Advances in the pharmacological and regulatory management of multidrug resistant Helicobacter pylori.
Antibiotic resistance of Helicobacter pylori (H. pylori) hampers the success of eradication and in recent years multidrug resistance (MDR) shows an increase worldwide. This review covers current aspects of pharmacological and regulatory management of MDR-resistant H. pylori infection. MDR H. pylori is increasing worldwide and its prevalence varies both between continents and countries. High consumption and misuse of antibiotics, H. pylori treatment failures and bacterial factors such as mutations, efflux pumps and biofilms are among the factors associated with MDR. Important steps for confronting the rise of MDR H. pylori strains should follow the principles of antibiotic stewardship, i.e. eradication regimens should be optimized with regard to all aspects of therapy, including drugs, doses, formulation, frequency of administration, administration in relation to meals and duration of therapy that reliably achieve at least 90% (preferably >95%) cure rates in adherent patients with susceptible infections.


Effects of Pomegranate (Punica Granatum L.) Seed and Peel Methanolic Extracts on Oxidative Stress and Lipid Profile Changes Induced by Methotrexate in Rats.
Purpose: Methotrexate (MTX) is prescribed in many diseases and can result in oxidative stress (OS) followed by injuries in some tissues. Antioxidants administration are effective in reducing OS. Pomegranate exhibits high anti-oxidant capacities. This study investigated whether pomegranate seed and peel methanolic extracts (PSE and PPE) could protect against MTX-induced OS and lipid profile changes in rats. Methods: Forty-eight rats were randomly divided into 6 groups: control group (normal salin), PSE group (500 mg/kg, orally), PPE group (500 mg/kg, orally), MTX group (10 mg/kg, IM), MTX and PSE group, and MTX and PPE group. Blood samples were taken for analysis in the end of the procedure. Results: The findings showed a significant reduction in Glutathione peroxidase (GPx) and Superoxide dismutase (SOD), and an enhancement in malondialdehyde (MDA) values after MTX treatment (p < 0.05). SOD and GPx levels reached the levels of the control group in MTX+SPE and MTX+PPE groups. No significant differences were observed in catalase (CAT) and total antioxidant capacity (TAC) levels between groups. The results showed a significant decrease in total cholesterol (TC), low density lipoprotein (LDL), and high density lipoprotein (HDL) in the MTX treated group (p < 0.01). The values of TC, HDL, and LDL became elevated to the normal control levels in the MTX+PSE and MTX+PPE treated groups. Conclusion: The results showed the OS induced by MTX and the protective effects of PSE and PPE against MTX-induced serum oxidative stress and lipid profile changes in rats.


Reticulate evolution and sea-level fluctuations together drove species diversification of slipper orchids (Paphiopedilum) in South-East Asia.
South-East Asia covers four of the world's biodiversity hotspots, showing high species diversity and endemism. Owing to the successive expansion and contraction of distribution and the fragmentation by geographical barriers, the tropical flora greatly diversified in this region during the Tertiary, but the evolutionary tempo and mode of species diversity remain poorly investigated. Paphiopedilum, the largest genus of slipper orchids comprising nearly 100 species, is mainly distributed in South-East Asia, providing an ideal system for exploring how plant species diversity was shaped in this region. Here, we investigated the evolutionary history of this genus with eight cpDNA regions and four low-copy nuclear genes. Discordance between gene trees and network analysis indicates that reticulate evolution occurred in the genus. Ancestral area reconstruction suggests that vicariance and long-distance dispersal together led to its current distribution. Diversification rate variation was detected and strongly correlated with the species diversity in subg. Paphiopedilum (~80 species). The shift of speciation rate in subg. Paphiopedilum was coincident with sea-level fluctuations in the late Cenozoic, which could have provided ecological opportunities for speciation and created bridges or barriers for gene flow. Moreover, some other factors (e.g. sympatric distribution, incomplete reproductive barriers and clonal propagation) might also be advantageous for the formation and reproduction of hybrid species. In conclusion, our study suggests that the interplay of reticulate evolution and sea-level fluctuations has promoted the diversification of the genus Paphiopedilum and sheds light into the evolution of Orchidaceae and the historical processes of plant species diversification in South-East Asia.


Modelling Visual Search with the Selective Attention for Identification Model (VS-SAIM): A Novel Explanation for Visual Search Asymmetries.
In earlier work, we developed the Selective Attention for Identification Model (SAIM [16]). SAIM models the human ability to perform translation-invariant object identification in multiple object scenes. SAIM suggests that central for this ability is an interaction between parallel competitive processes in a selection stage and a object identification stage. In this paper, we applied the model to visual search experiments involving simple lines and letters. We presented successful simulation results for asymmetric and symmetric searches and for the influence of background line orientations. Search asymmetry refers to changes in search performance when the roles of target item and non-target item (distractor) are swapped. In line with other models of visual search, the results suggest that a large part of the empirical evidence can be explained by competitive processes in the brain, which are modulated by the similarity between target and distractor. The simulations also suggest that another important factor is the feature properties of distractors. Finally, the simulations indicate that search asymmetries can be the outcome of interactions between top-down (knowledge about search items) and bottom-up (feature of search items) processing. This interaction in VS-SAIM is dominated by a novel mechanism, the knowledge-based on-centre-off-surround receptive field. This receptive field is reminiscent of the classical receptive fields but the exact shape is modulated by both, top-down and bottom-up processes. The paper discusses supporting evidence for the existence of this novel concept.


Folding-upon-Repair DNA Nanoswitches for Monitoring the Activity of DNA Repair Enzymes.
We present a new class of DNA-based nanoswitches that, upon enzymatic repair, could undergo a conformational change mechanism leading to a change in fluorescent signal. Such folding-upon-repair DNA nanoswitches are synthetic DNA sequences containing O6 -methyl-guanine (O6 -MeG) nucleobases and labelled with a fluorophore/quencher optical pair. The nanoswitches are rationally designed so that only upon enzymatic demethylation of the O6 -MeG nucleobases they can form stable intramolecular Hoogsteen interactions and fold into an optically active triplex DNA structure. We have first characterized the folding mechanism induced by the enzymatic repair activity through fluorescent experiments and Molecular Dynamics simulations. We then demonstrated that the folding-upon-repair DNA nanoswitches are suitable and specific substrates for different methyltransferase enzymes including the human homologue (hMGMT) and they allow the screening of novel potential methyltransferase inhibitors.


In vitro maturation of oocytes from Santa Ines ewes subjected to consecutive sessions of follicular aspiration by laparoscopy.
The success of embryo production in vitro depends upon the use of an efficient oocyte retrieval technique, and the best results have been obtained by laparoscopic aspiration. The aim of this study was to evaluate the effect of consecutive sessions of follicular aspiration on the quantity, quality and in vitro maturation competence of oocytes obtained from ewes subjected to hormonal stimulation. Six Santa Ines ewes underwent nine sessions of follicular aspiration by laparoscopy with a 7-day interval between sessions, totalling 56 aspirations. After 24 h of culture, oocytes were stained and classified according to the stage of nuclear and cytoplasmic maturation. Oocyte retrieval rate was 61.4 ± 2%, resulting in a total of 249 oocytes. No significant variation was observed between sessions (p > 0.05). The average number of oocytes retrieved from each ewe was 6.4 ± 2 per session and 42 ± 4 in total. No significant difference was observed between the frequencies of the different stages of nuclear maturation: 32.72% mature, 40.74% immature and 26.54% degenerated/indeterminate oocytes; however, a significant difference was observed between the frequencies of the different stages of cytoplasmic maturation: 10.7% mature, 73.25% immature and 16.05% degenerated/indeterminate oocytes. No significant difference was observed in nuclear or cytoplasmic maturation between the weeks of procedure. We conclude that after nine consecutive sessions of follicular aspiration, the quantity and quality of retrieved oocytes remained unchanged as well as the levels of nuclear and cytoplasmic maturation obtained, demonstrating the viability of this technique for repetitive follicular aspirations on the same donor.


Inhibition of lateral wall elongation by mecillinam stimulates cell division in certain cell division conditional mutants of Escherichia coli.
The effect of mecillinam, a beta-lactam antibiotic that specifically binds penicillin-binding protein 2 of Escherichia coli, causes transition from rod to coccal shape, and inhibits cell division in sensitive cells, has been tested on three different E. coli temperature-sensitive cell division mutants. At the nonpermissive temperature, the antibiotic allows an increase in cell number for strains BUG6 and AX655 but not for AX621. In strain AX655, the cell division stimulation was observed only if the antibiotic was added immediately after shifting to the nonpermissive temperature, whereas in BUG6, the rise in cell number was observed also when mecillinam was added after 90 min of incubation at the nonpermissive temperature. In all cases, cell division began occurring 30 min after addition of the antibiotic. Mecillinam had no effect on division of dnaA, dnaB temperature-sensitive mutants or on division of BUG6 derivatives made resistant to this antibiotic. Other beta-lactam antibiotics such as penicillin, ampicillin, cephalexin, and piperacillin and non beta-lactam antibiotics such as fosfomycin, teichomycin, and vancomycin that inhibit cell wall synthesis did not show any effect on cell division for any of the mutants. The response of the three cell division mutants to mecillinam is interpreted in terms of a recently proposed model for shape regulation in bacteria.


The Effect of Female Economic Empowerment Interventions on the Risk of Intimate Partner Violence: A Systematic Review and Meta-Analysis.
Women's economic empowerment is an essential component of the United Nations Sustainable Development Goals. Not only is it an end in itself but it has further been promoted for its potential to create positive externalities, including the reduction of intimate partner violence (IPV). However, the link between economic empowerment and the risk of IPV remains theoretically ambiguous. Marital dependency theory predicts that women with more financial resources hold higher bargaining power and are in a better position to leave potentially abusive relationships. Conversely, Resource theory posits that an increase in women's financial resources may clash with traditional gender roles, which may prompt their partner to reassert their status through violent means. In light of this debate, we conducted a meta-analysis of 19 randomized controlled trials assessing the impact of economic empowerment interventions on IPV. Based on a total sample size of 44,772 participants and robust variance estimation, our meta-analysis shows that women's economic empowerment was associated with a significant reduction in the pooled measure of emotional, sexual, and physical IPV. We further documented tentative evidence suggesting that these effects may be amplified when additional gender sensitization training is included in such programs. Despite the overall positive effects, some included studies reported increases in IPV, primarily in the form of partners exerting controlling behavior and dominance over financial resources. Our results therefore emphasize a need to prioritize women's safety in the process of designing economic empowerment programs and to closely monitor the potential risk of conflict and violence within beneficiaries' households.


[Breeding dynamic of corvids in urbanized landscapes of the European east].
On the basis of counting and mapping of nests of the rook, hooded crow, and magpie in Kirov in 1975-2012, it was found that, under the conditions of an industrial city, rook colonies are highly unstable. The elimination of the private sector and neglected tree and scrub thickets leads to a reduction in the number of magpies nesting in the city. The nesting abundance of crows is limited by the quarter layout and placement of containers for household waste.


Clusterin is a potential molecular predictor for ovarian cancer patient's survival: targeting clusterin improves response to paclitaxel.
Clusterin is a cytoprotective chaperone protein involved in numerous physiological processes, carcinogenesis, tumor growth and tissue remodelling. The purpose of this study was to investigate whether clusterin (CLU), an antiapoptotic molecule, could be a potential predictor molecule for ovarian cancer and whether or not targeting this molecule can improve survival of ovarian cancer patients. Clusterin expression was compared between ten primary and their recurrent tumors from same patients immunohistochemically. We analyzed prognostic significance of CLU expression in another 47 ovarian cancer tissue samples by immunohistochemistry. We used small interference RNA to knock down CLU in the chemo-resistant ovarian cancer cell lines. KF-TX and SKOV-3-TX, paclitaxel-resistant ovarian cancer cells, were established from parental KF and SKOV-3 chemo-sensitive cell lines, respectively. Either siRNA or second generation antisense oligodeoxynucleotide against CLU (OGX-011), which is currently evaluated in clinical phase II trials in other cancer s, was used to modulate sensitivity to paclitaxel (TX) in ovarian cancer cells in vitro. Cellular viability assay, FACS analysis and annexin V staining were used to evaluate the comparative effect of CLU knocking down in ovarian cancer cells. Immunohistochemical analysis of CLU expression in primary ovarian cancer tissue specimens and their recurrent counterparts from same patients demonstrated higher expression of CLU in the recurrent resistant tumors compared with their primary tumors. High expression of CLU by immunohistochemistry among 47 surgical tissue specimens of early-stage (stage I/II) ovarian cancer, who underwent complete cytoreduction as a primary surgery, significantly related to poor survival, while none of other clinicopathological factors analyzed were related to survival in this patient cohort. Secretory CLU (s-CLU; 60 KDa) expression was upregulated in TX-resistant ovarian cancer cells compared to parental cells. Transfection of siRNA or OGX-011 clearly reduced CLU expression. Cell viability assay, FACS analysis and annexin V staining demonstrated that targeting CLU expression by siRNA or OGX-011 sensitized ovarian cancer cells to TX. We conclude that CLU could be a potential molecular target to predict survival while targeting this s-CLU may improve survival of patients with ovarian cancer.


Antibody to heat shock protein can be used for early serological monitoring of Helicobacter pylori eradication treatment.
Infection with Helicobacter pylori induces humoral immune responses against various antigens of the bacterium. Heat shock proteins (hsps) are immunodominant antigens in various diseases including H. pylori infection. In the present study, we measured the anti-hsp antibody titers in 42 patients with H. pylori-infected peptic ulcers during a bacterial eradication study. The patients were treated with a proton pump inhibitor and antimicrobial agents to eradicate the organism. Their sera were obtained at pretreatment and at 1 month and 6 months after the eradication therapy. The titers of immunoglobulin G antibodies to the H. pylori hsp, whole-cell lysate, and urease (30-kDa subunit) antigens in serum were measured by a capture enzyme-linked immunosorbent assay. The levels of H. pylori hsp60 antibodies in sera collected 1 month after treatment had declined significantly, even when changes in the titers of antibodies to whole-cell and urease antigens were not apparent. These results suggest that measurement of antibodies to H. pylori hsp60 in serum is useful for the early monitoring of the effectiveness of eradication therapy.


Cross-national user priorities for housing provision and accessibility--findings from the European innovAge Project.
To develop an innovative information and communication technology (ICT) tool intended to help older people in their search for optimal housing solutions, a first step in the development process is to gain knowledge from the intended users. Thus the aim of this study was to deepen the knowledge about needs and expectations about housing options as expressed and prioritized by older people, people ageing with disabilities and professionals. A participatory design focus was adopted; 26 people with a range of functional limitations representing the user perspective and 15 professionals with a variety of backgrounds, participated in research circles that were conducted in four European countries. An additional 20 experts were invited as guests to the different research circle meetings. Three themes illustrating cross-national user priorities for housing provision and accessibility were identified: "Information barrier: accessible housing", "Information barrier: housing adaptation benefits", and "Cost barrier: housing adaptations". In conclusion, early user involvement and identification of cross-national differences in priorities and housing options will strengthen the development of a user-friendly ICT tool that can empower older people and people with disabilities to be more active consumers regarding housing provision.


[Risk of bias assessment: (9) Application of the risk of bias assessment results].
In this last paper of the series about risk of bias assessment, we introduce the application of risk of bias assessment results. Risk of bias assessment is one of the key steps in the assessment of quality of evidence. The risk of bias assessment results could be the "diagnosis" of individual studies, which helps decision making related to the inclusion and exclusion of individual studies, as well as the data analysis in the systematic review process. This paper focuses on how to incorporate risk of bias assessment results in the GRADE assessment for quality of evidence, including the principles and the tips for the application.


Delusion-proneness displays comorbidity with traits of autistic-spectrum disorders and ADHD.
There is an increasing body of evidence suggesting a significant comorbidity between psychotic disorders such as schizophrenia and attention-deficit/hyperactivity disorder (ADHD) or autism-spectrum disorders (ASD). Recently, research on psychosis-proneness in otherwise healthy individuals has been a promising way to better understand the mechanisms underlying psychosis. As both ADHD and ASD symptoms show a normal distribution in the general population, such trait comorbidity may confound studies on psychosis-proneness. Thus, understanding the extent to which psychosis-proneness relates to ADHD and ASD symptoms in healthy subjects is crucial for studies focusing on at-risk or psychosis-prone populations. In the present paper we tested the robustness of overlap between psychosis-proneness and ADHD/ASD symptoms, by studying correlations between the scores of three commonly-used questionnaires assessing delusion-proneness (Peters' Delusion Inventory), ADHD tendencies (Adult ADHD Self-Report Scale) and ASD tendencies (Autism Quotient), on a large sample of healthy individuals (n = 925) using raw scores, prototypical questions and a factor analysis. The results showed consistently positive correlations between psychosis-proneness and ADHD-, as well as ASD-symptoms. While the effect was weak for ASD, it was moderate for ADHD. The findings support the idea that when investigating psychosis-proneness it is crucial to also take ADHD- and ASD-tendencies into account, in order to conclude that the reported results in a given study are specific to psychosis-proneness. The observed trait correlations also suggest a common pathway in the underlying information processing of these states.


Effects of soy-protein supplementation on epithelial proliferation in the histologically normal human breast.
A high dietary intake of soy products (eg, as in Japan and Singapore) has been associated with a reduction in the incidence of breast cancer in premenopausal women. Phytoestrogens present in soybeans inhibit human breast cancer cell proliferation in vitro and breast cancer development in animal models, but no data exist on the effects of phytoestrogens on histologically normal human breasts. This study examines the effects of dietary soy supplementation on the proliferation rate of premenopausal, histologically normal breast epithelium and the expression of progesterone receptor. Women (n = 48) with benign or malignant breast disease were randomly assigned to receive their normal diet either alone or with a 60-g soy supplement (containing 45 mg isoflavones) taken daily for 14 d. Biopsy samples of normal breasts were labeled with [3H]thymidine to detect the number of cells in S phase and were immunocytochemically stained for the proliferation antigen Ki67. The phytoestrogens genistein, daidzein, equol, enterolactone, and enterodiol were measured in serum samples obtained before and after supplementation. Serum concentrations of the isoflavones genistein and daidzein increased in the soy group at 14 d. Results showed a strong correlation between Ki67 and the thymidine labeling index (r = 0.868, P < or = 0.001). The proliferation rate of breast lobular epithelium significantly increased after 14 d of soy supplementation when both the day of menstrual cycle and the age of patient were accounted for. Progesterone receptor expression increased significantly in the soy group. Short-term dietary soy stimulates breast proliferation; further studies are required to determine whether this is due to estrogen agonist activity and to examine the long-term effects of soy supplementation on the pituitary gland and breast.


Cannabis: A Neurological Remedy or a Drug of Abuse in India.
Since ancient times, the use of cannabis as a medicine is well documented due to its potential therapeutic activity while subsequently its use as drug of abuse spread increasingly. The present review sought to give an insight in the history of medical and recreational use of cannabis in India. Indian use of cannabis dates back to Vedic time, mostly for the ritualistic and religious purposes, as documented in the ancient literature. It was India that introduced the medical use of cannabis to neighboring countries. Nevertheless, in the same India, medical use did not propagate due to religious and social stigma related to the plant itself. The pharmacoactive constituents of cannabis and their therapeutic values in Ayurvetic medicine have been here described together with the adverse effects they can cause with special reference to neurological ones, including withdrawal symptoms. Finally, how cannabis made its route to the Indian society has also been discussed.


Interleukin-6 in neuromyelitis optica spectrum disorder pathophysiology.
Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder that preferentially affects the spinal cord and optic nerve. Most patients with NMOSD experience severe relapses that lead to permanent neurologic disability; therefore, limiting frequency and severity of these attacks is the primary goal of disease management. Currently, patients are treated with immunosuppressants. Interleukin-6 (IL-6) is a pleiotropic cytokine that is significantly elevated in the serum and the CSF of patients with NMOSD. IL-6 may have multiple roles in NMOSD pathophysiology by promoting plasmablast survival, stimulating the production of antibodies against aquaporin-4, disrupting blood-brain barrier integrity and functionality, and enhancing proinflammatory T-lymphocyte differentiation and activation. Case series have shown decreased relapse rates following IL-6 receptor (IL-6R) blockade in patients with NMOSD, and 2 recent phase 3 randomized controlled trials confirmed that IL-6R inhibition reduces the risk of relapses in NMOSD. As such, inhibition of IL-6 activity represents a promising emerging therapy for the management of NMOSD manifestations. In this review, we summarize the role of IL-6 in the context of NMOSD.


Cloning and sequence analysis of putative histidine protein kinases isolated from Lactococcus lactis MG1363.
Eight recombinant plasmids harboring chromosomal fragments of Lactococcus lactis MG1363 were shown to phenotypically suppress a histidine protein kinase (HPK) deficiency in either of two different E. coli strains. Sequence analysis of the plasmid inserts revealed five different complete or partial open reading frames (ORFs) specifying proteins with high similarity to HPKs. One of the plasmids also harbored an additional ORF, unrelated to HPKs, with suppressing activity.


Factors affecting the risk of relapsing-onset and progressive-onset multiple sclerosis.
It has been debated whether the different clinical disease courses in multiple sclerosis (MS) are the consequence of different pathogenic mechanisms, with distinct risk factors, or if all MS clinical phenotypes are variations of similar underlying disease mechanisms. We aimed to study environmental risk factors and their interactions with human leucocyte antigen DRB1*15:01 with regards to relapsing-onset and progressive-onset MS. We used two Swedish population-based case-control studies, including 7520 relapsing-onset cases, 540 progressive-onset cases and 11 386 controls matched by age, sex and residential area. Logistic regression was used to estimate ORs with 95% CIs for associations between the different MS phenotypes and a number of environmental and lifestyle factors. Interaction between the DRB1*15:01 allele and environmental risk factors was evaluated on the additive scale. All environmental and lifestyle factors associated with risk of developing MS apply to both relapsing-onset and progressive-onset disease. Smoking, obesity and Epstein-Barr virus nuclear antigen-1 (EBNA-1) antibody levels were associated with increased risk of both MS phenotypes, whereas snuff use, alcohol consumption and sun exposure were associated with reduced risk. Additive interactions between DRB1*15:01 and smoking, obesity, EBNA-1 antibody levels and sun exposure, respectively, occurred to increase MS risk regardless of the clinical phenotype. Our finding that the same environmental and lifestyle factors affect both relapsing-onset and progressive-onset MS supports the notion that the different clinical phenotypes share common underlying disease mechanisms.


[Trichinosis in the Kherson Region].
The paper describes the 2003-2004 outbreak oft richinosis in 2 districts of the Kherson Region. Pork was a source of infection. The disease occurred with the ingestion ofshashlik, raw meat, lard, or minced meat. The diagnosis of trichinosis was established 1-1.5 months after the onset of the disease. The patients received a course of therapy and were discharged in a satisfactory condition. The members of their families were prophylactically treated. Meats were bought at the markets and had negative veterinary sanitary tests. A package of antiepidemic and antiepizootic measures was implemented in the foci of trichinosis.


Eat, drink, and be merry, for tomorrow we diet: effects of anticipated deprivation on food intake in restrained and unrestrained eaters.
This study examined the effect of anticipated food deprivation on intake in restrained and unrestrained eaters. Participants were randomly assigned to a diet condition, in which they expected to diet for a week, or to a control (no-diet) condition. Immediately after being assigned to a condition, participants completed a taste-rating task in which food consumption was measured. Restrained eaters in the diet condition consumed significantly more food than did restrained eaters in the no-diet condition or unrestrained eaters in either condition. Unrestrained eaters consumed the same amount regardless of condition. These results confirm that merely planning to go on a diet can trigger overeating in restrained eaters, reflecting the dynamic connection between dieting and overeating.


Physicochemical and transcriptomic responses of Lactobacillus brevis JLD715 to sodium selenite.
Elemental selenium, as a new type of selenium supplement, can be prepared by microorganisms reducing inorganic selenium. In this study, Lactobacillus brevis JLD715 was incubated in broth containing different concentrations of sodium selenite (Na2 SeO3 ). The results showed that the bacterial biomass of L. brevis JLD715 decreased due to the inhibition of Na2 SeO3 . The cell membrane of L. brevis JLD715 treated with Na2 SeO3 was damaged, as evidenced by the reduction of intracellular ATP concentration, depolarization of cell membrane, reduction of intracellular pH and impairment of membrane integrity. In addition, we investigated the metabolism mechanism of Na2 SeO3 by L. brevis JLD715 based on transcriptome sequencing. A total of 461 genes were significantly differentially expressed under Na2 SeO3 treatment, of which 231 genes were up-regulated and 230 genes were down-regulated. These genes were involved in pathways such as pyruvate metabolism, fatty acid biosynthesis, selenocompound metabolism and nucleotide-binding oligomerization domain-like (NOD-like) receptor signaling. Meanwhile, the genes related to sulfhydryl oxidoreductase, electron carrier proteins and transmembrane transport proteins synthesis were significantly up-regulated. To sum up, the findings of this research will contribute to providing support for the application of L. brevis JLD715 in selenium-enriched functional foods. © 2021 Society of Chemical Industry.


Internalization and axonal transport of the HIV glycoprotein gp120.
The HIV glycoprotein gp120, a neurotoxic HIV glycoprotein that is overproduced and shed by HIV-infected macrophages, is associated with neurological complications of HIV such as distal sensory polyneuropathy, but interactions of gp120 in the peripheral nervous system remain to be characterized. Here, we demonstrate internalization of extracellular gp120 in a manner partially independent of binding to its coreceptor CXCR4 by F11 neuroblastoma cells and cultured dorsal root ganglion neurons. Immunocytochemical and pharmacological experiments indicate that gp120 does not undergo trafficking through the endolysosomal pathway. Instead, gp120 is mainly internalized through lipid rafts in a cholesterol-dependent manner, with a minor fraction being internalized by fluid phase pinocytosis. Experiments using compartmentalized microfluidic chambers further indicate that, after internalization, endocytosed gp120 selectively undergoes retrograde but not anterograde axonal transport from axons to neuronal cell bodies. Collectively, these studies illuminate mechanisms of gp120 internalization and axonal transport in peripheral nervous system neurons, providing a novel framework for mechanisms for gp120 neurotoxicity.


Possible role of aldosterone and T(3) in development of amiloride-blockable SCC across frog skin in vivo.
There are inconsistencies between the in vitro and in vivo effects of thyroid hormone and aldosterone (Aldo) on the development of an amiloride-blockable short-circuit current (SCC) across bullfrog skin [Takada, M., H. Yai, and K. Takayama-Arita. Am. J. Physiol. 268 (Cell Physiol. 37): C218-C226, 1995]. To address this issue, tadpoles were raised in Aldo + T(3). An amiloride-blockable SCC developed across the skin before forelimbs appeared. Noise analysis of the characteristics (single-channel current, blocking and unblocking rate coefficients, and apparent dissociation constant) of this amiloride-blockable Na(+) channel showed that it really was of the adult type. A similar SCC developed at stage XIX in the skin of tadpoles raised with Aldo alone. These results strongly support our hypothesis that the crucial hormone in the development of this SCC is Aldo but that a suppression mechanism attenuates its effect on SCC development until it is removed by the increase in the serum concentration of thyroid hormone (which starts at stages XVIII-XIX in vivo).


Effect of silver nanoparticles and antibiotics on antibiotic resistance genes in anaerobic digestion.
Water resource recovery facilities have been described as creating breeding ground conditions for the selection, transfer, and dissemination of antibiotic resistance genes (ARGs) among various bacteria. The objective of this study was to determine the effect of direct addition of antibiotic and silver nanoparticles (Ag NPs, or nanosilver) on the occurrence of ARGs in thermophilic anaerobic digesters. Test thermophilic digesters were amended with environmentally-relevant concentrations of Ag NP (0.01, 0.1, and 1.0 mg-Ag/L; corresponding to approximately 0.7, 7.0, and 70 mg-Ag/kg total solids) and sulfamethoxazole (SMX) that span susceptible to resistant classifications (1, 5, and 50 mg/L) as potential selection pressures for ARGs. Tetracycline (tet(O), tet(W)) and sulfonamide (sulI, sulII) ARGs and the integrase enzyme gene (intI1) associated with Class 1 integrons were measured in raw sludge, test thermophilic digesters, a control thermophilic digester, and a control mesophilic digester. There was no apparent effect of Ag NPs on thermophilic anaerobic digester performance. The maximum SMX addition (50 mg/L) resulted in accumulation of volatile fatty acids and low pH, alkalinity, and volatile solids reduction. There was no significant difference between ARG gene copy numbers (absolute or normalized to 16S rRNA genes) in amended thermophilic digesters and the control thermophilic digester. Antibiotic resistance gene copy numbers in digested sludge ranged from 10(3) to 10(6) copies per microL (approximately 8 x10(1) to 8 x 10(4) copies per microg) of sludge as result of a 1-log reduction of ARGs (2-log reduction for intI1). Quantities of the five ARGs in raw sludge ranged from 10(4) to 10(8) copies per microL (approximately 4 x 10(2) to 4 x 10(6) per microg) of sludge. Test and control thermophilic digesters (53 degrees C, 12-day solids retention time [SRT]) consistently reduced but did not eliminate levels of all analyzed genes. The mesophilic digester (37 degrees C, 20-day SRT) also reduced levels of sulI, sulII, and intI1 genes, but levels of tet(O) and tet(W) were the same or higher than in raw sludge. Antibiotic resistance gene reductions remained constant despite the application of selection pressures, which suggests that digester operating conditions are a strong governing factor of the bacterial community composition and thus the prevalence of ARGs.


Proposed diagnostic criteria for arrhythmogenic cardiomyopathy: European Task Force consensus report.
Arrhythmogenic cardiomyopathy (ACM) is a heart muscle disease characterized by prominent "non-ischemic" myocardial scarring predisposing to ventricular electrical instability. Diagnostic criteria for the original phenotype, arrhythmogenic right ventricular cardiomyopathy (ARVC), were first proposed in 1994 and revised in 2010 by an international Task Force (TF). A 2019 International Expert report appraised these previous criteria, finding good accuracy for diagnosis of ARVC but a lack of sensitivity for identification of the expanding phenotypic disease spectrum, which includes left-sided variants, i.e., biventricular (ABVC) and arrhythmogenic left ventricular cardiomyopathy (ALVC). The ARVC phenotype together with these left-sided variants are now more appropriately named ACM. The lack of diagnostic criteria for the left ventricular (LV) phenotype has resulted in clinical under-recognition of ACM patients over the 4 decades since the disease discovery. In 2020, the "Padua criteria" were proposed for both right- and left-sided ACM phenotypes. The presently proposed criteria represent a refinement of the 2020 Padua criteria and have been developed by an expert European TF to improve the diagnosis of ACM with upgraded and internationally recognized criteria. The growing recognition of the diagnostic role of CMR has led to the incorporation of myocardial tissue characterization findings for detection of myocardial scar using the late‑gadolinium enhancement (LGE) technique to more fully characterize right, biventricular and left disease variants, whether genetic or acquired (phenocopies), and to exclude other "non-scarring" myocardial disease. The "ring-like' pattern of myocardial LGE/scar is now a recognized diagnostic hallmark of ALVC. Additional diagnostic criteria regarding LV depolarization and repolarization ECG abnormalities and ventricular arrhythmias of LV origin are also provided. These proposed upgrading of diagnostic criteria represents a working framework to improve management of ACM patients.


Statistical error analysis of time and polarization resolved ultrasonic measurements.
The time and polarization resolved ultrasonic technique which we previously developed has been demonstrated to simultaneously provide measurements of the wave velocity in the coupling liquid, and the leaky surface wave and leaky longitudinal wave velocities in solid samples. To document the measurement precision associated with this technique, a statistical method is employed for the data fit and error analysis. With the help of statistical analysis, the simple ray model used to determine wave velocities in this technique is first confirmed by theoretical data which are predicted by the Green's function. Error analysis is then applied to the experimental data. The results show that this technique has a relative expanded uncertainty (equal to twice the standard deviation) of 0.03% for the wave velocity in water, and an uncertainty less than 0.2% and 2%, respectively, for the leaky surface and leaky longitudinal wave velocities in a crown glass sample. The uncertainty in the repeatability for leaky surface wave measurements is observed to be much less than the expanded uncertainty of a single measurement set. This methodology also has been applied to a set of steel samples. The results allow that the expanded uncertainty for leaky surface wave velocities is less than 0.07%, enabling a correlation of the measured velocities with specific sample heat treatments.


Titanium pyrochlore magnets: how much can be learned from magnetization measurements?
We report magnetization data for several titanium pyrochlore systems measured down to 0.5 K. The measurements, performed on single crystal samples in fields of up to 7 kOe, have captured the essential elements of the previously reported phase transitions in these compounds and have also revealed additional important features overlooked previously either because of the insufficiently low temperatures used, or due to limitations imposed by polycrystalline samples. For the spin-ice pyrochlores Dy(2)Ti(2)O(7) and Ho(2)Ti(2)O(7), an unusually slow relaxation of the magnetization has been observed in lower fields, while the magnetization process in higher fields is essentially hysteresis-free and does not depend on sample history. For the XY pyrochlore Er(2)Ti(2)O(7), the magnetic susceptibility shows nearly diverging behaviour on approach to a critical field, H(C) = 13.5 kOe, above which the magnetization does not saturate but continues to grow at a significant rate. For the Heisenberg pyrochlore Gd(2)Ti(2)O(7), the magnetic susceptibility shows a pronounced change of slope at both transition temperatures, T(N1) = 1.02 K and T(N2) = 0.74 K, contrary to the earlier reports.


Wolbachia Blocks Viral Genome Replication Early in Infection without a Transcriptional Response by the Endosymbiont or Host Small RNA Pathways.
The intracellular endosymbiotic bacterium Wolbachia can protect insects against viral infection, and is being introduced into mosquito populations in the wild to block the transmission of arboviruses that infect humans and are a major public health concern. To investigate the mechanisms underlying this antiviral protection, we have developed a new model system combining Wolbachia-infected Drosophila melanogaster cell culture with the model mosquito-borne Semliki Forest virus (SFV; Togaviridae, Alphavirus). Wolbachia provides strong antiviral protection rapidly after infection, suggesting that an early stage post-infection is being blocked. Wolbachia does appear to have major effects on events distinct from entry, assembly or exit as it inhibits the replication of an SFV replicon transfected into the cells. Furthermore, it causes a far greater reduction in the expression of proteins from the 3' open reading frame than the 5' non-structural protein open reading frame, indicating that it is blocking the replication of viral RNA. Further to this separation of the replicase proteins and viral RNA in transreplication assays shows that uncoupling of viral RNA and replicase proteins does not overcome Wolbachia's antiviral activity. This further suggests that replicative processes are disrupted, such as translation or replication, by Wolbachia infection. This may occur by Wolbachia mounting an active antiviral response, but the virus did not cause any transcriptional response by the bacterium, suggesting that this is not the case. Host microRNAs (miRNAs) have been implicated in protection, but again we found that host cell miRNA expression was unaffected by the bacterium and neither do our findings suggest any involvement of the antiviral siRNA pathway. We conclude that Wolbachia may directly interfere with early events in virus replication such as translation of incoming viral RNA or RNA transcription, and this likely involves an intrinsic (as opposed to an induced) mechanism.


Transgenic Strategies for Enhancement of Nematode Resistance in Plants.
Plant parasitic nematodes (PPNs) are obligate biotrophic parasites causing serious damage and reduction in crop yields. Several economically important genera parasitize various crop plants. The root-knot, root lesion, and cyst nematodes are the three most economically damaging genera of PPNs on crops within the family Heteroderidae. It is very important to devise various management strategies against PPNs in economically important crop plants. Genetic engineering has proven a promising tool for the development of biotic and abiotic stress tolerance in crop plants. Additionally, the genetic engineering leading to transgenic plants harboring nematode resistance genes has demonstrated its significance in the field of plant nematology. Here, we have discussed the use of genetic engineering for the development of nematode resistance in plants. This review article also provides a detailed account of transgenic strategies for the resistance against PPNs. The strategies include natural resistance genes, cloning of proteinase inhibitor coding genes, anti-nematodal proteins and use of RNA interference to suppress nematode effectors. Furthermore, the manipulation of expression levels of genes induced and suppressed by nematodes has also been suggested as an innovative approach for inducing nematode resistance in plants. The information in this article will provide an array of possibilities to engineer resistance against PPNs in different crop plants.


Hierarchical phenotypic and epigenetic variation in cloned swine.
Cloning by somatic cell nuclear transfer can result in the birth of animals with phenotypic and gene expression abnormalities. We compared adult cloned pigs and adult pigs from naturally bred control females using a series of physiological and genetic parameters, including detailed methylation profiles of selected genomic regions. Phenotypic and genetic analyses indicated that there are two classes of traits, one in which the cloned pigs have less variation than controls and another characterized by variation that is equally high in cloned and control pigs. Although cloning creates animals within the normal phenotypic range, it increases the variability associated with some traits. This finding is contrary to the expectation that cloning can be used to reduce the size of groups involved in animal experimentation and to reproduce an animal, including a pet, with a homogenous set of desired traits.


Insulin binding and action on fat cells from young healthy females and males.
Insulin binding and action were studied in fat cells from the gluteal region of young healthy subjects. Fat cells from females were larger than those of males, had higher insulin receptor binding and higher rates of noninsulin-stimulated and maximally insulin-stimulated rates of methylglucose transport and glucose metabolism when these data were expressed per cell number. However, when insulin binding and insulin effects were expressed per cell surface, which may be physiologically more relevant, no sex differences were found in insulin binding and glucose transport, whereas noninsulin-stimulated and maximally insulin-stimulated glucose metabolism was still significantly increased in female fat cells. The latter indicates postreceptor differences in glucose metabolism between females and males. The insulin concentrations causing half-maximal responses (a measure of the sensitivity to insulin) of glucose transport, glucose metabolism and lipolysis were similar in fat cells from the two sexes, which is consistent with the comparable values of insulin receptor binding when adjusted to cell surface. Studies of rate-determining steps for the glucose utilization of human fat cells showed that glucose transport was not the rate-limiting step at physiological glucose concentrations. Moreover, at physiological glucose levels, glucose metabolism exhibited a decreased maximal insulin responsiveness and an increased insulin sensitivity when compared with glucose metabolism at low glucose concentrations at which glucose transport is rate limiting for the fat cell glucose utilization.


The two murein lipoproteins of Salmonella enterica serovar Typhimurium contribute to the virulence of the organism.
Septic shock due to Salmonella and other gram-negative enteric pathogens is a leading cause of death worldwide. The role of lipopolysaccharide in sepsis is well studied; however, the contribution of other bacterial outer membrane components, such as Braun (murein) lipoprotein (Lpp), is not well defined. The genome of Salmonella enterica serovar Typhimurium harbors two copies of the lipoprotein (lpp) gene. We constructed a serovar Typhimurium strain with deletions in both copies of the lpp gene (lpp1 and lpp2) by marker exchange mutagenesis. The integrity of the cell membrane and the secretion of the effector proteins through the type III secretion system were not affected in the lpp double-knockout mutant. Subsequently, the virulence potential of this mutant was examined in a cell culture system using T84 intestinal epithelial and RAW264.7 macrophage cell lines and a mouse model of salmonellosis. The lpp double-knockout mutant was defective in invading and inducing cytotoxic effects in T84 and RAW264.7 cells, although binding of the mutant to the host cell was not affected when compared to the wild-type (WT) serovar Typhimurium. The motility of the mutant was impaired, despite the finding that the number of flagella was similar in the lpp double knockout mutant and the WT serovar Typhimurium. Deletion in the lpp genes did not affect the intracellular survival and replication of Salmonella in macrophages and T84 cells. Induction of the proinflammatory cytokines tumor necrosis factor alpha and interleukin-8 (IL-8) was significantly reduced in macrophages and T84 cells infected with the lpp double-knockout mutant. The levels of IL-8 remained unaffected in T84 cells when infected with either live or heat-killed WT and lpp mutant, indicating that invasion was not required for IL-8 production and that Toll-like receptor 2 signaling might be affected in the Lpp double-knockout mutant. These effects of the Lpp protein could be restored by complementation of the isogenic mutant. The lpp double-knockout mutant was avirulent in mice, and animals infected with this mutant were protected from a lethal challenge dose of WT serovar Typhimurium. The severe combined immunodeficient mice, on the other hand, were susceptible to infection by the lpp double-knockout mutant. The serovar Typhimurium mutants from which only one of the lpp (lpp1 or lpp2) genes was deleted were also avirulent in mice. Taken together, our data indicated that Lpp specifically contributed to the virulence of the organism.


Zizyphus mauritiana seed extract: Paving the way for next-generation bone constructs with nano-fluorohydroxyapatite/carboxymethyl chitosan nanocomposite scaffold.
This is the first study that explored the potential use of Zizyphus mauritiana seed extract (ZSE) to synthesize nano-fluorohydroxyapatite/carboxymethyl chitosan nanocomposite scaffolds at different concentrations (CFZ1, CFZ2 and CFZ3) using co-precipitation method. The proposed scaffolds showed presence of intermolecular H bonding interactions between the constituents, according to the FTIR. The mechanical studies revealed shore hardness of 72 ± 4.6 and optimal compressive modulus in case of CFZ3 [1654.48 ± 1.6 MPa], that was comparable with that of human cortical bone. The SEM, TEM and platelet adhesion images corroborated uniformly distributed needle like particles in case of CFZ3 with an average size ranging from 22 to 26 nm, linked rough morphology, and appropriate hemocompatibility. The markedly up regulation in the ALP activity and protein adsorption upon increasing ZSE concentration demonstrated that CFZ nanocomposite scaffolds were compatible with osteoblastic cells relative to CF nanocomposite. The cytotoxicity study indicated that CFZ nanocomposite do not induce toxicity over MG-63 and did not aggravate LDH leakage in contrast to CF. The histopathological investigations on albino rats confirmed significantly improved regeneration of bone in the repair of a critical-size [8 mm] calvarium defect. Therefore, CFZ3 nanocomposite scaffold represents a simple, off-the-shelf solution to the combined challenges associated with bone defects.


Detection of adventitious viruses in biologicals--a rare occurrence.
Adventitious virus assays are performed as part of raw materials testing, cell-line characterization, and lot-release testing of biologicals such as monoclonal antibodies, gene therapy vectors, recombinant proteins, and vaccines. The testing methods follow guidance provided in the 9 CFR (bovine and porcine raw materials testing, and certain vaccine products) or Points to Consider documents (cell line characterization and evaluation of the majority of biologicals). The methodologies used and the types of adventitious viruses detected during testing of the various types of samples are discussed in this paper. The detection of adventitious viruses is quite rare, especially during evaluation of cell banks and biologicals produced in human, mouse, or insect cell substrates. The most common detection scenarios include bovine viral diarrhoea virus in foetal bovine serum samples, porcine parvovirus in porcine substrates, and murine minute virus, REO virus, and Cache Valley virus in Chinese hamster cell-derived bulk harvests. The two last-named viral entities are believed to be introduced via bovine serum used during the manufacturing process (during scale-up or during the entire process). Knowledge of the types of agents being detected is useful in designing viral clearance methodologies for purification processes and in engineering manufacturing processes and facilities.


Combined Associations of Liver Enzymes and Obesity With Diabetes Mellitus Prevalence: The Tohoku Medical Megabank Community-based Cohort Study.
Alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) are enzymes associated with diabetes mellitus (DM) prevalence. However, limited information is available regarding the association of liver enzymes and DM consistently present in obese and non-obese individuals. We examined whether the combination of ALT and GGT enzymes is associated with the prevalence of DM, regardless of obesity, in a general Japanese population. We conducted a cross-sectional study of 62,786 participants aged ≥20 years who lived in Miyagi and Iwate, Japan. We divided all the participants into eight groups according to the ALT level (low: <30 IU/L and high: ≥30 IU/L), GGT level (low: <50 IU/L and high: ≥50 IU/L), and the presence of obesity. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic regression analysis, adjusting for potential confounders, to determine associations of the combination of ALT and GGT levels and obesity with DM prevalence. Overall, 6,008 participants (9.6%) had DM. Compared to non-obese individuals with low ALT and GGT levels, the participants with high ALT and GGT levels had high ORs for DM in both obese (OR 4.06; 95% CI, 3.61-4.56) and non-obese groups (OR 2.19; 95% CI, 1.89-2.52). The obese group had high ORs for DM, even at low ALT and GGT levels. High ALT and GGT levels are associated with DM prevalence in obese and non-obese participants. This finding suggests that correcting ALT and GGT levels and controlling obesity are important for the prevention of DM.


Ultrasensitive Vertical Piezotronic Transistor Based on ZnO Twin Nanoplatelet.
High sensitivity of pressure/strain sensors is the key to accurately evaluating external mechanical stimuli and could become more important in future generations of human-machine interfaces and artificial skin. Here we report the study of a two-terminal piezotronic transistor based on ZnO twin nanoplatelets (TNPT). Owing to the mirror symmetrical structure of ZnO twin nanplatelet, compressive pressure-induced positive piezoelectric polarization charges created at both metal-semiconductor interfaces can simultaneously lower both Schottky barrier heights and thus significantly modulate the carrier transport. Our device exhibits the highest pressure sensitivity of 1448.08-1677.53 meV/MPa, which is more than ∼20 times larger than the highest value reported previously, and a fast response time of <5 ms. In addition, it can be used as a photodector with an ultrahigh external photoresponsivity of ∼1.45 × 104 AW-1, which is ∼105 times larger in magnitude than that of commercial UV photodetectors. The coupling between the mirror symmetrical structure and strong piezotronic effect in ZnO twin nanoplatelets may enable the development of ultrasensitive pressure/strain sensors for various applications such as artificial skin, health monitoring, and adaptive biomedical probes.


Operative management of the flail chest.
The management of flail chest (FC) has been the subject of controversy for many years. The aim of our study was to compare results of the management of patients with FC after operative stabilization (OS) vs. nonoperative treatment (NT). One hundred and thirty-three consecutive patients with FC were assigned to treatment with OS (40 patients) and NT (93 patients). Different kinds of external extramedullar osteosynthesis were performed within 24 hour period after admission. NT includes endotracheal lung ventilation, epidural and regional anaesthesia. No difference in age, sex, shock ISS, severity pulmonary and heart contusion, extensive FC were found between both groups. Results of treatment are the following (for OS and NT respectively, p < 0.05): pneumonia 15% (6) vs. 34.4% (32); PaO2/FiO2 - 333.4 +/- 12.3 vs. 286.5 +/- 14.7; duration of lung ventilation (days) - 2.3 +/- 0.6 vs. 6.3 +/- 1.2; mortality rate - 22.5% (9) vs. 46.2% (43). Operative stabilization of chest wall should be considered when extensive FC occurs, particularly for patients with severe pulmonary and heart contusion.


Microscopic mechanism of shear bands in amorphous solids.
The fundamental instability responsible for the shear localization which results in shear bands in amorphous solids remains unknown despite an enormous amount of research, both experimental and theoretical. As this is the main mechanism for the failure of metallic glasses, understanding the instability is invaluable in finding how to stabilize such materials against the tendency to shear localize. In this Letter we explain the mechanism for shear localization under shear, which is the appearance of highly correlated lines of Eshelby-like quadrupolar singularities which organize the nonaffine plastic flow of the amorphous solid into a shear band. We prove analytically that such highly correlated solutions in which N quadrupoles are aligned with equal orientations are minimum energy states when the strain is high enough. The line lies at 45 degrees to the compressive stress.


Pharmacological Applications of Nrf2 Inhibitors as Potential Antineoplastic Drugs.
Oxidative stress (OS) is associated with many diseases ranging from cancer to neurodegenerative disorders. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is one of the most effective cytoprotective controller against OS. Modulation of Nrf2 pathway constitutes a remarkable strategy in the antineoplastic treatments. A big number of Nrf2-antioxidant response element activators have been screened for use as chemo-preventive drugs in OS associated diseases like cancer even though activation of Nrf2 happens in a variety of cancers. Research proved that hyperactivation of the Nrf2 pathway produces a situation that helps the survival of normal as well as malignant cells, protecting them against OS, anticancer drugs, and radiotherapy. In this review, the modulation of the Nrf2 pathway, anticancer activity and challenges associated with the development of an Nrf2-based anti-cancer treatment approaches are discussed.


The initial development and assessment of an automatic alert warning of acute kidney injury.
Acute kidney injury (AKI) recognition by clinicians has been shown to be suboptimal. Little work has focused on the use of an automated warning of a rise in a patient's creatinine, indicating AKI. Over 3 months in 2008 we ran a prospective observational study of 'alerts' sent by our Integrated Clinical Environment pathology system, identifying all patients with a ≥ 75% rise in their creatinine from its previous value. Information was collected on subsequent renal function, comorbidities and other potential predictors of survival. In the 3-month period 463 adults with a first episode of AKI were identified by an alert; 87% were hospital inpatients. Median follow-up was 404 days. In-hospital mortality was 36% for those who were admitted. After performing Weibull survival analysis, significant predictors of poorer survival were the presence of metastatic, haematological or lower risk malignancy, a residential or nursing home address and higher age, number of non-malignant comorbidities or C-reactive protein level. Predictors of better survival were higher serum albumin level or nadir GFR during the episode and Indian subcontinent ethnicity. A receiver-operator curve for a prognostic score developed from the analysis showed an area under the curve of 0.84. The alerts identified a group of AKI patients who are at moderately high risk of death. The prognostic score using a combination of covariates shows early promise. Both the alerts and the score warrant further development as tools for earlier intervention in AKI.


Point-of-care microdevices for blood plasma analysis in viral infectious diseases.
Each year, outbreaks of viral infections cause illness, disability, death, and economic loss. As learned from past incidents, the detrimental impact grows exponentially without effective quarantine. Therefore, rapid on-site detection and analysis are highly desired. In addition, for high-risk areas of viral contamination, close monitoring should be provided during the potential disease incubation period. As the epidemic progresses, a response protocol needs tobe rapidly implemented and the virus evolution fully tracked. For these scenarios, point-of-care microdevices can provide sensitive, accurate, rapid and low-cost analysis for a large population, especially in handling complex patient samples, such as blood, urine and saliva. Blood plasma can be considered as a mine of information containing sources and clues of biomarkers, including nucleic acids, immunoglobulin and other proteins, as well as pathogens for clinical diagnosis. However, blood plasma is also the most complicated body fluid. For targeted plasma biomarker detection or untargeted plasma biomarker discovery, the challenges can be as difficult as identifying a needle in a haystack. A useful platform must not only pursue single performance characteristics, but also excel at multiple performance parameters, such as speed, accuracy, sensitivity, selectivity, cost, portability, reliability, and user friendliness. Throughout the decades, tremendous progress has been made in point-of-care microdevices for viral infectious diseases. In this paper, we review fully integrated lab-on-chip systems for blood analysis of viral infectious disease.


Hemoglobin Gun Hill: deletion of five amino acid residues and impaired heme-globin binding.
Hemoglobin Gun Hill, a new variant of adult hemoglobin, was found in a Caucasian and one of his three daughters. The abnormal hemoglobin had only half of the expected number of heme groups. Five amino acid residues appeared to be missing from the beta-globin chains. These residues occur in linear sequence in normal beta-chains in a region involved in heme-globin binding. A deletion of five amino acids in the beta-chains of hemoglobin Gun Hill is postulated. The most likely mechanism for the origin of such a hemoglobin variant would appear to be unequal crossing-over during meiosis.


Effects of Lateral Size, Thickness, and Stabilizer Concentration on the Cytotoxicity of Defect-Free Graphene Nanosheets: Implications for Biological Applications.
In this work, we apply liquid cascade centrifugation to highly concentrated graphene dispersions produced by liquid-phase exfoliation in water with an insoluble bis-pyrene stabilizer to obtain fractions containing nanosheets with different lateral size distributions. The concentration, stability, size, thickness, and the cytotoxicity profile are studied as a function of the initial stabilizer concentration for each fraction. Our results show that there is a critical initial amount of stabilizer (0.4 mg/mL) above which the dispersions show reduced concentration, stability, and biocompatibility, no matter the lateral size of the flakes.


Blind Manipulation of Deformable Objects Based on Force Sensing and Finite Element Modeling.
In this paper, we present a novel pipeline to simultaneously estimate and manipulate the deformation of an object using only force sensing and an FEM model. The pipeline is composed of a sensor model, a deformation model and a pose controller. The sensor model computes the contact forces that are used as input to the deformation model which updates the volumetric mesh of a manipulated object. The controller then deforms the object such that a given pose on the mesh reaches a desired pose. The proposed approach is thoroughly evaluated in real experiments using a robot manipulator and a force-torque sensor to show its accuracy in estimating and manipulating deformations without the use of vision sensors.


Prognosis of resected well-differentiated neuroendocrine carcinoma of the lung.
Among lung tumors, well-differentiated neuroendocrine carcinomas are often misdiagnosed or may go unrecognized. Nineteen cases of well-differentiated neuroendocrine carcinoma (WDNC) were assessed at the National Cancer Institute of Milan over a ten-year period. There was only one woman and the age range was 50 to 77 years. Most of the patients were smokers (83 percent). All tumors were radically resected. There were 12 lobectomies, two sleeve-lobectomies, three bilobectomies, one pneumonectomy, and two segmentectomies (one patient had two synchronous WDNCs). There was neither operative mortality nor major complications. Sixteen tumors were stage 1, three were stage II, and one was stage IIIa. Five patients had adjuvant chemotherapy (cyclophosphamide, doxorubicin, and vincristine [CAV] regimen). One patient was given local or regional radiotherapy. In ten patients the tumors recurred, even though four had had adjuvant treatment. The brain was the first site of metastasis in seven cases. The pathologic stage seemed not to be closely related to the appearance of metastases (six patients with stage I disease had recurrences). Only two patients with recurrence were still alive 12 and 103 months after the procedure. The percentage of survival for patients with stage I disease after more than 100 months was 68 percent. WDNC is similar to small-cell lung carcinoma (SCLC) with regard to the neurotropism of metastases. Surgery is curative for more than one half of the patients with localized disease. Therefore, multimodal therapy, probably based on tumor behavior and investigations of tumor markers, is advisable.


Current perspectives on the diagnosis and management of functional anorectal disorders in patients with inflammatory bowel disease.
Despite advances in inflammatory bowel disease (IBD) therapies, a significant proportion of patients with quiescent disease experience persistent, debilitating symptoms of faecal incontinence (FI), urgency and defaecatory disorders due to anorectal dysfunction. Such symptoms are often underreported or misdiagnosed and can lead to potentially premature treatment 'escalation' and under-utilisation of pelvic floor investigations. In this review article, we consider putative pathophysiological post-inflammatory changes resulting in altered anorectal sensitivity, motility and neuromuscular coordination and how this may drive symptoms in quiescent IBD. Finally, we discuss a pragmatic approach to investigating and managing anorectal dysfunction and highlight areas for future research for this often-neglected group of patients.


The effect of human recombinant macrophage colony-stimulating factor (CSF-1) on the murine mononuclear phagocyte system in vivo.
Human recombinant macrophage CSF (CSF-1) was administered i.v. to mice. After four daily injections there was a dose-dependent increase in the responsiveness of bone marrow cells from the treated animals to CSF-1 in vitro. At the highest dose tested (20,000 U/day) there was a selective 10-fold increase in the circulating population of mature monocytes. CSF-1 treatment also increased the macrophage content of the liver and peritoneal cavity and caused splenomegaly. The macrophages isolated from the peritoneum of CSF-1-treated animals were larger and expressed higher levels of the macrophage-specific F4/80 Ag. These data demonstrate that CSF-1 can act as a circulating regulator of the mononuclear phagocyte system.


[Screening for breast cancer on basis of individual risk assessment for women ineligible for the national population screening program].
For healthy women, without malignancies in their personal histories, a positive family history for breast cancer is the single indication for individual breast surveillance outside the population screening. Management of women is based on individual risk assessment. A cumulative risk of 20% and more, as a result of a positive family history, will in practice be an indication for breast surveillance. This threshold is not evidence-based yet, nor are data available on the benefits of this surveillance efficacy. When a personal cumulative risk of more than 30% exists to develop breast cancer, a consultation with a clinical geneticist involved in a family cancer clinic should be offered. Surveillance of women with a high-risk cumulative risk should preferably be included in a prospective study design. Only in this way will data about compliance and the estimates of different ways of surveillance become available. There is no convincing evidence that population screening for women aged 40-49 years does lead to important mortality reduction in combination with a good balance between pros and cons for the women involved. Women in the age category 50-75 years, with breast cancer in their personal histories, who are not followed anymore, should be informed by their specialist about participating (again) in the population breast screening. There is no evidence of mortality reduction as a result of breast self-examination nor of palpation performed by a physician. However, awareness of the own body can be useful for early recognition of breast abnormalities; it may reduce the delay between the first recognizable symptom and the subsequently initiated therapy.


Reactivity of Cl atom with triple-bonded molecules. An experimental and theoretical study with alcohols.
The reactivities of the Cl atom with triple-bonded molecules were examined by determining the rate coefficients of reactions of four triple-bonded alcohols (TA), namely, 2-propyn-1-ol, 3-butyn-1-ol, 3-butyn-2-ol, and 2-methyl-3-butyn-2-ol, using the relative rate method, at 298 K. The rate coefficients (k) of reaction of the four alcohols with Cl vary in the range (3.5-4.3) × 10(-10) cm(3) molecule(-1) s(-1). These values imply significant contribution of the Cl reaction in the tropospheric degradation of TAs in the conditions of the marine boundary layer. A striking difference is observed in the reactivity trend of Cl from that of OH/O3. Although the reactivity of OH/O3 is lower with triple-bonded molecules, as compared to the double-bonded analogues, the reactivity of the Cl atom is similar for both. For a deeper insight, the reactions of Cl and OH with the simplest TA, 2-propyn-1-ol, are investigated theoretically. Conventional transition state theory is applied to compute the values of k, using the calculated energies at QCISD and QCISD(T) levels of theory of the optimized geometries of the reactants, transition states (TS), and the product radicals of all the possible reaction pathways at the MP2/6-311++G(d,p) level. The k values calculated at the QCISD level for Cl and the QCISD(T) level for OH reactions are found to be very close to the experimental values at 298 K. In the case of the Cl reaction, the abstraction of α-H atoms as well as the addition at the terminal and middle carbon atoms have submerged TS and the contribution of the abstraction reaction is found to be significant at room temperature, at all levels of calculations. Addition at the terminal carbon atom is prominent compared to that at the middle carbon. In contrast to the Cl reaction, only addition at the middle carbon is associated with such low lying TS in the case of OH. The individual rate coefficients of addition and abstraction of OH are lower than that of Cl. The negative temperature dependence of the computed rate coefficients in the temperature range 200-400 K shows that the difference in the TS energy of Cl and OH affects the pre-exponential factor more than the activation energy.


Incarceration and the tasks of grief: a narrative review.
This study is a report of a narrative review to explore the challenges facing prisoners and the corrections system in the presence of the death of a significant person to the prisoner. Death of a loved one is an important challenge, amplified for incarcerated men. There are unique aspects of incarceration that prevent prisoners from having access to usual ritual expressions and support structures. A search of the CINAHL, ProQuest Medical, PubMed, EBSCO and COCHRANE databases was conducted for papers published from 1998-2007. The search terms were bereavement and prison nursing. A hand search of material specific to grief and incarceration was also undertaken. A narrative technique involving reading, writing, thinking, interpreting, arguing and justifying was used to synthesize the material and create a convincing and cohesive story. Limited research is available specifically addressing the grief experience of incarcerated individuals or the impact of unresolved grief on recidivism. However, a number of potential challenges to the grieving process in the prison system are identified in the literature, such as the prison culture of toughness and limited options for funeral attendance. Whilst the literature is scant, it is clear that issues of masculinity and culture have a strong impact on the ability of incarcerated men to resolve grief issues. More research is required to understand the impact of this on issues, such as recidivism. In the meantime, prison nurses have an important role to play in supporting prisoners who have lost a loved one during their incarceration.


Rapamycin reverses pulmonary artery smooth muscle cell proliferation in pulmonary hypertension.
Pulmonary artery (PA) smooth muscle cell (SMC) proliferation in pulmonary hypertension (PH) may be linked to dysregulated mammalian target of rapamycin (mTOR) signaling. The mTOR pathway involves two independent complexes, mTORC1 and mTORC2, which phosphorylate S6 kinase (S6K) and serine/threonine kinase (Akt), respectively, and differ in their sensitivity to rapamycin. Here, we evaluated rapamycin-sensitive mTOR substrates and PA-SMC proliferation in rats with monocrotaline (MCT)-induced PH (MCT-PH). Compared with cells from control rats, cultured PA-SMCs from MCT-PH rats exhibited increased growth responses to platelet-derived growth factor, serotonin (5-hydroxytryptophan), IL-1β, insulin-like growth factor-1, or fetal calf serum (FCS), with increases in phosphorylated (Ser-473)Akt, (Thr-308)Akt, glycogen synthase kinase (GSK)3, and S6K reflecting activated mTORC1 and mTORC2 signaling. Treatment with rapamycin (0.5 μM) or the Akt inhibitor, A-443654 (0.5 μM), reduced FCS-stimulated growth of PA-SMCs from MCT-PH rats to the level in control rats while inhibiting Akt, GSK3, and S6K activation. Neither the tyrosine kinase inhibitor, imatinib (0.1 μM), nor the 5-hydroxytryptophan transporter inhibitor, fluoxetine (5 μM), normalized the increased PA-SMC growth response to FCS. Rapamycin treatment (5 mg/kg/d) of MCT-PH rats from Day 21 to Day 28 markedly reduced phoshop (p)-Aky, p-GSK3, and p-S6K in PAs, and normalized growth of derived PA-SMCs. This effect was not observed after 1 week of imatinib (100 mg/kg/d) or fluoxetine (20 mg/kg/d). Rapamycin given preventively (Days 1-21) or curatively (Days 21-42) inhibited MCT-PH to a greater extent than did imatinib or fluoxetine. Experimental PH in rats is associated with a sustained proliferative PA-SMC phenotype linked to activation of both mTORC1 and mTORC2 signaling and is suppressed by rapamycin treatment.


[Effect of testosterone on protein synthesis of prostate cells in hypo- and hyperprolactinemia].
The influence of testosterone on the concentration and synthesis of nuclear and cytoplasmic prostate proteins were studied in rats with hypo- and hyperprolactinemia. Hyperprolactinemia was induced by "Lactin", and the hypoprolactinemia was modelled by "Parlodel". The rats were injected with 14C-protein hydrolysate i.p. for the investigation of the proteins biosynthesis and concentration of prostate cells. The androgen inhibited catabolism of nonhistone proteins and the proteins of nuclear juice in intact rats organism. Testosterone increased the synthesis of all proteins in rats with prolactin deficiency, but this enlarge was not connected with an elevation of their concentration. Thus, we suggest that in this case the proteins disintegration may be increased. Under hyperprolactinemia the concentration of all proteins, besides nonhistone proteins, was declined that reflected the enhancement their catabolism.


Optical-force-induced artifacts in scanning probe microscopy.
In the practice of near-field scanning probe microscopy, it is typically assumed that the distance regulation is independent of the optical signal. However, we demonstrate that these two signals are entangled due to the inherent action of optically induced force. This coupling leads to artifacts in both estimating the magnitude of optical fields and recording topographic maps.


Methacrylated Cellulose Nanocrystals as Fillers for the Development of Photo-Cross-Linkable Cytocompatible Biosourced Formulations Targeting 3D Printing.
Cellulose nanocrystals (CNCs) from cotton were functionalized in aqueous medium using methacrylic anhydride (MA) to produce methacrylated cellulose nanocrystals (mCNCs) with a degree of methacrylation (DM) up to 12.6 ± 0.50%. Dispersible as-prepared CNCs and mCNCs were then considered as reinforcing fillers for aqueous 3D-printable formulations based on methacrylated carboxymethylcellulose (mCMC). The rheological properties of such photo-cross-linkable aqueous formulations containing nonmodified CNCs or mCNCs at 0.2 or 0.5 wt% in 2 wt% mCMC were fully investigated. The influence of the presence of nanoparticles on the UV-curing kinetics and dimensions of the photo-cross-linked hydrogels was probed and 13C CP-MAS NMR spectroscopy was used to determine the maximum conversion ratio of methacrylates as well as the optimized time required for UV postcuring. The viscoelasticity of cross-linked hydrogels and swollen hydrogels was also studied. The addition of 0.5 wt% mCNC with a DM of 0.83 ± 0.040% to the formulation yielded faster cross-linking kinetics, better resolution, more robust cross-linked hydrogels, and more stable swollen hydrogels than pure mCMC materials. Additionally, the produced cryogels showed no cytotoxicity toward L929 fibroblasts. This biobased formulation could thus be considered for the 3D printing of hydrogels dedicated to biomedical purposes using vat polymerization techniques, such as stereolithography or digital light processing.


Effect of evacuation and displacement on the association between flooding and mental health outcomes: a cross-sectional analysis of UK survey data.
Extensive flooding occurred during the winter of 2013-14 in England. Previous studies have shown that flooding affects mental health. Using data from the 2013-14 Public Health England National Study of Flooding and Health, we compared the prevalence of symptoms of depression, anxiety, and post-traumatic stress disorder between participants displaced by flooding and those flooded, but not displaced, 1 year after flooding. In this multivariable ordinal regression analysis, we collected data from a cross-sectional survey collected 1 year after the flooding event from flood-affected postcodes in five counties in England. The analysis was restricted to individuals whose homes were flooded (n=622) to analyse displacement due to flooding. The primary outcome measures were depression (measured by the PHQ-2 depression scale) and anxiety (measured by the two-item Generalised Anxiety Disorder [GAD]-2 anxiety scale), and post-traumatic stress disorder (measured by the Post-Traumatic Stress Disorder Checklist [PCL]-6 scale). We adjusted analyses for recorded potential confounders. We also analysed duration of displacement and amount of warning received. People who were displaced from their homes were significantly more likely to have higher scores on each scale; odds ratio (OR) for depression 1·95 (95% CI 1·30-2·93), for anxiety 1·66 (1·12-2·46), and for post-traumatic stress disorder 1·70 (1·17-2·48) than people who were not displaced. The increased risk of depression was significant even after adjustment for severity of flooding. Scores for depression and post-traumatic stress disorder were higher in people who were displaced and reported receiving no warning than those who had received a warning more than 12 h in advance of flooding (p=0·04 for depression, p=0·01 for post-traumatic stress disorder), although the difference in anxiety scores was not significant. Displacement after flooding was associated with higher reported symptoms of depression, anxiety, and post-traumatic stress disorder 1 year after flooding. The amount of warning received showed evidence of being protective against symptoms of the three mental illnesses studied, and the severity of flooding might be the reason for some, but not all, of the differences between the groups. National Institute for Health Research Health Protection Research Units (HPRU) in Emergency Preparedness and Response at King's College London, Environmental Change and Health at the London School of Hygiene and Tropical Medicine, and Evaluation of Interventions at the University of Bristol, Public Health England.


Parafunctional masseter muscle activity during waking is related to periodontitis progression: A pilot prospective cohort study.
The purpose of this pilot prospective cohort study was to investigate the effects of parafunctional masseter muscle activity on periodontitis progression among patients receiving supporting periodontal therapy (SPT). We collected data of patients treated at Okayama University Hospital from August 2014 to September 2018. The progression group was defined as patients with ≥2 teeth demonstrating a longitudinal loss of proximal attachment of ≥3 mm during the 3-year study period and/or at least one tooth extraction due to periodontitis progression. Surface electromyography of masseter muscles at baseline was continuously recorded while patients were awake and asleep. We analysed 48 patients (36 females) aged 66.8 ± 9.1 years (mean ± SD). The rate of parafunctional masseter muscle activity during waking hours and sleeping hours at baseline was 60.4% and 52.1%, respectively. Cox's proportional hazards regression model showed that the incidence of periodontitis progression was significantly associated with number of teeth present (p = 0.001) and parafunctional masseter muscle activity during waking hours (p = 0.041). Our results suggest that parafunctional masseter muscle activity during waking hours is a risk factor for periodontitis progression among patients receiving SPT.


The role of the reticuloendothelial system in mouse anaphylaxis as tested with homologous antibody-antigen complexes.
Blockade of the RES was accomplished by the intravenous injection of carbon particles, thorotrast, zymosan, or a suspension of Bordetella pertussis. The blockade resulted in a decrease in sensitivity to anaphylaxis produced by the intravenous injection of soluble antigen-antibody complexes consisting of an optimal shocking mixture of bovine plasma albumin and mouse antibody to this antigen. The decrease in sensitivity to anaphylaxis was dependent on the dose of blockading agent and on the time between blockade and challenge with complex. The loss of sensitivity to anaphylaxis could not be restored by the administration of fresh serum from normal mice nor by guinea pig complement. Antigen-antibody complexes were rapidly removed from the blood with an average half-time of 11.9 minutes in normal mice. Complexes were cleared at significantly more rapid rates in mice previously sensitized to antigen. Although not all the results can be explained on the basis of blockade the facts indicate that the RES does play an important but as yet undefined role in passive homologous anaphylaxis in the mouse.


[Neuronal death is basic problem of neurology and psychiatry].
The review deals with neuronal death in neurological and mental disorders. It considers two types of neuronal death in the central neuronal death: apoptosis and necrosis, as well as their mechanisms of development and regulation with the participation of apoptotic and antiapoptotic genes. At present, oxidative stress and excitotoxicity are considered to be the major mechanisms of cell death. Recent advances of molecular cell biology in the understanding the mechanisms responsible for neuronal death permit one to develop new therapeutical approaches in diseases of the central nervous system.


Perspectives on tissue adaptation related to allostatic load: Scoping review and integrative hypothesis with a focus on osteopathic palpation.
Osteopathic care may support an individual's adaptive capacity, including allostatic regulation and tissue changes in both health and disease. The palpatory findings which osteopaths claim are related to tissue changes may be linked to allostatic load. However, this putative link has not been formally investigated. We conducted a scoping review to critically appraise the relevant literature on the relationship between allostatic processes and tissue alterations. This review evaluates the use and relevance of palpatory findings in osteopathic care. We searched on PubMed, EMBASE, Cochrane library for research exploring the links between tissue adaptation, allostasis and osteopathic palpatory findings (OPF). Recent studies provide insights into the role of allostatic regulation on body systems' responses related to tissue alterations. These results provide new insights into the relevance of OPF to clinical practice. We build upon the findings of our review to propose a putative model for OPF in clinical practice. Although the clinical phenomena associated with OPF may be biologically plausible, it lacks the necessary underpinning research evidence. Arguably, the classical focus on the diagnosis of palpable tissue changes fails to integrate biological, social and neuropsychological aspects such as stress responses. Tissue alterations related to stress and allostatic load markers have been less studied. Tissue changes involved in the adaptive process may be useful to practitioners in the field of manual therapy, particularly in osteopathy. We propose that OPF are one of the multidimensional aspects that may inform osteopathic decision-making. However, they should be considered within a biopsychosocial perspective and taking into account concepts of allostatic load and regulation.


Anti-transglutaminase 6 Antibody Development in Children With Celiac Disease Correlates With Duration of Gluten Exposure.
Antibodies against transglutaminase 6 (anti-TG6) have been implicated in neurological manifestations in adult patients with genetic gluten intolerance, and it is unclear whether autoimmunity to TG6 develops following prolonged gluten exposure. We measured the anti-TG6 in children with celiac disease (CD) at the diagnosis time to establish a correlation between these autoantibodies and the duration of gluten exposure. We investigated a correlation between anti-TG6 and the presence of neurological disorders. Anti-TG6 (IgA/IgG) were measured by ELISA in sera of children with biopsy-proven CD and of children experiencing gastrointestinal disorders. CD patients positive for anti-TG6 were retested after 2 years of gluten-free diet (GFD). We analyzed the sera of 274 CD children and of 121 controls. Anti-TG6 were detected in 68/274 (25%) CD patients and in 19/121 (16%) controls, with significant difference between the 2 groups (P = 0.04). None of the CD patients and of the controls testing positive for anti-TG6 were experiencing neurological disorders. Eleven of 18 (61%) CD patients with other autoimmune diseases were positive for anti-TG6. In CD patients, a significant correlation between the gluten exposure before the CD diagnosis and anti-TG6 concentration was found (P = 0.006 for IgA; P < 0.0001 for IgG). After GFD anti-TG6 concentrations were significantly reduced (P < 0.001). No significant correlation was observed between anti-TG6 and anti-TG2 serum concentrations. Anti-TG6 are more prevalent in children with untreated CD in the absence of overt neurological disorders. The synthesis of the anti-TG6 is related to a longer exposure to gluten before the CD diagnosis, and the autoimmunity against TG6 is gluten dependent and disappeared during GFD.


A new mutation in the PDE6C gene in achromatopsia.
To report a case of achromatopsia with a new mutation in the PDE6C gene which has not been previously described. Case report. A single patient. A 35-year-old woman with poor vision and impaired color vision. Fundus examination of both eyes (OU) revealed small optic discs. Optical coherence tomography (OCT) showed photoreceptor segment defects and a disruption of the ellipsoid layer in the foveal region, with intact overlying outer limiting membrane and underlying RPE bands. The electroretinogram (ERG) showed scotopic responses: DA 0.01: normal amplitude, b-wave latency at upper limit of normal / slightly increased. DA 3 and DA 10: slightly increased b-wave latency, asymmetry in b amplitude, being lower in the left eye. Oscillatory potentials: no responses are obtained. Photopic responses: LA-3: greatly increased latencies, decreased amplitude. Subsequently, a case of incomplete achromatopsia was suspected. Therefore, a genetic study was carried out showing the homozygous presence of the undescribed pathogenic variant c.660_661del (p.Ser221Tyrfs * 15) in exon 3 of the PDE6C gene. Achromatopsia is an autosomal-recessive genetic disease characterized by decreased visual acuity, color blindness, photophobia, and nystagmus. Due to the variability of genetic mutations in achromatopsia, genetic characterization is mandatory in order to improve the efficiency in molecular diagnosis. This data may be useful in future therapeutic strategies. We present a previously undescribed mutation in the PDE6C gene in a patient with incomplete achromatopsia.


Development of Hospital MCI and Disaster Preparedness Assessment Tool for Thailand.
Hospital preparedness is a key component to mitigate the effects of mass casualty incidents (MCIs) and disasters. Improving hospital preparedness requires an assessment of the country's current health system capacity, readiness, and preparedness. Although a variety of assessment tools exist, none are entirely suitable for Thailand's healthcare system. To develop an assessment tool to evaluate hospital preparedness for MCI and disaster in Thailand. A cross-sectional study was conducted from 1 March 2015 to December 2016. The contents of the first drafted tool were prepared based on evidence from a systematic search of electronic databases published up to 31 December 2014. Key elements identification, extraction, and further organization were based on the World Health Organization health system framework. Validity was tested by experts and emergency management personnel in four domains using a 5-point scale evaluation form. The feasibility of using this assessment tool was carried out in 41 hospitals on a voluntary basis. The tool was considered valid if the item-objective congruence (IOC) index results were at least 0.6 and feasible for median values of at least 4. Seventy-six full texts and guidelines out of 5869 titles and abstracts from a systematic search were enrolled in the study. A constructive literature review was performed to develop a hospital assessment tool. The IOC index results of the assessment tool components were 1.0, 0.9, 0.7, and 1.0 in framework appropriateness, relevance of items, clearness, and usefulness, respectively. The median (interquartile range) values of framework appropriateness, relevance of items, clearness, and usefulness were 4.0 (4.0‒5.0), 4.3 (4.3‒4.5), 4.0 (4.0‒4.0), and 5.0 (4.0‒5.0), respectively. An assessment tool to evaluate hospital MCI and disaster preparedness based on the WHO health system framework was valid and feasible at the national level of Thailand.


Integrating Endocannabinoid Signaling and Cannabinoids into the Biology and Treatment of Posttraumatic Stress Disorder.
Exposure to stress is an undeniable, but in most cases surmountable, part of life. However, in certain individuals, exposure to severe or cumulative stressors can lead to an array of pathological conditions including posttraumatic stress disorder (PTSD), characterized by debilitating trauma-related intrusive thoughts, avoidance behaviors, hyperarousal, as well as depressed mood and anxiety. In the context of the rapidly changing political and legal landscape surrounding use of cannabis products in the USA, there has been a surge of public and research interest in the role of cannabinoids in the regulation of stress-related biological processes and in their potential therapeutic application for stress-related psychopathology. Here we review the current state of knowledge regarding the effects of cannabis and cannabinoids in PTSD and the preclinical and clinical literature on the effects of cannabinoids and endogenous cannabinoid signaling systems in the regulation of biological processes related to the pathogenesis of PTSD. Potential therapeutic implications of the reviewed literature are also discussed. Finally, we propose that a state of endocannabinoid deficiency could represent a stress susceptibility endophenotype predisposing to the development of trauma-related psychopathology and provide biologically plausible support for the self-medication hypotheses used to explain high rates of cannabis use in patients with trauma-related disorders.


Phosphorylation of 20S proteasome alpha subunit C8 (alpha7) stabilizes the 26S proteasome and plays a role in the regulation of proteasome complexes by gamma-interferon.
In animal cells there are several regulatory complexes which interact with 20S proteasomes and give rise to functionally distinct proteasome complexes. gamma-Interferon upregulates three immuno beta catalytic subunits of the 20S proteasome and the PA28 regulator, and decreases the level of 26S proteasomes. It also decreases the level of phosphorylation of two proteasome alpha subunits, C8 (alpha7) and C9 (alpha3). In the present study we have investigated the role of phosphorylation of C8 by protein kinase CK2 in the formation and stability of 26S proteasomes. An epitope-tagged C8 subunit expressed in mammalian cells was efficiently incorporated into both 20S proteasomes and 26S proteasomes. Investigation of mutants of C8 at the two known CK2 phosphorylation sites demonstrated that these are the two phosphorylation sites of C8 in animal cells. Although phosphorylation of C8 was not absolutely essential for the formation of 26S proteasomes, it did have a substantial effect on their stability. Also, when cells were treated with gamma-interferon, there was a marked decrease in phosphorylation of C8, a decrease in the level of 26S proteasomes, and an increase in immunoproteasomes and PA28 complexes. These results suggest that the down-regulation of 26S proteasomes after gamma-interferon treatment results from the destabilization that occurs after dephosphorylation of the C8 subunit.


Palliative and end-of-life care in South Dakota.
Geographical disparities play a significant role in palliative and end-of-life care access. This study assessed availability of palliative and end of life (hospice) care in South Dakota. Grounded in a conceptual model of advance care planning, this assessment explored whether South Dakota health care facilities had contact persons for palliative care, hospice services, and advance directives; health care providers with specialized training in palliative and hospice care; and a process for advance directives and advance care planning. Trained research assistants conducted a brief telephone survey. Of 668 health care eligible facilities, 455 completed the survey for a response rate of 68 percent (455 out of 668). Over one-half of facilities had no specific contact person for palliative care, hospice services and advance directives. Nursing homes reported the highest percentage of contacts for palliative care, hospice services and advance directives. Despite a lack of a specific contact person, nearly 75 percent of facilities reported having a process in place for addressing advance directives with patients; slightly over one-half (53 percent) reported having a process in place for advance care planning. Of participating facilities, 80 percent had no staff members with palliative care training, and 73 percent identified lack of staff members with end-of-life care training. Palliative care training was most commonly reported among hospice/home health facilities (45 percent). The results of this study demonstrate a clear need for a health care and allied health care workforce with specialized training in palliative and end-of-life care.


Speed of sound in normal and degenerated bovine articular cartilage.
The unknown and variable speed of sound may impair accuracy of the acoustic measurement of cartilage properties. In this study, relationships between the speed of sound and cartilage composition, mechanical properties and degenerative state were studied in bovine knee and ankle cartilage (n = 62). Further, the effect of speed variation on the determination of cartilage thickness and stiffness with ultrasound (US) indentation was numerically simulated. The speed of sound was significantly (n = 32, p < 0.05) dependent on the cartilage water content (r = -0.800), uronic acid content (per wet weight, r = 0.886) and hydroxyproline content (per wet weight, r = 0.887, n = 28), Young's modulus at equilibrium (r = 0.740), dynamic modulus (r = 0.905), and degenerative state (i.e., Mankin score) (r = -0.727). In addition to cartilage composition, mechanical and acoustic properties varied significantly between different anatomical locations. In US indentation, cartilage is indented with a US transducer. Deformation and thickness of tissue are calculated using a predefined speed of sound and used in determination of dynamic modulus. Based on the simulations, use of the mean speed of sound of 1627 m/s (whole material) induced a maximum error of 7.8% on cartilage thickness and of 6.2% on cartilage dynamic modulus, as determined with the US indentation technique (indenter diameter 3 mm). We believe that these errors are acceptable in clinical US indentation measurements.