bluuebunny/crossref_metadata_2025 huggingface dataset:
Water Activity
Authors: Nielsen O. F. , Bilde M. , Frosch M.
Published: July 2012

Microorganisms require water for their metabolic activities. Only a fraction of water in foodstuffs, the so‐called free water, is available for this purpose. The amounts of free water previously estimated by two different methods (Frosch et al. (2010), Frosch et al. (2011), and Low (1969)) are compared for aqueous solutions of four electrolytes, NaCl, NH4Cl, Na2SO4, (NH4)2SO4: (i) vapour pressure measurements of the solutions relative to that of pure water (water activities) and (ii) low‐wavenumber Raman spectra in the R(ν)‐representation. For each electrolyte deviations were found between results from the two methods. All water molecules in the illuminated volume contribute to the Raman data. The vapor pressure measurements refer to water molecules at the water/atmosphere interface where surface tension is important. Differences in surface tension for the four electrolytes qualitatively explain deviations between the amounts of “free water” observed by the two methods.
The Application of Biophysical Techniques to Study Antimicrobial Peptides
Authors: Torcato Inês M. , Castanho Miguel A. R. B. , Henriques Sónia T.
Published: July 2012

The increasing bacteria resistance to conventional antibiotics has led to the need for alternative therapies. Being part of the human innate defence system and with a broad spectrum of activity against bacteria, viruses, protozoa, and cancer cells, antimicrobial peptides (AMPs) are a very promising alternative. The mechanism of action of AMPs seems to broadly correlate with their ability to target the bacterial cell membrane. To understand and improve their effect, it is of major importance to unravel their mechanism of action and, in particular, to understand the peptide‐membrane binding. Several biophysical techniques such as fluorescence spectroscopy, circular dichroism, zeta potential determination, and atomic force microscopy can be used to achieve this goal. Characteristics of AMPs‐membranes interactions and the use of these biophysical techniques will be discussed.
The V30M Amyloidogenic Mutation Decreases the Rate of Refolding Kinetics of the Tetrameric Protein Transthyretin
Authors: Jesus Catarina S. H. , Vaz Daniela C. , Saraiva Maria J. M. , Brito Rui M. M.
Published: July 2012

Transthyretin (TTR) is a homotetrameric protein implicated in several amyloid diseases. The mechanism by which TTR is converted into elongated fibrillar assemblies has been extensively investigated, and numerous studies showed that dissociation of the native tetrameric structure into partially unfolded monomeric species precedes amyloid formation. The small differences observed in the crystal structures of different TTR variants, as well as the thermodynamics and kinetics of tetramer dissociation, do not seem to completely justify the amyloidogenic potential of different TTR variants. With this in mind, we have studied the refolding kinetics of WT‐TTR and its most common amyloidogenic variant V30M‐TTR, monitoring changes in intrinsic tryptophan fluorescence at different urea and protein concentrations. Our results demonstrate that the in vitro refolding mechanisms of WT‐ and V30M‐TTR are similar, involving a dimeric intermediate. However, there are large differences in the refolding rate constants for the two variants, specially close to physiological conditions. Interestingly, tetramer formation occurs at a much slower rate in the amyloidogenic variant V30M‐TTR than in WT‐TTR, which in the in vivo setting may promote the accumulation of monomeric species in the extracellular environment, resulting in higher susceptibility for aggregation and amyloid formation instead of spontaneous refolding.
Fluorescence Lifetime Imaging of Propranolol Uptake in Living Glial C6 Cells
Authors: Bisby Roger , Botchway Stanley , Crisostomo Ana , Parker Anthony , Scherer Kathrin
Published: July 2012

Uptake of the β‐blocker drug propranolol by living glial C6 cells has been observed using fluorescence lifetime imaging with two‐photon excitation at 630 nm. Both uptake and release of propranolol occur within minutes and are temperature dependent, being about 5 times faster at 37°C than at 20°C. The intracellular fluorescence lifetime of propranolol is generally shorter than the value of 9.8 ns determined in dilute neutral aqueous solution, and the difference is ascribed to concentration quenching. Within the cells, propranolol is accumulated within intracellular acidic vesicles and the cytoplasm but is excluded from the cell nucleus. On incubation of cells in medium containing 100 μM propranolol, the drug is accumulated to reach intracellular concentrations up to 10 mM in a process that is believed to be driven by protonation within acidic cellular compartments.
Impact of the Invasive Brown Marmorated Stink Bug,Halyomorpha halys(Stål), in Mid-Atlantic Tree Fruit Orchards in the United States: Case Studies of Commercial Management
Authors: Leskey Tracy C. , Short Brent D. , Butler Bryan R. , Wright Starker E.
Published: July 2012

Four commercial orchards in the mid-Atlantic region of the United States were surveyed weekly in 2010 and 2011 for the presence of brown marmorated stink bug and the injury caused to both apple and peaches. Among tested sampling techniques, pyramid traps baited with the aggregation pheromone ofPlautia staliScott, methyl-(2E,4E,6Z)-decatrienoate, yielded the most brown marmorated stink bug adults and nymphs, followed by visual observations. Brown marmorated stink bugs began to feed on apples and peaches soon after fruit set and continued to feed on fruit throughout the growing season. Injury to apple was relatively inconsequential until after mid-June, whereas feeding on peaches resulted in immediate economic injury as the surface became distorted, dented, discolored, and the flesh beneath turned brown. Significantly more apples were injured and with greater severity in 2010 than in 2011. Likewise, percent injury on the exterior portion of each apple plot was significantly greater than injury reported from the interior in both years. Growers increased the number of insecticide applications nearly 4-fold from 2010 to 2011. In addition to the increased number of targeted insecticide applications, growers also reduced the interval between treatments in 2011. A metric was created to compare the relative intensity of each grower's commercial management program between seasons and amongst each other.
Influence of Fixation Products Used in the Histological Processing in the FTIR Spectra of Lung Cells
Authors: Pereira Thiago Martini , Dagli Maria Lucia Zaidan , Mennecier Grégory , Zezell Denise Maria
Published: July 2012

The aim of the present study is to evaluate the differences on FTIR spectra of the normal lung cell (noncancerous mice lung epithelial cell line e10) due to different fixation protocols for histological processing. The results shown that formalin and methacarn (normally used in fixation) did cause many changes on the FTIR spectra of mice lung cells e10, mainly in the organic compounds (800–1800 cm−1) in lipids, DNA, and proteins, and the alcohol 70% fixation protocol caused almost no changes on the FTIR spectra compared to unfixed cells spectra (in PBS). It can be concluded that histological processing with alcohol 70% fixation protocol can be used in the FTIR study of mice lung cell line e10.
Barriers to Physical Activity in East Harlem, New York
Authors: Fox Ashley M. , Mann Devin M. , Ramos Michelle A. , Kleinman Lawrence C. , Horowitz Carol R.
Published: July 2012

Background. East Harlem is an epicenter of the intertwining epidemics of obesity and diabetes in New York. Physical activity is thought to prevent and control a number of chronic illnesses, including diabetes, both independently and through weight control. Using data from a survey collected on adult (age 18+) residents of East Harlem, this study evaluated whether perceptions of safety and community-identified barriers were associated with lower levels of physical activity in a diverse sample.Methods. We surveyed 300 adults in a 2-census tract area of East Harlem and took measurements of height and weight. Physical activity was measured in two ways: respondents were classified as having met the weekly recommended target of 2.5 hours of moderate physical activity (walking) per week (or not) and reporting having engaged in at least one recreational physical activity (or not). Perceived barriers were assessed through five items developed by a community advisory board and perceptions of neighborhood safety were measured through an adapted 7-item scale. Two multivariate logistic regression models with perceived barriers and concerns about neighborhood safety were modeled separately as predictors of engaging in recommended levels of exercise and recreational physical activity, controlling for respondent weight and sociodemographic characteristics.Results. The most commonly reported perceived barriers to physical activity identified by nearly half of the sample were being too tired or having little energy followed by pain with exertion and lack of time. Multivariate regression found that individuals who endorsed a greater number of perceived barriers were less likely to report having met their weekly recommended levels of physical activity and less likely to engage in recreational physical activity controlling for covariates. Concerns about neighborhood safety, though prevalent, were not associated with physical activity levels.Conclusions. Although safety concerns were prevalent in this low-income, minority community, it was individual barriers that correlated with lower physical activity levels.
Preoperative Evaluation with fMRI of Patients with Intracranial Gliomas
Authors: Kapsalakis Ioannis Z. , Kapsalaki Eftychia Z. , Gotsis Efstathios D. , Verganelakis Dimitrios , Toulas Panagiotis , Hadjigeorgiou Georgios , Chung Indug , Fezoulidis Ioannis , Papadimitriou Alexandros , Robinson Joe Sam , Lee Gregory P. , Fountas Kostas N.
Published: July 2012

Introduction. Aggressive surgical resection constitutes the optimal treatment for intracranial gliomas. However, the proximity of a tumor to eloquent areas requires exact knowledge of its anatomic relationships to functional cortex. The purpose of our study was to evaluate fMRI’s accuracy by comparing it to intraoperative cortical stimulation (DCS) mapping.Material and Methods. Eighty-seven patients, with presumed glioma diagnosis, underwent preoperative fMRI and intraoperative DCS for cortical mapping during tumor resection. Findings of fMRI and DCS were considered concordant if the identified cortical centers were less than 5 mm apart. Pre and postoperative Karnofsky Performance Scale and Spitzer scores were recorded. A postoperative MRI was obtained for assessing the extent of resection.Results. The areas of interest were identified by fMRI and DCS in all participants. The concordance between fMRI and DCS was 91.9% regarding sensory-motor cortex, 100% for visual cortex, and 85.4% for language. Data analysis showed that patients with better functional condition demonstrated higher concordance rates, while there also was a weak association between tumor grade and concordance rate. The mean extent of tumor resection was 96.7%.Conclusions. Functional MRI is a highly accurate preoperative methodology for sensory-motor mapping. However, in language mapping, DCS remains necessary for accurate localization.
Goal‐Programming‐Driven Genetic Algorithm Model for Wireless Access Point Deployment Optimization
Authors: Wang Chen-Shu , Chang Ching-Ter
Published: July 2012

Appropriate wireless access point deployment (APD) is essential for ensuring seamless user communication. Optimal APD enables good telecommunication quality, balanced capacity loading, and optimal deployment costs. APD is a typical NP‐complex problem because improving wireless networking infrastructure has multiple objectives (MOs). This paper proposes a method that integrates a goal‐programming‐driven model (PM) and a genetic algorithm (GA) to resolve the MO‐APD problem. The PM identifies the target deployment subject of four constraints: budget, coverage, capacity, and interference. The PM also calculates dynamic capacity requirements to replicate real wireless communication. Three experiments validate the feasibility of the PM. The results demonstrate the utility and stability of the proposed method. Decision makers can easily refer to the PM‐identified target deployment before allocating APs.
Antimicrobial Peptide from the Eusocial Bee Halictus sexcinctus Interacting with Model Membranes
Authors: Pazderková Markéta , Kočišová Eva , Pazderka Tomáš , Maloň Petr , Kopecký Vladimír , Monincová Lenka , Čeřovský Václav , Bednárová Lucie
Published: July 2012

Halictine‐1 (Hal‐1)—a linear antibacterial dodecapeptide isolated from the venom of the eusocial bee Halictus sexcinctus—has been subjected to a detailed spectroscopic study including circular dichroism, fluorescence, and vibrational spectroscopy. We investigated Hal‐1 ability to adopt an amphipathic α‐helical structure upon interaction with model lipid‐based bacterial membranes (phosphatidylcholine/phosphatidylglycerol‐based large unilamellar vesicles and sodium dodecylsulfate micelles) and helix inducing components (trifluoroethanol). It was found that Hal‐1 responds sensitively to the composition of the membrane model and to the peptide/lipid ratio. The amphipathic nature of the helical Hal‐1 seems to favour flat charged surfaces of the model lipid particles over the nondirectional interaction with trifluoroethanol. Increasing fraction of polyproline II type conformation was detected at low peptide/lipid ratios.
Thyroid Cancer: Molecular Aspects and New Therapeutic Strategies
Authors: Grande Enrique , Díez Juan José , Zafon Carles , Capdevila Jaume
Published: July 2012

Despite that thyroid cancer accounts for over 90% of tumors that arise from the endocrine system, these tumors barely represent 2% of solid tumors in adults. Many entities are grouped under the general term of thyroid cancer, and they differ in histological features as well as molecular and clinical behavior. Thus, the prognosis for patients with thyroid cancer ranges from a survival rate of >97% at 5 years, in the case of differentiated thyroid tumors sensitive to radioactive iodine, to a 4-month median survival for anaplastic tumors. The high vascularity in these tumors and the important role that oncogenic mutations may have in the RAS/RAF/MEK pathway and oncogenicity (as suggested by activating mutations and rearrangements of theRETgene) have led to the development of multitarget inhibitors in different histological subgroups of patients. The correct molecular characterization of patients with thyroid cancer is thought to be a key aspect for the future clinical management of these patients.
Applications of Infrared and Raman Microspectroscopy of Cells and Tissue in Medical Diagnostics: Present Status and Future Promises
Authors: Diem Max , Miljković Miloš , Bird Benjamin , Chernenko Tatyana , Schubert Jen , Marcsisin Ellen , Mazur Antonella , Kingston Erin , Zuser Evgenia , Papamarkakis Kostas , Laver Nora
Published: July 2012

This paper summarizes the progress achieved over the past fifteen years in applying vibrational (Raman and IR) spectroscopy to problems of medical diagnostics and cellular biology. During this time, a number of research groups have verified the enormous information content of vibrational spectra; in fact, genomic, proteomic, and metabolomic information can be deduced by decoding the observed vibrational spectra. This decoding process is aided enormously by the availability of high‐power computer workstations and advanced algorithms for data analysis. Furthermore, commercial instrumentation for the fast collection of both Raman and infrared microspectral data has rendered practical the collection of images based solely on spectral data. The progress in the field has been manifested by a steady increase in the number and quality of publications submitted by established and new research groups in vibrational biological and biomedical arenas.
Laminar Mixing in Stirred Tank Agitated by an Impeller Inclined
Authors: Takahashi Koji , Sugo Yoshiharu , Takahata Yasuyuki , Sekine Hitoshi , Nakamura Masayuki
Published: July 2012

The mixing performance in a vessel agitated by an impeller that inclined itself, which is considered one of the typical ways to promote mixing performance by the spatial chaotic mixing, has been investigated experimentally and numerically. The mixing time was measured by the decolorization method and it was found that the inclined impeller could reduce mixing time compared to that obtained by the vertically located impeller in laminar flow region. The effect of eccentric position of inclined impeller on mixing time was also studied and a significant reduction of mixing time was observed. To confirm the experimental results, the velocity profiles were calculated numerically and two novel numerical simulation methods were proposed.
Structural Perturbation of Superfolder GFP in the Presence of Guanidine Thiocyanate
Authors: Stepanenko Olesya V. , Stepanenko Olga V. , Kuznetsova Irina M. , Verkhusha Vladyslav V. , Turoverov Konstantin K.
Published: July 2012

The guanidine‐thiocyanate‐induced denaturation‐renaturation of sfGFP was studied. It was shown that the disruption of sfGFP native structure occurs in the range of guanidine thiocyanate concentrations from 0.5 to 2.5 M. This process was accompanied by simultaneous changes of all recorded parameters. It was found that the small guanidine thiocyanate concentrations (less then 0.1‐0.2 M) triggered local structural disturbances in protein which result in significant decrease of chromophore and tryptophan fluorescence intensity and change of protein visible absorption spectrum.
AIDS-Related Non-Hodgkin's Lymphoma in Sub-Saharan Africa: Current Status and Realities of Therapeutic Approach
Authors: Mwamba Peter M. , Mwanda Walter O. , Busakhala Naftali W. , Strother R. Matthew , Loehrer Patrick J. , Remick Scot C.
Published: July 2012

Today AIDS-related non-Hodgkin's lymphoma (AR-NHL) is a significant cause of morbidity and mortality in HIV-infected patients the world over, and especially in sub-Saharan Africa. While the overall incidence of AR-NHL since the emergence of combination antiretroviral therapy (cART) era has declined, the occurrence of this disease appears to have stabilized. In regions where access to cART is challenging, the impact on disease incidence is less clear. In the resource-rich environment it is clinically recognized that it is no longer appropriate to consider AR-NHL as a single disease entity and rather treatment of AIDS lymphoma needs to be tailored to lymphoma subtype. While intensive therapeutic strategies in the resource-rich world are clearly improving outcome, in AIDS epicenters of the world and especially in sub-Saharan Africa there is a paucity of data on treatment and outcomes. In fact, only one prospective study of dose-modified oral chemotherapy and limited retrospective studies with sufficient details provide a window into the natural history and clinical management of this disease. The scarcities and challenges of treatment in this setting provide a backdrop to review the current status and realities of the therapeutic approach to AR-NHL in sub-Saharan Africa. More pragmatic and risk-adapted therapeutic approaches are needed.
Initial‐Boundary Value Problem for Fractional Partial Differential Equations of Higher Order
Authors: Amanov Djumaklych , Ashyralyev Allaberen
Published: July 2012

The initial‐boundary value problem for partial differential equations of higher‐order involving the Caputo fractional derivative is studied. Theorems on existence and uniqueness of a solution and its continuous dependence on the initial data and on the right‐hand side of the equation are established.
Effectiveness ofMentha piperitain the Treatment of Infantile Colic: A Crossover Study
Authors: Alves João Guilherme Bezerra , de Brito Rita de Cássia Coelho Moraes , Cavalcanti Telma Samila
Published: July 2012

Background. Infantile colic is a distressing and common condition for which there is no proven standard treatment.Objective. To compare the efficacy ofMentha piperitawith simethicone in treatment for infantile colic.Methods. A double-blind crossover study was performed with 30 infants attending IMIP, Recife, Brazil. They were randomized to useMentha piperitaor simethicone in the treatment of infantile colic during 7 days with each drug. Primary outcomes were mother_s opinion about responses to the treatment, number of daily episodes of colic, and time spent crying, measured by a chronometer. Mann-Whitney and chi-square tests were used to compare the results. This study was previously approved by the Ethical Committee in Research at IMIP.Results. At baseline daily episodes of infantile colic was 3.9 (±1.1) and the mean crying time per day was 192 minutes (±51.6). At the end of the study daily episodes of colic fell to 1.6 (±0.6) and the crying duration decreased to 111 (±28) minutes. All mothers reported decrease of frequency and duration of the episodes of infantile colic and there were no differences between responses toMentha piperitaand simethicone.Conclusions. These findings suggest thatMentha piperitamay be used to help control infantile colic. However, these results must be repeated by others studies.
A Phase I Trial and Pharmacokinetic Study of Aflibercept (VEGF Trap) in Children with Refractory Solid Tumors: A Children's Oncology Group Phase I Consortium Report
Authors: Bender Julia Glade , Blaney Susan M. , Borinstein Scott , Reid Joel M. , Baruchel Sylvain , Ahern Charlotte , Ingle Ashish M. , Yamashiro Darrell J. , Chen Alice , Weigel Brenda , Adamson Peter C. , Park Julie R.
Published: July 2012

Purpose: Aflibercept is a novel decoy receptor that efficiently neutralizes circulating VEGF. A pediatric phase I trial was conducted to define the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of aflibercept.

Experimental Design: Cohorts of three to six children with refractory solid tumors received aflibercept intravenously over 60 minutes every 14 days, at 2.0, 2.5, or 3.0 mg/kg/dose. PK sampling and analysis of peripheral blood biomarkers were conducted with the initial dose.

Results: Twenty-one eligible patients were enrolled; 18 were fully evaluable for toxicity. One of six patients receiving 2.0 mg/kg/dose developed dose-limiting intratumoral hemorrhage and two of six receiving 3.0 mg/kg/dose developed either dose-limiting tumor pain or tissue necrosis. None of the six patients receiving 2.5 mg/kg/dose developed DLTs, defining this as the MTD. The most common non-DLTs were hypertension and fatigue. Three patients with hepatocellular carcinoma, hepatoblastoma and clear cell sarcoma had stable disease for >13 weeks. At the MTD, the ratio of free-to-bound aflibercept serum concentration was 2.10 on day 8 but only 0.44 by day 15. A rapid decrease in VEGF (P < 0.05) and increase in placental growth factor (PlGF; P < 0.05) from baseline was observed in response to aflibercept by day 2.

Conclusions: The aflibercept MTD in children of 2.5 mg/kg/dose every 14 days is lower than the adult recommended dose of 4.0 mg/kg. This dose achieves, but does not sustain, free aflibercept concentrations in excess of bound. Tumor pain and hemorrhage may be evidence of antitumor activity but were dose-limiting. Clin Cancer Res; 18(18); 5081–9. ©2012 AACR.
Ventral Striatal Activation during Reward Processing in Subjects with Ultra-High Risk for Schizophrenia
Authors: Juckel Georg , Friedel Eva , Koslowski Michael , Witthaus Henning , Özgürdal Seza , Gudlowski Yehonala , Knutson Brian , Wrase Jana , Brüne Martin , Heinz Andreas , Schlagenhauf Florian
Published: July 2012

Background: Early dysfunction of the brain reward system in schizophrenia might be already recognized in the prodromal phase of this illness. We used functional magnetic resonance imaging to assess the blood oxygen level-dependent response in the ventral striatum (VS) of subjects with ultra-high risk for psychosis during the presentation of reward-indicating and loss-indicating stimuli. Methods: Thirteen prodromal patients (mean age: 25.5 ± 4.6 years) and 13 age-matched healthy volunteers participated in an incentive monetary delay task, in which visual cues predicted that a rapid response to a subsequent target stimulus will gain money, avoid losing money or have no consequence. Results: Compared with the neutral condition, anticipation of reward loss-avoidance elicited significant activation of the VS in both healthy subjects and subjects with ultra-high risk for psychosis, but there was only a statistical tendency for less activation during loss-avoidance anticipation in prodromal compared to healthy subjects. Discussion: This study provides a first weak hint, as revealed by functional magnetic resonance imaging, for impaired activation of a central area of the mesolimbic dopaminergic brain reward system, the VS, already in subjects with ultra-high risk for psychosis, which is in line with results of patients with full-blown schizophrenic psychosis. This pilot study has, however, strong limitations, and its results need to be replicated first before they can be used e.g. for early recognition of patients in the schizophrenic prodrome.
Neurobiological Correlates of Delusion: Beyond the Salience Attribution Hypothesis
Authors: Pankow Anne , Knobel Astrid , Voss Martin , Heinz Andreas
Published: July 2012

Dopamine dysfunction is a mainstay of theories aimed to explain the neurobiological correlates of schizophrenia symptoms, particularly positive symptoms such as delusions and passivity phenomena. Based on studies revealing dopamine dysfunction in addiction research, it has been suggested that phasic or chaotic firing of dopaminergic neurons projecting to the (ventral) striatum attribute salience to otherwise irrelevant stimuli and thus contribute to delusional mood and delusion formation. Indeed, several neuroimaging studies revealed that neuronal encoding of usually irrelevant versus relevant stimuli is blunted in unmedicated schizophrenia patients, suggesting that some stimuli that are irrelevant for healthy controls acquire increased salience for psychotic patients. However, salience attribution per se may not suffice to explain anxieties and feelings of threat that often accompany paranoid ideation. Here, we suggest that beyond ventral striatal dysfunction, dopaminergic dysregulation in limbic areas such as the amygdala in interaction with prefrontal and temporal cortex may contribute to the formation of delusions and negative symptoms. Neuroleptic medication, on the other hand, appears to interfere with anticipation of reward in the ventral striatum and can thus contribute to secondary negative symptoms such as apathy and avolition.
Laparoscopic Removal of a Paracaval Air Gun Bullet in a Child
Authors: Murányi Mihály , Józsa Tamás , Benyó Mátyás , Salah Morshed , Flaskó Tibor
Published: July 2012

Air guns are known as low-velocity arms and are considered harmless. However, injuries from air weapons can be serious and even fatal, particularly in children. We present a potentially life-threatening penetrating retroperitoneal injury of a 3-year-old boy caused by an air gun, and the successful removal of the bullet via a laparoscopic approach. The patient was brought to our center with a penetrating air gunshot wound on his right side in the waist area. He was accidentally shot by his brother at their home. The patient’s clinical condition was stable. Computed tomography scan showed the bullet in the retroperitoneum near the inferior vena cava. A three-port laparoscopic transperitoneal approach was performed. The bullet was found just 0.5 cm caudal to the right renal hilum and 0.5 cm near the inferior vena cava; it was then removed. Operation time was 42 min and the postoperative course was uneventful. Thanks to improvements in laparoscopic surgical techniques, laparoscopy has become a feasible and effective treatment modality even for the removal of foreign bodies in children.
The Effect of Bilateral Globus Pallidus Internus Deep Brain Stimulation plus Ventralis Oralis Thalamotomy on Patients with Cerebral Palsy
Authors: Kim Joo Pyung , Chang Won Seok , Cho Sung-Rae , Chang Jin Woo
Published: July 2012

Objective: We compared bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) with bilateral GPi DBS plus ventralis oralis (Vo) thalamotomy to analyze the effect of the combined Vo thalamotomy. Methods: Between March 2003 and December 2008, 10 patients underwent DBS and/or Vo thalamotomy for treatment of cerebral palsy in our institute of neurosurgery and rehabilitation medicine. Four patients received bilateral posteroventral GPi DBS as group I and 6 patients received GPi DBS plus unilateral thalamotomy as group II. Results: The movement and disability scores of group I improved by 32 and 14.3%, respectively, at the last follow-up compared with baseline. The movement and disability scores of group II improved by 31.5 and 0.18%. The BFMDRS-movement subscores of group II demonstrated statistically significant improvement in the contralateral arm compared to group I (p = 0.042). Body pain, vitality and mental health seemed to improve in group II, in terms of health-related quality of life. Conclusions: Contrary to our expectations, we were unable to demonstrate clear improvements in overall BFMDRS scores between group I and group II. However, movements of the contralateral upper extremities improved and health-related quality of life in group II showed satisfactory results.
Evidence from Genetics for a Role of Autophagy and Innate Immunity in IBD Pathogenesis
Authors: Parkes Miles
Published: July 2012

The early identification of NOD2 (nucleotide-binding oligomerization domain-containing protein 2) as a susceptibility gene for Crohn’s disease first catalysed major interest in the role of innate immunity in IBD. This interest has been substantiated by genome-wide association studies with the identification of genetic association between Crohn’s disease and variants in two separate autophagy genes, ATG16L1 and IRGM. A variety of disease-predisposing mechanisms have been proposed for the NOD2 mutations, ranging from defects in viral sensing and reduced mucosal defensin production to abnormal autophagy induction. Recent work has also highlighted the complexity of the contribution made by ATG16L1 and IRGM. Thus ATG16 hypomorphic mice show major morphological change in Paneth cells – also observed in humans homozygous for the ATG16L1T300A. Further, these mice developed a Crohn’s-like phenotype – but only in the presence of an environmental stressor, an intact gut flora and a specific norovirus trigger. For IRGM, the risk alleles appear to affect mRNA transcription – in one study adversely impacting clearance by macrophages of CD-associated adherent-invasive Escherichia coli. There is now intriguing literature developing on the impact of ‘adaptive immunity’ genes on innate immune mechanisms. Buoncore et al. [Nature 2010;464:1371–1375] recently reported the accumulation of IL-23-responsive innate lymphoid cells in the colon, the former capable of producing IL-17 and interferon γ and mediating innate colitis in mice. Production of Th17 cytokines by analogous cells in humans appeared higher in IBD cases versus controls. Many other genes linked to various components of innate immunity are evident among the >100 confirmed IBD susceptibility loci. Intriguingly, association with epithelial barrier genes seems specific to ulcerative colitis – the converse of NOD2 and the autophagy genes which are Crohn’s-specific. These observations correlate nicely with ulcerative colitis being confined to the superficial layers of the colon, while the transmural inflammation of Crohn’s disease is caused by defects in cellular innate immunity and bacterial handling in the deeper layers of the gut wall.
Commensal-Innate Immune Miscommunication in IBD Pathogenesis
Authors: Cario Elke
Published: July 2012

Commensal microbiota plays a key role in the health and disease of the host. The innate immune system comprises an essential functional component of the intestinal mucosal barrier, maintaining hyporesponsiveness to omnipresent harmless commensals in the lumen, but rapidly recognizing and combating invading bacteria through diverse antimicrobial mechanisms. Interactions between commensals and innate immune cells are constant, multidimensional and entirely context-dependent. Environment, genetics and host defense differentially modulate commensal-innate immune effects and functions in the intestinal mucosa. In IBD, dysbiosis, mucus layer disruption, impairment in bacterial clearance, intestinal epithelial cell barrier dysfunction and/or immune cell deregulation may lead to commensal-innate immune miscommunication, which critically drives mucosal inflammation and associated cancer.
Lessons from Diversion Studies and Antibacterial Interventions
Authors: Flanagan Paul K. , Campbell Barry J. , Rhodes Jonathan M.
Published: July 2012

If bacteria cause IBD, then it should be possible to target the bacteria with therapies and cure or at least treat the disease. Discovery of a successful intervention, unless found by chance, will depend on knowing more about which bacteria are involved, where they are and how to remove them. Some evidence for the possible role of bacteria has come from in vivo studies of the effects of diverting the faecal stream away from sites of IBD. Alternative hypotheses arise from the diversion studies that could incriminate other components of the faecal stream that include bile acids and dietary components. Antibiotics will only really be adequately tested when we know what the target bacteria are and where they are, e.g. whether in the lumen or mucosa and whether intracellular or extracellular. Some encouraging responses have been observed, however, with empirical antibiotic therapy.
Epidemiology of the Transition from Early to Late Crohn’s Disease
Authors: Louis Edouard
Published: July 2012

Phenotypically, the transition from early to late Crohn’s disease is characterized by the occurrence of complications including strictures, intra-abdominal fistulas and perianal fistulas, all of them leading to various types of surgeries and currently non-reversible tissue damage. It must, however, be kept in mind that this transition is not at all a uniform and linear process. According to these simple phenotypic criteria, Crohn’s disease can already be a late disease at diagnosis while in other patients, it can still be an early disease after 20 years of evolution. This simply highlights the relativity of time in this field, actually reflecting the nature, location and severity of the inflammatory process. The risk over time of the development of these complications has been described, first in cohort studies and then in population-based studies. Globally, at diagnosis, between 19 and 38% only of Crohn’s disease patients have complicated Crohn’s disease. After 10 years, between 56 and 65% of patients have developed either stricturing or penetrating complications. After 20 years, these numbers are between 61 and 88%. In parallel to these structural changes, changes in the immunobiology of the disease also seem to occur; the latter seem to happen quicker with major modification already within 2 years of the diagnosis. Beside these general figures, important questions remain pending. First, the real timing of these changes is still unclear. Second, the precise role of genetics and environment in the development of these changes remains to be clarified. Third, the correlation between changes in immunobiology and intestinal structural damages has not been specifically studied.
Current Status of Mesenchymal Stem Cell Therapy and Bone Marrow Transplantation in IBD
Authors: Ricart Elena
Published: July 2012

Cellular therapy is a promising new approach to address unmet medical needs in patients with IBD, mainly Crohn’s disease (CD). Two series have reported autologous hematopoietic stem cell transplantation (HSCT) for CD. The largest one is a phase I study from Chicago including 24 patients with active CD refractory to conventional therapies. All patients went into remission with a CD Activity Index (CDAI) <150. The percentage of clinical relapse-free survival was 91% at 1 year, 63% at 2 years, 57% at 3 years, 39% at 4 years and 19% at 5 years. The percentage of patients in remission (CDAI <150), steroid-free or medication-free at any post-transplantation evaluation interval remained ≥70, ≥80 and ≥60%, respectively. In Europe and Canada, a currently ongoing randomized trial hopes to answer the question of whether autologous HSCT adds any benefit to the effect of immunosuppression used during mobilization. Although promising, HSCT for CD is still experimental and its toxicity leaves this option for a considerably reduced number of refractory patients in whom the disease is not amenable to surgical resection. A more recently developed, less aggressive approach involves the use of mesenchymal stem cells (MSCs). Successful pre-clinical studies using MSCs in models of autoimmunity, inflammation or tissue damage have paved the way for clinical trials. Two phase I studies on autologous bone marrow-derived MSCs for the treatment of active refractory CD have been published recently; one using systemic administration in patients with luminal CD and the other assessing the effects of local injection of MSCs for the treatment of fistulizing CD, showing that application of autologous MSCs is feasible, well tolerated and might produce clinical benefits.
Treat the Patient or Treat the Disease?
Authors: Hanauer Stephen B. , Kirsner Joseph B.
Published: July 2012

Our therapeutic goals for the treatment of ulcerative colitis and Crohn’s disease are evolving. Until the last decade the goals were primarily the treatment of symptoms. Regulatory approval for ulcerative colitis therapies have been based on short-term improvements in clinical indices and, most recently, the ability to heal the colonic mucosa, whereas approval for Crohn’s disease therapies have been based on reductions in the CDAI (Crohn’s Disease Activity Index). Over the past decade there has been increasing evidence in favor of more ‘objective’ measures of biologic disease activity including biomarkers such as C-reactive protein and mucosal healing in Crohn’s disease and the histologic resolution of active inflammation in ulcerative colitis. The objective changes have provided expanded therapeutic goals based on longer-term maintenance therapies with the potential to modify the chronic disease behavior and to reduce pharmacoeconomic costs (reductions in hospitalizations, surgeries and neoplasia).
Combined Immunosuppression Is More Dangerous than Monotherapy: What Is Fact and What Is Fiction?
Authors: Schölmerich Jürgen
Published: July 2012

A number of immunosuppressants are used in the treatment of IBD. They have different modes of action but most of them affect different cell types and all are able to increase the number of infections, in particular opportunistic infections. Some may also lead to an increased number of malignomas. This is of particular importance in a disease such as Crohn’s disease, which seems to be at least in part due to an immune deficiency. Data with regard to the differences of the effects of immunosuppressant combinations versus monotherapy are rare. Combinations with steroids, particularly, seem to pose a problem; however, an increased risk most probably also exists for other combinations. Therefore, in order to downregulate inflammation, we should use combined immunosuppression only if really necessary and only for short periods of time. The ultimate goal of the restitution of epithelial integrity and the maintenance of the mucosal barrier will better be achieved by other approaches.
Prevention and Management of Infectious Complications in IBD
Authors: Rahier Jean-François
Published: July 2012

In an era of increasing use of immunomodulating therapy and biologics, opportunistic infections have emerged as a pivotal safety concern for patients with IBD. Clinical studies, registries and case reports warn of the increased risk of infection, particularly opportunistic infections. The current challenge to physicians lies not only in managing IBD, but also in recognizing, preventing and treating common and uncommon infections. The European Crohn’s and Colitis Organization (ECCO) guidelines on the management and prevention of opportunistic infections in patients with IBD provide clinicians with guidance on the prevention, detection and management of such infections. The proposals therein may appear radical, potentially changing current practice, but we believe that these recommendations will help optimize patient outcome by reducing the morbidity and mortality related to these infections. In this ongoing process, prevention is by far the most important step; this relies on the recognition of risk factors for infection, the use of primary or secondary chemoprophylaxis, careful monitoring (clinical and laboratory work-up) before and during use of immunomodulators and the vaccination and education of the patient. Special recommendations should also be given to patients before and after travelling. Management of infection in IBD patients is case-dependent. Severe infection should be treated according to advice from infectious-disease experts.
How to Manage IBD in Patients with Infections or Malignancies?
Authors: Kohn Anna , Meddi Patrizia
Published: July 2012

Infections and malignancies are a major issue for clinicians in the management of patients with IBD because of concerns about the safety of drugs currently used in treatment, including immunosuppressive agents, steroids and tumor necrosis factor (TNF) antagonists. Infections are strongly associated with IBD both in their etiopathogenesis and in their clinical course. A number of viral infections, tuberculosis and other therapy-related infections create challenges for the successful management of intestinal disease with immunosuppressive agents or TNF antagonists. Recently published guidelines offer a strong support to deal with these issues. Major concern about IBD patients with malignancies is related to the consequences of chemotherapy on the intestinal disease, the risk of maintaining immunosuppressant or anti-TNF therapy after the diagnosis of malignancy and the management of a clinical relapse of IBD in patients with a recent diagnosis of malignancy. Further research is required to optimize strategies for IBD patients with malignancies. At the moment, all therapeutic choice is made on an individual basis, with an integrative multidisciplinary approach.
Towards a Novel Molecular Classification of IBD
Authors: Vermeire Severine
Published: July 2012

Classifying IBD patients is important for decisions on the intensity of follow-up, therapy and mode of delivery. The most recent classification of Crohn’s disease (CD) and ulcerative colitis (UC), the Montreal classification, is based on clinical grounds: for CD, the age at diagnosis and disease location and behavior and for UC, the age at diagnosis and the extent of disease. During the Working Party in 2005 in Montreal, it was judged by the panel of experts that a molecular reclassification using serology and/or genetic markers was too premature and not yet justified. In the meanwhile, the number of genes associated with IBD has increased to >100 and more antimicrobial peptides have also been identified. We recently showed that genetic variants enable the classification of CD patients in distinct clusters, which is different from clusters seen in healthy individuals. Furthermore, there was a poor relationship between the genetic-based subgroups and the clinical subphenotypes being used. The promising role for molecular markers lies most likely in disease stratification, the prediction of prognosis at the time of diagnosis and the prediction of therapy outcome. The behavior of CD and UC varies between patients, and the characteristic transmural inflammation in CD – when untreated – will often progress and lead to stricture or fistula formation over time. Predicting which patients are at risk for progression to complications and how fast this occurs could have therapeutic implications, as more aggressive treatment strategies could become defendable in the appropriate patient. Genetic factors are definitively more appealing for risk stratification on more solid grounds. Molecular markers may also better explain changes in disease behavior from a pathogenic standpoint, and by combining several markers this strategy can approach clinical utility. Before starting to apply molecular markers to predict disease behaviors, tools should be made available to score disease progression. Only then could the value of molecular markers to predict the speed of progression be fully explored in prospective studies.
Early-Onset Schizophrenia1
Authors: Remschmidt Helmut , Theisen Frank
Published: July 2012

The available study findings on the course and outcome of schizophrenia beginning in childhood or adolescence can be summarized as follows. (1) Schizophrenic psychoses that arise before the age of 13 have a very poor prognosis. The disease usually continues to progress in adolescence and adulthood. It can be diagnosed with the same criteria that are used for adults. (2) Patients whose disease is of acute onset, with productive schizophrenic manifestations such as hallucinations and delusions (positive manifestations), have a better prognosis than those whose disease begins insidiously and takes an unfavorable course, with depressive states and continually worsening impairment of cognitive function. (3) The patient’s premorbid personality plays a major role. Patients who were described as socially active, intelligent, and integrated children and adolescents before they became ill have a better prognosis than those who were intellectually impaired, timid, introverted and uncommunicative before they became ill. (4) The prognosis seems to be better for patients who have no family history of schizophrenia, those whose families cooperate well, and those whose condition improves rapidly during inpatient treatment. (5) The few available studies on the course and outcome of schizophrenia beginning in childhood and early adolescence confirm that they are much worse than in adult-onset schizophrenia. (6) A 42-year longitudinal study of patients with childhood-onset schizophrenia revealed their suicide rate to be higher than that of patients with adult-onset schizophrenia. No further longitudinal studies are available to confirm this finding.
Immunomodulatory Effect of Sertraline in a Rat Model of Rheumatoid Arthritis
Authors: Baharav Ehud , Bar Meytal , Taler Michal , Gil-Ad Irit , Karp Leon , Weinberger Abraham , Weizman Avraham
Published: July 2012

Objective: Previous studies suggest that selective serotonin reuptake inhibitors (SSRIs) modulate immune system functionality. SSRIs are the preferred treatment for major depressive disorder (MDD). A high rate of MDD is observed in rheumatoid arthritis (RA) patients. The aim of this study was to evaluate immunological effects of SSRIs in a rat model of RA. Methods: Adjuvant arthritis was induced in 8-week-old Lewis rats; in the first set of experiments following the induction, 15.3 or 30.6 mg/kg of sertraline was daily injected into the ankle joint of the left rear leg. Clinical disease activity was evaluated and the findings compared with the 3 untreated legs and with control groups given methotrexate (MTX) or vehicle only at the same site. In a second set of experiments, the effect of 5, 25 and 50 mg/kg daily oral sertraline was evaluated in the same rat model. Splenocyte viability and inflammatory mediators were evaluated. Results: The sertraline-treated rats showed a significant reduction in clinical arthritis compared to controls, at all doses given, accompanied by a significant increase in interleukin 10 and a decrease in tumor necrosis factor-α levels and cycloxygenase-2 production, without lymphotoxicity. There was no significant difference from MTX, the first-line treatment for RA patients. Oral sertraline had a significant anti-inflammatory effect at all doses. There was no treatment × time effect. Conclusion: The beneficial effects of sertraline in this rat model of arthritis have clinical implications for its use in humans. Large-scale clinical efficacy trials are needed.