bluuebunny/crossref_metadata_2025 huggingface dataset:
Infantile Scurvy: Two Case Reports
Authors: Ghedira Besbes Leila , Haddad Samir , Ben Meriem Chebil , Golli Mondher , Najjar Mohamed-fadhel , Guediche Mohamed-Néji
Published: September 2010

Background. Ascorbic acid (vitamin C) is necessary for the formation of collagen, reducing free radicals, and aiding in iron absorption. SCURVY, a disease of dietary ascorbic acid deficiency, is uncommon today. It still exists in high risk groups including economically disadvantaged populations with poor nutrition. The incidence of SCURVY in the pediatric population is very low.Cases Report. Here we report two cases of SCURVY revealed by subperiosteal hematoma in children with cerebral palsy and developmental delay.Conclusion. SCURVY is extremely rare in children. Musculoskeletal manifestations are prominent in pediatric SCURVY. Multiple subperiosteal hematomas are an important indicator for diagnosis.
The S-Layer Glycoprotein of the CrenarchaeoteSulfolobus acidocaldariusIs Glycosylated at Multiple Sites with Chitobiose-LinkedN-Glycans
Authors: Peyfoon Elham , Meyer Benjamin , Hitchen Paul G. , Panico Maria , Morris Howard R. , Haslam Stuart M. , Albers Sonja-Verena , Dell Anne
Published: September 2010

Glycosylation of the S-layer of the crenarchaeaSulfolobus acidocaldariushas been investigated using glycoproteomic methodologies. The mature protein is predicted to contain 31 N-glycosylation consensus sites with approximately one third being found in the C-terminal domain spanning residuesL1004-Q1395. Since this domain is rich in Lys and Arg and therefore relatively tractable to glycoproteomic analysis, this study has focused on mapping its N-glycosylation. Our analysis identified nine of the 11 consensus sequence sites, and all were found to be glycosylated. This constitutes a remarkably high glycosylation density in the C-terminal domain averaging one site for each stretch of 30–40 residues. Each of the glycosylation sites observed was shown to be modified with a heterogeneous family of glycans, with the largest having a composition Glc1Man2GlcNAc2plus 6-sulfoquinovose (QuiS), consistent with the tribranched hexasaccharide previously reported in the cytochromeb558/566ofS. acidocaldarius.S. acidocaldariusis the only archaeal species whose N-glycans are known to be linked via the chitobiose core disaccharide that characterises the N-linked glycans ofEukarya.
A Fixed Point Approach to the Stability of a General Mixed AQCQ‐Functional Equation in Non‐Archimedean Normed Spaces
Authors: Xu Tian Zhou , Rassias John Michael , Xu Wan Xin
Published: September 2010

Using the fixed point methods, we prove the generalized Hyers‐Ulam stability of the general mixed additive‐quadratic‐cubic‐quartic functional equation f(x + ky) + f(x − ky) = k2f(x + y) + k2f(x − y) + 2(1 − k2)f(x)+((k4 − k2)/12)[f(2y) + f(−2y) − 4f(y) − 4f(−y)] for a fixed integer k with k ≠ 0, ±1 in non‐Archimedean normed spaces.
Basal Cell Carcinomas in Gorlin Syndrome: A Review of 202 Patients
Authors: Jones Elizabeth A. , Sajid Mohammed Imran , Shenton Andrew , Evans D. Gareth
Published: September 2010

Gorlin syndrome (Naevoid Basal Cell Carcinoma Syndrome) is a rare autosomal dominant syndrome caused by mutations in thePTCHgene with a birth incidence of approximately 1 in 19,000. Patients develop multiple basal cell carcinomas of the skin frequently in early life and also have a predisposition to additional malignancies such as medulloblastoma. Gorlin Syndrome patients also have developmental defects such as bifid ribs and other complications such as jaw keratocysts. We studied the incidence and frequency of basal cell carcinomas in 202 Gorlin syndrome patients from 62 families and compared this to their gender and mutation type. Our data suggests that the incidence of basal cell carcinomas is equal between males and females and the mutation type cannot be used to predict disease burden.
Dietary Phenethyl Isothiocyanate Alters Gene Expression in Human Breast Cancer Cells
Authors: Moon Young Jin , Brazeau Daniel A. , Morris Marilyn E.
Published: September 2010

Phenethyl isothiocyanate (PEITC), a component in cruciferous vegetables, can block chemical carcinogenesis in animal models. Our objective was to determine the effect of treatment with PEITC on gene expression changes in MCF‐7 human breast cancer cells in order to evaluate potential mechanisms involved in its chemopreventive effects. MCF‐7 cells were treated for 48 hours with either PEITC (3 μM) or the vehicle. Total RNA was extracted from cell membrane preparations, and labeled cDNA′s representing the mRNA pool were reverse‐transcribed directly from total RNA isolated for use in the microarray hybridizations. Two specific human GE Array Kits (Superarray Inc.) that both contain 23 marker genes, related to signal transduction pathways or cancer/tumor suppression, plus 2 housekeeping genes (β‐actin and GAPDH), were utilized. Arrays from treated and control cells (n = 4 per group) were evaluated using a Student′s t‐test. Gene expression was significantly induced for tumor protein p53 (p53), cyclin‐dependent kinase inhibitor 1C (p57 Kip2), breast cancer Type 2 early onset (BRCA2), cAMP responsive element binding protein 2 (ATF‐2), interleukin 2 (IL‐2), heat shock 27 KD protein (hsp27), and CYP19 (aromatase). Induction of p57 Kip2, p53, BRCA2, IL‐2, and ATF‐2 would be expected to decrease cellular proliferation and increase tumor suppression and/or apoptosis. PEITC treatment produced significant alterations in some genes involved in tumor suppression and cellular proliferation/apoptosis that may be important in explaining the chemopreventive effects of PEITC.
Pseudo Almost‐Periodic Solution of Shunting Inhibitory Cellular Neural Networks with Delay
Authors: Wu Haihui
Published: September 2010

Shunting inhibitory cellular neural networks are studied. Some sufficient criteria are obtained for the existence and uniqueness of pseudo almost‐periodic solution of this system. Our results improve and generalize those of the previous studies. This is the first paper considering the pseudo almost‐periodic SICNNs. Furthermore, several methods are applied to establish sufficient criteria for the globally exponential stability of this system. The approaches are based on constructing suitable Lyapunov functionals and the well‐known Banach contraction mapping principle.
Black Tea and Theaflavins Assist Healing of Indomethacin‐Induced Gastric Ulceration in Mice by Antioxidative Action
Authors: Adhikary Biplab , Yadav Sudhir Kumar , Roy Kshama , Bandyopadhyay Sandip K. , Chattopadhyay Subrata
Published: September 2010

The healing activities of black tea (BT) and the theaflavins (TF) against the indomethacin‐induced stomach ulceration were studied in a mouse model. Indomethacin (18 mg/kg, p.o.) administration induced maximum ulceration in the glandular portion of the gastric mucosa on the 3rd day, accompanied by increased lipid peroxidation and protein oxidation, depletion of thiol‐defense and mucin, as well as reduced expressions of cyclooxygenases (COX) and prostaglandin (PG) E synthesis in the gastric tissues, and plasma total antioxidant status of mice. Treatment with BT (40 mg/kg), TF (1 mg/kg), and omeprazole (3 mg/kg) produced similar (74%–76%) ulcer healing, as revealed from the histopathological studies. Treatment with all the above samples reversed the adverse oxidative effects of indomethacin significantly. BT and TF also enhanced the PGE synthesis by augmenting the expressions of COX 1 and 2, but did not modulate acid secretion.
Comparison of Photopic Negative Response of Full-Field and Focal Electroretinograms in Detecting Glaucomatous Eyes
Authors: Machida Shigeki , Tamada Kunifusa , Oikawa Taku , Gotoh Yasutaka , Nishimura Tomoharu , Kaneko Muneyoshi , Kurosaka Daijiro
Published: September 2010

Purpose. To compare the photopic negative response (PhNR) of the full-field electroretinogram (ERG) to the PhNR of the focal ERGs in detecting glaucoma.Methods. One hundred and three eyes with glaucoma and 42 normal eyes were studied. Full-field ERGs were elicited by red stimuli on a blue background. The focal ERGs were elicited by a15∘white stimulus spot centered on the macula, the superotemporal or the inferotemporal areas of the macula.Results. In early glaucoma, the areas under the receiver operating characteristic curves (AUCs) were significantly larger for the focal PhNR (0.863–0.924) than those for the full-field PhNR (0.666–0.748) (P<.05). The sensitivity was significantly higher for the focal PhNR than for the full-field PhNR in early (P<.01) and intermediate glaucoma (P<.05). In advanced glaucoma, there was no difference in the AUCs and sensitivities between the focal and full-field PhNRs.Conclusions. The focal ERG has the diagnostic ability with higher sensitivity in detecting early and intermediate glaucoma than the full-field ERG.
Quercetin and Bornyl Acetate Regulate T‐Lymphocyte Subsets and INF‐γ/IL‐4 Ratio In Utero in Pregnant Mice
Authors: Wang Xiaodan , Ma Aituan , Shi Wanyu , Geng Meiying , Zhong Xiuhui , Zhao Yantao
Published: September 2010

The objective of this study is to investigate the antiabortive effects of Quercetin and Bornvl Acetate and their immunological modulation at maternal‐fetal interface. Lipopolysaccharide (LPS) was injected via tail vein to induce abortion in mice which received Quercetin and Bornvl Acetate at days 4–7 of gestation. Uterine CD4+/CD8+ T lymphocytes and IFN‐γ/IL‐4 of each group (n = 10) were detected by immunohistochemistry and enzyme‐linked immunosorbent assay, respectively. The ratio of CD4+/CD8+ increased significantly (P < .01) in the uterus of LPS‐induced abortion mice. In the Quercetin and Bornvl Acetate pretreated mice followed by LPS administration, the ratio of CD4+/CD8+ dropped to 0.562 ± 0.021, lower than that of LPS‐abortion group (P < .01). The mean value of IFN‐γ/IL‐4 in LPS‐treated mice was 0.310 ± 0.066, higher than that of Quercetin and Bornyl Acetate group. The results indicate that Quercetin and Bornyl Acetate have an antiabortive effect through modulation of immunological balance at maternal‐fetal interface.
Atoms and Nanoparticles of Transition Metals as Catalysts for Hydrogen Desorption from Magnesium Hydride
Authors: Bazzanella N. , Checchetto R. , Miotello A.
Published: September 2010

The hydrogen desorption kinetics of composite materials made of magnesium hydride with transition metal additives (TM: Nb, Fe, and Zr) was studied by several experimental techniques showing that (i) a few TM at.% concentrations catalyse the H2desorption process, (ii) the H2desorption kinetics results stabilized after a few H2sorption cycles when TM atoms aggregate by forming nanoclusters; (iii) the catalytic process occurs also at TM concentration as low as 0.06 at.% when TM atoms clustering is negligible, and (iv) mixed Fe and Zr additives produce faster H2desorption kinetics than single additive. The improved H2desorption kinetics of the composite materials can be explained by assuming that the interfaces between the MgH2matrix and the TM nanoclusters act as heterogeneous sites for the nucleation of the Mg phase in the MgH2matrix and promote the formation of fast diffusion channels for H migrating atoms.
Portable Filter-Based Microdevice for Detection and Characterization of Circulating Tumor Cells
Authors: Lin Henry K. , Zheng Siyang , Williams Anthony J. , Balic Marija , Groshen Susan , Scher Howard I. , Fleisher Martin , Stadler Walter , Datar Ram H. , Tai Yu-Chong , Cote Richard J.
Published: September 2010

Purpose: Sensitive detection and characterization of circulating tumor cells (CTC) could revolutionize the approach to patients with early-stage and metastatic cancer. The current methodologies have significant limitations, including limited capture efficiency and ability to characterize captured cells. Here, we report the development of a novel parylene membrane filter-based portable microdevice for size-based isolation with high recovery rate and direct on-chip characterization of captured CTC from human peripheral blood.

Experimental Design: We evaluated the sensitivity and efficiency of CTC capture in a model system using blood samples from healthy donors spiked with tumor cell lines. Fifty-nine model system samples were tested to determine the recovery rate of the microdevice. Moreover, 10 model system samples and 57 blood samples from cancer patients were subjected to both membrane microfilter device and CellSearch platform enumeration for direct comparison.

Results: Using the model system, the microdevice achieved >90% recovery with probability of 95% recovering at least one cell when five are seeded in 7.5 mL of blood. CTCs were identified in 51 of 57 patients using the microdevice, compared with only 26 patients with the CellSearch method. When CTCs were detected by both methods, greater numbers were recovered by the microfilter device in all but five patients.

Conclusions: This filter-based microdevice is both a capture and analysis platform, capable of multiplexed imaging and genetic analysis. The microdevice presented here has the potential to enable routine CTC analysis in the clinical setting for the effective management of cancer patients. Clin Cancer Res; 16(20); 5011–8. ©2010 AACR.
Vaccination of Metastatic Renal Cancer Patients with MVA-5T4: A Randomized, Double-Blind, Placebo-Controlled Phase III Study
Authors: Amato Robert J. , Hawkins Robert E. , Kaufman Howard L. , Thompson John A. , Tomczak Piotr , Szczylik Cezary , McDonald Mike , Eastty Sarah , Shingler William H. , de Belin Jackie , Goonewardena Madusha , Naylor Stuart , Harrop Richard
Published: September 2010

Purpose: The TroVax Renal Immunotherapy Survival Trial was a randomized, placebo-controlled phase III study that investigated whether modified vaccinia Ankara encoding the tumor antigen 5T4 (MVA-5T4) prolonged survival of patients receiving first-line standard-of-care (SOC) treatment for metastatic renal cell cancer.

Experimental Design: Patients with metastatic clear cell renal cancer, prior nephrectomy, and good or intermediate prognosis were randomized 1:1 to receive up to 13 immunizations of MVA-5T4/placebo in combination with either sunitinib, interleukin-2 or interferon-α. The primary end point was overall survival. Secondary end points included progression-free survival, overall response rate, and safety.

Results: Seven hundred thirty-three patients were recruited (365 MVA-5T4 and 368 placebo). Treatment arms were well balanced for SOC and prognosis. No significant difference in the incidence of adverse events or serious adverse events was observed. No significant difference in overall survival was evident in the two treatment arms (median 20.1 months MVA-5T4 versus 19.2 months placebo; P = 0.55). The magnitude of the 5T4-specific antibody response induced by vaccination with MVA-5T4 was associated with enhanced patient survival. Furthermore, exploratory analyses suggested a number of pretreatment hematologic factors that could identify patients who derive significant benefit from this vaccine.

Conclusion: MVA-5T4 in combination with SOC was well tolerated, but no difference in survival was observed in the overall study population. Exploratory analyses indicate that there may be subsets of patients who could gain significant benefit from MVA-5T4, but such results would need to be confirmed in future randomized clinical studies. Clin Cancer Res; 16(22); 5539–47. ©2010 AACR.
Expression of Noncoding Vault RNA in Human Malignant Cells and Its Importance in Mitoxantrone Resistance
Authors: Gopinath Subash C.B. , Wadhwa Renu , Kumar Penmetcha K.R.
Published: September 2010

Several noncoding RNAs do vital cellular functions, including gene regulation and cell differentiation. Previously, we reported that vault RNA (vRNA) has the ability to recognize chemotherapeutic compounds, such as mitoxantrone, based on biophysical and biochemical analyses. In the present study, we show that human glioblastoma-, leukemia-, and osteocarcinoma-derived cell lines overexpress vRNA and exhibit higher resistance toward mitoxantrone. Interestingly, when vRNA expression was suppressed by RNA interference in these cells, the resistance progressively decreased. In agreement with these findings, overexpression of vRNA-1 caused resistance to mitoxantrone. These results suggest a role of vRNA in mitoxantrone resistance in malignant cells and justify further studies on the importance and application of noncoding RNAs in cancer chemotherapeutics. Mol Cancer Res; 8(11); 1536–46. ©2010 AACR.
Loss of Inositol Polyphosphate 5-Phosphatase Is an Early Event in Development of Cutaneous Squamous Cell Carcinoma
Authors: Sekulic Aleksandar , Kim Su Y. , Hostetter Galen , Savage Stephanie , Einspahr Janine G. , Prasad Anil , Sagerman Paul , Curiel-Lewandrowski Clara , Krouse Robert , Bowden G. Timothy , Warneke James , Alberts David S. , Pittelkow Mark R. , DiCaudo David , Nickoloff Brian J. , Trent Jeffrey M. , Bittner Michael
Published: September 2010

Cutaneous squamous cell carcinoma (SCC) occurs commonly and can metastasize. Identification of specific molecular aberrations and mechanisms underlying the development and progression of cutaneous SCC may lead to better prognostic and therapeutic approaches and more effective chemoprevention strategies. To identify genetic changes associated with early stages of cutaneous SCC development, we analyzed a series of 40 archived skin tissues ranging from normal skin to invasive SCC. Using high-resolution array-based comparative genomic hybridization, we identified deletions of a region on chromosome 10q harboring the INPP5A gene in 24% of examined SCC tumors. Subsequent validation by immunohistochemistry on an independent sample set of 71 SCC tissues showed reduced INPP5A protein levels in 72% of primary SCC tumors. Decrease in INPP5A protein levels seems to be an early event in SCC development, as it also is observed in 9 of 26 (35%) examined actinic keratoses, the earliest stage in SCC development. Importantly, further reduction of INPP5A levels is seen in a subset of SCC patients as the tumor progresses from primary to metastatic stage. The observed frequency and pattern of loss indicate that INPP5A, a negative regulator of inositol signaling, may play a role in development and progression of cutaneous SCC tumors. Cancer Prev Res; 3(10); 1277–83. ©2010 AACR.
Stem Cell Therapy for Myocardial Infarction: Are We Missing Time?
Authors: ter Horst Kasper W.
Published: September 2010

The success of stem cell therapy in myocardial infarction (MI) is modest, and for stem cell therapy to be clinically effective fine-tuning in regard to timing, dosing, and the route of administration is required. Experimental studies suggest the existence of a temporal window of opportunity bound by the acute inflammatory response on one hand and by scar formation on the other. In the meantime, microenvironmental factors must favor stem cell homing, survival, differentiation, and integration for stem cell therapy to be effective. Clinical data on the optimal timing of treatment are scarce. Experimental studies and clinical subgroup analyses can provide a clue and useful guidance for further research. In this review, the fundamental mechanisms as well as trial results important for the determination of the optimal timing of stem cell therapy following MI are summarized and discussed. We conclude that optimization of stem cell therapy requires further research on the fundamental mechanisms responsible for stem cell homing, survival, differentiation, and integration. Clinically, randomized trials with bone-marrow-derived stem cells should be conducted timing therapy at different points within the first month after MI, which seems to be the most promising period for this cell type.
Cellular Scaling Rules for Primate Spinal Cords
Authors: Burish Mark J. , Peebles J. Klint , Baldwin Mary K. , Tavares Luciano , Kaas Jon H. , Herculano-Houzel Suzana
Published: September 2010

The spinal cord can be considered a major sensorimotor interface between the body and the brain. How does the spinal cord scale with body and brain mass, and how are its numbers of neurons related to the number of neurons in the brain across species of different body and brain sizes? Here we determine the cellular composition of the spinal cord in eight primate species and find that its number of neurons varies as a linear function of cord length, and accompanies body mass raised to an exponent close to 1/3. This relationship suggests that the extension, mass and number of neurons that compose the spinal cord are related to body length, rather than to body mass or surface. Moreover, we show that although brain mass increases linearly with cord mass, the number of neurons in the brain increases with the number of neurons in the spinal cord raised to the power of 1.7. This faster addition of neurons to the brain than to the spinal cord is consistent with current views on how larger brains add complexity to the processing of environmental and somatic information.
Early Improvement in Peripheral Vascular Tone following Smoking Cessation Using Nicotine Replacement Therapy: Aortic Wave Reflection Analysis
Authors: Roux Antoine , Motreff Pascal , Perriot Jean , Pereira Bruno , Lusson Jean-René , Duale Christian , Morand Dominique , Dubray Claude
Published: September 2010

Objectives: Cigarette smoking induces cardiovascular pathology and worsens arterial stiffness. Arterial stiffness can be assessed noninvasively based on 2 indices: pulse-wave velocity (PWV), indicating aortic stiffness, and the augmentation index (AIx), indicating aortic wave reflection. The impact of smoking cessation (SC) with nicotine replacement therapies (NRT) on arterial stiffness remains unknown. Methods: AIx and PWV were studied prospectively (using a SphygmoCor system) in 26 long-term smokers (>10 cigarettes/day; mean age 43 ± 6 years) before (visit 1) and 28 and 56 days (visit 2 and visit 3) after SC supported by NRT. Abstinence was ascertained when exhaled carbon monoxide (CO) was <10 ppm; the quantity of NRT absorbed was assessed based on the serum cotinine level. Results: Sixteen of 24 patients (67%) were abstinent at the end of the study; 8/24 had cut down on smoking, and 2 were lost to follow-up. CO and serum cotinine levels fell after SC. The mean AIx for the population as a whole was 23.4% at visit 1, with a significant early reduction by visit 2 (16.2%) and visit 3 (13.9%) (ANOVA, p < 0.001). The PWV, peripheral blood pressure, and heart rate were unchanged. Conclusions: The improvement in AIx and the stability of PWV after SC with NRT indicate improved peripheral vascular tone. This impact may account for the early clinical benefit of SC observed even when associated with NRT.
A Rare Instance of Multiple Valvular Lesions in a Patient with Wegener’s Granulomatosis
Authors: Koyalakonda Shiva Prasad , Krishnan Unni , Hobbs William Julian
Published: September 2010

Wegener’s granulomatosis (WG) is a systemic necrotising vasculitis involving the respiratory and renal tracts. Dual valvular involvement in WG is uncommon. We describe a 52-year-old patient with aortic regurgitation and mitral stenosis due to WG requiring replacement of both valves. We also discuss a strategy for follow-up of asymptomatic WG patients with suspected heart valve involvement.
Avian Influenza: Update
Authors: Adams Sean , Sandrock Christian
Published: September 2010

Avian influenza is an important zoonotic disease that has become endemic in Southeast Asia and in the case of highly pathogenic H5N1 has caused significant human mortality and morbidity. Avian influenza virus (AIV) infections may be asymptomatic or present as mild conjunctivitis in humans; however, H5N1 infections may present as severe pneumonia progressing to acute respiratory disease syndrome, multiorgan dysfunction syndrome and death. Since 2003, there have been a total of 436 cases and 262 deaths due to H5N1 infections. The number of cases has decreased steadily since 2006; however, the emergence of multiple genetically distinct sublineages of H5N1 has continued. These emerging sublineages display varying levels of drug resistance and in some cases an increased preference for binding to human α2,6-linked sialic acid cellular receptors. Though H5N1 has not shown efficient transmissibility between humans, the rapid evolution of the virus presents a concern for the emergence of a virus with this capability. Here we review the epidemiology, host range, clinical features, prophylaxis and treatment options, and preventative measures recommended for AIV with an emphasis on H5N1.
Relationship between Reactive Oxygen Metabolites and Carotid Intima-Media Thickness in Subjects with Hypercholesterolemia
Authors: Kotani Kazuhiko , Koibuchi Harumi , Miyamoto Michiaki , Yamada Toshiyuki , Taniguchi Nobuyuki
Published: September 2010

Objective: It was the aim of this study to investigate whether there is any relationship between oxidative stress, as assessed by the diacron reactive oxygen metabolite (d-ROM) test, and carotid atherosclerosis among hypercholesterolemic patients. Subjects and Methods: A well-defined group of patients with type II hypercholesterolemia (n = 81, mean age 59 years) was studied to observe the correlation between the levels of serum d-ROMs and carotid artery intima-media thickness (IMT) using B-mode ultrasound, in relation to the traditional atherosclerotic risk factors (age, sex, smoking, body mass index, blood pressure, glucose and lipid panels). Results: The mean level in low-density lipoprotein cholesterol (LDL-C) in this population was 4.45 mmol/l, d-ROMs were 323.2 Carr U, and IMT was 0.91 mm. A multiple regression analysis revealed a positive and significant correlation between IMT and d-ROMs (β = 0.27, p < 0.05), along with age and LDL-C. Conclusion: These results indicate that the increased oxidative stress levels using the d-ROM test, independent of aging and increased LDL-C levels, may be associated with carotid atherosclerosis even in hypercholesterolemic patients.
Genes and Environment: How Will Our Concepts on the Pathophysiology of IBD Develop in the Future?
Authors: Kaser Arthur , Zeissig Sebastian , Blumberg Richard S.
Published: September 2010

Inflammatory bowel disease (IBD) has long been known to arise from the interplay between host and environmental factors. From this, a picture is currently emerging in which IBD is likely the result of a continuum of diseases that range from mono- and oligogenically inherited familial forms at one extreme to sporadic forms at the other extreme, which are polygenic in origin and strongly influenced by environmental factors and especially those of infectious origin. The recent expansion of knowledge on the genetic underpinning of IBD has revealed several converging and inter-related functional host pathways that are central to the pathogenesis of these disorders. These include pathways such as autophagy, intracellular bacterial sensing and the unfolded protein response, which play specific roles at the interface between the host and the highly complex microbial communities within the intestines. As such they focus on the functional relationship between the intestinal epithelium and the unique microbial and immune environments along its luminal and abluminal surfaces. Thus, the genetic and environmental factors which are relevant to IBD seem to have the common property of influencing disease by virtue of their specific impact upon the functional relationship between these microbial communities and the intestinal immune system.
New Insights into IBD Epidemiology: Are There Any Lessons for Treatment?
Authors: Bernstein Charles N.
Published: September 2010

Changing trends in the epidemiology of IBD provide an opportunity to examine possible etiological hypotheses. Why did IBD emerge in developed nations in the middle of the 20th century? Why did it emerge initially as ulcerative colitis but now Crohn’s disease has become the predominate form of IBD in developed nations? Why is IBD emerging in recent years in developing nations and why is it that ulcerative colitis is the predominate form in these countries? In this chapter we will explore what is known about environmental issues that impact on disease presentation and where they provide opportunities for therapy. Managing smoking cessation in Crohn’s disease is substantiated by evidence showing that smokers have a worse course of disease than non-smokers or than persons who quit smoking. Introducing nicotine to patients with ulcerative colitis has not brought the positive results anticipated with the widespread observation that smoking cessation was associated with flaring of this disease. Assessing and managing stress in both Crohn’s disease and ulcerative colitis has emerged as an important consideration for clinicians caring for patients with IBD, especially for patients with active disease who may develop maladaptive coping mechanisms. Recent data suggest that stress may antedate flares. It is unknown what may induce changes in the gut flora of patients with IBD compared to controls. There are suggestions that antibiotic use in childhood and specific diets particularly those lower in ω-3 fatty acids may impact on disease presentation and the common mechanism may be through alteration of gut flora. For at-risk families (where there are affected family members) perhaps greater vigilance with antibiotic use in childhood and ensuring diets are higher in ω-3 fatty acids can be considered. In the future there may be approaches to modulate gut flora either with antibiotics targeted against identified noxious microbes or with selective probiotics that can rebalance the gut dysbiosis.
Smoking, Physical Activity, Nutrition and Lifestyle: Environmental Factors and Their Impact on IBD
Authors: Cosnes Jacques
Published: September 2010

Current smoking increases the risk of developing Crohn’s disease and worsens its course, increasing the need for steroids, immunosuppressants, and re-operations. On the contrary, smoking protects against ulcerative colitis and after disease onset improves its course, decreasing the need for colectomy. Smoking cessation improves Crohn’s disease and worsens ulcerative colitis. Achieving smoking cessation in Crohn’s disease is thus an important goal of therapy, whereas patients with ulcerative colitis should not be discouraged to quit, because the beneficial effect of smoking for their disease is counterbalanced by the deleterious respiratory and cardiovascular effects of tobacco. Physical activity improves quality of life without detrimental effect on disease activity, and may contribute to increase muscle mass and to prevent osteoporosis. Regarding nutrition, a Western diet may be associated with an increased risk of IBD, and a case-control study revealed an increased consumption of linoleic acid before diagnosis of ulcerative colitis. Liquid diets may improve Crohn’s disease flares and decrease the need for steroids; however, there are no defined diets able to improve the disease course, and in Crohn’s disease, supplementation with omega-3 fatty acids did not show a significant benefit. Obesity is becoming more prevalent in IBD and may be associated with higher disease activity. In total, adhering to four simple lifestyle factors – never smoking, physical activity, prudent diet and body mass index <25 – may have a strong impact both on the prevention of major chronic diseases and on the course of IBD.
MRI Enterography: The Future of Small Bowel Diagnostics?
Authors: Feuerbach S.
Published: September 2010

MRI plays an increasing role in small bowel imaging of Crohn’s disease. MR enterography (MRE) without nasojejunal intubation and radiation exposure offers similar results compared to MR enteroclysis (with intubation) and should be therefore the preferred method. Sensitivity and specificity is comparable to that of CT enterography. Capsule endoscopy is obviously superior to MRE in detecting superficial lesions, but this is limited to the mucosa and stenosis has to be excluded before examination using imaging, like MRE. There are no convincing studies in the literature regarding assessment of disease activity with imaging. Moreover, there is no consensus in the literature about a suitable reference standard.
Chromoendoscopy: What Is Its True Value for Ulcerative Colitis Surveillance?
Authors: Kiesslich Ralf
Published: September 2010

Advanced imaging technologies are enabling targeted biopsies or endoscopic resections due to better visualization of the mucosal architecture. This new concept of ‘smart biopsies’ is in particular important for patients with higher risk for development cancer (e.g. ulcerative colitis) but can also be beneficial for screening purposes. This short review will focus on new imaging modalities like chromoendoscopy, digital chromoendoscopy, high-definition endoscopy and confocal laser endomicroscopy in the lower GI tract which will be crucial in the future to detect colorectal neoplasia earlier then before.
Supportive Therapy in IBD: What Additional Diagnoses and Conditions Must Be Treated?
Authors: Swoger Jason M. , Binion David G.
Published: September 2010

Despite advances in our understanding of inflammatory bowel disease (IBD) pathogenesis and increased ability to treat patients with severe and refractory disease, patients continue to suffer from disease complications, and increasing numbers of both Crohn’s disease (CD) and ulcerative colitis (UC) patients are admitted annually in the USA. The rapid evolution in IBD medications and treatment paradigms has contributed to a disparity in clinical care which may vary between expert centers routinely treating large numbers of IBD patients and hospitals with low annual IBD admissions. High-volume centers handling in excess of 150 IBD annual admissions have improved operative and inpatient outcomes compared with hospitals caring for IBD patients less frequently. Although the precise reason for this disparity in clinical outcomes is not known, we hypothesize that expert centers provide superior IBD supportive therapy. This supportive care includes additional diagnostic and therapeutic approaches to help patients achieve optimal outcomes. We review information regarding disparities in the quality of IBD clinical care then focus on supportive therapy for IBD patients, including diagnostic approaches to identify confounding factors contributing to poor IBD outcome, supportive therapeutic approaches to optimize the outcome in hospitalized IBD patients, and future directions exploring brain-body interaction in the treatment of pain, stress and sleep deprivation in patients suffering from IBD.
What Is the Patient’s Perspective: How Important Are Patient-Reported Outcomes, Quality of Life and Disability?
Authors: Peyrin-Biroulet Laurent
Published: September 2010

Inflammatory bowel disease (IBD) is known to influence physical, psychological, familial and social dimensions of life. Over the past two decades, attention has been focused on the ability of IBD to alter patients’ quality of life. A number of general and disease-specific scales have been used to assess quality of life in patients with IBD. The Inflammatory Bowel Disease Questionnaire (IBDQ) is the most widely disease-specific tool used in clinical trials. Forty to fifty million individuals in the USA now live with potentially disabling conditions. Disability usually refers to an individual’s inability to perform a task successfully. Disability refers to the problems that are experienced in different areas or health domains, whereas quality of life refers to how the individual feels about these limitations and restrictions. Data about disability are objective descriptions that differ from subjective appraisals such as quality of life, well-being, and personal satisfaction with life. For instance, difficulties in walking (disability) may be in stark contrast to how the individual feels about this difficulty (quality of life). It should be emphasized that the concepts of health-related quality of life and disability are different but not mutually exclusive. When compared to quality of life, disability remains poorly investigated in IBD. Work is the only dimension of disability that has been widely assessed in IBD. Similar to multiple sclerosis and rheumatoid arthritis, developing a specific instrument capable of evaluating disability in IBD is a prerequisite to undertaking clinical trials aimed at identifying therapies capable of changing their clinical course.
Evolving Concepts in IBD Therapy: What Should Be Studied in the Future?
Authors: Schölmerich Jürgen
Published: September 2010

New knowledge regarding the etiopathophysiology of inflammatory bowel diseases (IBD) may provide new approaches for treatment. The most convincing concept at the moment is a defective mucosal barrier due to inappropriate recognition of the luminal flora or to a defective defense against those bacteria. These concepts indicate that the paradigm of immune suppression may not be the optimal concept. Therefore variable approaches to improve the barrier function or to modulate luminal components have to be studied in the future. This includes probiotics, bile acid receptor agonists, Toll-like receptor agonists and many other as yet hypothetical ideas. We still have much to learn about the concepts mentioned in order to achieve the goals of treatment, i.e. avoiding structural damage and complications.
New Keys to Maintenance Treatment in Ulcerative Colitis
Authors: Higgins Peter D.R.
Published: September 2010

Maintenance treatment in ulcerative colitis often fails to prevent flares and long term complications. The first key to maintenance is to use effective therapy, even when patients become asymptomatic. The second key is to communicate the importance of adherence to patients, and to help them achieve long term adherence. Simplified dosing schedules are of some benefit, but the bond between patient and doctor, and the patient’s belief in the efficacy of the therapy are essential. Decreased co-pays (a fixed amount paid by patients seeking care that is not reimbursed my medical insurance) have been associated with increased adherence, and incentives for patients may be a cost-effective approach to improving adherence. While the most substantial data on the association between adherence and clinical outcomes is in 5-ASAs, non-adherence can also limit the efficacy of thiopurines and biologics. The third key to maintenance treatment is monitoring and maintaining control of inflammation. Decreased histologic and endoscopic damage to the colon has been associated with decreased risk of colon cancer. The most cost-effective way to monitor smoldering inflammation is not known, but endoscopy, structured symptom indices, and biomarkers may be valuable approaches. The fourth key to maintenance treatment is optimizing immunomodulator therapy with thiopurines, and possibly methotrexate in the future. The fifth key to maintenance treatment in ulcerative colitis is maintaining biologic efficacy by avoiding low trough levels and being vigilant for subclinical inflammation and symptom recurrence at the end of dose intervals. Combination therapy with immunomodulators improves trough levels in Crohn’s, and may prove to have benefits for the maintenance of biologic efficacy in ulcerative colitis.
Phosphatidylcholine (Lecithin) and the Mucus Layer: Evidence of Therapeutic Efficacy in Ulcerative Colitis?
Authors: Stremmel Wolfgang , Hanemann Anja , Ehehalt Robert , Karner Max , Braun Annika
Published: September 2010

Colonic mucus protects against attacks from bacteria in stool. One component of mucus is phosphatidylcholine (PC) which is thought to be arranged as continuous lamellar layer in the apical mucus and to be responsible for establishing a protective hydrophobic surface. This ‘intestinal surfactant’ plays a key role in mucosal defense. Thus, a defective PC layer contributes to the development of inflammation. Analysis of rectoscopically acquired mucus aliquots revealed a 70% decrease in PC content in ulcerative colitis (UC) compared to Crohn´s disease (CD) and healthy controls – independent of disease activity. Accordingly, we propose that lack of mucus PC is a key pathogenetic factor in UC. In clinical studies a delayed-release oral PC preparation (rPC) was found to substitute the lack of PC in rectal mucus. Indeed, in non-steroid-treated active UC, 53% of rPC patients reached remission [clinical activity index (CAI) ≤3] compared to 10% of placebo patients (p ≤ 0.001). Endoscopic and histologic findings improved concomitantly. A second trial with 60 chronic-active, steroid-dependent UC patients was conducted to test for steroid-sparing effects. Complete steroid withdrawal with a concomitant achievement of remission (CAI ≤3) or clinical response (≧50% CAI improvement) was reached in 15 PC-treated patients (50%) but only in 3 (10%) placebo patients (p = 0.002). In conclusion, intrinsic reduction of PC (lecithin) in colonic mucus may be a key pathogenetic feature of UC. Topical supplement of PC by a delayed-released oral PC preparation is effective in resolving inflammatory activity of UC and may develop to a first-choice therapy for this disease.
Timing and Indications for Colectomy in Chronic Ulcerative Colitis: Surgical Consideration
Authors: Cima Robert R.
Published: September 2010

Total proctocolectomy (TPC) cures a patient of the intestinal manifestation of chronic ulcerative colitis. The timing of surgery during the illness will influence the choice of operation, the frequency of post-operative complications, and the long-term functional outcomes. Surgery is divided into emergency, urgent, and elective procedures. Emergency cases are performed for complications of fulminant colitis: hemorrhage, perforation, toxic megacolon or sepsis. A subtotal colectomy (STC) with a Brooke ileostomy (BI) is the procedure of choice. STC removes the bulk of the disease, allows the patient’s health to be restored, medication to be withdrawn, and permits a future restorative operation. Urgent operations occur in hospitalized patients with continued symptoms after seven days of maximal medical therapy. Once again the preferred operation is a STC-BI. Indications for elective colectomy include: persistent symptoms despite maximal medical therapy, medication side-effects, persistent chronic disease state, dysplasia/malignancy. Elective surgical options include TPC-BI, TPC with ileal-pouch anal anastomosis (IPAA), or STC-BI. The choice of operation is based upon patient preference and preoperative physiologic and functional status. Factors associated with increased post-operative complications are weight loss >10%, multiple preoperative blood transfusions, albumin <3.0 gm/dl, and degree of immuno-suppression. In high-risk patients, STC-BI should be performed. IPAA can be performed later after the patient’s health is restored. In conclusion, numerous factors affect the timing and choice of operation in patients with CUC. Avoiding complications in IPAA patients is essential as they negatively impact the long-term function and durability of the IPAA.
Hepatotoxicity of Agents Used in the Management of Inflammatory Bowel Disease
Authors: Khokhar Omar S. , Lewis James H.
Published: September 2010

Patients with inflammatory bowel disease (IBD) are at risk for hepatobiliary disease and toxicity, and the diagnosis of drug-induced liver disease in patients being treated for IBD can represent a clinical challenge. There are a number of disease states associated with IBD, which are primary sclerosing cholangitis, cholangiocarcinoma and autoimmune hepatitis. There is a wide spectrum of hepatic injury that can occur from the agents used to treat IBD, such as acute or chronic hepatic injury directly attributable to the drugs used to treat IBD (e.g. sulfasalazine, mesalamine, thiopurines, methotrexate, TNF antagonists, quinolone antibiotics); liver toxicity from drugs used to treat complications of immunomodulators and TNF antagonists (e.g. isoniazid for treatment of reactivation tuberculosis), and exacerbation of underlying chronic viral hepatitis with infliximab and other TNF antagonists. Thiopurines are also associated with the development of hepatic vascular lesions, such as nodular regenerative hyperplasia and peliosis hepatic. In addition, biologics can be associated with the reactivation of underlying chronic viral hepatitis, mandating universal screening prior to initiation of TNF-alpha antagonist therapy.
Vaccines and Inflammatory Bowel Disease
Authors: Kotton Camille Nelson
Published: September 2010

Patients with inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, are at increased risk for infection due to both their underlying disease and the immunosuppressive therapy used to treat the disease. Numerous groups and papers support the routine vaccination of IBD patients, yet many opportunities to vaccinate this vulnerable population are missed. While immunogenicity may be somewhat attenuated, some protection is likely to be provided, especially when vaccination is performed during periods of reduced immunosuppression. Live viral vaccines should be avoided during periods of more intense immunosuppression; further specific guidance on this as well as information on individual vaccines is provided.
State-of-the-Art: Immunosuppression and Biologic Therapy
Authors: Sandborn William J.
Published: September 2010

Azathioprine and 6-mercaptopurine are orally administered immunosuppressive drugs which are effective for the treatment of Crohn’s disease and ulcerative colitis. Azathioprine is rapidly converted to 6-mercaptopurine after administration. 6-Mercaptopurine is then either converted to the putative active metabolites, the 6-thioguinine nucleotides, or inactivated by the enzyme xanthine oxidase to 6-thiouric acid or alternatively inactivated to 6-methylmercaptopurine by the enzyme thiopurine methyltransferase. Thiopurine methyltransferase activity is genetically determined, with one in 300 patients having low or absent enzyme activity, one in 10 patients having intermediate enzyme activity, and 9 in 10 patients having normal enzyme activity. Patients with intermediate or low thiopurine methyltransferase activity are at risk for early leukopenia. Higher erythrocyte 6-thioguinine nucleotide concentrations are associated with a greater likelihood of clinical response. Azathioprine is modestly effective for Crohn’s disease and ulcerative colitis. Toxicity associated with azathioprine includes infection and lymphoma. Anti-TNF therapy with infliximab, adalimumab, and certolizumab pegol is effective for induction and maintenance treatment of Crohn’s disease, and infliximab is effective for ulcerative colitis. Toxicity associated with anti-TNF therapy includes infection and lymphoma. Combination therapy with infliximab and azathioprine is more effective for inducing and maintaining steroid-free remission and mucosal healing then monotherapy with either drug alone. Strategies to reduce immunogenicity of anti-TNF agents include combination therapy with azathioprine and administration of a loading dose followed by systematic maintenance dosing. Higher serum trough concentrations of infliximab occur more frequently in patients receiving combination therapy with azathioprine and are associated with better clinical outcomes. Combination therapy is associated with an increased relative risk of opportunistic infection, but is not associated with an increased absolute risk of serious infection. Clinical practice should change such that combination therapy with an anti-TNF agent and azathioprine replace azathioprine in patients failing first line therapy with mesalamine and/or steroids.