Reprotoxic effects of the systemic insecticide fipronil on the butterfly Pieris brassicae.
In addition to controlling pest organisms, the systemic neurotoxic pesticide fipronil can also have adverse effects on beneficial insects and other non-target organisms. Here, we report on the sublethal effects of fipronil on the farmland butterfly Pieris brassicae. Caterpillars were reared on plants that had been grown from seeds coated with fipronil or on leaf discs topically treated with a range of fipronil dosages (1-32 µg kg-1 on dry mass basis). Females that had developed on fipronil plants laid ca half the number of eggs than females that had developed on control plants. In the bioassay with leaf discs, longevity and lifetime egg production declined with increasing fipronil dosage. Remarkably, exposure to fipronil during larval development primarily affected the adult stage. Chemical analyses of leaf tissues collected from seed-treated plants revealed concentrations of fipronil and its degradation products close to the analytical limit of detection (less than or equal to 1 µg kg-1). The effective dosage was fivefold higher in the leaf-disc than in the whole-plant experiment. In the whole plant, degradation of fipronil to products that are more toxic than fipronil may explain this discrepancy. Neurotoxicity of insecticides at the level of detection decreases the probability of pinpointing insecticides as the causal agent of harmful effects on non-target organisms.


[Six-minute walking test for the evaluation of the status of patients with chronic cardiac failure].
The paper presents the results of application of the modified 6-minute walking test for assessment of exercise tolerance in follow-up of patients with ischemic heart disease (IHD) complicated by chronic cardiac failure (CCF). At admission and after 3-4 weeks of treatment 52 IHD patients underwent the walking test and described subjective effects according to modified Borg's questionnaire. The repeated test registered increased walking distance and subjective response. The results of the study confirm validity of using 6-minute walk test in combination with modified Borg questionnaire in routine hospital and outpatient practice as a simple, safe and informative method of control over IHD patients' condition and assessment of their treatment efficacy.


Karyotypic characteristics of borderline malignant tumors of the ovary: trisomy 12, trisomy 7, and r(1) as nonrandom features.
Clonal karyotypic abnormalities were detected in five of 14 cytogenetically analyzed borderline malignant ovarian tumors of clinical stages I-II. One mucinous and one seropapillary tumor had trisomy 7 and r(1)(p36q42) as the sole chromosome abnormality, respectively. Trisomy 12 was found in the remaining three cases. It was the only change in one mucinous and one serous tumor, whereas the third, a seropapillary borderline tumor, had the karyotype 49,XX,+5,+8, +12. These findings, especially when collated with those of previous reports on ovarian borderline tumor cytogenetics, indicate that +12 is the most consistent chromosomal aberration in this group of neoplasms and that also +7 and r(1) are nonrandom features. From the karyotypic point of view, benign ovarian tumors and well-differentiated carcinomas are similar to borderline ovarian tumors, with the possible exception that the former have no tendency to form r(1). Highly malignant carcinomas, on the other hand, are typically much more complex. Chromosome-level changes therefore cannot account for the putative phenotypic passage through the most innocuous tumor stages as epithelial ovarian neoplasms go from benign to fully malignant.


Mutagenesis analysis of the rGTP-specific binding site of hepatitis C virus RNA-dependent RNA polymerase.
Hepatitis C virus (HCV) nonstructural protein 5B (NS5B) is the virus-encoded RNA-dependent RNA polymerase (RdRp) essential for HCV RNA replication. An earlier crystallographic study identified a rGTP-specific binding site lying at the surface between the thumb domain and the fingertip about 30 A away from the active site of the HCV RdRp (S. Bressanelli, L. Tomei, F. A. Rey, and R. De Francesco, J. Virol 76:3482-3492, 2002). To determine its physiological importance, we performed a systematic mutagenesis analysis of the rGTP-specific binding pocket by amino acid substitutions. Effects of mutations of the rGTP-specific binding site on enzymatic activity were determined by an in vitro RdRp assay, while effects of mutations on HCV RNA replication were examined by cell colony formation, as well as by transient replication of subgenomic HCV RNAs. Results derived from these studies demonstrate that amino acid substitutions of the rGTP-specific binding pocket did not significantly affect the in vitro RdRp activity of purified recombinant NS5B proteins, as measured by their abilities to synthesize RNA on an RNA template containing the 3' untranslated region of HCV negative-strand RNA. However, most mutations of the rGTP-specific binding site either impaired or completely ablated the ability of subgenomic HCV RNAs to induce cell colony formation. Likewise, these mutations caused either reduction in or lethality to transient replication of the human immunodeficiency virus Tat-expressing HCV replicon RNAs in the cell. Collectively, these findings demonstrate that the rGTP-specific binding site of the HCV NS5B is not required for in vitro RdRp activity but is important for HCV RNA replication in vivo.


Analysis of antithrombotic therapy after cardioembolic stroke due to atrial fibrillation or flutter.
Guidelines recommend that all patients with atrial fibrillation and a history of ischemic stroke should receive an anticoagulant. Prior analyses show that warfarin is underutilized in most populations. To examine the use of antithrombotic and anticoagulant therapy in patients with atrial fibrillation or flutter during the index hospitalization for acute, ischemic stroke. Retrospective electronic medical record review of 200 patients treated at a tertiary care hospital with a primary ICD-9 code for ischemic stroke and a secondary ICD-9 code for atrial fibrillation or flutter. Exclusion criteria were active bleeding, pregnancy, age less than 18, pre-existing warfarin allergy, or dabigatran use. Fifty-two percent of patients received at least one dose of warfarin during the index hospitalization. There was no relationship between CHADS2 score and likelihood of receiving warfarin (P > .05). There was no significant difference in adverse event rate in patients receiving warfarin compared to those receiving aspirin (3.8% vs 9.1%; P = .14), but the rate of hemorrhagic transformation was lower in patients receiving warfarin (1% vs 7%; P = .03). The composite of hemorrhagic stroke or hemorrhagic transformation was significantly lower in patients receiving bridging therapy (0% vs 11%; P = .03). Sixteen patients were readmitted for stroke within 3 months of discharge. Ten were readmitted for ischemic stroke, 3 for hemorrhagic stroke or hemorrhagic transformation, and 3 for systemic bleeding. Ten patients (62.5%) were receiving warfarin at readmission, but only one of these patients had a therapeutic INR. Warfarin was underutilized as secondary stroke prophylaxis in these high-risk patients. Bridging therapy appeared to be safe and was not associated with an increase in adverse events.


How young adults with sickle cell disease define "being a good patient" in the adult healthcare system.
Young adulthood brings new challenges for managing sickle cell disease. There are fewer adult specialists, sickle cell disease morbidities accumulate, and mortality increases. Developmental changes in roles and responsibilities also affect management. This study explores how young adults with sickle cell disease experience their role as a patient. In this mixed-methods study at a sickle cell center, young adult participants completed the Sickle Cell Self Efficacy Survey, the Measures of Sickle Cell Stigma, and the Adult Sickle Cell Quality of Life Measurement Short-Forms. Semi-structured interviews on the patient role were conducted, transcribed, and then analyzed using thematic analysis. Twenty-four participants aged 19-25 years defined expectations of being a "good patient." Five definitional themes emerged: health maintenance, emotion regulation, self-advocacy, honest communication, and empathy for clinicians. Participants identified support from families and clinicians are important facilitators of role fulfillment. How young adult patients with sickle cell disease define being a "good patient" has implications for the transition of care for both pediatric and adult medicine practices. This understanding can inform healthcare system designs and programs aimed at supporting patients and families.


[Protein study on perilymph susbstitution during cerebrospinal fluid flow through cochlear aqueduct].
Total protein contents in the perilymphy of Scala vestibuli and Scala tympani as well as in the cerobrospinal fluid (CSF) of guinea-pigs were determined, by which specimens were taken under the following various conditions: With or without subarachnoidal puncture before perilymph collection, by varying the amount of perilymph taken from Scala tympani, by fractionating collection and under post mortem condition. The results suggest that under physiological conditions the CSF also flows through the cochleae aqueduct and the protein concentration in the Scala tympani decreases especially in the basal winding. Because the protein content in CSF is inaverage four times lower than in fluids of the inner ear it is of preference to consider the question of connection between the CSF and the fluids of the inner ear. In the specimens taken the blood contamination was estimated on the basisof erythrocytes in the connection capillaries under microscope. The protein content in the perilymph of Scala vestibuli was found significantly higher in relation to perilymph of Scala tympani.


Local Order-Disorder Transition Driving by Structural Heterogeneity in a Benzyl Functionalized Ionic Liquid.
A local order-disorder transition has been disclosed in the thermophysical behavior of the ionic liquid 1-benzyl-3-methylimidazolium dicyanamide, [Bzmim][N(CN)2], and its microscopic nature revealed by spectroscopic techniques. Differential scanning calorimetry and specific heat measurements show a thermal event of small enthalpy variation taking place in the range 250-260 K, which is not due to crystallization or melting. Molecular dynamic simulations and X-ray diffraction measurements have been used to discuss the segregation of domains in the liquid structure of [Bzmim][N(CN)2]. Raman and NMR spectroscopy measurements as a function of temperature indicate that the microscopic origin of the event observed in the calorimetric measurements comes from structural rearrangement involving the benzyl group. The results indicate that the characteristic structural heterogeneity allow for rearrangements within local domains implying the good glass-forming ability for the low viscosity ionic liquid [Bzmim][N(CN)2]. This work sheds light on our understanding of the microscopic origin behind complex thermal behavior of ionic liquids.


Influence of D-galactosamine upon the NAD-metabolism in rat liver.
After application of D-galactosamine a hepatitis develops in the rat liver. This can be prevented by different agents, including tryptophan. Yet it has not been possible to give definitive conclusions about the mechanism of galactosamine hepatitis. In this paper we report about the influence of galactosamine on the NAD metabolism. D-galactosamine inhibits the NAD synthesis initiated by nicotinamide in normal and adrenalectomized animals. The NAD synthesis from tryptophan is prevented in normal animals, in adrenalectomized ones however there is an increase of NAD in the presence of D-galactosamine reduces the activity of the ADPR transferase. Inhibitors of the ADPR transferase prevent the galactosamine hepatitis. From the results presented we conclude that the ADPR transferase plays an important role in the development of the galactosamine hepatitis.


Design of high-Q cavities in photonic crystal slab heterostructures by air-holes infiltration.
We design novel photonic crystal slab heterostructures, substituting the air in the holes with materials of refractive index higher than n=1. This can be achieved by infiltrating the photonic crystal slab (PCS) with liquid crystal, polymer or nano-porous silica. We find that the heterostructures designed in this way can have quality factors up to Q=10(6). This high-Q result is comparable with the result of previously reported designs in which the lattice is elongated in one direction. Unlike conventional heterostructures, our design does not require nanometre-scale changes in the geometry. Additionally, infiltrated PCS can be constructed at any time after PCS fabrication.


Inferior petrosal sinus sampling (IPSS) tumor lateralization and the surgical treatment of Cushing's disease: a meta-analysis and systematic review.
To determine whether accurate inferior petrosal sinus sampling (IPSS) tumor lateralization is associated with improved clinical outcomes following the surgical treatment of Cushing's disease. The presented study was performed in accordance with PRISMA guidelines. Data regarding patient demographics, IPSS tumor lateralization, and postoperative endocrinologic outcomes were abstracted and pooled with random effects meta-analysis models. Additional meta-regression models were used to examine the association between the accuracy of IPSS tumor lateralization and postoperative outcomes (recurrence/persistence or remission/cure). Statistical analyses were performed using the Comprehensive Meta-Analysis software (significance of P<0.05). Seventeen eligible articles were identified, yielding data on 461 patients. Within average follow-up duration (∼59 months), the rate of correct IPSS tumor lateralization was 69% [95% Confidence Interval: 61%, 76%], and the rate of postoperative remission/cure was 78% [67%, 86%]. Preoperative IPSS tumor lateralization was concordant with MRI lateralization for 53% of patients [40%, 66%]. There was no significant association between the rate of correct IPSS tumor lateralization and postoperative remission/cure among study-level data (P=0.735). Additionally, there was no association among subgroup analyses for studies using stimulatory agents during IPSS (corticotropin-releasing hormone or desmopressin, P=0.635), nor among subgroup analyses for adult (P=0.363) and pediatric (P=0.931) patients. Limited data suggest that the rate of correct IPSS tumor lateralization may not be positively associated with postoperative remission or cure in patients with Cushing's disease. These findings bring into question the utility of IPSS tumor lateralization in the context of preoperative planning and surgical approach rather than confirming a pituitary source.


Differing Src signaling levels have distinct outcomes in Drosophila.
High levels of Src activity are found in a broad spectrum of cancers. The roles of Src and its negative regulator Csk have been extensively studied, although results have often proved contradictory or the relevance to whole organisms is unclear. In Drosophila, overexpression of either Src orthologue resulted in apoptotic cell death, but paradoxically, reducing dCsk activity led to over-proliferation and tissue overgrowth. Here, we show that in Drosophila epithelia in situ, the levels of Src signaling determine the cellular outcome of Src activation. Apoptotic cell death was triggered specifically at high Src signaling levels; lower levels directed antiapoptotic signals while promoting proliferation. Furthermore, our data indicate that expression of kinase-dead Src isoforms do not necessarily act as dominant-negative factors, but can instead increase Src pathway activity, most likely by titrating Csk activity away from endogenous Src. The importance of Src activity levels was emphasized when we examined oncogenic cooperation between Src and Ras: malignant overgrowth was observed specifically when high Src signaling levels were achieved. We propose a model in which low levels of Src signaling promote survival and proliferation during early stages of tumorigenesis, whereas strong Src signaling, coupled with antiapoptotic signals, directs invasive migration and metastasis during advanced tumor stages.


Trends in Frailty and Use of Evidence-Based Pharmacotherapy for Heart Failure in Australian Hospitalised Patients: An Observational Study.
Frailty increases morbidity and mortality in heart failure (HF) patients. Current risk-adjustment models do not include frailty-status and the relationship between frailty and pharmacotherapy is unclear. This study explored trends in frailty over time and its relationship with prescription of heart failure specific pharmacotherapy in hospitalised HF patients. We used the Hospital Frailty Risk Score (HFRS) to determine frailty status of patients ≥18 years admitted between 2015-2019 at two tertiary hospitals in Australia. Patients with an HFRS ≥ 5 were classified as frail. In the 3706 patients with a mean (SD) age of 76.1 (14.4) years, 876 (23.6%) were classified as frail. HFRS was weakly correlated with age (r = 0.16) and Charlson-index (r = 0.35) (both p values < 0.001). Whilst frailty was more common in older HF patients (28.9% of patients ≥80 years), 15.1% of patients ≤65 years of age were also found to be frail. The proportion of frail patients increased from 19.4% in 2015 to 29.2% in 2019 despite no significant change in age during this period. The proportion of patients who received heart failure specific pharmacotherapy decreased from 86.7% in 2015 to 82.9% in 2019 (p value = 0.03) and frail patients were significantly less likely to be prescribed HF specific pharmacotherapy than non-frail patients (77.4% vs. 85.9%, p < 0.001).


Donepezil: an important prototype to the design of new drug candidates for Alzheimer's disease.
Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder, with a dramatic socioeconomic impact. The progress of AD is characterized by a severe loss in memory and cognition, leading to behavioral changing, depression and death. During the last decades, only a few anticholinergic drugs were launched in the market, mainly acetylcholinesterase inhibitors (AChEIs), with indications for the treatment of initial and moderate stages of AD. The search for new AChEIs, capable to overcome the limitations observed for rivastigmine and tacrine, led Sugimoto and co-workers to the discovery of donepezil. Besides its high potency, donepezil also exhibited high selectivity for AChE and a very low toxicity. In this review, we discuss the main structural and pharmacological attributes that have made donepezil the first choice medicine for AD, and a versatile structural model for the design of novel AChEIs, in spite of multipotent and multitarget-directed ligands. Many recent data from literature transdue great efforts worldwide to produce modifications in the donepezil structure that could result in new bioactive chemical entities with innovative structural pattern. Furthermore, multi-potent ligands have also been designed by molecular hybridization, affording rivastigmine-, tacrine- and huperzine-donepezil potent and selective AChEIs. In a more recent strategy, structural features of donepezil have been used as a model to design multitarget-directed ligands, aiming at the discovery of new effective drug candidates that could exhibit concomitant pharmacological activities as dual or multi- enzymatic inhibitors as genuine innovative therapeutic alternatives for the treatment of AD.


Non-alcoholic fatty liver disease.
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that affects a high proportion of the world's population. Insulin resistance and oxidative stress play a critical role in the pathogenesis of NAFLD. Clinical, biochemical and imaging studies are of value in the diagnostic evaluation of patients with NAFLD, but liver biopsy remains the most sensitive and specific means of providing important diagnostic and prognostic information. Simple steatosis has the best prognosis within the spectrum of NAFLD, but NAFLD has the potential to progress to steatohepatitis, fibrosis and even cirrhosis. No effective medical therapy is currently available for all patients with NAFLD. In patients with diabetes mellitus and hyperlipidemia, appropriate metabolic control is always recommended, but rarely effective in resolving the liver disease. Weight reduction, when achieved and sustained, may improve the liver disease, although the results with weight loss have been inconsistent. Pharmacological therapy aimed at the underlying liver disease holds promise. Several medications with different mechanisms of action and potential benefit are currently being evaluated in clinical trials. Liver transplantation is a life-extending therapeutic alternative for patients with end-stage NAFLD, but NAFLD may recur after liver transplantation.


Autoreactive epitope defined as the anticodon region of alanine transfer RNA.
Autoantibodies to aminoacyl-transfer RNA (tRNA) synthetases are common in the human autoimmune diseases polymyositis and dermatomyositis. Sera of the PL-12 specificity contain separate antibodies reacting with alanyl-tRNA synthetase and alanine tRNA (tRNAAla). The antibodies to tRNA recognize at least six distinguishable human tRNAAla species grouped into two sequence families. The antibody-reactive determinants on the tRNA were identified through ribonuclease protection and oligonucleotide binding experiments. The antibody binding site is a seven- to nine-nucleotide sequence containing the anticodon loop and requires an intact anticodon. No requirement for anticodon stem structure or sequence is observed, although the 5' portion of the stem is protected from nuclease attack. Antibodies from several patients appear to share the same specificitym, indicating that the antibodies are induced by a unique sequence feature in the immunogen.


Development and Validation of a Risk Prediction Model for Atherosclerotic Cardiovascular Disease in Japanese Adults: The Hisayama Study.
To develop and validate a new risk prediction model for predicting the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) in Japanese adults. A total of 2,454 participants aged 40-84 years without a history of cardiovascular disease (CVD) were prospectively followed up for 24 years. An incident ASCVD event was defined as the first occurrence of coronary heart disease or atherothrombotic brain infarction. A Cox proportional hazards regression model was used to construct the prediction model. In addition, a simplified scoring system was translated from the developed prediction model. The model performance was evaluated using Harrell's C statistics, a calibration plot with the Greenwood-Nam-D'Agostino test, and a bootstrap validation procedure. During a median of a 24-year follow-up, 270 participants experienced the first ASCVD event. The predictors of the ASCVD events in the multivariable Cox model included age, sex, systolic blood pressure, diabetes, serum high-density lipoprotein cholesterol, serum low-density lipoprotein cholesterol, proteinuria, smoking habits, and regular exercise. The developed models exhibited good discrimination with negligible evidence of overfitting (Harrell's C statistics: 0.786 for the multivariable model and 0.789 for the simplified score) and good calibrations (the Greenwood-Nam-D'Agostino test: P=0.29 for the multivariable model, 0.52 for the simplified score). We constructed a risk prediction model for the development of ASCVD in Japanese adults. This prediction model exhibits great potential as a tool for predicting the risk of ASCVD in clinical practice by enabling the identification of specific risk factors for ASCVD in individual patients.


Advanced practice nursing in Canada: overview of a decision support synthesis.
The objective of this decision support synthesis was to identify and review published and grey literature and to conduct stakeholder interviews to (1) describe the distinguishing characteristics of clinical nurse specialist (CNS) and nurse practitioner (NP) role definitions and competencies relevant to Canadian contexts, (2) identify the key barriers and facilitators for the effective development and utilization of CNS and NP roles and (3) inform the development of evidence-based recommendations for the individual, organizational and system supports required to better integrate CNS and NP roles into the Canadian healthcare system and advance the delivery of nursing and patient care services in Canada. Four types of advanced practice nurses (APNs) were the focus: CNSs, primary healthcare nurse practitioners (PHCNPs), acute care nurse practitioners (ACNPs) and a blended CNS/NP role. We worked with a multidisciplinary, multijurisdictional advisory board that helped identify documents and key informant interviewees, develop interview questions and formulate implications from our findings. We included 468 published and unpublished English- and French-language papers in a scoping review of the literature. We conducted interviews in English and French with 62 Canadian and international key informants (APNs, healthcare administrators, policy makers, nursing regulators, educators, physicians and other team members). We conducted four focus groups with a total of 19 APNs, educators, administrators and policy makers. A multidisciplinary roundtable convened by the Canadian Health Services Research Foundation formulated evidence-informed policy and practice recommendations based on the synthesis findings. This paper forms the foundation for this special issue, which contains 10 papers summarizing different dimensions of our synthesis. Here, we summarize the synthesis methods and the recommendations formulated at the roundtable.


Outcome after out-of-hospital ventricular fibrillation or pulseless ventricular tachycardia: comparison of before and after the implementation of the 2010 Guidelines in a single centre.
Improvements to guidelines and efforts to train and equip laypersons and medical professionals are expected to result in improvements in the outcomes of patients experiencing out-of-hospital cardiac arrest (OHCA). This study aimed to evaluate changes in the survival and neurological outcomes of patients before and after the implementation of the 2010 guidelines. In a retrospective chart review, we analysed the outcomes of 182 patients who suffered bystander-witnessed, out-of-hospital ventricular fibrillation or pulseless ventricular tachycardia of cardiac aetiology. These definitions were based on the Utstein style. Survival at hospital discharge (study period 2006 to 2015), 1-year survival (study period 2011 to 2015), neurological outcome (cerebral performance category [CPC] score) and the corresponding changes over time were evaluated. In addition, the results were compared with results obtained from a systematic review of the literature. Of 1423 confirmed OHCAs, 182 fulfilled our inclusion criteria. 91 were treated between 2006 and 2010, and 91 from 2011 to 2015. Thirty-one (34%) survived until hospital discharge in the first time period, 44 (48%) in the second time period (p = 0.071); 26/31 (83%) and 40/44 (91%) respectively had a CPC score of 1–2. Between 2011 and 2015, the 1-year survival rate of the patients discharged from hospital was 36/44 (82%). All of these 36 patients (100%) had a favourable neurological outcome (CPC 1–2). These results were well within the range reported in the literature, although this range is wide (11 to 52% for survival at discharge and 6 to 47% for survival at 1 year). Survival was found to be at the upper range of the results retrieved by the systematic literature review. However, we found no significant improvements over time. The neurological outcomes of the survivors were favourable. The generalisability of this study is limited by its small sample size. To further improve outcomes, more public health measures, such as a functioning chain of survival, are required (e.g. an effective first responder network).


Biophysical characteristics of meridians and acupoints: a systematic review.
As an integral part of traditional Chinese medicine (TCM), acupuncture is a convenient and effective therapy with fewer adverse effects. Recently, researches on meridian essence have become core issues of modern TCM. Numerous experiments have demonstrated the objective existence of meridians by different technologies since 1950s, such as biophysics, biochemistry, and molecular biology. In this paper, we review biophysical studies on electric, acoustic, thermal, optical, magnetic, isotopic, and myoelectric aspects of meridians and acupoints. These studies suggest that meridians/acupoints have biophysical characteristics which are different from nonacupuncture points. Owing to the limitations of previous studies, future research using high-throughput technologies such as omics and multicenter randomized controlled trials should be performed to explore the acupuncture's mechanisms of action and demonstration of efficacy.


The feeding biomechanics and dietary ecology of Australopithecus africanus.
The African Plio-Pleistocene hominins known as australopiths evolved a distinctive craniofacial morphology that traditionally has been viewed as a dietary adaptation for feeding on either small, hard objects or on large volumes of food. A historically influential interpretation of this morphology hypothesizes that loads applied to the premolars during feeding had a profound influence on the evolution of australopith craniofacial form. Here, we test this hypothesis using finite element analysis in conjunction with comparative, imaging, and experimental methods. We find that the facial skeleton of the Australopithecus type species, A. africanus, is well suited to withstand premolar loads. However, we suggest that the mastication of either small objects or large volumes of food is unlikely to fully explain the evolution of facial form in this species. Rather, key aspects of australopith craniofacial morphology are more likely to be related to the ingestion and initial preparation of large, mechanically protected food objects like large nuts and seeds. These foods may have broadened the diet of these hominins, possibly by being critical resources that australopiths relied on during periods when their preferred dietary items were in short supply. Our analysis reconciles apparent discrepancies between dietary reconstructions based on biomechanics, tooth morphology, and dental microwear.


Tunable fly's-eye lens made of patterned polymer-dispersed liquid crystal.
A fly's-eye lens was fabricated using polymer-dispersed liquid crystals and its optical properties were evaluated. The morphologies were examined under an optical microscope. The forming process has been simulated based on a patterned photo-polymerization technique in which the spatially modulated reaction rate has been coupled with the time-dependent Ginzburg-Landau (TDGL) equations with the free energies relating to isotropic mixing, nematic ordering, and network elasticity incorporated. The simulated results are in good agreement with the experimental results. The beam profile was tested using a CCD. The results showed that this fly's-eye lens could modulate a Gaussian beam into a mesa-like beam. Such device is potentially useful in beam shaping and many illumination systems that require uniform beam profile.


Nicotine-induced upregulation of human neuronal nicotinic alpha7-receptors is potentiated by modulation of cAMP and PKC in SH-EP1-halpha7 cells.
Chronic nicotine exposure induces upregulation of nicotinic receptors, but the mechanisms underlying this phenomenon are not well understood. The aim of this study was to examine the role of different second messenger systems in the nicotine-induced upregulation of alpha7-nicotinic receptors in SH-EP1-halpha7 human epithelial cells. We show here that chronic exposure to nicotine results in accumulation of cAMP. Furthermore, an enhanced cAMP signalling potentiates nicotine-induced upregulation of alpha7-nicotinic receptors measured by [3H]methyllycaconitine ([3H]MLA) binding suggesting that cAMP is involved in the alpha7-nicotinic receptor upregulation. Down-regulation of protein kinase C (PKC) with a phorbol ester abolishes the nicotine-induced upregulation of alpha7-nicotinic receptors. Furthermore, overexpression of PKCalpha in SH-EP1-halpha7 cells results in potentiation of nicotine-evoked upregulation indicating that PKC has a role in regulation of alpha7-nicotinic receptor number. The Ca2+-calmodulin kinase II (CaMKII) and extracellular signal regulated kinase 1/2 (ERK1/2) appear not to participate in alpha7-nicotinic receptor upregulation since the specific inhibitors of these kinases did not have an effect on the nicotine-induced upregulation. Taken together this study provides evidence that nicotine induces accumulation of cAMP and that the upregulation mechanisms of alpha7-nicotinic receptors are potentiated both by cAMP and PKC. As nicotine-evoked upregulation of heteromeric nicotinic receptors in SH-SY5Y cells was unaffected by the treatment with drugs affecting cAMP signalling or PKC activity, our results suggest that the upregulation mechanisms of homomeric alpha7-nicotinic receptors and heteromeric nicotinic receptors differ from each other.


Predictors of professional behaviour and academic outcomes in a UK medical school: A longitudinal cohort study.
Over the past 70 years, there has been a recurring debate in the literature and in the popular press about how best to select medical students. This implies that we are still not getting it right: either some students are unsuited to medicine or the graduating doctors are considered unsatisfactory, or both. To determine whether particular variables at the point of selection might distinguish those more likely to become satisfactory professional doctors, by following a complete intake cohort of students throughout medical school and analysing all the data used for the students' selection, their performance on a range of other potential selection tests, academic and clinical assessments throughout their studies, and records of professional behaviour covering the entire five years of the course. A longitudinal database captured the following anonymised information for every student (n = 146) admitted in 2007 to the Hull York Medical School (HYMS) in the UK: demographic data (age, sex, citizenship); performance in each component of the selection procedure; performance in some other possible selection instruments (cognitive and non-cognitive psychometric tests); professional behaviour in tutorials and in other clinical settings; academic performance, clinical and communication skills at summative assessments throughout; professional behaviour lapses monitored routinely as part of the fitness-to-practise procedures. Correlations were sought between predictor variables and criterion variables chosen to demonstrate the full range of course outcomes from failure to complete the course to graduation with honours, and to reveal clinical and professional strengths and weaknesses. Student demography was found to be an important predictor of outcomes, with females, younger students and British citizens performing better overall. The selection variable "HYMS academic score", based on prior academic performance, was a significant predictor of components of Year 4 written and Year 5 clinical examinations. Some cognitive subtest scores from the UK Clinical Aptitude Test (UKCAT) and the UKCAT total score were also significant predictors of the same components, and a unique predictor of the Year 5 written examination. A number of the non-cognitive tests were significant independent predictors of Years 4 and 5 clinical performance, and of lapses in professional behaviour. First- and second-year tutor ratings were significant predictors of all outcomes, both desirable and undesirable. Performance in Years 1 and 2 written exams did not predict performance in Year 4 but did generally predict Year 5 written and clinical performance. Measures of a range of relevant selection attributes and personal qualities can predict intermediate and end of course achievements in academic, clinical and professional behaviour domains. In this study HYMS academic score, some UKCAT subtest scores and the total UKCAT score, and some non-cognitive tests completed at the outset of studies, together predicted outcomes most comprehensively. Tutor evaluation of students early in the course also identified the more and less successful students in the three domains of academic, clinical and professional performance. These results may be helpful in informing the future development of selection tools.


Construction and phenotypes of double sporulation deficient mutants in Streptomyces coelicolor A3(2).
In whiA, B, G and H mutants of Streptomyces coelicolor A3(2), aerial hyphae develop but sporulation speta are not formed. Septa are produced by whiI mutants but are spaced abnormally far apart. Mutants in each locus have a distinctive aerial mycelium morphology, except for whiA and B mutants which are closely similar. Seven strains were made with pairwise combinations of whiA and B mutations with whiG, H and I mutations and with each other. The genotypes of these strains were confirmed by suitable crosses and their aerial mycelium morphology examined. An indirect procedure was used to determine the aerial mycelium morphology of whiGH, GI and HI double mutants. The double mutants always closely resembled one of the single mutant parent strains in morphology and a consistent scheme of epistasis was obtained--whiG being epistatic to whiH, A, B and I; whiH to whiA, B and I; and whiA or B to whiI. These results point to the absence of any complex interactions between gene products, which might have been revealed by the occurrence of novel phenotypes in double mutants or by inconsistencies in the epistasis scheme.


BIG1 is required for the survival of deep layer neurons, neuronal polarity, and the formation of axonal tracts between the thalamus and neocortex in developing brain.
BIG1, an activator protein of the small GTPase, Arf, and encoded by the Arfgef1 gene, is one of candidate genes for epileptic encephalopathy. To know the involvement of BIG1 in epileptic encephalopathy, we analyzed BIG1-deficient mice and found that BIG1 regulates neurite outgrowth and brain development in vitro and in vivo. The loss of BIG1 decreased the size of the neocortex and hippocampus. In BIG1-deficient mice, the neuronal progenitor cells (NPCs) and the interneurons were unaffected. However, Tbr1+ and Ctip2+ deep layer (DL) neurons showed spatial-temporal dependent apoptosis. This apoptosis gradually progressed from the piriform cortex (PIR), peaked in the neocortex, and then progressed into the hippocampus from embryonic day 13.5 (E13.5) to E17.5. The upper layer (UL) and DL order in the neocortex was maintained in BIG1-deficient mice, but the excitatory neurons tended to accumulate before their destination layers. Further pulse-chase migration assay showed that the migration defect was non-cell autonomous and secondary to the progression of apoptosis into the BIG1-deficient neocortex after E15.5. In BIG1-deficient mice, we observed an ectopic projection of corticothalamic axons from the primary somatosensory cortex (S1) into the dorsal lateral geniculate nucleus (dLGN). The thalamocortical axons were unable to cross the diencephalon-telencephalon boundary (DTB). In vitro, BIG1-deficient neurons showed a delay in neuronal polarization. BIG1-deficient neurons were also hypersensitive to low dose glutamate (5 μM), and died via apoptosis. This study showed the role of BIG1 in the survival of DL neurons in developing embryonic brain and in the generation of neuronal polarity.


Epigenetic Therapies in Ovarian Cancer Alter Repetitive Element Expression in a TP53-Dependent Manner.
Epithelial ovarian carcinomas are particularly deadly due to intratumoral heterogeneity, resistance to standard-of-care therapies, and poor response to alternative treatments such as immunotherapy. Targeting the ovarian carcinoma epigenome with DNA methyltransferase inhibitors (DNMTi) or histone deacetylase inhibitors (HDACi) increases immune signaling and recruits CD8+ T cells and natural killer cells to fight ovarian carcinoma in murine models. This increased immune activity is caused by increased transcription of repetitive elements (RE) that form double-stranded RNA (dsRNA) and trigger an IFN response. To understand which REs are affected by epigenetic therapies in ovarian carcinoma, we assessed the effect of DNMTi and HDACi on ovarian carcinoma cell lines and patient samples. Subfamily-level (TEtranscripts) and individual locus-level (Telescope) analysis of REs showed that DNMTi treatment upregulated more REs than HDACi treatment. Upregulated REs were predominantly LTR and SINE subfamilies, and SINEs exhibited the greatest loss of DNA methylation upon DNMTi treatment. Cell lines with TP53 mutations exhibited significantly fewer upregulated REs with epigenetic therapy than wild-type TP53 cell lines. This observation was validated using isogenic cell lines; the TP53-mutant cell line had significantly higher baseline expression of REs but upregulated fewer upon epigenetic treatment. In addition, p53 activation increased expression of REs in wild-type but not mutant cell lines. These data give a comprehensive, genome-wide picture of RE chromatin and transcription-related changes in ovarian carcinoma after epigenetic treatment and implicate p53 in RE transcriptional regulation. SIGNIFICANCE: This study identifies the repetitive element targets of epigenetic therapies in ovarian carcinoma and indicates a role for p53 in this process.


Prognostic impact of bim, puma, and noxa expression in human colon carcinomas.
Proapoptotic BH3-only proteins (Bim, Bad, Bid, Puma, and Noxa) initiate apoptosis by binding to regulatory sites on antiapoptotic Bcl-2 proteins, directly neutralizing their cytoprotective function. Expression of these proteins in colon cancer patients may account for differences in recurrence and survival rates. Archival tumor-node-metastasis stage II and III primary colon carcinomas from patients treated in 5-fluorouracil-based adjuvant therapy trials were studied. Immunohistochemical analysis of Bim, Puma, and Noxa proteins was done using tissue microarrays (n = 431). Immunoscores were determined and correlated with clinicopathologic variables and disease-free survival (DFS) and overall survival (OS) rates. Elevated expression of proapoptotic Bim (hazard ratio, 0.65; 95% confidence interval, 0.44-0.97; P = 0.033) and Puma (hazard ratio, 0.59; 95% confidence interval, 0.37-0.93; P = 0.022), but not Noxa, proteins in the tumor cytoplasm was significantly associated with more favorable OS in a univariate analysis, and elevated Bim expression was also associated with better DFS (P = 0.023). Patient age, tumor stage, and histologic grade were also prognostic. Multivariate Cox analysis showed that Bim (DFS, P = 0.030; OS, P = 0.045) and Puma (OS, P = 0.037) expression were independent predictors of OS after adjustment for histologic grade, tumor stage, age, and treatment. Furthermore, the combined variable of Bim and Puma was highly discriminant for both DFS (P = 0.0034) and OS (P = 0.0011). The proapoptotic BH3-only proteins Bim and Puma can provide prognostic information for stage II and III colon cancer patients receiving 5-fluorouracil-based adjuvant chemotherapy. Furthermore, our results support BH3-only proteins as molecular targets of novel anticancer drugs.


Inland navigation: PAH inventories in soil and vegetation after EU fuel regulation 2009/30/EC.
In January 2011, fuel quality in inland water vessels was changed by EU regulation 2009/30/EC, aiming at improving air quality along waterways. We hypothesized that the implementation of this regulation both lowered the total deposition of polycyclic aromatic hydrocarbons (PAHs) and changed their composition in river valleys. We analyzed parent-, alkylated- and thio-PAHs in soil and vine leaves, at two waterways (Rhine and Moselle, Germany), as well as in one ship-free reference area (Ahr, Germany). Samples were taken annually (2010-2013) in transects perpendicular to the rivers. We did not find any relation of PAH concentration and composition on vine leaves to inland navigation, likely because atmospheric exchange processes distorted ship-specific accumulation patterns. We did find, however, an accumulation of ship-borne PAHs in topsoil near the waterways (1543±788 and 581±252ngg-1 at Moselle and Rhine, respectively), leading to larger PAH concentrations at the Moselle Valley than at the reference area (535±404ngg-1) prior to EU fuel regulation. After fuel regulation, the PAH concentrations decreased in topsoils of the Moselle and Rhine Valley by 35±9 and 62±28%, respectively. These changes were accompanied by increasing proportions of dibenzothiophene (DBT) and low molecular weight PAHs. Both, changes in PAH concentrations and composition were traceable within 200 and 350m distance to the river front of Moselle and Rhine, respectively, and likely favored by erosion of topsoil in vineyards. We conclude that the EU regulation was effective in improving soil and thus also air quality within only three years. The impact was greater and spatially more relevant at the Rhine, which may be attributed to the larger traffic volume of inland navigation.


[Future reproductive ability in post-treatment Asherman's syndrome patients].
Hysteroscopy is the best approach for the management of Asherman syndrome with reproductive purposes, since it allows a quick diagnosis and treatment of partial or total uterine adhesions. However, there are a few studies on the reproductive outcome in patients with Asherman's syndrome. Evaluate the results of adherenciolisis hysteroscopy in women with Asherman's syndrome. We performed a cohort study of thirty-nine patients diagnosed with Asherman's syndrome and who underwent surgical hysteroscopic adherenciolisis by bipolar energy through the period from 2006 to June 2011. Thirty-nine cases were reviewed. All patients restored their menstrual cycle in the course of the first three months after surgery. The pregnancy rate after hysteroscopic treatment was 71.7% (28/39), with a son living at home in 28.2% of the cases (11/39). There was no statistical difference to achieve term pregnancy based on a cut-off point at 35 years of age. A history of menstrual pattern before hysteroscopy was associated with perinatal success. All pregnancies were achieved spontaneously within the first year after the procedure. Spontaneous pregnancy is possible after hysteroscopic adherenciolisis in Asherman's Syndrome. It confirms the viability of using bipolar energy to restore the size and shape of the uterine cavity with minimal endometrial damage and with an exclusive reproductive purpose.


Prokaryotic expression of soluble IFN-λ1 recombinant protein with cold-shock system.
Interferon (IFN)-λ1, a member of type III IFN, possesses unique antiviral, anti-tumor, and immune modulation properties. IFN-λ alone or combined with other drugs is considered an essential therapeutic regimen in the clinic. Obtaining high-quality, biologically-active recombinant human IFN-λ1 (rhIFN-λ1) is of great practical significance. In this study, pCold-II-IFN-λ1 expression plasmid was correctly constructed, the rhIFN-λ1 was expressed in BL21(DE3) E.coli and reached the highest level under the optimal condition of 15 °C culture temperature and at 1 μg/L IPTG induction for 12 h. The soluble rhIFN-λ1 was purified by Ni-NTA affinity chromatography. The purified rhIFN-λ1 can effectively activate the JAK1-STAT1 signaling pathway and induce the expression of a large number of interferon-stimulated genes (ISG) including ISG15, ISG54, ISG56, TRAIL, OAS1, MX1, IRF7 and IRF9. In addition, rhIFN-λ1 can effectively inhibit the growth/proliferation of cervical cancer HeLa cells in a dose-dependent pattern. Collectively, the soluble rhIFN-λ1 was successfully expressed in BL21(DE3) E.coli with the cold-shock system, and the purified rhIFN-λ1 demonstrated excellent biological activity. This study lays a solid basis for acquiring high-quality rhIFN-λ1 and its clinical application.


Apoptosis as the mode of cell death in antibody-dependent lymphocytotoxicity.
A light and electron microscopic study of antibody-dependent lymphocytotoxicity was carried out with the object of elucidating the mechanisms responsible for the cell killing, the basis for the research being the relationship that has recently been shown to exist between the morphology of cell death and its pathogenesis. Chang liver cells coated with a rabbit anti-human antibody were used as targets and normal human peripheral-blood lymphocytes as effector cells. Cytotoxicity assays using release of 51Cr demonstrated extensive K-cell killing, thus validating the suitability of the model for morphological studies. Cell death displaying the features of apoptosis correlated with K-cell activity. A small amount of cell death by classical necrosis was observed, but its extent appeared to be unrelated to the presence of lymphocytes, to pre-treatment of the target cells with antibody, or to the magnitude of 51Cr release. The results support evidence indicating that lymphocytotoxicity depends on activation of a self-destruct program within the target cell. They do not favour a mechanism involving the production of plasma membrane lesions analogous to those responsible for complement-mediated immune cytolysis.


Marine plastic pollution detection and identification by using remote sensing-meta analysis.
The persistent plastic litter, originating from different sources and transported from rivers to oceans, has posed serious biological, ecological, and chemical effects on the marine ecosystem, and is considered a global issue. In the past decade, many studies have identified, monitored, and tracked marine plastic debris in coastal and open ocean areas using remote sensing technologies. Compared to traditional surveying methods, high-resolution (spatial and temporal) multispectral or hyperspectral remote sensing data have been substantially used to monitor floating marine macro litter (FMML). In this systematic review, we present an overview of remote sensing data and techniques for detecting FMML, as well as their challenges and opportunities. We reviewed the studies based on different sensors and platforms, spatial and spectral resolution, ground sampling data, plastic detection methods, and accuracy obtained in detecting marine litter. In addition, this study elaborates the usefulness of high-resolution remote sensing data in Visible (VIS), Near-infrared (NIR), and Short-Wave InfraRed (SWIR) range, along with spectral signatures of plastic, in-situ samples, and spectral indices for automatic detection of FMML. Moreover, the Thermal Infrared (TIR), Synthetic aperture radar (SAR), and Light Detection and Ranging (LiDAR) data were introduced and these were demonstrated that could be used as a supplement dataset for the identification and quantification of FMML.


Experiences and motives of retirement-aged workers during the first wave of COVID-19 in Slovenia: "This was the first time in 40 years that I really saw spring".
Choosing to continue working after retirement eligibility can attract both negative and positive sentiments from the general public. Studies examining the motivations of older workers have so far been conducted in times of relative social and economic stability. However, little is known about what it means for older workers to work during a lockdown or pandemic situation. The present longitudinal study aimed to explore experiences of retirement-aged workers in Slovenia in relation to their motives for prolonged work activity amid the COVID-19 pandemic, using the theory of gerotranscendence as a theoretical framework. Nine workers were interviewed before and after the start of the pandemic. The qualitative analysis was based on 18 interviews and observations, juxtaposing two analytical methods in order to illustrate common themes across the data as well as tensions in specific situations within a narrative context. Four main themes are presented: Unchanged plans, Motive developments, Psychological preparation for retirement and Views of society. In addition, a narrative analysis is presented with a focus on self-transcending elements in some of the participants' narratives. The findings suggest that during a pandemic, older workers' individual experiences might be constructed more positively compared to other groups, especially if they develop agentic identity and pursue meaningful activities. We discuss an innovative approach to gerotranscendence, complementing this theory with concepts from occupational science to develop a clearer distinction from the now dated disengagement theory and examine the life trajectories of older workers in novel situations such as a pandemic.


Effective model hierarchies for dynamic and static classical density functional theories.
The origin and methodology of deriving effective model hierarchies are presented with applications to solidification of crystalline solids. In particular, it is discussed how the form of the equations of motion and the effective parameters on larger scales can be obtained from the more microscopic models. It will be shown that tying together the dynamic structure of the projection operator formalism with static classical density functional theories can lead to incomplete (mass) transport properties even though the linearized hydrodynamics on large scales is correctly reproduced. To facilitate a more natural way of binding together the dynamics of the macrovariables and classical density functional theory, a dynamic generalization of density functional theory based on the nonequilibrium generating functional is suggested.


Utility of testing for monoclonal bands in serum of patients with suspected osteoporosis: retrospective, cross sectional study.
To determine whether measuring monoclonal bands (M component) in serum should be part of the investigation of patients referred to osteoporosis clinics. Retrospective, cross sectional, observational study. Referral centre for osteoporosis in a university hospital, Denmark. 799 people (685 women) aged 19 to 94 years newly referred with suspected osteoporosis. Proportion of patients fulfilling the Nordic Myeloma Study Group definition for target condition and proportion of patients with other important haematological conditions. 4.9% (18 of 366) of patients with osteoporosis and 2.2% (9 of 408) of patients without osteoporosis had M component in serum (chi2 = 3.66, P = 0.04). Multiple myeloma was diagnosed in three patients with osteoporosis (absolute risk 0.8%, 95% confidence interval 0.11% to 1.7%). The relative risk of multiple myeloma in patients presenting with osteoporosis was 75 (10 to 160). As a diagnostic test for multiple myeloma in patients with osteoporosis, M component in serum had a specificity of 95.0% and a positive predictive value of 17.6%. 122 blood electrophoreses were carried out for each case of multiple myeloma diagnosed. All patients with multiple myeloma had a history of fragility fractures. If lymphoma was included as a target condition, the specificity increased to 95.3% and the positive predictive value increased to 23.5%. Monoclonal gammopathy of undetermined significance was diagnosed in 13 (3.6%) participants with osteoporosis and in eight (2.0%) participants with normal bone mineral density or osteopenia. Patients presenting with osteoporosis should be tested for M component in serum, as 1 in 20 patients with newly diagnosed osteoporosis had multiple myeloma or monoclonal gammopathy of undetermined significance.


A 3-year-old with spinal cord injury without radiographic abnormality (SCIWORA).
The results of hyperextension, flexion, and traction injuries can be devastating and permanent; the results of treatment, dismal. Reducing the incidence of spinal cord injury requires education about the proper use of automobile restraint devices, scene of injury immobilization, selection of child-appropriate furniture, diving safety, and increased awareness of the risks of contact sports. Immediate treatment should center on strict cervical spine immobilization until complete neurologic and radiologic evaluations have been completed, with special awareness of the possibility of SCIWORA.


Ambient Fabrication of Organic-Inorganic Hybrid Perovskite Solar Cells.
Organic-inorganic hybrid perovskite solar cells (PSCs) have attracted significant attention in recent years due to their high-power conversion efficiency, simple fabrication, and low material cost. However, due to their high sensitivity to moisture and oxygen, high efficiency PSCs are mainly constructed in an inert environment. This has led to significant concerns associated with the long-term stability and manufacturing costs, which are some of the major limitations for the commercialization of this cutting-edge technology. Over the past few years, excellent progress in fabricating PSCs in ambient conditions has been made. These advancements have drawn considerable research interest in the photovoltaic community and shown great promise for the successful commercialization of efficient and stable PSCs. In this review, after providing an overview to the influence of an ambient fabrication environment on perovskite films, recent advances in fabricating efficient and stable PSCs in ambient conditions are discussed. Along with discussing the underlying challenges and limitations, the most appropriate strategies to fabricate efficient PSCs under ambient conditions are summarized along with multiple roadmaps to assist in the future development of this technology.


Overcoming the response plateau in multiple myeloma: a novel bortezomib-based strategy for secondary induction and high-yield CD34+ stem cell mobilization.
This phase II study evaluated bortezomib-based secondary induction and stem cell mobilization in 38 transplant-eligible patients with myeloma who had an incomplete and stalled response to, or had relapsed after, previous immunomodulatory drug-based induction. Patients received up to six 21-day cycles of bortezomib plus dexamethasone, with added liposomal doxorubicin for patients not achieving partial response or better by cycle 2 or very good partial response or better (≥VGPR) by cycle 4 (DoVeD), followed by bortezomib, high-dose cyclophosphamide, and filgrastim mobilization. Gene expression/signaling pathway analyses were conducted in purified CD34+ cells after bortezomib-based mobilization and compared against patients who received only filgrastim ± cyclophosphamide. Plasma samples were similarly analyzed for quantification of associated protein markers. The response rate to DoVeD relative to the pre-DoVeD baseline was 61%, including 39% ≥ VGPR. Deeper responses were achieved in 10 of 27 patients who received bortezomib-based mobilization; postmobilization response rate was 96%, including 48% ≥ VGPR, relative to the pre-DoVeD baseline. Median CD34+ cell yield was 23.2 × 10(6) cells/kg (median of 1 apheresis session). After a median follow-up of 46.6 months, median progression-free survival was 47.1 months from DoVeD initiation; 5-year overall survival rate was 76.4%. Grade ≥ 3 adverse events included thrombocytopenia (13%), hand-foot syndrome (11%), peripheral neuropathy (8%), and neutropenia (5%). Bortezomib-based mobilization was associated with modulated expression of genes involved in stem cell migration. Bortezomib-based secondary induction and mobilization could represent an alternative strategy for elimination of tumor burden in immunomodulatory drug-resistant patients that does not impact stem cell yield.


In vitro effects of aged garlic extract and other nutritional supplements on sickle erythrocytes.
In the circulation of sickle cell anemia patients, a certain population of erythrocytes has an elevated density. These abnormally dense cells are believed to be at the root of the painful crisis and anemia of the patients. We have developed an in vitro method for the preparation of these heavier erythrocytes by a repeated deoxy-oxy cycling of erythrocytes from sickle cell anemia patients. By using this method, we studied whether certain nutritional supplements would inhibit the formation of dense cells in vitro. It was found that aged garlic extract (AGE) as well as its components with antioxidant activity, i.e., S-allylcysteine and N alpha-(1-deoxy-D-fructos-1-yl)-L-arginine (fructosyl arginine), inhibited the formation of dense cells in vitro. Vitamin C, vitamin E and the spin-trapping agents, 5-diethoxyphophoryl-5-methyl-1-pyrroline-N-oxide and alpha-(4-pyridyl-1-oxide)-N-t-butylnitrone were all found to inhibit the formation of dense cells in vitro. These results suggest that, when extremely stretched sickle-shaped cells are formed by the repeated deoxy-oxy cycling, the erythrocyte membrane becomes susceptible to oxidative injury by reactive oxygen species. The protection of the erythrocyte membrane from such an oxidative injury would prevent the membranes from becoming leaky to the calcium ion, thus inhibiting the activation of the calcium-activated potassium efflux channel and the formation of dense cells. We also developed a new ex vivo method of studying the possible efficacy of antioxidants taken orally on the dense cell formation in sickle cell patients. It involved the use of blood plasma taken from a healthy donor (with normal hemoglobin) of AB blood type who had consumed different types of antioxidants orally. By suspending sickle erythrocytes in such plasma and exposing them to the deoxy-oxy cycling, the degree of dense cell formation was determined. The degree of inhibition in vitro by antioxidants taken orally may be related to their efficacy in inhibiting dense cell formation in the patients. On the basis of these in vivo and ex vivo studies, we propose that a cocktail of antioxidants would have beneficial effects in lessening the incidence and severity of crisis and reducing anemia in sickle cell disease.


Prediction of impending hemorrhagic transformation in ischemic stroke using magnetic resonance imaging in rats.
Hemorrhagic transformation (HT) of ischemic brain tissue may occur in stroke patients either spontaneously or after thrombolysis. A method to assess the risk of HT in ischemic tissue after stroke would improve the safety of thrombolytic therapy. As a means of predicting HT, we investigated the role of contrast-enhanced MRI at acute time points in a rat middle cerebral artery occlusion model with reperfusion. Intraluminal suture occlusion of the middle cerebral artery was used to produce transient ischemia in male Wistar rats (n=11). Reperfusion was performed by withdrawal of the occluding filament after 2 (n=4), 3 (n=6), or 4 (n=1) hours. MRI studies were performed before and after reperfusion with the use of conventional T1-weighted imaging, with and without gadolinium (Gd-DTPA) contrast agent, and T2-weighted imaging. Follow-up MRI and histological studies were obtained at 24 hours. Petechial hemorrhage occurred by 24 hours in 9 of 11 animals. All animals showed brain swelling and cellular death throughout the ischemic region at 24 hours. A hyperintense region in the preoptic area became visible after Gd-DTPA injection within minutes after reperfusion in animals with subsequent HT. All animals showing acute Gd-DTPA enhancement subsequently developed petechial hemorrhage (or died) by 24 hours. In these animals, statistically significant differences in signal intensity (P=.0005) between the ipsilateral enhancing region and a homologous contralateral region were detected on post-Gd-DTPA T1-weighted imaging. There was also a statistically significant correlation (P=.01) between the rate of Gd-DTPA uptake and the size of the enhancing area. Two animals did not enhance with Gd-DTPA and did not exhibit hemorrhage on histological examination or MRI at 24 hours. No abnormalities were seen on precontrast T1-weighted images before and shortly after reperfusion or postcontrast T1-weighted images before reperfusion. The primary finding of this study was the detection of early Gd-DTPA parenchymal enhancement in 82% of the animals after reperfusion. Enhancement was seen before any detectable hemorrhage, suggesting that early endothelial ischemic damage occurs before gross brain infarction and hemorrhage. Thus, we suggest that acute Gd-DTPA enhancement may provide an early prediction of petechial hemorrhage.


Low-dose short synacthen test with salivary cortisol in patients with suspected central adrenal insufficiency.
The low-dose short synacthen test (LDSST) is recommended for patients with suspected central adrenal insufficiency (AI) if their basal serum cortisol (F) levels are not indicative of an intact hypothalamic-pituitary-adrenal (HPA) axis. To evaluate diagnostic threshold for salivary F before and 30 min after administering 1 μg of synacthen, performed before 09:30 h. A cross-sectional study from 2014 to 2020. A tertiary referral university hospital. In this study, 174 patients with suspected AI, 37 with central AI and 137 adrenal sufficient (AS), were included. The diagnostic accuracy (sensitivity (SE), specificity (SP)) of serum and salivary F levels measured, respectively, by chemiluminescence immunoassay and liquid chromatography-tandem mass spectrometry. Low basal serum or salivary F levels could predict AI. For the LDSST, the best ROC-calculated threshold for serum F to differentiate AI from AS was 427 nmol/L (SE 79%, SP 89%), serum F > 500 nmol/L reached SP 100%. A salivary F peak > 12.1 nmol/L after administering synacthen reached SE 95% and SP 84% for diagnosing central AI, indicating a conclusive reduction in the likelihood of AI. This ROC-calculated threshold for salivary F was similar to the 2.5th percentile of patients with a normal HPA axis, so it was considered sufficient to exclude AI. Considering AS those patients with salivary F > 12.1 nmol/L after LDSST, we could avoid unnecessary glucocorticoid treatment: 99/150 subjects (66%) had an inadequate serum F peak after synacthen, but salivary F was >12.1 nmol/L in 79 cases, who could, therefore, be considered AS. Salivary F levels > 12.1 nmol/L after synacthen administration can indicate an intact HPA axis in patients with an incomplete serum F response, avoiding the need to start glucocorticoid replacement treatment.


[Hotels and sanatoria: the influence of tuberculosis on mass tourism architecture].
The aim of this article is to verify the influence of tuberculosis on mass tourism architecture. To achieve this, the paper analyses the typological evolution of the hotel since the middle of the nineteenth century, when the first sanatoria appeared in the alpine resorts. A study that creates links between the progress in architecture and the medical therapy advances. The goal is to highlight the hybridisation process between both architectural typologies. Although this overlapping is developed until the Second World War, the influence of its mixture is still present in contemporary mass tourism architecture.


Developing professionalism in Italian medical students: an educational framework.
Developing and assessing professionalism in medical students is an international challenge. This paper, based on preliminary research at the Faculty of Medicine and Dentistry of the University Sapienza of Rome, Italy, briefly summarizes the main issues and experiences in developing professionalism among Italian undergraduate medical students. It concludes with a proposed framework suited to the Italian medical curricula. In our educational system, professionalism is defined as the context of medical expertise, the combination of rules, conditions, and meanings in which the act of health care occurs, as well as the ability of critical reflection on technical expertise. It is a multidimensional construct of ethical, sociocultural, relational, and epistemological competencies, requiring a wide range of tools for assessment. With reference to Italian versions of validated tools of measure, vignettes, videos, and a student's portfolio of reflective writings, this paper outlines the manner in which education for professionalism is embedded in the existing curriculum and overall framework of assessment.


Association study of gene polymorphisms and depression with abnormal humor in traditional Uighur medicine.
According to the humor theory of Traditional Uighur Medicine (TUM), a same disease is classified into different abnormal humor types and corresponding methods are applied to treat the diseases according to the type of abnormal humor characteristics. To date the biological foundation of classification of diseases by humor theory has been little studied and the mechanism of action is still unclear. In the present study, we aimed to investigate the association between some related gene polymorphisms and depression with abnormal humor in TUM. 201 cases of depression patients in a Uighur population were divided into two groups as: 107 cases of depression patients with abnormal black bile (ABB), 94 cases of depression patients with none abnormal black bile (nABB), and 50 healthy people were served as control group. Venous blood was used to isolate DNA samples, and the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used for genotyping of single nucleotide polymorphisms (SNPs). Polymorphisms in the serotonin 2A (5-HT2A) receptor gene, brain derived neurotrophic factor (BDNF), serotonin 1A (5-HT1A) receptor gene were investigated in each groups, respectively. The 5-HT2A A-1438G, 5-HT2A T102C, BDNF Val66Met, and 5-HT1A C-1019G gene polymorphisms showed significant association with ABB. However, no difference between nABB and controls was found for those genotype distribution and allele frequency. Moreover, the T102C and A1438G SNPs in the 5-HT2A receptor gene polymorphisms were in linkage disequilibrium. In addition, the OR associated with the combination of Val66Met-Val/Val genotype plus the presence of -1019C allele was 8.393 for ABB compared with controls (OR 8.393; 95% CI 1.807 ~ 38.991; P = 0.003). Moreover, the OR associated with the presence of -Met plus -1019C alleles was 12.194 for ABB compared with controls (OR 12.194; 95% CI 1.433 ~ 103.776; P = 0.005). The OR associated with the presence of -1438C/C plus Val/Val genotypes was 7.738 for ABB compared with controls (OR 7.738; 95% CI 1.566 ~ 38.241; P = 0.005). It was concluded that there were significant relationship between the gene polymorphisms and classification of depression with abnormal humor in TUM. The 5-HT2A A-1438G, 5-HT2A T102C, BDNF Val66Met, and 5-HT1A C-1019G gene polymorphisms might predict the incidence of depression with ABB.


Clinical spectrum of food allergy in children in Australia and South-East Asia: identification and targets for treatment.
The prevalence of atopic diseases is increasing worldwide for reasons that are not clear. Food allergies are the earliest manifestations of atopy. This review defines the foods most commonly involved in allergic reactions and identifies an emerging group of syndromes in which food allergy is involved. A study of the frequency of food allergies in Australia and South-East Asia has recently shown that egg, cow's milk and peanut are the most common food allergens in Australia, but there were divergent results from different regions of South-East Asia. It is not clear whether the differences in reactivity to foods are due to genetic or cultural factors, but the findings raise the possibility that genetic susceptibility to food allergy may operate at the T-cell level modulated by the major histocompatibility complex. The Melbourne Milk Allergy Study defined a wide range of clinical symptoms and syndromes that could be reproduced by dietary challenge. A subsequent analysis of the infants with hypersensitivity to cow's milk and other multiple food proteins identified a new syndrome, multiple food protein intolerance of infancy. Food challenges demonstrated reactions developing slowly days after commencement of low-allergen soy formula or extensively hydrolysed formula. Follow-up at the age of 3 years showed that most children with this disorder tolerated most foods apart from cow's milk, egg and peanut. Atopic dermatitis affects about 18% of infants in the first 2 years of life. In a community-based study we have shown a very strong association (RR 3.5) between atopic dermatitis and infants with immunoglobulin E allergy to cow's milk, egg or peanut. Family studies on these infants have shown a link between atopic dermatitis and the genomic region 5q31 adjacent to the interleukin-4 gene cluster. Infantile colic (distress) affects 15-40% of infants in the first 4 months of life. Many theories of causation have been proposed, but a study from our centre showed that dietary modification, particularly that of breastfeeding mothers whose infants present with colic before the age of 6 weeks, alleviated symptoms. Colic associated with vomiting has been attributed to gastro-oesophageal reflux (GOR). This has been considered primarily a motility disorder, but a secondary form resulting from food protein intolerance has been described recently. We have also recently identified a group of infants with distressed behaviour attributed to GOR who have failed to respond to H2-receptor antagonists, prokinetic agents and multiple formula changes. Symptoms resolved on commencement of an elemental amino acid-based formula. In two-thirds of the patients, symptoms relapsed when challenged with low-allergen soy formula or extensively hydrolysed formula. We propose that a period of food protein intolerance is a part of the normal development of the immune system as it encounters common dietary proteins in infancy and early childhood. Future targets for research are development of appropriate dietary and management strategies for these entities and identification of genetic markers for these disorders.


A systematic review of stress and stress management interventions for mental health nurses.
Health care professionals in the United Kingdom (UK) appear to have higher absence and sickness rates than staff in other sectors, and stress may be a reason for nurses leaving their jobs. These problems need to be addressed, particularly in the mental health field, if current service provision is to be maintained. The aim was to identify stressors, moderators and stress outcomes (i.e. measures included those related to stress, burnout and job satisfaction) for mental health nurses, as these have clear implications for stress management strategies. A systematic review of research published in English between 1966 and 2000 and undertaken in the UK that specifically identified participants as mental health nurses was carried out to determine the effectiveness of stress management interventions for those working in mental health nursing. Studies from non-UK countries were examined as potential models of good practice. The study was limited to primary research papers that specifically involved mental health nurses, where the health outcomes measured were stressors, moderators and stress outcomes and where sufficient data was provided. The initial search identified 176 papers, of these 70 met the inclusion criteria. Seven studies have been reported since the completion of the review and have been included in this article. Sixty-nine focused on the stressors, moderators and stress outcomes and eight papers identified stress management techniques. Relaxation techniques, training in behavioural techniques, stress management workshops and training in therapeutic skills were effective stress management techniques for mental health nurses. Methodological flaws however, were detracted from the rigour of many of the studies. The review demonstrated that a great deal is known about the sources of stress at work, about how to measure it and about the impact on a range of outcome indicators. What was found to be lacking was a translation of these results into practice, into research that assessed the impact of interventions that attempt to moderate, minimize or eliminate some of these stressors.


Complications and 30-Day readmission rates after craniotomy/craniectomy: A single Institutional study of 243 consecutive patients.
Early hospital readmission has become a proxy for quality of care and contributes significantly to high health care costs in the United States, with more than $20 billion health care dollars are spent on 30-day readmission annually. Cranial neurosurgical procedures (i.e., craniotomy, craniectomy) are associated with high readmission rates; however, studies examining readmission after cranial procedures are limited and relatively unknown. The aim of this study is to identify the drivers of 30-day unplanned readmission in consecutive patients undergoing craniotomies and craniectomies. The medical records of 243 consecutive patients undergoing either craniotomy or craniectomy at a major academic institution in 2011 were reviewed. Patient demographics, comorbidities, intra- and post-operative complication rates were collected for each patient. We identified all unplanned readmissions within 30 days of discharge. A total of 10 (4.1%) unplanned 30-day readmissions were identified. The mean ± SD age was 58.58 ± 15.12 years. The most common indication for surgery was malignancy (63.4%) followed by Chiari malformation (10.3%), epilepsy (5.3%), and skull lesion/deformity (2.9%). The majority of patients presented to the emergency department from home (80%), while 10% were readmitted from a skilled nursing facility and 10% were readmitted from an acute rehabilitation institution. The most common presented symptoms for readmitted patients were fever/presumed infection (40%) and altered mental status (40%), followed by new sensory/motor deficits (30%). This study suggests that infection, altered mental status, and new sensory/motor deficits were the primary complications leading to unplanned 30-day readmission after cranial neurosurgery.


Membrane particle arrays in SV40-transformed 3T3 cells.
The ultrastructural organization of the plasma membrane of untransformed and simian virus (SV)40-transformed 3T3 cells in culture was studied by an in situ freeze-fracturing technique. Both 3T3 and SV3T3 cells showed randomly distributed intramembrane particles as well as gap junctions. In addition, the plasma membrane (P-face) of confluent SV40-transformed 3T3 cells was found to display a unique membrane specialization which was not observed in normal 3T3 cells. This membrane specialization consisted of irregularly-shaped arrays of loosely dispersed large (11-12 nm) intramembrane particles, located in regions of close contact between adjacent SV3T3 cells. When a P- to E-fracture face transition occurred within the boundaries of a particle array, the intracellular space appeared uniformly reduced and arrays of pits coextensive with the P-face particles could be recognized on the E-face. Particle arrays appeared particularly prominent in SV3T3 cells grown in the presence of high serum concentrations (20% foetal calf serum or calf serum). Particle arrays resembling those found in SV3T3 cells were observed only in very rare instances in the plasma membrane of other virus-transformed cell lines. Several possible interpretations of the meaning of the particle arrays, including the hypothesis thay they represent an unusual or abortive form of intracellular junction, are discussed. The absence of similar membrane specializations in the plasma membrane of untransformed 3T3 cells points to a difference in membrane organization and cell contact ultrastructure between normal and SV40-transformed 3T3 cells.


Vitamin E and L-carnitine, separately or in combination, in the prevention of radiation-induced oral mucositis and myelosuppression: a controlled study in a rat model.
The aim of this study was to determine the effects of vitamin E (VE) and L-carnitine (LC) supplementation, separately or in combination, on radiation-induced oral mucositis and myelosuppression. Group 1 received no treatment (control). Group 2 received 15 Gray of 60Co gamma irradiation as a single dose to total cranium (IR). Group 3, 4, and 5 received irradiation plus 40 mg/kg/day VE (IR+VE) or 200 mg/kg/day LC (IR+LC) or in combination (IR+VE+LC) respectively. Clinically and histopathologically, assessments of mucosal reactions were performed by two independent experts in Radiation Oncology and Pathology, respectively. Hematologic analyses and antioxidant enzyme evaluations were also performed. Irradiation significantly increased oral mucositis, and decreased thrombocyte and White Blood Cell counts. A significant increase in malondialdehyde (MDA) levels and decrease in superoxide dismutase (SOD) and catalase (CAT) activities in plasma were found in the IR group. VE and LC administration, separately, plus irradiation significantly delayed the starting day, and reduced the severity of, oral mucositis. This administration also reduced a fall in the numbers of thrombocyte and WBC caused by irradiation, and decreased the MDA level, and increased the activity of SOD and CAT enzymes in the plasma. VE and LC, in combination, plus irradiation did not provide a superior radioprotection against radiation-induced toxicities.


Salicylic Acid Regulates Pollen Tip Growth through an NPR3/NPR4-Independent Pathway.
Tip growth is a common strategy for the rapid elongation of cells to forage the environment and/or to target to long-distance destinations. In the model tip growth system of Arabidopsis pollen tubes, several small-molecule hormones regulate their elongation, but how these rapidly diffusing molecules control extremely localized growth remains mysterious. Here we show that the interconvertible salicylic acid (SA) and methylated SA (MeSA), well characterized for their roles in plant defense, oppositely regulate Arabidopsis pollen tip growth with SA being inhibitory and MeSA stimulatory. The effect of SA and MeSA was independent of known NPR3/NPR4 SA receptor-mediated signaling pathways. SA inhibited clathrin-mediated endocytosis in pollen tubes associated with an increased accumulation of less stretchable demethylated pectin in the apical wall, whereas MeSA did the opposite. Furthermore, SA and MeSA alter the apical activation of ROP1 GTPase, a key regulator of tip growth in pollen tubes, in an opposite manner. Interestingly, both MeSA methylesterase and SA methyltransferase, which catalyze the interconversion between SA and MeSA, are localized at the apical region of pollen tubes, indicating of the tip-localized production of SA and MeSA and consistent with their effects on the apical cellular activities. These findings suggest that local generation of a highly diffusible signal can regulate polarized cell growth, providing a novel mechanism of cell polarity control apart from the one involving protein and mRNA polarization.


Increased Cell Adhesion Molecules, PECAM-1, ICAM-3, or VCAM-1, Predict Increased Risk for Flare in Patients With Quiescent Inflammatory Bowel Disease.
Predicting the risk of flare-ups for patients with inflammatory bowel disease (IBD) is difficult. Alterations in gut endothelial regulation of mucosal immune homeostasis might be early events leading to flares in IBD. Cell adhesion molecules (CAMs), in particular, are important in maintaining endothelial integrity and regulating the migration of leukocytes into the gut. We evaluated the mRNA expression of various tight junction proteins, with an emphasis on CAMs, in 40 patients with IBD in clinical remission. Patients were retrospectively assessed at 6, 12, and 24 months after baseline colonoscopy, and at the end of all available follow-up (maximum 65 mo), for flare events to determine whether baseline mRNA expression was associated with subsequent flares. At all follow-up points, the baseline expression of platelet endothelial cell adhesion molecule-1 (PECAM-1), ICAM-3, and VCAM-1 was significantly higher in patients who flared than in those who did not (2.4-fold elevation, P=0.012 for PECAM-1; 1.9-fold increased, P=0.03 for ICAM-3; and 1.4-fold increased, P=0.02 for VCAM-1). PECAM-1 and ICAM-3 expression was significantly increased in patients who flared as early as 6 months after baseline colonoscopy. In contrast, there were no significant differences between patients with and without flares in baseline expression of other CAMs (ESAM, ICAM-1, ICAM-2, E-selectin, P-selectin, and MadCAM1). Increased expression of PECAM-1, ICAM-3, and VCAM-1 in colonic biopsies from patients with IBD in clinical remission is associated with subsequent flares. This suggests that increases in the expression of these proteins may be early events that lead to flares in patients with IBD.


[Wound healing of the corneal posterior surface in animal experiments].
Autoradiographic studies using tritiated thymidine as a precursor of DNA synthesis show that the process of wound healing of the corneal endothelium in both rhesus monkeys and rabbits following scarification and cryocoagulation takes place for the most part by means of cell proliferation. After injection of tritiated thymidine into the anterior chamber immediately prior to sacrifice, autoradiographically labeled flat mounts and cross-section preparations of the corneas of 7 rhesus monkeys and 14 rabbits were examined at lesion ages ranging from 4 hours to 10 days. In the monkeys scarcely 10% of the endothelial cells in the areas of the corneal lesions or at their borders were in the S-phase in the autoradiographically labeled flat mounts 24 hours to 3 days after injury, whereas up to 39% of those in the rabbits were seen to be so after 18 hours. In the monkeys one could discern mitoses between the 2nd and 5th days, and amitoses (binuclear cells) were found in 1-day and 3-day animals. In rabbits numerous mitoses could be discerned between the 1st and 5st days, but no multinuclear cells were seen. Healing of the corneal endothelium in the monkeys occurred some-what later and was less pronounced than in the rabbits.


Preventing meningococcal infection in college students.
The incidence of invasive meningococcal disease in adolescents and young adults of high school and college age has recently increased in the United States. Recent studies indicate that certain groups of college students are at increased risk. This has led to the recent Advisory Committee Immunization Practices recommendation that college freshman dormitory residents be provided information about meningococcal infection and the benefits of vaccination. Future studies will need to focus on the potential vaccine prevention of the increased risk of meningococcal infection in persons of high school age, particularly as new conjugate meningococcal vaccines become available.


Inhibitory effect of oat products on non-haem iron absorption in man.
Oat products are increasingly used in human nutrition due to the rather high content of soluble fibre. Oat products, however, have a high content of phytate which may interfere with the absorption of non-haem iron. The iron balance situation is critical in several groups, especially in children, teenagers and women in their fertile years. It is therefore important to examine the effect of oat products on non-haem iron absorption in man. The present studies showed that oat bran and oat porridge markedly inhibited the absorption of non-haem iron. The inhibition can be explained by the high phytate content of oat products. This is partly due to a high resistance of oat phytate against exogenous phytase and partly to an inactivation of the endogenous phytase in oats caused by the usual heat treatment of oats which is made to prevent rancidity of oat lipids during storage. The inhibitory effect of oat products on iron absorption is sufficiently marked to be a serious consideration if such products are more regularly consumed.


Automated analysis of medial gastrocnemius muscle-tendon junction displacements in heathy young adults during isolated contractions and walking using deep neural networks.
Direct measurement of muscle-tendon junction (MTJ) position is important for understanding dynamic tendon behavior and muscle-tendon interaction in healthy and pathological populations. Traditionally, obtaining MTJ position during functional activities is accomplished by manually tracking the position of the MTJ in cine B-mode ultrasound images - a laborious and time-consuming process. Recent advances in deep learning have facilitated the availability of user-friendly open-source software packages for automated tracking. However, these software packages were originally intended for animal pose estimation and have not been widely tested on ultrasound images. Therefore, the purpose of this paper was to evaluate the efficacy of deep neural networks to accurately track medial gastrocnemius MTJ positions in cine B-mode ultrasound images across tasks spanning controlled loading during isolated contractions to physiological loading during treadmill walking. Cine B-mode ultrasound images of the medial gastrocnemius MTJ were collected from 15 subjects (6M/9F, 23 yr, 71.9 kg, 1.8 m) during treadmill walking at 1.25 m/s and during maximal voluntary isometric plantarflexor contractions (MVICs). Five deep neural networks were trained using 480 manually-labeled images collected during walking, defined as the ground truth, and were then used to predict MTJ position in images from novel subjects: 1) during walking (novel-subject) and 2) during MVICs (novel-condition). We found an average mean absolute error of 1.26±1.30 mm and 2.61±3.31 mm between the ground truth and predicted MTJ positions in the novel-subject and novel-condition evaluations, respectively. Our results provide support for the use of open-source software for creating deep neural networks to reliably track MTJ positions in B-mode ultrasound images. We believe this approach to MTJ position tracking is an accessible and time-saving solution, with broad applications for many fields, such as rehabilitation or clinical diagnostics.


A concept for improving Atlantic salmon Salmo salar smolt migration past hydro power intakes.
In this study, cost effective (in terms of reducing loss of power production) measures for increasing bypass migration of Atlantic salmon Salmo salar were developed and tested by establishing statistical models for timing of smolt migration and favourable diversion of water to the bypass. Initial tracking of radio-tagged smolts showed very low bypass migration under normal hydropower operations. Bypass migration increased when bypass discharge was experimentally increased and a model was developed that described relationships between total river discharge, bypass diversion and smolt migration route. Further improvements were obtained by installing two strobe lights at the power-production tunnel entrance that increased bypass migration during the night, but not during daytime. According to the behaviour of radio-tagged fish, the implemented measures contributed to increasing the annual percentage of bypass migration from 11 to 64%, and according to model predictions to 60-74% when the hydropower facilities were operated according to the developed models. To ensure correct timing of discharge diversion a smolt migration model was developed based on environmental variables that could successfully predict the general pattern of migration timing. The concept presented for improving smolt migration past hydropower intakes should be applicable in many systems where migration past hydropower installations cannot easily be solved by screening systems.


Entering into a system of care: A qualitative study of carers of older community-dwelling Australians.
Informal carers provide the majority of care to older Australians and play an essential role in assisting older people with complex care needs to remain living in their own homes. As such, carers are increasingly faced with systemic responsibilities, including coordinating services across multifaceted health and aged care systems and negotiating treatment and supports. The aim of this study was to explore how systemic complexity and associated work is experienced by carers of older adults and what personal capacities carers draw on in managing the systemic work. A descriptive phenomenological approach guided the research. Semistructured interviews were conducted with 16 carers of community-dwelling older adults with complex care needs recruited through a local health service. Giorgi's phenomenological data analysis methods (1997) was utilised for the data analysis. Two main themes were derived from the analysis: Becoming part of the caring system and Mastering the caring system. The findings indicate that the majority of carers perceived the work of interacting with multiple systems and services as a burden and an onerous obligation. Furthermore, change in the health or social circumstances of the older adult amplified differences in the nature of the systemic work and concomitantly revealed differences in carers' capacities. This paper reveals that the caring system is in some sense disposed to create disparities, as carers' specific capacities were integral to mastering the systemic work. An understanding of informal care work that supports older people to live in the community can assist health care professionals and service providers to better identify carer requirements and assess carer capacity to manage the work.


Familial warfarin resistance.
Warfarin, a coumarin anticoagulant, acts by interfering with the hepatic synthesis of the vitamin-K-dependent clotting factors. It is used clinically in the treatment or prophylaxis of venous thrombosis and embolisms. Resistance to the effects of the coumarin and indanedione anticoagulants has been reported in rats and man, but its incidence has been defined as extremely rare. Resistance has been described as relative, acquired, or hereditary. The first well-documented case was also the first report to identify a genetic basis for this resistance. Since that time, there has been only one other study that strengthened the evidence for a hereditary transmission, and only a few other reports have suggested hereditary influence as a reason for coumarin resistance. In this report, a patient who presented with a familial-type warfarin resistance is described. A discussion of previous reports and possible mechanisms for nonfamilial warfarin resistance is also included.


[Surgical procedures in selected proctological patients with local anesthesia. Study of 150 cases].
Experience in the treatment of 150 patients with anorectal disorders and disorders of the sacrococcygeal region who were operated on with local anesthesia at the University Hospital, ABC Medical School, São Bernardo do Campo, SP, Brazil, from March 1995 to March 1998. The anesthesia technique, the operations carried out and the tolerance to the procedure are reported. Intraoperative morbidity was 10.6% (16 patients), and postoperative morbidity was 6% (nine patients). The age of patients was between 15 and 92 years old, with mean age 42 years old; 58% of patients were male and 42% female. Surgical mean time was 45 minutes and the patients remained in the hospital for a mean time of 8 hours. All of patients was instructed about the anesthesia technique, their advantages and disadvantages, and only with their permit the surgery was programmed. Hospitalization was required in five patients (3.3%). The anesthesia technique employed was the same for all patients. Upon survey, 96.7% of the patients stated they did not feel pain during the surgery and that they would go through the procedure again. The authors conclude the surgical treatment of anorectal disorders and disorders of the sacrococcygeal region with local anesthesia is viable and safe, and in addition, is well accepted by the patients.


Experimental study of temporal-spatial binary pattern projection for 3D shape acquisition.
Three-dimensional (3D) acquisition of an object with modest accuracy and speed is of particular concern in practice. The performance of digital sinusoidal fringe pattern projection using an off-the-shelf digital video projector is generally discounted by the nonlinearity and low switch rate. In this paper, a binary encoding method to encode one computer-generated standard sinusoidal fringe pattern is presented for circumventing such deficiencies. In previous work [Opt. Eng.54, 054108 (2015)OPEGAR0091-328610.1117/1.OE.54.5.054108], we have developed a 3D system based on this encoding tactic and showed its prospective application. Here, we first build a physical model to explain the mechanism of how to generate good sinusoidality. The phase accuracy with respect to the conventional spatial binary encoding method and sinusoidal fringe pattern is also comparatively evaluated through simulation and experiments. We also adopt two phase-height mapping relationships to experimentally compare the measurement accuracy among them. The results indicate that the proposed binary encoding strategy has a comparable performance to that of sinusoidal fringe pattern projection and enjoys advantages over the spatial binary method under the same conditions.