Should disclosure of conflicts of interest in medicine be made public? Medical students' views.
Conflicts of interest (CoIs) are considered to be ubiquitous in health care and biomedicine. The disclosure of relevant interests is a first step in managing conflicts, although its usefulness is contested. Although several countries have mandated the public disclosure of doctors' financial relationships with the pharmaceutical industry, little is known about medical students' understanding of mandatory public disclosure. Six 90-minute focus groups were conducted with medical students in New South Wales, Australia. Participants ranged from first- to final-year students. Students were asked about their understanding and experiences of CoIs and, more specifically, for their views on and experiences of disclosure in medical education, mandatory disclosure and public registers. Qualitative data analysis was based on a framework approach. Participants were generally not supportive of mandatory public disclosure of financial relationships with industry, principally because of concerns about privacy, control over disclosure, and others' (mis)interpretations of disclosures. Further, they did not know how to assess the disclosures presented to them as part of their medical education and described a wide range of reactions to disclosed information. This study suggests that students are currently not well prepared for mandatory public disclosure of CoIs. The subsequent discussion draws on Bourdieu's doxa to highlight assumptions of altruism in medicine, assumptions that are potentially in tension with recent events that have exposed doctors to moral scrutiny by the public. Medical students could be better prepared for future obligations by encouraging disclosures, and contextualising and helping students to interpret them. Disclosure as a box-ticking exercise is unlikely to achieve goals implied by transparency, but a more reflective approach may assist both scrutinisers and the scrutinised.


A qualitative analysis of the perceived determinants of success in elite esports athletes.
The current study aimed to qualitatively investigate the perceived determinants of success in professional esports athletes. Guided by the bioecological model (Bronfenbrenner & Morris, 2006), thematic analysis was used to explore elite esports athletes' perceptions of success determinants. Semi-structured interviews were conducted with seven elite esports athletes. The interviews were used to investigate players' psychology when playing well, training in elite esports, and working in esports teams. Deductive and inductive analyses were conducted to capture the core themes of success in esports within the bioecological model. When playing well, elite esports athletes experienced high levels of confidence, uninterrupted focus, and flow states. Elite esport athletes use mental strategies to help regulate their emotions and remain mindful in the presence of "tilt". Furthermore, breathing techniques and tactical breaks were used when players felt nervous or when trying to "reset" from a stressful situation. When working in elite esport teams, players reported using strategies to improve team cohesion and that the biggest challenge was interpersonal disagreements. The results contribute to the growing body of literature highlighting the psychological similarities between elite esports and traditional sports athletes and serve as an index for future research into high-performance in esports.


Can anatomical morphomic variables help predict abdominal injury rates in frontal vehicle crashes?
Abdominal injuries resulting from vehicle crashes can be significant, in particular when undetected. In this study, abdominal injuries for occupants involved in frontal impacts were assessed using crash and medical data. Injury rates and patterns were first assessed with respect to thoracic injuries. A statistical analysis was then conducted to predict abdominal injury outcome using 18 covariate variables, including 4 vehicle, 4 demographic, and 10 morphomic, derived from computed tomography (CT) scans. More than 260,000 logistic regression models were fitted using all possible variable combinations. The models were ranked using the Akaike information criterion (AIC) and combined through the model-averaging approach to produce the optimal predictive model. The performance of the models was then assessed using the area under the curve (AUC). The rate of serious thoracic injury was 2.49 times higher than the rate of abdominal injury. The associated odds ratio was 2.31 (P <.01). These results suggest a strong association between serious abdominal and thoracic injuries. The optimal model AUC was 0.646 when using solely vehicle data, 0.696 when combining vehicle and demographic data, 0.866 when combining vehicle and morphomic data, and 0.879 when combining vehicle, demographic, and morphomic data. These results suggest that morphomic variables better predict abdominal injury outcomes than demographic variables. The most important morphomics variables included visceral fat area, trabecular bone density, and spine angulation. This study is the first to combine vehicle, demographic, and anatomical data to predict abdominal injury rates in frontal crashes.


[The neuronal background impulse activity of the cerebellar dentate nucleus in the rat].
The analysis of serial correlograms of spontaneous neuronal activity of the rat cerebellum dentate nucleus revealed six main dynamic versions of the impulse flows. Independent haphazard distribution of interspike intervals, irregular sequences of short and long intervals, periodic changes of the impulse flow rate, were predominant.


Activity of glucose oxidase functionalized onto magnetic nanoparticles.
BACKGROUND: Magnetic nanoparticles have been significantly used for coupling with biomolecules, due to their unique properties. METHODS: Magnetic nanoparticles were synthesized by thermal co-precipitation of ferric and ferrous chloride using two different base solutions. Glucose oxidase was bound to the particles by direct attachment via carbodiimide activation or by thiophene acetylation of magnetic nanoparticles. Transmission electron microscopy was used to characterize the size and structure of the particles while the binding of glucose oxidase to the particles was confirmed using Fourier transform infrared spectroscopy. RESULTS: The direct binding of glucose oxidase via carbodiimide activity was found to be more effective, resulting in bound enzyme efficiencies between 94-100% while thiophene acetylation was 66-72% efficient. Kinetic and stability studies showed that the enzyme activity was more preserved upon binding onto the nanoparticles when subjected to thermal and various pH conditions. The overall activity of glucose oxidase was improved when bound to magnetic nanoparticles CONCLUSION: Binding of enzyme onto magnetic nanoparticles via carbodiimide activation is a very efficient method for developing bioconjugates for biological applications.


Nanocytological field carcinogenesis detection to mitigate overdiagnosis of prostate cancer: a proof of concept study.
To determine whether nano-architectural interrogation of prostate field carcinogenesis can be used to predict prognosis in patients with early stage (Gleason 6) prostate cancer (PCa), which is mostly indolent but frequently unnecessarily treated. We previously developed partial wave spectroscopic microscopy (PWS) that enables quantification of the nanoscale intracellular architecture (20-200 nm length scale) with remarkable accuracy. We adapted this technique to assess prostate needle core biopsies in a case control study from men with Gleason 6 disease who either progressed (n = 20) or remained indolent (n = 18) over a ~3 year follow up. We measured the parameter disorder strength (Ld) characterizing the spatial heterogeneity of the nanoscale cellular structure and nuclear morphology from the microscopically normal mucosa ~150 histologically normal epithelial cells. There was a profound increase in nano-architectural disorder between progressors and non-progressors. Indeed, the Ld from future progressors was dramatically increased when compared to future non-progressors (1±0.065 versus 1.30±0.0614, respectively p = 0.002). The area under the receiver operator characteristic curve (AUC) was 0.79, yielding a sensitivity of 88% and specificity of 72% for discriminating between progressors and non-progressors. This was not confounded by demographic factors (age, smoking status, race, obesity), thus supporting the robustness of the approach. We demonstrate, for the first time, that nano-architectural alterations occur in prostate cancer field carcinogenesis and can be exploited to predict prognosis of early stage PCa. This approach has promise in addressing the clinically vexing dilemma of management of Gleason 6 PCa and may provide a paradigm for dealing with the larger issue of cancer overdiagnosis.


Preoperative prognostic factors for mortality in peptic ulcer perforation: a systematic review.
Mortality and morbidity following perforated peptic ulcer (PPU) is substantial and probably related to the development of sepsis. During the last three decades a large number of preoperative prognostic factors in patients with PPU have been examined. The aim of this systematic review was to summarize available evidence on these prognostic factors. MEDLINE (January 1966 to June 2009), EMBASE (January 1980 to June 2009), and the Cochrane Library (Issue 3, 2009) were screened for studies reporting preoperative prognostic factors for mortality in patients with PPU. The methodological quality of the included studies was assessed. Summary relative risks with 95% confidence intervals for the identified prognostic factors were calculated and presented as Forest plots. Fifty prognostic studies with 37 prognostic factors comprising a total of 29,782 patients were included in the review. The overall methodological quality was acceptable, yet only two-thirds of the studies provided confounder adjusted estimates. The studies provided strong evidence for an association of older age, comorbidity, and use of NSAIDs or steroids with mortality. Shock upon admission, preoperative metabolic acidosis, tachycardia, acute renal failure, low serum albumin level, high American Society of Anaesthesiologists score, and preoperative delay >24 h were associated with poor prognosis. In patients with PPU, a number of negative prognostic factors can be identified prior to surgery, and many of these seem to be related to presence of the sepsis syndrome.


Post-crystallization treatments for improving diffraction quality of protein crystals.
X-ray crystallography is the most powerful method for determining the three-dimensional structure of biological macromolecules. One of the major obstacles in the process is the production of high-quality crystals for structure determination. All too often, crystals are produced that are of poor quality and are unsuitable for diffraction studies. This review provides a compilation of post-crystallization methods that can convert poorly diffracting crystals into data-quality crystals. Protocols for annealing, dehydration, soaking and cross-linking are outlined and examples of some spectacular changes in crystal quality are provided. The protocols are easily incorporated into the structure-determination pipeline and a practical guide is provided that shows how and when to use the different post-crystallization treatments for improving crystal quality.


The UK medical response to the Sichuan earthquake.
At 14:48 on 12 May 2008 an earthquake of magnitude 8.0 struck the Wenchuan area of Sichuan province, China. A decision to offer/receive UK medical assistance was agreed at a Sino/British political level and a medical team was despatched to the earthquake area. This study describes the team's experience during the immediate aftermath of the earthquake and the following 18 months, during which there have been joint developments in emergency medicine, disaster planning/preparedness and the management of spinal cord injury. The long-term disability following sudden onset natural disaster and the wider impact on healthcare delivery may prove to be a greater burden to the country than the immediate medical needs, and, accordingly, emergency international aid may need to widen its focus. Although international teams usually arrive too late to support resuscitative measures, they can respond to specific requests for specialised assistance, for example plastic and reconstructive surgery to assist with the ongoing management of complex injury, relieve those who have worked continuously through the disaster, and when required maintain routine day-to-day services while local staff continue to manage the disaster. The timing of this does not necessarily need to be immediate. To maximise its impact, the team planned from the outset to build a relationship with Chinese colleagues that would lead to a sharing of knowledge and experience that would benefit major incident responses in both countries in the future. This has been established, and the linkage of emergency humanitarian assistance to longer term development should be considered by others the next time international emergency humanitarian assistance is contemplated.


Immunogenicity evaluation of DNA vaccines that target guinea pig cytomegalovirus proteins glycoprotein B and UL83.
Vaccines are needed for control of congenital human cytomegalovirus (HCMV) infection. Although the species-specificity of cytomegaloviruses precludes preclinical evaluation of HCMV vaccines in animal models, the guinea pig cytomegalovirus (GPCMV), which causes disease in utero, is a relevant model for the study of vaccines against congenital infection. We investigated whether DNA vaccines that target two GPCMV proteins, glycoprotein B (gB) and UL83 (pp65), are capable of eliciting immune responses in vivo. After cloning each gene into an expression vector, DNA was delivered by intramuscular inoculation and by pneumatic epidermal delivery. In Swiss-Webster mice, anti-gB titers were significantly higher after epidermal delivery. After epidermal inoculation in guinea pigs, all gB-immunized animals (n = 6) had antibody responses comparable to those induced by natural infection. Viral neutralization titers ranged from 1:64 to greater than 1:128. A GPCMV UL83 DNA vaccine also elicited an antibody response in all immunized guinea pigs (n = 6) after epidermal administration. Immunoprecipitation and Western blot assays confirmed that immune sera were immunoreactive with virion-associated UL83 and gB proteins. We conclude that DNA vaccines against GPCMV structural proteins are immunogenic, and warrant further investigation in the guinea pig model of congenital CMV infection.


Structural intermediates and directionality of the swiveling motion of Pyruvate Phosphate Dikinase.
Pyruvate phosphate dikinase (PPDK) is a vital enzyme in cellular energy metabolism catalyzing the ATP- and Pi-dependent formation of phosphoenolpyruvate from pyruvate in C4 -plants, but the reverse reaction forming ATP in bacteria and protozoa. The multi-domain enzyme is considered an efficient molecular machine that performs one of the largest single domain movements in proteins. However, a comprehensive understanding of the proposed swiveling domain motion has been limited by not knowing structural intermediates or molecular dynamics of the catalytic process. Here, we present crystal structures of PPDKs from Flaveria, a model genus for studying the evolution of C4 -enzymes from phylogenetic ancestors. These structures resolve yet unknown conformational intermediates and provide the first detailed view on the large conformational transitions of the protein in the catalytic cycle. Independently performed unrestrained MD simulations and configurational free energy calculations also identified these intermediates. In all, our experimental and computational data reveal strict coupling of the CD swiveling motion to the conformational state of the NBD. Moreover, structural asymmetries and nucleotide binding states in the PPDK dimer support an alternate binding change mechanism for this intriguing bioenergetic enzyme.


Predictors of coronary artery lesions after intravenous gamma-globulin treatment in Kawasaki disease.
We evaluated the efficacy of intravenous gamma-globulin (IVGG) administration for children with Kawasaki disease to establish whether additional, more advanced therapy is needed in intractable cases. A total of 193 children with Kawasaki disease were studied retrospectively. Patients were admitted 3 to 7 days after the onset of the disease, and IVGG was administered. Laboratory measurements including white blood cell (WBC), neutrophil, and platelet counts and C-reactive protein (CRP) and albumin concentrations were determined before and 2 to 3 days after IVGG treatment. The progression of coronary artery lesions (CALs) was monitored by serial echocardiography until 30 days after treatment. Of 193 children, 24 (12.2 %) had CALs including transient dilatation. In contrast to the other measurements, the WBC count increased in 21 of 24 (87.5%) children with CALs after IVGG therapy. The patients with increased neutrophil count and CRP concentration after IVGG therapy also had CAL formation at a high rate (78.3% and 66.7%, respectively). Among children with normal coronary arteries, elevations of the WBC and neutrophil counts and CRP concentration were observed after IVGG therapy in only 3, 6, and 8 patients, respectively (specificity: 98.2%, 97.0%, and 95.3%, respectively). Furthermore, multiple logistic regression indicated that these variables were useful predictors of CALs in KD. Though the introduction of IVGG therapy has improved the prognosis of Kawasaki disease, approximately 10% of patients still develop CALs. The need for more aggressive therapy in IVGG-resistant cases can be recognized early by increases in the WBC and neutrophil counts and serum CRP concentration after IVGG administration.


Metals of the bottom muds in Belize City Harbor, Belize.
Seven bottom samples extending from the ocean up through Belize Harbor and City were acid leached (EPA method 200.7) and analyzed using inductively coupled plasma spectrometry to measure the bioavailability of Cd, Cr, Cu, Pb and Zn. Soil and environmental chemists would compare data to world averages of unpolluted soils, these samples were higher than this average by a factor of 10 for Cd, 4 for Cu, 2.7 for Zn and 2.6 for Pb. Geochemists argue that it's hard to find unpolluted soil so their comparison is with world average of ancient (pre-man) shales and the Belize samples were higher than this shale average by a factor of 30 for Cd, 3.7 for Pb, 2.2 for Cu and 1.7 for Zn. Ecologists would argue that the metal effect on the biota is the correct way to analyze the data by using the biological effects toxicity method, and this way the samples were above the lower limit by a factor of 5.1 for Cd, 2.9 for Cu and 1.6 for Pb. By all three lines of reasoning, it can be concluded that Cd, Cu, Pb and Zn, in that order, pose environmental problems. Since this site is located in the middle of Belize Barrier Reef, a highly sensitive environmental area that is also economically important to Belize, it poses a critical problem that needs to be addressed further.


[Dimorphic (transitional-anaplastic) ductal cancer of the prostate].
Prostatic carcinoma of a specific structure with widespread metastasis in a 7 year-old patient who was treated with oestrogens and survived more than 4 years after the appearance of the first symptoms is described. Histologically in the primary tumour the combination of highly differentiated transitional-cell carcinoma (without cell degeneration and necrosis) and anaplastic, mainly small-cell carcinoma is found in the prostatic ducts. Pronounced degenerative and necrotic changes similar to those resulting from the oestrogen therapy with a positive effect are observed in the anaplastic carcinoma. Metastases had a structure of transitional-cell carcinoma.


Dental caries experience and tobacco use in 19-year-old Croatian army recruits.
The aim of this study is to investigate caries prevalence and smoking habit in the population of 19-year-old Croatian male recruits. Dental examination of 505 male recruits was conducted in 2001 in the military centre in Koprivnica. Caries status was described by the FS-T (Filled and Sound Teeth) index and DMFT (Decayed, Missing and Filled Teeth) index. Mean DMFT scores were 7.32 and FST 23.56. There was a significant statistical difference in comparison of smoking habits depending on the reason to visit the dentist (p = 0.001). The subjects who do not smoke tobacco have less decayed teeth (DT index with p < 0.001), and more teeth with fillings and/or sound teeth (FT with p = 0.005 and FST with p = 0.004). There is no statistically significant difference for the DMFT (p = 0.657) and MT (p = 0.703). In conclusion, it showed that FS-T is a more appropriate index for describing variation in the population with higher caries experience. In the population of Croatian recruits, there were an astonishing 58.6% of smokers.


Articular cartilage chondrons: form, function and failure.
The chondrocyte and its pericellular microenvironment together represent the chondron, historically considered the primary structural, functional and metabolic unit of articular and other hyaline cartilages. This review summarises research over the last 10 years to establish the molecular anatomy, functional properties and metabolic contribution of the chondron in articular cartilage homeostasis, and its failure during the initiation and progression of degenerative osteoarthritis.


Development of a sandwich ELISA for quantifying hepcidin in Rainbow trout.
One of the most widespread antimicrobial peptides (AMPs) in fish is the hepcidins, which have potent, broad-spectrum activity against viruses, bacteria, fungi, and parasites. Moreover, they play the role of central regulation of iron metabolism and their expression is over-regulated by bacterial and viral infections, inflammation and vaccination. Quantification of their expression is an important factor in understanding their function. We therefore generated two polyclonal antibodies using synthetic peptides in order to measure hepcidin expression via sandwich ELISA. The specificity of both antibodies was confirmed by identifying an absence of cross-reactivity with other peptides that have similar pI and with the detection by Western blot of only one 9.6 kDa immunoreactive band corresponding to the hepcidin prepropeptide. The sensitivity of the sandwich ELISA was in the order of 0.005 ng/μL of hepcidin, which allowed analysis of the presence of the peptide and its variation in different tissues of Oncorhynchus mykiss. With the sandwich ELISA it could be seen that hepcidin expression in rainbow trout challenged with Aeromonas salmonicida was increased twofold over the untreated fish in head kidney samples, in correlation with the increase in the observed transcriptional level in the head kidney cells. These results provide the first evidence for quantifying the presence of active hepcidin and may be a useful indicator of disease susceptibility, providing a new, sensitive tool for rapid screening of population health.


Zinner's Syndrome: Case report of a Developmental Anomaly of the Mesonephric Duct.
Zinner's syndrome is a rare congenital malformation characterized by the association of unilateral renal agenesis with ipsilateral seminal vesicle cyst and ejaculatory duct obstruction. Most patients are asymptomatic until the third or fourth decade of life when the syndrome is associated with dysuria, perineal pain, infertility, and painful ejaculation. In this report, we present the common imaging findings of this rare developmental anomaly involving the mesonephric duct in a 48-year-old male patient experiencing pelvic pain, recurrent dysuria, and pollakiuria.


FoxO6 integrates insulin signaling with MTP for regulating VLDL production in the liver.
Excessive production of triglyceride-rich very low-density lipoproteins (VLDL-TG) contributes to hypertriglyceridemia in obesity and type 2 diabetes. To understand the underlying mechanism, we studied hepatic regulation of VLDL-TG production by (forkhead box O6) FoxO6, a forkhead transcription factor that integrates insulin signaling to hepatic metabolism. We showed that transgenic mice expressing a constitutively active FoxO6 allele developed hypertriglyceridemia, culminating in elevated VLDL-TG levels and impaired postprandial TG clearance. This effect resulted in part from increased hepatic VLDL-TG production. We recapitulated these findings in cultured HepG2 cells and human primary hepatocytes, demonstrating that FoxO6 promoted hepatic VLDL-TG secretion. This action correlated with the ability of FoxO6 to stimulate hepatic production of microsomal triglyceride transfer protein (MTP), a molecular chaperone that catalyzes the rate-limiting step in VLDL-TG assembly and secretion. FoxO6 was shown to bind to the MTP promoter and stimulate MTP promoter activity in HepG2 cells. This effect was inhibited by insulin, consistent with the ability of insulin to promote FoxO6 phosphorylation and disable FoxO6 DNA-binding activity. Mutations of the FoxO6 target site within the MTP promoter abrogated FoxO6-mediated induction of MTP promoter activity. Hepatic FoxO6 expression became deregulated in insulin-resistant mice with obesity and type 2 diabetes. FoxO6 inhibition in insulin-resistant liver suppressed hepatic MTP expression and curbed VLDL-TG overproduction, contributing to the amelioration of hypertriglyceridemia in obese and diabetic db/db mice. These results characterize FoxO6 as an important signaling molecule upstream of MTP for regulating hepatic VLDL-TG production.


Moving the glycoprotein gene of vesicular stomatitis virus to promoter-proximal positions accelerates and enhances the protective immune response.
Vesicular stomatitis virus (VSV) is the prototype of the Rhabdoviridae and contains nonsegmented negative-sense RNA as its genome. The 11-kb genome encodes five genes in the order 3'-N-P-M-G-L-5', and transcription is obligatorily sequential from the single 3' promoter. As a result, genes at promoter-proximal positions are transcribed at higher levels than those at promoter-distal positions. Previous work demonstrated that moving the gene encoding the nucleocapsid protein N to successively more promoter-distal positions resulted in stepwise attenuation of replication and lethality for mice. In the present study we investigated whether moving the gene for the attachment glycoprotein G, which encodes the major neutralizing epitopes, from its fourth position up to first in the gene order would increase G protein expression in cells and alter the immune response in inoculated animals. In addition to moving the G gene alone, we also constructed viruses having both the G and N genes rearranged. This produced three variant viruses having the orders 3'-G-N-P-M-L-5' (G1N2), 3'-P-M-G-N-L-5' (G3N4), and 3'-G-P-M-N-L-5' (G1N4), respectively. These viruses differed from one another and from wild-type virus in their levels of gene expression and replication in cell culture. The viruses also differed in their pathogenesis, immunogenicity, and level of protection of mice against challenge with wild-type VSV. Translocation of the G gene altered the kinetics and level of the antibody response in mice, and simultaneous reduction of N protein expression reduced replication and lethality for animals. These studies demonstrate that gene rearrangement can be exploited to design nonsegmented negative-sense RNA viruses that have characteristics desirable in candidates for live attenuated vaccines.


Conchal bowl and postauricular flaps for reconstruction of the external auditory canal.
Two techniques for reconstructing the external auditory canal are presented; to our knowledge they have not been described previously. The first technique can be used for disease that does not affect the conchal bowl. The canal is reconstructed with an inferiorly based conchal bowl flap. A second inferiorly based postauricular flap, tunneled through the conchal cartilage, resurfaces the conchal bowl. The postauricular defect is closed primarily. The second technique can be used for disease affecting the conchal bowl. A posteriorly based flap that includes skin overlying the mastoid and posterior surfaces of the pinna is tunneled through the conchal cartilage and resurfaces the conchal bowl and external auditory canal. The defect on the posterior surface of the pinna is closed with tissue advanced from the anterior surface of the pinna at the conchal bowl-antihelical fold junction. The remainder of the retroauricular defect is closed primarily. The advantages of these techniques over current methods are described and illustrative cases presented.


Improving guideline adherence for cardiac rehabilitation in the Netherlands.
In 2004, the Netherlands Society of Cardiology released the current guideline on cardiac rehabilitation. Given its complexity and the involvement of various healthcare disciplines, it was supplemented with a clinical algorithm, serving to facilitate its implementation in daily practice. Although the algorithm was shown to be effective for improving guideline adherence, several shortcomings and deficiencies were revealed. Based on these findings, the clinical algorithm has now been updated. This article describes the process and the changes that were made. The revision consisted of three phases. First, the reliability of the measurement instruments included in the 2004 Clinical Algorithm was investigated by evaluating between-centre variations of the baseline assessment data. Second, based on the available evidence, a multidisciplinary expert advisory panel selected items needing revision and provided specific recommendations. Third, a guideline development group decided which revisions were finally included, also taking practical considerations into account. A total of nine items were revised: three because of new scientific insights and six because of the need for more objective measurement instruments. In all revised items, subjective assessment methods were replaced by more objective assessment tools (e.g. symptom-limited exercise instead of clinical judgement). In addition, four new key items were added: screening for anxiety/depression, stress, cardiovascular risk profile and alcohol consumption. Based on previously determined shortcomings, the Clinical Algorithm for Cardiac Rehabilitation was thoroughly revised mainly by incorporating more objective assessment methods and by adding several new key areas.


Socioeconomic position and stage of cervical cancer in Danish women diagnosed 2005 to 2009.
To reduce social disparities in cervical cancer survival, it is important to understand the mechanisms by which social position influence cancer prognosis. We investigated the relations between socioeconomic factors, comorbidity, time since last Papanicolau smear, and stage at diagnosis in Danish women with cervical cancer. We identified 1,651 cervical cancer cases diagnosed 2005 to 2009 from the Danish Gynaecological Cancer Database. Date of diagnosis, clinical cancer stage, tumor histology, and treating hospital were retrieved; Pap smear registrations were obtained from the Danish Pathology Register; data on comorbid conditions from the Danish National Patients Register; and data on education, income, and cohabitation from Statistics Denmark. Logistic regression models were used to analyze the relations between socioeconomic factors and cancer stage in a four-step model, with stepwise inclusion of mediators. The risk for advanced (stage II-IV) compared with early-stage cancer (stage I) was increased for women with short and medium education (OR = 2.40; 1.67-3.45 and 1.76; 1.44-2.16), women living without a partner (OR = 1.31; 1.10-1.55), and older women (OR = 1.07; 1.06-1.08 increase per year). The relations between socioeconomic factors and cancer stage were partly mediated by time since last Pap smear test and to a lesser extent by comorbidity. Shorter education, living alone, and older age were related to advanced stage cervical cancer, due partly to Pap smear testing and less to comorbidity. It is relevant to further investigate how to decrease delay in cervical cancer diagnosis among disadvantaged groups.


Abnormal autonomic and associated brain activities during rest in autism spectrum disorder.
Autism spectrum disorders are associated with social and emotional deficits, the aetiology of which are not well understood. A growing consensus is that the autonomic nervous system serves a key role in emotional processes, by providing physiological signals essential to subjective states. We hypothesized that altered autonomic processing is related to the socio-emotional deficits in autism spectrum disorders. Here, we investigated the relationship between non-specific skin conductance response, an objective index of sympathetic neural activity, and brain fluctuations during rest in high-functioning adults with autism spectrum disorder relative to neurotypical controls. Compared with control participants, individuals with autism spectrum disorder showed less skin conductance responses overall. They also showed weaker correlations between skin conductance responses and frontal brain regions, including the anterior cingulate and anterior insular cortices. Additionally, skin conductance responses were found to have less contribution to default mode network connectivity in individuals with autism spectrum disorders relative to controls. These results suggest that autonomic processing is altered in autism spectrum disorders, which may be related to the abnormal socio-emotional behaviours that characterize this condition.


Confounding: what it is and how to deal with it.
As confounding obscures the 'real' effect of an exposure on outcome, investigators performing etiological studies do their utmost best to prevent or control confounding. Unfortunately, in this process, errors are frequently made. This paper explains that to be a potential confounder, a variable needs to satisfy all three of the following criteria: (1) it must have an association with the disease, that is, it should be a risk factor for the disease; (2) it must be associated with the exposure, that is, it must be unequally distributed between exposure groups; and (3) it must not be an effect of the exposure; this also means that it may not be part of the causal pathway. In addition, a number of different techniques are described that may be applied to prevent or control for confounding: randomization, restriction, matching, and stratification. Finally, a number of examples outline commonly made errors, most of which result from 'overadjustment' for variables that do not satisfy the criteria for potential confounders. Such an example of an error frequently occurring in the literature is the incorrect adjustment for blood pressure while studying the relationship between body mass index and the development of end-stage renal disease. Such errors will introduce new bias instead of preventing it.


[Examination of gastric emptying with gamma camera. Clinically useful, uniform method now established].
Although more than 30 years have passed since the introduction of scintigraphic testing of gastric emptying there has been no well-defined standard. Eight Swedish hospitals have established a nationally standardized method for scintigraphic testing of gastric emptying of solids. 160 healthy subjects participated. The meal consisted of a 99mTc-labeled omelet (1300 kJ) and 150 ml unlabeled soft drink (290 kJ). There were no differences in calculated variables between the centers. Premenopausal women showed slower emptying than postmenopausals and men of any age, making separate reference values for younger women necessary.


Associations Between Workplace Exercise Interventions and Job Stress Reduction: A Systematic Review.
Background: High job stress is positively associated with reduced quality of life in workers, detrimental effects on worker health, and increased worker absenteeism and lower productivity. Exercise is a proven approach for coping with psychological stress in general. However, relatively few research studies have examined the effects of workplace exercise interventions on job stress reduction. The purpose of this systematic review was to identify associations between workplace exercise interventions and job stress reduction among employees. Methods: A literature search was performed using five databases (i.e., CINAHL, Medline via PubMed, Scopus, PsycINFO, and Embase), and eligible studies were written in English, and were published between January 1990 and October 2018. Studies were included if worker participants were subjected to a workplace exercise intervention, and their job stress was measured before and after the intervention. To assess the quality of these studies, van Tulder's risk of bias assessment tool was applied. Findings: Eight studies were identified, and six of those (75%) were found to be of relatively good quality. In only two of the studies (25%) was the workplace exercise program associated with a statistically significant reduction in job stress. The study findings suggest that relationships between workplace exercise interventions and job stress reduction have not been sufficiently evaluated in the literature. Conclusion and Application to Practice: Based on the limited data available, future intervention research should focus on randomized controlled trials of interventions incorporating both exercise and multidimensional strategies to reduce job stress.


Body size at birth and adulthood and the risk for germ-cell testicular cancer.
To assess the association between adult body size and germ-cell testicular cancer risk and to understand whether this association is independent from perinatal characteristics, a nested case-control study was conducted. Three hundred and seventy-one patients with testicular cancer, registered in the Swedish Cancer Registry between 1958 and 1996 and aged 20-54 years at diagnosis, and 1238 individually matched controls were identified. Information on adult body size at age 18 years was obtained for all subjects through the Military Service Conscription Register, whereas perinatal information was obtained through birth records at the subjects' respective maternity wards. Height was positively associated with testicular cancer risk, and the association persisted after taking into account perinatal characteristics. The adjusted odds ratio (OR) was 1.55 [95% confidence interval (CI), 1.10-2.17] for the third tertile of height as compared with the first. No association between the risk for testicular cancer and body mass index was found. Long duration of gestation was negatively associated with testicular cancer risk [OR = 0.64 (95% CI, 0.45-0.91), post-term compared with term], whereas high birth weight appeared to increase the risk [OR = 1.35 (95% CI, 0.99-1.85)]. In conclusion, adult height and perinatal factors acted independently, suggesting that both the fetal life and the childhood and adolescence periods are windows of susceptibility to exposures that influence the risk for testicular cancer.


Hepatitis B virus infection reactivation in patients under immunosuppressive therapies: Pathogenesis, screening, prevention and treatment.
With a 5.3% of the global population involved, hepatitis B virus (HBV) is a major public health challenge requiring an urgent response. After a possible acute phase, the natural history of HBV infection can progress in chronicity. Patients with overt or occult HBV infection can undergo HBV reactivation (HBVr) in course of immunosuppressive treatments that, apart from oncological and hem-atological diseases, are also used in rheumatologic, gastrointestinal, neurological and dermatological settings, as well as to treat severe acute respiratory syndrome coronavirus 2 infection. The risk of HBV reactivation is related to the immune status of the patient and the baseline HBV infection condition. The aim of the present paper is to investigate the risk of HBVr in those not oncological settings in order to suggest strategies for preventing and treating this occurrence. The main studies about HBVr for patients with occult hepatitis B infection and chronic HBV infection affected by non-oncologic diseases eligible for immunosuppressive treatment have been analyzed. The occurrence of this challenging event can be reduced screening the population eligible for immunosuppressant to assess the best strategies according to any virological status. Further prospective studies are needed to increase data on the risk of HBVr related to newer immunomodulant agents employed in non-oncological setting.


Australian and New Zealand clinical practice guidelines for the treatment of depression.
The Royal Australian and New Zealand College of Psychiatrists (RANZCP) is co-ordinating the development of clinical practice guidelines (CPGs) in psychiatry, funded under the National Mental Health Strategy (Australia) and the New Zealand Ministry of Health. The CPG team reviewed the treatment outcome literature, consulted with practitioners and patients and conducted meta-analyses of outcome research. Establish an effective therapeutic relationship; provide the patient with information about the condition, the rationale for treatment, the likelihood of a positive response and the expected timeframe; consider the patient's strengths, life stresses and supports. Treatment choice depends on the clinician's skills and the patient's circumstances and preferences, and should be guided but not determined by these guidelines. In moderately severe depression, all recognized antidepressants, cognitive behavioural therapy (CBT) and interpersonal psychotherapy (IPT) are equally effective; clinicians should consider treatment burdens as well as benefits, including side-effects and toxicity. In severe depression, antidepressant treatment should precede psychological therapy. For depression with psychosis, electroconvulsive therapy (ECT) or a tricyclic combined with an antipsychotic are equally helpful. Treatments for other subtypes are discussed. Caution is necessary in people on other medication or with medical conditions. If response to an adequate trial of a first-line treatment is poor, another evidence-based treatment should be used. Second opinions are useful. Depression has a high rate of recurrence and efforts to reduce this are crucial.


Does the insulin-like growth factor system interact with prostaglandins and proinflammatory cytokines during neurodegeneration?
Prostaglandins and proinflammatory cytokines are implicated in the etiology of neurodegenerative diseases, such as Alzheimer's disease. Signaling cascades initiated by these factors may result in reactive oxygen species generation and cell death. The insulin-like growth factors (IGF) are ubiquitous polypeptides involved in all aspects of growth and development. Additionally, the IGF are regarded as survival factors that display potent antiapoptotic activity. Interfering with IGF production, distribution, or signaling may result in greater susceptibility to apoptotic stimuli. In neurodegenerative conditions, the IGF appear to be antagonized by prostaglandins and proinflammatory cytokines. In this review, the relationship among specific prostaglandins, the proinflammatory factors, tumor necrosis factor, interleukin-1, and interleukin-6, and the IGF system will be investigated.


Purification and molecular cloning of a secreted, Frizzled-related antagonist of Wnt action.
Frizzled polypeptides are integral membrane proteins that recently were shown to function as receptors for Wnt signaling molecules. Here, we report the identification of a novel, secreted 36-kDa protein that contains a region homologous to a putative Wnt-binding domain of Frizzleds. This protein, called Frizzled-related protein (FRP), was first identified as a heparin-binding polypeptide that copurified with hepatocyte growth factor/scatter factor in conditioned medium from a human embryonic lung fibroblast line. Degenerate oligonucleotides, based on the NH2-terminal sequence of the purified protein, were used to isolate corresponding cDNA clones. These encoded a 313-amino acid polypeptide, containing a cysteine-rich domain of approximately 110 residues that was 30-40% identical to the putative ligand-binding domain of Frizzled proteins. A 4.4-kb transcript of the FRP gene is present in many organs, both in the adult and during embryogenesis, and homologs of the gene are detectable in DNA from several vertebrate species. In biosynthetic studies, FRP was secreted but, like Wnts, tended to remain associated with cells. When coexpressed with several Wnt family members in early Xenopus embryos, FRP antagonized Wnt-dependent duplication of the embryonic dorsal axis. These results indicate that FRP may function as an inhibitor of Wnt action during development and in the adult.


Nerve conduction studies in polyneuropathy: practical physiology and patterns of abnormality.
Nerve conduction studies are an essential part of the work-up of peripheral neuropathies. Many neuropathic syndromes can be suspected on clinical grounds, but optimal use of nerve conduction study techniques (in combination with needle electromyography) allows diagnostic classification and is therefore crucial to understanding and separation of neuropathies. Multifocal motor neuropathy, for example, may clinically present as ALS. Detection of evidence of demyelination (conduction blocks) leads to the correct diagnosis and to proper treatment. Nerve conduction studies provide essential information on (1) the spatial pattern of neuropathy, (2) the pattern of abnormalities distinguishing between primarily axonal and demyelinating pathology, and (3) the severity of neuropathic damage. This information is very comprehensive since many nerves and long segments of individual nerves can be sampled. Moreover the information is extremely detailed to the extent that the cellular pathology of a patient's neuropathy is usually defined best by physiological testing rather than by biopsy. Neuropathies can be generalized, focal, or multifocal; they can be symmetric or asymmetric; they can be distally predominant or proximal and distal. Primarily axonal neuropathies mainly affect sensory nerve and compound muscle action potential amplitudes, whereas demyelinating neuropathies lead to slowing of nerve conductions, and to increased temporal dispersion or conduction block. Usually, the pattern of demyelination allows to distinguish hereditary (uniform demyelination) from acquired (segmental demyelination) neuropathies. Electrodiagnostic criteria for primary demyelination are helpful to identify acquired demyelinating neuropathies.


Molecular and functional characteristics of receptor-interacting protein kinase 1 (RIPK1) and its therapeutic potential in Alzheimer's disease.
Inflammation and cell death processes positively control the organ homeostasis of an organism. Receptor-interacting protein kinase 1 (RIPK1), a member of the RIPK family, is a crucial regulator of cell death and inflammation, and control homeostasis at the cellular and tissue level. Necroptosis, a programmed form of necrosis-mediated cell death and tumor necrosis factor (TNF)-induced necrotic cell death, is mostly regulated by RIPK1 kinase activity. Thus, RIPK1 has recently emerged as an upstream kinase that controls multiple cellular pathways and participates in regulating inflammation and cell death. All the major cell types in the central nervous system (CNS) have been found to express RIPK1. Selective inhibition of RIPK1 has been shown to prevent neuronal cell death, which could ultimately lead to a significant reduction of neurodegeneration and neuroinflammation. In addition, the kinase structure of RIPK1 is highly conducive to the development of specific pharmacological small-molecule inhibitors. These factors have led to the emergence of RIPK1 as an important therapeutic target for Alzheimer's disease (AD).


A Novel Mobile Platform Enhances Motivation and Satisfaction of Academic Teachers.
With rising numbers of students, shorter hospital stays and increasing workload of academic teachers, teaching time have become a scarce resource. Thus, optimal preparation by teachers is key for good clinical teaching. Though a lot of teaching duties are performed by residents in Germany, they are not likely to have been educated in didactic techniques. We developed and evaluated a mobile teaching application using the "Learning Toolbox (LTB)" platform (Raycom BV, Utrecht, Netherlands) that was offered to academic teachers for preparation and support during curricular courses at our medical school. Courses were part of the curricula in Anaesthesiology, Emergency Medicine, and Orthopaedic and Trauma Surgery, and course length could vary up to 40 h per week. Information provided by the novel platform included logistic information, learning objectives, and curricula for the individual courses. A basic tutorial on didactic techniques, suggestions for providing feedback and for enhancing students' participation was also part of the platform. After one semester, interviews with teachers indicated an increase in overall satisfaction. Residents appreciated didactic aids and content provided for preparation, leading to higher motivation and self-confidence. The more experienced teachers were particularly satisfied with easy access to scheduling, teaching assignments and daily planning. The app increased teachers' satisfaction with their performance and enabled better integration of teaching in the daily schedule.


Efficient Micropropagation Protocol for the Conservation of the Endangered Aloe peglerae, an Ornamental and Medicinal Species.
A number of Aloe species are facing an extremely high risk of extinction due to habitat loss and over-exploitation for medicinal and ornamental trade. The last global assessment of Aloe peglerae Schönland (in 2003) ranked its global conservation status as 'endangered' with a decreasing population trend. In the National Red List of South African Plants, the extremely rapid decline of this species has resulted in its conservation status being elevated from 'endangered' to 'critically endangered' based on recent or new field information. This dramatic decline necessitates the development of a simple, rapid and efficient micropropagation protocol as a conservation measure. An in vitro propagation protocol was therefore established with the regeneration of 12 shoots per shoot-tip explant within 8 weeks using Murashige and Skoog (MS) medium supplemented with 2.5 µM meta-topolin riboside (an aromatic cytokinin). The rooting of the shoots with a 100% frequency on half-strength MS medium without any plant growth resulted in additional six shoots produced per cultured shoot. The resultant plantlets were successfully acclimatized with a 100% survival frequency after 6 weeks. Overall, the developed protocol can result in the production of 3906 transplantable shoots that are ready for rooting per annum from a single shoot-tip explant. It is simple and efficient for seedling production in the ex situ cultivation and conservation of the endangered A. peglerae.


Neuromuscular alterations in the dilated ileum of an adult patient with segmental lymphangiectasia.
Intestinal lymphangiectasia is a rare condition, which is characterized by the dilation of small bowel lymphatics and presents with signs and symptoms of protein-losing enteropathy. Some patients have complained of occlusive symptoms attributable to the mechanical obstruction caused by the considerable mucosal edema associated with the lymphatic dilation. On the basis of the hypothesis that alterations in the neuromuscular structures controlling clearance function or gut tone may play a role in ileal dilation, we examined the resected ileum of a 48-year-old male patient with segmental lymphangiectasia histologically, immunohistochemically (for S100 protein, PGP 9.5, Bcl-2, neuron-specific enolase, neurofilaments, synaptophysin, and CD117/C-kit), and by means of electron microscopy. Histology showed pseudocystic dilation of the mucosal, submucosal, and muscular lymphatics with fragmentation of the circular and longitudinal muscle layers. Hardly any neural expression of synaptophysin was observed, but the neural structures were otherwise morphologically normal and reacted normally to the other neural markers. This case shows that neuromuscular alterations can be found in the dilated ileum of patients with segmental lymphangiectasia.


Resident tracking health information system. Inpatient setting.
The tracking of residents' patient care activities in the hospital setting is valuable to the residency program directors for consideration of curricular changes and to the resident for documentation of experience. Furthermore, the cost-effective method of using patient data generated by hospital billing systems eliminates the need for double entry and assures a high degree of accuracy. This article discusses the use of a computerized tracking system, providing examples of data displays and interpretations.


Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy.
Few prospective, randomized controlled clinical trials address the diagnosis and management of patients with Alport syndrome or thin basement membrane nephropathy. Adult and pediatric nephrologists and geneticists from four continents whose clinical practice focuses on these conditions have developed the following guidelines. The 18 recommendations are based on Level D (Expert opinion without explicit critical appraisal, or based on physiology, bench research, or first principles-National Health Service category) or Level III (Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees-U.S. Preventive Services Task Force) evidence. The recommendations include the use of genetic testing as the gold standard for the diagnosis of Alport syndrome and the demonstration of its mode of inheritance; the need to identify and follow all affected members of a family with X-linked Alport syndrome, including most mothers of affected males; the treatment of males with X-linked Alport syndrome and individuals with autosomal recessive disease with renin-angiotensin system blockade, possibly even before the onset of proteinuria; discouraging the affected mothers of males with X-linked Alport syndrome from renal donation because of their own risk of kidney failure; and consideration of genetic testing to exclude X-linked Alport syndrome in some individuals with thin basement membrane nephropathy. The authors recognize that as evidence emerges, including data from patient registries, these guidelines will evolve further.


Differential expression and imprinting status of Ins1 and Ins2 genes in extraembryonic tissues of laboratory mice.
There are two functional insulin genes in the mouse genome. The Ins2 gene is imprinted and expressed monoallelically from the paternal allele in the yolk sac. In the present study we have re-examined the imprinting status of Ins1. We found that Ins1 is not expressed in the yolk sac of several laboratory mouse strains. The asynchrony of replication at the wild type locus was significantly lower than at imprinted loci and was more similar to non-imprinted loci. Finally, we have taken the advantage of the Ins1(neo) allele created by homologous recombination to examine the allelic usage at this locus. We observed that the neo gene inserted at the Ins1 locus was expressed from both the paternally and the maternally transmitted allele. Therefore, the Ins1 gene does not share any of the basic properties of imprinted genes. On the basis of these data, we concluded that Ins1 locus is unlikely to be imprinted in common laboratory mice.


Association Between Chronic Osteomyelitis and Risk of End-Stage Renal Disease: A Nationwide Population-Based Cohort Study.
Inflammation, which initiates endothelial dysfunction, vascular atherosclerosis, and oxidative stress, may negatively influence renal function and accelerate the development of end-stage renal disease (ESRD). The role of chronic osteomyelitis (COM), a chronic inflammatory disease, in the development of ESRD has not been investigated. This study explored whether patients with COM have a higher risk of ESRD than that of patients without COM.Taiwan National Health Insurance claims from 1997 to 2010 were used to identify 24,267 newly diagnosed patients with COM and 97,068 age- and sex-matched non-COM controls for comparison. The risks of ESRD among COM patients, with adjustment for comorbidities, namely, hypertension, diabetes, coronary artery disease, congestive heart failure, and hyperlipidemia, were assessed until the end of 2010.ESRD risk was 2.01-fold higher (95% confidence interval [CI]: 1.81-2.25) in the COM cohort than in the non-COM cohort. Regarding the joint effect of COM with comorbidity, the ESRD risk was 1.57-fold higher (95% CI: 1.23-2.00) for the COM cohort without comorbidities and increased to 2.25 (95% CI: 1.97-2.57) for the COM cohort with at least 1 comorbidity. Age-specific analysis revealed that the adjusted ESRD risk for the COM cohort increased as age decreased, with the highest hazard ratio being 17.8 (95% CI: 5.18-61.4) for patients aged 20-34 years.This was the first study to report that COM is associated with an increased risk of ESRD, particularly among patients with comorbidities and younger patients.


[Modified Rives technic in the treatment of recurrent inguinal hernia].
After the introduction of prosthetic material in hernia surgery the fundamental changes in operative strategy occurred. This is because the coverage of myopectineal orifitium with non-absorbable prosthesis decreases the incidence of recurrences. Because of the appearance of lateral re-recurrences after the classical Rives procedure, we modified the operative technique. The modified Rives technique consists of the following: always polypropilen mesh 15x10 cm; creation of the new internal inguinal ring between Poupart's ligament and mesh; no lateral notching the mesh and anchoring mesh 2-3 cm from the medial, inferior, lateral and superior edge. During the period January 2001-December 2003, 34 cases of recurrent hernias were operated on 7th dept. of I Surgical Clinic of CCS. The recurrences were managed by classical (10/34) or modified Rives technique through direct inguinal approach (22/34), less frequently Lichtenstein procedure (1/34) and McVay (1/34) technique. Among 10 patients with recurrent inguinal hernias managed by classical Rives technique 2 re-recurrences appeared (indirect and interstitial) and 2 cases of infection (immediately after the operation or 7 months after the operation), and in the group of 22 cases with recurrent inguinal hernias managed by modified Rives technique the aim complications didn't appear. Using the modified Rives technique we managed the primary hernias in 56 cases without recurrences and infections. The modified Rives technique, because of the way of mesh fixation (all around), no lateral notching of mesh and remaining hem in all directions secures abdominal wall protection 2-3 cm from the line of fixation and prevents any movement of the mesh. This procedure enables management of all inguinal hernias regardless to their size and full protection of the medial, femoral and lateral inguinal triangle. The modified Rives technique is the technique of choice for big multiple defects (giant inguino-scrotal and re-recurrences), especially among patients with increased intra-abdominal pressure when other techniques may be insufficient because of mesh protrusion.


CXCL16/CXCR6 Axis Drives Microglia/Macrophages Phenotype in Physiological Conditions and Plays a Crucial Role in Glioma.
Microglia are patrolling cells that sense changes in the brain microenvironment and respond acquiring distinct phenotypes that can be either beneficial or detrimental for brain homeostasis. Anti-inflammatory microglia release soluble factors that might promote brain repair; however, in glioma, anti-inflammatory microglia dampen immune response and promote a brain microenvironment that foster tumor growth and invasion. The chemokine CXCL16 is expressed in the brain, where it is neuroprotective against brain ischemia, and it has been found to be over-expressed in glioblastoma (GBM). Considering that CXCL16 specific receptor CXCR6 is diffusely expressed in the brain including in microglia cells, we wanted to investigate the role of CXCL16 in the modulation of microglia cell activity and phenotype, and in the progression of glioma. Here we report that CXCL16 drives microglia polarization toward an anti-inflammatory phenotype, also restraining microglia polarization toward an inflammatory phenotype upon LPS and IFNγ stimulation. In the context of glioma, we demonstrate that CXCL16 released by tumor cells is determinant in promoting glioma associated microglia/macrophages (GAMs) modulation toward an anti-inflammatory/pro-tumor phenotype, and that cxcr6ko mice, orthotopically implanted into the brain with GL261 glioma cells,survive longer compared to wild-type mice. We also describe that CXCL16/CXCR6 signaling acts directly on mouse glioma cells, as well as human primary GBM cells, promoting tumor cell growth, migration and invasion. All together these data suggest that CXCL16 signaling could represent a good target to modulate microglia phenotype in order to restrain inflammation or to limit glioma progression.


Significance of Aspergillus niger aggregate species as contaminants of food products in Spain regarding their occurrence and their ability to produce mycotoxins.
The Aspergillus niger aggregate contains 15 morphologically indistinguishable species which presence is related to ochratoxin A (OTA) and fumonisin B2 (FB2) contamination of foodstuffs. The taxonomy of this group was recently reevaluated and there is a need of new studies regarding the risk that these species might pose to food security. 258 isolates of A. niger aggregate obtained from a variety of products from Spain were classified by molecular methods being A. tubingensis the most frequently occurring (67.5%) followed by A. welwitschiae (19.4%) and A. niger (11.7%). Their potential ability to produce mycotoxins was evaluated by PCR protocols which allow a rapid detection of OTA and FB2 biosynthetic genes in their genomes. OTA production is not widespread in A. niger aggregate since only 17% of A. niger and 6% of A. welwitschiae isolates presented the complete biosynthetic cluster whereas the lack of the cluster was confirmed in all A. tubingensis isolates. On the other hand, A. niger and A. welwitschiae seem to be important FB2 producers with 97% and 29% of the isolates, respectively, presenting the complete cluster. The genes involved in OTA and FB2 were overexpressed in producing isolates and their expression was related to mycotoxin synthesis.


Development and validation of a liquid chromatography-tandem mass spectrometry method for the determination of xanthinol in human plasma and its application in a bioequivalence study of xanthinol nicotinate tablets.
A sensitive, rapid liquid chromatographic-electrospray ionization mass spectrometric method for the determination of xanthinol in human plasma was developed and validated. Xanthinol nicotinate in plasma (0.5 mL) was pretreated with 20% trichloroacetic acid for protein precipitation. The samples were separated using a Lichrospher silica (5 microm, 250 mm x 4.6 mm i.d.). A mobile phase of methanol-water containing 0.1% formic acid (50: 50, v/v) was used isocratically eluting at a flow rate of 1 mL/min. Xanthinol and its internal standard (IS), acyclovir, were measured by electrospray ion source in positive selected reaction monitoring mode. The method demonstrated that good linearity ranged from 10.27 to 1642.8 ng/mL with r=0.9956. The limit of quantification for xanthinol in plasma was 10.27 ng/mL with good accuracy and precision. The mean plasma extraction recovery of xanthinol was in the range of 90.9-100.2%. The intra- and inter-batch variability values were less than 4.8% and 7.9% (relative standard deviation, R.S.D.), respectively. The established method has been successfully applied to a bioequivalence study of two xanthinol nicotinate tablets for 20 healthy volunteers.


Art and multiple personality disorder: an expressive framework for occupational therapy.
Patients with multiple personality and dissociative disorders have learned to create an alternate identity system, originally designed to protect them from experiencing the pain of inescapable, unrelieved trauma and abuse. The resulting amnesia and identity confusion cause significant dysfunction in daily living. Issues of trust and control are paramount, and occupational therapists are challenged with the task of engaging these patients in meaningful activity. Although these patients often avoid structured groups, they have generally been responsive to expressive art opportunities as an initial activity. This paper outlines an expressive framework by which occupational therapists can therapeutically manage the artwork behaviors of the patient with dissociative or multiple personality disorder. The material presented is based on clinical observation of more than a dozen patients with multiple personality disorder in various stages of recovery and of many persons with dissociative trauma who may have multiple personality disorder. These observations took place within an acute care, inpatient occupational therapy setting. Guidelines for the creation of a positive working alliance and therapeutic climate for self-expression are outlined, and a progressive model for the viewing of patients' art products is described.


The serotonin hypothesis of (auto)aggression. Critical appraisal of the evidence.
Based on the relation found to exist between low CSF 5-HIAA and suicide attempt, in particular violent suicide attempt, both in depressed and in so-called nondepressed suicide attempters, the conclusion was drawn that decreased central 5-HT metabolism is related to (auto)aggression, rather than to depression. We challenged this conclusion and that for three reasons: Violent suicide attempt accumulates in certain types of depression making it impossible to conclude whether the biological variable relates to (auto)aggression or to that type of depression as such. Nondepressed suicide attempter is a diagnosis that should be based on presuicidal not on postsuicidal data, in order to avoid false-positive diagnoses. Suicide method is not a reliable index of seriousness of the attempt. Risk/rescue ratio should be used instead. Next the data are discussed that do support the hypothesis that diminished 5-HT metabolism in the brain is related to disregulation of aggression. Finally, the hypothesis is launched that both mood and aggression disorders are related to decreased 5-HT metabolism in the CNS. This would provide a biological explanation for the clinical observation that disorders in mood and in aggression often go hand in hand. Biological research of psychiatric disorders gains in informative value as the psychopathological analysis of the phenomena one studies is more comprehensive. Biological suicide research is no exception to this rule.


How I manage ibrutinib intolerance and complications in patients with chronic lymphocytic leukemia.
Chronic lymphocytic leukemia (CLL) therapy has changed dramatically with the introduction of several targeted therapeutics. Ibrutinib was the first approved for use in 2014 and now is used for initial and salvage therapy of CLL patients. With its widespread use in clinical practice, ibrutinib's common and uncommon adverse events reported less frequently in earlier clinical trials have been experienced more frequently in real-world practice. In particular, atrial fibrillation, bleeding, infections, and arthralgias have been reported. The management of ibrutinib's adverse events often cannot be generalized but must be individualized to the patient and their long-term risk of additional complications. When ibrutinib was initially developed, there were limited therapeutic alternatives for CLL, which often resulted in treating through the adverse events. At the present time, there are several effective alternative agents available, so transition to an alternative CLL directed therapy may be considered. Given the continued expansion of ibrutinib across many therapeutic areas, investigation of the pathogenesis of adverse events with this agent and also clinical trials examining therapeutic approaches for complications arising during therapy are needed. Herein, we provide strategies we use in real-world CLL clinical practice to address common adverse events associated with ibrutinib.


Impact of selection regime and introgression on deltamethrin resistance in the arbovirus vector Aedes aegypti - a comparative study between contrasted situations in New Caledonia and French Guiana.
Pyrethroid insecticides such as deltamethrin have been massively used against Aedes aegypti leading to the spread of resistance alleles worldwide. In an insecticide resistance management context, we evaluated the temporal dynamics of deltamethrin resistance using two distinct populations carrying resistant alleles at different frequencies. Three different scenarios were followed: a continuous selection, a full release of selection, or a repeated introgression with susceptible individuals. The responses of each population to these selection regimes were measured across five generations by bioassays and by monitoring the frequency of knockdown resistance (kdr) mutations and the transcription levels and copy number variations of key detoxification enzymes. Knockdown resistance mutations, overexpression and copy number variations of detoxification enzymes as a mechanism of metabolic resistance to deltamethrin was found and maintained under selection across generations. On comparison, the release of insecticide pressure for five generations did not affect resistance levels and resistance marker frequencies. However, introgressing susceptible alleles drastically reduced deltamethrin resistance in only three generations. The present study confirmed that strategies consisting to stop deltamethrin spraying are likely to fail when the frequencies of resistant alleles are too high and the fitness cost associated to resistance is low. In dead-end situations like in French Guiana where alternative insecticides are not available, alternative control strategies may provide a high benefit for vector control, particularly if they favor the introgression of susceptible alleles in natural populations. © 2021 Society of Chemical Industry.


Ibrutinib inhibits SDF1/CXCR4 mediated migration in AML.
Pharmacological targeting of BTK using ibrutinib has recently shown encouraging clinical activity in a range of lymphoid malignancies. Recently we reported that ibrutinib inhibits human acute myeloid leukemia (AML) blast proliferation and leukemic cell adhesion to the surrounding bone marrow stroma cells. Here we report that in human AML ibrutinib, in addition, functions to inhibit SDF1/CXCR4-mediated AML migration at concentrations achievable in vivo. It has previously been shown that SDF1/CXCR4-induced migration is dependent on activation of downstream BTK in chronic lymphocytic leukaemia (CLL) and multiple myeloma. Here we show that SDF-1 induces BTK phosphorylation and downstream MAPK signalling in primary AML blast. Furthermore, we show that ibrutinib can inhibit SDF1-induced AKT and MAPK activation. These results reported here provide a molecular mechanistic rationale for clinically evaluating BTK inhibition in AML patients and suggests that in some AML patients the blasts count may initially rise in response to ibrutinib therapy, analgous to similar clinical observations in CLL.


Dual recognition of the bacterial chemoreceptor by chemotaxis-specific domains of the CheR methyltransferase.
Adaptation to persisting stimulation is required for highly sensitive detection of temporal changes of stimuli, and often involves covalent modification of receptors. Therefore, it is of vital importance to understand how a receptor and its cognate modifying enzyme(s) modulate each other through specific protein-protein interactions. In the chemotaxis of Escherichia coli, adaptation requires methylation of chemoreceptors (e.g. Tar) catalyzed by the CheR methyltransferase. CheR binds to the C-terminal NWETF sequence of a chemoreceptor that is distinct from the methylation sites. However, little is known about how CheR recognizes its methylation sites or how it is distributed in a cell. In this study, we used comparative genomics to demonstrate that the CheR chemotaxis methyltransferase contains three structurally and functionally distinct modules: (i) the catalytic domain common to a methyltransferase superfamily; (ii) the N-terminal domain; and (iii) the beta-subdomain of the catalytic domain, both of which are found exclusively in chemotaxis methyltransferases. The only evolutionary conserved motif specific to CheR is the positively charged face of helix alpha2 in the N-terminal domain. The disulfide cross-linking analysis suggested that this face interacts with the methylation helix of Tar. We also demonstrated that CheR localizes to receptor clusters at cell poles via interaction of the beta-subdomain with the NWETF sequence. Thus, the two chemotaxis-specific modules of CheR interact with distinct regions of the chemoreceptor for targeting to the receptor cluster and for recognition of the substrate sites, respectively.


Signatures of the d^{*}(2380) Hexaquark in d(γ,pn[over →]).
We report a measurement of the spin polarization of the recoiling neutron in deuterium photodisintegration, utilizing a new large acceptance polarimeter within the Crystal Ball at MAMI. The measured photon energy range of 300-700 MeV provides the first measurement of recoil neutron polarization at photon energies where the quark substructure of the deuteron plays a role, thereby providing important new constraints on photodisintegration mechanisms. A very high neutron polarization in a narrow structure centered around E_{γ}∼570 MeV is observed, which is inconsistent with current theoretical predictions employing nucleon resonance degrees of freedom. A Legendre polynomial decomposition suggests this behavior could be related to the excitation of the d^{*}(2380) hexaquark.


Continuous opioid therapy (COT) is rarely advisable for refractory chronic daily headache: limited efficacy, risks, and proposed guidelines.
Intractable pain, headache or otherwise, is a devastating and life-controlling experience. The need to effectively and aggressively control pain is a fundamental tenet of clinical care. In the past several years, increasing advocacy for continuous opioid therapy has become an important, if not controversial, theme in the development of treatment guidelines and teaching programs. Ironically, the increasing willingness of physicians to prescribe scheduled opioids for their headache and pain patients has occurred in the absence of compelling data demonstrating efficacy or long-term safety. To the contrary, two meta-analyses on chronic noncancer pain (CNCP) and one long-term uncontrolled study on headache patients demonstrate a relatively small number of patients benefiting from the treatment. Recent neuroscience data on the effects of opioids on the brain raise serious concern for long-term safety and also provide the basis for the mechanism by which chronic opioid use might induce progression of headache frequency and severity. Significant adverse effects, including influence on sexual hormonal balances, physical and psychological dependence, the development of opioid-induced hyperalgesia, and cardiac arrhythmia and sudden death that can be seen with standard dosages of methadone, make a strong argument against widespread use of continuous opioid therapy (COT) in otherwise healthy young and middle-aged headache patients. We believe that COT should be used in rare circumstances for chronic headache patients, and propose initial guidelines for selecting patients and monitoring treatment. The physician should be well versed in the details of opioid prescribing, administration, and monitoring, and should be prepared to discontinue opioids when clinical justification, patient behavior, or failure to achieve therapeutic goals make discontinuance necessary.


Monitoring of the biological response to murine hindlimb ischemia with 64Cu-labeled vascular endothelial growth factor-121 positron emission tomography.
Vascular endothelial growth factor-121 (VEGF121), an angiogenic protein secreted in response to hypoxic stress, binds to VEGF receptors (VEGFRs) overexpressed on vessels of ischemic tissue. The purpose of this study was to evaluate 64Cu-VEGF121 positron emission tomography for noninvasive spatial, temporal, and quantitative monitoring of VEGFR2 expression in a murine model of hindlimb ischemia with and without treadmill exercise training. 64Cu-labeled VEGF121 and a VEGF mutant were tested for VEGFR2 binding specificity in cell culture. Mice (n=58) underwent unilateral ligation of the femoral artery, and postoperative tissue ischemia was assessed with laser Doppler imaging. Longitudinal VEGFR2 expression in exercised and nonexercised mice was quantified with 64Cu-VEGF121 positron emission tomography at postoperative day 8, 15, 22, and 29 and correlated with postmortem gamma-counting. Hindlimbs were excised for immunohistochemistry, Western blotting, and microvessel density measurements. Compared with the VEGF mutant, VEGF121 showed specific binding to VEGFR2. Perfusion in ischemic hindlimbs fell to 9% of contralateral hindlimb on postoperative day 1 and recovered to 82% on day 29. 64Cu-VEGF121 uptake in ischemic hindlimbs increased significantly (P < 0.001) from a control level of 0.61+/-0.17% ID/g (percentage of injected dose per gram) to 1.62+/-0.35% ID/g at postoperative day 8, gradually decreased over the following 3 weeks (0.59+/-0.14% ID/g at day 29), and correlated with gamma-counting (R2 = 0.99). Compared with nonexercised mice, 64Cu-VEGF121 uptake was increased significantly (P < or = 0.0001) in exercised mice (at day 15, 22, and 29) and correlated with VEGFR2 levels as obtained by Western blotting (R2 = 0.76). Ischemic hindlimb tissue stained positively for VEGFR2. In exercised mice, microvessel density was increased significantly (P<0.001) compared with nonexercised mice. 64Cu-VEGF121 positron emission tomography allows longitudinal spatial and quantitative monitoring of VEGFR2 expression in murine hindlimb ischemia and indirectly visualizes enhanced angiogenesis stimulated by treadmill exercise training.


Application of acute pre-exercise partial-body cryotherapy promotes jump performance, salivary α-amylase and athlete readiness.
This study aimed to evaluate the application of a single pre-exercise bout of partial-body cryotherapy (PBC) to augment jump performance, salivary biomarkers and self-reported performance readiness. Twelve male rugby union players (age 20.7 ± 3.2 yr; body mass 93.1 ± 13.9 kg; mean ± SD) were exposed to PBC for 3 min at -140°C or control condition prior to a pre-post series of loaded countermovement jumps (CMJ), salivary biomarker samples and performance readiness questionnaires. PBC elicited a moderately greater improvement in CMJ velocity of +4.7 ± 3.5% (mean ± 90% confidence limits) from baseline to 15 min in comparison with a -1.9 ± 4.8% mean difference in the control condition. The mean change in concentration of salivary α-amylase at 15 min was substantially increased by +131 ± 109% after PBC exposure, compared to a -4.2 ± 42% decrease in the control. Salivary testosterone concentrations were unclear at all timepoints in both the PBC and control interventions. Self-reported perceptions of overall performance readiness indicated small to moderate increases in mental fatigue, mood, muscle soreness and overall questionnaire score after PBC compared to control with a higher score more favourable for performance. The application of pre-exercise PBC can elicit favourable outcomes in controlled physical performance tests and holds promise to be applied to training or competition settings.


Parallel human immunodeficiency virus type 1-specific CD8+ T-lymphocyte responses in blood and mucosa during chronic infection.
Gut-associated lymphoid tissue is the major reservoir of lymphocytes and human immunodeficiency virus type 1 (HIV-1) replication in vivo, yet little is known about HIV-1-specific CD8+ T-lymphocyte (CTL) responses in this compartment. Here we assessed the breadth and magnitude of HIV-1-specific CTL in the peripheral blood and sigmoid colon mucosa of infected subjects not on antiretroviral therapy by enzyme-linked immunospot analysis with 53 peptide pools spanning all viral proteins. Comparisons of blood and mucosal CTL revealed that the magnitude of pool-specific responses is correlated within each individual (mean r2 = 0.82 +/- 0.04) and across all individuals (r2 = 0.75; P < 0.001). Overall, 85.1% of screened peptide pools yielded concordant negative or positive results between compartments. CTL targeting was also closely related between blood and mucosa, with Nef being the most highly targeted (mean of 2.4 spot-forming cells [SFC[/10(6) CD8+ T lymphocytes/amino acid [SFC/CD8/aa]), followed by Gag (1.5 SFC/CD8/aa). Finally, comparisons of peptide pool responses seen in both blood and mucosa (concordant positives) versus those seen only in one but not the other (discordant positives) showed that most discordant results were likely an artifact of responses being near the limit of detection. Overall, these results indicate that HIV-1-specific CTL responses in the blood mirror those seen in the mucosal compartment in natural chronic infection. For protective or immunotherapeutic vaccination, it will be important to determine whether immunity is elicited in the mucosa, which is a key site of initial infection and subsequent HIV-1 replication in vivo.


[The role of bemitil pharmacokinetics in realizing its therapeutic efficacy].
The pharmacokinetics of a new psychotropic drug bemithil was studied after single and long-term administrations under monotherapy and in combination with phenazepam in patients with asthenoneurotic disturbances. A high degree of correlation for some pharmacokinetic parameters of bemithil following the administration of the drug test dose and its global therapeutic effect was established.


Human pulmonary macrophages. Functional comparison of cells obtained from whole lung and by bronchoalveolar lavage.
Previous studies have demonstrated that pulmonary macrophages (PM) recovered from bronchoalveolar lavage (BAL) are relatively poor accessory cells for antigen-induced T-lymphocyte proliferation. These studies have suggested that the immune function of macrophages obtained by BAL is representative of the majority of PM. We compared macrophages obtained by BAL with PM from whole lung minces (MIN) for their ability to stimulate T-lymphocyte proliferation. Both populations of PM had similar expression of HLA-DR antigen and were of comparable maturity as determined by staining for MO2 antigen. Production of interleukin 1 by both groups of PM was similar and was significantly less than that produced by monocytes (p less than 0.05). Both populations of PM functioned poorly as antigen-presenting cells when compared with monocytes (p less than 0.05). However, PM from MIN stimulated a mixed leukocyte reaction significantly more (p less than 0.05) than did PM from BAL. Our data suggest that whereas BAL obtains a population of PM with an immunologic function that is largely similar to PM obtained from whole lung, some differences in function may exist.


The Role of Nitrogen Donors in Zinc Catalysts for Lactide Ring-Opening Polymerization.
The electronic effects of nitrogen donors in zinc catalysts for ring-opening polymerization of cyclic esters were investigated. Alkyl and benzyloxy zinc complexes supported by tridentate diamino- and aminoimino phenolate ligands were synthesized, and their solid-state and solution structures characterized. The solution-state structures showed that the alkyl complexes are mononuclear, while the alkoxy complexes are dimeric with the ligands coordinated with different denticities depending on the nature of the ligand donors. The catalytic activities of these compounds toward the ring-opening polymerization of racemic lactide were studied and showed that catalysts with secondary and imine nitrogen donors are more active than analogues with tertiary amines.


DNA damage and transcriptional changes in the gills of mytilus galloprovincialis exposed to nanomolar doses of combined metal salts (Cd, Cu, Hg).
Aiming at an integrated and mechanistic view of the early biological effects of selected metals in the marine sentinel organism Mytilus galloprovincialis, we exposed mussels for 48 hours to 50, 100 and 200 nM solutions of equimolar Cd, Cu and Hg salts and measured cytological and molecular biomarkers in parallel. Focusing on the mussel gills, first target of toxic water contaminants and actively proliferating tissue, we detected significant dose-related increases of cells with micronuclei and other nuclear abnormalities in the treated mussels, with differences in the bioconcentration of the three metals determined in the mussel flesh by atomic absorption spectrometry. Gene expression profiles, determined in the same individual gills in parallel, revealed some transcriptional changes at the 50 nM dose, and substantial increases of differentially expressed genes at the 100 and 200 nM doses, with roughly similar amounts of up- and down-regulated genes. The functional annotation of gill transcripts with consistent expression trends and significantly altered at least in one dose point disclosed the complexity of the induced cell response. The most evident transcriptional changes concerned protein synthesis and turnover, ion homeostasis, cell cycle regulation and apoptosis, and intracellular trafficking (transcript sequences denoting heat shock proteins, metal binding thioneins, sequestosome 1 and proteasome subunits, and GADD45 exemplify up-regulated genes while transcript sequences denoting actin, tubulins and the apoptosis inhibitor 1 exemplify down-regulated genes). Overall, nanomolar doses of co-occurring free metal ions have induced significant structural and functional changes in the mussel gills: the intensity of response to the stimulus measured in laboratory supports the additional validation of molecular markers of metal exposure to be used in Mussel Watch programs.


Field of view in monocentric multiscale cameras.
Conventionally, the field of view of a camera is understood as the angular extent of a convex circular or rectangular region. Parallel camera architectures with computational image stitching, however, allow implementation of a field of view with an arbitrary shape. Monocentric multiscale lenses further allow the implementation of an arbitrary field of view in camera volumes comparable to conventional single-lens systems. In contrast with conventional wide-field-of-view systems, multiscale design can also achieve nearly uniform resolution across the entire field of view. This paper presents several design studies obtaining unconventional fields of view using this approach.


Retrovirus antigens in brains of mice with scrapie- and murine leukemia virus-induced spongiform encephalopathy.
Wild mouse ecotropic virus-induced spongiform encephalomyelopathy pathologically similar to scrapie was associated with the expression of retrovirus antigens in mouse brains. However, scrapie-infected mice with spongiform encephalopathy showed no increased expression of retrovirus antigens in brain. Thus, the pathogenesis of the scrapie spongiform lesion does not appear to involve activation of endogenous retrovirus.


A noisy spring: the impact of globally rising underwater sound levels on fish.
The underwater environment is filled with biotic and abiotic sounds, many of which can be important for the survival and reproduction of fish. Over the last century, human activities in and near the water have increasingly added artificial sounds to this environment. Very loud sounds of relatively short exposure, such as those produced during pile driving, can harm nearby fish. However, more moderate underwater noises of longer duration, such as those produced by vessels, could potentially impact much larger areas, and involve much larger numbers of fish. Here we call attention to the urgent need to study the role of sound in the lives of fish and to develop a better understanding of the ecological impact of anthropogenic noise.


Management of Sporadic Renal Angiomyolipomas: A Systematic Review of Available Evidence to Guide Recommendations from the European Association of Urology Renal Cell Carcinoma Guidelines Panel.
Little is known about the natural history of sporadic angiomyolipomas (AMLs); there is uncertainty regarding the indications of treatment and treatment options. To evaluate the indications, effectiveness, harms, and follow-up of different management modalities for sporadic AML to provide guidance for clinical practice. A systematic review of the literature was undertaken, incorporating Medline, Embase, and the Cochrane Library (from 1 January 1990 to 30 June 2017), in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. No restriction on study design was imposed. Patients with sporadic AML were included. The main interventions included active surveillance, surgery (nephron-sparing surgery and radical nephrectomy), selective arterial embolisation, and percutaneous or laparoscopic thermal ablations (radiofrequency, microwaves, or cryoablation). The outcomes included indications for active treatment, AML growth rate, AML recurrence rate, risk of bleeding, post-treatment renal function, adverse events of treatments, and modalities of follow-up. Risk of bias assessment was performed using standard Cochrane methods. Among 2704 articles identified, 43 were eligible for inclusion (zero randomised controlled trials, nine nonrandomised comparative retrospective studies, and 34 single-arm case series). Most studies were retrospective and uncontrolled, and had a moderate to high risk of bias. In active surveillance series, spontaneous bleeding was reported in 2% of patients and active treatment was undertaken in 5%. Active surveillance is the most chosen option in 48% of the cases, followed by surgery in 31% and selective arterial embolisation in 17% of the cases. Selective arterial embolisation appeared to reduce AML volume but required secondary treatment in 30% of the cases. Surgery (particularly nephron-sparing surgery) was the most effective treatment in terms of recurrence and need for secondary procedures. Thermal ablation was an infrequent option. The association between AML size and the risk of bleeding remained unclear; as such the traditional 4-cm cut-off should not per se trigger active treatment. In spite of the limitations and uncertainties relating to the evidence base, the findings may be used to guide and inform clinical practice, until more robust data emerge. Sporadic angiomyolipoma (AML) is a benign tumour of the kidney consisting of a mixture of blood vessels, fat, and muscle. Large tumours may have a risk of spontaneous bleeding. However, the size beyond which these tumours need to be treated remains unclear. Most small AMLs can be monitored without any active treatment. For those who need treatment, options include surgical removal of the tumour or stopping its blood supply (selective embolisation). Surgery has a lower recurrence rate and lower need for a repeat surgical procedure.


Examining the sustainability and effectiveness of co-created physical activity interventions in vocational education and training: a multimethod evaluation.
Co-creation approaches are increasingly used in physical activity promotion to develop interventions tailored to the target group and setting. The resulting complexity of such interventions raises challenges in evaluation. Accordingly, little is known about the effectiveness of co-created interventions and the underlying processes that impact their sustainable implementation. In this study, we attempt to fill this gap by evaluating co-created multi-component physical activity interventions in vocational education and training in nursing care and automotive mechatronics regarding (1) their sustainable implementation at the institutional level and (2) the effectiveness of single intervention components at the individual level. Following a multimethod design, we conducted a questionnaire survey (n = 7) and semi-structured interviews (n = 4) to evaluate the sustainability of the interventions. Quantitative data were analyzed descriptively, and qualitative data were analyzed using qualitative content analysis. To examine the interventions' effectiveness, we conducted two non-randomized controlled trials (n = 111). Analysis of variance was used to examine differences between groups. At the institutional level, long-term implementation of single intervention components in nursing care was observed; in contrast, long-term implementation in automotive mechatronics was not observed. In this context, various factors at the outer contextual (e.g., COVID-19 pandemic), inner contextual (e.g., health-promoting leadership), intervention (e.g., acceptance), and personal levels (e.g., champion) influenced sustainability. At the individual level, no significant intervention effects were found for changes in physical activity behavior and physical activity-related health competence. The role of co-creation on the effectiveness and sustainability of physical activity promotion in vocational education and training cannot be answered conclusively. Only in the nursing care sector, a co-creation approach appeared promising for long-term intervention implementation. Sustainable implementation depends on various influencing factors that should be considered from the outset. Demonstrating effectiveness at the individual level was challenging. To conclusively clarify both the role and impact of co-creation, methodologically complex and elaborate evaluation designs will be required in future research projects. This study was retrospectively registered at clinicaltrials.gov on 24/08/2021 ( NCT05018559 ).


Primary pulmonary artery sarcoma.
A 66-year-old woman with a history of mitral valve replacement with a Starr-Edwards ball valve 25 years ago was treated for refractory heart failure but died of right heart failure. At autopsy, primary pulmonary artery sarcoma was found in the right ventricular outflow tract, main pulmonary trunk, and bilateral pulmonary artery, and had invaded the aortic arch. The pathohistologic diagnosis was osteosarcoma. Echocardiography, chest computed tomography and right ventriculography performed 1 year before death did not reveal the presence of a tumor in the pulmonary artery. The history of this patient shows that primary pulmonary artery sarcoma grows rapidly, with, in this case, the patient dying within 1 year of its appearance.


Sex Hormone-Binding Globulin Reduction in Metabolic Disorders May Play a Role in NAFLD Development.
Low plasma sex hormone-binding globulin (SHBG) levels are a hallmark in chronic metabolic diseases, including nonalcoholic fatty liver disease (NAFLD), which represents a spectrum of disease ranging from hepatocellular steatosis through steatohepatitis to fibrosis and irreversible cirrhosis. The functional link between altered SHBG production and NAFLD development and progression remains unclear. We investigated the effects of overexpressing human SHBG in 2 mouse models of NAFLD: a genetically induced double transgenic mouse and a diet-induced model. Remarkably, SHBG overexpression in both NAFLD models significantly reduced liver fat accumulation by reducing key lipogenic enzymes. These findings were corroborated by modulating SHBG expression and by adding exogenous SHBG in HepG2 cells, suggesting the cell autonomous nature of the mechanism. Mechanistically, exogenous SHBG treatment downregulated key lipogenic enzymes by reducing PPARγ messenger RNA and protein levels through activation of extracellular signal-regulated kinase-1/2 mitogen-activated protein kinase pathway. Taking together, we found that SHBG modulates hepatic lipogenesis. This is of importance because reduction of SHBG plasma levels in obese and type 2 diabetic subjects could be directly associated with NAFLD development through an increase in hepatic lipogenesis. Our results point to SHBG as a therapeutic target for preventing or arresting NAFLD development.


Regulation of purine metabolism by plasma membrane and cytoplasmic 5'-nucleotidases.
The contribution of plasma membrane 5'-nucleotidase (E.C. 18.104.22.168) to intracellular purine degradation and release was evaluated in cultured human lymphoblasts. B-lymphoblasts and T-lymphoblasts are characterized by high and low levels of plasma membrane 5'-nucleotidase activity, respectively. After radiolabeling of the cellular adenine nucleotide pools with [8-14C]adenine, deoxyglucose-induced purine nucleotide degradation resulted in a 2-2.5 times greater release of cellular radioactivity from the B-lymphoblasts than from the T-lymphoblasts. Specific inhibition of plasma membrane 5'-nucleotidase with 50 microM alpha, beta-methylene adenosine diphosphate (AMPCP) did not decrease purine release during deoxyglucose-induced nucleotide degradation. Similarly, the inhibition of B-lymphoblast membrane 5-nucleotidase did not alter the incorporation of [8-14C]adenine into the nucleotide pool. Therefore, to explain the relatively high release of purine nucleotide degradation products in B-lymphoblasts when compared with T-lymphoblasts, cytoplasmic 5'-nucleotidase activity was investigated in these cell lines. B-lymphoblasts have seven times more cytoplasmic 5'-nucleotidase activity for dAMP and two to three times more activity for other purine nucleoside 5'-monophosphates than do T-lymphoblasts at pH 7.4. Membrane and cytoplasmic nucleotidase activities are produced by different enzymes that can be distinguished by differences in pH optima, Michaelis constants for purine substrates, divalent cation requirements, and susceptibilities to AMPCP inhibition. The data suggest that plasma membrane 5'-nucleotidase hydrolyzes extracellular nucleoside 5'-monophosphates only. Cytoplasmic 5'-nucleotidase most likely regulates the degradation of intracellular nucleoside 5'-monophosphates and may be responsible for the increased purine release observed in B-lymphoblasts.