bluuebunny/crossref_metadata_2025 huggingface dataset:
DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers
Authors: de Cubas Aguirre A. , Korpershoek Esther , Inglada-Pérez Lucia , Letouzé Eric , Currás-Freixes Maria , Fernández Agustin F. , Comino-Méndez Iñaki , Schiavi Francesca , Mancikova Veronika , Eisenhofer Graeme , Mannelli Massimo , Opocher Guiseppe , Timmers Henri , Beuschlein Felix , de Krijger Ronald , Cascon Alberto , Rodríguez-Antona Cristina , Fraga Mario F. , Favier Judith , Gimenez-Roqueplo Anne-Paule , Robledo Mercedes
Published: April 2015

Purpose: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors, associated with highly variable postoperative evolution. The scarcity of reliable PPGL prognostic markers continues to complicate patient management. In this study, we explored genome-wide DNA methylation patterns in the context of PPGL malignancy to identify novel prognostic markers.

Experimental Design: We retrospectively investigated DNA methylation patterns in PPGL with and without metastases using high-throughput DNA methylation profiling data (Illumina 27K) from two large, well-characterized discovery (n = 123; 24 metastatic) and primary validation (n = 154; 24 metastatic) series. Additional validation of candidate CpGs was performed by bisulfite pyrosequencing in a second independent set of 33 paraffin-embedded PPGLs (19 metastatic).

Results: Of the initial 86 candidate CpGs, we successfully replicated 52 (47 genes), associated with metastatic PPGL. Of these, 48 CpGs showed significant associations with time to progression even after correcting for SDHB genotype, suggesting their value as prognostic markers independent of genetic background. Hypermethylation of RDBP (negative elongation factor complex member E) in metastatic tumors was further validated by bisulfite pyrosequencing [Δβmetastatic-benign = 0.29, P = 0.003; HR, 1.4; 95% confidence interval (CI), 1.1–2.0; P = 0.018] and may alter transcriptional networks involving (RERG, GPX3, and PDZK1) apoptosis, invasion, and maintenance of DNA integrity.

Conclusions: This is the first large-scale study of DNA methylation in metastatic PPGL that identifies and validates prognostic markers, which could be used for stratifying patients according to risk of developing metastasis. Of the three CpGs selected for further validation, one (RDBP) was clearly confirmed and could be used for stratifying patients according to the risk of developing metastases. Clin Cancer Res; 21(13); 3020–30. ©2015 AACR.
Complications of Flexible Ureteroscopic Treatment for Renal and Ureteral Calculi during the Learning Curve
Authors: Komori Masatsugu , Izaki Hirofumi , Daizumoto Kei , Tsuda Megumi , Kusuhara Yoshito , Mori Hidehisa , Kagawa Junichiro , Yamaguchi Kunihisa , Yamamoto Yasuyo , Fukumori Tomoharu , Takahashi Masayuki , Kanayama Hiro-omi , Sakaki Manabu , Nakatsuji Hiroyoshi , Hamao Takumi , Miura Hiroyasu
Published: April 2015

Background: The flexible ureterorenoscope (URS) and associated devices have developed rapidly. However, despite its therapeutic benefits, URS may be associated with some complications. To the best of our knowledge, there are no studies discussing the complications of flexURS during the learning curve. Methods: A retrospective review of the records of patients who underwent flexURS from January 2005 to June 2013 was performed. To compare the complications after the introduction of flexURS, patients were divided into four groups based on the surgeon's training experience, that is, based on the number of cases performed by the surgeon. A total of 219 cases underwent flexURS. Groups 1, 2, 3, and 4 included 35, 50, 50, and 84 cases, respectively. The complications were classified using the Clavien system (I-IV). Results: The mean operation time and stone-free rate were significantly different (p < 0.001, p = 0.013, respectively). The total complication rates were 13.6, 10, 8.3, and 3.2%, respectively (p = 0.068). The more the surgeon's experience, the less was the complication rate. Despite our best efforts, the incidence of urosepsis was not reduced (p = 0.902). Conclusions: To reduce severe complications, it is necessary to have performed about 100 cases. Increased surgeon experience tended to decrease the risk of severe complications, but the incidence of urosepsis was not reduced.
Clinical Symptoms Associated with Suicidality in Patients with Panic Disorder
Authors: Lim Se-Won , Ko Eun-Mi , Shin Dong-Won , Shin Young-Chul , Oh Kang-Seob
Published: April 2015

Background: Patients with panic disorder have higher rates of suicide than the general population. Among panic disorder subjects, early onset, female gender, alcohol abuse, and mood disorder increase the risk of suicidality. However, less is known about the unique relationships between discrete DSM-IV panic symptoms and higher suicidality. Therefore, in the current study we examined the panic symptom profile that is associated with higher suicidality in a sample of outpatients with panic disorder. Methods: This cross-sectional study included 427 patients diagnosed with current panic disorder on the basis of the DSM-IV-TR. In order to assess the contribution of the clinical variables, a univariate logistic regression was carried out examining the relationships between the demographic variables, suicidality from the suicide module of the Korean version of the MINI International Neuropsychiatric Interview Plus, and DSM-IV panic symptoms. Additionally, a multivariate logistic regression was performed to identify specific panic symptoms that were significant risk factors for suicidality among patients with current panic disorder. Results: We found that 74 (17.33%) panic disorder patients experienced high suicidality. Univariate analyses showed that high suicidality was significantly associated with a younger age (OR = 13.66; 95% CI 2.68-69.70), comorbid depressive disorders (OR = 4.57; 95% CI 2.57-8.11), and the following panic symptoms: palpitations (OR = 2.20; 95% CI 0.90-5.35), trembling (OR = 0.61; 95% CI 0.362-1.18), nausea or abdominal distress (OR = 1.77; 95% CI 0.96-3.27), fear of losing control or going crazy (OR = 2.18; 95% CI 1.12-4.23), and paresthesia (OR = 1.57; 95% CI 0.83-2.98). Multivariate logistic regression analyses demonstrated that specific panic symptoms, such as palpitations (adjusted OR = 2.69; 95% CI 1.08-6.73) and fear of losing control or going crazy (adjusted OR = 2.28; 95% CI 1.21-4.31), were related to suicidality after controlling for confounding factors. Conclusion: Some panic symptoms (e.g. palpitations and fear of losing control or going crazy) are associated with a risk of suicidality among patients with panic disorder. A priori identification of high-risk suicidal subjects could lead to effective treatment strategies for panic disorder.
Phase I/II Study of Amrubicin and Nedaplatin in Patients with Untreated, Advanced, Non-Small Cell Lung Cancer
Authors: Ogawara Daiki , Nakamura Yoichi , Fukuda Minoru , Nakatomi Katsumi , Yamaguchi Hiroyuki , Motoshima Kohei , Mizoguchi Kosuke , Nakano Hirofumi , Takemoto Shinnosuke , Gyotoku Hiroshi , Nagashima Seiji , Kohno Shigeru
Published: April 2015

A phase I/II study of combination chemotherapy with amrubicin and nedaplatin for patients with untreated, advanced, non-small cell lung cancer (NSCLC) was conducted. Amrubicin was given on days 1-3, with nedaplatin given on day 1. The treatment was repeated every 3 weeks. In the phase I trial, the initial amrubicin dose of 25 mg/m2 was escalated in 5-mg/m2 increments until the maximum tolerated dose was reached, with the dose of nedaplatin fixed at 100 mg/m2. In the phase II trial, the primary endpoint was the overall response rate (ORR), assuming 20% for a standard therapy and 40% for a target therapy (α = 0.05 and β = 0.20), and the estimated required total number of patients was 35. In the phase I study, nedaplatin 100 mg/m2 and amrubicin 25 mg/m2 was recommended. In the phase II study, 17 out of 35 patients achieved a partial response, and the ORR was 48.6%. Grade 3/4 neutropenia, grade 3 anemia and grade 3/4 thrombocytopenia occurred in 62.9, 11.4 and 11.4% of cycles, respectively. Febrile neutropenia occurred in 5 cycles (3.9%) and all cases were manageable. The recommended dose of this combination is well tolerated and effective in patients with advanced NSCLC.
A Qualitative Study of the Prodrome to First-Episode Major Depressive Disorder in Adolescents
Authors: Syed Sheriff Rebecca J. , McGorry Patrick D. , Cotton Sue , Yung Alison R.
Published: April 2015

Background: Currently, we lack a clear picture of the evolution of major depressive disorder (MDD) in adolescents. The period of disturbance preceding MDD can be conceptualised as the prodrome. The aim of the study was to explore the prodrome of first-episode MDD retrospectively in a group of help-seeking adolescents using qualitative methodologies. Sampling and Methods: Consecutively referred adolescents (15-18 years of age) with first-episode MDD were recruited for this study from Orygen Youth Health, Melbourne, Vic., Australia. After using quantitative methodologies to confirm the index episode of MDD and measure the extent of recovery, the prodrome was investigated in depth using qualitative techniques. Results: Twenty-nine adolescents (20 females and 9 males) and 7 informants (6 mothers and 1 grandmother) participated. All 29 participants had a prodrome of varying lengths (between 6 days and 4 years). The most noticeable symptoms initially were perplexity and confusion and, thereafter, sadness and irritability. A common pattern was a reduction in their ability to fulfil their role accompanied by guilt, self-blame and reduced self-esteem. Around half of the participants had increased thoughts of suicide and increased anxiety. There were gender differences in the patterns of symptoms noticed, with males more commonly noticing a change in how they related to the world and females more commonly noticing a change in the way that they related to others. All informants noticed a prodrome of varying lengths; in 2 cases longer, in 2 cases shorter and in 3 cases around the same time period as that noticed by the participant. The changes most commonly noticed by informants were sadness, upset, irritability and reduced self-esteem. The symptoms were fewer in number and sometimes varied from those noticed by the adolescents themselves. Conclusions: Whilst we recognise that this study is vulnerable to autobiographical bias, we took all reasonable measures to minimise this. Symptoms not included in the diagnostic criteria for depression were the earliest changes noticed by the adolescents themselves and are, therefore, potentially important in informing prevention strategies, as is the finding that there are gender differences in the patterns of changes noticed. In addition, parents may provide an additional avenue to help seeking.
Unilateral Conjunctival in situ Squamous Carcinoma with Bilateral Conjunctival Chlorpromazine-Induced Secondary Melanosis Masquerading as in situ and Invasive Melanoma
Authors: Sears Katharine S. , Rennie Ian G. , Mudhar Hardeep Singh
Published: April 2015

Purpose: To describe the clinical and histopathological features of a 61-year-old male with a history of eczema, asthma and schizophrenia on long-term chlorpromazine medication, who developed a unilateral limbal tumour in association with bilateral melanosis. Procedures: The patient was referred for a routine cataract assessment, and an incidental pink gelatinous limbal lesion was detected on the left side, associated with bilateral speckled brown conjunctival pigmentation. The limbal lesion and brown pigmentation were biopsied. The tissue was fixed in standard buffered formalin and processed to paraffin wax, and sections were stained with haematoxylin and eosin. Tissue from the pigmented area was also processed for transmission electron microscopy. Results: The biopsy from the limbal lesion showed an in situ squamous carcinoma associated with prominent numbers of intra-epithelial eosinophils. The biopsy of the pigmented area showed bilateral melanosis without atypia. The latter was attributable to an increase in melanin production rather than to melanocyte hyperplasia. Melanophages were also present in the adjacent substantia propria. These pigment changes were entirely compatible with chlorpromazine-induced secondary melanosis. Conclusions: This paper highlights the first documented occurrence of in situ squamous carcinoma with bilateral chlorpromazine-induced conjunctival secondary melanosis. This clinically masqueraded as in situ melanoma/primary acquired melanosis and invasive melanoma. Bilateral melanosis is rare, has many causes and, in this case, was drug induced. This highlights the importance of thorough history taking and illustrates that not all pigmented and amelanotic lesions are in situ melanomas, primary acquired melanosis or invasive melanomas. Lastly, atopy was a risk factor for the development of this in situ squamous carcinoma.
A Cell Type-Specific Role of Protein Tyrosine Phosphatase Non-Receptor Type 2 in Regulating ER Stress Signalling
Authors: Kasper Stephanie H. , Spalinger Marianne R. , Raselli Tina , Scharl Michael
Published: April 2015

Background/Aims: Genetic polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) have been associated with inflammatory bowel disease (IBD). A recent study demonstrated that PTPN2 regulates ER stress signalling in pancreatic β-cells. Therefore, we investigated whether PTPN2 regulates ER stress pathways, apoptosis and cytokine secretion in human intestinal epithelial cells (IECs) and monocytes. Methods: THP-1 and HT-29 IECs were stimulated with 2 µg/ml tunicamycin (TNM) for the indicated periods of time. For knockdown experiments, cells were transfected using a mixture of three different PTPN2-specific siRNA oligonucleotides. Cell lysates were analysed by Western blot and real-time PCR. Cytokine secretion was studied by ELISA measurements of cell culture supernatant. Results: TNM treatment reduced PTPN2 protein levels in HT-29 IECs and THP-1 monocytes. Knockdown of PTPN2 in THP-1 monocytes led to an exaggerated induction of phospho-eIF2α, enhanced PARP cleavage, indicative of apoptosis, and attenuated IL-8 and TNF secretion upon TNM stimulation. In HT-29 cells PTPN2 deficiency caused reduced phosphorylation of eIF2α and PARP cleavage under ER stress conditions. Conclusions: Whereas the knockdown of PTPN2 made THP-1 cells more susceptible to ER stress, PTPN2 deficiency reduced ER stress responses in HT-29 IECs. This suggests that PTPN2 regulates adaptation to ER stress in a cell type-specific manner.
Become Related: FIAS, an Intensive Early Intervention for Young Children with Autism Spectrum Disorders
Authors: Herbrecht Evelyn , Kievit Esther , Spiegel René , Dima Diana , Goth Kirstin , Schmeck Klaus
Published: April 2015

Background: In autism spectrum disorders (ASDs), impairments in fundamental social abilities and a lack of interest in social stimuli become apparent early in life. These impairments are thought to negatively affect further brain and behavioural development. Early intensive interventions can help to attenuate social-development and other risk factors and, thus, to ameliorate the deficits associated with ASDs. We present FIAS, an intensive early intervention approach for young children with ASD, which aims at developing children's social motivation. During 18 days, therapists work continuously for 6 h a day with the affected child, involving the whole family in a day care setting. Follow-up care at home over 1 year as well as fresh-up interventions and inclusion in kindergarten or a play group should stabilise the effects and help to respond to further challenges. Material and Methods: Here, we present observations from the first 12 patients (25-48 months of age) treated according to the FIAS approach. We evaluated changes in core autistic symptoms and level of functioning after the 18 days of intensive intervention. Beyond standardised assessment, two innovative video-based instruments (Autism Behaviour Coding System and Evaluationsfragebogen) have been developed to assess autistic symptoms and interaction parameters during intervention. Results: Improvements were noted in most core autistic symptom domains, with the highest effect sizes in domains like eye contact, communication, repetitive behaviour, imitation, motivation and reciprocity. In addition, the level of functioning significantly improved. Conclusions: The first evaluation of the FIAS approach shows promising results, as the FIAS intervention appears to improve core autistic symptom domains as well as the level of everyday functioning. Limitations of this study are the small sample size and the lack of a control group. A more comprehensive and longitudinal evaluation is in progress; this will focus on the stability of the observed effects and will attempt to identify potential predictors of treatment response.
Elastin Organization in Pig and Cardiovascular Disease Patients' Pericardial Resistance Arteries
Authors: Bloksgaard Maria , Leurgans Thomas M. , Nissen Inger , Jensen Pia Søndergaard , Hansen Maria Lyck , Brewer Jonathan R. , Bagatolli Luis A. , Marcussen Niels , Irmukhamedov Akhmadjon , Rasmussen Lars Melholt , De Mey Jo G.R.
Published: April 2015

Peripheral vascular resistance is increased in essential hypertension. This involves structural changes of resistance arteries and stiffening of the arterial wall, including remodeling of the extracellular matrix. We hypothesized that biopsies of the human parietal pericardium, obtained during coronary artery bypass grafting or cardiac valve replacement surgeries, can serve as a source of resistance arteries for structural research in cardiovascular disease patients. We applied two-photon excitation fluorescence microscopy to study the parietal pericardium and isolated pericardial resistance arteries with a focus on the collagen and elastin components of the extracellular matrix. Initial findings in pig tissue were confirmed in patient biopsies. The microarchitecture of the internal elastic lamina in both the pig and patient pericardial resistance arteries (studied at a transmural pressure of 100 mm Hg) is fiber like, and no prominent external elastic lamina could be observed. This microarchitecture is very different from that in rat mesenteric arteries frequently used for resistance artery research. In conclusion, we add three-dimensional information on the structure of the extracellular matrix in resistance arteries from cardiovascular disease patients and propose further use of patient pericardial resistance arteries for studies of the human microvasculature.
Latent Change Score Modeling as a Method for Analyzing the Antidepressant Effect of a Psychosocial Intervention in Alzheimer's Disease
Authors: Werheid Katja , Köhncke Ylva , Ziegler Matthias , Kurz Alexander
Published: April 2015

Background: Developing and evaluating interventions for patients with age-associated disorders is a rising field in psychotherapy research. Its methodological challenges include the high between-subject variability and the wealth of influencing factors associated with longer lifetime. Latent change score modeling (LCSM), a technique based on structural equation modeling, may be well suited to analyzing longitudinal data sets obtained in clinical trials. Here, we used LCSM to evaluate the antidepressant effect of a combined cognitive behavioral/cognitive rehabilitation (CB/CR) intervention in Alzheimer's disease (AD). Methods: LCSM was applied to predict the change in depressive symptoms from baseline as an outcome of the CORDIAL study, a randomized controlled trial involving 201 patients with mild AD. The participants underwent either the CORDIAL CB/CR program or standard treatment. Using LCSM, the model best predicting changes in Geriatric Depression Scale scores was determined based on this data set. Results: The best fit was achieved by a model predicting a decline in depressive symptoms between before and after testing. Assignment to the intervention group as well as female gender revealed significant effects in model fit indices, which remained stable at 6- and 12-month follow-up examinations. The pre-post effect was pronounced for patients with clinically relevant depressive symptoms at baseline. Conclusions: LCSM confirmed the antidepressant effect of the CORDIAL therapy program, which was limited to women. The effect was pronounced in patients with clinically relevant depressive symptoms at baseline. Methodologically, LCSM appears well suited to analyzing longitudinal data from clinical trials in aged populations, by accounting for the high between-subject variability and providing information on the differential indication of the probed intervention.
Influence of Dyadic Matching of Affect on Infant Self-Regulation
Authors: Noe Daniela , Schluckwerder Sabine , Reck Corinna
Published: April 2015

Background/Aims: Affective behavioural matching during face-to-face interaction fosters the transition from mutual regulation to infant self-regulation. Optimum midrange models of mother-infant interaction hold that moderate degrees of dyadic matching facilitate infant socio-emotional development. The aim of this study was to examine which degree of dyadic matching is most beneficial for infant self-regulation. Methods: To evaluate this model, 3 groups of highly, midrange and poorly matched dyads were created from a mixed sample of 68 dyads with healthy and post-partum depressed mothers and their infants (age range = 1-8 months, mean age = 3.9 months). Mother-infant interactions were videotaped in the face-to-face still-face paradigm (FFSF) and micro-analytically coded. Specifically, the relation between affective behavioural matching in FFSF play and infant positive and negative affect in FFSF still face and FFSF reunion was explored. Results: Contrary to our expectation, we found a monotonous trend for all groups: the more matching in FFSF play, the more positive and less negative affect the infant showed in FFSF still face and FFSF reunion, respectively. Conclusion: The present findings further illuminate the association between different degrees of dyadic matching in early mother-infant interaction and infant self-regulation. Further research should focus on the integration and replication of findings and conceptual approaches to further evaluate and refine the concept of midrange matching and make it applicable to therapeutic work with mothers and their infants.
Progression of Cutaneous Vitiligo in a Patient with Large Posterior Choroidal Melanoma: A Case Report
Authors: Ding Angela , Elizalde Javier , Barraquer Rafael Ignacio
Published: April 2015

Background/Aims: The aim of our study was to report a case of progression of cutaneous vitiligo after large posterior choroidal melanoma diagnosis. Methods: The clinical history, fundus findings and histopathological features suggest the diagnosis of cutaneous vitiligous progression after a diagnosis of large posterior choroidal melanoma. Results: A 30-year-old female, with a personal history of cutaneous vitiligo for 12 years, was diagnosed with choroidal melanoma 18 months previously. The cutaneous vitiligo had progressed over her back, body and arms during the preceding 3 years. She refused treatment because she was in her 28th week of pregnancy. When she came to our clinic her visual symptoms had worsened, and the fundus examination showed a melanocytic choroidal mass. After confirming that there was no extraocular extension, she was treated with enucleation. A histopathological study confirmed the choroidal melanoma diagnosis. Conclusion: The association between the progression of vitiligo and the diagnosis of uveal melanoma could be considered a good prognostic factor, as has been described in cases of cutaneous melanoma. A longer follow-up of these patients will allow us to confirm this association.
The Effects of the F-Actin Inhibitor Latrunculin A on the Pathogenic Yeast Cryptococcus neoformans
Authors: Kopecká Marie , Yamaguchi Masashi , Kawamoto Susumu
Published: April 2015

Background: This basic research aimed to investigate the effects of the actin inhibitor latrunculin A (LA) on the human pathogen Cryptococcus neoformans, by freeze-substitution (FS) and electron microscopy (EM), to determine whether the actin cytoskeleton can become a new antifungal target for inhibition of cell division. Methods: Cells treated with LA for 20 h in yeast-extract peptone dextrose medium were investigated by phase-contrast and fluorescent microscopy, FS and transmission EM, counted in a Bürker chamber and the absorbance was then measured. Results: The disappearance of actin patches, actin cables and actin rings demonstrated the response of the cells of C. neoformans to the presence of the actin inhibitor LA. The removal of actin cables and patches arrested proliferation and led to the production of cells that had ultrastructural disorder, irregular morphology of the mitochondria and thick aberrant cell walls. Budding cells lysed in the buds and septa. Conclusion: LA exerts fungistatic, fungicidal and fungilytic effects on the human pathogenic yeast C. neoformans.
Ketogenic Diet Attenuates NMDA-Induced Damage to Rat's Retinal Ganglion Cells in an Age-Dependent Manner
Authors: Zarnowski Tomasz , Choragiewicz Tomasz J. , Schuettauf Frank , Zrenner Eberhart , Rejdak Robert , Gasior Maciej , Zarnowska Iwona , Thaler Sebastian
Published: April 2015

Objective: This study was conducted to investigate neuroprotective effects of a high fat/low carbohydrate and protein diet (ketogenic diet, KD) in a model of N-methyl D-aspartate (NMDA)-induced retinal ganglion cell (RGC) damage in juvenile and young adult rats. Methods: Juvenile (30-35 days old) and young adult (56-70 days old) female Brown Norway rats were fed the KD for 21 days; rats exposed to a standard rodent diet (SRD) served as controls. The main constituents of the KD used in the present study were approximately 80% fats, 8% proteins, and less than 1% carbohydrates. On day 14 of exposure to the KD (or the SRD in the control group), each rat received a single intravitreal injection of NMDA; RGCs were then retrogradely labelled by hydroxystilbamidine on day 19 and collected on day 21 to assess the degree of damage induced by NMDA. Blood biomarkers to confirm the expected metabolic response to the KD (i.e. ketosis and hypoglycaemia) were also assessed. Results: Although both the juvenile and young adult rats developed comparable ketosis and hypoglycaemia when fed the KD, NMDA-induced loss in RGCs was significantly attenuated only in juvenile rats exposed to the KD in comparison with those fed the SRD; exposure to the KD had no protective effect in young adult rats. In summary, exposure to the KD had a neuroprotective effect in NMDA-induced RGC damage in juvenile rats, but not in young adult rats. Conclusion: These results support further exploration of metabolic interventions to treat optic neuropathies associated with neurodegeneration.
Impact of Metabolic Syndrome on the Hospitalization Rate of Crohn's Disease Patients Seen at a Tertiary Care Center: A Retrospective Cohort Study
Authors: Fitzmorris Paul Stephen , Colantonio Lisandro Damian , Torrazza Perez Euriko , Smith Ioana , Kakati Donny Debajyoti , Malik Talha Aziz
Published: April 2015

Background/Aims: Recent studies suggest that markers of mesenteric inflammation, such as increased adipose tissue, may be associated with poor outcomes in Crohn's disease (CD). This study's hypothesis is that CD patients with metabolic syndrome (MetS) have more CD-related hospitalizations than CD patients without MetS. Methods: We conducted a retrospective cohort study of CD patients seen from 2000 to 2012 at our tertiary care center. We analyzed crude and age-, sex- and duration of CD-adjusted incidence rate ratio (IRR) of CD-related hospitalization of those with MetS versus those without MetS. We also investigated possible associations between individual component conditions of MetS and rate of CD-related hospitalization. Results: A total of 868 CD patients were included. There were 37 (4%) patients with MetS at initial observation. After multi-variable adjustment, patients with MetS had a CD-related hospitalization rate twice that of those who did not have MetS. High triglycerides (TG), low high density lipoprotein (HDL) cholesterol and diabetes mellitus (DM) were associated with increased risk of CD-related hospitalization. Conclusions: CD patients with MetS have a higher rate of CD-related hospitalization compared to those without MetS. Hypertriglyceridemia, low HDL cholesterol and DM may be good markers of local and systemic inflammation as seen in CD.
Novel Splice Site Mutation in MAMLD1 in a Patient with Hypospadias
Authors: Igarashi Maki , Wada Yuka , Kojima Yoshiyuki , Miyado Mami , Nakamura Michiko , Muroya Koji , Mizuno Kentaro , Hayashi Yutaro , Nonomura Katsuya , Kohri Kenjiro , Ogata Tsutomu , Fukami Maki
Published: April 2015

MAMLD1 is a causative gene for disorders of sex development. Several MAMLD1 mutations have been shown to cause hypospadias by generating dysfunctional proteins and/or unstable mRNAs. Here, we identified an intronic mutation of MAMLD1 (g.IVS4−2A>G) in 1 of 180 hypospadias patients. RT-PCR of the patient's skin sample showed normal expression of full-length MAMLD1 and markedly reduced expression of a known splice variant lacking exon 4. A hitherto unreported splice variant that lacks exon 5 was similarly identified in samples of the patient and control individuals. The full-length transcript of the patient contained mutant mRNA lacking the first 10 nucleotides of exon 5 (c.1822_1831delACTCATGTAG, p.K609fsX1070). In vitro assays using cells expressing the full-length wild-type and mutant proteins revealed reduced expression of the mutant. The expression of the wild-type and mutant MAMLD1 showed parallel changes upon treatment with a proteasome inhibitor and a translation inhibitor. The mutant-expressing cells exerted low transactivation activity for the Hes3 promoter, which reflected limited expression of the mutant protein. These results imply that the pathogenic events resulting from MAMLD1 mutations include splice errors. Furthermore, this study raises the possibility of translation failure of MAMLD1 mutants, which deserves further investigation.
Activation of Innate Immunity in Graft-versus-Host Disease: Implications for Novel Targets?
Authors: Zeiser Robert
Published: April 2015

Acute graft-versus-host disease (GvHD) is mediated by alloreactive donor-derived T cells with a suitable T cell receptor recognizing recipient major histocompatibility complex or minor histocompatibility antigens. However, the process of T cell activation and tissue injury sensing is also dependent on innate immune cells and non-hematopoietic cells. Different cell types of the innate immune system have the ability to sense danger-associated and pathogen-associated molecular patterns via pattern recognition receptors which can be transmembrane Toll-like receptors or cytoplasmic nucleotide-binding oligomerization domain-like receptors. Infectious stimuli include bacterial, viral, and fungal components, while non-infectious stimuli can be components derived from damaged cells or extracellular matrix. A better understanding of the complex sensing and effector mechanisms of innate immune cells in GvHD may help to improve preventive and therapeutic strategies in GvHD.
Steroidogenic versus Metabolic Programming of Reproductive Neuroendocrine, Ovarian and Metabolic Dysfunctions
Authors: Cardoso Rodolfo C. , Puttabyatappa Muraly , Padmanabhan Vasantha
Published: April 2015

The susceptibility of the reproductive system to early exposure to steroid hormones has become a major concern in our modern societies. Human fetuses are at risk of abnormal programming via exposure to endocrine disrupting chemicals, inadvertent use of contraceptive pills during pregnancy, as well as from excess exposure to steroids due to disease states. Animal models provide an unparalleled resource to understand the developmental origin of diseases. In female sheep, prenatal exposure to testosterone excess results in an array of adult reproductive disorders that recapitulate those seen in women with polycystic ovary syndrome (PCOS), including disrupted neuroendocrine feedback mechanisms, increased pituitary sensitivity to gonadotropin-releasing hormone, luteinizing hormone excess, functional hyperandrogenism, and multifollicular ovarian morphology culminating in early reproductive failure. Prenatal testosterone treatment also leads to fetal growth retardation, insulin resistance, and hypertension. Mounting evidence suggests that developmental exposure to an improper steroidal/metabolic environment may mediate the programming of adult disorders in prenatal testosterone-treated females, and these defects are maintained or amplified by the postnatal sex steroid and metabolic milieu. This review addresses the steroidal and metabolic contributions to the development and maintenance of the PCOS phenotype in the prenatal testosterone-treated sheep model, including the effects of prenatal and postnatal treatment with an androgen antagonist or insulin sensitizer as potential strategies to prevent/ameliorate these dysfunctions. Insights obtained from these intervention strategies on the mechanisms underlying these defects are likely to have translational relevance to human PCOS.
Relationship Between Subclinical Cardiac Troponin I Elevation and Culprit Lesion Characteristics Assessed by Optical Coherence Tomography in Patients Undergoing Elective Percutaneous Coronary Intervention
Authors: Lee Tetsumin , Murai Tadashi , Yonetsu Taishi , Suzuki Asami , Hishikari Keiichi , Kanaji Yoshihisa , Matsuda Junji , Araki Makoto , Niida Takayuki , Isobe Mitsuaki , Kakuta Tsunekazu
Published: April 2015

Background—

The prevalence of subclinical, cardiac troponin I (cTnI) elevation in stable patients undergoing elective percutaneous coronary intervention and its relationship to culprit lesion characteristics assessed by optical coherence tomography (OCT) are unknown.

Methods and Results—

We studied 206 native de novo culprit coronary lesions from 206 patients with stable angina pectoris who underwent OCT before elective percutaneous coronary intervention. Patients were divided into 2 groups according to the presence (cTnI group; n=47; 22.8%) or absence (non-cTnI group; n=159; 77.2%) of cTnI ≥0.03 ng/mL at admission. The clinical and OCT findings were compared between these 2 groups. No significant difference was found in the clinical presentation between the groups except for the serum C-reactive protein levels and presence of multivessel disease. By OCT, cTnI elevation was associated with the presence of thin-cap fibroatheromas, a greater lipid arc, and a longer lipid length. In a multivariable analysis, the presence of positive C-reactive protein levels (odds ratio, 4.38; 95% confidence interval, 1.90–10.08;
P
=0.001) and OCT-derived thin-cap fibroatheromas (odds ratio, 2.89; 95% confidence interval, 1.22–6.86;
P
=0.016) were independent predictors of cTnI elevation. Periprocedural myocardial injury, defined as postpercutaneous coronary intervention peak cTnI levels >1.0 ng/mL (5× the upper reference limit), occurred more often in patients with cTnI elevation at admission (cTnI group: 41% versus non-cTnI group: 18%;
P
=0.001).

Conclusions—

The presence of subclinical cTnI elevation at admission was not uncommon and was associated with OCT-derived unstable plaque morphology in patients undergoing elective percutaneous coronary intervention, and may help to identify patients with stable angina pectoris at high risk for periprocedural myocardial injury.
Reperfusion of Very Low Cerebral Blood Volume Lesion Predicts Parenchymal Hematoma After Endovascular Therapy
Authors: Mishra Nishant K. , Christensen Søren , Wouters Anke , Campbell Bruce C.V. , Straka Matus , Mlynash Michael , Kemp Stephanie , Cereda Carlo W. , Bammer Roland , Marks Michael P. , Albers Gregory W. , Lansberg Maarten G.
Published: April 2015

Background and Purpose—

Ischemic stroke patients with regional very low cerebral blood volume (VLCBV) on baseline imaging have increased risk of parenchymal hemorrhage (PH) after intravenous alteplase–induced reperfusion. We developed a method for automated detection of VLCBV and examined whether patients with reperfused-VLCBV are at increased risk of PH after endovascular reperfusion therapy.

Methods—

Receiver operating characteristic analysis was performed to optimize a relative CBV threshold associated with PH in patients from the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution 2 (DEFUSE 2) study. Regional reperfused-VLCBV was defined as regions with low relative CBV on baseline imaging that demonstrated normal perfusion (
T
max
<6 s) on coregistered early follow-up magnetic resonance imaging. The association between VLCBV, regional reperfused-VLCBV and PH was assessed in univariate and multivariate analyses.

Results—

In 91 patients, the greatest area under the curve for predicting PH occurred at an relative CBV threshold of <0.42 (area under the curve, 0.77). At this threshold, VLCBV lesion volume ≥3.55 mL optimally predicted PH with 94% sensitivity and 63% specificity. Reperfused-VLCBV lesion volume was more specific (0.74) and equally sensitive (0.94). In total, 18 patients developed PH, of whom 17 presented with VLCBV (39% versus 2%;
P
=0.001), all of them had regional reperfusion (47% versus 0%;
P
=0.01), and 71% received intravenous alteplase. VLCBV lesion (odds ratio, 33) and bridging with intravenous alteplase (odds ratio, 3.8) were independently associated with PH. In a separate model, reperfused-VLCBV remained the single independent predictor of PH (odds ratio, 53).

Conclusions—

These results suggest that VLCBV can be used for risk stratification of patients scheduled to undergo endovascular therapy in trials and routine clinical practice.
Multivitamin Use and Risk of Stroke Mortality
Authors: Dong Jia-Yi , Iso Hiroyasu , Kitamura Akihiko , Tamakoshi Akiko
Published: April 2015

Background and Purpose—

An effect of multivitamin supplement on stroke risk is uncertain. We aimed to examine the association between multivitamin use and risk of death from stroke and its subtypes.

Methods—

A total of 72 180 Japanese men and women free from cardiovascular diseases and cancers at baseline in 1988 to 1990 were followed up until December 31, 2009. Lifestyles including multivitamin use were collected using self-administered questionnaires. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) of total stroke and its subtypes in relation to multivitamin use.

Results—

During a median follow-up of 19.1 years, we identified 2087 deaths from stroke, including 1148 ischemic strokes and 877 hemorrhagic strokes. After adjustment for potential confounders, multivitamin use was associated with lower but borderline significant risk of death from total stroke (HR, 0.87; 95% confidence interval, 0.76–1.01), primarily ischemic stroke (HR, 0.80; 95% confidence interval, 0.63–1.01), but not hemorrhagic stroke (HR, 0.96; 95% confidence interval, 0.78–1.18). In a subgroup analysis, there was a significant association between multivitamin use and lower risk of mortality from total stroke among people with fruit and vegetable intake <3 times/d (HR, 0.80; 95% confidence interval, 0.65–0.98). That association seemed to be more evident among regular users than casual users. Similar results were found for ischemic stroke.

Conclusions—

Multivitamin use, particularly frequent use, was associated with reduced risk of total and ischemic stroke mortality among Japanese people with lower intake of fruits and vegetables.
The Demographic Transformation of America
Authors: Olshansky S. Jay
Published: April 2015

The face of aging in America is about to change. Within the next thirty years, the U.S. population will experience a permanent change in its age structure, and there is reason to believe that cohorts reaching older ages in the future will be far different from those reaching older ages today. In this essay, I explain why life expectancy in the United States is likely to diverge from that experienced by the rest of the developed world; describe recent trends in healthy life expectancy; and examine how the age structure of the United States will by mid-century be different from that found today.
Homeostatic Plasticity for Single Node Delay-Coupled Reservoir Computing
Authors: Toutounji Hazem , Schumacher Johannes , Pipa Gordon
Published: April 2015

Supplementing a differential equation with delays results in an infinite-dimensional dynamical system. This property provides the basis for a reservoir computing architecture, where the recurrent neural network is replaced by a single nonlinear node, delay-coupled to itself. Instead of the spatial topology of a network, subunits in the delay-coupled reservoir are multiplexed in time along one delay span of the system. The computational power of the reservoir is contingent on this temporal multiplexing. Here, we learn optimal temporal multiplexing by means of a biologically inspired homeostatic plasticity mechanism. Plasticity acts locally and changes the distances between the subunits along the delay, depending on how responsive these subunits are to the input. After analytically deriving the learning mechanism, we illustrate its role in improving the reservoir’s computational power. To this end, we investigate, first, the increase of the reservoir’s memory capacity. Second, we predict a NARMA-10 time series, showing that plasticity reduces the normalized root-mean-square error by more than 20%. Third, we discuss plasticity’s influence on the reservoir’s input-information capacity, the coupling strength between subunits, and the distribution of the readout coefficients.
Cortical Spatiotemporal Dimensionality Reduction for Visual Grouping
Authors: Cocci Giacomo , Barbieri Davide , Citti Giovanna , Sarti Alessandro
Published: April 2015

The visual systems of many mammals, including humans, are able to integrate the geometric information of visual stimuli and perform cognitive tasks at the first stages of the cortical processing. This is thought to be the result of a combination of mechanisms, which include feature extraction at the single cell level and geometric processing by means of cell connectivity. We present a geometric model of such connectivities in the space of detected features associated with spatiotemporal visual stimuli and show how they can be used to obtain low-level object segmentation. The main idea is to define a spectral clustering procedure with anisotropic affinities over data sets consisting of embeddings of the visual stimuli into higher-dimensional spaces. Neural plausibility of the proposed arguments will be discussed.
Framing, Parataxis, and the Poetics of Exemplarity in Petrus Alfonsi’s Disciplina Clericalis
Authors: Ford Gabriel
Published: April 2015

Critics have seen the structure of Petrus Alfonsi’s Disciplina clericalis (c. 1110) as either entirely haphazard or consistently framed. I will argue that its distinct structure emerges from a balance of framed and paratactic relationships. When viewed in this way, the dialogic exemplum sequence—or framed series of tales told in a conversation—becomes one of the most significant structural units in the work. Having identified that unit, I demonstrate its value for the exemplary poetics at work in Disciplina clericalis by analyzing the longest dialogic exemplum sequence in the text. Petrus uses the delicate balance between framing and parataxis to situate a sophisticated theory of exemplarity that analyzes representation and emphasizes the importance of interpreting moralized tales.
Arabic into Hebrew, A Case Study: Isaac Israeli’s Book on Fevers
Authors: Ferre Lola , Delgado José Martínez
Published: April 2015

Translations in the Middle Ages were the clearest route for the transmission of knowledge between countries and cultures. Furthermore, translation led to the creation a body of scientific terminology for languages that lacked their own, as in the case of Medieval Hebrew. This paper examines one of these translations: Isaac Israeli’s Book on Fevers. Two paragraphs from the Hebrew translation of the Book on Fevers (one from the opening, the other describing medicinal substances) have been selected to analyze how the translator worked with a medical text in Hebrew. The terminology in both was compared with that of other medieval medical books in Hebrew to better understand how a medical lexicon was built and how it developed in the Christian environment where these translations were made. The conclusion of this study contributes to the understanding of translation as part of the intellectual interaction among Jews, Muslims and Christians.
Arnebia purpurea: a new member of formerly monotypic genus Huynhia (Boraginaceae-Lithospermeae)
Authors: Coppi Andrea , Cecchi Lorenzo , Nocentini Daniele , Selvi Federico
Published: April 2015

The taxonomic position and affinities of the rare Turkish endemic Arnebia purpurea are analyzed using nuclear and plastid DNA sequence data and morphological characters. Phylogenetic analysis of a wide sample of old-world Lithospermeae consistently retrieved a clade with this species sister to Huynhia pulchra, the only member of the genus Huynhia. All other members of Arnebia s.l. (including Macrotomia) formed a separate clade subdivided in two lineages corresponding to the groups of the annual and the perennial species. Consequently, Arnebia does not appear monophyletic. Floral and palynological characters support the affinity of A. purpurea to Huynhia pulchra, in especially the stamens inserted at different heights in the corolla tube and the pollen grains with a single row of endoapertures along the equatorial belt. We therefore advocate the placement of A. purpurea in Huynhia and propose a new combination, implying that the latter is no longer a monotypic genus but includes two species with a sharply allopatric range in the Middle-East. Further studies with additional markers and a wider taxon sampling will help to elucidate relationships in Arnebia s.l..
Stellarioides exigua (Asparagaceae, Scilloideae), a new species from South Africa
Authors: Martínez-Azorín Mario , Crespo Manuel B. , Dold Anthony P. , Pinter Michael , Wetschnig Wolfgang
Published: April 2015

Within the framework of a taxonomic revision of the genus Stellarioides we here describe a new species from South Africa, Stellarioides exigua. This taxon is, at first sight, related to S. arida and S. tenuifolia s.l., but it can be clearly differentiated by the small general size; the filiform, free leaves; the small narrowly lanceolate capsules and the small seeds. A complete description of the species is presented, and data on morphology, ecology, and distribution are reported. Affinities and divergences with other taxonomically closely related taxa are also discussed.
Taxonomic notes on three species of Epimedium (Berberidaceae) endemic to China
Authors: Zhang Yanjun , Dang Haishan , Li Jianqiang , Wang Ying
Published: April 2015

Three species of Epimedium (Berberidaceae), E. reticulatum, E. shuichengense and E. truncatum, are controversial based on flower characteristics. In this paper, the descriptions of their flower characters of these three species are revised based on our extensive studies in herbaria and observations in the field and cultivation. E. reticulatum is transferred from ser. Brachycerae to ser. Campanulatae, and E. shuichengense is recognized as a member of ser. Davidianae. The holotype and isotypes of E. reticulatum represent two species, E. reticulatum and E. membranaceum, and the type material of E. truncatum has been lost. Here we lectotypy E. reticulatum and neotypify E. truncatum.