bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural and Immunological Characterization of Recombinant Pan b 1, a Major Allergen of Northern Shrimp, Pandalus borealis
Authors: Myrset Heidi R. , Barletta Bianca , Di Felice Gabriella , Egaas Eliann , Dooper Maaike M.B.W.
Published: October 2012

Background: Shellfish allergy is one of the major causes of life-threatening allergic reactions to food. The shrimp species Pandalus borealis is the commercially most important coldwater shrimp species, and its protein extract is commonly used in shrimp allergy diagnostics. However, the DNA sequence of its major allergen, tropomyosin, designated Pan b 1, was not previously described. Our aim was to identify the cDNA sequence of Pan b 1 and to generate a recombinant protein with similar structure and allergenicity as the natural protein. Methods:P. borealis shrimps were caught in the Oslofjord (Norway). cDNA from Pan b 1 was generated, an N-terminal histidine tag was added, and the protein was expressed in Escherichia coli. The recombinant Pan b 1 was characterized by structural and IgE-binding studies and investigated further with basophil activation tests (BATs) and skin prick tests (SPTs) on Norwegian shrimp-allergic individuals. Results: The open reading frame encoded 284 amino acids that shared 97–100% identity with other shrimp tropomyosins. Mass spectroscopy of natural Pan b 1 confirmed the protein’s molecular mass and indicated the absence of posttranslational modifications. Circular dichroism spectroscopy revealed virtually identical spectra between recombinant and natural Pan b 1, which together with native PAGE and size exclusion chromatography results indicated a similar structure. Furthermore, immunoblot and ELISA studies as well as BATs and SPTs showed equivalent results of recombinant and natural Pan b 1. Conclusion: A recombinant tropomyosin from P. borealis was generated that can be used in diagnostics and further studies on tropomyosin allergenicity and specific immunotherapy.
Flexible Cystoscope for Evaluating Pelvic Fracture Urethral Distraction Defects
Authors: Li Xu , Sa Ying Long , Xu Yue Min , Fu Qiang , Zhang Jiong
Published: October 2012

Objective: To describe the value of flexible cystoscopy versus conventional urethrography (retrograde urethrography and cystourethrography) in diagnosing pelvic fracture urethral distraction defects (PFUDDs). Patients and Methods: Between May 2010 and June 2011, 120 male patients with PFUDDs were evaluated. In this study, all patients underwent conventional urethrography after admission. Flexible cystoscopy was also used for comparison, followed by conventional urethrography. The flexible cystoscope was introduced into the posterior urethra and the area was evaluated for the length of the proximal urethra and any possible fistulas, false passages, calculi or displacement of the posterior urethra. Results: Severe allergic reaction or obvious discomfort did not occur in any patients after conventional urethrography or flexible cystoscopy. By comparing the data obtained from flexible cystoscopy to those from conventional urethrography, no statistical difference was found in the measured length of the proximal posterior urethra (4.31 ± 2.28 vs. 4.02 ± 3.12, p > 0.05). However, the rate of detection in other abnormalities was higher in flexible cystoscopy than in conventional urethrography (48.3 vs. 10.8%, p < 0.05). Seventeen (14.2%), 9 (7.5%) and 32 (26.7%) patients were detected with fistula, false passage and calculus, respectively, according to flexible cystoscopy. In comparison, fistula, false passage and calculus were only observed in 2 (1.7%), 7 (5.8%) and 4 (3.3%) patients, respectively, through conventional urethrography imaging. Conclusions: Flexible cystoscopy is a valuable procedure in the evaluation of the posterior urethra and bladder neck, and in patients with urethral distraction defects before surgery. More details about fistulas, false passages, calculi and urethral defects could be obtained through this method.
Overweight is Associated with Airflow Obstruction and Poor Disease Control but Not with Exhaled Nitric Oxide Change in an Asthmatic Population
Authors: Pisi Roberta , Aiello Marina , Tzani Panagiota , Marangio Emilio , Olivieri Dario , Pisi Giovanna , Chetta Alfredo
Published: October 2012

Background: The role of an elevated body mass index (BMI) in asthma remains controversial. Objectives: To investigate the relationship between overweight (BMI >25 and ≤30), lung function, disease control, and airway inflammation in an asthmatic population. Methods: We consecutively studied 348 patients (age 43 ± 16 years; 211 females). In all patients, BMI, spirometry, the Asthma Control Test (ACT), and fractional exhaled nitric oxide (FeNO; ppb) were measured. Results: One hundred forty-five patients were overweight and, as compared to those with normal BMI, had lower values of FVC, FEV1, and FEV1/FVC and of FEF25–75 even when normalized for FVC (p < 0.05 for each comparison). The ratio between the number of patients with well-controlled asthma (ACT ≥20) and that of patients with poorly controlled asthma (ACT < 20) was significantly lower in overweight patients (1.07 vs. 1.84; χ2 = 6.030, p < 0.01). In overweight patients, the odds ratio of uncontrolled asthma expressed by logistic regression analysis was 1.632 (95% CI = 1.043–2.553), independently of gender, atopy, smoking habit, and inhaled steroid therapy. No difference was observed in FeNO values between overweight and normal weight patients (27.7 ± 2.3 vs. 27.9 ± 2.2 ppb). Conclusions: Our results show that, in an asthmatic population, overweight is associated with airflow obstruction and poor disease control but not with FeNO change. The findings of the present study support the view that other factors besides airway inflammation alone may explain the relationship between asthma and an elevated BMI.
Autoimmune Hepatitis: New Guidelines, New Therapies
Authors: Strassburg Christian P.
Published: October 2012

Autoimmune hepatitis (AIH) was the first chronic liver disease which responded favorably to drug therapy. It has a dismal prognosis when not treated. Since the original description in 1950 by Waldenström the treatment option initially reported is still practiced today and is the core of the basic therapeutic strategy of inducing remission with steroids and azathioprine. It is important to establish the diagnosis before cirrhosis develops. Later, the avoidance of immunosuppressant side effects, nonresponders to standard induction therapy, and adherence to therapy are among the greatest challenges in treating AIH. Alternative immunosuppressive drugs have been tested in small series and have included commonly used transplant immunosuppressants, albeit with mixed results and many unwanted drug side effects. A recent large multicenter prospective treatment trial suggests that budesonide may offer an alternative in noncirrhotic AIH patients capable of minimizing unwanted steroid effects. The ultimate treatment approach upon drug treatment failure is liver transplantation. Only 4% of transplant candidates are transplanted for AIH. After liver transplantation, there is a considerable risk for graft loss because of recurrent AIH, and lifelong vigilance and therapeutic attention is important.
What Is New in Primary Biliary Cirrhosis?
Authors: Bogdanos Dimitrios P. , Gershwin M. Eric
Published: October 2012

Primary biliary cirrhosis is a chronic cholestatic liver disease characterized by immune-mediated destruction of the small- and medium-sized intrahepatic bile ducts. The disease mainly affects middle-aged women who frequently suffer from concomitant autoimmune diseases. This review discusses the most recent findings in the epidemiology, natural history and approaches used for the accurate diagnosis of the disease. We critically review emerging data reporting on the role of genetics such as those of genome-wide association studies. Special attention is given to recent studies reporting on the immunopathogenesis of the disease and the role of plasma cells, apotopes, immunosenescence, autophagy and the involvement of components of the innate immunity in the induction of this enigmatic disease.
Primary Sclerosing Cholangitis: New Approaches to Diagnosis, Surveillance and Treatment
Authors: Trauner Michael , Halilbasic Emina , Baghdasaryan Anna , Moustafa Tarek , Krones Elisabeth , Fickert Peter , Hofer Harald , Penner Edward
Published: October 2012

Primary sclerosing cholangitis (PSC) is a chronic inflammatory bile duct disease of unknown etiology, frequently associated with inflammatory bowel disease and leading to end-stage liver disease requiring liver transplantation. Moreover, PSC is a premalignant condition associated with an increased risk for hepatobiliary and colorectal malignancy. Since effective medical therapy for PSC is still lacking, this disorder represents a potentially fatal disease with poor prognosis. This article is a summary of an overview given at the 5th Falk Gastro Conference in Munich 2012 and reviews the challenges associated with diagnosis, surveillance and therapy of PSC.
Innate Immunity and Alcoholic Liver Disease
Authors: Szabo Gyongyi , Petrasek Jan , Bala Shashi
Published: October 2012

Innate immunity provides the primary response to danger signals from pathogens or injured host cells and tissues. The cells of the innate immune system include monocytes, macrophages, dendritic cells, neutrophils, NK cells and NKT cells that orchestrate innate immune and initiate adaptive immune responses via cell interactions, cytokines, chemokines and other mediators. The most robust and common response of the innate immune system to danger signals is inflammation. In the multifactorial pathophysiology of alcoholic liver disease (ALD), activation of innate immune cells and the inflammatory cascade play a central role. Recent studies have demonstrated that Toll-like receptors (TLRs), the sensors of microbial and endogenous danger signals, are expressed and activated in innate immune cells as well as in parenchymal cells in the liver, and thereby contribute to ALD. The importance of gut-derived endotoxin and its recognition by TLR4 expressed on innate immune cells and liver parenchymal cells and the specificity of TLR4-induced downstream signaling via the interferon regulator factor 3 (IRF3) has recently been investigated. We have shown that mice deficient in IRF3 or TLR4 expression are protected from alcohol-induced liver steatosis, inflammation and hepatocyte injury. In addition to pathogen-derived danger molecules, the inflammatory cascade can also be activated by endogenous danger signals released from damaged cells. The inflammasome, a multiprotein complex, senses endogenous danger molecules to result in caspase-1-mediated cleavage of IL-1β. Our recent results suggest that inflammasome and caspase-1 activation occur in ALD and that IL-1 significantly contributes to both steatosis and inflammation in the liver in ALD.
Nonalcoholic Fatty Liver Disease: What the Pathologist Can Tell the Clinician
Authors: Brunt Elizabeth M.
Published: October 2012

Liver biopsy evaluation continues to serve a significant, often primary, role in clinical care, as well as in fundamental aspects of investigation in nonalcoholic fatty liver disease (NAFLD). This is a review of the major features of liver pathology in NAFLD and specifically what role liver biopsy continues to play in both clinical management and scientific investigation. Diagnostic criteria for NAFLD and nonalcoholic steatohepatitis in adults and children are discussed, as are other histologic features that may be encountered. Histologic features for diagnostic classification(s) of NAFLD and semiquantitative methods of assessment are reviewed. The unique patterns of injury and fibrosis that characterize this disease are emphasized, and reasons why histologic scoring and diagnosis are considered as interrelated but separate exercises given. In addition, pros and cons and recognized limitations of liver biopsy in NAFLD are discussed.
Clinical Spectrum and Therapy of Non-Alcoholic Steatohepatitis
Authors: Day Christopher Paul
Published: October 2012

Non-alcoholic fatty liver disease is increasingly being diagnosed worldwide and considered to be the commonest liver disorder in Western countries. It comprises a disease spectrum ranging from simple steatosis (fatty liver) through non-alcoholic steatohepatitis (NASH) to fat with fibrosis and, ultimately, cirrhosis. Simple steatosis is largely benign and non-progressive, whereas NASH can lead to cirrhosis, liver failure and hepatocellular carcinoma. Therapeutic strategies can be divided into those directed at components of the metabolic syndrome with potential beneficial liver effects and those directed specifically at the liver. Recent data suggest that diet and exercise improve NASH, particular in those achieving >7% weight loss. Obesity surgery has been shown to improve steatosis in all studies and inflammation and fibrosis in some. With respect to anti-diabetic drugs, results for metformin have not been convincing and concerns over the safety of glitazones have reduced the initial enthusiasm for their use. ACE inhibitors and angiotensin II receptor blockers hold the most promise as anti-hypertensive agents for patients with NASH and hypertension. With respect to more specific liver-directed therapies, there have been promising studies of antioxidants, including betaine and probucol, and vitamin E may improve NASH in adults and children. The TNF-α-lowering agent pentoxifylline may have beneficial effects on NASH. Liver transplantation is successful, but the disease recurrence rate is high in the absence of treatment of the underlying metabolic syndrome.
Toll-Like Receptors in Gastrointestinal Diseases
Authors: Wagner Hermann
Published: October 2012

Innate immune cells – and many other cells – express evolutionarily conserved, germline-encoded receptors that recognize seemingly pathogen-derived ligands (also termed pathogen-associated molecular patterns), thereby allowing the host to perceive infection. Although they were the first to be discovered, Toll-like receptors (TLRs) are not the only pattern recognition receptors. TLRs are unlikely to discriminate between commensals and pathogens in the gut microbiota. There is, however, increasing evidence that TLRs shape intestinal function. In addition, certain bacteria appear to drive either Th1/Th17 proinflammatory immune responses, or T regulatory responses. Furthermore, TLRs appear to trigger ‘sterile’ autoinflammatory responses by sensing metabolically altered host (self) components.
Predicting the Course of IBD: Light at the End of the Tunnel?
Authors: Lee James C.
Published: October 2012

Prognosis in Crohn’s disease (CD) and ulcerative colitis (UC) varies substantially between patients. Accordingly, no single treatment strategy will be suitable for everyone. ‘Top-down’ strategies inevitably overtreat patients destined to experience indolent disease (and risk unnecessary immunosuppression), whilst ‘step-up’ strategies expose patients with aggressive disease to avoidable disease-related morbidity. Accordingly, for personalised medicine to succeed in IBD, a reliable method of predicting prognosis is critical. In oncology, gene expression profiling enables reliable prediction of several aspects of tumour behaviour. Unfortunately, this technology has been less successful in other disease areas – often because heterogeneous cell populations are studied, producing gene signatures that simply reflect compositional differences in the starting material. This can be overcome by analysing purified cell populations. Previously, we discovered a prognostic gene expression signature in purified CD8+ T cells from patients with systemic lupus erythematosus and ANCA-associated vasculitis. We therefore investigated whether the same signature might exist in other relapsing-remitting diseases driven by immune responses to antigen, and detected an analogous signature in CD and UC. This signature was detectable from diagnosis, but did not correlate with contemporaneous clinical or biochemical data. A significant association with prognosis was detected in both UC and CD, with patients who were enriched for the signature (subgroup ‘IBD1’) experiencing a more aggressive disease course, characterised by frequent flares and a higher incidence of treatment failure. This suggests that gene expression profiling could stratify patients with CD or UC at diagnosis according to their future disease course, and represents a step towards personalised therapy.
New Drug Therapies on the Horizon for IBD
Authors: Perrier Clémentine , Rutgeerts Paul
Published: October 2012

IBD are diseases of the GI tract causing important morbidity. Several anti-TNF-α agents are currently used to treat Crohn’s disease and ulcerative colitis. Although these molecules have dramatically improved the treatment of IBD, up to half of the patients have no sustained benefit due to nonresponse, loss of response or intolerance. New anti-TNF strategies are under development. Novel therapies targeting other immune pathways are under study, such as antibodies targeting the IL-12/IL-23 pathway, and have shown interesting preliminary results. In parallel, antiadhesion therapies limiting the recruitment of cells to the gut will reach the clinic in the coming years. Small molecules inhibiting the production of proinflammatory cytokines are already used in the clinic for rheumatoid arthritis, and Tofacitinib, a Janus kinase inhibitor, seems to have great potential to treat ulcerative colitis. In this review we focus on the novel molecules that are likely to reach the clinic in the near future for the treatment of IBD.
A Real-Life Study on Acquired Skills from Using an Adrenaline Autoinjector
Authors: Topal Erdem , Bakirtas Arzu , Yilmaz Ozlem , Ertoy Ilbilge Hacer , Arga Mustafa , Demirsoy Mehmet Sadik , Turktas Ipek
Published: October 2012

Background: Training programs performed by allergists have increased the ability of patients’ recognition and management of anaphylaxis. We aim to investigate the permanence of effect of an anaphylaxis training program and to determine the factors affecting it beyond training given by allergists. Methods: Children and/or their caregivers who had been prescribed an adrenaline autoinjector at least 1 year before were invited to take part in the study. The knowledge about anaphylaxis was assessed using a questionnaire and the skills were practically tested. Results: Sixty-four (50 caregivers/14 children >12 years of age) of 80 patients who accepted the invitation were included in the study. Fifty-nine patients obtained the autoinjector after initial prescription. Among them, 42 (71%) still had the device at the time of the study. The most common reason for not having the autoinjector was no longer feeling it was necessary (54.6%). Of the cases, 39.4% were competent in autoinjector use. There was a significant relation between adrenaline autoinjector competency and regular allergy visits (p = 0.010), believing that it is necessary (p = 0.04), having an adrenaline autoinjector (p = 0.003), and previous history of severe anaphylaxis (p = 0.010). Autoinjector competency score decreased as time elapsed from the last visit (rho = –0.382; p = 0.002) and the first instruction (rho = –0.317; p = 0.01). Regular visits (p = 0.009) and history of severe anaphylaxis (p = 0.007) were found as independent factors having an effect on adrenaline autoinjector competency. Conclusions: Training of patients/caregivers by allergists does not guarantee the permanence of acquired skills on anaphylaxis in the long run. Regular follow-up visits should be fostered.
Circulating Fibrocytes in Ischemia-Reperfusion Injury and Chronic Renal Allograft Fibrosis
Authors: Kimura Shogo , Asaka Mitsuhiro , Atsumi Hirokatsu , Imura Junko , Fujimoto Keiji , Chikazawa Yoshihiro , Nakagawa Masaru , Okuyama Hiroshi , Yamaya Hideki , Yokoyama Hitoshi
Published: October 2012

Background: Interstitial fibrosis in chronic allograft injury has been suggested as a major cause of the loss of allograft. Methods: To clarify the involvement of circulating fibrocytes (CF) and α-smooth muscle actin (SMA)-positive cells in renal allograft injury, we investigated 36 renal transplanted cases at 0 h, 1 h, 2–4 weeks, 4–8 weeks, and 1 year, and 5 normal controls. Double immunofluorescence analysis for both COL1 and CD45 indicating CF (/mm2), and the positive area (%) of α-SMA and Masson trichrome (MT) stain were detected by an image analyzing system. Results: The mean number of CF was 0 in controls and 4.0 in total transplanted specimens (p < 0.05). CF correlated with the α-SMA-positive area in the graft (R2 = 0.39, p < 0.01), but not with Banff 2005 scores. The number of CF increased in 2–4 weeks; however, decreased 1 year after transplantation. α-SMA-positive area gradually increased at 1 year concomitant with the increase of MT-positive area. A similar phenomenon was observed in a case of primary nonfunction kidney from 0 h to 6 weeks after transplantation. The electron microscopy score of fibrosis around peritubular capillaries was correlated positively with COL1-positive area (R2 = 0.72, p < 0.01), but negatively with infiltrated CF (R2 = 0.25, p < 0.05). Conclusion: CF were transiently induced, probably due to ischemia-reperfusion injury, but fibrosis only slightly progressed in this process. The α-SMA-positive myofibroblasts may accelerate the expansion of fibrosis around peritubular capillaries in chronic allograft injury.
Does Alzheimer’s Disease Protect against Cancers? A Nationwide Population-Based Study
Authors: Ou Shuo-Ming , Lee Yi-Jung , Hu Yu-Wen , Liu Chia-Jen , Chen Tzeng-Ji , Fuh Jong-Ling , Wang Shuu-Jiun
Published: October 2012

Background: Previous studies suggested a decreased risk of cancer among patients with Alzheimer’s disease (AD). There is still a lack of data on the specific types of cancer, the risk factors, and the impact of cholinesterase inhibitors on developing cancer in AD. Methods: We performed a nationwide population-based study of 6,960 patients with AD between 1997 and 2006 using Taiwan’s National Health Insurance database. Patterns of cancer incidence in AD patients were compared with those of the general population using standardized incidence ratios (SIRs). Results: Patients with AD had a reduced risk of developing overall cancer [SIR = 0.88, 95% confidence interval (CI) = 0.80–0.97]. Specifically, patients with AD were protected from lung cancers (SIR = 0.75, 95% CI = 0.57–0.98), especially men (SIR = 0.61, 95% CI = 0.40–0.88). In subgroup analyses, women, patients aged 60–79 years, and those diagnosed as having AD for more than 1 year were more likely to be protected from cancers. Conclusions: Our study demonstrates a decreased incidence of overall cancers in patients with AD, a finding lower than but consistent with Western countries. Patients with AD had a significantly decreased risk of lung cancer. Further investigation of genetic evidence linking AD to cancer is warranted.
Secreted and Membrane-Bound Mucins and Idiopathic Peptic Ulcer Disease
Authors: Niv Yaron , Boltin Doron
Published: October 2012

The incidence of Helicobacter pylori and non-steroidal anti-inflammatory drug (NSAID)-negative peptic ulcer disease has increased over the last two decades, especially in the Western world and in countries with low H. pylori infection rates. Idiopathic peptic ulcer disease is a recently described entity which relates to peptic ulcers not caused by H. pylori, NSAID/aspirin therapy, other ulcerogenic organisms and drugs, or other rare malignant and benign diseases. Structural and secreted mucins create the unstirred gastric mucus layer and maintain a stable pH above the gastric mucosa. This mucous layer prevents enzymatic attack by acid and pepsin. Inhibition of cyclooxygenase by NSAID and aspirin inhibits prostaglandin production, inhibits mucin and bicarbonate secretion, and exposes the mucosa to the toxic effects of acid and intragastric enzymes. There is also a complex relationship between H. pylori and different mucin subtypes which on one hand facilitates mucin invasion but on the other hand protects the gastric mucosa. Genetic and epigenetic changes in the mucin molecule may be responsible for idiopathic peptic ulcer disease, but this hypothesis must be further investigated. Herein, the mucin hypothesis of idiopathic peptic ulcer disease is explored.
Extracellular Pyrophosphate in the Kidney: How Does It Get There and What Does It Do
Authors: Moochhala Shabbir H.
Published: October 2012

Pyrophosphate (PPi) is well known as a regulator of calcification, and the ANKH (ANK in mouse) protein has a role in the membrane transport of PPi. Earlier work concentrated on bones and joints, but ANKH is also likely to have important roles in the kidney, with newer studies focusing on vascular calcification in renal failure. Renal calcification can occur due to a naturally occurring ANK mouse mutation, yet other ANK mutations do not cause a renal phenotype. Despite evidence over 10 years of ANKH’s involvement in PPi transport, efflux of PPi via ANKH has never been demonstrated. Rather than physically moving PPi, the ANKH protein may assist its membrane transport in other ways such as by hydrolysis and compartmentalisation. Protein complexes may account for effects of ANKH that are specific to particular tissues. In the kidney, recent localisation data may be helpful in suggesting physiological roles for ANKH, such as its co-localisation with aquaporin-2 and cilial proteins. Such diverse functions would reflect the ubiquitous nature of ANKH in tissues and its profound evolutionary conservation.
Acoustic Rhinometry and Aspirin Nasal Challenge in the Diagnosis of Aspirin-Intolerant Asthma: Clinical Finding and Safety Aspects
Authors: Muñoz-Cano R. , Bartra J. , Sanchez-Lopez J. , Picado C. , Bissinger I. , Valero A.
Published: October 2012

Background: The safety and utility of nasal provocation tests with lysine-aspirin (l-ASA) in the diagnosis of aspirin-intolerant asthma (AIA) have previously been described in a short series of patients. Objectives: To describe the clinical features and safety of an l-ASA challenge test in patients with AIA. Methods: We evaluated 72 patients (79% women), with a mean ± SD age of 47.9 ± 14.5 years. All patients were submitted to an l-ASA nasal provocation test (29 mg in each nostril) under acoustic rhinometry (AcR) control. Symptom score (0–3), visual analogical scale and nitric oxide determinations were performed at baseline and at 15, 30, 60 and 90 min. A decrease in nasal volume of at least 25% was considered a positive test. Nasal nitric oxide (nNO) and forced expiratory volume in 1 s were measured. Results: Nasal congestion and rhinorrhea represented 51 and 32%, respectively, of total symptoms. According to AcR data, the l-ASA challenge test was positive in 20% of patients at 15 min, an additional 36% were positive at 30 min, 18% at 60 min, and the remaining 26% at 90 min. nNO nasal values decreased but did not reach statistical significance. No pulmonary or systemic reactions were observed. Conclusions: Symptoms of nasal congestion associated with the reduction in nasal volume measured by AcR are the most useful parameters for establishing the diagnosis of AIA using the l-ASA nasal challenge. The method is very well tolerated and can be safely used even in patients with severe asthma.
Ara h 2 and Ara h 6 Have Similar Allergenic Activity and Are Substantially Redundant
Authors: Chen Xueni , Wang Qian , El-Mezayen Rabab , Zhuang Yonghua , Dreskin Stephen C.
Published: October 2012

Background: The moderately homologous (approx. 60%) proteins Ara h 2 and Ara h 6 are the most potent peanut allergens. This study was designed to define the relative individual contributions of Ara h 2 and Ara h 6 to the overall allergenic activity of a crude peanut extract (CPE). Methods: Ara h 2 and Ara h 6 were removed from CPE by gel filtration chromatography. Ara h 2.01, Ara h 2.02 and Ara h 6 were further purified (>99%). The potency of each allergen and the ability of these allergens to reconstitute the allergenic activity of CPE depleted of Ara h 2 and Ara h 6 was measured with RBL SX-38 cells sensitized with IgE from sensitized peanut allergic patients. Results: The potency of the native proteins were significantly different (p < 0.0001) although not dramatically so, with a rank order of Ara h 2.01 > Ara h 2.02 > Ara h 6. The addition of either purified Ara h 2 or Ara h 6 independently at their original concentration to CPE depleted of both Ara h 2 and Ara h 6 restored 80–100% of the original CPE allergenic activity. Addition of both Ara h 2 and Ara h 6 consistently completely restored the allergenic activity of CPE. Conclusions: These studies indicate that either Ara h 2 or Ara h 6 independently can account for most of the allergenic activity in a CPE and demonstrate important redundancy in the allergenic activity of these related molecules.
Clinical Features of Children with Venom Allergy and Risk Factors for Severe Systemic Reactions
Authors: Yavuz S. Tolga , Sahiner Umit M. , Buyuktiryaki Betul , Soyer Ozge U. , Sackesen Cansin , Sekerel Bulent E. , Tuncer Ayfer
Published: October 2012

Background: Severe systemic reactions (SRs) to insect venom are rare in childhood and there are few data on this study population. The aim of our study is to analyze the clinical features and to document the risk factors for severe SRs in children with insect venom allergy. Methods: Children with SRs after Hymenoptera sting were analyzed. The diagnosis was based on medical history, skin tests and/or specific IgE testing. Results: Seventy-six children were included [57 boys (75%), mean age 9.8 ± 3.4 years]. The mean age of children at the time of SR was 8.3 ± 3.4 years. Reactions were accounted for Vespula (wasp) venom in 58 (76%) and Apis mellifera (bee) venom in 18 (24%) patients. Twenty-six percent of patients had aeroallergen sensitization and 33% had atopic disease, whereas 66% had experienced previous stings. The upper limb was the most frequent area of sting (43%), and the cutaneous system (99%) was the most frequent involved system. SRs occurred in 59% of patients. Multivariate logistic regression analysis revealed eosinophilia (>5%) [odds ratio (OR) 12.6; confidence interval (CI) 1.5–109.7; p = 0.022], female sex (OR 6.4; CI 1.5–26.9; p = 0.011) and accompanying atopic disease (OR 3.4; CI 1.2–12.3; p = 0.016) as significant risk factors for severe SRs. Ninety-seven percent of patients were admitted to the emergency department; however, epinephrine was used in only 46% of patients. Conclusions: There was a high frequency of hypersensitivity to wasp venom among the study population, and severe reactions were related to mild eosinophilia, female sex and concomitant atopic diseases. A better understanding of the risk factors may lead to effective utilization of health care sources in the future.
Evaluation of Allergenicity of Acid-Hydrolyzed Wheat Protein Using an in vitro Elicitation Test
Authors: Nakamura Rika , Nakamura Ryosuke , Adachi Reiko , Itagaki Yasuharu , Fukutomi Yuma , Teshima Reiko
Published: October 2012

Background: We performed an in vitro elicitation test to determine the ability of different types of wheat-allergic patients’ IgE to induce humanized mast cell activation after the addition of various time-treated acid-hydrolyzed wheat proteins (HWPs). Methods: The reactivity of heat- and various time-treated acid-hydrolyzed glutens (acid-HGs) and commercial acid-HWP (HWP1), using serum IgE from wheat allergy accompanied by skin and rhinoconjunctival sensitization to HWP1 in the facial soap, pediatric subjects with food allergy to native wheat, adult wheat-dependent exercise-induced anaphylaxis subjects, and nonatopic healthy subjects, was elucidated by dot blot and a luciferase assay-based in vitro elicitation test (EXiLE test). Results: Serum from subjects sensitized with HWP1 reacted only to acid-HGs (acid-HGs treated for 0.5–3 or 6 h), but not native gluten, in the results of the dot blot. In contrast, sera from pediatric subjects sensitized with native wheat reacted to native gluten more strongly and showed only slight reactions to 0.5- to 1-hour-treated acid-HGs. The results of the in vitro elicitation test showed that acid hydrolyzation of the gluten attenuated antigen-induced luciferase expression in a time-dependent manner for sera from native-wheat-sensitized pediatric subjects. On the other hand, in the sera from HWP1-sensitized subjects, acid hydrolyzation of the gluten for 0.5 h dramatically increased luciferase expression. Conclusions: Even after prolonged hydrolyzation, acid-HGs still retained the ability to activate mast cells in the case of HWP1-sensitized subjects.
NK Cells in Hepatitis C: Role in Disease Susceptibility and Therapy
Authors: Lunemann Sebastian , Schlaphoff Verena , Cornberg Markus , Wedemeyer Heiner
Published: October 2012

Hepatitis C is caused by infection with the hepatitis C virus (HCV), a single-stranded RNA virus, which was first described in 1989. Hepatitis C is a major global health burden with approximately 150 million people chronically infected worldwide. Chronic HCV infection is a main cause of liver cirrhosis and hepatocellular carcinoma. Current treatment of hepatitis C is based on the administration of peg-IFN-α and ribavirin. However, this therapy can be associated with severe side effects. The role of NK cells in the pathogenesis of acute and chronic liver disease in HCV infection has only been studied in recent years, but those studies indicate an important role for this cell type. NK cells are a major component of the innate arm of the immune system. We summarize the current knowledge on NK cell phenotype and function in acute and chronic HCV infection. Moreover, we discuss the role of NK cells in IFN-α-based antiviral therapy. Understanding the mode of function and role of NK cells during HCV infection and therapy will become even more important in the near future, when new IFN-α-free treatment regimens become available.
Stereotactic Operations Using the O-Arm
Authors: Katisko Jani Petri Antton , Kauppinen Mikko Tapio , Koivukangas John Pertti , Heikkinen Esa Raimo
Published: October 2012

Background: In stereotactic operations, intraoperative imaging is crucial in several stages of the procedure. The aim was to utilize the O-arm intraoperatively for (1) planning the trajectories of stereotactic instruments, (2) calculating the coordinates of the targets, (3) identification of normal intracranial structures, (4) verification of the trajectories of the stereotactic instruments, and (5) visualization of intracranial hematoma. This is the first study using the O-arm for calculations of the target coordinates in frame-based stereotaxy. Methods: Utilization of the O-arm as a full-scale intraoperative imaging system in stereotactic surgery required a new concept. The concept consists of the O-arm as an intraoperative imaging system and the Leksell stereotactic system with a modified CT coordinate indicator box, with the idea to widen limited imaging volume. The accuracy and feasibility of the concept were studied. Results: The use of O-arm imaging was found to be clinically feasible, enabling the achievement of adequate technical accuracy for stereotactic operations with submillimeter errors in the calculation of target coordinates, and for multiple intraoperative control images when required. Conclusions: The O-arm could be used alone, with high accuracy, as an intraoperative imaging system for planning and controlling in stereotactic operations. In addition, it can be used to exclude serious complications, especially intracerebral hematoma.
The Safety and Tolerability of Ferric Citrate as a Phosphate Binder in Dialysis Patients
Authors: Sinsakul Marvin , Sika Mohammed , Koury Mark , Shapiro Warren , Greene Tom , Dwyer Jamie , Smith Mark , Korbet Stephen , Lewis Julia ,   for the Collaborative Study Group
Published: October 2012

Background: A phase II open-label study was conducted in hemodialysis patients evaluating the short-term safety, tolerability, and iron absorption with ferric citrate when used as a phosphate binder. Methods: Enrollment occurred in two periods. Period 1 recruited patients taking 6–15 pills/day of binder with phosphorus of ≥2.5 mg/dl. Period 2 recruited patients taking ≥12 pills/day of binder with phosphorus of ≥3.5 mg/dl. Participants with ferritin ≥1,000 µg/l or transferrin iron saturation (TSAT) ≥50% at screening were excluded. Subjects discontinued their previous binders and started 4.5 g/day of ferric citrate (period 1) or 6 g/day (period 2) and were titrated for 4 weeks to maintain a phosphorus of 3.5–5.5 mg/dl. Chemistries and complete blood count were obtained weekly and a gastrointestinal questionnaire was administered at drug initiation and final visit. Iron therapy was permitted if the ferritin was <500 µg/l and TSAT <30%. Results: Fifty-five subjects were enrolled. Four serious adverse events were reported; none were related to the study drug. Findings from the gastrointestinal questionnaire included stool discoloration (69%), constipation (15%), and bloating (7%). Mean iron parameters at the beginning of the study were ferritin 554 ± 296 µg/l, iron 68 ± 21 µg/dl, and iron saturation 30 ± 7.8%. At the end of study, mean ferritin was 609 ± 340 µg/l (p = 0.02), iron 75 ± 27 µg/dl (p = 0.04), and TSAT was 35 ± 13% (p = 0.001). Mean phosphorus and calcium levels were unchanged from baseline at the end of study. Conclusion: Ferric citrate was well tolerated by patients after 4 weeks with no significant clinical or biochemical adverse events related to exposure.
Patent Foramen Ovale, Ischemic Stroke and Migraine: Systematic Review and Stratified Meta-Analysis of Association Studies
Authors: Davis Daniel , Gregson John , Willeit Peter , Stephan Blossom , Al-Shahi Salman Rustam , Brayne Carol
Published: October 2012

Background: Observational data have reported associations between patent foramen ovale (PFO), cryptogenic stroke and migraine. However, randomized trials of PFO closure do not demonstrate a clear benefit either because the underlying association is weaker than previously suggested or because the trials were underpowered. In order to resolve the apparent discrepancy between observational data and randomized trials, we investigated associations between (1) migraine and ischemic stroke, (2) PFO and ischemic stroke, and (3) PFO and migraine. Methods: Eligibility criteria were consistent; including all studies with specifically defined exposures and outcomes unrestricted by language. We focused on studies at lowest risk of bias by stratifying analyses based on methodological design and quantified associations using fixed-effects meta-analysis models. Results: We included 37 studies of 7,686 identified. Compared to reports in the literature as a whole, studies with population-based comparators showed weaker associations between migraine with aura and cryptogenic ischemic stroke in younger women (OR 1.4; 95% CI 0.9–2.0; 1 study), PFO and ischemic stroke (HR 1.6; 95 CI 1.0–2.5; 2 studies; OR 1.3; 95% CI 0.9–1.9; 3 studies), or PFO and migraine (OR 1.0; 95% CI 0.6–1.6; 1 study). It was not possible to look for interactions or effect modifiers. These results are limited by sources of bias within individual studies. Conclusions: The overall pairwise associations between PFO, cryptogenic ischemic stroke and migraine do not strongly suggest a causal role for PFO. Ongoing randomized trials of PFO closure may need larger numbers of participants to detect an overall beneficial effect.
The Impact of Estimated Glomerular Filtration Rate Reporting on Nephrology Referral Pattern, Patient Characteristics and Outcome
Authors: Naimark David M.J. , Harel Ziv , Moineddin Rahim , Bergman Arik
Published: October 2012

Background: Chronic kidney disease (CKD) is a growing public health problem worldwide. The estimated glomerular filtration rate (eGFR) has been advocated as a means to detect CKD. In January 2006, community laboratories in Ontario, Canada, began to report eGFR values along with every serum creatinine result. The present study sought to investigate the impact of eGFR reporting on nephrology referrals and patient outcome. Methods: We conducted a retrospective analysis of referrals to an adult general nephrology clinic 24 months before and after eGFR reporting took effect. Results: eGFR reporting was associated with a significant rise in the number of referrals (1,330–1,496, p = 0.009), a 33% rise in patient waiting time (from 75 to 100 days, p < 0.001), and an increase in nephrologists’ workload. Patients referred after eGFR reporting were older, but suffered from fewer comorbidities such as hypertension and vascular disease. There was an increase in the number of patients referred with stage 3 CKD, but a drop in the proportion of stage 4 and 5 CKD referrals and no change in time to renal replacement therapy. Conclusion: Laboratory reporting of eGFR increased nephrology referral volume, patient waiting times, and nephrologists’ workload, without a demonstrable benefit in terms of detection and referral of severe (stage 4 and 5) CKD, nor in the reduction of end-stage renal disease frequency.
Omega–3 Fatty Acids Ameliorate Proteinuria but Not Renal Function in IgA Nephropathy: A Meta-Analysis of Randomized Controlled Trials
Authors: Chou Hsin-Hsu , Chiou Yuan-Yow , Hung Peir-Haur , Chiang Pei-Chung , Wang Shan-Tair
Published: October 2012

Background/Aim: The effects of ω–3 fatty acids (O3FAs) on renal function and proteinuria in immunoglobulin A nephropathy (IgAN) are not fully understood. Thus, we conducted an up-to-date meta-analysis of the currently available randomized controlled trials (RCTs) to validate the effects of O3FA in IgAN. Methods: A literature search was performed in PubMed, Medline, Embase and the Cochrane Central Registry of Controlled Trials using an extended search strategy to identify RCTs that assessed the treatment efficacy of O3FA in IgAN. The dose-effect relationships of O3FA on renal function and proteinuria were also determined. Results: Five RCTs with a total of 233 patients were included in our analysis. Our results demonstrated that while O3FA does not have any beneficial effects in preserving renal function in IgAN, proteinuria was significantly reduced. Furthermore, patients who received a high dose of O3FA (>3 g/day) did not differ from those who received a low dose of O3FA (≤3 g/day) in renal function or proteinuria. Conclusion: The currently available evidence suggests that O3FA has no benefit in preserving renal function, but can ameliorate proteinuria in IgAN. However, the effects of O3FA on proteinuria are not dose dependent.
Clarithromycin Stops Lung Function Decline in Airway-Centered Interstitial Fibrosis
Authors: Jouneau S. , Kerjouan M. , Caulet-Maugendre S. , Guillot S. , Meunier C. , Desrues B. , Delaval P.
Published: October 2012

Airway-centered interstitial fibrosis (ACIF) is a distinct type of lung interstitial fibrosis characterized by lesions centered on the airways. Several cases reported in the literature showed little to no effect of corticosteroids and a high mortality rate in the absence of lung transplantation. No other efficient approach is described for the treatment of this type of fibrosis. We report for the first time the case of a 44-year-old patient diagnosed with ACIF on surgical lung biopsy and stabilized with clarithromycin after failure of systemic corticosteroids. We need to confirm this benefit in other patients to ascertain the anti-inflammatory effect of macrolides, which are far less harmful compared to corticosteroids or immunosuppressant drugs.
Intracoronary Monocyte Chemoattractant Protein 1 and Vascular Endothelial Growth Factor Levels Are Associated with Necrotic Core, Calcium and Fibrous Tissue Atherosclerotic Plaque Components: An Intracoronary Ultrasound Radiofrequency Study
Authors: Fuchs Shmuel , Lavi Ifat , Tzang Omer , Bessler Hana , Brosh David , Bental Tamir , Dvir Danny , Einav Shmuel , Kornowski Ran
Published: October 2012

Aims: To investigate the relationship between various serum biomarkers and coronary atherosclerotic plaque composition obtained by intravascular ultrasound virtual histology (IVUS-VH). Methods: Using ELISA, we measured the serum levels of CD40 ligand, C-reactive protein, monocyte chemoattractant protein 1 (MCP-1), metalloproteinase 9, P-selectin and vascular endothelial growth factor (VEGF) in 40 patients with manifested coronary artery disease. Results: Correlation analysis between biomarkers levels, IVUS grayscale parameters and VH-defined necrotic core (NC), calcium, fibrous and fibrofatty components was performed. MCP-1 and VEGF levels correlated with the severity of area stenosis (r = 0.35, p = 0.03 and r = 0.38, p = 0.017, respectively) and inversely correlated with the remodeling index (r = –0.35, p = 0.03 and r = 0.35, p = 0.02, respectively). Higher levels of MCP-1 were associated with increased calcium (r = 0.47, p = 0.004), NC (r = 0.38, p = 0.02) and less fibrous tissue components (r = –0.34, p = 0.03), whereas VEGF had an inverse correlation with both calcium components (r = –0.37, p = 0.02) and NC (r = –0.34, p = 0.036) but was strongly associated with increased fibrous components (r = 0.47, p = 0.003). No significant correlation was noted for any of the other biomarkers. Conclusions: MCP-1 and VEGF serum levels in patients with ischemic heart disease are correlated with coronary artery plaque burden and composition.
Efficient Removal of Serum Bilirubin by a Novel Artificial Liver Support System Using Albumin Convection: A Pilot Study
Authors: Gong Dehua , Ji Daxi , Zhu Dongdong , Xu Bin , Liu Zhihong
Published: October 2012

Background/Aims: To compare the efficacy of a new artificial liver support system, fractionated plasma separation and adsorption integrated with hemofiltration, with the old system, plasma adsorption. Methods: Sixteen patients with acute liver failure each received a first session of treatment using the old system, in which plasma was perfused through an adsorber. They then received a second session using the new system, in which albumin-rich plasma separated using a fraction plasma separator was ultrafiltrated using a hemofilter and perfused through an adsorber before being returned to blood. Results: The new system had a higher clearance of bilirubin and slower decline of clearance over time. There was a lower reduction ratio of bilirubin, bile acid, urea, and creatinine; longer prolongation of coagulation parameters; and greater decline in albumin level using the old system compared with the new one. Conclusions: Use of the novel system results in more efficient removal of toxins and fewer deterious effects than the old system.
Two-Year Follow-Up of the Lidcombe Program in Ten Swedish-Speaking Children
Authors: Femrell Lovisa , Åvall Marita , Lindström Elisabeth
Published: October 2012

Purpose: The purpose of this semicontrolled prospective study was to report on the outcomes of 10 Swedish-speaking children treated with the Lidcombe Program and how the parents viewed the treatment. Method: Ten children at an age from 2:9 to 5:8 (years:months) referred to two clinics for communication disorders were consecutively included in the study. The children had been stuttering for 0:9 to 3:3 with a mean stuttering frequency of 10.1% syllables stuttered (%SS; 0.8–33.9) before treatment. Parents and teachers filled out questionnaires concerning the children’s speech and the parents also answered questions on their views on the program. Results: Eight children completed the program and were reassessed upon completion of the program, about 2 years after progressing to stage 2. There was a significant decrease in mean %SS before and after treatment (7.6 vs. 0.1%, respectively) with a large Cohen effect size (d = 2.9). Parents and teachers found that the treatment had a positive effect on the children’s stuttering and all parents would recommend the Lidcombe Program to other families. Conclusion: The results of this preliminary study suggest that the Lidcombe Program can be an effective treatment for Swedish-speaking preschool children who stutter.