Interaction of two walkers: wave-mediated energy and force.
A bouncing droplet, self-propelled by its interaction with the waves it generates, forms a classical wave-particle association called a "walker." Previous works have demonstrated that the dynamics of a single walker is driven by its global surface wave field that retains information on its past trajectory. Here we investigate the energy stored in this wave field for two coupled walkers and how it conveys an interaction between them. For this purpose, we characterize experimentally the "promenade modes" where two walkers are bound and propagate together. Their possible binding distances take discrete values, and the velocity of the pair depends on their mutual binding. The mean parallel motion can be either rectilinear or oscillating. The experimental results are recovered analytically with a simple theoretical framework. A relation between the kinetic energy of the droplets and the total energy of the standing waves is established.


Large-scale synthesis of mixed valence K3[Fe2S4] with high dielectric and ferrimagnetic characteristics.
High yields of phase-pure K3[Fe2S4] are obtained using a fast, straight-forward, and efficient synthetic technique starting from the binary precursors K2S and FeS, and elemental sulphur. The compound indicates soft ferrimagnetic characteristics with magnetization of 15.23 A m2 kg-1 at 300 K due to the mixed valence of FeII/FeIII. Sintering at different temperatures allows the manipulation of the microstructure as well as the ratio of grains to grain boundaries. This results in a variation of dielectric and impedance properties. Samples sintered at 923 K demonstrate a dielectric constant (κ) of around 1750 at 1 kHz, which lies within the range of well-known high-κ dielectric materials, and an ionic conductivity of 4 × 10-2 mS cm-1 at room temperature. The compound has an optical band gap of around 2.0 eV, in agreement with tailored quantum chemical calculations. These results highlight its potential as a material comprising non-toxic and abundant elements for electronic and magnetic applications.


A malnutrition-inflammation score is correlated with morbidity and mortality in maintenance hemodialysis patients.
Malnutrition inflammation complex syndrome (MICS) occurs commonly in maintenance hemodialysis (MHD) patients and may correlate with increased morbidity and mortality. An optimal, comprehensive, quantitative system that assesses MICS could be a useful measure of clinical status and may be a predictor of outcome in MHD patients. We therefore attempted to develop and validate such an instrument, comparing it with conventional measures of nutrition and inflammation, as well as prospective hospitalization and mortality. Using components of the conventional Subjective Global Assessment (SGA), a semiquantitative scale with three severity levels, the Dialysis Malnutrition Score (DMS), a fully quantitative scoring system consisting of 7 SGA components, with total score ranging between 7 (normal) and 35 (severely malnourished), was recently developed. To improve the DMS, we added three new elements to the 7 DMS components: body mass index, serum albumin level, and total iron-binding capacity to represent serum transferrin level. This new comprehensive Malnutrition-Inflammation Score (MIS) has 10 components, each with four levels of severity, from 0 (normal) to 3 (very severe). The sum of all 10 MIS components ranges from 0 to 30, denoting increasing degree of severity. These scores were compared with anthropometric measurements, near-infrared-measured body fat percentage, laboratory measures that included serum C-reactive protein (CRP), and 12-month prospective hospitalization and mortality rates. Eighty-three outpatients (44 men, 39 women; age, 59 +/- 15 years) on MHD therapy for at least 3 months (43 +/- 33 months) were evaluated at the beginning of this study and followed up for 1 year. The SGA, DMS, and MIS were assessed simultaneously on all patients by a trained physician. Case-mix-adjusted correlation coefficients for the MIS were significant for hospitalization days (r = 0.45; P < 0.001) and frequency of hospitalization (r = 0.46; P < 0.001). Compared with the SGA and DMS, most pertinent correlation coefficients were stronger with the MIS. The MIS, but not the SGA or DMS, correlated significantly with creatinine level, hematocrit, and CRP level. During the 12-month follow-up, 9 patients died and 6 patients left the cohort. The Cox proportional hazard-calculated relative risk for death for each 10-unit increase in the MIS was 10.43 (95% confidence interval, 2.28 to 47.64; P = 0.002). The MIS was superior to its components or different subversions for predicting mortality. The MIS appears to be a comprehensive scoring system with significant associations with prospective hospitalization and mortality, as well as measures of nutrition, inflammation, and anemia in MHD patients. The MIS may be superior to the conventional SGA and the DMS, as well as to individual laboratory values, as a predictor of dialysis outcome and an indicator of MICS.


Energetics of bacterial growth: balance of anabolic and catabolic reactions.
Biomass formation represents one of the most basic aspects of bacterial metabolism. While there is an abundance of information concerning individual reactions that result in cell duplication, there has been surprisingly little information on the bioenergetics of growth. For many years, it was assumed that biomass production (anabolism) was proportional to the amount of ATP which could be derived from energy-yielding pathways (catabolism), but later work showed that the ATP yield (YATP) was not necessarily a constant. Continuous-culture experiments indicated that bacteria utilized ATP for metabolic reactions that were not directly related to growth (maintenance functions). Mathematical derivations showed that maintenance energy appeared to be a growth rate-independent function of the cell mass and time. Later work, however, showed that maintenance energy alone could not account for all the variations in yield. Because only some of the discrepancy could be explained by the secretion of metabolites (overflow metabolism) or the diversion of catabolism to metabolic pathways which produced less ATP, it appeared that energy-excess cultures had mechanisms of spilling energy. Bacteria have the potential to spill excess ATP in futile enzyme cycles, but there has been little proof that such cycles are significant. Recent work indicated that bacteria can also use futile cycles of potassium, ammonia, and protons through the cell membrane to dissipate ATP either directly or indirectly. The utility of energy spilling in bacteria has been a curiosity. The deprivation of energy from potential competitors is at best a teleological explanation that cannot be easily supported by standard theories of natural selection. The priming of intracellular intermediates for future growth or protection of cells from potentially toxic end products (e.g., methylglyoxal) seems a more plausible explanation.


The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3 expression and liver damage.
The patatin-like phosholipase domain-containing 3 (PNPLA3) rs738409 polymorphism (I148M) is a major determinant of hepatic fat and predisposes to the full spectrum of liver damage in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate whether additional PNPLA3 coding variants contribute to NAFLD susceptibility, first in individuals with contrasting phenotypes (with early-onset NAFLD vs. very low aminotransferases) and then in a large validation cohort. Rare PNPLA3 variants were not detected by sequencing coding regions and intron-exon boundaries either in 142 patients with early-onset NAFLD nor in 100 healthy individuals with alanine aminotransferase <22/20 IU/mL. Besides rs738409 I148M, the rs2294918 G>A polymorphism (E434K sequence variant) was over-represented in NAFLD (adjusted P = 0.01). In 1,447 subjects with and without NAFLD, the 148M-434E (P < 0.0001), but not the 148M-434K, haplotype (P > 0.9), was associated with histological NAFLD and steatohepatitis. Both the I148M (P = 0.0002) and E434K variants (P = 0.044) were associated with serum ALT levels, by interacting with each other, in that the 434K hampered the association with liver damage of the 148M allele (P = 0.006). The E434K variant did not affect PNPLA3 enzymatic activity, but carriers of the rs2294918 A allele (434K) displayed lower hepatic PNPLA3 messenger RNA and protein levels (P < 0.05). Rare loss-of-function PNPLA3 variants were not detected in early-onset NAFLD. However, PNPLA3 rs2294918 E434K decreased PNPLA3 expression, lessening the effect of the I148M variant on the predisposition to steatosis and liver damage. This suggests that the PNPLA3 I148M variant has a codominant negative effect on triglycerides mobilization from lipid droplets, mediated by inhibition of other lipases.


Acculturation and the oral health of a nationally representative sample of Hispanic children in the United States: an analysis of 2011-2012 National Survey of Children's Health data.
Oral disease is a serious public health issue, and Hispanic children in the United States (US) are more likely than children of other racial/ethnic groups to experience dental caries. Although Hispanic children are a growing segment of the US population there is limited research on the association between acculturation and oral health outcomes in this population. This study examined the associations between household acculturation and pediatric oral health in the Hispanic population using a nationally representative sample of children. Data from the 2011-2012 National Survey of Children's Health were analyzed; analyses included Hispanic children ages 1 to 17. Household acculturation was assessed with a combination of language and parental nativity, while oral health was assessed via parents'/guardians' reports of children's dental caries. Logistic regression was used to examine the association between acculturation and oral health, adjusting for other demographic and social determinants of pediatric oral health. We assessed significance at the p < 0.05 level, and all analyses accounted for the survey's complex sample design. Analyses included 9143 Hispanic children. In total, 24.9% (95% CI: 22.9-27.0%) experienced dental caries, and there were significant associations between household acculturation and oral health. In unadjusted analyses, 32.0% (95% CI: 28.9-35.4%) of children in low acculturation households, 20.3% (95% CI: 16.0-25.4%) of children in moderate acculturation households, and 16.9% (95% CI: 14.2-20.0%) of children in high acculturation households experienced dental caries (p < 0.001). In adjusted analyses, children in high acculturation households were significantly less likely than those in low acculturation households to experience dental caries (p < 0.001; OR = 0.50; 95% CI: 0.35-0.70). The difference between children in moderate and low acculturation households approached but did not reach statistical significance (p = 0.057; OR = 0.69; 95% CI: 0.48-1.01). A dose-response relationship was observed between household acculturation and the oral health of Hispanic children in the US. As acculturation increases, the likelihood of a child experiencing dental caries decreases. These findings suggest that public health and community-based interventions intended to reduce oral health disparities in Hispanic children would likely be most impactful if the acculturation levels of the children's households are considered during program development.


BOMP: a program to predict integral beta-barrel outer membrane proteins encoded within genomes of Gram-negative bacteria.
This work describes the development of a program that predicts whether or not a polypeptide sequence from a Gram-negative bacterium is an integral beta-barrel outer membrane protein. The program, called the beta-barrel Outer Membrane protein Predictor (BOMP), is based on two separate components to recognize integral beta-barrel proteins. The first component is a C-terminal pattern typical of many integral beta-barrel proteins. The second component calculates an integral beta-barrel score of the sequence based on the extent to which the sequence contains stretches of amino acids typical of transmembrane beta-strands. The precision of the predictions was found to be 80% with a recall of 88% when tested on the proteins with SwissProt annotated subcellular localization in Escherichia coli K 12 (788 sequences) and Salmonella typhimurium (366 sequences). When tested on the predicted proteome of E.coli, BOMP found 103 of a total of 4346 polypeptide sequences to be possible integral beta-barrel proteins. Of these, 36 were found by BLAST to lack similarity (E-value score < 1e-10) to proteins with annotated subcellular localization in SwissProt. BOMP predicted the content of integral beta-barrels per predicted proteome of 10 different bacteria to range from 1.8 to 3%. BOMP is available at http://www.bioinfo.no/tools/bomp.


ArrayMining: a modular web-application for microarray analysis combining ensemble and consensus methods with cross-study normalization.
Statistical analysis of DNA microarray data provides a valuable diagnostic tool for the investigation of genetic components of diseases. To take advantage of the multitude of available data sets and analysis methods, it is desirable to combine both different algorithms and data from different studies. Applying ensemble learning, consensus clustering and cross-study normalization methods for this purpose in an almost fully automated process and linking different analysis modules together under a single interface would simplify many microarray analysis tasks. We present ArrayMining.net, a web-application for microarray analysis that provides easy access to a wide choice of feature selection, clustering, prediction, gene set analysis and cross-study normalization methods. In contrast to other microarray-related web-tools, multiple algorithms and data sets for an analysis task can be combined using ensemble feature selection, ensemble prediction, consensus clustering and cross-platform data integration. By interlinking different analysis tools in a modular fashion, new exploratory routes become available, e.g. ensemble sample classification using features obtained from a gene set analysis and data from multiple studies. The analysis is further simplified by automatic parameter selection mechanisms and linkage to web tools and databases for functional annotation and literature mining. ArrayMining.net is a free web-application for microarray analysis combining a broad choice of algorithms based on ensemble and consensus methods, using automatic parameter selection and integration with annotation databases.


Efficacy and safety of livwin (polyherbal formulation) in patients with acute viral hepatitis: A randomized double-blind placebo-controlled clinical trial.
The study was planned to evaluate the efficacy and safety of Livwin (polyherbal formulation) in acute viral hepatitis. In this study, there were 29 patients in each group, receiving either Livwin (containing Ashwagandha, Arjuna, Bhumyamalaki, Daruharidra, Guduchi, Kutki and Punarnava) or placebo capsules containing lactose powder (500 mg). Both drugs were given orally two capsules two times a day for eight weeks followed by treatment free period of four weeks. Recovery of patients was assessed by noting symptomatic recovery and by measuring levels of serum bilirubin, serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), alkaline phosphatase at baseline, 2, 4, 8 and 12 weeks. Significant earlier recovery of weakness was observed with Livwin as compared to placebo at 2, 4 and 8 weeks. Serum bilirubin and ALT was observed in normal range in significantly more number of patients with Livwin treatment as compared to placebo at 2, 4 and 8 weeks. AST was observed in normal range in significantly more number of patients with Livwin treatment as compared to placebo at 2 and 4 weeks. Livwin is found effective in uncomplicated patients of acute viral hepatitis. Epigastric pain and diarrhea were reported with Livwin treatment.


Biomechanics of bacterial walls: studies of bacterial thread made from Bacillus subtilis.
Bacterial threads of up to 1 m in length have been produced from filaments of separation-suppressed mutants of Bacillus subtilis. Individual threads may contain 20,000 cellular filaments in parallel alignment. The tensile properties of bacterial threads have been examined by using conventional textile engineering techniques. The kinetics of elongation at constant load are indicative of a viscoelastic material. Both Young's modulus and breaking stress are highly dependent upon relative humidity. By extrapolation to 100% relative humidity, it appears that cell walls may be able to bear only internal osmotic pressures of about 2 atmospheres (2.03 X 105(5) Pa) in living cells. Similarly, the strength of wall material limits the amount of cell-surface charge permissible to only a small fraction of that known to be carried by the negatively charged wall polymers.


Can post-mortem MRI be used as a proxy for in vivo? A case study.
Post-mortem in situ MRI has been used as an intermediate between brain histo(patho)logy and in vivo imaging. However, it is not known how comparable post-mortem in situ is to ante-mortem imaging. We report the unique situation of a patient with familial early-onset Alzheimer's disease due to a PSEN1 mutation, who underwent ante-mortem brain MRI and post-mortem in situ imaging only 4 days apart. T1-weighted and diffusion MRI was performed at 3-Tesla at both time points. Visual atrophy rating scales, brain volume, cortical thickness and diffusion measures were derived from both scans and compared. Post-mortem visual atrophy scores decreased 0.5-1 point compared with ante-mortem, indicating an increase in brain volume. This was confirmed by quantitative analysis; showing a 27% decrease of ventricular and 7% increase of whole-brain volume. This increase was more pronounced in the cerebellum and supratentorial white matter than in grey matter. Furthermore, axial and radial diffusivity decreased up to 60% post-mortem whereas average fractional anisotropy of white matter increased approximately 10%. This unique case study shows that the process of dying affects several imaging markers. These changes need to be taken into account when interpreting post-mortem MRI to make inferences on the in vivo situation.


Deletion of EFL1 results in heterogeneity of the 60 S GTPase-associated rRNA conformation.
Previous work suggested that the release of the nucleolar Tif6 from nascent 60 S subunits occurs in the cytoplasm and requires the cytoplasmic EF-2-like GTPase, Efl1. To check whether this release involves an rRNA structural rearrangement mediated by Efl1, we analyzed the rRNA conformation of the GTPase center of 80 S ribosomes in three contexts: wild-type, Deltaefl1 and a dominant suppressor R1 of Deltaefl1. This analysis was restricted to domain II and VI of 25 S rRNA. The rRNA analysis of R1 ribosomes allows us to distinguish the effects due to depletion of Efl1 from the resulting nucleolar deficit of Tif6. Efl1 inhibits the EF-2 GTPase activity, suggesting that the two proteins share a similar ribosome-binding site. The 80 S ribosomes from either type failed to show any difference of conformation in the two rRNA domains analyzed. However, the same analysis performed on the pool of free 60 S subunits reveals several rRNA conformational differences between wild-type and Deltaefl1 subunits, whereas that from the suppressor strain is similar to wild-type. This suggests that the nucleolar deficit of Tif6 during assembly of the 60 S preribosomes is responsible for the changes in rRNA conformation observed in Deltaefl1 60 S subunits. We also purified 60 S preribosomes from the three genetic contexts by TAP-tagging Tif6. The protein content of 60 S preribosomes associated with Tif6p in a Deltaefl1 strain are obtained at a lower yield but have, surprisingly, a protein composition that is a priori similar to that of wild-type and the suppressor strain.


SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons.
Defects in DNA repair have been linked to cognitive decline with age and neurodegenerative disease, yet the mechanisms that protect neurons from genotoxic stress remain largely obscure. We sought to characterize the roles of the NAD(+)-dependent deacetylase SIRT1 in the neuronal response to DNA double-strand breaks (DSBs). We found that SIRT1 was rapidly recruited to DSBs in postmitotic neurons, where it showed a synergistic relationship with ataxia telangiectasia mutated (ATM). SIRT1 recruitment to breaks was ATM dependent; however, SIRT1 also stimulated ATM autophosphorylation and activity and stabilized ATM at DSB sites. After DSB induction, SIRT1 also bound the neuroprotective class I histone deacetylase HDAC1. We found that SIRT1 deacetylated HDAC1 and stimulated its enzymatic activity, which was necessary for DSB repair through the nonhomologous end-joining pathway. HDAC1 mutations that mimic a constitutively acetylated state rendered neurons more susceptible to DNA damage, whereas pharmacological SIRT1 activators that promoted HDAC1 deacetylation also reduced DNA damage in two mouse models of neurodegeneration. We propose that SIRT1 is an apical transducer of the DSB response and that SIRT1 activation offers an important therapeutic avenue in neurodegeneration.


Conservation status and historical relatedness of Italian cattle breeds.
In the last 50 years, the diversity of cattle breeds has experienced a severe contraction. However, in spite of the growing diffusion of cosmopolite specialized breeds, several local cattle breeds are still farmed in Italy. Genetic characterization of breeds represents an essential step to guide decisions in the management of farm animal genetic resources. The aim of this work was to provide a high-resolution representation of the genome-wide diversity and population structure of Italian local cattle breeds using a medium-density single nucleotide polymorphism (SNP) array. After quality control filtering, the dataset included 31,013 SNPs for 800 samples from 32 breeds. Our results on the genetic diversity of these breeds agree largely with their recorded history. We observed a low level of genetic diversity, which together with the small size of the effective populations, confirmed that several breeds are threatened with extinction. According to the analysis of runs of homozygosity, evidence of recent inbreeding was strong in some local breeds, such as Garfagnina, Mucca Pisana and Pontremolese. Patterns of genetic differentiation, shared ancestry, admixture events, and the phylogenetic tree, all suggest the presence of gene flow, in particular among breeds that originate from the same geographical area, such as the Sicilian breeds. In spite of the complex admixture events that most Italian cattle breeds have experienced, they have preserved distinctive characteristics and can be clearly discriminated, which is probably due to differences in genetic origin, environment, genetic isolation and inbreeding. This study is the first exhaustive genome-wide analysis of the diversity of Italian cattle breeds. The results are of significant importance because they will help design and implement conservation strategies. Indeed, efforts to maintain genetic diversity in these breeds are needed. Improvement of systems to record and monitor inbreeding in these breeds may contribute to their in situ conservation and, in view of this, the availability of genomic data is a fundamental resource.


Why are sex and gender important to basic physiology and translational and individualized medicine?
Sex refers to biological differences between men and women. Although sex is a fundamental aspect of human physiology that splits the population in two approximately equal halves, this essential biological variable is rarely considered in the design of basic physiological studies, in translating findings from basic science to clinical research, or in developing personalized medical strategies. Contrary to sex, gender refers to social and cultural factors related to being a man or a woman in a particular historical and cultural context. Unfortunately, gender is often used incorrectly by scientists and clinical investigators as synonymous with sex. This article clarifies the definition of sex and gender and reviews evidence showing how sex and gender interact with each other to influence etiology, presentation of disease, and treatment outcomes. In addition, strategies to improve the inclusion of female and male human beings in preclinical and clinical studies will be presented, and the importance of embedding concepts of sex and gender into postgraduate and medical curricula will be discussed. Also, provided is a list of resources for educators. In the history of medical concepts, physiologists have provided pivotal contributions to understanding health and disease processes. In the future, physiologists should provide the evidence for advancing personalized medicine and for reducing sex and gender disparities in health care.


Role of detection of microsatellite instability in Chinese with hereditary nonpolyposis colorectal cancer or ordinary hereditary colorectal cancer.
To detect microsatellite instability (MSI) in patients with hereditary nonpolyposis colorectal cancer or ordinary hereditary colorectal cancer and to provide criteria for screening the kindreds with hereditary nonpolyposis colorectal cancer at molecular level. MSI was detected in the specimens from 20 cases with HNPCC, 20 cases with ordinary hereditary colorectal cancer and 20 cases with sporadic colorectal cancer by means of polymerase chain reaction-single strand conformation polymorphism. The positive rate of MSI was 85% (17/20) in HNPCC group, 40% (8/20) in ordinary hereditary colorectal cancer group and 10% (2/20) in the sporadic colorectal cancer group respectively. The differences were significant. The mean ages of the three groups were 43.6, 52.2, and 61.8 years respectively, which increased gradually. The incidence of right hemicolon cancer was 64.7%, 37.5%, and 0% respectively, which decreased gradually and had significant difference. The expression ratio of BAT26 and BAT25 was 94.1% respectively, which was highest in the 5 gene sites studied. The incidence of poorly differentiated adenocarcinoma was 70.6% in HNPCC group among high frequency microsatellite instability (MSI-H), which was higher than the other two groups, which had 50% and 50% respectively. The incidence of MSI-H is higher in HNPCC group. The detection of MSI is simple and economical and has high correlation with the clinicopathologic feature of HNPCC and can be used as a screening method to detect the germ line mutation of the mismatch repair gene.


A non-coding RNA balancing act: miR-346-induced DNA damage is limited by the long non-coding RNA NORAD in prostate cancer.
miR-346 was identified as an activator of Androgen Receptor (AR) signalling that associates with DNA damage response (DDR)-linked transcripts in prostate cancer (PC). We sought to delineate the impact of miR-346 on DNA damage, and its potential as a therapeutic agent. RNA-IP, RNA-seq, RNA-ISH, DNA fibre assays, in vivo xenograft studies and bioinformatics approaches were used alongside a novel method for amplification-free, single nucleotide-resolution genome-wide mapping of DNA breaks (INDUCE-seq). miR-346 induces rapid and extensive DNA damage in PC cells - the first report of microRNA-induced DNA damage. Mechanistically, this is achieved through transcriptional hyperactivation, R-loop formation and replication stress, leading to checkpoint activation and cell cycle arrest. miR-346 also interacts with genome-protective lncRNA NORAD to disrupt its interaction with PUM2, leading to PUM2 stabilisation and its increased turnover of DNA damage response (DDR) transcripts. Confirming clinical relevance, NORAD expression and activity strongly correlate with poor PC clinical outcomes and increased DDR in biopsy RNA-seq studies. In contrast, miR-346 is associated with improved PC survival. INDUCE-seq reveals that miR-346-induced DSBs occur preferentially at binding sites of the most highly-transcriptionally active transcription factors in PC cells, including c-Myc, FOXA1, HOXB13, NKX3.1, and importantly, AR, resulting in target transcript downregulation. Further, RNA-seq reveals widespread miR-346 and shNORAD dysregulation of DNA damage, replication and cell cycle processes. NORAD drives target-directed miR decay (TDMD) of miR-346 as a novel genome protection mechanism: NORAD silencing increases mature miR-346 levels by several thousand-fold, and WT but not TDMD-mutant NORAD rescues miR-346-induced DNA damage. Importantly, miR-346 sensitises PC cells to DNA-damaging drugs including PARP inhibitor and chemotherapy, and induces tumour regression as a monotherapy in vivo, indicating that targeting miR-346:NORAD balance is a valid therapeutic strategy. A balancing act between miR-346 and NORAD regulates DNA damage and repair in PC. miR-346 may be particularly effective as a therapeutic in the context of decreased NORAD observed in advanced PC, and in transcriptionally-hyperactive cancer cells.


Life-span extension by caloric restriction is determined by type and level of food reduction and by reproductive mode in Brachionus manjavacas (Rotifera).
We measured life span and fecundity of three reproductive modes in a clone of the monogonont rotifer Brachionus manjavacas subjected to chronic caloric restriction (CCR) over a range of food concentrations or to intermittent fasting (IF). IF increased life span 50%-70% for all three modes, whereas CCR increased life span of asexual females derived from sexually or asexually produced eggs, but not that of sexual females. The main effect of CR on both asexual modes was to delay death at young ages, rather than to prevent death at middle ages or to greatly extend maximum life span; in contrast CR in sexual females greatly increased the life span of a few long-lived individuals. Lifetime fecundity did not decrease with CCR, suggesting a lack of resource allocation trade-off between somatic maintenance and reproduction. Multiple outcomes for a clonal lineage indicate that different responses are established through epigenetic programming, whereas differences in life-span allocations suggest that multiple genetic mechanisms mediate life-span extension.


The innate immune protein calprotectin promotes Pseudomonas aeruginosa and Staphylococcus aureus interaction.
Microorganisms form biofilms containing differentiated cell populations. To determine factors driving differentiation, we herein visualize protein and metal distributions within Pseudomonas aeruginosa biofilms using imaging mass spectrometry. These in vitro experiments reveal correlations between differential protein distribution and metal abundance. Notably, zinc- and manganese-depleted portions of the biofilm repress the production of anti-staphylococcal molecules. Exposure to calprotectin (a host protein known to sequester metal ions at infectious foci) recapitulates responses occurring within metal-deplete portions of the biofilm and promotes interaction between P. aeruginosa and Staphylococcus aureus. Consistent with these results, the presence of calprotectin promotes co-colonization of the murine lung, and polymicrobial communities are found to co-exist in calprotectin-enriched airspaces of a cystic fibrosis lung explant. These findings, which demonstrate that metal fluctuations are a driving force of microbial community structure, have clinical implications because of the frequent occurrence of P. aeruginosa and S. aureus co-infections.


A migraine variant with abdominal colic and Alice in Wonderland syndrome: a case report and review.
Abdominal migraine is a commonly described migraine variant in children and young adults, but associations with Alice in Wonderland syndrome and lilliputian hallucinations are exceptional. A 20 years-old male experienced frequent and prolonged attacks of abdominal colic associated with autonomic manifestations started at the age of ten. At the age of 17, he additionally described prolonged attacks (>or= 7 days) of distortions of shape, size or position of objects or subjects. He said "Quite suddenly, objects appear small and distant (teliopsia) or large and close (peliopsia). I feel as I am getting shorter and smaller "shrinking" and also the size of persons are not longer than my index finger (a lilliputian proportion). Sometimes I see the blind in the window or the television getting up and down, or my leg or arm is swinging. I may hear the voices of people quite loud and close or faint and far. Occasionally, I experience attacks of migrainous headache associated with eye redness, flashes of lights and a feeling of giddiness. I am always conscious to the intangible changes in myself and my environment". There is a strong family history of common migraine. Clinical examination, brain-MRI and EEG were normal. Transcranial magnetic stimulation and evoked potentials revealed enhanced cortical excitability in multiple brain regions. Treatment with valproate resulted in marked improvement of all clinical and neurophysiological abnormalities. The association between the two migraine variants (abdominal migraine and Alice in Wonderland Syndrome) might have clinical, pathophysiological and management implications. I think this is the first description in the literature.


Antioxidant therapy for pain relief in patients with chronic pancreatitis: systematic review and meta-analysis.
Currently, there is no specific therapy for chronic pancreatitis (CP). The treatment of micronutrient antioxidant therapy for painful CP has been sporadically used for more than 30 years, however, its efficacy are still poorly understood. The purpose of this meta-analysis is to investigate the safety and efficacy of antioxidant therapy for pain relief in patients with CP. University Hospital in China Systematic review and meta-analysis Two authors independently reviewed the search results and extracted data and disagreements were resolved by discussion. Effects were summarized using standardized mean differences (SMDs), weighted mean differences, or odds ratio (OR) according to the suitable effect model. MEDLINE, PsycINFO, Scopus, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from 1980 through December 2012. Randomized controlled trials (RCTs) that studied antioxidant supplementation for pain relief in patients with CP were analyzed. Nine randomized controlled trials (RCTs) involving 390 patients were included. Overall, there was no association of antioxidant therapy with pain reduction in CP patients (SMD, -0.55; 95% CI, -1.22 to 0.12; P = 0.67). However, antioxidant therapy significantly increased blood levels of antioxidants in CP patients versus the placebo group (SMD, 1.08; 95% CI, 0.74 to 1.43; P < 0.00001). Interestingly, combined antioxidant (selenium, β-carotene, vitamin C, vitamin E, methionine) therapy was found to be associated with pain relief (SMD, -0.93; 95% CI, -1.72 to -0.14; P = 0.02), while the trials in which a single antioxidant was used revealed no significant pain relief (SMD, -0.12; 95% CI, -1.23 to 0.99; P = 0.83) in CP patients. Strong evidence was obtained that the antioxidants increased adverse effects (OR, 6.09; 95% CI, 2.29 to 16.17, P < 0.01); nevertheless, none was serious. Because of the small sample, a consolidated conclusion cannot be reached based on current RCTs. Large-sample RCTs are needed to clarify the analgesic effect of antioxidants in CP patients. Combined antioxidant therapy seems to be a safe and effective therapy for pain relief in CP patients. Measures of total antioxidant status may not help to monitor the efficacy of antioxidant therapy for patients with CP.


Cardiopulmonary resuscitation skills retention and self-confidence of preclinical medical students.
Sudden cardiac death is the most common lethal manifestation of heart disease and often the first and only indicator. Prompt initiation of cardiopulmonary resuscitation (CPR) undoubtedly saves lives. Nevertheless, studies report a low level of competency of medical students in CPR, mainly due to deterioration of skills following training. To evaluate the retention of CPR skills and confidence in delivering CPR by preclinical medical students. A questionnaire and the Objective Structured Clinical Examination (OSCE) were used to assess confidence and CPR skills among preclinical, second and third-year medical students who had passed a first-aid course during their first year but had not retrained since. The study group comprised 64 students: 35 were 1 year after training and 29 were 2 years after training. The groups were demographically similar. Preparedness, recollection and confidence in delivering CPR were significantly lower in the 2 years after training group compared to those 1 year after training (P < 0.05). The mean OSCE score was 19.8 +/- 5.2 (of 27) lower in those 2 years post-training than those 1 year post-training (17.8 +/- 6.35 vs. 21.4 +/- 3.4 respectively, P = 0.009). Only 70% passed the OSCE, considerably less in students 2 years post-training than in those 1 year post-training (52% vs. 86%, P < 0.01). Lowest retention was found in checking safety, pulse check, airway opening, rescue breathing and ventilation technique skills. A 1 year interval was chosen by 81% of the participants as the optimal interval for retraining (91% vs. 71% in the 2 years post-training group vs. the 1 year post- training group respectively, P = 0.08). Confidence and CPR skills of preclinical medical students deteriorate significantly within 1 year post-training, reaching an unacceptable level 2 years post-training. We recommend refresher training at least every year.


A potent antiplatelet peptide, triflavin, from Trimeresurus flavoviridis snake venom.
The interaction of fibrinogen with its receptors on platelet surfaces leads to platelet aggregation. A snake-venom peptide, trigramin, has previously been demonstrated to inhibit platelet aggregation by acting as a fibrinogen-receptor antagonist. By means of gel filtration, ionic-exchange chromatography and reverse-phase h.p.l.c., a potent platelet-aggregation inhibitor, triflavin, has now been purified from the venom of Trimeresurus flavoviridis. The purified triflavin is a single-chain polypeptide, consisting of about 71 amino acid residues with a molecular mass of 7600 Da, and its N-terminal sequence is Gly-Glu-Glu-Cys-Asp. Triflavin dose-dependently inhibited human platelet aggregation stimulated by ADP, adrenaline, collagen, thrombin or prostaglandin endoperoxide analogue U46619 in preparations of platelet-rich plasma, platelet suspension and whole blood. Its IC50 ranged from 38 to 84 nM, depending on the aggregation inducer used and the platelet preparation. However, triflavin apparently did not affect the platelet shape change and ATP-release reactions caused by these agonists. Triflavin inhibited fibrinogen-induced aggregation of human elastase-treated platelets in a dose-dependent manner, indicating that it directly interferes with the binding of fibrinogen to its receptors on platelet membranes exposed by elastase treatment. Additionally, triflavin dose-dependently blocked 125I-labelled fibrinogen binding to ADP-activated platelets. In conclusion, triflavin inhibits platelet aggregation through the blockade of fibrinogen binding to fibrinogen receptors on platelet membranes.


Combining functional neuroimaging with off-line brain stimulation: modulation of task-related activity in language areas.
Repetitive TMS (rTMS) provides a noninvasive tool for modulating neural activity in the human brain. In healthy participants, rTMS applied over the language-related areas in the left hemisphere, including the left posterior temporal area of Wernicke (LTMP) and inferior frontal area of Broca, have been shown to affect performance on word recognition tasks. To investigate the neural substrate of these behavioral effects, off-line rTMS was combined with fMRI acquired during the performance of a word recognition task. Twenty right-handed healthy men underwent fMRI scans before and after a session of 10-Hz rTMS applied outside the magnetic resonance scanner. Functional magnetic resonance images were acquired during the performance of a word recognition task that used English or foreign-language words. rTMS was applied over the LTMP in one group of 10 participants (LTMP group), whereas the homologue region in the right hemisphere was stimulated in another group of 10 participants (RTMP group). Changes in task-related fMRI response (English minus foreign languages) and task performances (response time and accuracy) were measured in both groups and compared between pre-rTMS and post-rTMS. Our results showed that rTMS increased task-related fMRI response in the homologue areas contralateral to the stimulated sites. We also found an effect of rTMS on response time for the LTMP group only. These findings provide insights into changes in neural activity in cortical regions connected to the stimulated site and are consistent with a hypothesis raised in a previous review about the role of the homologue areas in the contralateral hemisphere for preserving behavior after neural interference.


Deoxycorticosterone-adenine interactions in a crystalline complex.
Deoxycorticosterone-adenine monohydrate is the first complex involving a steroid and a component of DNA to be successfully crystallized and studied by single crystal x-ray analysis. Hydrogen bonds between O(20) and N(6) as well as O(21) and N(1) connect the corticoid side chain to an adenine molecule. The molecules are also packed such that a second adenine moiety is situated over the delta4-3-one region of the steroid. These observations of the solid state suggest ways in which steroids and nucleic acids may interact in vivo.


Surgical treatment of thoracoabdominal aortic aneurysm with graft inclusion technique.
Two male patients with huge thoracoabdominal aortic aneurysms were treated surgically at the National Taiwan University Hospital (NTUH) during the last 6 years. Case 1 was 70 years old with a case of malignant lymphoma. A huge thoracoabdominal aortic aneurysm was found which ruptured suddenly during the course of chemotherapy for malignant lymphoma. An emergency operation was performed because the patient suffered from profound shock. Case 2 was 34 years old and was referred to our hospital with a huge pulsating mass over his abdomen and progressive dysphagia. Both had atherosclerosis, thought to be the underlying etiology. The surgical technique we employed was the graft inclusion technique with major branch vessel reattachment to the side holes of the graft. Postoperative surgical results were excellent. Neither spinal cord complications nor visceral organ failure was found in either case. Case 1 unfortunately died 3 months after surgery because of advanced lymphoma with many organs being involved and upper GI bleeding. Case 2 is doing well and being followed up at our OPD at present.


Maternal modulation of the inheritable meiosis I error Dipl I in mouse oocytes is associated with the type of mitochondrial DNA.
The ovulation of diploid oocytes, abnormally arrested at or during the first meiotic division, is an inheritable trait (DiplI) in mice and modulated by a maternally transmitted factor. By repeated backcrossing, mouse strains with identical nuclear encoded genes and differing only in their mitochondrial genomes can be created. NMB mice represent such a strain having acquired the nuclear genome of C57BL/6J but still possessing mitochondria and therewith mitochondrial DNA (mtDNA) of NMRI/Bom, their female progenitor. The strains NMB and C57BL/6J were used to characterize a new mitochondrial trait, namely the ability to modulate the expression of the inheritable meiosis I error Dipl I in oocytes. We show that an increased rate of ovulated diploid oocytes is associated with the mtDNA type of C57BL/6J. These results corroborate the assumption that mitochondria do play an important role in meiosis of mammalian oocytes and hence seem to be involved also in the orderly segregation of chromosomes.


ICU Outcome Predictions using Physiologic Trends in the First Two Days.
This study aims to accurately predict patient mortality in the ICU. Given all physiologic measurements in the first 48 hours of the ICU stay, the Bayesian model of the study predicts outcome with a posterior probability. This study modeled the outcome as a binary random variable dependent on trends of daily physiologic measures of the patient, where trends were conditionally independent given the outcome. A two-day trend is a sequence of two discrete values, one for each day. Each value (low, medium, high or unmeasured) is a function of the arithmetic mean of that measure on the corresponding day. The prediction performance of the model was measured as the minimum of sensitivity and positive predictive values. The model yielded a score of 0.39 along with a Hosmer-Lemeshow H statistic of 36, which measures calibration. The perfect scores would be 1.0 and 0, respectively. The prediction performance of the study was an improvement over the established ICU scoring metric SAPS-I, whose score was 0.32. Calibration of the model outputs was comparable to that of SAPS-I.


The 'intrinsic adjuvanticity' and immunogenicity of trinitrophenylated lipopolysaccharide.
One thymus-independent immunogen, trinitrophenylated lipopolysaccharide (TNP-LPS) has been studied in vivo and in vitro in C3H/He and C3H/HeJ strains of mice. C3H/HeJ mice have been shown to be low responders, and C3H/He mice high responders to this immunogen. This 'low responder' status of C3H/HeJ mice has been demonstrated to be consequent to an intrinsic defect present at least at the level of B cells. It was demonstrated that high responder cells or 'in vivo milieu' could not restore this deficit to C3H/HeJ cells. It is proposed that the adjuvanticity, mitogenicity and polyclonal activating capacity of LPS are all fundamental to its property of acting as a thymus-independent carrier for the TNP determinant. This observation is discussed from the point of view that the T-cell independence for an antigen cannot derive solely from its multivalency but must depend upon the intrinsic adjuvanticity of that molecule.


The role of cognitive costs, attitudes about aging, and intrinsic motivation in predicting engagement in everyday activities.
Engagement in cognitively demanding everyday activities has been shown to benefit cognitive health in later life. We investigated the factors that influence engagement, with specific interest in determining the extent to which the costs of engaging cognitive resources are associated with intrinsic motivation and, ultimately, participation in everyday activities. Older adults (N = 153) aged from 65 to 81 years completed a challenging cognitive task, with the costs of cognitive engagement-operationalized as the effort required to maintain performance-assessed using systolic blood pressure responses (SBP-R). We also assessed participation in everyday activities using both 2-year retrospective reports and five daily reports over a 5-week period. Structural models revealed that lower levels of costs were associated with more positive attitudes about aging, which in turn were associated with higher levels of intrinsic motivation. Motivation was subsequently predictive of everyday activity engagement, with the effect being specific to those activities thought to place demands on cognitive resources. The measure of engagement had minimal impact on the nature of the observed effects, suggesting that the retrospective and weekly assessments were tapping into similar constructs. Taken together, the results are consistent with expectations derived from Selective Engagement Theory (Hess, 2014), which argues that engagement in demanding activities is related to the cost associated with such engagement, which in turn leads to selective participation through changes in motivation. (PsycINFO Database Record


Assessment of morbidity following resection of cingulate gyrus gliomas. Clinical article.
The morbidity associated with resection of tumors in the cingulate gyrus (CG) is not well established. The goal of the present study is to define the short- and long-term morbidity profile associated with resection of gliomas within this region. Ninety consecutive patients with gliomas involving the CG were analyzed. Resections were classified by zones corresponding to functionally defined regions of the CG as follows: Zone I (perigenual, anterior), Zone II (midcingulate), Zone III (posterior), and Zone IV (retrosplenial). Basic demographic, imaging, operative details, and pre- and postoperative neurological examinations were recorded for each patient. Patients in whom neurological morbidity was documented during their initial postoperative examination who did not completely improve by the 6-month follow-up examination were considered to have a permanent deficit. For each patient with surgery-related morbidity, postoperative MR imaging and operative notes were reviewed, and the cortical regions incorporated in the surgical trajectory were recorded. The analysis was carried out for tumors confined to the CG (> 90% of tumor contained within the CG) as well as those involving the CG but extending into adjacent cortical structures. Analysis of the entire patient cohort demonstrated that 29% of patients experienced a new or worsened neurological deficit immediately after surgery. The most common deficits were supplementary motor area (SMA) syndrome (20%), weakness (6%), and sensory changes (2%). All patients with an SMA syndrome in our series had intentional resection of SMA as part of the surgical approach. Patients with resections including Zone II or III had a higher rate of total morbidity and SMA syndrome than patients with Zone I resections (p < 0.05). Only 4% of patients had a persistent neurological deficit at 6 months postoperatively. A similar morbidity profile was observed in the subset analysis of patients with tumors confined to the CG, with no additional morbidity related to known cingulate-specific functions. Resection of gliomas involving the CG can be performed with minimal, predictable long-term morbidity (< 5%). Surgical morbidity is primarily a function of surgical trajectory rather than the particular cingulate region resected.


Financial incentives for smoking cessation in pregnancy: protocol for a single arm intervention study.
Smoking during pregnancy and in the postnatal period is a major cause of low birth weight and a range of adverse infant health outcomes. Stop smoking services can double quit rates, but only 17% of pregnant women smoking at the time they book for antenatal care use these services. In a recent Cochrane review on the effectiveness of smoking cessation interventions in pregnancy, financial incentives were found to be the single most effective intervention. We describe a single arm intervention study offering participation in a financial incentive scheme for smoking cessation to all pregnant smokers receiving antenatal care in one area in England. The aim of the study is to assess the potential effectiveness of using financial incentives to achieve smoking cessation in pregnant women who smoke, to inform the use of financial incentive schemes in routine clinical practice as well as the interpretation of existing trials and the design of future studies. 500 consecutive pregnant smokers are offered participation in the scheme, which involves attending for up to 32 assessments until six months post-partum, to verify smoking cessation by self report and a negative exhaled carbon monoxide measurement. At each visit when cessation is verified, participants receive a shopping voucher starting at a value of £8 and increasing by £1 at each consecutive successful visit. Assessments decline in frequency, occurring most frequently during the first two weeks after quitting and the first two weeks after delivery. The maximum cumulative total that can be earned through the scheme is £752. The results of this study will inform the use of financial incentive schemes in routine clinical practice as well as the interpretation of existing trials and the design of future studies. The main results are (a) an estimate of the proportion of pregnant smokers who enrol in the scheme; (b) estimates of the proportion of pregnant smokers who participate in the scheme and who achieve prolonged abstinence at: i. delivery and ii. six months postpartum; (c) predictors of i. participation in the scheme, and ii. smoking cessation; and (d) estimates of the adverse effects of using incentives to achieve quitting as indexed by: i. the delay in quitting smoking to enrol in an incentive scheme and, ii. false reporting of smoking status, either to gain entry into the scheme or to gain an incentive.


3D nanofabrication by volumetric deposition and controlled shrinkage of patterned scaffolds.
Lithographic nanofabrication is often limited to successive fabrication of two-dimensional (2D) layers. We present a strategy for the direct assembly of 3D nanomaterials consisting of metals, semiconductors, and biomolecules arranged in virtually any 3D geometry. We used hydrogels as scaffolds for volumetric deposition of materials at defined points in space. We then optically patterned these scaffolds in three dimensions, attached one or more functional materials, and then shrank and dehydrated them in a controlled way to achieve nanoscale feature sizes in a solid substrate. We demonstrate that our process, Implosion Fabrication (ImpFab), can directly write highly conductive, 3D silver nanostructures within an acrylic scaffold via volumetric silver deposition. Using ImpFab, we achieve resolutions in the tens of nanometers and complex, non-self-supporting 3D geometries of interest for optical metamaterials.


Glucotypes reveal new patterns of glucose dysregulation.
Diabetes is an increasing problem worldwide; almost 30 million people, nearly 10% of the population, in the United States are diagnosed with diabetes. Another 84 million are prediabetic, and without intervention, up to 70% of these individuals may progress to type 2 diabetes. Current methods for quantifying blood glucose dysregulation in diabetes and prediabetes are limited by reliance on single-time-point measurements or on average measures of overall glycemia and neglect glucose dynamics. We have used continuous glucose monitoring (CGM) to evaluate the frequency with which individuals demonstrate elevations in postprandial glucose, the types of patterns, and how patterns vary between individuals given an identical nutrient challenge. Measurement of insulin resistance and secretion highlights the fact that the physiology underlying dysglycemia is highly variable between individuals. We developed an analytical framework that can group individuals according to specific patterns of glycemic responses called "glucotypes" that reveal heterogeneity, or subphenotypes, within traditional diagnostic categories of glucose regulation. Importantly, we found that even individuals considered normoglycemic by standard measures exhibit high glucose variability using CGM, with glucose levels reaching prediabetic and diabetic ranges 15% and 2% of the time, respectively. We thus show that glucose dysregulation, as characterized by CGM, is more prevalent and heterogeneous than previously thought and can affect individuals considered normoglycemic by standard measures, and specific patterns of glycemic responses reflect variable underlying physiology. The interindividual variability in glycemic responses to standardized meals also highlights the personal nature of glucose regulation. Through extensive phenotyping, we developed a model for identifying potential mechanisms of personal glucose dysregulation and built a webtool for visualizing a user-uploaded CGM profile and classifying individualized glucose patterns into glucotypes.


Molecular Basis for Spirocycle Formation in the Paraherquamide Biosynthetic Pathway.
The paraherquamides are potent anthelmintic natural products with complex heptacyclic scaffolds. One key feature of these molecules is the spiro-oxindole moiety that lends a strained three-dimensional architecture to these structures. The flavin monooxygenase PhqK was found to catalyze spirocycle formation through two parallel pathways in the biosynthesis of paraherquamides A and G. Two new paraherquamides (K and L) were isolated from a ΔphqK strain of Penicillium simplicissimum, and subsequent enzymatic reactions with these compounds generated two additional metabolites, paraherquamides M and N. Crystal structures of PhqK in complex with various substrates provided a foundation for mechanistic analyses and computational studies. While it is evident that PhqK can react with various substrates, reaction kinetics and molecular dynamics simulations indicated that the dioxepin-containing paraherquamide L is the favored substrate. Through this effort, we have elucidated a key step in the biosynthesis of the paraherquamides and provided a rationale for the selective spirocyclization of these powerful anthelmintic agents.


Body temperature variability (Part 2): masking influences of body temperature variability and a review of body temperature variability in disease.
This is the second of a two-part review on body temperature variability. Part 1 discussed historical and modern findings on average body temperatures. It also discussed endogenous sources of temperature variability, including variations caused by site of measurement; circadian, menstrual, and annual biological rhythms; fitness; and aging. Part 2 reviews the effects of exogenous masking agents - external factors in the environment, diet, or lifestyle that can be a significant source of body temperature variability. Body temperature variability findings in disease states are also reviewed.


Assessing contributors to cost of care in nursing homes.
In 1994 12.7% of the population was 65 and over, while 10.6% were 85 and over. Expenditures for nursing homes reached $72.3 billion in 1994 (much of which is tax-supported) accounting for 8.7% of all personal health money spent. Data from the 1993 Missouri Medicaid cost reports for 403 nursing homes were reviewed to determine differences in costs per resident day (PRD) and discover which factors most influenced these differences. Mid-sized facilities with 60-120 beds reported the lowest resident-related PRD costs. PRD expenses for aides and orderlies were higher in tax-exempt facilities, which was thought to be related to their "more altruistic" mission. Investor-owned facilities showed significantly greater administrative costs PRD, which may relate to higher administrative salaries and fancier offices. The authors suggest further study that would incorporate location, occupancy rate, quality of care, case mix, and payer mix data.


Seven-Year Experience From the National Institute of Neurological Disorders and Stroke-Supported Network for Excellence in Neuroscience Clinical Trials.
One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders. National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presentations or posters and 9 invited presentations were given at regional, national, and international meetings. NeuroNEXT initiated 8 studies, successfully enrolled participants at or ahead of schedule, collected high-quality data, published primary results in high-impact journals, and provided mentorship, expert statistical, and trial management support to several new investigators. Partnerships were successfully created between government, academia, industry, foundations, and patient advocacy groups. Clinical trial consortia can efficiently and successfully address a range of important neurologic research and therapeutic questions.


Exercise for premenstrual syndrome: a systematic review and meta-analysis of randomised controlled trials.
Exercise is recommended as a treatment for premenstrual syndrome (PMS) in clinical guidelines, but this is currently based on poor-quality trial evidence. To systematically review the evidence for the effectiveness of exercise as a treatment for PMS. This systematic review searched eight major databases, including MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL), and two trial registries from inception until April 2019. Randomised controlled trials (RCTs) comparing exercise interventions of a minimum of 8-weeks duration with non-exercise comparator groups in women with PMS were included. Mean change scores for any continuous PMS outcome measure were extracted from eligible trials and standardised mean differences (SMDs) were calculated where possible. Random-effects meta-analysis of the effect of exercise on global PMS symptoms was the primary outcome. Secondary analyses examined the effects of exercise on predetermined clusters of psychological, physical, and behavioural symptoms. A total of 436 non-duplicate returns were screened, with 15 RCTs eligible for inclusion (n = 717). Seven trials contributed data to the primary outcome meta-analysis (n = 265); participants randomised to an exercise intervention reported reduced global PMS symptom scores (SMD = -1.08; 95% confidence interval [CI] = -1.88 to -0.29) versus comparator, but with substantial heterogeneity (I 2 = 87%). Secondary results for psychological (SMD = -1.67; 95% CI = -2.38 to -0.96), physical (SMD = -1.62; 95% CI = -2.41 to -0.83) and behavioural (SMD = -1.94; 95% CI = -2.45 to -1.44) symptom groupings displayed similar findings. Most trials (87%) were considered at high risk of bias. Based on current evidence, exercise may be an effective treatment for PMS, but some uncertainty remains.


Oxidative lipidomics coming of age: advances in analysis of oxidized phospholipids in physiology and pathology.
Oxidized phospholipids are now well recognized as markers of biological oxidative stress and bioactive molecules with both pro-inflammatory and anti-inflammatory effects. While analytical methods continue to be developed for studies of generic lipid oxidation, mass spectrometry (MS) has underpinned the advances in knowledge of specific oxidized phospholipids by allowing their identification and characterization, and it is responsible for the expansion of oxidative lipidomics. Studies of oxidized phospholipids in biological samples, from both animal models and clinical samples, have been facilitated by the recent improvements in MS, especially targeted routines that depend on the fragmentation pattern of the parent molecular ion and improved resolution and mass accuracy. MS can be used to identify selectively individual compounds or groups of compounds with common features, which greatly improves the sensitivity and specificity of detection. Application of these methods has enabled important advances in understanding the mechanisms of inflammatory diseases such as atherosclerosis, steatohepatitis, leprosy, and cystic fibrosis, and it offers potential for developing biomarkers of molecular aspects of the diseases. The future in this field will depend on development of improved MS technologies, such as ion mobility, novel enrichment methods and databases, and software for data analysis, owing to the very large amount of data generated in these experiments. Imaging of oxidized phospholipids in tissue MS is an additional exciting direction emerging that can be expected to advance understanding of physiology and disease.


Glucose dependent K+-channels in pancreatic beta-cells are regulated by intracellular ATP.
The resting conductance of cultured beta-cells from murine pancreases was investigated using the whole-cell, cell-attached and isolated patch modes of the patch-clamp technique. Whole-cell experiments revealed a high input resistance of the cells (greater than 20 G omega per cell or greater than 100 k omega X cm2), if the medium dialysing the cell interior contained 3 mM ATP. The absence of ATP evoked a large additional K+ conductance. In cell-attached patches single K+-channels were observed in the absence of glucose. Addition of glucose (20 mM) to the bath suppressed the channel activity and initiated action potentials. Similar single-channel currents were recorded from isolated patches. In this case the channels were reversibly blocked by adding ATP (3 mM) to the solution at the intracellular side of the membrane. The conductances (51 pS and 56 pS for [K+]0 = 145 mM, T = 21 degrees C) and kinetics (at -70 mV: tau open = 2.2 ms and 1.8 ms, tau closed = 0.38 ms and 0.33 ms) of the glucose- and ATP-dependent channels were found to be very similar. It is concluded that both channels are identical. The result suggests that glucose could depolarize the beta-cell by increasing the cytoplasmic concentration of ATP.


Pre-clinical diabetic cardiomyopathy: prevalence, screening, and outcome.
Diabetic cardiomyopathy, characterized by left ventricular (LV) dysfunction and LV hypertrophy independent of myocardial ischaemia and hypertension, could contribute to the increased life-time risk of congestive heart failure seen in patients with diabetes. We assessed prospectively the prevalence, effectiveness of screening methods [brain natriuretic peptide (BNP) and C-reactive protein in combination with clinical parameters], and outcome of pre-clinical diabetic cardiomyopathy. We studied 100 adults (mean age 57.4 +/- 10.2 years, 44% females) with diabetes and no previous evidence of structural heart disease. By echocardiography, diabetic cardiomyopathy was present in 48% of patients. Screening with combinations of clinical parameters (gender, systolic blood pressure, and body mass index), but not BNP, resulted in high negative predictive values for diabetic cardiomyopathy. During a mean follow-up of 48.5 +/- 9.0 months, in the groups with and without diabetic cardiomyopathy, 12.5 vs. 3.9% (P < 0.2) patients died or experienced cardiovascular events and 37.5 vs. 9.6% (P < 0.002) had a deterioration in NYHA functional class. Overall event-free survival was 54 vs. 87% (P = 0.001) in the groups with and without diabetic cardiomyopathy, respectively. Brain natriuretic peptide was an independent predictor of events [odds ratio 3.5 (1.1-10.9), P = 0.02]. Pre-clinical diabetic cardiomyopathy is common. Screening with combinations of simple clinical parameters, but not BNP, can be useful to identify those patients needing further evaluation. Patients with pre-clinical diabetic cardiomyopathy are at increased risk for functional deterioration and possibly cardiovascular events during follow-up. Brain natriuretic peptide was shown to be an independent predictor of future events.


The pediatric acenocoumarol dosing algorithm: the Children Anticoagulation and Pharmacogenetics Study.
Essentials A pediatric pharmacogenetic dosing algorithm for acenocoumarol has not yet been developed. We conducted a multicenter retrospective follow-up study in children in the Netherlands. Body surface area and indication explained 45.0% of the variability in dose requirement. Adding the genotypes of VKORC1, CYP2C9 and CYP2C18 to the algorithm increased this to 61.8%. Background The large variability in dose requirement of vitamin K antagonists is well known. For warfarin, pediatric dosing algorithms have been developed to predict the correct dose for a patient; however, this is not the case for acenocoumarol. Objectives To develop dosing algorithms for pediatric patients receiving acenocoumarol with and without genetic information. Methods The Children Anticoagulation and Pharmacogenetics Study was designed as a multicenter retrospective follow-up study in Dutch anticoagulation clinics and children's hospitals. Pediatric patients who used acenocoumarol between 1995 and 2014 were selected for inclusion. Clinical information and saliva samples for genotyping of the genes encoding cytochrome P450 (CYP) 2C9, vitamin K epoxide reductase complex subunit 1 (VKORC1), CYP4F2, CYP2C18 and CYP3A4 were collected. Linear regression was used to analyze their association with the log mean stable dose. A stable period was defined as three or more consecutive International Normalized Ratio measurements within the therapeutic range over a period of ≥ 3 weeks. Results In total, 175 patients were included in the study, of whom 86 had a stable period and no missing clinical information (clinical cohort; median age 8.9 years, and 49% female). For 80 of these 86 patients, genetic information was also available (genetic cohort). The clinical algorithm, containing body surface area and indication, explained 45.0% of the variability in dose requirement of acenocoumarol. After addition of the VKORC1, CYP2C9, and CYP2C18 genotypes to the algorithm, this increased to 61.8%. Conclusions These findings show that clinical factors had the largest impact on the required dose of acenocoumarol in pediatric patients. Nevertheless, genetic factors, and especially VKORC1, also explained a significant part of the variability.


Interscholastic Athletics and Bone Strength: The Iowa Bone Development Study.
Pashkova, A, Hartman, JM, Letuchy, EM, and Janz, KF. Interscholastic athletics and bone strength: the Iowa bone development study. J Strength Cond Res 36(5): 1271-1276, 2022-The objective of this study was to determine the relationship between adolescents' participation in various interscholastic sports and differences in bone strength outcomes. Subjects (N = 380) were recruited from the Iowa Bone Development Study and categorized based on sport participation into 3 power groups: no-power, low-power, and high-power. Sports such as basketball, cheerleading/poms, gymnastics, volleyball, track, football, tennis, and soccer were considered high-power. Peripheral quantitative computed tomography (pQCT) was used to determine bone measures of polar stress-strain index (measure of torsion strength), cortical content (measure of cortical bone size and area at the 66% tibia site), and bone strength index (measure of compression strength based on total bone density and area at the 4% tibia site). Adjusted pairwise comparison for group least squares means high-power sport participation compared with no-power sport participation showed significant differences in all bone strength outcomes for both men and women (p value < 0.01). There was a significant difference in all bone strength measures between low-power and no-power groups for men (p value < 0.05), but not women. Because of decreasing levels of physical activity in late adolescence, the promotion of high-power sports may be particularly important for optimal bone development in the final years before peak bone mass.


An in vitro based investigation of the cytotoxic effect of water extracts of the Chinese herbal remedy LD on cancer cells.
Long Dan Xie Gan Wan (LD), a Chinese herbal remedy formulation, is traditionally used to treat a range of conditions, including gall bladder diseases, hepatitis, hyperthyroidism, migraines but it is not used for the management or treatment of cancer. However some of its herbal constituents, specifically Radix bupleuri, Radix scutellariae and Rhizoma alismatis have been shown to inhibit the growth of cancer cells. Thus, the aim of the study was to investigate the impact of LD on cancer cells in vitro. HL60 and HT29 cancer cell lines were exposed to water extracts of LD (1:10, 1:50, 1:100 and/or 1:1000 prepared from a 3 mg/30 ml stock) and for both cell lines growth, apoptotic induction, alterations in cell cycle characteristics and genotoxicity were investigated. The specificity of the action of LD on these cancer cell lines was also investigated by determining its effect on human peripheral blood lymphocytes. Preliminary chemical analysis was carried out to identify cytotoxic constituents of LD using HPLC and LCMS. LD was significantly cytotoxic to, and induced apoptosis in, both cell lines. Apoptotic induction appeared to be cell cycle independent at all concentrations of LD used (1:10, 1:50 and 1:100) for the HL60 cell lines and at 1:10 for the HT29 cell line. At 1:50 and 1:100 apoptotic induction by LD appeared to be cell cycle dependent. LD caused significant genotoxic damage to both cell lines compared to their respective controls. The specificity study showed that LD exerted a moderate cytotoxic action against non-proliferating and proliferating blood lymphocytes but not apoptosis. Chemical analysis showed that a number of fractions were found to exert a significant growth inhibitory effect. However, the molecular weights of compounds within these fractions did not correspond to those from the herbal constituents of LD. It is possible that LD may have some chemotherapeutic potential. However, further studies are required to determine its cytotoxic constituents.


The role of perspective in identifying domains of reference.
We used the contrastive expectation associated with scalar adjectives to examine whether listeners are sensitive to the distinction between common and privileged information during real-time reference resolution. Our results show that listeners used this distinction to narrow the set of potential referents to objects with contrasts in common ground from the earliest moments. These results extend previous evidence that ground information influences real-time language processing by showing that the distinction between common and privileged information is used without being triggered by unusual circumstances.


Temporal difference models describe higher-order learning in humans.
The ability to use environmental stimuli to predict impending harm is critical for survival. Such predictions should be available as early as they are reliable. In pavlovian conditioning, chains of successively earlier predictors are studied in terms of higher-order relationships, and have inspired computational theories such as temporal difference learning. However, there is at present no adequate neurobiological account of how this learning occurs. Here, in a functional magnetic resonance imaging (fMRI) study of higher-order aversive conditioning, we describe a key computational strategy that humans use to learn predictions about pain. We show that neural activity in the ventral striatum and the anterior insula displays a marked correspondence to the signals for sequential learning predicted by temporal difference models. This result reveals a flexible aversive learning process ideally suited to the changing and uncertain nature of real-world environments. Taken with existing data on reward learning, our results suggest a critical role for the ventral striatum in integrating complex appetitive and aversive predictions to coordinate behaviour.


Cell Boundary Confinement Sets the Size and Position of the E. coli Chromosome.
Although the spatiotemporal structure of the genome is crucial to its biological function, many basic questions remain unanswered on the morphology and segregation of chromosomes. Here, we experimentally show in Escherichia coli that spatial confinement plays a dominant role in determining both the chromosome size and position. In non-dividing cells with lengths increased to 10 times normal, single chromosomes are observed to expand > 4-fold in size. Chromosomes show pronounced internal dynamics but exhibit a robust positioning where single nucleoids reside robustly at mid-cell, whereas two nucleoids self-organize at 1/4 and 3/4 positions. The cell-size-dependent expansion of the nucleoid is only modestly influenced by deletions of nucleoid-associated proteins, whereas osmotic manipulation experiments reveal a prominent role of molecular crowding. Molecular dynamics simulations with model chromosomes and crowders recapitulate the observed phenomena and highlight the role of entropic effects caused by confinement and molecular crowding in the spatial organization of the chromosome.


Thyroid enlargement and its relationship to clinicopathological parameters and T(4) status in suspected hyperthyroid cats.
To relate thyroid size to routine blood parameters and T(4) status the ventral neck of 161 cats with clinical signs consistent with hyperthyroidism was examined by two independent observers using a semi-quantitative palpation system. Thyroid gland size of each side was scored from 0 (non-palpable) to a maximum of 6 (>25 mm). In 127 of the 161 cats, at least one thyroid gland was palpable. The palpation score was significantly correlated with the T(4) concentration. The 17 hyperthyroid cats had significantly higher palpation scores than the 110 euthyroid cats. Euthyroid animals with a palpation score >or=3 were significantly older, had higher body weights, lower alkaline phosphatase, alanine aminotransferase, phosphate, and urine specific gravity, but higher lipase and creatinine concentrations than hyperthyroid cats. Our study demonstrates that although no reliable conclusion on the functional status of the thyroid can be drawn based on its size the likelihood of hyperthyroidism increases with increasing size of the gland.


Epigenomic changes during leukemia cell differentiation: analysis of histone acetylation and cytosine methylation using CpG island microarrays.
Dysregulation of epigenetic control is an important participant in carcinogenesis. The PML/RAR alpha translocation in acute promyelocytic leukemia (APL) is an example where the resultant fusion protein recruits histone deacetylase complexes to target genes resulting in their inappropriate transcriptional repression. All-trans-retinoic acid (ATRA) acts as a ligand that relieves this repression and produces an epigenetic transcriptional reprogramming of the cancer cell. CpG island microarrays were used to analyze the DNA methylation and histone acetylation state of the human APL cell line NB4 before and after differentiation with ATRA as well as normal peripheral blood mononuclear cells (PBMC). Over 70 CpG islands within 1 kb of transcription start of a known gene are aberrantly methylated in NB4 cells compared with PBMC; however, no changes in cytosine methylation were detected following ATRA-induced differentiation. With respect to histone H4 acetylation, over 100 single-copy CpG islands within 1 kb of transcription start of a known human gene became hyperacetylated following ATRA-induced differentiation. One CpG island was aberrantly methylated in NB4 cells, but became hyperacetylated and was induced following ATRA treatment and was associated with the HoxA1 gene, suggesting it may be a target gene of ATRA in APL. In addition to single-copy sequences, a selective increase in acetylation was detected in satellite DNA when compared with other high-copy sequences, such as Alu or rDNA. In summary, ATRA stimulates complex epigenomic changes during leukemic cell differentiation, and monitoring these changes may help to identify new targets of epigenetic dysfunction.


TT virus in the nasal secretions of children with acute respiratory diseases: relations to viremia and disease severity.
The natural history and pathogenic potential of the recently identified TT virus (TTV) are currently a matter of intensive investigation. In an attempt to shed some light on these issues, nasal and blood specimens of 1- to 24-month-old children hospitalized with a clinical diagnosis of acute respiratory disease (ARD) were examined for the presence, load, and genetic characteristics of TTV. The results have indicated that at least in young children, the respiratory tract not only represents a route by which abundant TTV can be shed into the environment but also may be a site of primary infection and continual replication. Although we found no compelling evidence that TTV was the direct cause of ARD in some of the children studied, the average loads of TTV were considerably higher in patients with bronchopneumonia (BP) than in those with milder ARD, raising interesting questions about the pathophysiological significance of TTV at this site. Furthermore, group 4 TTV was detected almost exclusively in children with BP.


Fabry Disease: prevalence of affected males and heterozygotes with pathogenic GLA mutations identified by screening renal, cardiac and stroke clinics, 1995-2017.
Fabry Disease (FD), an X linked lysosomal storage disease due to pathogenic α-galactosidase A (GLA) mutations, results in two major subtypes, the early-onset Type 1 'Classic' and the Type 2 'Later-Onset' phenotypes. To identify previously unrecognised patients, investigators screened cardiac, renal and stroke clinics by enzyme assays. However, some screening studies did not perform confirmatory GLA mutation analyses, and many included recently recognised 'benign/likely-benign' variants, thereby inflating prevalence estimates. Online databases were searched for all FD screening studies in high-risk clinics (1995-2017). Studies reporting GLA mutations were re-analysed for pathogenic mutations, sex and phenotype. Phenotype-specific and sex-specific prevalence rates were determined. Of 67 studies, 63 that screened 51363patients (33943M and 17420F) and provided GLA mutations were reanalysed for disease-causing mutations. Of reported GLA mutations, benign variants occurred in 47.9% of males and 74.1% of females. The following were the revised prevalence estimates: among 36820 (23954M and 12866F) haemodialysis screenees, 0.21% males and 0.15% females; among 3074 (2031M and 1043F) renal transplant screenees, 0.25% males and no females; among 5491 (4054M and 1437F) cardiac screenees, 0.94% males and 0.90% females; and among 5978 (3904M and 2074F) stroke screenees, 0.13% males and 0.14% females. Among male and female screenees with pathogenic mutations, the type 1 Classic phenotype was predominant (~60%), except more male cardiac patients (75%) had type 2 Later-Onset phenotype. Compared with previous findings, reanalysis of 63 studies increased the screenee numbers (~3.4-fold), eliminated 20 benign/likely benign variants, and provided more accurate sex-specific and phenotype-specific prevalence estimates, ranging from ~0.13% of stroke to ~0.9% of cardiac male or female screenees.


[Controversies in the pharmacological management of acute asthma in children].
To present a review of controversial issues related to the pharmacological management of the treatment of acute asthma in children. Articles published in national and international scientific journals. Data were selected from Lilacs and Medline databases. The article was organized into topics, presenting aspects on which there is consensus regarding the pharmacological treatment of asthma in children. Issues related to the use of metered dose inhaler versus nebulizers, the role of beta2-adrenergic drugs administered intravenously as well as the role of methylxanthine and magnesium sulfate are approached critically. Inhaled beta2-agonist drugs combined with corticosteroids remain the treatment of choice for acute episodes of asthma in children. Either nebulizers or metered dose inhalers connected to spacers are efficient for the relief of acute symptoms. Patients who are refractory to conventional treatment and develop severe acute asthma should receive beta2-agonist drugs intravenously, provided they are properly monitored. Methylxanthine and magnesium sulfate should be considered a second choice for selected patients.


A mutation in the 3' region of the human immunodeficiency virus type 1 reverse transcriptase (Y318F) associated with nonnucleoside reverse transcriptase inhibitor resistance.
The Y318F substitution in the 3' region of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) has been linked to nonnucleoside RT inhibitor (NNRTI) resistance in vitro. A systematic search of a large phenotypic-genotypic database (Virco) linked the Y318F substitution with a >10-fold decrease in NNRTI susceptibility in >85% of clinically derived isolates. There was a significant association between Y318F and use of delavirdine (P = 10(-11)) and nevirapine (P = 10(-6)) but not efavirenz (P = 0.3). Site-directed HIV-1 Y318F mutants in an HXB2 background displayed 42-fold-decreased susceptibility to delavirdine but <3-fold-decreased susceptibility to nevirapine or efavirenz. Combinations of Y318F with K103N, Y181C, or both resulted in decreased efavirenz susceptibility of 43-, 3.3-, and 84-fold, respectively, as well as >100- and >60-fold decreases in delavirdine and nevirapine susceptibility, respectively. These results indicate the importance of the Y318F substitution in HIV-1 drug resistance.


Energizing an invertebrate embryo: bafilomycin-dependent respiration and the metabolic cost of proton pumping by the V-ATPase.
We examine herein the contribution of V-ATPase activity to the energy budget of aerobically developing embryos of Artemia franciscana and discuss the results in the context of quiescence under anoxia. (31)P-NMR analysis indicates that intracellular pH and NTP levels are unaffected by acute incubation of dechorionated embryos with the V-ATPase inhibitor, bafilomycin A(1). Bafilomycin A(1) also has no significant effect on oxygen consumption by isolated mitochondria. Taken together, these data indicate that bafilomycin does not affect energy-producing pathways in the developing embryo. However, the V-ATPase inhibitor exhibits a concentration-dependent inhibition of oxygen consumption in aerobic embryos. A conservative analysis of respirometric data indicates that proton pumping by the V-ATPase, and processes immediately dependent on this activity, constitutes approximately 31% of the aerobic energy budget of the preemergent embryo. Given the complete absence of detectable Na(+)K(+)-ATPase activity during the first hours of aerobic development, it is plausible that the V-ATPase is performing a role in both the acidification of intracellular compartments and the energization of plasma membranes. Importantly, the high metabolic cost associated with maintaining these diverse proton gradients requires that V-ATPase activity be downregulated under anoxia in order to attain the almost complete metabolic depression observed in the quiescent embryo.


Measurement properties of the incremental shuttle walk test. a systematic review.
Background: The incremental shuttle walk test (ISWT) was developed > 20 years ago and has been used to assess peak exercise capacity in a variety of chronic diseases. The aim of this systematic review is to describe the measurement properties of the ISWT in a clinical population.Methods: Of 800 articles identified by electronic and hand searches, 35 were included. Twenty-one articles included data on the validity of the ISWT, 18 on the reliability, four on the responsiveness,and four on the interpretability.Results: Most of the studies were conducted in patients with COPD (n = 13) or cardiac disease(n = 8). For criterion validity, comparisons between distance covered during the ISWT and peak oxygen consumption reported correlations ranging from 0.67 to 0.95 ( P <.01). Intraclass correlation coefficients for test-retest reliability ranged from 0.76 to 0.99. The ISWT was shown to be responsive to pulmonary rehabilitation and bronchodilator administration. The minimal clinically important difference (MCID) in patients with COPD was 48 m. Predictive equations for the distance in the ISWT are available for healthy individuals.Conclusions: The ISWT can be considered a valid and reliable test to assess maximal exercise capacity in individuals with chronic respiratory diseases. The ISWT has been shown to be responsive to pulmonary rehabilitation and bronchodilator use in individuals with COPD, cystic fibrosis,and asthma. Further studies examining responsiveness and the MCID of the ISWT in patients with conditions other than lung diseases are required for the interpretation of interventions in other populations.


Requirement for Lim1 in head-organizer function.
Lim1 is a homeobox gene expressed in the organizer region of mouse embryos. To investigate the role of Lim1 during embryogenesis, a targeted deletion of the Lim1 gene was generated in embryonic stem cells. Embryos homozygous for the null allele lacked anterior head structures but the remaining body axis developed normally. A partial secondary axis developed anteriorly in some mutant embryos. Lim1 is thus an essential regulator of the vertebrate head organizer.


Robotic urethral reconstruction: redefining the paradigm of posterior urethroplasty.
Outlet procedures for benign prostatic hypertrophy, prostate cancer therapy, and trauma can result in stenosis of the posterior urethra, a complex reconstructive problem that often fails conservative endoscopic management, necessitating more aggressive and definitive reconstructive solutions. This is typically done with an open technique which may require a combined abdominoperineal approach, pubectomy, and/or flap interposition. Implementation of a robot-assisted platform affords several potential advantages including smaller incisions, magnified field of vision, near-infrared fluorescence (NIRF) imaging to characterize tissue integrity, enhanced dexterity within the deep and narrow confines of the male pelvis, sparing of the perineal planes, and shorter convalescence. Herein, we describe important surgical considerations for robotic posterior urethral reconstruction.


What's in a name? Intolerance of uncertainty, other uncertainty-relevant constructs, and their differential relations to worry and generalized anxiety disorder.
A number of studies have examined the association of intolerance of uncertainty (IU) to trait worry and generalized anxiety disorder (GAD). However, few studies have examined the extent of overlap between IU and other psychological constructs that bear conceptual resemblance to IU, despite the fact that IU-type constructs have been discussed and examined extensively within psychology and other disciplines. The present study investigated (1) the associations of IU, trait worry, and GAD status to a negative risk orientation, trait curiosity, indecisiveness, perceived constraints, self-oriented and socially prescribed perfectionism, intolerance of ambiguity, the need for predictability, and the need for order and structure and (2) whether IU is a unique correlate of trait worry and of the presence versus absence of Probable GAD, when overlap with other uncertainty-relevant constructs is accounted for. N = 255 adults completed self-report measures of the aforementioned constructs. Each of the constructs was significantly associated with IU. Only IU, and a subset of the other uncertainty-relevant constructs were correlated with trait worry or distinguished the Probable GAD group from the Non-GAD group. IU was the strongest unique correlate of trait worry and of the presence versus absence of Probable GAD. Indecisiveness, self-oriented perfectionism and the need for predictability were also unique correlates of trait worry or GAD status. Implications of the findings are discussed, in particular as they pertain to the definition, conceptualization, and cognitive-behavioral treatment of IU in GAD.


Comparative glycomics analysis of influenza Hemagglutinin (H5N1) produced in vaccine relevant cell platforms.
Hemagglutinin (HA) is the major antigen in influenza vaccines, and glycosylation is known to influence its antigenicity. Embryonated hen eggs are traditionally used for influenza vaccine production, but vaccines produced in mammalian and insect cells were recently licensed. This raises the concern that vaccines produced with different cell systems might not be equivalent due to differences in their glycosylation patterns. Thus, we developed an analytical method to monitor vaccine glycosylation through a combination of nanoLC/MS(E) and quantitative MALDI-TOF MS permethylation profiling. We then used this method to examine glycosylation of HAs from two different influenza H5N1 strains produced in five different platforms, including hen eggs, three different insect cell lines (High Five, expresSF+ and glycoengineered expresSF+), and a human cell line (HEK293). Our results demonstrated that (1) sequon utilization is not necessarily equivalent in different cell types, (2) there are quantitative and qualitative differences in the overall N-glycosylation patterns and structures produced by different cell types, (3) ∼20% of the N-glycans on the HAs produced by High Five cells are core α1,3-fucosylated structures, which may be allergenic in humans, and (4) our method can be used to monitor differences in glycosylation during the cellular glycoengineering stages of vaccine development.


¹¹¹Indium-labeled ultrafine carbon particles; a novel aerosol for pulmonary deposition and retention studies.
Continuous environmental or occupational exposure to airborne particulate pollution is believed to be a major hazard for human health. A technique to characterize their deposition and clearance from the lungs is fundamental to understand the underlying mechanisms behind their negative health effects. In this work, we describe a method for production and follow up of ultrafine carbon particles labeled with radioactive ¹¹¹Indium (¹¹¹In). The physicochemical and biological properties of the aerosol are described in terms of particle size and concentration, agglomeration rate, chemical bonding stability, and human lung deposition and retention. Preliminary in vivo data from a healthy human pilot exposure and 1-week follow up of the aerosol is presented. More than 98% of the generated aerosol was labeled with Indium and with particle sizes log normally distributed around 79 nm count median diameter. The aerosol showed good generation reproducibility and chemical stability, about 5% leaching 7 days after generation. During human inhalation, the particles were deposited in the alveolar space, with no central airways involvement. Seven days after exposure, the cumulative activity retention was 95.3%. Activity leaching tests from blood and urine samples confirmed that the observed clearance was explained by unbound activity, suggesting that there was no significant elimination of ultrafine particles. Compared to previously presented methods based on Technegas, ¹¹¹In-labelled ultrafine carbon particles allow for extended follow-up assessments of particulate pollution retention in healthy and diseased lungs.


Formation of methylthio metabolites of indene in the guinea pig and the rat.
The formation of methylthio metabolites of epoxides has been shown to be a significant route of metabolism in some species. Several aspects of this metabolic conversion for indene were examined. Two isomers of hydroxy(methylthio)indane were found in the urine of guinea pigs administered indene (14.3 and 100 mg/kg, ip). The major isomer, 2-hydroxy-1-methylthioindane (I) was present as 6-9% of the administered dose after 24 hr, while lower amounts (0-0.6%) of a minor isomer (II) were observed. A significant amount of isomer I was found as a urinary metabolite of indene oxide (14% of 12.5 mg/kg, ip). To further elucidate the route of formation of I, the glutathione (I-GLU) and mercapturic acid (I-MER) conjugates of indene oxide were synthesized and administered to the guinea pig. The methylthio metabolite I was present as a significant urinary metabolite of both conjugates of indene oxide, comprising 9.6% and 5.7% of the dose of I-GLU (5 mg, ip) and I-MER (4 mg, ip), respectively. These results show that the formation of a hydroxy(methylthio)indane is a significant route of metabolism for indene and indene oxide in the guinea pig, and that this metabolite arises via further metabolism of conjugates in the glutathione pathway. In the rat, isomer I is a minor metabolite. Mechanistic aspects of the formation of these thioether metabolites are discussed.


Comparison of Disease Phenotypes and Clinical Characteristics Among South Asian and White Patients with Inflammatory Bowel Disease at a Tertiary Referral Center.
The prevalence and clinical features of inflammatory bowel disease (IBD) vary among different racial and ethnic groups. The aim of this study was to compare the clinical and phenotypic features of Crohn's disease (CD) and ulcerative colitis (UC) in South Asian patients living in the United States with those of a white cohort. The demographic, clinical, and phenotypic characteristics of 73 South Asian patients (31 CD and 42 UC) who presented initially to our tertiary referral center from 2012 to 2016 and had subsequent follow-up were retrospectively compared with those of 408 consecutive white patients (245 CD and 163 UC). South Asian IBD patients were significantly more likely to have UC (58.0% vs 40.0%; P = 0.005) than white patients. South Asians with CD were less likely to have a family history of IBD (9.7% vs 26.9%; P = 0.037) and required fewer CD-related surgeries (22.5% vs 46.1; P = 0.012). South Asians were also less likely to be active or former smokers in both the CD (P = 0.004) and UC (P = 0.020) groups. South Asians with UC had a higher incidence of Clostridium difficile infection compared with white patients (19.0% vs 8.6%; P = 0.050). A cohort of South Asian patients with IBD were more likely to have UC and had differing family and tobacco risk factors, requirements for surgery, and Clostridium difficile infection rates as compared with white patients.