Influence of neighborhood deprivation, gender and ethno-racial origin on smoking behavior of Canadian youth.
Deprived neighborhoods play an important role in adult smoking behavior, but little research exists about youth on this topic. This study explored the relationship between deprivation and youth smoking to examine whether this association differs by gender and ethno-racial origin. Individual-level data from the Canadian Community Health Survey (2000-2005) were combined with neighborhood-level data from the 2001 Canada Census to assess smoking among youth aged 12-18 (n = 15,615). Youth who were female (OR = 1.27, 95%CI:1.16-1.38), White (OR = 1.95, 95%CI:1.71-2.21) and living in deprived neighborhoods (OR = 1.22, 95%CI:1.16-1.28) were more likely to smoke. In multilevel models, White females were more likely to smoke relative to non-White females and males (OR = 1.42, 95%CI:1.06-1.89). Youth with a strong sense of community belonging and living in deprived neighborhoods were at increased risk of smoking (OR = 1.18, 95%CI:1.06-1.32). The individual-level risk factor, household smoker, contributed substantially to youth smoking reducing the bivariate association between material deprivation and smoking by 33%. White females, youth cohabiting with other smokers and youth living in poor neighborhoods with a strong sense of community belonging, are at an increased risk of smoking. Future anti-smoking efforts might have greater impact if they target at-risk youth as well as household members who cohabit with youth.


Glial process elongation and branching in the developing murine neocortex: a qualitative and quantitative immunohistochemical analysis.
Cells of astroglial lineage in the murine cerebrum undergo a succession of transformations during prenatal and early postnatal development. The bipolar radial cell, the earliest astroglial form to appear, provides a radially aligned, parallel array of fibers that serves as a guide to neuronal migration. The multipolar astrocyte is the representative of this lineage that persists in the adult cerebrum. The processes of the multipolar astrocytes form a complex reticulum, which is considered critical to the development, function, and maintenance of neural circuits. A monopolar radial cell appears to be transitional between the two. The shift from the radial glial fiber system to a diffuse glial network is achieved largely in the E17-P2 interval in the mouse. This phenomenon has been studied qualitatively and quantitatively by staining cerebral tissue with monoclonal antibody RC2, a specific and sensitive ligand for cells of astroglial lineage in the mouse. Elongation and branching of glial processes contribute to the glial transformation. Elongation of radial fibers occurs under the guidance of other radial glial fibers (fasciculated elongation) or independently of other fibers (nonfasciculated elongation). Fasciculated elongation results in an increase in the density of radial glial fibers that span the cortical layers. Nonfasciculated elongation appears to be associated with process branching. This is the initial event in transformation of the bipolar radial cells to monopolar radial or multipolar cells. Only nonfasciculated elongation is characteristic of processes of the monopolar radial cells and multipolar astrocytes. Branching of the processes of all three cell forms appears to occur both by bifurcation at the elongating tip and by sprouting from the fiber shaft. Elongating fibers are tipped by growth cones that are relatively simple in shape as compared to those observed at the tips of elongating axons. Growth cones at the tips of nonfasciculated fibers are more complex in form than those at the tips of radial fibers elongating in contact with other radial fibers.


GO2MSIG, an automated GO based multi-species gene set generator for gene set enrichment analysis.
Despite the widespread use of high throughput expression platforms and the availability of a desktop implementation of Gene Set Enrichment Analysis (GSEA) that enables non-experts to perform gene set based analyses, the availability of the necessary precompiled gene sets is rare for species other than human. A software tool (GO2MSIG) was implemented that combines data from various publicly available sources and uses the Gene Ontology (GO) project term relationships to produce GSEA compatible hierarchical GO based gene sets for all species for which association data is available. Annotation sources include the GO association database (which contains data for over 200000 species), the Entrez gene2go table, and various manufacturers' array annotation files. This enables the creation of gene sets from the most up-to-date annotation data available. Additional features include the ability to restrict by evidence code, to remap gene descriptors, to filter by set size and to speed up repeat queries by caching the GO term hierarchy. Synonymous GO terms are remapped to the version preferred by the GO ontology supplied. The tool can be used in standalone form, or via a web interface. Prebuilt gene set collections constructed from the September 2013 GO release are also available for common species including human. In contrast human GO based sets available from the Broad Institute itself date from 2008. GO2MSIG enables the bioinformatician and non-bioinformatician alike to generate gene sets required for GSEA analysis for almost any organism for which GO term association data exists. The output gene sets may be used directly within GSEA and do not require knowledge of programming languages such as Perl, R or Python. The output sets can also be used with other analysis software such as ErmineJ that accept gene sets in the same format. Source code can be downloaded and installed locally from http://www.bioinformatics.org/go2msig/releases/ or used via the web interface at http://www.go2msig.org/cgi-bin/go2msig.cgi.


Right Atrial Diverticulum in an Adult Woman with Left Bundle Branch Block.
Right atrial diverticulum is a very rare anomaly. It is an outpouching arising from the right atrial free wall. Clinical presentations vary widely but some cases are associated with supraventricular tachycardia and atrial flutter/fibrillation. The incidence/prevalence of this anomaly is not available because only a few cases have been reported. We report a 38-year-old female patient who presented to the Heart Clinic, Tehran, Iran in 2019 with a history of dyspnea and chest pain. Electrocardiography revealed left bundle branch block. Following a magnetic resonance imaging study, the patient was diagnosed with a right atrial diverticulum. She underwent surgical resection of the diverticulum. The post-operative course was uneventful and no recurrence of the arrhythmia was detected during the six months of follow-up. To the best of the authors' knowledge, this combination has not been described in the literature.


A comparison of granulopoiesis in culture from blood and marrow cells of nonleukemic individuals and patients with acute leukemia.
The objective of this study was to compare the concentration of committed granulopoietic progenitor cells (CFU-C) in marrow and blood. For individuals without leukemia, a highly significant correlation was observed between the concentration of CFU-C obtained from the two sites. However, CFU-C in blood had a slower sedimentation velocity than that reported for marrow and were found not to be in the DNA synthetic phase of the cycle using the tritiated thymidine suicide tehcnique. In patients with acute leukemia, no correlation was observed between concentrations of CFU-C in marrow and peripheral blood, regardless of whether the patients were newly diagnosed, in remission, or in relapse. We concluded that studies of the peripheral blood do not yield the same information in respect to granulopoietic progenitor cells as do studies of the marrow.


"I Am Now Five Steps Ahead": How Co-design Platforms Sustain Kenyan Community Health Volunteer Engagement.
The aim of this study is to examine how humancentered design (HCD) as a platform for co-production might function to explain community health volunteer (CHV) motivation in self-directed and self-funded community health activities. Sustaining engagement has been difficult for CHVs who lack monetary incentives, expense reimbursement, and are rarely given opportunity to give their own voice to local health priorities. Qualitative study utilized focus group discussions 12 months post intervention and included both an inductive and deductive level of analysis. Three community health units (CHU) representing Kenya's diversity were selected with the local Ministry of Health including peri-urban slum, rural agrarian, and a unit where informal day labor and rented housing was the norm. The participants were selected according to Kenya's community health strategy norms and had previously had the standard basic community health training. A 3-day training rooted in HCD utilized multiple quality improvement tools (asset mapping, root cause analysis, key drivers) in order to help CHVs uncover unarticulated community needs and assumptions and encourage behavior change. Action plans with Plan-Do-Study-Act cycles were tracked longitudinally. Key themes were self-interest, common goal, gratitude/indebtedness. Additional thematic analysis identified altruism as supporting sustained engagement. This study supports HCD as a platform for sustained CHV engagement. It builds the evidence for self-interest, common goal, and gratitude/indebtedness as sustaining factors. These factors are also seen in process-based theories that operationalize and measure trust building reciprocity cycles that mirror the iterative P-D-S-A cycles seen in HCD.


[Various reasons for changes in the phospholipid composition of high density lipoproteins in hypoalphacholesterolemia].
In men without any symptoms of ischemic heart disease, living in two different geographical zones (Moscow and Chuckchee land) low level of high density lipoprotein (HDL) cholesterol was accompanied by alterations in phospholipid composition of HDL2 and HDL3: decrease in the ration of lecithin and increase in sphingomyelin and kephalin content. The alteration in the phospholipid composition of these two HDL subclasses occurred simultaneously with changes in fatty acid composition of HDL lecithin: decrease in the ratio of linoleic acid as well as in stearic and arachidonic or eucosepentaenic acids. At the same time, phospholipid composition of the HDL subclasses was dissimilar in men and women without any symptoms of ischemic heart disease. Role of alterations in the fatty acid composition of phosphatide acid as well as effect of hormones on alterations in the phospholipid composition of HDL in hypoalphacholesterolemia are discussed.


Ciclopirox Hydroxypropyl Chitosan: Efficacy in Mild-to-Moderate Onychomycosis.
The severity and percentage of nail involvement are usually considered the main prognostic factors for the treatment of onychomycosis. This study investigated the efficacy of P-3051 (ciclopirox [CPX] 8% nail lacquer in hydroxypropyl chitosan technology) in a population subset of the pivotal study, selected according to the criteria used in recent onychomycosis pivotal studies. The original study was a multicenter, randomized, three-arm, placebo-controlled, parallel groups, evaluator-blinded study comparing P-3051 with reference CPX (standard, insoluble 8% CPX nail lacquer) and placebo (P-3051 vehicle) in a 2: 2: 1 ratio, applied once daily for 48 weeks to 467 patients with onychomycosis, followed by a 12-week follow up. The primary endpoint was complete cure (negative mycology and 100% clear nail) at the end of treatment. Among the secondary endpoints, response rate (negative mycology and ≥90% clear nail) and negative culture were chosen as most representative for a clinical setting. A population subset (modified intention-to-treat population, 302 patients) was selected, excluding those with more severe disease (> 50% nail involvement), in line with recent onychomycosis pivotal trials. P-3051 was superior to placebo in all parameters but culture at week 60 and was superior to reference CPX in cure and response rates at week 60. Compared to the overall patient population, efficacy rates in the P-3051 group were higher in the subset excluding patients with nail involvement > 50%. Results increased by 33% (from 5.7 to 7.6%) at week 48 and by 19.0% (from 12.7 to 15.1%) at week 60 for cure rate, by 33% (from 24.0 to 31.9%) and 20% (from 28.7 to 34.5%) for response rate, and by 3% (from 89.1 to 91.6%) and 4.0% (from 79.0 to 82.4%) for culture conversion to negative. This post hoc analysis confirms that the severity of onychomycosis is a prognostic factor for responsiveness to antifungal treatments and that this can significantly affect reported efficacy data. The different inclusion criteria should be taken into account when reviewing the efficacy of antifungal agents from different studies.


Dermoscopy in the era of dermato-oncology: from bed to bench side and retour.
Today dermoscopy is standard-of-care in the diagnosis and management of patients with benign and malignant skin tumors because it increases the diagnostic accuracy of skin lesions compared to the naked-eye examination up to 25%. Despite its role in the routine dermato-oncology, it increasingly gained interest as a bridge connecting clinical with basic molecular research in dermato-oncology. Here, we correlate dermoscopy patterns of nevi and melanomas with high and low susceptibility genes and somatic mutations, provide an overview on the clinical and dermoscopic patterns of cutaneous melanoma subtypes, and highlight the role of dermoscopy in the diagnosis of skin eruptions during systemic treatments of advanced melanoma including targeted therapies and immunotherapies.


Primary hypophosphatemic rickets. Effect of oral phosphate and vitamin D on growth and surgical treatment.
Failure to diagnose and treat hypophosphatemic rickets during childhood resulted in stunted growth and progressive deformities of the lower limb. When the deformities were treated surgically, recurrent deformity and non-union of osteotomies developed, and further major opeative procedures were required to remedy these complications. Treatment from early childhood with oral phosphate and vitamin D improved the rate of growth and controlled the progression of bowleg deformity. Residual varus deformity was corrected by osteotomy through the proximal tibial metaphysis at skeletal maturity, when the results were predictable. Genu valgum deformity was corrected by stapling the medial part of the distal femoral epiphysis prior to skeletal maturity. With early postoperative mobilization and adequate medication, the complications of delayed tibial union and failure to correct the femoral valgus deformity were avoided.


Milk insulin, GH and TSH: relationship to changes in milk lactose, glucose and protein during lactogenesis in women.
Changes in concentration of insulin, growth hormone (GH) and thyroid stimulating hormone (TSH) in the whey fraction of mammary secretion of women during late pregnancy and lactogenesis were determined by radioimmunoassay. The milk hormone changes were compared to changes in the concentration of milk lactose, glucose and proteins which reflect the transition from colostrum to milk production during lactogenesis. During late pregnancy the average concentrations of insulin, GH and TSH in the colostrum of 2 women were 114.6 microU ml-1, 21.7 microU ml-1 and 14.1 microU ml-1, respectively. The concentrations of these hormones fell from high to low levels between day 1 and day 2 post partum concomitantly with the changes in the concentration of milk lactose, glucose and protein. On day 5 post partum the average milk concentrations of insulin, GH and TSH were 21.0 microU ml-1, 4.0 microU ml-1, and 5.0 microU ml-1, respectively. Similar milk hormone changes occurred in non breast feeding women during the first 11 days post partum. During 2 to 13 months of lactation one woman, the average concentration of milk insulin was 12 microU ml-1. In another woman, from 0 to 22 days after termination of breast feeding, the concentration of insulin increased from 19 to 56 microU ml-1. There were significant positive correlations between hormones and total protein and negative correlations between hormones and lactose, and hormones and glucose in women during lactogenesis and involution. The results showed that the changes in insulin, GH and TSH in milk were closely related to changes in secretory activity and permeability of the breast.


Negative osmoregulation of the Salmonella ompS1 porin gene independently of OmpR in an hns background.
The ompS1 gene encodes a quiescent porin in Salmonella enterica serovars Typhi and Typhimurium. By using random mariner transposon mutagenesis, mutations that caused derepression of ompS1 expression were isolated, one in S. enterica serovar Typhi and two in S. enterica serovar Typhimurium. All of them mapped in the hns gene in the region coding for the carboxy terminus of the H-NS nucleoid protein. The derepressed ompS1 expression was subject to negative regulation at high osmolarity, both in the presence and in the absence of OmpR. This observation was possible due to the fact that there are two promoters: P1, which is OmpR dependent, and P2, which does not require OmpR for activation (rather, OmpR represses P2). The sequences upstream from position -88, a region previously shown to be involved in the negative regulation of ompS1, can form a static bend, and the integrity of this region was required for function and binding of H-NS and for osmoregulation, as determined with gene reporter fusions of different lengths and with a 31-bp deletion mutant. This is consistent with the notion that this region determines a structure required for repression. Hence, ompS1 shares negative regulation by H-NS with other loci, such as the bgl operon and the ade gene.


Endothelial nitric oxide synthase polymorphisms/haplotypes are strong modulators of oral cancer risk in Serbian population.
Oral carcinoma is the sixth most common malignancy worldwide, with survival rates of approximately 50%. The major type of oral cancer, present in 90% of the cases, is oral squamous cell carcinoma (OSCC). The genetic background predisposing an individual to OSCC is complex and largely unknown. Studies have suggested that endothelial nitric oxide synthase (eNOS) gene polymorphisms modulate the cancer risk, prompting us to assess the impact of three functional eNOS gene polymorphisms on OSCC risk. The present study included 50 patients with OSCC and 110 controls. Polymerase chain reaction and restriction fragment length polymorphism analysis were used for genotyping of single-nucleotide polymorphisms -786 T/C (rs2070744) and 894 G/T (rs1799983) and variable number of tandem repeats (VNTR) intron 4b/a polymorphism. Homozygous carriers of -786 T/C and intron 4b/a VNTR variant alleles paired with a significant increase of oral cancer risk [odds ratio (OR): 3.63, 95% confidence interval (CI): 1.08-12.21; P = 0.045 and OR: 11.29, 95% CI: 2.71-47.11; P < 0.001, respectively]. When combined, CC and 4b4a genotypes together led to a 21-fold OSCC risk increase (OR: 21, 95% CI: 2.07-213.29; P = 0.006). Haplotype analysis showed that the C-G-4b haplotype conferred an 11-fold increase in OSCC risk. In conclusion, eNOS polymorphisms considerably influence levels of OSCC risk in the Serbian population.


Human C3b/C4b receptor (CR1). Demonstration of long homologous repeating domains that are composed of the short consensus repeats characteristics of C3/C4 binding proteins.
10 overlapping CR1 cDNA clones that span 5.5 kb were isolated from a tonsillar library and sequenced in whole or in part. A single long open reading frame beginning at the 5' end of the clones and extending 4.7 kb downstream to a stop codon was identified. This sequence represents approximately 80% of the estimated 6 kb of coding sequence for the F allotype of CR1. Three tandem, direct, long homologous repeats (LHRs) of 450 amino acids were identified. Analysis of the sequences of tryptic peptides provided evidence for a fourth LHR in the F allotype of CR1. Amino acid identity between the LHRs ranged from 70% between the first and third repeats to 99% between the NH2-terminal 250 amino acids of the first and second repeats. Each LHR comprises seven short consensus repeats (SCRs) of 60-70 amino acids that resemble the SCRs of other C3/C4 binding proteins, such as complement receptor type 2, factors B and H, C4 binding protein, and C2. Two additional SCRs join the LHRs to a single membrane-spanning domain of 25 amino acids; thus, the F allotype of CR1 probably contains at least 30 SCRs, 23 of which have been sequenced. Each SCR is predicted to form a triple loop structure in which the four conserved half-cystines form disulfide linkages. The linear alignment of 30 SCRs as a semi-rigid structure would extend 1,140A from the plasma membrane and might facilitate the interaction of CR1 with C3b and C4b located within the interstices of immune complexes and microbial cell walls. The COOH-terminal cytoplasmic domain of 43 residues contains a six-amino-acid sequence that is homologous to the sequence in the epidermal growth factor receptor that is phosphorylated by protein kinase C.


Comparison of Cox and Gray's survival models in severe sepsis.
Although survival is traditionally modeled using Cox proportional hazards modeling, this approach may be inappropriate in sepsis, in which the proportional hazards assumption does not hold. Newer, more flexible models, such as Gray's model, may be more appropriate. To construct and compare Gray's model and two different Cox models in a large sepsis cohort. To determine whether hazards for death after sepsis were nonproportional. To explore how well the different survival modeling approaches describe these data. Analysis of combined data from the treatment and placebo arms of a large, negative, sepsis trial. Intensive care units at 136 U.S. medical centers. A total of 1090 adults aged 18 yrs or older with signs and symptoms of severe sepsis and documented or probable Gram-negative infection. We considered 27 potential baseline risk factors and modeled survival over the 28 days after the onset of sepsis. We tested proportionality in single-variable Cox analysis using Schoenfeld residuals and log-log plots. We constructed a traditional multivariable Cox model, a multivariable Cox model with time-varying covariates, and a multivariable Gray's model. In single-variable analyses, 20 of the 27 potential factors were significantly associated with mortality, and 10 of 20 had nonproportional hazards. In multivariate analysis, all three models retained a very similar set of significant covariates (two models retained the identical set of nine variables, and the third differed only in that it retained the same nine plus a tenth variable). Four of the nine common covariates had nonproportional hazards. Of the three models, Gray's model best captured these changing hazard ratios over time. We confirm that many of the important predictors of mortality in severe sepsis are nonproportional and find that Gray's model seems best suited for modeling survival in this condition.


Folding pattern recognition in proteins using spectral analysis methods.
Divergence in sequence through evolution precludes sequence alignment based homology methodologies for protein folding prediction from detecting structural and folding similarities for distantly related protein. Homolog coverage of actual data bases is also a factor playing a critical role in the performance of those methodologies, the factor being conspicuously apparent in what is called the twilight zone of sequence homology in which proteins of high degree of similarity in both biological function and structure are found but for which the amino acid sequence homology ranges from about 20% to less than 30%. In contrast to these methodologies a strategy is proposed here based on a different concept of sequence homology. This concept is derived from a periodicity analysis of the physicochemical properties of the residues constituting proteins primary structures. The analysis is performed using a front-end processing technique in automatic speech recognition by means of which the cepstrum (measure of the periodic wiggliness of a frequency response) is computed that leads to a spectral envelope that depicts the subtle periodicity in physicochemical characteristics of the sequence. Homology in sequences is then derived by alignment of spectral envelopes. Proteins sharing common folding patterns and biological function but low sequence homology can then be detected by the similarity in spectral dimension. The methodology applied to protein folding recognition underscores in many cases other methodologies in the twilight zone.


DNA damage response factors from diverse pathways, including DNA crosslink repair, mediate alternative end joining.
Alternative end joining (Alt-EJ) chromosomal break repair involves bypassing classical non-homologous end joining (c-NHEJ), and such repair causes mutations often with microhomology at the repair junction. Since the mediators of Alt-EJ are not well understood, we have sought to identify DNA damage response (DDR) factors important for this repair event. Using chromosomal break reporter assays, we surveyed an RNAi library targeting known DDR factors for siRNAs that cause a specific decrease in Alt-EJ, relative to an EJ event that is a composite of Alt-EJ and c-NHEJ (Distal-EJ between two tandem breaks). From this analysis, we identified several DDR factors that are specifically important for Alt-EJ relative to Distal-EJ. While these factors are from diverse pathways, we also found that most of them also promote homologous recombination (HR), including factors important for DNA crosslink repair, such as the Fanconi Anemia factor, FANCA. Since bypass of c-NHEJ is likely important for both Alt-EJ and HR, we disrupted the c-NHEJ factor Ku70 in Fanca-deficient mouse cells and found that Ku70 loss significantly diminishes the influence of Fanca on Alt-EJ. In contrast, an inhibitor of poly ADP-ribose polymerase (PARP) causes a decrease in Alt-EJ that is enhanced by Ku70 loss. Additionally, the helicase/nuclease DNA2 appears to have distinct effects from FANCA and PARP on both Alt-EJ, as well as end resection. Finally, we found that the proteasome inhibitor Bortezomib, a cancer therapeutic that has been shown to disrupt FANC signaling, causes a significant reduction in both Alt-EJ and HR, relative to Distal-EJ, as well as a substantial loss of end resection. We suggest that several distinct DDR functions are important for Alt-EJ, which include promoting bypass of c-NHEJ and end resection.


Factors influencing myocardial response to metabolic acidosis in isolated rat hearts.
We assessed the effects of metabolic acidosis in Langendorff rat hearts to identify factors influencing myocardial response to metabolic acidosis. Intracellular pH (pHi), beta-ATP, phosphocreatine, and inorganic phosphate (Pi) content were measured by 31P nuclear magnetic resonance spectroscopy along with simultaneous measurements of coronary flow and developed pressure during 30 min of perfusion at pH = 6.8, followed by 15 min of reequilibration at pH = 7.4. Under high work-load conditions, pHi, high-energy phosphates, coronary flow, and developed pressure were severely reduced during metabolic acidosis. Each of these hearts exhibited a progressive decline in developed pressure and stopped beating during reequilibration. Lowering work load prevented severe biochemical or mechanical deterioration, allowing complete recovery during reequilibration. In the presence of high work load, factors found to improve myocardial tolerance to metabolic acidosis included maintaining base-line or higher levels of coronary flow with vasodilators or substitution of pyruvate for glucose as the energy-producing substrate. Raising perfusate osmolality did not prevent severe decreases in coronary flow and developed pressure during acidosis, but did allow a dramatic recovery during reequilibration. Recovery of biochemical and mechanical performance after 30 min of metabolic acidosis was directly related to 1) ln[ATP]/[ADP]f[Pi] greater than or equal to 4.1, where [ADP]f is the concentration of free ADP; 2) pHi greater than 6.40; and 3) ATP level greater than or equal to 75% of control.


The antiosteoporotic effects of Cheonggukjang containing vitamin k2 (menaquinone-7) in ovariectomized rats.
The effect of dietary vitamin K2 (menaquinone-7, MK-7) and cheonggukjang (CGJ) on the prevention of ovariectomy (OVX)-induced bone loss was studied in rats. Female Sprague-Dawley rats were divided into eight groups: sham-operated; OVX control; OVX treated with MK-7 at doses of 2, 4, and 8 μg/day; and OVX treated with CGJ at doses of 0.063, 0.125, and 0.250 g/day referenced to MK-7 levels at 2, 4, and 8 μg/day, respectively. After 8 weeks of treatment, the preventive effects of MK-7 and CGJ were evaluated by measuring body weights, serum levels of bone turnover markers, bone mineral content (BMC), bone mineral density (BMD), trabecular microarchitectural properties, and bone histological characteristics. Our results showed that rats treated with a high dose of MK-7 (8 μg/day) exhibited a minor inhibitory effect on OVX-induced bone loss, as indicated by a significant increase in trabecular number, as well as BMC and BMD (P<.01). Moreover, the preventive effects of MK-7 were augmented by administration of CGJ at the same MK-7 dose. In addition, the preventive effects of CGJ were shown to be dose dependent, with the highest dose (0.250 g/day) significantly (P<.01) increasing BMC and BMD by 31.8% and 47.6%, respectively. In summary, these results suggest that administration of CGJ containing abundant levels of MK-7 may be a promising approach for the treatment and prevention of osteoporosis.


Transgenic expression of TaMYB2A confers enhanced tolerance to multiple abiotic stresses in Arabidopsis.
Osmotic stresses such as drought, salinity, and cold are major environmental factors that limit agricultural productivity. Transcription factors play essential roles in abiotic stress signaling in plants. Three TaMYB2 members were identified and designated TaMYB2A, TaMYB2B, and TaMYB2D based on their genomic origins. The cis-regulatory elements in the promoter regions were compared, and their diverse expression patterns under different abiotic stress conditions were identified. TaMYB2A was further characterized because of its earlier response to stresses. Subcellular localization revealed that TaMYB2A localized in the nucleus. To examine the role of TaMYB2A under various environmental stresses, transgenic Arabidopsis plants carrying TaMYB2A controlled by the CaMV 35S promoter were generated and subjected to severe abiotic stress. TaMYB2A transgenics had enhanced tolerance to drought, salt, and freezing stresses, which were confirmed by the enhanced expressions of abiotic stress-responsive genes and several physiological indices, including decreased rate of water loss, enhanced cell membrane stability, improved photosynthetic potential, and reduced osmotic potential. TaMYB2A is a multifunctional regulatory factor. Its overexpression confers enhanced tolerance to multiple abiotic stresses while having no obvious negative effects on phenotype under well-watered and stressed conditions; thus, TaMYB2A has the potential for utilization in transgenic breeding to improve abiotic stress tolerances in crops.


SCN: Switchable Context Network for Semantic Segmentation of RGB-D Images.
Context representations have been widely used to profit semantic image segmentation. The emergence of depth data provides additional information to construct more discriminating context representations. Depth data preserves the geometric relationship of objects in a scene, which is generally hard to be inferred from RGB images. While deep convolutional neural networks (CNNs) have been successful in solving semantic segmentation, we encounter the problem of optimizing CNN training for the informative context using depth data to enhance the segmentation accuracy. In this paper, we present a novel switchable context network (SCN) to facilitate semantic segmentation of RGB-D images. Depth data is used to identify objects existing in multiple image regions. The network analyzes the information in the image regions to identify different characteristics, which are then used selectively through switching network branches. With the content extracted from the inherent image structure, we are able to generate effective context representations that are aware of both image structures and object relationships, leading to a more coherent learning of semantic segmentation network. We demonstrate that our SCN outperforms state-of-the-art methods on two public datasets.


Multi-scenario optimization of land use structure and prediction of ecosystem service value in Guanzhong Plain urban agglomeration.
Rapid economic development has led to significant changes in land use in the Guanzhong Plain urban agglomeration, which alters regional ecosystem service value (ESV). Based on the land use and driver data of the Guanzhong Plain urban agglomeration, we used the system dynamics (SD) model coupled with the mixed-cell cellular automata (MCCA) model to predict the subtle spatial and temporal changes of ESV within the land use unit in 2040 under the scenarios of natural development, economic development, ecological protection, and arable land conservation, to reveal the responses of ESV to the socio-economic evolution. We examined the impacts of land use change on ESV by using the sensitivity index. The results showed that land use transformation between 2000 and 2020 in the study area was mainly the conversion between arable land, forest, grassland, and the conversion of arable land to construction land. Due to increased forest and water, ESV increased slightly during this period. In 2040, compared with the ecological protection scenario, the proportion of forest in the economic development scenario decreased by 1.8%, and the construction land increased by 1.3%. During 2020-2040, under the economic development scenario, ESV showed a downward trend in the central and eastern regions but an upward trend under the arable land conservation scenario, with hydrological and climatic regulation contributing the most to ESV. Total ESV showed a decreasing trend except for the ecological conservation scenario. In the ecological protection scenario, land use change positively impacted ESV. In contrast, ESV had a negative response to land use change in other scenarios, with the greatest reduction in the economic development scenario. The research could provide new methods for multi-scenario land use simulation and ESV prediction and have scientific and practical significance for optimizing land space layout, land resource planning management, and sustainable development path strategy of urban agglomerations.


Bidirectional associations between loneliness and problematic internet use: A meta-analytic review of longitudinal studies.
Loneliness and problematic Internet use (PIU) are both major public health concerns around the world. These two constructs have long been linked, but there is conflicting evidence regarding the temporal nature of the loneliness-PIU relationship. We searched 8 databases to identify studies examining longitudinal associations between loneliness and PIU published on or before August 2023. From the 316 articles identified, 26 studies were included with a total of 23,382 participants. Moderate, positive, and significant prospective pathways were found from loneliness to PIU (r = 0.287, p < 0.001, 95 % CI [0.241, 0.331]), and from PIU to loneliness (r = 0.255, p < 0.001, 95 % CI [0.205, 0.303]). Moderator analyses suggested that the association of loneliness with PIU was stronger in samples from Eastern countries, with more males, more young adults, less time passed, and in more recent years. The association of PIU with loneliness was stronger in samples from Eastern countries, with more males, more young adults, and in more recent years. This meta-analytic review provided the first estimation for the overall bidirectional longitudinal associations between loneliness and PIU. A deeper comprehension of the relations has implications for loneliness and PIU intervention programs, where interventions targeting both constructs might be fruitfully applied.


Percutaneous core biopsy of palpable breast lesions: accuracy of frozen section histopathological exam in the diagnosis of breast cancer.
to evaluate the accuracy of frozen section histopathology from fragments of tissue obtained by percutaneous core needle biopsy of palpable tumors in the diagnosis of breast cancer. a cohort study was performed on 57 patients with palpable tumors and suspected breast cancer undergoing percutaneous thick needle core biopsy. The fragments were analyzed by the same pathologist. frozen section diagnosed 16 benign cases (28.6%) and 40 malignant (71.4%), whereas paraffin showed that 15 were benign (26.8%) and 41 malignant (73.2%). Histopathological examinations were concordant in 55 cases and there was one false-negative (6.2%). Statistics rates were: negative predictive value of 93.8%, positive predictive value of 100%, no false-positive (0%), one false negative (6.2%), specificity of 100%, sensitivity of 97 6%; observed agreement = 98.2%; expected agreement = 59.9%, Kappa = 0.955 [ 95% CI = 0.925-0.974, p < 0.01 ]. frozen section histopathological findings showed excellent correlation with the findings by the technique in paraffin in the fragments of palpable breast tumors obtained by thick needle percutaneous core biopsy (98.2% accuracy). Therefore, in these patients, it was possible to anticipate the diagnosis, staging and the breast cancer treatment planning.


Urine C-peptide, beta-cell function, and insulin requirement.
Urinary C-peptide excretion was investigated as a method for monitoring beta-cell function in diabetic patients and for studying the contribution of endogenous insulin production to diabetic control. Control subjects had variations in serum and urine C-peptide immunoreactivity that correlated with basal and meal-related insulin secretion. In a group of well-controlled juvenile diabetic patients, those receiving high doses of insulin had low or negligible C-peptide excretion, whereas most patients with low exogenous insulin requirements had near-normal urinary C-peptide excretion. Patients treated for diabetic ketoacidosis had recovery of beta-cell function as measured by C-peptide immunoreactivity in serial urine specimens. Thus, measurement of urinary C-peptide excretion is a simple technique that may be useful in assessing endogenous insulin production in juvenile diabetic patients.


A Systematic Review of Measurement Tools for the Proactive Assessment of Patient Safety in General Practice.
Primary care physicians have reported a difficulty in understanding how best to measure and improve patient safety in their practices. The aims of the study were to identify measures of patient safety suitable for use in primary care and to provide guidance on proactively monitoring and measuring safety. Searches were conducted using Medline, Embase, CINAHL and PsycInfo in February 2016. Studies that used a measure assessing levels of or attitudes toward patient safety in primary care were considered for inclusion. Only studies describing tools focused on the proactive assessment of safety were reviewed. Two independent reviewers extracted data from articles and applied the Quality Assessment Tool for Studies with Diverse Designs. More than 2800 studies were screened, of which 56 were included. Most studies had used healthcare staff survey or interviews to assess patient safety (n = 34), followed by patient chart audit (n = 14) or use of a practice assessment checklist (n = 7). Survey or interview of patients, active monitoring systems, and simulated patients were used with less frequency. A lack of appropriate measurement tools has been suggested to limit the ability to monitor patient safety in primary care and to improve patient care. There is no evident "best" method of measuring patient safety in primary care. However, many of the measures are readily available, quick to administer, do not require external involvement, and are inexpensive. This synthesis of the literature suggests that it is possible for primary care physicians to take a proactive approach to measuring and improving safety.


Multi-Incidence Holographic Profilometry for Large Gradient Surfaces with Sub-Micron Focusing Accuracy.
Surface reconstruction for micro-samples with large discontinuities using digital holography is a challenge. To overcome this problem, multi-incidence digital holographic profilometry (MIDHP) has been proposed. MIDHP relies on the numerical generation of the longitudinal scanning function (LSF) for reconstructing the topography of the sample with large depth and high axial resolution. Nevertheless, the method is unable to reconstruct surfaces with large gradients due to the need of: (i) high precision focusing that manual adjustment cannot fulfill and (ii) preserving the functionality of the LSF that requires capturing and processing many digital holograms. In this work, we propose a novel MIDHP method to solve these limitations. First, an autofocusing algorithm based on the comparison of shapes obtained by the LSF and the thin tilted element approximation is proposed. It is proven that this autofocusing algorithm is capable to deliver in-focus plane localization with submicron resolution. Second, we propose that wavefield summation for the generation of the LSF is carried out in Fourier space. It is shown that this scheme enables a significant reduction of arithmetic operations and can minimize the number of Fourier transforms needed. Hence, a fast generation of the LSF is possible without compromising its accuracy. The functionality of MIDHP for measuring surfaces with large gradients is supported by numerical and experimental results.


Feasibility of Surgeon-Delivered Audit and Feedback Incorporating Peer Surgical Coaching to Reduce Fistula Incidence following Cleft Palate Repair: A Pilot Trial.
Improving surgeons' technical performance may reduce their frequency of postoperative complications. The authors conducted a pilot trial to evaluate the feasibility of a surgeon-delivered audit and feedback intervention incorporating peer surgical coaching on technical performance among surgeons performing cleft palate repair, in advance of a future effectiveness trial. A nonrandomized, two-arm, unblinded pilot trial enrolled surgeons performing cleft palate repair. Participants completed a baseline audit of fistula incidence. Participants with a fistula incidence above the median were allocated to an intensive feedback intervention that included selecting a peer surgical coach, observing the coach perform palate repair, reviewing operative video of their own surgical technique with the coach, and proposing and implementing changes in their technique. All others were allocated to simple feedback (receiving audit results). Outcomes assessed were proportion of surgeons completing the baseline audit, disclosing their fistula incidence to peers, and completing the feedback intervention. Seven surgeons enrolled in the trial. All seven completed the baseline audit and disclosed their fistula incidence to other participants. The median baseline fistula incidence was 0.4 percent (range, 0 to 10.5 percent). Two surgeons were unable to receive the feedback intervention. Of the five remaining surgeons, two were allocated to intensive feedback and three to simple feedback. All surgeons completed their assigned feedback intervention. Among surgeons receiving intensive feedback, fistula incidence was 5.9 percent at baseline and 0.0 percent following feedback (adjusted OR, 0.98; 95 percent CI, 0.44 to 2.17). Surgeon-delivered audit and feedback incorporating peer coaching on technical performance was feasible for surgeons.


A DNA topoisomerase I inhibitor blocks the differentiation of rat granulosa cells induced by follicle-stimulating hormone.
Follicle-stimulating hormone (FSH), acting through a cycle AMP-mediated mechanism, promotes differentiation of rat granulosa cells cultured in a defined medium. Camptothecin, a DNA topoisomerase I blocker, inhibited the increase in progesterone and oestradiol production stimulated by FSH. This effect was not due to non-specific inhibition of protein synthesis, as shown by measurement of [35S]methionine incorporation. A transient increase in DNA topoisomerase I activity was observed after 24 h of culture in the presence of FSH or dibutyryl cyclic AMP. Our results are consistent with a key role for DNA topoisomerase I in the modulation of gene expression by FSH in rat granulosa cells.


Assessing Speech Discrimination in Individual Infants.
Assessing speech discrimination skills in individual infants from clinical populations (e.g., infants with hearing impairment) has important diagnostic value. However, most infant speech discrimination paradigms have been designed to test group effects rather than individual differences. Other procedures suffer from high attrition rates. In this study, we developed 4 variants of the Visual Habituation Procedure (VHP) and assessed their robustness in detecting individual 9-month-old infants' ability to discriminate highly contrastive nonwords. In each variant, infants were first habituated to audiovisual repetitions of a nonword (seepug) before entering the test phase. The test phase in Experiment 1 (extended variant) consisted of 7 old trials (seepug) and 7 novel trials (boodup) in alternating order. In Experiment 2, we tested 3 novel variants that incorporated methodological features of other behavioral paradigms. For the oddity variant, only 4 novel trials and 10 old trials were used. The stimulus alternation variant was identical to the extended variant except that novel trials were replaced with "alternating" trials-trials that contained repetitions of both the old and novel nonwords. The hybrid variant incorporated elements from both the oddity and the stimulus alternation variants. The hybrid variant proved to be the most successful in detecting statistically significant discrimination in individual infants (8 out of 10), suggesting that both the oddity and the stimulus alternation features contribute to providing a robust methodology for assessing discrimination in individual infants. In Experiment 3, we found that the hybrid variant had good test-retest reliability. Implications of these results for future infant speech perception work with clinical populations are discussed.


Magnetic resonance electrical impedance tomography (MREIT) for high-resolution conductivity imaging.
Cross-sectional imaging of an electrical conductivity distribution inside the human body has been an active research goal in impedance imaging. By injecting current into an electrically conducting object through surface electrodes, we induce current density and voltage distributions. Based on the fact that these are determined by the conductivity distribution as well as the geometry of the object and the adopted electrode configuration, electrical impedance tomography (EIT) reconstructs cross-sectional conductivity images using measured current-voltage data on the surface. Unfortunately, there exist inherent technical difficulties in EIT. First, the relationship between the boundary current-voltage data and the internal conductivity distribution bears a nonlinearity and low sensitivity, and hence the inverse problem of recovering the conductivity distribution is ill posed. Second, it is difficult to obtain accurate information on the boundary geometry and electrode positions in practice, and the inverse problem is sensitive to these modeling errors as well as measurement artifacts and noise. These result in EIT images with a poor spatial resolution. In order to produce high-resolution conductivity images, magnetic resonance electrical impedance tomography (MREIT) has been lately developed. Noting that injection current produces a magnetic as well as electric field inside the imaging object, we can measure the induced internal magnetic flux density data using an MRI scanner. Utilization of the internal magnetic flux density is the key idea of MREIT to overcome the technical difficulties in EIT. Following original ideas on MREIT in early 1990s, there has been a rapid progress in its theory, algorithm and experimental techniques. The technique has now advanced to the stage of human experiments. Though it is still a few steps away from routine clinical use, its potential is high as a new impedance imaging modality providing conductivity images with a spatial resolution of a few millimeters or less. This paper reviews MREIT from the basics to the most recent research outcomes. Focusing on measurement techniques and experimental methods rather than mathematical issues, we summarize what has been done and what needs to be done. Suggestions for future research directions, possible applications in biomedicine, biology, chemistry and material science are discussed.


Evaluation of the Cancer Council NSW Eat It To Beat It Healthy Lunch Box Sessions: A short intervention to promote the intake of fruit and vegetables among families of primary school children in NSW Australia.
Children and adults in Australia are not eating the recommended amounts of fruits and vegetables. Our objective was to assess the effectiveness of a health promotion intervention to improve fruit and vegetable intake among primary school children and their families in NSW. The Cancer Council New South Wales Healthy Lunch Box sessions were a 25-minute session delivered to parents of primary school-aged children. The sessions provided information and resources about fruit and vegetables and healthy school lunch boxes. The evaluation is a quantitative uncontrolled pre-post design. Data were collected using three questionnaires, pre-intervention, 1 week post-intervention and 6 months post-intervention. A total of 204 parents completed all three evaluation questionnaires to 6 months. Knowledge of recommended intakes and serving sizes of fruit and vegetables improved significantly after the intervention. There was an increase in parents reporting packing vegetables (often/always) in the child's lunch box at 1 week (47%) and 6 months post-intervention (40%) compared to pre-intervention (32%). The proportion of parents reporting that they were confident in packing a healthy lunch box increased from 45% pre-intervention to 62% after the intervention. The Healthy Lunch Box sessions were effective in improving parental knowledge and practices related to fruit and vegetables and parental confidence with packing a healthy lunch box. SO WHAT?: This short intervention could be a useful component of a portfolio of interventions to support parents with knowledge and resources to pack a healthy lunch box for their children.


Abdominal aortic aneurysms: endovascular repair.
Since its introduction 2 decades ago, endovascular repair of abdominal aortic aneurysms has continued to evolve, and many now consider it the optimal treatment modality for infrarenal abdominal aortic aneurysms. There are currently 5 commercially approved endografts, each with its unique design, and all can be utilized with excellent technical results. The endovascular repair is performed with radiographic guidance utilizing general, spinal, or local anesthesia. Endoleak is the most common complication and unique to the procedure. Routine postoperative surveillance imaging is essential to ensure long-term success. Clinical trials have demonstrated lower perioperative mortality and morbidity for endovascular repair of abdominal aortic aneurysms compared with open repair. However, evidence for long-term survival benefits is lacking. Furthermore, the benefits of endovascular repair in "high-risk" patients remain unclear. Though there is a subset of patients who benefit from endovascular repair of abdominal aortic aneurysms, objective identification of this population remains a challenge. Practitioners currently recommend elective repair for aneurysms > or = 5.5 cm in diameter and in selected patients with smaller aneurysms. Current studies are underway to evaluate the utility of endovascular repair in small aneurysms. Patients with ruptured aneurysms, due to the high morbidity and mortality associated with their management, may significantly benefit from endovascular repair. Although there is a lack of sufficient randomized controlled trial data, available evidence does support the use of endovascular repair for ruptured abdominal aortic aneurysms. Multiple newer endovascular devices are under clinical investigation to address the limitations of available devices. Ultimately, we may be able to treat the vast majority of patients with all types of abdominal and thoracoabdominal aortic aneurysms with endovascular devices. Mt Sinai J Med 77:238-249, 2010. (c) 2010 Mount Sinai School of Medicine.


Novel insights into the molecular pathogenesis of CYP4V2-associated Bietti's retinal dystrophy.
Bietti's crystalline dystrophy (BCD) is a rare, autosomal recessive retinal degenerative disease associated with mutations in CYP4V2. In this study, we describe the genetic and clinical findings in 19 unrelated BCD patients recruited from five international retinal dystrophy clinics. Patients underwent ophthalmic examinations and were screened for CYP4V2 mutations by Sanger sequencing and quantitative polymerase chain reaction (qPCR) copy number variation screening. Eight CYP4V2 mutations were found in 10/19 patients, including three patients in whom only monoallelic mutations were detected. Four novel mutations were identified: c.604G>A; p.(Glu202Lys), c.242C>G; p.(Thr81Arg), c.604+4A>G; p.(?), and c.1249dup; p.(Thr417Asnfs*2). In addition, we identified a heterozygous paternally inherited genomic deletion of at least 3.8 Mb, encompassing the complete CYP4V2 gene and several other genes, which is novel. Clinically, patients demonstrated phenotypic variability, predominantly showing choroidal sclerosis, attenuated vessels, and crystalline deposits of varying degrees of severity. To our knowledge, our study reports the first heterozygous CYP4V2 deletion and hence a novel mutational mechanism underlying BCD. Our results emphasize the importance of copy number screening in BCD. Finally, the identification of CYP4V2-negative patients with indistinguishable phenotypes from CYP4V2-positive patients might suggest the presence of mutations outside the coding regions of CYP4V2, or locus heterogeneity, which is unreported so far.


Time-dependent reorganization of the brain components underlying memory retention in trace eyeblink conditioning.
Many studies have confirmed the time-limited involvement of the hippocampus in mnemonic processes and suggested that there is reorganization of the responsible brain circuitry during memory consolidation. To clarify such reorganization, we chose trace classical eyeblink conditioning, in which hippocampal ablation produces temporally graded retrograde amnesia. Here, we extended the temporal characterization of retrograde amnesia to other regions that are involved in acquisition during this task: the medial prefrontal cortex (mPFC) and the cerebellum. At a various time interval after establishing the trace conditioned response (CR), rats received an aspiration of one of the three regions. After recovery, the animals were tested for their CR retention. When ablated 1 d after the learning, both the hippocampal lesion and the cerebellar lesion group of rats exhibited a severe impairment in retention of the CR, whereas the mPFC lesion group showed only a slight decline. With an increase in interval between the lesion and the learning, the effect of the hippocampal lesion diminished and that of the mPFC lesion increased. When ablated 4 weeks after the learning, the hippocampal lesion group exhibited as robust CRs as its corresponding control group. In contrast, the mPFC lesion and the cerebellar lesion groups failed to retain the CRs. These results indicate that the hippocampus and the cerebellum, but only marginally the mPFC, constitute a brain circuitry that mediates recently acquired memory. As time elapses, the circuitry is reorganized to use mainly the mPFC and the cerebellum, but not the hippocampus, for remotely acquired memory.


Integrated Telehealth and Telecare for Monitoring Frail Elderly with Chronic Disease.
Objective: To investigate the potential of an integrated care system that acquires vital clinical signs and habits data to support independent living for elderly people with chronic disease. Materials and Methods: We developed an IEEE 11073 standards-based telemonitoring platform for monitoring vital signs and activity data of elderly living alone in their home. The platform has important features for monitoring the elderly: unobtrusive, simple, elderly-friendly, plug and play interoperable, and self-integration of sensors. Thirty-six (36) patients in a primary care practice in the United Kingdom (mean [standard deviation] age, 82 [10] years) with congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD) were provided with clinical sensors to measure the vital signs for their disease (blood pressure [BP] and weight for CHF, and oxygen saturation for COPD) and one passive infrared (PIR) motion sensor and/or a chair/bed sensor were installed in a patient's home to obtain their activity data. The patients were asked to take one measurement each day of their vital signs in the morning before breakfast. All data were automatically transmitted wirelessly to the remote server and displayed on a clinical portal for clinicians to monitor each patient. An alert algorithm detected outliers in the data and indicated alerts on the portal. Patient data have been analyzed retrospectively following hospital admission, emergency room visit or death, to determine whether the data could predict the event. Results: Data of patients who were monitored for a long period and had interventions were analyzed to identify useful parameters and develop algorithms to define alert rules. Twenty of the 36 participants had a clinical referral during the time of monitoring; 16 of them received some type of intervention. The most common reason for intervention was due to low oxygen levels for patients with COPD and high BP levels for CHF. Activity data were found to contain information on the well-being of patients, in particular for those with COPD. During exacerbation the activity level from PIR sensors increased slightly, and there was a decrease in bed occupancy. One subject with CHF who felt unwell spent most of the day in the bedroom. Conclusions: Our results suggest that integrated care monitoring technologies have a potential for providing improved care and can have positive impact on well-being of the elderly by enabling timely intervention. Long-term BP and pulse oximetry data could indicate exacerbation and lead to effective intervention; physical activity data provided important information on the well-being of patients. However, there remains a need for better understanding of long-term variations in vital signs and activity data to establish intervention protocols for improved disease management.


DNA microarray profiling of genes differentially regulated by the histone deacetylase inhibitors vorinostat and LBH589 in colon cancer cell lines.
Despite the significant progress made in colon cancer chemotherapy, advanced disease remains largely incurable and novel efficacious chemotherapies are urgently needed. Histone deacetylase inhibitors (HDACi) represent a novel class of agents which have demonstrated promising preclinical activity and are undergoing clinical evaluation in colon cancer. The goal of this study was to identify genes in colon cancer cells that are differentially regulated by two clinically advanced hydroxamic acid HDACi, vorinostat and LBH589 to provide rationale for novel drug combination partners and identify a core set of HDACi-regulated genes. HCT116 and HT29 colon cancer cells were treated with LBH589 or vorinostat and growth inhibition, acetylation status and apoptosis were analyzed in response to treatment using MTS, Western blotting and flow cytometric analyses. In addition, gene expression was analyzed using the Illumina Human-6 V2 BeadChip array and Ingenuity Pathway Analysis. Treatment with either vorinostat or LBH589 rapidly induced histone acetylation, cell cycle arrest and inhibited the growth of both HCT116 and HT29 cells. Bioinformatic analysis of the microarray profiling revealed significant similarity in the genes altered in expression following treatment with the two HDACi tested within each cell line. However, analysis of genes that were altered in expression in the HCT116 and HT29 cells revealed cell-line-specific responses to HDACi treatment. In addition a core cassette of 11 genes modulated by both vorinostat and LBH589 were identified in both colon cancer cell lines analyzed. This study identified HDACi-induced alterations in critical genes involved in nucleotide metabolism, angiogenesis, mitosis and cell survival which may represent potential intervention points for novel therapeutic combinations in colon cancer. This information will assist in the identification of novel pathways and targets that are modulated by HDACi, providing much-needed information on HDACi mechanism of action and providing rationale for novel drug combination partners. We identified a core signature of 11 genes which were modulated by both vorinostat and LBH589 in a similar manner in both cell lines. These core genes will assist in the development and validation of a common gene set which may represent a molecular signature of HDAC inhibition in colon cancer.


Spirometry in 3- to 6-year-old children with cystic fibrosis.
Spirometry is routinely used to assess pulmonary function of older children and adults with cystic fibrosis (CF); however, few data exist concerning the preschool age group. We have reported normative spirometric data for 3- to 6-year-old children. The current study was designed to assess a similarly aged group of clinically stable patients with CF. Thirty-three of 38 children with CF were able to perform 2 or 3 technically acceptable maneuvers. These patients had significantly decreased FVC, FEV(1), FEV(1)/FVC, and FEF(25-75) when expressed as z scores (number of SD from predicted): -0.75 +/- 1.63, -1.23 +/- 1.97, -0.87 +/- 1.33, and -0.74 +/- 1.63, respectively. There were significant positive correlations of the Brasfield radiological score with FVC and FEV(1) z scores (r(2) = 0.26, p < 0.01 and r(2) = 0.24, p < 0.01). In addition, homozygous patients for the DeltaF508 mutation had lower z scores for FVC (-1.21 versus 0.47, p < 0.01) and FEV(1) (-1.38 versus 0.21, p < 0.05) than heterozygous patients. Of the 14 patients who had full flow-volume spirometric measurements during infancy, 10 had FEF(25-75) z scores greater than -2 at both evaluations. Our findings suggest that spirometry can successfully be used to assess lung function in preschool children with CF and has the potential for longitudinal assessment from infancy through adulthood.


Novel methods of targeted drug delivery: the potential of multifunctional nanoparticles.
Nanomaterials have been demonstrated as useful tools for molecular imaging, molecular diagnosis and targeted therapy in biomedical research. The main advantages of such nanomaterials are improved circulation times, precise targeting, enhancement of dissolution rates and enhanced contrast. A challenge and opportunity for nanotechnological strategies is that multiple functionalities, such as therapeutics, targeting, imaging and stimuli responsiveness can be achieved within one nanoparticle. Multifunctional nanoparticles are now actively under investigation and are imminent as the next generation of nanoparticles for providing custom and tailored treatment. This review considers contemporary approaches and possible future directions in the emerging area of multifunctional nanoparticles with a special focus on targeted drug delivery.


[Intraocular hemorrhage in a goat with thrombocytopenia and metastasis of an adenocarcinoma in the iris].
This case report describes the findings in a 10-year-old goat with metastasis of an adenocarcinoma in the iris. Two weeks before admission, the owner had noticed blepharospasm of the left eye. Clinical examination by the referring veterinarian revealed unilateral intraocular hemorrhage. The goat was referred to our clinic for further work-up. The rectal temperature was 40 degrees C. The most important haematological result was severe thrombocytopenia. There was mild corneal oedema of the left eye. Approximately 75 per cent of the anterior chamber was filled with non-coagulated blood. The fluid in the anterior chamber dorsal to the blood was cloudy, and the corpora nigra could not be seen clearly. All other internal parts of the eye could not be seen. Ultrasonography of the left eye confirmed cloudiness of the anterior chamber and revealed moderate thickening of the iris. The right prescapular lymph node was markedly enlarged. Cytological examination of a fine needle aspirate of the lymph node showed a mixed population of neoplastic cells. Based on immunohistochemical evaluation of the cells metastasis of a carcinoma was diagnosed. The goat was subjected to euthanasia, and a postmortem examination was carried out. The anterior chamber of the left eye contained blood, and the iris was thicker than normal and adhered to the posterior surface of the cornea. There were neoplastic alterations in the iris, the oesophagus, the lung lobes, the liver, the kidney and in the prescapular, retropharyngeal, mediastinal and hepatic lymph nodes. Histologically, a diagnosis of carcinoma was confirmed, but the origin of the tumour could not be determined.


A classification of response scale characteristics that affect data quality: a literature review.
Quite a lot of research is available on the relationships between survey response scales' characteristics and the quality of responses. However, it is often difficult to extract practical rules for questionnaire design from the wide and often mixed amount of empirical evidence. The aim of this study is to provide first a classification of the characteristics of response scales, mentioned in the literature, that should be considered when developing a scale, and second a summary of the main conclusions extracted from the literature regarding the impact these characteristics have on data quality. Thus, this paper provides an updated and detailed classification of the design decisions that matter in questionnaire development, and a summary of what is said in the literature about their impact on data quality. It distinguishes between characteristics that have been demonstrated to have an impact, characteristics for which the impact has not been found, and characteristics for which research is still needed to make a conclusion.


George David Pollock and the development of skin grafting.
George David Pollock, F.R.C.S., convinced the world of the efficacy of skin autografting and homografting. Previous studies on the priority of skin grafting are reviewed. The life of Pollock, including a glimpse of the surgical world of the Victorian era is described. A detailed analysis of the roles and relationships of Pollock, Reverdin, and Gosselin is given.


Multiple isomers of inositol pentakisphosphate in Epstein-Barr-virus- transformed (T5-1) B-lymphocytes. Identification of inositol 1,3,4,5,6-pentakisphosphate, D-inositol 1,2,4,5,6-pentakisphosphate and L-inositol 1,2,4,5,6-pentakisphosphate.
Substantial amounts of three [3H]InsP5 isomers were detected in [3H]inositol-labelled human lymphoblastoid (T5-1) cells. Their structures were determined by h.p.l.c. [Phillippy & Bland (1988) Anal. Biochem. 175, 162-166], and by utilizing a stereospecific D-inositol 1,2,4,5,6-pentakisphosphate 3-kinase from Dictyostelium discoideum [Stephens & Irvine (1990) Nature (London) 346, 580-583]. The structures were: inositol 1,3,4,5,6-pentakisphosphate, D-inositol 1,2,4,5,6-pentakisphosphate and L-inositol 1,2,4,5,6-pentakisphosphate. The relative proportions of these isomers (approx. 73:14:14 respectively) were unaffected by cross-linking anti-IgD receptors. The T5-1 cells also contained InsP6 and three Ins P4s, which were identified as the 1,3,4,5, 1,3,4,6 and 3,4,5,6 isomers. In incubations with permeabilized T5-1 cells, both 1,3,4,6 and 3,4,5,6 isomers of InsP4 were phosphorylated solely to Ins(1,3,4,5,6)P5. Permeabilized cells also dephosphorylated InsP6, even in the presence of a large excess of glucose 6-phosphate to saturate non-specific phosphatases. In the latter experiments the following isomers of InsP5 accumulated: D- and/or L-Ins(1,2,3,4,5)P5, plus D- and/or L-Ins(1,2,4,5,6)P5. This demonstration that multiple isomers of InsP5 may be formed in vivo and in vitro by a transformed lymphocyte cell line adds a new level of complexity to the study of inositol polyphosphate metabolism and function.


Pathogenesis of arrhythmias in a model of CKD.
Patients with CKD have an increased risk of cardiovascular mortality from arrhythmias and sudden cardiac death. We used a rat model of CKD (Cy/+) to study potential mechanisms of increased ventricular arrhythmias. Rats with CKD showed normal ejection fraction but hypertrophic myocardium. Premature ventricular complexes occurred more frequently in CKD rats than normal rats (42% versus 11%, P=0.18). By optical mapping techniques, action potential duration (APD) at 80% of repolarization was longer in CKD rats (78±4ms) than normal rats (63±3 ms, P<0.05) at a 200-ms pacing cycle length. Calcium transient (CaT) duration was comparable. Pacing cycle length thresholds to induce CaT alternans or APD alternans were longer in CKD rats than normal rats (100±7 versus 80±3 ms and 93±6 versus 76±4 ms for CaT and APD alternans, respectively, P<0.05), suggesting increased vulnerability to ventricular arrhythmia. Ventricular fibrillation was induced in 9 of 12 CKD rats and 2 of 9 normal rats (P<0.05); early afterdepolarization occurred in two CKD rats but not normal rats. The mRNA levels of TGF-β, microRNA-21, and sodium calcium-exchanger type 1 were upregulated, whereas the levels of microRNA-29, L-type calcium channel, sarco/endoplasmic reticulum calcium-ATPase type 2a, Kv1.4, and Kv4.3 were downregulated in CKD rats. Cardiac fibrosis was mild and not different between groups. We conclude that cardiac ion channel and calcium handling are abnormal in CKD rats, leading to increased vulnerability to early afterdepolarization, triggered activity, and ventricular arrhythmias.


Kinetics and thermodynamics of the formation of mixed micelles of egg phosphatidylcholine and bile salts.
The kinetics of dissolution of dispersions of egg phosphatidylcholine (lecithin) by bile salts was studied by observing the decrease in turbidity as mixed micelles of lecithin and bile salt were formed. The rate of dissolution of lecithin corresponding to the formation of mixed micelles was studied in the presence of dihydroxy bile salts, sodium deoxycholate, sodium chenodeoxycholate, sodium ursodeoxycholate, and one trihydroxy bile salt, sodium cholate. The rate of dissolution of lecithin and mixed micelle formation decreased in the order: chenodeoxycholate greater than deoxycholate greater than cholate greater than ursodeoxycholate. Kinetic solvent isotope studies in D2O, along with measurement of enthalpies of mixed micelle formation both in H2O and D2O, appear to indicate that the formation and stabilization of mixed micelles is related to "hydrophobicity" as estimated by high performance liquid chromatography retention factors.


Increased interleukin-1 (IL-1) and imbalance between IL-1 and IL-1 receptor antagonist during acute inflammation in experimental Shigellosis.
Infection by the enteric bacterial pathogen Shigella results in intense mucosal inflammation and destruction of the colonic and rectal epithelium in infected humans. Initial bacterial translocation occurs through the follicle-associated epithelium. Previous experiments suggest that interleukin-1 (IL-1) is crucial to trigger inflammation, particularly in the follicular zones. During the first 4 hours of infection in a rabbit ligated-loop model of intestinal invasion, there are two salient characteristics: (i) a high concentration of IL-1alpha and IL-1beta, both in infected Peyer's patch tissue and in the corresponding efferent mesenteric blood, and (ii) a very low level of expression of IL-1 receptor antagonist (IL-1ra). These may reflect a combination of regulation of expression and secretion of IL-1alpha, IL-1beta, and IL-1ra by both resident and recruited phagocytes and the induction of mononuclear phagocyte apoptosis by Shigella. This low IL-1ra/IL-1 ratio likely accounts for the rapid, uncontrolled inflammation characteristic of shigellosis.


Adjustment of occupational exposure limits for unusual work schedules.
A review of literature relating to the issue of adjustments of occupational exposure limits for unusual work shifts and unusual work schedules is described. The important issues relating to various adjustment models are discussed, and a number of conclusions are drawn. Tables of adjustment factors for 34 specific contaminants for 2 unusual schedules are given. A simple approach for use by industrial hygienists is proposed.


[Effects of an implicit internal working model on attachment in information processing assessed using Go/No-Go Association Task].
The purposes of the present study were (a) to use both a relational-anxiety Go/No-Go Association Task (GNAT) and an avoidance-of-intimacy GNAT in order to assess an implicit Internal Working Model (IWM) of attachment; (b) to verify the effects of both measured implicit relational anxiety and implicit avoidance of intimacy on information processing. The implicit IWM measured by GNAT differed from the explicit IWM measured by questionnaires in terms of the effects on information processing. In particular, in subliminal priming tasks involving with others, implicit avoidance of intimacy predicted accelerated response times with negative stimulus words about attachment. Moreover, after subliminally priming stimulus words about self, implicit relational anxiety predicted delayed response times with negative stimulus words about attachment.


Shaping appropriate locomotive motor output through interlimb neural pathway within spinal cord in humans.
Direct evidence supporting the contribution of upper limb motion on the generation of locomotive motor output in humans is still limited. Here, we aimed to examine the effect of upper limb motion on locomotor-like muscle activities in the lower limb in persons with spinal cord injury (SCI). By imposing passive locomotion-like leg movements, all cervical incomplete (n = 7) and thoracic complete SCI subjects (n = 5) exhibited locomotor-like muscle activity in their paralyzed soleus muscles. Upper limb movements in thoracic complete SCI subjects did not affect the electromyographic (EMG) pattern of the muscle activities. This is quite natural since neural connections in the spinal cord between regions controlling upper and lower limbs were completely lost in these subjects. On the other hand, in cervical incomplete SCI subjects, in whom such neural connections were at least partially preserved, the locomotor-like muscle activity was significantly affected by passively imposed upper limb movements. Specifically, the upper limb movements generally increased the soleus EMG activity during the backward swing phase, which corresponds to the stance phase in normal gait. Although some subjects showed a reduction of the EMG magnitude when arm motion was imposed, this was still consistent with locomotor-like motor output because the reduction of the EMG occurred during the forward swing phase corresponding to the swing phase. The present results indicate that the neural signal induced by the upper limb movements contributes not merely to enhance but also to shape the lower limb locomotive motor output, possibly through interlimb neural pathways. Such neural interaction between upper and lower limb motions could be an underlying neural mechanism of human bipedal locomotion.


Structural alteration in isolated rat liver nuclei after removal of template restriction by polyanions.
Specific polyanions release DNA template restrictions for DNA synthesis in isolated rat liver nuclei. The degree to which DNA synthesis is enhanced can be correlated with a spectrum of changes in nuclear structure Each polyanion which is effective in the release of template restriction produces a characteristic alteration in nuclear ultrastructure. Polyanions which have no effect on DNA synthesis do not appear to cause any change in nuclear organization or ultrastructure. Parallel measurements of nuclear DNA release and nuclear volume changes also indicate that template-activating polyanions cause remarkable changes in the structural organization of the treated nuclei. These results indicate that DNA template activation involves direct interactions between polyanions and nuclear constituents and suggest the possibility that naturally occurring polyanions might have a role in the control of gene activity


Cognition in pregnancy and motherhood: prospective cohort study.
Research has reported that pregnant women and mothers become forgetful. However, in these studies, women are not recruited prior to pregnancy, samples are not representative and studies are underpowered. The current study sought to determine whether pregnancy and motherhood are associated with brief or long-term cognitive deterioration using a representative sample and measuring cognition during and before the onset of pregnancy and motherhood. Women aged 20-24 years were recruited prospectively and assessed in 1999, 2003 and 2007. Seventy-six women were pregnant at follow-up assessments, 188 became mothers between study waves and 542 remained nulliparous. No significant differences in cognitive change were found as a function of pregnancy or motherhood, although late pregnancy was associated with deterioration on one of four tests of memory and cognition. The hypothesis that pregnancy and motherhood are associated with persistent cognitive deterioration was not supported. Previous negative findings may be a result of biased sampling.


Research output on primary care in Australia, Canada, Germany, the Netherlands, the United Kingdom, and the United States: bibliometric analysis.
To compare the volume and quality of original research in primary care published by researchers from primary care in the United Kingdom against five countries with well established academic primary care. Bibliometric analysis. United Kingdom, United States, Australia, Canada, Germany, and the Netherlands. Studies reviewed Research publications relevant to comprehensive primary care and authored by researchers from primary care, recorded in Medline and Embase, with publication dates 2001-7 inclusive. Volume of published activity of generalist primary care researchers and the quality of the research output by those publishing the most using citation metrics: numbers of cited papers, proportion of cited papers, and mean citation scores. 82,169 papers published between 2001 and 2007 in the six countries were classified as research on primary care. In a 15% pragmatic random sample of these records, 40% of research on primary care from the United Kingdom and 46% from the Netherlands was authored by researchers employed in a primary care setting or employed in academic departments of primary care. The 141 researchers with the highest volume of publications reporting research findings published between 2001 and 2007 (inclusive) authored or part authored 8.3% of the total sample of papers. For authors with the highest proportion of publications cited at least five times, the best performers came from the United States (n=5), United Kingdom (n=4), and the Netherlands (n=2). In the top 10 of authors with the highest proportions of publications achieving 20 or more citations, six were from the United Kingdom and four from the United States. The mean Hirsch index (measure of a researcher's productivity and impact of the published work) was 14 for the Netherlands, 13 for the United Kingdom, 12 for the United States, 7 for Canada, 4 for Australia, and 3 for Germany. This international comparison of the volume and citation rates of papers by researchers from primary care consistently placed UK researchers among the best performers internationally.


A clinical study to evaluate efficacy and safety of AHPL/AYTAB/0313 tablet in subjects suffering from osteoarthritis of knee(s).
Osteoarthritis (OA) is the most common form of arthritis with unsatisfactory treatment outcomes. To evaluate efficacy and safety of AHPL/AYTAB/0313 tablet in subjects with OA of knee joint. Prospective, open-label, single-arm clinical study conducted in daily clinical practice setting. Subjects were advised to take 2 AHPL/AYTAB/0313 tablets twice daily orally after meals for 180 days. 48 subjects completed the study. The primary endpoints were changes in mean visual analogue scale (VAS) pain score and WOMAC score. Secondary endpoints were quality of life, time to walk 50 feet, knee joint swelling, use of analgesic drug as rescue medicine, and safety parameters. At baseline visit, the mean index knee joint pain (VAS) score was 82.29 ± 15.19, which reduced significantly to 19.38 ± 13.75 on day 180. The mean WOMAC combined score at baseline was 39.94 ± 11.67, which reduced significantly to 09.58 ± 05.77 (76.0%) on day 180. The mean WOMAC pain score at baseline was 09.65 ± 02.91, which reduced significantly to 02.06 ± 01.46 on day 180. The mean WOMAC stiffness score at baseline was 03.48 ± 01.58, which reduced significantly to 00.63 ± 01.08 on day 180. The mean WOMAC difficulty score at baseline was 26.81 ± 09.63, which reduced significantly to 06.90 ± 04.78 on day 180. The mean walking time to walk 50 feet reduced significantly by 40% on day 180. Not a single subject was known to have knee joint swelling from 150 days onwards. Only 5 subjects were using analgesic as rescue medicine on day 180. Twenty-six subjects had adverse events (AEs). Most of the AEs were not associated with the study medication. Vitals and all the safety laboratory parameters were within normal limits both at baseline and on day 180. "AHPL/AYTOP/0113" tablet is safe and significantly effective in reducing pain, swelling, and stiffness of knee joints and improving mobility of knee joints in patients with OA. CTRI registration No. is CTRI/2015/09/006177.


Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke.
Deferoxamine (DFO) is a high-affinity iron chelator approved by the Food and Drug Administration for treating iron overload. Preclinical research suggests that systemically administered DFO prevents and treats ischemic stroke damage and intracerebral hemorrhage. However, translation into human trials has been limited, probably because of difficulties with DFO administration. A noninvasive method of intranasal administration has emerged recently as a rapid way to bypass the blood-brain barrier and target therapeutic agents to the central nervous system. We report here that intranasal administration targets DFO to the brain and reduces systemic exposure, and that intranasal DFO prevents and treats stroke damage after middle cerebral artery occlusion (MCAO) in rats. A 6-mg dose of DFO resulted in significantly higher DFO concentrations in the brain (0.9-18.5 microM) at 30 min after intranasal administration than after intravenous administration (0.1-0.5 microM, p < 0.05). Relative to blood concentration, intranasal delivery increased targeting of DFO to the cortex approximately 200-fold compared with intravenous delivery. Intranasal administration of three 6-mg doses of DFO did not result in clinically significant changes in blood pressure or heart rate. Pretreatment with intranasal DFO (three 6-mg doses) 48 h before MCAO significantly decreased infarct volume by 55% versus control (p < 0.05). In addition, post-treatment with intranasal administration of DFO (six 6-mg doses) immediately after reperfusion significantly decreased infarct volume by 55% (p < 0.05). These experiments suggest that intranasally administered DFO may be a useful treatment for stroke, and a prophylactic for patients at high risk for stroke.


Support to address barriers to learning for learners who are deaf.
There is great importance in support services for successfully addressing the barriers to learning optimally or learners who are deaf. The study, though conducted in South Africa, has national and international appeal. The aim of the study was to identify educator reflections on support services needed for them to address barriers to learning of learners who are deaf. The study used a qualitative design for collecting data in natural settings. A sample size of 11 educators of learners who are deaf was purposively selected from two provinces of South Africa. The study used an open ended individual interview questionnaire. Data was analysed using qualitative content analysis considering the context of the schools in which the study was carried out. Results showed that there was: limited curriculum support in special schools; lack of support and inadequate teaching and learning materials; overcrowding in one school and; limited support of multidisciplinary professionals in most schools. The study provided a framework for support services important for research, policy and practice. Of significance was the relevance of the Universal Design for Learning (UDL) theoretical framework in implementing support services programmes in schools.


Sex differences in the sympathoexcitatory response to insulin in obese rats: role of neuropeptide Y.
Intracerebroventricular insulin increased sympathetic nerve activity (SNA) and baroreflex control of SNA and heart rate more dramatically in obese male rats; in obese females, the responses were abolished. In obese males, the enhanced lumbar SNA (LSNA) responses were associated with reduced tonic inhibition of LSNA by neuropeptide Y (NPY) in the PVN. However, PVN NPY injection decreased LSNA similarly in obesity prone/obesity resistant/control rats. Collectively, these results suggest that NPY inputs were decreased. In obese females, NPY inhibition in the PVN was maintained. Moreover, NPY neurons in the arcuate nucleus became resistant to the inhibitory effects of insulin. A high-fat diet did not alter arcuate NPY neuronal InsR expression in males or females. Obesity-induced 'selective sensitization' of the brain to the sympathoexcitatory effects of insulin and leptin may contribute to elevated basal SNA, and therefore hypertension development, in males with obesity. These data may explain in part why obesity increases SNA less in women compared to men. Obesity increases sympathetic nerve activity (SNA) in men but not women; however, the mechanisms are unknown. We investigated whether intracerebroventricular insulin infusion increases SNA more in obese male than female rats and if sex differences are mediated by changes in tonic inhibition of SNA by neuropeptide Y (NPY) in the paraventricular nucleus (PVN). When consuming a high-fat diet, obesity prone (OP) rats accrued excess fat, whereas obesity resistant (OR) rats maintained adiposity as in rats eating a control (CON) diet. Insulin increased lumbar SNA (LSNA) similarly in CON/OR males and females under urethane anaesthesia. The LSNA response was magnified in OP males but abolished in OP females. In males, blockade of PVN NPY Y1 receptors with BIBO3304 increased LSNA in CON/OR rats but not OP rats. Yet, PVN nanoinjections of NPY decreased LSNA similarly between groups. Thus, tonic PVN NPY inhibition of LSNA may be lost in obese males as a result of a decrease in NPY inputs. By contrast, in females, PVN BIBO3304 increased LSNA similarly in OP, OR and CON rats. After insulin, PVN BIBO3304 failed to increase LSNA in CON/OR females but increased LSNA in OP females, suggesting that with obesity NPY neurons become resistant to the inhibitory effects of insulin. These sex differences were not associated with changes in arcuate NPY neuronal insulin receptor expression. Collectively, these data reveal a marked sex difference in the impact of obesity on the sympathoexcitatory actions of insulin and implicate sexually dimorphic changes in NPY inhibition of SNA in the PVN as one mechanism.


Potential of E3 Ubiquitin Ligases in Cancer Immunity: Opportunities and Challenges.
Cancer immunotherapies, including immune checkpoint inhibitors and immune pathway-targeted therapies, are promising clinical strategies for treating cancer. However, drug resistance and adverse reactions remain the main challenges for immunotherapy management. The future direction of immunotherapy is mainly to reduce side effects and improve the treatment response rate by finding new targets and new methods of combination therapy. Ubiquitination plays a crucial role in regulating the degradation of immune checkpoints and the activation of immune-related pathways. Some drugs that target E3 ubiquitin ligases have exhibited beneficial effects in preclinical and clinical antitumor treatments. In this review, we discuss mechanisms through which E3 ligases regulate tumor immune checkpoints and immune-related pathways as well as the opportunities and challenges for integrating E3 ligases targeting drugs into cancer immunotherapy.


Improvements in heart rate variability with exercise therapy.
Heart rate variability (HRV) is a noninvasive, practical and reproducible measure of autonomic nervous system function. A heart rate that is variable and responsive to demands is believed to bestow a survival advantage, whereas reduced HRV may be associated with poorer cardiovascular health and outcomes. In recent years, many researchers have investigated the prognostic implications of HRV in a variety of clinical populations. Evidence suggests that reduced HRV has prognostic significance for individuals with myocardial infarction, chronic heart failure, unstable angina and diabetes mellitus. Interventions to increase HRV, such as exercise therapy, have also been examined. The findings of the present review suggest that exercise therapy may improve HRV in myocardial infarction, chronic heart failure and revascularization patients by increasing vagal tone and decreasing sympathetic activity. One hypothesis is that a shift toward greater vagal modulation may positively affect the prognosis of these individuals. While the underlying mechanisms by which exercise training improves vagal modulation are speculative at present, angiotensin II and nitric oxide may be potential mediators.


Veterans with poor PTSD treatment adherence: Exploring their loved ones' experience of PTSD and understanding of PTSD treatment.
Trauma-focused psychotherapies such as cognitive processing therapy (CPT) and prolonged exposure (PE) are some of the most effective treatments available for posttraumatic stress disorder (PTSD). These treatments have been widely disseminated and promoted throughout the VA Health care System. However, adherence to and completion of these protocols among veterans is often poor, resulting in diminished impact. "Support persons" (SPs) such as relatives and close friends may provide a source of emotional or practical support in treatment, but little is known about how SPs are involved in or exposed to treatment principles and activities. The primary goal of the current research was to examine the experience of SPs of veterans who had poor adherence to treatment. We were interested in SPs' knowledge about the treatment, their level of involvement in treatment activities or sessions, and their potential interest in more participation or education. Qualitative analyses were used to examine data collected from interviews with 19 SPs of veterans who had an unsuccessful course of CPT or PE. Results indicated generally very low levels of knowledge and treatment participation. However, among most SPs there was substantial interest in the possibility of more treatment involvement, particularly in order to receive guidance from the clinician about how to respond to the veteran's symptoms. We suggest that it is possible and desirable to incorporate loved ones more formally into such protocols. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


A molecular phylogeny of the tiger beetles (Cicindelidae): congruence of mitochondrial and nuclear rDNA data sets.
As a basis for comparative studies in the family Cicindelidae (tiger beetles), a phylogenetic hypothesis for major groups was established based on molecular data, focusing on the taxa of the New World. Two markers, mitochondrial 16S rRNA and nuclear 18S rRNA, were sequenced for a total of 912 nucleotides and 30 taxa. All Cicindelidae were inferred to be a monophyletic group by the presence of a segment in the 5' region of the 18S rDNA which is predicted to fold into a single stem-loop structure not present in the outgroup. The total number of variable and potentially informative positions was smaller in the 18S data set, but their higher internal consistency resulted in a strong phylogenetic signal. Inferred relationships were stable over a wide range of alignment parameters, but the inclusion of alignment-sensitive positions and presumptive gap characters added substantially to the resolution and overall support of the tree. Both data sets were in general congruence. The combined evidence suggests that relationships in Cicindelidae as currently recognized have to be reconsidered. No convincing evidence could be found for the traditional subdivision into two subfamilies, Cicindelinae and Collyrinae. The latter is embedded within the Cicindelinae and clearly not the sister to all other cicindelids. Most of the current tribes and subtribes, particularly in the Megacephalini, are paraphyletic groups, whereas monophyly of the large tribe Cicindelini is well supported by the molecular data.


Aminoglycoside antibiotics and lysosomal enzymes of human tears.
We examined biochemically the effect of six aminoglycoside antibiotics on the activity of lysozyme, acid phosphatase, and N-acetyl-beta-D-glucosaminidase in human tears. All six antibiotics strongly inhibited lysozyme activity, the degree of inhibition depending on the dose administered. Except for bekanamycin, antibiotics had little effect on the activity of acid phosphatase or N-acetyl-beta-D-glucosaminidase. The nature of the inhibition was competitive. Other kinds of antibiotics, such as sulbenicillin or erythromycin, had no inhibitory effect on lysozyme, acid phosphatase, or N-acetyl-beta-D-glucosaminidase. These results suggested that the inhibition of lysozyme by aminoglycosides is specific and that the decreased effectiveness of a protective system against bacterial infection in the eye is highly possible when aminoglycoside antibiotics are used without prior sensitivity testing.


Sex and Age Impact CD4+ T Cell Susceptibility to HIV In Vitro through Cell Activation Dynamics.
Cellular composition and the responsiveness of the immune system evolve upon aging and are influenced by biological sex. CD4+ T cells from women living with HIV exhibit a decreased viral replication ex vivo compared to men's. We, thus, hypothesized that these findings could be recapitulated in vitro and infected primary CD4+ T cells with HIV-based vectors pseudotyped with VSV-G or HIV envelopes. We used cells isolated from twenty donors to interrogate the effect of sex and age on permissiveness over a six-day activation kinetics. Our data identified an increased permissiveness to HIV between 24 and 72 h post-stimulation. Sex- and age-based analyses at these time points showed an increased susceptibility to HIV of the cells isolated from males and from donors over 50 years of age, respectively. A parallel assessment of surface markers' expression revealed higher frequencies of activation marker CD69 and of immune checkpoint inhibitors (PD-1 and CTLA-4) in the cells from highly permissive donors. Furthermore, positive correlations were identified between the expression kinetics of CD69, PD-1 and CTLA-4 and HIV expression kinetics. The cell population heterogeneity was assessed using a single-cell RNA-Seq analysis and no cell subtype enrichment was identified according to sex. Finally, transcriptomic analyses further highlighted the role of activation in those differences with enriched activation and cell cycle gene sets in male and older female cells. Altogether, this study brought further evidence about the individual features affecting HIV replication at the cellular level and should be considered in latency reactivation studies for an HIV cure.


Inferring Active Metabolic Pathways from Proteomics and Essentiality Data.
Here, we propose an approach to identify active metabolic pathways by integrating gene essentiality analysis and protein abundance. We use two bacterial species (Mycoplasma pneumoniae and Mycoplasma agalactiae) that share a high gene content similarity yet show significant metabolic differences. First, we build detailed metabolic maps of their carbon metabolism, the most striking difference being the absence of two key enzymes for glucose metabolism in M. agalactiae. We then determine carbon sources that allow growth in M. agalactiae, and we introduce glucose-dependent growth to show the functionality of its remaining glycolytic enzymes. By analyzing gene essentiality and performing quantitative proteomics, we can predict the active metabolic pathways connected to carbon metabolism and show significant differences in use and direction of key pathways despite sharing the large majority of genes. Gene essentiality combined with quantitative proteomics and metabolic maps can be used to determine activity and directionality of metabolic pathways.