bluuebunny/crossref_metadata_2025 huggingface dataset:
Nigrostriatal neuronal death following chronic dichlorvos exposure: crosstalk between mitochondrial impairments, α synuclein aggregation, oxidative damage and behavioral changes
Authors: BK Binukumar , Bal Amanjit , Kandimalla Ramesh JL , Gill Kiran Dip
Published: December 2019

Background

In recent years, several lines of evidence have shown an increase in Parkinson's disease prevalence in rural environments where pesticides are heavily used. Although, the underlying mechanism for neuronal degeneration in sporadic PD remains unknown, mitochondrial dysfunction, oxidative stress and proteasomal dysfunction are proposed as contributing factors. In this study rats were chronically and continuously exposed to the pesticide, dichlorvos to identify the molecular mechanism of nigrostaital neuronal degeneration.

Result

Chronic dichlorvos exposure (2.50 mg/kg b.wt.s.c/daily for 12 weeks) caused nigrostriatal dopaminergic degeneration. The degenerative changes were accompanied by a loss of 60-80% of the nigral dopamine neurons and 60-70% reduction in striatal dopamine and tyrosine hydroxylase levels. Dichlorvos exposed animals also showed α -synuclein and ubiquitin positive inclusions along with swollen, dystrophic neurites and mitochondrial abnormalities like decreased complex I&IV activities, increased mitochondrial size, axonal degeneration and presence of electron dense perinuclear cytoplasmic inclusions in the substantia nigra of rats. These animals also showed evidence of oxidative stress, including increased mitochondrial ROS levels, decreased MnSOD activity and increased lipid peroxidation. Measurable impairments in neurobehavioral indices were also observed. Notable exacerbations in motor impairments, open field and catalepsy were also evident in dichlorvos exposed animals.

Conclusion

All these findings taken together indicate that chronic dichlorvos exposure may cause nigrostaital neurodegenaration and significant behavioral impairments.
Gradient estimation in dendritic reinforcement learning
Authors: Schiess Mathieu , Urbanczik Robert , Senn Walter
Published: December 2019

We study synaptic plasticity in a complex neuronal cell model where NMDA-spikes can arise in certain dendritic zones. In the context of reinforcement learning, two kinds of plasticity rules are derived, zone reinforcement (ZR) and cell reinforcement (CR), which both optimize the expected reward by stochastic gradient ascent. For ZR, the synaptic plasticity response to the external reward signal is modulated exclusively by quantities which are local to the NMDA-spike initiation zone in which the synapse is situated. CR, in addition, uses nonlocal feedback from the soma of the cell, provided by mechanisms such as the backpropagating action potential. Simulation results show that, compared to ZR, the use of nonlocal feedback in CR can drastically enhance learning performance. We suggest that the availability of nonlocal feedback for learning is a key advantage of complex neurons over networks of simple point neurons, which have previously been found to be largely equivalent with regard to computational capability.
The relationship between hand osteoarthritis and serum leptin concentration in participants of the Third National Health and Nutrition Examination Survey
Authors: Massengale Mei , Reichmann William M , Losina Elena , Solomon Daniel H , Katz Jeffrey N
Published: December 2019

Introduction

Leptin has been suspected to contribute to the development of osteoarthritis (OA). However, this hypothesis has not been tested in large-scale hand OA cohorts. Our study aimed to determine whether there is a cross-sectional relationship between serum leptin levels and hand OA in a population-based sample of US adults.

Method

We used the Third National Health and Nutrition Examination Survey (NHANES III), a national cross-sectional population-based survey, to study the relationship between hand OA and serum leptin concentration. We applied previously established classification criteria for hand OA. Patients with rheumatoid arthritis were excluded. Potential confounders included sex, body mass index, the presence of polyarticular OA, diabetes, and total cholesterol. We estimated unadjusted mean leptin concentration by hand OA status and by all confounders. We further developed a linear regression model to assess mean leptin levels, adjusted for appropriate confounders.

Results

Of 2,477 subjects in the NHANES III sample that had a hand examination and did not have rheumatoid arthritis, 1,056 (42.6%) had a leptin measurement and were included in the analysis. Subjects with and without leptin measurement had similar demographic characteristics. We did not find any significant differences in mean serum leptin levels in subjects with symptomatic hand OA (7.38 ng/ml in males (95% confidence interval (CI) = 5.31, 9.46) and 21.55 ng/ml in females (95% CI = 17.08, 26.02)), asymptomatic hand OA (6.69 ng/ml in males (95% CI = 5.19, 8.18) and 17.09 ng/ml in females (95% CI = 15.00, 19.18)), and no hand OA (8.22 ng/ml in males (95% CI = 7.47, 8.97) and 20.77 ng/ml in females (95% CI = 18.01, 23.53)) in the unadjusted analysis. In a multivariable linear regression model that included variables of hand OA status, age, race/ethnicity, and obesity status, we found no statistically significant association between serum leptin and hand OA status.

Conclusions

In this cross-sectional study of a large representative US cohort, we did not find any evidence to support the hypothesis that serum leptin is associated with hand OA.
A few of our favorite unconfirmed ideas
Authors: Marini John J , Gattinoni Luciano , Ince Can , Kozek-Langenecker Sibylle , Mehta Ravindra L , Pichard Claude , Westphal Martin , Wischmeyer Paul , Vincent Jean-Louis
Published: December 2019

Medical practice is rooted in our dependence on the best available evidence from incremental scientific experimentation and rigorous clinical trials. Progress toward determining the true worth of ongoing practice or suggested innovations can be glacially slow when we insist on following the stepwise scientific pathway, and a prevailing but imperfect paradigm often proves difficult to challenge. Yet most experienced clinicians and clinical scientists harbor strong thoughts about how care could or should be improved, even if the existing evidence base is thin or lacking. One of our Future of Critical Care Medicine conference sessions encouraged sharing of novel ideas, each presented with what the speaker considers a defensible rationale. Our intent was to stimulate insightful thinking and free interchange, and perhaps to point in new directions toward lines of innovative theory and improved care of the critically ill. In what follows, a brief background outlines the rationale for each novel and deliberately provocative unconfirmed idea endorsed by the presenter.
Intravenous fluids: should we go with the flow?
Authors: Kozek-Langenecker Sibylle A
Published: December 2019

Sensitive monitoring should be used when prescribing intravenous fluids for volume resuscitation. The extent and duration of tissue hypoperfusion determine the severity of cellular damage, which should be kept to a minimum with timely volume substitution. Optimizing the filling status to normovolaemia may boost the resuscitation success. Macrocirculatory pressure values are not sensitive in this indication. While the Surviving Sepsis Campaign guidelines focus on these conventional pressure parameters, the guidelines from the European Society of Anaesthesiology (ESA) on perioperative bleeding management recommend individualized care by monitoring the actual volume status and correcting hypovolaemia promptly if present. The motto is: 'give what is missing'. The credo of the ESA guidelines is to use management algorithms with predefined intervention triggers. Stop signals should help in avoiding hyper-resuscitation. The high-quality evidence-based S3 guidelines on volume therapy in adults have recently been prepared by 14 German scientific societies. Statements include, for example, repeated clinical inspection including turgor of the skin and mucosa. Adjunctive laboratory parameters such as central venous oxygen saturation, lactate, base excess and haematocrit should be considered. The S3 guidelines propose the use of flow-based and/or dynamic preload parameters for guiding volume therapy. Fluid challenges and/or the leg-raising test (autotransfusion) should be performed. The statement from the Co-ordination group for Mutual Recognition and Decentralized Procedures--Human informs healthcare professionals to consider applying individualized medicine and using sensitive monitoring to assess hypovolaemia. The authorities encourage a personalized goal-directed volume resuscitation technique.
Paradigm shifts in critical care medicine: the progress we have made
Authors: Vincent Jean-Louis , Creteur Jacques
Published: December 2019

There have really been no single, major, advances in critical care medicine since the specialty came into existence. There has, however, been a gradual, continuous improvement in the process of care over the years, which has resulted in improved patient outcomes. Here, we will highlight just a few of the paradigm shifts we have seen in processes of critical care, including the move from small, closed units to larger, more open ICUs; from a paternal "dictatorship" to more "democratic" team-work; from intermittent to continuous, invasive to less-invasive monitoring; from "more" interventions to "less" thus reducing iatrogenicity; from consideration of critical illness as a single event to realization that it is just one part of a trajectory; and from "four walls" to "no walls" as we take intensive care outside the physical ICU. These and other paradigm shifts have resulted in improvements in the whole approach to patient management, leading to more holistic, humane care for patients and their families. As critical care medicine continues to develop, further paradigm shifts in processes of care are inevitable and must be embraced if we are to continue to provide the best possible care for all critically ill patients.
The race against the "septic shark"
Authors: Westphal Martin , Kampmeier Tim
Published: December 2019

Great white sharks are responsible for about 10 cases of death annually worldwide, as compared with millions of deaths caused by sepsis. However, the basic principles of avoiding shark attacks and fighting sepsis seem to be similar: avoidance, attention, and speed, if necessary. The present review discusses the current status of the systemic inflammatory response syndrome (SIRS) criteria, which are actually content for discussion because of their low specificity. Current data suggest that one in eight patients with severe sepsis does not fulfill the SIRS criteria and is consequently missed, and therefore the calls for new definitions of sepsis are getting louder. Furthermore, the need for early treatment of sepsis and fast admission to an intensive care unit (ICU) with experienced stuff is reviewed as well as the early and appropriate initiation of therapy, namely antibiotic and volume therapy. A key feature is the analysis of the studies from the so-called "Sepsis Trilogy" (ProCESS, ARISE, and ProMiSe studies), with a focus on the status of early goal-directed therapy (EGDT). The authors of the "Sepsis Trilogy" concluded that there is no benefit regarding survival in septic patients by using EGDT as compared with standard therapy. However, the low mortality of the control groups within the "Sepsis Trilogy" studies as compared with the Rivers et al. study from 2001 leads to the conclusion that there has been an improvement in the therapy of septic patients, most probably due to the early initiation of therapy as a kind of "standard" in sepsis therapy. Finally, the phenomenon of a "large trial disease" is discussed, exemplary in a trial which investigated the maintenance of the "right" mean arterial pressure in sepsis patients. Even if the result of a large randomized trial might be that there is no difference between two study groups, the real exercise is to identify the patient collectives who might benefit or experience harm due to an intervention. In summary, as compared with swimming in dangerous waters, high attention is needed in handling septic patients. Once an attack has occurred, speed is of utmost importance (i.e., initiation of therapy and admission to the ICU) because it appears logical that time is critical in septic patients This may have resulted in the implementation of early (goal-directed) treatment as a "standard" in the treatment of sepsis with significant improvement in survival.
The roles of metabolic pathways in maintaining primary dormancy of Pinus koraiensis seeds
Authors: Song Yuan , Zhu Jiaojun
Published: December 2019

Background

Korean pine seeds have primary dormancy following dispersal, leading to poor seed germination and seedling establishment. Metabolic homeostasis determines whether the seeds are dormant or non-dormant. However, the specific metabolic pathways that maintain the primary dormancy of pine seeds are poorly understood.

Results

Metabolic analysis was employed on the embryos of PDRS (seeds released from primary dormancy) and PDS (primary dormant seeds) on days 0, 5 and 11 after incubation under a germination-inductive temperature. A larger metabolic switch occurred in PDRS embryos from days 0 to 11. The contents of ninety metabolites were significantly changed from days 0 to 5, 83% of which (including most sugars, organic acids and amino acids) increased, reflecting that biosynthetic metabolism processes are initiated. The contents of ninety-two metabolites showed distinct variations from days 5 to 11, 71% of which (including most organic acids and almost all amino acids) reduced substantially. Fructose 6-phosphate, inositol-3-phosphate, 3-phosphoglyceric and D-glucose-6-phosphate contents showed the most decrease with decreasing 409-, 75-, 58- and 41-fold, indicating that the glycolysis and tricarboxylic acid (TCA) cycle strongly slowed down. The contents of the most metabolites in PDS embryos also displayed a relatively larger alteration only from days 0 to 5. Although 64% of metabolites increased from days 0 to 5, their levels were still lower compared with PDRS embryos. Furthermore, most metabolites were not further accumulated from days 5 to 11. Unlike PDRS embryos, almost all amino acids in PDS embryos did not exhibit a substantial decrease from days 5 to 11. Also, there was not a major decrease in the levels of metabolites involved mainly in glycolysis and TCA cycle, while some intermediates even increased.

Conclusions

The attenuated biosynthetic metabolism processes, the lower utilization rate of amino acids and the higher operation rate of glycolysis and TCA in embryos maintain primary dormancy.
Mutation in MPT64 gene influencing diagnostic accuracy of SD Bioline assay (capilia)
Authors: Singh Kamal , Kumari Richa , Tripathi Rajneesh , Gupta Ankush , Anupurba Shampa
Published: December 2019

Background

Success of India’s TB control program relies on rapid case detection, monitoring, care and treatment of drug resistance. Patients on multidrug resistance (MDR) treatment are monitored by follow up cultures. Discordant results (culture and smear positive while capilia negative) are usually declared negative Mycobacterium tuberculosis complex (MTBC). This study was designed to understand the possible causes of discordant results.

Methods

The capilia kit was evaluated to test its utility among 4737 follow up MDR patients enrolled during a period of 1 year. A total of 889 were liquid culture positive, 3375 were negative and 473 were contaminated. Of the 889 cultures positive, 829 were found positive by ZN smear, capilia test and MTBDR plus assay. The cultures which gave a positive result on Mycobacterium Growth Indicator Tube 960 (MGIT 960) and ZN smear but were negative on capilia test with no growth on Brain Heart Infusion agar (BHI) were included in this study. The conflicting results of capilia were compared with other molecular techniques; MTBDR plus assay and DNA sequence analysis of MPT64 gene.

Results

Out of 889 culture positive, 60 (6.7%) were found positive on liquid culture and ZN smear but were negative on capilia. Of these 60 cultures, 10 (16.7%) were found positive by both MTBDR plus assay and PCR. The sequencing analysis revealed that all of the capilia negative isolates had mutations within the MPT64 gene.

Conclusion

Re-evaluation of culture positive but capilia negative isolates should be done before declaring them as Mycobacterium other than tuberculosis (MOTT) because such cases can act as chronic carriers of TB in the population which can lead to the rise of this lethal disease.
Predicting recurrence of depression using lifelog data: an explanatory feasibility study with a panel VAR approach
Authors: Kumagai Narimasa , Tajika Aran , Hasegawa Akio , Kawanishi Nao , Horikoshi Masaru , Shimodera Shinji , Kurata Ken’ichi , Chino Bun , Furukawa Toshi A.
Published: December 2019

Background

Although depression has a high rate of recurrence, no prior studies have established a method that could identify the warning signs of its recurrence.

Methods

We collected digital data consisting of individual activity records such as location or mobility information (lifelog data) from 89 patients who were on maintenance therapy for depression for a year, using a smartphone application and a wearable device. We assessed depression and its recurrence using both the Kessler Psychological Distress Scale (K6) and the Patient Health Questionnaire-9.

Results

A panel vector autoregressive analysis indicated that long sleep time was a important risk factor for the recurrence of depression. Long sleep predicted the recurrence of depression after 3 weeks.

Conclusions

The panel vector autoregressive approach can identify the warning signs of depression recurrence; however, the convenient sampling of the present cohort may limit the scope towards drawing a generalised conclusion.
Lessons learned from engaging communities for Ebola vaccine trials in Sierra Leone: reciprocity, relatability, relationships and respect (the four R’s)
Authors: Dada Sara , McKay Gillian , Mateus Ana , Lees Shelley
Published: December 2019

Background

Building trust and engaging the community are important for biomedical trials. This was core to the set up and delivery of the EBOVAC-Salone and PREVAC Ebola vaccine trials in Sierra Leone during and following the 2014–2016 West African Ebola epidemic. Local community liaison teams (CLT) engaged with the community through public meetings, radio chat shows, and other activities, while a social science team (SST) assessed community members’ and participants’ perceptions and regularly updated the clinical team to adapt procedures to improve the acceptability and compliance of the trial. The objective of this study was to examine the community engagement (CE) program in these trials and to identify potential barriers and facilitators.

Methods

Fifteen CLT and SST members participated in in-depth interviews and 23 community members attended three focus groups to discuss the Ebola vaccine trials and their experiences and perspectives of the CE activities.

Results

A key aim of the CE program was to build trust between the community and the trial. Four main principles (the “four R’s”) evolved from the discussions with team members and the community that influenced this trust: reciprocity, relatability, relationships and respect. The CLT and SST ensured reciprocal communication between the trial team and the community. The CLT delivered key messages from the trial, whilst the SST completed ethnographic research in the field to uncover rumors and perceptions of the trial in the community. These ethnographic findings were shared with the CLT and addressed in targeted messaging to the community. Both the CLT and SST approached the communities in an egalitarian manner, by dressing modestly, speaking local dialects, and using relatable examples. Appreciation and understanding of the importance of interpersonal relationships and respect for the people, their customs, and traditions also played a large role in the CE program.

Conclusion

These findings provide an in-depth understanding of how interdisciplinary community liaison and social science teams can work with a clinical team to strengthen trust. The four R’s suggest the ways in which trust relations are central to CE and confidence in vaccine trials, and could offer an approach to CE in vaccine trials.
Morphological analysis of Apolipoprotein E binding to Aβ Amyloid using a combination of Surface Plasmon Resonance, Immunogold Labeling and Scanning Electron Microscopy
Authors: Islam Tohidul , Gharibyan Anna L. , Lee Cheng Choo , Olofsson Anders
Published: December 2019

Background

Immunogold labeling in combination with transmission electron microscopy analysis is a technique frequently used to correlate high-resolution morphology studies with detailed information regarding localization of specific antigens. Although powerful, the methodology has limitations and it is frequently difficult to acquire a stringent system where unspecific low-affinity interactions are removed prior to analysis.

Results

We here describe a combinatorial strategy where surface plasmon resonance and immunogold labeling are used followed by a direct analysis of the sensor-chip surface by scanning electron microscopy. Using this approach, we have probed the interaction between amyloid-β fibrils, associated to Alzheimer’s disease, and apolipoprotein E, a well-known ligand frequently found co-deposited to the fibrillar form of Aβ in vivo. The results display a lateral binding of ApoE along the amyloid fibrils and illustrates how the gold-beads represent a good reporter of the binding.

Conclusions

This approach exposes a technique with generic features which enables both a quantitative and a morphological evaluation of a ligand-receptor based system. The methodology mediates an advantage compared to traditional immunogold labeling since all washing steps can be monitored and where a high stringency can be maintained throughout the experiment.
Assessment of anterior-posterior spinal curvatures in children suffering from hypopituitarism
Authors: Kobylińska Magdalena , Malak Roksana , Majewska Katarzyna , Kędzia Andrzej , Samborski Włodzimierz
Published: December 2019

Background

Body posture may be disordered by vestibular dysfunction, neurological disorders, problems with the distribution of muscle tone, brain injuries, and other dysfunctions. Growth hormone deficiency (GHD) can lead to many disorders, particularly of the musculoskeletal system. During treatment with recombinant human growth hormone (rhGH), an increase in muscle mass and an improvement in bone structure can be observed in children suffering from hypopituitarism from GHD.

Methods

The study involved 33 children suffering from hypopituitarism with GHD (9 girls and 24 boys), aged 10–14 years old. Measurements of the magnitude of their anterior–posterior spinal curvatures were made using an inclinometer. The children were examined at the medianus of the sacrum bone, the Th12–L1 intervertebral area, and the C7–Th1 intervertebral area. In order to characterize the anterior–posterior curvature of the spine, the results were compared with the general norms reported by Saunders. Statistical calculations were carried out using the statistical package Statistica 10 PL.

Results

Lumbar lordosis angles were higher in the patients currently receiving growth hormone (GH) treatment than in those who had yet to receive it. There is a statistically significant positive correlation between the length of growth hormone treatment and the alpha angle. There are also statistically significant correlations between age at the beginning of growth hormone therapy and the angle of lordosis. Statistically significant correlations were also seen between age at the beginning of growth hormone therapy and the alpha angle.

Conclusions

Although there may be changes in posture at the beginning of rhGH treatment, the sooner growth hormone therapy begins, the better the body posture. The longer the growth hormone treatment, the better the posture, as expressed by the alpha angle in the sagittal plane.
No increased risk of glucose metabolism disorders in adults with growth hormone deficiency undergoing long-term treatment with biosimilar somatropin (Omnitrope®): data from an observational, longitudinal study
Authors: Beck-Peccoz Paolo , Höybye Charlotte , Murray Robert D. , Simsek Suat , Zabransky Markus , Zouater Hichem , Stalla Günter
Published: December 2019

Background

To evaluate the impact of treatment with recombinant human growth hormone (rhGH; Omnitrope®) on the risk of diabetes mellitus in adults with growth hormone deficiency (GHD), using data from the ongoing PATRO Adults post-marketing surveillance study.

Methods

PATRO Adults is an ongoing post-marketing surveillance study being conducted in hospitals and specialized endocrinology clinics across Europe. All enrolled patients who receive ≥1 dose of Omnitrope® are included in the safety population. Patient profiles, containing all available study database information for each specific patient, were generated for all patients with adverse events (AEs) of diabetes mellitus while participating in the study. Diabetes mellitus was confirmed if fasting plasma glucose was ≥7.0 mmol/L or 2-h plasma glucose ≥11.1 mmol/L during oral glucose tolerance test or glycated hemoglobin ≥6.5%.

Results

Up to July 2018, 1293 patients had been enrolled in the study, and 983 (76.0%) remained active. Just under half (n = 687, 49.3%) of the patients were growth hormone (GH) treatment-naïve on entering the study, and most (n = 1128, 87.2%) had multiple pituitary hormone deficiency (MPHD). Diabetes mellitus/inadequate control (worsening) of diabetes mellitus was reported in 21 patients (22 events). The cases were newly diagnosed in 15 patients (age 29–84 years; incidence rate 3.61 per 1000 patient-years) and occurred in 6 patients with pre-existing diabetes mellitus at baseline (age 45–72 years). Most cases of newly diagnosed diabetes mellitus occurred in patients with adult-onset MPHD (n = 13); the remaining cases of new-onset diabetes mellitus occurred in a patient with childhood-onset MPHD who had previously received GH replacement therapy (n = 1), and a patient with adulthood-onset isolated GHD who was naïve to GH replacement therapy (n = 1). All cases of inadequate control/worsening of diabetes mellitus occurred in patients with adult-onset MPHD.

Conclusions

Based on this snapshot of data from PATRO Adults, Omnitrope® treatment is tolerated in adult patients with GHD in a real-life clinical practice setting. No signals of an increased risk for diabetes mellitus have been noted so far, although continued follow-up (both during and after rhGH therapy) is required to confirm this.

Trial registration

Not applicable.
Comparative efficacy between atorvastatin and rosuvastatin in the prevention of cardiovascular disease recurrence
Authors: Perez-Calahorra Sofía , Laclaustra Martin , Marco-Benedi Victoria , Pinto Xavier , Sanchez-Hernandez Rosa M. , Plana Núria , Ortega Emilio , Fuentes Francisco , Civeira Fernando
Published: December 2019

Background

There is no randomized clinical trials with recurrence of atherosclerotic cardiovascular disease (ASCVD) as a major outcome with rosuvastatin. In order to analyze potential differences in the clinical response to atorvastatin and rosuvastatin in secondary ASCVD prevention, we have analyzed the clinical evolution of those subjects of the Dyslipemia Registry of the Spanish Society of Arteriosclerosis (SEA) who at the time of inclusion in the Registry had already suffered an ASCVD.

Methods

This observational, retrospective, multicenter, national study was designed to determine potential differences between the use of atorvastatin and rosuvastatin in the ASCVD recurrence. Three different follow-up start-times were performed: time of inclusion in the registry; time of first event if this occurred after 2005, and time of first event without date restriction.

Results

Baseline characteristics were similar between treatment groups. Among atorvastatin or rosuvastatin users, 89 recurrences of ASCVD were recorded (21.9%), of which 85.4% were coronary. At the inclusion of the subject in the registry, 345 participants had not suffered a recurrence yet. These 345 subjects accumulated 1050 person-years in a mean follow-up of 3 years. Event rates were 2.73 (95% CI: 1.63, 4.25) cases/100 person-years and 2.34 (95% CI: 1.17, 4.10) cases/100 person-years in the atorvastatin and rosuvastatin groups, respectively. There were no statistically significant differences between the two groups independently of the follow-up start-time.

Conclusions

This study does not find differences between high doses of rosuvastatin and atorvastatin in the recurrence of ASCVD, and supports their use as clinically equivalent in secondary prevention of ASCVD.
Duodeno-pancreatic and extrahepatic biliary tree trauma: WSES-AAST guidelines
Authors:   WSES-AAST Expert Panel, Coccolini Federico , Kobayashi Leslie , Kluger Yoram , Moore Ernest E. , Ansaloni Luca , Biffl Walt , Leppaniemi Ari , Augustin Goran , Reva Viktor , Wani Imitiaz , Kirkpatrick Andrew , Abu-Zidan Fikri , Cicuttin Enrico , Fraga Gustavo Pereira , Ordonez Carlos , Pikoulis Emmanuil , Sibilla Maria Grazia , Maier Ron , Matsumura Yosuke , Masiakos Peter T. , Khokha Vladimir , Mefire Alain Chichom , Ivatury Rao , Favi Francesco , Manchev Vassil , Sartelli Massimo , Machado Fernando , Matsumoto Junichi , Chiarugi Massimo , Arvieux Catherine , Catena Fausto , Coimbra Raul
Published: December 2019

Duodeno-pancreatic and extrahepatic biliary tree injuries are rare in both adult and pediatric trauma patients, and due to their anatomical location, associated injuries are very common. Mortality is primarily related to associated injuries, but morbidity remains high even in isolated injuries. Optimal management of duodeno-bilio-pancreatic injuries is dictated primarily by hemodynamic stability, clinical presentation, and grade of injury. Endoscopic and percutaneous interventions have increased the ability to non-operatively manage these injuries. Late diagnosis and treatment are both associated to increased morbidity and mortality. Sequelae of late presentations of pancreatic injury and complications of severe pancreatic trauma are also increasingly addressed endoscopically and with interventional radiology procedures. However, for moderate and severe extrahepatic biliary and severe duodeno-pancreatic injuries, immediate operative intervention is preferred as associated injuries are frequent and commonly present with hemodynamic instability or peritonitis. The aim of this paper is to present the World Society of Emergency Surgery (WSES) and American Association for the Surgery of Trauma (AAST) duodenal, pancreatic, and extrahepatic biliary tree trauma management guidelines.
The largest reported intrathoracic lipoma: a case report and current perspectives review
Authors: Aldahmashi Mohammed , Elmadawy Abdalmotaleb , Mahdy Mahmoud , Alaa Mohamed
Published: December 2019

Background

The huge size intrathoracic lipomas are very rare. Few cases have been reported worldwide. To our knowledge, this presented case is one of the few cases reported. Here we report a single case as very huge intrathoracic lipoma compressing the right lung and displacing the diaphragm and liver downward. It has been managed by right posterolateral thoracotomy and complete excision, with excellent outcome.

Case presentation

A 32-year-old male presented with a symptomatic right intrathoracic mass, which was confirmed to be a lipomatous tumor using computed tomography. A penduculated tumor originating from the mediastinal pleura was resected through the conventional right posterior thoracotomy. Pathological examination indicated a diagnosis of fibrolipoma.

Conclusion

The tumor was symptomatic and relatively huge when detected during a medical checkup. This enabled the successful tumor resection via conventional thoracotomy approach. Although intrathoracic lipomas are histologically benign, careful observation and follow-up are crucial due to the possibility of recurrence.
An analysis of orphan medicine expenditure in Europe: is it sustainable?
Authors: Mestre-Ferrandiz Jorge , Palaska Christina , Kelly Tom , Hutchings Adam , Parnaby Adam
Published: December 2019

Background

Orphan medicinal product (OMP) prices are considered by some to be a challenge to the sustainability of healthcare expenditure. These concerns are compounded by the increasing number of OMPs receiving marketing authorisation (MA) annually. The aim of this study was to explore the sustainability of OMP expenditure within the context of total European pharmaceutical expenditure.

Methods

Using historical IQVIA data, an analysis was conducted on total pharmaceutical and OMP expenditure in eight countries (using values / volumes) in the branded, non-branded and overall pharmaceutical market. Country level and aggregated data was considered for EU5 countries, Austria, Belgium and Ireland.

Three key analyses were conducted:

The OMP share of total pharmaceutical expenditure was calculated from 2000 to 2017, to assess its evolution over time.

The results of this analysis were compared with a 2011 forecast of OMP budget impact.

The evolution of the total pharmaceutical market and its different segments (branded OMPs, non-OMP branded and unbranded) were assessed by estimating the compound annual growth rate (CAGR) and percentage of pharmaceutical expenditure for each market segment from 2010 to 2017.

Results

Across countries, OMP share of total pharmaceutical expenditure has increased each year since 2000, rising to 7.2% of total pharmaceutical expenditure in 2017. OMP expenditure has increased at a CAGR of 16% since 2010. The number of OMPs receiving MA each year showed a CAGR of 11% since 2001, four percentage points greater than the CAGR for all medicines receiving MA over the same period. OMP share of total pharmaceutical expenditure is higher than forecasted in 2011 due to slower than expected growth in the non-OMP market. OMP growth has been offset by reduced expenditure in the general market and increased use of generics and biosimilars.

Conclusions

Relative spending on OMPs has increased over the last 20 years, but this has been largely compensated for within the current allocation of total pharmaceutical spending by flat expenditure for non-OMPs and increased volumes of (lower-priced) generics/biosimilars, reflecting a shift towards expenditure in higher cost, lower volume patient populations and a shift in drug development towards more specialised targeting of diseases.
Wnt/β-catenin signalling in ovarian cancer: Insights into its hyperactivation and function in tumorigenesis
Authors: Nguyen Vu Hong Loan , Hough Rebecca , Bernaudo Stefanie , Peng Chun
Published: December 2019

Epithelial ovarian cancer (EOC) is the deadliest female malignancy. The Wnt/β-catenin pathway plays critical roles in regulating embryonic development and physiological processes. This pathway is tightly regulated to ensure its proper activity. In the absence of Wnt ligands, β-catenin is degraded by a destruction complex. When the pathway is stimulated by a Wnt ligand, β-catenin dissociates from the destruction complex and translocates into the nucleus where it interacts with TCF/LEF transcription factors to regulate target gene expression. Aberrant activation of this pathway, which leads to the hyperactivity of β-catenin, has been reported in ovarian cancer. Specifically, mutations ofCTNNB1,AXIN, or APC,have been observed in the endometrioid and mucinous subtypes of EOC. In addition, upregulation of the ligands, abnormal activation of the receptors or intracellular mediators, disruption of the β-catenin destruction complex, inhibition of the association of β-catenin/E-cadherin on the cell membrane, and aberrant promotion of the β-catenin/TCF transcriptional activity, have all been reported in EOC, especially in the high grade serous subtype. Furthermore, several non-coding RNAs have been shown to regulate EOC development, in part, through the modulation of Wnt/β-catenin signalling. The Wnt/β-catenin pathway has been reported to promote cancer stem cell self-renewal, metastasis, and chemoresistance in all subtypes of EOC. Emerging evidence also suggests that the pathway induces ovarian tumor angiogenesis and immune evasion. Taken together, these studies demonstrate that the Wnt/β-catenin pathway plays critical roles in EOC development and is a strong candidate for the development of targeted therapies.
Correction to: Common metabolic networks contribute to carbon sink strength of sorghum internodes: implications for bioenergy improvement
Authors: Li Yin , Tu Min , Feng Yaping , Wang Wenqin , Messing Joachim
Published: December 2019

The original version of the article [1] unfortunately contained a mistake in author’s first name. The name of the author has been corrected from Wenqing Wang to Wenqin Wang in this correction article. The original article [1] has been corrected.
Diagnosing bovine parafilariosis: utility of the cytochrome c oxidase subunit 1 gene and internal transcribed spacer region for PCR detection of Parafilaria bovicola in skin biopsies and serohemorrhagic exudates of cattle
Authors: Oehm Andreas W. , Stoll Alexander , Silaghi Cornelia , Pfitzner-Friedrich Annette , Knubben-Schweizer Gabriela , Strube Christina
Published: December 2019

Background

Parafilaria bovicola(Nematoda: Filariidae) causes cutaneous bleedings in bovine species. Flies serve as intermediate hosts. In recent years, reports on bovine parafilariosis have become more frequent, corroborating the necessity of reliable diagnostic interventions especially since no molecular or serological test has been available. We aimed to establish a polymerase chain reaction assay to detect DNA ofP. bovicolain flies, skin biopsies and serohemorraghic exudates of bleeding spots.

Methods

PCRs targeting the cytochromecoxidase subunit 1 (cox1) gene and the internal transcribed spacer region (ITS) of the ribosomal RNA gene cluster were evaluated for their diagnostic sensitivity as well as performance and specificity on biopsy and serohemorrhagic exudate samples fromP. bovicola-infected cattle.

Results

Using serohemorrhagic exudates (n = 6), biopsies (n = 2) and flies (n = 1), the PCR targeting thecox1 gene resulted in a gel band of almost 700 bp. Cloning, sequencing, and removal of primer sequences yielded a 649-bp fragment of theP. bovicola cox1 gene. The PCR targeting the ITS region showed a band of about 1100 bp. Cloning, sequencing, and removal of primer sequences resulted in a 1083 bp stretch of theP. bovicolaITS region. Testing samples from presumably affected animals, thecox1-PCR resulted in bands with the expected size and they were all confirmed asP. bovicolaby sequencing. In contrast, the ITS-PCR proved to be less sensitive and less specific and additionally amplified the ITS region ofMusca domesticaor buttercup DNA. When analysing for sensitivity, thecox1-PCR yielded visible bands up to 2 ng of genomic DNA, whereas the ITS-PCR produced bands up to 3 ng. In a plasmid dilution series, the minimum number of target DNA copies was 102for thecox1-PCR and 101in the ITS-PCR.

Conclusions

The evaluatedcox1-PCR enables reliable detection ofP. bovicolaDNA in skin biopsies and serohemorrhagic exudates. This PCR and, to a limited extent, the ITS-PCR, may help evaluate different therapeutic approaches. Furthermore, thecox1-PCR may be useful for epidemiological studies on the geographical distribution ofP. bovicola. Further understanding of the epidemiology of this parasite will help develop and implement effective control strategies.
Activation of natural killer cells by rituximab in granulomatosis with polyangiitis
Authors: Urlaub Doris , Zhao Shuyang , Blank Norbert , Bergner Raoul , Claus Maren , Tretter Theresa , Lorenz Hanns-Martin , Watzl Carsten , Merkt Wolfgang
Published: December 2019

Objective

In the last few years, anti-CD20 antibody rituximab profoundly changed the therapeutic landscape of granulomatosis with polyangiitis (GPA). Here, we investigated whether natural killer (NK) cells may play a role in rituximab’s mechanism of action in GPA.

Methods

B cell depletion, NK cell degranulation, and the expression of CD69 and CD16 on NK cells were measured in a series of in vitro experiments using peripheral blood mononuclear cells (PBMCs). In vivo activation of NK cells was investigated in patients receiving rituximab infusions. Cells were analyzed by seven-color flow cytometry.

Results

NK cells from GPA patients were activated by immobilized rituximab. Also soluble rituximab activated NK cells, provided that B cells were present. NK cells degranulated and expressed the activation marker CD69 while CD16 expression was decreased. This activation of NK cells by soluble rituximab was accompanied by a reduction of B cells. The next-generation anti-CD20 antibody obinutuzumab showed stronger effects compared to rituximab on both the reduction of B cells and the activation of NK cells. Finally, we found that rituximab led to the activation of NK cells in vivo, provided that B cells were not depleted due to prior rituximab infusions.

Conclusion

B cell-bound rituximab activates NK cells in GPA. While NK cells therefore participate in rituximab’s mechanism of action in humans, their potential may be more efficiently exploited, e.g., by Fc engineering of therapeutic antibodies.
The value of MRI examination on bilateral hands including proximal interphalangeal joints for disease assessment in patients with early rheumatoid arthritis: a cross-sectional cohort study
Authors: Mo Ying-Qian , Yang Ze-Hong , Wang Jun-Wei , Li Qian-Hua , Du Xin-Yun , Huizinga T. W. , Matthijssen X. M. E. , Shi Guang-Zi , Shen Jun , Dai Lie
Published: December 2019

Background

Bilateral hands including proximal interphalangeal joints (PIPJs) are recommended on physical, X-ray radiographic, or ultrasonographic examination by clinical guidelines of rheumatoid arthritis (RA), but MRI still tends to examine unilateral wrists and/or MCPJs. We aimed to demonstrate the advantages of MRI examination on bilateral hands including PIPJs for disease assessment in early RA patients.

Methods

Active early RA patients received 3.0T whole-body MRI examination with contrast-enhanced imaging on bilateral wrists, MCPJs, and PIPJs. MRI features were scored referring to the updated RAMRIS. Clinical assessments were conducted on the day of MRI examination.

Results

The mean time of MRI examination was 24 ± 3 min. MRI bone erosion in MCPJs would be missed-diagnosed in 23% of patients if non-dominant MCPJs were scanned unilaterally, while osteitis in MCPJs would be missed-diagnosed in 16% of patients if dominant MCPJs were scanned unilaterally. MRI synovitis severity was also asymmetric: 21% of patients showing severe synovitis unilaterally in non-dominant MCPJs/PIPJs and other 20% showing severe synovitis unilaterally in dominant MCPJs/PIPJs. Among these early RA patients, MRI tenosynovitis occurred the most frequently in wrist extensor compartment I, while MRI examination on bilateral hands demonstrated no overuse influence present. However, overuse should be considered in dominant PIPJ2, PIPJ4, and IPJ of thumb of which MRI tenosynovitis prevalence was respectively 18%, 17%, or 16% higher than the non-dominant counterparts. Early MRI abnormality of nervus medianus secondary to severe tenosynovitis occurred either in dominant or non-dominant wrists; MRI of unilateral hands would take a risk of missed-diagnosis. Common MRI findings in PIPJs were synovitis and tenosynovitis, respectively in 87% and 69% of patients. MRI tenosynovitis prevalence in IPJ of thumb or PIPJ5 was much higher than the continued wrist flexor compartments. MRI synovitis or tenosynovitis in PIPJs independently increased more than twice probability of joint tenderness (OR = 2.09 or 2.83, both p < 0.001).

Conclusions

In consideration of asymmetric MRI features in early RA, potential overuse influence for certain tenosynovitis in dominant hands, and high prevalence of MRI findings in PIPJs, MRI examination on bilateral hands including PIPJs is deserved for disease assessment in early RA patients.
Autism and the right to education in the EU: policy mapping and scoping review of Nordic countries Denmark, Finland, and Sweden
Authors: van Kessel Robin , Walsh Sebastian , Ruigrok Amber N. V. , Holt Rosemary , Yliherva Anneli , Kärnä Eija , Moilanen Irma , Hjörne Eva , Johansson Shruti Taneja , Schendel Diana , Pedersen Lennart , Jørgensen Meta , Brayne Carol , Baron-Cohen Simon , Roman-Urrestarazu Andres
Published: December 2019

Introduction

The universal right to education for people with disabilities has been highlighted by the Universal Declaration on Human Rights and the Convention on the Rights of Persons with Disabilities. In this paper, we mapped policies addressing the right to education and special education needs of autistic children in Denmark, Sweden, and Finland.

Methods

A policy path analysis was carried out using a scoping review as an underlying framework for data gathering. Policy mapping was performed independently by both lead authors to increase reliability.

Results and discussion

The values of the Universal Declaration of Human Rights and the Convention on the Rights of Persons with Disabilities have been closely translated into the respective education systems of the countries under study, offering special education needs services and support in mainstream education with the aim of including as many children into mainstream education as possible. Even though the education systems are comparable, the approaches between the countries under study are slightly different. Denmark and Sweden have passed several policies specifically geared towards special education needs, while Finland incorporates this more in general education policy.

Conclusion

All countries under study have incorporated the values of the Universal Declaration of Human Rights and the Convention on the Rights of Persons with Disabilities in their respective education systems while emphasising the need to include as many children in the mainstream system as possible.
Osteogenesis imperfecta and pregnancy: a case report
Authors: Chamunyonga Felix , Masendeke Kudzaishe Lloyd , Mateveke Bismark
Published: December 2019

Background

Osteogenesis imperfecta is a rare connective tissue disorder of varying phenotypic presentations. In pregnancies complicated by osteogenesis imperfecta, there is an increased risk to both the mother and fetus.

Case presentation

We present a case of a 34-year-old, wheelchair-bound, primigravid African (Zimbabwean) patient with short stature and skeletal deformities. Her care, requiring a multidisciplinary team approach, resulted in the delivery of a live baby girl with a birth weight of 2100 g, also with osteogenesis imperfecta.

Conclusion

Good outcomes are reported when a multidisciplinary team is involved in the care of patients with osteogenesis imperfecta. Pregnancies can be carried to term but require close antenatal surveillance. Prenatal diagnosis is possible with ultrasound and genetic testing. Delivery should be carefully planned by a multidisciplinary team. Decisions on delivery mode should be made on a case-by-case basis.