bluuebunny/crossref_metadata_2025 huggingface dataset:
Is a Patient Controller for Parkinson’s Disease Patients with Subthalamic Nucleus Deep Brain Stimulation Reasonable?
Authors: Allert Niels , Mehnert Caroline , Lehrke Ralph , Maarouf Mohammed , Sturm Volker
Published: April 2017

Background: A patient controller (PC) is an optional device for patients with deep brain stimulation (DBS) to have limited control of their stimulator system. Objectives: We investigated the impact of a PC on DBS safety, most notably the handling/prevention of unexpected DBS failure in patients with Parkinson’s disease (PD). Methods: PD patients with subthalamic DBS were educated in the use of a PC. After a first impulse generator (IPG) replacement, data on the use of the PC were obtained from the patients’ records and by a patient questionnaire. Results: A total of 27 patients with IPG replacements after 4.4 ± 0.8 years (118.8 patient-years) were included. Thirteen patients transiently used the PC to optimize stimulation amplitudes. Eighteen patients reported events when they used the PC to ensure DBS being on. No accidental switch off by environmental electromagnetism was confirmed. In contrast, 4 patients accidentally turned the IPG off with the PC. Sixteen patients regularly checked the IPG battery but only 1 patient noted a low battery status before quarterly control visits. Of the 27 patients, 26 had anticipated and only 1 an unanticipated IPG replacement. Conclusions: A PC is not needed for patient safety. However, in some patients, a PC is helpful to optimize stimulation amplitudes and to increase the patients’ own perception of safety.
Modulation of Liver Fibrosis by Adipokines
Authors: Marra Fabio , Navari Nadia , Vivoli Elisa , Galastri Sara , Provenzano Angela
Published: April 2017

Hepatic fibrosis is an integrated process triggered by chronic liver damage, leading to the accumulation of extracellular matrix. In patients with chronic liver disease, this process is favored by the presence of obesity or overweight, which are also relevant risk factors for the progression of nonalcoholic steatohepatitis. In this paper, we review the available evidence indicating the modulation of the fibrogenic process by adipokines, a group of cytokines secreted primarily by adipose tissue. In particular, we discuss in detail the role of leptin and adiponectin, which favor and limit the fibrogenic process, respectively. The possible involvement of other recently identified adipokines is also briefly outlined.
Requirements and Challenges of a Preclinical Autoimmune Hepatitis Mouse Model
Authors: Hardtke-Wolenski Matthias , Noyan Fatih , Jaeckel Elmar
Published: April 2017

Autoimmune hepatitis (AIH) is a chronic autoimmune inflammation of the liver usually requiring life-long immunosuppression. Steroids and azathioprin are the standard therapy, but the therapy is accompanied by strong side effects. Due to the fact that AIH is often recognized during late course of disease, it is difficult to obtain knowledge about the immunological mechanisms responsible for initiation of the disease. Current AIH models were helpful for understanding and modulating liver immune responses, but are not suited to study mechanisms in chronic AIH or to develop new therapies. While transgenic AIH models deal with short-term hepatitis, models with natural antigens are either self-limited or have unknown target antigens. Therefore, new animal models with defined onset of AIH and a standard course of the disease are essential for a more defined understanding of the disease and its pathophysiology. To obtain a preclinical platform for new therapeutic approaches or to be able to prevent onset of AIH, a positive impact of conventional standard therapeutic interventions in the model would be helpful. For decades, AIH research has lacked such a reliable preclinical model with chronic immune response against the liver. Initial results in breaking tolerance against hepatocytes have only led to mild and transient hepatitis. Transgenic models were helpful in understanding different aspects for hepatic immune regulation. Nowadays, the fate of T cells, especially CD8+ T cells, is the focus of research. Especially ignorance, anergy, deletion or TCR downregulation of T cells are mechanisms of tolerance against hepatic antigens. Furthermore, the importance of professional antigen-presenting cells and particularly liver sinusoidal cells in liver tolerance has been demonstrated in many studies. Other models have shown the mechanism of interaction of adaptive and innate immune cells in the liver. Recently, approaches have been made to establish AIH models reflecting the situation in AIH patients. This will allow new studies in the field and will provide an opportunity to study the onset and pathophysiology of AIH. Furthermore, these models will try new options for therapeutic approaches and might show options of how to prevent onset of disease.
High Indoor Microbial Levels Are Associated with Reduced Th1 Cytokine Secretion Capacity in Infancy
Authors: Lappalainen Mikko Harri Juhani , Hyvärinen Anne , Hirvonen Maija-Riitta , Rintala Helena , Roivainen Jarkko , Renz Harald , Pfefferle Petra Ina , Nevalainen Aino , Roponen Marjut , Pekkanen Juha
Published: April 2017

Background: Exposure to microbes and their components may affect the maturation of the immune system. We examined the association of house dust microbial content with cytokine-producing capacity at birth and at the age of 1 year. Methods: Production of TNF-α, IFN-γ, IL-5, IL-8 and IL-10 at birth (n = 228) and at the age of 1 year (n = 200) following 24- and 48-hour whole-blood stimulation with staphylococcal enterotoxin B (SEB), lipopolysaccharide and the combination of phorbol ester and ionomycin was measured. Concentrations of ergosterol (marker for fungal biomass), muramic acid (marker for Gram-positive bacteria) and 3-hydroxy fatty acids with a carbon chain length from 10 to 14 (marker for Gram-negative bacteria) in living room floor dust were analyzed using gas chromatography-tandem mass spectrometry. Five single microbial species or groups were determined using a quantitative polymerase chain reaction method. Results: A high total level of the studied Gram-positive bacteria in general or Mycobacterium spp. in house dust was associated with decreased SEB-stimulated IFN-γ production, especially at the age of 1 year. The total level of indoor fungi analyzed (Penicillium spp., Aspergillus spp. and Paecilomyces variotii group, Trichoderma viride/atroviride/koningii,Wallemia sebi) was also inversely associated with IFN-γ production at the age of 1 year, but this association did not remain significant after adjustment for potential confounders. A few associations were found between microbial exposures and other measured cytokines. Conclusions: High indoor microbial exposures may affect immune development in early life by reducing T helper type 1 cytokine secretion capacity. The observed hyporesponsiveness may reflect the adaptation of the immune system to environmental antigens. In future, more attention should be paid especially to the immunomodulatory role of exposures to Gram-positive bacteria.
Serum IL-23 Strongly and Inversely Correlates with FEV1 in Asthmatic Children
Authors: Ciprandi Giorgio , Cuppari Caterina , Salpietro Anna Maria , Tosca Maria Angela , Rigoli Luciana , Grasso Luisa , La Rosa Mario , Marseglia Gian Luigi , del Giudice Michele Miraglia , Salpietro Carmelo
Published: April 2017

Background: Recently, Th17 cells have been found to participate in the pathogenesis of allergic asthma. IL-23 is a cytokine that may be implicated in modulating Th17 response. This study aimed at evaluating IL-23 and relating it to lung function in asthmatic children. Methods: Seventy-eight asthmatic children and 40 healthy children were evaluated. Spirometry and serum IL-23 measurement (ELISA kit) were performed in all asthmatic children. Results: IL-23 levels were higher in asthmatic than in healthy children (p < 0.001). There was a strong inverse relationship between FEV1 and IL-23 (r = –0.787). Conclusions: This preliminary study suggests that serum IL-23 could be a suitable marker of bronchial function impairment in allergic asthmatic children.
Innovation in Surfactant Therapy II: Surfactant Administration by Aerosolization
Authors: Pillow J. Jane , Minocchieri S.
Published: April 2017

Instilled bolus surfactant is the only approved surfactant treatment for neonatal respiratory distress syndrome. However, recent trends towards increased utilization of noninvasive respiratory support for preterm infants with surfactant deficiency have created a demand for a similarly noninvasive means of administering exogenous surfactant. Past approaches to surfactant nebulization met with varying success due to inefficient aerosol devices resulting in low intrapulmonary delivery doses of surfactant with variable clinical effectiveness. The recent development of vibrating membrane nebulizers, coupled with appropriate positioning of the interface device, indicates that efficient delivery of aerosolized surfactant is now a realistic goal in infants. Evidence of clinical effect despite low total administered dose in pilot studies, together with suggestions of enhanced homogeneity of pulmonary distribution indicate that this therapy may be applied in a cost-effective manner, with minimal patient handling and disruption. These studies need to be subjected to appropriately designed randomized controlled trials. Further work is also required to determine the optimum delivery route (mask, intranasal prong, nasopharyngeal or laryngeal), dosing amount and redosing interval.
Current Technology in the Diagnosis of Developmentally Related Lung Disorders
Authors: Hamvas Aaron
Published: April 2017

Respiratory disorders that present in the newborn period may result from structural, functional, or acquired mechanisms that limit gas exchange between the airspace and vascular bed. Exciting new imaging, gene sequencing, mass spectrometry, and molecular and cell-based techniques are enhancing our understanding of mechanisms of disease; highlighting the complexity of interactions between genes, development, and environment in the manifestation of health and disease; and becoming part of the clinical armamentarium for the care of patients. Some of these technologies and their clinical potential are briefly reviewed in this paper.
Epidemiology of Uromodulin-Associated Kidney Disease – Results from a Nation-Wide Survey
Authors: Lhotta Karl , Piret Sian E. , Kramar Reinhard , Thakker Rajesh V. , Sunder-Plassmann Gere , Kotanko Peter
Published: April 2017

Background/Aims: Uromodulin-associated kidney disease (UAKD) is caused by uromodulin mutations and leads to end-stage renal disease. Our objective was to examine the epidemiology of UAKD. Methods: Data from all UAKD families in Austria were collected. Patients included in the Austrian Dialysis and Transplantation Registry (OEDTR) with unclear diagnoses or genetic diseases were asked whether they had (1) a family history of kidney disease or (2) had suffered from gout. Patients with gout and autosomal dominant renal disease underwent mutational analysis. Kaplan-Meier and Cox analysis was employed to estimate time to renal failure. Results: Of the 6,210 patients in the OEDTR, 541 were approached with a questionnaire; 353 patients answered the questionnaire. Nineteen of them gave two affirmative answers. In 7 patients, an autosomal dominant renal disease was found; in 1 patient a UMOD mutation was identified. One family was diagnosed through increased awareness as a consequence of the study. At present, 14 UAKD patients from 5 families are living in Austria (1.67 cases per million), and 6 of them require renal replacement therapy (0.73 per 1,000 patients). Progression to renal failure was significantly associated with UMOD genotype. Conclusion: UAKD patients can be identified by a simple questionnaire. UMOD genotype may affect disease progression.
Methyl Sulfone Manifests Anticancer Activity in a Metastatic Murine Breast Cancer Cell Line and in Human Breast Cancer Tissue - Part I: Murine 4T1 (66cl-4) Cell Line
Authors: Caron Joan McIntyre , Bannon Marissa , Rosshirt Lindsay , O'Donovan Lisa
Published: April 2017

Background: The spread of cancer (metastasis) is usually associated with death. We have identified a new approach that may be useful for treating metastatic cancer. Methods: Here we studied the murine breast cancer cell line 66cl-4, because these cells are highly aggressive, potent inducers of metastasis and estrogen receptor negative. Results: We found that 200 mM methyl sulfone did not induce apoptosis in cancerous cells but instead decreased cell proliferation and DNA synthesis, inhibited migration of cells through an extracellular matrix and induced contact inhibition and anchorage-dependent growth. Methyl sulfone promoted proper wound healing, reversed the epithelial to mesenchymal transition associated with metastatic disease and increased expression of α-smooth muscle actin, a differentiation protein of breast myoepithelial cells. Conclusion: Methyl sulfone did not kill the cancer cells but instead decreased metastatic phenotypes and increased normal differentiated phenotypes.
Rho Kinase Inhibitor Fasudil Regulates Microglia Polarization and Function
Authors: Zhang Haifei , Li Yanhua , Yu Jiezhong , Guo Mingfang , Meng Jian , Liu Chunyun , Xie Yong , Feng Ling , Xiao Baoguo , Ma Cungen
Published: April 2017

Macrophages/microglia exhibit phenotypic and functional heterogeneity under physiological and pathological conditions. Owing to this heterogeneity, the polarization of macrophages/microglia is capable of effecting both detrimental and beneficial outcomes in various disease processes. In this study, murine microglial cell line BV-2 and primary microglia were used as cell models to elucidate the polarization of microglia. Using flow cytometry, Western blot, chemical/enzymatic determination, and immunohistochemistry, treatment with LPS primed microglia into the M1 phenotype in both BV-2 cells and primary microglia, while fasudil skewed LPS-stimulated M1 toward M2 microglia, which showed lower NF-κB activity and inflammatory cytokines IL-1ß, IL-6, and TNF-a, and increased anti-inflammatory cytokine IL-10. To examine whether the regulatory role of LPS and fasudil on microglia can occur in vivo, mice were administered LPS (25 µg/10 µl) via nasal instillation every other day for 1 month. The results demonstrated that LPS also triggered iNOS+/CD11b+ M1 microglia in the brain, while fasudil increased Arg-1+/CD11b+ M2 microglia, although the difference did not reach statistical significance. Fasudil-conditioned microglia medium promoted a neuroprotective effect against PC12 neurons, suggesting that fasudil-induced M2 microglia contribute to the survival of neurons. These results indicate a new treatment option whereby fasudil inhibits the inflammatory response by controlling a helpful polarization in microglia/macrophages.
Reproducibility and Diagnostic Outcomes of Two Visual-Tactile Criteria Used by Dentists to Assess Caries Lesion Activity: A Cross-Over Study
Authors: Tikhonova S.M. , Feine J.S. , Pustavoitava N.N. , Allison P.J.
Published: April 2017

The aim of this study was to evaluate the reproducibility and differences in diagnostic outcomes by practicing dental clinicians previously inexperienced in using the Nyvad criteria and the ICDAS II criteria with the Lesion Activity Assessment system (ICDAS II + LAA). Four volunteer dentists were randomly allocated to one of two groups. Both groups of dentists examined the same voluntary sample (n = 140) of caries active young adults using Nyvad and ICDAS II + LAA criteria in different sequences. The first group used the Nyvad criteria during period 1, followed by ICDAS II + LAA during period 2; the second group did the examinations in the opposite sequence. Before the period 1 and 2 examinations, dentists from both groups were trained with the Nyvad or ICDAS II + LAA criteria, depending on the group to which they were assigned. Intra-examiner agreement for lesion severity was high for both diagnostic instruments (weighted kappa 0.62-0.80). For lesion activity the intra-examiner unweighted kappa values ranged from 0.31 to 0.61 for ICDAS II + LAA and from 0.36 to 0.51 for Nyvad. The mean number of active non-cavitated caries lesions was significantly higher for ICDAS II + LAA (6.14 ± 5.4) than for Nyvad (3.90 ± 3.9) (p < 0.001). Active cavitated/dentinal caries lesions were significantly higher for ICDAS II + LAA (4.14 ± 4.1) than for Nyvad (2.13 ± 3.1) (p < 0.001). Both the Nyvad and ICDAS II + LAA diagnostic criteria showed high reproducibility for lesion severity assessment. The mean number of active caries lesions among high caries risk subjects was significantly higher using the ICDAS II + LAA criteria, which may subsequently lead to more caries treatment. Trial registration: ISRCTN65592532.
Effect of Early Stage Kidney Disease on Cardiac Mass: Comparison to Post-Donation Renal Function
Authors: Rugale Caroline , Du Cailar Guilhem , Fesler Pierre , Ribstein Jean , Mourad Georges , Mimran Albert
Published: April 2017

Background/Aim: In chronic renal failure the increase in cardiovascular risk is in part related to the high prevalence of left ventricular hypertrophy. The aim of the present monocentric retrospective study was to evaluate the influence of the presence of parenchymal kidney disease on left ventricular geometry in normotensive (arterial pressure <140/90 mm Hg) patients (KD+, n = 50, mean age 39 ± 19 years) with mild to moderate renal failure (stage 2-3 chronic kidney disease). Methods: Left ventricular geometry was estimated by echocardiography and compared to a group of healthy subjects with similarly reduced renal function as a consequence of renal donation (KD-, n = 63, mean age 52 ± 12 years). Results: Subjects with and without kidney disease had similar blood pressure, body mass index and isotopic glomerular filtration rate. Left ventricular mass (LVM) indexed to body surface area was greater in KD+ as compared to KD- subjects and the difference was more pronounced in women than in men. The increase in LVM in KD+ patients was associated with lower albuminemia and hematocrit, and a higher plasma renin activity and aldosterone as compared to KD- subjects. In multivariate analysis, kidney disease emerged as an important determinant of LVM index independently of age, gender and blood pressure. Conclusion: This observation suggests that the presence of kidney disease has an independent amplifying effect on LVM which could be related to volume overload and/or prohypertrophic factors such as aldosterone.
Assessment of Labile Plasma Iron in Patients Who Undergo Hematopoietic Stem Cell Transplantation
Authors: Naoum Flávio Augusto , Espósito Breno Pannia , Ruiz Lílian Piron , Ruiz Milton Artur , Tanaka Paula Yurie , Sobreira Juliana Tavora , Cançado Rodolfo Delfini , de Barros José Carlos
Published: April 2017

Body iron disorders have been reported after myeloablative conditioning in patients undergoing hematopoietic stem cell transplantation (HSCT). There is a concern that labile plasma iron (LPI), the redox-active form of iron, can be involved in the occurrence of toxicity and other complications commonly observed in the early post-HSCT period. In order to better understand the LPI kinetics and its determinants and implications, we undertook sequential LPI determinations before and after conditioning until engraftment in 25 auto-HSCT patients. Increased LPI was present in only 5 patients before starting conditioning. Shortly after conditioning, LPI levels were increased in 23 patients, with peak at day 0, returning to normal range upon engraftment in 21 patients. Overall, LPI levels correlated weakly with serum ferritin and more strongly with transferrin saturation; however, both parameters were apparently not applicable as surrogate markers for increased LPI. Although this was a small cohort, logistic regression suggested that baseline LPI levels could predict occurrence of grade III or IV toxicity. In conclusion, LPI kinetics is influenced by aplasia following conditioning and engraftment. Measuring LPI before starting conditioning can offer an opportunity to predict toxicity and, perhaps, the need for chelation therapy.
Cardiac Structure and Function and Insulin Resistance in Morbidly Obese Patients: Does Superobesity Play an Additional Role?
Authors: Antonini-Canterin Francesco , Mateescu Anca D. , Vriz Olga , La Carrubba Salvatore , Di Bello Vitantonio , Carerj Scipione , Zito Concetta , Sparacino Lina , Marzano Bernardo , Usurelu Cătălin , Ticulescu Răzvan , Ginghină Carmen , Nicolosi Gian Luigi , Popescu Bogdan A.
Published: April 2017

Objective: To evaluate the impact of superobesity, defined as body mass index (BMI) ≥50, on cardiac structure and function. Methods: Using echocardiography, we studied 198 asymptomatic patients (mean age 48 ± 13 years, 29.3% were men) with a BMI ≥40. Insulin resistance was measured using the Homeostasis Model Assessment of insulin resistance (HOMA-IR). Patients were divided into 2 groups: morbidly obese (BMI ≥40 and <50; n = 160) and superobese (BMI ≥50; n = 38). Results: There were no significant differences in age, gender, hypertension and diabetes between groups. Superobese patients had higher LV mass (66.0 ± 14.7 vs. 59.9 ± 11.9 g/m2.7, p = 0.007), left ventricular (LV) end-diastolic (33.8 ± 7.7 vs. 31.5 ± 7.1 ml/m2.7, p = 0.041) and end-systolic (12.2 ± 3.6 vs. 10.9 ± 2.8 ml/m2.7, p = 0.016) volumes, left atrial volume (13.8 ± 4.5 vs. 12.2 ± 3.9 ml/m2.7, p = 0.029), peak velocity of transmitral flow in early diastole/early diastolic peak myocardial velocity ratio (9.1 ± 2.6 vs. 8.2 ± 2.2, p = 0.03) and HOMA-IR (9.7 ± 7.3 vs. 7.3 ± 6.5, p = 0.047). LV ejection fraction was similar. Conclusions: Superobesity is associated with insulin resistance and a worse impact on cardiac remodeling and LV diastolic function than morbid obesity. Prospective studies are needed to evaluate whether such further classification of morbid obesity could stratify the cardiovascular risk in these patients more accurately.
Type I and II Pneumocyte Differentiation in the Developing Fetal Chicken Lung: Conservation of Pivotal Proteins from Birds to Human in the Struggle for Life at Birth
Authors: Bjørnstad Sigrid , Paulsen Ragnhild E. , Erichsen Aage , Glover Joel C. , Roald Borghild
Published: April 2017

Background: Antenatal corticosteroids and surfactant replacement therapy have dramatically reduced mortality caused by lung disease in premature babies. Knowledge about mechanisms regulating epithelial differentiation of the respiratory membrane is limited, as are effects of pharmacological interventions. The chicken fetus is a valuable model for exploring pharmacological actions on developing organs. However, more precise information about the timing of developmental events in the chicken lung is needed for human correlation. Objectives: Characterization of morphological development and protein expression in the respiratory membrane of the developing chicken lung to create a platform for pharmacological testing in a human context. Methods: Fetal chicken lungs, embryonic days (E) 7-20, were characterized by morphology and protein expression of epithelial differentiation markers. This was compared with publications on the same processes during human lung development. Results: The respiratory membranes of developing chicken and human lungs show basic similarities. In chicken, surfactant protein B is expressed in cuboidal type II epithelial cells from E17. Aquaporin 5 is expressed in the epithelium from E7 and selectively in type I pneumocytes from E17. The type I pneumocyte and endothelial marker, caveolin 1, is expressed in the endothelium from E7 to E20. Conclusion: Despite phylogenetic distance, central aspects of cellular development in the chicken and human lung are similar. The fetal chicken model has important additional advantages to mammalian models, including fetal independence and short incubation, and is thus well suited for in vivo studies of lung maturation relevant to human development.
Retreatment after Secondary Resistance or Mixed Response: A Pilot Study
Authors: Naing Aung , Agarwal Rishi , Falchook Gerald , Hong David S. , Janku Filip , Wheler Jennifer , Fu Siqing , Kurzrock Razelle
Published: April 2017

Objective: Oncologists usually avoid retreatment with drugs to which patients have shown secondary resistance or a mixed response. Here, we report our findings in a pilot study in patients rechallenged with agents previously producing prolonged stable disease (SD), partial or complete remission (PR/CR) or a mixed response, followed by progression. Results: Eleven individuals with advanced cancers (median number of prior systemic therapies in the metastatic setting = 4, range 2-7) were included (8 men; median age 57 years; median Eastern Cooperative Oncology Group performance status of 1). The median duration between initial treatment and retreatment was 92 weeks. Eight of 11 patients (73%) on a retreatment regimen showed SD ≥24 weeks/PR/CR. Of these 8 individuals, 2 were retreated with the same agent(s), 1 with a different agent possessing the same mechanism of action (e.g., in case of an epidermal growth factor receptor inhibitor, using gefitinib first, then erlotinib), and 5 with the same agent(s) in combination with other agents. Conclusion: Our pilot data suggest that patients who develop acquired resistance after durable SD/CR/PR or who have an initial mixed response may attain SD ≥6 months/PR/CR with a retreatment approach.
Sensitization of Erythrocytes to Suicidal Erythrocyte Death Following Water Deprivation
Authors: Abed Majed , Feger Martina , Alzoubi Kousi , Pakladok Tatsiana , Frauenfeld Leonie , Geiger Corinna , Towhid Syeda T , Lang Florian
Published: April 2017

Background/Aims: Klotho deficiency results in excessive formation of 1,25(OH)2D3, accelerated ageing and early death. Moreover, klotho deficiency enhances eryptosis, the suicidal erythrocyte death characterized by phosphatidylserine exposure at the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca2+-activity ([Ca2+]i), glucose depletion, hyperosmotic shock and oxidative stress. Klotho expression is decreased and 1,25(OH)2D3-formation enhanced by dehydration. The present study thus explored whether dehydration influences eryptosis. Methods: Blood was drawn from hydrated or 36h dehydrated mice. Plasma osmolarity was determined by vapour pressure method, plasma 1,25(OH)2D3 and aldosterone concentrations using ELISA, and plasma Ca2+-concentration utilizing photometry. Erythrocytes were exposed to Ca2+-ionophore ionomycin (1 µM, 30 min), energy depletion (12 h glucose removal), hyperosmotic shock (500 mM sucrose added, 2 h) and oxidative stress (100 µM tert-butyl-hydroperoxide, 30 min) and phosphatidylserine exposure at the erythrocyte surface estimated from annexin V binding. Results: Dehydration increased plasma osmolarity and plasma 1,25(OH)2D3 and aldosterone concentrations. Dehydration did not significantly modify phosphatidylserine-exposure of freshly drawn erythrocytes but significantly enhanced the increase of phosphatidylserine-exposure under control conditions and following treatment with ionomycin, glucose-deprivation, hyperosmolarity or tert-butyl-hydroperoxide. Conclusions: Dehydration sensitizes the erythrocytes to spontaneous eryptosis and to the triggering of eryptosis by excessive Ca2+-entry, energy depletion, hyperosmotic shock and oxidative stress.
A New PKD1 Mutation Discovered in a Chinese Family with Autosomal Polycystic Kidney Disease
Authors: Wang Zhendi , Wang Yang , Xiong Jing
Published: April 2017

Background/Aims: Autosomal-dominant polycystic kidney disease (ADPKD), a heterogeneous genetic disorder characterized by massive kidney enlargement and progressive chronic kidney disease, is due to abnormal proliferation of renal tubular epithelium. ADPKD is known to be caused by mutations in PKD1 and PKD2 genes. Methods: In the present study, the mutation analysis of PKD genes was performed in a new Chinese family with ADPKD using Long-Range (LR) PCR sequencing and targeted next-generation sequencing (targeted DNA-HiSeq). Results: A unique 28 bp deletion (c.12605_12632del28) in exon 46 of the PKD1 gene was identified in two affected family members by LR PCR method, but not in any unaffected relatives or unrelated controls. Higher accuracy and less missing detection presented in LR PCR method compared with targeted DNA-HiSeq. This mutation c.12605_12632del28 (p.Arg4202ProextX146) resulted in a delayed termination of amino acid code, and was highly speculated pathogenic in this ADPKD family. Moreover, this newly identified frame-shift change was compared to the PKD gene database, but no similar mutation was yet reported. Conclusion: A novel frame-shift mutation, c. 12605_12632del28, in the PKD1 gene was found in a Chinese ADPKD family. All evidence available suggested that it might be the mutation responsible for the disease in that family.
Solitary Functioning Kidney in Children - A Follow-Up Study
Authors: Kolvek Gabriel , Podracka Ludmila , Rosenberger Jaroslav , Stewart Roy E. , van Dijk Jitse P. , Reijneveld Sijmen A.
Published: April 2017

Background/Aims: This study aims to assess the cumulative incidence of elevated albuminuria, hypertension and decreased estimated glomerular filtration rate (eGFR) to identify possible renal injury in children with SFK. Methods: Forty-two children with SFK (23 boys; 27 congenital) were included in a prospective follow-up study. Blood pressure, albuminuria and eGFR were assessed repeatedly and the cumulative incidence rate of various forms of renal injury, overall and by type of etiology, were evaluated. Finally, renal injury-free survival was analyzed. Results: Mean follow-up was until age 11.3 years (SD 6.3 years). During follow-up, 16 (38.1%) patients met the criteria for renal injury, defined as hypertension (10; 23.8%), severely increased albuminuria (3; 7.1%) and a significantly impaired eGFR (<60ml/min/1.73m2) (5; 11.9%) and/or use of antihypertensive or antiproteinuric medication (11; 26.2%). Children with CAKUT in SFK had a significantly higher incidence of renal injury. The median time to develop renal injury was 12.8 years. Conclusion: A substantial proportion of children with SFK develop renal injury during childhood, especially those with CAKUT in the SFK. Therefore, close follow-up of albuminuria, blood pressure and eGFR are warranted to identify chronic kidney disease in its early stages.
Effects of Freeze-Dried Strawberry Supplementation on Metabolic Biomarkers of Atherosclerosis in Subjects with Type 2 Diabetes: A Randomized Double-Blind Controlled Trial
Authors: Moazen Sara , Amani Reza , Homayouni Rad Aziz , Shahbazian Hajieh , Ahmadi Kambiz , Taha Jalali Mohammad
Published: April 2017

Background: To our knowledge there has been no study investigating the impact of freeze-dried strawberry (FDS) supplementation on metabolic biomarkers of atherosclerosis in subjects with type 2 diabetes (T2D). Objective: This study was carried out to determine the effects of FDS supplementation on glycemic control, biomarkers of oxidative stress, inflammation and serum total antioxidant status in subjects with T2D compared to matched control subjects. Methods: Thirty-six subjects with T2D (23 females; mean body mass index 27.90 ± 3.7; mean age 51.57 ± 10 years) were randomly divided into two groups. The treatment group consumed 2 cups of FDS beverage (50 g of FDS is equivalent to 500 g of fresh strawberries) or macronutrient matched placebo powder with strawberry flavor daily for 6 weeks in a randomized double-blind controlled trial. Anthropometric measurements, dietary intakes, hemoglobin (Hb)A1c, antioxidant status, C-reactive protein and malondialdehyde (MDA) levels were assessed at baseline and 6 weeks post-intervention. Results: FDS supplementation significantly decreased C-reactive protein levels as a biomarker of inflammation (2.5 vs. 2.04 mg/l, p < 0.05) and lipid peroxidation in the form of MDA (3.36 vs. 2.7 nmol/ml, p < 0.05) at 6 weeks compared to the baseline. Moreover, supplementation led to a decreasing trend in HbA1c (-5.7%, p < 0.05) and significant increase in total antioxidant status in the FDS group (1.44 vs. 1.26 mmol/l, p < 0.01) compared to the placebo group. No significant changes were observed in serum glucose concentrations and anthropometric indices. Conclusions: FDS improved glycemic control and antioxidant status, and reduced lipid peroxidation and inflammatory response in patients with T2D. Supplementation with freeze-dried berry products, as natural sources of antioxidants with low glycemic index, could be considered as an adjunctive therapy in ameliorating metabolic complications of T2D.
Separating the Contributions of Olivocochlear and Middle Ear Muscle Reflexes in Modulation of Distortion Product Otoacoustic Emission Levels
Authors: Wolter Nikolaus E. , Harrison Robert V. , James Adrian L.
Published: April 2017

Objectives: Mediated by the medial olivocochlear system (MOCS), distortion product otoacoustic emission (DPOAE) levels are reduced by presentation of contralateral acoustic stimuli. Such acoustic signals can also evoke a middle ear muscle reflex (MEMR) that also attenuates recorded DPOAE levels. Our aim is to clearly differentiate these two inhibitory mechanisms and to analyze each separately, perhaps allowing the development of novel tests of hearing function. Methods: DPOAE were recorded in real time from chinchillas with normal auditory brainstem response thresholds and middle ear function. Amplitude reduction and its onset latency caused by contralateral presentation of intermittent narrow-band noise (NBN) were measured. Stapedius and tensor tympani muscle tendons were divided without disturbing the ossicular chain, and DPOAE testing was repeated. Results: Peak reduction of (2f1 - f2) DPOAE levels occurred when the center frequency of contralateral NBN approximated the primary tone f2, indicating an f2-frequency-specific response. For a 4.5-kHz centered NBN, DPOAE (f2 = 4.4 kHz) inhibition was 0.1 dB (p < 0.001). This response remained present after tendon division, consistent with an MOCS origin. Low-frequency NBN (center frequency: 0.5 kHz) reduced otoacoustic emission levels (0.1 dB, p < 0.001) across a wide range of DPOAE frequencies. This low-frequency response was abolished by division of the middle ear muscle tendons, clearly indicating MEMR involvement. Conclusions: Following middle ear muscle tendon division, DPOAE inhibition by contralateral stimuli approximating the primary tone f2 persists, whereas responses evoked by lower contralateral frequencies are abolished. This distinguishes the different roles of the MOCS (f2 frequency specific) and MEMR (low frequency only) in contralateral modulation of DPOAE. This analysis helps clarify the pathways involved in an objective test that might have clinical benefit in the testing of neonates.
Characteristics and Prognosis of Hearing Loss Associated with Vogt-Koyanagi-Harada Disease
Authors: Morita Shinya , Nakamaru Yuji , Obara Nobuyuki , Masuya Masayori , Fukuda Satoshi
Published: April 2017

Objective: To clarify the characteristics and prognosis of hearing loss associated with Vogt-Koyanagi-Harada (VKH) disease. Methods: We retrospectively examined 85 patients diagnosed with VKH disease between January 1996 and December 2012. The control group included age- and gender-matched individuals without definitive ear disease. The patients with VKH disease were treated with high-dose systemic corticosteroids, which were tapered off gradually over a period of 6 months or more by the treating ophthalmologists according to the severity of the ocular inflammation. The features of hearing loss were analyzed based on pure tone audiometric data obtained at the initial presentation according to diagnostic criteria based on the ISO 7029 standard. The efficacy of corticosteroid therapy was evaluated by audiometry at the initial presentation and during therapy for 3-6 months. Results: In patients with VKH disease, the rate of hearing loss detected by audiometry was significantly higher than that of either subjective hearing loss (p < 0.001) or tinnitus (p < 0.001). Bilateral symmetrical hearing loss was the most common type of auditory disturbance associated with VKH disease. The degree of hearing loss was generally low, with no patients showing profound hearing loss. Hearing thresholds were significantly elevated at high frequencies compared with those at low-to-mid frequencies (p < 0.001). Hearing thresholds at all frequencies after high-dose corticosteroid therapy were significantly better than those at initial presentation (p < 0.001), and the rate of patients who returned to within normal-range pure tone thresholds at all frequencies was 74.8%. Conclusions: As auditory manifestations cannot be detected through history taking alone, audiometry should be performed to evaluate hearing loss associated with VKH disease. Early administration of high-dose systemic corticosteroids is effective for treating the auditory manifestations, which generally show a relatively good short-term prognosis.
Erythrocyte n-3 Polyunsaturated Fatty Acids and the Risk of Type 2 Diabetes in Koreans: A Case-Control Study
Authors: Jo Sunyoung , An Won-Suk , Park Yongsoon
Published: April 2017

Background: There is inconsistent epidemiologic evidence for an association between tissue levels of n-3 polyunsaturated fatty acids (PUFAs) and the risk of type 2 diabetes. The purpose of the present study was to investigate whether erythrocyte levels of n-3 PUFAs are negatively associated with the risk of type 2 diabetes and correlated with levels of glucose and HbA1c in Koreans. Methods: A total of 130 patients with type 2 diabetes and 260 age- and sex-matched controls participated in this study. Results: The risk of type 2 diabetes was negatively associated with erythrocyte levels of 22:5n3 and 22:6n3, which were negatively correlated with HbA1c levels after adjusting for age, sex and body mass index. Additionally, the risk of type 2 diabetes was negatively associated with erythrocyte levels of 18:0 and 20:4n6, but positively associated with erythrocyte levels of 16:0, 18:1n9, 18:3n3, 18:2n6, 18:3n6, n-6/n-3 PUFA ratio, 18:1t and 18:2n6t, and Δ-6 desaturase (18:3n6/18:2n6) and Δ-9 desaturase (18:1n9/18:0) activities. Conclusions: The risk of type 2 diabetes was negatively associated with erythrocyte levels of n-3 PUFA, which were negatively correlated with HbA1c levels in Koreans, suggesting that n-3 PUFAs might reduce the risk of type 2 diabetes in Asians.
HLA-A29-Positive Uveitis: Birdshot Chorioretinopathy, What Else
Authors: Zucchiatti Ilaria , Miserocchi Elisabetta , Sacconi Riccardo , Bandello Francesco , Modorati Giulio
Published: April 2017

Birdshot chorioretinopathy (BSCR) is a relatively rare form of uveitis, which is strongly correlated with the histocompatibility leukocyte antigen (HLA)-A29 class I type. Nevertheless, HLA typing is not diagnostic. The purpose of the present study was to retrospectively evaluate the ocular manifestations associated with the presence of HLA-A29 other than typical BSCR. Charts of consecutive patients with a diagnosis of intraocular inflammation and who were found to be positive for the presence of HLA-A29 were retrospectively reviewed. Only 7 patients met the criteria for a definite diagnosis of BSCR. Among the other 11 patients, the disease was bilateral in 7 patients and unilateral in 4 patients. A definite diagnosis of the following conditions were found: intraocular and CNS lymphoma in 1 patient, posterior tubercular uveitis with occlusive vasculitis in 1 patient, latent ocular tuberculosis in 1 patient, Fuchs' uveitis in 1 patient, herpetic panuveitis in 1 patient and HLA-B27 anterior uveitis in another patient. Although BSCR is strongly related to the HLA-A29 phenotype, and its presence confers a relative risk of disease, the definite diagnosis requires specific ocular characteristics. HLA-A29 typing alone is not a diagnostic requirement for the definite diagnosis of BSCR and should only be considered as a supportive finding.
Genomic Profiling in Triple-Negative Breast Cancer
Authors: Liedtke Cornelia , Bernemann Christof , Kiesel Ludwig , Rody Achim
Published: April 2017

Triple-negative breast cancer (TNBC) is defined by a lack of hormone receptor expression as well as lack of over-expression/amplification of HER2/neu. Patients with TNBC show a significantly worse prognosis compared to patients with other breast cancer subtypes. TNBC, however, is a heterogeneous entity both with regard to clinical/pathological characteristics and molecular biology. This review summarizes the current data on TNBC with a particular focus on mutational and gene expression profiling and the association between TNBC and breast cancer stem cells.
State-of-the-Art and Emerging Treatment Options in the Management of Head and Neck Cancer: News from 2013
Authors: Denaro Nerina , Russi Elvio Grazioso , Adamo Vincenzo , Merlano Marco Carlo
Published: April 2017

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cause of cancer death worldwide. Its treatment is complex and evolving. In general, early-stage disease may be managed with single-modality treatment while an advanced stage (about 60% of clinical presentation) needs a multidisciplinary approach. In this setting concurrent chemoradiation has been associated with improvement in locoregional control and organ preservation, but at the cost of significant acute and chronic toxicity. Molecular target therapies specially directed to epidermal growth factor receptor (EGFR) might improve the outcomes and reduce toxicities. In recurrent-metastatic (R/M) HNSCC, cetuximab, a monoclonal antibody against EGFR, plus platinum-based chemotherapy (CT) allow an overall survival (OS) of about 10 months. However, the prognosis for R/M-HNSCC remains dismal and additional efforts are needed. At the 2013 American Society of Clinical Oncology (ASCO) Meeting, data on induction CT, anti-EGFR inhibitors, innovative molecular targets and predictor factors were reported. Further results on target therapies were presented at the European Cancer Congress (ECC) 2013, where a large study also showed that hyperfractionated radiotherapy (RT) improve OS rates compared with standard RT. The aim of this review is to discuss current standards and emerging therapies by considering recent new updates.
Idiopathic Intracranial Hypertension and Obesity
Authors: Andrews Laura E. , Liu Grant T. , Ko Melissa W.
Published: April 2017

Idiopathic intracranial hypertension (IIH), also known as primary pseudotumor cerebri syndrome (PTCS), is a condition of unknown etiology which affects primarily overweight, reproductive-aged women and causes increased intracranial pressure (ICP). This review discusses the recently revised diagnostic criteria for PTCS for adults and children. Additionally, the role of obesity in the epidemiology, etiology, and management of IIH as well as the current knowledge of obesity profiles and markers in IIH are reviewed. We also highlight the emerging, unifying theory of the neuroendocrine effects on the mineralocorticoid receptor to explain a possible mechanism for the increased cerebrospinal fluid production and ICP in secondary PTCS.
Evolution and Development of the Mammalian Cerebral Cortex
Authors: Molnár Zoltán , Kaas Jon H. , de Carlos Juan A. , Hevner Robert F. , Lein Ed , Němec Pavel
Published: April 2017

Comparative developmental studies of the mammalian brain can identify key changes that can generate the diverse structures and functions of the brain. We have studied how the neocortex of early mammals became organized into functionally distinct areas, and how the current level of cortical cellular and laminar specialization arose from the simpler premammalian cortex. We demonstrate the neocortical organization in early mammals, which helps to elucidate how the large, complex human brain evolved from a long line of ancestors. The radial and tangential enlargement of the cortex was driven by changes in the patterns of cortical neurogenesis, including alterations in the proportions of distinct progenitor types. Some cortical cell populations travel to the cortex through tangential migration whereas others migrate radially. A number of recent studies have begun to characterize the chick, mouse and human and nonhuman primate cortical transcriptome to help us understand how gene expression relates to the development and anatomical and functional organization of the adult neocortex. Although all mammalian forms share the basic layout of cortical areas, the areal proportions and distributions are driven by distinct evolutionary pressures acting on sensory and motor experiences during the individual ontogenies.
Increased Mean Corpuscular Volume of Red Blood Cells in Patients Treated with Capecitabine for Advanced Breast and Colon Cancer
Authors: Scarabelli Laura , Giovanardi Filippo , Gervasi Erika , Prati Giuseppe , Pezzuolo Debora , Scaltriti Laura
Published: April 2017

Purpose: Capecitabine has demonstrated significant activity in metastatic breast and colorectal cancer. During the course of treatment with capecitabine, we observed that a relevant number of patients developed elevated levels of the mean corpuscular volume (MCV) of red blood cells. Methods: This retrospective analysis reviewed treatment with capecitabine in 35 patients with histologically proven advanced breast and colon cancer. After 9 weeks of treatment, restaging was performed using the criteria proposed by the Committee of the Response Evaluation Criteria in Solid Tumours. Results: Prior to the first cycle of capecitabine treatment, there were no abnormalities in red blood cells, white blood cells, haemoglobin or platelets. The median haemoglobin level prior to the first cycle was 13 g/dl and the MCV (normal range 80-98 fl) was 86.5 fl in colon cancer patients and 12.8 g/dl and 88.7 fl in breast cancer patients, respectively. During the course of treatment, 12 weeks after the baseline evaluation, an increase in MCV was documented, while haemoglobin levels remained stable. An MCV increase was documented between baseline and the end of treatment. We noticed an increase in MCV at the end of treatment both in patients with stable disease or a partial response (n = 17) compared to patients with tumour progression (n = 11) at the first evaluation (12-14 weeks). Discussion: Preliminary results showed that there is a significant MCV increase in patients receiving capecitabine for metastatic colon and breast cancer after 12 weeks of treatment. However, when we compared the MCV rise after 12 weeks that occurred with stable disease or a partial response compared to that in patients with disease progression at the first evaluation, the analysis was not statistically significant.