bluuebunny/crossref_metadata_2025 huggingface dataset:
White Matter Changes in Patients with Parkinson's Disease Carrying Small CGG Expansion FMR1 Alleles: A Pilot Study
Authors: Trost Nicholas , Cook Mark , Hammersley Eleanor , Bui Minh Q. , Brotchie Peter , Burgess Trent , Slater Howard , Storey Elsdon , Loesch Danuta Z.
Published: January 2014

Background/Aims: Alleles of the FMR1 gene containing small expansions of the CGG-trinucleotide repeat comprise premutation and grey-zone alleles. Premutation alleles may cause late-onset Fragile X-associated tremor/ataxia syndrome attributed to the neurotoxic effect of elevated FMR1 transcripts. Our earlier data suggested that both grey-zone and low-end premutation alleles might also play a significant role in the acquisition of the parkinsonian phenotype due to mitochondrial dysfunction caused by elevated FMR1 mRNA toxicity. These data were obtained through clinical and molecular comparisons between carriers of grey-zone/low-end premutation alleles and group-matched non-carrier controls from patients with idiopathic Parkinson's disease (iPD). We aimed to explore the relationship between grey-zone alleles, parkinsonism and white matter changes. Methods: This study compared the extent and severity of white matter hyperintensity (WMH) on magnetic resonance imaging, using a semi-quantitative method, between 11 grey-zone/low-end premutation carriers and 20 non-carrier controls with iPD from our earlier study. Relationships between WMH scores, and cognitive and motor test scores were assessed for carriers and non-carriers. Results: Supratentorial WMH scores, and tremor and ataxia motor scores were significantly higher in carriers compared with disease controls. Moreover, some associations between cognitive decline and WMH scores were specific for each respective carrier status category. Conclusions: The results support our earlier claim that grey-zone alleles contribute to the severity of parkinsonism and white matter changes.
Diazepam Binding Inhibitor and Dehydroepiandrosterone Sulphate Plasma Levels in Borderline Personality Disorder Adolescents
Authors: Conti Elisa , Nacinovich Renata , Bomba Monica , Uccellini Orlando , Rossi Maria Sara , Casati Marco , Neri Francesca , Ferrarese Carlo , Tremolizzo Lucio
Published: January 2014

Background: Borderline personality disorder (BPD) patients display a complex and heterogeneous clinical phenotype that plausibly implies variable underlying pathogenic mechanisms. A dysregulation of peripheral benzodiazepine receptors has previously been shown in BPD peripheral tissues, implying possible alterations of its ligand, the diazepam binding inhibitor (DBI) or of the downstream products of its activation, i.e. neuroactive steroids. Methods: The aim of this work consisted in assessing, by ELISA, fasting plasma levels of DBI and dehydroepiandrosterone sulphate (DHEA-S), including cortisol and the cortisol-to-DHEA-S molar ratio (CDR), in 17 BPD adolescents versus 13 healthy controls, testing the possibility that clinical scales related to depressive or anxious traits (CDI, STAI-Y) or to disease severity (BPDCL) might be associated with a selective dysregulation of these parameters. Results: DBI plasma levels were unchanged, while DHEA-S ones were significantly increased (approx. 70%) and the CDR decreased in BPD patients. No meaningful correlations with clinical variables emerged. Conclusion: Our results indicate that a dysfunction of the neurosteroid system might be operative in BPD in spite of unchanged DBI plasma levels and that DHEA-S might represent a generalized trait marker for the altered stress response that is associated with this disorder.
Increasing Glutamate Promotes Ischemia-Reperfusion-Induced Ventricular Arrhythmias in Rats in vivo
Authors: Sun Xianlin , Zhong Jingquan , Wang Deguo , Xu Jian , Su Hao , An Chunsheng , Zhu Hongjun , Yan Ji
Published: January 2014

Background: Glutamate mediates cerebral ischemia injury via N-methyl-D-aspartate (NMDA) receptor-coupled ion channels, but the activities of glutamate in the heart remain unclear. Aims: To investigate whether or not glutamate contributes to ischemia- and reperfusion (IR)-induced arrhythmias. Methods: Myocardial IR was induced by occlusion of the left anterior descending coronary artery for 30 min and reperfusion for another 30 min. A score system was used to quantify arrhythmias. MK801 (a noncompetitive NMDA receptor antagonist), dihydrokainate (DHK, a glutamate transporter inhibitor) and gabapentin (GBP, a glutamate release inhibitor) were used before ischemia. Serum glutamate levels, Ca2+-ATPase activity, SERCA2a protein expression and myocardial mitochondrial Ca2+ content were assayed. Results: Myocardial IR caused a significant increase in serum glutamate and high incidences of ventricular arrhythmias. GBP and MK801 significantly ameliorated ventricular arrhythmias, improved SERCA2a expression and sarcoplasmic reticulum Ca2+-ATPase activity and reduced Ca2+ accumulated in mitochondria. By contrast, DHK significantly exacerbated reperfusion-related arrhythmias and mitochondrial Ca2+ overload while it decreased SERCA2a expression and activity. Conclusion: This study showed that glutamate mediates reperfusion arrhythmias, and the corresponding mechanism may be associated with Ca2+ overload via the NMDA receptor. Reperfusion arrhythmias may be prevented by inhibiting the release of glutamate or by antagonizing NMDA receptors.
Pharmacokinetics of Dalteparin during Haemodialysis
Authors: Nigten Jeannet , de Groot Karina A. , Grootendorst Diana C. , Koolen Stijn L.W. , Herruer Martien H. , Schut Niels H.
Published: January 2014

Background/Aims: Usually, the appropriate dosage of low-molecular-weight heparin during haemodialysis is empirically based on the clinical effect. We studied the pharmacokinetics of dalteparin during standard haemodialysis in different groups of patients to assess the added value of measuring the anti-Xa activity for dose monitoring and adjustments. Methods: The pharmacokinetics of intravenously administered dalteparin during haemodialysis was studied in 9 patients during 27 haemodialysis sessions. Six patients received a single bolus dose of dalteparin (group 1), and 3 patients received a higher initial bolus dose of dalteparin followed by a second bolus dose after 2 h (group 2). The clinical effect was evaluated by visual inspection for clot formation in the extracorporeal circuit. Results: The pharmacokinetic curve suggests a zero-order process of elimination. The mean decrease in anti-Xa activity (slope) was comparable in all patients. The mean anti-Xa activity at the end of haemodialysis (Clast) was 0.15 IU/ml in group 1 and 0.60 IU/ml in group 2. Conclusion: We conclude that measuring anti-Xa activity can be used to monitor the elimination of dalteparin during haemodialysis and is highly reproducible.
Investigating the Role of Cardiovascular Biomarkers in Children with Pre-Dialysis Chronic Kidney Disease: A Substitute to Echocardiography to Detect Increased Left Ventricular Mass?
Authors: Clothier Joanna C. , Simpson John M. , Turner Charles , Dalton R. Neil , Rasmussen Pernille , Rawlins Debbie , Booth Caroline J. , Peacock Janet L. , Sinha Manish D.
Published: January 2014

Background: Children with chronic kidney disease (CKD) are at increased risk of future cardiovascular (CV) events. Our aim in this prospective single-centre cross-sectional analysis was to assess the relationship of a novel panel of CV biomarkers with left ventricular hypertrophy (LVH). Methods: A panel of five CV biomarkers (asymmetric dimethyl arginine, high sensitivity C-reactive protein, homocysteine, N-terminal pro-B type natriuretic peptide and uric acid) were measured on the same day as an echocardiogram assessment, in paediatric patients with pre-dialysis stages 3-5 of CKD. Results: Of 73 children aged 5-18 years, LVH, all eccentric, was identified in 38%. Systolic blood pressure (BP), glomerular filtration rate (GFR) and higher intake of calcium-based phosphate binders were significantly worse in children with LVH. In multivariate models analysing each biomarker one at a time with confounders [GFR, systolic BP z-score, anti-hypertensive medication (yes/no) and elemental calcium intake], clinic systolic BP z-score and elemental calcium intake consistently displayed a significant relationship with indexed left ventricular mass (LVMI). None of the evaluated CV biomarkers displayed a significant relationship with LVMI. Conclusions: In our cohort of children with moderately severe pre-dialysis CKD we have identified no suitable biomarkers to detect LVH. We would therefore recommend that echocardiographic determination of LVMI remains the technique of choice for detection of LVH in children with CKD.
Trabeculectomy Using Mitomycin C versus an Atelocollagen Implant: Clinical Results of a Randomized Trial and Histopathologic Findings
Authors: Rosentreter André , Gaki Stergiani , Cursiefen Claus , Dietlein Thomas S.
Published: January 2014

Purpose: To assess the efficacy of trabeculectomy with a biodegradable Ologen™ implant (OLO) versus mitomycin C (MMC) in patients in a prospective randomized clinical trial. Methods: In the MMC group (15 patients), trabeculectomy was performed according to standard protocols. In the OLO group (15 patients) after standard trabeculectomy, the implant was positioned on top of the scleral flap, and no MMC was applied. Results: Mean preoperative intraocular pressure (IOP) levels (OLO: 28.0 ± 9.4; MMC: 23.9 ± 5.0 mm Hg; p = 0.21) and medication score (OLO: 3.4 ± 1.6; MMC: 3.6 ± 1.5; p = 0.56) were comparable in both groups. One year after surgery, the mean IOP was 15.9 ± 4.5 mm Hg in the OLO group (p < 0.01, 43% reduction) and 11.0 ± 2.6 mm Hg in the MMC group (p < 0.01, 54% reduction). The surgical success rate 12 months after surgery was 93.3% in the MMC group and 40% in the OLO group (p = 0.01). Conclusions: With the atelocollagen-glycosaminoglycan matrix OLO it was not possible to reach the surgical success rate and pressure reduction achieved in the MMC group.
Comparisons of Pattern Visually Evoked Potentials Elicited by Different Response Time Liquid Crystal Display Screens
Authors: Matsumoto Celso Soiti , Shinoda Kei , Matsumoto Harue , Funada Hideaki , Sasaki Kakeru , Minoda Haruka , Mizota Atsushi
Published: January 2014

Purpose: To evaluate the usefulness of a liquid crystal display (LCD) with higher driving frequency and shorter response time (2 ms) as a visual stimulator to elicit pattern reversal visually evoked potentials (p-VEPs). Method: p-VEPs were recorded from 12 eyes of 12 healthy volunteers (28.3 ± 9 years). The p-VEPs elicited by a conventional cathode ray tube (CRT) screen were compared to those elicited by a high-speed LCD screen (2-ms LCD, GD245HQbid, Acer, Taipei, Taiwan). The luminance changes of each monitor were measured with a photodiode. Results: During the reversal phase the luminance of the 2-ms LCD screen with 97% contrast was transiently reduced, which can elicit an electroretinogram (ERG) and therefore a flash VEP. The 2-ms LCD with 81% contrast checkerboard had a minimal luminance reduction during the reversal phase, and therefore no ERGs were elicited. No significant differences in the amplitude of P100 and the implicit times of N75 and P100 were observed in the p-VEPs elicited by a CRT or the 2-ms LCD screens as stimulators. Conclusion: The luminance change can elicit flash VEPs, and this artifact can be minimized by using a 2-ms LCD screen with reduced contrast of the checkerboard stimulus.
New Antiangiogenic Strategies beyond Inhibition of Vascular Endothelial Growth Factor with Special Focus on Axon Guidance Molecules
Authors: Pircher Andreas , Wellbrock Jasmin , Fiedler Walter , Heidegger Isabel , Gunsilius Eberhard , Hilbe Wolfgang
Published: January 2014

Since the approval of the first antiangiogenic agent bevacizumab, a neutralizing antibody against the vascular endothelial growth factor (VEGF), antiangiogenic therapies augmented the standard armamentarium of anticancer therapies and proved their clinical efficacy. Nevertheless, antiangiogenic strategies could not fulfill the expected hopes. In clinical routine, therapy responses to antiangiogenic therapies were mostly transient and most of the patients developed evasive resistance mechanisms during therapy. Further, no predictive biomarker for therapy response could be developed, hampering the clinical development of these agents and triggering skepticism. In the past years, knowledge on the biology of angiogenesis increased and the role of tumor hypoxia was better characterized and identified as the driver for angiogenic regulation mechanisms. Besides VEGF, new angiogenic and antiangiogenic factors were characterized and the process of endothelial cell migration, proliferation and vessel formation was better elucidated. Thus, a strong connection to neural development and axon guidance molecules like netrins, Slit proteins, semaphorins, ephrins and their cognate receptors UNC5, Robo1-4, neuropilin and EphB was identified. The aim of this review is to present the importance of these axon guidance molecules with special focus on Robo4 and semaphorins in tumor angiogenesis and to highlight their value as potential targets for new antiangiogenic therapies.
Serum Concentration of 17α-Hydroxyprogesterone in Children from Birth to Adolescence
Authors: Ballerini María Gabriela , Chiesa Ana , Morelli Carina , Frusti Mauro , Ropelato María Gabriela
Published: January 2014

Background: Reference intervals (RI) of serum 17α- hydroxyprogesterone (17OHP) are useful to confirm congenital adrenal hyperplasia (CAH) in neonates with abnormal screening results and nonclassical forms of CAH in symptomatic children. We aimed to establish serum 17OHP RI in normal children and adolescents using a current 17OHP radioimmunoassay (RIA). Methods: Serum 17OHP was measured via a current RIA (Diasource) in children, i.e. 111 infants aged <1 year [before (NE-17OHP) and after extraction (E-17OHP)] and 216 children aged 1-17 years. Forty NE serum samples from subjects aged >1 year, covering the whole analytical range, were simultaneously measured to compare 17OHP RIA from Diagnostic System Laboratories (DSL) (withdrawn) and Diasource by Passing Bablok linear regression and ratio plot. The equation obtained was used to correct our own previous RI (DSL RIA) for infancy for the Diasource RIA. Samples from infants aged <1 year were used to verify the calculated RI with evaluator protocol C28-A3. The influence of age, gender, and Tanner's classification (T) was assessed in children aged >1 year by ANOVA. Results: E-17OHP as measured via the Diasource RIA was significantly lower than NE-17OHP in infants aged <1 year (p < 0.0001). The 17OHP measurement from the Diasource RIA was negatively biased compared to the value obtained using the DSL RIA (Diasource (ng/ml) = 0.85 DSL (ng/ml) -0.32 ng/ml, r = 0.952). Most infants (93%) had age- and gender-adjusted NE-17OHP and E-17OHP levels within the recalculated RI. Serum 17OHP significantly increased throughout prepuberty (p < 0.001). Sexual dimorphism was only observed at T IV-V. Conclusion: When evaluating 17OHP during childhood, we recommend taking into account the extraction procedure in neonates, the method used, age, and the Tanner's stage.
Neurotensin Receptor 1 Gene Polymorphisms Are Associated with Personality Traits in Healthy Chinese Individuals
Authors: Ma Hui , Huang Yinglin , Zhang Bo , Jin Ling , Cong Zhengtu , Wang Yuan , Li Jingying , Zhu Gang
Published: January 2014

Aims: Neurotensin receptor 1 (NTR1) is a neurotensin (NT) receptor subtype with a high affinity for NT. NT and NTR1 signaling are involved in modulating the dopamine system. Individual variations in the dopamine system have been demonstrated to determine certain dimensions of personality, but no studies have thus far investigated the involvement of the NTR1 in the biological determination of personality. We therefore examined this link in a Chinese Han population. Methods: We genotyped 3 single nucleotide polymorphisms (SNPs) (rs6090453C/G, rs6011914C/G, and rs2427422A/G) of the NTR1 gene and collected the data about the personality traits of novelty seeking (NS), harm avoidance (HA), and reward dependence (RD), as well as their subscales (measured by the Tridimensional Personality Questionnaire), in 575 healthy Chinese Han subjects. Then we examined the association between the 3 NTR1 gene polymorphisms and each personality trait. Results: There were significant differences in the HA2, HA3 and RD1 scores between rs6090453C/G genotypes (F = 3.425, 5.651, 4.054, p = 0.033, 0.004, 0.018, respectively), in the HA2 and total RD scores between rs6011914C/G genotypes (F = 4.080, 3.712, p = 0.017, 0.025, respectively), and in the total RD (χ2 = 7.301, p = 0.026) and RD3 (F = 4.119, p = 0.017) scores between the rs2427422A/G genotypes. There were significant male-specific differences in the RD1 scores between the rs6090453C/G genotypes (F = 3.334, p = 0.037), in the total HA (F = 3.043, p = 0.049), HA2 (F = 4.472, p = 0.012) and RD3 (χ2 = 6.997, p = 0.030) scores between the rs6011914C/G genotypes, and in the HA2 (F = 3.177, p = 0.043), total RD (χ2 = 7.032, p = 0.030), and RD3 (F = 4.563, p = 0.011) scores between the rs2427422A/G genotypes. We also demonstrated a significant female-specific difference in the total RD scores between the rs6011914C/G genotypes (F = 3.677, p = 0.026). There was no significant difference in the total NS and subscale scores between the genotypes of all 3 SNPs (all p > 0.05). Conclusions: The variations in the NTR1 gene were involved in the biological mechanisms of HA and RD personality traits; however, the effect is influenced by gender.
Autochthonous Hepatitis E Virus Infections: A New Transfusion-Associated Risk?
Authors: Dreier Jens , Juhl David
Published: January 2014

Hepatitis E virus (HEV) has been recognized since 2004 as a transfusion-transmissible infectious agent, and recent epidemiological data suggest that it may pose a safety threat to the blood supply. It has recently become obvious that hepatitis E is endemic in industrialized countries, and that more infections are autochthonous than travel-associated. Epidemiological and phylogenetic analysis suggests that HEV infection has to be considered as a zoonosis and that viral transmission from animals (pigs, wild animals) occurs through food or direct contact. The seroprevalence and incidence of HEV in the general population and blood donors in European countries indicate an underestimated risk for transfusion transmissions. Recently reported cases of transfusion transmission of HEV infection, and detection of viremic, asymptomatic blood donors in nucleic acid amplification technique screening programs give an indication of the importance of this virus. Diagnostic assays for detection of anti-HEV antibodies, HEV antigens and RNA are discussed. Recent studies support the idea that active immunization can prevent hepatitis E, highlighting the need for vaccination programs. Here we review current knowledge of HEV and its epidemiology, blood transmission and prevention of this disease with emphasis on blood supply.
Prevention of Transfusion-Transmitted Cytomegalovirus Infections: Which is the Optimal Strategy?
Authors: Ziemann Malte , Hennig Holger
Published: January 2014

Traditionally, leukoreduction and selection of blood products from seronegative donors have been used as alternative strategies to reduce the risk of transfusion-transmitted cytomegalovirus infections (TT-CMV) in atrisk patients. After the introduction of universal leukoreduction for red blood cell and platelet concentrates in Germany, a controversy evolved as to whether the additional selection of blood products from seronegative donors would reduce or even increase the risk of TT-CMV. This review summarizes the current knowledge about CMV infections in blood donors and the implications of this information on the effect of potential transfusion strategies. Even though there are conflicting data about the incidence of TT-CMV remaining after the introduction of leukodepletion, it has been clearly shown that both prevalence and concentration of CMV DNA in peripheral blood are highest in newly seropositive donors. Therefore, avoidance of blood products from these donors is the most important goal of any transfusion strategy. This goal can be reached by: i) selection of blood products from seronegative donors, ii) provision of CMV DNA-negative blood products, or iii) provision of blood from long-term seropositive donors. In cases of suspected TT-CMV, all implicated donors should be investigated carefully to gather further knowledge on which donors confer the lowest risk for TT-CMV.
Novel indel Mutation in the GDF5 Gene Is Associated with Brachydactyly Type C in a Four-Generation Turkish Family
Authors: Uyguner Z.O. , Kocaoğlu M. , Toksoy G. , Basaran S. , Kayserili H.
Published: January 2014

Heterozygous loss-of-function mutations of GDF5 are reported to cause hypoplasia/aplasia of certain skeletal elements (brachydactyly), and heterozygous gain-of-function mutations, occurring either on the gene itself or through the loss of its inhibitor noggin, result in joint fusion (symphalangism). We present here the clinical and molecular investigation of a family with disproportionate shortness of the second and third fingers which comprises 9 variably affected members spanning 4 generations. In this study, we performed clinical and radiographical examinations of 2 patients of this family, sequencing of GDF5 and 3D protein modeling of the wildtype and mutated polypeptide to predict the structural alteration. Diagnoses were compatible with familial brachydactyly type C. GDF5 analysis revealed a novel heterozygous in-frame indel mutation (c.803_ 827del25ins25), involving the propeptide domain of GDF5 that alters the number of random coil and beta-strand structures, creating a 1-turn-helix at the mutated site. The mutation described here is the second indel reported in GDF5. The previously published homozygous indel mutation affected the TGF-beta like domain and was associated with Du Pan syndrome. The novel mutation reported here presents further allelic heterogeneity and a probable intrafamilial variable clinical expressivity of GDF5.
Prevalence of CD44-Positive Glomerular Parietal Epithelial Cells Reflects Podocyte Injury in Adriamycin Nephropathy
Authors: Okamoto Takayuki , Sasaki Satoshi , Yamazaki Takeshi , Sato Yasuyuki , Ito Hironobu , Ariga Tadashi
Published: January 2014

Background/Aims: Recent study suggests that activation of parietal epithelial cells (PECs) contributes to pathogenesis of glomerulosclerosis and the activation marker CD44 increases in evolving glomerulosclerosis. Here we examined the pathogenic roles of CD44+ epithelial cells in mouse adriamycin nephropathy (ADRN), a representative rodent model for idiopathic focal segmental glomerulosclerosis (FSGS). We also evaluated whether the prevalence of CD44+ PECs reflects different levels of podocyte injuries. Methods: As a model of FSGS with different degrees of podocyte injury, ADRN models in mice of different ages were utilized. Immunohistochemistry and immunofluorescence were used to determine roles of CD44 expression. Results: By immunohistochemistry, CD44 expression became positive in claudin-1+ PECs and an increase in CD44+ PECs was associated with reduced expression of synaptopodin and podocin in diseased glomeruli. Furthermore, immunofluorescence staining demonstrated co-expression with osteopontin, a CD44 ligand that plays a significant role in the progression of glomerulosclerosis, thereby suggesting interactions between these molecules. Analysis of the number of WT-1+ podocytes and the levels of electron microscopic foot process effacement revealed a milder degree of podocyte injury in younger ADRN models compared to older ones. Comparative immunohistochemical analysis indicated that the prevalence of CD44+ PECs consistently reflects different degrees of podocyte injury within each different-aged ADRN model. Conclusion: CD44+ PECs play significant roles in progressive glomerulosclerosis and the prevalence of the cells reflects different degrees of podocyte injury in ADRN.
Beneficial Effects of Short-Term Calorie Restriction against Cisplatin-Induced Acute Renal Injury in Aged Rats
Authors: Ning Yi-Chun , Cai Guang-Yan , Zhuo Li , Gao Jian-Jun , Dong Dan , Cui Shao-Yuan , Shi Suo-Zhu , Feng Zhe , Zhang Li , Sun Xue-Feng , Chen Xiang-Mei
Published: January 2014

Background: The therapeutic use of the antineoplastic drug cisplatin (DDP) in the elderly is limited by its nephrotoxic effects. The aim of this study was to examine the effect of short-term calorie restriction (CR) on DDP-induced nephrotoxicity in aged rats. Methods: A group of 25-month-old male Sprague-Dawley rats were divided into two groups: ad libitum (AL) and CR, which were fed 60% of the food consumed by AL rats for 8 weeks. The two groups were each further randomly divided into two subgroups: OAL control, OAL+DDP, OCR control, and OCR+DDP. A single dose of DDP (6 mg/kg) was injected intraperitoneally. Functional and structural changes of the kidneys were evaluated quantitatively by biochemical, histopathological, and morphometric analyses. Results: At the end of the 8 weeks, rats in the OCR group lost 14.8% more body mass than rats in the OAL group. Pretreatment with CR had several effects: (1) it reduced the levels of blood urea nitrogen and serum creatinine, (2) it reduced the magnitude of the renal tubular epithelial damage, and (3) it significantly reduced the incidence of activated caspase-3 and TUNEL-positive cells in kidneys injured by DDP. However, SIRT1 had the opposite trend after DDP application between the two groups. Conclusions: Short-term CR exhibits a renoprotective effect in experimental DDP-induced renal injury, the mechanism of which may involve CR antiapoptotic effects and promotion of SIRT1.
We Can Treat Alzheimer's Disease Successfully in Mice but Not in Men: Failure in Translation? A Perspective
Authors: Windisch Manfred
Published: January 2014

Background: Animal models closely resembling the etiopathogenesis of Alzheimer's disease (AD) are needed for research on disease mechanisms and for drug development. No natural model of AD is available, so big hopes arose from transgenic and knockout technology, expecting that modulation and expression of pathogenetically important proteins resemble human brain pathology and functional deficits in the expected morphological and temporal pattern. Objective: The real usefulness of these models should be discussed from an objective point of view. Results: Not a single one of the published transgenic rodent models fulfils this hope, and even complex multiple transgenic animals do not suffer from real AD. It is crucial to be aware that all of the commonly used mice and rats are just models, and therefore results from drug efficacy testing have to be interpreted with care. Repeated experience with failed trials of new treatments that previously had been published as successful in animals has led to the wrong conclusion that animal models are of low predictive value or even of no use. Often clinical trials replicate exactly what was shown in the animal proof-of-concept studies. Conclusion: The value of animal models depends mainly on the careful experimentation and correct interpretation of results. Appropriate planning of experiments will help to increase the predictive value in drug development programs, though this may also increase negative findings. However, the early failure may enable a faster focus on more promising strategies.
Fasting Therapy - an Expert Panel Update of the 2002 Consensus Guidelines
Authors: Wilhelmi de Toledo Françoise , Buchinger Andreas , Burggrabe Hilmar , Hölz Gunter , Kuhn Christian , Lischka Eva , Lischka Norbert , Lützner Hellmut , May Wolfgang , Ritzmann-Widderich Martha , Stange Rainer , Wessel Anna , Boschmann Michael , Peper Elisabeth , Michalsen Andreas
Published: January 2014

Fasting for medical purpose (fasting therapy) has a long tradition in Europe and is established as a defined therapeutic approach in specialized fasting hospitals or within clinical departments for integrative medicine. In 2002, the first guidelines for fasting therapy were published following an expert consensus conference; here we present a revised update elaborated by an expert panel. Historical aspects and definitions, indications, methods, forms, and accompanying procedures of fasting as well as safety and quality criteria of fasting interventions are described. Fasting has shown beneficial effects in various chronic diseases with highest level of evidence for rheumatic diseases. Preliminary clinical and observational data and recently revealed mechanisms of fasting and caloric restriction indicate beneficial effects of fasting also in other chronic conditions such as metabolic diseases, pain syndromes, hypertension, chronic inflammatory diseases, atopic diseases, and psychosomatic disorders. Fasting can also be applied for preventing diseases in healthy subjects. In order to guarantee successful use of fasting and to ensure adherence of all safety and quality standards it is mandatory that all interventions during fasting are guided/accompanied by physicians/therapists trained and certified in fasting therapy.
Autoimmune Polyglandular Syndrome Presenting with Jaundice and Thrombocytopenia
Authors: Norasyikin A.W. , Rozita M. , Mohd Johan M.J. , Suehazlyn Z.
Published: January 2014

Objective: To report an uncommon presentation of a rare case of autoimmune polyglandular syndrome type IIIb in an elderly woman. Clinical Presentation and Intervention: A 62-year-old woman presented with anaemic symptoms and jaundice. Blood tests showed macrocytic anaemia due to vitamin B12 deficiency with Coombs negative haemolysis. A thyroid function test was consistent with hypothyroidism. Autoimmune antibody assays were positive for anti-parietal cell, anti-intrinsic factor and anti-thyroid peroxidase antibodies. A final diagnosis of autoimmune thyroiditis with pernicious anaemia, which constituted autoimmune polyglandular syndrome type IIIb, was made and the patient was treated with L-thyroxine, vitamin B12 injection and a blood transfusion. She was discharged uneventfully after a week of hospitalization. Conclusion: This case showed that the presence of one autoimmune endocrine disease should prompt clinicians to look for other coexisting autoimmune diseases which may be asymptomatic despite positive autoantibodies.
Parvovirus B19 Infections and Blood Counts in Blood Donors
Authors: Juhl David , Steppat Dagmar , Görg Siegfried , Hennig Holger
Published: January 2014

Objectives: Parvovirus B19 (B19V) is a transfusion-transmissible virus. To obtain data about the prevalence, incidence, the course of B19V infection in blood donors and whether B19V might impair their blood counts, samples from blood donors with B19V infection were investigated. Methods: Blood donations were screened for B19V DNA using the Cobas TaqScreen DPX Test® in mini-pools. B19V DNA concentration, anti-B19V IgG antibody titer and blood counts were determined in positive donors. Results: 157/23,889 (0.66%) donors provided 347 B19V DNA-positive samples. Prevalence of B19V infection was 0.45%, incidence 0.20%. B19V DNA concentrations were predominantly low; only in 8 samples were viral loads of ≥105 IU B19V DNA/ml plasma detectable. Besides a slight decrease in hemoglobin, hematocrit, mean corpuscular volume, mean cellular hemoglobin and mean hemoglobin concentration, no major differences in blood counts occurred in B19V DNA-positive samples. In samples with a low B19V DNA concentration, anti-B19V IgG titers were rather high. 98 donors provided at least 1 B19V DNA-positive follow-up sample, indicating a prolonged viremia. Conclusions: B19V infection induced no major impairment in the blood counts. In donors with low-level viremia, infectivity through their donations is probably reduced by high antibody titers. Low-level viremia is prolonged, probably exceeding 1 year in many cases.
Emergency Superficial Temporal Artery to Middle Cerebral Artery Bypass after Intravenous Recombinant Tissue Plasminogen Activator Administration for Acute Cerebral Ischemia in a Patient with Moyamoya Disease
Authors: Tabuchi Sadaharu , Nakajima Sadao , Suto Yutaka , Nakayasu Hiroyuki
Published: January 2014

There are few study data to help in the decision whether to perform aggressive surgical revascularization, such as emergency bypass, after intravenous recombinant tissue plasminogen activator (rt-PA) administration in patients with progressive symptoms due to acute cerebral ischemia. A 33-year-old healthy male with no known previous medical history developed right hemiparesis and motor aphasia. No acute lesion was observed on admission computed tomography. According to the treatment protocol, emergency intravenous rt-PA administration was indicated within 3 h. After rt-PA administration, symptoms progressed to complete right hemiplegia. Emergency magnetic resonance imaging (MRI) showed an acute ischemic lesion in the left basal ganglia. MR angiography showed severe stenosis of the bilateral terminal portion of the internal carotid artery and occlusion of the left middle cerebral artery (MCA). Obvious diffusion-perfusion mismatch was detected. We performed digital subtraction angiography and diagnosed this condition as acute cerebral ischemia induced by moyamoya disease. We decided to perform emergency superficial temporal artery (STA)-MCA bypass to prevent further damage. The operation began 7 h after the administration of rt-PA and successful bypass was achieved. Symptoms stabilized and improved postoperatively. The majority of the area with preoperative hypoperfusion was rescued. Four months after surgery, the patient resumed his previous employment and continues to do well after 1.5 years of follow-up. This is the first report of emergency STA-MCA bypass performed after intravenous rt-PA administration for acute cerebral ischemia in a patient with moyamoya disease. We conclude that emergency STA-MCA bypass is a viable option for patients with moyamoya disease even after administration of rt-PA.
Uneven Futures of Human Lifespans: Reckonings from Gompertz Mortality Rates, Climate Change, and Air Pollution
Authors: Finch Caleb E. , Beltrán-Sánchez Hiram , Crimmins Eileen M.
Published: January 2014

The past 200 years have enabled remarkable increases in human lifespans through improvements in the living environment that have nearly eliminated infections as a cause of death through improved hygiene, public health, medicine, and nutrition. We argue that the limit to lifespan may be approaching. Since 1997, no one has exceeded Jeanne Calment's record of 122.5 years, despite an exponential increase of centenarians. Moreover, the background mortality may be approaching a lower limit. We calculate from Gompertz coefficients that further increases in longevity to approach a life expectancy of 100 years in 21st century cohorts would require 50% slower mortality rate accelerations, which would be a fundamental change in the rate of human aging. Looking into the 21st century, we see further challenges to health and longevity from the continued burning of fossil fuels that contribute to air pollution as well as global warming. Besides increased heat waves to which elderly are vulnerable, global warming is anticipated to increase ozone levels and facilitate the spread of pathogens. We anticipate continuing socioeconomic disparities in life expectancy.
Concurrent Reactivation of Herpes Simplex and Varicella Zoster Viruses Confirmed by the Loop-Mediated Isothermal Amplification Assay
Authors: Kobayashi Tsukane , Yagami Akiko , Suzuki Kayoko , Yoshikawa Tetsushi , Matsunaga Kayoko
Published: January 2014

Concurrent reactivation of herpes simplex and varicella zoster viruses is rare. Here, we describe the case of an elderly patient with herpes labialis and herpes zoster manifesting as a right-side facial eruption with vesicles and crusting. The loop-mediated isothermal amplification (LAMP) assay demonstrated the presence of both herpes simplex virus type 1 and varicella zoster virus in swab samples taken from the face, which was confirmed by real-time PCR, suggesting concurrent reactivation of both viruses. The use of the LAMP assay in the present case indicates its usefulness in the diagnosis of atypical herpes infections.
Emerging Pathogens - How Safe is Blood?
Authors: Schmidt Michael , Geilenkeuser Wolf-Jochen , Sireis Walid , Seifried Erhard , Hourfar Kai
Published: January 2014

During the last few decades, blood safety efforts were mainly focused on preventing viral infections. However, humanity's increased mobility and improved migration pathways necessitate a global perspective regarding other transfusion-transmitted pathogens. This review focuses on the general infection risk of blood components for malaria, dengue virus, Trypanosoma cruzi (Chagas disease) and Babesia spp. Approximately 250 million people become infected by Plasmodium spp. per year. Dengue virus affects more than 50 million people annually in more than 100 countries; clinically, it can cause serious diseases, such as dengue haemorrhagic fever and dengue shock syndrome. Chagas disease, which is caused by Trypanosoma cruzi, mainly occurs in South America and infects approximately 10 million people annually. Babesia spp. is a parasitic infection that infects red blood cells; although many infections are asymptomatic, severe clinical disease has been reported, especially in the elderly. Screening assays are available for all considered pathogens but make screening strategies more complex and more expensive. A general pathogen inactivation for all blood components (whole blood) promises to be a long-term, sustainable solution for both known and unknown pathogens. Transfusion medicine therefore eagerly awaits such a system.
Spontaneous Healing of Corneal Perforation after Temporary Discontinuation of Erlotinib Treatment
Authors: Morishige Naoyuki , Hatabe Nanami , Morita Yukiko , Yamada Naoyuki , Kimura Kazuhiro , Sonoda Koh-Hei
Published: January 2014

Purpose: To report a case of corneal perforation associated with oral administration of erlotinib and its spontaneous healing after temporary discontinuation of drug treatment. Case Report: A 65-year-old man with metastatic lung cancer was treated with erlotinib (150 mg/day), a specific tyrosine kinase inhibitor of the epidermal growth factor receptor. He was referred to our corneal service for the treatment of bilateral corneal disorders, diagnosed with mild aqueous-deficient dry eye, and treated by insertion of punctal plugs. His corneal epithelial disorders initially improved, but subsequently worsened, as manifested by the development of bilateral corneal ulceration with corneal perforation in the right eye. The oral administration of erlotinib was interrupted in preparation for tectonic keratoplasty, but 2 days later the corneal perforation of the right eye and the bilateral epithelial defects had healed spontaneously. Treatment with erlotinib was resumed at half the initial dose, and the cornea of both eyes has remained apparently healthy. Discussion: Erlotinib may be secreted into tear fluid and thereby adversely affect the corneal epithelium. The development of corneal epithelial disorders in patients receiving this drug may be reversed by reducing its dose.
Mechanistic Relationship Between Membrane Type-1 Matrix Metalloproteinase and the Myocardial Response to Pressure Overload
Authors: Zile Michael R. , Baicu Catalin F. , Stroud Robert E. , Van Laer An O. , Jones Jeffrey A. , Patel Risha , Mukherjee Rupak , Spinale Francis G.
Published: January 2014

Background—

Although matrix metalloproteinases (MMPs) were initially thought to result primarily in extracellular matrix degradation, certain MMP types, such as membrane type-1 (MT1) MMP, may also be involved in profibrotic cascades through hydrolysis of latency-associated transforming growth factor–binding protein (LTBP-1) and activation of transforming growth factor–dependent profibrotic signaling. The present study tested the hypothesis that MT1-MMP plays a direct role in the matrix remodeling response to a left ventricular (LV) pressure overload (PO) stimulus.

Methods and Results—

Wild-type (WT) and transgenic mice with cardiac-restricted MT1-MMP overexpression or MT1-MMP reduced expression underwent PO for 4 weeks. PO resulted in a 57% increase in LV mass (no change in LV end diastolic volume, resulting in an increase in the LV mass/volume ratio consistent with concentric remodeling), a 60% increase in MT1-MMP–mediated LTBP-1 hydrolysis and a 190% increase in collagen content in WT mice. Although LV mass was similar among WT, MT1-MMP overexpression, and MT1-MMP reduced expression after PO, significant differences in LV function, MT1-MMP–mediated LTBP-1 hydrolysis, and collagen content occurred. PO in MT1-MMP overexpression increased LTBP-1 hydrolysis (18%), collagen content (60%), and left atrial dimension (19%; indicative of LV diastolic dysfunction) when compared with WT. PO in MT1-MMP reduced expression reduced left atrial dimension (19%), LTBP-1 hydrolysis (40%), and collagen content (32%) when compared with both WT.

Conclusions—

Despite an equivalent PO stimulus and magnitude of LV myocardial growth, altering MT1-MMP levels caused specific matrix-dependent changes in remodeling, thereby demonstrating a mechanistic role in the development of the maladaptive remodeling and myocardial fibrotic response to PO.
Histone Deacetylase Inhibition Blunts Ischemia/Reperfusion Injury by Inducing Cardiomyocyte Autophagy
Authors: Xie Min , Kong Yongli , Tan Wei , May Herman , Battiprolu Pavan K. , Pedrozo Zully , Wang Zhao V. , Morales Cyndi , Luo Xiang , Cho Geoffrey , Jiang Nan , Jessen Michael E. , Warner John J. , Lavandero Sergio , Gillette Thomas G. , Turer Aslan T. , Hill Joseph A.
Published: January 2014

Background—

Reperfusion accounts for a substantial fraction of the myocardial injury occurring with ischemic heart disease. Yet, no standard therapies are available targeting reperfusion injury. Here, we tested the hypothesis that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor approved for cancer treatment by the US Food and Drug Administration, will blunt reperfusion injury.

Methods and Results—

Twenty-one rabbits were randomly assigned to 3 groups: (1) vehicle control, (2) SAHA pretreatment (1 day before and at surgery), and (3) SAHA treatment at the time of reperfusion only. Each arm was subjected to ischemia/reperfusion surgery (30 minutes coronary ligation, 24 hours reperfusion). In addition, cultured neonatal and adult rat ventricular cardiomyocytes were subjected to simulated ischemia/reperfusion to probe mechanism. SAHA reduced infarct size and partially rescued systolic function when administered either before surgery (pretreatment) or solely at the time of reperfusion. SAHA plasma concentrations were similar to those achieved in patients with cancer. In the infarct border zone, SAHA increased autophagic flux, assayed in both rabbit myocardium and in mice harboring an RFP-GFP-LC3 transgene. In cultured myocytes subjected to simulated ischemia/reperfusion, SAHA pretreatment reduced cell death by 40%. This reduction in cell death correlated with increased autophagic activity in SAHA-treated cells. RNAi-mediated knockdown of ATG7 and ATG5, essential autophagy proteins, abolished SAHA’s cardioprotective effects.

Conclusions—

The US Food and Drug Administration–approved anticancer histone deacetylase inhibitor, SAHA, reduces myocardial infarct size in a large animal model, even when delivered in the clinically relevant context of reperfusion. The cardioprotective effects of SAHA during ischemia/reperfusion occur, at least in part, through the induction of autophagic flux.
Left Ventricular Strain and Transmural Distribution of Structural Remodeling in Hypertensive Heart Disease
Authors: Ishizu Tomoko , Seo Yoshihiro , Kameda Yuri , Kawamura Ryo , Kimura Taizou , Shimojo Nobutake , Xu Dongzhu , Murakoshi Nobuyuki , Aonuma Kazutaka
Published: January 2014

Left ventricular (LV) systolic wall strain is a new candidate for prognostic indicator of hypertensive heart failure. It remains unclear how underlying transmural structural remodeling corresponds to LV wall systolic deformation as hypertensive hypertrophy progresses. We fed 68 Dahl salt–sensitive rats a high-salt (hypertensive group) or low-salt diet (control group) from 6 weeks old. At 10, 14, and 18 weeks, pressure–volume relation, transmural distribution of LV fibrosis, and myocyte hypertrophy were evaluated. LV global longitudinal and circumferential strain was measured with speckle tracking echocardiography. Emax was preserved throughout the study period, whereas τ and end-diastolic pressure–volume relation progressively deteriorated from 14 weeks (diastolic dysfunction stage). Lung weight increased significantly at 18 weeks (decompensated stage). Histological percentage area fibrosis and collagen type I/III, myocyte hypertrophy, and α-myosin heavy chain isoform increased in the subendocardial layer at 14 weeks and progressed into the midlayer at 18 weeks. Longitudinal strain progressively deteriorated in the hypertensive group versus control group at 14 weeks (hypertensive group: −17±3%, control: −27±4%;
P
<0.001), and circumferential strain decreased at 18 weeks (hypertensive group: −17±2%, control: −27±3%;
P
=0.002). After adjustment for systolic wall stress, subendocardial percentage area fibrosis was selected as the independent determinant of longitudinal strain. This study showed that LV wall strain alternations were accompanied by fibrosis and myocyte hypertrophy from subendocardium to epicardium, and longitudinal strain related significantly to subendocardial layer fibrosis. Longitudinal strain could be a surrogate of subendocardial fibrotic changes and may be useful for risk stratification of hypertensive heart failure.
Interferon Regulatory Factor 7 Functions as a Novel Negative Regulator of Pathological Cardiac Hypertrophy
Authors: Jiang Ding-Sheng , Liu Yu , Zhou Heng , Zhang Yan , Zhang Xiao-Dong , Zhang Xiao-Fei , Chen Ke , Gao Lu , Peng Juan , Gong Hui , Chen Yingjie , Yang Qinglin , Liu Peter P. , Fan Guo-Chang , Zou Yunzeng , Li Hongliang
Published: January 2014

Cardiac hypertrophy is a complex pathological process that involves multiple factors including inflammation and apoptosis. Interferon regulatory factor 7 (IRF7) is a multifunctional regulator that participates in immune regulation, cell differentiation, apoptosis, and oncogenesis. However, the role of IRF7 in cardiac hypertrophy remains unclear. We performed aortic banding in cardiac-specific IRF7 transgenic mice, IRF7 knockout mice, and the wild-type littermates of these mice. Our results demonstrated that IRF7 was downregulated in aortic banding–induced animal hearts and cardiomyocytes that had been treated with angiotensin II or phenylephrine for 48 hours. Accordingly, heart-specific overexpression of IRF7 significantly attenuated pressure overload–induced cardiac hypertrophy, fibrosis, and dysfunction, whereas loss of IRF7 led to opposite effects. Moreover, IRF7 protected against angiotensin II–induced cardiomyocyte hypertrophy in vitro. Mechanistically, we identified that IRF7-dependent cardioprotection was mediated through IRF7 binding to inhibitor of κB kinase-β, and subsequent nuclear factor-κB inactivation. In fact, blocking nuclear factor-κB signaling with cardiac-specific inhibitors of κBα
S32A/S36A
super-repressor transgene counteracted the adverse effect of IRF7 deficiency. Conversely, activation of nuclear factor-κB signaling via a cardiac-specific conditional inhibitor of κB kinase-β
S177E/S181E
(constitutively active) transgene negated the antihypertrophic effect of IRF7 overexpression. Our data demonstrate that IRF7 acts as a novel negative regulator of pathological cardiac hypertrophy by inhibiting nuclear factor-κB signaling and may constitute a potential therapeutic target for pathological cardiac hypertrophy.