Transcription of the gene encoding TNF-α is increased by IL-1β in rat and human islets and β-cell lines.
Synthesis and secretion of immunomodulatory proteins, such as cytokines and chemokines, controls the inflammatory response within pancreatic islets. When this inflammation does not resolve, destruction of pancreatic islet β-cells leads to diabetes mellitus. Production of the soluble mediators of inflammation, such as TNF-α and IL-1β, from resident and invading immune cells, as well as directly from islet β-cells, is also associated with suboptimal islet transplantation outcomes. In this study, we found that IL-1β induces rapid increases in TNF-α mRNA in rat and human islets and the 832/13 clonal β-cell line. The surge in transcription of the TNF-α gene required the inhibitor of kappa B kinase beta (IκKβ), the p65 subunit of the NF-κB and a signal-specific recruitment of RNA polymerase II to the gene promoter. Of note was the increased intracellular production of TNF-α protein in a manner consistent with mRNA accumulation in response to IL-1β, but no detectable secretion of TNF-α into the media. Additionally, TNF-α specifically induces expression of CD11b, but not CD11c, on neutrophils, which could contribute to the inflammatory milieu and diabetes progression. We conclude that activation of the NF-κB pathway in pancreatic β-cells leads to rapid intracellular production of the pro-inflammatory TNF-α protein through a combination of specific histone covalent modifications and NF-κB signaling pathways.


Engineering the plant metabolic system by exploiting metabolic regulation.
Plants are the most sophisticated biofactories and sources of food and biofuels present in nature. By engineering plant metabolism, the production of desired compounds can be increased and the nutritional or commercial value of the plant species can be improved. However, this can be challenging because of the complexity of the regulation of multiple genes and the involvement of different protein interactions. To improve metabolic engineering (ME) capabilities, different tools and strategies for rerouting the metabolic pathways have been developed, including genome editing and transcriptional regulation approaches. In addition, cutting-edge technologies have provided new methods for understanding uncharacterized biosynthetic pathways, protein degradation mechanisms, protein-protein interactions, or allosteric feedback, enabling the design of novel ME approaches.


PRMT5 Circular RNA Promotes Metastasis of Urothelial Carcinoma of the Bladder through Sponging miR-30c to Induce Epithelial-Mesenchymal Transition.
Circular RNAs (circRNAs), a novel class of noncoding RNAs, have recently drawn lots of attention in the pathogenesis of human cancers. However, the role of circRNAs in cancer cells epithelial-mesenchymal transition (EMT) remains unclear. In this study, we aimed to identify novel circRNAs that regulate urothelial carcinoma of the bladder (UCB) cells' EMT and explored their regulatory mechanisms and clinical significance in UCBs. We first screened circRNA expression profiles using a circRNA microarray in paired UCB and normal tissues, and then studied the clinical significance of an upregulated circRNA, circPRMT5, in a large cohort of patients with UCB. We further investigated the functions and underlying mechanisms of circPRMT5 in UCB cells' EMT. Moreover, we evaluated the regulation effect of circPRMT5 on miR-30c, and its target genes, SNAIL1 and E-cadherin, in two independent cohorts from our institute and The Cancer Genome Atlas (TCGA). We demonstrated that upregulated expression of circPRMT5 was positively associated with advanced clinical stage and worse survival in patients with UCB. We further revealed that circPRMT5 promoted UCB cell's EMT via sponging miR-30c. Clinical analysis from two independent UCB cohorts showed that the circPRMT5/miR-30c/SNAIL1/E-cadherin pathway was essential in supporting UCB progression. Importantly, we identified that circPRMT5 was upregulated in serum and urine exosomes from patients with UCB, and significantly correlated with tumor metastasis. CircPRMT5 exerts critical roles in promoting UCB cells' EMT and/or aggressiveness and is a prognostic biomarker of the disease, suggesting that circPRMT5 may serve as an exploitable therapeutic target for patients with UCB.


Valid and powerful second-level group statistics for decoding accuracy: Information prevalence inference using the i-th order statistic (i-test).
In functional magnetic resonance imaging (fMRI) decoding studies using pattern classification, a second-level group statistical test is typically performed after first-level decoding analyses for individual participants. In the second-level test, the mean decoding accuracy across participants is often tested against the chance-level accuracy (for example, one-sample Student t-test) to check whether information about the label, such as, experimental condition or cognitive content, is included in brain activation. Meanwhile, Allefeld et al., (2016) highlighted that significant results for such tests only indicate that "there are some people in the population whose fMRI data carry information about the experimental condition." Therefore, such tests failed to conclude whether the effect is typical in the population. Based on this argument, they proposed an alternative method implementing the prevalence inference. In the present study, that method is extended to propose a novel statistical test called as the "information prevalence inference using the i-th order statistic" (i-test). The i-test has a high statistical power compared with the method proposed in Allefeld et al., (2016) and provides an inference regarding the typical effect in the population. In the i-test, the i-th lowest sample decoding accuracy (the i-th order statistic) is compared to the null distribution to verify whether the proportion of higher-than-chance decoding accuracy in the population (information prevalence) is higher than the threshold. Hence, a significant result in the i-test is interpreted as a majority of the population has information about the label in the brain. Theoretical details of the i-test are provided, its high statistical power is identified by numerical calculation, and the application of this method in an fMRI decoding is demonstrated.


Rehabilitation of the patient with a spinal cord injury.
The goal of rehabilitation of the person with spinal cord inury is to enable the individual to live successfully in the community. This implies that persons are prepared to care for themselves (or to direct others in their care) and are independent to the greatest extent possible. They are also able to maintain a healthy and adjusted social and vocational life. Independent living centers, providing access to services such as attendant care, have allowed the most severely disabled perons to live indenpendently in the community.


[Effects of thymosin alpha-1 on radiation-induced pneumonitis].
Radiation-induced lung injure is one of the major factors of limitation in radiotherapy for lung cancer. Whether the use of thymosin and radiotherapy simultaneously would increase the radiation-induced lung injure is unclear. The aim of this study is to evaluate the effects of thymosin alpha-1 on radiation induced pneumonitis in mice. Three groups of mice, control (C), radiation alone (RT), thymosin alpha-1 plus radiation (T+RT), were entered into the study. The weight and mortality of mice, pleural effusion, quantity of protein and cell count in the bronchoalvealar lavage (BAL) and pulmonary fibrosis score were evaluated as the outcome measures. The mortality ratio of the T+RT and RT groups were 3/14, 2/10, respectively. The time of death were all in the 23-24 weeks after radiotherapy. There was no pleural effusion in the T+RT group other than 2/2 occurred in RT group. The quantity of protein, cell number and neutrophil number in the BAL and lung coefficient in mice of T+RT group were remarkably lower than that of RT group, but the BALF macrophages number was remarkably higher than that in RT group in the 8 weeks. The quantity of protein, cell number, neutrophil number and macrophages number in the BAL, lung coefficient, the scores of lung fibrosis in mice of T+RT group were significantly lower than that of RT group in the 24 weeks. All test data were lowest in mice of C group. And there was no obvious pulmonary fibrosis in the mice of C group. Thymosin alpha-1 could relieve radiation-induced acute and late pulmonary injuries.


Process improvement approach to the care of patients with type 2 diabetes. Providing physicians with tools to increase compliance and improve outcomes.
Diabetes care relies on patient/physician-initiated programs of periodic evaluation, monitoring, and treatment interventions. Clinical practice guidelines can assist clinicians in diabetes care. To improve outcomes, these methods must be designed and implemented in a way that promotes change in physician behavior. When guidelines are corrected to real-time reminder protocols (at the time the physician is making clinical decisions with the patient), compliance with recommended tests and procedures is increased. Follow-up analysis of performance and comparison with peers assists physicians in making the necessary clinical interventions that improve the management of these conditions and reduce complications. Integrated electronic medical records are a key initial component for motivating physicians and initiating effective diabetes management plans.


[Accumulation of 99mTc-pyrophosphate and structural changes in cardiac muscle during pharmacologic correction of stress injuries of the heart].
It has been established that natrium oxybutirate, prolactin, inderal and ionol affecting different links of pathogenetic chain of stress injury, efficiently prevent structural damage to cardiomyocytes and the accumulation of 99mTc-pyrophosphate in the myocardium.


When do we simulate non-human agents? Dissociating communicative and non-communicative actions.
There is strong evidence that we automatically simulate observed behavior in our motor system. Previous research suggests that this simulation process depends on whether we observe a human or a non-human agent. Measuring a motor priming effect, this study investigated the question of whether agent-sensitivity of motor simulation depends on the specific action observed. Participants saw pictures depicting end positions of different actions on a screen. All postures featured either a human or non-human agent. Participants had to produce the matching action with their left or right hand depending on the hand presented on the screen. Three different actions were displayed: a communicative action (emblem), a transitive (goal-directed) action and an intransitive action. We found motor priming effects of similar size for human and non-human agents for transitive and intransitive actions. However, the motor priming effect for communicative actions was present for the human agent, but absent for the non-human agent. These findings suggest that biological tuning of motor simulation is highly action-selective and depends on whether the observed behavior appears to be driven by a reasonable goal.


Discriminatory power of indicators predictors of visceral adiposity evaluated by computed tomography in adults and elderly individuals.
Identifying anthropometric methods of abdominal adiposity, predictors of excess area of visceral adipose tissue (VAT) allows rapid and low cost evaluation for the risk of cardiovascular diseases in the elderly. To evaluate the discriminatory power of anthropometric indicators for detection of excess of the area of VAT. Cross-sectional study comprising 194 adults and elderly individuals for comparison of both sexes and age groups. Anthropometric variables: waist-to-height Ratio (WHtR), waist-tothigh Ratio (WTR), Abdominal Diameter Index (ADI) and Sagittal Abdominal Diameter Height Index (SAD/Height). The VAT area was identified by computed tomography (CT). Analysis with the ROC curve. There was a high correlation between the VAT area and most of the anthropometric indicators (p ≤0.001). Among elderly men, WHtR showed areas under the ROC curve over 0.90 and cutoff of 0.55 (sens: 85.7%; spec: 82.4%, PPV: 99.9%). For older women, the WHtR cutoff was 0.58 (sens: 81.0%; spec: 78.6%). For the SAD/Height, the areas under the ROC curve were ≥0.83 (p ≤0.01), with cutoffs of 0.12 for men and 0.13 for women. There was a strong discriminatory power of the anthropometric indicators abdominal visceral obesity. The WHtR and SAD/Height showed better performance to predict the VAT area of risk in elderly, without the need of measuring it by computed tomography.


Biomechanical Evaluation of Aortic Valve Stenosis by Means of a Virtual Stress Test: A Fluid-Structure Interaction Study.
The impact of aortic valve stenosis (AS) extends beyond the vicinity of the narrowed leaflets into the left ventricle (LV) and into the systemic vasculature because of highly unpredictable valve behavior and complex blood flow in the ascending aorta that can be attributed to the strong interaction between the narrowed cusps and the ejected blood. These effects can become exacerbated during exercise and may have implications for disease progression, accurate diagnosis, and timing of intervention. In this 3-D patient-specific study, we employ strongly coupled fluid-structure interaction (FSI) modeling to perform a comprehensive biomechanical evaluation of systolic ejection dynamics in a stenosed aortic valve (AV) during increasing LV contraction. Our model predictions reveal that the heterogeneous ∆P vs. Q relationship that was observed in our previous clinical study can be attributed to a non-linear increase (by ~ 1.5-fold) in aortic valve area as LV heart rate increases from 70 to 115 bpm. Furthermore, our results show that even for a moderately stenotic valve, increased LV contraction during exercise can lead to high-velocity flow turbulence (Re = 11,700) in the aorta similar to that encountered with a severely stenotic valve (Re ~ 10,000), with concomitant greater viscous loss (~3-fold increase) and elevated wall stress in the ascending aorta. Our FSI predictions also reveal that individual valve cusps undergo distinct and highly non-linear increases (>100%) in stress during exercise, potentially contributing to progressive calcification. Such quantitative biomechanical evaluations from realistic FSI workflows provide insights into disease progression and can be integrated with current stress testing for AS patients to comprehensively predict hemodynamics and valve function under both baseline and exercise conditions.


Alternative transplantation sites for pancreatic islet grafts.
The liver is the current site of choice for pancreatic islet transplantation, even though it is far from being an ideal site because of immunologic, anatomic, and physiologic factors leading to a significant early graft loss. A huge amount of alternative sites have been used for islet transplantation in experimental animal models to provide improved engraftment and long-term survival minimizing surgical complications. The pancreas, gastric submucosa, genitourinary tract, muscle, omentum, bone marrow, kidney capsule, peritoneum, anterior eye chamber, testis, and thymus have been explored. Site-specific differences exist in term of islet engraftment, but few alternative sites have potential clinical translation and generally the evidence of a post-transplant islet function better than that reached after intraportal infusion is still lacking. This review discusses site-specific benefits and drawbacks taking into account immunologic, metabolic, and technical aspects to identify the ideal microenvironment for islet function and survival.


Variations in the management of pneumonia in pediatric emergency departments: compliance with the guidelines.
We sought to assess compliance with evidence-based guidelines for the management of pediatric pneumonia, including the variations in tests ordered and antimicrobials prescribed. Our primary hypothesis was that compliance with the treatment recommendations from the most current guidelines would be low for antimicrobial prescriptions. We conducted a chart review at the Children's Hospital in London, Ont., to assess variation in the management of pediatric pneumonia. All patients aged 3 months to 18 years seen at the pediatric emergency department between Apr. 1, 2006, and Mar. 31, 2007, with a diagnosis of pneumonia were eligible for inclusion in the study. Compliance with management guidelines was 59.7% (95% confidence interval [CI] 53%-66%, n = 211) in children 5-18 years old and 83.0% (95% CI 80%-86%, n = 605) in children 3 months to 5 years old. Significant variation existed in the choice of antimicrobial agent for children with pneumonia, with nonrecommended agents frequently prescribed. Significant variation existed in the management of pediatric pneumonia, and adherence to guidelines was low for the group of patients aged 5-18 years. Future studies should attempt to provide guidance to distinguish between viral and bacterial etiology to allow judicious use of antimicrobials.


An estimation of the prevalence of genomic disorders using chromosomal microarray data.
Multiple genomic disorders result from recurrent deletions or duplications between low copy repeat (LCR) clusters, mediated by nonallelic homologous recombination. These copy number variants (CNVs) often exhibit variable expressivity and/or incomplete penetrance. However, the population prevalence of many genomic disorders has not been estimated accurately. A subset of genomic disorders similarly characterized by CNVs between LCRs have been studied epidemiologically, including Williams-Beuren syndrome (7q11.23), Smith-Magenis syndrome (17p11.2), velocardiofacial syndrome (22q11.21), Prader-Willi/Angelman syndromes (15q11.2q12), 17q12 deletion syndrome, and Charcot-Marie-Tooth neuropathy type 1/hereditary neuropathy with liability to pressure palsy (PMP22, 17q11.2). We have generated a method to estimate prevalence of highly penetrant genomic disorders by (1) leveraging epidemiological data for genomic disorders with previously reported prevalence estimates, (2) obtaining chromosomal microarray data on genomic disorders from a large medical genetics clinic; and (3) utilizing these in a linear regression model to determine the prevalence of this syndromic copy number change among the general population. Using our algorithm, the prevalence for five clinically relevant recurrent genomic disorders: 1q21.1 microdeletion (1/6882 live births) and microduplication syndromes (1/6309), 15q13.3 microdeletion syndrome (1/5525), and 16p11.2 microdeletion (1/3021) and microduplication syndromes (1/4216), were determined. These findings will inform epidemiological strategies for evaluating those conditions, and our method may be useful to evaluate the prevalence of other highly penetrant genomic disorders.


Frequency of spinocerebellar ataxia type 1, dentatorubropallidoluysian atrophy, and Machado-Joseph disease mutations in a large group of spinocerebellar ataxia patients.
The spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders varying in both clinical manifestations and mode of inheritance. Six different genes causing autosomal dominant SCA are mapped: SCA1, SCA2, Machado-Joseph disease (MJD)/SCA3, SCA4, SCA5, and dentatorubropallidoluysian atrophy (DRPLA). Expansions of an unstable trinucleotide CAG repeat cause three of these disorders: SCA type 1 (SCA1), MJD, and DRPLA. We determine the frequency of the SCA1, DRPLA, and MJD mutations in a large group of unrelated SCA patients with various patterns of inheritance and different ethnic backgrounds. We studied 92 unrelated SCA patients. The frequency of the SCA1 mutation was 3% in the overall patient group and 10% in the non-Portuguese dominantly inherited SCA subgroup. We found that DRPLA mutation in only one Japanese patient, who was previously diagnosed with this disease. We identified the MJD mutation in 41% of the overall patient group, which included 38 autosomal dominant kindreds of Portuguese origin; the frequency of the MJD mutation among the non-Portuguese dominantly inherited cases was 17%. These results suggest that SCA may be occasionally caused by the SCA1 mutation and rarely caused by the DRPLA mutation and that, to date, the MJD mutation seems to be the most common cause of dominantly inherited SCA. Finally, our results suggest that recessively inherited cases of SCA are not caused by the known trinucleotide repeat expansions.


After corona: there is life after the pandemic.
The current pandemic of Coronavirus Disease 2019 (COVID-19) has focused the attention of medical-care providers away from non-life-threatening diseases, including infertility. Although infertility does not jeopardize the physical survival of infertile couples, it does jeopardize their future quality of life. Human infertility can be caused by a number of factors, some of which are age-dependent, and their effects may become irreversible if appropriate measures are not taken in time to prevent irreversible childlessness. Accordingly, each case of infertility should be evaluated comprehensively to establish its position of priority. Assisted reproductive technology (ART) makes it possible to separate fertilization and pregnancy in time. Whereas pregnant women infected with coronavirus may have an increased risk of adverse neonatal outcomes, gametes do not transmit COVID-19. Thus, performing ovarian stimulation and fertilization without delay, freezing the resulting embryos and delaying embryo transfer until the end of the pandemic appears to be the best strategy at present.


Potentiation of cyanide neurotoxicity by blockade of ATP-sensitive potassium channels.
Exposure of primary hippocampal cultures to NaCN (2 mM) or glyburide (5 microM) alone for 3 h did not produce a rise in extracellular lactic dehydrogenase (LDH) activity. Coincubation with NaCN and glyburide produced a significant efflux of LDH from the neurons. Diazoxide or D-2-amino-5-phosphovalerate (APV) partially reversed the release of LDH by the combination of NaCN and glyburide. These observations indicate ATP-sensitive potassium channels (KATP) are activated by nonlethal concentrations of cyanide and their blockade with glyburide unmasks cyanide's toxicity. The cytotoxicity of cyanide appears to result from a combination of processes resulting in altered ion handling and excitotoxicity.


Determination of basal acetylcholine release in vivo by rat brain dialysis with a U-shaped cannula: effect of SM-10888, a putative therapeutic drug for Alzheimer's disease.
A U-shaped dialysis cannula was implanted into rat frontal cortex, hippocampus and striatum, and after 1 day for surgical recovery the cannula was perfused with Ringer's solution without any acetylcholinesterase (AChE) inhibitor under freely moving conditions. With a highly sensitive assay method for acetylcholine (ACh), the basal ACh content in the dialysates were detectable in those brain regions for several hours. The basal levels in the frontal cortex, hippocampus and striatum were 82 +/- 9, 72 +/- 4, 70 +/- 8 fmol/20 microliters (mean +/- S.E.M.), respectively. When SM-10888, a novel AChE inhibitor and putative therapeutic drug for Alzheimer's disease, was injected intraperitoneally, ACh in the dialysate of the cortex increased in a dose-dependent manner. Changes in the levels of hippocampal and striatal ACh release evoked by SM-10888 were similar to, but smaller than, that in the cortex. These data suggest that since the present assay method is able to determine in vivo basal ACh release in the dialysate without any AChE inhibitor, it is possible to study the effect of a novel drug such as SM-10888 in the brain regions.


Intravenous rt-PA for acute stroke: comparing its effectiveness in younger and older patients.
To study the short and long term differences in outcome between patients > or =80 years of age and those < or =79 years of age who received intravenous recombinant tissue plasminogen activator (iv rt-PA) for acute stroke within the first 3 hours of symptom onset. We studied consecutive patients treated with iv rt-PA for acute stroke, with prospective follow up of up to 3 years. Outcome measures included National Institutes of Health Stroke Scale (NIHSS) score, Barthel Index (BI), modified Rankin score (MRS), and stroke mortality. Patients were split into two groups: younger (< or =79 years) and older (> or =80 years). There were 65 patients in the younger cohort and 31 patients in the older. Older patients were more likely to present with more severe baseline stroke (p = 0.04; odds ratio (OR) 3.04; 95% confidence interval (CI) 1.03 to 8.98). Stroke mortality at 90 days was 10.8% in the younger and 32.3% in the older cohort (p = 0.01). At 90 days' follow up, patients in the older cohort with more severe stroke (NIHSS score > or =11) were nearly 10 times more likely to have poor outcome compared with their younger counterparts presenting with severe stroke (p = 0.001; OR = 10.36; 95% CI 2.16 to 49.20). Baseline stroke severity and age were the only independent and equal predictors for stroke outcome. No threshold was found for age or baseline stroke severity predicting outcome. Older patients presenting with more severe baseline stroke are much less likely to benefit from iv rt-PA as compared with their younger counterparts.


Surgical Management of Posterior Communicating Artery Aneurysms in the Presence of a Low-Coursing Internal Carotid Artery and Narrowed Retrocarotid Window.
Anatomical variations of the course of the internal carotid artery (ICA) may complicate surgical clipping of posterior communicating artery (PCoA) aneurysms by narrowing the retrocarotid window. We evaluated the efficacy of the periclinoid surgical maneuvers for expanding the retrocarotid window and analyzed computed tomography angiography (CTA) data from patients with PCoA aneurysms to define parameters for low-coursing ICAs. Using cadaveric specimens, standard pterional craniotomies were fashioned and extradural or intradural periclinoid surgical maneuvers-cutting of the meningo-orbital band, anterior clinoidectomy, and cutting of the distal dural ring (DDR)-were performed, and their relative advantages for expanding the retrocarotid window were assessed. Additionally, preoperative CTA data from 24 patients with PCoA aneurysms used to calculate the angles of the ICA relative to the skull base. Periclinoid maneuvers, especially the anterior clinoidectomy, provided additional exposure of the retrocarotid space. Cutting of the DDR allowed for partial mobilization of the ICA and widened the retrocarotid surgical window, enhancing maneuverability. The anterior clinoidectomy with cutting of the DDR allowed for enhanced exposure of the medial, middle, and posterolateral aspects of the retrocarotid space. Cutting the anterior petroclinoid fold and mobilizing cranial nerve III provided wide exposure of the lateral aspect of retrocarotid space. When clipping PCoA aneurysms in the presence of normal-coursing ICAs (approximately ≥30° ICA angle), a standard pterional craniotomy with anterior clinoidectomy and cutting of the DDR allows for substantial expansion of the retrocarotid window.


The development of tertiary interactions during the folding of a large protein.
We have used protein engineering and relaxation kinetics to examine the order in which secondary structure elements assemble during folding. Aliphatic contacts in the core of a large domain within the monomeric protein phosphoglycerate kinase (PGK) were disrupted in order to map the development of interactions between beta-strand and alpha-helix residues, both near and distant in the sequence. Mutations which break sequence-local alpha-beta contacts destabilize the first identifiable intermediate in folding, showing that these contacts develop early in the folding pathway. In contrast, the removal of sequence-distant alpha-beta interactions has little effect at this stage, but reduces the rate at which the intermediate converts to the native state. Thus, contacts between these remote segments of secondary structure start to form later on in the process, during the rate-limiting transition. In the case of this large protein domain, our results support the hypothesis that folding proceeds by a hierarchic pathway. Interactions form rapidly between sequence-local groups to produce microdomains before the establishment of the long-range contacts necessary to define the global fold, which proceeds through a highly hydrated transition state.


Origin of taurine in developing rat brain.
The amounts of taurine supplied to the developing rat pup and rat brain by the mother, both in utero throughout gestation, and by the milk throughout weaning, have been determined. Since the total taurine status of the rats is known, the amount biosynthesized at each of these developmental times has been calculated. The surprising result was obtained that 40% of the taurine present in each rat pup, and in brain, at birth has already been obtained through biosynthesis by the fetus during gestation. In comparison, the adult rat derives 80% of its total taurine by biosynthesis, and obtains 20% from its diet. From birth to weaning, the mother contributes a similar amount of taurine to the whole rats as she did during gestation, although a smaller fraction of this taurine is present in brain. Both the rate of disappearance of labelled taurine in brain derived from the mother in utero compared to that derived from the mother in utero compared to that of [3H]taurine in brain derived from a postnatal intraperitoneal injection, suggest the presence of a small pool of taurine in the mitochondria, synaptosomes, and microsomes which is not freely exchangeable.


Comment on: Surgical and oncological outcome after laparoscopic versus open nephroureterectomy for non-metastatic, upper-tract urothelial carcinoma. A single-centre experience.
[No Abstract Available].


Cytomorphometry. A methodologic study of preparation techniques, selection methods and sample sizes.
The influence of methodologic aspects on cytomorphometric features was studied using preparations of hepatoma and/or mastocytoma cells. First, two preparation techniques (smear and oese) were compared. Second, four methods of selecting cells for cytomorphometric analysis (two conventional and two stratified methods) were tested for reproducibility. Third, heterogeneous cell populations were used to estimate the required sample size using the running coefficient of variation (CV), and the results were compared with expected (theoretical) values of the required sample size calculated using the standard error of the mean. The results showed significantly lower CVs for the smear preparation technique. The stratified methods appeared to be superior to the conventional methods for selecting cells for measurement. The experimentally assessed sample sizes were considerably lower than the corresponding theoretical calculations. These findings suggest that morphometric assessments in cytologic smears should utilize a stratified cell selection method. While experimentally assessed sample sizes are relatively small and therefore better routinely applicable, they may yield less reliable results in some cases. The need to test a sample for its reproducibility as well as its discriminatory power is emphasized.


Kynurenine pathway is altered in BDNF Val66Met knock-in mice: Effect of physical exercise.
The Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism has been correlated with increased predisposition to develop cognitive and psychiatric disorders, and with a reduced response to some therapeutic treatments. However, the mechanisms underlying these impairments are currently not completely understood. Remarkably, kynurenine pathway alterations have also been implicated in cognitive and psychiatric disorders. Moreover, recent evidence suggests that physical exercise may promote beneficial effects by controlling kynurenine metabolism in the muscle. The aim of the present study was to assess whether the kynurenine pathway was differentially regulated in sedentary and exercising wild-type (BDNFVal/Val) and homozygous knock-in BDNF Val66Met (BDNFMet/Met) mice. We found that plasma and hippocampal levels of kynurenic acid and the hippocampal mRNA levels of IDO1 and KAT2 protein levels were increased in BDNFMet/Met mice and were not modulated by physical exercise. On the contrary, KAT1 protein levels in the gastrocnemius muscle were reduced, whereas MCP1 mRNA in the gastrocnemius muscle and GFAP protein in the hippocampus were increased in BDNFMet/Met mice compared to BDNFVal/Val mice, and reduced by physical exercise. Physical exercise increased plasmatic kynurenine levels only in BDNFMet/Met mice, and protein levels of KAT1 and KAT4 in the gastrocnemius muscle and hippocampus respectively, regardless of the genotype. Finally, we found that physical exercise was able to enhance the hippocampal-dependent memory only in the BDNFVal/Val mice. Overall our results showing an overactivation of the kynurenine pathway in the BDNFMet/Met mice may suggest a possible mechanism underlying the cognitive deficits reported in the BDNF Val66Met carriers.


Sonodynamic Treatment Induces Selective Killing of Cancer Cells in an In Vitro Co-Culture Model.
Sonodynamic Therapy (SDT) is a new anticancer strategy based on ultrasound (US) technique and is derived from photodynamic therapy (PDT); SDT is still, however, far from clinical application. In order to move this therapy forward from bench to bedside, investigations have been focused on treatment selectivity between cancer cells and normal cells. As a result, the effects of the porphyrin activation by SDT on cancer (HT-29) and normal (HDF 106-05) cells were studied in a co-culture evaluating cell cytotoxicity, reactive oxygen species (ROS) production, mitochondrial function and plasma membrane fluidity according to the bilayer sonophore (BLS) theory. While PDT induced similar effects on both HT-29 and HDF 106-05 cells in co-culture, SDT elicited significant cytotoxicity, ROS production and mitochondrial impairment on HT-29 cells only, whereas HDF 106-05 cells were unaffected. Notably, HT-29 and HDF 106-05 showed different cell membrane fluidity during US exposure. In conclusion, our data demonstrate a marked difference between cancer cells and normal cells in co-culture in term of responsiveness to SDT, suggesting that this different behavior can be ascribed to diversity in plasma membrane properties, such as membrane fluidity, according to the BLS theory.


Investigation of thiol compounds (L-cysteine, thioacetic acid and ethanethiol) with V(V) and V(IV) using combined spectroscopy and chromatography.
The interactions of V(V) and L-cysteine, thioacetic acid and ethanethiol were studied in aqueous solution using chromatographic and spectral analysis. The chromatographic determination of V(V) and V(IV) species in the presence of thiols was enabled by inducing the ligand exchange reaction with EDTA as the competing ligand. Analytical setup allowed investigation of the possible redox and structural transformations of V(V) in the presence of thiols used over a wide pH range. Obtained data strongly suggest that the reduction of V(V) is proton catalyzed in case of L-cysteine and thioacetic acid. In the case of ethanethiol, the reduction did not seem to be proton dependent, as no reduction was observed above pH = 2. Thus, reduction was inhibited by the deprotonation of L-cysteine and thioacetic acid, with L-cysteine being the strongest reducing agent of V(V), followed by thioacetic acid and finally ethanethiol. Apart from structural thiol properties, the reduction reaction seems to be influenced by the aqueous V(V) speciation due to the observed nonlinear kinetics. In the case of all investigated thiols, the formation of V(V)-thioester intermediate species was an essential step for V(V) reduction. The structural properties of the V(IV)-thiol complexes were also found to be pH-dependent.


Investment incentive reduced by climate damages can be restored by optimal policy.
Increasing greenhouse gas emissions are likely to impact not only natural systems but economies worldwide. If these impacts alter future economic development, the financial losses will be significantly higher than the mere direct damages. So far, potentially aggravating investment responses were considered negligible. Here we consistently incorporate an empirically derived temperature-growth relation into the simple integrated assessment model DICE. In this framework we show that, if in the next eight decades varying temperatures impact economic growth as has been observed in the past three decades, income is reduced by ~ 20% compared to an economy unaffected by climate change. Hereof ~ 40% are losses due to growth effects of which ~ 50% result from reduced incentive to invest. This additional income loss arises from a reduced incentive for future investment in anticipation of a reduced return and not from an explicit climate protection policy. Under economically optimal climate-change mitigation, however, optimal investment would only be reduced marginally as mitigation efforts keep returns high.


Ethnobotanical Uses, Phytochemistry and Pharmacology of Different Rheum Species (Polygonaceae): A Review.
Today, there is an increased tendency to use herbal remedies. Rhubarb refers to several species of the genus Rheum L. in the Polygonaceae family. This species-rich genus is mainly distributed in Asian countries. Several medicinal effects have been attributed to the Rheum spp. in the traditional and modern medicine such as healing lungs, liver, kidney, womb and bladder diseases, cancer, diabetes, insect bites, relapsing fevers, diarrhea and constipation. Various in vitro, in vivo and clinical studies have investigated the therapeutic effect of extracts, fractions and pure compounds isolated from different species of this genus. Considering the positive findings, several pharmaceutical formulations containing rhubarb extract like capsules, drops, mouthwashes and different topical formulations are now present in the market. However, there are other traditional therapeutic effects of rhubarb that have not been studied yet and it is of great importance to perform confirmatory experiments or clinical investigations. The current review summarizes general information regarding botany, phytochemistry, ethnobotany and pharmacological aspects of Rheum spp. It is hoped that the present review could motivate subsequent research on the other medicinal properties of these plants that have been neglected until today.


18F-FDG PET/CT in Infective Endocarditis: Indications and Approaches for Standardization.
Additional imaging modalities, such as FDG-PET/CT, have been included into the workup for patients with suspected infective endocarditis, according to major international guidelines published in 2015. The purpose of this review is to give an overview of FDG-PET/CT indications and standardized approaches in the setting of suspected infective endocarditis. There are two main indications for performing FDG-PET/CT in patients with suspected infective endocarditis: (i) detecting intracardiac infections and (ii) detection of (clinically silent) disseminated infectious disease. The diagnostic performance of FDG-PET/CT for intracardiac lesions depends on the presence of native valves, prosthetic valves, or implanted cardiac devices, with a sensitivity that is poor for native valve endocarditis and cardiac device-related lead infections, but much better for prosthetic valve endocarditis and cardiac device-related pocket infections. Specificity is high for all these indications. The detection of disseminated disease may also help establish the diagnosis and/or impact patient management. Based on current evidence, FDG-PET/CT should be considered for detection of disseminated disease in suspected endocarditis. Absence of intracardiac lesions on FDG-PET/CT cannot rule out native valve endocarditis, but positive findings strongly support the diagnosis. For prosthetic valve endocarditis, standard use of FDG-PET/CT is recommended because of its high sensitivity and specificity. For implanted cardiac devices, FDG-PET/CT is also recommended, but should be evaluated with careful attention to clinical context, because its sensitivity is high for pocket infections, but low for lead infections. In patients with prosthetic valves with or without additional aortic prosthesis, combination with CTA should be considered. Optimal timing of FDG-PET/CT is important, both during clinical workup and technically (i.e., post tracer injection). In addition, procedural standardization is key and encompasses patient preparation, scan acquisition, reconstruction, subsequent analysis, and clinical interpretation. The recommendations discussed here will hopefully contribute to improved standardization and enhanced performance of FDG-PET/CT in the clinical management of patients with suspected infective endocarditis.


The effect of temperature on the reaction of carbon monoxide with oxygenated haemoglobin.
1. The rate at which carbon monoxide displaces oxygen from its combination with haemoglobin in solution, has been measured spectrophotometrically, using a rapid-mixing stopped-flow technique. 2. In the presence of carbon dioxide, the reaction proceeds by a unimolecular dissociation, with a rate constant r. 3. The relationship of the reciprocal of r to the ratio PO2/PCO is non-linear, and a different curve is obtained at each carbon monoxide concentration. 4. From measurements of the rate constant at temperatures between 5 and 35 degrees C, it is concluded that the non-linearity is due to the formation at a finite rate of an intermediate complex, CO2Hb4O6, by the reaction of carbon dioxide with Hb4O6.


Intussusception reduction: Effect of air vs. liquid enema on radiation dose.
Both air and radiopaque liquid contrast are used to reduce ileocolic intussusception under fluoroscopy. Some suggest air lowers radiation dose due to shorter procedure times. However, air enema likely lowers radiation dose regardless of fluoroscopy time due to less density over the automatic exposure control cells. We test the hypothesis that air enema reduction of ileocolic intussusception results in lower radiation dose than liquid contrast enema independent of fluoroscopy time. We describe a role for automatic exposure control in this dose difference. We retrospectively evaluated air and liquid intussusception reductions performed on a single digital fluoroscopic unit during a 26-month period. We compared patient age, weight, gender, exam time of day and year, performing radiologist(s), radiographic image acquisitions, grid and magnification use, fluoroscopy time and dose area product. We compared categorical and continuous variables statistically using chi-square and Mann-Whitney U tests, respectively. The mean dose area product was 2.7-fold lower for air enema, 1.3 ± 0.9 dGy·cm2, than for liquid, 3.5 ± 2.5 dGy·cm2 (P<0.005). The mean fluoroscopy time was similar between techniques. The mean dose area product/min was 2.3-fold lower for air, 0.6 ± 0.2 dGy·cm2/min, than for liquid, 1.4 ± 0.5 dGy·cm2/min (P<0.001). No group differences were identified in other measured dose parameters. Fluoroscopic intussusception reduction using air enema uses less than half the radiation dose of liquid contrast enema. Dose savings are independent of fluoroscopy time and are likely due to automatic exposure control interaction.


Ascaris in gallbladder: report of a case and review.
A case of an Ascaris infection of the gallbladder is reported in a 29 years old female. The biological check-up was normal. The diagnosis was confirmed by ultrasonography and the patient was cured by albendazole. Such a localization is uncommon (2.1% of the hepatobiliary ascariasis), and the abdominal ultrasonography is the best way to confirm the diagnosis. Albendazole is the current treatment, but cholecystectomy is sometimes a must.


Pyoderma gangrenosum treated with clofazimine. Report of three cases.
Three cases of pyoderma gangrenosum (PG) responsive to clofazimine are reported. The ulcers were recalcitrant to other forms of therapy, and the patients were incapacitated. Healing began within 2 or 3 weeks. To our knowledge, these are the first reported cases of PG responsive to clofazimine in the United States.


Taurine inhibition of metal-stimulated catecholamine oxidation.
Taurine is an abundant amino acid found in mammalian tissues and it has been suggested to have cytoprotective functions. The aim of the present study was to determine if taurine had the potential to reduce oxidative stress associated with metal-stimulated catecholamine oxidation. Taurine and structural analogs of taurine were tested for their ability to inhibit metal-stimulated quinone formation from dopamine or L-dopa. Oxidative damage to proteins and lipids were also assessed in vitro and the effects of taurine were determined. Taurine (20 mM) was found to decrease significantly ferric iron (50-500 microM)- and manganese (10 microM)-stimulated L-dopa or dopamine oxidation. Taurine had no effect on zinc-induced dopamine oxidation and slightly potentiated copper- and NaIO(4)-stimulated quinone formation. Ferric iron-stimulated lipid peroxidation was not affected by taurine (1-20 mM). Protein carbonyl formation induced by ferric iron (500 microM) and L-dopa (500 microM) was significantly reduced by 10 mM taurine. The cytotoxicity of L-dopa (250 microM) and ferric chloride (75 microM) to LLC-PK(1) cells was attenuated by 10 mM taurine or hypotaurine. Homotaurine alone stimulated L-dopa oxidation and potentiated the cytotoxic effects of ferric iron. Homotaurine was found to be cytotoxic when combined with L-dopa or L-dopa/iron. In contrast, hypotaurine inhibited quinone formation and protected LLC-PK(1) cells. These studies suggest that taurine may exhibit cytoprotective effects against the oxidation products of catecholamines by acting as a scavenger for free radicals and cytotoxic quinones.


Current concepts in diagnosis and treatment of venous malformations.
Venous malformations are the most common type of vascular malformation, usually detected at birth or during puberty. By occurring during human growth or through localized trauma, pain, functional impairment and aesthetic disfigurement is often observed. Ultrasonography, Doppler flow Imaging, and Magnetic Resonance Imaging are the most informative techniques which reveal the extent of tissue involvement and differentiate between high and low flow anomalies. Therapeutic options for treatment of venous malformations are sclerotherapy with alcohol, ethoxysclerol and bleomycin, laser therapy (Nd:YAG), surgery and combined therapeutic modalities. The aim of percutaneous sclerotherapy is the successive reduction of the volume of the lesion by aseptic inflammation. This is a review of 51 patients with venous malformation treated by the Interdisciplinary Center for Vascular Anomalies at the University Hospital Tübingen, (Germany), from July, 2002 until January, 2007. The mean age of first consultation in our outpatient department was 26.4 years (median). 12 patients were treated by sclerotherapy with highly concentrated alcohol, 9 by surgery, and 7 by laser therapy. In some cases we combined different treatments. 9 patients had only sclerotherapy, while 3 had a combination of pre-operative sclerotherapy and surgery. We obtained positive results in patients treated with sclerotherapy and combined sclerotherapy and surgery. Sclerotherapy is safe (under fluoroscopic control), efficient, and can be repeated multiple times. Therefore, it should be considered as first-line treatment in venous malformations. A combination of a sclerotherapy with surgery is also useful in many cases.


Alteration of secretory leukocyte protease inhibitor in human myometrium during labor.
Secretory leukocyte protease inhibitor (SLPI) has been shown to have antimicrobial and antiinflammatory properties. The aim of this study was to verify its expression in human myometrium. Myometrium was obtained at time of cesarean delivery with (n = 9) or without (n = 11) labor. Expression of SLPI was detected using real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemistry. SLPI expression relative to nuclear factor-kappaB p65 subunit was compared between subjects. SLPI response to inflammatory mediators was studied in myometrial explants. SLPI was predominantly localized in the nuclei of myocytes and colocalized with CD68(+) macrophages. The nuclear immunoreactivity of SLPI was increased after the onset of labor and was associated with increased nuclear translocation of nuclear factor-kappaB p65 subunit. Treatment with lipopolysaccharide, interleukin-1beta, or tumor necrosis factor-alpha increased SLPI messenger RNA and protein concentrations slightly in myometrium explants. SLPI was expressed in human myometrium and increased after the onset of labor.


Acidification reversal in low mountain range streams of Germany.
This study evaluates the acidification status and trends in streams of forested mountain ranges in Germany in consequence of reduced anthropogenic deposition since the mid 1980s. The analysis is based on water quality data for 86 long-term monitored streams in the Ore Mountains, the Bavarian Forest, the Fichtelgebirge, the Harz Mountains, the Spessart, the Black Forest, the Thuringian Forest, and the Rheinisches Schiefergebirge of Germany and the Vosges of France. Within the observation period, which starts for the individual streams between 1980 and 2001 and ends between 1990 and 2009, trends in chemical water quality were calculated with the Seasonal Mann Kendall Test. About 87% of the streams show significant (p < 0.05) negative trends in sulfate. The general reduction in acid deposition resulted in increased pH values (significant for 66% of the streams) and subsequently decreased base cation concentrations in the stream water (for calcium significant in 58% and magnesium 49% of the streams). Reaction products of acidification such as aluminum (significant for 50%) or manganese (significant for 69%) also decreased. Nitrate (52% with significant decrease) and chloride (38% with significant increase) have less pronounced trends and more variable spatial patterns. For the quotient of acidification, which is the ratio of the sum of base cations and the sum of acid anions, no clear trend is observed: in 44% of the monitored streams values significantly decreased and in 23% values significantly increased. A notable observation is the increasing DOC concentration, which is significant for 55% of the observed streams.


Subxiphoid incisional hernias post median sternotomy: A literature review.
Subxiphoid incisional hernias are one of the complications following a median sternotomy, a surgical procedure to provide access to the mediastinum. Incidence has been reported between 1% and 4%, although the true incidence is not well known due to its asymptomatic nature. A comprehensive search was performed on multiple sites. Keywords included "incisional hernia OR Subxiphoid hernia" AND "Median sternotomy OR Cardiac Surgery OR Coronary artery bypass graft OR Transplant OR Valve replacement". Articles up to August 1, 2020, were included in this study. Eight articles were included in the study, with a total number of 132 patients identified. The incidence ranged from 0.81% to 3.44%. There was a mixture of repair methods and follow-up period reported. Recurrence post repair ranged from 10% to 43%. Subxiphoid incisional hernias remain challenging to manage. We have discussed the incidence, risk factors, preventions, and management of subxiphoid incisional hernias including both the open and laparoscopic techniques.


Laryngeal keratosis and carcinoma in the Rochester, MN, population 1935-1984.
An attempt was made to identify all laryngeal carcinomas (LSCC), carcinomas in situ (LCIS), and clinical keratoses (LK) in a defined community and to observe them retrospectively via medical records from 1935 to 1984. In Rochester, MN, 108, 7, and 52 cases of LK, LCIS, and LSCC, respectively, were diagnosed, providing mean annual incidence rates of 5.8, 0.4, and 3.3/100,000 person-years. LSCC and LK incidence rates increased more than threefold between 1935 and 1984, while LCIS incidence remained constant. A strong male predilection was noted for all three diseases. The peak age-specific incidence for LK (45 to 54 years of age) occurred a decade earlier than for LSCC. Although 16.2% of LKs had LSCC or LCIS at initial diagnosis over half of LK patients were followed without initial biopsy and only one cancer developed in that group. Clinicopathologic characterization is provided for all three diseases.


Student Annotations of Published Data as a Collaboration between an Online Laboratory Course and the C. elegans Database, WormBase.
Course-based undergraduate research experiences (CUREs) provide the same benefits as individual, mentored faculty research while expanding the availability of research opportunities. One important aspect of CUREs is students' engagement in collaboration. The shift to online learning during the COVID-19 pandemic created an immediate need for meaningful, collaborative experiences in CUREs. We developed a partnership with the Caenorhabditis elegans (C. elegans) database, WormBase, in which students submitted annotations of published manuscripts to the website. Due to the stress on students during this time of crisis, qualitative data were collected in lieu of quantitative pre- and postanalyses. Most students reported on cognitive processes that represent mid-level Bloom's categories. By partnering with WormBase, students gained insight into the scientific community and contributed as community members. We describe possible modifications for future courses, potential expansion of the WormBase collaboration, and future directions for quantitative analysis.


Increasing synthetic efficiency via direct C-H functionalization: formal synthesis of an inhibitor of botulinum neurotoxin.
A new and efficient scheme for the synthesis of one of the best known inhibitors of botulinum neurotoxin serotype A (BoNTA) is reported herein. The synthetic route involves two palladium-catalyzed C-H functionalization reactions, formally activating three C-H bonds.


Performance of Nano-Hydroxyapatite/Beta-Tricalcium Phosphate and Xenogenic Hydroxyapatite on Bone Regeneration in Rat Calvarial Defects: Histomorphometric, Immunohistochemical and Ultrastructural Analysis.
Synthetic biomaterials have played an increasingly prominent role in the substitution of naturally derived biomaterials in current surgery practice. In vitro and in vivo characterization studies of new synthetic biomaterials are essential to analyze their physicochemical properties and the underlying mechanisms associated with the modulation of the inflammatory process and bone healing. This study compares the in vivo tissue behavior of a synthetic biomaterial nano-hydroxyapatite/beta-tricalcium phosphate (nano-HA/ß-TCP mixture) and deproteinized bovine bone mineral (DBBM) in a rat calvarial defect model. The innovation of this work is in the comparative analysis of the effect of new synthetic and commercially xenogenic biomaterials on the inflammatory response, bone matrix gain, and stimulation of osteoclastogenesis and osteoblastogenesis. Both biomaterials were inserted in rat defects. The animals were divided into three groups, in which calvarial defects were filled with xenogenic biomaterials (group 1) and synthetic biomaterials (group 2), or left unfilled (group 3, controls). Sixty days after calvarial bone defects filled with biomaterials, periodic acid Schiff (PAS) and Masson's trichrome staining, immunohistochemistry tumor necrosis factor-alpha (TNF-α), matrix metalloproteinase-9 (MMP-9), and electron microscopy analyses were conducted. Histomorphometric analysis revealed powerful effects such as a higher amount of proteinaceous matrix and higher levels of TNF-α and MMP-9 in bone defects treated with alloplastic nano-HA/ß-TCP mixture than xenogenicxenogic biomaterial, as well as collagen-proteinaceous material in association with hydroxyapatite crystalloids. These data indicate that the synthetic nano-HA/ß-TCP mixture enhanced bone formation/remodeling in rat calvarial bone defects. The nano-HA/ß-TCP did not present risks of cross-infection/disease transmission. The synthetic nano-hydroxyapatite/beta-tricalcium phosphate mixture presented adequate properties for guided bone regeneration and guided tissue regeneration for dental surgical procedures.


Development and assessment of a real-time pcr assay for rapid and sensitive detection of a novel thermotolerant bacterium, Lactobacillus thermotolerans, in chicken feces.
A new real-time PCR assay was successfully developed using a TaqMan fluorescence probe for specific detection and enumeration of a novel bacterium, Lactobacillus thermotolerans, in chicken feces. The specific primers and probe were designed based on the L. thermotolerans 16S rRNA gene sequences, and these sequences were compared to those of all available 16S rRNA genes in the GenBank database. The assay, targeting 16S rRNA gene, was evaluated using DNA from a pure culture of L. thermotolerans, DNA from the closely related bacteria Lactobacillus mucosae DSM 13345(T) and Lactobacillus fermentum JCM 1173(T), and DNA from other lactic acid bacteria in quantitative experiments. Serial dilutions of L. thermotolerans DNA were used as external standards for calibration. The minimum detection limit of this technique was 1.84 x 10(3) cells/ml of an L. thermotolerans pure culture. The assay was then applied to chicken feces in two different trials. In the first trial, the cell population was 10(4) cells/g feces on day 4 and 10(5) cells/g feces on days 11 to 18. However, cell populations of 10(6) to 10(7) cells/g feces were detected in the second trial. The total bacterial count, measured by 4',6-diamidino-2-phenylindole (DAPI) staining, was approximately 10(11) cells/g feces. These results suggest that in general, L. thermotolerans is a normal member of the chicken gut microbiota, although it is present at relatively low levels in the feces.


An fMRI study of the cerebral macro network involved in 'cue invariant' form perception and how it is influenced by stimulus complexity.
We investigated the influence of stimulus complexity on the macro network of visual areas involved in 'cue invariant' form perception. Functional MRI imaging on 14 healthy, adult volunteers was performed during a two alternative forced choice (2-AFC) form discrimination task. The functional load imposed onto the visual system was varied by using simple and complex shapes. The figures were defined using a luminance, a chromatic or a motion contrast cue. The three cues activated the same visual areas in the ventral pathway, including area 'LO'. Activation of visual area 'V3v' but not area 'KO' in the dorsal pathway was observed to the motion contrast cue. The simple shapes induced a larger BOLD response in BA18 than the complex shapes, reflecting the selectivity of this region for the features in the stimuli such as edges and vertices. The brain regions yielding a larger BOLD signal to the complex shapes were areas know to be selective to the orthographic content of our complex stimuli. The processing requirement was assessed by comparing the subjects' reaction time. We found no significant difference in the reaction times to the simple and complex shapes. The reaction times to the luminance contrast cue and the chromatic contrast cue were identical but that to the motion contrast cue were 200 ms longer. This finding concurs with neurophysiological studies, reporting a longer onset latency for motion contrast stimuli. It further lends support to the idea that the motion contrast cue requires auxiliary processing by the visual areas of the dorsal pathway before entry into the ventral pathway.


Non-pharmacological Treatment for Chronic Pain in US Veterans Treated Within the Veterans Health Administration: Implications for Expansion in US Healthcare Systems.
Consensus guidelines recommend multimodal chronic pain treatment with increased use of non-pharmacological treatment modalities (NPM), including as first-line therapies. However, with many barriers to NPM uptake in US healthcare systems, NPM use may vary across medical care settings. Military veterans are disproportionately affected by chronic pain. Many veterans receive treatment through the Veterans Health Administration (VHA), an integrated healthcare system in which specific policies promote NPM use. To examine whether veterans with chronic pain who utilize VHA healthcare were more likely to use NPM than veterans who do not utilize VHA healthcare. Cross-sectional nationally representative study. US military veterans (N = 2,836). In the 2019 National Health Interview Survey, veterans were assessed for VHA treatment, chronic pain (i.e., past 3-month daily or almost daily pain), symptoms of depression and anxiety, substance use, and NPM (i.e., physical therapy, chiropractic/spinal manipulation, massage, psychotherapy, educational class/workshop, peer support groups, or yoga/tai chi). Chronic pain (45.2% vs. 26.8%) and NPM use (49.8% vs. 39.4%) were more prevalent among VHA patients than non-VHA veterans. After adjusting for sociodemographic characteristics, psychiatric symptoms, physical health indicators, and use of cigarettes or prescription opioids, VHA patients were more likely than non-VHA veterans to use any NPM (adjusted odds ratio [aOR] = 1.52, 95% CI: 1.07-2.16) and multimodal NPM (aOR = 1.80, 95% CI: 1.12-2.87) than no NPM. Among veterans with chronic pain, VHA patients were more likely to use chiropractic care (aOR = 1.90, 95% CI = 1.12-3.22), educational class/workshop (aOR = 3.02, 95% CI = 1.35-6.73), or psychotherapy (aOR = 4.28, 95% CI = 1.69-10.87). Among veterans with chronic pain, past-year VHA use was associated with greater likelihood of receiving NPM. These findings may suggest that the VHA is an important resource and possible facilitator of NPM. VHA policies may offer guidance for expanding use of NPM in other integrated US healthcare systems.


The medical theory of Richard Koch II: natural philosophy and history.
Richard Koch(1) became known in the 1920s with works on basic medical theory. Among these publications, the character of medical action and its status within the theory of science was presented as the most important theme. While science is inherently driven by the pursuit of knowledge for its own sake, medicine pursues the practical purpose of helping the sick. Therefore, medicine must be seen as an active relationship between a helping and a suffering person. While elucidating this relationship, Koch discusses the fundamental elements of medicine found in natural philosophy and the relationship of medicine to its own history. One of his aims is to unite natural history and the history of ideas without reducing intellectual processes to biological ones. Koch considers free will as something intuitively certain. It must serve as an axiom which will capture human as well as non-human reality. Based on the fact that human free will, considered a psychic quality, evolved out of inanimate matter, Koch grants matter (proto-) psychic qualities. They are evoked through specific constellations of matter. - With regard to history, Koch rejects the notion of constant progress. The history of medicine has provided insights that cannot be surpassed but can be obscured. Historical self-contemplation serves as a means for avoiding any deviations which may prevent medicine from fulfilling its ultimate purpose. Koch connects nature and history through the concept of a unity between natural history and the historical development of medicine. Medicine is considered an especially complex development of a purposive reaction to harmful stimuli, a reaction which can already be encountered in unicellular organisms. Without intending to reduce historical and mental processes to biological ones, Koch sets for himself the aim of gathering different phenomena and presenting them in one encapsulating unity.


Timing of biochar dosage for anaerobic digestion treating municipal leachate: Altered conversion pathways of volatile fatty acids.
In this study, the anaerobic digestion (AD) applications of early & late biochar dosage were compared for municipal leachate treatment, with the objective of studying the flexible use of biochar as a mitigation measure for biomethane recovery. In two experimental phases, biochar was favourable for the immediate promotion of AD performances, as revealed by Gompertz's model of reduced lag phases, higher biomethane generation rates, and increased biomethane yields. Irrespective of late biochar dosage, it could still retrieve 89% of the ultimate biomethane potential. Comparing the residual VFAs (volatile fatty acids) compositions, it was found that the fraction of long-chain VFAs accounted for 81% of total VFAs in reactor set of early biochar dosage, while it was only 38% in the reactor of late one. Parallel evidence suggested that the schedule of biochar dosage not only could affect methanogenic responses but also the VFAs conversion pathways.


Endovascular coil embolization of a large tibioperoneal trunk pseudoaneurysm.
Infrapopliteal artery aneurysms are rare, and tibioperoneal trunk aneurysms are even rarer. We herein report an unusual case of large tibioperoneal trunk pseudoaneurysm. The patient underwent successful endovascular exclusion of the pseudoaneurysm by coil embolization with stent assistance. The clinical features and management of tibioperoneal trunk aneurysms are also discussed in this article.


Comparison among different insulin sensitivity indices in obese patients.
Recently, several indices have been proposed for the measurement of insulin sensitivity (IS). We set out to make a comparison between fasting insulin, and different IS indices in obese subjects. Fasting and post load (75 g) glucose and insulin were measured in a consecutive series of 767 (626 F, 141 M) obese (body mass index > 30 kg/m(2)) out-patients, with no known history of diabetes (DM). Mean (+/- sd) age was 46.7 +/- 13.8 years in females and 45.6 +/- 14.3 years in males. Indices of IS based on fasting homeostasis assessment model (HOMA) and post-load (ISI) glucose and insulin and either parameter (1A, and 1B scores) were determined. DM was diagnosed in 21.4% of females, and 20.6% of males, and impaired glucose tolerance in 24% females and 21.3% males. Fasting and post-load glucose, triglyceride and HDL-cholesterol were correlated with all indices in both sexes (P < 0.05). The relative risk of different conditions in the upper quartile of ISI was similar to that observed in the upper quartile of HOMA. The HOMA index was similarly associated with low HDL-cholesterol and hypertriglyceridaemia as fasting insulin, while it showed a greater association with diabetes; ISI was similarly associated with all three conditions as the HOMA index. Indices of IS based on fasting glucose and insulin show a greater association with diabetes, but not with other abnormalities related to insulin resistance, when compared with fasting insulin levels. Indices based on post-load glucose and insulin do not offer any advantage over those based on fasting values.


[Importance of flicker contrast tests in functional glaucoma diagnostics].
One of the many unsolved problems concerning glaucoma is early detection and many different methodologies have been developed. This article concentrates on methodologies belonging to the class of flicker contrast tests which present dynamic stimuli (with temporal frequencies generally above 10 Hz) and assess the perceptual thresholds for contrast, be it global or locally resolved. The tests include global flicker sensitivity, flicker perimetry (current embodiment: Pulsar), Rauschfeld campimetry, frequency doubling perimetry and flicker-defined edge perimetry. These different approaches are placed into historical perspective and are critically assessed.


Prenatal Lead Exposure, Type 2 Diabetes, and Cardiometabolic Risk Factors in Mexican Children at Age 10-18 Years.
Several cross-sectional studies have assessed the association of lead exposure with type 2 diabetes and cardiometabolic risk factors in adults; however, studies of such associations in childhood are rare. We assessed the prospective associations of prenatal exposure to lead with type 2 diabetes and cardiometabolic risk factors in children. The Early Life Exposure in Mexico to Environmental Toxicants is a birth cohort study of pregnant women and their offspring. Public hospitals in Mexico City. Women were recruited during pregnancy; their offspring were recruited for a follow-up visit at age 10 to 18 years (n = 369). We measured fasting serum markers of type 2 diabetes and cardiometabolic risk factors in children, including fasting glucose, insulin, and lipids. The index of insulin resistance was calculated. The geometric mean of maternal blood lead levels (BLLs) during pregnancy was 4.3 µg/dL (95% confidence interval [CI]): 4.0-4.6 µg/dL) in the entire sample. In boys, those with maternal BLLs ≥ 5 µg/dL (compared with those with BLLs < 5 µg/dL) had significantly lower z scores for total cholesterol (β = -0.41, 95% CI: -0.71, -0.12), high-density lipoprotein cholesterol (β = -0.32, 95% CI: -0.59, -0.05), and low-density lipoprotein cholesterol (β = -0.52, 95% CI: -0.81, -0.22), adjusting for covariates. No associations were detected in girls. In our study, we found that higher prenatal exposure to lead was associated with lower levels of cholesterol in children following a sex-specific pattern. Further studies with a larger sample size that examine whether sex is a potential modifier are needed to confirm our findings.


Leveraging on the 2017/2018 measles vaccination campaign to improve health workers knowledge and practice on injection safety: A case study of north-central states, Nigeria.
Globally, knowledge of health workers has been documented to be key in effective immunisation service delivery. The parenteral route of drug administration is a vital healthcare procedure used in the administration of medicines using needle and syringe. Despite the importance of this procedure, improper handling of the device has resulted in an unsafe practice among health workers who attend to patients receiving injectable medications. A phased measles vaccination campaign (MVC) was conducted in 2017/2018 with a key objectives of training health workers on injection safety. This paper examines the association between improvement on knowledge of health workers through improved training curriculum and their practice on injection safety. We reviewed information on handling and administration of the measles vaccine from the open data kit (ODK) platform finalised microplans and the training curriculum used during the 2015/2016 and 2017/2018 MVC. We analysed our results using paired t-test analysis, SPSS and Microsoft Excel spreadsheet and reported results in frequencies and proportions using charts and tables. Our findings revealed more health workers were trained during the 2017/2018 MVC as compared to 2015/2016 MVC. The curriculum adopted during the 2017/2018 MVC showed that multiple techniques were adopted during training compared to only class lectures used during the 2015/2016 MVC. A paired t-test analysis comparing the impact of training on the knowledge of the health workers during 2015/2016 and 2017/2018 MVC revealed significant improvement across five states during the 2017/2018 MVC, with mean ranging from 6.5% in the FCT to 23.7% in Nassarawa state. The review of training curriculum and use of multiple training styles during the 2017/2018 MVC improved the knowledge of health workers. Immunisation programmes will benefit from adopting the training curriculum to meet the specific needs of the health workers.


Facilitation of enkephalins-induced delta-opioid behavioral responses by chronic amisulpride treatment.
The endogenous opioid system is known to have a great influence on the dopaminergic system. Conversely, blockade of the dopaminergic system in D2 receptor knock-out mice triggers an increase in enkephalin supporting the important physiological relationship between both systems. Therefore, the aim of this study was to investigate whether or not chronic treatment with the specific D2 antagonist amisulpride (20mg/kg, i.p., twice daily for 5 days) could lead to a facilitation of behavioral effects of enkephalins, protected from their enzymatic degradation by the dual inhibitor N-[(R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-oxopropyl]-l-phenylalanine benzyl ester (RB101) (5mg/kg, i.v.) in mice. RB101 induced an increase in locomotor activity, antidepressant-like effects in the forced swim test, and antinociceptive effects in the hot-plate test. Chronic treatment with amisulpride potentiated the action of RB101 and this effect seemed to be restricted to behavioral responses induced by opioids acting on delta-opioid receptors (locomotor activity and forced swim test). This was confirmed by the use of the selective delta-opioid receptor agonist, (+)-4-[alpha-R*)-alpha-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80; 2.5mg/kg, i.p.), and antagonist, naltrindole (5mg/kg, i.p.). Considering the involvement of delta-opioid receptors in mood regulation, the interaction between amisulpride and RB101 could lead to a new therapeutic approach in the treatment of some mood disorders.


The Prevalence of Salmonella and Campylobacter on Broiler Meat at Different Stages of Commercial Poultry Processing.
In poultry processing, Salmonella and Campylobacter contaminations are major food safety concerns. Peracetic acid (PAA) is an antimicrobial commonly used in commercial poultry processing to reduce pathogen prevalence so as to meet the USDA-FSIS performance standards. The objective of this study was to determine the prevalence of Salmonella and Campylobacter on broiler meat in various steps of commercial poultry processing in plants that use PAA. Post-pick, pre-chill, post-chill, and drumstick chicken samples were collected from three processing plants and mechanically deboned meat (MDM) was collected from two of the three plants. Each plant was sampled thrice, and 10 samples were collected from each processing step during each visit. Among the 420 samples, 79 were contaminated with Salmonella and 155 were contaminated with Campylobacter. Salmonella and Campylobacter contamination on the post-pick samples averaged 32.2%. Significant reductions in Salmonella and Campylobacter were observed in pre-chill to post-chill samples, where the prevalence was reduced from 34% and 64.4% to nondetectable limits and 1.1%, respectively (p < 0.001). Salmonella and Campylobacter remained undetectable on the drumstick samples in all three processing plants. However, the prevalence of Salmonella and Campylobacter on MDM was similar to the post-pick prevalence, which suggests substantial cross-contamination from post-chill to MDM.


Optimization of GaAs Nanowire Pin Junction Array Solar Cells by Using AlGaAs/GaAs Heterojunctions.
We optimized the performance of GaAs nanowire pin junction array solar cells by introducing AlGaAs/GaAs heterejunctions. AlGaAs is used for the p type top segment for axial junctions and the p type outer shell for radial junctions. The AlGaAs not only serves as passivation layers for GaAs nanowires but also confines the optical generation in the active regions, reducing the recombination loss in heavily doped regions and the minority carrier recombination at the top contact. The results show that the conversion efficiency of GaAs nanowires can be greatly enhanced by using AlGaAs for the p segment instead of GaAs. A maximum efficiency enhancement of 8.42% has been achieved in this study. And for axial nanowire, by using AlGaAs for the top p segment, a relatively long top segment can be employed without degenerating device performance, which could facilitate the fabrication and contacting of nanowire array solar cells. While for radial nanowires, AlGaAs/GaAs nanowires show better tolerance to p-shell thickness and surface condition.


Safety and efficacy of a new high-dose regimen of panobinostat, gemcitabine, busulfan, and melphalan for 1st or 2nd salvage ASCT for refractory/relapsed or high-risk myeloma: Matched-pair comparisons with concurrent control cohorts.
Improvement of autologous stem-cell transplantation (ASCT) for myeloma is needed. Building on our prior work, we prospectively evaluated panobinostat and gemcitabine/busulfan/melphalan (GemBuMel) with ASCT in this population. Patients aged 18-65 years with relapsed/refractory or high-risk myeloma and adequate end-organ function were eligible. Treatment included panobinostat (20 mg/day, days -9 to -2) and GemBuMel (days -8 to -2). Patients were enrolled in 1st (ASCT-1) or 2nd ASCT (ASCT-2) cohorts. We compared their outcomes with all our other concurrent ASCT patients who met eligibility criteria but received melphalan or BuMel off study, matched for age, prior therapy lines, high-risk cytogenetics, and response at ASCT. We enrolled 80 patients, 48 and 32 in the ASCT-1 and ASCT-2 cohorts, respectively; in these two cohorts, high-risk cytogenetics were noted in 33 and 15 patients, respectively; unresponsive disease in 12 and 11 patients, respectively, after a median of 2 and 3 therapy lines, respectively. Transplant-related mortality (TRM) occurred in two ASCT-2 patients. One-year PFS rates were 69% (ASCT-1) and 72% (ASCT-2); 1-year OS rates were 79% (ASCT-1) and 84% (ASCT-2). Minimal residual disease negativity improved after ASCT-1 (8.5%-23%, p < .0001) and ASCT-2 (34%-55%, p = .02), which correlated with improved outcomes. Trial patients and controls (N = 371) had similar TRM and post-ASCT maintenance. Trial patients had better PFS after either a 1st (p = .02) or a 2nd ASCT (p = .04) than matched-paired control patients. In conclusion, panobinostat/GemBuMel is effective for relapsed/refractory or high-risk myeloma patients, with better PFS than concurrent matched controls receiving melphalan or BuMel.


Direct imaging and quantification of carotid plaque calcification.
Carotid plaque calcification normally appears as a signal void with clinical MR sequences. Here, we describe the use of an adiabatic inversion recovery prepared two-dimensional ultrashort echo time sequence to image and characterize carotid plaque calcification using a clinical 3-T scanner. T(1), T 2*, and free water content were measured for seven carotid samples, and the results were compared with micro-CT imaging. Conventional gradient echo and fast spin echo images were also acquired for comparison. Correlations between T(1), T 2*, free water concentration, and mineral density were performed. There was a close correspondence between inversion recovery prepared two-dimensional ultrashort echo time morphologic and micro-CT appearances. Carotid plaque calcification varied significantly from sample to sample, with T(1) s ranging from 94 ± 19 to 328 ± 21 msec, T 2*s ranging from 0.31 ± 0.12 to 2.15 ± 0.25 msec, and free water concentration ranging from 5.7 ± 2.3% to 16.8 ± 3.4%. There was a significant positive correlation between T(1)(R = 0.709; P < 0.074), T 2* (R = 0.816; P < 0.025), and free water concentration, a negative correlation between T(1) (R = 0.773; P < 0.042), T 2* (R = 0.948; P < 0.001) and CT measured mineral density, and a negative correlation between free water concentration (R = 0.936; P < 0.002) and mineral density.


Ki-67 and ProExC are useful immunohistochemical markers in esophageal squamous intraepithelial neoplasia.
Esophageal squamous intraepithelial neoplasia has been widely recognized as a precursor lesion for esophageal squamous cell carcinoma. Early detection offers the best prognosis for esophageal squamous cell carcinoma. The differentiation of squamous dysplasia from reactive change and the classification of squamous dysplasia into high-grade or low-grade are sometimes subjective and challenging. In this study, we sought to evaluate multiple biomarkers and to develop clinically useful adjunct tools for difficult esophageal squamous intraepithelial neoplasia cases. Immunohistochemical stains using antibodies against Ki-67, ProExC, p16, and p53 were performed on esophageal biopsy or resection specimens from 25 patients including 35 foci of high-grade dysplasia and 25 foci of low-grade dysplasia, and from 10 control cases containing 52 foci of normal/reactive hyperplasia. In situ hybridization tests for human papillomavirus were performed in 11 cases. The immunostains for all 4 markers were scored as negative, intermediate, and strong according to established criteria. Intermediate and strong Ki-67 and ProExC staining showed similar detecting power and exhibited very high sensitivity and specificity for distinguishing normal/reactive hyperplasia from esophageal squamous intraepithelial neoplasia and normal/reactive hyperplasia from low-grade esophageal squamous intraepithelial neoplasia. Strong Ki-67 staining was exclusively seen in high-grade esophageal squamous intraepithelial neoplasia, which provided additional value in distinguishing high-grade from low-grade esophageal squamous intraepithelial neoplasia. Strong ProExC staining was also seen in most high-grade esophageal squamous intraepithelial neoplasia foci (80%). Although the frequencies of intermediate/strong staining patterns of p53 increased with increasing degree of dysplasia, the sensitivity of p53 was much lower than that of Ki-67 and ProExC. p16 did not show consistent immunostain pattern in the normal/reactive hyperplasia and esophageal squamous intraepithelial neoplasia. Two (18%) of 11 tested cases were positive for human papillomavirus infection. This study demonstrates that both Ki-67 and ProExC can be used as an adjunct tool for diagnosing difficult cases of esophageal squamous intraepithelial neoplasia.


Effect of deadtime loss on quantitative measurement of cerebral blood flow with technetium-99m hexamethylpropylene amine oxime.
Deadtime count loss may cause error in quantitative measurements with a gamma camera. We evaluated the effect of deadtime loss on the measurement of cerebral blood flow (CBF). Radionuclide angiography with technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO) was performed in 20 patients. A reference source was placed on the periphery of the detector to monitor deadtime loss, and CBF was calculated based on the data of radionuclide angiography with and without deadtime correction. In ten patients injected with 1110 MBq of the tracer, the CBF value without correction was 9.9%+/-1.8% higher than that with correction. This shows that deadtime loss may cause significant overestimation. The difference between CBF values obtained with and without correction was smaller in ten patients with an injected dose of 370 MBq (3.0%+/-1.2%). These results suggest a substantial effect of deadtime loss on CBF as measured by radionuclide angiography and 99mTc-HMPAO.


Remdesivir for the treatment of Covid-19: the value of biochemical studies.
The nucleotide analogue prodrug remdesivir remains the only FDA-approved antiviral small molecule for the treatment of infection with SARS-CoV-2. Biochemical studies revealed that the active form of the drug targets the viral RNA-dependent RNA polymerase and causes delayed chain-termination. Delayed chain-termination is incomplete, but the continuation of RNA synthesis enables a partial escape from viral proofreading. Remdesivir becomes embedded in the copy of the RNA genome that later serves as a template. Incorporation of an incoming nucleotide triphosphate is now inhibited by the modified template. Knowledge on the mechanism of action matters. Enzymatic inhibition links to antiviral effects in cell cultures, animal models and viral load reduction in patients, which provides the logical chain that is expected for a direct acting antiviral. Hence, remdesivir also serves as a benchmark in current drug development efforts that will hopefully lead to orally available treatments to the benefit of a broader population.


Training standardized patients for a high-stakes Clinical Performance Examination in the California Consortium for the Assessment of Clinical Competence.
The use of standardized patients in teaching and assessment of clinical skills has become more ubiquitous in medical schools in the United States and Canada since Dr Howard Barrows introduced the first standardized patient at the University of Southern California in 1963. This increased usage is also due to the fact that the national licensing examination in the United States, includes a component to assess the clinical skills of the learners (United States Medical Licensure Examination Step 2 CS). The eight medical schools in California form a Consortium for the Assessment of Clinical Competence, which enables them to develop and implement a common clinical assessment tool, the Clinical Performance Examination (CPX), for final year medical students across the state. All medical schools in the Consortium share the same standardized patient cases and checklists. The standardization of training across the eight medical schools is presented. This paper describes the methods that have been used to train the SPs so that they can portray the gestalt of the patient, provide effective feedback, and reliably evaluate the students at the Keck School of Medicine of the University of Southern California. Quality assurance measures to ensure both performance and checklist accuracy are also described.


Stem cells to replace the optic nerve.
Methods that exist now and that might be developed are suggested to replace retinal ganglion cells and their axons in the optic nerve, ultimately to re-establish functional vision in eyes blind from glaucoma.


Netrin-1 attenuates cerebral ischemia/reperfusion injury by limiting mitochondrial ROS and Ca2+ levels via activation of AKT phosphorylation and mitochondrial m-AAA protease AFG3L2.
Cerebral ischemia-reperfusion (I/R) injury as the consequence of revascularization after ischemic stroke is associated with mitochondrial dysfunction, oxidative stress, and neuron loss. In this study, we used a deprivation/reoxygenation (OGD/R) model to determine whether interactions between Netrin-1, AKT, and the mitochondrial AAA protease AFG3L2 could influence mitochondrial function in neurons after I/R. We found that Netrin-1 protects primary cortical neurons from OGD/R-induced cell death and regulates mitochondrial reactive oxygen species (ROS) and Ca2+ levels. The accumulation of mitochondrial calcium uniporter (MCU) subunits was monitored in cells by immunoblot analysis. Although the regulatory subunits MICU1 and MICU2 were relatively unaffected, the accumulation of the essential MCU regulator (EMRE) subunit was impaired. In OGD/R-induced cells, the 7 kDa form of EMRE was significantly reduced. Netrin-1 inhibited the accumulation of EMRE and mitochondrial Ca2+ levels by upregulating AFG3L2 and AKT activation. Loss of AFG3L2 or inhibition of AKT increased levels of 7 kDa EMRE. Moreover, overexpression of AKT increased the expression of AFG3L2 in Netrin-1-knockdown neurons after OGD/R. Our results demonstrate that Netrin-1 enhanced AFG3L2 protein expression via activation of AKT. We also observed that overexpression of Netrin-1 significantly reduced infarction size in an I/R-induced brain injury model in rats but not when AKT was inhibited. Our data suggest that AFG3L2 is a protein substrate of AKT and indicate that Netrin-1 attenuates cerebral I/R injury by limiting mitochondrial ROS and Ca2+ levels through activating AKT phosphorylation and AFG3L2.


The song of Anorexia Nervosa: a specific evoked potential response to musical stimuli in affected participants.
Research applying electroencephalography (EEG) to Anorexia Nervosa (AN) is still limited, even though in other psychiatric disorders EEG has permitted to find out the hallmarks of the disorder. The aim of the study was to explore whether EEG basal activity and reactivity to musical stimulation differ in participants with AN as compared to healthy subjects (HS). Twenty female participants (respectively 10 with AN and 10 healthy controls) were administered a battery of psychometric tests and underwent EEG under three different conditions: (1) at baseline; (2) after a generic music stimulation; and (3) after a favorite musical stimulation. In participants with AN, basal EEG showed the higher absolute amplitude of cortical slow waves (theta) in the parieto-occipital and temporal derivations, with a deficit in the beta band. In AN, there was a higher N100 latency and a reduced P300 latency compared to HS. While the N100 and P300 latencies were sensitive to the musical stimulus in HS, there was no difference after music stimulation in AN. These data suggest that AN is accompanied by a state of brain hyperarousal with abnormal reactivity to environmental stimuli, similar to the state of HS after musical stimulation. If confirmed, this finding may have treatment implications. III, Evidence obtained from well-designed cohort or case-control analytic studies.


Evidence-based European recommendations for the dietary management of diabetes.
Diabetes management relies on effective evidence-based advice that informs and empowers individuals to manage their health. Alongside other cornerstones of diabetes management, dietary advice has the potential to improve glycaemic levels, reduce risk of diabetes complications and improve health-related quality of life. We have updated the 2004 recommendations for the nutritional management of diabetes to provide health professionals with evidence-based guidelines to inform discussions with patients on diabetes management, including type 2 diabetes prevention and remission. To provide this update we commissioned new systematic reviews and meta-analyses on key topics, and drew on the broader evidence available. We have strengthened and expanded on the previous recommendations to include advice relating to dietary patterns, environmental sustainability, food processing, patient support and remission of type 2 diabetes. We have used the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach to determine the certainty of evidence for each recommendation based on findings from the commissioned and identified systematic reviews. Our findings indicate that a range of foods and dietary patterns are suitable for diabetes management, with key recommendations for people with diabetes being largely similar for those for the general population. Important messages are to consume minimally processed plant foods, such as whole grains, vegetables, whole fruit, legumes, nuts, seeds and non-hydrogenated non-tropical vegetable oils, while minimising the consumption of red and processed meats, sodium, sugar-sweetened beverages and refined grains. The updated recommendations reflect the current evidence base and, if adhered to, will improve patient outcomes.


The use of affinity chromatography in purification of cyclic nucleotide receptor proteins.
Biospecific affinity chromatography has been used to purify specific cyclic AMP and cyclic GMP receptor proteins. Several variables are important for successful purification of the cyclic AMP receptor protein, the most critical being the length of the aliphatic spacer side arm. 8-(2-Aminoethyl)-amino-cyclic AMP coupled to the aliphatic spacer side arm. 8-(2-Aminoethyl)-amino-cyclic AMP coupled to agarose specifically retains the cyclic AMP receptor protein by interaction with the immobilized nucleotide. Binding of the cyclic AMP receptor subunit of cyclic AMP-dependent protein kinase to the immobilized nucleotide results in dissociation of the catalytic protein phosphokinase subunit which is not retained. The retained cyclic AMP receptor protein is subsequently eluted by cyclic AMP. Homogeneous cyclic AMP receptor protein prepared from rabbit skeletal muscle by affinity chromatography has been characterized. The molecular weight of the native protein as determined by analytical ultracentrifugation and polyacrylamide gel electrophoresis at varying acrylamide concentrations is 76 800 and 82 000, respectively. The protein is asymmetric with frictional and axial ratios of 1.64 and 12. SDS and urea polyacrylamide gel electrophoresis indicate that the native cyclic AMP receptor is composed of two identical subunits of 42 700 molecular weight. The native protein dimer binds 2 moles of cyclic AMP per mole of protein and is active in suppressing activity of isolated catalytic subunits of cyclic AMP-dependent protein kinase. Cyclic GMP receptor protein from bovine lung has been purified using the same affinity chromatography media. Since cyclic nucleotide binding to cyclic GMP-dependent protein kinase does not result in dissociation of regulatory receptor and catalytic phosphotransferase subunits, the cyclic GMP-dependent protein kinase holoenzyme is retained on the column and can be subsequently specifically eluted with cyclic GMP.


The influence of FDBA and autogenous bone particles on regeneration of calvaria defects in the rabbit: a pilot study.
The histological behavior of bone formation using three biomaterials was examined including whether an 8mm rabbit calvarial defect would behave as a critical size defect. Four trephine defects of 8mm diameter in were created six rabbit parietal bones. A control defect was maintained only with coagulum and others were filled with autologous bone, FDBA (freeze dried bone allograft) and a mixture of autologous bone with FDBA, respectively. The animals were sacrificed after between 15 and 90 days at intervals of two weeks and the extracted samples were processed for histological evaluation. All control defects showed incomplete bone formation during 90 days of observation. The defects filled with FDBA and mixture of FDBA-autologous bone exhibited a higher regeneration degree than autologous bone after 60 days; however, the only biomaterial revealing complete mineralization of the original defect at 90 days was FDBA. In conclusion, 8mm defects can be considered as critical size defects and only FDBA showed mature lamellar bone at 90 days.


A transcription terminator located upstream of the mouse rDNA initiation site affects rRNA synthesis.
Mouse ribosomal genes have a short sequence upstream of the transcription initiation site that is related in structure and function to the terminator boxes previously identified at the 3' end of the transcription unit. This upstream terminator recognizes the same protein factor as the 3'-terminal sites and is able to terminate RNA polymerase I transcription in vitro. S1 mapping and nucleolar run-on experiments reveal the presence of 5'-terminal spacer transcripts that are terminated at this site. These transcripts probably derive from spacer promoters, one of which has been identified approximately 2 kb upstream of the pre-rRNA start site. The interaction of a specific nuclear factor with the upstream terminator increases the efficiency of initiation, suggesting that transcription termination and initiation at the adjacent promoter work in an interrelated fashion.


Immunomodulatory role of Withania somnifera root powder on experimental induced inflammation: An in vivo and in vitro study.
The aqueous suspension of Withania somnifera root powder was investigated for their in vivo and in vitro immunomodulatory properties. W. somnifera showed potent inhibitory activity towards the complement system, mitogen induced lymphocyte proliferation and delayed-type hypersensitivity reaction. Administration of W. somnifera root powder did not have a significant effect on humoral immune response in rats. Our results report immunosuppressive effect of W. somnifera root powder, thus it could be a candidate for developing as an immunosuppressive drug for the inflammatory diseases.


Disseminated infection with a mycobacterium related to Mycobacterium triplex with central nervous system involvement associated with AIDS.
We report on a case of disseminated infection with central nervous system involvement due to an atypical mycobacterium related to Mycobacterium triplex in a severely immunodepressed human immunodeficiency virus-infected man.


Video education for critical care nurses to assess pain with a behavioural pain assessment tool: A descriptive comparative study.
To evaluate the impact of video education on critical care nurses' knowledge and skills in using a behavioural pain assessment tool for intensive care patients and to explore the nurses' experiences with video education. Forty-eight nurses in one intensive care unit watched an educational video on the use of the Critical-Care Pain Observation Tool, then assessed pain in two patients with the tool and took a knowledge test. The researcher made parallel pain assessments. Interrater reliability of patients' pain assessment between nurses and the researcher was determined to examine nurses' skills in using the tool after education. Twenty nurses were interviewed about their experiences with the video education. Interviews were analysed with deductive thematic analysis. The knowledge test scores indicated that the nurses learned the principles of how to use the tool. The interrater reliability of pain assessments reached a moderate level of agreement during the painful procedure, with a weighted kappa coefficient value of 0.48, CL [0.37, 0.58]. The nurses perceived video education positively, but requested additional interaction. Video education is useful in teaching the principles of using a pain assessment tool. Additional clinical training is required for nurses to reach adequate skills in using the tool.