BOLD repetition decreases in object-responsive ventral visual areas depend on spatial attention.
Functional imaging studies of priming-related repetition phenomena have become widely used to study neural object representation. Although blood oxygenation level-dependent (BOLD) repetition decreases can sometimes be observed without awareness of repetition, any role for spatial attention in BOLD repetition effects remains largely unknown. We used fMRI in 13 healthy subjects to test whether BOLD repetition decreases for repeated objects in ventral visual cortices depend on allocation of spatial attention to the prime. Subjects performed a size-judgment task on a probe object that had been attended or ignored in a preceding prime display of 2 lateralized objects. Reaction times showed faster responses when the probe was the same object as the attended prime, independent of the view tested (identical vs. mirror image). No behavioral effect was evident from unattended primes. BOLD repetition decreases for attended primes were found in lateral occipital and fusiform regions bilaterally, which generalized across identical and mirror-image repeats. No repetition decreases were observed for ignored primes. Our results suggest a critical role for attention in achieving visual representations of objects that lead to both BOLD signal decreases and behavioral priming on repeated presentation.


Assessing the Methods, Tools, and Statistical Approaches in Google Trends Research: Systematic Review.
In the era of information overload, are big data analytics the answer to access and better manage available knowledge? Over the last decade, the use of Web-based data in public health issues, that is, infodemiology, has been proven useful in assessing various aspects of human behavior. Google Trends is the most popular tool to gather such information, and it has been used in several topics up to this point, with health and medicine being the most focused subject. Web-based behavior is monitored and analyzed in order to examine actual human behavior so as to predict, better assess, and even prevent health-related issues that constantly arise in everyday life. This systematic review aimed at reporting and further presenting and analyzing the methods, tools, and statistical approaches for Google Trends (infodemiology) studies in health-related topics from 2006 to 2016 to provide an overview of the usefulness of said tool and be a point of reference for future research on the subject. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for selecting studies, we searched for the term "Google Trends" in the Scopus and PubMed databases from 2006 to 2016, applying specific criteria for types of publications and topics. A total of 109 published papers were extracted, excluding duplicates and those that did not fall inside the topics of health and medicine or the selected article types. We then further categorized the published papers according to their methodological approach, namely, visualization, seasonality, correlations, forecasting, and modeling. All the examined papers comprised, by definition, time series analysis, and all but two included data visualization. A total of 23.1% (24/104) studies used Google Trends data for examining seasonality, while 39.4% (41/104) and 32.7% (34/104) of the studies used correlations and modeling, respectively. Only 8.7% (9/104) of the studies used Google Trends data for predictions and forecasting in health-related topics; therefore, it is evident that a gap exists in forecasting using Google Trends data. The monitoring of online queries can provide insight into human behavior, as this field is significantly and continuously growing and will be proven more than valuable in the future for assessing behavioral changes and providing ground for research using data that could not have been accessed otherwise.


Gastric hyperplastic polyp occurring at the resection site of gastric adenoma.
Endoscopic mucosal resection was carried out in a 70-year-old man with a gastric adenoma. Endoscopy 1 year later revealed a subpedunculated polyp about 1 cm in diameter at the resection site. Pathological examination of the resected specimen showed hyperplasia of the regenerative epithelium. The mechanism of occurrence of hyperplastic polyp at the resection site is discussed.


A cross-layer diversity technique for multicarrier OFDM multimedia networks.
Diversity can be used to combat multipath fading and improve the performance of wireless multimedia communication systems. In this work, by considering transmission of an embedded bitstream over an orthogonal frequency division multiplexing (OFDM) system in a slowly varying Rayleigh faded environment, we develop a cross-layer diversity technique which takes advantage of both multiple description coding and frequency diversity techniques. More specifically, assuming a frequency-selective channel, we study the packet loss behavior of an OFDM system and construct multiple independent descriptions using an FEC-based strategy. We provide some analysis of this cross-layer approach and demonstrate its superior performance using the set partitioning in hierarchical trees image coder.


[Mechanism of action of ginsenoside Rb1 in decreasing intracellular Ca2+].
Using fluorescent probe Fura-2/AM, ginsenoside Rb1 (10, 50 and 100 mumol.L-1) was shown to dose-dependently reduce intracellular Ca2+ concentration of freshly dissociated brain cells isolated from newborn rats. It was also found to increase the fluidity of synaptosome membrane impaired by FeSO4-Cystein. Rb1 (10 mumol.L-1) shifted the dose-response curve to the right and decreased the maximal response in isolated mouse tail artery. Rb1 (10 and 100 mumol.L-1) was also found to reduce 5-HT-induced contraction of isolated rat basilar artery. With the whole-cell patch clamp technique, Rb1 (100 mumol.L-1) was shown to have no obvious effect on calcium current and potassium current. However, Rb1 was shown to increase Na(+)-K+ ATPase and Ca(2+)-Mg2+ ATPase activities at low dose in rat cerebral cortical synaptosomes. The results indicate that decrease of [Ca2+]i by Rb1 may be attributed to increase of ATPase activity.


Fenestrated and branched endovascular aortic repair for chronic type B aortic dissection with thoracoabdominal aneurysms.
The treatment of patients with arch and thoracoabdominal aortic aneurysms (TAAAs) and chronic dissections is challenging. We report the results of fenestrated and branched endovascular aortic repair (FEVAR) of such aneurysms. A single-center prospective FEVAR trial enrolled 356 patients (2006 to 2011), of whom 30 had chronic dissections with arch aneurysm or TAAAs, or both. Patients were divided into group A, 15 patients (mean age, 58 years) with extensive dissections extending from the arch through the visceral segment, and group B, 15 patients (mean age, 74 years old) with focal dissections and no extension into the thoracic aorta. Inclusion criterion was aneurysm size >5.5 cm in diameter. Customized grafts were implanted into the true lumen, and branches were extended into the true lumen of the supra-aortic trunk (arch branch devices) and visceral vessels. Patients were monitored annually with clinical, imaging, and laboratory studies. Outcome analyses included survival, rupture, spinal cord ischemia, endoleak, morbidity (cardiac, renal or pulmonary), reinterventions, dissection, and aneurysm growth. The mean time from the onset of dissection to the FEVAR performed in group A was 10.4 years. The mean maximum aneurysm diameter was 60 mm. Follow-up averaged 1.7 years. There were no perioperative deaths. One aortic-related death occurred at 87 days due to progression of a pre-existing untreated arch dissection. No ruptures, cardiac, renal, pulmonary, or spinal cord ischemia complications occurred. Despite the initially narrow true lumen dimensions, stent grafts expanded to their nominal diameters after implantation without any blood flow disturbance of branched visceral vessels and distal aorta. No graft compression occurred. Post-FEVAR growth was noted in two patients, related to type II endoleaks. Sac regression was similar (-6.8 vs -11.4 mm; P = .43), but early endovascular reinterventions were more common in group A (8 patients). Patients with extensive dissection were younger, and the dissection more likely to be associated with a defined connective tissue disease (Marfan syndrome or Loeys-Dietz mutations, 40% vs 0%; P = .006). FEVAR is feasible for patients with chronic dissections and TAAA. Concerns regarding visceral vessel access and graft compression resulting from narrow true lumen diameters were not relevant in our experience. Favorable sac and lumen morphologic changes, coupled with a low mortality and complication risk, makes this an attractive means of handling this clinical problem.


Methoxetamine toxicity reported to the National Poisons Information Service: clinical characteristics and patterns of enquiries (including the period of the introduction of the UK's first Temporary Class Drug Order).
To report the demographic and clinical characteristics of cases of methoxetamine toxicity reported to The National Poisons Information Service (NPIS) by healthcare professionals. To assess the pattern of enquiries from health professionals to the UK NPIS related to methoxetamine, including the period of the making of the UK first Temporary Class Drug Order (TCDO). All telephone enquiries to and user sessions for TOXBASE, the NPIS on-line information resource, related to methoxetamine (and synonyms 'MXE', 'mket' and '2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone') were reviewed from 1 April 2010 to 1 August 2012. Data were compared for the 3 months before and after the TCDO. There were 47 telephone enquiries and 298 TOXBASE sessions regarding methoxetamine during the period of study. Comparing the 3 months before and after the TCDO, TOXBASE sessions for methoxetamine fell by 79% (from 151 to 32) and telephone enquiries by 80% (from 15 to 3). Clinical features reported by enquirers were consistent with case reports of analytically confirmed methoxetamine toxicity and typical toxidromes were of stimulant (36%), reduced consciousness (17%), dissociative (11%) and cerebellar (6.4%) types, but also particularly featured acute disturbances in mental heath (43%). Structured NPIS data may reveal trends in drugs of abuse use and toxicity when interpreted within their limitations. Since April 2012, there have been fewer enquiries to NPIS from clinicians, indicating reduced presentations with suspected methoxetamine toxicity to healthcare services. It is unclear if this is related to the TCDO made on 5 April 2012.


[Dental implants in tooth grinders].
Bruxism (tooth grinding and clenching) is generally considered a contraindication for dental implants, although the evidence is usually based on clinical experience only. So far, studies to the possible cause-and-effect relationship between bruxism and implant failure do not yield consistent and specific outcomes. This is partly due to the large variation in the technical and the biological aspects of the investigations. Although there is still no proof that bruxism causes overload of dental implants and their suprastructures, a careful approach is recommended. Practical advices as to minimize the chance of implant failure are given. Besides the recommendation to reduce or eliminate bruxism itself, these advices concern the number and dimensions of the implants, the design of the occlusion and articulation patterns, and the use of a hard nightguard.


Prognostic significance of cancer within 1 mm of the circumferential resection margin in oesophageal cancer patients following neo-adjuvant chemotherapy.
The prognostic significance of the circumferential resection margin (CRM) status in oesophageal cancer patients treated with neo-adjuvant chemotherapy and radical resection is controversial. Furthermore, it is currently unclear whether patients with cancer located at the CRM have a prognosis different from that of those with cancer within 1 mm of the CRM. This is the first study aiming to establish the optimal tumour-free distance from the CRM of an oesophagectomy in patients who have undergone neo-adjuvant chemotherapy. The clinicopathological data of 232 oesophageal cancer patients from two UK centres were analysed. The CRM status was classified as Group A (cancer at the CRM), Group B (cancer within 1 mm but not at the CRM) and Group C (no cancer within 1 mm from the CRM). The relationship between the CRM status and patient survival was investigated. Thirty-eight specimens were classified as Group A, 89 as Group B and 105 as Group C. CRM status was related to the depth of tumour invasion (P < 0.001) and lymph node status (P < 0.001). The prognoses of the Group A and the Group B patients were similar. Both were poorer than that of the Group C patients (P = 0.008). Lymph node status was the only independent prognostic marker in multivariate analysis. Oesophageal cancer patients treated with preoperative chemotherapy with cancer cells at the CRM or within 1 mm of the CRM of the resected specimen have a significantly worse survival than patients with no cancer cells within 1 mm of the margin. However, this study suggests that the overall prognostic significance of the CRM status is limited in this cohort and the postoperative lymph node status is the most important prognostic factor in oesophageal cancer patients treated with neo-adjuvant chemotherapy and surgery.


Insertional inactivation of pac and rmlB genes reduces the release of tumor necrosis factor alpha, interleukin-6, and interleukin-8 induced by Streptococcus mutans in monocytic, dental pulp, and periodontal ligament cells.
Streptococcus mutans possesses different cell wall molecules, such as protein of the I/II family, the serotype f polysaccharide rhamnose glucose polymer (RGP), and lipoteichoic acid (LTA), which act as adhesins and modulins, allowing S. mutans to colonize teeth and cause dental caries and pulpitis. We tested several isogenic mutants of S. mutans defective in protein I/II and/or RGP, as well as purified modulins such as protein I/II, RGP, and LTA, for their binding and activation abilities on monocytic, dental pulp (DP), and periodontal ligament (PDL) cells. Our results demonstrate that both protein I/II and RGP play important roles in streptococcal adherence to human monocytic and fibroblastic cells, whereas LTA is only a minor adhesin. In the activation process, the cytokine response elicited is polarized toward a Th1 response which seems principally due to protein I/II and RGP. Even if protein I/II seems to be more efficient in its purified form in triggering cells to release interleukin-8 (IL-8), RGP is the most efficient cytokine-stimulating component in intact bacteria, while LTA plays only a minor role. In cell activation, we showed, by using either cytochalasin D or coated ligands, that internalization of either S. mutans, S. mutans isogenic mutants, or purified ligands is not necessary to trigger cells to release IL-8. We also showed that, besides the implication of monocytes in pulpal inflammation, fibroblast-like cells such as DP and PDL cells are also actively implicated in local inflammation and in the generation of a Th1 response after stimulation with S. mutans cells or antigens.


Induction of mutant p53-dependent apoptosis in human hepatocellular carcinoma by targeting stress protein mortalin.
Stress protein mortalin (mtHSP70) is highly expressed in cancer cells. It was shown to contribute to carcinogenesis by sequestrating the wild type p53, a key tumor suppressor protein, in the cytoplasm resulting in an abrogation of its transcriptional activation function. We have found that the level of mortalin expression has significant correlation with human hepatocellular carcinoma (HCC) malignancy and therefore investigated whether it interacts with and influences the activities of mutant p53, frequently associated with HCC development. We have detected mortalin-p53 interactions in liver tumor and five HCC cell lines that harbored mutant p53. The data was in contrast to the normal liver and immortalized normal hepatocytes that lacked mortalin-p53 interaction. Furthermore, we have found that the shRNA-mediated mortalin silencing could induce mutant p53-mediated tumor-specific apoptosis in HCC. Such allotment of apoptotic function to mutant p53 by targeting mortalin-p53 interaction in cancer cells is a promising strategy for HCC therapy.


Altered glucose carrier expression: mechanism of intestinal adaptation during streptozocin-induced diabetes in rats.
Intestinal adaptation of glucose transport during streptozocin-induced diabetes in rats was examined using microdensitometric analysis of [3H]phlorizin binding. Results of specific phlorizin binding were correlated with measurements of maximal transport capacity, carrier affinity, villus height, and enterocyte birth rate determined by the metaphase arrest technique. Animals diabetic for 14 days (acute) and 60 days (chronic) were compared with age-matched controls. In the jejunum, adaptation occurred only in chronically diabetic rats and consisted of a 10-fold increase in the density of phlorizin binding sites in the upper villus region (i.e., that portion normally transporting glucose), while in the ileum, adaptation occurred both in acute and chronically diabetic rats and consisted of 1) a 3-fold increase in density of phlorizin binding sites in the upper villus region of acutely diabetic rats and 2) an increased density in the upper villus region as well as the recruitment of phlorizin binding sites in the mid to lower villus region (i.e., that portion not normally transporting glucose) of chronically diabetic rats. Enhancement of glucose Vmax and villus length accompanied changes in binding, whereas enterocyte birth rates were similar in each group.


Making Sense of Multifunctional Proteins: Human Immunodeficiency Virus Type 1 Accessory and Regulatory Proteins and Connections to Transcription.
Viruses are completely dependent upon cellular machinery to support replication and have therefore developed strategies to co-opt cellular processes to optimize infection and counter host immune defenses. Many viruses, including human immunodeficiency virus type 1 (HIV-1), encode a relatively small number of genes. Viruses with limited genetic content often encode multifunctional proteins that function at multiple stages of the viral replication cycle. In this review, we discuss the functions of HIV-1 regulatory (Tat and Rev) and accessory (Vif, Vpr, Vpu, and Nef) proteins. Each of these proteins has a highly conserved primary activity; however, numerous additional activities have been attributed to these viral proteins. We explore the possibility that HIV-1 proteins leverage their multifunctional nature to alter host transcriptional networks to elicit a diverse set of cellular responses. Although these transcriptional effects appear to benefit the virus, it is not yet clear whether they are strongly selected for during viral evolution or are a ripple effect from the primary function. As our detailed knowledge of these viral proteins improves, we will undoubtedly uncover how the multifunctional nature of these HIV-1 regulatory and accessory proteins, and in particular their transcriptional functions, work to drive viral pathogenesis.


Evaluation of OnabotulinumtoxinA Treatment in Patients with Concomitant Chronic Migraine and Temporomandibular Disorders.
Migraine and temporomandibular disorders (TMD) are both common diseases and TMD are reported as a risk factor in migraine progression. OnabotulinumtoxinA is used in the treatment of chronic migraine (CM), and also has a potential role in TMD treatment. In this study, it is aimed to compare the efficacy of onabotulinumtoxinA treatment in CM patients with and without TMD. In this retrospective study, 30 CM patients (age range: 18-65 years), satisfying the inclusion and follow-up criteria in their medical records were investigated. The PREEMPT injection protocol was taken as reference and onabotulinumtoxinA 155-195 U with fixed-dose has been administered into 31 specific sites within the head/neck muscles in included subjects. Two cycles of treatment were assessed in all patients at the baseline and 12 weeks later. The headache diaries, which were completed routinely one month before, and during 6 months follow-up after the treatment, were assessed. The effect of onabotulinumtoxinA treatment was compared between CM patients with and without TMD/bruxism. Of 30 female patients, 17 had concomitant TMD. In week 24, there were significant improvement in the groups with and without TMD regarding to the mean change of frequencies in the days with migraine compared to the initial findings (p<0.001). However, there was no significant difference between the two groups. OnabotulinumtoxinA is an effective and safe treatment for CM. Its efficacy appears to be similar in CM patients with and without TM, speculating that the comorbidity of TMD did not play a role for the treatment response.


A general method for determining the functional role of a muscle.
This paper presents a general classification method for determining the functional role of any muscle, and a procedure for determining the sensitivity of that role to small changes in system parameters. The classification method is based on the premise that the system model, when acted upon solely by the muscle of interest, will depart from any initial rest configuration in such a way as to decrease the muscle's length. This method is particularly useful for multiple-joint muscles, and is illustrated by examining a slider-crank mechanism and straight line muscle model to determine the functional role of the hamstrings during a constrained leg flexion motion.


Evidence that behavioural and electrocortical sleep induced by guanfacine is due to stimulation of alpha 2-adrenoceptors.
The effects of guanfacine and other drugs acting at alpha 1- and alpha 2-adrenoceptors on behaviour, electrocortical activity and ECoG spectrum power were studied in chicks and rats. Guanfacine, given systematically in chicks, produced behavioural and electrocortical slow-wave sleep lasting 100-200 min, depending on the dose; these effects were prevented by yohimbine, a selective antagonist, at alpha 2-adrenoceptors and potentiated by prazosin, a selective antagonist, at alpha 1-adrenoceptors. Similar behavioural and electrocortical effects were obtained after systemic or intraventricular infusion of guanfacine in rats. In addition, a significant increase in total and in lower frequency band (0-4; 4-8 Hz) voltage power was observed. Behavioural and ECoG effects of guanfacine were prevented by phentolamine or yohimbine, whereas prazosin and propranolol were ineffective. Yohimbine itself, given systemically in chicks, produced behavioural stimulation, vocalization, increase in locomotor activity and ECoG desynchronization, with a significant fall in total and 0-3, 3-6, 6-9 and 9-12 Hz voltage power lasting approx. 3 h. Desipramine, an inhibitor of noradrenaline reuptake, produced in chicks behavioural and ECoG arousal, vocalization, pecking, escape responses and aggressive behaviour. In conclusion, the present experiments show that guanfacine sedative effects seem to be mediated predominantly via an activation of presynaptic alpha 2-adrenoceptors and suggest that arousal is due to stimulation of post-synaptic alpha 1-adrenoceptors.


High efficiency removal of Pb(ii) in aqueous solution by a biochar-supported nanoscale ferrous sulfide composite.
A biochar-supported nanoscale ferrous sulfide composite was prepared and applied for the treatment of Pb(ii) ions in aqueous solution. The experimental results of SEM, EDS, XRD, and FT-IR spectroscopy clearly implied that the biochar was successfully modified with nanoscale ferrous sulfide composite. The maximum adsorption capacity of Pb(ii) ions by FeS@biochar reached 88.06 mg g-1. Compared with other reported adsorbents, the removal rate of Pb(ii) ions by FeS@biochar was higher. The pseudo-second-order kinetic model and Langmuir isotherm model could better fit the experimental adsorption results. The removal rate of Pb(ii) ions by FeS@biochar was controlled by the chemical reaction and monolayer adsorption on the surface of FeS@biochar. The mechanisms of Pb(ii) removal from aqueous solutions by biochar involved electrostatic attraction, hydrogen bonding, physical adsorption, ion exchange, and chemical precipitation. Additionally, the chemical stability and reusability of FeS@biochar were good. It is also an environment-friendly material for low-cost wastewater treatment.


Is self-reporting workplace activity worthwhile? Validity and reliability of occupational sitting and physical activity questionnaire in desk-based workers.
With the advent of workplace health and wellbeing programs designed to address prolonged occupational sitting, tools to measure behaviour change within this environment should derive from empirical evidence. In this study we measured aspects of validity and reliability for the Occupational Sitting and Physical Activity Questionnaire that asks employees to recount the percentage of work time they spend in the seated, standing, and walking postures during a typical workday. Three separate cohort samples (N = 236) were drawn from a population of government desk-based employees across several departmental agencies. These volunteers were part of a larger state-wide intervention study. Workplace sitting and physical activity behaviour was measured both subjectively against the International Physical Activity Questionnaire, and objectively against ActivPal accelerometers before the intervention began. Criterion validity and concurrent validity for each of the three posture categories were assessed using Spearman's rank correlation coefficients, and a bias comparison with 95 % limits of agreement. Test-retest reliability of the survey was reported with intraclass correlation coefficients. Criterion validity for this survey was strong for sitting and standing estimates, but weak for walking. Participants significantly overestimated the amount of walking they did at work. Concurrent validity was moderate for sitting and standing, but low for walking. Test-retest reliability of this survey proved to be questionable for our sample. Based on our findings we must caution occupational health and safety professionals about the use of employee self-report data to estimate workplace physical activity. While the survey produced accurate measurements for time spent sitting at work it was more difficult for employees to estimate their workplace physical activity.


Nudging the obese: a UK-US consideration.
Over recent years, nudge policies have become increasingly popular (if somewhat confused) internationally. This article attempts to clarify what a nudge entails, and critically summarises some of the nudge policies that have been proposed to motivate weight loss in the United Kingdom and the United States. Despite the fact that most of the evidence on nudge-related policy has so far been produced in the United States, and that the leading nudge champions are American, the United Kingdom, at least with respect to considering policy interventions of this kind at the national level, appears to be relatively advanced. That said, nudge interventions remain of marginal practical import everywhere, and are never going to solve completely the obesity problem. Nonetheless, even a marginal effect may extend and improve many lives, a result that would satisfy most behavioural economists.


Stain-free detection of embryo polarization using deep learning.
Polarization of the mammalian embryo at the right developmental time is critical for its development to term and would be valuable in assessing the potential of human embryos. However, tracking polarization requires invasive fluorescence staining, impermissible in the in vitro fertilization clinic. Here, we report the use of artificial intelligence to detect polarization from unstained time-lapse movies of mouse embryos. We assembled a dataset of bright-field movie frames from 8-cell-stage embryos, side-by-side with corresponding images of fluorescent markers of cell polarization. We then used an ensemble learning model to detect whether any bright-field frame showed an embryo before or after onset of polarization. Our resulting model has an accuracy of 85% for detecting polarization, significantly outperforming human volunteers trained on the same data (61% accuracy). We discovered that our self-learning model focuses upon the angle between cells as one known cue for compaction, which precedes polarization, but it outperforms the use of this cue alone. By compressing three-dimensional time-lapsed image data into two-dimensions, we are able to reduce data to an easily manageable size for deep learning processing. In conclusion, we describe a method for detecting a key developmental feature of embryo development that avoids clinically impermissible fluorescence staining.


Prevalence of different subtypes of serrated polyps and risk of synchronous advanced colorectal neoplasia in average-risk population undergoing first-time colonoscopy.
A growing body of evidence indicates that patients with sessile serrated adenoma/polyp (SSA/P) and traditional serrated adenoma (TSA) are at risk for subsequent malignancy. Despite increasing knowledge on histological categorization of serrated polyps (SPs) data are lacking on the actual prevalence and the association of each SP subtype with advanced colorectal neoplasia. We prospectively determined the prevalence of different SP subtypes and evaluate the association with synchronous advanced neoplasia in asymptomatic average-risk subjects undergoing first-time colonoscopy. All retrieved polyps were examined by two independent pathologists. Serrated lesions were classified into hyperplastic polyps (HP), SSA/P (without and with cytological dysplasia, SSA/P/DIS), and TSA, and were screened for BRAF and K-ras mutations. Among 258 polyps detected in 985 subjects, the proportion of SSA/P and TSA was 8.9% and 1.9% with an overall prevalence of 2.3% and 0.6%, respectively. SSA/Ps were small without significant difference in their location between proximal and distal colon; TSA were predominantly left-sided. BRAF mutation was common in SSA/Ps and K-ras mutation was present in all TSA. Independent predictors of advanced neoplasia were male sex (odds ratio (OR)=2.0, 95% confidence interval (CI) 1.0-4.0), increasing age (OR=4.5, 95% CI 1.5-13.4 for 50-69 years and OR=9.9, 95% CI 3.1-31.5 for >70 years), current smoking (OR=2.0, 95% CI 1.3-6.8), >3 tubular adenoma (OR=3.6, 95% CI 1.9-6.4), and SSA/P (OR=6.0, 95% CI 1.9-19.5). The substantial prevalence of BRAF-mutated SSA/P and the independent association with synchronous advanced colorectal neoplasia in asymptomatic average-risk subjects support the overall impact of the serrated pathway on colorectal cancer (CRC) risk in general population. The endoscopic characteristics of SSA/P emphasize the need of high-quality colonoscopy as a key factor for an effective CRC screening program.


Metabolism of 7,12-dimethylbenz[a]anthracene by Cunninghamella elegans.
The metabolites of 7,12-dimethylbenz[a]anthracene (DMBA), a carcinogenic polycyclic aromatic hydrocarbon, in cultures of Cunninghamella elegans were isolated by high-pressure liquid chromatography and characterized by UV spectroscopy and mass spectrometry. The major metabolites were DMBA-trans-8,9-dihydrodiol and DMBA-trans-3,4-dihydrodiol. The 7-hydroxymethyl and the 12-hydroxymethyl derivatives of these dihydrodiol metabolites were also formed. The metabolic profile described in this report contrasts with those obtained in our earlier experiments in which the incubation of DMBA with Pseudomonas aeruginosa and Penicillium notatum produced no dihydrodiol metabolites but only methyl-hydroxylated metabolites.


Identification of small non-coding RNAs from mitochondria and chloroplasts.
Small non-protein-coding RNAs (ncRNAs) have been identified in a wide spectrum of organisms ranging from bacteria to humans. In eukarya, systematic searches for ncRNAs have so far been restricted to the nuclear or cytosolic compartments of cells. Whether or not small stable non-coding RNA species also exist in cell organelles, in addition to tRNAs or ribosomal RNAs, is unknown. We have thus generated cDNA libraries from size-selected mammalian mitochondrial RNA and plant chloroplast RNA and searched for small ncRNA species in these two types of DNA-containing cell organelles. In total, we have identified 18 novel candidates for organellar ncRNAs in these two cellular compartments and confirmed expression of six of them by northern blot analysis or RNase A protection assays. Most candidate ncRNA genes map to intergenic regions of the organellar genomes. As found previously in bacteria, the presumptive ancestors of present-day chloroplasts and mitochondria, we also observed examples of antisense ncRNAs that potentially could target organelle-encoded mRNAs. The structural features of the identified ncRNAs as well as their possible cellular functions are discussed. The absence from our libraries of abundant small RNA species that are not encoded by the organellar genomes suggests that the import of RNAs into cell organelles is of very limited significance or does not occur at all.


Nonsense mutations in the human beta-globin gene lead to unexpected levels of cytoplasmic mRNA accumulation.
Generally, nonsense codons 50 bp or more upstream of the 3'-most intron of the human beta-globin gene reduce mRNA abundance. In contrast, dominantly inherited beta-thalassemia is frequently associated with nonsense mutations in the last exon. In this work, murine erythroleukemia (MEL) cells were stably transfected with human beta-globin genes mutated within each of the 3 exons, namely at codons 15 (TGG-->TGA), 39 (C-->T), or 127 (C-->T). Primer extension analysis after erythroid differentiation induction showed codon 127 (C-->T) mRNA accumulated in the cytoplasm at approximately 20% of the normal mRNA level. Codon 39 (C-->T) mutation did not result in significant mRNA accumulation. Unexpectedly, codon 15 (TGG-->TGA) mRNA accumulated at approximately 90%. Concordant results were obtained when reticulocyte mRNA from 2 carriers for this mutation was studied. High mRNA accumulation of codon 15 nonsense-mutated gene was revealed to be independent of the type of nonsense mutation and the genomic background in which this mutation occurs. To investigate the effects of other nonsense mutations located in the first exon on the mRNA level, nonsense mutations at codons 5, 17, and 26 were also cloned and stably transfected into MEL cells. After erythroid differentiation induction, mRNAs with a mutation at codon 5 or 17 were detected at high levels, whereas the mutation at codon 26 led to low mRNA levels. These findings suggest that nonsense-mediated mRNA decay is not exclusively dependent on the localization of mutations relative to the 3'-most intron. Other factors may also contribute to determine the cytoplasmic nonsense-mutated mRNA level in erythroid cells. (Blood. 2000;96:2895-2901)


Public perception regarding anterior cruciate ligament reconstruction.
Relatively little information exists regarding the public's perception of anterior cruciate ligament (ACL) injuries and their treatment. The objective of this study was to test the hypothesis that the public's understanding of ACL surgery may be incorrect with regard to various aspects of this procedure and to identify issues to emphasize in patient education. This study utilized a forty-three-question survey designed to measure an individual's knowledge base and perception of ACL reconstruction with regard to the anatomy, function, indications, operative technique, risks, recovery time, and overall benefits of the procedure. Eligible individuals were between fifteen and sixty years of age. Study participants were recruited from an academic orthopaedic sports medicine clinic, a collegiate athletic training room, and various public venues. A total of 210 individuals (106 men and 104 women) with a mean age of thirty were surveyed. Educational level of the respondents varied widely. Twenty-seven percent of the respondents were employed in a health-care setting. Sixty-five percent of the respondents rated their ACL knowledge level as "little" or "none." Participants' self-perception of ACL knowledge was highly correlated with their survey scores on questions with a specific correct answer (p < 0.001). Almost one-third thought that surgical treatment involved repair of the torn ligament rather than reconstruction. Over half (56%) of the respondents preferred an autograft for ligament reconstruction, compared with 4% who preferred an allograft. The ability to return to sports after ACL surgery was the most important concern, followed by the risk of developing osteoarthritis. There is wide variability in the lay public's knowledge level of ACL injuries; a substantial number of misguided perceptions were identified. Return to sports and risk for future osteoarthritis following ACL surgery appear to be the most important factors to the lay public. Focusing educational efforts on areas of knowledge deficits may be particularly important for patients of physicians who treat ACL injuries.


Validity of Boston marathon qualifying times.
To assess the validity of Boston Marathon qualifying (BMQ) standards for men and women. Percent differences between BMQ and current world records (WR) by sex and age group were computed. WR was chosen as the criterion comparison because it is not confounded by intensity, body composition, lifestyle, or environmental factors. A consistent difference across age groups would indicate an appropriate slope of the age-vs-BMQ curve. Inconsistent differences were corrected by adjusting BMQ standards to achieve a uniform percentage difference from WR. BMQ standards for men were consistently ~50% slower than WR (mean 51.5% ± 1.4%, range 49.6-54.4%), thus demonstrating acceptable validity. However, BMQ standards for women indicated convergence with WR as age increased (mean 45.8% ± 13.7%, range 17.5-58.9%). The women's BMQ standards were revised to yield a consistent 50% deviation from WR across age groups (50.9% ± 0.8%, range 49.2-52.2%). Applied to all 16,773 women in the 2012 Chicago Marathon, the suggested BMQ standards would lead to a 4.90% success rate, compared with 8.39% using the current standard. This compared with a 9.6% success rate for all 20,681 men of the same race. The current women's BMQ standards appear too lenient for women 18-54 y and too strict for women 55-80 y but yield equitable gender representation in percentage of qualifiers. The current men's and suggested women's BMQ standards appear valid but would lead to approximately 40% fewer women achieving BMQ standards.


Acrylamide toxicity in aquatic animals and its mitigation approaches: an updated overview.
Acrylamide (ACR) is widely applied in various industrial activities, as well as in the water purification process. Furthermore, ACR is synthesized naturally in some starchy grains exposed to high temperatures for an extended time during the cooking process. Because of its widespread industrial usage, ACR might be released into water stream sources. Also, ACR poses a high risk of contaminated surface and ground-water resources due to its high solubility and mobility in water. Furthermore, animal studies have indicated that ACR exposure may cause cancer (in many organs such as lung, prostate, uterus, and pancreas), genetic damage (in both somatic and germ cells), and severe effects on reproduction and development. Recently, numerous studies have shown that ACR has a mild acute cytotoxic impact on aquatic species, particularly during early life stages. Besides, wide-spectrum usage of ACR in many industrial activities presented higher environmental risks as well as major hazards to consumer health. This literature was designed to include all potential and accessible reports on ACR toxicity related with aquatic species. The Preferred Reporting Items for Systematic Reviews were applied to evaluate the risk effects of ACR on aquatic organisms, the ACR sub-lethal concentration in the ecosystem, and the possible protective benefits of various feed additives against ACR toxicity in fish. The major findings are summarized in Tables 2 and 3. The primary aim of this literature was to specify the hazards of ACR toxicity related with fish welfare and possible suggested strategies to reduce its risks.


Neuropsychological and Clinical Profiles of Children and Adolescents Diagnosed with Childhood Obsessive Compulsive Disorder.
The differential features of childhood-onset obsessive compulsive disorder (OCD) compared to adult-onset OCD are being more of a focus of attention in recent years. The aim of this study was to determine the clinical and neuropsychological profiles of children and adolescents diagnosed with childhood-onset OCD and to investigate the association between the duration, severity, comorbidity, and family history of the disorder and clinical and neuropsychological functional impairments. Thirty-five OCD patients (patient group) and 35 healthy control subjects (control group) between 8-15 years of age were included. To investigate the neuropsychological profiles, the Wisconsin Card Sorting Test (WCST), Stroop Test, and Continuous Performance Test (CPT) were applied. To assess the clinical and behavioral profiles, the Children's Depression Inventory (CDI), Conner's Parent Rating Scale (CPRS-48), and the Yale Brown Obsessive Compulsive Scale (YB-OCS) and Yale Global Tic Severity Rating Scale (YGTSRS) were given. Based on the performance in the WCST, Stroop Test, and SPT, the results of the study reveal that childhood-onset OCD patients have statistically significant worse performance compared to healthy controls in terms of executive functions, sustained attention, and motor inhibition tasks. Excluding the comorbid diagnoses, childhood-onset OCD patients did not show a difference in behavioral problems, but they had higher levels of anxiety compared to healthy controls. The findings of this study reveal that independent of the duration, severity, comorbid problems, and anxiety levels, the disorder itself is associated with worse performance in executive functions, attention, and motor inhibition processes, and a positive family history of OCD is an important risk factor. Long-term follow-up studies with patients diagnosed with childhood-onset OCD would be a logical next step in order to determine the cause-effect relation between the disorder and cognitive impairments.


Hyperammonemia alters the modulation by different neurosteroids of the glutamate-nitric oxide-cyclic GMP pathway through NMDA- GABAA - or sigma receptors in cerebellum in vivo.
Several neurosteroids modulate the glutamate-nitric oxide (NO)-cGMP pathway in cerebellum through modulation of NMDA- GABAA - or sigma receptors. Hyperammonemia alters the concentration of several neurosteroids and impairs the glutamate-NO-cGMP pathway, leading to impaired learning ability. This work aimed to assess whether chronic hyperammonemia alters the modulation by different neurosteroids of GABAA, NMDA, and/or sigma receptors and of the glutamate-NO-cGMP pathway in cerebellum. Neurosteroids were administered through microdialysis probes, and extracellular cGMP and citrulline were measured. Then NMDA was administered to assess the effects on the glutamate-NO-cGMP pathway activation. Hyperammonemia completely modifies the effects of pregnanolone and pregnenolone. Pregnanolone acts as a GABAA receptor agonist in controls, but as an NMDA receptor antagonist in hyperammonemic rats. Pregnenolone does not induce any effect in controls, but acts as a sigma receptor agonist in hyperammonemic rats. Hyperammonemia potentiates the actions of tetrahydrodeoxy-corticosterone (THDOC) as a GABAA receptor agonist, allopregnanolone as an NMDA receptor antagonist, and pregnenolone sulfate as an NMDA receptor activation enhancer. Neurosteroids that reduce the pathway (pregnanolone, THDOC, allopregnanolone, DHEAS) may contribute to cognitive impairment in hyperammonemia and hepatic encephalopathy. Pregnenolone would impair cognitive function in hyperammonemia. Neurosteroids that restore the pathway in hyperammonemia (pregnenolone sulfate) could restore cognitive function in hyperammonemia and encephalopathy.


[Sonographic study of Béclard's nucleus as a method of determining the maturity of the newborn infant].
The size of the distal femoral epiphysis is an important criterion for determining the maturity of a neonate. The distal femoral epiphysis has been demonstrated and measured sonographically in two planes during the first month of life in 174 neonates. The sum of the epiphyseal diameters has been related to gestational age. The average sum of the sagittal and transverse diameter of both distal femoral epiphysis was 10.9 mm in the 35th week (standard deviation 7.6 mm) and increases to 38.4 mm at 43 weeks (standard deviation 6.3 mm). Linear regression of the mean values of the sum of the epiphyseal diameters y against gestational age x shows a correlation coefficient of 0.95 (regression gradient y = -117.7 + 3.7 x). Sonographic demonstration and measurements of the distal femoral epiphyses is a valid alternative to radiological examination.


Prognostic significance of exercise-induced premature ventricular complexes: a systematic review and meta-analysis of observational studies.
Exercise-induced premature ventricular complexes (EI-PVCs) are common during exercise stress tests. Their optimal management and prognostic significance remain uncertain. To perform meta-analysis of observational studies on the prognostic significance of EI-PVCs. A search was conducted on Medline and Embase. Inclusion criteria were observational studies comparing the prognosis of patients with and without EI-PVCs whilst exclusion criteria were studies without confounder adjustment and studies with zero endpoints. Composite endpoints included all-cause mortality, cardiac mortality and cardiovascular events. Relative risk of endpoints were analysed with random effects model. Meta-regression and sensitivity analysis were performed. Ten studies were included. In asymptomatic patients who had no clinical evidence of heart disease, EI-PVCs were associated with a pooled risk ratio of 1.82 (95% CI 1.44 to 2.30) of developing adverse cardiovascular events over 16 years. The corresponding pooled RR for patients with symptomatic heart disease was 1.36 (95% CI 1.18 to 1.57) over 5.4 years. Sensitivity analysis: only EI-PVCs on the recovery phase of an exercise test, not during exercise, had adverse prognostic significance. EI-PVCs are correlated with a higher risk of all cause death or cardiovascular events in the long term. This risk is elevated in asymptomatic patients without clinical heart disease and in patients with symptomatic heart disease. The fact that only EI-PVCs during recovery, and not during exercise, have poor prognostic value suggests that autonomic dysfunction may play a role in this association. Further studies are needed to see if autonomic manipulation by drugs or catheter-based methods can improve the poor prognosis associated with EI-PVCs.


Transfection with the isolated herpes simplex virus thymidine kinase genes. II. Evidence for amplification of viral and adjacent cellular DNA sequences.
We have previously described several series of biochemical transformation experiments in which small defined portions of herpes simplex virus (HSV-1 and HSV-2) DNA encompassing the thymidine kinase (TK) gene were introduced into Ltk- cells by the calcium transfection procedure. The presence of authentic virus TK enzyme in several subcloned cell lines derived from these experiments was confirmed by either the specific incorporation of [125I]iododeoxycytidine into their nuclei or the inhibition of cell growth by the antiviral drug arabinosyl thymine. A panel of 24 independent Ltk+ cell lines receiving either isolated virus DNA fragments or cleaved plasmid DNAs was examined by blot hybridization for both the presence and copy number of virus TK DNA sequences. Most cell lines contained a single virus DNA fragment covalently joined to host (or carrier Ltk-) mouse DNA sequences, but several contained multiple copies of the TK gene. Examination of the structural arrangement of the virus DNA in two early passage multicopy cell lines indicated that the TK gene had integrated into Ltk- cell DNA and then subsequently both viral and flanking cellular sequences were amplified to create up to 20 tandem duplications. In one case, mapping of the adjacent cellular sequences has revealed that the total repeat unit is greater that 23 kilobases (kb) in size. On subsequent passaging, even in HAT medium, the amplified repeat units were not stable and fell to only three to four copies per haploid cell genome. These cell lines should prove useful for additional studies to examine the expression of co-selected non-TK virus sequences and the influence of adjacent cellular DNA sequences on transcription and retransfection of the resident TK gene.


Rapid Isolation of Single Cells from Mouse and Human Teeth.
Mouse and human teeth represent challenging organs for quick and efficient cell isolation for single-cell transcriptomic or other applications. The dental pulp tissue, rich in the extracellular matrix, requires a long and tedious dissociation process that is typically beyond the reasonable time for single-cell transcriptomics. For avoiding artificial changes in gene expression, the time elapsed from euthanizing an animal until the analysis of single cells needs to be minimized. This work presents a fast protocol enabling to obtain single-cell suspension from mouse and human teeth in an excellent quality suitable for scRNA-seq (single-cell RNA-sequencing). This protocol is based on accelerated tissue isolation steps, enzymatic digestion, and subsequent preparation of final single-cell suspension. This enables fast and gentle processing of tissues and allows using more animal or human samples for obtaining cell suspensions with high viability and minimal transcriptional changes. It is anticipated that this protocol might guide researchers interested in performing the scRNA-seq not only on the mouse or human teeth but also on other extracellular matrix-rich tissues, including cartilage, dense connective tissue, and dermis.


Lifestyle behaviors and physician advice for change among overweight and obese adults with prediabetes and diabetes in the United States, 2006.
The objective of this study was to examine the lifestyle behaviors of overweight and obese people with prediabetes or diabetes and to determine whether an association exists between reported behaviors and physician advice for behavior change. This investigation included overweight and obese people (body mass index ≥25.0 kg/m(2)) with prediabetes and diabetes aged 40 years or older identified from the 2006 National Health Interview Survey. Respondents reported attempts to control or lose weight, reduce the amount of fat or calories in their diet, and increase physical activity. Respondents also reported receipt of a physician recommendation for behavioral change in 1 or more of these areas. Data analysis included use of logistic regression stratified by sex and prediabetes/diabetes status to model odds of behavior by physician advice. Most people reported trying to control or lose weight (prediabetes, 82%; diabetes, 75%). Fewer identified efforts to reduce the amount of fat or calories in their diet (prediabetes, 62%; diabetes, 71%) or increase physical activity (prediabetes, 53%; diabetes, 57%). Approximately one-third reported not receiving physician advice for each of these behavior changes. In logistic regression, physician advice for reducing the amount of fat or calories in the diet and increasing physical activity was generally associated with the reported corresponding behavior. Many respondents reported trying to control or lose weight, but fewer reported actually reducing fat or calories in their diet or increasing physical activity. Physician advice may influence attempts at behavior change among overweight and obese patients with prediabetes and diabetes.


Concomitant immunization by the fully antigenic counterparts prevents modulated tumor cells from escaping cellular immune elimination.
In a mathematical model of the cellular antitumor immune response, we studied the possible role of antigenic modulation as a tumor escape mechanism. Modulated tumor cells arise from normal (fully antigenic) tumor cells when the latter interact with antibodies. Modulated tumor cells demodulate when antibody concentrations are sufficiently low. Through modulation, tumor cells become less sensitive to cytotoxic macrophages (cell lysis) and contribute less to the stimulation of the immune system. These experimental data are incorporated in a model which we have analyzed previously. The model incorporates interactions between macrophages and T lymphocytes, which lead to cellular antitumor immune reactions (i.e., to cytotoxic macrophages). Parameters were derived from the immune resistance of DBA/2 mice to the SL2 tumor. Although all parameters were chosen deliberately to favor the modulation process (i.e., modulation proceeds fast, demodulation slowly, and the killing rate is reduced 50-fold), modulation is found to be a poor tumor escape mechanism. Heterogeneous populations of modulated and normal tumor cells are easily rejected. Homogeneous populations of modulated cells do escape, however. We conclude that the impact of modulation as an escape mechanism remains small because modulated tumor cells do not appear until the immune system has been stimulated (immunized) by the fully antigenic tumor cells. Thus, the elimination of modulated tumor cells generally occurs merely as a side effect of the immune response which is directed primarily against the fully antigenic tumor cells. Parameter sensitivity analysis shows that this conclusion holds true only for cellular immunity. Conversely, the parameter analysis suggests that antigenic modulation plays a deleterious role in cytotoxic antibody responses (e.g., monoclonal antibody therapy).


Vedolizumab for Ulcerative Colitis: Treatment Outcomes from the VICTORY Consortium.
We aimed to quantify the safety and effectiveness of vedolizumab (VDZ) when used for UC, and to identify predictors of response to treatment. Retrospective review (May 2014-December 2016) of VICTORY Consortium data. Adults with follow-up after starting VDZ for clinically active UC were included. Primary effectiveness outcomes were cumulative rates of clinical remission (resolution of all UC-related symptoms) and endoscopic remission (Mayo endoscopic sub-score 0). Key secondary effectiveness outcomes included cumulative rates of corticosteroid-free remission and deep remission (clinical remission and endoscopic remission). Cox proportional hazard analyses were used to identify independent predictors of treatment effectiveness. Non-response imputation (NRI) sensitivity analyses were performed for effectiveness outcomes. Key safety outcomes were rates of serious infection, serious adverse events, and colectomy. We included 321 UC patients (71% prior TNFα antagonist exposure, median follow-up 10 months). The 12-month cumulative rates of clinical remission and endoscopic remission were 51% and 41%, respectively. Corresponding rates for corticosteroid-free remission and deep remission were 37% and 30%, respectively. Using NRI, 12-month rates were 20% (n = 64/321) for clinical remission, 17% (n = 35/203) for endoscopic remission, 15% (n = 30/195) for corticosteroid-free remission, and 14% (n = 28/203) for deep remission. A majority of the patients without adequate follow-up at 12 months who were deemed non-responders using NRI had already achieved clinical remission (n = 70) or a significant clinical response (n = 36) prior to 12 months. VDZ discontinuation prior to 12 months was observed in 91 patients, for lack of response (n = 56), need for surgery (n = 29), or adverse event (n = 6). On multivariable analyses, prior exposure to a TNFα antagonist was associated with a reduced probability of achieving clinical remission (HR 0.53, 95% CI 0.38-0.75) and endoscopic remission (HR 0.51, 95% CI 0.29-0.88). Serious adverse events and serious infections were reported in 6% and 4% of patients, respectively. Overall cumulative rates of colectomy over 12 months were 13%, with lower rates observed in patients naive to TNFα antagonist therapy (2%) than those who had been exposed to TNFα antagonists (19%). In this large real-world cohort we observed that VDZ was well tolerated and effective in achieving key clinical outcomes.


Paternal smoking is associated with a decreased prevalence of type 1 diabetes mellitus among offspring in two national British birth cohort studies (NCDS and BCS70).
An association between paternal age and type 1 diabetes (IDDM) among their offspring was recently reported as well as transgenerational responses in humans. This paper aims to assess the association of markers for prenatal exposures with IDDM. We analysed data from two birth cohorts in Great Britain on 5214 cohort members from the National Child Development Study (NCDS) and 6068 members of the 1970 British Birth Cohort Study (BCS70) with full information on IDDM and explanatory variables using multivariate logistic regression. IDDM prevalence was 0.7% (95% CI 0.5-1.0%; n=38) in the NCDS and 0.4% (95% CI 0.3-0.6%; n=27) in the BCS70 cohort. Paternal age was not associated with IDDM possibly due to lack of sample power. Unexpectedly, a lowered prevalence of IDDM was observed among offspring of smoking fathers in both cohorts, with a combined odds ratio of 0.44 (95% CI 0.25-0.75). This association could not be explained by maternal smoking prior to, during or after pregnancy, number of siblings, parental social class, maternal and paternal age, or cohort. Maternal smoking in pregnancy did not alter the IDDM prevalence among offspring. This unexpected finding may be explained by germ-line mutations or other mechanisms associated with paternal smoking. This phenomenon should be investigated and these results should not be used as a justification for smoking. Paternal exposures may be important in determining IDDM risk.


Ultrastructural analysis between fetal and adult wound healing process of marsupial opossum skin.
The opossum delivers a newborn baby equivalent to tremature fetus state by postpregnancy. The peculiarity is advantageous for studies of fetus, because operations to take out fetus from the uterus of a mother are not necessary. When mammalian skin is wounded by full-thickness excision, fetal and adult wound healing processes differ. Fetal-type wound healing does not leave a scar. However, studies of how the fetal wound healing process differs in detail from the adult type are not advanced. We first observed the normal skin development of the gray short-tailed opossum (Monodelphis domestica) using an electron microscope. As for normal skin, an epidermis became multi-layered, and thickened from birth through to 7 days after birth. The quantity of extracellular matrix of the dermis increased thereafter, and several types of cells were found in the dermis. To examine the wound healing, we used material from a 1 day-old newborn baby, and from another 15 days after birth, and compared the wound healing style morphologically. Differences in the constitution of cells and fine structures of the skin were observed, it was obviously suggested that change in the wound healing style from fetal-type to adult-type occurred between 1 to 15 days after birth.


Circulating T and B lymphocytes in progressive systemic sclerosis.
Thymus derived (T) and bone-marrow derived (B) lymphocytes were quantitated in 11 untreated patients with progressive systemic sclerosis (PSS) and in 11 age and sex matched controls. T and B lymphocytes were identified according to their receptor sites for sheep red blood cells and activated complement, respectively. All patients had a normal lymphocyte count. The mean per cent value of circulating T lymphocytes was less in PSS patients (38 per cent) as compared with controls (56 per cent) (P less than 0.005), while no significant difference existed for the circulating B lymphocytes (PSS 14 per cent; controls 11 per cent). The mitogenic response to phytohemagglutinin (PHA) was assessed by comparing dose response curves in PSS with those obtained from matched controls. No significant difference could be detected between these groups.


The molecular basis of brown, an old mouse mutation, and of an induced revertant to wild type.
The murine b locus encodes the tyrosinase related protein, TRP-1, a putative membrane-bound, copper-containing enzyme having about 40% amino acid identity with tyrosinase. The protein is essential for production of black rather than brown hair pigment. We show that skin of mutant brown mice contains the same amount of TRP-1 mRNA as wild type. On sequencing the coding region of the mutant mRNA we find four nucleotide differences from the wild-type (Black) sequence. Two of these differences result in different amino acid residues encoded by the brown allele. By sequencing the TRP-1 gene from a mouse in which a reversion from brown to Black has been induced by ethylnitrosourea we are able to show that only one of these amino acid changes, which substitutes a tyrosine for a conserved cysteine, is the cause of the brown phenotype. This mutation is adjacent to another cysteine at which, in the analogous position in tyrosinase a mutation results in the albino phenotype. The sequence of the revertant is the first report of DNA sequence of an ethylnitrosourea-induced genetic change in mouse.


H pylori-induced thrombocytopenia in a Caucasian female: a case report.
We present a rare, but increasingly recognised, cause of thrombocytopenia in a 69-year-old Caucasian female. Complete haematological investigation, including blood films and autoantibody screen, did not reveal a cause for her thrombocytopenia. Omission of potentially offending medication did not improve the low platelet count. She had no features of systemic infection or inflammatory disease on history and examination. In light of persistent thrombocytopenia, Helicobacter pylori stool antigen was tested, and found to be positive. Platelet count improved after eradication therapy for H pylori. This prevented the need for steroid and immunoglobulin treatment in this patient.


Mood sensitivity to estradiol predicts depressive symptoms in the menopause transition.
The risk for depression markedly rises during the 5-6 years leading up to the cessation of menstruation, known as the menopause transition. Exposure to extreme estradiol levels may help explain this increase but few studies have examined individual sensitivity to estradiol in predicting perimenopausal depression. The current study recruited 101 perimenopausal women. During Phase 1, we quantified each woman's sensitivity to changes in estradiol using 12 weekly measures of estrone-3-glucuronide (E1G), a urinary metabolite of estradiol, and concurrent depressive symptoms. The weekly cortisol awakening response was measured to examine the hypothalamic-pituitary-adrenal (HPA) axis in mediating mood sensitivity to estradiol. In Phase 2, depressive symptoms and major depression diagnoses were assessed monthly for 9 months. The relationship between Phase 1 E1G sensitivity and Phase 2 depressive symptoms and major depressive episodes was examined. Several baseline characteristics were examined as potential moderators of this relationship. The within-person correlation between weekly E1G and mood varied greatly from woman to woman, both in strength and direction. Phase 1 E1G mood sensitivity predicted the occurrence of clinically significant depressive symptoms in Phase 2 among certain subsets of women: those without a prior history of depression, reporting a low number of baseline stressful life events, and reporting fewer months since their last menstrual period. HPA axis sensitivity to estradiol fluctuation did not predict Phase 2 outcomes. Mood sensitivity to estradiol predicts risk for perimenopausal depression, particularly among women who are otherwise at low risk and among those who are early in the transition.


Immunopeptidomics-based design of mRNA vaccine formulations against Listeria monocytogenes.
Listeria monocytogenes is a foodborne intracellular bacterial pathogen leading to human listeriosis. Despite a high mortality rate and increasing antibiotic resistance no clinically approved vaccine against Listeria is available. Attenuated Listeria strains offer protection and are tested as antitumor vaccine vectors, but would benefit from a better knowledge on immunodominant vector antigens. To identify novel antigens, we screen for Listeria peptides presented on the surface of infected human cell lines by mass spectrometry-based immunopeptidomics. In between more than 15,000 human self-peptides, we detect 68 Listeria immunopeptides from 42 different bacterial proteins, including several known antigens. Peptides presented on different cell lines are often derived from the same bacterial surface proteins, classifying these antigens as potential vaccine candidates. Encoding these highly presented antigens in lipid nanoparticle mRNA vaccine formulations results in specific CD8+ T-cell responses and induces protection in vaccination challenge experiments in mice. Our results can serve as a starting point for the development of a clinical mRNA vaccine against Listeria and aid to improve attenuated Listeria vaccines and vectors, demonstrating the power of immunopeptidomics for next-generation bacterial vaccine development.


Differential regulation of the Kar3p kinesin-related protein by two associated proteins, Cik1p and Vik1p.
The mechanisms by which kinesin-related proteins interact with other proteins to carry out specific cellular processes is poorly understood. The kinesin-related protein, Kar3p, has been implicated in many microtubule functions in yeast. Some of these functions require interaction with the Cik1 protein (Page, B.D., L.L. Satterwhite, M.D. Rose, and M. Snyder. 1994. J. Cell Biol. 124:507-519). We have identified a Saccharomyces cerevisiae gene, named VIK1, encoding a protein with sequence and structural similarity to Cik1p. The Vik1 protein is detected in vegetatively growing cells but not in mating pheromone-treated cells. Vik1p physically associates with Kar3p in a complex separate from that of the Kar3p-Cik1p complex. Vik1p localizes to the spindle-pole body region in a Kar3p-dependent manner. Reciprocally, concentration of Kar3p at the spindle poles during vegetative growth requires the presence of Vik1p, but not Cik1p. Phenotypic analysis suggests that Cik1p and Vik1p are involved in different Kar3p functions. Disruption of VIK1 causes increased resistance to the microtubule depolymerizing drug benomyl and partially suppresses growth defects of cik1Delta mutants. The vik1Delta and kar3Delta mutations, but not cik1Delta, partially suppresses the temperature-sensitive growth defect of strains lacking the function of two other yeast kinesin-related proteins, Cin8p and Kip1p. Our results indicate that Kar3p forms functionally distinct complexes with Cik1p and Vik1p to participate in different microtubule-mediated events within the same cell.


Discovery of two novel families of proteins that are proposed to interact with prokaryotic SMC proteins, and characterization of the Bacillus subtilis family members ScpA and ScpB.
Structural maintenance of chromosomes (SMC) proteins are present in all eukaryotes and in many prokaryotes. Eukaryotic SMC proteins form complexes with various non-SMC subunits, which affect their function, whereas the prokaryotic homologues had no known non-SMC partners and were thought to act as simple homodimers. Here we describe two novel families of proteins, widespread in archaea and (Gram-positive) bacteria, which we denote 'segregation and condensation proteins' (Scps). ScpA genes are localized next to smc genes in nearly all SMC- containing archaea, suggesting that they belong to the same operon and are thus involved in a common process in the cell. The function of ScpA was studied in Bacillus subtilis, which also harbours a well characterized smc gene. Here we show that scpA mutants display characteristic phenotypes nearly identical to those of smc mutants, including temperature- sensitive growth, production of anucleate cells, formation of aberrant nucleoids, and chromosome splitting by the so-called guillotine effect. Thus, both SMC and ScpA are required for chromosome segregation and condensation. Interestingly, mutants of another B. subtilis gene, scpB, which is localized downstream from scpA, display the same phenotypes, which indicate that ScpB is also involved in these functions. ScpB is generally present in species that also encode ScpA. The physical interaction of ScpA and SMC was proven (i) by the use of the yeast two-hybrid system and (ii) by the isolation of a complex containing both proteins from cell extracts of B. subtilis. By extension, we speculate that interaction of orthologues of the two proteins is important for chromosome segregation in many archaea and bacteria, and propose that SMC proteins generally have non-SMC protein partners that affect their function not only in eukaryotes but also in prokaryotes.


ESI mutagenesis: a one-step method for introducing mutations into bacterial artificial chromosomes.
Bacterial artificial chromosome (BAC)-based transgenes have emerged as a powerful tool for controlled and conditional interrogation of protein function in higher eukaryotes. Although homologous recombination-based recombineering methods have streamlined the efficient integration of protein tags onto BAC transgenes, generating precise point mutations has remained less efficient and time-consuming. Here, we present a simplified method for inserting point mutations into BAC transgenes requiring a single recombineering step followed by antibiotic selection. This technique, which we call exogenous/synthetic intronization (ESI) mutagenesis, relies on co-integration of a mutation of interest along with a selectable marker gene, the latter of which is harboured in an artificial intron adjacent to the mutation site. Cell lines generated from ESI-mutated BACs express the transgenes equivalently to the endogenous gene, and all cells efficiently splice out the synthetic intron. Thus, ESI mutagenesis provides a robust and effective single-step method with high precision and high efficiency for mutating BAC transgenes.


Population-attributable risk of childhood sexual abuse for symptoms of depression and suicidal ideation in adulthood.
Objective. The aim of the study was to assess the population-attributable risks (PAR) of childhood sexual abuse (CSA) for depressive symptoms and suicidal ideation in adulthood. Method. A total of 2501 adult participants were randomly recruited and interviewed using a computer-assisted telephone interviewing system. They responded to items designed to assess depressive symptoms (SF-12), suicidal ideation (GHQ-28), and other distressing events, including CSA, as part of a broader, mental health survey of the South Australian population. Results. Logistic regression analyses indicated that CSA was associated with both depressive symptoms and suicidal ideation. However, PAR estimates indicated that only 0.8% of depressive symptoms could be attributed to CSA. Similarly, only 2.2% of suicidal ideation in the population could be attributed to CSA. Conclusions. Notwithstanding the individual distress associated with CSA, a population perspective indicated that the impact of CSA in adulthood was not as great as one might interpret from media reports.


Military medical research in the IDF: an array of fields and interests.
War is as old as history. Some may say it is older. The first Biblical war, dated 1880-1875 BCE, is depicted in the book of Genesis between nine kings in the vicinity of the Jordan river near Jericho. By the end of the war, Abraham (Abram) gets involved in saving his nephew Lot. In addition to war, military medicine also has its roots in historical times. Hippocrates (460-377 BCE), the father of medicine, derived his medical knowledge from the battlefield, and Sushruta [1], the father of plastic surgery, mentioned the physician's preventive role in noting environmental hazards: "A common practice of the enemy is to poison the wells on the roadside, the articles of food, the shades of trees, and the fuel and forage for cattle; hence, it is incumbent on a physician marching with the troops to inspect, examine, and purify these before using any of them, in case they are poisoned." The Greeks stated new ideas of military health, pointing to fitness promotion, gymnastics, and healthy diets to prevent illness. Over the centuries, from Alexander the Great to Napoleon's army and wars in the 20th century, military conflicts have led to the death of hundreds of millions of people from trauma and war-related disease. Amazingly analyses of the 18th and 19th centuries have shown that 80% of the soldiers died from disease, and historians and military personnel agree that during armed conflicts in known history, only a minority of soldiers perished by the sword. In Israel, the Israel Defense Forces-Medical Corps (IDF-MC) holds a unique position embedded in military and civilian national medicine. All medical personnel (e.g., physicians, nurses, technicians, veterinarians) who work in the IDF-MC receive their diplomas from civilian universities, train in civilian hospitals, and continue to practice in the national health system. The majority of these professionals continue to work in different civilian medical platforms in Israel after finishing their mandatory service. The IDF-MC's primary mission is to provide optimal medical care to IDF soldiers at all times (including wartime), to prevent disease and promote health, advance military medicine, and aid the civilian sector as ordered by the Government of Israel. In this special issue of Israel Medical Association Journal (IMAJ) is to expose readers to the continuous efforts of the IDF-MC to fulfill its mission by promoting research in multiple medical fields, including trauma, ambulatory care, health administration. In addition, in this issue of IMAJ, authors discuss the unique collaboration with the civilian system during the coronavirus disease 2019 (COVID-19) pandemic. Trauma and trauma-related injuries are the main focus of military medical research. Ben-Avi and colleagues [2] described outcomes of emergent exploratory thoracotomies on military casualties and addresses parameters that may impact the survival of these casualties. Minervini [3] further discussed the issue. Bez et al. [4] researched the impact of isolated versus non-isolated traumatic brain injuries on injury identification and decision-making by care providers in austere scenarios. Tsur and co-authors [5] described the characteristics of a unique type of terror attack: vehicle ramming. Additional examples of treatments provided in the military prehospital arena were analyzed by Nakar and colleagues [6] who discussed how to assess pain medications administered to trauma casualties in the past two decades by IDF-MC care providers. Rittblat et al. [7] further described the use of freeze-dried plasma, a blood component used in the prehospital arena and administered via intraosseous vascular access. The IDF-MC is a continuously changing organization emphasizing the adoption of advanced technologies and devices. Chen et al. [8] presented a blinded study on the use of point-of-care ultrasound and remote telementored ultrasound by inexperienced operators, and Sorkin et al. [9] described the BladeShield 101: a novel device for the battlefield designed to continuously measure vital signs and medical treatment provided and to transfer data through roles of care. In this special issue of IMAJ, authors also discusse gender-related aspects at the core of medical treatment. Segal et al. [10] examined whether missed injuries were related to the medical provider's gender, while Gelikas et al. [11] assessed whether treatment with analgesia was associated with casualty gender in the military prehospital trauma setting Over the past two and a half years, the COVID-19 pandemic has been a significant part of our lives. During these years, medical systems and teams throughout Israel and around the world struggled to adapt to this new disease and save lives fighting the pandemic. Geva et al. [12] and Shental et al. [13] discussed the impact of COVID-19 on the IDF medical system, lessons learned during the outbreak, and effects of different diseases during these times on medical treatment provided by the IDF to soldiers.


Sleep satisfaction and cognitive complaints in Chinese middle-aged and older persons living with HIV: the mediating role of anxiety and fatigue.
Middle-aged and older persons living with HIV (PLWH) suffer from sleep distress and cognitive disorders due to HIV infection and aging. We aim to explore the relationship between sleep satisfaction and cognitive complaints, and the mediating role of anxiety and fatigue in this relationship among middle-aged and older PLWH. We used data from a multicenter cross-sectional study in China (Shanghai, Kunming, Nanning, Hengyang, and Changning) conducted in 2017. The data analysis included 435 PLWH aged 45 years and over. Multiple linear regression models showed that worse sleep satisfaction was significantly associated with lower cognitive complaints after controlling for anxiety, fatigue, demographic variables, and clinical variables (β = -0.246, p < 0.01). Both anxiety and fatigue were significant partial mediators in the relationship between sleep satisfaction and cognitive complaints. The serial multiple mediation models of sleep satisfaction-anxiety (M1)-fatigue (M2)-cognitive complaints were supported and the alternative model of sleep satisfaction-fatigue (M2)-anxiety (M1)-cognitive complaints were both supported. Our study indicates that it is important to improve sleep quality to promote cognitive function among Chinese middle-aged and older PLWH. Prevention and treatment programs for sleep satisfaction and cognitive function should include the assessment and reduction of fatigue and anxiety.


Metabolic excretion associated with nutrient-growth dysregulation promotes the rapid evolution of an overt metabolic defect.
In eukaryotes, conserved mechanisms ensure that cell growth is coordinated with nutrient availability. Overactive growth during nutrient limitation ("nutrient-growth dysregulation") can lead to rapid cell death. Here, we demonstrate that cells can adapt to nutrient-growth dysregulation by evolving major metabolic defects. Specifically, when yeast lysine-auxotrophic mutant lys- encountered lysine limitation, an evolutionarily novel stress, cells suffered nutrient-growth dysregulation. A subpopulation repeatedly evolved to lose the ability to synthesize organosulfurs (lys-orgS-). Organosulfurs, mainly reduced glutathione (GSH) and GSH conjugates, were released by lys- cells during lysine limitation when growth was dysregulated, but not during glucose limitation when growth was regulated. Limiting organosulfurs conferred a frequency-dependent fitness advantage to lys-orgS- by eliciting a proper slow growth program, including autophagy. Thus, nutrient-growth dysregulation is associated with rapid organosulfur release, which enables the selection of organosulfur auxotrophy to better tune cell growth to the metabolic environment. We speculate that evolutionarily novel stresses can trigger atypical release of certain metabolites, setting the stage for the evolution of new ecological interactions.


Hybridization and invasiveness in the freshwater snail Melanoides tuberculata: hybrid vigour is more important than increase in genetic variance.
Many invasive taxa are hybrids, but how hybridization boosts the invasive process remains poorly known. We address this question in the clonal freshwater snail Melanoides tuberculata from Martinique, using three parental and two hybrid lines. We combine an extensive field survey (1990-2003) and a quantitative genetic experiment to show that hybrid lines have outcompeted their parents in natural habitats, and that this increased invasiveness co-occurred with pronounced shifts in life-history traits, such as growth, fecundity and juvenile size. Given the little time between hybrid creation and sampling, and the moderate standing genetic variance for life-history traits in hybrids, we show that some of the observed trait changes between parents and hybrids were unlikely to arise only by continuous selection. We therefore suggest that a large part of hybrid advantage stems from immediate heterosis upon hybridization.


Fibronectin overexpression in retinal microvessels of patients with diabetes.
To examine whether fibronectin is synthesized in the adult human retina and whether diabetes alters its amount, level of expression, and pattern of splicing. Retinas were obtained after death from 24 patients (age, 64 +/- 6 years) with 8 +/- 5 years of diabetes and 24 age-matched control subjects. Retinal localization of fibronectin and its amount in retinal vessels were examined with the immunoperoxidase technique. Fibronectin mRNA in the total retina was studied with reverse transcriptase-polymerase chain reaction using primers encompassing the alternatively spliced exon ED-A. The levels of fibronectin mRNA were measured relative to an internal standard (beta-actin mRNA). To detect and measure fibronectin expression in microvessels, retinal trypsin digests were studied by in situ hybridization. In the adult human retina, fibronectin is present exclusively in the walls of the vessels, including capillaries, and in the internal limiting membrane. In diabetic vessels, immunoreactive fibronectin was increased 1.4-fold over levels in control vessels (P = 0.05). Fibronectin is synthesized locally, and the predominant mRNA species excludes the ED-A region. The splicing pattern was not altered by diabetes. However, in the retinas of patients with diabetes, the levels of fibronectin mRNA were increased 1.3-fold over levels in control retinas (P = 0.028), whereas actin mRNA levels were similar in the two groups. Levels of fibronectin mRNA showed a substantial increase in the microvessels of patients with diabetes (0.49 +/- 0.18 grains/cell versus 0.15 +/- 0.12 grains/cell in control microvessels; P = 0.009. Fibronectin is synthesized in the adult human retina. Diabetes increases the amount of fibronectin in retinal vessels and upregulates its expression without changing the splicing pattern of the ED-A segment. Increased synthesis and deposition of fibronectin by microvascular cells may modify the interactions of cells and matrix with functional consequences relevant to the lesions of retinopathy.


Diurnal variation and reproducibility of predischarge submaximal exercise testing after myocardial infarction.
Diurnal variation and reproducibility of abnormalities occurring during predischarge postinfarction treadmill exercise testing were investigated in 41 patients. Each patient was exercised using a limited Naughton protocol before 0800 and after 1800 h on two consecutive days. No complications arose. Individual ischaemic abnormalities were poorly reproducible in any patient. No abnormality and no patient showed significant diurnal variation. When the presence of any one of three ischaemic abnormalities (ST segment depression or elevation and angina) was analysed the reproducibility of an ischaemic result in the two morning and the two evening tests was 72% and 95% respectively with no significant difference between the two. The reproducibility of an ischaemic result in all four tests was 66%. The reproducibility of the test for either the presence or absence of an ischaemic result was 71%. No training effect could be shown either for the group as a whole or for any individual patient. There were no appreciable differences in either the heart rates or systolic blood pressures during exercise among those patients with non-reproducible ischaemic test results. Thus it is concluded that an assessment of any one of three ischaemic abnormalities improves the reproducibility of the result of submaximal exercise testing after infarction. Mechanisms other than increased myocardial oxygen consumption related to increased heart rate and systolic blood pressure at submaximal exercise tolerance are needed to explain non-reproducible ischaemic test results.


[Areas of safe use of bone nails on the forearm].
On the basis of the data of topography-anatomical study, carried out at 30 upper extremities, are proposed zones and directions of safe application of wires of the compression-distraction apparatus at 4 forearm levels, developed with allowance made for individual differences in structure and topography of vessels and nerves as well as functional position of the segment. An experimental examination (30 extremities) and clinical approval (30 patients) of the proposed zones and directions have confirmed the practical use of the obtained data that allows to recommend them to be widely introduced into the clinical practice.


Biomimetic modeling of copper complexes: a study of enantioselective catalytic oxidation on d-(+)-catechin and L-( - )-epicatechin with copper complexes.
The biomimetic catalytic oxidations of the dinuclear and trinuclear copper(II) complexes versus two catechols, namely, D-(+)-catechin and L-( - )-epicatechin to give the corresponding quinones are reported. The unstable quinones were trapped by the nucleophilic reagent, 3-methyl-2-benzothiazolinone hydrazone (MBTH), and have been calculated the molar absorptivities of the different quinones. The catalytic efficiency is moderate, as inferred by kinetic constants, but the complexes exhibit significant enantio-differentiating ability towards the catechols, albeit for the dinuclear complexes, this enantio-differentiating ability is lower. In all cases, the preferred enantiomeric substrate is D-(+)-catechin to respect the other catechol, because of the spatial disposition of this substrate.


Optimization of microwave-assisted extraction of polyphenols from Myrtus communis L. leaves.
Phytochemicals, such as phenolic compounds, are of great interest due to their health-benefitting antioxidant properties and possible protection against inflammation, cardiovascular diseases and certain types of cancer. Maximum retention of these phytochemicals during extraction requires optimised process parameter conditions. A microwave-assisted extraction (MAE) method was investigated for extraction of total phenolics from Myrtus communis leaves. The total phenolic capacity (TPC) of leaf extracts at optimised MAE conditions was compared with ultrasound-assisted extraction (UAE) and conventional solvent extraction (CSE). The influence of extraction parameters including ethanol concentration, microwave power, irradiation time and solvent-to-solid ratio on the extraction of TPC was modeled by using a second-order regression equation. The optimal MAE conditions were 42% ethanol concentration, 500 W microwave power, 62 s irradiation time and 32 mL/g solvent to material ratio. Ethanol concentration and liquid-to-solid ratio were the significant parameters for the extraction process (p<0.01). Under the MAE optimised conditions, the recovery of TPC was 162.49 ± 16.95 mg gallic acidequivalent/gdry weight(DW), approximating the predicted content (166.13 mg GAE/g DW). When bioactive phytochemicals extracted from Myrtus leaves using MAE compared with UAE and CSE, it was also observed that tannins (32.65 ± 0.01 mg/g), total flavonoids (5.02 ± 0.05 mg QE/g) and antioxidant activities (38.20 ± 1.08 μg GAE/mL) in MAE extracts were higher than the other two extracts. These findings further illustrate that extraction of bioactive phytochemicals from plant materials using MAE method consumes less extraction solvent and saves time.


Oxygen isotopes of East Asian dinosaurs reveal exceptionally cold Early Cretaceous climates.
Early Cretaceous vertebrate assemblages from East Asia and particularly the Jehol Biota of northeastern China flourished during a period of highly debated climatic history. While the unique characters of these continental faunas have been the subject of various speculations about their biogeographic history, little attention has been paid to their possible climatic causes. Here we address this question using the oxygen isotope composition of apatite phosphate (δ ) from various reptile remains recovered from China, Thailand, and Japan. δ values indicate that cold terrestrial climates prevailed at least in this part of Asia during the Barremian-early Albian interval. Estimated mean air temperatures of about 10 ± 4 °C at midlatitudes (∼ 42 °N) correspond to present day cool temperate climatic conditions. Such low temperatures are in agreement with previous reports of cold marine temperatures during this part of the Early Cretaceous, as well as with the widespread occurrence of the temperate fossil wood genus Xenoxylon and the absence of thermophilic reptiles such as crocodilians in northeastern China. The unique character of the Jehol Biota is thus not only the result of its evolutionary and biogeographical history but is also due to rather cold local climatic conditions linked to the paleolatitudinal position of northeastern China and global icehouse climates that prevailed during this part of the Early Cretaceous.


General and MicroRNA-Mediated mRNA Degradation Occurs on Ribosome Complexes in Drosophila Cells.
The translation and degradation of mRNAs are two key steps in gene expression that are highly regulated and targeted by many factors, including microRNAs (miRNAs). While it is well established that translation and mRNA degradation are tightly coupled, it is still not entirely clear where in the cell mRNA degradation takes place. In this study, we investigated the possibility of mRNA degradation on the ribosome in Drosophila cells. Using polysome profiles and ribosome affinity purification, we could demonstrate the copurification of various deadenylation and decapping factors with ribosome complexes. Also, AGO1 and GW182, two key factors in the miRNA-mediated mRNA degradation pathway, were associated with ribosome complexes. Their copurification was dependent on intact mRNAs, suggesting the association of these factors with the mRNA rather than the ribosome itself. Furthermore, we isolated decapped mRNA degradation intermediates from ribosome complexes and performed high-throughput sequencing analysis. Interestingly, 93% of the decapped mRNA fragments (approximately 12,000) could be detected at the same relative abundance on ribosome complexes and in cell lysates. In summary, our findings strongly indicate the association of the majority of bulk mRNAs as well as mRNAs targeted by miRNAs with the ribosome during their degradation.


Lung ultrasound volume sweep imaging for respiratory illness: a new horizon in expanding imaging access.
Respiratory illness is a leading cause of morbidity in adults and the number one cause of mortality in children, yet billions of people lack access to medical imaging to assist in its diagnosis. Although ultrasound is highly sensitive and specific for respiratory illness such as pneumonia, its deployment is limited by a lack of sonographers. As a solution, we tested a standardised lung ultrasound volume sweep imaging (VSI) protocol based solely on external body landmarks performed by individuals without prior ultrasound experience after brief training. Each step in the VSI protocol is saved as a video clip for later interpretation by a specialist. Dyspneic hospitalised patients were scanned by ultrasound naive operators after 2 hours of training using the lung ultrasound VSI protocol. Separate blinded readers interpreted both lung ultrasound VSI examinations and standard of care chest radiographs to ascertain the diagnostic value of lung VSI considering chest X-ray as the reference standard. Comparison to clinical diagnosis as documented in the medical record and CT (when available) were also performed. Readers offered a final interpretation of normal, abnormal, or indeterminate/borderline for each VSI examination, chest X-ray, and CT. Operators scanned 102 subjects (0-89 years old) for analysis. Lung VSI showed a sensitivity of 93% and a specificity of 91% for an abnormal chest X-ray and a sensitivity of 100% and a specificity of 93% for a clinical diagnosis of pneumonia. When any cases with an indeterminate rating on chest X-ray or ultrasound were excluded (n=38), VSI lung ultrasound showed 92% agreement with chest X-ray (Cohen's κ 0.83 (0.68 to 0.97, p<0.0001)). Among cases with CT (n=21), when any ultrasound with an indeterminate rating was excluded (n=3), there was 100% agreement with VSI. Lung VSI performed by previously inexperienced ultrasound operators after brief training showed excellent agreement with chest X-ray and high sensitivity and specificity for a clinical diagnosis of pneumonia. Blinded readers were able to identify other respiratory diseases including pulmonary oedema and pleural effusion. Deployment of lung VSI could benefit the health of the global community.


Maternal Antihypertensive Medication Use and Congenital Heart Defects: Updated Results From the National Birth Defects Prevention Study.
Previous NBDPS (National Birth Defects Prevention Study) findings from 1997 to 2003 suggested that maternal antihypertensive use was associated with congenital heart defects (CHDs). We re-examined associations between specific antihypertensive medication classes and specific CHDs with additional NBDPS data from 2004 to 2011. After excluding mothers missing hypertension information or who reported pregestational diabetes mellitus, a multiple birth, or antihypertensive use but no hypertension, we compared self-reported maternal exposure data on 10 625 CHD cases and 11 137 nonmalformed controls. We calculated adjusted odds ratios [95% confidence intervals] to estimate the risk of specific CHDs associated with antihypertensive use during the month before conception through the third month of pregnancy, controlling for maternal age, race/ethnicity, body mass index, first trimester cigarette smoking, and NBDPS site. Overall, 164 (1.5%) case mothers and 102 (0.9%) control mothers reported early pregnancy antihypertensive use for their hypertension. We observed increased risk of 4 CHD phenotypes, regardless of antihypertensive medication class reported: coarctation of the aorta (2.50 [1.52-4.11]), pulmonary valve stenosis (2.19 [1.44-3.34]), perimembranous ventricular septal defect (1.90 [1.09-3.31]), and secundum atrial septal defect (1.94 [1.36-2.79]). The associations for these phenotypes were statistically significant for mothers who reported β-blocker use or renin-angiotensin system blocker use; estimates for other antihypertensive medication classes were generally based on fewer exposed cases and were less stable but remained elevated. Our results support and expand on earlier NBDPS findings that antihypertensive medication use may be associated with increased risk of specific CHDs, although we cannot completely rule out confounding by underlying disease characteristics.


The Experience of Patients with Alcohol Misuse after Surviving a Critical Illness. A Qualitative Study.
Alcohol misuse is common in patients admitted to the intensive care unit (ICU), but there is currently no evidence-based approach to address drinking in ICU survivors. We sought to describe the experience of ICU survivors with alcohol misuse during their hospitalization and the 3 months after hospital discharge to inform an alcohol-specific intervention for this unique population. We conducted a descriptive qualitative study of ICU survivors from medical ICUs in three separate hospitals with a positive screening result on the Alcohol Use Disorders Identification Test. Semistructured interviews were conducted 3 months after hospital discharge of patients. Patients were also allowed to nominate up to two friends or family members for enrollment to provide additional perspective on the patient's experience. We enrolled 50 patients and 22 of their friends and/or family members. The average APACHE II score was 23, 80% of patients were male, and the average age was 50 years; 70% of patients and 77% of friends/family members completed the semistructured interview 3 months after hospital discharge. We identified three domains that could inform an alcohol-specific intervention, each with multiple themes: motivation with complications (anxiety and depression, critical illness as a catalyst, delirium and cognitive impairment); therapeutic alliance (autonomy, failure and opportunities to build a therapeutic alliance); and the return to the home milieu (lack of screening for depression and anxiety, social network support for drinking, social isolation, social network support for abstinence, lack of available and affordable treatment, and negative experiences with Alcoholics Anonymous). An alcohol intervention for ICU survivors would account for the context in which patients are making a decision about their drinking and optimize the patient-provider interaction. Contrary to current paradigms that focus on addressing alcohol consumption only during a hospitalization, an intervention for ICU survivors should continue as patients transition from the hospital to home.


Relating information needs to the cancer experience: 1. Information as a key coping strategy.
Information-seeking behaviour is a strategy that many people use as a means of coping with, and reducing stress, throughout their cancer experience. The importance of providing information to people with cancer and many of the problems encountered with its provision have been well documented. Individuals frequently express dissatisfaction with the information given to them and experience difficulty in retaining and processing information. Lack of information may well lead to increased problems with anxiety and coping. This paper reviews and explores the literature associated with the information needs of people with cancer and the use of information as a coping strategy. The review forms part of a phenomenological study, conducted to explore the important issues for people with cancer that arose out of their cancer experience. Much of the literature discusses information-giving from the viewpoint of healthcare professionals rather than from the viewpoint of users and concentrates solely on information needs relating to the disease and its medical treatment. There is scant reference to the need for information on other issues such as available financial and community resources, or coping strategies.