bluuebunny/crossref_metadata_2025 huggingface dataset:
Utilization of Liquid Chromatography Mass Spectrometry Analyses to Identify LKB1–APC Interaction in Modulating Wnt/β-Catenin Pathway of Lung Cancer Cells
Authors: Jian Shu-Fang , Hsiao Chang-Chun , Chen Shin-Yi , Weng Ching-Chieh , Kuo Tzu-Lei , Wu Deng-Chyang , Hung Wen-Chun , Cheng Kuang-Hung
Published: January 2014

STK11/LKB1, a serine/threonine protein kinase and tumor suppressor, is a key upstream kinase of adenine monophosphate-activated protein kinase, which is a kinase involved in controlling cell polarity and maintaining cellular energy homeostasis. LKB1 is mutated in a significant number of Peutz–Jeghers syndrome (PJS) cases and sporadic cancers, and is most frequently mutated in lung adenocarcinomas; however, little is known about how LKB1 is involved in lung cancer progression. In this study, immunoprecipitation-HPLC tandem mass spectrometry (IP-LC-MS/MS) was performed to identify novel proteins interacting with LKB1 in lung cancer. Interestingly, many LKB1-interacting proteins acquired from the LC-MS/MS approach were mapped, using MetaCore pathway analysis, to the cystic fibrosis transmembrane conductance regulator activation pathway. Moreover, it was determined that LKB1 directly interacts with APC, and this LKB1–APC interaction was further confirmed by reverse immunoprecipitation assays, but GSK3β was dispensable for the association of LKB1 and APC. Importantly, LKB1 binds to APC to suppress the Wnt/β-catenin signaling pathway, which is known to be involved in cell proliferation and migration. Subsequent analysis of the downstream targets of the Wnt/TCF pathway led to the identification of several Wnt-regulated genes, such as CD44, COX-2, survivin, and c-Myc, whose expression levels are downregulated by LKB1. In summary, these results demonstrate that LKB1 regulates the Wnt pathway through a direct interaction with APC to suppress the tumorigenic/metastatic potential of lung tumors.

Implications: LKB1 status influences the molecular circuitry (Wnt/β-catenin pathway), cellular biology, and may serve as a potential therapeutic node in genetically defined subsets of lung cancer. Mol Cancer Res; 12(4); 622–35. ©2014 AACR.
PI3K-AKT Signaling Is a Downstream Effector of Retinoid Prevention of Murine Basal Cell Carcinogenesis
Authors: So Po-Lin , Wang Grace Y. , Wang Kevin , Chuang Mindy , Chiueh Venice Calinisan , Kenny Paraic A. , Epstein Ervin H.
Published: January 2014

Basal cell carcinoma (BCC) is the most common human cancer. We have demonstrated previously that topical application of the retinoid prodrug tazarotene profoundly inhibits murine BCC carcinogenesis via retinoic acid receptor γ–mediated regulation of tumor cell transcription. Because topical retinoids can cause adverse cutaneous effects and because tumors can develop resistance to retinoids, we have investigated mechanisms downstream of tazarotene's antitumor effect in this model. Specifically we have used (i) global expression profiling to identify and (ii) functional cell-based assays to validate the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway as a downstream target pathway of tazarotene's action. Crucially, we have demonstrated that pharmacologic inhibition of this downstream pathway profoundly reduces murine BCC cell proliferation and tumorigenesis both in vitro and in vivo. These data identify PI3K/AKT/mTOR signaling as a highly attractive target for BCC chemoprevention and indicate more generally that this pathway may be, in some contexts, an important mediator of retinoid anticancer effects. Cancer Prev Res; 7(4); 407–17. ©2014 AACR.
Piper Betel Leaf: A Reservoir of Potential Xenohormetic Nutraceuticals with Cancer-Fighting Properties
Authors: Gundala Sushma R. , Aneja Ritu
Published: January 2014

Plants contain a much greater diversity of bioactive compounds than any man-made chemical library. Heart-shaped Piper betel leaves are magnificent reservoirs of phenolic compounds with antiproliferative, antimutagenic, antibacterial, and antioxidant properties. Widely consumed in South Asian countries, the glossy leaf contains a multitude of biophenolics such as hydroxychavicol, eugenol, chavibetol, and piperols. Convincing data underscore the remarkable chemotherapeutic and chemopreventive potential of betel leaves against a variety of cancer types. The leaf constituents modulate an extensive array of signaling molecules such as transcription factors as well as reactive oxygen species (ROS) to control multiple nodes of various cellular proliferation and death pathways. Herein, we provide an overall perspective on the cancer-fighting benefits of the phenolic phytochemicals in betel leaves and a comprehensive overview of the mechanisms responsive to dose-driven ROS-mediated signaling cascades conscripted by bioactive phenolics to confer chemotherapeutic and chemopreventive advantages. Intriguingly, these ROS-triggered responses are contextual and may either elicit a protective xenohormetic antioxidant response to premalignant cells to constitute a chemopreventive effect or generate a curative chemotherapeutic response by pro-oxidatively augmenting the constitutively elevated ROS levels in cancer cells to tip the balance in favor of selective apoptosis induction in cancer cells while sparing normal ones. In conclusion, this review provides an update on how distinct ROS levels exist in normal versus cancer cells and how these levels can be strategically modulated and exploited for therapeutic gains. We emphasize the yet untapped potential of the evergreen vine, betel leaf, for chemopreventive and chemotherapeutic management of cancer. Cancer Prev Res; 7(5); 477–86. ©2014 AACR.
Headache from the Doctors' Perspective
Authors: Gil-Gouveia Raquel
Published: January 2014

Background: General practitioners (GPs) and neurologists are involved in treating headache patients in Portugal. Having migraine themselves might influence the way they perceive and treat migraine patients. Objective: To identify clinicians' perceptions about migraine, their own headache status and management of their own migraine. Methods: An observational cross-sectional survey of GPs and neurologists using anonymous questionnaires including demographic data, headache and migraine status and migraine perception questions. Results: Of 348 respondent physicians, 20% were neurologists and 53% were females with an average age of 48 years. The majority had an interest in migraine and considered it disabling (93%), although 65-85% reported management difficulties, GPs more often than neurologists. Satisfaction with current treatment options was high (69-79%). 63 physicians suffered from migraine and 81% felt it influenced their perception of the disease. Portuguese physicians preferentially treat their own migraines with NSAIDs (33%), analgesics (29%) and triptans (20%). Conclusion: Portuguese physicians treating migraine patients have realistic perceptions about the disease and those with migraine feel their perception is influenced by their experience. Although reporting management difficulties, the majority of physicians are satisfied with current treatment options for migraine.
Gait Disturbance due to Foot Drop Is Refractory to Treatment in Nonsystemic Vasculitic Neuropathy
Authors: Hirahara Tomoo , Yamashita Satoshi , Misumi Yohei , Kawakami Kensuke , Hori Hiroko , Honda Shoji , Watanabe Masaki , Ikeda Tokunori , Yamashita Taro , Maeda Yasushi , Ando Yukio
Published: January 2014

Background: Nonsystemic vasculitic neuropathy (NSVN) is a vasculitis syndrome clinically restricted to the peripheral nervous system. Although treatment may improve prognosis, daily activities of such patients after treatment have not been well studied. Methods: We evaluated clinical features, laboratory data, nerve conduction, and sural nerve biopsy findings for 16 unbiased consecutive patients with NSVN. Results: Initial symptoms included neuropathic pain (31%) and lower limb sensory disturbance (19%). The mean duration between disease onset and initial treatment was 4.1 ± 4.8 months. Mean modified Rankin scale scores were 3.13 at hospital admission and 2.69 at final follow-up. The poor outcome group had significantly decreased compound muscle action potentials of peroneal nerves and significantly more patients presenting with foot drop compared with the good outcome group. No other significant differences were found. Conclusion: Pretreatment foot drop signaled poor outcome in daily activities of patients with NSVN, and earlier treatment may be critical for these patients.
Dietary Herb Extract Rikkunshi-To Ameliorates Gastroparesis in Parkinson's Disease: A Pilot Study
Authors: Doi Hirokazu , Sakakibara Ryuji , Sato Mitsutoshi , Hirai Shigekazu , Masaka Tohru , Kishi Masahiko , Tsuyusaki Yohei , Tateno Akihiko , Tateno Fuyuki , Takahashi Osamu , Ogata Tsuyoshi
Published: January 2014

Objective: To perform an open trial on the effects of the extract of the dietary herb Rikkunshi-to (RKT) on gastroparesis in Parkinson's disease (PD) patients, using objective parameters given by the 13C-sodium acetate expiration breath test (gastric emptying study). Methods: Twenty patients with PD were enrolled into this study. Eleven patients were male and 9 were female, with the following characteristics (mean ± SD): age, 69.4 ± 8.17 years; disease duration, 4.34 ± 4.03 years; modified Hoehn and Yahr stage, 2.37 ± 0.98, and Unified Parkinson's Disease Rating Scale Part 3 motor score, 16.6 ± 7.37. Fourteen patients came to the clinic due to constipation; 16 patients were taking 288 ± 72 mg/day levodopa/carbidopa, 2 were taking dopamine agonists, and the others were not treated yet. All patients underwent the breath test. Statistical analysis was performed using Student's t test. Results: RKT was well tolerated by all patients and none experienced abdominal pain or other adverse effects, except for its bitter taste. RKT significantly reduced the peak time of the 13C-dose-excess curve (p < 0.05). Conclusion: In this pilot trial, we found a significant shortening of the gastric emptying time after administration of the dietary herb extract RKT in PD patients. Further studies examining both gastric emptying and delayed-on in PD are warranted.
Brain Natriuretic Peptide upon Admission as a Biological Marker of Short-Term Mortality after Intracerebral Hemorrhage
Authors: Goya Yoshino , Shibazaki Kensaku , Sakai Kenichiro , Aoki Junya , Uemura Jyunichi , Saji Naoki , Isa Katsunori , Ohya Yusuke , Kimura Kazumi
Published: January 2014

Background and Purpose: The purpose of the present study was to test the hypothesis that plasma brain natriuretic peptide (BNP) is associated with short-term mortality after intracerebral hemorrhage (ICH). Methods: We prospectively enrolled 271 patients (median age 72 years; 109 females) who were admitted within 24 h of ICH onset between April 2007 and July 2011 and in whom plasma BNP levels were measured upon admission. The patients were assigned to two groups according to survival within 1 month of ICH. Factors associated with mortality were determined by multivariate logistic regression analysis. Results: Within 1 month of ICH, 48 (17.7%) of the 271 enrolled patients died. The median (interquartile range) level of plasma BNP was significantly higher in the group of non-survivors than in the group of survivors [102.5 (48.7-205.0) vs. 32.4 (17.3-85.0) pg/ml; p < 0.001]. A cutoff BNP level of 60.0 pg/ml could predict death within 1 month of ICH. Multivariate logistic regression analysis showed that a plasma BNP of >60.0 pg/ml (OR 4.7; 95% CI 1.43-15.63; p = 0.011) was independently associated with mortality within 1 month after ICH. Conclusions: A high BNP level upon admission is associated with mortality within 1 month after ICH.
Evaluation of Cognitive Characteristics of Patients Developing Manifestations of Parkinsonism Secondary to Long-Term Ephedrone Use
Authors: Koksal Ayhan , Keskinkılıc Cahit , Sozmen Mehmet Vedat , Dirican Ayten Ceyhan , Aysal Fikret , Altunkaynak Yavuz , Baybas Sevim
Published: January 2014

Aim: In this study, cognitive functions of 9 patients developing parkinsonism due to chronic manganese intoxication by intravenous methcathinone solution were investigated using detailed neuropsychometric tests. Method: Attention deficit, verbal and nonverbal memory, visuospatial function, constructive ability, language, and executive (frontal) functions of 9 patients who were admitted to our clinic with manifestations of chronic manganese intoxication and 9 control subjects were assessed using neuropsychometric tests. Two years later, detailed repeat neuropsychometric tests were performed in the patient group. The results were evaluated using the χ2 test, Fisher's exact probability test, Student's t test and the Mann-Whitney U test. Results: While there was no statistically significant difference between the two groups in language functions, visuospatial functions and constructive ability, a statistically significant difference was noted between both groups regarding attention (p = 0.032), calculation (p = 0.004), recall and recognition domains of verbal memory, nonverbal memory (p = 0.021) and some domains of frontal functions (Stroop-5 and spontaneous recovery) (p = 0.022 and 0.012). Repeat neuropsychometric test results of the patients were not statistically significant 2 years later. Conclusion: It has been observed that cognitive dysfunction seen in parkinsonism secondary to chronic manganese intoxication may be long-lasting and may not recover as observed in motor dysfunction.
An Exploratory Study to Subtype Obese Binge Eaters by Personality Traits
Authors: Leombruni Paolo , Rocca Giuseppe , Fassino Secondo , Gastaldi Filippo , Nicotra Barbara , Siccardi Sara , Lavagnino Luca
Published: January 2014

Background: Obesity and binge eating disorder (BED) are prevalent conditions that severely affect the quality of life of many people in developed countries, but an effective treatment remains elusive. Personality traits have been studied extensively in this population, leading to different, and at times conflicting, results. Subtyping BED people along these features could add to our knowledge of the disorder. Methods: We applied a two-step cluster analysis, followed by bootstrapping validation, to the Temperament and Character Inventory scores of 462 subjects affected by obesity and BED or subthreshold BED. Results: We found two clusters of subjects; however, the categorization in clusters 1 and 2 did not appear to strictly overlap with the distinction between BED and subthreshold BED. The first cluster showed higher harm avoidance and a lower self-directedness. Cluster 1 patients had higher depression, higher eating impulsivity, greater problems with their body image and poorer quality of life than cluster 2 patients. Conclusions: Our results seem to confirm the heterogeneity of the binge eater population and suggest the importance of harm avoidance and self-directedness to subtype these subjects. These results could generate exploratory works regarding personality in obese people with BED to discover more targeted treatments.
Clinical Significance of Epithelial-Mesenchymal Transition-Associated Markers in Malignant Pleural Mesothelioma
Authors: Iwanami Takashi , Uramoto Hidetaka , Nakagawa Makoto , Shimokawa Hidehiko , Yamada Sohsuke , Kohno Kimitoshi , Tanaka Fumihiro
Published: January 2014

Epithelioid tumors with aggressive behavior have been reported; however, the epithelioid type of malignant pleural mesothelioma (MPM) has a less aggressive behavior. Few studies have evaluated the prognostic value of epithelial-mesenchymal transition (EMT) markers in MPM. We hypothesized that mesenchymal characteristics might predominate in the tumors. Tumor specimens were collected from 33 consecutive patients. We analyzed the EMT expression levels in tumor samples by an immunohistochemical analysis. Positive expression of E-cadherin, γ-catenin, vimentin, fibronectin, Twist and YB-1 was observed in 25, 14, 21, 1, 19 and 18 patients, respectively. No significant association between these markers and the clinicopathological characteristics was found. γ-Catenin demonstrated a trend towards decreased expression in sarcomatoid tumors compared to epithelioid tumors. On the other hand, a trend was noted towards higher expression of vimentin, Twist and YB-1 in sarcomatoid tumors. The survival curves demonstrated that the patients with negative γ-catenin and positive Twist staining had a tendency to have a worse prognosis. Although the individual proteins might not significantly affect the progression of MPM, the combination of γ-catenin and Twist staining can predict the prognosis of patients with MPM.
Impact of Academic Affiliation and Training on Knowledge of Hereditary Colorectal Cancer
Authors: Chan V. , Blazey W. , Tegay D. , Harper B. , Koehler S. , Laurent B. , Lipka S. , Cohn J. , Jung M.-K. , Krishnamachari B.
Published: January 2014

Background: Knowledge about hereditary colorectal cancer (CRC) can aid cancer screening and prevention in high-risk patients. Genetic testing, once conducted primarily at academic centers, is now routinely performed in a variety of clinics. Nonacademic physicians may not be aware of hereditary CRC standards of care. Methods: From August to November 2012, a survey was administered to predominantly primary care physicians evaluating academic center affiliation, past training in genetics and knowledge regarding hereditary CRC. Results: One hundred forty physicians completed the survey. Knowledge of hereditary CRC was neither associated with academic affiliation nor with training during medical school or residency, but with continuing medical education (CME) training. Those with CME training were more likely to know that screening could be enhanced for patients with a hereditary cancer risk (OR = 4.49, 95% CI = 1.40-14.38) and that an individual with hereditary CRC would have different screening recommendations (OR = 7.49, 95% CI = 1.37-40.81). Residency training and CME training were associated with more frequent hereditary risk assessment. Conclusion: Genetics training may be associated with physicians' knowledge and assessment of hereditary CRC. Training at the CME level in particular may be integral to the delivery of genetic services in clinical practice.
An Attempt to Identify Single Nucleotide Polymorphisms Contributing to Possible Relationships between Personality Traits and Oxytocin-Related Genes
Authors: Haram Marit , Tesli Martin , Dieset Ingrid , Steen Nils Eiel , Røssberg Jan Ivar , Djurovic Srdjan , Andreassen Ole A. , Melle Ingrid
Published: January 2014

Background: The neuropeptides oxytocin and vasopressin play a central role in social behavior. Trials with intranasal oxytocin have been conducted and many indicate that the hormone facilitates affiliative behavior and trust. Intranasal oxytocin administration is suggested as a treatment option for psychiatric illnesses with altered sociability as a core symptom and the effects may be due to differences in variants of oxytocin- and vasopressin-related genes. The purpose of the present study was to investigate the endogenous oxytocin system by exploring the relationship between variants in the oxytocin gene factors and personality traits closely related to trust, anxiety and social behavior. Methods: 72 single nucleotide polymorphisms (SNPs) in the genes coding for oxytocin (OXT), vasopressin (AVP), the oxytocin receptor (OXTR) and CD38 (CD38), including polymorphisms reported earlier to be related to social phenotypes and novel SNPs, were investigated in 196 healthy subjects. Association analysis between these variants and 3 personality traits (agreeableness, neuroticism and extraversion) measured by the Neuroticism-Extraversion-Openness Five-Factor Inventory was performed. Results: We found 7 nominally significant associations for personality traits: agreeableness [rs857240 (AVP, p = 0.0075), rs2270463 (OXTR, p = 0.047)], neuroticism [rs3756242 (CD38, p = 0.024), rs13104011 (CD38, p = 0.024), rs6816486 (CD38, p = 0.024), rs7655635 (CD38, p = 0.034)] and extraversion [rs237878 (OXTR, p = 0.019)]. None of these associations remained significant after the Bonferroni correction (p threshold = 2.31 × 10-4). Conclusion: Our results do not contradict the hypothesis of associations between personality traits and oxytocin-related gene variants; however, there are no statistically significant associations after correcting for multiple testing, warranting replication in larger samples.
Neuropsychological Performance Is Positively Associated with Plasma Albumin in Healthy Adults
Authors: Lam Virginie , Albrecht Matthew A. , Takechi Ryusuke , Heidari-Nejad Sayeh , Foster Jonathan K. , Mamo John C.L.
Published: January 2014

Background: Albumin serves a range of physiological functions that are vital to overall brain and cognitive health. Indeed, associations between cognitive performance and albumin have been demonstrated in individuals with chronic liver or kidney disease and in patients with a high urinary excretion of albumin. However, an association of plasma albumin with cognitive performance has not been reported in otherwise healthy participants with clinically acceptable plasma albumin concentrations. Method: This study utilized a wide-ranging neuropsychological test battery to investigate the relationship between cognitive performance and plasma albumin homeostasis in 222 healthy participants (143 females) between the ages of 43 and 84 years (mean 65 years). Results: Albumin both with and without the covariates of age, sex and acute-phase proteins was positively associated with enhanced performance on a range of neuropsychological domains including perceptual speed, Stroop and verbal ability. Albumin manifested generally positive but less robust associations with secondary and primary memory. Conclusion: The results indicate that there is a positive association between albumin and cognitive performance in physiologically healthy participants free of chronic renal or liver disease.
Associations between Infants' Crying, Sleep and Cortisol Secretion and Mother's Sleep and Well-Being
Authors: Brand Serge , Furlano Raoul , Sidler Marc , Schulz Jürgen , Holsboer-Trachsler Edith
Published: January 2014

Background: Infants' continuous crying is a challenge both for the child and the principal caregiver. However, the links between infants' sleep, crying and cortisol secretion and mothers' well-being and sleep have been scarcely investigated. The aim of the present study was therefore to examine the link between cortisol secretion, crying and sleep of infants characterized by infantile colic (IC) and mothers' psychological well-being and own sleep. Methods: Mothers of 24 infants characterized by IC (mean age = 8 weeks, SD = 1.5 weeks) completed a series of questionnaires regarding the infant's crying and sleeping patterns. Infants' sleep was objectively assessed with actigraphs. Cortisol secretion was measured by means of saliva samples in the mornings after waking. After 4 weeks, infants were assessed once again. Mothers completed questionnaires assessing their psychological well-being (depressive symptoms, family strain) and sleep. Results: Mothers' psychological well-being and sleep was greatly predicted by infants' morning saliva cortisol levels, sleep disruptions and crying intensity, whereas infants' crying duration and volume had low predictive value. Conclusions: Mothers with infants characterized by IC are at increased risk for reporting impaired sleep, developing depressive symptoms and reporting higher family strain. Most importantly, this risk seems to be greater if their infants' sleep is fragmented.
Structural Abnormalities in Schizophrenia: Further Evidence on the Key Role of the Anterior Cingulate Cortex
Authors: Salgado-Pineda P. , Landin-Romero R. , Fakra E. , Delaveau P. , Amann B.L. , Blin O.
Published: January 2014

Objective: The present study examined whole-brain structural abnormalities in schizophrenia, with a special focus on the anterior and posterior cingulate cortex (ACC, PCC) as this is an understudied issue in schizophrenia. Method: Whole-brain voxel-based morphometry analyses of gray matter (GM) and white matter (WM) were performed to detect volumetric differences between 14 patients with schizophrenia and 14 healthy controls matched for age, sex, educational level and parents' educational level. We examined within-group GM and WM correlations and completed the analysis with measurements of sulci in medial cortical areas. Results: Compared with the healthy controls, the schizophrenic patients showed significant decreases in GM volumes in the ACC and PCC, and in neighboring WM regions such as the corpus callosum and the fimbriae of the fornix. Moreover, the patient group also displayed a negative correlation between volumes of GM and WM in the ACC. Finally, the patients showed significantly reduced volumes in the right cingulate sulci and left inferior frontal sulci. Conclusion: Our results replicate typical brain-structural abnormalities with new findings in the medial prefrontal cortex, suggested to be a key region in this disorder.
Bendamustine as Monotherapy and in Combination Regimens for the Treatment of Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma: A Retrospective Analysis
Authors: Hus Iwona , Jawniak Dariusz , Gorska-Kosicka Magdalena , Butrym Aleksandra , Dzietczenia Justyna , Wrobel Tomasz , Grzegorz Mazur , Lech-Maranda Ewa , Warzocha Krzysztof , Waszczuk-Gajda Anna , Jedrzejczak W. Wiktor , Krawczyk-Kulis Małgorzata , Kyrcz-Krzemien Sławomira , Poplawska Lidia , Walewski Jan , Dmoszynska Anna
Published: January 2014

Background/Aim: In this study, we carried out a retrospective analysis of the efficacy and toxicity of bendamustine in patients with B-cell lymphoproliferative diseases. Methods: Bendamustine was administered both as monotherapy and in combined protocols to 92 patients, including 76 patients with chronic lymphocytic leukemia (CLL) and 16 patients with indolent lymphomas. Bendamustine plus rituximab was used to treat 65.2% of the patients, and 34.8% of the patients received bendamustine as monotherapy. Results: The overall response rate was 64.2%, including the complete response rate (18.5%) and the partial response rate (45.7%). The median overall survival (OS) was 11.5 months. Among the pretreatment parameters, β2-microglobulin (RR = 1.413; p = 0.001) and hemoglobin levels (RR = 0.85; p = 0.03) significantly influenced survival. The OS was significantly longer in patients who received ≤2 lines of previous therapy compared to >3 lines (p = 0.043; log-rank test) and those who received ≥4 courses of therapy with bendamustine (p = 0.0007; log-rank test). Toxicity was predominantly hematological, including grade III/IV neutropenia in 33.7%, thrombocytopenia in 13%, and anemia in 13% of patients. Conclusion: Bendamustine, both in monotherapy and in combination regimens, is an effective therapy with a favorable toxicity profile in patients with indolent B-cell malignancies.
The Integrative Management of Treatment-Resistant Depression: A Comprehensive Review and Perspectives
Authors: Carvalho Andre F. , Berk Michael , Hyphantis Thomas N. , McIntyre Roger S.
Published: January 2014

Background: Major depressive disorder is a prevalent and disabling illness. Notwithstanding numerous advances in the pharmacological treatment of depression, approximately 70% of patients do not remit after first-line antidepressant treatment. Methods: The MEDLINE/PubMed, EMBASE and ClinicalTrials.gov electronic databases were searched from inception to October 1, 2013, for randomized controlled trials (RCT), relevant open-label trials, meta-analyses and ongoing trials of pharmacological and psychotherapeutic approaches to treatment-resistant depression (TRD). Results: Switching to a different antidepressant is a useful option following nonresponse to a first-line agent. Although widely used in clinical practice, there is limited evidence to support antidepressant combination for TRD. Notwithstanding evidence for lithium or T3 augmentation to be successful in TRD, most studies were carried out when participants were treated with tricyclic antidepressants (TCA). Of the available strategies to augment the response to new-generation antidepressants, the use of some atypical antipsychotics is best supported by evidence. Several novel therapeutic options are currently discussed. Evidence suggests that cognitive therapy (CT) is an effective strategy for TRD. Conclusions: The success of switching to a different antidepressant following a first-line agent is supported by evidence, but there is limited evidence for effective combination strategies. Lithium and T3 augmentation of TCA have the strongest evidence base for successful treatment of TRD. The use of augmentation of newer-generation antidepressants with atypical antipsychotics is supported by a growing evidence base. Current evidence supports CT as an effective strategy for TRD. There is a need for additional large-scale RCT of TRD. The development of new antidepressants targeting novel pathways opens a promising perspective for the management of TRD.
Essential Tremor in aCharcot-Marie-Tooth Type 2C Kindred Does Not Segregate with the TRPV4 R269H Mutation
Authors: Louis Elan D. , Hernandez Nora , Ottman Ruth , Ionita-Laza Iuliana , Clark Lorraine N.
Published: January 2014

Background: We investigated 4 members of a family with type 2C Charcot-Marie-Tooth (CMT) and self-reported essential tremor (ET). A heterozygous missense mutation, R269H, in the TRPV4 gene was previously reported in this family. Our genotypic data provided a rare opportunity to determine the etiology of the tremor. Methods: Family study; the 4 tremor cases underwent a detailed neurological assessment. Results: The clinical diagnosis of ET was confirmed in all 4 tremor cases based on stringent published research criteria. Two of these also had CMT. We genotyped all 4 family members for the TRPV4 R269H mutation. We confirmed the presence of the TRPV4 R269H mutation in the 2 family members with ET and CMT; however, the TRPV4 R269H mutation did not segregate with ET in the same family. Conclusions: In this particular CMT family, the tremor was clinically attributed to ET. Furthermore, genotype data indicated that the tremor was unlikely to be caused by incomplete penetrance or variable expressivity of the TRPV4 R269H mutation. Hence, the tremor likely represents ET. This establishes that in some CMT families the tremor diathesis likely represents a second disorder, namely ET.
THC:CBD Spray and MS Spasticity Symptoms: Data from Latest Studies
Authors: Rekand Tiina
Published: January 2014

New clinical experience with 9-delta-tetrahydocannabinol (THC) and cannabidiol (CBD) oromucosal spray (Sativex®) involving more than an additional 1,000 patients with MS spasticity (approximately 150 in clinical studies and 900 in post-marketing surveillance studies) have become available in 2013 and are reviewed. A randomized, placebo controlled long-term follow-up clinical trial with THC:CBD spray versus placebo demonstrated that it was not associated with cognitive decline, depression or significant mood changes after 12 months of treatment. Furthermore, in a prospective observational pilot study involving 33 patients (60% female) aged 33-68 years and a mean disease duration of 6.6 years, THC:CBD oromucosal spray did not adversely influence standard driving ability in patients with moderate to severe MS spasticity. Other new long term observational data about the use of THC:CBD oromucosal spray in clinical practice are available from patient registries in the UK, Germany and Spain. Findings to date reinforce the efficacy and safety observed in Phase III clinical trials. It is of interest that in practice average dosages used by patients tended to be lower than those reported in clinical studies (5-6.4 vs. >8 sprays/day), and effectiveness was maintained in the majority of patients. Importantly, no additional safety concerns were identified in the registry studies which included findings from patients who have been treated for prolonged periods (in the German/UK registry 45% of patients had >2 years exposure). Thus, these new data support a positive benefit-risk relationship for THC:CBD oromucosal spray during longer-term use.
FVB/NJ Mice Demonstrate a Youthful Sensitivity to Noise-Induced Hearing Loss and Provide a Useful Genetic Model for the Study of Neural Hearing Loss
Authors: Ho Maria K. , Li Xin , Wang Juemei , Ohmen Jeffrey D. , Friedman Rick A.
Published: January 2014

The hybrid mouse diversity panel (HMDP), a panel of 100 strains, has been employed in genome wide association studies (GWAS) to study complex traits in mice. Hearing is a complex trait and the CBA/CaJ mouse strain is a widely used model for age-related hearing impairment (ARHI) and noise-induced hearing loss (NIHL). The youthful sensitivity to noise and limited age-related hearing loss of the CBA/CaJ strain led us to attempt the identification of additional strains segregating a similar phenotype for our panel. FVB/NJ is part of the HMDP and has been previously described as having a similar ARHI phenotype to CBA/CaJ. For these reasons, we have studied the FVB/NJ mouse for ARHI and NIHL phenotypes in the hopes of incorporating its phenotype into HMDP studies. We demonstrate that FVB/NJ exhibits ARHI at an earlier age than CBA/CaJ and young FVB/NJ mice are vulnerable to NIHL up to 10-12 weeks. This suggests that FVB/NJ may be used as an additional genetic model for neural forms of progressive hearing loss and for the study of youthful sensitivity to noise.
Clinical Benefit Response in Pancreatic Cancer Trials Revisited
Authors: Bernhard Jürg , Dietrich Daniel , Glimelius Bengt , Bodoky György , Scheithauer Werner , Herrmann Richard
Published: January 2014

Objectives: Clinical benefit response (CBR), based on changes in pain, Karnofsky performance status, and weight, is an established palliative endpoint in trials for advanced gastrointestinal cancer. We investigated whether CBR is associated with survival, and whether CBR reflects a wide-enough range of domains to adequately capture patients' perception. Methods: CBR was prospectively evaluated in an international phase III chemotherapy trial in patients with advanced pancreatic cancer (n = 311) in parallel with patient-reported outcomes (PROs). Results: The median time to treatment failure was 3.4 months (range: 0-6). The majority of the CBRs (n = 39) were noted in patients who received chemotherapy for at least 5 months. Patients with CBR (n = 62) had longer survival than non-responders (n = 182) (hazard ratio = 0.69; 95% confidence interval: 0.51-0.94; p = 0.013). CBR was predicted with a sensitivity and specificity of 77-80% by various combinations of 3 mainly physical PROs. A comparison between the duration of CBR (n = 62, median = 8 months, range = 4-31) and clinically meaningful improvements in the PROs (n = 100-116; medians = 9-11 months, range = 4-24) showed similar intervals. Conclusion: CBR is associated with survival and mainly reflects physical domains. Within phase III chemotherapy trials for advanced gastrointestinal cancer, CBR can be replaced by a PRO evaluation, without losing substantial information but gaining complementary information.
Trigeminal Neuralgia as the First Clinical Manifestation of Anti-Hu Paraneoplastic Syndrome Induced by a Borderline Ovarian Mucinous Tumor
Authors: Kalanie Hossein , Harandi Ali Amini , Mardani Masoud , Shahverdi Zohre , Morakabati Arman , Alidaei Shapoor , Heydari Daryoosh , Soroush Ziaeddin , Pakdaman Hossein , Hosseinzadeh Zahra
Published: January 2014

Paraneoplastic neurologic syndrome (PNS) is an uncommon manifestation of cancer that is not caused by the tumor or metastasis. Trigeminal neuralgia (TN) is an initial symptom of this disease, but it has rarely been reported in the literature. Here, we report the case of a 76-year-old woman who presented with classic TN, followed by limbic encephalitis due to an underlying ovarian intestinal-type mucinous borderline tumor, with the presence of anti-Hu antibodies. She recovered quickly after removal of the tumor and was essentially free of symptoms 2 weeks after surgery. Because PNS precedes the tumor in approximately 60% of cases, its rapid detection and treatment are crucial. Therefore, we propose that PNS be considered during the management of TN when brain imaging is normal, as it is followed by other central and/or peripheral neurological manifestations as well as the presence of systemic symptoms such as anemia, fatigability, loss of appetite, or weight loss.
European Society for Paediatric Endocrinology Consensus Guidelines on Screening, Diagnosis, and Management of Congenital Hypothyroidism
Authors: Léger Juliane , Olivieri Antonella , Donaldson Malcolm , Torresani Toni , Krude Heiko , van Vliet Guy , Polak Michel , Butler Gary ,   on behalf of ESPE-PES-SLEP-JSPE-APEG-APPES-ISPAE, and the Congenital Hypothyroidism Consensus Conference Group
Published: January 2014

Objective: The aim was to formulate practice guidelines for the diagnosis and management of congenital hypothyroidism (CH). Evidence: A systematic literature search was conducted to identify key articles relating to the screening, diagnosis, and management of CH. The evidence-based guidelines were developed with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, describing both the strength of recommendations and the quality of evidence. In the absence of sufficient evidence, conclusions were based on expert opinion. Consensus Process: Thirty-two participants drawn from the European Society for Paediatric Endocrinology and five other major scientific societies in the field of pediatric endocrinology were allocated to working groups with assigned topics and specific questions. Each group searched the literature, evaluated the evidence, and developed a draft document. These papers were debated and finalized by each group before presentation to the full assembly for further discussion and agreement. Recommendations: The recommendations include: worldwide neonatal screening, approaches to assess the cause (including genotyping) and the severity of the disorder, the immediate initiation of appropriate L-T4 supplementation and frequent monitoring to ensure dose adjustments to keep thyroid hormone levels in the target ranges, a trial of treatment in patients suspected of transient CH, regular assessments of developmental and neurosensory functions, consulting health professionals as appropriate, and education about CH. The harmonization of diagnosis, management, and routine health surveillance would not only optimize patient outcomes, but should also facilitate epidemiological studies of the disorder. Individuals with CH require monitoring throughout their lives, particularly during early childhood and pregnancy.
A Case of Choroidal Neovascularization Secondary to Unilateral Retinal Pigment Epithelium Dysgenesis
Authors: Shimoyama Tsuyoshi , Imai Hisanori , Honda Shigeru , Negi Akira
Published: January 2014

Aim: To report a case of choroidal neovascularization secondary to unilateral retinal pigment epithelium dysgenesis (URPED), which was resistant to posterior subtenon injection of triamcinolone acetonide (STTA) and intravitreal bevacizumab injection (IVB). Case Report: An 8-year-old boy was referred to us because of a unilateral unique clinical appearance on funduscopic examination in his left eye (OS). A geometric lesion at the retinal pigment epithelium level of the interpapillomacular area was disclosed OS. The optic nerve was slightly hyperemic OS. Findings from the right fundus examination were normal. Based on these characteristic findings, he was diagnosed as having URPED. Best corrected Landolt ring chart visual acuity (BCVA) was 1.0 in both eyes. Twenty-three months after the first visit, the patient presented with visual disturbance OS. Funduscopic examination showed an expansion of the geometric lesion and the development of a subfoveal choroidal neovascularization (CNV). BCVA was 0.4 OS. Two-time STTA (40 mg/1 ml) was performed at the onset of CNV and 6 months later, and additional IVB (1.25 mg/0.05 ml) was done 10 months later for the treatment of CNV, but the geometric lesion and CNV were resistant to the treatment and continued to expand. Seven years after the first visit, the geometric lesion and the CNV kept expanding steadily. Conclusion: URPED is a rare clinical entity, and the prognosis of this disease is still unclear. The visual prognosis may depend on whether CNV fully develops.
Comparison of the Serum Lipidome in Patients With Abdominal Aortic Aneurysm and Peripheral Artery Disease
Authors: Moxon Joseph V. , Liu Dawei , Wong Gerard , Weir Jacquelyn M. , Behl-Gilhotra Ratnesh , Bradshaw Barbara , Kingwell Bronwyn A. , Meikle Peter J. , Golledge Jonathan
Published: January 2014

Background—

Currently, the relationship between circulating lipids and abdominal aortic aneurysm (AAA) is unclear. We conducted a lipidomic analysis to identify serum lipids associated with AAA presence. Secondary analyses assessed the ability of models incorporating lipidomic features to improve stratification of patient groups with and without AAA beyond traditional risk factors.

Methods and Results—

Serum lipids were profiled via liquid chromatography tandem mass spectrometry analysis of serum from 161 patients with AAA and 168 controls with peripheral artery disease. Binary logistic regression was used to identify AAA-associated lipids. Classification models were created based on a combination of (1) traditional risk factors only or (2) lipidomic features and traditional risk factors. Model performance was assessed using receiver operator characteristic curves. Three diacylglycerols and 7 triacylglycerols were associated with AAA. Combining lipidomic features with traditional risk factors significantly improved stratification of AAA and peripheral artery disease groups when compared with traditional risk factors alone (mean area under the receiver operator characteristic curve [95% confidence interval], 0.760 [0.756–0.763] and 0.719 [0.716–0.723], respectively;
P
<0.05).

Conclusions—

A group of linoleic acid containing triacylglycerols and diacylglycerols were significantly associated with AAA presence. Inclusion of lipidomic features in multivariate analyses significantly improved prediction of AAA presence when compared with traditional risk factors alone.
A new species of Grapholita Treitschke (Lepidoptera: Tortricidae) from the midwestern USA
Authors: HARRISON ERRY L. , GIBSON LORAN D. , GILLIGAN TODD M.
Published: January 2014

Grapholita orbexilana, new species, is described from Illinois, Kentucky, and Ohio, USA. The larvae feed exclusively on Orbexilum onobrychis (Fabaceae), a plant of conservation interest in the Midwest. The moth is univoltine; its complete annual life cycle is detailed. Adult morphology readily distinguishes G. orbexilana from all other midwestern species of Grapholita; diagnostic information is provided. Observations on morphology, larval host plant preference, and pheromone attraction are presented to support the assignment of G. orbexilana to the jungiella species group of the subgenus Grapholita
Description of Dociostaurus biskrensis sp. nov. and male allotypes of four species: Pamphagulus bodenheimeri dumonti, P. uvarovi, Sphingonotus ebneri and Notopleura pygmaea (Orthoptera: Acridoidea) in the region of Biskra, Algeria
Authors: MOUSSI ABDELHAMID , ABBA ABDERRAHMANE , HARRAT ABBOUD , PETIT DANIEL
Published: January 2014

The new species Dociostaurus biskrensis Moussi & Petit 2013 was collected in the region of Biskra, at the arido-Saharan limit of Eastern Algerian. We also describe the males of four species for which only females were known: Pamphagulus bodenheimeri dumonti, P. uvarovi, Notopleura pygmaea and Sphingonotus ebneri. The key to the genus Dociostaurus in North Africa is given. The species P. uvarovi and Notopleura pygmaea are new for the Algeria. The diets and life cycles of D. biskrensis and of the two species of Pamphagulus are defined.
A Flexible Parameterization for Shortwave Optical Properties of Ice Crystals*
Authors: van Diedenhoven Bastiaan , Ackerman Andrew S. , Cairns Brian , Fridlind Ann M.
Published: January 2014

A parameterization is presented that provides extinction cross section σe, single-scattering albedo ω, and asymmetry parameter g of ice crystals for any combination of volume, projected area, aspect ratio, and crystal distortion at any wavelength in the shortwave. Similar to previous parameterizations, the scheme makes use of geometric optics approximations and the observation that optical properties of complex, aggregated ice crystals can be well approximated by those of single hexagonal crystals with varying size, aspect ratio, and distortion levels. In the standard geometric optics implementation used here, σe is always twice the particle projected area. It is shown that ω is largely determined by the newly defined absorption size parameter and the particle aspect ratio. These dependences are parameterized using a combination of exponential, lognormal, and polynomial functions. The variation of g with aspect ratio and crystal distortion is parameterized for one reference wavelength using a combination of several polynomials. The dependences of g on refractive index and ω are investigated and factors are determined to scale the parameterized g to provide values appropriate for other wavelengths. The parameterization scheme consists of only 88 coefficients. The scheme is tested for a large variety of hexagonal crystals in several wavelength bands from 0.2 to 4 μm, revealing absolute differences with reference calculations of ω and g that are both generally below 0.015. Over a large variety of cloud conditions, the resulting root-mean-squared differences with reference calculations of cloud reflectance, transmittance, and absorptance are 1.4%, 1.1%, and 3.4%, respectively. Some practical applications of the parameterization in atmospheric models are highlighted.
Assessing the Risk of Persistent Drought Using Climate Model Simulations and Paleoclimate Data
Authors: Ault Toby R. , Cole Julia E. , Overpeck Jonathan T. , Pederson Gregory T. , Meko David M.
Published: January 2014

Projected changes in global rainfall patterns will likely alter water supplies and ecosystems in semiarid regions during the coming century. Instrumental and paleoclimate data indicate that natural hydroclimate fluctuations tend to be more energetic at low (multidecadal to multicentury) than at high (interannual) frequencies. State-of-the-art global climate models do not capture this characteristic of hydroclimate variability, suggesting that the models underestimate the risk of future persistent droughts. Methods are developed here for assessing the risk of such events in the coming century using climate model projections as well as observational (paleoclimate) information. Where instrumental and paleoclimate data are reliable, these methods may provide a more complete view of prolonged drought risk. In the U.S. Southwest, for instance, state-of-the-art climate model projections suggest the risk of a decade-scale megadrought in the coming century is less than 50%; the analysis herein suggests that the risk is at least 80%, and may be higher than 90% in certain areas. The likelihood of longer-lived events (>35 yr) is between 20% and 50%, and the risk of an unprecedented 50-yr megadrought is nonnegligible under the most severe warming scenario (5%–10%). These findings are important to consider as adaptation and mitigation strategies are developed to cope with regional impacts of climate change, where population growth is high and multidecadal megadrought—worse than anything seen during the last 2000 years—would pose unprecedented challenges to water resources in the region.