bluuebunny/crossref_metadata_2025 huggingface dataset:
Definition of Genetic Events Directing the Development of Distinct Types of Brain Tumors from Postnatal Neural Stem/Progenitor Cells
Authors: Hertwig Falk , Meyer Katharina , Braun Sebastian , Ek Sara , Spang Rainer , Pfenninger Cosima V. , Artner Isabella , Prost Gaëlle , Chen Xinbin , Biegel Jaclyn A. , Judkins Alexander R. , Englund Elisabet , Nuber Ulrike A.
Published: June 2012

Although brain tumors are classified and treated based upon their histology, the molecular factors involved in the development of various tumor types remain unknown. In this study, we show that the type and order of genetic events directs the development of gliomas, central nervous system primitive neuroectodermal tumors, and atypical teratoid/rhabdoid-like tumors from postnatal mouse neural stem/progenitor cells (NSC/NPC). We found that the overexpression of specific genes led to the development of these three different brain tumors from NSC/NPCs, and manipulation of the order of genetic events was able to convert one established tumor type into another. In addition, loss of the nuclear chromatin-remodeling factor SMARCB1 in rhabdoid tumors led to increased phosphorylation of eIF2α, a central cytoplasmic unfolded protein response (UPR) component, suggesting a role for the UPR in these tumors. Consistent with this, application of the proteasome inhibitor bortezomib led to an increase in apoptosis of human cells with reduced SMARCB1 levels. Taken together, our findings indicate that the order of genetic events determines the phenotypes of brain tumors derived from a common precursor cell pool, and suggest that the UPR may represent a therapeutic target in atypical teratoid/rhabdoid tumors. Cancer Res; 72(13); 3381–92. ©2012 AACR.
Outcome of Patients with Platelet-Derived Growth Factor Receptor Alpha–Mutated Gastrointestinal Stromal Tumors in the Tyrosine Kinase Inhibitor Era
Authors: Cassier Philippe A. , Fumagalli Elena , Rutkowski Piotr , Schöffski Patrick , Van Glabbeke Martine , Debiec-Rychter Maria , Emile Jean-François , Duffaud Florence , Martin-Broto Javier , Landi Bruno , Adenis Antoine , Bertucci François , Bompas Emmanuelle , Bouché Olivier , Leyvraz Serge , Judson Ian , Verweij Jaap , Casali Paolo , Blay Jean-Yves , Hohenberger Peter ,   for the European Organisation for Research and Treatment of Cancer
Published: June 2012

Purpose: Platelet-derived growth factor receptor-alpha (PDGFRA) mutations are found in approximately 5% to 7% of advanced gastrointestinal stromal tumors (GIST). We sought to extensively assess the activity of imatinib in this subgroup.

Experimental Design: We conducted an international survey among GIST referral centers to collect clinical data on patients with advanced PDGFRA-mutant GISTs treated with imatinib for advanced disease.

Results: Fifty-eight patients were included, 34 were male (59%), and median age at treatment initiation was 61 (range, 19–83) years. The primary tumor was gastric in 40 cases (69%). Thirty-two patients (55%) had PDGFRA-D842V substitutions whereas 17 (29%) had mutations affecting other codons of exon 18, and nine patients (16%) had mutation in other exons. Fifty-seven patients were evaluable for response, two (4%) had a complete response, eight (14%) had a partial response, and 23 (40%) had stable disease. None of 31 evaluable patients with D842V substitution had a response, whereas 21 of 31 (68%) had progression as their best response. Median progression-free survival was 2.8 [95% confidence interval (CI), 2.6–3.2] months for patients with D842V substitution and 28.5 months (95% CI, 5.4–51.6) for patients with other PDGFRA mutations. With 46 months of follow-up, median overall survival was 14.7 months for patients with D842V substitutions and was not reached for patients with non-D842V mutations.

Conclusions: This study is the largest reported to date on patients with advanced PDGFRA-mutant GISTs treated with imatinib. Our data confirm that imatinib has little efficacy in the subgroup of patients with D842V substitution in exon 18, whereas other mutations appear to be sensitive to imatinib. Clin Cancer Res; 18(16); 4458–64. ©2012 AACR.
ATP Citrate Lyase Knockdown Induces Growth Arrest and Apoptosis through Different Cell- and Environment-Dependent Mechanisms
Authors: Zaidi Nousheen , Royaux Ines , Swinnen Johannes V. , Smans Karine
Published: June 2012

ATP citrate lyase (ACLY) is a cytosolic enzyme that catalyzes generation of acetyl-CoA, which is a vital building block for fatty acid, cholesterol, and isoprenoid biosynthesis. ACLY is upregulated in several types of cancer, and its inhibition induces proliferation arrest in certain cancer cells. As ACLY is involved in several pathways, its downregulation may affect multiple processes. Here, we have shown that short hairpin RNA-mediated ACLY silencing in cell lines derived from different types of cancers induces proliferation, cell-cycle arrest, and apoptosis. However, this antiproliferative effect of ACLY knockdown was observed only when cells were cultivated under lipid-reduced growth conditions. Proliferation arrest induced by ACLY silencing was partially rescued by supplementing the media with fatty acids and/or cholesterol. This indicates that the ACLY knockdown-mediated growth arrest might be the result of either fatty acid or cholesterol starvation or both. In the absence of ACLY, the cancer cells displayed elevated expression of sterol regulatory element binding protein–regulated downstream genes involved in de novo fatty acid and cholesterol biosynthesis. Furthermore, ACLY suppression resulted in elevated expression of acyl-CoA synthetase short-chain family member 2 (ACSS2), an enzyme that also produces acetyl-CoA using acetate as a substrate. Acetate supplementation partially rescued the cancer cells from ACLY suppression–induced proliferation arrest. We also observed that the absence of ACLY enhanced ACSS2-dependent lipid synthesis. These findings provide new insights into the role of ACLY in cancer cell growth and give critical information about the effects of ACLY silencing on different pathways. This information is crucial in understanding the possible application of ACLY inhibition in cancer therapeutics. Mol Cancer Ther; 11(9); 1925–35. ©2012 AACR.
Paleopathology in South American Mummies: A Review and New Findings
Authors: Gerszten Enrique , Allison Marvin J. , Maguire Brianna
Published: June 2012

This article is a review of research and additional unpublished diseases that have been discovered and documented in naturally mummified remains recovered from South America. A new impetus in paleopathological studies was the work and discovery of a solution for rehydration of mummified tissues by Sir Marc Armand Ruffer in 1913. This solution allows the paleopathologist, after performing the autopsy, to process the tissues in a manner similar to current practices in pathology. In our studies, the most common diseases were infectious in nature, similar to the diseases that are most prominent today in the same regions.
Lymph Node Metastasis in Patients with Frozen Section Analyses That Are Negative for Tumors
Authors: Lee Se Kyung , Lee Kyo Won , Kim Sangmin , Choi Min-Young , Kim Jiyoung , Lee Jeonghui , Jung Seung Pil , Choe Jun-Ho , Kim Jung-Han , Kim Jee Soo , Lee Jeong Eon , Yang Jung-Hyun , Nam Seok Jin
Published: June 2012

Objectives: This study was designed to assess the necessity of delayed complete axillary lymph node dissection (cALND) for patients whose sentinel lymph nodes (SLNs) were negative for tumors on intraoperative frozen section analysis, but later proven positive on hematoxylin and eosin staining or immunohistochemistry. Methods: We identified 341 patients who underwent sentinel lymph node biopsy (SLNB) with cALND at the Samsung Medical Center between 1998 and 2008, and reviewed the clinicopathological records of women diagnosed with invasive carcinoma of the breast. Results: Of the 341 patients, 59 underwent delayed cALND due to negative results on frozen section. Only 1 patient had a non-SLNs metastasis in the group of delayed cALND. Delayed cALND was associated with higher rates of breast-conserving surgery, smaller primary tumor and metastasis size in SLNs, fewer metastatic lymph nodes and SLNs and a lower TNM stage. The detection of metastases of SLNs on frozen section and the number of metastatic SLNs were related to the detection of additional metastases of nonsentinel lymph nodes (NSLNs) in cALND. Conclusion: Our findings suggest that the lack of detection of metastases on frozen sections may be a predictive factor for nonmetastasis in NSLNs. cALND could therefore be omitted in such cases.
Nonalcoholic Fatty Liver Disease/Steatohepatitis: Epidemiology, Pathogenesis, Clinical Presentation and Treatment
Authors: Milić Sandra , Štimac Davor
Published: June 2012

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic hepatic disorder in Western countries, with a prevalence of 20–30%. NAFLD comprises ‘silent liver disease’, in which simple steatosis is the only histological finding and which is benign in course, and nonalcoholic steatohepatitis, which is characterized by hepatocellular injury and inflammation with or without fibrosis. NAFLD is clinically important, because even benign fatty liver can progress to steatohepatitis in many patients, which can lead to liver cirrhosis and its complications and hepatocellular carcinoma. NAFLD is a hepatic manifestation of metabolic syndrome; it is closely related to other clinical features of metabolic syndrome, and thus to cardiovascular morbidity. There are several different noninvasive techniques for formal diagnosis and follow-up, but liver biopsy remains the gold standard. The most important therapeutic strategies include lifestyle changes, including changes in dietary habits aimed at weight loss and blood pressure regulation, with a consequent decrease in insulin resistance. For some patients with NAFLD/nonalcoholic steatohepatitis, pharmacological treatment is the best option, although further studies are needed to confirm its efficacy and tolerability.
Targets for Medical Therapy in Obesity
Authors: Baretić Maja
Published: June 2012

Obesity has more than doubled since 1980 all over the world, and in the European perspective it does not seem to be better. Obesity-related diseases like diabetes, hypertension, coronary heart disease, stroke and hyperlipidemia are the main cause of mortality and morbidity in developed countries. These are the reasons for continuous search for efficient treatment of obesity. One of the options is medical therapy. Over history, many anti-obesity drugs were introduced and subsequently removed from the market due to various side effects. Unfortunately, there is still no ideal drug for the treatment of obesity, and the current ones are very strictly evaluated. The anti-obesity drug should target patients that have previously failed to lose weight with lifestyle interventions, with body mass index (BMI) ≥30, or those with BMI ≥27 plus concomitant obesity-related risk factors or diseases. The only drug currently approved in Europe is orlistat, a pancreatic lipase inhibitor. Sibutramine, an appetite suppressant (serotonin-norepinephrine reuptake inhibitor), has been off the market since 2010 due to cardiovascular side effects. There is a large group of drugs used for other indications with weight loss effects, e.g. incretin mimetics or analogues used in the treatment of diabetes type 2, topiramate used as an anticonvulsant, and fluoxetine and sertraline used in the treatment of depression.
Diagnosis and Management of Acute and Early Complications of/after Bariatric Surgery
Authors: Car Peterko A. , Kirac I. , Gaurina A. , Diklić D. , Bekavac-Bešlin M.
Published: June 2012

The number of obese people is over one billion worldwide, and the trend is increasing. Frequent failure of conservative approach has been observed. Therefore, various surgical techniques, such as bariatric surgery, are accepted today as a safe and effective treatment of morbid obese condition, and are associated with low perioperative morbidity and mortality rates. The most popular and commonly performed procedures are those related to minimum complications and adequate weight loss: laparoscopic adjustable gastric banding and laparoscopic Roux-en-Y gastric bypass. Since major and minor complications occur in the perioperative, early and late postoperative period, we discuss most frequent complications and importance of early recognition as well as adequate interventions.
Endoscopic Approaches to Obesity
Authors: Štimac Davor , Majanović Sanja Klobučar
Published: June 2012

Given the emerging role of endoscopic procedures in the treatment of obesity and rapid changes in endoscopic technologies and techniques, this review considers the current state of endoscopic management of obesity. Endoluminal interventions performed entirely through the GI tract by using flexible endoscopy offer the potential for an ambulatory weight loss procedure that may be safer and more cost- effective compared with current surgical approaches. Endoscopic techniques attempt to mimic the anatomic features of bariatric surgery. Accordingly, there are two main endoscopic weight loss modalities – restrictive and malabsorptive. Restrictive procedures act to decrease gastric volume by space-occupying prosthesis and/or by suturing or stapling devices, while malabsorptive procedures tend to create malabsorption by preventing food contact with the duodenum and proximal jejunum. The former include intragastric balloon treatment, endoluminal vertical gastroplasty, transoral gastroplasty and transoral endoscopic restrictive implant system, while the latter include duodenojejunal bypass sleeve. Gastroduodenojejunal bypass sleeve is a combination of both procedures. Except for intragastric balloon, all mentioned procedures are rather new, tested on a small number of human subjects, with a high rate of success, but with limited knowledge on safety and long-term efficacy. The role of gastric electrical stimulation and intragastric injections of botulinum toxin in obesity treatment is also considered as is the role of minimally invasive bariatric endoscopic interventions.
The Role of Autoimmunity in Gastroenterology
Authors: Krejsek Jan , Hrncirova Lucia , Kondelkova Katerina , Andrys Ctirad
Published: June 2012

Crohn’s disease (CD) is an immune-mediated chronic intestinal disorder thought to be the result of an aggressive immune response to a subset of enteric bacteria in a genetically predisposed host. Numerous environmental factors are apparently involved in disease pathogenesis. Impaired ability of CD patients to control the gut microflora is associated with defects in the production of some antibacterial compounds (cryptdins) by epithelial cells. In addition, there are the defects in cytoplasmic NOD-like receptors which are sensing intracellularly localized bacteria in CD patients. These defects together with the failure to induce autophagy lead to lack of bacterial clearance and subsequently to mucosal immunopathology.
The Role of Autoantibodies in Inflammatory Bowel Disease
Authors: Herszényi László , Tulassay Zsolt
Published: June 2012

The search for the underlying trigger of an inappropriate inflammatory reaction characteristic of inflammatory bowel diseases (IBD) has led to the discovery of several antibodies. The panel of serologic markers for IBD is rapidly expanding. Serologic markers hold the promise of helping researchers and clinicians to better understand IBD heterogeneity and natural history. The real importance of the antibodies produced against various microbial and autoantigens is still uncertain. Whether these antibodies play a primary role in the pathogenesis of IBD, or their presence is only a consequence of the inflamed mucosa is a fundamental question that remains to be clarified. The impact of the routine evaluation of these serologic markers in the everyday clinical IBD diagnostic algorithm is questionable due to their limited sensitivity. Despite their great potential, the routine use of serologic markers for diagnosis and follow-up is currently not justified. However, their correlation with disease phenotype and behavior is more established. A combination of serum markers has been shown to be of more value compared to using single markers alone. The ongoing challenge is how to best utilize these serologic markers to provide clinically relevant information in a cost-effective manner. Further prospective clinical trials are needed to determine their exact role in pathogenesis and practical clinical importance. We review the current standpoint of the clinical impact of various established and newly suggested markers in Crohn’s disease and ulcerative colitis.
Diagnosis and Treatment of Autoimmune Hepatitis
Authors: Lata Jan
Published: June 2012

Autoimmune hepatitis (AIH) is a generally progressive, chronic liver disease of unknown etiology, relatively uncommon, associated with chronic hepatic inflammation. An environmental agent is hypothesized to trigger an immune-mediated attack directed against liver antigens in genetically predisposed individuals. The disease can lead to potentially fatal liver dysfunction. AIH is characterized by female predominance (sex ratio 3.6:1), hypergammaglobulinemia, circulating autoantibodies and association with human leukocyte antigens DR3 or DR4. The diagnosis of AIH is based on the revised descriptive criteria reported by the International Autoimmune Hepatitis Group in 1999. Without appropriate immunosuppressive therapy AIH has a very poor prognosis with 10-year survival rates as low as 10%, but usually very good response to immunosuppression, and survival rates of responders to the treatment are similar to those of healthy counterparts from the same population.
Immunoglobulin G4-Related Cholangitis: A Variant of IgG4-Related Systemic Disease
Authors: Novotný Ivo , Dítě Petr , Trna Jan , Lata Jan , Husová Libuše , Geryk Edvard
Published: June 2012

IgG4-related sclerosing cholangitis as part of IgG4 systemic-related diseases is commonly associated with autoimmune pancreatitis. Major clinical manifestations of IgG4-related sclerosing diseases are apparent in the organs in which tissue fibrosis with obstructive phlebitis is pathologically induced. IgG4-related sclerosing cholangitis is included within the heterogeneous group of ‘sclerosing cholangitis’. Sclerosing cholangitis may be associated with choledocholithiasis, infection or biliary malignancies. Sclerosing cholangitis of unknown etiology is called primary sclerosing cholangitis (PSC). Conservative therapy of PSC is usually unsuccessful, the disease involves extra- and/or intrahepatic biliary tree, and the end point of this disease is liver cirrhosis. Typically, PSC is identified at the age of 30 to 40 years, and the disease is frequently associated with inflammatory bowel diseases. On the other hand, IgG4-related sclerosing cholangitis is not associated with inflammatory bowel diseases. In patients with IgG4-related sclerosing cholangitis, a first symptom can be obstructive jaundice, whereas obstructive jaundice is rarely present in PSC. Clinically, patients with IgG4-related sclerosing cholangitis are older at diagnosis compared to patients with PSC. A typical diagnostic feature of IgG4-related sclerosing cholangitis is elevation of serum immunoglobulin G4. In patients with IgG4-related sclerosing cholangitis, response to steroid therapy is high; in patients with PSC corticosteroid therapy is unsuccessful. Histochemically abundant infiltration of IgG4-positive plasma cells is detected in the biliary duct wall. Histologically, we can identify dense lymphoplasmacytic infiltration of the bile duct wall, transmural fibrosis, lymphoplasmacytic infiltration and fibrosis in the periportal area of the liver – a typically obliterative phlebitis. The biliary epithelium is usually intact in contrast to PSC, where mucosal erosion is often present. Steroids are the first-choice therapy of IgG4-related sclerosing cholangitis. In the literature, cholangiocarcinoma in patients with IgG4- related sclerosing cholangitis was not described, whereas cholangiocarcinoma develops in up to 10–30% of patients with PSC.
Food Allergy: From Diagnosis to Treatment
Authors: Scarpellini E. , Tack J.
Published: June 2012

Adverse food reactions, an adverse health effect arising from an immune or nonimmune response that occurs reproducibly on the exposure to a given food, can be divided into toxic and hypersensitivity reactions. When an immunologic mechanism has been shown, hypersensitivity food reactions should be referred to as food allergy that may be IgE- or non-IgE-mediated. Food allergy diagnosis is mainly guided by a correct and accurate history and physical examination, thus leading to prick test and elimination diets. The treatment gold standard is still represented by an elimination diet together with antihistamines and corticosteroid usage in order to reduce the gastrointestinal and potentially life-threatening systemic symptoms. Other treatments are currently under investigation with promising results.
Clinical Spectrum of Movement Disorders after Stroke in Childhood and Adulthood
Authors: Béjot Yannick , Giroud Maurice , Moreau Thibault , Benatru Isabelle
Published: June 2012

Although rare, many different types of hyperkinetic and hypokinetic movement disorders have been described after both ischemic and hemorrhagic stroke in children and in adults. Current knowledge about these disorders comes from single case reports or small series of cases compiled from retrospective studies. Data from hospital-based studies suggest a prevalence of poststroke movement disorders ranging from 1.1 to 3.9%. However, despite the development of emergency care for stroke, these clinical syndromes remain insufficiently recognized. Poststroke movement disorders take place in the acute phase or following a variable delay after stroke onset, and could be transient or persistent. Dystonia is the most frequent movement disorder, occurring after a delay of several months, while chorea and hemiballism are most frequent in the acute stages. Amongst transient movement disorders, limb shaking is associated with high-grade stenosis or occlusion of the internal carotid artery, while myoclonus and asterixis are rare. From a pathophysiological point of view, most of these symptoms are induced by a lesion involving the basal ganglia, the thalamus, or the frontal subcortical pathways. In this article, we updated the clinical spectrum, neuropathophysiological mechanisms, and prognosis of stroke-induced movement disorders in adults and children.
Markers for Gastric Cancer Premalignant Lesions: Where Do We Go?
Authors: Leja Marcis , Wex Thomas , Malfertheiner Peter
Published: June 2012

Only a small proportion of patients infected with Helicobacter pylori develop gastric cancer during their lifetime. At the same time, this type of cancer remains an important cause of mortality globally. The current interventional strategies have not been successful in decreasing the global burden of the disease; therefore, biomarkers for the identification of the individuals at high risk as well as those in the early stage of the disease is of high importance. In addition, predicting the point of no return for the development of the malignancy is of particular interest; whether atrophy, intestinal or spasmolytic polypeptide-expressing metaplasia, or some of their subtypes correspond to this point, still needs to be answered. The current review addresses the place of ‘old markers’, in particular pepsinogen tests for the identification of increased risk conditions. More data in Caucasian populations are required before these tests can be recommended for routine screening. Several of the host genetic factors are related to the development of sporadic gastric cancer; still their importance is probably not so high as initially thought, and at this stage host genetic factors cannot be used to identify high-risk groups. The detection of specific microRNAs could become a potential field in marker development, and several other new approaches for marker identification are emerging. To achieve the goal, a screening marker has to be not only accurate, but also available and cost-effective in the target populations, many of which are from low-income countries. This has to be considered when developing a marker or set of markers offered for gastric cancer screening programs.
Novel Prognostic Biomarkers in Colorectal Cancer
Authors: Malesci Alberto , Laghi Luigi
Published: June 2012

The main predictor of outcome of patients with colorectal cancer (CRC) remains the TNM staging system. Biomarkers, i.e. biological indicators of disease progression or of responsiveness to a pharmacological intervention, are expected to be of help in the management of CRC. Despite high expectations, biomarkers have not entered into clinical practice due to contradictory results of large-scale studies and to some complexity in data interpretation. Here we briefly review the main genetic and immunological changes that have been considered potential CRC biomarkers and that might be considered for further testing aimed at clinical use, at least in specific disease settings.
Microsatellite Instability and Therapeutic Consequences in Colorectal Cancer
Authors: Laghi Luigi , Malesci Alberto
Published: June 2012

Microsatellite instability (MSI), the molecular phenotype of colorectal cancers with mismatch repair defects was discovered in the last decade of the previous century. As a field of investigation which successfully joins basic and clinical science, MSI is an example of real translational science, starting from the molecular basis of a disease and extending to the clinical arena. In clinical settings, MSI is a diagnostic biomarker leading to the diagnosis of hereditary nonpolyposis colorectal cancer. However, the clinical implication of MSI testing extends to the role of prognostic marker, due to the better outcome of patients with MSI colorectal cancer. Additionally, MSI identified a general lack of response to neo-adjuvant therapy employing 5-fluorouracil. Like predictive markers of response to chemotherapy, the role of MSI is likely not exhausted, as chemotherapy regimens need to take into account the peculiar biological and clinical behavior of MSI cancers.
Usefulness of the Preoperative Administration of Tegafur Suppositories as Alternative Adjuvant Chemotherapy for Patients with Resectable Stage II or III Colorectal Cancer: A KODK4 Multicenter Randomized Control Trial
Authors: Okabayashi Koji , Hasegawa Hirotoshi , Watanabe Masahiko , Ohishi Takashi , Hisa Akio , Kitagawa Yuko
Published: June 2012

Objective: The aim of this study was to evaluate the feasibility and conferred protection against recurrence of preoperatively administered tegafur suppositories following the intravenous and oral administration of fluoropyrimidine in a multicenter randomized control trial. Methods: Patients with clinical T3/4 colorectal cancer were randomly assigned to receive the preoperative administration of tegafur suppositories (group A) or no preoperative treatment (group B). The primary end points were disease-free survival (DFS) and overall survival (OS). Results: The mean follow-up periods were 80.9 ± 31.0 months in group A and 64.5 ± 28.8 months in group B. The 5-year DFS rates were 89.3% in group A and 70.3% in group B (p = 0.045), whereas the 5-year OS rates were 91.4% in group A and 73.2% in group B (p = 0.051). Furthermore, a significant difference in the cumulative distant metastatic rate was observed (group A, 7.4% vs. group B, 23.4%; p = 0.03). However, no significant difference in the cumulative local recurrence rate was seen (group A, 4.6% vs. group B, 8.2%; p = 0.68). Conclusion: Despite a relatively small sample size, preoperative tegafur suppositories might protect recurrences and improve survival rates, mainly by preventing distant metastasis. These findings suggest the utility of tegafur suppositories as an alternative neoadjuvant treatment in modern chemotherapy for colorectal cancer.
Varying Allergen Composition and Content Affects the in vivo Allergenic Activity of Commercial Dermatophagoides pteronyssinus Extracts
Authors: Casset Anne , Mari Adriano , Purohit Ashok , Resch Yvonne , Weghofer Margit , Ferrara Rosetta , Thomas Wayne R. , Alessandri Claudia , Chen Kuan-Wei , de Blay Frédéric , Valenta Rudolf , Vrtala Susanne
Published: June 2012

Background: Diagnosis and immunotherapy of house-dust mite (HDM) allergy is still based on natural allergen extracts. The aim of this study was to analyze commercially available Dermatophagoides pteronyssinus extracts from different manufacturers regarding allergen composition and content and whether variations may affect their allergenic activity. Methods: Antibodies specific for several D. pteronyssinus allergens (Der p 1, 2, 5, 7, 10 and 21) were used to analyze extracts from 10 different manufacturers by immunoblotting. Sandwich ELISAs were used to quantify Der p 1 and Der p 2 in the extracts. Mite-allergic patients (n = 45) were skin-tested with the extracts and tested for immunoglobulin E (IgE) reactivity to a panel of 10 mite allergens (Der p 1, 2, 4, 5, 7, 8, 10, 14, 20 and 21) by dot blot. Results: Only Der p 1 and Der p 2 were detected in all extracts but their concentrations and ratios showed high variability (Der p 1: 6.0–40.8 µg ml–1; Der p 2: 1.7–45.0 µg ml–1). At least 1 out of 4 allergens (i.e. Der p 5, 7, 10 and 21) was not detected in 8 of the studied extracts. Mite-allergic subjects showed different IgE reactivity profiles to the individual mite allergens, the extracts showed different allergenic activity in skin-prick tests and false-negative results. Conclusions: Commercially available D. pteronyssinus extracts lack important allergens, show great variability regarding allergen composition and content and some gave false-negative diagnostic test results in certain patients.
Transcutaneous Electrical Nerve Stimulation Improves Low Back Pain during Pregnancy
Authors: Keskin E.A. , Onur O. , Keskin H.L. , Gumus I.I. , Kafali H. , Turhan N.
Published: June 2012

Background: To compare the efficiency of transcutaneous electrical nerve stimulation (TENS) with those of exercise and acetaminophen for the treatment of pregnancy-related low back pain (LBP) during the third trimester of pregnancy. Methods: This prospective study included 79 subjects (≥32 gestational weeks) with visual analog scale (VAS) pain scores ≥5. Participants were divided randomly into a control group (n = 21) and three treatment groups [exercise (n = 19); acetaminophen (n = 19); TENS (n = 20)]. The VAS and the Roland-Morris disability questionnaire (RMDQ) were completed before and 3 weeks after treatment to assess the impact of pain on daily activities. Results: During the study period, pain intensity increased in 57% of participants in the control group, whereas pain decreased in 95% of participants in the exercise group and in all participants in the acetaminophen and TENS groups. Post-treatment VAS and RMDQ values were significantly lower in the treatment groups (p < 0.001). VAS and RMDQ scores indicated a significantly greater degree of pain relief in the TENS group than in the exercise and acetaminophen groups (p < 0.001). No adverse effect of TENS application on pregnant women was observed during the study. Conclusion: TENS is an effective and safe treatment modality for LBP during pregnancy. TENS improved LBP more effectively than did exercise and acetaminophen.
Urinary Urgency Medications May Compromise Discrete rather than Global Cognitive Skills
Authors: Monnot Marilee , Ross Elliott
Published: June 2012

Background/Aims: Prior research about cognitive problems associated with the use of urinary urgency medication (UUM) has reported mixed results that suggest procedures and/or assessments may need to be refined. Methods: Ten elderly subjects who were actively taking a UUM were assessed with neuropsychological testing before and after a 4-week UUM washout period. Results were evaluated by examining discrete subtest results, full-scale scores, and the reliable change index methodology. Results: Four controls and 5 subjects with mild cognitive impairment showed significant improvement in at least one subtest score on well-characterized instruments. Conclusion: In this case study of 10 subjects, withdrawal of oxybutynin and tolterodine resulted in significant changes in subtest scores with different patterns for each subject that were not necessarily reflected in their total scores. Thus, future clinical studies should always include analysis of subtest results as these changes may be the only indication that cognition has been improved or has declined significantly.
Plasma D-Dimer Level as a Mortality Predictor in Patients with Advanced or Recurrent Colorectal Cancer
Authors: Yamamoto Manabu , Yoshinaga Keiji , Matsuyama Ayumi , Iwasa Tokiomi , Osoegawa Atsushi , Tsujita Eiji , Yamashita Yoichi , Tsutsui Shinichi , Ishida Teruyoshi
Published: June 2012

Objective: Plasma D-dimer levels are elevated in patients with a variety of solid tumors. Recently, it has been reported that the level before curative surgery is a prognostic factor for colorectal cancer (CRC). We investigated whether the plasma D-dimer level before systemic chemotherapies is a predictor for advanced or recurrent unresectable CRC. Methods: This study included 42 patients treated with systemic chemotherapies for advanced or recurrent unresectable CRC. Variables including clinicopathological factors, plasma D-dimer levels and the modified Glasgow Prognostic Factor Score (mGPS) were evaluated. Results: The plasma D-dimer level was closely related to the mGPS. Survival was shorter for patients with plasma D-dimer levels >5 µg/ml than for those with lower levels. Compared with an mGPS of 0 or 1, an mGPS of 2 was predictive of poor prognosis (p < 0.0001). Old age, advanced stage, plasma D-dimer level and mGPS were significantly associated with mortality, but plasma D-dimer level was the only independent risk factor in multivariate analysis, and was significant related to the clinical response to chemotherapy (p < 0.05). Conclusions: Survival was significantly shorter in patients with elevated plasma D-dimer levels having advanced or recurrent CRC. The plasma D-dimer level before systemic chemotherapies was an independent mortality predictor.
Long-Term Outcome of Patients with Antiphospholipid Syndrome Who Undergo Percutaneous Coronary Intervention
Authors: Perl Leor , Netzer Adi , Rechavia Eldad , Bental Tamir , Assali Abid , Codner Pablo , Mager Aviv , Battler Alexander , Kornowski Ran , Lev Eli I.
Published: June 2012

Objectives: Patients with antiphospholipid antibody syndrome (APS) have an increased risk of atherothrombotic complications. There are limited data regarding the outcome of patients with APS who undergo percutaneous coronary intervention (PCI). Accordingly, we aimed to assess the long-term outcomes of these patients. Methods: Nineteen APS patients who underwent PCI between the years 2003 and 2008 were compared to 380 patients who had undergone PCI during the same period (PCI group) and were matched by age (±5 years), gender, diabetes and hypertension. In addition, APS patients were compared to 1,458 patients with ST segment elevation myocardial infarction (MI) who were treated with PCI during the same period. Six-month to 4-year clinical outcomes were evaluated. Results: The indication for PCI in the APS group was acute coronary syndrome in 52.6% of patients. After 1 year of follow-up, patients with APS had higher rates of target vessel revascularization than the other two groups, which translated to higher rates of major adverse cardiac events. There were no differences in MI or mortality rates between the groups. Conclusions: Patients with APS who undergo PCI have worse long-term clinical outcomes, driven by higher rates of revascularization, than other patients undergoing PCI. Further study is warranted to examine the mechanisms underlying these findings.
Heart Rate Response to a Timed Walk and Cardiovascular Outcomes in Older Adults: The Cardiovascular Health Study
Authors: Girotra Saket , Kitzman Dalane W. , Kop Willem J. , Stein Phyllis K. , Gottdiener John S. , Mukamal Kenneth J.
Published: June 2012

Objectives: To determine the relationship between heart rate response during low-grade physical exertion (6-min walk) with mortality and adverse cardiovascular outcomes in the elderly. Methods: Participants in the Cardiovascular Health Study who completed a 6-min walk test were included. We used delta heart rate (difference between postwalk heart rate and resting heart rate) as a measure of chronotropic response and examined its association with (1) all-cause mortality and (2) incident coronary heart disease event, using multivariable Cox regression models. Results: We included 2,224 participants (mean age 77 ± 4 years; 60% women; 85% white). The average delta heart rate was 26 beats/min. Participants in the lowest tertile of delta heart rate (<20 beats/min) had higher risk-adjusted mortality [hazard ratio (HR) 1.18, 95% confidence interval (CI) 1.00–1.40] and incident coronary heart disease (HR 1.37, 95% CI 1.05–1.78) compared to subjects in the highest tertile (≥30 beats/min), with a significant linear trend across tertiles (p for trend <0.05 for both outcomes). This relationship was not significant after adjustment for distance walked. Conclusion: Impaired chronotropic response during a 6-min walk test was associated with an increased risk of mortality and incident coronary heart disease among the elderly. This association was attenuated after adjusting for distance walked.
Bioequivalence of Intravenous and Oral Formulations of the Antiepileptic Drug Lacosamide
Authors: Cawello Willi , Bonn Rainer , Boekens Hilmar
Published: June 2012

Background/Aims: To evaluate the bioequivalence of intravenous and oral lacosamide (tablet), an antiepileptic drug. Methods: Two randomized, single-dose (200 mg) trials were conducted: a 2-way trial (study A, 15-min infusion, oral tablet) and a 3-way crossover trial (study B, 30- and 60-min infusions, oral tablet). Twenty four healthy men participated in study A and 27 in study B. Eighteen blood samples were taken before to 72 h after lacosamide administration during each treatment period, followed by a 1-week washout. Safety and the ratio of intravenous/oral lacosamide for AUC0–tz (area under the concentration-time curve from zero up to the last measurable plasma concentration) and Cmax (maximum plasma concentration) were evaluated. Results: For AUC0–tz and Cmax, 90% confidence intervals for the ratio of intravenous/oral lacosamide fell within the predetermined bioequivalence range (80–125%) for 30- and 60-min infusions. In study A, all adverse events (AEs) were mild, with no discontinuations. In study B, 3 volunteers discontinued due to AEs; one serious AE (epiglottitis) was reported. No clinically relevant effects on vital signs, electrocardiograms or laboratory parameters and no AEs relating to infusion site were reported. Conclusion: Intravenous infusions (15, 30 and 60 min) of 200 mg lacosamide are as well tolerated as the oral tablet. Bioequivalence was demonstrated for 30- and 60-min infusions; therefore, direct conversion from oral to intravenous lacosamide, or vice versa, is possible.
Age-Related Aspects of Addiction
Authors: Koechl Birgit , Unger Annemarie , Fischer Gabriele
Published: June 2012

Research has shown that substance use, abuse and addiction are not limited to a specific age group. Problems related to substance addiction are an important cause of morbidity in the population aged 65 years and above, especially the abuse of prescription drugs and legal substances. A lack of evidence-based studies and tailored treatment options for the aging population is evident. Appropriate and effective health care is an important goal to improve the health-related quality of life of elderly people. Research in the increasingly aging population needs to include an age- and gender-sensitive approach.
Vitamin D May Not Improve Lipid Levels
Authors: Ponda Manish P. , Huang Xiaohua , Odeh Mouneer A. , Breslow Jan L. , Kaufman Harvey W.
Published: June 2012

Background—

Vitamin D deficiency is highly prevalent and is associated with dyslipidemia and cardiovascular disease. The impact of correcting vitamin D deficiency on blood lipids, strong cardiovascular disease prognostic factors, is unknown.

Methods and Results—

To determine relationships between 25-hydroxyvitamin D levels and lipids, we analyzed 4.06 million deidentified patient laboratory test results from September 2009 through February 2011. We performed a cross-sectional study of this population to determine associations between 25-hydroxyvitamin D levels and lipids across clinically defined strata. We also conducted a retrospective cohort study of vitamin D deficient patients to investigate how changes in 25-hydroxyvitamin D levels relate to changes in lipid levels. After exclusions, 107 811 patients with serial testing were selected for cross-sectional analysis. Compared with vitamin D deficient patients (<20 ng/mL), those with optimal levels (≥30 ng/mL) had lower mean total cholesterol (−1.9 mg/dL; 95% confidence interval [95% CI], −1.2 to −2.7;
P
<0.0001), lower low-density lipoprotein cholesterol (−5.2 mg/dL; 95% CI, −4.5 to −5.8;
P
<0.0001), higher high-density lipoprotein cholesterol (4.8 mg/dL; 95% CI, 4.5–5.0;
P
<0.0001), and lower triglycerides (−7.5 mg/dL; 95% CI, −6.2 to −8.7;
P
<0.0001). For the retrospective cohort analysis, raising vitamin D levels from <20 to ≥30 ng/mL (n=6260), compared with remaining at <20 ng/mL (n=2332), was associated with a mean increase in total cholesterol (0.77 mg/dL; 95% CI, 0.18–1.36;
P
=0.01) and high-density lipoprotein cholesterol (0.42 mg/dL; 95% CI, 0.08–0.76;
P
=0.02) but nonsignificant changes in low-density lipoprotein cholesterol (0.32 mg/dL; 95% CI, −0.01 to 0.66;
P
=0.06) and triglycerides (0.04 mg/dL; 95% CI, −2.16 to 2.23 mg/dL;
P
=0.97).

Conclusions—

Although vitamin D deficiency is associated with an unfavorable lipid profile in cross-sectional analyses, correcting for a deficiency might not translate into clinically meaningful changes in lipid concentrations; however, data from intervention trials are required to confirm these findings.
Independent Representations of Verbs and Actions in Left Lateral Temporal Cortex
Authors: Peelen Marius V. , Romagno Domenica , Caramazza Alfonso
Published: June 2012

Verbs and nouns differ not only on formal linguistic grounds but also in what they typically refer to: Verbs typically refer to actions, whereas nouns typically refer to objects. Prior neuroimaging studies have revealed that regions in the left lateral temporal cortex (LTC), including the left posterior middle temporal gyrus (pMTG), respond selectively to action verbs relative to object nouns. Other studies have implicated the left pMTG in action knowledge, raising the possibility that verb selectivity in LTC may primarily reflect action-specific semantic features. Here, using functional neuroimaging, we test this hypothesis. Participants performed a simple memory task on visually presented verbs and nouns that described either events (e.g., “he eats” and “the conversation”) or states (e.g., “he exists” and “the value”). Verb-selective regions in the left pMTG and the left STS were defined in individual participants by an independent localizer contrast between action verbs and object nouns. Both regions showed equally strong selectivity for event and state verbs relative to semantically matched nouns. The left STS responded more to states than events, whereas there was no difference between states and events in the left pMTG. Finally, whole-brain group analysis revealed that action verbs, relative to state verbs, activated a cluster in pMTG that was located posterior to the verb-selective pMTG clusters. Together, these results indicate that verb selectivity in LTC is independent of action representations. We consider other differences between verbs and nouns that may underlie verb selectivity in LTC, including the verb property of predication.
Ventral and Dorsal Stream Interactions during the Perception of the Müller-Lyer Illusion: Evidence Derived from fMRI and Dynamic Causal Modeling
Authors: Plewan Thorsten , Weidner Ralph , Eickhoff Simon B. , Fink Gereon R.
Published: June 2012

The human visual system converts identically sized retinal stimuli into different-sized perceptions. For instance, the Müller-Lyer illusion alters the perceived length of a line via arrows attached to its end. The strength of this illusion can be expressed as the difference between physical and perceived line length. Accordingly, illusion strength reflects how strong a representation is transformed along its way from a retinal image up to a conscious percept. In this study, we investigated changes of effective connectivity between brain areas supporting these transformation processes to further elucidate the neural underpinnings of optical illusions. The strength of the Müller-Lyer illusion was parametrically modulated while participants performed either a spatial or a luminance task. Lateral occipital cortex and right superior parietal cortex were found to be associated with illusion strength. Dynamic causal modeling was employed to investigate putative interactions between ventral and dorsal visual streams. Bayesian model selection indicated that a model that involved bidirectional connections between dorsal and ventral stream areas most accurately accounted for the underlying network dynamics. Connections within this network were partially modulated by illusion strength. The data further suggest that the two areas subserve differential roles: Whereas lateral occipital cortex seems to be directly related to size transformation processes, activation in right superior parietal cortex may reflect subsequent levels of processing, including task-related supervisory functions. Furthermore, the data demonstrate that the observer's top–down settings modulate the interactions between lateral occipital and superior parietal regions and thereby influence the effect of illusion strength.
Temporal Dynamics of Neural Activity at the Moment of Emergence of Conscious Percept
Authors: Noguchi Yasuki , Yokoyama Takemasa , Suzuki Megumi , Kita Shinichi , Kakigi Ryusuke
Published: June 2012

From which regions of the brain do conscious representations of visual stimuli emerge? This is an important but controversial issue in neuroscience because some studies have reported a major role of the higher visual regions of the ventral pathway in conscious perception, whereas others have found neural correlates of consciousness as early as in the primary visual areas and in the thalamus. One reason for this controversy has been the difficulty in focusing on neural activity at the moment when conscious percepts are generated in the brain, excluding any bottom–up responses (not directly related to consciousness) that are induced by stimuli. In this study, we address this issue with a new approach that can induce a rapid change in conscious perception with little influence from bottom–up responses. Our results reveal that the first consciousness-related activity emerges from the higher visual region of the ventral pathway. However, this activity is rapidly diffused to the entire brain, including the early visual cortex. These results thus integrate previous “higher” and “lower” views on the emergence of neural correlates of consciousness, providing a new perspective for the temporal dynamics of consciousness.