Wall Contrast Enhancement of Thrombosed Intracranial Aneurysms at 7T MRI.
The pathophysiology of wall contrast enhancement in thrombosed intracranial aneurysms is incompletely understood. This in vivo study aimed to investigate wall microstructures with gadolinium-enhanced 7T MR imaging. Thirteen patients with 14 thrombosed intracranial aneurysms were evaluated using a 7T whole-body MR imaging system with nonenhanced and gadolinium-enhanced high-resolution MPRAGE. Tissue samples were available in 5 cases, and histopathologic findings were correlated with 7T MR imaging to identify the gadolinium-enhancing microstructures. Partial or complete inner wall enhancement correlated with neovascularization of the inner wall layer and the adjacent thrombus. Additional partial or complete outer wall enhancement can be explained by formation of vasa vasorum in the outer aneurysm wall layer. The double-rim enhancement correlated with perifocal edema and wall histologic findings suggestive of instability. Two distinct aneurysm wall microstructures responsible for gadolinium enhancement not depictable at lower spatial resolutions can be visualized in vivo using high-resolution gadolinium-enhanced 7T MR imaging.


Iron transporters in rat mammary gland: effects of different stages of lactation and maternal iron status.
Mechanisms regulating iron transfer from maternal circulation into milk are yet unknown. Whether intestinal iron transporters, divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1), are present in the mammary gland and are involved in iron transfer into milk are unknown. The objective was to examine DMT1 and FPN1 in rat mammary gland at different stages of lactation and to evaluate the effects of maternal iron status. Rats were fed either 35 mg Fe (control rats) or 8 mg Fe (low-iron rats) per kg diet for 3 wk and were fed the same diet throughout pregnancy and lactation. Mammary gland DMT1, FPN1, transferrin receptor, and ferritin were examined in control rats on days 1, 5, 10, and 20 of lactation and in low-iron rats on days 10 and 20 of lactation. Tissue and milk iron were measured. Milk iron, DMT1, and FPN1 decreased throughout lactation. Iron status was compromised in low-iron rats, whereas milk iron was maintained. On day 10 of lactation, mammary gland iron and ferritin were lower in the low-iron rats. DMT1, FPN1, and transferrin receptor values were unchanged; however, a smaller-size DMT1 protein was observed in the low-iron rats. On day 20, transferrin receptor increased in the low-iron rats, whereas mammary gland iron, ferritin, DMT1, and FPN1 were unchanged. The results show that DMT1 and FPN1 concentrations are higher during early lactation and are possibly involved in iron transfer into milk. Mammary gland regulation of DMT and FPN1 during low iron status appears to be different from that in the intestine.


Mediterranean Diet and Motivation in Sport: A Comparative Study Between University Students from Spain and Romania.
The Mediterranean Diet (MD) is one of the healthiest dietary models worldwide, being an essential mean of preventing pathologies along with the practice of physical activity. Through a comparative study carried out across different countries, it has been demonstrated how this type of habits vary depending on the geographical context. The aim of this research was to evaluate the adherence to MD and its relationships with motivational climate in sport on a sample of university students from Spain and Romania; Methods: A cross-sectional study was conducted on a sample of university students [specialization: Physical Education (n = 605; 20.71 ± 2.42 years old)], using as main instruments the Mediterranean Diet Quality Index (KIDMED) for students and adolescents and the Perceived Motivational Climate in Sport Questionnaire-2 (PMCSQ-2); Results: It was shown that students from Spain had a high adherence to the MD (6.65 ± 2.63 vs. 5.06 ± 1.31). Spanish university students got higher scores in task-oriented motivational climate (4.03 ± 0.62 vs. 3.11 ± 0.55) while ego-oriented climate was higher in university students from Romania (3.24 ± 0.54 vs. 2.07 ± 0.75). Finally, it was observed that the task-oriented motivational climate was related to a lower adherence to MD in Spanish students (4.49 ± 0.37 vs. 3.98 ± 0.62). In contrast, in Romanian youth, a medium adherence to the MD was associated with higher scores for the ego-oriented motivational climate (3.27 ± 0.53 vs. 3.00 ± 0.54); Conclusions: As main conclusions, it was shown that the students from Spain had a high adherence to the MD. In addition, it has been demonstrated that ego-oriented climates are linked to a better adherence to MD, especially due to the importance of following a proper diet in sport contexts, as demonstrated by young Romanians.


Personal utility in genomic testing: is there such a thing?
In ethical and regulatory discussions on new applications of genomic testing technologies, the notion of 'personal utility' has been mentioned repeatedly. It has been used to justify direct access to commercially offered genomic testing or feedback of individual research results to research or biobank participants. Sometimes research participants or consumers claim a right to genomic information with an appeal to personal utility. As of yet, no systematic account of the umbrella notion of personal utility has been given. This paper offers a definition of personal utility that places it in the middle of the spectrum between clinical utility and personal perceptions of utility, and that acknowledges its normative charge. The paper discusses two perspectives on personal utility, the healthcare perspective and the consumer perspective, and argues that these are too narrow and too wide, respectively. Instead, it proposes a normative definition of personal utility that postulates information and potential use as necessary conditions of utility. This definition entails that perceived utility does not equal personal utility, and that expert judgment may be necessary to help determine whether a genomic test can have personal utility for someone. Two examples of genomic tests are presented to illustrate the discrepancies between perceived utility and our proposed definition of personal utility. The paper concludes that while there is room for the notion of personal utility in the ethical evaluation and regulation of genomic tests, the justificatory role of personal utility is not unlimited. For in the absence of clinical validity and reasonable potential use of information, there is no personal utility.


Phagocytosis of boar spermatozoa in vitro and in vivo.
For successful conception, fertilization-competent spermatozoa must be present at the site of fertilization in adequate numbers until ovulation has taken place. In pigs, a large volume of semen is delivered into the uterus. Most, if not all, of the inseminated liquid is voided from the vulva within a few hours after insemination and approximately 45% of the spermatozoa are lost. Large numbers of spermatozoa are also lost due to phagocytosis by polymorphonuclear leukocytes (PMNs). In pigs, the recruitment of PMNs to the uterine lumen appears to be triggered by insemination of a volume of liquid, rather than by specific components of that liquid or by spermatozoa or seminal plasma. However, persistence of large numbers of PMNs in the uterine lumen at > 12 h after insemination appears to depend on the presence of spermatozoa in the inseminate. In vitro studies have indicated that damaged, killed or capacitated spermatozoa are not phagocytosed preferentially, but that capacitation treatment strongly reduced phagocytosis of spermatozoa. Recent studies have also shown that PMN recruitment and phagocytosis of spermatozoa in vivo can be reduced by addition of caffeine plus CaCl2 to the inseminate, which appeared to have positive consequences for the longer term availability of spermatozoa at the site of fertilization.


Gut feedback mechanisms and food intake: a physiological approach to slow carbohydrate bioavailability.
Glycemic carbohydrates in foods are an important macronutrient providing the biological fuel of glucose for a variety of physiological processes. A classification of glycemic carbohydrates into rapidly digestible carbohydrate (RDC) and slowly digestible carbohydrate (SDC) has been used to specify their nutritional quality related to glucose homeostasis that is essential to normal functioning of the brain and critical to life. Although there have been many studies and reviews on slowly digestible starch (SDS) and SDC, the mechanisms of their slow digestion and absorption were mostly investigated from the material side without considering the physiological processes of their in vivo digestion, absorption, and most importantly interactions with other food components and the gastrointestinal tract. In this article, the physiological processes modulating the bioavailability of carbohydrates, specifically the rate and extent of their digestion and absorption as well as the related locations, in a whole food context, will be discussed by focusing on the activities of the gastrointestinal tract including glycolytic enzymes and glucose release, sugar sensing, gut hormones, and neurohormonal negative feedback mechanisms. It is hoped that a deep understanding of these physiological processes will facilitate the development of innovative dietary approaches to achieve desired carbohydrate or glucose bioavailability for improved health.


Developing junior doctor-delivered teaching.
There are increasing opportunities for junior doctors to deliver teaching as well as formally develop teaching skills. Near-peer teaching (NPT) programmes, like that established in South-East Scotland, not only provide additional learning opportunities for students but also have potential benefits for the teachers. Achieving the multiple competencies required of both the medical school and the foundation programme poses significant challenges. Medical students have reduced exposure to bedside teaching, which may be contributing to the concerns raised regarding the clinical skills of recently graduated junior doctors. NPT increases the pool of tutors available to students, helps facilitate both practical and small group teaching and has other advantages, such as peer tutors being more approachable than senior staff. The NPT programme in South-East Scotland was devised by a group of junior doctors keen to improve, expand and formalise NPT. It started in 2006 as one NPT programme, with 73 tutorials delivered by 18 tutors. Last year across four NPT programmes, 324 tutorials were delivered by 108 tutors, with all tutors receiving formal tutor training. In this article we describe the South-East Scotland model, and offer guidance for those interested in setting up similar programmes elsewhere. NPT, delivered by trained junior doctors, is now well established in every hospital in South-East Scotland. Our NPT model facilitates evidence-based teaching by junior doctors, is popular amongst both junior doctors and students, is sustainable and can be used as a practical example for how to generate NPT programmes elsewhere.


[The style of leadership idealized by nurses].
This study focuses on nursing leadership on the basis of Grid theories. According to the authors, these theories are an alternative that allows for leadership development in nursing. The research aimed to identify and analyze the style of leadership idealized by nurses, according to their own view, and to compare the styles of leadership idealized by nurses between the two research institutions. Study subjects were 13 nurses. The results show that nurses at both institutions equally mention they idealize style 9.9, followed by 5.5 and 1.9, with a tendency to reject styles 9.1 and 1.1.


A diastrophic dysplasia sulfate transporter (SLC26A2) mutant mouse: morphological and biochemical characterization of the resulting chondrodysplasia phenotype.
Mutations in the diastrophic dysplasia sulfate transporter (DTDST or SLC26A2) cause a family of recessively inherited chondrodysplasias including, in order of decreasing severity, achondrogenesis 1B, atelosteogenesis 2, diastrophic dysplasia (DTD) and recessive multiple epiphyseal dysplasia. The gene encodes a widely distributed sulfate/chloride antiporter of the cell membrane whose function is crucial for the uptake of inorganic sulfate, which is needed for proteoglycan sulfation. To provide new insights in the pathogenetic mechanisms leading to skeletal and connective tissue dysplasia and to obtain an in vivo model for therapeutic approaches to DTD, we generated a Dtdst knock-in mouse with a partial loss of function of the sulfate transporter. In addition, the intronic neomycine cassette in the mutant allele contributed to the hypomorphic phenotype by inducing abnormal splicing. Homozygous mutant mice were characterized by growth retardation, skeletal dysplasia and joint contractures, thereby recapitulating essential aspects of the DTD phenotype in man. The skeletal phenotype included reduced toluidine blue staining of cartilage, chondrocytes of irregular size, delay in the formation of the secondary ossification center and osteoporosis of long bones. Impaired sulfate uptake was demonstrated in chondrocytes, osteoblasts and fibroblasts. In spite of the generalized nature of the sulfate uptake defect, significant proteoglycan undersulfation was detected only in cartilage. Chondrocyte proliferation and apoptosis studies suggested that reduced proliferation and/or lack of terminal chondrocyte differentiation might contribute to reduced bone growth. The similarity with human DTD makes this mouse strain a useful model to explore pathogenetic and therapeutic aspects of DTDST-related disorders.


[Ileocoecal intussusception of the terminal ileum caused by a carcinoid tumor].
Intussusception of the intestine is a frequent reason for intestinal obstruction in infants; the course is acute but the causes are often not recognizable. In adults intussusception is the cause for bowel obstruction in only 1% of cases. The course is subacute and in over 90% a benign or malignant process in this part of the intestine is found. We report the case of a 45-year-old male with abdominal discomfort, increasing over weeks. The preoperative ultrasonography and computed tomography of the abdomen revealed the typical finding of ileocoecal intussusception. An ileocoecal resection was performed. The histopathological workup showed a small carcinoid tumour of the terminal ileum.


Increase in mucociliary clearance in normal man induced by oral high frequency oscillation.
Data on the effect on mucociliary clearance of oral high frequency oscillation is conflicting. By means of a technique to superimpose high frequency oscillation on tidal breathing, changes in mucociliary clearance during high frequency oscillation were studied in seven normal non-smokers by monitoring the clearance of inhaled radiolabelled aerosol from the lungs. After inhalation of 5 microns technetium 99m labelled particles under controlled conditions, whole lung clearance was monitored by scintillation counters half hourly for six hours with a final count at 24 hours, from which tracheobronchial deposition and clearance could be calculated. Control and high frequency oscillation studies were performed on separate days in random order. Oral high frequency oscillation was applied by a bass loudspeaker through a mouthpiece to superimpose sinewave oscillations (RMS input pressure 1.2 cm H2O, mean pressure zero) on normal breaths. On high frequency oscillation days 30 minutes of oscillation alternated with 30 min of rest. Between 3 and 4.5 hours mucociliary clearance with high frequency oscillation exceeded control by about 10% (p less than 0.05). The mean time taken to eliminate 90% of deposited radioaerosol from the tracheobronchial tree fell from 4 hours 50 minutes (range 1 h 52 min-6 h 50 min) during control to 3 hours 43 minutes (range 2 hr 28 min-5 hr 54 min) during the high frequency oscillation run (p less than 0.05). Possibly this comfortable, simple technique would be of therapeutic benefit to patients with chronic sputum retention and merits further investigation.


Solitary cystic cerebellar metastasis in a patient with invasive transitional cell carcinoma of the bladder.
Transitional cell carcinoma of the bladder (TCC) represents nearly 90% of genitourinary malignancies and typically presents with locally invasive symptoms. Metastasis to the central nervous system (CNS) is uncommon occurring in <5% of patients. When present, metastatic lesions are typically solid, isolated and located in the cerebrum. We report a case of a patient with a history of TCC who presented with lethargy and ataxia and was found to have a solitary cystic cerebellar lesion consistent with metastatic disease. Unfortunately, the prognosis for patients with TCC and CNS metastases is poor. Treatment options include debulking surgery, whole brain radiation, stereotactic radiosurgery and chemotherapy. Unfortunately, treatment may not appreciably extend survival and care is often supportive in previously reported cases. Though uncommon, TCC can metastasise to the CNS and should be considered in the differential diagnosis of patients, particularly those who were treated with aggressive surgery or combination chemotherapy previously.


Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders.
Autism Spectrum Disorders (ASD) and Schizophrenia (SCZ) are cognitive disorders with complex genetic architectures but overlapping behavioral phenotypes, which suggests common pathway perturbations. Multiple lines of evidence implicate imbalances in excitatory and inhibitory activity (E/I imbalance) as a shared pathophysiological mechanism. Thus, understanding the molecular underpinnings of E/I imbalance may provide essential insight into the etiology of these disorders and may uncover novel targets for future drug discovery. Here, we review key genetic, physiological, neuropathological, functional, and pathway studies that suggest alterations to excitatory/inhibitory circuits are keys to ASD and SCZ pathogenesis.


Environmental exposure to xylenes in drivers and petrol station workers by urinary methylhippuric Acid.
The aims of this study were evaluation of exposed to xylenes in low concentration and compare urinary level of methyl hippuric acid in taxi drivers and petrol stations workers in West of Iran. This observation study was carried out on samples of the exposed men to xylenes in two occupational groups in Hamadan City (west of Iran) from March 2003 to March 2004. Subjects included 45 taxi drivers and 25 petrol station workers. The study group was selected from 54 workers at petrol stations and 300 drivers by simple random sampling. Xylenes was analyzed using gas chromatography equipped with a Flame Ionization Detector (FID). The urinary methyl hippuric acid (MHA) was analyzed with High performance Liquid Chromatography (HPLC) equipped with an ultraviolet (UV) detector. Total xylene exposure was 1.05±0.55 ppm (mean±SD) with a range of 0.20-2.55 ppm that was about 4 times more than taxi drivers' exposure. The poor correlation coefficient was seen between xylenes concentration and urinary MHA for drivers (r2= 0.09 to 0.42) but significant associations were noted between urinary MHA and xylene in the breathing zone of petrol station workers (r2= 0.69 to 0.77; P< 0.05). High xylenes levels are emitted in petrol stations at Iran. Urinary MHA level has a poor correlation with exposure to xylenes in drivers but has good correlation in petrol station workers.


[Star fruit as a cause of acute kidney injury].
The star fruit belongs to the family Oxalidacea, species Averrhoa carambola. It is rich in minerals, vitamin A, C, B complex vitamins and oxalic acid. Recent studies show that the toxicity of the fruit differs between the patients and may be explained by single biological responses, age, and the intake quantity of the neurotoxin in each fruit in addition to glomerular filtration rate given by each patient. Additionally, the nephrotoxicity caused by the fruit is dose-dependent and may lead to the deposition of crystals of calcium oxalate intratubular, as well as by direct injury to the renal tubular epithelium, leading to apoptosis of the same. We report the case of a patient who after ingestion of the juice and fresh fruit, developed acute renal failure requiring dialysis, evolving with favourable outcome and recovery of renal function.


Antioxidative effects of 6-methoxysorigenin and its derivatives from Rhamnus nakaharai.
In the search for potential antioxidants, the naphthalenic compounds, 6-methoxysorigenin (2) and its glycosides [i.e. 6-methoxysorigenin-8-O-glucoside (3), alpha-sorinin (4), and 6-methoxysorigenin-8-rutinoside (5)] isolated from Rhamnus nakaharai together with two acylates (peracetate and perpropionate) of 2 were evaluated for antioxidant activities using 2,2-diphenyl-1-picrylhydrazyl (DPPH), metal chelating, and electron spin resonance (ESR) assays as well as anti-lipid peroxidation assay. The results showed that 2 possesses the most potent DPPH radical scavenging, metal chelating, and anti-lipid peroxidation activities with IC50 values of 3.48, 615.90, and 5.95 microg/ml, respectively. The glycosides 3, 4, and 5 showed decreasing antioxidant activity that was related to an increased substitution at 1,8-dihydroxyl with sugar molecules. This suggests the importance of 1,8-dihydroxyl of 2 in the antioxidative effect. The iron chelation result could further explain the main cause of increasing antioxidant activity in 2. The acylates of 2 (2a peracetate and 2b perpropionate), although lacking a free hydroxyl, also exhibited significant anti-lipid peroxidation effect. ESR results further demonstrated that 2 possesses strong antioxidant activities. Taken together, this study shows that 2 is a potent antioxidant and may also be used for designing new iron chelators for clinical applications.


Cytomegalovirus reactivation after matched sibling donor reduced-intensity conditioning allogeneic hematopoietic stem cell transplant correlates with donor killer immunoglobulin-like receptor genotype.
Cytomegalovirus reactivation is common after reduced-intensity conditioning allogeneic hematopoietic stem cell transplant. Natural killer and T cells mediate immunity against viruses including cytomegalovirus. The alloreactivity of natural killer cells and some T-cell subsets is mediated through the interaction of their killer immunoglobulin-like receptors with target cell ligands. This study sought to assess whether donor inhibitory or activating killer immunoglobulin-like receptor genotypes may influence post-transplant cytomegalovirus reactivation in transplant recipients. We analyzed 64 patients who underwent T-cell replete, matched sibling donor reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation at our institution. Transplant recipients were categorized according to their HLA inhibitory killer immunoglobulin-like receptor ligand groups. Donor killer immunoglobulin-like receptor genotypes were determined and then were assessed for correlations with cytomegalovirus reactivation in transplant recipients. No differences in cytomegalovirus reactivation were observed when comparing those with or without missing inhibitory killer immunoglobulin-like receptor ligands. When considering the number of donor activating killer immunoglobulin-like receptor genes, those with 5 or 6 had less cytomegalovirus reactivation than those with 1 to 4 (19% vs 48%; P = .029). The difference could not be attributed to baseline patient or transplant characteristics. No specific activating killer immunoglobulin-like receptor genotype was found to be associated with cytomegalovirus reactivation. These observations indicate that assessment of donor killer immunoglobulin-like receptor genotype may have important implications for predicting cytomegalovirus reactivation after T-cell replete, matched sibling donor reduced intensity conditioning allogeneic hematopoietic stem cell transplant.


[Co60 gamma-ray sensitivity of a series of strains of Saccharomyces cerevisiae yeasts bearing different mutations. I. Radiosensitivity of haploid strains].
Sensitivity to gamma-rays Co60 of haploid strains of Saccharomyces cerevisiae carrying ade1-6 mutations and dominant, semidoninant and recessive suppressors was investigated. It was shown that 3 out of 4 studied strains with ade1-6 mutation had reliable increased radioresistance. The increased radioresistance was observed also in strains carrying, beside ade1-6 mutation, dominant and semidominant suppressors. However the strain carrying a recessive suppressive mutation turned to be radiosensitive. A conclusion is drawn that rediosensitivity of yeast cells can be influenced by different mutations affecting the process of cell metabolism.


The effect of boron supplementation on its urinary excretion and selected cardiovascular risk factors in healthy male subjects.
Boron (B) is an essential trace element for plants and its interrelationship with mineral and bone metabolism and endocrine function in humans has been proposed. Relatively little is known about the occurrence of B in the food chain and hence a biomarker which reflects its intake is required. Two studies were carried out to quantify the urinary B concentration of subjects consuming their habitual diet and the effect of supplementation. In addition, the effect of supplementation on plasma lipoprotein cholesterol concentrations and susceptibility to oxidation and plasma steroid hormones were determined. Boron excretion, obtained on two different occasions from 18 healthy male subjects, was found to be in the range 0.35-3.53 mg/day, with no significant difference between the two occasions. Supplementation with 10 mg B/d for 4 wk resulted in 84% of the supplemented dose being recovered in the urine. Plasma estradiol concentrations increased significantly as a result of supplementation (51.9 +/- 21.4 to 73.9 +/- 22.2 pmol/L; p < 0.004) and there was a trend for plasma testosterone levels to be increased. However, there was no difference in plasma lipids or the oxidizability of low-density lipoprotein. Our studies suggest that the absorption efficiency of B is very high and estimation of the urinary B concentration may provide a useful reflection of B intake. In addition, the elevation of endogenous estrogen as a result of supplementation suggests a protective role for B in atherosclerosis.


Safety and clinical outcome of erythropoiesis-stimulating agents in patients with ST-elevation myocardial infarction: a meta-analysis of individual patient data.
Erythropoiesis-stimulating agents (ESAs) have been investigated in small studies in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Erythropoiesis-stimulating agents did not show a clear effect on left ventricular function or clinical outcome, but some studies suggested an increased risk of thromboembolic events. A systematic literature search in MEDLINE was performed, until December 2012. We included randomized clinical trials investigating the effect of ESAs in STEMI patients undergoing primary PCI, with ≥30 days of follow-up. The primary end point was a composite of all-cause mortality, myocardial infarction, and stent thrombosis after PCI. Secondary end point was all-cause mortality. Individual patient data were obtained from 10 of 11 trials, including 97.3% (1,242/1,277) of all patients randomized to control (n = 600) or to ESAs (n = 642). Baseline characteristics were well balanced between the treatment allocations. Mean follow-up time was 248 (±131) days. The primary end point occurred in 3.5% (20/577) in the control group and in 2.1% (13/610) in the ESA group (hazard ratio for ESAs, 0.63; 95% CI [0.31-1.27]; P = .20). Mortality occurred in 13 (2.3%) in the control group and 5 (0.8%) in the ESA group (hazard ratio for ESAs, 0.38; 95% CI [0.13-1.06]; P = .06). Erythropoiesis-stimulating agent administration does not result in an increased risk of adverse cardiac events in STEMI patients undergoing primary PCI. Results of ongoing studies may provide further insight to the potential beneficial clinical effects of ESAs in STEMI patients.


APCs present A beta(k)-derived peptides that are autoantigenic to type B T cells.
Type B T cells recognize peptide provided exogenously but are ignorant of the same epitope derived from intracellular processing. In this study, we demonstrate the existence of type B T cells to an abundant autologous peptide derived from processing of the I-A(k) beta-chain. T cell hybridomas raised against this peptide fail to recognize syngeneic APC despite abundant presentation of the naturally processed epitope but react in a dose-dependent manner to exogenous peptide. Moreover, these hybridomas respond to Abeta(k) peptide extracted from the surface of I-A(k)-expressing APC. This peptide was isolated from B cell lines where it was found in high abundance; it was also present in lines lacking HLA-DM, but in considerably lower amounts. Therefore, type B T cells exist in the naive repertoire to abundant autologous peptides. We discuss the implications of these findings to the potential biological role of type B T cells in immune responses and autoimmune pathology.


Comparing biological motion perception in two distinct human societies.
Cross cultural studies have played a pivotal role in elucidating the extent to which behavioral and mental characteristics depend on specific environmental influences. Surprisingly, little field research has been carried out on a fundamentally important perceptual ability, namely the perception of biological motion. In this report, we present details of studies carried out with the help of volunteers from the Mundurucu indigene, a group of people native to Amazonian territories in Brazil. We employed standard biological motion perception tasks inspired by over 30 years of laboratory research, in which observers attempt to decipher the walking direction of point-light (PL) humans and animals. Do our effortless skills at perceiving biological activity from PL animations, as revealed in laboratory settings, generalize to people who have never before seen representational depictions of human and animal activity? The results of our studies provide a clear answer to this important, previously unanswered question. Mundurucu observers readily perceived the coherent, global shape depicted in PL walkers, and experienced the classic inversion effects that are typically found when such stimuli are turned upside down. In addition, their performance was in accord with important recent findings in the literature, in the abundant ease with which they extracted direction information from local motion invariants alone. We conclude that the effortless, veridical perception of PL biological motion is a spontaneous and universal perceptual ability, occurring both inside and outside traditional laboratory environments.


Psychology of addictive behaviors.
Having served as Associate Editor of Psychology of Addictive Behaviors (PAB) with three distinguished editors, Dr. Nancy Petry, Dr. Stephen Maisto, and Dr. Howard Shaffer, the author learned from the very best how to work with authors and reviewers to publish cutting-edge papers that will have a strong and sustained impact on the field. The author is grateful for their mentoring and the opportunity to apply what she has learned as Interim Editor of PAB, albeit under the untimely circumstances of Dr. Petry's death from cancer in July 2018. The author is to continue Dr. Petry's vision of PAB as one of the few journals to cover the full range of addictions, including behavioral addictions such as gambling, excessive Internet use, online gaming, and food addiction. An upcoming special issue of PAB, edited by Dr. Catherine Stanger and Dr. John Roll, will honor the broad and lasting impact of Dr. Petry's research program in multiple areas in the field of addiction: contingency management, behavioral economics, and gambling behavior, to name just a few. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


An alternative to sutures.
Cyanoacrylate tissue adhesives are used in numerous settings to close wounds without the use of sutures. The product and its use for closing chest tube wounds is discussed.


Positive Psychological Wellbeing Is Required for Online Self-Help Acceptance and Commitment Therapy for Chronic Pain to be Effective.
The web-based delivery of psychosocial interventions is a promising treatment modality for people suffering from chronic pain, and other forms of physical and mental illness. Despite the promising findings of first studies, patients may vary in the benefits they draw from self-managing a full-blown web-based psychosocial treatment. We lack knowledge on moderators and predictors of change during web-based interventions that explain for whom web-based interventions are especially (in)effective. In this study, we primarily explored for which chronic pain patients web-based Acceptance and Commitment Therapy (ACT) was (in)effective during a large three-armed randomized controlled trial. Besides standard demographic, physical and psychosocial factors we focused on positive mental health. Data from 238 heterogeneously diagnosed chronic pain sufferers from the general Dutch population following either web-based ACT (n = 82), or one of two control conditions [web-based Expressive Writing (EW; n = 79) and Waiting List (WL; n = 77)] were analysed. ACT and EW both consisted of nine modules and lasted nine to 12 weeks. Exploratory linear regression analyses were performed using the PROCESS macro in SPSS. Pain interference at 3-month follow-up was predicted from baseline moderator (characteristics that influence the outcome of specific treatments in comparison to other treatments) and predictor (characteristics that influence outcome regardless of treatment) variables. The results showed that none of the demographic or physical characteristics moderated ACT treatment changes compared to both control conditions. The only significant moderator of change compared to both EW and WL was baseline psychological wellbeing, and pain intensity was a moderator of change compared to EW. Furthermore, higher pain interference, depression and anxiety, and also lower levels of emotional well-being predicted higher pain interference in daily life 6 months later. These results suggest that web-based self-help ACT may not be allocated to chronic pain sufferers experiencing low levels of mental resilience resources such as self-acceptance, goals in life, and environmental mastery. Other subgroups are identified that potentially need specific tailoring of (web-based) ACT. Emotional and psychological wellbeing should receive much more attention in subsequent studies on chronic pain and illness.


Comparative Effectiveness of Targeted vs Empirical Antibiotic Prophylaxis to Prevent Sepsis from Transrectal Prostate Biopsy: A Retrospective Analysis.
We compared the effectiveness of targeted prophylaxis to the effectiveness of empirical prophylaxis for preventing sepsis after transrectal prostate biopsy using a retrospective multicenter quality improvement study. A total of 13 Kaiser Permanente urology departments participated in a 1-year retrospective analysis of a quality improvement study. In the targeted prophylaxis group rectal cultures were performed before transrectal prostate biopsy and antibiotic sensitivities of Escherichia coli were used to guide the selection of a single agent antibiotic for prophylaxis. Cultures were plated on 10 μg/ml ciprofloxacin infused MacConkey agar at a central laboratory. Urologists using empirical prophylaxis continued the usual regimen of ciprofloxacin monotherapy prophylaxis but sometimes added an additional prophylactic antibiotic. The primary outcome of post-biopsy sepsis was compiled by a search of the electronic medical record for the appropriate ICD-9 codes. A total of 5,355 prostate biopsy procedures were performed between May 1, 2013 and April 30, 2014. Targeted prophylaxis was used in 1,802 procedures (34%) and empirical prophylaxis was used in 3,553 (66%). The overall incidence of post-biopsy sepsis was 0.52% (28 of 5,355 cases). The incidence of sepsis was 0.44% (8 of 1,802 cases) in the targeted prophylaxis group and 0.56% (20 of 3,553) in the empirical prophylaxis group (p = 0.568). The prevalence of ciprofloxacin resistant E. coli on rectal culture was 25% (444 of 1,802 cases). Seven of the 8 patients (88%) on targeted prophylaxis in whom sepsis developed used a prophylactic antibiotic to which the bacteria causing post-biopsy sepsis were sensitive. The targeted prophylaxis protocol enabled physicians to avoid using more than 1 broad-spectrum empirical antibiotic while simultaneously achieving an overall rate of sepsis similar to the rate seen with empirical prophylaxis.


Mitochondrial dysfunction links ceramide activated HRK expression and cell death.
Cell death is an essential process in normal development and homeostasis. In eyes, corneal epithelial injury leads to the death of cells in underlying stroma, an event believed to initiate corneal wound healing. The molecular basis of wound induced corneal stromal cell death is not understood in detail. Studies of others have indicated that ceramide may play significant role in stromal cell death following LASIK surgery. We have undertaken the present study to investigate the mechanism of death induced by C6 ceramide in cultures of human corneal stromal (HCSF) fibroblasts. Cultures of HCSF were established from freshly excised corneas. Cell death was induced in low passage (p<4) cultures of HCSF by treating the cells with C6 ceramide or C6 dihydroceramide as a control. Cell death was assessed by Live/Dead cell staining with calcein AM and ethidium homodimer-1 as well as Annexin V staining, caspase activation and TUNEL staining Mitochondrial dysfunction was assessed by Mito Sox Red, JC-1 and cytochrome C release Gene expression was examined by qPCR and western blotting. Our data demonstrate ceramide caused mitochondrial dysfunction as evident from reduced MTT staining, cyto c release from mitochondria, enhanced generation of ROS, and loss in mitochondrial membrane potential (ΔΨm). Cell death was evident from Live -Dead Cell staining and the inability to reestablish cultures from detached cells. Ceramide induced the expression of the harikari gene(HRK) and up-regulated JNK phosphorylation. In ceramide treated cells HRK was translocated to mitochondria, where it was found to interact with mitochondrial protein p32. The data also demonstrated HRK, p32 and BAD interaction. Ceramide-induced expression of HRK, mitochondrial dysfunction and cell death were reduced by HRK knockdown with HRK siRNA. Our data document that ceramide is capable of inducing death of corneal stromal fibroblasts through the induction of HRK mediated mitochondria dysfunction.


Anti-Porphyromonas gingivalis and anti-inflammatory activities of A-type cranberry proanthocyanidins.
A-type cranberry proanthocyanidins (AC-PACs) have recently been reported to be beneficial for human health, especially urinary tract health. The effect of these proanthocyanidins on periodontitis, a destructive disease of tooth-supporting tissues, needs to be investigated. The purpose of this study was to investigate the effects of AC-PACs on various virulence determinants of Porphyromonas gingivalis as well as on the inflammatory response of oral epithelial cells stimulated by this periodontopathogen. We examined the effects of AC-PACs on P. gingivalis growth and biofilm formation, adherence to human oral epithelial cells and protein-coated surfaces, collagenase activity, and invasiveness. We also tested the ability of AC-PACs to modulate the P. gingivalis-induced inflammatory response by human oral epithelial cells. Our results showed that while AC-PACs neutralized all the virulence properties of P. gingivalis in a dose-dependent fashion, they did not interfere with growth. They also inhibited the secretion of interleukin-8 (IL-8) and chemokine (C-C motif) ligand 5 (CCL5) but did not affect the secretion of IL-6 by epithelial cells stimulated with P. gingivalis. This anti-inflammatory effect was associated with reduced activation of the nuclear factor-kappaB (NF-kappaB) p65 pathway. AC-PACs may be potentially valuable bioactive molecules for the development of new strategies to treat and prevent P. gingivalis-associated periodontal diseases.


Fear in a Handful of Dust: The Epidemiological, Environmental, and Economic Drivers of Death by PM2.5 Pollution.
This study evaluates numerous epidemiological, environmental, and economic factors affecting morbidity and mortality from PM2.5 exposure in the 27 member states of the European Union. This form of air pollution inflicts considerable social and economic damage in addition to loss of life and well-being. This study creates and deploys a comprehensive data pipeline. The first step consists of conventional linear models and supervised machine learning alternatives. Those regression methods do more than predict health outcomes in the EU-27 and relate those predictions to independent variables. Linear regression and its machine learning equivalents also inform unsupervised machine learning methods such as clustering and manifold learning. Lower-dimension manifolds of this dataset's feature space reveal the relationship among EU-27 countries and their success (or failure) in managing PM2.5 morbidity and mortality. Principal component analysis informs further interpretation of variables along economic and health-based lines. A nonlinear environmental Kuznets curve may describe the fuller relationship between economic activity and premature death from PM2.5 exposure. The European Union should bridge the historical, cultural, and economic gaps that impair these countries' collective response to PM2.5 pollution.


Do men regret prostate biopsy: Results from the PiCTure study.
Understanding men's experience of prostate biopsy is important as the procedure is common, invasive and carries potential risks. The psychological aspects of prostate biopsy have been somewhat neglected. The aim of this study was to explore the level of regret experienced by men after prostate biopsy and identify any associated factors. Men attending four clinics in Republic of Ireland and two in Northern Ireland were given a questionnaire to explore their experience of prostate biopsy. Regret was measured on a Likert scale asking men how much they agreed with the statement "It [the biopsy] is something I regret." Three hundred thirty-five men responded to the survey. The mean age was 63 years (SD ±7 years). Three quarters of respondents (76%) were married or co-habiting, and (75%) finished education at primary or secondary school level. For just over two thirds of men (70%) their recent biopsy represented their first ever prostate biopsy. Approximately one third of men reported a diagnosis of cancer, one third a negative biopsy result, and the remaining third did not know their result. Two thirds of men reported intermediate or high health anxiety. 5.1% of men agreed or strongly agreed that they regretted the biopsy. Level of regret was low overall. Health anxiety was the only significant predictor of regret, with men with higher anxiety reporting higher levels of regret than men with low anxiety (OR = 3.04, 95% CI 1.58, 5.84). Men with high health anxiety may especially benefit from careful counselling before and after prostate biopsy.


Characterization of the African Swine Fever Virus Decapping Enzyme during Infection.
African swine fever virus (ASFV) infection is characterized by a progressive decrease in cellular protein synthesis with a concomitant increase in viral protein synthesis, though the mechanism by which the virus achieves this is still unknown. Decrease of cellular mRNA is observed during ASFV infection, suggesting that inhibition of cellular proteins is due to an active mRNA degradation process. ASFV carries a gene (Ba71V D250R/Malawi g5R) that encodes a decapping protein (ASFV-DP) that has a Nudix hydrolase motif and decapping activity in vitro Here, we show that ASFV-DP was expressed from early times and accumulated throughout the infection with a subcellular localization typical of the endoplasmic reticulum, colocalizing with the cap structure and interacting with the ribosomal protein L23a. ASFV-DP was capable of interaction with poly(A) RNA in cultured cells, primarily mediated by the N-terminal region of the protein. ASFV-DP also interacted with viral and cellular RNAs in the context of infection, and its overexpression in infected cells resulted in decreased levels of both types of transcripts. This study points to ASFV-DP as a viral decapping enzyme involved in both the degradation of cellular mRNA and the regulation of viral transcripts.IMPORTANCE Virulent ASFV strains cause a highly infectious and lethal disease in domestic pigs for which there is no vaccine. Since 2007, an outbreak in the Caucasus region has spread to Russia, jeopardizing the European pig population and making it essential to deepen knowledge about the virus. Here, we demonstrate that ASFV-DP is a novel RNA-binding protein implicated in the regulation of mRNA metabolism during infection, making it a good target for vaccine development.


Association of V249I and T280M variants of fractalkine receptor CX3CR1 with carotid intima-media thickness in a mexican population with type 2 diabetes.
To evaluate the association of the V249I and T280M variants of CX3CR1 fractalkine gene with carotid intima-media thickness in Mexican subjects with and without type 2 diabetes. We analyzed the V249I and T280M variants of the CX3CR1 receptor by TaqMan assays in 111 subjects with type 2 diabetes and 109 healthy controls. Hemoglobin A1c, glucose, and lipid profile were determined. A significant increase in carotid intima-media thickness was observed in type 2 diabetes patients (0.979 ± 0.361 mm) compared to healthy controls (0.588 ± 0.175 mm). In subjects carrying the MM variant of the T280M polymorphism, hemoglobin A1c was higher (p = 0.008). Classic risk factors for atherosclerosis showed no differences between carriers of the T280M and V249I variants. Controls with the II249 genotype associated with carotid intima-media thickness (0.747 ± 0.192 mm; p = 0.041), and this difference remained significant even after adjusting factors such as age, gender, and body mass index (OR: 7.7; 95% CI: 1.269-47.31; p = 0.027). V249I genotype of the fractalkine receptor showed a protector role in patients with type 2 diabetes. The T280M genotype is associated with increased carotid intima-media thickness in Mexican individuals with or without type 2 diabetes.


A novel glutamate agonist, TAN-950 A, isolated from streptomycetes.
A novel antifungal amino acid antibiotic, TAN-950 A ([S]-2-amino-3-(2,5-dihydro-5-oxo-4-isoxazolyl)propanoic acid), was found to have affinity for three excitatory amino acid (EAA) receptors and to inhibit [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid ([3H]AMPA), [3H]kainate and [3H]3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid ([3H]CPP) binding competitively. It caused excitation of rat hippocampal CA1 neurons in vitro, an effect that was antagonized by an AMPA/kainate antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX). Chemical modification of TAN-950 A brought about a large change in its pharmacological activity. Alkylation at the C-3 position of the isoxazolone ring markedly increased the ability to elicite neuronal firing. This agonistic effect was also antagonized by DNQX. The (R) enantiomer of TAN-950 A had increased selectivity for the N-methyl-D-aspartate (NMDA) receptor subtype. This selectivity was further enhanced by removal of the methylene group from the amino acid moiety. The most potent NMDA agonistic activity was observed with [R]-2-amino-2-(2,5-dihydro-3-methyl-5-oxo-4-isoxazolyl)acetic acid. These derivatives of TAN-950 A might be useful agents for investigating the pharmacological and physiological roles of EAA receptors.


Deficiency of the B cell-activating factor receptor results in limited CD169+ macrophage function during viral infection.
The B cell-activating factor (BAFF) is critical for B cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFF receptor (BAFFR)-deficient mice, we characterized BAFFR-related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). We identified a critical role for BAFFR signaling in the generation and maintenance of the CD169(+) macrophage compartment. Consequently, Baffr(-) (/) (-) mice exhibited limited induction of innate type I interferon production after viral infection. Lack of BAFFR signaling reduced virus amplification and presentation following viral infection, resulting in highly reduced antiviral adaptive immune responses. As a consequence, BAFFR-deficient mice showed exacerbated and fatal disease after viral infection. Mechanistically, transient lack of B cells in Baffr(-) (/) (-) animals resulted in limited lymphotoxin expression, which is critical for maintenance of CD169(+) cells. In conclusion, BAFFR signaling affects both innate and adaptive immune activation during viral infections. Viruses cause acute and chronic infections in humans resulting in millions of deaths every year. Innate immunity is critical for the outcome of a viral infection. Innate type I interferon production can limit viral replication, while adaptive immune priming by innate immune cells induces pathogen-specific immunity with long-term protection. Here, we show that BAFFR deficiency not only perturbed B cells, but also resulted in limited CD169(+) macrophages. These macrophages are critical in amplifying viral particles to trigger type I interferon production and initiate adaptive immune priming. Consequently, BAFFR deficiency resulted in reduced enforced viral replication, limited type I interferon production, and reduced adaptive immunity compared to BAFFR-competent controls. As a result, BAFFR-deficient mice were predisposed to fatal viral infections. Thus, BAFFR expression is critical for innate immune activation and antiviral immunity.


[Job satisfaction among Norwegian doctors].
Doctors' job satisfaction has been discussed internationally in recent years based on reports of increasing professional dissatisfaction. We have studied Norwegian doctors' job satisfaction and their general satisfaction with life. A survey was conducted among a representative sample of practicing Norwegian doctors in 2008. The validated 10-item Job Satisfaction Scale was used to assess job satisfaction. 1,072 (65 %) doctors responded. They reported a mean job satisfaction of 5.3 on a scale from 1 (very dissatisfied) to 7 (very satisfied). Job satisfaction increased with increasing age. Private practice specialists reported the highest level of job satisfaction (5.8), and general practitioners reported higher job satisfaction (5.5) than hospital doctors (5.1). Among specialty groups, community doctors scored highest (5.6) and doctors in surgical disciplines lowest (5.0). While long working hours was negatively correlated with job satisfaction, the perception of being professionally updated and having part-time affiliation(s) in addition to a regular job were positively correlated with job satisfaction. 52.9 % of doctors reported a very high general satisfaction. Norwegian doctors have a high level of job satisfaction. Satisfaction with life in general is also high and at least in line with that in the Norwegian population.


Iron in Friedreich Ataxia: A Central Role in the Pathophysiology or an Epiphenomenon?
Friedreich ataxia is a neurodegenerative disease with an autosomal recessive inheritance. In most patients, the disease is caused by the presence of trinucleotide GAA expansions in the first intron of the frataxin gene. These expansions cause the decreased expression of this mitochondrial protein. Many evidences indicate that frataxin deficiency causes the deregulation of cellular iron homeostasis. In this review, we will discuss several hypotheses proposed for frataxin function, their caveats, and how they could provide an explanation for the deregulation of iron homeostasis found in frataxin-deficient cells. We will also focus on the potential mechanisms causing cellular dysfunction in Friedreich Ataxia and on the potential use of the iron chelator deferiprone as a therapeutic agent for this disease.


Deep-learning in situ classification of HIV-1 virion morphology.
Transmission electron microscopy (TEM) has a multitude of uses in biomedical imaging due to its ability to discern ultrastructure morphology at the nanometer scale. Through its ability to directly visualize virus particles, TEM has for several decades been an invaluable tool in the virologist's toolbox. As applied to HIV-1 research, TEM is critical to evaluate activities of inhibitors that block the maturation and morphogenesis steps of the virus lifecycle. However, both the preparation and analysis of TEM micrographs requires time consuming manual labor. Through the dedicated use of computer vision frameworks and machine learning techniques, we have developed a convolutional neural network backbone of a two-stage Region Based Convolutional Neural Network (RCNN) capable of identifying, segmenting and classifying HIV-1 virions at different stages of maturation and morphogenesis. Our results outperformed common RCNN backbones, achieving 80.0% mean Average Precision on a diverse set of micrographs comprising different experimental samples and magnifications. We expect that this tool will be of interest to a broad range of researchers.


Nucleophosmin mutations in Chinese adults with acute myelogenous leukemia.
Recently, mutations in the nucleophosmin (NPM1) gene were detected in 50-60% of adult acute myelogenous leukemia (AML) patients, mainly with a normal karyotype. In this study, we detected typical NPM1 mutations (types A, B, D) in untreated Chinese AML patients using real-time quantitative polymerase chain reaction (RQ-PCR) followed by sequence analysis. The detection rate of NPM1 mutations in 220 AML patients was 16.4%, including 107 (14.2%) with the French-American-British (FAB) subtype M2, 43 (2.3%) with M3, and 52 (30.8%) with M4/M5. Only one case each with an NPM1 mutation was detected in four M0, seven M1, five M6, and two M7 cases. Eight patients were followed up after treatment, and five patients in hematologic remission continued to test negative for NPM1 mutations within 2-14 months of follow-up. Sequence analysis revealed that all the 36 positive cases were heterozygous for the mutation with 4-bp insertions at nt 959; the 36 cases included 29 (80.6%) cases with type A, four (11.1%) cases with type B, and one rare DD-3 mutation. We also detected two new mutations, namely, CTCG and CAAG insertions, named BJ-01 and BJ-02, respectively. Further, 38.9% (14/36) patients with NPM1 mutations simultaneously exhibited internal tandem duplications in the FLT3 gene, and 66.7% (22/33) patients did not express CD34. The results demonstrated that RQ-PCR was a reliable and sensitive method for detecting NPM1 mutations, for screening AML, and for the quantitative analysis of minimal residual diseases.


β-Cyclodextrin-based hollow nanoparticles with excellent adsorption performance towards organic and inorganic pollutants.
In this work, β-cyclodextrin (β-CD) based hollow nanoparticles (denoted as β-CDHN) with abundant active sites and high specific surface area were first fabricated via a facile one-step method. The β-CDHN presented a maximum adsorption capacity of 2080.35, 427.35 and 120.48 mg g-1 towards the cationic dye methylene blue (MB), heavy metal ions (Pb2+) and bisphenol A (BPA), respectively, much higher than those of many other adsorbents. Furthermore, β-CDHN also exhibited fast adsorption kinetics towards these pollutants with adsorption rate constants 6 to 200 times higher than those of activated carbon and other β-CD-based adsorbents, meaning the former can remove these pollutants at a much faster adsorption rate than the latter adsorbents. More importantly, the removal efficiency of these pollutants on β-CDHN almost remained stable after 10 regeneration cycles with favorable recyclability. The prepared β-CDHN show great potential in practical applications due to their low costs and high efficiency in the treatment of organic and inorganic pollutants from wastewater.


Social information changes stress hormone receptor expression in the songbird brain.
Social information is used by many vertebrate taxa to inform decision-making, including resource-mediated movements, yet the mechanisms whereby social information is integrated physiologically to affect such decisions remain unknown. Social information is known to influence the physiological response to food reduction in captive songbirds. Red crossbills (Loxia curvirostra) that were food reduced for several days showed significant elevations in circulating corticosterone (a "stress" hormone often responsive to food limitation) only if their neighbors were similarly food restricted. Physiological responses to glucocorticoid hormones are enacted through two receptors that may be expressed differentially in target tissues. Therefore, we investigated the influence of social information on the expression of the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA in captive red crossbill brains. Although the role of MR and GR in the response to social information may be highly complex, we specifically predicted social information from food-restricted individuals would reduce MR and GR expression in two brain regions known to regulate hypothalamic-pituitary-adrenal (HPA) activity - given that reduced receptor expression may lessen the efficacy of negative feedback and release inhibitory tone on the HPA. Our results support these predictions - offering one potential mechanism whereby social cues could increase or sustain HPA-activity during stress. The data further suggest different mechanisms by which metabolic stress versus social information influence HPA activity and behavioral outcomes.


Structure-based in silico identification of ubiquitin-binding domains provides insights into the ALIX-V:ubiquitin complex and retrovirus budding.
The ubiquitylation signal promotes trafficking of endogenous and retroviral transmembrane proteins. The signal is decoded by a large set of ubiquitin (Ub) receptors that tether Ub-binding domains (UBDs) to the trafficking machinery. We developed a structure-based procedure to scan the protein data bank for hidden UBDs. The screen retrieved many of the known UBDs. Intriguingly, new potential UBDs were identified, including the ALIX-V domain. Pull-down, cross-linking and E3-independent ubiquitylation assays biochemically corroborated the in silico findings. Guided by the output model, we designed mutations at the postulated ALIX-V:Ub interface. Biophysical affinity measurements using microscale-thermophoresis of wild-type and mutant proteins revealed some of the interacting residues of the complex. ALIX-V binds mono-Ub with a K(d) of 119 μM. We show that ALIX-V oligomerizes with a Hill coefficient of 5.4 and IC(50) of 27.6 μM and that mono-Ub induces ALIX-V oligomerization. Moreover, we show that ALIX-V preferentially binds K63 di-Ub compared with mono-Ub and K48 di-Ub. Finally, an in vivo functionality assay demonstrates the significance of ALIX-V:Ub interaction in equine infectious anaemia virus budding. These results not only validate the new procedure, but also demonstrate that ALIX-V directly interacts with Ub in vivo and that this interaction can influence retroviral budding.


Cirrhotic patients in the medical intensive care unit: early prognosis and long-term survival.
To reassess the prognosis of patients with cirrhosis admitted to the intensive care unit. A retrospective study in a medical intensive care unit in a teaching hospital in France. All patients with cirrhosis without previous liver transplantation admitted in the period from 2005 to 2008. None. One hundred thirty-eight patients were studied. Survival rates in the intensive care unit, in hospital, and at 6 months were 59% (95% confidence interval, 50%-67%), 46% (95% confidence interval, 38%-54%), and 38% (95% confidence interval, 30%-47%), respectively. In-hospital survival rates for patients requiring vasopressors, mechanical ventilation, or renal replacement therapy were 20%, 33%, and 31%, respectively. On day 1, independent risk factors for in-hospital mortality were age, albuminemia, international normalized ratio, and the Sequential Organ Failure Assessment score computed after discarding points for hematologic failure (modified Sequential Organ Failure Assessment score). Liver disease severity, assessed using a clinical classification, did not correlate with in-hospital mortality. In patients still alive after 3 days, the only prognostic factor was the modified Sequential Organ Failure Assessment score computed after 3 days. To predict in-hospital mortality, the modified Sequential Organ Failure Assessment score on day 1 had a greater area under the receiver operating characteristic curve (0.84) than the Simplified Acute Physiology Score II (0.78), the Child-Pugh score (0.76), the model for end-stage liver disease score (0.77), or the model for end-stage liver disease-natremia score (0.75). The in-hospital mortality rate with three or four nonhematologic organ failures on day 1 was not >70%, whereas it was 89% with three nonhematologic organ failures after 3 days spent in the intensive care unit. In-hospital survival rate of intensive care unit-admitted cirrhotic patients seemed acceptable, even in patients requiring life-sustaining treatments and/or with multiple organ failure on admission. The most important risk factor for in-hospital mortality was the severity of nonhematologic organ failure, as best assessed after 3 days. A trial of unrestricted intensive care for a few days could be proposed for select critically ill cirrhotic patients.


A novel function of neuroglobin for neuroregeneration in mice after optic nerve injury.
Neuroglobin (Ngb) is a recently discovered heme protein in the vertebrate brain that can bind to oxygen molecules. Mammalian Ngb plays a crucial role in neuroprotection under conditions of oxidative stress. To investigate other potential functions of Ngb, we investigated the mouse retinal Ngb system following optic nerve injury. In the retina of control mice, Ngb immunoreactivity was limited to the retinal ganglion cell (RGC) layer, and this immunoreactivity rapidly decreased to less than 50% of the control level 5 days after optic nerve injury. On the basis of this decrease, we designed in vivo experiments with enhanced expression of Ngb using adult mouse retina. The enhanced expression of Ngb was achieved by injecting chimeric human Ngb protein, which included the cell membrane-penetrating module of fish Ngb. One-day pretreatment with chimeric Ngb increased immunoreactivity levels of Ngb two-fold in mouse RGCs and increased the number of surviving RGCs three-fold by 14 days after optic nerve injury compared with vehicle controls. Furthermore, in the mouse retinas showing enhanced Ngb expression, several regenerating central optic axons exhibited outgrowth and were found to pass through the nerve crush site 14 days after nerve injury. No such regenerating optic axons were observed in the control mouse optic nerve during the same time frame. The data obtained from in vivo experiments strongly indicate that mammalian Ngb has neuroprotective and neuroregenerative properties.


The association of amputations and peripheral artery disease in patients with type 2 diabetes mellitus receiving sodium-glucose cotransporter type-2 inhibitors: real-world study.
The aim of this study was to evaluate the temporal pattern of amputations in patients with type 2 diabetes mellitus (T2DM), the risk of amputations by new and older anti-diabetic drugs (ADDs), and the interplay of peripheral artery disease (PAD) with therapy and amputation risk. Using Centricity Electronic Medical Records from USA, 3 293 983 patients with T2DM were identified: 169 739 received sodium-glucose cotransporter type-2 inhibitors (SGLT-2i; no exposure to incretins); 149 826 received glucagon-like peptide 1 receptor agonists [GLP-1RA, no SGLT-2i or dipeptidyl peptidase-4 inhibitor (DPP-4i) exposure]; 448 225 received DPP-4i (no exposure to GLP-1RA or SGLT-2i); and 1 954 353 received other ADDs. The proportion of incident amputations per 10 000 adults ranged between 4.7 and 6.8 during 2000-08 and significantly increased to 12.3 in 2017. Over 17 211 719 person-years follow-up post T2DM diagnosis, the rates per 1000 person-years of any and lower limb amputations (LLAs) were similar between SGLT-2i and incretins [95% confidence interval (CI) range: 1.06-1.67], and significantly higher in other groups (95% CI range: 1.96-2.29). In propensity score-adjusted pairwise analyses, the risk of LLA was not higher in SGLT-2i vs. GLP1-RA [hazard ratio (HR) (95% CI): 0.88 (0.73, 1.05)], and lower in SGLT-2i vs. DPP-4i/other ADD [HR (95% CI): 0.65 (0.56, 0.75)/0.43 (0.37, 0.49)]. The rate of LLA was similar in patients treated with canagliflozin, empagliflozin, or dapagliflozin. Patients with PAD had more than four-fold higher LLA risk (range of 95% CI of HR: 3.6-6.0). The risk of amputation in patients treated with SGLT-2i and incretins was not higher compared with other ADDs. Pre-existing PAD was the greatest driver of amputation risk.


Comparative genomics of mitochondrial DNA in Drosophila simulans.
The current study compares the nucleotide variation among 22 complete mitochondrial genomes of the three distinct Drosophila simulans haplotypes with intron 1 of the alcohol dehydrogenase-related locus. This is the first study to investigate the sequence variation of multiple complete mitochondrial genomes within distinct mitochondrial haplotypes of a single species. Patterns of variation suggest distinct forces are influencing the evolution of mitochondrial DNA (mtDNA) and autosomal DNA in D. simulans. First, there is little variation within each mtDNA haplotype but strong differentiation among them. In contrast, there is no support for differentiation of the mitochondrial haplotypes at the autosomal locus. Second, there is a significant deficiency of mitochondrial variation in each haplotype relative to the autosomal locus. Third, the ratio of nonsynonymous to synonymous substitutions is not equal in all branches of the well-resolved phylogeny. There is an excess of nonsynonymous substitutions relative to synonymous substitutions within each D. simulans haplotype. This result is similar to that previously observed within the mtDNA of distinct species. A single evolutionary force may be causally linked to the observed patterns of mtDNA variation-a rickettsia-like microorganism, Wolbachia pipientis, which is known to directly influence mitochondrial evolution but have a less direct influence on autosomal loci.


Oscillating modes of driven colloids in overdamped systems.
Microscopic colloidal particles suspended in liquids are a prominent example of an overdamped system where viscous forces dominate over inertial effects. Frequently, colloids are used as sensitive probes, e.g., in biophysical applications from which molecular forces are inferred. The interpretation of such experiments rests on the assumption that, even when the particles are driven, the liquid remains in equilibrium. Here we experimentally demonstrate that this is not valid for particles in viscoelastic fluids. Even at small driving forces, we observe particle oscillations with several tens of seconds. They are attributed to non-equilibrium fluctuations of the fluid being excited by the particle's motion. The oscillatory dynamics is in quantitative agreement with an overdamped Langevin equation with negative friction-memory term being equivalent to a stochastically driven underdamped oscillator. Such oscillatory modes are expected to widen the use of colloids as model systems but must also be considered in colloidal probe experiments.


The neural correlates of fatigue: an exploratory imaginal fatigue provocation study in chronic fatigue syndrome.
Fatigue is the central symptom in chronic fatigue syndrome (CFS) and yet very little is known about its neural correlates. The aim of this study was to explore the functional brain response, using functional magnetic resonance imaging (fMRI), to the imaginal experience of fatigue in CFS patients and controls. We compared the blood oxygen level dependent (BOLD) responses of 12 CFS patients and 11 healthy controls to a novel fatigue provocation procedure designed to mimic real-life situations. A non-fatiguing anxiety-provoking condition was also included to control for the non-specific effects of negative affect. During the provocation of fatigue, CFS patients reported feelings of both fatigue and anxiety and, compared to controls, they showed increased activation in the occipito-parietal cortex, posterior cingulate gyrus and parahippocampal gyrus, and decreased activation in dorsolateral and dorsomedial prefrontal cortices. The reverse pattern of findings was observed during the anxiety-provoking scenarios. The results may suggest that, in CFS patients, the provocation of fatigue is associated with exaggerated emotional responses that patients may have difficulty suppressing. These findings are discussed in relation to the cognitive-behavioural model of CFS.


Use of Model-Based Compartmental Analysis and a Super-Child Design to Study Whole-Body Retinol Kinetics and Vitamin A Total Body Stores in Children from 3 Lower-Income Countries.
Model-based compartmental analysis has been used to describe and quantify whole-body vitamin A metabolism and estimate total body stores (TBS) in animals and humans. We applied compartmental modeling and a super-child design to estimate retinol kinetic parameters and TBS for young children in Bangladesh, Guatemala, and the Philippines. Children ingested [13C10]retinyl acetate and 1 or 2 blood samples were collected from each child from 6 h to 28 d after dosing. Temporal data for fraction of dose in plasma [13C10]retinol were modeled using WinSAAM software and a 6-component model with vitamin A intake included as weighted data. Model-predicted TBS was 198, 533, and 1062 μmol for the Bangladeshi (age, 9-17 mo), Filipino (12-18 mo), and Guatemalan children (35-65 mo). Retinol kinetics were similar for Filipino and Guatemalan groups and generally faster for Bangladeshi children, although fractional transfer of plasma retinol to a larger exchangeable storage pool was the same for the 3 groups. Recycling to plasma from that pool was ∼2.5 times faster in the Bangladeshi children compared with the other groups and the recycling number was 2-3 times greater. Differences in kinetics between groups are likely related to differences in vitamin A stores and intakes (geometric means: 352, 727, and 764 μg retinol activity equivalents/d for the Bangladeshi, Filipino, and Guatemalan children, respectively). By collecting 1 or 2 blood samples from each child to generate a composite plasma tracer data set with a minimum of 5 children/time, group TBS and retinol kinetics can be estimated in children by compartmental analysis; inclusion of vitamin A intake data increases confidence in model predictions. The super-child modeling approach is an effective technique for comparing vitamin A status among children from different populations. These trials were registered at www.clinicaltrials.gov as NCT03000543 (Bangladesh), NCT03345147 (Guatemala), and NCT03030339 (Philippines).


Cytoplasmic helical structure associated with Acholeplasma laidlawii.
A distinct spiral protein structure was found in three species of Acholeplasma, but was not found in the Mycoplasma species studied. The spirals, which are 14 nm in width and of variable length from 50 to 300 nm, are formed by a helical arrangement of 7-nm subunits. A rosette-like structure 45 nm in diameter also composed of 7-nm subunits was found in close association with the spirals and may be a taut in vivo form of the spiral. The electrophoretic profile in sodium dodecyl sulfate-polyacrylamide gels indicated that the spirals are composed of a predominant polypeptide with an apparent molecular weight of 100,000. No evidence can be found for inferring actin-like properties for this structure.


Allogeneic hematopoietic stem cell transplantation in pediatric myelodysplastic syndromes: a multicenter experience from Argentina.
Allogeneic hematopoietic stem cell transplantation (AHSCT) represents the only curative treatment for the majority of pediatric patients with Myelodysplastic Syndrome (MDS). We aimed to evaluate overall survival (OS), disease-free survival (DFS), non-relapse mortality (NRM) and relapse incidence in children who underwent AHSCT for MDS in six institutions from Argentina. A retrospective analysis of 54 AHSCT was carried out in 52 patients (mean age: 9 years; range: 2-19; 35 males). MDS subtypes were refractory cytopenia of childhood (RCC) (n: 26, 50%), refractory anemia with excess blasts (RAEB) (n: 9, 18%), RAEB in transformation (RAEB-T) (n: 8, 15%) and juvenile myelomonocytic leukemia (JMML) (n: 9, 17%). At time of transplant, seven (13%) patients transformed to acute myeloid leukemia (AML) and two patients with RCC to RAEB. Donors were related in 32 cases (59%) and the stem cells source was: bone marrow (63%), peripheral blood (26%), and umbilical cord blood (11%). Five-year DFS and OS were 50% and 55% respectively; and for patients with JMML, 57% and 67% respectively. Cumulative incidence of NRM and relapse were 27% and 21% respectively. In the multivariate analysis, umbilical cord blood (HR 4.07; P = 0.025) and age ≥ 9 years at transplantation (HR 3.28; P = 0.017) were associated with lower OS; age and graft-versus-host disease (GVHD) had a higher NRM. In our series, more than half of the patients achieved long term OS with AHSCT. Less toxic conditioning regimens or more intensive GVHD prophylaxis could lead to better results in some children.


[Assessing aggression in patients of the mental health crisis service].
Care workers of the outreach psychiatric crisis team are frequently confronted with aggressive patients. To prevent dangerous situations from developing it could be advantageous to have in place a method of risk assessment that is based on information about patients before they are actually contacted by the crisis team. To test the predictive validity of an instrument specifically designed to assess the risks of aggression from severely disturbed psychiatric patients before they are seen by the crisis team. Over a period of two years and prior to any outreach contact with patients in crisis situations a Checklist of Risks to the Crisis team (CRC) was completed. Then, following outreach contact with the patient any perceived aggression was recorded by means of the Staff Observation Aggression Scale-Revised (SOAS-R). Aggressive behaviour by patients was observed during 51 of 499 crisis contacts with members of the outreach crisis team. On the basis of three factors in the CRC, namely the clinical assessment on a visual-analogue scale, an estimate of the number of aggressive persons in the vicinity of the crisis patient concerned and the reporting of crises by the patient himself, it was possible to predict outwardly directed aggression with a sensitivity of 74% and a specificity of 84%. Although the findings still need to be reproduced, an instrument such as the crc could be very useful to members of the crisis service.


New insight into the discharge mechanism of silicon-air batteries using electrochemical impedance spectroscopy.
The mechanism of discharge termination in silicon-air batteries, employing a silicon wafer anode, a room-temperature fluorohydrogenate ionic liquid electrolyte and an air cathode membrane, is investigated using a wide range of tools. EIS studies indicate that the interfacial impedance between the electrolyte and the silicon wafer increases upon continuous discharge. In addition, it is shown that the impedance of the air cathode-electrolyte interface is several orders of magnitude lower than that of the anode. Equivalent circuit fitting parameters indicate the difference in the anode-electrolyte interface characteristics for different types of silicon wafers. Evolution of porous silicon surfaces at the anode and their properties, by means of estimated circuit parameters, is also presented. Moreover, it is found that the silicon anode potential has the highest negative impact on the battery discharge voltage, while the air cathode potential is actually stable and invariable along the whole discharge period. The discharge capacity of the battery can be increased significantly by mechanically replacing the silicon anode.


Effects of oxidative stress on the virulence profile of Prevotella intermedia during experimental infection in gnotobiotic mice.
Prevotella intermedia is a component of the indigenous microbiota but is also responsible for anaerobic infections of the gastrointestinal tract and oral cavity. The aim of the present study was to investigate the influence of oxidative stress on the in vivo pathogenicity of P. intermedia. Germ-free mice were challenged intraperitoneally with parental (wt) or oxidative stress adapted (aero) strains. Bacterial virulence was evaluated by histopathology, hyperaemia and blood analysis [C-reactive protein (CRP), serum albumin and white blood cells (WBCs)], 3 and 10 days after challenge. CRP levels and WBC count were higher in animals challenged with the aero strain, and the albumin level was lower in this group, only 10 days after infection (P<0.05). Body weight gain was significantly reduced whereas hyperaemia and ratios of spleen/organ weight were increased in animals challenged with the aero strain (P<0.05). The liver of animals challenged with the aero strain showed hyperaemia, vasodilatation as well as an increase in the number of inflammatory cells and liver/organ weight ratio (P<0.05). Similar, but more discrete, alterations were observed in the small intestine of animals challenged with the aero strain. Studies on stress responses of this putative pathogen may help to better understand the aggressive potential and virulence markers of anaerobic bacteria.


Mmp12 Is Translationally Regulated in Macrophages during the Course of Inflammation.
Despite the importance of rapid adaptive responses in the course of inflammation and the notion that post-transcriptional regulation plays an important role herein, relevant translational alterations, especially during the resolution phase, remain largely elusive. In the present study, we analyzed translational changes in inflammatory bone marrow-derived macrophages upon resolution-promoting efferocytosis. Total RNA-sequencing confirmed that apoptotic cell phagocytosis induced a pro-resolution signature in LPS/IFNγ-stimulated macrophages (Mϕ). While inflammation-dependent transcriptional changes were relatively small between efferocytic and non-efferocytic Mϕ; considerable differences were observed at the level of de novo synthesized proteins. Interestingly, translationally regulated targets in response to inflammatory stimuli were mostly downregulated, with only minimal impact of efferocytosis. Amongst these targets, pro-resolving matrix metallopeptidase 12 (Mmp12) was identified as a translationally repressed candidate during early inflammation that recovered during the resolution phase. Functionally, reduced MMP12 production enhanced matrix-dependent migration of Mϕ. Conclusively, translational control of MMP12 emerged as an efficient strategy to alter the migratory properties of Mϕ throughout the inflammatory response, enabling Mϕ migration within the early inflammatory phase while restricting migration during the resolution phase.


Lifetime History of Depression Predicts Increased Amyloid-β Accumulation in Patients with Mild Cognitive Impairment.
Mounting evidence associates a lifetime history of major depression (LMD) with an increased risk for Alzheimer's disease (AD). Studies have shown that major depression (MD) is strongly linked to pathophysiological markers of AD, such as cortical amyloid-β (Aβ) burden. However, no imaging studies have shown in vivo whether an LMD is linked to increased Aβ accumulation in patients with mild cognitive impairment (MCI) in four cortical regions that have been highly associated with increased Aβ deposition in previous literature: frontal, cingulate, parietal, and temporal. Drawing from the ADNI database, we found that patients with amnestic MCI (aMCI) and an LMD (n = 39) had significantly higher 18F-Florbetapir standardized uptake value ratios, a surrogate measure of Aβ deposition, mainly in the bilateral frontal cortex, compared to patients with aMCI without an LMD (n = 39) (p = 0.02). This difference was not explained by current depressive symptoms, vascular risk factors, or the use of different PET scanners. The results were reliable employing two independent methods for analysis: region-of-interest and voxel-based analyses. Increased Aβ in the bilateral frontal lobes may be a biomarker of depressive symptomology in aMCI patients. Further studies should test whether higher Aβ predicts future conversion into AD in this population.


Phonemic and semantic fluencies in traumatic brain injury patients with focal frontal lesions.
The purpose of this study was to investigate the effect of focal frontal lesions, identified by magnetic resonance imaging (MRI), in a group of traumatic brain injured (TBI) patients, in order to clarify the sensitivity of phonemic and semantic fluency tasks as tests of frontal lobe functioning. Thirteen TBI patients were included and matched with a normal control group of 26 subjects. Frontal lobe patients produced significantly fewer words than the control group in the phonemic fluency condition. Semantic performance correlated with lesion size, but phonemic performance did not, corroborating the idea that the two have different brain-based substrates. Although, as a group effect, frontal lesions impaired fluency, not all patients were impaired, even in the presence of large bilateral frontal lesions.


Reduced encoding diffusion spectrum imaging implemented with a bi-Gaussian model.
Diffusion spectrum imaging (DSI) can map complex fiber microstructures in tissues by characterizing their 3-D water diffusion spectra. However, a long acquisition time is required for adequate q-space sampling to completely reconstruct the 3-D diffusion probability density function. Furthermore, to achieve a high q-value encoding for sufficient spatial resolution, the diffusion gradient duration and the diffusion time are usually lengthened on a clinical scanner, resulting in a long echo time and low signal-to-noise ratio of diffusion-weighted images. To bypass long acquisition times and strict gradient requirements, the reduced-encoding DSI (RE-DSI) with a bi-Gaussian diffusion model is presented in this study. The bi-Gaussian extrapolation kernel, based on the assumption of the bi-Gaussian diffusion signal curve across biological tissue, is applied to the reduced q-space sampling data in order to fulfill the high q-value requirement. The crossing phantom model and the manganese-enhanced rat model served as standards for accuracy assessment in RE-DSI. The errors of RE-DSI in estimating fiber orientations were close to the noise limit. Meanwhile, evidence from a human study demonstrated that RE-DSI significantly decreased the acquisition time required to resolve complex fiber orientations. The presented method facilitates the application of DSI analysis on a clinical magnetic resonance imaging system.


In vitro analog of operant conditioning in aplysia. I. Contingent reinforcement modifies the functional dynamics of an identified neuron.
Previously, an analog of operant conditioning in Aplysia was developed using the rhythmic motor activity in the isolated buccal ganglia. This analog expressed a key feature of operant conditioning, namely a selective enhancement in the occurrence of a designated motor pattern by contingent reinforcement. Different motor patterns generated by the buccal central pattern generator were induced by monotonic stimulation of a peripheral nerve (i.e., n.2,3). Phasic stimulation of the esophageal nerve (E n.) was used as an analog of reinforcement. The present study investigated the neuronal mechanisms associated with the genesis of different motor patterns and their modifications by contingent reinforcement. The genesis of different motor patterns was related to changes in the functional states of the pre-motor neuron B51. During rhythmic activity, B51 dynamically switched between inactive and active states. Bursting activity in B51 was associated with, and predicted, characteristic features of a specific motor pattern (i.e., pattern I). Contingent reinforcement of pattern I modified the dynamical properties of B51 by decreasing its resting conductance and threshold for eliciting plateau potentials and thus increased the occurrences of pattern I-related activity in B51. These modifications were not observed in preparations that received either noncontingent reinforcement (i.e., yoke control) or no reinforcement (i.e., control). These results suggest that a contingent reinforcement paradigm can regulate the dynamics of neuronal activity that is centrally programmed by the intrinsic cellular properties of neurons.


Sex and Gender in Lung Diseases and Sleep Disorders: A State-of-the-Art Review: Part 2.
There is now ample evidence that differences in sex and gender contribute to the incidence, susceptibility, presentation, diagnosis, and clinical course of many lung diseases. Some conditions are more prevalent in women, such as pulmonary arterial hypertension and sarcoidosis. Some life stages-such as pregnancy-are unique to women and can affect the onset and course of lung disease. Clinical presentation may differ as well, such as the higher number of exacerbations experienced by women with cystic fibrosis (CF), more fatigue in women with sarcoidosis, and more difficulty in achieving smoking cessation. Outcomes such as mortality may be different as well, as indicated by the higher mortality in women with CF. In addition, response to therapy and medication safety may also differ by sex, and yet, pharmacogenomic factors are often not adequately addressed in clinical trials. Various aspects of lung/sleep biology and pathobiology are impacted by female sex and female reproductive transitions. Differential gene expression or organ development can be impacted by these biological differences. Understanding these differences is the first step in moving toward precision medicine for all patients. This article is the second part of a state-of-the-art review of specific effects of sex and gender focused on epidemiology, disease presentation, risk factors, and management of selected lung diseases. We review the more recent literature and focus on guidelines incorporating sex and gender differences in pulmonary hypertension, CF and non-CF bronchiectasis, sarcoidosis, restless legs syndrome and insomnia, and critical illness. We also provide a summary of the effects of pregnancy on lung diseases and discuss the impact of sex and gender on tobacco use and treatment of nicotine use disorder.


Effectiveness of an interactive virtual telerehabilitation system in patients after total knee arthoplasty: a randomized controlled trial.
To compare the effectiveness of a new interactive virtual telerehabilitation system and a conventional programme following total knee arthroplasty. Randomized, controlled, single-blind clinical trial. A total of 142 total knee arthroplasty patients. Participants were randomly assigned to receive either: (i) conventional out-patient physical therapy; or (ii) interactive virtual telerehabilitation system. The main outcome was function assessed with active range of knee movement. Other variables, such as muscle strength, walk speed, pain and the Western Ontario and McMaster Universities osteoarthritis index, were also collected. Comparisons were made on the basis of data collected routinely before surgery, at the end of the rehabilitation programme, and at 3 months follow-up. Quantitative variables were compared by Mann-Whitney U test. The agreed alpha risk for all hypothesis testing was 0.05. Baseline characteristics between groups were comparable. All participants improved after the 2-week intervention on all outcome variables (p < 0.05). Patients in the interactive virtual telerehabilitation group achieved improvements in the functional variables similar to those achieved in the conventional therapy group. A 2-week interactive virtual telerehabilitation programme is at least as effective as conventional therapy. Telerehabilitation is a promising alternative to traditional face-to-face therapies after discharge from total knee arthroplasty, especially for those patients who have difficulty with transportation to rehabilitation centres.


Translesion synthesis past guanine(C8)-thymine(N3) intrastrand cross-links catalyzed by selected A- and Y-family polymerases.
Oxidatively generated guanine radicals in DNA can undergo various nucleophilic reactions including the formation of C8-guanine cross-links with adjacent or nearby N3-thymines in DNA in the presence of O2. These G[8-3]T lesions have been identified in the DNA of human cells exposed to oxidative stress, and are most likely genotoxic if not removed by cellular defence mechanisms. The abilities of several representative polymerases to bypass the G[8-3]T lesions in two different sequence contexts, G*T* and G*CT*, were assessed in vitro. The polymerase BF (bacillus fragment) from Bacillus stearothermophilus, the Y-family archaeal polymerases Dpo4 from Sulfolobus sulfataricus P2, and human DNA pol κ and pol η were selected for the study. The A-family polymerase BF was strongly blocked, while relatively weak translesion synthesis was observed in the case of Y-family polymerases Dpo4 and pol κ. Primer extension catalyzed by pol η was also partially stalled at various positions at or near the G[8-3]T cross-linked bases, but a significant and distributive primer extension was observed beyond the sites of the lesions with the efficiency being consistently greater in the case of G*CT* than in the case of G*T* lesions. The results obtained with pol η are compared with translesion synthesis past other intrastrand cross-linked lesions with previously published results of others that include the isomeric G[8-5m]T lesions generated by ionizing radiation, the cis-syn cyclobutane pyrimidine dimer and the 6-4 photoproduct generated by UV irradiation, and the Pt-G*G* lesions derived from the reactions of the chemotherapeutic agent cisplatin with DNA.


[Combined lesions of the chest and abdomen].
The structure of combined thoracic and abdominal trauma was analysed in 500 injured persons for 1984-1994 period. Mortality in the open trauma was 13.4% and in the closed one--20.4%.


Results of the 2015 National Certified Pharmacy Technician Workforce Survey.
The results of the 2015 National Certified Pharmacy Technician Workforce Survey are described. A survey was e-mailed to a randomized sample of 5,000 certified pharmacy technicians (CPhTs) throughout the United States, with response reminders employed. Survey items eliciting demographic and work characteristics and work life attitudes were generated from the literature and qualitative interviews. This study aimed to describe job satisfaction, sources of stress, profession and employer commitment, education and training, and reasons for entry into the profession among CPhTs and determine relationships between those variables and CPhTs' level of involvement in various work activities, with particular attention paid to differences in practice setting. Frequency statistics, correlation analysis, and means testing were used to meet study objectives and identify significant differences. A total of 516 CPhTs currently working as a pharmacy technician responded to the survey. The CPhTs reported high levels of involvement in more traditional activities but less involvement in those that involve greater cognitive load. Respondents reported moderate levels of job satisfaction and commitment and somewhat high levels of stress overall. Most CPhTs chose to be a pharmacy technician because they desired to enter a healthcare field and help people and were recruited. CPhTs derived benefit from all aspects of education and training evaluated and most from on-the-job training. Perceived value of education and training was associated with higher satisfaction and commitment and with lower stress. There were a number of differences in these work life attitudes across practice settings and by involvement in various job functions. The results of the survey indicated that job satisfaction and commitment were moderate and that stress levels were somewhat high among CPhTs. There were a number of differences in work life attitudes across practice settings and by involvement in various job activities.


Laparoscopic transabdominal preperitoneal repair of spigelian hernia-closure of the fascial defect is not necessary.
Spigelian hernia (SH) is rare and is traditionally repaired using an open technique. There has been an increasing popularity of laparoscopic methods, with transabdominal preperitoneal (TAPP) repair being one of the popular techniques. Currently, most surgeons using the TAPP technique close the fascial defect prior to mesh placement. Here we report our experience with a TAPP repair that deliberately excludes approximation of the fascial defect. Prospective data were collected on consecutive patients undergoing elective SH repair under the care of a single surgeon between 2001 and 2012. Diagnosis was confirmed preoperatively using ultrasonography or computerized tomography. A laparoscopic TAPP repair was used without closing the defect. Following discharge all patients were followed up at 3 and 12 months. The clinical records were reviewed at the time this article was written. The technique, epidemiological characteristics, operative findings, hospital stay, morbidity, and follow-up are presented. Twenty-six patients (16 males) with a median age of 63 years were operated on. The follow-up period ranged between 6 months and 11 years (median, 4 years). Hernia defect size ranged from 2 to 10 cm. Mean operating time for unilateral defects was 45 minutes; that for bilateral defects was 70 minutes. Twenty-two patients were discharged on the same day. There were no postoperative complications or recurrences. Laparoscopic TAPP repair of SH without closing the defect is safe, effective, and durable. There is no additional benefit from routine closure of the fascial defect. On the contrary, there may be potential advantages in leaving the defect unopposed.


Stability analysis of neural-network interconnected systems.
This paper is concerned with the stability problem of a neural-network (NN) interconnected system which consists of a set of NN models. First, a linear difference inclusion (LDI) state-space representation is established for the dynamics of each NN model. Subsequently, based on the LDI state-space representation, a stability criterion in terms of Lyapunov's direct method is derived to guarantee the asymptotic stability of NN interconnected systems. Finally, a numerical example with simulations is given to demonstrate the results.


Oral nucleic acid therapy using multicompartmental delivery systems.
Nucleic acid-based therapeutics has the potential for treating numerous diseases by correcting abnormal expression of specific genes. Lack of safe and efficacious delivery strategies poses a major obstacle limiting clinical advancement of nucleic acid therapeutics. Oral route of drug administration has greater delivery challenges, because the administered genes or oligonucleotides have to bypass degrading environment of the gastrointestinal (GI) tract in addition to overcoming other cellular barriers preventing nucleic acid delivery. For efficient oral nucleic acid delivery, vector should be such that it can protect encapsulated material during transit through the GI tract, facilitate efficient uptake and intracellular trafficking at desired target sites, along with being safe and well tolerated. In this review, we have discussed multicompartmental systems for overcoming extracellular and intracellular barriers to oral delivery of nucleic acids. A nanoparticles-in-microsphere oral system-based multicompartmental system was developed and tested for in vivo gene and small interfering RNA delivery for treating colitis in mice. This system has shown efficient transgene expression or gene silencing when delivered orally along with favorable downstream anti-inflammatory effects, when tested in a mouse model of intestinal bowel disease. WIREs Nanomed Nanobiotechnol 2018, 10:e1478. doi: 10.1002/wnan.1478 This article is categorized under: Biology-Inspired Nanomaterials > Nucleic Acid-Based Structures Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies.


Successful management of a widespread osteosarcoma. A case report.
To report the case of a 23-year-old woman with widespread osteosarcoma including skeletal, pulmonary and pleural metastases, who had a remarkable response to combined chemo- and radiotherapy. A 23-year-old Indonesian woman presented in October 1999 with a swelling of the right thigh, severe generalized pain and progressive left hemiparesis. Radiological examination revealed osteolytic lesions in the cervical spine. CT scan of the chest showed multiple pulmonary metastases and a huge left pleural effusion. Bone scan with technetium-99m hydroxymethylene diphosphonate showed intense uptake of the radiopharmaceutical in the distal right femur, generalized deposits throughout the skeleton and in the right hemithorax corresponding to the lung findings. Bone marrow and kidney function tests as well as serum calcium level were normal. Alkaline phosphatase was markedly elevated, 8,000 IU/l (normal <250 IU/l). Histopathology from the femoral tumor showed osteosarcoma. Treatment was started with radiotherapy to the cervical spine followed immediately by a combination chemotherapy with ifosfamide, cisplatin, etoposide and mesna rescue. In addition, the patient received bisphosphonates regularly. Eleven cycles of chemotherapy were given with a remarkable response. The patient was successfully treated with a combination of radio- and chemotherapy. She recovered fully and is in almost complete remission. The disease remained stable 24 months after the discontinuation of the treatment.