Education, Dietary Intakes and Exercise.
This paper examines the relationship between education and health behaviours, focusing on potential offsetting responses between calories in (i.e. dietary intakes) and calories out (i.e. physical activity). It exploits the 1972 British compulsory schooling law that raised the minimum school leaving age from 15 to 16 to estimate the effects of education on diet and exercise around middle age. Using a regression discontinuity design, the findings suggest that the reform led to a worsening of the quality of the diet, with increases in total calories, fats and animal proteins. However, I find that these changes are partially offset by a discontinuous increase in physical activity. Back-of-the-envelope calculations suggest little effect on the balance of calories. As such, the findings show that focusing on the two components of energy balance provides additional information that is concealed in analyses that only use a measure of obesity.


A controlled study of agoraphobia and the independent effect of virtual reality exposure therapy.
Past controlled clinical trials centred on virtual reality exposure therapy (VRET) for agoraphobia mostly used multicomponent therapy with success. However, the present paper aimed to evaluate the independent effect of VRET for agoraphobia. A controlled study involving 18 agoraphobic participants assigned to two groups: VRET only and VRET with cognitive therapy. Nine specific virtual environments were developed using an affordable game level editor. Questionnaires, behavioural tests and physiological measures indicated a positive effect of VRET. Correlations supported the predictive value of presence towards treatment outcome. The addition of cognitive therapy did not provide significant additional benefit. Overall, the isolated effects of VRET did not seem to be significantly less than the effects of VRET combined with cognitive therapy. Future research should explore the use of other components in addition to cognitive therapy and VRET for agoraphobia as well as its possible use in patients' homes.


Comparison of pulmonary function and back muscle strength according to the degree of spinal curvature of healthy adults.
[Purpose] Degree of curvature on the spine is known to affect respiratory function and back muscle activation. We compared pulmonary function and back muscle strength according to the degree of curvature of the spine of healthy adults. [Subjects and Methods] Twenty-three healthy volunteers were enrolled. They were divided into two groups according to the degree of curvature of the spine: the below 2° group, and the above 2° group. The degree of curvature was assessed using the Adams forward bending test and a scoliometer. A pulmonary function test (PFT) was conducted, and back muscle strength was measured. [Results] No significant differences in PFT were found between the below 2° group and the above 2° group, in terms of forced vital capacity (FVC), forced expiratory volume in one second (FEV1), ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC), or peak expiratory flow (PEF). However, back muscle strength in the below 2 group was significantly higher than that of the above 2 group. [Conclusion] Our findings indicate that the degree of curvature of the spine is associated with back muscle strength in subjects who have spinal curvature within the normal range. Therefore, evaluation and treatment of back muscle strength might be helpful for preventing the progress of curvature of the spine in adolescents with potential scoliosis.


Topological versus chemical ordering in network glasses at intermediate and extended length scales.
Atomic ordering in network glasses on length scales longer than nearest-neighbour length scales has long been a source of controversy. Detailed experimental information is therefore necessary to understand both the network properties and the fundamentals of glass formation. Here we address the problem by investigating topological and chemical ordering in structurally disordered AX2 systems by applying the method of isotopic substitution in neutron diffraction to glassy ZnCl2. This system may be regarded as a prototypical ionic network forming glass, provided that ion polarization effects are taken into account, and has thus been the focus of much attention. By experiment, we show that both the topological and chemical ordering are described by two length scales at distances greater than nearest-neighbour length scales. One of these is associated with the intermediate range, as manifested by the appearance in the measured diffraction patterns of a first sharp diffraction peak at 1.09(3) A(-1); the other is associated with an extended range, which shows ordering in the glass out to 62(4) A. We also find that these general features are characteristic of glassy GeSe2, a prototypical covalently bonded network material. The results therefore offer structural insight into those length scales that determine many important aspects of supercooled liquid and glass phenomenology.


Eyes versus hands: How perceived stimuli influence motor actions.
Many studies showed that biological (e.g., gaze-shifts or hand movements) and non-biological stimuli (e.g., arrows or moving points) redirect attention. Biological stimuli seem to be more suitable than non-biological to perform this task. However, the question remains if biological stimuli do have different influences on redirecting attention and if this property is dependent on how we react to those stimuli. In two separate experiments, participants interact either with a biological or a non-biological stimulus (experiment 1), or with two biological stimuli (gaze-shifts, hand movements)(experiment 2) to which they responded with two different actions (saccade, button press), either in a congruent or incongruent manner. Results from experiment 1 suggest that interacting with the biological stimulus lead to faster responses, compared to the non-biological stimulus, independent of the response type. Results from experiment 2 show longer reaction times when the depicted stimulus was not matching the response type (e.g., reacting with hand movements to a moving object or gaze-shift) compared to a matching condition, while especially the gaze-following condition (reacting with a gaze shift to a perceived gaze shift) led to the fastest responses. These results suggest that redirecting attention is not only dependent on the perceived stimulus but also on the way how those stimuli are responded to.


Chlorpromazine versus metiapine for schizophrenia.
Chlorpromazine, a widely available and inexpensive antipsychotic drug, is considered the benchmark treatment for schizophrenia worldwide. Metiapine, a dibenzothiazepine derivative, has been reported to have potent antipsychotic characteristics. However, no evidence currently exists on the effectiveness of chlorpromazine in treatment of people with schizophrenia compared to metiapine, a newer antipsychotic. To compare the effect of chlorpromazine versus metiapine for the treatment of people with schizophrenia SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials in November 2015 and 2016. All randomised controlled trials (RCTs) focusing on chlorpromazine versus metiapine for adults with schizophrenia. We included trials meeting our selection criteria and reporting useable data. We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference between groups and its 95% CI. We employed a random-effects model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE. We included three studies randomising 161 people with schizophrenia. Data were available for only two of our seven prestated main outcomes. Clinically important improvement in global state was measured using the Clinical Global Impression (CGI). There was no clear difference between chlorpromazine and metiapine groups (2 RCTs, n = 120, RR 1.11, 95% CI 0.84 to 1.47, very low quality evidence) and numbers of participants with parkinsonism at eight weeks were similar (2 RCTs, n = 70, RR 0.97, 95% CI 0.46 to 2.03, very low quality evidence). There were no useable data available for the other key outcomes of clinically important improvement in mental state, readmission due to relapse, satisfaction with treatment, aggressive or violent behaviour, or cost of care. Chlorpromazine has been the mainstay treatment for schizophrenia for decades, yet available evidence comparing this drug to metiapine fails to provide high-quality trial based data. However, the need to determine whether metiapine is more or less effective than chlorpromazine seems to be lacking in clinical relevance and future research on this comparison seems unlikely.


Diabetes-induced expression of activating transcription factor 3 in mouse primary sensory neurons.
Diabetic neuropathy (DN) is a complication of diabetes that affects the distal terminals of lengthy-projecting sensory axons. To determine whether diabetes-induced axonal degeneration induces gene expression similar to nerve injury, the expression of activating transcription factor 3 (ATF3) by primary sensory neurons was examined in an experimental mouse model of DN. Diabetes was induced using streptozotocin in C57BL/6 mice, and ATF3 expression in lumbar dorsal root ganglia was assessed at different time points and correlated with the markers of unmyelinated and myelinated neuronal populations. ATF expression was first evident 3 weeks after diabetes induction in both small unmyelinated and large myelinated neurons, but it was more prevalent in larger neurons. At 6 weeks, ATF3 was expressed by neurons among smaller size ranges, but this shift occurred principally within myelinated populations. The retrograde labeling of neurons innervating the flank and paw skin using Fluoro-Gold labeled appropriate percentages of ATF3-positive neurons at 3 weeks, suggesting ATF3 is expressed by neurons capable of transporting substances. However, the percentage of double-labeled neurons was substantially reduced at 6 weeks, suggesting this capacity decreases during disease progression. Finally, behavioral responses to noxious cutaneous stimuli were assessed. Although no differences to radiant heat were observed, diabetic mice developed severe mechanical hypoalgesia 4-5 weeks after diabetes induction. These results demonstrate that the diabetes-induced damage of sensory axons can induce the expression of genes linked to peripheral nerve injury and may identify neurons undergoing nerve damage. Finally, the ability to detect sensory deficits in diabetic mice occurs after the expression of injury-related gene ATF3, suggesting that nerve damage may be underway prior to the appearance of behavioral deficits.


Perspectives on invasive amphibians in Brazil.
Introduced species have the potential to become invasive and jeopardize entire ecosystems. The success of species establishing viable populations outside their original extent depends primarily on favorable climatic conditions in the invasive ranges. Species distribution modeling (SDM) can thus be used to estimate potential habitat suitability for populations of invasive species. Here we review the status of six amphibian species with invasive populations in Brazil (four domestic species and two imported species). We (i) modeled the current habitat suitability and future potential distribution of these six focal species, (ii) reported on the disease status of Eleutherodactylus johnstonei and Phyllodytes luteolus, and (iii) quantified the acoustic overlap of P. luteolus and Leptodactylus labyrinthicus with three co-occurring native species. Our models indicated that all six invasive species could potentially expand their ranges in Brazil within the next few decades. In addition, our SDMs predicted important expansions in available habitat for 2 out of 6 invasive species under future (2100) climatic conditions. We detected high acoustic niche overlap between invasive and native amphibian species, underscoring that acoustic interference might reduce mating success in local frogs. Despite the American bullfrog Lithobates catesbeianus being recognized as a potential reservoir for the frog-killing fungus Batrachochytrium dendrobatidis (Bd) in Brazil, we did not detect Bd in the recently introduced population of E. johnstonei and P. luteolus in the State of São Paulo. We emphasize that the number of invasive amphibian species in Brazil is increasing exponentially, highlighting the urgent need to monitor and control these populations and decrease potential impacts on the locally biodiverse wildlife.


Assessment of Endothelial Reactivity by Measurement of Vascular Material Response to Shear Stress: A Feasibility Study.
Flow-mediated dilation (FMD) evaluates the relative change in arterial diameter during hyperemia to assess the endothelial response due to a shear stimulus. However, conventional FMD measures diameter response alone and the alterations in the arterial wall's material properties during reactive hyperemia, which also influence dilation, go unaddressed. In this work, we examine the material response (MR) of the artery during reactive hyperemia using clinically relevant stiffness markers for the assessment of endothelial reactivity (ER). For this, we have developed an in-house brachial cuff control (BCC) system to continuously acquire brachial pressure which can be integrated with simultaneous measurement of brachial diameter and used to quantify the relative changes in wall property during hyperemia non-invasively. The assessment of endothelial reactivity using material response (ERAMR) was conducted on 20 healthy participants (12M/8F) and the results were compared with conventional FMD (FMD%). The mean pressure response gave an inverse trend to that of diameter response with varying magnitudes during reactive hyperemia (18.71% from baseline for diameter and 2.45% for pressure), there was a significant difference in the measurement of FMD and ERAMR (P < 0.05). The larger distribution of ERAMR compared to FMD% in box-plots further implies the inclusion of within-subject variations. Hence, ERAMR can be a potential estimate of ER, given the need for intensive validations in this line on larger cohorts.Clinical Relevance- This study demonstrates the independent role of arterial wall material properties to quantify endothelial reactivity in response to a shear stimulus.


The Appropriateness of Adapting the Australian Environmental Assessment Tool-High Care (EAT-HC) for Persons With Dementia in Singapore.
This study investigated the level of acceptance in Singapore of the eight principles of design underpinning the Environmental Assessment Tool-High Care (EAT-HC), which is commonly used in Australia to evaluate environments for the care of people living with dementia. A secondary goal was to identify topics particularly relevant to the Singaporean context, which are not included in the Australian EAT-HC. This study was undertaken in preparation for the development of a Singaporean version of the Australian EAT-HC. Discussions from 23 focus groups involving 150 family caregivers, aged care staff, administrators, and architects were recorded and thematically analyzed to identify the characteristics of the principles underpinning the EAT-HC that are unlikely to be relevant in a Singaporean version and to identify additional topics required to tailor it to reflect the Singaporean culture. The thematic analysis was supplemented with quantitative data obtained through the use of simple Likert-type scales measuring the appropriateness of each principle in the Singaporean context. The principles of design that underpin the EAT-HC were highly accepted by participants and provided a framework for a systematic exploration of Singaporean residential care for people with dementia. Some topics of particular relevance to Singapore were identified. These can be subsumed by the principles without the need for the principles to be changed. The results support the use of the design principles underpinning the EAT-HC as the foundation of a tool for the evaluation of Singaporean dementia facilities.


The Exploration of Chemical Reaction Networks.
Modern computational chemistry has reached a stage at which massive exploration into chemical reaction space with unprecedented resolution with respect to the number of potentially relevant molecular structures has become possible. Various algorithmic advances have shown that such structural screenings must and can be automated and routinely carried out. This will replace the standard approach of manually studying a selected and restricted number of molecular structures for a chemical mechanism. The complexity of the task has led to many different approaches. However, all of them address the same general target, namely to produce a complete atomistic picture of the kinetics of a chemical process. It is the purpose of this overview to categorize the problems that should be targeted and to identify the principal components and challenges of automated exploration machines so that the various existing approaches and future developments can be compared based on well-defined conceptual principles.


Needle brush in the diagnosis of lung mass or nodule through flexible bronchoscopy.
Transbronchial needle aspiration (TBNA), in comparison with cytology brush and forceps biopsy, in the diagnosis of a pulmonary mass or coin lesions has been studied by Shure and Wang in the past. Both studies concluded that TBNA markedly increased the diagnostic yield. A new instrument, a "needle brush" (Mill Rose Lab), has been developed and compared with the following three instruments: a regular cytology brush was used first, followed by needle brush, TBNA, and forceps biopsy under fluoroscopy. Twenty-four patients were studied. A specific diagnosis was made in 16 patients (15 malignancies; one granuloma); in three patients, results were suspicious for malignancy, three patients had negative results, and in two patients the study was not complete. "Needle brush" biopsy was positive in 11 patients (exclusively in four); TBNA was positive in eight (exclusively in two). Regular brush biopsy was positive in seven (exclusively in none). Forceps biopsy was positive in four (exclusively in one; granuloma). We conclude that the needle brush and TBNA have a higher diagnostic yield in malignant lung masses or nodules. The use of regular brush and forceps biopsy did not increase the diagnostic yield in malignancy. Forceps biopsy might be more useful in benign diseases.


Risk factors for hip fracture in older home care clients.
Little information is available on hip fracture risks among community-dwelling persons receiving home care. Our aim was to identify risk factors for hip fracture from health information routinely collected for older home care clients. This was a cohort study involving secondary analysis of data on 40,279 long-stay (>60 days) home care clients aged 65 and older in Ontario, Canada; occurrence of hip fracture as well as potential risk factor information were measured using the Resident Assessment Instrument (RAI)/Minimum Data Set-Home Care assessment instrument. In all, 1,003 clients (2.5%) had hip fracture on follow-up assessment. Older (85+ vs 65-74, relative risk [95% confidence interval]: 0.52 [0.43-0.64]) clients are at increased risk; males are at reduced risk [0.60 (0.51-0.70)]. Other risk factors include osteoporosis (1.19 [1.03-1.36]), falls (1.31 [1.15-1.49]), unsteady gait (1.18 [1.03-1.36]), use of ambulation aide (1.39 [1.21-1.59]), tobacco use (1.42, [1.13-1.80]), severe malnutrition (2.61 [1.67-4.08]), and cognitive impairment (1.30 [1.12-1.51]). Arthritis (0.86 [0.76-0.98]) and morbid obesity (0.34 [0.16-0.72]) were associated with reduced risk. Males and females demonstrated different risk profiles. Important risk factors for hip fracture can be identified from routinely collected data; these could be used to identify at-risk clients for further investigation and prevention strategies.


Cell biology of vascular hypertrophy in systemic hypertension.
Recent data demonstrate that in addition to its conduit function, the blood vessel is an active synthetic and secretory organ containing several autocrine and paracrine systems that are involved with the local regulation of its own function (i.e., structure and growth). The endothelium secretes vasorelaxant and vasoconstrictive substances, growth factors and inflammatory mediators that exert paracrine influences on vascular myocyte function. The vascular myocyte also expresses autocrine substances that influence its own function. The autocrine systems include angiotensin, prostaglandins, platelet-derived growth factor, insulin-like growth factor and heparin. These local factors exert modulatory influences on myocyte contractility and growth. These autocrine and paracrine systems serve as an adaptive mechanism by which the vasculature autoregulates its structural and functional state. We speculate that an alteration in this delicate balance of these local factors, due to genetic or acquired abnormalities, can result in increased vascular tone and vessel hypertrophy and thereby contribute to the pathogenesis of hypertension.


Novel tumor necrosis factor alpha-regulated genes in rheumatoid arthritis.
To determine novel genes regulated by tumor necrosis factor alpha (TNFalpha) signaling in primary rheumatoid arthritis synovial fibroblasts (RASFs). Oligonucleotide microarrays were used to measure gene expression levels in 6 independent replicate samples of RASFs. RASFs were transfected for 18 hours with AdIkappaB-dominant negative (AdIkappaB-DN) (n = 3) or with control AdTet expressing the reverse tetracycline trans-activator (n = 3). The cells were stimulated for 3 hours with TNFalpha, and total RNA was prepared. Several novel parametric and nonparametric methods were used to rank genes in terms of the magnitude and significance of intergroup differences. Microarray expression differences were confirmed by real-time quantitative reverse transcription-polymerase chain reaction. Small interfering RNA (siRNA) was used to specifically down-modulate microarray-identified genes to demonstrate their role in the promotion of apoptosis, proliferation, or matrix metalloproteinase (MMP) expression. Blocking of NF-kappaB by AdIkappaB-DN was associated with a down-modulation of antiapoptosis genes, including BIRC-3, and several novel genes, including GG2-1, a TNFalpha-inducible FLIP-like gene. Other families of genes that were significantly down-regulated by AdIkappaB-DN included cytokines/chemokines (interleukin-1beta [IL-1beta], IL-8, IL-15, and RANTES), adhesion molecule (vascular cell adhesion molecule 1, intercellular adhesion molecule 1), and unique genes that have not previously been reported to be regulated by TNFalpha in RA. Inhibition of the GG2-1 gene using the siRNA technique resulted in significantly enhanced apoptosis, decreased proliferation, and decreased production of MMP-1 in TNFalpha-stimulated RASFs. These studies provide a comprehensive analysis of genes that are differentially regulated by TNFalpha signaling and NF-kappaB nuclear translocation in RASFs and demonstrate methods for confirming the expression and functional significance of such genes.


Double-headed sulfur-linked amino acids as first inhibitors for betaine-homocysteine S-methyltransferase 2.
Betaine-homocysteine S-methyltransferase 2 (BHMT-2) catalyzes the transfer of a methyl group from S-methylmethionine to l-homocysteine, yielding two molecules of l-methionine. It is one of three homocysteine methyltransferases in mammals, but its overall contribution to homocysteine remethylation and sulfur amino acid homeostasis is not known. Moreover, recombinant BHMT-2 is highly unstable, which has slowed research on its structural and catalytic properties. In this study, we have prepared the first series of BHMT-2 inhibitors to be described, and we have tested them with human recombinant BHMT-2 that has been stabilized by copurification with human recombinant BHMT. Among the compounds synthesized, (2S,8RS,11RS)-5-thia-2,11-diamino-8-methyldodecanedioic acid (11) was the most potent (K(i)(app) ∼77 nM) and selective inhibitor of BHMT-2. Compound 11 only weakly inhibited human BHMT (IC(50) about 77 μM). This compound (11) may be useful in future in vivo studies to probe the physiological significance of BHMT-2 in sulfur amino acid metabolism.


MicroRNA-24/MODY gene regulatory pathway mediates pancreatic β-cell dysfunction.
Overnutrition and genetics both contribute separately to pancreatic β-cell dysfunction, but how these factors interact is unclear. This study was aimed at determining whether microRNAs (miRNAs) provide a link between these factors. In this study, miRNA-24 (miR-24) was highly expressed in pancreatic β-cells and further upregulated in islets from genetic fatty (db/db) or mice fed a high-fat diet, and islets subject to oxidative stress. Overexpression of miR-24 inhibited insulin secretion and β-cell proliferation, potentially involving 351 downregulated genes. By using bioinformatic analysis combined with luciferase-based promoter activity assays and quantitative real-time PCR assays, we identified two maturity-onset diabetes of the young (MODY) genes as direct targets of miR-24. Silencing either of these MODY genes (Hnf1a and Neurod1) mimicked the cellular phenotype caused by miR-24 overexpression, whereas restoring their expression rescued β-cell function. Our findings functionally link the miR-24/MODY gene regulatory pathway to the onset of type 2 diabetes and create a novel network between nutrient overload and genetic diabetes via miR-24.


Temporal genomic contrasts reveal rapid evolutionary responses in an alpine mammal during recent climate change.
Many species have experienced dramatic changes in their abundance and distribution during recent climate change, but it is often unclear whether such ecological responses are accompanied by evolutionary change. We used targeted exon sequencing of 294 museum specimens (160 historic, 134 modern) to generate independent temporal genomic contrasts spanning a century of climate change (1911-2012) for two co-distributed chipmunk species: an endemic alpine specialist (Tamias alpinus) undergoing severe range contraction and a stable mid-elevation species (T. speciosus). Using a novel analytical approach, we reconstructed the demographic histories of these populations and tested for evidence of recent positive directional selection. Only the retracting species showed substantial population genetic fragmentation through time and this was coupled with positive selection and substantial shifts in allele frequencies at a gene, Alox15, involved in regulation of inflammation and response to hypoxia. However, these rapid population and gene-level responses were not detected in an analogous temporal contrast from another area where T. alpinus has also undergone severe range contraction. Collectively, these results highlight that evolutionary responses may be variable and context dependent across populations, even when they show seemingly synchronous ecological shifts. Our results demonstrate that temporal genomic contrasts can be used to detect very recent evolutionary responses within and among contemporary populations, even in the face of complex demographic changes. Given the wealth of specimens archived in natural history museums, comparative analyses of temporal population genomic data have the potential to improve our understanding of recent and ongoing evolutionary responses to rapidly changing environments.


Extended focused imaging for digital holograms of macroscopic three-dimensional objects.
When a digital hologram is reconstructed, only points located at the reconstruction distance are in focus. We have developed a novel technique for creating an in-focus image of the macroscopic objects encoded in a digital hologram. This extended focused image is created by combining numerical reconstructions with depth information extracted by using our depth-from-focus algorithm. To our knowledge, this is the first technique that creates extended focused images of digital holograms encoding macroscopic objects. We present results for digital holograms containing low- and high-contrast macroscopic objects.


Classification of the degradability of 30 pharmaceuticals in water with ozone, UV and H2O2.
Experiments were conducted to assess the degradability of 30 PPCPs, selected on the basis of consumption and environmental relevance, by O3 process, UV process and AOPs consisting of UV/ H2O2, O3/UV and O3/H2O2. A batch reactor with volume of 22L of water including the PPCPs was used. For UV process, combination of UV and H2O2 or O3 that can generate OH radicals was capable of degrading the PPCPs faster than UV radiation alone. On the other hand, O3 process and O3-based/UV-based AOPs could remove a variety of the PPCPs effectively, while some PPCPs such as 2-QCA, DEET and cyclophosphamide showed a relatively low degradability compared with the other PPCPs. However, further evaluation on formation of intermediate products resulting from the degradation of the parent PPCPs will be needed because DOC concentration was not decreased with lowered concentrations of the PPCPs.


Indole diketopiperazine alkaloids from the deep-sea-derived fungus Aspergillus sp. FS445.
Twelve indole diketopiperazine alkaloids (1‒12) including four new ones aspechinulins A‒D (1, 3, 5 and 12) were isolated from the deep-sea-derived fungus Aspergillus sp. FS445. Their structures were elucidated through spectroscopic analysis and the absolute configurations were determined by analyzing the experimental ECD data as well as the quantum chemical calculations. Compounds 1, 3 and 5 represented the first examples of indole diketopiperazine derivatives constructing a C5 unit at 11-NH through an imide linkage. The NO production inhibitory activity of the isolated compounds was evaluated and compounds 2‒5, 7 and 9 exhibited potential inhibitory activities against NO production with the IC50 values in the range of 20 ∼ 90 µM.[Formula: see text].


Centromere protein F and survivin are associated with high risk and a poor prognosis in colorectal gastrointestinal stromal tumours.
Colorectal gastrointestinal stromal tumours (GISTs) are considered to be tumours with a relatively poor prognosis. Few reports have been performed to investigate the mechanisms behind their malignant behaviour and to identify new therapeutic strategies for their treatment. The authors conducted this study to explore potential targets for the treatment of colorectal GISTs (CRGISTs). In the current study, the authors focused on centromere protein F and survivin, two markers that are known to affect the malignant behaviour of other tumours. Expression of centromere protein F and survivin was detected through the immunohistochemical staining of paraffin-embedded tumour tissues and then scored. The relationship between the expression of the two markers and their clinical parameters was analysed. Associated Survival analysis was available based on follow-up information. The authors demonstrated for the first time that centromere protein F and survivin expression were significantly associated with high risk and a poor prognosis (p<0.05) in CRGISTs. The authors also found that centromere protein F expression was more prevalent in males (p=0.002). The results suggest that centromere protein F and survivin are malignant behaviour markers for CRGISTs. The expression of centromere protein F or survivin points to a poor clinical outcome. Interfering with centromere protein F and/or survivin expression might be a potentially therapeutic strategy for treating malignant CRGISTs.


Targeting progastrin enhances radiosensitization of colorectal cancer cells.
A high percentage of advanced rectal cancers are resistant to radiation. Therefore, increasing the efficacy of radiotherapy by targeting factors involved in radioresistance seems to be an attractive strategy. Here we demonstrated that the pro-hormone progastrin (PG), known to be over-expressed in CRC, and recognized as a pro-oncogenic factor, is a radioresistance factor that can be targeted to sensitize resistant rectal cancers to radiations. First, we observed an increase in PG mRNA expression under irradiation. Our results also demonstrated that down-regulating PG mRNA expression using a shRNA strategy, significantly increases the sensitivity to irradiation (IR) in a clonogenic assay of different colorectal cancer cell lines. We also showed that the combination of PG gene down-regulation and IR strongly inhibits tumours progression in vivo. Then, we demonstrated that targeting PG gene radiosensitizes cancer cells by increasing radio-induced apoptosis shown by an increase in annexin V positive cells, caspases activation and PARP cleavage. We also observed the up-regulation of the pro-apoptotic pathway, JNK and the induction of the expression of pro-apoptotic factors such as BIM. In addition, we demonstrated in this study that inhibition of PG gene expression enhances radiation-induced DNA damage. Our data also suggest that, in addition to increase radio-induced apoptosis, targeting PG gene also leads to the inhibition of the survival pathways, AKT and ERK induced by IR. Taken together, our results highlight the role of PG in radioresistance and provide a preclinical proof of concept that PG represents an attractive target for sensitizing resistant rectal tumours to irradiation. .


Implementation study of the 2021 German guideline for diagnosis and treatment of multiple sclerosis.
In May 2021, a new guideline on the diagnosis and treatment of multiple sclerosis and related disorders was released in Germany. Since the success of a guideline depends on how it integrates into everyday clinical practice, the German Society for Neurology (DGN) has launched a multimethod implementation project. Here we report on the results based on the consultation version of the guideline. We used qualitative and quantitative data analyses to capture the nature and extent of barriers and facilitating factors to the implementation. We centered on the guideline's chapter A on diagnosis, relapse therapy, and immunotherapy of multiple sclerosis. We performed nine online focus group discussions and a web-based survey and analyzed emails and letters with comments from stakeholders and independent parties that were sent spontaneously or by invitation. 94 neurologists answered the survey, and ≥70% agreed with the recommendations of the guideline on each major content topic. Barriers to implementation were detected in group discussions and written input. The most controversial issues of the guideline were "early treatment", "criteria for starting or switching therapy", "stepwise escalation versus early aggressive treatment", "classification of drugs into three categories of efficacy" and the scenarios on "treatment cessation". Some appreciated the highly structured recommendations, but others felt that the guideline restricts the free choice of therapy, or they were afraid of recourse claims. Some considered the guideline as too cautious regarding treatment initiation, possibly delaying necessary therapies. Others appreciated that conflicts of interests of the guideline's authoring group were minimized and thought that the new guideline is clearer, more extensive and practical. In contrast to the survey, feedback in the focus group discussions and from individuals was diverse and sometimes more critical. Based on the overall feedback rate of about 250 people in relation to the number of 6500 board-certified neurologists in Germany, the overall appreciation of the guideline can only be considered as an indicator and not proof of acceptance. Results of this analysis were incorporated into several adjustments to the final guideline of 2021. Since the guideline is to be updated regularly under the auspices of a "living guideline", active interaction with users will continue to matter and help to improve it.


Guidelines of guidelines: a review of urethral stricture evaluation, management, and follow-up.
Our objective is to report a comparative review of recently released guidelines for the evaluation, management, and follow-up of urethral stricture disease. This is an analysis of the American Urologic Association (AUA) and Société Internationale d'Urologie (SIU) guidelines on urethral stricture. Strength of recommendations is stratified according to letter grade that corresponds to the level of evidence provided by the literature. Although few, the discrepancies between the recommendations offered by the two guidelines can be best explained by varying interpretations of the literature and available evidence on urethral strictures. When comparing the AUA guidelines and the SIU guidelines on urethral stricture, there are very few discrepancies. Perhaps the most notable difference is in the use of repeat DVIU or urethral dilation after an initial failed attempt. SIU guidelines state that there are instances where repeat DVIU or urethral dilation can be indicated, and they give a range of time at which stricture recurrence post procedure mandates an urethroplasty (less than 3 to 6 months). The AUA guidelines definitively state that repeat endoscopic procedures should not be offered as an alternative to urethroplasty, and they do not mention time of stricture recurrence as a factor. SIU guidelines allow for management of urethral stricture with indwelling urethral stenting. Overall there is a need for more high quality research in the work up, management, and follow up care of urethral stricture.


Targeting tumor endothelial marker 8 in the tumor vasculature of colorectal carcinomas in mice.
Tumor endothelial marker 8 (TEM8) is a recently described protein that is preferentially expressed within tumor endothelium. We have developed a fusion protein that targets TEM8 and disrupts tumor vasculature by promoting localized thrombosis. Fusion protein specificity and function were evaluated using Western blot analysis, ELISA, and enzymatic assays. A xenograft model of colorectal carcinoma was used to test the efficacy of targeted and control fusion proteins. Mice treated with the gene encoding anti-TEM8/truncated tissue factor exhibited a 53% reduction in tumor volume when compared with the untreated animals (P < 0.0001; n = 10) and achieved a 49% increase in tumor growth delay by Kaplan-Meier analysis (P = 0.0367; n = 6). Immunohistochemistry confirmed tumor endothelial expression of TEM8, fusion protein homing to tumor vasculature, decrease in vessel density, and localized areas of thrombosis. These data support the hypothesis that targeting TEM8 can be an effective approach to influence tumor development by disrupting tumor vasculature.


Molecular subtypes of colorectal cancer in pre-clinical models show differential response to targeted therapies: Treatment implications beyond KRAS mutations.
Molecular subtypes of colorectal tumors are associated with prognosis and prediction for treatment benefit from chemotherapy. The purpose of this study was two-fold: 1) to determine the association of colorectal (CRC) molecular subtypes with response to targeted therapies in pre-clinical models and 2) to identify treatments for CRC stem-like subtype because these tumors are associated with a very poor patient prognosis. Eleven CRC cell lines were classified into molecular subtypes and tested for their response to pan-ERBB, MEK, and ERK inhibitors as single agents and in combination. All six inflammatory or TA cell lines were exquisitely sensitive to the combination of MEK and neratinib whereas all five stem-like cell lines were resistant. Growth inhibition in sensitive cell lines was greater with the combination than with either drug alone even in cell lines with KRAS mutations. The combination inhibited pERK in inflammatory cell lines but not in four out of five stem-like cell lines. MEK162 plus neratinib were synergistic in cell culture and xenograft models in inflammatory cell lines. The ERK inhibitor, SCH772984, down-regulated pERK, decreased cell viability, and was synergistic with neratinib in both inflammatory and stem-like subtypes. These results suggest that inhibition of pERK is a critical node in decreasing cell viability of stem-like CRC tumors. Our results also suggest that CRC molecular subtypes may yield predictive information and may help to identify patients who may respond to targeted inhibitors.


Individual monitoring for internal exposures in Europe: conclusions of an EURADOS action.
Once the EC Directive 96/29 has been implemented into national regulation across Europe, the coordination of dosimetry laboratories for the monitoring of occupational exposures becomes the principal aim to achieve. Within this framework the European Radiation Dosimetry Group, EURADOS, carried out an Action on 'Harmonisation of Individual Monitoring' (2000-2004) to promote coordination in the field of individual monitoring of occupational exposures throughout Europe. With reference to internal exposures, the main aims were the completion of a catalogue of internal dosimetry services and an inventory of methods and techniques used for individual monitoring at European internal dosimetry facilities. At the end of this EURADOS Action, a report was published in Radiation Protection Dosimetry in 2004. The information collected related to various topics: the equipments used for the measurement of internal exposures, calibration and sensitivity data, the methods applied for the assessment of internal doses, Quality Control procedures, Quality Assurance Programmes in the facilities and legal requirements. The information to be presented here will give a general overview of the actual status of individual monitoring for internal exposures in Europe.


Primitive and definitive erythropoiesis in the yolk sac: a bird's eye view.
The yolk sac is the sole niche and source of cells for primitive erythropoiesis from E1 to E5 of chicken development. It is also the main niche and source of cells for early definitive erythropoiesis from E5 to E12. A transition occurs during late embryonic development, after which the bone marrow becomes the major niche and intraembryonically-derived cells the major source. How the yolk sac is involved in these three phases of erythropoiesis is discussed in this review. Prior to the establishment of circulation at E2, specification of primitive erythrocytes is discussed in relation to that of two other cell types formed in the extraembryonic mesoderm, namely the smooth muscle and endothelial cells. Concepts of blood island, hemangioblast and hemogenic endothelium are also discussed. It is concluded that the chick embryo remains a powerful model for studying developmental hematopoiesis and erythropoiesis.


Regional myocardial deformation in children with hypertrophic cardiomyopathy: morphological and clinical correlations.
Hypertrophic cardiomyopathy (HCM) is a disease with marked regional differences in wall thickness. However, the relation between myocardial function and wall thickness has not been well studied. Ultrasonic strain rate (SR) imaging makes it possible to study the regional myocardial deformation. We investigated whether regional systolic deformation is reduced in paediatric patients with HCM and evaluated its relation with wall thickness, electrocardiographic pattern, and exercise capacity. We studied 41 children with asymmetric HCM (mean age 12.3 years) and 29 controls. Electrocardiograms, exercise testing (when feasible), and echocardiograms with tissue Doppler imaging were performed. Peak systolic SR, strain, post-systolic shortening, and time to maximal strain were calculated in the longitudinal direction from the basal septum, mid-septum, and basal lateral myocardial segments and in the radial direction from the basal antero-septal and infero-lateral myocardial segments. Children with HCM had a significant reduction in deformation in all myocardial segments when compared with controls. In the HCM group, peak systolic SR and strain were significantly lower in the basal septum when compared with the mid-septal and basal lateral myocardial segments. In the basal septum, post-systolic shortening was significantly higher and time to maximal strain significantly longer than in mid-septal and lateral myocardial segments. A strong inverse curvilinear relation between peak systolic strain and wall thickness was found (r = -0.86, P < 0.001), with no further decrease in the regional myocardial function demonstrated once maximal wall thickness exceeded a Z-score of 3.5. Peak systolic strain in the basal part of the septum correlated inversely with exercise capacity (r = 0.68, P < 0.01). Systolic deformation is significantly and inhomogeneously reduced in children with HCM. This reduction in myocardial function is related to maximal wall thickness and decreased exercise capacity.


Physical, cognitive, social and mental health in near-centenarians and centenarians living in New York City: findings from the Fordham Centenarian Study.
Despite their strong increase, the population of the very old, including near-centenarians and centenarians, represent an unstudied and underserved population. Available studies mostly concentrate on predictors of exceptional longevity, but rarely extend their focus to other areas of functioning. Also, little is known about what contributes to experiencing a quality life in very old age. The present population-based study aims at providing a comprehensive picture of key domain of functioning, including physical, cognitive, social and mental function in very old individuals and to determine predictors of mental health indicators. A total of 119 individuals aged 95 to 107 living in private dwellings and residential care facilities were recruited based on the New York City Voters Registry. Participants answered questions regarding their health and activities of daily living. Their cognitive functioning was determined using the Mini-Mental State Examination and the Global Deterioration Scale. Social resources were measured with number of children and the Lubben Scale. Mental health was assessed with the Geriatric Depression Scale and the Satisfaction with Life Scale. An unexpectedly large proportion of the sample lived in the community. On average, cognitive functioning was high. Although five diseases were reported on average, participants reported good health. Functional status was reduced. Most participants had at least one person for communication/social support. On average, depression was below cut-off, and most participants reported high life satisfaction. Regression analyses indicated that individual differences in depression were associated with subjective health, IADL and relatives support. For life satisfaction, subjective health, ADL and number of children were most important. Demographic characteristics, number of illnesses or cognitive status were not significant. Despite reduced levels of physical functioning and social resources, very old participants were in good mental health suggesting high resilience and ability to adapt to age-associated challenges. That a large proportion of them lived in the community further highlights their desire for leading an autonomous life, which may have been facilitated by New York service culture. More research is necessary to provide guidance for the development of well-suited services for this very old population.


Discovery of antagonists of PqsR, a key player in 2-alkyl-4-quinolone-dependent quorum sensing in Pseudomonas aeruginosa.
The pqs quorum sensing communication system of Pseudomonas aeruginosa controls virulence factor production and is involved in biofilm formation, therefore playing an important role for pathogenicity. In order to attenuate P. aeruginosa pathogenicity, we followed a ligand-based drug design approach and synthesized a series of compounds targeting PqsR, the receptor of the pqs system. In vitro evaluation using a reporter gene assay in Escherichia coli led to the discovery of the first competitive PqsR antagonists, which are highly potent (K(d,app) of compound 20: 7 nM). These antagonists are able to reduce the production of the virulence factor pyocyanin in P. aeruginosa. Our finding offers insights into the ligand-receptor interaction of PqsR and provides a promising starting point for further drug design.


Effect of interfacial structure on bioinert properties of poly(2-methoxyethyl acrylate)/poly(methyl methacrylate) blend films in water.
In this study, we found that the surface made of a mixture of poly(2-methoxyethyl acrylate) (PMEA) and poly(methyl methacrylate) (PMMA) exhibited excellent blood compatibility by inhibiting platelet adhesion. To obtain a better understanding of this bioinertness, the polymer/water interface was characterized by neutron reflectivity measurements and sum frequency generation spectroscopy, in conjunction with bubble contact angle measurements. Based on the results, we can say that the outermost region of the blend film was reorganized in water. When the orientation of PMEA segments at the water interface became random with increasing immersion time, the fractional amount of lower-coordinated water molecules increased at the interface. Such an interfacial structure caused the suppression of platelet adhesion.


[Research Progress in Treatment of Chronic Lymphocytic Leukemia --Review].
Chronic lymphocytic leukemia (CLL) is a low-grade lymphoproliferative tumor that occurs frequently in middle-aged and elderly people. Early and precise intervention can effectively improve the clinical prognosis of CLL patients. In the past, chemotherapy was the main treatment plan. With the development of molecular biology and the continuous advent of immune targeting drugs, targeted drugs targeting B cell receptor signaling pathway have shown high clinical application value in the diagnosis and treatment path of CLL. Cellular immunotherapies such as CAR-T also offer hope for patients with relapsed and refractory CLL. Allogeneic hematopoietic stem cell transplantation and multi-drug combination have also shown remarkable results in clinical practice. The purpose of this article is to review the latest research progress in the treatment of CLL.


[Role of glutamine in enteral nutrition in intestinal insufficiency].
In this review the role of glutamine in enteral nutrition in intestinal insufficiency is shown. It is emphasized, that glutamine plays an important role in preservation of structure and function of intestines in normal state and under stressful condition.


Central nervous system involvement in Multiple Myeloma-Diagnosis, treatment and outcome: A case report.
Multiple Myeloma is a clonal proliferation of plasma cells with bone marrow as the primary site of occurrence. Extramedullary multiple myeloma is uncommonly seen either at presentation or later during the course of the disease. Central nervous system involvement by multiple myeloma is an extremely rare entity with a dismal outcome. This case report focuses on a 45-year-old male who presented with bone aches. Investigation findings leading to the diagnosis included elevated calcium levels, lytic lesions on radiological examination and clonal plasma cells in bone marrow biopsy. During his treatment, the patient was given chemotherapy regimens containing Lenalidomide, Bortezomib, Cyclophosamide, and Prednisolone. Thereafter, he developed neurological complications (CNS myelomatosis), which resulted in his demise. The clinical presentation, diagnosis, treatment and outcome of this rare condition is detailed below.


Photoaffinity labeling and fatty acid permeation in 3T3-L1 adipocytes.
Long chain fatty acid uptake was investigated in 3T3-L1 cells. Differentiation of these cells from fibroblasts to adipocytes was accompanied by an 8.5-fold increase in the rate of oleate uptake. This was saturable in adipocytes with apparent Kt and Vmax values of 78 nM and 16 nmol/min/mg cell protein, respectively. A number of proteins in various subcellular fractions of differentiated cells were labeled with the photoreactive fatty acid 11-m-diazirinophenoxy[11-3H]undecanoate. A 15-kDa cytoplasmic protein was induced upon differentiation to adipocytes. This protein was labeled with the photoreactive fatty acid in cytoplasm isolated from differentiated adipocytes, but not in cytoplasm from undifferentiated, fibroblastic cells. Furthermore, a high affinity fatty acid binding protein of 22 kDa was identified in plasma membranes of undifferentiated cells, and its level of labeling increased 2-fold upon differentiation. These results indicate the usefulness of the photoreactive fatty acid in identifying cellular fatty acid binding proteins, and its potential to elucidate the spatial and temporal distribution of fatty acids in intact cells.


Genomic Disorders and Neurocognitive Impairment in Pediatric CKD.
Children with CKD are at increased risk for neurocognitive impairment, but whether neurocognitive dysfunction is solely attributable to impaired renal function is unclear. Data from the CKD in Children Study Chronic Kidney Disease in Children (CKiD) Study indicate that a subset of children with CKD have unsuspected genomic disorders that predispose them to organ malformations and neurocognitive impairment. We therefore tested whether the CKiD Study participants with genomic disorders had impaired neurocognitive performance at enrollment. Compared with noncarriers (n=389), children with genomic disorders (n=31) scored significantly poorer on all measures of intelligence, anxiety/depressive symptoms, and executive function (differences of 0.6-0.7 SD; P=1.2×10-3-2.4×10-4). These differences persisted after controlling for known modifiers, including low birth weight, maternal education, seizure disorder, kidney disease duration, and genetically defined ancestry. The deleterious effect of genomic disorders on neurocognitive function was significantly attenuated in offspring of mothers with higher education, indicating the potential for modification by genetic and/or environmental factors. These data indicate that impaired neurocognitive function in some children with CKD may be attributable to genetic lesions that affect both kidney and neurocognitive development. Early identification of genomic disorders may provide opportunity for early diagnosis and personalized interventions to mitigate the effect on neurocognitive function.


The trend of radiological severity of hip fractures over a 30 years period: a cohort study.
Despite advances in operative techniques and preoperative care, proximal femur fractures (PFF) still represent a great public health problem. Displacement and fracture stability have been assumed as important determinants of treatment modality and outcome in such fractures. Purpose of this study was to determine whether the radiological severity of PFF fractures has increased over time. In a cohort study, the plain radiographs of all patients with PFF aged over 50 years who were admitted to Umeå University Hospital in 1981/82, 2002 and 2012 were recruited to examine the types of fractures. The ratio of undisplaced to displaced femoral neck (FN) fractures was 30 to 70% in 1981/82, 28 to 72% in 2002 and 25 to 75% in 2012. The ratio of stable to unstable intertrochanteric (IT) fractures was 64 to 36% in 1981/82, 68 to 32% in 2002 and 75 to 25% in 2012. The ratio of simple to comminute subtrochanteric fractures was 35 to 65% in 1981/82, 16 to 84% in 2002 and 12 to 88% in 2012. In both FN and IT fractures we found no statistical difference among these 3 study periods, p = 0.67 and p = 0.40. In subtrochanteric fractures we saw a tendency towards more comminute subtrochanteric fractures (1981/82 to 2012), p = 0.09. We found no significant increment in the radiological severity of FN and IT over a 30 years' period. However, there was tendency towards an increase in comminute subtrochanteric fractures.


Review on chronic metabolic diseases surrounding bile acids and gut microbiota: What we have explored so far.
Bile acid, the final product of cholesterol breakdown, functions as a complex regulator and signaling factor in human metabolism. Chronic metabolic diseases pose significant medical challenges. Growing research underscores bile acids' capacity to enhance metabolism via diverse pathways, regulating disorders and offering treatment potential. Numerous bile-acid-triggered pathways have become treatment targets. This review outlines bile acid synthesis, its role as a signal in chronic metabolic diseases, and highlights its interaction with gut microbiota in different metabolic conditions. Exploring host-bacteria-bile acid links emerges as a valuable future research direction with clinical implications.


Biomarkers in Ewing Sarcoma: The Promise and Challenge of Personalized Medicine. A Report from the Children's Oncology Group.
A goal of the COG Ewing Sarcoma (ES) Biology Committee is enabling identification of reliable biomarkers that can predict treatment response and outcome through the use of prospectively collected tissues and correlative studies in concert with COG therapeutic studies. In this report, we aim to provide a concise review of the most well-characterized prognostic biomarkers in ES, and to provide recommendations concerning design and implementation of future biomarker studies. Of particular interest and potentially high clinical relevance are studies of cell-cycle proteins, sub-clinical disease, and copy number alterations. We discuss findings of particular interest from recent biomarker studies and examine factors important to the success of identifying and validating clinically relevant biomarkers in ES. A number of promising biomarkers have demonstrated prognostic significance in numerous retrospective studies and now need to be validated prospectively in larger cohorts of equivalently treated patients. The eventual goal of refining the discovery and use of clinically relevant biomarkers is the development of patient specific ES therapeutic modalities.


Survey regarding the use of endodontic posts among dentists of twin cities, Rawalpindi and Islamabad, Pakistan.
The purpose of the study was to assess the knowledge, attitude, and practices of dentists of twin cities regarding the use of endodontic posts in root canal treated tooth. A questionnaire was created and distributed among dentists of Rawalpindi and Islamabad via social media platforms regarding the use of posts. The results revealed that majority (60%) of the participants used endodontic posts for teeth with adequate ferrule, and believed that the function of endodontic posts is to retain the core material (50.5%). Glass fibre posts were preferred for anterior teeth (87%), whereas metal posts were favoured in posterior teeth (63%). It was concluded that the main function of the endodontic post is to retain the core material. The commonest indication is when there is at least 2mm of ferrule present and the optimal post length is 2/3rd of the root canal.


Regeneration of inner retinal neurons after intravitreal injection of ouabain in zebrafish.
We examined the regenerative capacity of the adult zebrafish retina by intravitreal injection of a low ouabain concentration to rapidly damage the ganglion cell layer (GCL) and inner nuclear layer (INL) with minimal photoreceptor cell damage. By 24 h after ouabain injection, maximal numbers of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL)-positive cells were detected in the INL and GCL, with low numbers of TUNEL-positive cells in the outer nuclear layer. Immunolabeling revealed that approximately 85% of the HuC/D-positive amacrine and ganglion cells were lost by 7 d post-ouabain injection (dpi). This ganglion cell loss was consistent with the small, but statistically significant, decrease in the optic nerve diameter. The regeneration response began within 1 dpi with increased proliferating cell nuclear antigen (PCNA) expression in both the INL and GCL. By 3 dpi, PCNA expression is primarily restricted to the Müller glia. By 5 dpi, most of the PCNA expression was localized to neuronal progenitors expressing the olig2:egfp transgene rather than the Müller glia. By 7 dpi, the neuronal progenitors began committing to the ganglion cell fate based on the coexpression of the atoh7:EGFP transgene and the zn5 antigen. The regeneration of ganglion and amacrine cells continued until 60 dpi, when they reached 75% of their uninjected control number. This demonstrates that inner retinal damage, without extensive photoreceptor damage, is sufficient to induce a regeneration response that is marked by the Müller glial cells reentering the cell cycle to produce neuronal progenitor cells that regenerate INL and ganglion cells in the zebrafish retina.


Inhalation toxicokinetics of p-dichlorobenzene and daily absorption and internal accumulation in chronic low-level exposure to humans.
Inhalation toxicokinetics of p-dichlorobenzene ( p-DCB) in humans was evaluated, and the amounts of daily absorption and internal accumulation were estimated in order to obtain fundamental data for the risk assessment of chronic low-level exposure in the general population. Seven male subjects continuously inhaled about 2.5 ppm of p-DCB vapor for 1 h, and the concentration-time courses of p-DCB in their exhaled air and serum and of urinary 2,5-dichlorophenol (2,5-DCP), a major metabolite of p-DCB, were examined. The toxicokinetics of p-DCB was evaluated on the basis of the time courses using a linear two-compartment model. The amounts of p-DCB absorbed daily and the internal accumulation in chronic low-level exposure were extrapolated using the estimated toxicokinetic parameters. p-DCB was transferred from inhaled air to the body with a constant high absorption rate during exposure. The major route for elimination from the body was urinary excretion followed by metabolism, not exhalation. However, during 9-11 h after the start of exposure, the fraction of p-DCB excreted in urine was only 5-16% of the amount absorbed. Furthermore, most of the absorbed p-DCB seemed to be distributed rapidly to the tissues, such as fat, according to toxicokinetic analysis. Consequently, p-DCB seems to require a long time to be completely eliminated from the body. The amounts of daily absorption and internal accumulation were extrapolated to average 0.27 mg/day and 2.9 mg, respectively, in the subjects exposed chronically to 1 ppb of p-DCB. The amount absorbed daily agreed approximately with that extrapolated from rats which inhaled p-DCB in our previous study.


Smokeless tobacco advertising at the point of sale: prevalence, placement, and demographic correlates.
We aimed to describe the prevalence, in-store location, and neighborhood predictors of point-of-sale smokeless tobacco advertising. In 2007, we conducted assessments of smokeless tobacco advertising at the point of sale in 484 establishments, which held tobacco licenses and sold tobacco products in a Midwest metropolitan area. Associations between store characteristics, neighborhood characteristics (based on U.S. 2000 census block groups), and smokeless tobacco advertising were calculated. Advertisements for smokeless tobacco were found in 21% (n = 103) of stores. Approximately, 12% (n = 58) of stores had ads within 6 feet of the counter, 3% (n = 14) had ads less than 3 feet from the ground, and 2% (n = 9) had advertisement less than 1 foot from candy or snacks. The racial/ethnic composition and number of households on public assistance within the block group in which a store was situated were related to the amount of smokeless advertising in stores. For instance, having a higher proportion of the population identifying as White was associated with more advertising. Gas stations/convenience stores had more advertising than any other store types. Chain stores had double the amount of advertising as independent stores (p < .05) even after adjustment for other factors. Smokeless tobacco advertising is not uncommon even in an urban metropolitan community. These products are being advertised in a way that youth, especially those living in neighborhoods with certain demographic characteristics, can encounter. With Food and Drug Administration regulation, there are new opportunities to regulate advertising at the point of sale.


Differential expression of toll-like receptor mRNA in corneal epithelium of ruminants.
The present study was carried out to identify and assess the expression levels of toll-like receptors (TLRs) 1-10 mRNA in corneal epithelial cells of buffalo, goat, sheep and bull. The globes from the respective species were collected and the corneal epithelium was denuded. The expression levels of the different TLR mRNAs were assessed by densitometry of the band intensities following reverse transcriptase polymerase chain reaction (RT-PCR). In all species TLR5 and TLR7 were highly expressed with lower levels of TLR10. The TLR6 mRNA levels were the lowest in the cornea of bull. The TLR2 expression was high in sheep and bulls, while TLR4 mRNA was higher in sheep alone. The level of the other TLRs varied across other species. Based on these observations it may be inferred that these animals would be resistant to flagellin (TLR5) and single-stranded RNA viruses (TLR7), while sheep alone may show more resistance to lipo-polysaccharide (TLR4) and peptidoglycan (TLR2)-mediated injury of the cornea. This work reports for the first time the expression of TLR mRNAs in the corneal epithelial cells of farm animals. The relationship of the TLR mRNA levels to corneal disease susceptibilities and pathogenicity remains to be explored further.


[Primary multiple tumors in women treated for cancer of the cervix uteri].
Observations of primary multiple tumors in patients with cervical cancer, treated during the period of 1946--1970, are analysed. It was found that the number of patients with multiple tumors increased considerably as compared with the period of 1926--1947. Most frequently, the second malignant tumor was observed in the internal genitalia, mammary gland and digestive tract.


Internet sex addiction treated with naltrexone.
Malfunctioning of the brain's reward center is increasingly understood to underlie all addictive behavior. Composed of mesolimbic incentive salience circuitry, the reward center governs all behavior in which motivation has a central role, including acquiring food, nurturing young, and having sex. To the detriment of normal functioning, basic survival activities can pale in importance when challenged by the allure of addictive substances or behaviors. Dopamine is the neurotransmitter driving both normal and addictive behavior. Other neurotransmitters modulate the amount of dopamine released in response to a stimulus, with the salience determined by the intensity of the dopamine pulse. Opiates (either endogenous or exogenous) exemplify such modulators. Prescribed for treating alcoholism, naltrexone blocks opiates' capacity to augment dopamine release. This article reviews naltrexone's mechanism of action in the reward center and describes a novel use for naltrexone in suppressing a euphorically compulsive and interpersonally devastating addiction to Internet pornography.


Predictors of successful at-home chemical cardioversion in new-onset atrial fibrillation.
Prehospital treatment of new-onset supraventricular arrhythmias can be attempted by physician-staffed mobile intensive care units to decrease the hospitalization rate and expense. Identification of patients suitable for at-home pharmacological treatment may help in the triage of patients with new-onset atrial fibrillation (AF). In the present investigation, the value of several clinical variables to predict the success of pharmacological at-home cardioversion was tested. A total of 924 patients with new onset (less than 24 h) AF, rescued by the Florence Mobile Coronary Care Unit (MCCU), were included in the study. By univariate analysis, female sex, palpitations as symptoms leading to MCCU call and a short delay between symptom onset and MCCU intervention were associated with a favourable outcome of treatment, whilst dyspnoea as the main complaint requiring MCCU intervention and the association of AF with an acute cardiovascular event (angina, acute myocardial infarction or pulmonary oedema) were negatively associated with the success rate of treatment. The cardioversion rate was not significantly different in patients with underlying heart disease or in patients with lone atrial fibrillation. By multivariate analysis, only sex and the drug employed for treatment (positive relation for propafenone and bunaftine, negative for amiodarone, digoxin and verapamil) were significant predictors of the outcome of MCCU intervention. Our results suggest that patients with new-onset (less than 24 h) AF with or without underlying heart disease whose main complaint is palpitation can be successfully cardioverted at home with a class IC drug (propafenone). Patients with acute coronary syndromes or left ventricular failure are good candidates for elective cardioversion after hospitalization.


Responses to Increased Salinity and Severe Drought in the Eastern Iberian Endemic Species Thalictrum maritimum (Ranunculaceae), Threatened by Climate Change.
Thalictrum maritimum is an endangered, endemic species in East Spain, growing in areas of relatively low salinity in littoral salt marshes. A regression of its populations and the number of individuals has been registered in the last decade. This study aimed at establishing the causes of this reduction using a multidisciplinary approach, including climatic, ecological, physiological and biochemical analyses. The climatic data indicated that there was a direct negative correlation between increased drought, especially during autumn, and the number of individuals censused in the area of study. The susceptibility of this species to water deficit was confirmed by the analysis of growth parameters upon a water deficit treatment applied under controlled greenhouse conditions, with the plants withstanding only 23 days of complete absence of irrigation. On the other hand, increased salinity does not seem to be a risk factor for this species, which behaves as a halophyte, tolerating in controlled treatments salinities much higher than those registered in its natural habitat. The most relevant mechanisms of salt tolerance in T. maritimum appear to be based on the control of ion transport, by (i) the active transport of toxic ions to the aerial parts of the plants at high external salinity-where they are presumably stored in the leaf vacuoles to avoid their deleterious effects in the cytosol, (ii) the maintenance of K+ concentrations in belowground and aboveground organs, despite the increase of Na+ levels, and (iii) the salt-induced accumulation of Ca2+, particularly in stems and leaves. This study provides useful information for the management of the conservation plans of this rare and endangered species.


Intratelencephalic projections of the avian visual dorsal ventricular ridge: Laminarly segregated, reciprocally and topographically organized.
Recent reports have shown that the avian visual dorsal ventricular ridge (DVR) is organized as a trilayered complex, in which the forming layers-the thalamo-recipient entopallium (E), an overlaying nidopallial stripe called intermediate nidopallium (NI), and the dorsally adjacent mesopallium ventrale-appear to be extensively interconnected by topographically organized columns of reciprocal axonal processes running perpendicular to the layers, an arrangement highly reminiscent to that of the sensory cortices of mammals. In the present report, we implemented in vivo anterograde and retrograde tracing techniques aiming to elucidate the organization of the connections of this complex with other pallial areas. Previous studies have shown that the efferent projections of the visual DVR originate mainly from the NI and E, reaching several distinct associative and premotor nidopallial areas. We found that the efferents from the visual DVR originated solely from the NI, and confirmed that the targets of these projections were the pallial areas described by previous studies. We also found novel projections from the NI to the visual hyperpallium, and to the lateral striatum. Moreover, we found that these projections were reciprocal, topographically organized, and originated from different cell populations within the NI. We conclude that the NI constitutes a specialized layer of the visual DVR that form the core of a dense network of highly specific connections between this region and other higher order areas of the avian pallium. Finally, we discuss to what extent these hodological properties resemble those of the mammalian cortical layers II/III.


Personalized medicine in coronary artery disease: insights from genomic research.
Prior clinical studies have demonstrated that a family history of coronary artery disease (CAD) is associated with future cardiovascular events. Although there are several Mendelian disorders that are associated with CAD, most common forms of CAD are believed to be multifactorial and the result of many genes with small individual effects. The identification of these genes and their variation would be very helpful for the prediction, prevention, and management of CAD; linkage analysis or candidate gene case-control studies have been largely unsuccessful. On the contrary, recent advances in genomic techniques have generated a large amount of deoxyribonucleic acid (DNA)-based information. The link between CAD and inflammation and biological pathways has been highlighted. In particular, several genome-wide association studies have replicated a novel gene marker on chromosome 9p21. The information gained from genomic studies, in combination with clinical data, is expected to refine personalized approaches to assess risk and guide management for CAD. Genetic risk scores derived from several functional single nucleotide polymorphisms (SNPs) or haplotypes in multiple genes may improve the prediction of CAD. Despite the complexity of CAD genetics, steady progress is expected.


Clinical interprofessional education in the health professions: a scoping review protocol.
The objective of this scoping review is to identify, characterize, and summarize evidence from the published literature on clinical interprofessional education. Clinical interprofessional education refers to learning within clinical learning environments, such as hospitals, primary care clinics, and long-term care facilities. The learning involves direct interaction with real patients, where learners collaborate to deliver care and improve health outcomes. This scoping review will consider clinical interprofessional education activities in the context of patient care. Criteria include two or more health professions, two or more learner groups, and involvement of real patients/patient care. This review will be conducted in accordance with the JBI methodology for scoping reviews. Databases searched will include PubMed, CINAHL, and Scopus. Results will be limited to English language publications from 2015 to the present. Extracted data will include the different types of clinical learning environments, the professions involved, the targeted learning/competency outcomes, and the measurement tools used by the authors. Titles/abstracts and full texts of articles will be screened by two reviewers for potential inclusion, with discrepancies resolved by a third reviewer if necessary. Extracted data will be presented in diagrammatic or tabular format. A narrative summary will accompany the tabulated and/or charted results, describing how the results relate to the review objective and research questions, and how the results might inform future clinical interprofessional education in health professions education.


Influence of Cardiorespiratory Fitness on Risk of Dementia and Dementia Mortality: A Systematic Review and Meta-Analysis of Prospective Cohort Studies.
The purpose of this meta-analysis was to investigate the influence of cardiorespiratory fitness (CF) levels on dementia risk and dementia mortality. MEDLINE and EMBASE databases were used to search for eligible studies from January 1990 to September 2019. To be included, the study was required to be a prospective cohort study that provided CF measurements and indicated relative risk and confidence intervals for the associations between CF and dementia risk and mortality. A total of six studies were selected for this meta-analysis. Low-level CF was associated with nearly three times greater risk of dementia (2.93, 95% confidence interval [1.31, 6.57]; p < .05) compared with a high-level CF. Enhanced CF levels decreased the risk of dementia, and an increase of one metabolic equivalent of task in the CF level reduced the risk of dementia and dementia mortality. Maintaining more than 12 metabolic equivalents of task of CF level was required to substantially decrease dementia risk and dementia mortality.


Reciprocal translocations: tracing their meiotic behavior.
Segregation and interchromosomal effect studies have been performed in reciprocal translocation carriers by sperm-fluorescent in situ hybridization reporting a great heterogeneity. The divergences have been attributed to the particular cytogenetic characteristics of each rearrangement. Nevertheless, there is no consensus in the factors that are responsible for such variability. The purpose of this study was to determine which cytogenetic features influence in the segregation and interchromosomal effect outcome. Segregation and interchromosomal effects analyses were performed in 14 reciprocal translocation carriers, selected because they presented very different cytogenetic features regarding the tetravalent pairing geometry. In each segregation study, a customized combination of probes was used to identify all the segregation products. In the interchromosomal effect study, we used a triple-color fluorescent in situ hybridization for chromosomes X, Y, and 18. A preferential segregation pattern with a gradually decreasing production of Alternate, Adjacent I, Adjacent II, and 3:1 segregation was observed in the segregation analysis. Some specific features have been observed to influence this distribution: size of the translocated and centric segments and the presence of centromeres from acrocentric chromosomes in the center of the cross. Aneuploidy/diploidy screening revealed increased frequencies of numerical anomalies in seven carriers. Our data suggest that reciprocal translocations display a more homogeneous behavior than described in the literature. The interchromosomal effects represent an additional source of imbalances in these carriers.


Refractive outcomes of combined cataract and glaucoma surgery.
This study was designed to evaluate the refractive outcomes of combined cataract extraction and glaucoma surgery. Retrospective case series. A retrospective chart review of patients undergoing simultaneous cataract extraction with trabeculectomy or glaucoma drainage device surgery was performed. The main outcome measure evaluated was whether or not spherical equivalent of -1.00 to +0.50 D was achieved at 3 to 6 months postoperatively. Secondary outcomes included: reduction in intraocular pressure, amount of cylinder induced by combined surgery, and individual patient characteristics that may have affected refractive outcome. Outcomes were compared with an age-matched and sex-matched control group of patients who had uncomplicated cataract surgery during the same time period. Forty-three eyes of 36 patients underwent combined cataract extraction and glaucoma surgery. A refractive outcome of spherical equivalent between -1.00 and +0.50 D was achieved in 32 of 43 eyes (74%) at 3 to 6 months after surgery. Logistic regression analysis found a 1.14 increased risk of the refraction being outside this defined refractive range in older compared with younger patients (by year, 95% CI, 1.04-1.27). Type of lens implant used, type of glaucoma surgery, and preoperative best-corrected visual acuity did not significantly affect refractive outcome. In a subset of 22 eyes with available preoperative keratometry measures, a mean 1.31 D (SD=0.86; range, 0.26 to 3.76) of corneal astigmatism was induced by combined surgery. In comparison, a matched control group who had cataract surgery alone achieved target refractive outcome in 34 of 40 eyes (85%, P=0.001) and had a trend for less induced cylinder (0.99, SD=0.72, P=0.11). Favorable refractive outcomes were achieved in the majority of patients despite the potential alteration of preoperative measurements and introduction of error into lens selection when using a combined approach. There does not seem to be a difference in the refractive outcome with regard to the type of glaucoma surgery performed. Control patients who had cataract surgery alone had a higher percentage of achieving target refractive goal and less induced cylinder.


Differences in patterns of participation between youths with cerebral palsy and typically developing peers.
This study investigated the effects of cerebral palsy (CP) and gender on youth participation in activities outside of formal school. Twenty-two participants with CP and 30 typically developing peers, ages 12-16 years, completed the Children's Assessment of Participation and Enjoyment (CAPE; King et al., 2004). Typically developing youths engaged in a broader range of activities and did so more frequently than did youths with CP. Similar levels of enjoyment in activity were found in both groups. In some scales of the CAPE, youths with CP participated in proportionally more activities alone and at home. Gender differences and Group x Gender interaction were found in some scales with respect to participation in and enjoyment of activities. Physical limitations associated with CP may affect the frequency of a child's participation in activity outside of school. However, youths with CP may express levels of enjoyment similar to those of typically developing peers while participating in activity.


Importance of right ventricular outflow tract angiography in distinguishing critical pulmonary stenosis from pulmonary atresia.
To investigate the spectrum of pulmonary atresia and critical pulmonary stenosis using right ventricular outflow tract angiography and explore its implications for catheter interventional treatment. Prospective clinical study. Two paediatric cardiology centres. 11 neonates or infants (aged 1 day to 8 months; weighing 2.3 to 7.8 kg) with pulmonary atresia or where the differentiation of pulmonary atresia from critical pulmonary stenosis was unclear on either echocardiography or angiography. Right ventricular outflow tract angiography was performed on all patients to distinguish pulmonary atresia from critical pulmonary stenosis before opening the right ventricular outflow tract. Right ventricular outflow tract angiography showed that three of seven patients diagnosed as pulmonary atresia by echocardiography had pin hole jets across the pulmonary valve; another had a probe patent valve that appeared imperforate on both echocardiography and right ventricular outflow tract angiography. Three of the four patients diagnosed by echocardiography as critical pulmonary stenosis were found on right ventricular outflow tract angiography to have pulmonary atresia. The remaining patient had such a tiny orifice that a second orifice had to be created with a radiofrequency catheter. The right ventricular outflow tract was opened successfully in 10 of the 11 patients, six of whom required application of radiofrequency energy. The right ventricular to aortic systolic pressure ratio fell from 1.4 (0.9 to 1.9) to 0.6 (0.2 to 1.1) (P < 0.05). All 11 patients were alive and well with transcutaneous oxygen saturations ranging from 84% to 95% at a median follow up duration of nine months. Critical pulmonary stenosis and pulmonary atresia cannot always be accurately distinguished by echocardiography. Right ventricular outflow tract angiography helps to distinguish the two groups. In most cases the right ventricular outflow tract can be opened without mortality and with short to medium term survival.


The moderated relationship of appearance valence on appearance self consciousness: development and testing of new measures of appearance schema components.
This paper describes the creation and psychometric properties of two independent measures of aspects of appearance schematicity--appearance salience and valence, assessed by the CARSAL and CARVAL, and their relation to appearance self-consciousness. Five hundred and ninety two participants provided data in a web based task. The results demonstrate the sound psychometric properties of both scales. This was demonstrated by good item total characteristics, good internal reliability of each scale, and the independence of the two scales shown through principal components analysis. Furthermore, the scales show independent and moderated relationships with valid measures of appearance related psychosocial distress. Negatively valenced appearance information was associated with increased appearance self-consciousness. More crucially, the impact of negative valence on appearance self-consciousness was exacerbated by the moderating effect increased salience of appearance.


Expression, detection and assay of a neoantigen (Neo-CRP) associated with a free, human C-reactive protein subunit.
It has previously been reported that human C-reactive protein (CRP) can exist in at least two molecular conformations distinguished by antigenic, electrophoretic and ligand-binding reactivities. In the present study we describe the formation, detection and distinctiveness of a conformation expressing a CRP neoantigen (neo-CRP), and report that this form is characteristic in vitro of a free CRP subunit. Soluble native-CRP was found to express neo-CRP antigenicity upon treatment with acid; upon urea-chelation or heating in the absence of calcium; and upon adsorption onto uncoated polystyrene plates. Native-CRP bound by capture ELISA to phosphorylcholine-containing ligand or anti-native-CRP did not express neo-CRP antigenicity, suggesting that PC ligand- or antibody binding is not sufficient to induce expression of the neoantigen. Human CRP which expressed neo-CRP antigenicity had limited solubility and tended to aggregate in buffers of ionic strength 0.15, but remained soluble when the ionic strength was reduced to 0.015. Soluble urea-chelated or acid-treated CRP molecules expressing neo-CRP antigenicity chromatographed and electrophoresed as a single protein with a Mr of approx. 22,000, indicating that the CRP neoantigen can be expressed on free CRP subunits and this expression need not require proteolysis. Further, molecules expressing neo-CRP antigenicity were detected in the plasma of patients with rheumatoid arthritis. The identification and characterization of this CRP neoantigen should serve as a useful marker in studies of CRP subunits and biologically relevant forms of CRP, and should contribute to the elucidation of the role of CRP in the acute inflammatory response.


Destabilization of Bcr-Abl/Jak2 Network by a Jak2/Abl Kinase Inhibitor ON044580 Overcomes Drug Resistance in Blast Crisis Chronic Myelogenous Leukemia (CML).
Bcr-Abl is the predominant therapeutic target in chronic myeloid leukemia (CML), and tyrosine kinase inhibitors (TKIs) that inhibit Bcr-Abl have been successful in treating CML. With progression of CML disease especially in blast crisis stage, cells from CML patients become resistant to imatinib mesylate (IM) and other TKIs, resulting in relapse. Because Bcr-Abl is known to drive multiple signaling pathways, the study of the regulation of stability of Bcr-Abl in IM-resistant CML cells is a critical issue as a possible therapeutic strategy. Here, we report that a new dual-kinase chemical inhibitor, ON044580, induced apoptosis of Bcr-Abl+ IM-sensitive, IM-resistant cells, including the gatekeeper Bcr-Abl mutant, T315I, and also cells from blast crisis patients. In addition, IM-resistant K562-R cells, cells from blast crisis CML patients, and all IM-resistant cell lines tested had reduced ability to form colonies in soft agar in the presence of 0.5 µM ON044580. In in vitro kinase assays, ON044580 inhibited the recombinant Jak2 and Abl kinase activities when the respective Jak2 and Abl peptides were used as substrates. Incubation of the Bcr-Abl+ cells with ON044580 rapidly reduced the levels of the Bcr-Abl protein and also reduced the expression of HSP90 and its client protein levels. Lysates of Bcr-Abl+ cell lines were found to contain a large signaling network complex composed of Bcr-Abl, Jak2, HSP90, and its client proteins as detected by a gel filtration column chromatography, which was rapidly disrupted by ON044580. Therefore, targeting Jak2 and Bcr-Abl kinases is an effective way to destabilize Bcr-Abl and its network complex, which leads to the onset of apoptosis in IM-sensitive and IM-resistant Bcr-Abl+ cells. This inhibitory strategy has potential to manage all types of drug-resistant CML cells, especially at the terminal blast crisis stage of CML, where TKIs are not clinically useful.


The Interplay of Peer, Parent, and Adolescent Drinking.
To explore variability in the link between peer and adolescent drinking by parental drinking. Stress and differential susceptibility perspectives led to hypotheses that adolescents with drinking parents would be more reactive to peer drinking but also to peer abstention. Using data from the National Longitudinal Study of Adolescent to Adult Health, regressions estimated whether the association between peer alcohol use and increased drinking among adolescents was moderated by parental drinking. A regions of significance test identified the level of peer drinking that predicted adolescent drinking in the context of parental drinking. Adolescents with binge-drinking parents were more likely to increase drinking at every level of peer drinking, supporting the stress perspective; such adolescents did not accrue benefits from abstaining peers, going against the differential susceptibility perspective. Far from monolithic, peer influences on adolescent risky behaviors may require family environments and genetic predispositions conducive to those behaviors.


[Changes of cerebral glucose metabolism in patients with multiple sclerosis and their role in formation of the clinical picture and progression of the disease].
Multiple sclerosis is an autoimmune disease, which characterized by CNS myelin lesion. The pathological changes include distinct demyelination foci well identified by MRI. However, because their volume and localizations weakly correlate with clinical appearances and progression of the disease, functional changes may exert a greater influence on disablement indices than regular MRI data. Positron emission tomography (PET), using a labeled native glucose analogue [18F] fluorinedesoxyglucose (FDG-PET) enables to evaluate cerebral glucose metabolism and specify an association between brain metabolism and clinical appearances. FDG-PET has been administered to 87 patients: 57 with valid MS, remitted course (group 1) and 30 with primary-, remitted- and secondary-progressive course (group 2). Besides, a patient's state was evaluated with EDSS and FS scales. A regional to global activity ratio was calculated according to ICVRglu indices. In both groups, significant negative correlation between glucose metabolism in the majority of the brain regions and MS duration was found, being more distinct in group 2. Also, cerebellum metabolism reverse correlated with FS 2 scale scores. In group 2, ICVRglu index in subcortical structures positively correlated with FS 1 scores. Positive correlation between ICVRglu in somatosensor area and EDSS and FS scores was detected. The associations with PET demonstrated a relationship between clinical syndromes, MS duration and cerebral metabolism level, being mostly pronounced in the group with progressive course. Both hypo- and hyper metabolism may be clinically significant. In the patients with progressive MS, hyper metabolism in sensomotor area is likely to be of compensatory importance.


Circadian rhythmicity and photic plasticity of myosin gene transcription in fast skeletal muscle of Atlantic cod (Gadus morhua).
The circadian rhythm is a fundamental adaptive mechanism to the daily environmental changes experienced by many organisms, including fish. Myosins constitute a large family of contractile proteins that are essential functional components of skeletal muscle. They are known to display thermal plasticity but the influence of light on myosin expression remains to be investigated in fish. In the present study, we have examined the circadian rhythmicity and photoperiodic plasticity of myosin gene transcription in Atlantic cod (Gadus morhua) fast skeletal muscle. In silico mining of the Atlantic cod genome resulted in the identification of 76 myosins representing different classes, many of which were hitherto uncharacterized. Among the 23 fast skeletal muscle myosin genes, myh_tc, myh_n1, myh_n4, myo18a_2, and myo18b_2 displayed circadian rhythmic expression and contained several circadian-related transcription factor binding sites (Creb, Mef2 and E-box motifs) within their putative promoter regions. Also, the circadian expression of these 5 myosins strongly correlated with the transcription pattern of clock genes in fast skeletal muscle. Under ex vivo conditions, myosin transcript levels lost their circadian rhythmicity. Nonetheless, different photoperiod regimes influenced the mRNA levels of myh_n4, myo18a_2 and myo18b_2 in fast skeletal muscle explants. Photoperiod manipulation in Atlantic cod juveniles revealed that continuous light significantly elevated mRNA levels of several myosins in fast skeletal muscle when compared to natural photoperiod. The daily rhythmicity observed in some fast skeletal muscle myosin genes suggests that they may be under circadian clock regulation. In addition, the influence of photoperiod on their expression implies that myosins may be involved in the photic plasticity of muscle growth observed in Atlantic cod.


Aflatoxin-producing potential of isolates of the Aspergillus flavus-oryzae group from peanuts (Arachis hypogaea).
Seventy-eight samples of farmer stock peanuts, representing peanuts grown in nine different geographical areas during 1964, were assayed for aflatoxin and examined for associated microflora. Only two samples contained more than 50 ppb of aflatoxin. Infestation by members of the Aspergillus flavus-oryzae group varied from 35 to 100% of the kernels per area and from 1 to 100% of the kernels per sample. Aflatoxin production by individual isolates ranged from 0 to 349,143 ppb under the test conditions employed. In general, the isolates produced 8 to 10 times more B(1) than B(2), and no isolate producing aflatoxins G(1) or G(2) was found. The importance of proper postharvest handling of peanuts is emphasized by the prevalence of isolates of A. flavus-oryzae capable of producing aflatoxins on farmers stock peanuts.


The role of cyclic AMP-mediated regulation of glycogen metabolism in levamisole-perfused Ascaris suum muscle.
The effects of levamisole on muscle contraction and glycogen metabolism have been examined in isolated muscle-cuticle sections of the roundworm Ascaris suum. Muscle contraction occurred when various levels of levamisole were perfused through the preparation. At a levamisole concentration of 0.42 mM, the period of contraction lasted only about 6 min and was followed by a period of relaxation. During this relaxation period, there was an activation of glycogen synthase (EC 18.104.22.168), as evidenced by a decrease in the Ka values of glucose 6-phosphate for glycogen synthase to 0.26 mM from control values of 0.50 mM. The glycogen phosphorylase (EC 126.96.36.199) activity ratio decreased from 0.85 to 0.65, which indicated an inactivation of this enzyme. Concomitant with this activation of glycogen synthase and inactivation of phosphorylase there was an increased synthesis of glycogen. In addition, the presence of levamisole prevented both the serotonin-induced cyclic AMP accumulation and the activation of the cyclic AMP-dependent protein kinase (EC 188.8.131.52). However, levamisole did not significantly affect the changes in glycogen synthase and phosphorylase brought about by perfusion with the neurostimulator acetylcholine. Collectively, the data indicated that levamisole caused a transient muscle contraction followed by muscle relaxation, and the muscle relaxation effect appeared to be the result of a levamisole-inhibited cyclic AMP-mediated pathway of glycogen utilization.


Altered Macular Microvasculature in Mild Cognitive Impairment and Alzheimer Disease.
The goal of the present study was to analyze the macular microvacular network in mild cognitive impirment (MCI) and Alzheimer disease (AD). Twelve patients with AD and 19 patients with MCI were recruited together with 21 cognitively normal controls with a similar range of ages. Optical coherence tomography angiography was used to image the retinal microvascular network at the macular region, including retinal vascular network (RVN), superficial vascular plexus (SVP), and deep vascular plexus (DVP). Fractal analysis (box counting, Dbox) representing the microvascular density was performed in different annular zones and quadrantal sectors. The macular ganglion cell-inner plexiform layer (GC-IPL) thickness was measured using Zeiss OCT. The relationship between the retinal microvasculature and clinical manifestations was analyzed. Patients with AD had lower densities of RVN, SVP, and DVP in the annulus, from 0.6 to 2.5 mm in diameter (P < 0.05) in comparison with controls. Patients with MCI had lower density of DVP in the superior nasal quadrant (P < 0.05) than that of the controls. There were no significant differences of GC-IPL thickness among groups (P > 0.05). There was a trend of vascular density loss from control to MCI then AD (P < 0.05). Retinal microvascular density of DVP was correlated with GC-IPL thickness (P < 0.05) in patients with AD, but not in patients with MCI and controls. Patients with AD had less density of retinal microvascular networks than controls. Our findings suggest the presence of retinal microvascular dysfunction in AD.