HapHop-Physio: a computer game to support cognitive therapies in children.
Care and support of children with physical or mental disabilities are accompanied with serious concerns for parents, families, healthcare institutions, schools, and their communities. Recent studies and technological innovations have demonstrated the feasibility of providing therapy and rehabilitation services to children supported by computer games. The aim of this paper is to present HapHop-Physio, an innovative computer game that combines exercise with fun and learning, developed to support cognitive therapies in children. Conventional software engineering methods such as the Scrum methodology, a functionality test and a related usability test, were part of the comprehensive methodology adapted to develop HapHop-Physio. The game supports visual and auditory attention therapies, as well as visual and auditory memory activities. The game was developed by a multidisciplinary team, which was based on the Hopscotch® platform provided by Fraunhofer Institute for Digital Media Technology IDMT Institute in Germany, and designed in collaboration with a rehabilitation clinic in Colombia. HapHop-Physio was tested and evaluated to probe its functionality and user satisfaction. The results show the development of an easy-to-use and funny game by a multidisciplinary team using state-of-the-art videogame technologies and software methodologies. Children testing the game concluded that they would like to play again while undergoing rehabilitation therapies.


In vivo zinc transport by rat small intestine after extensive small bowel resection.
We studied the effects of intestinal resection on in vivo zinc transport and intestinal tissue zinc in remnant duodenum and ileum 4 wk after two-thirds small bowel enterectomy. In situ duodenal and ileal intestinal segments from resected and sham-operated control rats were perfused through the lumen with an isotonic solution containing 0.077 mM zinc with isotopic 65Zn as tracer. After resection there was significant mucosal growth in both segments, but segment transport specific activities (transport per gram mucosa) were unchanged. Therefore, increased segment transport capacities (transport per centimeter segment length) in both segments approximated increased mucosal mass. Comparisons with transport data from our earlier studies on other luminal substrates in rats after small bowel resection showed that adaptive transport mechanisms vary not only with the luminal substrate examined but may also differ in remaining proximal and distal small bowel. In the present study about 12% of the absorbed radiotracer zinc remained in the intestinal wall after perfusion of both duodenum and ileum of resected and control animals, and there were no effects of resection on tissue radiotracer 65Zn concentrations or specific activities in the mucosal fraction or underlying tissues. Calculations of mucosal entry and exit fluxes per centimeter segment length showed that the major effect of resection was to increase the zinc entry flux at the luminal surface of the mucosa. At the basal surface of the mucosa, both entry and exit fluxes increased.(ABSTRACT TRUNCATED AT 250 WORDS)


Inhibiting Wipf2 downregulation by transgenic expression of its 3' mRNA-untranslated region improves cytotoxicity and vaccination response.
Lymphocyte activation results in profound changes in the abundance of mRNA transcripts many of which are downregulated. The Wiskott-Aldrich syndrome (WAS) protein (WASP) family is critical for productive T-cell receptor signaling and actin reorganization. The WASP signal pathway includes the WAS/WAS-like (WASL) interacting protein family 2 (WIPF2) gene also known as WIRE/WICH. We show that both human WIPF2 and mouse Wipf2 are mice, alternatively spliced within the 3' untranslated region (3'UTR) resulting in two major transcripts of approximately 4.5 and 6 kb in size. Following T-cell activation, the level of human WIPF2 and mouse Wipf2 mRNA rapidly declines. In mice, this decline is accompanied by a marked reduction in WIPF2 protein levels. Transgenic expression of a 240-bp fragment derived from a highly conserved terminal 3'UTR found within the 6-kb transcript blocks Wipf2 downregulation. These effects may be mediated by competitive inhibition of microinhibitory RNA (miRNA) regulation since the 6-kb-derived transgene and the 4.5-kb transcript share functional binding sites for miRNA146a. Blocking Wipf2 gene and protein repression resulted in improved T-cell responses to antigen immunization in vivo as well as in vitro cytotoxic T-cell killing. Collectively, these data suggest that early downregulation of this immunologically relevant gene controls the intensity of selective lymphocyte functions.


Studies on the development of ornithine-keto acid aminotransferase activity in rat liver.
1. During the normal development of the rat, the specific activity of liver ornithine-keto acid aminotransferase exhibits a transient elevation around term, and subsequently increases to adult activity levels during the third postnatal week. 2. The synthetic glucocorticoid triamcinolone, administered as a single injection, produces a marked elevation of the ornithine-keto acid aminotransferase activity within 24hr. if given postnatally before the natural increase in ornithine-keto acid aminotransferase activity has occurred. In foetal and adult animals, triamcinolone does not induce any increase in this enzyme activity. 3. The repeated administration of puromycin completely prevents the rise in ornithine-keto acid aminotransferase activity that follows triamcinolone administration. 4. If adult rats are fed with a protein-free carbohydrate diet, or one free of arginine, the ornithine-keto acid aminotransferase activity diminishes to a fraction of the normal. When such diets are given, a single injection of triamcinolone does not increase the enzyme activity within 24hr. 5. Partial hepatectomy, and repeated injections of growth hormone, depress the ornithine-keto acid aminotransferase activity in adult rats. 6. The findings are discussed in relation to the mechanisms concerned with developmental and adaptive changes in enzyme activities in the liver.


Enhancement of the hypothermic response of mice to delta-9-tetrahydrocannabinol by subhypothermic doses of chlorpromazine and phentolamine.
Pretreatment with subhypothermic doses of chlorpromazine, given directly into the IIIrd cerebral ventricle via a chronically implanted cannula (50 micrograms) or subcutaneously (0.75 mg/kg), was found to enhance the hypothermic response to delta-9-tetrahydrocannabinol (THC: 5 20 mg/kg i.p.) in unrestrained adult male MF1 mice, kept at 22 degrees C. Subcutaneous pretreatment with a subhypothermic dose of phentolamine (30 mg/kg) had a similar effect, whereas pretreatment with desipramine (10 mg/kg s.c.), mepyramine (2.3 and 11.5 mg/kg s.c.), methysergide (2 mg/kg s.c.), pimozide (1 and 5 mg/kg s.c.) or lignocaine (50 mg/kg s.c.), had no effect. Intracerebroventricular pretreatment with phentolamine was also without effect and it is concluded that this drug interacts with THC at some site located outside the brain. Since, in mg/kg terms, chlorpromazine was more potent in enhancing THC-induced hypothermia when given subcutaneously than when injected into the IIIrd ventricle, it too may interact with THC at a peripheral site. Indeed, chlorpromazine and phentolamine may both increase the hypothermic response to THC by antagonizing alpha-adrenoceptors on cutaneous blood vessels, thereby decreasing the capacity of animals to minimise peripheral blood flow by vasoconstriction. Alternatively, since the distribution of chlorpromazine within the brain may well have been less efficient after intraventricular than after subcutaneous injection, the possibility remains that chlorpromazine interacted centrally with THC.


Generation and immunogenicity of a recombinant pseudorabies virus expressing cap protein of porcine circovirus type 2.
Porcine circovirus type 2 (PCV2) is associated with post-weaning multisystemic wasting syndrome (PMWS), which is an important economical disease affecting the pig industry worldwide. In order to develop an effective vaccine for PMWS, a recombinant pseudorabies virus (PRV) was generated and tested in piglets in this study. The PCV2 open reading frame 2 (ORF2) gene was inserted into pIECMV plasmid and co-transfected with PRV Tk-/gE-/LacZ+ genome into IBRS-2 cells to generate a recombinant Tk-/gE-/ORF2(+) virus. The expression of PCV2 ORF2 gene in the recombinant virus was confirmed by Western blotting and indirect immunofluorescence assay (IFA). Four-week-old piglets were immunized by the recombinant virus, and the immunogenicity of PRV Tk-/gE-/ORF2(+) was tested by PRV-enzyme-linked immunosorbent assay (ELISA), PRV neutralizing assay, ORF2-ELISA and ORF2 specific lymphocyte proliferation response. PRV Tk-/gE-/ORF2(+) elicited significant humoral immune responses to both PRV and PCV2, and the PCV2-specific lymphocyte proliferation response could be detected on day 49 of this experiment. These findings suggest that the recombinant PRV Tk-/gE-/ORF2(+) may be a potential vaccine against both PCV2 and PRV.


Prevention of renal failure in Chinese patients with newly diagnosed type 2 diabetes: A cost-effectiveness analysis.
Diabetic kidney disease (DKD) is the second leading cause (16.4%) of end-stage renal disease in China. The current study assessed the cost-effectiveness of preventing DKD in patients with newly diagnosed type 2 diabetes from the Chinese healthcare perspective. A lifetime Markov decision model was developed according to the disease course of DKD. Patients with newly diagnosed type 2 diabetes might receive treatment according to one of the following three strategies: (i) "do nothing" strategy (control strategy); (ii) treatment with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (universal strategy); (iii) or screening for microalbuminuria followed by angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker treatment (screening strategy). Clinical and utility data were obtained from the published literature. Direct medical costs and resource utilization in the Chinese healthcare setting were considered. Sensitivity analyses were undertaken to test the impact of a range of variables and assumptions on the results. Compared with the control strategy, both the screening and universal strategies were cost-saving options that showed lower costs and better health benefits. The incremental cost-effectiveness ratio of the universal strategy over the screening strategy was US $30,087 per quality-adjusted life-year, which was higher than the cost-effectiveness threshold of China. The sensitivity analyses showed robust results, except for the probability of developing macroalbuminuria from microalbuminuria. Screening for microalbuminuria could be a cost-saving option for the prevention of DKD in the Chinese setting.


Serotonin levels in aqueous humor of patients with primary open-angle glaucoma.
Glaucoma is an optic neuropathy characterized by a high intraocular pressure (IOP), alterations in optic nerve head, and loss of visual field that could lead to bilateral blindness. Serotonin (5-HT) is a biogenic monoamine that is synthesized from hydroxylation of tryptophan and acts by three ways, dissemination, metabolism, and reuptake in synaptic cleft through specific systems of the membrane. The purpose of this study is to evaluate the 5-HT and 5-HIAA (5-hydroxiindolacetic acid) levels in the aqueous humor of patients with primary open-angle glaucoma (POAG). We performed a case-control study, and the patients recruited were classified into two groups, 1) 30 patients with POAG (GG) and 2) 30 patients with cataracts (CG), who acted as the controls. Aqueous humor samples of each patient were obtained by paracentesis at the beginning of the surgical procedures. 5-HT and 5-HIAA levels were determined by high performance liquid chromatography (HPLC) with electrochemical detection. There were no statistical differences between age (71.3 +/- 7.2 years in GG, 73.5 +/- 9.0 years in CG; p=0.2581) or gender (sex ratio 0.765 in GG and 0.667 in CG). 5-HT levels were lower in GG, but this difference was not significant (p=0.820). We observed a statistically significant higher level of 5-HIAA in GG (p=0.001). The 5-HT turnover (5-HIAA/5-HT) were higher in GG than in CG (p<0.05), but the difference was not significant (p=0.598). The level of 5-HT was lower in GG patients, and the level of 5-HIAA was higher in GG patients than in CG patients.


Pathophysiological aspects of myocardial hypertrophy.
Heart hypertrophy in response to increased workload is a complex process in which this organ adapts to the environment by increasing the muscle mass in terms of additional contractile units and formation of different types of contractile proteins (myosin isozymes). In addition, augmentation of membrane function with respect to calcium transport activities of sarcolemma and sarcoplasmic reticulum occurs at early stages of cardiac hypertrophy associated with hyperfunction of the myocardium. However, if cardiac hypertrophy is left unattended beyond a certain period, physiological hypertrophy is converted to pathological hypertrophy whereby the cardiac muscle is unable to generate an adequate amount of contractile activity. It appears that the sympathetic nervous system is activated for producing beneficial effects at early stages but an elevated level of sympathetic tone for a prolonged period could result in dysfunction of the cardiac muscle. The transition of physiological hypertrophy to pathological hypertrophy seems to be due to the occurrence of intracellular calcium overload in the myocardial cell as a consequence of defects in the membrane calcium transport systems. It is suggested that careful attention should be paid not only to removal of the stimulus responsible for cardiac hypertrophy but also to lowering sympathetic tone. Efforts should also be made to prevent the occurrence of intracellular calcium overload due to membrane defects.


Disproportionate longer-term opioid use among U.S. adults with mood disorders.
Adults with mood disorders frequently use prescription opioids. The factors associated with this increased use remain unclear. We used the Medical Expenditure Panel Surveys from 2005 to 2011 to measure the association of mood disorders with new opioid use and the transition to longer-term opioid use for a variety of pain conditions before and after controlling for patient characteristics and clinical disability. We analyzed 33,450 adults with likely acute or potentially chronic pain conditions who were not using opioids at baseline. Among respondents with likely acute pain conditions, those with mood disorders initiated opioids more frequently for that pain condition compared with those without mood disorders (19.3%, vs 17.2%, P = 0.01). After initiation, they also transitioned to longer-term opioid therapy more frequently (11.7% vs 5.3%, P < 0.01). Among respondents with potentially chronic pain conditions, adults with mood disorders initiated opioid therapy more frequently for their chronic pain condition (11.5% vs 9.2%, P < 0.01) and transitioned to longer-term therapy more frequently (36.8% vs 19.9%, P < 0.01). After adjusting for sociodemographics and clinical disability, there was no association between mood disorders and new opioid use for likely acute (adjusted odds ratio [aOR] 1.05 [0.92-1.20]) or potentially chronic pain (aOR 0.91 [0.80-1.03]). However, there remained a strong association between mood disorders and the transition to longer-term opioid use for likely acute (aOR 1.77 [1.15-2.72]) and potentially chronic pain (aOR 1.95 [1.42-2.68]). Targeting the transition to longer-term opioid use may help clinicians reduce potentially inappropriate opioid prescriptions in this high-risk population.


Cross-Sectional and Longitudinal Effects of CREB1 Genotypes on Individual Differences in Memory and Executive Function: Findings from the BLSA.
Purpose: Previously, we have shown that the SNP rs10932201 genotype of the cyclic AMP responsive element binding protein 1 gene (CREB1) contributes to individual differences in executive and memory function at the neural system and behavioral levels in healthy, young adults. However, longitudinal effects of CREB1 genotypes on cognition have not yet been addressed. Furthermore we were interested in replicating associations between CREB1 genotypes and human cognition in previous cross-sectional studies and explore whether APOE𝜀4 status might modify these relations. Materials and Methods: We investigated whether common, independent tag SNPs within CREB1 (rs2253206, rs10932201, rs6785) influence individual differences in age-related longitudinal change and level of executive function and memory performance independent of baseline age, sex, APOE𝜀4 status, and education. Our analysis included data from cognitively unimpaired older adults participating in the Baltimore Longitudinal Study of Aging. Eleven measures from six cognitive tests (sample sizes range 617-786) were analyzed using linear mixed effects and generalized estimating equations models. Mean baseline age ranged from 50 to 69 years and mean time of follow-up (interval) ranged from 8 to 22 years. Results: We found significant effects of all three CREB1 SNPs on performance level and/or longitudinal change in performance based on eight measures assessing semantic memory, episodic memory, or both executive function and semantic memory. SNP rs10932201 showed the most significant and largest effect (Cohen's d = -0.70, p < 0.01) on age-related longitudinal decline of semantic memory. Additionally, we show interactions between all three CREB1 SNPs and APOE𝜀4 status on age-related longitudinal declines and levels of memory and executive function. Conclusion: Our results suggest that CREB1 genotypes independently and by interactions with APOE𝜀4 status contribute to individual differences in cognitive aging.


Fractional-Fourier-transform calculation through the fast-Fourier-transform algorithm.
A method for the calculation of the fractional Fourier transform (FRT) by means of the fast Fourier transform (FFT) algorithm is presented. The process involves mainly two FFT's in cascade; thus the process has the same complexity as this algorithm. The method is valid for fractional orders varying from -1 to 1. Scaling factors for the FRT and Fresnel diffraction when calculated through the FFT are discussed.


Oligoclonal restriction of antiviral immunoreaction in oligoclonal band-negative MS patients.
Presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a diagnostic hallmark of multiple sclerosis (MS). However, up to 10% of patients were OCB negative in routine laboratory tests. The aim of this study was to determine whether there is at least an oligoclonal restriction of intrathecal antibody synthesis against measles, rubella and/or varicella zoster virus (MRZ-specific OCB) in CSF from oligoclonal bands-negative patients with MS. CSF and serum samples from 17 well-defined OCB-negative patients with MS were analysed for MRZ-specific OCB. We performed isoelectric focusing (IEF) combined with affinity blotting using viral antigens, detection with a highly sensitive chemiluminescence technique and recording with X-ray films. Controls included 18 OCB-positive patients with MS and 11 patients with pseudotumor cerebri (PTC). Exclusive or predominant MRZ-specific OCB in CSF against at least one virus species were present in 8 of 17 patients with MS (47.1%; P = 0.0422), suggesting an oligoclonal intrathecal immune response, although OCB of total IgG were absent. Only a very weak oligoclonal reaction against varicella zoster virus in CSF from one of the PTC controls was detectable. Thirteen of 18 (72.2%; P = 0.0013) OCB-positive patients with MS showed also MRZ-specific oligoclonal bands against at least 1 neurotropic virus in CSF. MRZ-specific OCB argue for existence of a chronic intrathecal immune reaction also in routine laboratory-OCB-negative patients with MS. This phenomenon reflects oligoclonal restriction of the humoral immunoreaction as well as polyspecific intrathecal antibody synthesis, which are both characteristics in the chronic inflammatory process of MS.


Nucleosome organizations in induced pluripotent stem cells reprogrammed from somatic cells belonging to three different germ layers.
Nucleosome organization determines the chromatin state, which in turn controls gene expression or silencing. Nucleosome remodeling occurs during somatic cell reprogramming, but it is still unclear to what degree the re-established nucleosome organization of induced pluripotent stem cells (iPSCs) resembles embryonic stem cells (ESCs), and whether the iPSCs inherit some residual gene expression from the parental fibroblast cells. We generated genome-wide nucleosome maps in mouse ESCs and in iPSCs reprogrammed from somatic cells belonging to three different germ layers using a secondary reprogramming system. Pairwise comparisons showed that the nucleosome organizations in the iPSCs, regardless of the iPSCs' tissue of origin, were nearly identical to the ESCs, but distinct from mouse embryonic fibroblasts (MEF). There is a canonical nucleosome arrangement of -1, nucleosome depletion region, +1, +2, +3, and so on nucleosomes around the transcription start sites of active genes whereas only a nucleosome occupies silent transcriptional units. Transcription factor binding sites possessed characteristic nucleosomal architecture, such that their access was governed by the rotational and translational settings of the nucleosome. Interestingly, the tissue-specific genes were highly expressed only in the parental somatic cells of the corresponding iPS cell line before reprogramming, but had a similar expression level in all the resultant iPSCs and ESCs. The re-established nucleosome landscape during nuclear reprogramming provides a conserved setting for accessibility of DNA sequences in mouse pluripotent stem cells. No persistent residual expression program or nucleosome positioning of the parental somatic cells that reflected their tissue of origin was passed on to the resulting mouse iPSCs.


Use of patient self-report oral health outcome measures in assessment of dental treatment outcomes.
To assess the sensitivity of a newly developed brief measure of oral health-related quality of life (OQOL). Self-assessed oral health and OQOL were measured in three groups of patients who had presented for either prophylaxis (n = 32), endodontic care (n = 15), or for a denture (n = 16) in a dental school setting before and after treatment. Main outcome measures included the single-item self-report of oral health (OH-1) and the 6- and 12-item versions of a new OQOL instrument. General linear modeling was used to compute means of self-reported oral health by treatment group. Of the 63 patients who completed the baseline questionnaire, 44 (70 percent) returned questionnaires after treatment. The sample averaged 43 +/- 15 years, 48 percent male and 55 percent with some college education. Ethnic representation included 35 percent White, 33 percent Black, and 32 percent other - mostly Latino. The mean self-reported number of teeth was 20.6. In terms of sensitivity, significant differences were observed between the treatment groups on the items assessing being upset (P < 0.05), feeling depressed (P < 0.05), and uncomfortable about the appearance of teeth or dentures (P < 0.05). However, magnitude of change, as measured by an effect size, was characterized as minimal to small in the recall and endodontic groups and borderline moderate in the denture group. The measure was sensitive to differences within groups, with a small to borderline magnitude of change.


Feasibility of a 3D-printed anthropomorphic patient-specific head phantom for patient-specific quality assurance of intensity-modulated radiotherapy.
This study evaluated the feasibility of utilizing a 3D-printed anthropomorphic patient-specific head phantom for patient-specific quality assurance (QA) in intensity-modulated radiotherapy (IMRT). Contoured left and right head phantoms were converted from DICOM to STL format. Fused deposition modeling (FDM) was used to construct an anthropomorphic patient-specific head phantom with a 3D printer. An established QA technique and the patient-specific head phantom were used to compare the calculated and measured doses. When the established technique was used to compare the calculated and measured doses, the gamma passing rate for γ ≤ 1 was 97.28%, while the gamma failure rate for γ > 1 was 2.72%. When the 3D-printed patient-specific head phantom was used, the gamma passing rate for γ ≤ 1 was 95.97%, and the gamma failure rate for γ > 1 was 4.03%. The 3D printed patient-specific head phantom was concluded to be highly feasible for patient-specific QA prior to complicated radiotherapy procedures such as IMRT.


Cyclic, Condition-Independent Activity in Primary Motor Cortex Predicts Corrective Movement Behavior.
Reaching movements are known to have large condition-independent (CI) neural activity and cyclic neural dynamics. A new precision center-out task was performed by rhesus macaques to test the hypothesis that cyclic, CI neural activity in the primary motor cortex (M1) occurs not only during initial reaching movements but also during subsequent corrective movements. Corrective movements were observed to be discrete with time courses and bell-shaped speed profiles similar to the initial movements. CI cyclic neural trajectories were similar and repeated for initial and each additional corrective submovement. The phase of the cyclic CI neural activity predicted the time of peak movement speed more accurately than regression of instantaneous firing rate, even when the subject made multiple corrective movements. Rather than being controlled as continuations of the initial reach, a discrete cycle of motor cortex activity encodes each corrective submovement.


All-inside meniscus repair: a systematic review.
All-inside meniscus repairs are becoming more common with the invention of meniscal arrows, darts, screws, staples, and other suture devices. With the rising popularity of these new all-inside meniscal repair devices, it is necessary to assess the effectiveness of various all-inside surgical interventions used in the treatment of meniscal tears. We performed an evidence based review of the outcomes of all-inside meniscus repair devices. Seventy-seven percent of identified studies were case series; 10% were retrospective comparative studies; 6.5% were prospective comparative studies; and 6.5% were prospective randomized studies. The failure rates ranged from 0 to 43.5%. We found no substantial differences in the failure rates among various meniscus devices. We also found no substantial differences in failure rates with length of followup. Given the paucity of randomized controlled studies comparing different all-inside meniscal repairs, no definite conclusions can be made regarding the difference in clinical outcomes of various all-inside meniscal repair devices.


Presence of a truncated form of the vitamin D receptor (VDR) in a strain of VDR-knockout mice.
As part of our studies on the membrane-initiated actions of 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] and its localization in caveolae membrane fractions, we used a vitamin D receptor (VDR)-knockout (KO) mouse model to study the binding of [(3)H]-1alpha,25(OH)(2)D(3) in the presumed absence of the VDR. In this mouse model, known as the Tokyo strain, the second exon of the VDR gene, which encodes the first of the two zinc fingers responsible for DNA binding, was removed, and the resulting animals have been considered to be VDR-null mice. To our surprise, several tissues in these KO mice showed significant (5-50% of that seen in wild-type animals) specific binding of [(3)H]-1alpha,25(OH)(2)D(3) in nuclear and caveolae membrane fractions. The dissociation constants of this binding in samples from VDR-KO and wild-type mice were indistinguishable. RT-PCR analysis of intestinal mRNA from the VDR-KO animals revealed an mRNA that lacks exon 2 but contains exons 3-9 plus two 5'-untranslated exons. Western analysis of intestinal extracts from VDR-KO mice showed a protein of a size consistent with the use of Met52 as the translational start site. Transfection of a plasmid construct containing the sequence encoding the human analog of this truncated form of the receptor, VDR(52-C), into Cos-1 cells showed that this truncated form of the receptor retains full [(3)H]-1alpha,25(OH)(2)D(3) binding ability. This same construct was inactive in transactivation assays using the osteocalcin promoter in CV1 cells. Thus, we have determined that this widely used strain of the VDR-KO mouse can express a form of the VDR that can bind ligand but not activate gene transcription.


Decreasing the pH of milk replacer containing soy flour affects nutrient digestibility, digesta pH, and gastrointestinal development of preweaned calves.
We evaluated the effect of feeding soy flour-containing milk replacer (MR) with a lower than normal pH on growth, nutrient digestibility, digesta pH, and gastrointestinal development of preweaned calves. The study consisted of 48 neonatal calves, allocated to 8 treatments in a 2-factor 4×2 randomized design. The calves received 2 types of MR containing soy flour. The proportion of soy crude protein (CP) to total CP (SP/CP) in MR was 50% (MR50 treatment) or 80% (MR80 treatment), respectively. The pH of the reconstituted MR was decreased by 1 N HCl from to 6.2 to 5.5, 5.0, or 4.5. We measured body weight and dry matter intake and calculated feed conversion rate in the MR50 treatment. We monitored urinary and fecal pH consecutively for 5h when calves were 25d old. We also conducted a digestion trial to determine nutrient digestibility from 49 to 55d of age. At 63d old, calves were slaughtered, and gastrointestinal pH, mass index, and morphology were evaluated. Reducing the pH of MR containing soy flour improved average daily gain and feed conversion rate, increased Ca digestibility, and reduced urinary, fecal, and digesta pH in the rumen, reticulum, and omasum. Although treatments had no effect on gastrointestinal mass index, the pH 5.0 treatment led to favorable ruminal epithelium growth, and the pH 5.5 treatment led to better intestinal epithelium growth. Increasing SP/CP from 50 to 80% decreased P digestibility and fecal and digesta pH in rumen, reticulum, and omasum. Moreover, the MR80 treatment reduced the mass index of the abomasums and jejunum. In conclusion, decreasing the pH of MR containing soy flour to a pH of 5.0 to 5.5 improved the digestive tract of preweaned calves. A pH reduction to 4.5 had adverse effects on intestinal epithelium growth.


Effectiveness of Persea major Kopp (Lauraceae) extract against Enterococcus faecalis: a preliminary in vitro study.
Persea major Kopp (Lauraceae) is a plant with wound healing, antibacterial, and analgesic properties. The aim of this study was to assess the in vitro antibacterial activity of the concentrated crude extract (CCE) and ethyl acetate fraction (EAF) of this plant against Enterococcus faecalis and compare it with calcium hydroxide [Ca(OH)2] paste and 2% chlorhexidine digluconate (CHX). The plant material was collected, and an extract was prepared according to the requirements of the study (CCE and EAF). The minimum inhibitory concentrations (MICs) of CCE, EAF, Ca(OH)2, Ca(OH)2 + CCE, and CHX against E. faecalis were determined using the broth microdilution method RESULTS: The EAF inhibited E. faecalis at concentrations of 166.50, 83.25, and 41.62 mg mL-1, and 1.00, 0.50, and 0.25% of CHX solutions showed antimicrobial activity. The MICs of Ca(OH)2 paste were 166.50 and 83.25 mg mL-1, whereas Ca(OH)2 + CCE showed antimicrobial activity only at a concentration of 166.50 mg mL-1. CCE showed no inhibitory effect at any of the concentrations tested CONCLUSIONS: The CCE did not show any antimicrobial activity against E. faecalis; however, the EAF was the most effective among the three highest concentrations tested.


Metastatic Malignant Melanoma Mimicking Mammary Mass: A Rare Presentation.
Breast lump in perimenopausal women is considered a primary malignancy unless proved otherwise. Metastasis to the breast from extramammary sites is rare. Malignant melanoma (MM) is known for its ability to spread to distant sites, which can be both hematogenous and lymphatic. The common sites are skin, lung, liver, brain, etc. However, reports of melanoma metastasizing to the breast are rare. We present a case of 50-year-old female patient, who underwent wide local excision and split skin grafting for MM right leg. She did not undergo any adjuvant therapy and one year later presented to us with a solitary lump occupying the upper inner quadrant of the right breast. The breast lump turned out to be metastatic deposit from MM based on the presence of melanin in cells on fine needle aspiration cytology (FNAC). Therefore, breast lump in perimenopausal is not always a primary malignancy, and differential diagnosis should also include metastatic tumors.


The evolution of an operant ecologist.
George Collier has maintained a research program concerned with the controls of eating for forty-three years. In the first ten years, Collier approached the problem within the operant conditioning framework proposed by Skinner. This consisted of the intrameal analysis of the reflex strength of a food-rewarded operant in short sessions in food-deprived rats. At the end of the first decade, Collier shifted his attack on the problem by studying the ecological control of meal patterns by procurement and consummatory costs in free-feeding rats. This paper analyzes the reasons for this apparently abrupt evolution from operant conditioning to operant ecology and concludes that they accumulated over about ten years and were intellectual and personal, not technical or professional. This paper also summarizes the major achievements of the research program of operant ecology, notes some emerging problems with economic explanations of ecological controls, and argues that Collier's robust and quantitative behavioral results are ripe for physiological analysis.


Patellofemoral contact pressures.
A test rig for studying the biomechanical behaviour of post-mortem human knees is built. For loading the quadriceps tendon a special clamping device is constructed, so the forces up to 3000 N could easily be transferred to the tendon. Several post-mortem human knees used in this study are tested to collect data about the general biomechanics of knee joint during squatting. The forces in the quadriceps tendon and in the tibia are measured continuously; the flexion angle is also measured. On this modular test rig, the contact pressures of the patellofemoral joint are measured as well. Therefore a thin pressure film is used. Not only are measured the contact pressures, but the changing contact area is also visualized and measured. The forces and rotations measured in the joint and in the contact area allowed us to obtain perfectly reproducible values as well as a positive relation between contact area, contact position and working direction of the quadriceps tendon.


Pregnancy outcome analysis of 94 patients with pulmonary arterial hypertension during pregnancy.
The aim of the study was to analyze the pregnancy outcomes of patients with pulmonary arterial hypertension to provide a reference for clinical diagnosis and treatment. Clinical data of 94 patients with a pregnancy complicated by pulmonary hypertension were retrospectively analyzed. The means and percentages of the pregnancy outcomes were calculated, and the analysis of variance, Chi-square test, and Fisher's exact test were applied for comparison. The pregnancy outcomes were less favorable in the severe pulmonary arterial hypertension group compared to the mild and moderate groups. The more severe the pulmonary arterial hypertension, the worse the heart function. A poorer heart function was associated with a poorer prognosis across different pregnancy outcomes. A pregnancy with more severe pulmonary arterial hypertension and worse cardiac function has a poorer maternal and infant prognosis and pregnancy outcome. Cesarean section is the preferred delivery method for patients with severe pulmonary arterial hypertension, whereas vaginal delivery is preferred for patients with mild or moderate pulmonary arterial hypertension and good cardiac function.


Immunoliposomes containing antibodies to costimulatory molecules as adjuvants for HIV subunit vaccines.
Immunoliposomes containing monoclonal antibodies (MAbs) to the costimulatory molecules CD28 and CTLA4 and their counterreceptors B7-1 (CD80) and B7-2 (CD86) were evaluated for the ability to increase the immune response to recombinant envelope protein rgp120 of the MN strain of human immunodeficiency virus type 1 (HIV-1) during vaccination. MAbs were attached to rgp120-containing liposomes via a biotin-avidin-biotin bridge. Mice vaccinated with immunoliposomes were found to have a strong delayed-type hypersensitivity (DTH) response to the weakly immunogenic gp120 that was dependent on the presence of the MAbs. However, this vaccination protocol did not induce humoral immunity. The DTH response was not accompanied by increased production of interferon gamma (IFN-gamma) or interleukin 4 (IL-4), implying that the primary cellular interaction was between the immunoliposomes and cells of the reticuloendothelial system and not helper T (Th) cells. This strategy of incorporating antibodies to costimulatory molecules on the surface of antigen-containing particulates, such as liposomes or microspheres, can be used to increase DTH immune responses to protein or peptide vaccines.


Cloning and expansion of antigen-specific T cells using iPS cell technology: development of "off-the-shelf" T cells for the use in allogeneic transfusion settings.
Recent advances in adoptive immunotherapy using cytotoxic T lymphocytes (CTLs) have led to moderate therapeutic anti-cancer effects in clinical trials. However, a critical issue, namely that CTLs collected from patients are easily exhausted during expansion culture, has yet to be solved. To address this issue, we have been developing a strategy which utilizes induced pluripotent stem cell (iPSC) technology. This strategy is based on the idea that when iPSCs are produced from antigen-specific CTLs, CTLs regenerated from such iPSCs should show the same antigen specificity as the original CTLs. Pursuing this idea, we previously succeeded in regenerating melanoma antigen MART1-specific CTLs, and more recently in producing potent CTLs expressing CD8αβ heterodimer. We are now developing a novel method by which non-T derived iPSCs are transduced with exogenous T cell receptor genes. If this method is applied to Human Leukocyte Antigen (HLA) haplotype-homozygous iPSC stock, it will be possible to prepare "off-the-shelf" T cells. As a first-in-human trial, we are planning to apply our strategy to relapsed acute myeloid leukemia patients by targeting the WT1 antigen.


Current state of insect proteins: extraction technologies, bioactive peptides and allergenicity of edible insect proteins.
This review aims to provide an updated overview of edible insect proteins and the bioactivity of insect-derived peptides. The essential amino acid content of edible insects is compared with well-known protein sources to demonstrate that edible insects have the potential to cover the protein quality requirements for different groups of the population. Then the current methodologies for insect protein extraction are summarized including a comparison of the protein extraction yield and the final protein content of the resulting products for each method. Furthermore, in order to improve our understanding of insect proteins, their functional properties (such as solubility, foaming capacity, emulsifying, gelation, water holding capacity and oil holding capacity) are discussed. Bioactive peptides can be released according to various enzymatic hydrolysis protocols. In this context, the bioactive properties of insect peptides (antihypertensive, antidiabetic, antioxidant and anti-inflammatory properties) have been discussed. However, the allergens present in insect proteins are still a major concern and an unsolved issue for insect-based product consumption; thus, an analysis of cross reactivity and the different methods available to reduce allergenicity are proposed. Diverse studies of insect protein hydrolysates/peptides have been ultimately promoting the utilization of insect proteins for future perspectives and the emerging processing technologies to enhance the wider utilization of insect proteins for different purposes.


Experimental Analysis of Passenger Comfort with Variable Preloaded Rear Springs on a Low-Cylinder Motorcycle.
The present study contains an experimental analysis of the vibratory response in a low-cylinder engine motorcycle at varying suspension preloads. Three different speed bumps of varying heights were used to subject the motorcycle to different vibrations. The analysis was carried out in three domains: time, frequency, and time-frequency. A triaxial accelerometer was used to measure the vibrations at the seat of the vehicle. The results indicated that the suspension system became more differentiated as the height of the bumps increased. However, for lower bumps, the action of the three spring preloads studied was quite similar. Quantitatively, only the higher bump showed a significant difference between the set preloads. The spectral distribution revealed that the frequency of interest was below 20 Hz for all the studied cases, which is in the same range of human body natural frequencies. The findings of this research can be utilized to enhance the design of low-cost motorcycles, thereby improving the safety and comfort of their drivers and passengers. This study constitutes a significant step towards developing an affordable system capable of gathering sufficient data to support the creation of evidence-based public health policies and propose new transport industry standards based on field measurements.


Putidaredoxin-to-cytochrome P450cam electron transfer: differences between the two reductive steps required for catalysis.
Cytochrome P450cam (P450cam) is the terminal monooxygenase in a three-component camphor-hydroxylating system from Pseudomonas putida. The reaction cycle requires two distinct electron transfer (ET) processes from the [2Fe-2S] containing putidaredoxin (Pdx) to P450cam. Even though the mechanism of interaction and ET between the two proteins has been under investigation for over 30 years, the second reductive step and the effector role of Pdx are not fully understood. We utilized mutagenesis, kinetic, and computer modeling approaches to better understand differences between the two Pdx-to-P450cam ET events. Our results indicate that interacting residues and the ET pathways in the complexes formed between reduced Pdx (Pdx(r)) and the ferric and ferrous dioxygen-bound forms of P450cam (oxy-P450cam) are different. Pdx Asp38 and Trp106 were found to be key players in both reductive steps. Compared to the wild-type Pdx, the D38A, W106A, and delta106 mutants exhibited considerably higher Kd values for ferric P450cam and retained ca. 20% of the first electron transferring ability. In contrast, the binding affinity of the mutants for oxy-P450cam was not substantially altered while the second ET rates were <1%. On the basis of the kinetic and modeling data we conclude that (i) P450cam-Pdx interaction is highly specific in part because it is guided/controlled by the redox state of both partners; (ii) there are alternative ET routes from Pdx(r) to ferric P450cam and a unique pathway to oxy-P450cam involving Asp38; (iii) Pdx Trp106 is a key structural element that couples the second ET event to product formation possibly via its "push" effect on the heme-binding loop.


Expenditure and payment sources for treating acute respiratory infections in rural Vietnam.
This paper highlights important effects of the health sector reform in rural Vietnam, such as the expenditure for treatment, payment sources among patients and provision of private services. Using a cross-sectional design with a structured questionnaire, the occurrence of illnesses and utilization of health care for 4,769 members in randomly selected households were investigated, with a focus on acute respiratory infections (ARI). Three hundred and seventy people were reported to have suffered from an ARI in the four weeks prior to interview. In 96% of the cases some action had been taken, most often self-medication. The average expenditure for the first treatment was high, 25,000 Dong (US$ 1.7), which is appropriately equal to one third of the monthly per capita in the district. The majority of the expenditure was for drug purchasing in the private or public services. Expenditure for treatment of acute respiratory infections was highest in the hospitals, lower in commune health stations and private clinics, and lowest in the case of self-medication. There was no consultation fee at the commune health stations and private clinics. About half of the patients had borrowed money or sold agricultural products to pay for treatment. Only 2% of the patients benefited from health insurance. High burden of ARI, high cost of treatment and poor coverage of health insurance may create severe economic problems in poor families. Our findings indicate a need to develop pre-payment schemes and the appropriate allocation of resources in order to establish an efficient and equitable health care system.


Potassium, magnesium, and calcium: their role in both the cause and treatment of hypertension.
Despite advances in the prevention and treatment of hypertension over the past decade, hypertension remains an important public health challenge. Recent efforts to reduce the prevalence of hypertension have focused on nonpharmacologic means, specifically diet. An increased intake of minerals such as potassium, magnesium, and calcium by dietary means has been shown in some but not all studies to reduce blood pressure in patients with hypertension. This review will discuss the roles of potassium, magnesium, and calcium in the prevention and treatment of essential hypertension with specific emphasis on clinical trial evidence, mechanism of action, and recommendations for dietary intake of these minerals. A high intake of these minerals through increased consumption of fruits and vegetables may improve blood pressure levels and reduce coronary heart disease and stroke.


Direct Growth of Graphene Films on 3D Grating Structural Quartz Substrates for High-Performance Pressure-Sensitive Sensors.
Conformal graphene films have directly been synthesized on the surface of grating microstructured quartz substrates by a simple chemical vapor deposition process. The wonderful conformality and relatively high quality of the as-prepared graphene on the three-dimensional substrate have been verified by scanning electron microscopy and Raman spectra. This conformal graphene film possesses excellent electrical and optical properties with a sheet resistance of <2000 Ω·sq(-1) and a transmittance of >80% (at 550 nm), which can be attached with a flat graphene film on a poly(dimethylsiloxane) substrate, and then could work as a pressure-sensitive sensor. This device possesses a high-pressure sensitivity of -6.524 kPa(-1) in a low-pressure range of 0-200 Pa. Meanwhile, this pressure-sensitive sensor exhibits super-reliability (≥5000 cycles) and an ultrafast response time (≤4 ms). Owing to these features, this pressure-sensitive sensor based on 3D conformal graphene is adequately introduced to test wind pressure, expressing higher accuracy and a lower background noise level than a market anemometer.


Long-term maintenance of response across multiple fibromyalgia symptom domains in a randomized withdrawal study of pregabalin.
To determine the incidence and duration of response of clinically meaningful improvements with pregabalin across several key symptoms of fibromyalgia (FM). This was a post hoc analysis of data from a multicenter, double-blind, placebo-controlled, randomized, withdrawal study, originally designed to evaluate the efficacy of pregabalin monotherapy for durability of effect on FM pain based on pain and Patient Global Impression of Change (PGIC) criteria. Responder criteria for Fibromyalgia Impact Questionnaire total score (≥16-point change), Medical Outcomes Study Sleep Scale Sleep Disturbance subscale (≥15.8-point change), and the 36-item Short-Form Health Survey Vitality scale (≥10-point change) were used to evaluate the incidence and duration of improvements in function, sleep, and fatigue for pregabalin versus placebo among pain and PGIC responders. A composite responder index consisting of pain, PGIC, function, and sleep endpoints was used to explore multidimensional response. Approximately 80% of patients meeting pain and PGIC improvement criteria at randomization had clinically meaningful improvement in fatigue, sleep, or function. Higher proportions of patients in the pregabalin group maintained a clinically meaningful response, and pregabalin-treated patients had a significantly longer time to loss of therapeutic response compared with the placebo group. Composite responder Kaplan-Meier analysis, performed with patients demonstrating clinically meaningful improvements in pain, PGIC, function, and sleep at randomization showed a significantly longer median time to loss of therapeutic response for pregabalin-treated patients. The results from this post hoc analysis indicate that pregabalin provides long-term effects across multiple domains of FM (ClinicalTrials.gov registry ID: NCT00151489).


Surgical treatment of complex regional pain syndrome type II with regional subcutaneous venous sympathectomy.
The effectiveness of a new surgical technique for the treatment of severe chronic pain stages was evaluated. For the last 140 years, the treatment of complex regional pain syndrome type II (CRPS II) has been an unsolved problem. Therapeutic approaches have included conventional pain medication, physical therapy, sympathetic blocks, transcutaneous or spinal cord stimulation, injections or infusion therapies, and sympathectomy. When used alone or in combination, these therapies often yield unfavorable results. The majority of physicians who treat patients with CRPS are convinced that a surgical treatment of the affected extremity only exacerbates the symptoms, especially its hallmark excruciating pain. Sixteen patients with a CRPS type II of the upper or lower limb were included in the study after ineffective pain therapy for more than 6 months. The most proximal region of pain associated with CRPS was localized, and 2% lidocaine was injected into that area. Once the sympathetic, deep, burning pain had been blocked, the subcutaneous veins in the previously determined area were surgically removed. A visual analog scale, the Nottingham Health Profile, and physical examinations were used to evaluate the outcome of the operation. Twelve (75%) surgically treated patients showed significant improvement in limb function, the visual analog scale, and the Nottingham Health Profile. These data and recent findings in animal models conclude that CRPS type II is maintained by a coupling of newly sprouted sympathetic and sensible fibers. These fibers can be resected with a regional subcutaneous venous sympathectomy. Therapeutic study, level III.


Evaluation of associations between genotypes of Mycobacterium avium subsp. paratuberculsis and presence of intestinal lesions characteristic of paratuberculosis.
Mycobacterium avium subsp. paratuberculosis (MAP) is the causative agent of paratuberculosis affecting ruminants worldwide. Depending on the MAP-Type (MAP-C or MAP-S, cattle or sheep type), strains differ in virulence and host preference. There is not yet any strong evidence indicating that individual field strains of the same MAP-subgroup exhibit differences in virulence. The aim of this study was to evaluate a potential association between the genotype of individual field strains belonging to the MAP-C group and the presence of macroscopic intestinal lesions characteristic of paratuberculosis in the infected animals. 88 MAP-C isolates were sampled from clinically healthy cows at slaughter. Cows were grouped as A (n=46) with, and B (n=42) without macroscopic intestinal lesions. Sampled cows from both the A and B groups came from different farms and had a similar age distribution. MAP isolates were characterized by MIRU-VNTR and IS900-RFLP analysis. Resulting genotypes were examined for an association with the presence of macroscopic intestinal lesions characteristic of paratuberculosis. MAP isolates from groups A and B exhibited similar strain diversity: 20 and 18 combined genotypes, altogether 32 genotypes. Six of these genotypes were detected in both groups. Although no association was found between individual combined genotypes and presence of macroscopic intestinal lesions, IS900-RFLP-(BstEII)-Type-C1 (the most common type worldwide) was found more often in group A (p<0.01). The data give only weak indication for the existence of differences in virulence among MAP-cattle type isolates. Differences in the development and severity of lesions may rather depend on unknown host factors or inoculation dose. Virulence properties of IS900-RFLP-(BstEII)-Type-C1 isolates should be examined in more detail.


[Research progress on autophagy regulating excessive inflammation].
Autophagy is a highly conserved cellular self-digestion pathway, by which intracellular damaged proteins or organelles are delivered to lysosomes for degradation, so as to protect from various dangerous stimuli and maintain cellular homeostasis. Inflammation is a defensive response to injury or pathogens, through which various inflammatory mediators coordinate host defense and repair. However, uncontrolled inflammatory responses can lead to secondary damage and pathogenesis of inflammatory disease. Recent studies indicate that autophagy pathway and related proteins may play important roles in regulating immune response and controlling excessive inflammation. This review introduced research progress in the role of autophagy in regulating excessive inflammation and possible mechanisms.


CRISPR-Cas-Based Engineering of Probiotics.
Probiotics are the treasure of the microbiology fields. They have been widely used in the food industry, clinical treatment, and other fields. The equivocal health-promoting effects and the unknown action mechanism were the largest obstacles for further probiotic's developed applications. In recent years, various genome editing techniques have been developed and applied to explore the mechanisms and functional modifications of probiotics. As important genome editing tools, CRISPR-Cas systems that have opened new improvements in genome editing dedicated to probiotics. The high efficiency, flexibility, and specificity are the advantages of using CRISPR-Cas systems. Here, we summarize the classification and distribution of CRISPR-Cas systems in probiotics, as well as the editing tools developed on the basis of them. Then, we discuss the genome editing of probiotics based on CRISPR-Cas systems and the applications of the engineered probiotics through CRISPR-Cas systems. Finally, we proposed a design route for CRISPR systems that related to the genetically engineered probiotics.


A multicentre retrospective study on extra-thoracic solitary fibrous tumour: preoperative MRI findings predict intraoperative findings and postoperative prognosis.
The present study investigated the relationships between the preoperative and operative findings of solitary fibrous tumour (SFT) and between preoperative findings and prognosis. We reviewed 50 SFT patients treated at our musculoskeletal oncology hospital group. We analyzed preoperative clinical findings, particularly MRI imaging findings, and intraoperative information as well as the relationship between preoperative findings and outcomes. Mean age was 48.9 years and the mean follow-up was 51.8 months. Prior to surgery, needle biopsy was performed on 27 patients and open biopsy on 14. T2-weighted images showed a high signal intensity in 24 patients and heterogeneous signal intensity in 20. Tumours had polylobular contours in 17 patients and smooth and round contours in 27. Collateral feeding vessels were detected in 22 patients. Gd-enhanced MRI was performed on 23 patients, and showed 15 with homogeneous enhancement and 8 with heterogeneous enhancement. Surgical times were significantly longer in patients with a retroperitoneal origin, a tumour of 10 cm or more, and polylobular-type tumours. Intraoperative blood loss was significantly greater in patients with a retroperitoneal origin and heterogeneous Gd-MRI-enhanced tumours. In histopathological evaluations, surgical margins were positive in 12 patients. Local recurrence was observed in one patient. Distant metastasis was noted in eight patients, four of whom had pulmonary metastases. Positive surgical margins were more common in polylobular-type tumours. Distant metastases were more likely to appear in patients with observable collateral feeding vessels and heterogeneous Gd-MRI enhancement. The present results suggest that preoperative clinical findings in SFT patients predict longer surgical times and the risk of increased intraoperative blood loss. Moreover, the risk of a positive surgical margin and postoperative distant metastases may be predicted based on preoperative MRI.


Comparison of the Sensitivity of QuantiFERON-TB Gold In-Tube and T-SPOT.TB According to Patient Age.
Currently, there are two types of interferon-gamma release assays (IGRAs) in use for the detection of tuberculosis (TB) infection, the QuantiFERON-TB Gold In-Tube test (GFT-GIT) and T-SPOT.TB. Owing to contradictory reports regarding whether the results of these IGRAs are affected by the age of the patient, we aimed to determine if these two tests have age-related differences in sensitivity. We retrospectively reviewed the medical records of diagnosed TB patients who were tested using either QFT-GIT or T-SPOT.TB from February 2008 to December 2013. The positivity of the two tests was analyzed and compared with true TB infection, which was defined as active TB based on either a positive Mycobacterium culture or a positive TB polymerase chain reaction. The QFT-GIT group included 192 TB patients, and the T-SPOT.TB group included 212 TB patients. Of the patients with pulmonary TB, 76 (39.6%) were in the QFT-GIT group and 143 (67.5%) in the T-SPOT.TB group. The overall sensitivity was 80.2% for QFT-GIT and 91.0% for T.SPOT.TB. The sensitivities of QFT-GIT and T-SPOT.TB according to age group were as follows: <29 years, 93.3% and 96.7%; 30-49 years, 86.5% and 94.7%; 50-69 years, 76.8% and 87.5%; and >70 years, 68.3% and 85.7%, respectively. The trend of age-related changes in sensitivity was significant for both QFT-GIT (p = 0.004) and T.SPOT.TB (p = 0.039). However, only QFT-GIT was significantly related to age in the multivariate analysis. QFT-GIT, but not T-SPOT.TB, was significantly affected by patient age.


A Memorizing and Generalizing Framework for Lifelong Person Re-Identification.
In this paper, we introduce a challenging yet practical setting for person re-identification (ReID) task, named lifelong person re-identification (LReID), which aims to continuously train a ReID model across multiple domains and the trained model is required to generalize well on both seen and unseen domains. It is therefore critical to learn a ReID model that can learn a generalized representation without forgetting knowledge of seen domains. In this paper, we propose a new MEmorizing and GEneralizing framework (MEGE) for LReID, which can jointly prevent the model from forgetting and improve its generalization ability. Specifically, our MEGE is composed of two novel modules, i.e., Adaptive Knowledge Accumulation (AKA) and differentiable Ranking Consistency Distillation (RCD). Taking inspiration from the cognitive processes in the human brain, we endow AKA with two special capacities, knowledge representation and knowledge operation by graph convolution networks. AKA can effectively mitigate catastrophic forgetting on seen domains while improving the generalization ability to unseen domains. By considering the ranking factor that is specifically important in ReID, RCD is designed to distill the ranking knowledge in a differentiable manner, which can further prevent the catastrophic forgetting. To supporting the study of LReID, we build a new and large-scale benchmark with two practical evaluation protocols that consider the metrics of non-forgetting and generalization. Experiments demonstrate that 1) our MEGE framework can effectively improve the performance on seen and unseen domains under the domain-incremental learning constraint, and that 2) the proposed MEGE outperforms state-of-the-art competitors by large margins.


Diagnosis of foregut and tailgut cysts by endosonographically guided fine-needle aspiration.
Foregut, hindgut, and tailgut cysts are uncommon developmental anomalies. Clinical and radiological diagnosis can present many challenges, especially in adult patients or when the lesions are in unique locations. Thus, diagnosis has traditionally been provided upon surgical resection. We describe the diagnoses of a gastric foregut cyst and a retrorectal tailgut cyst by endosonographically guided fine-needle aspiration in two adults. The common cytologic features of the specimens are ciliated epithelial cells, proteinaceous material with degenerated debris, histiocytes, and benign appearing epithelium of squamous and/or gastrointestinal type that lack cytologic atypia. The identification of ciliated columnar cells is the key finding. Cytologic diagnosis via endosonographically guided fine-needle aspiration of foregut/hindgut cyst is accurate and less traumatic than surgical biopsies.


The cross-talk between LncRNAs and JAK-STAT signaling pathway in cancer.
Long non-coding RNAs (lncRNAs) are non-coding RNAs that were transcribed from the human genome and have become important regulators in a number of cellular activities, mostly via controlling gene expression. A growing body of evidence shows that lncRNAs regulate various factors to impact various biological activities that are related to tumorigenesis, including the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. lncRNAs influence the JAK-STAT signaling pathway either by directly targeting or via indirectly modulating other upstream or downstream pathways' components like members of the suppressor of cytokine signaling (SOCS) family, and other genes that regulate cell proliferation, apoptosis, migration, invasion, and epithelial-mesenchymal transition. Furthermore, lncRNAs can act as downstream effectors of the JAK-STAT pathway and mediates tumorigenesis. The relationship between JAK-STAT signaling and lncRNAs differs among various types of cancers. Besides, lncRNAs, as biological molecules, have been shown to play a dual role in either tumorigenesis or tumor suppression in various cancers. In this review, we focus on the reciprocated regulation and functions of lncRNAs and the JAK-STAT signaling pathway in cancer, as well as narrate the latest research progress on this association. A deeper understanding of this correlation may simplify the recognition of potential targets for clinical therapeutics.


Pterygium syndrome.
The pterygium syndrome consists of the neck, the antecubital fossae and the popliteal regions together with flexion deformities of the limb joints and anomalies of the vertebrae. A family, three offspring of which appear to be affected with the same disorder, is presented. All three are female; there is also a normal female child of the same union.


Dimer dynamics and filament organization of the bacterial cell division protein FtsA.
FtsA is a bacterial actin homolog and one of the core proteins involved in cell division. While previous studies have demonstrated the capability of FtsA to polymerize, little is known about its polymerization state in vivo or if polymerization is necessary for FtsA function. Given that one function of FtsA is to tether FtsZ filaments to the membrane, in vivo polymerization of FtsA imposes geometric constraints and requires a specific polymer curvature direction. Here, we report a series of molecular dynamics simulations probing the structural dynamics of FtsA as a dimer and as a tetrameric single filament. We found that the FtsA polymer exhibits a preferred bending direction that would allow for its placement parallel with FtsZ polymers underneath the cytoplasmic membrane. We also identified key interfacial amino acids that mediate FtsA-FtsA interaction and propose that some amino acids play more critical roles than others. We performed in silico mutagenesis on FtsA and demonstrated that, while a moderate mutation at the polymerization interface does not significantly affect polymer properties such as bending direction and association strength, more drastic mutations change both features and could lead to non-functional FtsA.


Rapid Antimicrobial Susceptibility Testing of Patient Urine Samples Using Large Volume Free-Solution Light Scattering Microscopy.
The emergence of antibiotic resistance has prompted the development of rapid antimicrobial susceptibility testing (AST) technologies that will enable evidence-based treatment and promote antimicrobial stewardship. To date, many rapid AST methods have been developed, but few are able to be performed on clinical samples directly. Here we developed a large volume light scattering microscopy technique that tracks phenotypic features of single bacterial cells directly in clinical urine samples without sample enrichment or culturing. The technique demonstrated rapid (90 min) detection of Escherichia coli in 24 clinical urine samples with 100% sensitivity and 83% specificity and rapid (90 min) AST in 12 urine samples with 87.5% categorical agreement with two antibiotics, ampicillin and ciprofloxacin.


Nonencapsulated, intact omeprazole granules effectively suppress intragastric acidity when administered via a gastrostomy.
Because of its acid-labile nature, omeprazole is usually administered as encapsulated enteric-coated granules. The gelatin capsule and acid-resistant coating are essential for effective drug absorption and optimal bioavailability. This study tested the effectiveness of nonencapsulated, intact omeprazole granules in suppressing intragastric acidity when administered through a gastrostomy. Fourteen male patients with established gastrostomies underwent a baseline 24-h intragastric pH monitoring study while off any acid-suppressing medication. Via the gastrostomy, they then received 7 days of dosing with 20 mg omeprazole as intact granules in orange juice. Twenty-four-hour intragastric pH monitoring was repeated on the seventh day. Mean intragastric pH during the baseline study was 1.8 (+/- SD 0.7). This pH increased to 4.9 +/- 0.8 with omeprazole granules (p < 0.0001). Median intragastric pH rose from 1.3 to 5.3 (p < 0.0001). During the baseline study, intragastric pH was above 3 for 21.2 +/- 14.1%, above 4 for 14.9 +/- 11.0%, and above 5 for 9.5 +/- 8.4% of the 24-h recording period. Corresponding values after 7 days of omeprazole were 80 +/- 15.1%, 72.5 +/- 16.3%, and 59.1 +/- 16.6% (p < 0.0001 for each comparison with pretreatment values). Omeprazole effectively suppresses intragastric acidity when given through a gastrostomy tube as nonencapsulated, intact granules.


Medical connections: use of the internet and traditional sources of health information by rural Alabama households.
Rural household adoption of the PC and Internet for accessing medical and healthcare information was investigated using survey data collected from 305 households randomly selected from non-metropolitan, rural counties across Alabama. The diffusion-adoption model for new technologies was employed to create five adoption stages relevant to this technology and its applications to communication of information in the health field. Descriptive household characteristics of age, education, income, and children revealed differences between adoption stages, with age and education having major impacts. Use of traditional sources of health information and the Internet were compared in relation to age and availability of medical services. Older, less educated households lagged behind in use of the Internet for health information. Medical professionals, doctors and pharmacists, were the most utilized information source by rural households; but those households connected to the Internet used on-line sources, even e-mail to communicate with their doctors.


The Association of Maternal Lifestyle with Birth Defects in Shaanxi Province, Northwest China.
The main objective was to investigate the burden of birth defects among alive infants and explore the impact of maternal lifestyle during pregnancy on the burden of birth defects in Northwest China. A stratified multi-stage sampling method was used to study infants born during 2010-2013 (and their mothers) in Shaanxi province of Northwest China. Socio-demographic information was collected using a structured questionnaire, and medical records from the local hospitals were used to determine the final diagnosis of birth defects. Poisson regression analysis was performed to assess the association between maternal lifestyles during pregnancy and the burden of birth defects, while adjusting for potential confounders. We sampled 29098 infants, of whom 629 (i.e. 216.17 per 10000) were observed to have congenital defects. Cardiovascular system defects (77.32 per 10000) were found to be the most common. Mothers who had ever consumed alcohol during pregnancy were found to have infants with a higher prevalence of some categories of birth defects, including nervous system (Prevalence Rate Ratio, PRR:14.67, 95% CI: 1.94, 110.92), cardiovascular system (PRR:3.22, 95% CI: 1.02, 10.16) and oral clefts (PRR:9.02, 95% CI: 2.08, 39.10) in contrast to infants of mothers without any alcohol consumption. Maternal passive smoking during pregnancy lead to the increased burden of malformations of eye, ear, face and neck (PRR:1.95, 95% CI: 1.15, 3.33), cardiovascular system (PRR:1.70, 95% CI: 1.25, 2.31) and respiratory system (PRR:9.94, 95% CI: 2.37, 41.76) in their newborns. Further, tea or coffee consumption during pregnancy was positively correlated with the burden of specific birth defects, such as cardiovascular system (PRR: 2.44, 95% CI: 1.33, 4.46) and genital organs (PRR:14.72, 95% CI: 1.87, 116.11) among infants. The prevalence of birth defects was high in Shaanxi province of Northwest China. The unhealthy lifestyles of mothers during pregnancy may increase the prevalence of congenital malformations. These findings in future may have some important implications for prevention of birth defects in Northwest China.


Bifunctional N-heterocyclic carbene catalyzed [3+4] annulation of enals and aurones.
Bifunctional N-heterocyclic carbenes with a free hydroxy group are demonstrated as efficient catalysts for the [3+4] annulation of enals with aurones to give the corresponding benzofuran-fused ε-lactones in good yields with good diastereoselectivities and excellent enantioselectivities. Control experiments reveal that the [3+4] cycloadducts are kinetically favored and could be transformed to the thermodynamically favored [3+2] cycloadducts with a non-bifunctional NHC catalyst.


[Hypoadiponectinemia implies the development of atherosclerosis in carotid and coronary arteries].
Adiponectin is an adipocyte-derived endocrine factor. Hypoadiponectinemia has been observed in obese patients, and plasma adiponectin levels are reported to increase during weight reduction. Moreover, hypoadiponectinemia has also been observed in patients with coronary artery diseases. The present study investigated the relationships between levels of adiponectin and carotid intimal-medial thickness, a marker of early vascular disease, and carotid artery plaque and the severity of coronary artery disease, a marker of advanced vascular disease. Four hundred thirty-one consecutive patients were enrolled from inpatients without acute coronary syndrome who underwent coronary angiography between August 2001 and August 2003. The residual adiponectin levels were calculated by adjusting for sex, age, and body mass index, and a logarithmic transformation was applied. The severity of coronary artery disease was evaluated by coronary angiography and divided into four groups (Group 0: no significant organic stenosis, Group 1: 1-vessel disease, Group 2: 2-vessel disease, Group 3: 3-vessel disease or left main coronary trunk disease). Carotid plaque was evaluated by ultrasonography and divided into two groups [Group(-) : patients without carotid plaque, Group (+): patients with carotid plaque]. The intimal-medial thickness was measured on a longitudinal scan of the common carotid artery at a point 1 cm proximal from the bifurcation bulb. The logarithmic-transformed levels of residual adiponectin were associated with severity of coronary artery disease (Group 0: 0.18 +/- 0.59 microg/ml, Group 1: -0.02 +/- 0.56 microg/ml, Group 2: - 0.09 +/- 0.58 microg/ml, Group 3: - 0.10 +/- 0.66 microg/ml, p = 0.0013). The logarithmic-transformed levels of residual adiponectin were decreased in patients with carotid plaque [Group (-): 0.08 +/- 0.59 microg/ml, Group (+): - 0.08 +/- 0.59 microg/ml, p = 0.045]. However, the logarithmic-transformed levels of residual adiponectin were not associated with intimal-medial thickness (p = 0.6398). Hypoadiponectinemia adjusted for sex, age, body mass index implies the progression of carotid and coronary sclerosis.


Methodologic quality of cost-effectiveness analyses of surgical procedures.
The purpose of this study was to evaluate the methodologic quality of economic analyses of surgical procedures and to compare quality across publications. With healthcare resources limited and technologies rapidly advancing across specialties, including surgery, there is increasing demand for evidence of cost-effectiveness. A MEDLINE search identified English-language articles published from 1995 to 2004 that included economic analyses of surgical procedures. Two of the authors reviewed 110 studies and scored each based on compliance with 10 methodologic criteria. Data analyses used Cohen's kappa statistic, regression models, Mann-Whitney U tests, and Kruskal-Wallis tests. The 110 articles appeared in 79 different journals, including 57 articles in 37 surgical journals. Most journals (75%) had only 1 article eligible for inclusion. The average number of criteria met was 4.1, with 10 articles meeting all 10 methodologic standards. Compliance rates for the 5 methodologic criteria most frequently neglected ranged from 34% to 45% in nonsurgical journals and 9% to 14% in surgical journals (P < 0.001). While methodologic guidelines for cost-effectiveness analyses have appeared in the medical literature, studies of cost-effectiveness in surgery often do not meet these criteria. As healthcare policy seeks to incorporate information from economic evaluations, it is increasingly important that surgical journals adhere to accepted guidelines and perform quality assurance on these studies. This may be aided by wider promulgation of the methodologic criteria in surgical journals or at surgical meetings.


Remote control.
On a remote Scottish island, technology is helping patients monitor their own pulmonary disease and alert nurses to any deterioration.


Targeted Plasma Membrane Delivery of a Hydrophobic Cargo Encapsulated in a Liquid Crystal Nanoparticle Carrier.
The controlled delivery of drug/imaging agents to cells is critical for the development of therapeutics and for the study of cellular signaling processes. Recently, nanoparticles (NPs) have shown significant promise in the development of such delivery systems. Here, a liquid crystal NP (LCNP)-based delivery system has been employed for the controlled delivery of a water-insoluble dye, 3,3'-dioctadecyloxacarbocyanine perchlorate (DiO), from within the NP core to the hydrophobic region of a plasma membrane bilayer. During the synthesis of the NPs, the dye was efficiently incorporated into the hydrophobic LCNP core, as confirmed by multiple spectroscopic analyses. Conjugation of a PEGylated cholesterol derivative to the NP surface (DiO-LCNP-PEG-Chol) enabled the binding of the dye-loaded NPs to the plasma membrane in HEK 293T/17 cells. Time-resolved laser scanning confocal microscopy and Förster resonance energy transfer (FRET) imaging confirmed the passive efflux of DiO from the LCNP core and its insertion into the plasma membrane bilayer. Finally, the delivery of DiO as a LCNP-PEG-Chol attenuated the cytotoxicity of DiO; the NP form of DiO exhibited ~30-40% less toxicity compared to DiOfree delivered from bulk solution. This approach demonstrates the utility of the LCNP platform as an efficient modality for the membrane-specific delivery and modulation of hydrophobic molecular cargos.


Prevalence and blood concentrations of desoxypipradrol (2-DPMP) in drivers suspected of driving under the influence of drugs and in post-mortem cases.
The aim of this study was to assess the incidence of the use of desoxypipradrol (2-DPMP) among drivers apprehended on suspicion of driving under the influence of drugs (DUID) and the prevalence of the drug in post-mortem cases in Finland. Serum samples from drivers apprehended on suspicion of DUID and blood samples from post-mortem cases in Finland between October 2010 and May 2012 were analysed for the presence of desoxypipradrol. All samples were analysed for desoxypipradrol by mass spectrometric methods following comprehensive drug screening. Psychomotor performance of subjects was assessed by a clinician. There were 106 positive desoxypipradrol samples from apprehended drivers (1.7% of all confirmed DUID cases) in the study period. In most cases amphetamine and/or benzodiazepines were also present. The median (range) desoxypipradrol concentration was 0.073 mg/L (0.006-0.890 mg/L). The presence of other psychoactive drugs confounded assessment of the effect of desoxypipradrol on psychomotor performance except for one case in which it was the only drug present at pharmacologically active levels. Desoxypipradrol was found in 5 autopsy cases (0.05% of the investigated cases) and thought to contribute to death in two of these. Even though there are few data available on the pharmacology of desoxypipradrol, based on our findings, and the growing number of users, it is reasonable to assume that desoxypipradrol - a long-acting psychostimulant with dangerous side effects has an increasing detrimental impact on traffic safety in Finland. However, it was only rarely found to be the cause of death in post-mortem cases.


The Risk of Malignancy in Korean Patients with Rheumatoid Arthritis.
To investigate the overall cancer risk and risk for specific cancers in rheumatoid arthritis (RA) patients in Korea by comparing cancer incidence between RA patients and the general population. Individuals diagnosed with RA between 1996 and 2009 who underwent treatment at the Daegu Catholic University Medical Center were retrospectively examined. 1885 patients with RA were included in the analyses. Occurrence of cancer and death during follow up was ascertained by linking medical records to the Korean Central Cancer Registry and national death certificates. For comparing cancer incidence between RA patients and general population, standardized incidence ratios (SIR) were calculated. The 95% confidence intervals (CIs) of SIRs were calculated using the shortcut method introduced by Vandenbroucke. The total follow-up time was 10218.9 person-years. During follow up, 100 patients (31 men and 69 women) were diagnosed with cancer. Both men and women had greater risks of having malignancy, although cancer risk was greater in men. Men showed increased risks of lung cancer (SIR=5.46, 95% CI: 2.60-9.36) and leukemia (SIR=16.7, 95% CI: 1.58-47.9). Women showed increased risks of thyroid cancer (SIR=1.75, 95% CI: 1.02-2.68), cervical cancer (SIR=3.65, 95% CI: 1.65-6.42), non-Hodgkin's lymphoma (SIR=6.47, 95% CI: 2.04-13.4), and gallbladder cancer (SIR=3.87, 95% CI: 1.01-8.60). Disease-modifying anti-rheumatic drugs usage and cancer were not related: the relative risks of developing malignancy were not elevated for each medicine. The overall cancer incidence was increased in Korean men and women with RA. Increased risk of specific malignancy differed according to sex.


Role of Rac1 in a bleomycin-induced scleroderma model using fibroblast-specific Rac1-knockout mice.
Activated adhesive signaling is a hallmark of fibroblasts isolated from the scars of scleroderma (systemic sclerosis [SSc]) lesions. Rac1 plays a key role in adhesive signaling. The aim of the present study was to examine the role of Rac1 in bleomycin-induced scleroderma, using mice with a fibroblast-specific deletion of Rac1. Cutaneous sclerosis was induced by subcutaneous injection of bleomycin. Control groups were treated with phosphate buffered saline. Mice with a fibroblast-specific deletion of Rac1 and control mice were investigated. Dermal thickness, inflammation, collagen production, and the number of alpha-smooth muscle actin-positive cells were determined. The quantity of the collagen-specific amino acid hydroxyproline was also measured. Bleomycin treatment induced marked cutaneous thickening, inflammation, and fibrosis in control mice. Conversely, deletion of Rac1 resulted in resistance to bleomycin-induced fibrosis and inflammation. Rac1 expression by fibroblasts is required for fibrogenesis. Inhibition of Rac1 may be a viable method to alleviate the development of cutaneous sclerosis.


The characteristic function, a method-specific alternative to the Horwitz function.
The Horwitz function is compared with the characteristic function as a descriptor of the precision of individual analytical methods. The Horwitz function describes the trend of reproducibility SDs observed in collaborative trials in the food sector over a wide range of concentrations of the analyte. However, it is imperfectly adaptable for describing the precision of individual methods, which is the role of the characteristic function. An essential difference between the two functions is that the characteristic function can accommodate a detection limit. This makes it a useful alternative when the precision of a method down to a detection limit is of interest. Many characteristic functions have a simple mathematical form, the parameters of which can be estimated with the usual resources. The Horwitz function serves an additional role as a fitness-for-purpose criterion in the form of the Horwitz ratio (HorRat). This use also has some shortcomings. The functional form of the characteristic function (with suitable prescribed parameters) is better adapted to this task.


[Serum platelet-activating factor acetylhydrolase activity in dengue patients of African or mestizo descendency].
Severe dengue infection is characterized by enhanced vascular permeability produced by cytokines and biochemical mediators. One of these mediators is the platelet-activating factor. Degradation of platelet-activating factor is accomplished by its specific acetylhydrolase. Down or up regulation of this enzyme has been linked to several diseases. However, the role of this enzyme in dengue infection is unknown, a well as whether differential activity occurs by ethnic group. The activity of the platelet-activating factor-acetylhydrolase was compared in patients infected with dengue virus in two ethnic groups. A descriptive, prospective and longitudinal study was made in two states of Colombia (Antioquia and Chocó). Serum samples were taken from 43 mestizo patients and 33 patients of African descent, each taken during five consecutive days of the acute dengue phase. A second serum sample was taken during the convalescent phase. The mestizo patients showed higher frequency of dengue hemorrhagic fever than the patients of African descent (23.3% vs. 12.1%, p=0.25). The serum activity of the platelet-activating factor acetylhydrolase was higher in African descendents than in mestizos (0.89, CI: 0.72-1.10 vs. 0.76 CI: 0-1.03, p<0.001). This relationship is maintained for occurence of dengue fever (0.89, CI: 0.73–1.10 vs. 0.73, CI: 0–1.05, p<0.001), but not significant for dengue hemorrhagic fever (0.88, CI: 0.69–1.12 vs. 0.83, CI: 0.71–1.08, p=0.89). CONCLUSION. An increased production of platelet-activating factor-acetylhydrolase occurs in the serum of dengue-infected African descendants. However, a study of the frequencies of polymorphisms for this enzyme will permit more conclusive support for these observations.


Point of view of Italian regions.
The tragic chain of mortal events, that have happened to workers and people who have been exposed to asbestos, proposes clearly an accentuation of the efforts that have been undertaken up to now, even in absence of precise national directives, in order to give an answer to worries and, sometimes, to real consequences of citizens' and workers' asbestos exposure. Region of Tuscany, following the initiatives which have been carried out in national and regional field for the formerly asbestos-exposed or other carcinogenic agents workers, performed a guideline that was just titled "Guidelines on sanitary surveillance of formerly exposed to occupational carcinogens workers". The debate, which had risen around the sanitary surveillance of the formerly-exposed to occupational carcinogenic agents workers, had induced indeed many institutions to take decisions on issues which were not yet explicitly regulated by the national law. For example the guidelines provided suggestions regarding what bodies--either public or private--should be appointed to this task, or the kind of protocols should be adopted with all the related collective and individual consequences.


A Case/Control Study: AGBL1 Polymorphism Related to Lung Cancer Risk in Chinese Nonsmoking Females.
ATP/GTP binding protein like 1 (AGBL1) plays a role in controlling the length of polyglutamate side chains. Polymorphism rs4513061 in AGBL1 is suspected to influence the risk of lung cancer. A case/control study was performed involving 556 cases and 563 controls from a hospital participating in donation. The relationship between rs4513061 and the risk of lung cancer and the interaction between rs4513061 and environmental exposure were determined by the chi-square tests, logistic regression analysis, and crossover analysis. The survival analysis was conducted by Cox proportional hazard regression. The results showed that rs4513061 polymorphism is associated with the risk of lung cancer. The stratified analysis suggested the protective effect of rs4513061 to different histological types of lung cancer, including lung adenocarcinoma (AA vs. GG: odds ratio [OR] = 0.505, 95% confidence interval [CI] = 0.337-0.756, p < 0.001), squamous cell lung cancer (AG vs. GG: OR = 0.488, 95% CI = 0.269-0.883, p = 0.018), and small-cell lung cancer (AA vs. GG: OR = 0.421, 95% CI = 0.216-0.819, p = 0.011). Nevertheless, there was no significant interaction between rs4513061 and cooking oil fume. Significant impact was not observed between the rs4513061 polymorphism and survival time of lung cancer. Our study indicated that rs4513061 in AGBL1 decreases the risk of lung cancer in nonsmoking females from northeast China.


Epiblast cells gather onto the anterior mesendoderm and initiate brain development without the direct involvement of the node in avian embryos: Insights from broad-field live imaging.
Live imaging of migrating and interacting cells in developing embryos has opened a new means for deciphering fundamental principles in morphogenesis and patterning, which was not possible with classic approaches of experimental embryology. In our recent study, we devised a new genetic tool to sparsely label cells with a green-fluorescent protein in the broad field of chicken embryos, enabling the analysis of cell migration during the early stages of brain development. Trajectory analysis indicated that anterior epiblast cells from a broad area gather to the head axis to form the brain primordia or brain-abutting head ectoderm. Grafting the mCherry-labeled stage (st.) 4 node in an anterior embryonic region resulted in the anterior extension of the anterior mesendoderm (AME), the precursor for the prechordal plate and anterior notochord, from the node graft at st. 5. Grafting the st. 4 node or st. 5 AME at various epiblast positions that otherwise develop into the head ectoderm caused local cell gathering to the graft-derived AME. The node was not directly associated with this local epiblast-gathering activity. The gathered anterior epiblast cells developed into secondary brain tissue consisting of consecutive brain portions, e.g., forebrain and midbrain or midbrain and hindbrain, reflecting the brain portion specificities inherent to the epiblast cells. The observations indicated the bipotentiality of all anterior epiblast cells to develop into the brain or head ectoderm. Thus, a new epiblast brain field map is proposed, allowing the reinterpretation of classical node graft data, and the role of the AME is highlighted. The new model leads to the conclusion that the node does not directly participate in brain development.


Trapping transient protein-protein interactions in polyketide biosynthesis.
Transient biomolecular interactions are essential for biological processes, but strategies for studying them have remained elusive. A paper in this issue shows how natural enzymatic activities can be exploited to examine protein-protein interactions in fatty acid synthase.


The distribution of ixodid ticks (Acari: Ixodidae) in central Ethiopia.
Ixodid ticks were collected from domestic animals, mainly cattle, in 11 administrative zones covering 84 districts in central Ethiopia over a period of 2 years (July 1996 to June 1998). Nineteen tick species were identified. Four of these belonged to the genus Amblyomma, one to Boophilus, two to Haemaphysalis, three to Hyalomma and nine to Rhipicephalus. Amblyomma variegatum and Rhipicephalus evertsi evertsi were present in all 11 administrative zones and, with the exception of Afar, Boophilus decoloratus was present in nearly every district in which collections were made. These three species constituted more than 50% of all ticks collected. Amblyomma cohaerens and Rhipicephalus bergeoni were common in the west of the survey region and Rhipicephalus pulchellus in the east. Except for B. decoloratus, of which more females than males were collected, the numbers of male ticks recovered were equal to or exceeded those of females. Mortality in crossbred dairy cattle caused by heartwater (Cowdria ruminantium infection) was reported during the survey period. An integrated approach to tick control is suggested.


TET proteins and 5-methylcytosine oxidation in hematological cancers.
DNA methylation has pivotal regulatory roles in mammalian development, retrotransposon silencing, genomic imprinting, and X-chromosome inactivation. Cancer cells display highly dysregulated DNA methylation profiles characterized by global hypomethylation in conjunction with hypermethylation of promoter CpG islands that presumably lead to genome instability and aberrant expression of tumor suppressor genes or oncogenes. The recent discovery of ten-eleven-translocation (TET) family dioxygenases that oxidize 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) in DNA has led to profound progress in understanding the mechanism underlying DNA demethylation. Among the three TET genes, TET2 recurrently undergoes inactivating mutations in a wide range of myeloid and lymphoid malignancies. TET2 functions as a bona fide tumor suppressor particularly in the pathogenesis of myeloid malignancies resembling chronic myelomonocytic leukemia (CMML) and myelodysplastic syndromes (MDS) in human. Here we review diverse functions of TET proteins and the novel epigenetic marks that they generate in DNA methylation/demethylation dynamics and normal and malignant hematopoietic differentiation. The impact of TET2 inactivation in hematopoiesis and various mechanisms modulating the expression or activity of TET proteins are also discussed. Furthermore, we also present evidence that TET2 and TET3 collaborate to suppress aberrant hematopoiesis and hematopoietic transformation. A detailed understanding of the normal and pathological functions of TET proteins may provide new avenues to develop novel epigenetic therapies for treating hematological malignancies.


Predicting longitudinal changes in joint contact forces in a juvenile population: scaled generic versus subject-specific musculoskeletal models.
Subject-specific musculoskeletal model use in clinical settings is limited due to development-associated time and effort burdens together with potential medical imaging unavailability. As an alternative, this study investigated consistency in estimating longitudinal changes in joint contact forces (JCF) between scaled generic and subject-specific models. For 11 children, joint kinematics and JCF were calculated using subject-specific and scaled generic models. JCF changes estimated by both models were strongly correlated for the hip and knee although JCF estimates varied between models. Findings suggest that within specified limits of accuracy, scaled generic models are sensitive enough to detect JCF changes consistent with subject-specific models.


The effect of dietary fat content on amino acid digestibility in young pigs.
Studies were carried out with 12 pigs (Yorkshire x Landrace) to determine the effect of dietary fat content on amino acid digestibility. The pigs were weaned at 21 d of age and fitted with a simple T-cannula at the distal ileum at 27 or 28 d of age. After a 7-d recuperation period, the pigs were fed one of four isonitrogenous cornstarch-based soybean meal diets (22.5% CP) containing 3.2, 6.2, 9.2, or 12.2% canola oil according to a balanced two-period change-over design. The pigs were fed four times daily, equal amounts, at 6-h intervals. The diets were supplied at a rate of 5% of the average body weight that was determined at the initiation of the first (11.0 kg) and second (12.5 kg) experimental period. Each experimental period consisted of 10 d. Feces were collected for 48 h on d 6 and 7 and ileal digesta for 24 h during d 8, 9, and 10. Chromic oxide was used as digestibility marker. The apparent ileal digestibilities of most of the amino acids increased linearly (P < .05) with increasing dietary fat levels. There were differences (P < .05) in the ileal digestibilities of most of the amino acids between the diets containing 3.2 and 12.2% canola oil. Conversely, the dietary level of inclusion of canola oil did not affect (P > .05) the fecal amino acid digestibilities. The protein-sparing effect of additional canola oil inclusion results, in part, from an increase in ileal amino acid digestibility.


Distinct Expression and Function of FcεRII in Human B Cells and Monocytes.
FcεRII is a multifunctional low-affinity IgER that is involved in the pathogenesis of allergic, inflammatory, and neoplastic diseases. Although discrepancies in FcεRII-mediated functions are being increasingly recognized, the consequences of FcεRII activation are not completely understood. In this study, we evaluated the expression of FcεRII on human blood cells and found that it was primarily expressed on monocytes and B cells. Although IL-4 promoted expression of the FcεRIIb isoform on B cells and monocytes, the expression of the FcεRIIa isoform was not dependent on IL-4. Furthermore, FcεRII predominantly bound allergen-IgE complexes on B cells but not on monocytes. FcεRII-mediated allergen-IgE complex uptake by B cells directed Ags to MHC class II-rich compartments. FcεRII-bearing monocytes and B cells expressed high levels of the FcεRII sheddase a disintegrin and metalloproteinase 10, which implies that they are important sources of soluble FcεRII. Moreover, we identified that IgE immune complex stimulation of FcεRII activated intracellular tyrosine phosphorylation via Syk in B cells but not in monocytes. Importantly, FcεRII-mediated signaling by allergen-IgE immune complexes increased IFN-γ production in B cells of allergic patients during the build-up phase of allergen-specific immunotherapy. Together, our results demonstrate that FcεRII mediates cell type-dependent function in allergic reactions. In addition, the results identify a novel allergen-IgE complex/FcεRII/Syk/IFN-γ pathway in allergic responses and suggest that FcεRII may play a role in regulating allergic reactions via modulating IFN-γ production in B cells.


Conservation of components of the Escherichia coli export machinery in prokaryotes.
The SecA and SecB proteins are involved in protein translocation in Escherichia coli. Immunoblot analysis was used to investigate the possible conservation of these proteins in prokaryotes. Cross-reacting proteins were detected in all other Enterobacteriaceae tested, but not in microorganisms more distantly related from Escherichia coli.


The epigenomics of schizophrenia, in the mouse.
Large-scale consortia including the Psychiatric Genomics Consortium, the Common Minds Consortium, BrainSeq and PsychENCODE, and many other studies taken together provide increasingly detailed insights into the genetic and epigenetic risk architectures of schizophrenia (SCZ) and offer vast amounts of molecular information, but with largely unexplored therapeutic potential. Here we discuss how epigenomic studies in human brain could guide animal work to test the impact of disease-associated alterations in chromatin structure and function on cognition and behavior. For example, transcription factors such as MYOCYTE-SPECIFIC ENHANCER FACTOR 2C (MEF2C), or multiple regulators of the open chromatin mark, methyl-histone H3-lysine 4, are associated with the genetic risk architectures of common psychiatric disease and alterations in chromatin structure and function in diseased brain tissue. Importantly, these molecules also affect cognition and behavior in genetically engineered mice, including virus-mediated expression changes in prefrontal cortex (PFC) and other key nodes in the circuitry underlying psychosis. Therefore, preclinical and small laboratory animal work could target genomic sequences affected by chromatin alterations in SCZ. To this end, in vivo editing of enhancer and other regulatory non-coding DNA by RNA-guided nucleases including CRISPR-Cas, and designer transcription factors, could be expected to deliver pipelines for novel therapeutic approaches aimed at improving cognitive dysfunction and other core symptoms of SCZ.