prostate tissue is associated with prostate cancer grade and both endogenous and exogenous antioxidants.
Psoriasis and Diabetes: A Multicenter Study in 222078 Type 2 Diabetes Patients Reveals High Levels of Depression
Authors: Schwandt Anke , Bergis Dominik , Dapp Albrecht , Ebner Stefan , Jehle Peter M. , Köppen Stefan , Risse Alexander , Zimny Stefan , Holl Reinhard W.
Published: August 2015

Objective. This study aimed to investigate the association between psoriasis and disease outcome in type 2 diabetes (T2D).Methods. 222078 T2D patients (≥10 years old) from the prospective, multicenter diabetes patient registry were analyzed. Specific search items were used to identify psoriasis patients. Multiple regression models were fitted and adjusted for demographic confounder.Results. 232 T2D patients had comorbid psoriasis. After adjusting psoriasis patients revealed a higher BMI (31.8 [31.0; 32.6] versus 30.6 [30.5; 30.6] kg/m2,p=0.004) and HbA1c (64.8 [62.1; 67.6] versus 59.0 [58.9; 59.1] mmol/mol,p<0.0001). Insulin was used more frequently (62.3 [55.7; 68.5] versus 50.9 [50.7; 51.1] %,p=0.001), only OAD/GLP-1 was similar, and nonpharmacological treatment was less common (13.3 [9.5; 18.3] versus 21.9 [21.7; 22.1] %,p=0.002). Severe hypoglycemia (0.31 [0.238; 0.399] versus 0.06 [0.057; 0.060] events per patient-year,p<0.0001), hypertension (86.1 [81.1; 90.0] versus 68.0 [67.8; 68.2] %,p<0.0001), and thyroid disease (14.0 [10.1; 19.2] versus 4.6 [4.5; 4.7] %,p<0.0001) were more prevalent. Depression occurred more often (10.5 [7.1; 15.2] versus 2.8 [2.7; 2.8] %,p<0.0001).Conclusions. Clinical diabetes characteristics in psoriasis T2D patients were clearly worse compared to patients without psoriasis. Comorbid conditions and depression were more prevalent, and more intensive diabetes therapy was required.
A Dynamic Intrusion Detection System Based on Multivariate Hotelling’s T2 Statistics Approach for Network Environments
Authors: Avalappampatty Sivasamy Aneetha , Sundan Bose
Published: August 2015

The ever expanding communication requirements in today’s world demand extensive and efficient network systems with equally efficient and reliable security features integrated for safe, confident, and secured communication and data transfer. Providing effective security protocols for any network environment, therefore, assumes paramount importance. Attempts are made continuously for designing more efficient and dynamic network intrusion detection models. In this work, an approach based on Hotelling’s T2 method, a multivariate statistical analysis technique, has been employed for intrusion detection, especially in network environments. Components such as preprocessing, multivariate statistical analysis, and attack detection have been incorporated in developing the multivariate Hotelling’s T2 statistical model and necessary profiles have been generated based on the T‐square distance metrics. With a threshold range obtained using the central limit theorem, observed traffic profiles have been classified either as normal or attack types. Performance of the model, as evaluated through validation and testing using KDD Cup’99 dataset, has shown very high detection rates for all classes with low false alarm rates. Accuracy of the model presented in this work, in comparison with the existing models, has been found to be much better.
Effect of the Common Fat Mass and Obesity Associated Gene Variants on Obesity in Pakistani Population: A Case-Control Study
Authors: Shabana  , Hasnain Shahida
Published: August 2015

Background/Objective. Obesity has become a global epidemic due to an increase in the number of obese individuals worldwide. There is little research in the field of obesity genetics in Pakistan. The aim of the current study was to analyze the association of common variants in Fat Mass and Obesity associated(FTO)gene with obesity in Pakistan, to find out the effect of the selected SNPs on anthropometric and biochemical traits, and to observe whether these variants act synergistically.Methods. Samples from 631 subjects were taken after informed consent and were used for serum parameters and genetic analysis. Lipid profile was determined, tetra-ARMS PCR was used for genotyping, and allele/genotype frequencies and genescore were calculated.Results. AllFTOvariants were associated with obesity, and some biochemical and anthropometric measures and had higher minor allele frequencies than those reported for Asian populations previously. The risk allele of each single nucleotide polymorphism resulted in an increase in BMI in a quantitative manner.Conclusion. Common forms of obesity are due to a combined net effect of many variants presented in same or different genes. The more the number of risk alleles present, the higher the risk and severity of obesity resulting from an increase in BMI.
Alkaloids inErythrinaby UPLC-ESI-MS andIn VivoHypotensive Potential of Extractive Preparations
Authors: Merlugo Liara , Santos Marí C. , Sant’Anna Liane S. , Cordeiro Everson W. F. , Batista Luiz A. C. , Miotto Silvia T. S. , Garcia Cássia V. , Moreira Cleci M. , Mendez Andreas S. L.
Published: August 2015

Erythrinaspecies are used in popular medicine as sedative, anxiolytic, anti-inflammatory, and antihypertensive. In this work, we investigated the chemical composition of extracts obtained from leaves ofE. falcataandE. crista-galli. The hypotensive potential ofE. falcataand the mechanism of action were also studied. The extracts were obtained by maceration and infusion. The total content of phenolic compounds and flavonoids was estimated by spectrophotometric methods. The chemical constituents were studied performing a chromatographic analysis by UPLC-ESI-MS. Forin vivoprotocols, blood pressure and heart rate were measured by the invasive hemodynamic monitoring method. Different concentrations of extracts and drugs such as L-NAME, losartan, hexamethonium, and propranolol were administrated i.v. The results of total phenolic contents forE. falcataandE. crista-galliwere 1.3193–1.4989 mgGAE/mL for maceration and 0.8771–0.9506 mgGAE/mL for infusion. In total flavonoids, the content was 7.7829–8.1976 mg RE/g for maceration and 9.3471–10.4765 RE mg/g for infusion. The chemical composition was based on alkaloids, suggesting the presence of erythristemine, 11β-methoxyglucoerysodine, erysothiopine, 11β-hydroxyerysodine-glucose, and 11-hydroxyerysotinone-rhamnoside. A potent dose-dependent hypotensive effect was observed forE. falcata, which may be related to the route ofβ-adrenergic receptors.
Efficacy of Once Daily Darunavir/Ritonavir in PI-Naïve, NNRTI-Experienced Patients in the ODIN Trial
Authors: Geretti Anna Maria , Moeketsi Mathe , Demasi Ralph , van Delft Yvon , Mohammed Perry
Published: August 2015

Background. An exploratory subanalysis of the ODIN trial was performed to evaluate the efficacy of darunavir/ritonavir (DRV/r) 800/100 mg OD versus 600/100 mg BID in patients who were NNRTI-experienced but PI-naïve.Methods. ODIN was a phase III, 48-week study comparing DRV/r OD versus BID in 590 treatment-experienced patients with no DRV resistance-associated mutations (RAMs) at screening. Patients received DRV/r 800/100 mg OD or DRV/r 600/100 mg BID plus ≥2 NRTIs. Of the 590 patients randomized, 272 (46%) were NNRTI-experienced but PI-naïve.Results. Overall, 272 patients received DRV/r ODn=135or BIDn=137plus ≥2 optimised NRTIs. The mean age was 39 years; 35% were female; 27% were Black, 24% Caucasian, 26% Oriental/Asian, and 23% other races; 17% were recruited in South Africa; and 48% had non-B HIV-1 subtypes. Mean baseline plasma HIV-1 RNA load was4.10 log10⁡copies/mL; median CD4 cell count was 258 cells/μL. At week 48, 111/135 (82%) of DRV/r OD and 109/137 (80%) of DRV/r BID patients achieved an HIV-1 RNA load <50 copies/mL. No patient developed primary PI RAMs.Conclusion. DRV/r 800/100 mg OD in combination with ≥2 optimised NRTIs led to virological suppression <50 copies/mL in 82% of NNRTI-experienced, PI-naïve patients by week 48.
Hepatocyte Growth Factor/cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Carcinoma
Authors: Phan Liem M. , Fuentes-Mattei Enrique , Wu Weixin , Velazquez-Torres Guermarie , Sircar Kanishka , Wood Christopher G. , Hai Tao , Jimenez Camilo , Cote Gilbert J. , Ozsari Levent , Hofmann Marie-Claude , Zheng Siyuan , Verhaak Roeland , Pagliaro Lance , Cortez Maria Angelica , Lee Mong-Hong , Yeung Sai-Ching J. , Habra Mouhammed Amir
Published: August 2015

Adrenocortical carcinoma is a rare malignancy with poor prognosis and limited response to chemotherapy. Hepatocyte growth factor (HGF) and its receptor cMET augment cancer growth and resistance to chemotherapy, but their role in adrenocortical carcinoma has not been examined. In this study, we investigated the association between HGF/cMET expression and cancer hallmarks of adrenocortical carcinoma. Transcriptomic and immunohistochemical analyses indicated that increased HGF/cMET expression in human adrenocortical carcinoma samples was positively associated with cancer-related biologic processes, including proliferation and angiogenesis, and negatively correlated with apoptosis. Accordingly, treatment of adrenocortical carcinoma cells with exogenous HGF resulted in increased cell proliferation in vitro and in vivo while short hairpin RNA–mediated knockdown or pharmacologic inhibition of cMET suppressed cell proliferation and tumor growth. Moreover, exposure of cells to mitotane, cisplatin, or radiation rapidly induced pro-cMET expression and was associated with an enrichment of genes (e.g., CYP450 family) related to therapy resistance, further implicating cMET in the anticancer drug response. Together, these data suggest an important role for HGF/cMET signaling in adrenocortical carcinoma growth and resistance to commonly used treatments. Targeting cMET, alone or in combination with other drugs, could provide a breakthrough in the management of this aggressive cancer. Cancer Res; 75(19); 4131–42. ©2015 AACR.
Transcriptome Sequencing Reveals PCAT5 as a Novel ERG-Regulated Long Noncoding RNA in Prostate Cancer
Authors: Ylipää Antti , Kivinummi Kati , Kohvakka Annika , Annala Matti , Latonen Leena , Scaravilli Mauro , Kartasalo Kimmo , Leppänen Simo-Pekka , Karakurt Serdar , Seppälä Janne , Yli-Harja Olli , Tammela Teuvo L.J. , Zhang Wei , Visakorpi Tapio , Nykter Matti
Published: August 2015

Castration-resistant prostate cancers (CRPC) that arise after the failure of androgen-blocking therapies cause most of the deaths from prostate cancer, intensifying the need to fully understand CRPC pathophysiology. In this study, we characterized the transcriptomic differences between untreated prostate cancer and locally recurrent CRPC. Here, we report the identification of 145 previously unannotated intergenic long noncoding RNA transcripts (lncRNA) or isoforms that are associated with prostate cancer or CRPC. Of the one third of these transcripts that were specific for CRPC, we defined a novel lncRNA termed PCAT5 as a regulatory target for the transcription factor ERG, which is activated in approximately 50% of human prostate cancer. Genome-wide expression analysis of a PCAT5-positive prostate cancer after PCAT5 silencing highlighted alterations in cell proliferation pathways. Strikingly, an in vitro validation of these alterations revealed a complex integrated phenotype affecting cell growth, migration, invasion, colony-forming potential, and apoptosis. Our findings reveal a key molecular determinant of differences between prostate cancer and CRPC at the level of the transcriptome. Furthermore, they establish PCAT5 as a novel oncogenic lncRNA in ERG-positive prostate cancers, with implications for defining CRPC biomarkers and new therapeutic interventions. Cancer Res; 75(19); 4026–31. ©2015 AACR.
Interactions between Ibrutinib and Anti-CD20 Antibodies: Competing Effects on the Outcome of Combination Therapy
Authors: Skarzynski Martin , Niemann Carsten U. , Lee Yuh Shan , Martyr Sabrina , Maric Irina , Salem Dalia , Stetler-Stevenson Maryalice , Marti Gerald E. , Calvo Katherine R. , Yuan Constance , Valdez Janet , Soto Susan , Farooqui Mohammed Z.H. , Herman Sarah E.M. , Wiestner Adrian
Published: August 2015

Purpose: Clinical trials of ibrutinib combined with anti-CD20 monoclonal antibodies (mAb) for chronic lymphocytic leukemia (CLL) report encouraging results. Paradoxically, in preclinical studies, in vitro ibrutinib was reported to decrease CD20 expression and inhibit cellular effector mechanisms. We therefore set out to investigate effects of in vivo ibrutinib treatment that could explain this paradox.

Experimental Design: Patients received single-agent ibrutinib (420 mg daily) on an investigator-initiated phase II trial. Serial blood samples were collected pretreatment and during treatment for ex vivo functional assays to examine the effects on CLL cell susceptibility to anti-CD20 mAbs.

Results: We demonstrate that CD20 expression on ibrutinib was rapidly and persistently downregulated (median reduction 74%, day 28, P < 0.001) compared with baseline. Concomitantly, CD20 mRNA was decreased concurrent with reduced NF-κB signaling. An NF-κB binding site in the promoter of MS4A1 (encoding CD20) and downregulation of CD20 by NF-κB inhibitors support a direct transcriptional effect. Ex vivo, tumor cells from patients on ibrutinib were less susceptible to anti-CD20 mAb-mediated complement-dependent cytotoxicity than pretreatment cells (median reduction 75%, P < 0.001); however, opsonization by the complement protein C3d, which targets cells for phagocytosis, was relatively maintained. Expression of decay-accelerating factor (CD55) decreased on ibrutinib, providing a likely mechanism for the preserved C3d opsonization. In addition, ibrutinib significantly inhibited trogocytosis, a major contributor to antigen loss and tumor escape during mAb therapy.

Conclusions: Our data indicate that ibrutinib promotes both positive and negative interactions with anti-CD20 mAbs, suggesting that successfully harnessing maximal antitumor effects of such combinations requires further investigation. Clin Cancer Res; 22(1); 86–95. ©2015 AACR.
The Role of Activated Microglia and Resident Macrophages in the Neurovascular Unit during Cerebral Ischemia: Is the Jury Still Out?
Authors: Barakat Rawan , Redzic Zoran
Published: August 2015

Paracrine signaling in the neurovascular unit (NVU) is aimed to adjust the supply of oxygen and nutrients to metabolic demands of the brain in a feed-forward manner. Cerebral ischemia (CI) severely disrupts this homeostatic mechanism and also causes activation of microglia and resident macrophages in the brain. Contradictory data exist on the time pattern of microglial activation and polarization during CI, on molecular mechanisms that trigger them and on effects of microglia-derived cytokines on brain cells. It appears that conditions that occur during transient ischemia or in the penumbra of focal ischemia in vivo or equivalent conditions in vitro trigger polarization of resting microglia/macrophages into the M2 phenotype, which mainly exerts anti-inflammatory and protective effects in the brain, while prolonged ischemia with abundant necrosis promotes microglial polarization into the M1 phenotype. During the later stages of recovery, microglia that polarized initially into the M2 phenotype can shift into the M1 phenotype. Thus, it appears that cells with both phenotypes are present in the affected area, but their relative amount changes in time and probably depends on the proximity to the ischemic core. It was assumed that cells with the M1 phenotype exert detrimental effects on neurons and contribute to the blood-brain barrier opening. Several M1 phenotype-specific cytokines exert protective effects on astrocytes, which could be important for reactive gliosis occurring after ischemia. Thus, whether or not suppression of microglial activity after CI is beneficial for neurological outcome still remains unclear and current evidence suggests that no simple answer could be given to this question.
Correlation of Physical Activities and Breast Cancer Characteristics: A Prospective Analysis with Special Focus on Triple Negative Breast Cancer
Authors: Vallard Alexis , Falk Alexander Tuan , Antoine Pascale , Guy Jean-Baptiste , Guichard Jean-Baptiste , Espenel Sophie , Langrand-Escure Julien , Trone Jane-Chloé , Méry Benoîte , Ben Mrad Majed , Diao Peng , Wang Guoping , Roche Frédéric , Bosacki Claire , Chargari Cyrus , Bourmaud Aurélie , Magné Nicolas
Published: August 2015

Objective: Several studies have demonstrated that daily physical activity (PA) prevents the development of breast cancer. Our objective was to examine the relationship between PA and clinical and biological tumor characteristics in breast cancer patients in order to determine the impact of energy expenditure (EE) on tumor prognosis. Methods: We pooled data from two prospective studies, including a total of 121 breast cancer patients. The measure of PA was done using the self-completion Population Physical Activity Questionnaire, which was answered by each patient. Results: Ten patients harbored triple negative (TN) tumors. The mean body mass index (BMI) in the general population and in patients with TN tumors was 24.3 and 25.6, respectively. The mean daily EE (DEE) was 10,266 kJ × 24 h-1 in the general population and 11,212 kJ × 24 h-1 in patients with TN tumors. In the whole population, there was an inverse statistical correlation between BMI and DEE, rest, low PA, and high PA (p = 0.0002, p = 0.003, p < 0001, and p = 0.03, respectively). There was a positive correlation between negative estrogen receptor status and intensive PA (p = 0.041) and DEE (p = 0.007). For TN tumors, there was no significant correlation between BMI and categories of EE. Conclusions: Lifestyle (weight regulation, PA) should be adapted and personalized according to biological, clinical, and epidemiological characteristics of the tumors.
Recombinant Thrombomodulin Modulates Murine Colitis Possibly via High-Mobility Group Box 1 Protein Inhibition
Authors: Ueda Toshihide , Higashiyama Masaaki , Narimatsu Kazuyuki , Yasutake Yuichi , Kurihara Chie , Okada Yoshikiyo , Watanabe Chikako , Yoshikawa Kenichi , Maruta Koji , Komoto Shunsuke , Tomita Kengo , Nagao Shigeaki , Hokari Ryota , Miura Soichiro
Published: August 2015

Background and Aim: Thrombomodulin (TM) is an anticoagulant cofactor protein. We hypothesized that its recombinant soluble TM (rhTM) form, widely used to treat disseminated intravascular coagulation, might have anti-inflammatory action in inflammatory bowel disease (IBD), possibly through its inhibition of high-mobility group box 1 protein (HMGB1). Methods: We investigated inflammatory effects of HMGB1 and anti-inflammatory effect of rhTM in dextran sulfate sodium (DSS)-treated mice, some cell lines and ulcerative colitis (UC) patients, particularly focusing on changes of vascular endothelial adhesion molecules. Results: Treatments with rhTM significantly attenuated DSS-treated mice clinically and histologically. The mRNA levels of proinflammatory cytokines and adhesion molecules were decreased by rhTM. Increased inflammatory cells in the colonic mucosa strongly expressed HMGB1 in the cytoplasm in the DSS-treated mice and UC patients' colonic mucosa, which were significantly decreased by rhTM in mice. In in vitro experiments, rhTM significantly decreased the mRNA levels of tumor necrosis factor-alpha (TNF-α) and adhesion molecules increased by endotoxin exposures in RAW 264.7 (macrophage cell line) and bEND.3 cells (endothelial cell line), suggesting the proinflammatory role of HMGB1 in TNF-α production from macrophages. Conclusions: These findings suggest that rhTM may be useful for the treatment of IBD by attenuating inflammatory cytokine production and adhesion molecule expression, partly because of its inhibition of HMGB1.
Pachyonychia Congenita (K16) with Unusual Features and Good Response to Acitretin
Authors: Almutawa Fahad , Thusaringam Thusanth , Watters Kevin , Gayden Tenzin , Jabado Nada , Sasseville Denis
Published: August 2015

Background: Pachyonychia congenita (PC) is a rare autosomal dominant disease whose main clinical features include hypertrophic onychodystrophy and palmoplantar keratoderma. The new classification is based on genetic variants with mutations in keratin KRT6A, KRT6B, KRT6C, KRT16, KRT17, and an unknown mutation. Here, we present a case of PC with unusual clinical and histological features and a favorable response to oral acitretin. Case: A 49-year-old male presented with diffuse and striate palmoplantar keratoderma, thickened nails, knuckle pads, and pseudoainhum. Histology showed compact hyperkeratosis, prominent irregular acanthosis, and extensive epidermolytic hyperkeratosis, suggestive of Vörner's palmoplantar keratoderma. However, keratin 9 and 1 were not mutated, and full exome sequencing showed heterozygous missense mutation in type I keratin K16. Conclusion: To our knowledge, epidermolytic hyperkeratosis has not been previously described with PC. Our patient had an excellent response, maintained over the last 5 years, to a low dose of acitretin. We wish to emphasize the crucial role of whole exome sequencing in establishing the correct diagnosis.
Pazopanib-Induced Severe Acute Pancreatitis
Authors: Kawakubo Kazumichi , Hata Hiroo , Kawakami Hiroshi , Kuwatani Masaki , Kawahata Shuhei , Kubo Kimitoshi , Imafuku Keisuke , Kitamura Shinya , Sakamoto Naoya
Published: August 2015

Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptors, platelet-derived growth factor receptors, and c-Kit approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Nonselective kinase inhibitors, such as sunitinib and sorafenib, are known to be associated with acute pancreatitis. There are few case reports of severe acute pancreatitis induced by pazopanib treatment. We present a case of severe acute pancreatitis caused by pazopanib treatment for cutaneous angiosarcoma. The patient was an 82-year-old female diagnosed with cutaneous angiosarcoma. She had been refractory to docetaxel treatment and began pazopanib therapy. Three months after pazopanib treatment, CT imaging of the abdomen showed the swelling of the pancreas and surrounding soft tissue inflammation without abdominal pain. After she continued pazopanib treatment for 2 months, she presented with nausea and appetite loss. Abdominal CT showed the worsening of the surrounding soft tissue inflammation of the pancreas. Serum amylase and lipase levels were 296 and 177 IU/l, respectively. She was diagnosed with acute pancreatitis induced by pazopanib treatment and was managed conservatively with discontinuation of pazopanib, but the symptoms did not improve. Subsequently, an abdominal CT scan demonstrated the appearance of a pancreatic pseudocyst. She underwent endoscopic ultrasound-guided pseudocyst drainage using a flared-end fully covered self-expandable metallic stent. Then, the symptoms resolved without recurrence. Due to the remarkable progress of molecular targeted therapy, the oncologist should know that acute pancreatitis was recognized as a potential adverse event of pazopanib treatment and could proceed to severe acute pancreatitis.
Accuracy and Usability of a Self-Administered 6-Minute Walk Test Smartphone Application
Authors: Brooks Gabriel C. , Vittinghoff Eric , Iyer Sivaraman , Tandon Damini , Kuhar Peter , Madsen Kristine A. , Marcus Gregory M. , Pletcher Mark J. , Olgin Jeffrey E.
Published: August 2015

Background—

The 6-minute walk test (6MWT) independently predicts congestive heart failure severity, death, and heart failure hospitalizations, but must be administered in clinic by qualified staff on a premeasured course. As part of the Health eHeart Study, we sought to develop and validate a self-administered 6MWT mobile application (SA-6MWTapp) for independent use at home by patients.

Methods and Results—

We performed a validation study of an SA-6MWTapp in 103 participants. In phase 1 (n=52), we developed a distance-estimation algorithm for the SA-6MWTapp by comparing step counts from an Actigraph and measured distance on a premeasured 6MWT course with step counts and estimated distance obtained simultaneously from our SA-6MWTapp (best estimation algorithm, r=0.89 [95% confidence interval 0.78–0.99]). In phase 2, 32 participants (including those with congestive heart failure and pulmonary hypertension) used the SA-6MWTapp independently in clinic, and the distance estimated by the SA-6MWTapp was compared with the measured distance (r=0.83 [95% confidence interval 0.79–0.92]). In phase 3, 19 patients with congestive heart failure and pulmonary hypertension consecutively enrolled from clinic performed 3.2±1 SA-6MWTapp tests per week at home over 2 weeks. Distances estimated from the SA-6MWTapp during home 6MWTs were highly repeatable (coefficient of variation =4.6%) and correlated with in-clinic–measured distance (r=0.88 [95% confidence interval 0.87–0.89]). Usability surveys performed during the second (in-clinic) and third (at-home) phases demonstrated that the SA-6MWTapp was simple and easy to use independently.

Conclusions—

An SA-6MWTapp is easy to use and yields accurate repeatable measurements in the clinic and at home.
Oscillations or Synchrony? Disruption of Neural Synchrony despite Enhanced Gamma Oscillations in a Model of Disrupted Perceptual Coherence
Authors: Castelhano João , Bernardino Inês , Rebola José , Rodriguez Eugenio , Castelo-Branco Miguel
Published: August 2015

It has been hypothesized that neural synchrony underlies perceptual coherence. The hypothesis of loss of central perceptual coherence has been proposed to be at the origin of abnormal cognition in autism spectrum disorders and Williams syndrome, a neurodevelopmental disorder linked with autism, and a clearcut model for impaired central coherence. We took advantage of this model of impaired holistic processing to test the hypothesis that loss of neural synchrony plays a separable role in visual integration using EEG and a set of experimental tasks requiring coherent integration of local elements leading to 3-D face perception. A profound reorganization of brain activity was identified. Neural synchrony was reduced across stimulus conditions, and this was associated with increased amplitude modulation at 25–45 Hz. This combination of a dramatic loss of synchrony despite increased oscillatory activity is strong evidence that synchrony underlies central coherence. This is the first time, to our knowledge, that dissociation between amplitude and synchrony is reported in a human model of impaired perceptual coherence, suggesting that loss of phase coherence is more directly related to disruption of holistic perception.
Steady-state BOLD Response to Higher-order Cognition Modulates Low-Frequency Neural Oscillations
Authors: Wang Yi-Feng , Dai Gang-Shu , Liu Feng , Long Zhi-Liang , Yan Jin H. , Chen Hua-Fu
Published: August 2015

Steady-state responses (SSRs) reflect the synchronous neural oscillations evoked by noninvasive and consistently repeated stimuli at the fundamental or harmonic frequencies. The steady-state evoked potentials (SSEPs; the representative form of the SSRs) have been widely used in the cognitive and clinical neurosciences and brain–computer interface research. However, the steady-state evoked potentials have limitations in examining high-frequency neural oscillations and basic cognition. In addition, synchronous neural oscillations in the low frequency range (<1 Hz) and in higher-order cognition have received a little attention. Therefore, we examined the SSRs in the low frequency range using a new index, the steady-state BOLD responses (SSBRs) evoked by semantic stimuli. Our results revealed that the significant SSBRs were induced at the fundamental frequency of stimuli and the first harmonic in task-related regions, suggesting the enhanced variability of neural oscillations entrained by exogenous stimuli. The SSBRs were independent of neurovascular coupling and characterized by sensorimotor bias, an indication of regional-dependent neuroplasticity. Furthermore, the amplitude of SSBRs may predict behavioral performance and show the psychophysiological relevance. Our findings provide valuable insights into the understanding of the SSRs evoked by higher-order cognition and how the SSRs modulate low-frequency neural oscillations.
Electrophysiological and Kinematic Correlates of Communicative Intent in the Planning and Production of Pointing Gestures and Speech
Authors: Peeters David , Chu Mingyuan , Holler Judith , Hagoort Peter , Özyürek Aslı
Published: August 2015

In everyday human communication, we often express our communicative intentions by manually pointing out referents in the material world around us to an addressee, often in tight synchronization with referential speech. This study investigated whether and how the kinematic form of index finger pointing gestures is shaped by the gesturer's communicative intentions and how this is modulated by the presence of concurrently produced speech. Furthermore, we explored the neural mechanisms underpinning the planning of communicative pointing gestures and speech. Two experiments were carried out in which participants pointed at referents for an addressee while the informativeness of their gestures and speech was varied. Kinematic and electrophysiological data were recorded online. It was found that participants prolonged the duration of the stroke and poststroke hold phase of their gesture to be more communicative, in particular when the gesture was carrying the main informational burden in their multimodal utterance. Frontal and P300 effects in the ERPs suggested the importance of intentional and modality-independent attentional mechanisms during the planning phase of informative pointing gestures. These findings contribute to a better understanding of the complex interplay between action, attention, intention, and language in the production of pointing gestures, a communicative act core to human interaction.
Competition between Mutually Exclusive Object States in Event Comprehension
Authors: Solomon Sarah H. , Hindy Nicholas C. , Altmann Gerry T. M. , Thompson-Schill Sharon L.
Published: August 2015

Successful language comprehension requires one to correctly match symbols in an utterance to referents in the world, but the rampant ambiguity present in that mapping poses a challenge. Sometimes the ambiguity lies in which of two (or more) types of things in the world are under discussion (i.e., lexical ambiguity); however, even a word with a single sense can have an ambiguous referent. This ambiguity occurs when an object can exist in multiple states. Here, we consider two cases in which the presence of multiple object states may render a single-sense word ambiguous. In the first case, one must disambiguate between two states of a single object token in a short discourse. In the second case, the discourse establishes two different tokens of the object category. Both cases involve multiple object states: These states are mutually exclusive in the first case, whereas in the second case, these states can logically exist at the same time. We use fMRI to contrast same-token and different-token discourses, using responses in left posterior ventrolateral prefrontal cortex (pVLPFC) as an indicator of conflict. Because the left pVLPFC is sensitive to competition between multiple, incompatible representations, we predicted that state ambiguity should engender conflict only when those states are mutually exclusive. Indeed, we find evidence of conflict in same-token, but not different-token, discourses. Our data support a theory of left pVLPFC function in which general conflict resolution mechanisms are engaged to select between multiple incompatible representations that arise in many kinds of ambiguity present in language.
Escape-hatching responses of individual treefrog embryos vary with threat level in wasp attacks: a mechanistic analysis
Authors: Hughey Myra C. , Rogge Jessica R. , Thomas Kristen , McCoy Michael W. , Warkentin Karen M.
Published: August 2015

Theory predicts that prey behavioural responses should reflect the level of risk posed by predators. We investigated how red-eyed treefrog embryos perceive and respond to spatially variable risk during wasp attacks on their clutches. First, we spatially restricted wasp activity on clutches and compared hatching of wasp-exposed, adjacent, and protected embryos. Hatching occurred in all zones but increased with exposure, being highest in directly exposed embryos. Second, we videotaped wasps attacking clutches and compared the experiences of embryos that hatched first and those that did not hatch until later. Embryos that hatched first experienced more predatory wasp activity directed at themselves or at siblings within a 2-egg radius. Models predicting hatching indicate that cues used to assess risk originate from the behaviour of wasps, rather than other embryos. This research demonstrates that embryos can integrate information about predator behaviour and proximity to respond appropriately based on their level of risk.
Between Surplus and Lack
Authors: Wing Wang Alwyn Lau
Published: August 2015

Political theology finds itself at an impasse between those which trumpet traditional views of divine surplus and transcendence, and atheologies which deconstruct faith and the divine to a barely coherent (let alone recognizable) point. This article aims to map out the contours of a reworked political theology, one with forgiveness and divine suffering at its centre (juxtaposing the transcendent in the immanent) yet one which is neither held confined by the need for dogmatic assent nor rendered unintelligible by a rejection of the conceptual.
Public Theology avant la lettre in Spain
Authors: Villagrán Gonzalo
Published: August 2015

It is possible to identify a public approach to theology in some contemporary Spanish theologians, although the term itself is foreign in Spanish theological circles. The theological reflections of Alfonso Álvarez Bolado and Olegario González de Cardedal are a great example in this sense. The former sheds a theological view on Franco’s dictatorship to criticize its supposedly religious legitimation. The latter is an attempt to clarify the confusion between Spanish citizenship and Catholicism in the young Spanish democracy. The work of these two authors also helps us identify the main traits of the Spanish context that will shape the future of public theology in this country. Any future effort for developing a public theology in Spain necessarily should be done based on this previous tradition.
Difficult Forgiveness? Engaging Paul Ricoeur on Public Forgiveness within the Context of Social Change in South Africa
Authors: Vosloo Robert
Published: August 2015

In the context of public discourse in South Africa, this article engages Paul Ricoeur’s influential and thought-provoking work on forgiveness, also as it intersects with the work of Jacques Derrida. The article argues that Ricoeur’s discussion of ‘difficult forgiveness’ provides important conceptual clarification in the search for responsible discourse on forgiveness, and offers some brief remarks regarding the promise and pitfalls of using the notion of ‘difficult forgiveness’ in post-conflict situations marked by historical injustice, such as South Africa. It is argued that Ricoeur’s discussion of forgiveness helpfully demonstrates the complexities involved in forgiving in a way that resists cheap forgiveness, and that his nuanced attempt to make room for the spirit of forgiveness to touch institutions enriches the discourse on public forgiveness and its role in the humanization of polarized societies. Given the eschatological tone of Ricoeur’s discussion of forgiveness, the article also points towards the need for future-orientated memory to deal with historical injustices.
Nullum Crimen and International Criminal Law: The Relevance of the Foreseeability Test
Authors: van der Wilt Harmen
Published: August 2015

This article traces the development of the foreseeability test in the context of the nullum crimen principle. While the European Court of Human Rights has introduced the ‘accessibility and foreseeability’ criteria long ago in the Sunday Times case, the Court has only recently started to apply this standard with respect to international crimes. In the Kononov case, judges of the European Court of Human Rights exhibited strongly divergent opinions on the question whether the punishment of alleged war crimes that had been committed in 1944 violated the nullum crimen principle. According to this author, the dissension of the judges demonstrates the lack of objective foreseeability, which should have served as a starting point for the assessment of the subjective foreseeability and a – potentially exculpating – mistake of law of the perpetrator. The Court should therefore have concluded that the nullum crimen principle had been violated.
Mango Trees, Offices and Altars: The Role of Relatives, Non-governmental Organisations and Churches After Rape in Northern Uganda
Authors: Porter Holly E.
Published: August 2015

This article reflects on why so many women never access justice or take advantage of available services after rape in northern Uganda. It focuses on roles of three prominent non-governmental actors: lineage-based kinship authority, churches, and non-governmental organisations examining the parts they played after 94 instances of rape in this study and more broadly, how they have shaped notions of rape and appropriate responses to it. Evidence from this study (participant observation over three years and 187 in-depth interviews) suggests that although non-governmental organizations and churches have impacted evolution of social norms, reactions to wrongdoing are primarily decided by extended family structures, and are subject to a primary value of social harmony.
Women’s Land Claims in the Acholi Region of Northern Uganda: What Can Be Learned from What Is Contested
Authors: Hopwood Julian
Published: August 2015

Women are often understood to be highly marginalised in typical African customary land regimes. The research presented in this article found that in the Acholi region of northern Uganda this is not the case. The crisis of land conflict that followed the twenty-year lra insurgency and mass rural displacement has seemingly passed, notwithstanding a minimal contribution from the formal justice, law and order sector: local state actors as well as clan elders are mediating and adjudicating disputes on the basis of custom. However some social institutions, in particular traditional marriage, have been deeply affected by displacement and the consequent poverty. In this context, custom appears to be becoming more responsive to the needs of women, including those who are divorced or separated. While women’s customary land claims are often challenged, they appear to be generally respected and supported by communities and those with responsibilities for settling disputes.
Hayden White’s Metahistory and the Irony of the Archive
Authors: Peden Knox
Published: August 2015

Hayden White’s contention that “moral and aesthetic” preferences are primary in shaping a historian’s vision of the past seems to play in to various contemporary efforts to consider history at a scale conducive to insight into climate change and global political dilemmas. Nevertheless, his critique of the archive as a repository of truth acquires new resonance as the naturalist and technological reconfiguration of the archive accompanying these developments gets underway. The signal value of White’s polemical intervention in historical theory was to divorce claims of moral right and political justice from truth claims about the objective reality of the past. It remains so today.
The Natural History of Aesthetics
Authors: Ford Thomas H.
Published: August 2015

Art has been crucial for Western philosophy roughly since Kant – that is, for what is becoming known as “correlationist” philosophy – because it has so often had assigned to it a singular ontological status. The artwork, in this view, is material being that has been transfigured and shot through with subjectivity. The work of art, what art does and how it works have all been understood as mediating between the otherwise irreconcilable opposites of historical spirit and the mute material world, between communicative thought and the unresponsiveness otherness of nature. I revisit this aesthetic tradition from the perspective of the Anthropocene, the proposed name of the new geological epoch of the present, distinguished by the fact that collective human action has now acquired the scale of a world-shaping natural force. The Anthropocene is at once a geological epoch and a historical period. What forms of narrative might possibly relate these two temporal orders together? What other aesthetic categories might help us think through the conceptual impasse of the Anthropocene present? How might aesthetic experience illuminate the history of Anthropocene? What natural histories might artworks tell today? My speculative endpoint: the Anthropocene globe is the universal artwork of the contemporary moment.
Underdetermination Skepticism and Skeptical Dogmatism
Authors: Walker Mark
Published: August 2015

The Mundane World Hypothesis (mwh) says that we have material bodies, we have brains located inside our bodies, we have sense organs which process visual information, the direct cause of our perceptual judgments is typically macroscopic material objects, and we live in a material world. Skeptics using underdetermination arguments arguemwhhas no more epistemic merit than some skeptical competitor, e.g., that we are in the Matrix. Since such competitor hypotheses are equipollent, we are not justified in believingmwh. This paper takes the underdetermination skeptic’s premises to a more radical conclusion: skeptical dogmatism, which is the view thatmwhis probably false based on the idea that there are many equipollent competitors tomwh.