Influence of Lysobacter enzymogenes Strain C3 on Nematodes.
Chitinolytic microflora may contribute to biological control of plant-parasitic nematodes by causing decreased egg viability through degradation of egg shells. Here, the influence of Lysobacter enzymogenes strain C3 on Caenorhabditis elegans, Heterodera schachtii, Meloidogyne javanica, Pratylenchus penetrans, and Aphelenchoides fragariae is described. Exposure of C. elegans to L. enzymogenes strain C3 on agar resulted in almost complete elimination of egg production and death of 94% of hatched juveniles after 2 d. Hatch of H. schachtii eggs was about 50% on a lawn of L. enzymogenes strain C3 on agar as compared to 80% on a lawn of E. coli. Juveniles that hatched on a lawn of L. enzymogenes strain C3 on agar died due to disintegration of the cuticle and body contents. Meloidogyne javanica juveniles died after 4 d exposure to a 7-d-old chitin broth culture of L. enzymogenes strain C3. Immersion of A. fragariae, M. javanica, and P. penetrans juveniles and adults in a nutrient broth culture of L. enzymogenes strain C3 led to rapid death and disintegration of the nematodes. Upon exposure to L. enzymogenes strain C3 cultures in nutrient broth, H. schachtii juveniles were rapidly immobilized and then lysed after three days. The death and disintegration of the tested nematodes suggests that toxins and enzymes produced by this strain are active against a range of nematode species.


Acute, transient hemorrhagic hypotension does not aggravate structural damage or neurologic motor deficits but delays the long-term cognitive recovery following mild to moderate traumatic brain injury.
Posttraumatic hypotension is believed to increase morbidity and mortality in traumatically brain-injured patients. Using a clinically relevant model of combined traumatic brain injury with superimposed hemorrhagic hypotension in rats, the present study evaluated whether a reduction in mean arterial blood pressure aggravates regional brain edema formation, regional cell death, and neurologic motor/cognitive deficits associated with traumatic brain injury. Experimental prospective, randomized study in rodents. Experimental laboratory at a university hospital. One hundred nineteen male Sprague-Dawley rats weighing 350-385 g. Experimental traumatic brain injury of mild to moderate severity was induced using the lateral fluid percussion brain injury model in anesthetized rats (n = 89). Following traumatic brain injury, in surviving animals one group of animals was subjected to pressure-controlled hemorrhagic hypotension, maintaining the mean arterial blood pressure at 50-60 mm Hg for 30 mins (n = 47). The animals were subsequently either resuscitated with lactated Ringer's solution (three times shed blood volume, n = 18) or left uncompensated (n = 29). Other groups of animals included those with isolated traumatic brain injury (n = 34), those with isolated hemorrhagic hypotension (n = 8), and sham-injured control animals receiving anesthesia and surgery alone (n = 22). The withdrawal of 6-7 mL of arterial blood significantly reduced mean arterial blood pressure by 50% without decreasing arterial oxygen saturation or Pao2. Brain injury induced significant cerebral edema (p < .001) in vulnerable brain regions and cortical tissue loss (p < .01) compared with sham-injured animals. Neither regional brain edema formation at 24 hrs postinjury nor the extent of cortical tissue loss assessed at 7 days postinjury was significantly aggravated by superimposed hemorrhagic hypotension. Brain injury-induced neurologic deficits persisted up to 20 wks after injury and were also not aggravated by the hemorrhagic hypotension. Cognitive dysfunction persisted for up to 16 wks postinjury. The superimposition of hemorrhagic hypotension significantly delayed the time course of cognitive recovery. A single, acute hypotensive event lasting 30 mins did not aggravate the short- and long-term structural and motor deficits but delayed the speed of recovery of cognitive function associated with experimental traumatic brain injury.


BACE1 inhibitor drugs in clinical trials for Alzheimer's disease.
β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the β-secretase enzyme required for the production of the neurotoxic β-amyloid (Aβ) peptide that is widely considered to have a crucial early role in the etiology of Alzheimer's disease (AD). As a result, BACE1 has emerged as a prime drug target for reducing the levels of Aβ in the AD brain, and the development of BACE1 inhibitors as therapeutic agents is being vigorously pursued. It has proven difficult for the pharmaceutical industry to design BACE1 inhibitor drugs that pass the blood-brain barrier, however this challenge has recently been met and BACE1 inhibitors are now in human clinical trials to test for safety and efficacy in AD patients and individuals with pre-symptomatic AD. Initial results suggest that some of these BACE1 inhibitor drugs are well tolerated, although others have dropped out because of toxicity and it is still too early to know whether any will be effective for the prevention or treatment of AD. Additionally, based on newly identified BACE1 substrates and phenotypes of mice that lack BACE1, concerns have emerged about potential mechanism-based side effects of BACE1 inhibitor drugs with chronic administration. It is hoped that a therapeutic window can be achieved that balances safety and efficacy. This review summarizes the current state of progress in the development of BACE1 inhibitor drugs and the evaluation of their therapeutic potential for AD.


Vocal learning in the functionally referential food grunts of chimpanzees.
One standout feature of human language is our ability to reference external objects and events with socially learned symbols, or words. Exploring the phylogenetic origins of this capacity is therefore key to a comprehensive understanding of the evolution of language. While non-human primates can produce vocalizations that refer to external objects in the environment, it is generally accepted that their acoustic structure is fixed and a product of arousal states. Indeed, it has been argued that the apparent lack of flexible control over the structure of referential vocalizations represents a key discontinuity with language. Here, we demonstrate vocal learning in the acoustic structure of referential food grunts in captive chimpanzees. We found that, following the integration of two groups of adult chimpanzees, the acoustic structure of referential food grunts produced for a specific food converged over 3 years. Acoustic convergence arose independently of preference for the food, and social network analyses indicated this only occurred after strong affiliative relationships were established between the original subgroups. We argue that these data represent the first evidence of non-human animals actively modifying and socially learning the structure of a meaningful referential vocalization from conspecifics. Our findings indicate that primate referential call structure is not simply determined by arousal and that the socially learned nature of referential words in humans likely has ancient evolutionary origins.


Incidence and Predictors of Multiple Fractures Despite High Adherence to Oral Bisphosphonates: A Binational Population-Based Cohort Study.
Oral bisphosphonates (BPs) are highly effective in preventing fractures and are recommended first-line therapies for patients with osteoporosis. We identified the incidence and predictors of oral BP treatment failure, defined as the incidence of two or more fractures while on treatment (≥2 FWOT) among users with high adherence. Fractures were considered from 6 months after treatment initiation and up to 6 months after discontinuation. Data from computerized records and pharmacy invoices were obtained from Sistema d'Informació per al Desenvolupament de l'Investigació en Atenció Primària (SIDIAP; Catalonia, Spain) and Danish Health Registries (Denmark) for all incident users of oral BPs in 2006-2007 and 2000-2001, respectively. Fine and Gray survival models using backward-stepwise selection (p-entry 0.049; p- exit 0.10) and accounting for the competing risk of therapy cessation were used to identify predictors of ≥2 FWOT among patients having persisted with treatment ≥6 months with overall medication possession ratio (MPR) ≥80%. Incidence of ≥2 FWOT was 2.4 (95% confidence interval [CI], 1.8 to 3.2) and 1.7 (95% CI, 1.2 to 2.2) per 1000 patient-years (PYs) within Catalonia and Denmark, respectively. Older age was predictive of ≥2 FWOT in both Catalonian and Danish cohorts: subhazard ratio (SHR) = 2.28 (95% CI, 1.11 to 4.68) and SHR = 2.61 (95% CI, 0.98 to 6.95), respectively, for 65 to <80 years; and SHR = 3.19 (95% CI, 1.33 to 7.69) and SHR = 4.88 (95% CI, 1.74 to 13.7), respectively, for ≥80 years. Further significant predictors of ≥2 FWOT identified within only one cohort were dementia, SHR = 4.46 (95% CI, 1.02 to 19.4) (SIDIAP); and history of recent or older fracture, SHR = 3.40 (95% CI, 1.50 to 7.68) and SHR = 2.08 (95% CI: 1.04-4.15), respectively (Denmark). Even among highly adherent users of oral BP therapy, a minority sustain multiple fractures while on treatment. Older age was predictive of increased risk within both study populations, as was history of recent/old fracture and dementia within one but not both populations. Additional and/or alternative strategies should be investigated for these patients.


Body composition in children with juvenile idiopathic arthritis: effect of dietary intake of macronutrient: results from a cross sectional study.
The aim of this study was to evaluate the relationship between macronutrient intake, body composition (lean body mass and fat mass) and bone mineral content in Moroccan children with juvenile idiopathic arthritis (JIA). A cross-sectional study, conducted between May 2010 and June 2011, covering out patient with JIA. The characteristics of patients were collected. The nutritional status was assessed by a food questionnaire including data of food intake during 7 consecutive days using 24-hour dietary recall. Food intake was quantified using the software Bilnut (Bilnut version 2.01, 1991). Dietary intake of macronutrients was expressed as percentage contribution to total energy. Body composition was evaluated with DXA total-body measurements (bone mineral content BMC expressed in g, lean body mass LBM and fat mass FM expressed in kg). 33 patients were included. The mean age was 10.4 ± 4.3 years. The median disease duration was 2 (1-4.5) years. The median of LBM, FM and BMC were 19 kg (13.82-33.14), 5 kg (3.38-9.14) and 1044.90 g (630.40-1808.90) respectively. We found a positive correlation between LBM and dietary intake of carbohydrate (r= 0.4; p = 0.03). There were no significant association between LBM and intake of lipids, or protein. Moreover, no association was found between FM, BMC and intake of carbohydrates, lipids and proteins. This study suggests that there is a positive correlation between carbohydrates intake and LBM; however, dietary intake does not influence FM and BMC. Prospective studies with larger numbers of patients appear to be needed to confirm our findings.


Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.
Autosomal recessive inherited neurodevelopmental disorders are highly heterogeneous, and many, possibly most, of the disease genes are still unknown. To promote the identification of disease genes through confirmation of previously described genes and presentation of novel candidates and provide an overview of the diagnostic yield of exome sequencing in consanguineous families. Autozygosity mapping in families and exome sequencing of index patients were performed in 152 consanguineous families (the parents descended from a same ancestor) with at least 1 offspring with intellectual disability (ID). The study was conducted from July 1, 2008, to June 30, 2015, and data analysis was conducted from July 1, 2015, to August 31, 2016. Of the 152 consanguineous families enrolled, 1 child (in 45 families [29.6%]) or multiple children (107 families [70.4%]) had ID; additional features were present in 140 of the families (92.1%). The mean (SD) age of the children was 10.3 (9.0) years, and 171 of 297 (57.6%) were male. In 109 families (71.7%), potentially protein-disrupting and clinically relevant variants were identified. Of these, a clear clinical genetic diagnosis was made in 56 families (36.8%) owing to 57 (likely) pathogenic variants in 50 genes already established in neurodevelopmental disorders (46 autosomal recessive, 2 X-linked, and 2 de novo) or in 7 previously proposed recessive candidates. In 5 of these families, potentially treatable disorders were diagnosed (mutations in PAH, CBS, MTHFR, CYP27A1, and HIBCH), and in 1 family, 2 disease-causing homozygous variants in different genes were identified. In another 48 families (31.6%), 52 convincing recessive variants in candidate genes that were not previously reported in regard to neurodevelopmental disorders were identified. Of these, 14 were homozygous and truncating in GRM7, STX1A, CCAR2, EEF1D, GALNT2, SLC44A1, LRRIQ3, AMZ2, CLMN, SEC23IP, INIP, NARG2, FAM234B, and TRAP1. The diagnostic yield was higher in individuals with severe ID (35 of 77 [45.5%]), in multiplex families (42 of 107 [39.3%]), in patients with additional features (30 of 70 [42.9%]), and in those with remotely related parents (15 of 34 [44.1%]). Because of the high diagnostic yield of 36.8% and the possibility of identifying treatable diseases or the coexistence of several disease-causing variants, using exome sequencing as a first-line diagnostic approach in consanguineous families with neurodevelopmental disorders is recommended. Furthermore, the literature is enriched with 52 convincing candidate genes that are awaiting confirmation in independent families.


Meaning in Life for Patients With Severe Dementia: A Qualitative Study of Healthcare Professionals' Interpretations.
The need for meaning in life is a key aspect of being human, and a central issue in the psychology of religion. Understanding experience of meaning for persons with severe dementia is challenging due to the impairments associated with the illness. Despite these challenges, this article argues that meaning in life is as important for a person with severe dementia as it is for everyone else. This study was conducted in a Norwegian hospital and nursing home context and was part of a research project on meaning in life for persons with severe dementia. The study builds on two other studies which focused on how meaning-making and experience of meaningfulness appeared in patients with severe dementia. By presenting the findings from these two studies for a group of healthcare professionals and introducing them to research on meaning in life, the aim of this study was to explore how healthcare professionals interpret the patients' experience of meaning in life in practise for patients with severe dementia in a hospital and nursing home context, and to highlight its clinical implications. The study was conducted using a qualitative method with exploratory design. The data were collected at a round table conference, a method inspired by a mode of action research called "co-operative inquiry." Altogether 27 professional healthcarers, from a variety of professions, with high competence in dementia care participated together with six researchers authoring this article. This study revealed that healthcare professionals were constantly dealing with different forms of meaning in their everyday care for people with dementia. The findings also showed clear connexions between understanding of meaning and fundamental aspects of good dementia care. Meaning corresponded well with the principles of person-centred care, and this compatibility allowed the healthcare professionals to associate meaning in life as a perspective into their work without having much prior knowledge or being familiar with the use of this perspective. The study points out that awareness of meaning in life as an integrated perspective in clinical practise will contribute to a broader and enhanced repertoire, and hence to improved dementia care. Facilitating experience of meaning calls for increased resources in personnel and competence in future dementia care.


Mass spectrometric U-series dating of Huanglong Cave in Hubei Province, Central China: evidence for early presence of modern humans in Eastern Asia.
Most researchers believe that anatomically modern humans (AMH) first appeared in Africa 160-190 ka ago, and would not have reached eastern Asia until ∼50 ka ago. However, the credibility of these scenarios might have been compromised by a largely inaccurate and compressed chronological framework previously established for hominin fossils found in China. Recently there has been a growing body of evidence indicating the possible presence of AMH in eastern Asia ca. 100 ka ago or even earlier. Here we report high-precision mass spectrometric U-series dating of intercalated flowstone samples from Huanglong Cave, a recently discovered Late Pleistocene hominin site in northern Hubei Province, central China. Systematic excavations there have led to the in situ discovery of seven hominin teeth and dozens of stone and bone artifacts. The U-series dates on localized thin flowstone formations bracket the hominin specimens between 81 and 101 ka, currently the most narrow time span for all AMH beyond 45 ka in China, if the assignment of the hominin teeth to modern Homo sapiens holds. Alternatively this study provides further evidence for the early presence of an AMH morphology in China, through either independent evolution of local archaic populations or their assimilation with incoming AMH. Along with recent dating results for hominin samples from Homo erectus to AMH, a new extended and continuous timeline for Chinese hominin fossils is taking shape, which warrants a reconstruction of human evolution, especially the origins of modern humans in eastern Asia.


Dynamical Constants and Time Universals: A First Step toward a Metrical Definition of Ordered and Abnormal Cognition.
From the point of view of the cognitive dynamicist the organization of brain circuitry into assemblies defined by their synchrony at particular (and precise) oscillation frequencies is important for the correct correlation of all independent cortical responses to the different aspects of a given complex thought or object. From the point of view of anyone operating complex mechanical systems, i.e., those comprising independent components that are required to interact precisely in time, it follows that the precise timing of such a system is essential - not only essential but measurable, and scalable. It must also be reliable over observations to bring about consistent behavior, whatever that behavior is. The catastrophic consequence of an absence of such precision, for instance that required to govern the interference engine in many automobiles, is indicative of how important timing is for the function of dynamical systems at all levels of operation. The dynamics and temporal considerations combined indicate that it is necessary to consider the operating characteristic of any dynamical, cognitive brain system in terms, superficially at least, of oscillation frequencies. These may, themselves, be forensic of an underlying time-related taxonomy. Currently there are only two sets of relevant and necessarily systematic observations in this field: one of these reports the precise dynamical structure of the perceptual systems engaged in dynamical binding across form and time; the second, derived both empirically from perceptual performance data, as well as obtained from theoretical models, demonstrates a timing taxonomy related to a fundamental operator referred to as the time quantum. In this contribution both sets of theory and observations are reviewed and compared for their predictive consistency. Conclusions about direct comparability are discussed for both theories of cognitive dynamics and time quantum models. Finally, a brief review of some experimental data measuring sensitivity to visual information presented to the visual blind field (blindsight), as well as from studies of temporal processing in autism and schizophrenia, indicates that an understanding of a precise and metrical dynamic structure may be very important for an operational understanding of perception as well as more general cognitive function in psychopathology.


Separate F-Type Plasmids Have Shaped the Evolution of the H30 Subclone of Escherichia coli Sequence Type 131.
The extraintestinal pathogenic Escherichia coli (ExPEC) H30 subclone of sequence type 131 (ST131-H30) has emerged abruptly as a dominant lineage of ExPEC responsible for human disease. The ST131-H30 lineage has been well described phylogenetically, yet its plasmid complement is not fully understood. Here, single-molecule, real-time sequencing was used to generate the complete plasmid sequences of ST131-H30 isolates and those belonging to other ST131 clades. Comparative analyses revealed separate F-type plasmids that have shaped the evolution of the main fluoroquinolone-resistant ST131-H30 clades. Specifically, an F1:A2:B20 plasmid is strongly associated with the H30R/C1 clade, whereas an F2:A1:B- plasmid is associated with the H30Rx/C2 clade. A series of plasmid gene losses, gains, and rearrangements involving IS26 likely led to the current plasmid complements within each ST131-H30 sublineage, which contain several overlapping gene clusters with putative functions in virulence and fitness, suggesting plasmid-mediated convergent evolution. Evidence suggests that the H30Rx/C2-associated F2:A1:B- plasmid type was present in strains ancestral to the acquisition of fluoroquinolone resistance and prior to the introduction of a multidrug resistance-encoding gene cassette harboring bla CTX-M-15. In vitro experiments indicated a host strain-independent low frequency of plasmid transfer, differential levels of plasmid stability even between closely related ST131-H30 strains, and possible epistasis for carriage of these plasmids within the H30R/Rx lineages. IMPORTANCE A clonal lineage of Escherichia coli known as ST131 has emerged as a dominating strain type causing extraintestinal infections in humans. The evolutionary history of ST131 E. coli is now well understood. However, the role of plasmids in ST131's evolutionary history is poorly defined. This study utilized real-time, single-molecule sequencing to compare plasmids from various current and historical lineages of ST131. From this work, it was determined that a series of plasmid gains, losses, and recombinational events has led to the currently circulating plasmids of ST131 strains. These plasmids appear to have evolved to acquire similar gene clusters on multiple occasions, suggesting possible plasmid-mediated convergent evolution leading to evolutionary success. These plasmids also appear to be better suited to exist in specific strains of ST131 due to coadaptive mutations. Overall, a series of events has enabled the evolution of ST131 plasmids, possibly contributing to the lineage's success.


Outbreak of Listeriosis in South Africa Associated with Processed Meat.
An outbreak of listeriosis was identified in South Africa in 2017. The source was unknown. We conducted epidemiologic, trace-back, and environmental investigations and used whole-genome sequencing to type Listeria monocytogenes isolates. A case was defined as laboratory-confirmed L. monocytogenes infection during the period from June 11, 2017, to April 7, 2018. A total of 937 cases were identified, of which 465 (50%) were associated with pregnancy; 406 of the pregnancy-associated cases (87%) occurred in neonates. Of the 937 cases, 229 (24%) occurred in patients 15 to 49 years of age (excluding those who were pregnant). Among the patients in whom human immunodeficiency virus (HIV) status was known, 38% of those with pregnancy-associated cases (77 of 204) and 46% of the remaining patients (97 of 211) were infected with HIV. Among 728 patients with a known outcome, 193 (27%) died. Clinical isolates from 609 patients were sequenced, and 567 (93%) were identified as sequence type 6 (ST6). In a case-control analysis, patients with ST6 infections were more likely to have eaten polony (a ready-to-eat processed meat) than those with non-ST6 infections (odds ratio, 8.55; 95% confidence interval, 1.66 to 43.35). Polony and environmental samples also yielded ST6 isolates, which, together with the isolates from the patients, belonged to the same core-genome multilocus sequence typing cluster with no more than 4 allelic differences; these findings showed that polony produced at a single facility was the outbreak source. A recall of ready-to-eat processed meat products from this facility was associated with a rapid decline in the incidence of L. monocytogenes ST6 infections. This investigation showed that in a middle-income country with a high prevalence of HIV infection, L. monocytogenes caused disproportionate illness among pregnant girls and women and HIV-infected persons. Whole-genome sequencing facilitated the detection of the outbreak and guided the trace-back investigations that led to the identification of the source.


Induction of intestinal P-glycoprotein by St John's wort reduces the oral bioavailability of talinolol.
St John's wort (SJW) is known to induce cytochrome P450 (CYP) 3A4 and P-glycoprotein through pregnane X-receptor activation. Our study evaluated the effects of long-term SJW administration on oral and intravenous pharmacokinetics of the nonmetabolized in vivo probe of P-glycoprotein, talinolol, in relation to intestinal P-glycoprotein expression. In a controlled, randomized study (N=9), the pharmacokinetics of oral (50 mg) and intravenous talinolol (30 mg) was determined before and after 12 days SJW (900 mg daily, Jarsin 300). Duodenal biopsies were taken and MDR1 genotypes assessed. SJW reduced the oral talinolol bioavailability by 25% (P=0.049) compared with water control. A 93% increase in oral clearance (P=0.177) and a 31% reduction in area under the serum concentration time curve (AUC; P=0.030) were observed. Renal and nonrenal clearance (CLNR), elimination half-life, peak serum drug concentration (Cmax), and time to reach Cmax were not significantly altered. After intravenous talinolol, SJW affected only CLNR (35% increase compared with water, P=0.006). SJW increased MDR1 messenger ribonucleic acid (mRNA) as well as P-glycoprotein levels in the duodenal mucosa. Subjects with the combined MDR1 genotype comprising 1236C>T, 2677G>T/A, and 3435C>T polymorphisms had lower intestinal MDR1 mRNA levels and displayed an attenuated inductive response to SJW as assessed by talinolol disposition. Long-term SJW decreased talinolol AUC with a corresponding increase in intestinal MDR1 expression, suggesting that SJW has a major inductive effect on intestinal P-glycoprotein. Interestingly, the magnitude of induction appeared to be affected by MDR1 genotype.


Effects of Chronic Cannabidiol Treatment in the Rat Chronic Unpredictable Mild Stress Model of Depression.
Several neuropharmacological actions of cannabidiol (CBD) due to the modulation of the endocannabinoid system as well as direct serotonergic and gamma-aminobutyric acidergic actions have recently been identified. The current study aimed to reveal the effect of a long-term CBD treatment in the chronic unpredictable mild stress (CUMS) model of depression. Adult male Wistar rats (n = 24) were exposed to various stressors on a daily basis in order to induce anhedonia and anxiety-like behaviors. CBD (10 mg/kg body weight) was administered by daily intraperitoneal injections for 28 days (n = 12). The effects of the treatment were assessed on body weight, sucrose preference, and exploratory and anxiety-related behavior in the open field (OF) and elevated plus maze (EPM) tests. Hair corticosterone was also assayed by liquid chromatography-mass spectrometry. At the end of the experiment, CBD-treated rats showed a higher rate of body weight gain (5.94% vs. 0.67%) and sucrose preference compared to controls. A significant increase in vertical exploration and a trend of increase in distance traveled in the OF test were observed in the CBD-treated group compared to the vehicle-treated group. The EPM test did not reveal any differences between the groups. Hair corticosterone levels increased in the CBD-treated group, while they decreased in controls compared to baseline (+36.01% vs. -45.91%). In conclusion, CBD exerted a prohedonic effect in rats subjected to CUMS, demonstrated by the increased sucrose preference after three weeks of treatment. The reversal of the effect of CUMS on hair corticosterone concentrations might also point toward an anxiolytic or antidepressant-like effect of CBD, but this needs further confirmation.


Cerebrospinal fluid proteomics and biological heterogeneity in Alzheimer's disease: A literature review.
Alzheimer's disease (AD) is the most common cause of dementia and is characterized by aggregation of amyloid and tau proteins in the brain. Results from genetic studies suggest that the pathophysiology underlying AD is complex, but studying this complexity in patients remains difficult. The cerebrospinal fluid (CSF) proteome contains a large number of proteins that can reflect ongoing biological processes. Proteomics techniques can be used to measure many proteins simultaneously in individual patients and may therefore provide an opportunity to study AD disease mechanisms. Here, we review the CSF proteomics literature to identify proteins consistently associated with AD, and perform pathway analyses on these proteins to study which biological processes may be involved in the disease.We performed a literature search of studies that investigated CSF proteomic alterations related to AD. We included original research articles when they measured at least 10 proteins in (antemortem) CSF in at least 10 individuals with AD, mild cognitive impairment (MCI) or controls. We examined if proteins were consistently related to AD, defined as consistent increase or decrease in AD vs. controls across studies. Next, we used the proteins identified as input to pathway analyses using Reactome to investigate which biological processes were enriched.In total, 29 studies were included that investigated AD-related changes to the CSF proteome, including a total of 1434 individuals with AD (of whom 47.1% had a CSF biomarker profile and 9.6% a postmortem examination consistent with AD) and 1380 controls. The studies reported 1 to 138 proteins associated with AD, of which 97 proteins were reported by two or more studies. Among proteins that were measured in more than one study, 27 (27.8%) showed consistent increases, 15 (15.5%) consistent decreases and 55 (56.7%) had contrasting results. Pathway analyses showed that AD-related proteins were enriched for hemostasis, lipoprotein and extracellular matrix pathways.These results indicate that proteomic alterations in CSF associated with AD reflect involvement of various biological pathways. The frequent occurrence of inconsistent protein level changes reported by different studies suggests that additional biological and/or (pre)analytical factors may influence the CSF proteome in AD, which should be further investigated in order to improve understanding of the biological complexity underlying AD.


Genetic Ancestry Analysis Reveals Misclassification of Commonly Used Cancer Cell Lines.
Given the scarcity of cell lines from underrepresented populations, it is imperative that genetic ancestry for these cell lines is characterized. Consequences of cell line mischaracterization include squandered resources and publication retractions. We calculated genetic ancestry proportions for 15 cell lines to assess the accuracy of previous race/ethnicity classification and determine previously unknown estimates. DNA was extracted from cell lines and genotyped for ancestry informative markers representing West African (WA), Native American (NA), and European (EUR) ancestry. Of the cell lines tested, all previously classified as White/Caucasian were accurately described with mean EUR ancestry proportions of 97%. Cell lines previously classified as Black/African American were not always accurately described. For instance, the 22Rv1 prostate cancer cell line was recently found to carry mixed genetic ancestry using a much smaller panel of markers. However, our more comprehensive analysis determined the 22Rv1 cell line carries 99% EUR ancestry. Most notably, the E006AA-hT prostate cancer cell line, classified as African American, was found to carry 92% EUR ancestry. We also determined the MDA-MB-468 breast cancer cell line carries 23% NA ancestry, suggesting possible Afro-Hispanic/Latina ancestry. Our results suggest predominantly EUR ancestry for the White/Caucasian-designated cell lines, yet high variance in ancestry for the Black/African American-designated cell lines. In addition, we revealed an extreme misclassification of the E006AA-hT cell line. Genetic ancestry estimates offer more sophisticated characterization leading to better contextualization of findings. Ancestry estimates should be provided for all cell lines to avoid erroneous conclusions in disparities literature.


Activin A balance regulates epithelial invasiveness and tumorigenesis.
Activin A (Act A) is a member of the TGFβ superfamily. Act A and TGFβ have multiple common downstream targets and have been described to merge in their intracellular signaling cascades and function. We have previously demonstrated that coordinated loss of E-cadherin and TGFβ receptor II (TβRII) results in epithelial cell invasion. When grown in three-dimensional organotypic reconstruct cultures, esophageal keratinocytes expressing dominant-negative mutants of E-cadherin and TβRII showed activated Smad2 in the absence of functional TβRII. However, we could show that increased levels of Act A secretion was able to induce Smad2 phosphorylation. Growth factor secretion can activate autocrine and paracrine signaling, which affects crosstalk between the epithelial compartment and the surrounding microenvironment. We show that treatment with the Act A antagonist Follistatin or with a neutralizing Act A antibody can increase cell invasion in organotypic cultures in a fibroblast- and MMP-dependent manner. Similarly, suppression of Act A with shRNA increases cell invasion and tumorigenesis in vivo. Therefore, we conclude that maintaining a delicate balance of Act A expression is critical for homeostasis in the esophageal microenvironment.


Effects of gratitude meditation on neural network functional connectivity and brain-heart coupling.
A sense of gratitude is a powerful and positive experience that can promote a happier life, whereas resentment is associated with life dissatisfaction. To explore the effects of gratitude and resentment on mental well-being, we acquired functional magnetic resonance imaging and heart rate (HR) data before, during, and after the gratitude and resentment interventions. Functional connectivity (FC) analysis was conducted to identify the modulatory effects of gratitude on the default mode, emotion, and reward-motivation networks. The average HR was significantly lower during the gratitude intervention than during the resentment intervention. Temporostriatal FC showed a positive correlation with HR during the gratitude intervention, but not during the resentment intervention. Temporostriatal resting-state FC was significantly decreased after the gratitude intervention compared to the resentment intervention. After the gratitude intervention, resting-state FC of the amygdala with the right dorsomedial prefrontal cortex and left dorsal anterior cingulate cortex were positively correlated with anxiety scale and depression scale, respectively. Taken together, our findings shed light on the effect of gratitude meditation on an individual's mental well-being, and indicate that it may be a means of improving both emotion regulation and self-motivation by modulating resting-state FC in emotion and motivation-related brain regions.


How do we diagnose and treat epilepsy with myoclonic-atonic seizures (Doose syndrome)? Results of the Pediatric Epilepsy Research Consortium survey.
To obtain and assess opinions on EMAS diagnostic criteria, recommended investigations, and therapeutic options, from a large group of physicians who care for children with EMAS. The EMAS focus group of PERC created a survey to assess the opinions of pediatric neurologists who care for children with EMAS regarding diagnosis and treatment of this condition, which was sent to members of PERC, AES, and CNS. A Likert scale was used to assess the respondents' opinions on the importance of diagnostic and exclusion criteria (five point scale), investigations (four point scale), and treatment (six point scale) of EMAS. Inclusion/exclusion criteria were then classified as critical, strong, or modest. Investigations were classified as essential, recommended, or possible. Therapies were classified as first line, beneficial, indeterminate benefit, or contraindicated. Survey results from the 76 participants determined the following: EMAS inclusion criteria: history suggestive of MAS (critical), recorded or home video suggestive of MAS, generalized discharges on inter-ictal EEG, normal neuroimaging, normal development prior to seizure onset (strong). EMAS exclusionary criteria: epileptic spasms, abnormal neuroimaging, focal abnormal exam, seizure onset <six months or >six years (strong). EEG and MRI (essential), amino acids, organic acids, fatty acid/acylcarnitine profile, microarray, genetic panel, lactate/pyruvate, CSF and serum glucose/lactate (strong). Valproic acid (first line), topiramate, zonisamide, levetiracetam, benzodiazepines, and dietary therapies (beneficial). To date, no similar surveys have been published, even though early syndrome identification and initiation of effective treatment have been associated with improved outcome in EMAS. Medications that exacerbate seizures in EMAS have also been identified. This survey identified critical and preferred diagnostic electro clinical features, investigations, and treatments for EMAS. It will guide future research and is a crucial first step in defining specific diagnostic criteria, recommended evaluation, and most effective therapies for EMAS.


Visual Stimulus Speed Does Not Influence the Rapid Emergence of Direction Selectivity in Ferret Visual Cortex.
Sensory experience is necessary for the development of some receptive field properties of neurons in primary sensory cortical areas. However, it remains unclear whether the parameters of an individual animal's experience play an instructive role and influence the tuning parameters of cortical sensory neurons as selectivity emerges, or rather whether experience merely permits the completion of processes that are fully seeded at the onset of experience. Here we have examined whether the speed of visual stimuli that are presented to visually naive ferrets can influence the parameters of speed tuning and direction selectivity in cortical neurons. Visual experience is necessary for the development of direction selectivity in carnivores. If, during development, cortical neurons had the flexibility to choose from among different inputs with a range of spatial positions and temporal delays, then correlation-based plasticity mechanisms could instruct the precise spatiotemporal selectivity that underlies speed tuning and direction selectivity, and the parameters of an individual animal's experience would influence the tuning that emerges. Alternatively, the tuning parameters of these neurons may already be established at the onset of visual experience, and experience may merely permit the expression of this tuning. We found that providing different groups of animals with either slow (12.5 deg/s) or fast (50 deg/s) visual stimuli resulted in emergence of direction selectivity, but that speed tuning and direction selectivity were similar in the two groups. These results are more consistent with a permissive role for experience in the development of direction selectivity.SIGNIFICANCE STATEMENT The proper development of brain circuits and neural response properties depends on both nature (factors independent of experience) and nurture (factors dependent on experience). In this study, we examined whether the quality of visual experience of an individual animal influences the development of basic sensory detectors in primary visual cortex. We found that, although visual experience is required for the development of direction selectivity, tuning for stimulus speed could not be altered by specific experience with slow or fast stimuli. These results suggest that the tuning parameters for direction selectivity are specified independently of an animal's sensory experience, and that a range of experiences can promote the proper mature expression of direction selectivity in primary visual cortex.


Generation of Trichoderma atroviride mutants with constitutively activated G protein signaling by using geneticin resistance as selection marker.
Species of the fungal genus Trichoderma are important industrial producers of cellulases and hemicellulases, but also widely used as biocontrol agents (BCAs) in agriculture. In the latter function Trichoderma species stimulate plant growth, induce plant defense and directly antagonize plant pathogenic fungi through their mycoparasitic capabilities. The recent release of the genome sequences of four mycoparasitic Trichoderma species now forms the basis for large-scale genetic manipulations of these important BCAs. Thus far, only a limited number of dominant selection markers, including Hygromycin B resistance (hph) and the acetamidase-encoding amdS gene, have been available for transformation of Trichoderma spp. For more extensive functional genomics studies the utilization of additional dominant markers will be essential. We established the Escherichia coli neomycin phosphotransferase II-encoding nptII gene as a novel selectable marker for the transformation of Trichoderma atroviride conferring geneticin resistance. The nptII marker cassette was stably integrated into the fungal genome and transformants exhibited unaltered phenotypes compared to the wild-type. Co-transformation of T. atroviride with nptII and a constitutively activated version of the Gα subunit-encoding tga3 gene (tga3Q207L) resulted in a high number of mitotically stable, geneticin-resistant transformants. Further analyses revealed a co-transformation frequency of 68% with 15 transformants having additionally integrated tga3Q207L into their genome. Constitutive activation of the Tga3-mediated signaling pathway resulted in increased vegetative growth and an enhanced ability to antagonize plant pathogenic host fungi. The neomycin phosphotransferase II-encoding nptII gene from Escherichia coli proved to be a valuable tool for conferring geneticin resistance to the filamentous fungus T. atroviride thereby contributing to an enhanced genetic tractability of these important BCAs.


Psychometric validation of the Clinical Impairment Assessment in a UK eating disorder service.
A number of studies have provided data on young women for the Clinical Impairment Assessment (CIA, v. 3.0), a measure of psychosocial impairment in eating disorders. However, little data exists on eating disorder samples. The aim of the current study was to investigate psychometric properties of the CIA in a clinical sample, using confirmatory factor analysis based on the originally-proposed model. The CIA was administered alongside with the Eating Disorder Examination (EDE) to 190 individuals referred to an eating disorder service. Psychometric properties of the CIA were acceptable, based on model fit and factor loadings. The CIA appears to be a useful and valid measure for the assessment of impairment in eating disorders.


How do patients with severe mental diagnosis cope in everyday life - a qualitative study comparing patients' experiences of self-referral inpatient treatment with treatment as usual?
Several hospitals in Norway provide short self-referral inpatient treatment to patients with severe mental diagnosis. No studies have compared the experiences of patients who have had the opportunity to self-refer to inpatient treatment with patients who have received treatment as usual. This qualitative study was nested within a randomised controlled trial investigating the effect of self-referral to inpatient treatment. The aim was to explore how patients with severe mental diagnosis coped four months after signing a contract for self-referral, as compared to patients receiving treatment as usual. Data was collected using qualitative individual interviews with patients with severe mental diagnosis, conducted four months after being randomised either to a contract for self-referral (intervention group) or to treatment as usual (control group). Twenty-five patients participated in interviews - 11 from the intervention group and 14 from the control group. Results four months after randomisation showed that patients with a contract for self-referral appeared to have more confidence in strategies to cope with mental illness and to apply more active cognitive strategies. Patients with a contract also expressed less resignation, hopelessness and powerlessness than patients without a contract. In addition, patients with a contract seemed to be closer to the ideal of living a "normal" life and being a "normal" person. The results indicate that the patients who had a contract for self-referral had come further in the recovery process and should possibly be better off during treatment.


Identification of risk factors for in-hospital death of COVID - 19 pneumonia -- lessions from the early outbreak.
To examine the clinical characteristics and identify independent risk factors for in-hospital mortality of 2019 novel coronavirus (COVID-19) pneumonia. A total of 156 patients diagnosed with COVID-19 pneumonia at the Central Hospital of Wuhan from January 29, 2020, to March 20, 2020, and 20 healthy individuals were enrolled in this single-centered retrospective study. The epidemiological parameters, clinical presentations, underlying diseases, laboratory test results, and disease outcomes were collected and analyzed. The median age of all enrolled patients was 66 years. At least one underlying disease was identified in 101 COVID-19 patients, with hypertension being the most common one, followed by cardiovascular disease and diabetes. The most common symptoms identified upon admission were fever, cough, dyspnea, and fatigue. Compared to survival cases, patients who died during hospitalization had higher plasma levels of D-dimer, creatinine, creatine kinase, lactate dehydrogenase, lactate, and lower percentage of lymphocytes (LYM [%]), platelet count and albumin levels. Most enrolled patients received antibiotics and anti-viral treatment. In addition, 60 patients received corticosteroids, and 51 received intravenous immunoglobulin infusion. Forty-four patients received noninvasive ventilation and 19 received invasive ventilation. Respiratory failure was the most frequently observed complication (106 [67.9%]), followed by sepsis (103 [66.0%]), acute respiratory distress syndrome (ARDS) (67 [42.9%]), and septic shock (50 [32.1%]). Multivariable regression suggested that advanced age (OR [odds ratio] = 1.098, 95% CI [confidence interval]: 1.006-1.199, P = 0.037), shorter duration from onset to admission (OR = 0.853, 95% CI: 0.750-0.969, P = 0.015) and elevated lactate level upon admission (OR = 2.689, 95% CI: 1.044-6.926, P = 0.040) were independent risk factors for in-hospital mortality for COVID-19 infection. Meanwhile, increased LYM (%) at admission (OR = 0.787, 95% CI: 0.686-0.903, P = 0.001) indicated a better prognosis. In this study, we discovered that age, duration from onset to admission, LYM (%), and lactate level upon admission were independent factors that affecting the in-hospital mortality rate.


STARD-BLCM: Standards for the Reporting of Diagnostic accuracy studies that use Bayesian Latent Class Models.
The Standards for the Reporting of Diagnostic Accuracy (STARD) statement, which was recently updated to the STARD2015 statement, was developed to encourage complete and transparent reporting of test accuracy studies. Although STARD principles apply broadly, the checklist is limited to studies designed to evaluate the accuracy of tests when the disease status is determined from a perfect reference procedure or an imperfect one with known measures of test accuracy. However, a reference standard does not always exist, especially in the case of infectious diseases with a long latent period. In such cases, a valid alternative to classical test evaluation involves the use of latent class models that do not require a priori knowledge of disease status. Latent class models have been successfully implemented in a Bayesian framework for over 20 years. The objective of this work was to identify the STARD items that require modification and develop a modified version of STARD for studies that use Bayesian latent class analysis to estimate diagnostic test accuracy in the absence of a reference standard. Examples and elaborations for each of the modified items are provided. The new guidelines, termed STARD-BLCM (Standards for Reporting of Diagnostic accuracy studies that use Bayesian Latent Class Models), will facilitate improved quality of reporting on the design, conduct and results of diagnostic accuracy studies that use Bayesian latent class models.


The putative effects of green tea on body fat: an evaluation of the evidence and a review of the potential mechanisms.
The increase in the prevalence of obesity in recent years has prompted research into alternative methods of modulating body weight and body fat. The last decade has reflected this with a surge in studies investigating the potential of green tea as a natural agent of weight loss, with a view to confirming and elucidating the mechanisms underlying its effect on the body. Currently, it is widely believed that the polyphenolic components present in green tea have an anti-obesogenic effect on fat homeostasis, by increasing thermogenesis or reducing fat absorption among other ways. The data published to date, however, are inconsistent, with numerous putative modes of action suggested therein. While several unimodal mechanisms have been postulated, a more plausible explanation of the observed results might involve a multimodal approach. Such a mechanism is suggested here, involving simultaneous inhibition of the enzymes catechol-O-methyltransferase, acetyl-CoA carboxylase, fatty acid synthase and impeding absorption of fat via the gut. An evaluation of the available evidence supports a role of green tea in weight loss; however the extent of the effects obtained is still subject to debate, and requires more objective quantification in future research.


Caffeic acid phenethyl ester down-regulates claudin-2 expression at the transcriptional and post-translational levels and enhances chemosensitivity to doxorubicin in lung adenocarcinoma A549 cells.
Claudin-2 is highly expressed in human lung adenocarcinoma cells and involved in the promotion of proliferation. Here, we searched for a compound, which can decrease claudin-2 expression using lung adenocarcinoma A549 cells. In the screening using compounds included in royal jelly and propolis, the protein level of claudin-2 was dose-dependently decreased by caffeic acid phenethyl ester (CAPE), whereas the mRNA level and promoter activity were only decreased by 50 μM CAPE. These results suggest that CAPE down-regulates claudin-2 expression mediated by two different mechanisms. CAPE (50 μM) decreased the level of p-NF-κB, whereas it increased that of IκB. The CAPE-induced decrease in promoter activity of claudin-2 was blocked by the mutation in an NF-κB-binding site. The inhibition of NF-κB may be involved in the decrease in mRNA level of claudin-2. The CAPE (10 μM)-induced decrease in claudin-2 expression was inhibited by chloroquine, a lysosomal inhibitor. CAPE increased the expression and activity of protein phosphatase (PP) 1 and 2A. The CAPE-induced decrease in claudin-2 expression was blocked by cantharidin, a potent PPs inhibitor. The cell proliferation was suppressed by CAPE, which was partially rescued by ectopic expression of claudin-2. In addition, the toxicity and accumulation of doxorubicin in 3D spheroid cells were enhanced by CAPE, which was inhibited by ectopic expression of claudin-2. Taken together, CAPE down-regulates claudin-2 expression at the transcriptional and post-translational levels, and enhances sensitivity of cells to doxorubicin in 3D culture conditions. CAPE may be a useful adjunctive compound in the treatment of lung adenocarcinoma.


Anisotropic microfibres of a liquid-crystalline diketopyrrolopyrrole by self-assembly-assisted electrospinning.
Electrospinning is a well-established technique for the preparation of nanofibres from polymer solution or melt, however it is rarely applied for small molecules. Here we report a unique example of a liquid-crystalline (LC) diketopyrrolopyrrole (DPP) dye that was successfully used for electrospinning. Micrometric fibres with anisotropic alignment of DPP dye were produced by this process as shown by polarized optical microscopy and selected area electron diffraction. This newly designed DPP dye self-assembles in solution by hydrogen bonding and π-π-interactions and forms columnar LC phases in the bulk. X-ray scattering and polarized FT-IR studies in the LC state revealed a hierarchical arrangement of DPP molecules into columnar structures. The successful preparation of anisotropic microfibers by electrospinning is attributed to the hydrogen bond-directed supramolecular polymerization of the new DPP dye in solution and its LC properties.


Ectopic expression of fatty acid-binding protein 4 in the glomerulus is associated with proteinuria and renal dysfunction.
Fatty acid-binding proteins (FABPs) are a family of intracellular lipid chaperones. Among FABPs, FABP1 (liver FABP) is expressed in proximal tubular epithelial cells in the kidney, and urinary FABP1 has been reported to reflect damage of proximal tubular epithelial cells. However, roles of other FABP isoforms in renal pathologies have not been reported. Recently, FABP4 (adipocyte FABP/aP2) was reported to be expressed in peritubular capillaries (PTCs), but not in glomerular capillaries in the normal kidney. We examined the hypothesis that pathological conditions alter the level and localization of FABP4 expression in the kidney, which mediates renal dysfunction. A total of 112 consecutive patients who underwent renal biopsy were retrospectively enrolled. Expression of FABP4 protein and mRNA in the kidney was examined by immunohistochemistry and in situ hybridization, respectively. The ratio of FABP4-positive area to total area within glomeruli (G-FABP4-Area), urinary protein level (U-Protein), and change in estimated glomerular filtration rate (eGFR) 1 year after biopsy were examined. FABP4 protein and mRNA were expressed not only in PTCs, but also in endothelial cells and macrophages in the glomerulus. G-FABP4-Area was correlated with U-Protein (r = 0.497, p < 0.001). As a subanalysis, in patients with IgA nephropathy (n = 34), G-FABP4-Area was significantly larger in cases with an endocapillary proliferative lesion, and change in eGFR was negatively correlated with G-FABP4-Area at baseline (r = -0.537, p = 0.008). Ectopic FABP4 expression in the glomerulus is induced by renal diseases and is closely associated with proteinuria and renal dysfunction.


Modeling long-term changes in daily within-person associations: An application of multilevel SEM.
Short-term within-person associations are considered to reflect unique dynamic characteristics of an individual and are frequently used to predict distal outcomes. These effects are typically examined with a 2-step statistical process. The present research demonstrates how long-term changes in short-term within-person associations can be modeled simultaneously within a multilevel structural equation modeling framework. We demonstrate the utility of this model using measurement burst data from the National Study of Daily Experiences (NSDE) embedded within the Midlife in the United States (MIDUS) longitudinal study. Two measurement bursts were separated by 9 years, with each containing daily measures of stress and affect across 8 consecutive days. Measures of life satisfaction and psychological well-being were also assessed across the 9-year period. Three-level structural equation models were fit to simultaneously model short-term within-person associations between stress and negative affect and long-term changes in these associations over the 9-year period. Individual differences in long-term changes of the short-term dynamics between stress and affect predicted well-being levels. We highlight how characterizing individuals based on the strength of their within-person associations across multiple time scales can be informative in predicting distal outcomes. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Autoregulation of thromboinflammation on biomaterial surfaces by a multicomponent therapeutic coating.
Activation of the thrombotic and complement systems is the main recognition and effector mechanisms in the multiple adverse biological responses triggered when biomaterials or therapeutic cells come into blood contact. We have created a surface which is auto-protective to human innate immunity by combining three fundamentally different strategies, all developed by us previously, which have been shown to induce substantial, but incomplete hemocompatibility when used separately. In summary, we have conjugated a factor H-binding peptide; and an ADP-degrading enzyme; using a PEG linker on both material and cellular surfaces. When exposed to human whole blood, factor H was specifically recruited to the modified surfaces and inhibited complement attack. In addition, activation of platelets and coagulation was efficiently attenuated, by degrading ADP. Thus, by inhibiting thromboinflammation using a multicomponent approach, we have created a hybrid surface with the potential to greatly reduce incompatibility reactions involving biomaterials and transplantation.


Nrf2 status affects tumor growth, HDAC3 gene promoter associations, and the response to sulforaphane in the colon.
The dietary agent sulforaphane (SFN) has been reported to induce nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2)-dependent pathways as well as inhibiting histone deacetylase (HDAC) activity. The current investigation sought to examine the relationships between Nrf2 status and HDAC expression in preclinical and translational studies. Wild type (WT) and Nrf2-deficient (Nrf2(-/+)) mice were treated with the colon carcinogen 1,2-dimethylhydrazine (DMH) followed by 400 ppm SFN in the diet (n = 35 mice/group). WT mice were more susceptible than Nrf2(-/+) mice to tumor induction in the colon. Tumors from WT mice had higher HDAC levels globally and locally on genes such as cyclin-dependant kinase inhibitor 2a (Cdkn2a/p16) that were dysregulated during tumor development. The average tumor burden was reduced by SFN from 62.7 to 26.0 mm(3) in WT mice and from 14.6 to 11.7 mm(3) in Nrf2(-/+) mice. The decreased antitumor activity of SFN in Nrf2(-/+) mice coincided with attenuated Cdkn2a promoter interactions involving HDAC3. HDAC3 knockdown in human colon cancer cells recapitulated the effects of SFN on p16 induction. Human subjects given a broccoli sprout extract supplement (200 μmol SFN equivalents), or reporting more than five cruciferous vegetable servings per week, had increased p16 expression that was inversely associated with HDAC3 in circulating peripheral blood mononuclear cells (PBMCs) and in biopsies obtained during screening colonoscopy. Nrf2 expression varies widely in both normal human colon and human colon cancers and likely contributes to the overall rate of tumor growth in the large intestine. It remains to be determined whether this influences global HDAC protein expression levels, as well as local HDAC interactions on genes dysregulated during human colon tumor development. If corroborated in future studies, Nrf2 status might serve as a biomarker of HDAC inhibitor efficacy in clinical trials using single agent or combination modalities to slow, halt, or regress the progression to later stages of solid tumors and hematological malignancies.


Genetic variation in the dopamine pathway and smoking cessation.
Twin and family studies have established that genetic factors account for much of the variation in tobacco dependence. Therefore, identification of genetic variants predictive of successful smoking cessation has implications for the future prospect of personalized smoking cessation therapies. Converging data implicate the dopamine pathway as an important neural substrate for tobacco dependence. Several candidate genes within the dopamine pathway (e.g., DRD2 and COMT) have been reported to be associated with the efficacy of bupropion and nicotine replacement therapy, and others (e.g., SLC6A3 and DRD4) have been reported to be associated with smoking cessation independent of pharmacotherapy. However, few of these candidate genes are present within regions of suggestive or significant linkage or overlap with genome-wide linkage or association studies of tobacco dependence or smoking cessation. Future studies should seek to replicate genome-wide association analyses with individual-level genotyping, and use better-defined smoking cessation phenotypes. Once robust evidence for association is established, which may take several more years, further research into the likely cost-effectiveness, feasibility and acceptability of personalized medicine for smoking cessation will be necessary before it can be translated into practice.


In situ observations of aerosol and chlorine monoxide after the 1991 eruption of mount pinatubo: effect of reactions on sulfate aerosol.
Highly resolved aerosol size distributions measured from high-altitude aircraft can be used to describe the effect of the 1991 eruption of Mount Pinatubo on the stratospheric aerosol. In some air masses, aerosol mass mixing ratios increased by factors exceeding 100 and aerosol surface area concentrations increased by factors of 30 or more. Increases in aerosol surface area concentration were accompanied by increases in chlorine monoxide at mid-latitudes when confounding factors were controlled. This observation supports the assertion that reactions occurring on the aerosol can increase the fraction of stratospheric chlorine that occurs in ozone-destroying forms.


Sociodemographic differences in fast food price sensitivity.
Fiscal food policies (eg, taxation) are increasingly proposed to improve population-level health, but their impact on health disparities is unknown. To estimate subgroup-specific effects of fast food price changes on fast food consumption and cardiometabolic outcomes. Twenty-year follow-up (5 examinations) in a biracial US prospective cohort: Coronary Artery Risk Development in Young Adults (CARDIA) (1985/1986-2005/2006, baseline N = 5115). Participants were aged 18 to 30 years at baseline; design indicated equal recruitment by race (black vs white), educational attainment, age, and sex. Community-level price data from the Council for Community and Economic Research were temporally and geographically linked to study participants' home address at each examination. Participant-reported number of fast food eating occasions per week, body mass index (BMI), and homeostasis model assessment insulin resistance (HOMA-IR) from fasting glucose and insulin concentrations. Covariates included individual-level and community-level social and demographic factors. In repeated measures regression analysis, multivariable-adjusted associations between fast food price and consumption were nonlinear (quadratic, P < .001), with significant inverse estimated effects on consumption at higher prices; estimates varied according to race (interaction P = .04), income (P = .07), and education (P = .03). At the 10th percentile of price ($1.25/serving), blacks and whites had mean fast food consumption frequency of 2.20 (95% CI, 2.07-2.33) and 1.55 (1.45-1.65) times/wk, respectively, whereas at the 90th percentile of price ($1.53/serving), respective mean consumption estimates were 1.86 (1.75-1.97) and 1.50 (1.41-1.59) times/wk. We observed differential price effects on HOMA-IR (inverse for lower educational status only [interaction P = .005] and at middle income only [interaction P = .02]) and BMI (inverse for blacks, less education, and middle income; positive for whites, more education, and high income [all interaction P < .001]). We found greater fast food price sensitivity on fast food consumption and insulin resistance among sociodemographic groups that have a disproportionate burden of chronic disease. Our findings have implications for fiscal policy, particularly with respect to possible effects of fast food taxes among populations with diet-related health disparities.


Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery.
Despite thromboprophylaxis, major knee surgery carries a high risk of venous thromboembolism. Fondaparinux, the first of a new class of synthetic antithrombotic agents, may reduce this risk. In a double-blind study, we randomly assigned 1049 consecutive patients undergoing elective major knee surgery to receive subcutaneous doses of either 2.5 mg of fondaparinux once daily or 30 mg of enoxaparin twice daily, with both treatments initiated postoperatively. The primary efficacy outcome was venous thromboembolism up to postoperative day 11, defined as deep-vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep-vein thrombosis, or documented symptomatic pulmonary embolism. The primary safety outcome was major bleeding. The primary efficacy outcome was assessed in 724 patients. The fondaparinux group had a significantly lower incidence of venous thromboembolism by day 11 (12.5 percent [45 of 361 patients]) than the enoxaparin group (27.8 percent [101 of 363 patients]; reduction in risk, 55.2 percent; 95 percent confidence interval, 36.2 to 70.2; P<0.001). Major bleeding (including overt bleeding with a bleeding index of 2 or more) occurred more frequently in the fondaparinux group (P=0.006), but there were no significant differences between the two groups in the incidence of bleeding leading to death or reoperation or occurring in a critical organ. In patients undergoing elective major knee surgery, postoperative treatment with 2.5 mg of fondaparinux once daily was significantly more effective in preventing deep-vein thrombosis than 30 mg of enoxaparin twice daily.


Prediction of dementia risk in low-income and middle-income countries (the 10/66 Study): an independent external validation of existing models.
To date, dementia prediction models have been exclusively developed and tested in high-income countries (HICs). However, most people with dementia live in low-income and middle-income countries (LMICs), where dementia risk prediction research is almost non-existent and the ability of current models to predict dementia is unknown. This study investigated whether dementia prediction models developed in HICs are applicable to LMICs. Data were from the 10/66 Study. Individuals aged 65 years or older and without dementia at baseline were selected from China, Cuba, the Dominican Republic, Mexico, Peru, Puerto Rico, and Venezuela. Dementia incidence was assessed over 3-5 years, with diagnosis according to the 10/66 Study diagnostic algorithm. Discrimination and calibration were tested for five models: the Cardiovascular Risk Factors, Aging and Dementia risk score (CAIDE); the Study on Aging, Cognition and Dementia (AgeCoDe) model; the Australian National University Alzheimer's Disease Risk Index (ANU-ADRI); the Brief Dementia Screening Indicator (BDSI); and the Rotterdam Study Basic Dementia Risk Model (BDRM). Models were tested with use of Cox regression. The discriminative accuracy of each model was assessed using Harrell's concordance (c)-statistic, with a value of 0·70 or higher considered to indicate acceptable discriminative ability. Calibration (model fit) was assessed statistically using the Grønnesby and Borgan test. 11 143 individuals without baseline dementia and with available follow-up data were included in the analysis. During follow-up (mean 3·8 years [SD 1·3]), 1069 people progressed to dementia across all sites (incidence rate 24·9 cases per 1000 person-years). Performance of the models varied. Across countries, the discriminative ability of the CAIDE (0·52≤c≤0·63) and AgeCoDe (0·57≤c≤0·74) models was poor. By contrast, the ANU-ADRI (0·66≤c≤0·78), BDSI (0·62≤c≤0·78), and BDRM (0·66≤c≤0·78) models showed similar levels of discriminative ability to those of the development cohorts. All models showed good calibration, especially at low and intermediate levels of predicted risk. The models validated best in Peru and poorest in the Dominican Republic and China. Not all dementia prediction models developed in HICs can be simply extrapolated to LMICs. Further work defining what number and which combination of risk variables works best for predicting risk of dementia in LMICs is needed. However, models that transport well could be used immediately for dementia prevention research and targeted risk reduction in LMICs. National Institute for Health Research, Wellcome Trust, WHO, US Alzheimer's Association, and European Research Council.


Cold-Water Immersion for Athletic Recovery: One Size Does Not Fit All.
The use of cold-water immersion (CWI) for postexercise recovery has become increasingly prevalent in recent years, but there is a dearth of strong scientific evidence to support the optimization of protocols for performance benefits. While the increase in practice and popularity of CWI has led to multiple studies and reviews in the area of water immersion, the research has predominantly focused on performance outcomes associated with postexercise CWI. Studies to date have generally shown positive results with enhanced recovery of performance. However, there are a small number of studies that have shown CWI to have either no effect or a detrimental effect on the recovery of performance. The rationale for such contradictory responses has received little attention but may be related to nuances associated with individuals that may need to be accounted for in optimizing prescription of protocols. To recommend optimal protocols to enhance athletic recovery, research must provide a greater understanding of the physiology underpinning performance change and the factors that may contribute to the varied responses currently observed. This review focuses specifically on why some of the current literature may show variability and disparity in the effectiveness of CWI for recovery of athletic performance by examining the body temperature and cardiovascular responses underpinning CWI and how they are related to performance benefits. This review also examines how individual characteristics (such as physique traits), differences in water-immersion protocol (depth, duration, temperature), and exercise type (endurance vs maximal) interact with these mechanisms.


Apolipoprotein E phenotypes, lipoprotein composition, and xanthelasmas.
The different types of serum lipoproteins, including apolipoprotein E phenotypes, were measured in 50 patients with xanthelasma. Half of them were found to be hyperlipemic. The normolipemic and hyperlipemic groups with xanthelasma were compared with two control groups (one a group of normolipemic patients and another a group of hyperlipemic patients without xanthelasma) selected as homogeneously as possible with regard to age, sex, degree of obesity, and hyperlipemic phenotype. The only significant differences found among the groups, regardless of the presence of hyperlipemia, were the increased levels of total and high-density lipoprotein phospholipids, and lower levels of apolipoprotein B, found in the group with xanthelasmas. The distribution of apolipoprotein E phenotypes was the same in both groups, with slight differences between the normolipemic and hyperlipemic groups. Patients with xanthelasmas showed slight deviations in the metabolism of lipoproteins that require further clarification.


Knee synovial cyst presenting as iliotibial band friction syndrome.
We present the case of a 28-year-old competitive runner with iliotibial band (ITB) friction syndrome associated with a synovial cyst. Magnetic resonance imaging (MRI) did not demonstrate a fluid collection. However, open exploration revealed a large cyst beneath the ITB arising from the capsule of the knee proximal to the lateral meniscus. The cyst disappeared on extension. The pre-operative MRI scan may have revealed the cyst, if it had been taken with the knee flexed.


Role of tunnel ionization in high harmonic generation from substituted benzenes.
We theoretically study high-harmonic generation in toluene, ortho-xylene and fluorobenzene driven by a 1.8 μm ultrashort pulse. We find that the chemical substitutions have a strong influence on the amplitude and phase of the emission from the highest occupied molecular orbital, despite having a small influence on the orbital itself. We show that this influence is due to the tunnel ionization step, which depends critically on the sign and amplitude of the asymptotic part of the wave function. We discuss how these effects would manifest in phase-sensitive high-harmonic generation spectroscopy experiments.


Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium.
To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.


Neurotrophic effects of tianeptine on hippocampal neurons: a proteomic approach.
Tianeptine, an atypical tricyclic antidepressant with unique characteristics, can improve memory and prevent stress-induced hippocampal damage. It has neuroplastic and neurotrophic effects on hippocampal neurons and can prevent dendritic atrophy of the hippocampus in certain pathological conditions. To obtain a better understanding of the underlying mechanisms, we performed a proteomic analysis on tianeptine-treated hippocampal neurons. Primary hippocampal neurons were prepared from fetal Sprague-Dawley rats, eliminating glia cells by addition of cytosine beta-D-arabinofuranoside at day 2 in vitro (DIV2). The neurons were treated with tianeptine (10 microg/mL) or vehicle at DIV3, then harvested at DIV4 or DIV9 for immunocytochemical analysis of, respectively, neurite outgrowth or synapse formation. A proteomics analysis was performed on DIV4 neurons and the data were confirmed by Western blot analysis. Using specific markers, we demonstrated that tianeptine can augment neurite growth and promote synaptic contacts in cultured hippocampal neurons. The proteomics analysis identified 11 differentially expressed proteins, with roles in neurite growth, metabolism of neurotrophic substances, synaptogenesis, and synaptic activity homeostasis. The data shed light on the mechanisms underlying the neurotrophic effect of tianeptine observed in both animal studies and the clinic.


Comparison of gatifloxacin, moxifloxacin and ciprofloxacin for treatment of experimental Burkholderia pseudomallei infection.
To compare the efficacy of moxifloxacin, gatifloxacin and ciprofloxacin for the post-exposure prophylaxis and treatment of experimental Burkholderia pseudomallei infection. The presence of persistent infection in treated animals and the rate of relapse following dexamethasone treatment were also investigated. BALB/c mice were inoculated subcutaneously with 1.75 x 10(6) cfu of B. pseudomallei strain 576. Gatifloxacin, moxifloxacin and ciprofloxacin (100 mg/kg) were given orally at 12 hourly intervals for 14 days starting at 6 h, 7 days or 12 days post-challenge. Control mice did not receive antibiotic therapy. No regimen gave 100% protection. Prophylaxis was most effective when started 6 h post-challenge, with survival rates at 42 days for ciprofloxacin, gatifloxacin and moxifloxacin being 58%, 75% and 75%, respectively. For treatment started at day 7 post-challenge, survival rates were 17%, 11% and 44%, respectively. When antibiotic treatment was delayed until day 12 post-challenge, survival rates fell to 21%, 17% and 28%, respectively. Following dexamethasone treatment of survivors at 42 days post-challenge, relapses occurred in all treatment groups. Fluoroquinolones do not provide good post-exposure protection against infection with B. pseudomallei. The newer agents moxifloxacin and gatifloxacin are not significantly better than ciprofloxacin for this purpose.


Open operative treatment for anterior shoulder instability: when and why?
The treatment of anterior glenohumeral instability continues to evolve. Open capsulolabral repairs are time-tested and reliable. In an era in which arthroscopic techniques continue to improve, open surgery remains an acceptable option, and there are still certain injury patterns that cannot be adequately addressed arthroscopically. Decision-making regarding surgery for instability is influenced by the surgeon's experience and the relevant pathological findings. Open operative treatment is the preferred approach in many instances of recurrent anterior instability, particularly when there is bone and soft-tissue loss and in revision settings.


Perineal care.
Over 85% of women having a vaginal birth suffer some perineal trauma. Spontaneous tears requiring suturing are estimated to occur in at least a third of women in the UK and US, with anal sphincter tears in 0.5% to 7% of women. Perineal trauma can lead to long-term physical and psychological problems. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of intrapartum surgical and non-surgical interventions on rates of perineal trauma? What are the effects of different methods and materials for primary repair of first- and second-degree tears and episiotomies? What are the effects of different methods and materials for primary repair of obstetric anal sphincter injuries (third- and fourth-degree tears)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 38 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: active pushing, spontaneous pushing, and sustained breath-holding (Valsalva) method of pushing; continuous support during labour; conventional suturing; different methods and materials for primary repair of obstetric anal sphincter injuries; episiotomies (midline and mediolateral incisions); epidural analgesia; forceps; methods of delivery ("hands-on" method, "hands poised"); water births; non-suturing of muscle and skin (or perineal skin alone); passive descent in the second stage of labour; positions (supine or lithotomy positions, upright position during delivery); restrictive or routine use of episiotomy; sutures (absorbable synthetic sutures, catgut sutures, continuous sutures, interrupted sutures); and vacuum extraction.


Design, fabrication and transmitted properties of terahertz paper photonic crystals.
The terahertz paper photonic crystals, including one-dimensional stacks, two-dimensional square and hexagonal lattices as well as three-dimensional body-centered cubic lattice, are designed and fabricated. Femtosecond laser direct writing is employed to process paper layers. The transmission properties of these photonic crystals in THz range are characterized using time-domain THz spectroscopy. The experimental results are in good agreement with the numerical simulations and well explained by the photonic band-structure calculated by the plane wave expansion method. Our results demonstrate that paper photonic crystals have a good performance on molding the flow of THz radiation. From another point of view, the fabrication method proposed in this work can be widely extended to manufacture different micro-structures on various materials.


Long-term mortality in mothers with perinatal losses and risk modification by surviving children and attained education: a population-based cohort study.
To assess the association between perinatal losses and mother's long-term mortality and modification by surviving children and attained education. A population-based cohort study. Norwegian national registries. We followed 652 320 mothers with a first delivery from 1967 and completed reproduction before 2003, until 2010 or death. We excluded mothers with plural pregnancies, without information on education (0.3%) and women born outside Norway. Main outcome measures were age-specific (40-69 years) cardiovascular and non-cardiovascular mortality. We calculated mortality in mothers with perinatal losses, compared with mothers without, and in mothers with one loss by number of surviving children in strata of mothers' attained education (<11 years (low), ≥11 years (high)). Mothers with perinatal losses had increased crude mortality compared with mothers without; total: HR 1.3 (95% CI 1.3 to 1.4), cardiovascular: HR 1.8 (1.5 to 2.1), non-cardiovascular: HR 1.3 (1.2 to 1.4). Childless mothers with one perinatal loss had increased mortality compared with mothers with one child and no loss; cardiovascular: low education HR 2.7 (1.7 to 4.3), high education HR 0.91 (0.13 to 6.5); non-cardiovascular: low education HR 1.6 (1.3 to 2.2), high education HR 1.8 (1.1 to 2.9). Mothers with one perinatal loss, surviving children and high education had no increased mortality, whereas corresponding mothers with low education had increased mortality; cardiovascular: two surviving children HR 1.7 (1.2 to 2.4), three or more surviving children HR 1.6 (1.1 to 2.4); non-cardiovascular: one surviving child HR 1.2 (1.0 to 1.5), two surviving children HR 1.2 (1.1 to 1.4). Irrespective of education, we find excess mortality in childless mothers with a perinatal loss. Increased mortality in mothers with one perinatal loss and surviving children was limited to mothers with low education.


Disruption of a -35 kb Enhancer Impairs CTCF Binding and MLH1 Expression in Colorectal Cells.
Purpose:MLH1 is a major tumor suppressor gene involved in the pathogenesis of Lynch syndrome and various sporadic cancers. Despite their potential pathogenic importance, genomic regions capable of regulating MLH1 expression over long distances have yet to be identified.Experimental Design: Here, we use chromosome conformation capture (3C) to screen a 650-kb region flanking the MLH1 locus to identify interactions between the MLH1 promoter and distal regions in MLH1-expressing and nonexpressing cells. Putative enhancers were functionally validated using luciferase reporter assays, chromatin immunoprecipitation, and CRISPR-Cas9-mediated deletion of endogenous regions. To evaluate whether germline variants in the enhancer might contribute to impaired MLH1 expression in patients with suspected Lynch syndrome, we also screened germline DNA from a cohort of 74 patients with no known coding mutations or epimutations at the MLH1 promoter.Results: A 1.8-kb DNA fragment, 35 kb upstream of the MLH1 transcription start site enhances MLH1 gene expression in colorectal cells. The enhancer was bound by CTCF and CRISPR-Cas9-mediated deletion of a core binding region impairs endogenous MLH1 expression. A total of 5.4% of suspected Lynch syndrome patients have a rare single-nucleotide variant (G > A; rs143969848; 2.5% in gnomAD European, non-Finnish) within a highly conserved CTCF-binding motif, which disrupts enhancer activity in SW620 colorectal carcinoma cells.Conclusions: A CTCF-bound region within the MLH1-35 enhancer regulates MLH1 expression in colorectal cells and is worthy of scrutiny in future genetic screening strategies for suspected Lynch syndrome associated with loss of MLH1 expression. Clin Cancer Res; 24(18); 4602-11. ©2018 AACR.


Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation.
New therapeutic approaches are needed to treat leukemia effectively. Dietary restriction regimens, including fasting, have been considered for the prevention and treatment of certain solid tumor types. However, whether and how dietary restriction affects hematopoietic malignancies is unknown. Here we report that fasting alone robustly inhibits the initiation and reverses the leukemic progression of both B cell and T cell acute lymphoblastic leukemia (B-ALL and T-ALL, respectively), but not acute myeloid leukemia (AML), in mouse models of these tumors. Mechanistically, we found that attenuated leptin-receptor (LEPR) expression is essential for the development and maintenance of ALL, and that fasting inhibits ALL development by upregulation of LEPR and its downstream signaling through the protein PR/SET domain 1 (PRDM1). The expression of LEPR signaling-related genes correlated with the prognosis of pediatric patients with pre-B-ALL, and fasting effectively inhibited B-ALL growth in a human xenograft model. Our results indicate that the effects of fasting on tumor growth are cancer-type dependent, and they suggest new avenues for the development of treatment strategies for leukemia.


Trends in lung cancer death rates in Belgium and The Netherlands: a systematic analysis of temporal patterns.
Belgium and The Netherlands have fairly similar smoking prevalence patterns, but distinct tobacco control policies. It is our aim to use lung cancer death rates, especially among the youngest age groups (30-39 years), as indicators of past smoking behavioral patterns to evaluate recent tobacco control efforts in both countries. Lung cancer mortality rates from 1954 to 1997 and from 1950 to 2000 were investigated in Belgium and The Netherlands, respectively, using the joinpoint regression modeling technique (log-linear Poisson models) to calculate annual percent change in death rate. In the most recent period (1984-2000) overall male lung cancer death rates have been declining at a faster rate in The Netherlands than in Belgium. In contrast, overall female lung cancer death rates (between 1950 and 2000) have been increasing at a faster rate in The Netherlands than in Belgium. Since 1988, however, APCs in death rates among Dutch females have begun to level off. Interestingly, during this same period, a significant annual decline of 7.7% among the youngest Dutch women (30-39 years) has been observed. Tobacco use prevention and interventions seem to have an impact on smoking prevalence, especially among younger age groups. In The Netherlands, where aggressive anti-tobacco campaigns were introduced a few years earlier than in Belgium, male lung cancer mortality rates have been declining more rapidly, and female lung cancer mortality rates have begun to level off.


Effects of seawater pH and temperature on foraging behavior of the Japanese stone crab Charybdis japonica.
We examined prey selection and foraging behaviors of the crab Charybdis japonica exposed to four combinations of pH (7.3 and 8.1) and temperature (18°C and 25°C). The order of prey selection by C. japonica was Potamocorbula laevis, Ruditapes philippinarum, Tegillarca granosa and Mactra veneriformis. Under high pCO2, times for searching, breaking, eating and handling were all significantly longer than those at the normal pCO2, and the prey profitability and predation rate under high pCO2 were significantly lower than normal pCO2. Moreover, temperature significantly influenced the foraging behaviors, but its effects were not as strong as those of pH; times for searching, eating and handling under high temperature were significantly lower than the low temperature, and the prey predation rates under high temperature was significantly higher than low temperature. In conclusion, high pCO2 negatively affected the foraging behavior, but high temperature actively stimulated the foraging behaviors of crabs.


A Fast and Efficient Technique for the Automatic Tracing of Corneal Nerves in Confocal Microscopy.
We describe a novel fully automatic method capable of tracing the subbasal plexus nerves from human corneal confocal images. Following an increasing interest in the automatic analysis of corneal nerves, a few approaches have been proposed. These, however, cannot cope with large images, such as mosaics, in due time. The rationale of the proposed method is to minimize required computing time while still providing accurate results. Our method consists of two sequential steps - a thresholding step followed by a supervised classification. For the classification we use a support vector machines (SVM) approach. Initially, a large set of features is computed, which is later reduced using a backward-elimination based on segmentation accuracy. To validate the obtained tracings, we evaluated the tracing accuracy and reliability of extracted clinical parameters (corneal nerves density and tortuosity). The proposed algorithm proved capable to correctly trace 0.89 ± 0.07 of the corneal nerves. The obtained performance level was comparable to a second human grader. Furthermore, the proposed approach compares favorably to other methods. For both evaluated clinical parameters the proposed approach performed well. An execution time of 0.61 ± 0.07 seconds per image was achieved. The proposed algorithm was applied successfully to mosaic images, with run times of the order of tens of seconds. The achieved quality and processing time of the proposed method appear adequate for the application of this technique to clinical practice. The automatic tracing of corneal nerves is an important step for the quantitative analysis of corneal nerves in daily clinical practice. The proposed fast technique allows features, such as corneal nerve density and tortuosity, to be computed in a few seconds. The application of nerve tracing to mosaics covering a large area can be a key component in clinical studies aimed at investigating neuropathy influence in various ocular or systemic diseases.


The influence of quadriceps strength asymmetry on patient-reported function at time of return to sport after anterior cruciate ligament reconstruction.
An objective assessment of quadriceps strength after anterior cruciate ligament reconstruction (ACLR) is an important clinical measure to determine readiness to return to sport (RTS). Not all clinicians are equipped with the means to objectively quantify quadriceps strength limb symmetry indices (Q-LSIs) via lower extremity isokinetic dynamometers, as recommended by previous studies. The purpose of this study was to determine whether the International Knee Documentation Committee 2000 Subjective Knee Form (IKDC) score at time of RTS was a predictor of quadriceps strength in a young, athletic population after ACLR. Two hypotheses were tested: (1) Individuals with higher self-reports of function would demonstrate better quadriceps strength of the involved limb than individuals with lower self-reports of function at the time of RTS, and (2) individuals with higher self-reports of function would have normal quadriceps strength limb symmetry. Cohort study (diagnosis); Level of evidence, 2. At time of RTS, 139 subjects who had undergone ACLR completed the IKDC. In addition, an isometric quadriceps strength test (Biodex dynamometer) was performed on both lower extremities. Peak torques were calculated, as was the Q-LSI, determined by the formula (involved limb peak torque/uninvolved limb peak torque) × 100%. Participants were dichotomized based on IKDC scores: high IKDC (IKDC ≥90) and low IKDC (IKDC <90). Two-way analysis of variance was used to determine the effect of limb (involved vs uninvolved) and group (high vs low IKDC) on isometric quadriceps strength. Chi-square and logistic regression analyses were then performed to determine whether IKDC scores could predict Q-LSI. At time of RTS, a significant correlation between IKDC scores and (1) peak isometric torque (r = 0.282, P < .001) and (2) Q-LSI (r = 0.357, P < .001) was observed. Individuals with IKDC scores ≥90 were 3 times (OR = 3.4; 95% CI, 1.71-6.93) more likely to demonstrate higher Q-LSI (≥90%). An IKDC score ≥94.8 predicted Q-LSI ≥90% with high sensitivity (0.813) and moderate specificity (0.493). Participants with higher IKDC scores demonstrated an increased likelihood of presenting with greater involved limb quadriceps strength and better Q-LSI. Based on the results of this study, a patient-reported outcome measure, such as the IKDC, may be able to serve as a valuable screening tool for the identification of quadriceps strength deficits in this population; however, it should not be considered an accurate surrogate for isokinetic dynamometry. Furthermore, a score of ≥94.8 on the IKDC is likely to indicate that a patient's quadriceps strength is at an acceptable RTS level.


Establishment of a Cytocompatible Cell-Free Intervertebral Disc Matrix for Chondrogenesis with Human Bone Marrow-Derived Mesenchymal Stromal Cells.
Tissue-engineered intervertebral discs (IVDs) utilizing decellularized extracellular matrix (ECM) could be an option for the reconstruction of impaired IVDs due to degeneration or injury. The objective of this study was to prepare a cell-free decellularized human IVD scaffold and to compare neotissue formation in response to recellularization with human IVD cells (hIVDCs) or human bone marrow-derived (hBM) mesenchymal stromal cells (MSCs). IVDs were decellularized via freeze-thaw cycles, detergents and trypsin. Histological staining was performed to monitor cell removal and glycosaminoglycan (GAG) removal. The decellularized IVD was preconditioned using bovine serum albumin and fetal bovine serum before its cytocompatibility for dynamically cultured hBM-MSCs (chondrogenically induced or not) and hIVDCs was compared after 14 days. In addition, DNA, total collagen and GAG contents were assessed. The decellularization protocol achieved maximal cell removal, with only few remaining cell nuclei compared with native tissue, and low toxicity. The DNA content was significantly higher in scaffolds seeded with hIVDCs compared with native IVDs, cell-free and hBM-MSC-seeded scaffolds (p < 0.01). The GAG content in the native tissue was significantly higher compared to the others groups except for the scaffolds reseeded with chondrogenically induced hBM-MSCs (p < 0.05). In addition, there was a significantly increased total collagen content in the chondrogenically induced hBM-MSCs group (p < 0.01) compared with the native IVDs, cell-free and hIVDC-seeded scaffolds (p < 0.01); both recolonizing cell types were more evenly distributed on the scaffold surface, but only few cells penetrated the scaffold. The resulting decellularized ECM was cytocompatible and allowed hBM-MSCs/hIVDCs survival and ECM production.