Weak evidence on nalmefene creates dilemmas for clinicians and poses questions for regulators and researchers.
Nalmefene has been approved in Europe for the treatment of alcohol dependence and subsequently recommended by the UK National Institute for Health and Care Excellence (NICE). This study examines critically the evidence base underpinning both decisions and the issues arising. Published studies of nalmefene were identified through a systematic search, with documents from the European Medicines Agency, the NICE appraisal and public clinical trial registries also examined to identify methodological issues. Efficacy data used to support the licensing of nalmefene suffer from risk of bias due to lack of specification of a priori outcome measures and sensitivity analyses, use of post-hoc sample refinement and the use of inappropriate comparators. Despite this, evidence for the efficacy of nalmefene in reducing alcohol consumption in those with alcohol dependence is, at best, modest, and of uncertain significance to individual patients. The relevance of existing trial data to routine primary care practice is doubtful. Problems with the registration, design, analysis and reporting of clinical trials of nalmefene did not prevent it being licensed and recommended for treating alcohol dependence. This creates dilemmas for primary care clinicians and commissioning organisations where nalmefene has been heavily promoted, and poses wider questions about the effectiveness of the medicines regulation system and how to develop the alcohol treatment evidence base.


Transdermal Photothermal Sterilization and Abscess Elimination Research of BSA-CuS Nanoparticles in vivo.
The treatment of subcutaneous abscess caused by drug-resistant bacteria is facing great difficulties and receiving more attention. In this work, we employed BSA-CuS nanoparticles as a photothermal reagent to apply photothermal therapy (PTT) to combat drug-resistant bacteria in vitro and subcutaneous abscess in vivo. The BSA-CuS nanoparticles were found to be stable and biocompatible without cytotoxicity toward NIH3T3 and 4T1 cells. In vitro experiments showed that three species of drug-resistant pathogens, including Escherichia coli, Staphylococcus aureus, and Candida albicans, could be effectively sterilized under co-incubation with BSA-CuS nanoparticles and then irradiation with 1064 nm NIR laser via tissue penetration. BSA-CuS nanoparticles together with 1064 nm NIR laser irradiation could also effectively diminish subcutaneous abscesses caused by drug-resistant bacteria on mice under PTT and depth PTT without causing any serious side effects and organic damage in vivo.That is OK, thank you!


Energetics: An emerging frontier in cellular mechanosensing: Reply to comments on "Cellular mechanosensing of the biophysical microenvironment: A review of mathematical models of biophysical regulation of cell responses".
How do cells can sense the substrate stiffness? Our recent review highlighted a range of theoretical models and simulations that have been proposed to answer this important question. In response to this review, three leading groups in the field noted some important omissions not only from our review itself but also from the field. These groups noted, correctly, that much of our understanding of cellular mechanosensing arises from models that take advantage of equilibrium thermodynamics, and that this is inappropriate because living cells are never in thermodynamic equilibrium. In this response, we highlight some promising research aimed at resolving this conundrum.


1-(2,3-Di-cyano-phen-yl)pyridin-1-ium-4-olate monohydrate.
In the crystal structure of the title compound, C13H7N3O·H2O, the components are associated into chains along [010] through strong O-H⋯O hydrogen bonds with the free water mol-ecules as bridging ligands. These chains are further cross-linked by C-H⋯O and C-H⋯N hydrogen bonds, forming a three-dimensional structure.


Antiproliferation effect of guanosine on HCT 116 cells involves MAPK and AMPK pathways.
This study aims to investigate the mechanisms associated with the antiproliferation effect of guanosine on human colon carcinoma HCT 116 cells. In this study, guanosine induced more drastic cell cycle arrest effect than cell death effect on HCT 116 cells. The cell cycle arrest effect of guanosine on HCT 116 cells appeared to be associated with the increased activation of mitogen-activated protein kinases (MAPK) such as ERK1/2, p38 and JNK. The decrease of AMP-activated protein kinase (AMPK) activation and cyclin D1 expression was also involved. Thus, the antiproliferation of colon cancer cells of guanosine could be mediated by the disruption of MAPK and AMPK pathways.


Evidence-based emergency medicine/skills for evidence-based emergency care. Interval likelihood ratios: another advantage for the evidence-based diagnostician.
Emergency physicians are often confronted with making diagnostic decisions on the basis of a test result represented on a continuous scale. When the results of continuous data are expressed as binary outcomes using a single cutoff, loss of information and distortion may occur. In this setting, interval likelihood ratios provide a distinct advantage in interpretation over those based on a dichotomized sensitivity and specificity. Dividing the data into intervals uses more of the information contained in the data and allows the clinician to more appropriately interpret the test results and to make valid clinical decisions. This article illustrates the advantages of interval likelihood ratios with examples and demonstrates how to calculate them on the basis of different data formats. Authors and journals need to be encouraged to report the results of studies of performance of diagnostic tests using interval ranges rather than simple dichotomization when the tests involve continuous variables.


Polysaccharide from edible alga Gloiopeltis furcata attenuates intestinal mucosal damage by therapeutically remodeling the interactions between gut microbiota and mucin O-glycans.
Gloiopeltis furcata is an edible alga that has long been consumed in China. However, the bioactive polysaccharides from G. furcata have been largely unexplored. Here, we show for the first time that a sulfated polysaccharide from G. furcata (SAO) could improve the integrity of the colonic epithelial layer and protect against dextran sulfate sodium-induced intestinal mucosal damage. Mechanistically, SAO attenuated colonic mucosal damage by therapeutically remodeling the interactions between gut microbiota and mucin O-glycans. Specifically, SAO increased the proportions of complex long-chain mucin O-glycans in the epithelial layer with two terminal N-acetylneuraminic acid residues and promoted the growth of probiotic bacteria including Roseburia spp. and Muribaculaceae. Altogether, our study demonstrates a novel application of SAO for the treatment of inflammatory bowel disease-associated mucosal damage and forms the basis to understand the therapeutic effects of natural polysaccharides from the perspective of symbiotic interactions between host mucin O-glycome and gut microbiome.


Molecular and Direct Detection Tests for Treponema pallidum Subspecies pallidum: A Review of the Literature, 1964-2017.
Direct detection methods for Treponema pallidum include dark-field microscopy (DFM), direct fluorescence antibody (DFA) testing, immunohistochemistry (IHC), and nucleic acid amplification tests (NAATs). Here, we reviewed the relevant syphilis diagnostic literature to address 2 main questions with respect to T. pallidum direct detection techniques: "What are the performance characteristics for each direct detection test for T. pallidum and what are the optimal specimen types for each test?" and "What options are available for T. pallidum molecular epidemiology?" To answer these questions, we searched 5 electronic databases (OVID Medline, OVID Embase, CINAHL, Cochrane Library, and Scopus) from 1964 to 2017 using relevant search terms and identified 1928 articles, of which 37 met our inclusion criteria. DFM and DFA sensitivities ranged from 73% to 100% in cases of primary syphilis; and while sensitivity using silver stain histopathology for T. pallidum was generally low (0%-41%), higher performance characteristics were observed for T. pallidum-specific IHC (49-92%). Different genes have been targeted by T. pallidum-specific NAATs, with the majority of studies indicating that sensitivity is primarily dependent on the type of collected biological sample, with highest sensitivity observed in primary lesion exudate (75-95%). Given the rising incidence of syphilis, the development of direct, Food and Drug Administration-cleared T. pallidum NAATs should be considered an immediate priority.


Pharmacogenetics and healthcare outcomes in patients with chronic heart failure.
To test for associations between genetic polymorphisms of adrenergic receptors (AR) and other candidate genes and healthcare utilization in heart failure patients, taking into account other important factors, such as medication adherence. One year-hospital utilization data were collected from 140 participants with heart failure, aged 50 years or older. Medication adherence was measured. Hospitalization and emergency department (ED) visits due to heart failure were used as healthcare outcomes. The genotypes of polymorphisms in six genes were determined: α(2C)-AR (ADRA2C), β₁-AR (ADRB1), β₂-AR (ADRB2), endothelial nitric oxide synthase (eNOS), angiotensin converting enzyme (ACE), and CYP4A11. Haplotypes for ADRB1 and ADRB2 were estimated. The genotype effects on healthcare outcomes were examined using log-linear regression models. Compared to ADRB1 Arg389 carriers, homozygous Gly389Gly carriers experienced fewer ED visits [incidence rate ratio (IRR) 0.07, 95 % confidence interval (CI) 0.01-0.54, P = 0.022]. Compared to ADRB2 homozygous Gly16Gly carriers, Arg16Gly carriers had fewer ED visits (IRR 0.23, 95 % CI 0.09-0.59, P = 0.006). Polymorphisms in ADRB1 as well as those in ADRB2 were in linkage disequilibrium, with three defining haplotypes, respectively. For ADRB2, the risk of hospitalizations and ED visits were relatively lower in Arg16/Gln27 carriers but relatively higher in homozygous Gly16/Gln27 carriers (P < 0.05). Compared to eNOS 894TT homozygous variants, 894GG and 894GT carriers had notably fewer ED visits (IRR 0.05, 95 % CI 0.01-0.25, P = 0.0013 and IRR 0.10, 95 % CI 0.02-0.42, P = 0.006, respectively). The other polymorphisms showed no association with healthcare outcomes. After controlling for demographics, functional status, and treatment adherence, polymorphisms in ADRB1, ADRB2 and eNOS are associated with healthcare outcomes in heart failure patients.


Combined targeting of EGFR and BRAF triggers regression of osimertinib resistance by using osimertinib and vemurafenib concurrently in a patient with heterogeneity between different lesions.
Acquired BRAF V600E mutation can occur in tumors with EGFR mutation and is suspected as a resistance mechanism to third-generation EGFR-tyrosine kinase inhibitors (TKIs). However, the treatment strategy for the coexistence of EGFR and acquired BRAF mutation with heterogeneity in lung cancer has not been systematically established. Here, we report a patient in whom BRAF V600E and EGFR 19del mutation in a metastatic lesion followed by disease progression on osimertinib was detected. Treatment with single-agent vemurafenib was effective for treatment of the metastatic lesion in this patient but the primary lesion progressed. A concurrent combination of vemurafenib and osimertinib was therefore administered and a partial response of both primary and metastatic lesions was achieved with progression-free survival (PFS) of 7 months. The concurrent combination treatment was well tolerated by the patient through dosing modification and supportive medical care. This case highlights the consideration of heterogeneity between different lesions and provides a successful example of the concurrent therapy with vemurafenib and osimertinib for triggering regression of osimertinb resistance induced by BRAF mutation.


Pace yourself: Neural activation and connectivity changes over time vary by task type and pacing.
Performance deterioration over time, or time-on-task (TOT) effects, can be observed across a variety of tasks, but little attention has been paid to how TOT-related brain activity may differ based on task pacing and cognitive demands. Here, we employ a set of three closely related tasks to investigate the effect of these variables on fMRI activation and connectivity. When participants dictated the pace of their own responses, activation and network connectivity within the dorsal attention network (DAN) increased over short time scales (~2-3 min), a phenomenon that was not observed when participants had no control over their pace of work. Reaction time slowing was also the most pronounced in this self-paced task. In contrast, TOT-related changes in default-mode network (DMN) activity and connectivity, DAN-DMN anti-correlations, and pupil diameter did not differ based on pacing or task instructions. Over a longer (~10 min) time scale, task-positive activation and connectivity decreased in all paradigms, in agreement with older findings. These results highlight dynamic patterns of resource allocation that have not previously been observed in fMRI experiments, and speak to the idea that the brain may strategically allocate resources depending on the task at hand and the time scale of work.


'Atrophic telogen effluvium' from cytotoxic drugs and a randomized controlled trial to investigate the possible protective effect of pretreatment with a topical vitamin D analogue in humans.
Hair loss from cytotoxic drugs is classically ascribed to the loss of fractured hairs (anagen effluvium). Telogen hair loss has also been described but some authors have denied any effect on the hair cycle. There are conflicting reports on a protective effect of pretreatment with a vitamin D analogue on cytotoxic drug-induced hair loss in rodents. To investigate the process of cytotoxic hair loss and any protective effect on the hair of pretreatment with topical calcipotriol. Breast cancer patients who were about to receive cycles of chemotherapy with cyclophosphamide 600 mg m(-2), methotrexate 40 mg m(-2) and 5-fluorouracil 600 mg m(-2) were recruited and randomized to receive calcipotriol scalp solution 50 microg mL(-1) or vehicle. The solution was applied twice daily from 4 days prior to chemotherapy and continued for 14 days in each treatment cycle. Shed, plucked and cut hairs were sampled. Absolute shed rates, the proportion of major hair types, the presence of proximal hair shaft changes, regrowth (using the new anagen hair count) and hair density were assessed. Ten patients receiving calcipotriol and 14 receiving vehicle completed three treatment cycles and nine from both groups completed six cycles. There was no detectable effect of calcipotriol on the proportion of patients experiencing minimal hair loss from chemotherapy, shed rates, plucked telogen and fractured hair counts, the morphology of shed and plucked hair, hair regrowth or hair density. Combining results of the treatment groups, there was a large variation in the impact of chemotherapy on hair loss, from total loss in five patients to no obvious loss in five. Excluding the latter, during chemotherapy shed telogen hairs (mean 81% of shed hairs) predominated over fractured (12%) and anagen hairs (6%) (P = 0.0002). The major pathological change was proximal hair shaft tapering, baseline mean 3% of shed hairs rising to 48% (P = 0.0005) during treatment, and there was a consequent decrease in normal telogen hairs, baseline mean 98% of all telogen hairs falling to 55% (P = 0.0005) during treatment. The pathological tapered telogen hairs had normal or small, sometimes diminutive, bulbs. Fracturing of hairs with diminutive bulbs produced typical 'exclamation mark' hairs. The cardinal effects of cytotoxic drugs found in this study were tapering of the proximal hair shaft and premature entry of the follicle into telogen, conflicting with the conventional view that affected hair follicles continue in anagen. There was a resulting effluvium of a mixture of tapering telogen hairs and fractured hairs. As entry into telogen is an integral part of the process, cytotoxic hair loss may be regarded as a variant of the conventional 'telogen effluvium' and we propose the term 'atrophic telogen effluvium'. There was no obvious protective effect on the hair loss of prior treatment with topical calcipotriol.


Relationship between CO2 drive and characteristics of apneas in obstructive and central sleep apnea.
Previously we showed that CO2 drive is increased in patients with obstructive sleep apnea (OSA). In the present study we would like to evaluate a possible relationship between CO2 drive and characteristics of apneas in obstructive and central sleep apnea (CSA). We compared the hypercapnic ventilatory response (HCVR) between patients with OSA and CSA. HCVR was correlated with total event time and mean event duration in both groups. 17 normocapnic patients in each group and 14 controls were studied. The apnea patients were matched for apnea-hypopnea index, age, sex, and BMI. SHCVR (slope) tended to be higher in apnea patients than in controls without statistical significancy: controls 1.65 (0.16), CSA 2.17 (0.22), OSA 2.55 (0.35) (l/min per mmHg) (P = 0.13). A significant correlation was found between HCVR and event time in CSA (0.52, P = 0.04) and between HCVR and apnea mean duration in OSA (r = 0.52, P = 0.04). We conclude that while CO2 drive was not statistically increased in both apnea types, small changes can contribute to breathing instability and may increase the total event time (in CSA) but may also shorten the apnea duration (in OSA).


Salvage high-dose-rate (HDR) brachytherapy for recurrent head-and-neck cancer.
A significant portion of head-and-neck cancer patients will develop persistent or recurrent disease after definitive treatment. Radiation therapy is often used as definitive therapy or as an adjunct to surgery. Recurrent cancer of the head and neck in the previously irradiated field is, thus, a common occurrence and poses a therapeutic challenge. Some studies have evaluated low-dose-rate (LDR) brachytherapy as a therapeutic option, including a large case series with long-term follow-up by our own institution. High-dose-rate (HDR) brachytherapy offers therapeutic advantages over LDR brachytherapy. This study evaluates the local control and outcomes of patients with previously irradiated recurrent head-and-neck cancer treated with HDR interstitial brachytherapy. Between 1997 and 2002, 30 patients who received prior radiation therapy for primary tumors of the head and neck were treated for biopsy-proven recurrent disease. All patients received previous radiation as definitive therapy alone or as adjunct to surgery. All patients were inoperable, refused surgery, or had gross residual disease after salvage surgery for their recurrent disease. Thirty-six sites on the 30 patients were implanted by application of high-dose-rate interstitial brachytherapy techniques with mean tumor dose of 34 Gy (18-48 Gy) in twice daily fractions of 300 to 400 cGy per fraction. At a minimum follow-up of 12 months, local tumor control was achieved in 69% of implanted sites. Disease-specific survival at 1 and 2 years was 54% and 45%, respectively. Overall survival at 1 and 2 years was 56% and 37%, respectively. Grade 3/4 late complications occurred in 16% of the patients. No fatal complications occurred. HDR brachytherapy can play an important role in the salvage treatment of previously irradiated recurrent head-and-neck cancer. This study shows that comparable results are obtained by HDR brachytherapy with fewer late complications than were indicated by previously reported data for LDR brachytherapy.


[Eating disorders in males: a representative survey].
The present study examined the prevalence of eating disorders in a male representative random sample in Tyrol. The data were collected by telephone. Of the 1000 men, 8 (0.8%) met the DSM-IV diagnostic criteria for binge eating disorder. An additional 42 subjects (4.2%) exhibited a partial binge eating syndrome. These two otherwise widely identical groups of binge eaters were separated only by the DSM-IV frequency criterion. Five subjects (0.5%) met the DSM-IV criteria for the diagnosis of bulimia nervosa, and 94 men (9.4%) reported recurrent overeating. Men with any eating disorder were mostly overweight or obese. The findings show that there is a significant difference in eating disorders between men and women, but certain eating disorders are frequent not only in women but also in men.


Infantile hemangiomas: an emerging health issue linked to an increased rate of low birth weight infants.
A total of 420 children with infantile hemangioma (IH) were compared with 353 age-matched controls. Using multivariate logistic regression, low birth weight was the most significant risk factor; for every 500-g decrease in birth weight, the risk of IH increased by 40%. A positive family history also increased the risk of IH (33% vs 15% of controls; P < .001).


Supramolecular Control of the Oxidative Addition as a Way To Improve the Catalytic Efficiency of Pincer-Rhodium (I) Complexes.
1 H NMR studies using a cationic complex with a pyridine-di-imidazolylidene pincer ligand of formula [Rh(CNC)(CO)]+ revealed that this compound showed high binding affinity with coronene in CH2 Cl2 . The interaction between coronene and the planar RhI complex is established by means of π-stacking interactions. This interaction has a strong impact on the electron-donating strength of the pincer CNC ligand, which is increased significantly, as demonstrated by the shifting of the ν(CO) stretching bands to lower frequencies. The addition of coronene increases the reaction rate of the nucleophilic attack of methyl iodide on the rhodium (I) pincer complex, and also has a positive effect on the performance of the complex as a catalyst in the cycloisomerization of 4-pentynoic acid. These findings highlight the importance of supramolecular interactions for tuning the reactivity and catalytic activity of square-planar metal complexes.


Immunomodulatory effects of blood transfusions: the synergic role of soluble HLA Class I free heavy-chain molecules detectable in blood components.
Over the past decades, the weight of the published literature demonstrates that blood transfusions can induce clinically significant immunosuppression in recipients. Several studies showed significant improved clinical outcomes in the patients receiving leukoreduced transfusions, compared with control patients who received nonleukoreduced transfusions. Moreover, the immunosuppressive potential of blood products grows with the time of their storage and becomes highest in nonleukoreduced blood products stored for a long time. The interest was previously focused on the determination of immunomodulatory soluble molecules such as soluble HLA Class I (sHLA-I) and soluble Fas ligand (sFasL) in different blood components and on the evaluation of their immunomodulatory activities. On this basis, whether soluble beta2-microglobulin free HLA Class I heavy chains (sHLA-beta2fHC) could be detected and immunochemically characterized in different blood components was evaluated. Immunomodulatory activity of detectable sHLA-beta2fHC molecules was evaluated by apoptosis inducing capacity in interleukin-2-activated antigen-specific cytotoxic T lymphocytes (CTL). Double-determinant immunoenzymatic assay indicates that sHLA-beta2fHC levels in red blood cells stored for up to 30 days and in random-donor platelets are significantly (p < 0.001) higher than in other blood components, and the immunochemical characterization suggests that the major source of sHLA-beta2fHC molecules might be the residual white cells that undergo membrane damage during storage. Finally, allogeneic CD8+ CTL apoptosis induction confirmed biofunctionality of sHLA-beta2fHC molecules. These data are comparable with those previously reported dealing with contaminant soluble molecules in allogeneic and autologous blood components, suggesting that sHLA-beta2fHC molecules could contribute to the immunosuppressive effects of blood transfusions.


Trauma-informed yoga training in Kenya: A qualitative pilot study on feasibility and acceptability.
The current study presents a pilot qualitative exploration of the collaboration of two yoga service agencies in implementing a trauma-informed mindfulness-based teaching curriculum in Kenya, Africa. Yoga and mindfulness practices have been demonstrated as successful complementary and alternative approaches to managing the impacts of stress trauma. This study explores the feasibility and acceptability of mindfulness programming for yoga teachers in the Nairobi region of Kenya. Grounded theory is used to explore survey results. Outcomes demonstrate promise for both acceptability and feasibility. Curriculum tools were viewed as effective, and participants indicated intention to both utilize and share tools. Reflections on program effectiveness and impacts are addressed, as are potential considerations for improved program translation. Findings suggest the potential benefit for future collaborations, and also suggest best practices considerations for global implementation of embodied mindfulness programming.


Monkey rotavirus binding to alpha2beta1 integrin requires the alpha2 I domain and is facilitated by the homologous beta1 subunit.
Rotaviruses utilize integrins during virus-cell interactions that lead to infection. Cell binding and infection by simian rotavirus SA11 were inhibited by antibodies (Abs) to the inserted (I) domain of the alpha2 integrin subunit. To determine directly which integrins or other proteins bind rotaviruses, cell surface proteins precipitated by rotaviruses were compared with those precipitated by anti-alpha2beta1 Abs. Two proteins precipitated by SA11 and rhesus rotavirus RRV from MA104 and Caco-2 cells migrated indistinguishably from alpha2beta1 integrin, and SA11 precipitated beta1 from alpha2beta1-transfected CHO cells. These viruses specifically precipitated two MA104 cell proteins only, but an additional 160- to 165-kDa protein was precipitated by SA11 from Caco-2 cells. The role of the alpha2 I domain in rotavirus binding, infection, and growth was examined using CHO cell lines expressing wild-type or mutated human alpha2 or alpha2beta1. Infectious SA11 and RRV, but not human rotavirus Wa, specifically bound CHO cell-expressed human alpha2beta1 and, to a lesser extent, human alpha2 combined with hamster beta1. Binding was inhibited by anti-alpha2 I domain monoclonal Abs (MAbs), but not by non-I domain MAbs to alpha2, and required the presence of the alpha2 I domain. Amino acid residues 151, 221, and 254 in the metal ion-dependent adhesion site of the alpha2 I domain that are necessary for type I collagen binding to alpha2beta1 were not essential for rotavirus binding. Rotavirus-alpha2beta1 binding led to increased virus infection and RRV growth. SA11 and RRV require the alpha2 I domain for binding to alpha2beta1, and their binding to this integrin is distinguishable from that of collagen.


Randomized controlled trial of a repeat mammography intervention: effect of adherence definitions on results.
As overall mammography rates approach national goals, mammography promotion efforts must increasingly focus on repeat adherence. This randomized controlled trial examined the effect of two interventions on repeat mammography utilization using various adherence definitions. 1,558 women aged 40-63 receiving a mammogram through a federally funded screening program were randomized to three groups: mailed reminder (minimum group); mailed thank you card, newsletters, and reminder (maximum group); no mailings (control). The primary outcome (repeat mammogram) was assessed 13, 15, 18, and 24 months after the qualifying mammogram using administrative data. The proportions receiving a repeat mammogram within 13 months were 0.28, 0.30, and 0.32 for control, minimum, and maximum groups, respectively. The corresponding proportions were 0.38, 0.43, and 0.45 at 15 months; 0.43, 0.49, and 0.51 at 18 months; and 0.47, 0.52, and 0.54 at 24 months. There were no significant differences across study groups at 13 months. The differences between control and maximum subjects at 15, 18, and 24 months were statistically significant. The differences between control and minimum subjects were significant only at 18 months. The two low-cost mailed interventions evaluated modestly increased repeat mammography utilization. However, effects were not visible until at least 15 months after the qualifying mammogram.


Alu-related transcript of TJP2 gene as a marker for colorectal cancer.
Identifying diagnostic markers is very important in cancer biology. Transposable elements (TEs) account for 45% of the human genome and are usually silent in normal tissues. Contrary to this, in cancer tissues, TEs have been found to be expressed specifically with genomic instability. Here, we investigated the transcripts related to TEs using bioinformatic tools and RT-PCR analysis in tumor and adjacent normal tissues as well as in cancer cell lines. From this analysis, we identified the Alu-related transcript of TJP2 gene (TJP2-Alu transcript) that was differentially expressed between tumor and normal tissues. Its expression was higher in colon cancer cell lines and tumor tissues of colorectal cancer patients. These results could contribute to a better understanding of the involvement of TEs in human colorectal cancer, and to evaluating their potential as diagnostic markers for colorectal cancer.


Linear trends and seasonality of births and perinatal outcomes in Upper East Region, Ghana from 2010 to 2014.
Seasonal variations greatly influence birth patterns differently from country to country. In Ghana, there is paucity of information on birth seasonal patterns. This retrospective study described the trends and seasonality of births and perinatal outcomes in Upper East Region of Ghana. Births occurring in each month of the calendar years (2010-2014; inclusive) were extracted from the District Health Information Management System (DHIMS2) database of the Bolgatanga Municipal Health Directorate and exported into Microsoft Excel spread sheet and Epi Ifo for analysis. Analysis was carried out by calculating average number of births per month correcting for unequal month length using 30 days. A Chi-square test for trend was performed to check for statistical significance (p < 0.05) in trends and seasonality of birth and perinatal outcomes. There were 24,171 health facility deliveries, of which 97.7% were singleton deliveries and 2.3% were multiple (two or three) deliveries. There was a consistent rise in the annual health facility deliveries controlled for the number of fertile women, from 4169 in 2010 to 5474 in 2014 (p < 0.0001). Monthly birth distribution displayed a periodic pattern with peaks in May, September and October and troughs during the months of January, February and July (p < 0.0001). Women were likely to give birth during the raining season than the dry season. Caesarean Section (CS) rate showed a steady rise over the years (124 per 1000 births in 2010 to 185 per 1000 births in 2014 (p < 0.0001) with overall rate of 14.6%. Stillbirth (SB) rate, however decreased slightly over the years from 29 per 1000 births to 23 per 1000 births (p = 0.197) with overall SB rate of 2.6%. Similarly, Low Birth Weight (LBW) declined from 77 per 1000 live births to 71 per 1000 live births from 2010 to 2014 (p < 0.0001). Seasonal (rainy and dry) distributions did not show a clear difference in birth frequencies. Health facility delivery was persistently high in the Bolgatanga Municipality with birth peaking in May, September and October. Despite the rising rate of caesarean section, stillbirth rate did not significantly improved over the years. A prospective study may reveal the reasons for the increasing caesarean section rate. Additionally, understanding the factors that affect the decreasing trends of low birth weight in the municipality is crucial to public health policy makers in Ghana.


Immunoproteomic analyses of outer membrane antigens of Actinobacillus pleuropneumoniae grown under iron-restricted conditions.
Actinobacillus pleuropneumoniae, a bacterial pathogen of swine and agent of porcine pneumonia, causes a highly infectious disease of economic importance in the pig industry. Commercial vaccines for A. pleuropneumoniae include whole-cell bacterins and second generation subunit vaccines but they only confer partial protective immunity. Our search for new vaccine candidates identified antigens that are expressed during conditions that mimic infection; the outer membrane (OM) proteome of A. pleuropneumoniae serotype 5b was examined under iron restriction. Quantitative profiling by 2D-DiGE technology revealed that iron restriction induced expression of previously described transferrin binding proteins (TbpA, TbpB) plus four lipoproteins including spermidine/putrescine binding periplasmic protein 1 precursor (PotD2). Immunoproteomic analyses with antisera from naïve animals and from infected pigs were able to differentiate antigens within the OM proteome that were specifically recognized during A. pleuropneumoniae infection. Immunoblots of iron-restricted profiles detected PotD2, heme-binding protein A (HbpA), and capsule polysaccharide export protein (CpxD) as well as surface antigens TbpA, TbpB, and OmlA. These data identify OM proteins that demonstrate immunogenicity and upregulation under conditions mimicking infection, providing emphasis on lipoproteins as an important class of antigens to exploit for vaccine development for A. pleuropneumoniae.


Molecular characterization of β-thalassemia intermedia in the West Bank, Palestine.
We aimed to investigate the molecular basis of β-Thalassemia intermedia (TI) in the West Bank region and its management practices. This was a case series multi-center study and included 51 cases of TI. DNA sequencing was used to analyze β-globin gene mutations. Common α-globin gene mutations were screened by Gap-PCR (-α3.7, -α4.2, --MED, αααanti3.7) or DNA sequencing (α2-IVS II 5 nt del). XmnI -158 C > T polymorphisms of Gγ-globin gene was determined by RFLP-PCR. Seven β-globin gene mutations were observed, namely IVS-I -6 C > T, IVS-I-110 G > A, IVS-II-1 G > A, IVS-I-1 G > A, Codon 37 Trp > Stop, beta - 101 and IVS-II-848 C > A. Ten genotypes were observed. Homozygosity for IVS-I-6 accounted for the majority of TI cases with a frequency of 74.5%. The second common β-globin gene genotype was homozygote IVS-I-110 G > A (5.8%) and homozygote IVS-II-1 G > A (5.8%). The remaining seven genotypes were each detected in about 2% of patients. α-Thalassemia mutations were seen in five patients (9.8%), and included (-α3.7, αααanti3.7 and α2-IVSII-5 nt del). XmnI polymorphism was observed in four patients (7.8%), three homozygotes and one heterozygote. Homozygosity for the mild β-globin gene IVS-I-6 allele was the major contributing factor for the TI phenotype among the study subjects. The role of XmnI SNP and α-thalassemia mutations in ameliorating the TI phenotype was observed in few patients for each factor. The beta - 101 C > T mutation was diagnosed in one patient in homozygote state for the first time in Palestine.


The evaluation of fabrics in relation to their use as protective garments in nursing and surgery. I. Physical measurements and bench tests.
Eleven fabrics selected to provide a representative range of yarns and weaves have been examined microscopically and subjected to a series of tests. The observations were directed towards assessing the potential ability of each fabric to resist penetration by particles, such as skin scales, which might carry micro-organisms. The number, size and shape of pores penetrating through the material were estimated and the penetration of test dusts assessed in several ways. While, generally, the relative merits of the fabrics are similar whatever test or measurement is considered there are a number of significant exceptions which reflect peculiarities of the test system or of a fabric. Comparison with the results of dispersal experiments with volunteers wearing garments made of the fabrics is made in a following paper.


Biologic rhythm disorders, depression, and phototherapy. A new hypothesis.
Disturbances of the circadian timing system are implicated in the pathogenesis of numerous clinical syndromes, including sleep and affective disorders. Abnormalities of circadian rhythms can now be directly measured in the clinical laboratory and potentially corrected. Sleep scheduling disorders are most commonly due to phase misalignments between the endogenous circadian pacemaker and the socioenvironmental schedule. Current research is increasing our understanding of the influence of bright light exposure on the circadian timing system and has begun to be used successfully in the management of these conditions. There is substantial evidence that abnormalities of the circadian timing system are associated with depression. However, the application of new biologic rhythm diagnostic techniques would be required to establish whether circadian dysfunction is involved in the pathogenesis of these conditions. We propose a new hypothesis that phototherapy for seasonal depression may act by increasing an abnormally low circadian amplitude in those patients, such as that reported in endogenously depressed patients. The powerful effect of light on the circadian system indicates that phototherapy may become an important tool in the management of disorders of circadian etiology.


Gas regulation of complex II reversal via electron shunting to fumarate in the mammalian ETC.
The electron transport chain (ETC) is a major currency converter that exchanges the chemical energy of fuel oxidation to proton motive force and, subsequently, ATP generation, using O2 as a terminal electron acceptor. Discussed herein, two new studies reveal that the mammalian ETC is forked. Hypoxia or H2S exposure promotes the use of fumarate as an alternate terminal electron acceptor. The fumarate/succinate and CoQH2/CoQ redox couples are nearly iso-potential, revealing that complex II is poised for facile reverse electron transfer, which is sensitive to CoQH2 and fumarate concentrations. The gas regulators, H2S and •NO, modulate O2 affinity and/or inhibit the electron transfer rate at complex IV. Their induction under hypoxia suggests a mechanism for how traffic at the ETC fork can be regulated.


Aging-related changes in neuroimmune-endocrine function: implications for hippocampal-dependent cognition.
Healthy aged individuals are more likely to suffer profound memory impairments following a challenging life event such as a severe bacterial infection, surgery, or an intense psychological stressor, than are younger adults. Importantly, these peripheral challenges are capable of producing a neuroinflammatory response, (e.g., increased pro-inflammatory cytokines). In this review we will present the literature demonstrating that in the healthy aged brain this response is exaggerated and prolonged. Normal aging primes or sensitizes microglia and this appears to be the source of this amplified response. We will review the growing literature suggesting that a dysregulated neuroendocrine response in the aged organism is skewed toward higher brain CORT levels, and that this may play a critical role in priming microglia. Among the outcomes of an exaggerated neuroinflammatory response are impairments in synaptic plasticity, and reductions in key downstream mediators such as Arc and BDNF. We will show that each of these mechanisms is important for long-term memory formation, and is compromised by elevated pro-inflammatory cytokines.


Endothelial extracellular vesicles promote tumour growth by tumour-associated macrophage reprogramming.
Tumour-derived extracellular vesicles (EVs) participate in tumour progression by deregulating various physiological processes including angiogenesis and inflammation. Here we report that EVs released by endothelial cells in a mammary tumour environment participate in the recruitment of macrophages within the tumour, leading to an immunomodulatory phenotype permissive for tumour growth. Using RNA-Seq approaches, we identified several microRNAs (miRNAs) found in endothelial EVs sharing common targets involved in the regulation of the immune system. To further study the impact of these miRNAs in a mouse tumour model, we focused on three miRNAs that are conserved between humans and mouse, that is, miR-142-5p, miR-183-5p and miR-222-3p. These miRNAs are released from endothelial cells in a tumour microenvironment and are transferred via EVs to macrophages. In mouse mammary tumour models, treatment with EVs enriched in these miRNAs leads to a polarization of macrophages toward an M2-like phenotype, which in turn promotes tumour growth.


Cancer Burden Variations and Convergences in Globalization: A Comparative Study on the Tracheal, Bronchus, and Lung (TBL) and Liver Cancer Burdens Among WHO Regions from 1990 to 2019.
Lung cancer and liver cancer are the leading and third causes of cancer death, respectively. Both lung and liver cancer are with clear major risk factors. A thorough understanding of their burdens in the context of globalization, especially the convergences and variations among WHO regions, is useful in precision cancer prevention worldwide and understanding the changing epidemiological trends with the expanding globalization. The Global Burden of Disease (GBD) and WHO Global Health Observatory (GHO) database were analyzed to evaluate the burden metrics and risk factors of trachea, bronchus, and lung (TBL) cancer and liver cancer. Western Pacific Region (WPR) had the highest age-standardized incidence rate (ASIR) for both liver cancer (11.02 [9.62-12.61] per 100,000 population) and TBL cancer (38.82 [33.63-44.04] per 100,000 population) in 2019. Disability-adjusted life years (DALYs) for liver and TBL cancer elevated with the increasing sociodemographic index (SDI) level, except for liver cancer in WPR and TBL cancer in European Region (EUR). Region of the Americas (AMR) showed the biggest upward trends of liver cancer age-standardized rates (ASRs), as well as the biggest downward trends of TBL cancer ASRs, followed by Eastern Mediterranean Region (EMR). Alcohol use and smoking were the leading cause of liver and TBL cancer death in most WHO regions. Variances of ASRs for liver and TBL cancer among WHO memberships have been decreasing during the past decade. The homogenization and convergence of cancer burdens were also demonstrated in different agegroups and sexes and in the evolution of associated risk factors and etiology. In conclusion, our study reflects the variations and convergences in the liver and lung cancer burdens among the WHO regions with the developing globalization, which suggests that we need to be acutely aware of the global homogeneity of the disease burden that accompanies increasing globalization, including the global convergences in various populations, risk factors, and burden metrics.


[The surgical innovation: From the legal framework through the veritable ethics innovation - Technical aspects and practical applications].
Grace to the creativity of surgeons and the introduction of new technologies, second half of the XXth century opened the era of innovations and decisive progress. At the same time, however, is born the feeling of distrust and claiming which has come with the graving and threatening juridiciarisation. The evolution of complex structures of our society joined the ingenuity researchers unlimited makes formal law and the legal framework constantly to adapt oneself to circumstances. In the field of surgery, it's necessary to make work in integrity the innovation and protection at the patient's and their dignity. The legal framework that governs today innovation in surgery must still to go further and will precise. Dignity, compelling paradigm for all those who seek to better understand and better protect human starred as impassable limit any search and any experimentation. To make this chapter more alive, we have supplemented it and illustrated by the testimony some of the most fruitful French last years innovative in order to enrich our thinking of the fruit of their large and brilliant experience.


The anterior nucleus of the thalamus plays a role in the epileptic network.
We investigated both the metabolic differences and interictal/ictal discharges of the anterior nucleus of the thalamus (ANT) in patients with epilepsy to clarify the relationship between the ANT and the epileptic network. Nineteen patients with drug-resistant epilepsy who underwent stereoelectroencephalography were studied. Metabolic differences in ANT were analyzed using [18F] fluorodeoxyglucose-positron emission tomography with three-dimensional (3D) visual and quantitative analyses. Interictal and ictal discharges in the ANT were analyzed using visual and time-frequency analyses. The relationship between interictal discharge and metabolic differences was analyzed. We found that patients with temporal lobe epilepsy (TLE) showed significant metabolic differences in bilateral ANT compared with extratemporal lobe epilepsy in 3D visual and quantitative analyses. Four types of interictal activities were recorded from the ANT: spike, high-frequency oscillation (HFO), slow-wave, and α-rhythmic activity. Spike and HFO waveforms were recorded mainly in patients with TLE. Two spike patterns were recorded: synchronous and independent. In 83.3% of patients, ANT was involved during seizures. Three seizure onset types of ANT were recorded: low-voltage fast activity, rhythmic spikes, and theta band discharge. The time interval of seizure onset between the seizure onset zone and ANT showed two patterns: immediate and delayed. ANT can receive either interictal discharges or ictal discharges which propagate from the epileptogenic zones. Independent epileptic discharges can also be recorded from the ANT in some patients. Metabolic anomalies and epileptic discharges in the ANT indicate that the ANT plays a role in the epileptic network in most patients with epilepsy, especially TLE.


Testing informative missingness in genetic studies using case-parent triads.
In genetic studies, the transmission/disequilibrium test (TDT) using case-parent triads has gained popularity attributable to its robustness to population admixture. Several extensions have been proposed to accommodate incomplete triads. Some strategies assume that parental genotypes are missing completely at random (MCAR) to insure an unbiased conclusion and some methods allow parental genotypes to be missing informatively, resulting in reduced power when the missing data pattern is indeed MCAR. However, these tests assumed that offspring genotypes were MCAR. Recently, Guo indicated that when offspring genotypes were missing informatively, an occurrence that can be considered as ascertainment bias, inflated type-I error and/or reduced power may occur using the TDT when incomplete triads are excluded. In an effort to avoid an erroneous conclusion, we propose a strategy called testing informative missingness (TIM) that compares conditional distributions of parental genotypes among complete triads and incomplete data with only one parent to examine the missing data pattern. Through computer simulations, TIM has decent power to detect informative missingness and is robust to population admixture. In addition, we illustrate TIM with an application to the Framingham Heart Study.


Teaching patients with life-threatening illnesses. Cardiovascular disease, transplantation, and organ donation.
Providing teaching for open heart and transplant patients and their families is an important and rewarding role for the professional nurse. Through patient teaching, the nurse provides the patient with information that facilitates informed consent, prepares the patient for pre- and postoperative experiences, hastens postoperative recovery, and eases the transition from hospital to home.


The impalpable Implanon: a case report.
This is a case report of an Implanon contraceptive device that was impalpable after insertion and a discussion of the management of the impalpable Implanon.


Productive Amyrin Synthases for Efficient α-Amyrin Synthesis in Engineered Saccharomyces cerevisiae.
α-Amyrin is a plant-derived pentacyclic triterpenoid, with a lot of important physiological and pharmacological activities. The formation of α-amyrin from (3 S)-2,3-oxidosqualene is catalyzed by α-amyrin synthase (α-AS), a member of the oxidosqualene cyclase (OSC) protein family. However, α-amyrin is not yet commercially developed due to its extremely low productivity in plants. The engineered Saccharomyces cerevisiae with efficient α-amyrin production pathway could be used as an alternative and sustainable solution to produce α-amyrin from renewable raw materials. To efficiently improve α-amyrin production in S. cerevisiae, we identified two α-ASs, EjAS and MdOSC1 from Eriobotrya japonica and Malus × domestica, respectively, through strict bioinformatics screening criteria and phylogenetic analysis. The specific activities of purified EjAS and MdOSC1 were 0.0032 and 0.0293 μmol/min/mg, respectively. EjAS produced α-amyrin and β-amyrin at a ratio of 17:3, MdOSC1 produced α-amyrin, β-amyrin and lupeol at a ratio of 86:13:1, indicating MdOSC1 had significantly higher specific activity and higher ratio of α-amyrin than EjAS. Furthermore, MdOSC1 was introduced into S. cerevisiae combining with the increased supply of (3 S)-2,3-oxidosqualene to achieve the encouraging α-amyrin production, and the titer of α-amyrin achieved 11.97 ± 0.61 mg/L, 5.8 folds of the maximum production reported.


Final 5-year outcomes from the Endeavor zotarolimus-eluting stent clinical trial program: comparison of safety and efficacy with first-generation drug-eluting and bare-metal stents.
The aim of this study was to evaluate late safety and efficacy outcomes among patients enrolled in clinical trials comparing Endeavor zotarolimus-eluting stents (E-ZES) (Medtronic, Inc., Santa Rosa, California) with first-generation drug-eluting stents (DES) and bare-metal stents (BMS). Despite demonstration of higher angiographic luminal loss and restenosis with E-ZES compared with alternative DES, whether differences in these early angiographic measures translate into more disparate late clinical events is uncertain. Among 3,616 patients undergoing percutaneous coronary revascularization in 5 registration trials, late safety and efficacy events were compared between E-ZES (n = 2,132) versus sirolimus- or paclitaxel-eluting stents (n = 888) or BMS (n = 596). Compared with a parallel cohort of patients treated with first-generation DES and BMS, 5-year rates of cardiac death/myocardial infarction (MI) (5.8% vs. 8.8% DES, p = 0.003; vs. 8.4% BMS, p = 0.02) and major adverse cardiac events (16.1% vs. 20.6% DES, p = 0.009; vs. 24.6% BMS, p < 0.001) were significantly lower with E-ZES. The E-ZES was associated with significantly lower target lesion revascularization (TLR) compared with BMS (7.4% vs. 16.3%, p < 0.001) but similar to comparator DES (7.4% vs. 8.1%, p = 0.63). Despite higher TLR in the first year with E-ZES compared with DES, between 1- and 5-year follow-up, rates of cardiac death/MI, TLR, and definite/probable stent thrombosis were significantly lower with E-ZES. Over 5 years, significant differences in cardiac death/MI and composite endpoints favored treatment with E-ZES over comparator BMS and DES. Rates of clinical restenosis and safety events, including stent thrombosis beyond the first year of revascularization, remain stable with E-ZES, leading to significant differences compared with first-generation DES.


Gastric emptying is accelerated in diabetic BB rats and is slowed by subcutaneous injections of amylin.
Gastric emptying was measured in normal and insulin-treated spontaneously diabetic BB rats using the retention of an acaloric methylcellulose gel containing phenol red delivered by gavage. Dye content in stomachs removed after killing 20 min later was determined spectroscopically, and was compared to that in rats killed immediately after gavage to assess emptying. Diabetic rats had a markedly greater gastric emptying (90.3 +/- 1.7% passed) compared to normal Harlan Sprague Dawley rats (49.1 +/- 4.7% passed; p < 0.001) and non-diabetic BB rats (61.1 +/- 9.2% passed; p < 0.001). The pancreatic beta-cell peptide, amylin, which is deficient in insulin-dependent diabetes mellitus, dose-dependently inhibited gastric emptying in both normal and diabetic rats. The ED50 of the response in normal rats measured by phenol red and novel [3-3H]glucose gavage techniques was approximately 0.4 microgram. This dose was estimated to increase plasma amylin concentration by a mean of approximately 20 pmol/l to concentrations within the range observed in vivo. It is proposed that amylin could participate in the physiological control of nutrient entry into the duodenum and that the accelerated gastric emptying seen in BB rats could be related to their lack of amylin secretion.


A mixed Th1/Th2 response elicited by a liposomal formulation of Leishmania vaccine instructs Th1 responses and resistance to Leishmania donovani in susceptible BALB/c mice.
In this study, we have developed a vaccine with Leishmania donovani promastigote membrane antigens (leishmanial antigens (LAg)) encapsulated in a liposome carrier formulated with distearyol (DSPC, transition temperature (Tc) = 54 degrees C) derivative of l-alpha-phosphatidyl choline, for immunizing BALB/c mice against progressive visceral leishmaniasis. This formulation could limit hepatosplenomegaly to almost normal levels and conferred strong levels of protection in both liver and spleen against challenge infection. Immunization with liposomal LAg activated peritoneal macrophages for enhanced leishmanicidal activity in association with NO production, and induced antibody as well as T-cell mediated immune responses. Production of both IFN-gamma and IL-4 by splenic T cells, and serum IgG1 and IgG2a, suggest induction of a mixed Th1/Th2 response following immunization. Experimental challenge corresponded with elevated DTH, and mitogen and antigen specific cellular responses. Increased production of NO and IFN-gamma by spleen cells, and down regulation of IL-4, demonstrate that an initial stimulation of a mixed Th1/Th2 response by vaccination instructs Th1 responses and resistance against a progressive infection by L. donovani.


Antifungal immune responses in mosquitoes (Diptera: Culicidae): A review.
Mosquitoes transmit many parasites and pathogens to humans that cause significant morbidity and mortality. As such, we are constantly looking for new methods to reduce mosquito populations, including the use of effective biological controls. Entomopathogenic fungi are excellent candidate biocontrol agents to control mosquitoes. Understanding the complex ecological, environmental, and molecular interactions between hosts and pathogens are essential to create novel, effective and safe biocontrol agents. Understanding how mosquitoes recognize and eliminate pathogens such as entomopathogenic fungi may allow us to create insect-order specific biocontrol agents to reduce pest populations. Here we summarize the current knowledge of fungal infection, colonization, development, and replication within mosquitoes and the innate immune responses of the mosquitoes towards the fungal pathogens, emphasizing those features required for an effective mosquito biocontrol agent.


Temperature adaptation of lactate dehydrogenase. Structural, functional and genetic aspects.
Comparison of the primary structures of thermophilic, mesophilic and psychrophilic lactate dehydrogenase (LDH) reveals a multitude of temperature-related amino acid substitutions. In the substitutions amino acid residues occurring preferentially in thermophilic, mesophilic (psychrophilic) LDH were found. On this basis, amino acid residues could be classified in an order from typical thermophilic (thermostabilizing) to typical mesophilic (thermolabilizing, increasing dynamics of the enzyme molecule) residues. The temperature-dependent ratio between thermostabilizing and thermolabilizing amino acid residues forms the basis for the specific structural and functional properties of thermophilic or mesophilic LDH. It is interesting that there appears to be a relationship between this order from thermophilic to mesophilic amino acid residues and the type of bases coding for these individual residues in the translation step of protein biosynthesis. Temperature-related amino acid substitutions are based on temperature-related base substitutions. A possible mechanism of temperature adaptation of LDH through alternative selection of thermophilic and mesophilic amino acid residues at the level of tRNA (anticodon)-mRNA (codon) interactions is discussed. These temperature-adaptation processes are evolutionary events in which the evolution and structure of the genetic code are involved.


A comparison of some gradient-encoded volume-selection techniques for in vivo NMR spectroscopy.
Four of the techniques proposed for in vivo volume-selected NMR spectroscopy have been compared using a simple phantom with a large background water signal which was outside the region of interest. The methods VSE, SPACE, SPARS, and DIGGER all use pulsed field gradients for spatial encoding and were tested with a symmetric and an asymmetric phantom. SPACE was used to obtain volume-selected 1H NMR spectra of a human leg, demonstrating excellent discrimination between bone marrow and muscle.


Trace element profiles in oesophageal neoplasms determined by proton-induced X-ray emission.
Trace element concentrations were determined in surgically resected, cancerous human oesophageal tissue by proton-induced X-ray emission (PIXE) analysis. Each sample was divided into six zones, E3 and E4 formed the central tumour region, E1 and E2 were proximal to the oesophagus and E5 and E6 distal to the oesophagus. Malignancy was confirmed histopathologically in all cases. Samples were dissolved in NaOH solution and pipetted onto a thin mylar film for analysis by a proton beam from a Van de Graaff accelerator. Titanium, Fe, Cu, Zn, As, Rb, Br and Pb were detected in varying concentrations. Of these, Ti, Fe, Cu, Zn and As showed specific behaviour in the six zones.


Hormonal control of sexual and scent marking behaviors of male gerbils in relation to the sexually dimorphic area of the hypothalamus.
The sexual and scent marking behaviors of male gerbils are stimulated by testosterone (T) action in the preoptic area (POA) of the hypothalamus. The sexually dimorphic area (SDA) in the posterior POA, which also responds to T, is implicated in this process. This research studied the sensitivities of mating, marking, and the SDA to T metabolites and other steroids. Experiment 1 focused on mating. Male gerbils were implanted at castration with 2-mm Silastic capsules containing T, dihydrotestosterone (DHT), 19-nortestosterone (19-nor T), estradiol (E), or no hormone and were tested 3-7 weeks later. T, E, and 19-nor T maintained intromissions, but E-treated males rarely ejaculated. Controls and DHT-treated males stopped mounting. Experiment 2 compared the ability of these steroids to reinstate marking and mating using the same dose and a larger one (5 mm). Androstenedione, 19-hydroxytestosterone (19-OHT), and E plus DHT were studied as well. Volumes of the SDA and SDA pars compacta (SDApc) were also measured. Only T, 19-nor T, E, and E + DHT reinstated sexual behavior, but all steroids except 19-OHT stimulated marking. E and DHT synergized to elicit mating. For marking, they were no more effective together than alone. Steroid-treated males had larger SDAs than controls. Moreover, steroids that stimulated sexual activity produced larger SDAs than steroids that did not. SDA size correlated with copulatory rate, but not with copulatory efficiency. SDApc size correlated with copulatory efficiency, but not with copulatory rate. Like copulatory rate and efficiency, sizes of the SDA and SDApc did not correlate with each other.


Association of 3'----5' exodeoxyribonuclease activity with DNA replitase complex from S-phase Chinese hamster embryo fibroblast cells.
DNA replitase has been described as a complex of enzymes/proteins that are associated with both DNA precursor biosynthesis and DNA replication in mammalian cells [Reddy, G. P. V., and Pardee, A. B. (1980) Proc. Natl. Acad. Sci. USA 77, 3312-3316]. We demonstrate for the first time a 3'----5' exodeoxyribonuclease activity is associated with the replitase complex. As much as 60% of this exonuclease activity was similar to that associated with DNA polymerase delta based upon its sensitivity to inhibition by GMP and by butyl-phenyl-deoxyguanosine triphosphate (BuPdGTP). Association of 3'----5' exonuclease activity with the DNA polymerase in the replitase complex was also demonstrated by analyzing dTTP turnover to dTMP in an in vitro DNA polymerase assay system. The DNA polymerase activity in replitase complex exhibited a sensitivity to BuPdGTP which both was similar to that of DNA replication in permeable cells and was intermediate between the BuPdGTP inhibition of purified DNA polymerases alpha and delta. These studies suggest that the replitase complex contains 3'----5' exonuclease activity associated with the DNA polymerase activity responsible for nuclear DNA replication in mammalian cells. Further studies are required to determine if these activities are at least partially attributed to DNA polymerase delta.


Estimating efficacy and drug ED50's using von Frey thresholds: impact of weber's law and log transformation.
The use of von Frey filaments, originally developed by Maximilian von Frey, has become the cornerstone for assaying mechanical sensitivity in animal models and is widely used for human assessment. While there are certain limitations associated with their use that make comparisons between studies not straightforward at times, such as stimulus duration and testing frequency, von Frey filaments provide a good measurement of mechanosensation. Here we describe the application of von Frey filaments to testing in animal models, specifically with respect to determining changes in sensory thresholds in a pain state using the Dixon up-down method. In a literature survey, we found that up to 75% of reports using this method analyze the data with parametric statistical analysis and of those that used nonparametric analysis, none took into account that mechanical sensation is perceived on a logarithmic scale (Weber's Law) when calculating efficacy. Here we outline a more rigorous analysis for calculating efficacy and ED(50)'s from von Frey data that incorporates Weber's Law. We show that this analysis makes statistical and biological sense and provide a specific example of how this change affects data analysis that brings results from animal models more in line with clinical observations. This focus article argues that analyzing von Frey paw withdrawal threshold data obtained by using the Dixon up-down method without considering Weber's Law is inappropriate. An analysis method that incorporates how mechanical sensation is perceived and how its application brings results from animal models more in line with clinical data is presented.


Molecular characterization revealed the role of catalases under abiotic and arsenic stress in bread wheat (Triticum aestivum L.).
Catalases are crucial antioxidant enzymes that reduce the excessive level of H2O2 caused by various environmental stresses and metal toxicity and hence protect the plant cells. In this study, a total of ten TaCAT genes, forming three homeologous groups, were identified in the genome of bread wheat (Triticum aestivum L.) and named as per the wheat gene symbolization guidelines. The identified catalases were characterized for various structural and physicochemical features. The proximal active-site (F(D/A)RERIPERVVHAKGASA) and heme-ligand (R(I/V)F(S/A)Y(A/S)DTQ) signature motifs, catalytic residues and peroxisomal targeting peptides were found conserved. Phylogenetic analysis clustered TaCATs into three classes, which showed conserved functional specialization based on their tissue specific expression. Modulated spatio-temporal expression of various TaCAT genes and alteration in total catalase enzyme activity during heat, drought, salt and arsenic (AsIII and AsV) treatment suggested their roles in abiotic stress response and arsenic tolerance. Molecular cloning and overexpression of TaCAT3-B gene in Escherichia coli showed tolerance against heat, drought, salt and varied concentrations of AsIII and AsV treatments. The results further confirmed their role in stress tolerance and recommended that these genes can be used in future stress management strategies for the development of abiotic and arsenic stress resistant transgenic crops.


From breast to baby: quality assurance for breast milk management.
Breast milk is a body fluid capable of transmitting blood-borne pathogens when ingested. High-risk infants are frequently fed mother's expressed breast milk and may be at risk if they receive the wrong mother's milk. A multidisciplinary team at this 42-bed Level III regional NICU developed a quality assurance program and audit aimed at reducing the risk of feeding expressed breast milk (EBM) to the wrong high-risk infant in the unit. Changes to the old system included modernizing the handling, storing, and distribution of EBM. Elimination of feeding errors was the priority. A specific protocol to minimize EBM feeding errors became part of the quality assurance program and is consistent with the recommendations of the NICU multidisciplinary team.


Early exercise training after mitral valve repair: a multicentric prospective French study.
Surgical mitral valve (MV) repair is now the best technique to correct mitral regurgitation (MR). However, clinical studies have shown that without exercise training (ET), there is no significant postoperative exercise tolerance improvement. Moreover, healing duration of the MV wound is not well known; thus, the feasibility of an early ET program (ETP) may be discussed. To evaluate safety and feasibility of an early ETP after MV repair. All patients hospitalized in 13 postoperative centers after MV repair from September 2002 to June 2003 were included in this prospective study. They underwent an ETP during 3 weeks on average. Transthoracic echocardiography and a cardiopulmonary exercise test were performed before and after the ETP. Two hundred fifty-one consecutive patients (male gender, 70%; mean age, 59 +/- 14 years [+/- SD]) were included 16 +/- 10 days after MV repair. There was no MR occurrence or worsening after the ETP. Left ventricular ejection fraction slightly increased (53 +/- 10% vs 55 +/- 9%, p = 0.004). Peak oxygen consumption and anaerobic threshold increased from 16.3 +/- 4.5 to 20.0 +/- 6.0 mL/kg/min (22% increase) and from 12.2 +/- 3.8 to 14.2 +/- 4.3 mL/kg/min (16% increase) respectively, (p < 0.0001). ET after MV repair does not deteriorate the outcome of recent surgery and seems efficient.


Developing a driving Safety Index using a Delphi stated preference experiment.
Whilst empirical evidence is available concerning the effect of some aspects of driving behaviour on safety (e.g. speed choice), there is scant knowledge about safety thresholds, i.e. the point at which behaviour can be considered unsafe. Furthermore, it is almost impossible to ascertain the interaction between various aspects of driving behaviour. For example, how might drivers' lateral control of a vehicle be mediated by their speed choice-are the effects additive or do they cancel each other out. Complex experimental or observational studies would need to be undertaken to establish the nature of such effects. As an alternative, a Delphi study was undertaken to use expert judgement as a way of deriving a first approximation of these threshold and combinatory effects. Using a stated preference technique, road safety professionals make judgements about drivers' safe or unsafe behaviour. The aim was to understand the relative weightings that are assigned to a number of driver behaviours and thereby to construct a Safety Index. As expected, experts were able to establish thresholds, above (or below) which changes to the behavioural parameters had minimal impact on safety. This provided us with a Safety Index, based on a model that had face validity and a convincing range of values. However, the experts found the task of combining these driver behaviours more difficult, reflecting the elusive nature of safety estimates. Suggestions for future validation of our Safety Index are provided.


Staphylococcal biofilms.
Staphylococcus epidermidis and Staphylococcus aureus are the most frequent causes of nosocomial infections and infections on indwelling medical devices, which characteristically involve biofilms. Recent advances in staphylococcal molecular biology have provided more detailed insight into the basis of biofilm formation in these opportunistic pathogens. A series of surface proteins mediate initial attachment to host matrix proteins, which is followed by the expression of a cationic glucosamine-based exopolysaccharide that aggregates the bacterial cells. In some cases, proteins may function as alternative aggregating substances. Furthermore, surfactant peptides have now been recognized as key factors involved in generating the three-dimensional structure of a staphylococcal biofilm by cell-cell disruptive forces, which eventually may lead to the detachment of entire cell clusters. Transcriptional profiling experiments have defined the specific physiology of staphylococcal biofilms and demonstrated that biofilm resistance to antimicrobials is due to gene-regulated processes. Finally, novel animal models of staphylococcal biofilm-associated infection have given us important information on which factors define biofilm formation in vivo. These recent advances constitute an important basis for the development of anti-staphylococcal drugs and vaccines.


[Diagnosis and therapy of acute complaints after "whiplash injury" in Germany. Results of a representative survey at surgical and trauma departments in Germany].
Whiplash injury of the cervical spine is a relevant medical and socioeconomic problem, which is still the subject of controversy. We performed a survey to evaluate the current status of diagnostics, classification, treatment, and doctors' subjective opinions at surgical and trauma departments in Germany. A total of 1568 hospitals were addressed to answer a standardized questionnaire on their proceedings and opinions concerning whiplash injury. We received 540 (34.44%) completed questionnaires. There was overall agreement concerning the need for physical examination. The radiological assessment included an a.p. and a lateral plain X-ray of the cervical spine in 82.6%. The indication for functional X-rays in flexion/extension was inconsistent. On average they were performed in 39.1% of all patients. In most cases (68.9%) whiplash injury was not classified; 13.2% of doctors used the classification according to the Quebec Task Force and 13.9% according to Erdmann. A cervical collar was prescribed in 85%. While 30% of patients received only a cervical collar, 55.6% underwent additional physiotherapy. Only 8.3% were treated by physiotherapy without immobilization. The doctors' subjective opinions indicated psychological factors to be important for long-lasting problems, but not for the acute period of complaints. There is no homogeneous concept for diagnostics, classification, and treatment of patients who suffered a whiplash injury in Germany. This situation reflects the current problems in management of this condition. Scientific evidence for functional treatment to avoid adverse influence of immobilization by cervical collars has not yet been transferred to our daily routine in Germany.


Two sources of autonomy support and depressive symptoms among Chinese gay men: The sequential mediating effect of internalized homonegativity and rumination.
A high level of depressive symptoms is a universal phenomenon among gay groups. Autonomy support, which refers to supporting an opportunity for others to authentically express themselves and behave consistently with their own beliefs, values and interests, is considered a critical protective factor facilitating the relief of depressive symptoms in gay men. The aim of the current study was to examine the relationships between two sources of autonomy support (from parents and friends) and depressive symptoms in a Chinese context and evaluate the mediating effects of internalized homonegativity and rumination. Altogether, 385 Chinese gay men (mean age = 24.00 years old, standard deviation (SD) = 4.84) who were voluntarily recruited by web-sampling were measured on scales regarding autonomy support, internalized homonegativity, rumination and depressive symptoms. Autonomy support from both parents and friends were negatively correlated with depressive symptoms among Chinese gay men. Internalized homonegativity and rumination played a sequential mediating role between friends' autonomy support and depressive symptoms, yet this sequential mediation effect was not significant between parental autonomy support and depressive symptoms. The cross-sectional design limited casual inferences between variables. The effects of domain-specific autonomy support were not involved in this study, and other mediators between autonomy support and depressive symptoms and more sociodemographic variables should be considered. Autonomy support from both parents and friends might be protective factors against depressive symptoms in Chinese gay men. Friends' autonomy support was related to decreased depressive symptoms via lower internalized homonegativity and rumination, while parental autonomy support was related to less depressive symptoms through other possible mechanisms.


The effect of gonadotropin-releasing hormone agonist on thyroid-stimulating hormone and prolactin secretion in adult premenopausal women.
To investigate the effects of chronic administration of GnRH agonists (GnRH-a) on pituitary TSH and PRL secretion in adult women. Prospective case-controlled study. Academic division of Reproductive Endocrinology, Department of Obstetrics and Gynecology. Ten ovulatory women and 10 women treated with monthly depot injections of leuprolide acetate (3.75 mg) were studied. All subjects underwent pituitary stimulation with human thyrotropin-releasing hormone (TRH), 500 micrograms IV. Basal and post-TRH-stimulated serum levels of TSH and PRL at 15, 30, 45, 60, 90, 120, and 180 minutes were compared among the two groups. Also, basal of T4, triiodothyronine, and triiodothyronine resin uptake studies were obtained and compared among the GnRH-a-treated and control groups. No statistically significant difference between baseline or TRH-stimulated serum TSH and PRL could be detected between control and GnRH-a-treated groups of women. Furthermore, these groups were similar with respect to routine thyroid function assays. Gonadotropin-releasing hormone agonist does not significantly affect baseline or TRH-stimulated TSH and PRL levels nor basal serum T4 and triiodothyronine levels or triiodothyronine resin uptake in adult women.


Hemorrhage induces an increase in serum TNF which is not associated with elevated levels of endotoxin.
Although tumor necrosis factor (TNF) and interleukin 6 (IL 6) are purported to be important mediators of inflammatory responses following trauma, it is not known if the serum levels of these cytokines are altered by simple hemorrhage. The objective of this study therefore was to determine whether or not: 1) there is any elevation of TNF or IL 6, and 2) if endotoxin, an important upregulator of these cytokines, is also increased following hemorrhage. To study this, C3H/HeN mice were bled to, and maintained at a mean blood pressure of 35 mmHg for 60 min, and then resuscitated with their own shed blood and adequate fluid. Mice were sacrificed at 30 min into hemorrhage and at 2, 4 or 24 hr post-hemorrhage to obtain serum samples. IL 6 and TNF levels were measured using cytokine dependent cellular assays. Using a quantitative Limulus amebocyte lysate assay, endotoxin levels were determined. TNF levels were significantly elevated at 30 min into hemorrhage, remaining so at 2 hr after resuscitation, but absent by 4 hr. Although there was a trend toward elevated IL 6 levels at 2 hr following hemorrhage, which was sustained up to 24 hr, the values were not significantly different from sham controls. When compared to controls, no marked increase in endotoxin was seen at any time point during or following hemorrhage. These results indicate that hemorrhage, in the absence of significant tissue trauma, causes enhanced TNF release which is not the result of increased endotoxin.


Induction of high voluntary ethanol intake in dependent rats.
The experimental conditions under which oral high intake may be induced in previously intoxicated rats have been investigated. Seventeen rats were administered intragastrically with 10 g/kg/day of ethanol for 15 days. At cessation of treatment, they were presented a single bottle of alcoholic solution (10% v/v) during 24 hr. For the following 6 days, they received either an ethyl alcohol solution or water in alternation for 8 hours each. Ethanol treated rats exhibited a high oral intake of ethanol equivalent to the previously injected doses. Controls displayed a significantly lower intake of ethanol. It is concluded that the suppression of the withdrawal state by an initial priming oral intake of ethanol in physically dependent rats is a condition for the development of a conditioned taste preference for ethanol as a basis for the behavioral dependence.


Measuring Overall Severity of Myasthenia Gravis (MG): Evidence for the Added Value of the MG Symptoms PRO.
Accurate measurement of myasthenia gravis (MG) severity is required for appropriate clinical monitoring of patients with MG and assessment of the benefit of new treatments in clinical trials. Our objective was to explore how MG severity can be measured and to determine how the newly developed MG Symptoms Patient-Reported Outcome (PRO) instrument complements the available measures of MG severity. The conceptual coverage of the Quantitative MG (QMG), MG Composite (MGC), MG-Activities of Daily Living (MG-ADL), and MG Symptoms PRO was scrutinized against core symptoms of MG: muscle weakness in three muscle groups (ocular, bulbar, and respiratory), muscle weakness fatigability, and physical fatigue. Post hoc analyses of the MG0002 study, a Phase 2a clinical trial of rozanolixizumab in adults with moderate to severe generalized MG, included correlation and Rasch model analyses. The qualitative appraisal highlighted that only the MG Symptoms PRO captured physical fatigue. Data from 541 assessments (43 unique patients) were used for the analyses. Correlations ranged between 0.56 and 0.74 for the MG-ADL, QMG, MGC, and MG Symptoms PRO Muscle Weakness Fatigability score, and between 0.20 and 0.71 for the MG Symptoms PRO scores focusing on independent muscle groups. Analyses with the Rasch model estimated a meaningful continuum of severity of MG, including all items, except ocular muscles, from the four instruments. The QMG and MG Symptoms PRO had the broadest coverage of the MG severity continuum. Muscle fatigability and physical fatigue were more characteristic of low severity while bulbar weakness indicated more severe MG. The severity of MG can be reflected in a meaningful continuum underpinned by the MG-specific outcome measures. Only ocular muscle manifestations were shown to reflect a possibly different facet of MG severity. With its modular nature and comprehensive content, the MG Symptoms PRO provides complementary information to the outcome measures widely used in MG. ClinicalTrials.gov identifier: NCT03052751.


Engineering Saccharomyces cerevisiae for production of simvastatin.
Simvastatin is a semisynthetic cholesterol-lowering medication and one of the top-selling statins in the world. Currently, industrial production of simvastatin acid (SVA) is a multistep process starting from the natural product lovastatin. For this reason, there is significant interest in direct production of simvastatin from a microbial host. In this study, six heterologous biosynthetic genes were introduced into Saccharomyces cerevisiae and the acyl-donor dimethylbutyryl-S-methyl mercaptopropionate (DMB-SMMP) was added, resulting in initial production of 0.5 mg/L SVA. Switching the yeast strain from JHY686 to BJ5464-NpgA increased total polyketide production to over 60 mg/L and conversion from dihydromonacolin L acid to monacolin J acid (MJA) was increased from 60% to 90% by tuning the copy number of the P450 lovA. Increasing the media pH to 8.7 led to a further 10-fold increase in SVA production. Optimized chemical lysis of the cell walls in situ after maximum MJA production led to 55 mg/L SVA titer, representing nearly complete conversion from MJA and a 110-fold increase in titer from the initial SVA production strain. The yeast strains developed in this work can be used as an alternative production method for SVA, and the strategies employed can be broadly applied for heterologous production of other fungal polyketides and semisynthetic compounds in yeast.


When and why do retrieval attempts enhance subsequent encoding?
Unsuccessful retrieval attempts can enhance subsequent encoding and learning. In three experiments, subjects either attempted to retrieve word pairs prior to studying them (e.g., attempting to recall tide-? before studying tide-beach) or did not attempt retrieval and retention of the studied targets was assessed on a subsequent cued recall test. Experiment 1 showed that attempting retrieval enhanced subsequent encoding and recall relative to not attempting retrieval when the word pairs were semantically related, but not when the pairs were unrelated. In Experiment 2, studying a different word pair prior to the correct pair (e.g., studying tide-wave prior to tide-beach) did not produce the same effect as attempting retrieval prior to studying. Constraining retrieval to a particular candidate word prior to study (e.g., recalling tide-wa__ before studying tide-beach) produced a negative effect on subsequent recall. Experiment 3 showed that attempting retrieval did not enhance encoding when a brief delay occurred between the retrieval attempt and the subsequent study trial. The results support the idea that a search set of candidates related to the retrieval cue is activated during retrieval and that this retrieval-specific activation can enhance subsequent encoding of those candidates.


In vitro virulence activity of Pseudomonas aeruginosa, enhanced by either Acinetobacter baumannii or Enterococcus faecium through the polymicrobial interactions.
Microbes within an infection impact neighbors' pathogenicity. This study aimed to address in vitro virulence activity of Pseudomonas aeruginosa under the binary interaction with Acinetobacter baumannii or Enterococcus faecium, co-isolated from two chronic wound infections. The biofilm formation of Pseudomonas was enhanced 1.5- and 1.4-fold when it was simultaneously cultured with Acinetobacter and Enterococcus, respectively. Pseudomonas motility was increased by 1.9- and 1.5-fold (swimming), 3.6- and 1.9-fold (swarming), and 1.5- and 1.5-fold (twitching) in the dual cultures with Acinetobacter and Enterococcus, respectively. The synergistic hemolysis activity of Pseudomonas was observed with the heat-killed Acinetobacter and Enterococcus cells. The minimum inhibitory concentration of ciprofloxacin against Pseudomonas was increased from (μg mL-1) 25 to 400 in the individual and mixed cultures, respectively. The pyocyanin production by Pseudomonas in the single and mixed cultures with Acinetobacter and Enterococcus was (μg/mL) 1.8, 2.3, and 2.9, respectively. The expression of lasI, rhlI, and pqsR genes was up-regulated by 1.0-, 1.9-, and 16.3-fold, and 4.9-, 1.0-, and 9.3-fold when Pseudomonas was incubated with Acinetobacter and Enterococcus, respectively. Considering the entire community instead of a single pathogen may lead to a more effective therapeutic design for persistent infections caused by Pseudomonas.


Neural oscillations in the ventral striatum reveal differences between the encoding of palatable food and ethanol consumption.
Across multiple levels of investigation, there appear to be convergent neuronal processes underlying substance use and other motivated behaviors (i.e., the pursuit and consumption of rewarding substances). The consumption of alcohol and sweet, high-fat food engages many of the same brain regions, especially, the ventral striatum. In the current study, we hypothesized that ventral striatal local field potentials (LFPs) recorded during self-administration sessions could be used to detect when the consumption of 10% ethanol or sweet-fat food (SF) was occurring compared to all other behaviors, including naturalistic controls (i.e., water or house-chow). We used an intermittent limited access approach to condition Sprague-Dawley rats to consume either ethanol or SF while we recorded LFPs. We used machine learning and simple logistic regressions to determine whether LFP features could classify when consumption of each substance was occurring, and whether a general model could predict consumption of both substances. We report performance as the average area under the receiver operator characteristic curve (AUROC). Consumption of a single substance was differentiable from all other behaviors, as evidenced by the AUROC (ethanol = 0.84 and SF = 0.83, p < 0.01). Models built from the combined dataset (general) did modestly overall (general → general = 0.68, p < 0.05), and did not detect the consumption of the two substances similarly (general → SF = 0.5 and general → ethanol = 0.63, p > 0.05). Models successfully classified ethanol and SF consumption versus all other behavior/naturalistic controls. However, the findings highlight differences in how the ventral striatum represents the consumption of ethanol and SF and show that, although there is potential for finding biomarkers related to substance use, it may be difficult to build a model that performs well detecting multiple substances.


Synthesis and evaluation of a UMI-77-based fluorescent probe for selective detecting Mcl-1 protein and imaging in living cancer cells.
Development of efficient fluorescent probes for detecting the overexpressed Mcl-1 protein in living cells is imperative for the diagnosis and treatment of cancers. In this paper, a new UMI-77 based fluorescent probe (DNSH), was synthesized and characterized. DNSH bound to the hydrophobic pockets of Mcl-1 protein tightly and the binding affinity was 20-fold higher than that of previous developed Mcl-1 probe. DNSH exhibited specific fluorescence response to Mcl-1 protein rather than other proteins. In the presence of Mcl-1 protein, fluorescence emission of DNSH can be switched on. Furthermore, fluorescence colocalization experiment demonstrated that DNSH can be successfully used for imaging mitochondrial Mcl-1 protein in human prostate cancer cells without a washing process. These results showed that DNSH may find useful applications in biological research such as tracking Mcl-1 protein in living biological specimens.


Exploring the Role of Self-Kindness in Making Healthier Eating Choices: A Preliminary Study.
Food selection is an important factor in the prevalence of obesity, and regularly choosing nutrient-poor high-energy foods can have negative health consequences. The present study tested whether the use of mindful construal diaries (MCD) combined with self-kindness could promote healthier eating choices. Ninety participants were randomly assigned to either a self-kindness to the mind condition or self-kindness to the mind and body condition, and were served M&Ms and grapes as an unhealthy and healthy option, respectively. The results suggested that a difference in consumption was found between the two conditions, with participants in the self-kindness to the mind condition consuming significantly more grapes than those in the self-kindness to the mind and body condition. However, this difference was restricted to those who are usually low consumers of fruit and vegetable. The effect of self-kindness towards promoting heathier eating whilst considering the body thus appears to require further investigation. Limitations and recommendations for future research are discussed.


Kinetics and crystal structure of human purine nucleoside phosphorylase in complex with 7-methyl-6-thio-guanosine.
Purine nucleoside phosphorylase (PNP) catalyzes the reversible phosphorolysis of nucleosides and deoxynucleosides, generating ribose 1-phosphate and the purine base, which is an important step of purine catabolism pathway. The lack of such an activity in humans, owing to a genetic disorder, causes T-cell impairment, and drugs that inhibit this enzyme may have the potential of being utilized as modulators of the immunological system to treat leukemia, autoimmune diseases, and rejection in organ transplantation. Here, we describe kinetics and crystal structure of human PNP in complex with 7-methyl-6-thio-guanosine, a synthetic substrate, which is largely used in activity assays. Analysis of the structure identifies different protein conformational changes upon ligand binding, and comparison of kinetic and structural data permits an understanding of the effects of atomic substitution on key positions of the synthetic substrate and their consequences to enzyme binding and catalysis. Such knowledge may be helpful in designing new PNP inhibitors.


Design of immobilized biocatalyst and optimal conditions for tyrosol β-galactoside production.
Tyrosol β-galactoside (TG) is a phenylethanoid glycoside with proven neuroprotective properties. This work deals with its biocatalytic production from tyrosol and lactose using Aspergillus oryzae β-galactosidase in immobilized form. Six commercial carriers were examined to find the optimal biocatalyst. Besides standard biocatalyst performance characteristics, adsorption of the hydrophobic substrate on immobilization carrier matrices was also investigated. The adsorption of tyrosol was significant, but it did not have adverse effects on TG production. On the contrary, TG yield was improved for some biocatalysts. A biocatalyst prepared by covalent binding of β-galactosidase on an epoxy-activated carrier was used for detailed investigation of the effect of reaction conditions on glycoside production. Temperature had a surprisingly weak effect on the overall process rate. A lactose concentration of 0.83 M was found to be optimal to enhance TG formation. The impact of tyrosol concentration was rather complex. This substrate caused inhibition of all reactions. Its concentration had a strong effect on the hydrolysis of lactose and all products. Higher tyrosol concentrations, 30-40 g/L, were favorable as pseudo-equilibrium concentrations of TG and galactooligosaccharide were reached. Repeated batch results revealed excellent operational stability of the biocatalyst.


Erratum regarding previously published articles.
[This corrects the article DOI: 10.1016/j.cccb.2021.100012.][This corrects the article DOI: 10.1016/j.cccb.2021.100024.][This corrects the article DOI: 10.1016/j.cccb.2021.100025.][This corrects the article DOI: 10.1016/j.cccb.2020.100003.][This corrects the article DOI: 10.1016/j.cccb.2021.100015.][This corrects the article DOI: 10.1016/j.cccb.2021.100027.][This corrects the article DOI: 10.1016/j.cccb.2021.100030.].


Neuroendoscopic stent procedure in obstructive hydrocephalus due to both foramina of monro occluding craniopharyngioma: technical note.
The development of various neuroendoscopic surgical instruments has offered more options for endoscopic procedures in the treatment of intraventricular tumors. Not only tumor biopsy or tumor resection but also restoration of an obstructed cerebral spinal fluid (CSF) pathway can be performed using the same approach. A 76-year-old woman with a cardiac pacemaker for an underlying heart disease was diagnosed with obstructive hydrocephalus because of a third ventricular tumor 8 years ago. The patient had been treated with ventriculo-peritoneal shunt placement. At admission she presented with a subcutaneous infection of the shunt catheter and an abdominal mass of unknown etiology. Neuroendoscopic stenting between lateral and third ventricle was performed to restore the obstructed CSF pathway, and the infected shunt system was removed in the same setting. The postoperative course was uneventful. Contrast ventriculography demonstrated a restored CSF pathway between the lateral and third ventricle. Histologic examination of the intraventricular tumor revealed a craniopharyngioma, and the abdominal mass was diagnosed as a gastrointestinal adenocarcinoma. The neuroendoscopic foraminoplasty technique should be considered as an alternative treatment for patients who present with an obstructive hydrocephalus caused by a tumor that occludes both foramina of Monro when shunt placement or endoscopic third ventriculostomy is not feasible.


The Impact of Severe COVID-19 on Corneal Endothelial Cells-Analysis of the In Vivo Noncontact Specular Microscopy.
This study aimed to investigate the effects of severe COVID-19 infection on the corneal endothelium via in vivo specular microscopy. This was an observational, prospective, and controlled study including 56 eyes of 56 severe COVID-19 patients, compared to after-recovery and 56 eyes of 56 age- and gender-matched healthy controls. Endothelial cell density was lower in the active disease period compared to healthy controls (p = .001) and decreased even more after recovery (p < .0001). After recovery, the average cell area and coefficient of variation were higher compared to the active disease period (p < .0001 and p = .008, respectively) and the healthy controls (for both, p < .0001), whereas hexagonality was lower (p < .0001). Central corneal thickness increased in the active disease period compared to after recovery (p < .0001) and healthy controls (p = .002). These results may be due to direct host-virus interaction or linked to immune dysregulation, subclinical corneal endotheliitis, or still yet a viral-mediated inflammation.


An improved method for using the DTL fibre in electroretinography.
An improved method using DTL fibre for electroretinography is described. The DTL fibre is comfortable and easy to apply. Corneal anaesthesia is unnecessary. The DTL fiber does not interfere with the retinal image and has been used successfully to record both pattern and flash electroretinograms from subjects of all ages.


Domestication has reduced leaf water use efficiency associated with the anatomy of abaxial stomata in cotton.
Crop domestication for increasing growth rates and yields appears to have altered the features of adaxial and abaxial stomata, but its effect on leaf water use efficiency (WUE) have not been experimentally verified. In this study, we characterized stomatal anatomy and carbon isotope discrimination (δ13C) in 32 wild and 36 domesticated genotypes of cotton grown under agricultural field conditions. The results showed that domesticated genotypes possessed lower WUE, as indicated by low or more negative δ13C compared with wild genotypes. Higher theoretical maximum stomatal conductance (gsmax) after domestication was accounted for by more stomata rather than significantly enlarged stomata. Specifically, abaxial stomatal density was higher whilst there was no change in the adaxial density. The size of both adaxial and abaxial stomata was greater due to larger guard cells but without there being any increase in pore size. However, there was a negative relationship between δ13C and stomatal size across wild and domesticated genotypes, especially on the abaxial leaf surface, because bigger stomata resulted in a lower maximum stomatal response rate to fluctuating canopy light, resulting in increased water loss. Overall, our results indicate that cotton domestication has resulted in substantial variation in stomatal anatomy, and that WUE and drought tolerance can potentially be improved in future breeding by decreasing the size of abaxial stomata to produce a faster stomatal response and hence a reduction in unnecessary water loss.


Chronic hepatitis C: modern notions of pathogenesis and morphogenesis. Concept of antiviral protection in hepatocytes.
Here we review modern notions about biological properties of hepatitis C virus, geographic distribution of its genotypes, peculiarities of immune reactions during chronic HCV infection, and role of viral replication in the infectious process. The concept of antiviral protection in liver parenchymal cells suggests suppression of biosynthetic reactions in hepatocytes resulting in inhibition of viral replication and focal degradation of the cytoplasm in infected cells followed by exocytosis and elimination of viral particles (cytosanation without cytodestruction). The recovery of structural characteristics in hepatocytes is associated with intracellular regeneration. Special accent is placed on reversibility of liver fibrosis in chronic HCV infection due to resorption of collagen fibers by hepatocytes. These data indicate that the therapy of liver fibrosis holds much promise.