bluuebunny/crossref_metadata_2025 huggingface dataset:
Die Nutzung natürlicher Killerzellen für die Therapie des Melanoms
Authors: Hölsken Oliver , Miller Matthias , Cerwenka Adelheid
Published: January 2015

In den letzten Jahren hat die Immuntherapie wesentlichen Einfluss auf die klinische Therapie des malignen Melanoms gewonnen. Neben vielversprechenden T‐Lymphozyten‐basierten Ansätzen erhalten natürliche Killerzellen (NK‐Zellen) zunehmende Aufmerksamkeit als Antitumor‐Effektor‐Zellen. HLA‐Klasse‐I‐Moleküle inhibieren die Aktivierung von NK‐Zellen, so dass diese präferentiell Tumorzellen angreifen, die HLA‐Klasse‐I‐Moleküle in nur geringem Maß exprimieren. Der teilweise oder vollständige Verlust der HLA‐Klasse‐I‐Expression ist ein häufiges Ereignis bei der Melanomentstehung. Gleichzeitig werden bei der malignen Transformation NK‐Zell‐Rezeptor‐aktivierende Liganden induziert. Daher werden Melanomzellen durch NK‐Zellen zumindest in vitro erkannt und lysiert. In vivo haben Melanome jedoch umfassende Strategien entwickelt, um dem durch NK‐Zellen vermittelten Angriff zu entgehen. Eine Vielzahl neuartiger Ansätze zielt darauf ab, NK‐Zellen zu nutzen, um Melanompatienten wirksam zu therapieren und den bestehenden “Escape‐Mechanismen” der Tumorzellen entgegenzuwirken. Dieser Übersichtsartikel fasst die aktuellen Fortschritte auf diesem Gebiet zusammen.
Assessment of melanoma histotypes and associated patient related factors: Basis for a predictive statistical model
Authors: Haenssle Holger A. , Hoffmann Saskia , Buhl Timo , Emmert Steffen , Schön Michael P. , Bertsch Hans Peter , Rosenberger Albert
Published: January 2015

Background

Certain melanoma histotypes carry a worse prognosis than others. We aimed to identify patient related factors associated with specific melanoma histotypes.

Patients and methods

Single center study including 347 melanoma patients, prospectively assessed for 22 variables leading to a database of more than 7 600 features.

Results

Melanomas were histologically categorized as superficial spreading (SSM, 70.6 %), nodular (NM; 12.7 %), acrolentiginous (ALM; 4.0 %), lentigo maligna (LMM; 3.8 %), or unclassified melanoma (UCM; 8.9 %). Well recognized melanoma risk indicators (i. e. many atypical nevi, freckles, previous melanoma), were significantly associated with SSM and LMM histotypes. NM and ALM patients carried significantly less common and/or atypical nevi. NM were mostly self‐detected or detected by relatives. In contrast, SSM, LMM, and ALM were most frequently detected by dermatologists. NM and UCM were preferentially located on poorly observable sites, SSM on the lower limbs, ALM on plantar sites, and LMM on the head and neck. ALM and LMM patients were significantly older than other patients. A multinomial logistic model was designed to predict a certain melanoma histotype (overall accuracy 81 %), which could be helpful to focus the attention of clinicians or may be integrated into fully automated diagnostic algorithms.

Conclusions

Melanoma histotypes show significant differences regarding patients’ characteristics.
Subtypen des malignen Melanoms und assoziierte patientenbezogene Faktoren: Grundlage für ein prädiktives statistisches Modell
Authors: Haenssle Holger A. , Hoffmann Saskia , Buhl Timo , Emmert Steffen , Schön Michael P. , Bertsch Hans Peter , Rosenberger Albert
Published: January 2015

Hintergrund

Bestimmte Subtypen des Melanoms haben eine schlechtere Prognose als andere. Unser Ziel war es, patientenbezogene Faktoren zu identifizieren, die mit spezifischen Subtypen des Melanoms vergesellschaftet sind.

Patienten und Methoden

Monozentrische Studie an 347 Melanompatienten, bei denen prospektiv 22 patientenbezogene Variablen erhoben wurden, woraus eine Datenbank mit mehr als 7600 Merkmalen erstellt wurde.

Ergebnisse

Melanome wurden histologisch als superfiziell‐spreitend (SSM, 70,6 %), nodulär (NM; 12,7 %), akrolentiginös (ALM; 4,0 %), Lentigo maligna (LMM; 3,8 %) oder nicht klassifiziertes Melanom (UCM; 8,9 %) klassifiziert. Bekannte Risikofaktoren (i. e. zahlreiche atypische Nävi, Sommersprossen, Z. n., Melanom) waren signifikant mit den Subtypen SSM und LMM assoziiert. NM und ALM‐Patienten wiesen signifikant weniger gewöhnliche oder atypische Nävi auf. NM waren zumeist vom Patienten selbst oder einem Verwandten entdeckt worden, wohingegen SSM, LMM und ALM zumeist vom Dermatologen entdeckt wurden. NM und UCM waren präferentiell an schlecht beobachtbaren Körperstellen lokalisiert, SSM an der unteren Extremität, ALM im Plantarbereich und LMM an Kopf und Hals. ALM und LMM‐Patienten waren signifikant älter als die anderen Patienten. Wir entwickelten ein multinomiales logistisches Modell zur Vorhersage eines Melanomsubtyps (Gesamtgenauigkeit 81 %), welches geeignet sein könnte, um die Aufmerksamkeit klinisch tätiger Ärzte entsprechend zu fokussieren oder in vollautomatisierte Diagnosealgorithmen eingeschlossen zu werden.

Schlussfolgerungen

Melanomsubtypen zeigen signifikante Unterschiede hinsichtlich patientenbezogener Faktoren.
Obscure gastrointestinal bleeding: Diagnosis and treatment
Authors: Ohmiya Naoki , Nakagawa Yoshihito , Nagasaka Mituso , Tahara Tomomitsu , Shibata Tomoyuki , Nakamura Masanao , Hirooka Yoshiki , Goto Hidemi , Hirata Ichiro
Published: January 2015

Small‐bowel bleeding comprises a majority of obscure gastrointestinal bleeding, but is caused by various kinds of diseases. For its diagnosis, history‐taking and physical examination is requisite, leading to a suspicion of what diseases are involved. Next, cross‐sectional imaging such as computed tomography should be done, followed by the latest enteroscopy, videocapsule endoscopy and deep enteroscopy according to the severity of hemorrhage and patient conditions. After comprehensive diagnosis, medical, enteroscopic, or surgical treatment should be selected.
Pathogenicity of ophiostomatoid fungi on Picea abies in Slovenia
Authors: Repe A. , Bojović S. , Jurc M.
Published: January 2015

Pathogenic fungi can survive and develop in living plants, often causing diseases in the host. Some theories speculate that pathogenic ophiostomatoid fungi provide benefits to its vectors – bark beetles – by overcoming the tree's defence mechanisms. This study reports the results of an experiment in south‐eastern Europe in which mature and seedling Norway spruce trees were artificially inoculated with various ophiostomatoid fungi. The aim of the experiment was to determine the relative virulence of ophiostomatoid fungi by assessing the ability of the fungi to stimulate host tree defence mechanisms through inoculation experiments. Experiments were performed by inoculation of Picea abies in seedling and mature trees. The following fungi were used in low‐density and seedling inoculations: Ophiostoma ainoae, O. brunneo‐ciliatum, Grosmannia cucullata and an unidentified Leptographium sp., O. bicolor, O. fuscum, O. piceae, G. penicillata and G. piceiperda. Endoconidiophora polonica was used in mass and seedling inoculations. Various characteristics such as host vitality, blue stain, lesion and resin outflow were measured before and after the trees were felled. E. polonica caused blue stain, induced large lesions and killed some of the mature trees and seedlings, confirming earlier reports that it is a strong wound pathogen. Only E. polonica, Leptographium sp. and O. ainoae caused blue stains in the sapwood of inoculated seedlings. In low‐density inoculations, G. piceiperda induced intense necrosis and had higher values for all the characteristics monitored. Some of the other ophiostomatoid fungi showed a moderate level of pathogenicity. Fungi with the capacity to stimulate a host defence mechanism could play a role in the establishment of bark beetle populations.
Quality of supervision: postgraduate dental research trainees’ perspectives
Authors: Beaudin A. , Emami E. , Palumbo M. , Tran S. D.
Published: January 2015

Introduction

Supervision is a pillar in enhancing the student's learning environment throughout her/his higher education. Multiple studies qualify graduate supervision among the most important contributors to the successful completion of a higher education degree and to graduate students' positive academic experience. The aim of this study was to assess the views of graduate students enrolled in the Dental Sciences and Craniofacial Research Graduate Programs at McGill University (n = 64) regarding the quality of supervision they are receiving.

Methods and materials

An online questionnaire composed of 22 open and closed‐ended format items was used and covered five domains: student profile, supervisory relationship, conflict resolution, student progress/thesis writing and career development. Descriptive statistics, chi‐square tests and interpretative qualitative analysis were used to evaluate students' perspectives.

Results

Fifty‐nine students completed the survey (92.2%). The distribution of sample in regard to the graduate student level was almost identical (M.Sc. level n = 28, Ph.D. n = 31). Overall, most graduate students appeared satisfied with the supervision they received and had similar perspectives about the surveyed domains. There was one statistically significant difference (P < 0.05) between MSc and PhD students when asked if their supervisors aided them in career development outside the supervisory relationship, where 77.4% (n = 24) of doctoral students agreed as opposed to 21.4% (n = 12) of Masters’ students.

Conclusions

Our results showed that McGill graduate students appeared to be overall satisfied with the supervision they received. The main elements contributing to a positive supervision experience were support, guidance, availability and good communication between supervisees and supervisors.
Non‐genetic risk factors and their influence on the management of patients in the clinic
Authors: Álvarez Teresa , Soto Immaculada , Astermark Jan
Published: January 2015

The development of inhibitors is the most serious iatrogenic complication affecting patients with haemophilia. This complication is associated with impaired vital or functional prognosis, reduced quality of life and increased cost of treatment. The reasons why some patients develop antibodies to factor replacement and others do not remain unclear. It is however clear that inhibitor development results from a complex multifactorial interaction between genetic and non‐genetic risk factors. Environmental influences implicated in increasing the risk of inhibitor formation can be viewed as modifiable risk factors. Therefore, identification of the non‐genetic risk factors may offer the possibility of personalising haemophilia therapy by modifying treatment strategies in high‐risk patients in the critical early phase of factor VIII exposure. In this article, we review the non‐genetic factors reported as well as the potential impact of danger signals and the different scores for inhibitor development risk stratification.
Genetic risk factors for inhibitors in haemophilia A
Authors: Bardi Edit , Astermark Jan
Published: January 2015

The current most serious side effect of haemophilia treatment is inhibitor development. Significant progress has been made over the last decades to understand why this complication occurs in some patients and it seems clear that both genetic and non‐genetic factors are involved. Several issues however remain to be settled. A review was undertaken to summarise some key findings regarding the current view and available data on genetic markers of potential importance within this area. The causative F8 mutation, together with the HLA class II alleles, plays a pivotal pathophysiological role in inhibitor development. The types of mutation most frequently associated with inhibitors are large deletions, nonsense mutations, inversions, small deletions/insertions without A‐runs, splice‐site mutations at conserved nucleotides and certain missense mutations. Regarding HLA class II allele, it has been hard to consistently identify risk alleles. Ethnicity has consistently been associated with inhibitor risk, but the causality of this has so far not been resolved. Among immune regulatory molecules, several polymorphic molecules have been suggested to be of importance. Most of these need additional studies and immune system challenges have to be fully evaluated. Inhibitor risk should be further defined, as patients in the future may be offered non‐immunogenic treatments.
Various regimens for prophylactic treatment of patients with haemophilia
Authors: Schwarz Rudolf , Ljung Rolf , Tedgård Ulf
Published: January 2015

Haemophilia prophylaxis is superior to on‐demand treatment to prevent joint damage. ‘High‐dose prophylaxis’ as used in Sweden is more effective in preventing arthropathy than an ‘intermediate‐dose regimen’ (the Netherlands) and the Canadian tailored primary prophylaxis. Prophylaxis may reduce the risk of developing inhibitors. There is no difference in inhibitor risk between plasma derived and recombinant factor VIII (rFVIII) products but the Rodin study showed increased risk with second‐generation rFVIII products. MRI is a new and very sensitive tool to detect the symptoms of early arthropathy but some results (soft tissue changes in ‘bleed‐free joints’) still need to be investigated. Ultrasound is a very helpful method to aid diagnosis especially during the acute phase of a bleed. The risk of infection with central venous access remains a matter of debate. A fully implanted central venous access device (CVAD) has a significant lower risk of infection compared to external CVADs. Patient's age under 6 yr and inhibitor presence are additional risk factors for infections. The role of arteriovenous fistulae needs to be investigated because significant complications have been reported. Disease‐specific quality of life instruments are complementary to generic instruments evaluating QoL in patients with haemophilia and have become important health outcome measures.
The ageing patient with haemophilia
Authors: Canaro Mariana , Goranova‐Marinova Veselina , Berntorp Erik
Published: January 2015

Older patients with haemophilia (PWH) face many challenges related not only to haemophilia but also to general comorbidities associated with ageing. This article discusses the clinical experience published about the high prevalence of diseases in older PWH. These conditions are managed in the general population by healthcare workers with little training in haemophilia. Haemophilic arthropathy is common in elderly PWH. Prophylaxis starting at an early age in sufficient dose regimens to prevent arthropathy did not occur in patients who are now older than around 40 yr. Many PWH above this age thus have limitations in their activities of daily life. Cardiovascular diseases have become increasingly common in the growing, ageing cohort of PWH. Lifestyle issues such as sexual dysfunction may be exacerbated by the medical issues and psychological problems associated with haemophilia. Hepatitis C virus is a leading problem in PWH. Coinfection with HIV accelerates the progression to end‐stage liver disease. Acute and chronic renal failure is more common in adult PWH than in general population. Other comorbidities are reviewed. The evidence is scarce, so it is imperative to report any experience regarding the diagnosis and treatment of these entities, to improve the quality of life of older PWH.
One‐stage vs. chromogenic assays in haemophilia A
Authors: Potgieter Joachim J. , Damgaard Michael , Hillarp Andreas
Published: January 2015

Haemophilia A severity is closely correlated to the factor VIII (FVIII) activity, which can be measured in different ways. The original one‐stage clotting assay is still the most widely used. The two‐stage coagulation assay eliminated many of the drawbacks of the one‐stage assay and was further developed into the chromogenic assay, a two‐staged test with purified coagulation factors in the first stage, and a FXa‐specific chromogenic substrate in the second stage. In many patients with mild or moderate haemophilia A, there is a discrepancy between the one‐stage and the two‐stage assays. If only the one‐stage assay is used, some patients will have normal FVIII levels and not be diagnosed as having haemophilia or be considered to have a milder bleeding risk than is the case. Other patients who have normal FVIII activity will be diagnosed as haemophilia A. All haemophilia treatment centre laboratories should have access to both one‐stage and chromogenic FVIII:C assays. Appropriate standards should be employed to enable accurate FVIII:C measurement. Different assays to measure inhibitor activity to infused FVIII have been developed since 1959. Inhibitor results based on the one‐stage or chromogenic FVIII:C assays are well correlated, but the one‐stage assay may be influenced by nonspecific inhibition.
Strategies for reducing inhibitor formation in severe haemophilia
Authors: Tunstall Oliver , Astermark Jan
Published: January 2015

The greatest barrier to successful haemophilia A care in resource‐rich countries is the development of inhibitors to therapeutic factor VIII. Children with inhibitors suffer through increased bleeding and joint damage as well as frequent venepuncture. Costs associated with inhibitors are beyond many healthcare systems. Over the last two decades, there has been no improvement in our ability to reduce inhibitor development. Current strategies based on early prophylaxis and avoidance of immunological danger signals have given rise to conflicting results. Registry data suggest an increasing problem. Our understanding of the immunological systems involved in inhibitor formation should inform efforts to prevent inhibitors. Great efforts with mouse models are being undertaken in this field. However, there is no guarantee of the availability of any new agents arising from experimental work in the near future. Global immunomodulatory agents may be one solution. Compounds with a long history of use in inflammatory conditions have demonstrated efficacy in preventing antibodies to protein therapeutics both in animal models and in humans. As these compounds have a long history of use in humans, including babies, it may be that these agents offer an option for reducing inhibitor formation in previously untreated patients.
BH3‐only proteins: a 20‐year stock‐take
Authors: Doerflinger Marcel , Glab Jason A. , Puthalakath Hamsa
Published: January 2015

BH3‐only proteins are the sentinels of cellular stress, and their activation commits cells to apoptosis. Since the discovery of the first BH3‐only protein BAD almost 20 years ago, at least seven more BH3‐only proteins have been identified in mammals. They are regulated by a variety of environmental stimuli or by developmental cues, and play a crucial role in cellular homeostasis. Some are considered to be tumor suppressors, and also play a significant role in other pathologies. Their non‐apoptotic functions are controversial, but there is broad consensus emerging regarding their role in apoptosis, which may help in designing better therapeutic agents for treating a variety of human diseases.
Epigenetics and memory: causes, consequences and treatments for post‐traumatic stress disorder and addiction
Authors: Pizzimenti C. L. , Lattal K. M.
Published: January 2015

Understanding the interaction between fear and reward at the circuit and molecular levels has implications for basic scientific approaches to memory and for understanding the etiology of psychiatric disorders. Both stress and exposure to drugs of abuse induce epigenetic changes that result in persistent behavioral changes, some of which may contribute to the formation of a drug addiction or a stress‐related psychiatric disorder. Converging evidence suggests that similar behavioral, neurobiological and molecular mechanisms control the extinction of learned fear and drug‐seeking responses. This may, in part, account for the fact that individuals with post‐traumatic stress disorder have a significantly elevated risk of developing a substance use disorder and have high rates of relapse to drugs of abuse, even after long periods of abstinence. At the behavioral level, a major challenge in treatments is that extinguished behavior is often not persistent, returning with changes in context, the passage of time or exposure to mild stressors. A common goal of treatments is therefore to weaken the ability of stressors to induce relapse. With the discovery of epigenetic mechanisms that create persistent molecular signals, recent work on extinction has focused on how modulating these epigenetic targets can create lasting extinction of fear or drug‐seeking behavior. Here, we review recent evidence pointing to common behavioral, systems and epigenetic mechanisms in the regulation of fear and drug seeking. We suggest that targeting these mechanisms in combination with behavioral therapy may promote treatment and weaken stress‐induced relapse.
Behavioral flexibility in rats and mice: contributions of distinct frontocortical regions
Authors: Hamilton D. A. , Brigman J. L.
Published: January 2015

Research examining the contribution of genetics to behavior is increasingly focused on higher order behavioral and cognitive processes including the ability to modify behaviors when environmental demands change. The frontal cortices of mammals, including rodents, subserve a diverse set of behavioral and cognitive functions including motor planning, social behavior, evaluation of expected outcomes and working memory, which may be particularly sensitive to genetic factors and interactions with experience (e.g. stress). Behavioral flexibility is a core attribute of these functions. This review orients readers to the current landscape of the literature on the frontocortical bases of behavioral flexibility in rodent laboratory experiments. Studies are divided into three broad categories: reversal learning, inhibitory learning and set‐shifting. Functional dissociations within the broader scope of behavioral flexibility are reviewed, followed by discussion of the associations between specific components of frontal cortex and specific aspects of relevant behavioral processes. Finally, the authors identify open questions that need to be addressed to better establish the constituents of frontal cortex underlying behavioral flexibility.
Sleep‐like behavior and 24‐h rhythm disruption in the Tc1 mouse model of Down syndrome
Authors: Heise I. , Fisher S. P. , Banks G. T. , Wells S. , Peirson S. N. , Foster R. G. , Nolan P. M.
Published: January 2015

Down syndrome is a common disorder associated with intellectual disability in humans. Among a variety of severe health problems, patients with Down syndrome exhibit disrupted sleep and abnormal 24‐h rest/activity patterns. The transchromosomic mouse model of Down syndrome, Tc1, is a trans‐species mouse model for Down syndrome, carrying most of human chromosome 21 in addition to the normal complement of mouse chromosomes and expresses many of the phenotypes characteristic of Down syndrome. To date, however, sleep and circadian rhythms have not been characterized in Tc1 mice. Using both circadian wheel‐running analysis and video‐based sleep scoring, we showed that these mice exhibited fragmented patterns of sleep‐like behaviour during the light phase of a 12:12‐h light/dark (LD) cycle with an extended period of continuous wakefulness at the beginning of the dark phase. Moreover, an acute light pulse during night‐time was less effective in inducing sleep‐like behaviour in Tc1 animals than in wild‐type controls. In wheel‐running analysis, free running in constant light (LL) or constant darkness (DD) showed no changes in the circadian period of Tc1 animals although they did express subtle behavioural differences including a reduction in total distance travelled on the wheel and differences in the acrophase of activity in LD and in DD. Our data confirm that Tc1 mice express sleep‐related phenotypes that are comparable with those seen in Down syndrome patients with moderate disruptions in rest/activity patterns and hyperactive episodes, while circadian period under constant lighting conditions is essentially unaffected.
Hypothalamic gene expression underlying pre‐hibernation satiety
Authors: Schwartz C. , Hampton M. , Andrews M. T.
Published: January 2015

Prior to hibernation, 13‐lined ground squirrels (Ictidomys tridecemlineatus) enter a hypophagic period where food consumption drops by an average of 55% in 3 weeks. This occurs naturally, while the ground squirrels are in constant environmental conditions and have free access to food. Importantly, this transition occurs before exposure to hibernation conditions (5°C and constant darkness), so the ground squirrels are still maintaining a moderate level of activity. In this study, we used the Illumina HiSeq 2000 system to sequence the hypothalamic transcriptomes of ground squirrels before and after the autumn feeding transition to examine the genes underlying this extreme change in feeding behavior. The hypothalamus was chosen because it is known to play a role in the control and regulation of food intake and satiety. Overall, our analysis identified 143 genes that are significantly differentially expressed between the two groups. Specifically, we found five genes associated with feeding behavior and obesity (VGF, TRH, LEPR, ADIPOR2, IRS2) that are all upregulated during the hypophagic period, after the feeding transition has occurred. We also found that serum leptin significantly increases in the hypophagic group. Several of the genes associated with the natural autumnal feeding decline in 13‐lined ground squirrels show parallels to signaling pathways known to be disrupted in human metabolic diseases, like obesity and diabetes. In addition, many other genes were identified that could be important for the control of food consumption in other animals, including humans.
Treatment of symptomatic coronary artery disease in patients with end‐stage renal disease on hemodialysis with paclitaxel‐eluting TAXUS stent
Authors: Wiernek Szymon L. , Kiesz R. Stefan , Wiernek Barbara K. , Buszman Piotr P. , Janas Adam , Martin Jack L. , Trela Blazej , Szewc Robert G. , Buszman Pawel E.
Published: January 2015

Percutaneous coronary intervention (PCI) utilizing drug‐eluting stents is becoming a very common revascularization technique in the dialysis cohort; therefore, we sought to identify the impact of dialysis on outcomes in this group of patients. This is a multicenter registry comparing results of 290 patients (186 with normal kidney function, 104 on dialysis) who underwent PCI with exclusive use of paclitaxel‐eluting TAXUS stent. The primary endpoint was an assessment of major adverse cardiac events (MACE) at 1‐ and 2‐year observation. Mean follow‐up was 23.3 ± 6.1 months. Results at 12 months showed: MACE 11.8% vs. 7.7% (P = not significant [ns]), composite major adverse cardiac and cerebrovascular events (MACCE) 12.4% vs. 11.5% (P = ns), all‐cause death 2.7% vs. 8.6% (P < 0.05), cardiac death 2.7% vs. 1.9% (P = ns), target vessel revascularization (TVR) 9.1% vs. 6.7% (P = ns), acute myocardial infarction (AMI) 3.8% vs. 2.9% (P = ns), cerebrovascular events (CVA) 0.5% vs. 1.0% (P = ns); and results at 24 months showed: MACE 17.7% vs. 18.3% (P = ns), MACCE 21.5% vs. 26.0% (P = ns), all‐cause death 4.3% vs. 14.4% (P < 0.01), cardiac death 3.2% vs. 1.9% (P = ns), TVR 14.0% vs. 16.3% (P = ns), AMI 5.4% vs. 5.8% (P = ns), CVA 3.2% vs. 2.9% (P = ns) for non–end‐stage renal disease (ESRD) and dialysis group, respectively. Prior coronary artery bypass graft (CABG) was found to be single risk factor for MACE, TVR, and MACCE in patients with ESRD, while dialysis and prior CABG were found to be single risk factors for death in the entire population. PCI with TAXUS is a feasible procedure and presents promising results in dialysis‐dependent patients.
Gadolinium‐ethoxybenzyl‐diethylenetriamine pentaacetic acid‐enhanced magnetic resonance imaging as a useful detection method for advanced primary biliary cirrhosis
Authors: Takeyama Yasuaki , Tsuchiya Naoaki , Kunimoto Hideo , Fukunaga Atsushi , Sakurai Kunitoshi , Hirano Genryu , Yokoyama Keiji , Morihara Daisuke , Anan Akira , Irie Makoto , Shakado Satoshi , Sohda Tetsuro , Sakisaka Shotaro
Published: January 2015

Aim

In primary biliary cirrhosis (PBC), damaged hepatocytes resulting from chronic cholestasis follow a compensatory mechanism that alters hepatobiliary transporter expression to reduce the accumulation of potentially toxic compounds such as bile acid. Organic anion transporter peptide 1B3 (OATP1B3), which transports agents such as gadolinium‐ethoxybenzyl‐diethylenetriamine pentaacetic acid (Gd‐EOB‐DTPA), has reduced expression in the late stages of PBC. Therefore, we investigated the use of Gd‐EOB‐DTPA‐enhanced magnetic resonance imaging (MRI) as a useful detection method for the advanced staging of PBC.

Methods

Stage I−III PBC (non‐liver cirrhosis [LC]‐PBC, n = 12), stage IV (LC‐PBC, n = 6), and non−PBC patients (control group, n = 4) were included in this study. We obtained liver tissue samples by percutaneous liver biopsy. Hepatic OATP1B3 expression was determined immunohistochemically, and OATP1B3 mRNA levels were assessed using real‐time reverse transcription polymerase chain reaction. The relative enhancement (RE) in the hepatobiliary phase was calculated using the signal intensity of Gd‐EOB‐DTPA‐enhanced MRI.

Results

Immunohistochemistry revealed markedly reduced expression of OATP1B3 in hepatocytes around the central vein in LC‐PBC patients. Hepatic OATP1B3 mRNA expression in LC‐PBC patients was significantly lower than that in non‐LC‐PBC patients (P < 0.05). The RE on MRI was significantly decreased in the LC‐PBC group (0.33 ± 0.14) compared with the non‐LC‐PBC (0.91 ± 0.15, P < 0.01) and control (0.92 ± 0.20, P < 0.01) groups.

Conclusion

Gd‐EOB‐DTPA‐enhanced MRI may provide a useful detection method for liver disease in patients with LC‐PBC.
Disentangling the influence of plants and herbivores on the local diversity of parasitoids in the Brazilian Cerrado
Authors: Nascimento André R. , Almeida‐Neto Mário , Almeida Adriana M. , Fonseca Carlos R. , Lewinsohn Thomas M. , Penteado‐Dias Angélica
Published: January 2015

This study investigated the extent to which host plants and their associated herbivores determine the local diversity of parasitoids, which depend, directly or indirectly, on these two groups as food resource or shelter for their development.

The tritrophic system studied here is composed of Asteraceae, endophagous herbivores associated with their flower heads and parasitoid wasps. Samplings were undertaken in 18 remnants of the Brazilian Cerrado.

Path analysis was used to unveil the direct and indirect effects of species richness, average taxonomic distinctness (AvTD), and sampling effort of plants and herbivores on parasitoid richness and AvTD.

Plant species richness had only an indirect effect – mediated by herbivores – on parasitoid species richness. On the other hand, there were both direct and indirect effects of plant species richness on the AvTD of parasitoids.

An implication of our findings is that the local extinction of plant species promotes not only the local loss of their herbivores but also the loss of parasitoid species and a decrease in the phylogenetic diversity of parasitoids, which can jeopardise their future evolutionary history.
Improved Poly (D,L‐lactide) nanoparticles‐based formulation for hair follicle targeting
Authors: Fernandes B. , Silva R. , Ribeiro A. , Matamá T. , Gomes A. C. , Cavaco‐Paulo A. M.
Published: January 2015

Synopsis

Objective

Hair follicles are widely recognized as the preferential target and site of accumulation for nanoparticles after topical application. This feature is of particular importance for hair cosmetics, having the potential to refine the treatment of several hair follicle‐related disorders. The aim of this work was to improve the preparation of Poly (D,L‐lactide) (PLA) nanoparticles for in vivo follicular target and drug delivery.

Methods

Envisaging a future industrial scale‐up of the process, nanoprecipitation method was used to prepare PLA nanoparticles: the effect of several processing parameters on their properties was examined and the yield of nanoparticles formation determined. Encapsulation efficiencies and in vitro release profiles of lipophilic and hydrophilic model compounds were also assessed. In vitro cytotoxicity and ex vivo penetration studies were performed on a reference skin cell line (NCTC2455, human skin keratinocytes) and porcine skin, respectively.

Results

Using acetone : ethanol (50 : 50, v/v) as the solvent phase, 0.6% (w/w) of Pluronic® F68 as a surfactant agent and agitation to mix the solvent and non‐solvent phases, a monodispersed population of non‐cytotoxic spherical nanoparticles of approximately 150 nm was obtained. The yield of nanoparticles for this formulation was roughly 90%. After encapsulation of model compounds, no significant changes were found in the properties of particles and the entrapment efficiencies were above 80%. The release kinetics of dyes from PLA nanoparticles indicate an anomalous transport mechanism (diffusion and polymer degradation) for Nile Red (lipophilic) and a Fickian diffusion of first order for fluorescein 5(6)‐isothiocyanate (hydrophilic). Ex vivo skin penetration studies confirmed the presence of nanoparticles along the entire follicular ducts.

Conclusions

The optimized method allows the preparation of ideal PLA nanoparticles‐based formulations for hair follicle targeting. PLA nanoparticles can effectively transport and release lipophilic and hydrophilic compounds into the hair follicles, and the yields obtained are acceptable for industrial purposes.
Studies on the stability of preservatives under subcritical water conditions
Authors: Kapalavavi B. , Marple R. , Gamsky C. , Yang Y.
Published: January 2015

Synopsis

Objective

The goal of this work was to further validate the subcritical water chromatography (SBWC) methods for separation and analysis of preservatives through the evaluation of analyte stability in subcritical water.

Methods

In this study, the degradation of preservatives was investigated at temperatures of 100–200°C using two different approaches. First, the peak areas obtained by SBWC at high temperatures were compared with those achieved using the traditional high‐performance liquid chromatography (HPLC) at 25°C. In the second approach, several preservatives and water were loaded into a vessel and heated at high temperatures for 30 or 60 min. The heated mixtures were then analysed by GC/MS to determine the stability of preservatives.

Results

The t‐ and F‐test on the results of the first approach reveal that the peak areas achieved by HPLC and SBWC are not significantly different at the 95% confidence level, meaning that the preservatives studied are stable during the high‐temperature SBWC runs. Although the results of the second approach show approximately 10% degradation of preservatives into mainly p‐hydroxybenzoic acid and phenol at 200°C, the preservatives studied are stable at 100 and 150°C. This is in good agreement with the validation results obtained by the first approach.

Conclusion

The findings of this work confirm that SBWC methods at temperatures up to 150°C are reliable for separation and analysis of preservatives in cosmetic and other samples.
Combinations of bacterial species associated with symptomatic endodontic infections in a Chinese population
Authors: Qi Z. , Cao H. , Jiang H. , Zhao J. , Tang Z.
Published: January 2015

Aim

To use microarrays to detect 11 selected bacteria in infected root canals, revealing bacterial combinations that are associated with clinical symptoms and signs of primary endodontic infections in a Chinese population.

Methodology

DNA was extracted from 90 samples collected from the root canals of teeth with primary endodontic infections in a Chinese population, and the 16S rRNA gene was amplified by polymerase chain reaction (PCR). The PCR products were hybridized to microarrays containing specific oligonucleotide probes targeting 11 species, and the arrays were screened with a confocal laser scanner. Pearson's chi‐squared test and cluster analysis were performed to investigate the associations between the bacterial combinations and clinical symptoms and signs using SAS 8.02.

Results

Seventy‐seven samples (86%) yielded at least one of the 11 target species. Parvimonas micra (56%), Porphyromonas endodontalis (51%), Tannerella forsythia (48%), Prevotella intermedia (44%) and Porphyromonas gingivalis (37%) were the most prevalent taxa and were often concomitant. The following positive associations were found between the bacterial combinations and clinical features: P. endodontalis and T. forsythia with abscess; P. gingivalis and P. micra with sinus tract; P. gingivalis and P. endodontalis or P. micra and P. endodontalis with abscess and sinus tract; and the combination of P. endodontalis, P. micra, T. forsythia and P. gingivalis with sinus tract (P < 0.05).

Conclusions

Various combinations of P. micra, P. endodontalis, T. forsythia and P. gingivalis may contribute to abscesses or sinus tracts of endodontic origin with bacterial synergism in a Chinese population.
Main Source of Microwave Loss in Transition‐Metal‐Doped Ba(Zn1/3Ta2/3)O3 and Ba(Zn1/3Nb2/3)O3 at Cryogenic Temperatures
Authors: Zhang Shengke , Devonport Alex , Newman Nathan
Published: January 2015

Microwave resonator measurements were performed on high‐performance microwave ceramics Ba(Zn1/3Ta2/3)O3 (BZT) and Ba(Zn1/3Nb2/3)O3 (BZN) containing additives commonly used by commercial manufacturers (i.e., Co, Mn, and Ni). We find that the loss tangent, even in ambient magnetic fields, is dominated by electron paramagnetic resonance (EPR) absorption by exchange‐coupled 3d electrons in transition metal clusters at cryogenic temperatures. The large orbital angular momentum in Co2+ and Ni2+ ions of L = 3 causes strong anisotropic‐broadened dipolar interactions that extend EPR losses to zero applied field. This effect is greatest in BZN with Co concentrations greater than 0.5 mol%, dominating the losses at liquid nitrogen temperatures (77 K) and below. In samples containing Mn2+ ions with L = 0, the dipolar interactions and associated EPR losses in ambient fields are smaller. We show the magnetic‐field‐dependent changes in the EPR losses (i.e., tan δ) and magnetic reactive response (i.e., μr) are from the same mechanism, as they follow the Kramers–Kronig relation. Finally, we note that these materials can make ultra‐high Q passive microwave devices with externally controlled transfer functions, as the quality factor (Q) of the composition Ba(Co1/15Zn4/15Nb2/3)O3 at 77 K can be tuned from 1 100 to 12 000 at 10 GHz by applying practical magnetic fields.
A method to approximate the inverse of a part of the additive relationship matrix
Authors: Faux P. , Gengler N.
Published: January 2015

Single‐step genomic predictions need the inverse of the part of the additive relationship matrix between genotyped animals (A22). Gains in computing time are feasible with an algorithm that sets up the sparsity pattern of (SP algorithm) using pedigree searches, when is close to sparse. The objective of this study is to present a modification of the SP algorithm (RSP algorithm) and to assess its use in approximating when the actual is dense. The RSP algorithm sets up a restricted sparsity pattern of by limiting the pedigree search to a maximum number of searched branches. We have tested its use on four different simulated genotyped populations, from 10 000 to 75 000 genotyped animals. Accuracy of approximation is tested by replacing the actual by its approximation in an equivalent mixed model including only genotyped animals. Results show that limiting the pedigree search to four branches is enough to provide accurate approximations of , which contain approximately 80% of zeros. Computing approximations is not expensive in time but may require a great amount of memory (at maximum, approximately 81 min and approximately 55 Gb of RAM for 75 000 genotyped animals using parallel processing on four threads).
Regardless of central obesity, metabolic syndrome is a significant predictor of type 2 diabetes in Japanese Americans
Authors: Sakashita Yu , Nakanishi Shuhei , Yoneda Masayasu , Nakashima Reiko , Yamane Kiminori , Kohno Nobuoki
Published: January 2015

Aims/Introduction

The impact of metabolic syndrome (MetS) on the development of type 2 diabetes has been reported in different ethnic populations. However, whether central obesity is an essential component as a diagnostic criterion for MetS remains a controversial topic. The aim of the present study was to investigate the association between MetS and the incidence of type 2 diabetes with or without central obesity in a Japanese American population.

Materials and Methods

We examined whether MetS predicts incident type 2 diabetes among 928 Japanese American participants who did not have diabetes enrolled in an ongoing medical survey between 1992 and 2007. MetS was defined on the basis of American Heart Association/National Heart, Lung, and Blood Institute criteria. The average follow‐up period was approximately 6.8 years.

Results

During the follow‐up period, 116 new cases of diabetes were diagnosed. Compared to the participants without MetS, the hazard ratio (HR) for incident type 2 diabetes was significantly higher in participants with MetS, after adjustment for sex, age and impaired glucose tolerance (HR 1.64, 95% CI 1.11–2.42). The risk of type 2 diabetes was found to be significantly higher in participants with MetS but without central obesity (HR 2.07, 95% CI 1.25–3.41), as well as in participants with MetS and with central obesity (HR 2.46, 95% CI 1.51–4.01) than in participants with neither MetS nor central obesity, after adjustment for sex, age and impaired glucose tolerance.

Conclusions

These results show that the presence of MetS, with or without central obesity, could independently predict the development of type 2 diabetes in Japanese Americans.
The 8‐item Morisky Medication Adherence Scale translated in German and validated against objective and subjective polypharmacy adherence measures in cardiovascular patients
Authors: Arnet Isabelle , Metaxas Corina , Walter Philipp N. , Morisky Donald E. , Hersberger Kurt E.
Published: January 2015

Rationale, aims and objectives

To translate in German the 8‐item Morisky Medication Adherence Scale (MMAS‐8D). To validate it against objective and subjective measures of adherence in cardiovascular patients with polypharmacy.

Methods

A standard forward‐backward procedure was used to translate the MMAS‐8 into German. Validation took place on a convenience sample of ambulatory patients on chronic antiplatelet therapy between June 2010 and June 2011. Objective adherence was obtained from electronically monitored multi‐drug punch cards. Internal consistency was assessed using Cronbach's alpha coefficient, construct validity using exploratory factor analyses and correlations between MMAS‐8D and related measures. Convergent validity was assessed with a subjective questionnaire about beliefs about medicines (BMQ Specific, two sub‐scales).

Results

A total of 70 patients were included (mean age 65.7 ± 9.9 years; 31.4% women). The mean score of the MMAS‐8D was 7.5 (SD 0.8; range 4.5–8). Moderate internal consistency (alpha = 0.31) was observed due to multidimensionality of the scale. Factor analysis yielded four components that accounted for 71.7% of the total variance. Convergent validity was supported by significant correlations with BMQ Necessity (r = 0.31, P < 0.01), BMQ Concerns (r = −0.16, P < 0.05) and with electronic adherence reports (U‐values 44 and 471, P < 0.05). Platelet aggregation values were within therapeutic range for 80% of the patients. Blood values of the antiplatelet agent within therapeutic range were associated with a higher MMAS‐8D score (U‐value 125, P < 0.05).

Conclusions

The German MMAS‐8 appears to be a reliable instrument to catch medication adherence in cardiovascular patients. It may be useful in patients with chronic therapy for detecting non‐adherence.
A national survey of defensive medicine among orthopaedic surgeons, trauma surgeons and radiologists in Austria: evaluation of prevalence and context
Authors: Osti Michael , Steyrer Johannes
Published: January 2015

Rationale, aims and objectives

Defensive medical practice represents an increasing concern in European countries and is reported to account for rising health care expenditures. Malpractice liability, current jurisdiction and the increasing claim for accountability appear to result in additional diagnostic requests with marginal clinical benefit. Investigations that evaluate the national Austrian prevalence and contextual principles and consequences of defensive medicine are lacking so far.

Method

Orthopaedic and trauma surgeons as well as radiologists from public hospitals in Austria were invited to complete a study questionnaire retrieving personal estimation of the quantity of patient contacts and defensive requests in a typical month, subjective judgement of medico‐legal climate, evolving defensive trends, working time usage for defensive considerations and prior confrontations with malpractice liability claims.

Results

The prevalence of defensive medicine was found to be 97.7%. The average orthopaedic or trauma surgeon requests 19.6 investigations per month for defensive reasons, which represents 28% of all diagnostic examinations. High‐quality imaging modalities and short‐term admissions yield increasing defensive significance. Participants are confronted with 1.4 liability claims per month. During the treatment of high‐risk patients, 81% of doctors request additional diagnostic procedures for defensive considerations. Expenditure of time for defensive practice amounts to 9.2 hours/month in radiology and to 17 and 18% of total working time, respectively, in orthopaedic and trauma surgery.

Conclusion

Defensive medical practice represents a serious and common challenge in Austria. Our results indicate the urgent necessity for confrontation with and solution for the increasing effort of self‐protection within the health care system.
Commercial Pressures on Professionalism in American Medical Care: From Medicare to the Affordable Care Act
Authors: Marmor Theodore R. , Gordon Robert W.
Published: January 2015

This essay describes how longstanding conceptions of professionalism in American medical care came under attack in the decades since the enactment of Medicare in 1965 and how the reform strategy and core provisions of the 2010 Affordable Care Act (ACA) illustrate the weakening of those ideas and the institutional practices embodying them.

The opening identifies the dominant role of physicians in American medical care in the two decades after World War II. By the time Medicare was enacted in 1965, associations of American physicians were almost completely in charge of medical education, specialist certification, and the enforcement of professional norms on their members. Who could be a doctor, what education and training would be required, and what collegial oversight was operative was first a professional matter and only secondly implicated the state through malpractice or major corporations via the employment of physicians.
Economism and the Commercialization of Health Care
Authors: Brody Howard
Published: January 2015

Pay-for-performance (P4P) represents an effort to improve the quality of health care by paying physicians more if they meet specified target measures. There are both empirical and theoretical reasons to be deeply suspicious of P4P schemes applied at the level of the individual physician or health provider. Most P4P programs were implemented before there were any good data to demonstrate that they achieved the desired results. Once such schemes were in use, the available data are far from reassuring. Common findings are that providers may do more of the specific procedure that is being measured, but in the process may neglect to do other things that equally affect quality of care. Payers often find that the cost of implementing a P4P program far exceeds the value of the very modest resulting improvements; and payments may unfairly benefit providers who are already meeting quality targets while disadvantaging those who make the most strenuous efforts to improve.