Continuous theta-burst stimulation over the primary somatosensory cortex modulates interhemispheric inhibition.
One mechanism thought to mediate hand and upper limb control across motor cortices is called interhemispheric inhibition (IHI). Somatosensory cortices are important in the motor control of the hand, although the neural mechanisms by which somatic loci act are not fully understood. In the present study, we study the possibility that the primary somatosensory cortex (SI) influences IHI as one mechanism to modulate hand control. IHI from the motor cortices was measured before and after continuous theta-burst stimulation (cTBS) was delivered over the left-hemisphere SI. IHI was evoked using paired-pulse transcranial magnetic stimulation and measured using electromyography electrodes over the first dorsal interosseous muscles of both hands at short (10 ms) and long (40 ms) intervals to evoke short interval IHI and long interval IHI, respectively. Measures were taken before and for up to 1 h after 600 pulse cTBS was delivered over SI. Results indicate that cTBS over SI increases short interval IHI in the left hand (i.e. ipsilateral to cTBS) for 45-60 min after stimulation. These results indicate that SI is indeed able to modify IHI, and this is therefore one neural mechanism by which SI may influence hand control.


Encapsulation Using Plant Proteins: Thermodynamics and Kinetics of Wetting for Simple Zein Coacervates.
Traditionally, complex coacervates of oppositely charged biopolymers have been used to form coatings around oil droplets for encapsulation of oil-soluble payloads. However, many proteins can form coacervates by themselves under certain conditions. Here, we revisit the well-known simple coacervates of prolamins such as zein in mixed solvents to explore whether they can be used for plant-based encapsulation systems. We show that, for zein in mixed water/propylene glycol (PG) solvents, we can encapsulate limonene droplets but only under specific conditions. We illustrate that this limitation is due to the very different physical properties of the simple zein coacervates as compared to those of the more extensively studied complex coacervates. Droplets of simple coacervates of zein can carry a significant net charge, whereas complex coacervates are usually close to being charge-balanced. In particular, we demonstrate that the spreading of zein coacervates at the interface of the droplets is thermodynamically favorable due to their extremely low interfacial tensions in both the dispersed (∼0.24 mN/m) and oil phases (∼0.68 mN/m), but the kinetics of coacervate droplet deposition and the interactions among coacervate droplets that oppose coacervate droplet coalescence are highly pH-dependent, leading to a sharp pH optimum (around pH 8) for capsule formation.


Management of HBV in immunocompromised patients.
Hepatitis B virus (HBV) infection is more frequent in immune deficient populations than in the general population with lower rates of spontaneous recovery in acute cases, thus explaining the high rate of chronic infection and the increased risk of cirrhosis and hepatocellular carcinoma, resulting in increased morbidity-mortality in these patients. The negative impact of immune deficiency on chronic HBV infection is related to two non-exclusive factors: (i) high viral load enhances the progression of fibrosis and may result in a rare severe liver disease called fibrosing cholestatic hepatitis, which reflects the direct toxicity of high levels of HBV proteins; (ii) The pathobiology of HBV infection is mainly immune-mediated via HBV-specific T lymphocytotoxicity. The reduction or discontinuation of immune deficiency may result in severe liver disease including fulminant hepatitis from immune restoration. Thus, immune deficiency enhances the hepatitis B viral load, which results in the progression of fibrosis and/or acute exacerbation of underlying liver disease (HBV reactivation) on one hand, whereas reduction in immune deficiency may also be harmful because of immune restoration on the other hand. This double-edged sword explains why the diagnosis and evaluation of the impact of HBV infection on the liver must be especially rigorous in cases of immune deficiency whatever the cause: transplantation, oncology, haematology, internal medicine (rheumatology, gastroenterology …) or HIV infection, and why pre-emptive therapy by HBV nucleos(t)ide analogues should be considered for all HBV-infected patients.


Monocytes and macrophages in abdominal aortic aneurysm.
Abdominal aortic aneurysm (AAA) is a life-threatening disease associated with high morbidity, and high mortality in the event of aortic rupture. Major advances in open surgical and endovascular repair of AAA have been achieved during the past 2 decades. However, drug-based therapies are still lacking, highlighting a real need for better understanding of the molecular and cellular mechanisms involved in AAA formation and progression. The main pathological features of AAA include extracellular matrix remodelling associated with degeneration and loss of vascular smooth muscle cells and accumulation and activation of inflammatory cells. The inflammatory process has a crucial role in AAA and substantially influences many determinants of aortic wall remodelling. In this Review, we focus specifically on the involvement of monocytes and macrophages, summarizing current knowledge on the roles, origin, and functions of these cells in AAA development and its complications. Furthermore, we show and propose that distinct monocyte and macrophage subsets have critical and differential roles in initiation, progression, and healing of the aneurysmal process. On the basis of experimental and clinical studies, we review potential translational applications to detect, assess, and image macrophage subsets in AAA, and discuss the relevance of these applications for clinical practice.


Intermittent vs Continuous Administration of Nerve Growth Factor to Injured Medial Septal Cholinergic Neurons in Rat Basal Forebrain.
Many medial septal neurons of the basal forebrain are dependent on nerve growth factor (NGF) from the hippocampus for survival and maintenance of a cholinergic phenotype. When deprived of their source of NGF by axotomy, medial septal neuronal cell bodies atrophy and lose their cholinergic markers. This is similar to what is observed in the basal forebrain during Alzheimer's disease (AD). In the present study, medial septal neurons were axotomized in female rats by way of a fimbria/fornix lesion. For fourteen days following axotomy, varying NGF doses (1 - 250 μg/ml) were administered to the lateral cerebral ventricle with either mini-osmotic infusion or daily injection. The responsiveness of medial septal neurons was evaluated with choline acetyltransferase immunohistochemistry. Within the mini-osmotic pumps, NGF activity diminished greatly during the first five days of implantation, but increased dramatically in the CSF after five days of infusion. The responsiveness of medial septal neurons to NGF was dose dependent and the ED50 for NGF injection was determined to be 14.08 μg/ml compared to 27.60 μg/ml for NGF infusion. Intermittent injections at varying intervals were evaluated with 30 μg/ml NGF over a fourteen-day time period (2, 3, 6, or 12 injections). No differences occurred in the number of choline acetyltransferase neurons from rats that received weekly injections to those that received daily injections of NGF. NGF administration has been suggested as a therapy for AD. The results of these studies continue to highlight the need for NGF stability within the delivery system and AD patient CSF, the choice of delivery system, frequency of administration, and the NGF dose for maintaining basal forebrain cholinergic neurons during AD.


Modification of pressure natriuresis by long-term losartan in spontaneously hypertensive rats.
The goal of this study was to determine how long-term treatment of spontaneously hypertensive rats with losartan affects the pressure-natriuresis curve. Rats were treated with losartan (12 to 15 mg.kg-1.d-1 in drinking water) starting at 4 to 5 weeks of age. At 8 to 9 weeks of age, pressure natriuresis was studied in treated and untreated anesthetized rats using a preparation involving volume expansion and fixed neural and hormonal influences on the kidney. In some untreated rats, losartan (10 or 30 mg.kg-1 i.v.) was given acutely. Average initial mean arterial pressure (+/- SEM) for untreated rats was 164 +/- 2 mm Hg (n = 13) and 131 +/- 3 mm Hg (n = 13) for rats treated chronically with losartan (P < .01). Short-term losartan did not alter arterial pressure significantly. Glomerular filtration rate was not altered significantly by losartan, and renal blood flow was increased modestly by long- and short-term (10 mg.kg-1) losartan at several levels of renal artery pressure. At renal artery pressures of 130 to 175 mm Hg, there were no significant differences between untreated and short-term losartan rats for urine flow, total and fractional sodium excretions, and renal interstitial hydrostatic pressure. The relation between renal artery pressure and urine flow, sodium excretion, or fractional sodium excretion was shifted to the left by long-term losartan treatment. At identical renal artery pressures, renal interstitial hydrostatic pressure was not significantly different among losartan-treated (short or long term) and respective control groups.(ABSTRACT TRUNCATED AT 250 WORDS)


A new web-based method for automated analysis of muscle histology.
Duchenne muscular dystrophy is an inherited degenerative neuromuscular disease characterised by rapidly progressive muscle weakness. Currently, curative treatment is not available. Approaches for new treatments that improve muscle strength and quality of life depend on preclinical testing in animal models. The mdx mouse model is the most frequently used animal model for preclinical studies in muscular dystrophy research. Standardised pathology-relevant parameters of dystrophic muscle in mdx mice for histological analysis have been developed in international, collaborative efforts, but automation has not been accessible to most research groups. A standardised and mainly automated quantitative assessment of histopathological parameters in the mdx mouse model is desirable to allow an objective comparison between laboratories. Immunological and histochemical reactions were used to obtain a double staining for fast and slow myosin. Additionally, fluorescence staining of the myofibre membranes allows defining the minimal Feret's diameter. The staining of myonuclei with the fluorescence dye bisbenzimide H was utilised to identify nuclei located internally within myofibres. Relevant structures were extracted from the image as single objects and assigned to different object classes using web-based image analysis (MyoScan). Quantitative and morphometric data were analysed, e.g. the number of nuclei per fibre and minimal Feret's diameter in 6 month old wild-type C57BL/10 mice and mdx mice. In the current version of the module "MyoScan", essential parameters for histologic analysis of muscle sections were implemented including the minimal Feret's diameter of the myofibres and the automated calculation of the percentage of internally nucleated myofibres. Morphometric data obtained in the present study were in good agreement with previously reported data in the literature and with data obtained from manual analysis. A standardised and mainly automated quantitative assessment of histopathological parameters in the mdx mouse model is now available. Automated analysis of histological parameters is more rapid and less time-consuming. Moreover, results are unbiased and more reliable. Efficacy of therapeutic interventions, e.g. within the scope of a drug screening or therapeutic exon skipping, can be monitored. The automatic analysis system MyoScan used in this study is not limited exclusively to dystrophin-deficient mice but also represents a useful tool for applications in the research of other dystrophic pathologies, various other skeletal muscle diseases and degenerative neuromuscular disorders.


Efficient allelic exchange and transposon mutagenesis in Mycobacterium tuberculosis.
A better understanding of Mycobacterium tuberculosis virulence mechanisms is highly dependent on the design of efficient mutagenesis systems. A system enabling the positive selection of insertional mutants having lost the delivery vector was developed. It uses ts-sacB vectors, which combine the counterselective properties of the sacB gene and a mycobacterial thermosensitive origin of replication and can therefore be efficiently counterselected on sucrose at 39 degrees C. This methodology allowed the construction of M. tuberculosis transposition mutant libraries. Greater than 10(6) mutants were obtained, far exceeding the number theoretically required to obtain at least one insertion in every nonessential gene. This system is also efficient for gene exchange mutagenesis as demonstrated with the purC gene: 100% of the selected clones were allelic exchange mutants. Therefore, a single, simple methodology has enabled us to develop powerful mutagenesis systems, the lack of which was a major obstacle to the genetic characterization of M. tuberculosis.


Increase in production of matrix metalloproteinase 13 by human articular chondrocytes due to stimulation with S100A4: Role of the receptor for advanced glycation end products.
S100 proteins have been implicated in various inflammatory conditions, including arthritis. The aims of this study were to determine whether chondrocytes produce S100A4 and whether S100A4 can stimulate the production of matrix metalloproteinase 13 (MMP-13) by articular chondrocytes via receptor for advanced glycation end products (RAGE)-mediated signaling. The expression of chondrocyte S100A4 was analyzed by immunohistochemistry using normal and osteoarthritic (OA) cartilage and by immunoblotting of chondrocyte cell lysates. RAGE signaling was examined by stimulating chondrocytes with S100A4 and monitoring for the activation of MAP kinases and NF-kappaB. Production of MMP-13 was determined in the conditioned medium. A pulldown assay using biotin-labeled S100A4 was used to demonstrate binding to RAGE. S100A4 expression was detected in human articular chondrocytes by immunoblotting and appeared to increase in the cell lysates from OA tissue. Marked positive immunostaining for S100A4 was also noted in sections of human cartilage with changes due to OA. Stimulation of chondrocytes with S100A4 increased the phosphorylation of Pyk-2, MAP kinases, and activated NF-kappaB, followed by increased production of MMP-13 in the conditioned medium. This signaling was inhibited in cells pretreated with soluble RAGE, advanced glycation end product-bovine serum albumin, or the antioxidant Mn(III)tetrakis (4-benzoic acid) porphyrin, or by overexpression of a dominant-negative RAGE construct. A pulldown assay showed that S100A4 binds to RAGE in chondrocytes. This is the first study to demonstrate that S100A4 binds to RAGE and stimulates a RAGE-mediated signaling cascade, leading to increased production of MMP-13. Since both S100A4 and RAGE are up-regulated in OA cartilage, this signaling pathway could contribute to cartilage degradation in OA.


National differences in publishing papers on adverse drug reactions.
To examine how countries differ in attitudes to adverse drug reactions by examining published scientific papers. We searched Ovid EMBASE for publications indexed by the category "therapeutic agents", and the subcategory "adverse effects", by country for 43 countries. We counted 1 810 202 papers world-wide regarding therapeutic agents during 14 years, of which 195 154 (10.8%) were included in the adverse effects subcategory. There were substantial differences between countries, not explained by population, economic variation, overall publication rate on therapeutic agents, or the presence of large indigenous pharmaceutical companies. Many local cultural factors influence the ratio of papers on adverse reactions to all drug effects, so it may be difficult to improve their recognition and reporting by international efforts.


The new anthelmintic tribendimidine is an L-type (levamisole and pyrantel) nicotinic acetylcholine receptor agonist.
Intestinal parasitic nematodes such as hookworms, Ascaris lumbricoides, and Trichuris trichiura are amongst most prevalent tropical parasites in the world today. Although these parasites cause a tremendous disease burden, we have very few anthelmintic drugs with which to treat them. In the past three decades only one new anthelmintic, tribendimidine, has been developed and taken into human clinical trials. Studies show that tribendimidine is safe and has good clinical activity against Ascaris and hookworms. However, little is known about its mechanism of action and potential resistance pathway(s). Such information is important for preventing, detecting, and managing resistance, for safety considerations, and for knowing how to combine tribendimidine with other anthelmintics. To investigate how tribendimidine works and how resistance to it might develop, we turned to the genetically tractable nematode, Caenorhabditis elegans. When exposed to tribendimidine, C. elegans hermaphrodites undergo a near immediate loss of motility; longer exposure results in extensive body damage, developmental arrest, reductions in fecundity, and/or death. We performed a forward genetic screen for tribendimidine-resistant mutants and obtained ten resistant alleles that fall into four complementation groups. Intoxication assays, complementation tests, genetic mapping experiments, and sequencing of nucleic acids indicate tribendimidine-resistant mutants are resistant also to levamisole and pyrantel and alter the same genes that mutate to levamisole resistance. Furthermore, we demonstrate that eleven C. elegans mutants isolated based on their ability to resist levamisole are also resistant to tribendimidine. Our results demonstrate that the mechanism of action of tribendimidine against nematodes is the same as levamisole and pyrantel, namely, tribendimidine is an L-subtype nAChR agonist. Thus, tribendimidine may not be a viable anthelmintic where resistance to levamisole or pyrantel already exists but could productively be used where resistance to benzimidazoles exists or could be combined with this class of anthelmintics.


Diabetes exacerbates the functional deficiency of NO/cGMP pathway associated with erectile dysfunction in human corpus cavernosum and penile arteries.
Diabetic men with erectile dysfunction (ED) are less responsive to therapy with type 5 phosphodiesterase (PDE5) inhibitors. Although an impairment of the nitric oxide (NO)/cyclic guanosin-monophosphate (cGMP) pathway has been shown in diabetic ED vs. non-diabetic ED, the functionality of NO/cGMP pathway in non-diabetic and diabetic ED patients with respect to non-ED patients has not been established. The aim of this study is to evaluate the function of NO/cGMP signalling in human erectile tissues from ED patients exploring the added impact of diabetes. Corpus cavernosum strips (human corpus cavernosum [HCC]) and penile resistance arteries (HPRA) were collected from penile specimens from organ donors (OD) and from diabetic and non-diabetic men with ED undergoing penile prosthesis implantation. Relaxations to acetylcholine, electrical field stimulation, sodium nitroprusside, and sildenafil were evaluated in phenylephrine-contracted HCC and norepinephrine-contracted HPRA. cGMP content in HCC was also determined. The impairment of endothelium-dependent relaxation in HCC and HPRA from ED patients was exacerbated by diabetes (E(max) 76.1, 62.9, and 49.3% in HCC and 73.1, 59.8, and 46.0% in HPRA from OD, non-diabetic and diabetic ED, respectively). Hypertension, hypercholesterolemia, or aging did not exert a further impairment of endothelial relaxation among ED patients. Diabetes also causes a further impairment of neurogenic relaxation in HCC and HPRA. The basal and stimulated content of cGMP in HCC was significantly decreased in patients with ED, but specially reduced in diabetic patients. Diabetes clearly impaired PDE5 inhibitor-induced vasodilation of HPRA from ED patients. ED is related to impaired vasodilation, reduced relaxant capacity, and diminished cGMP content in penile tissue. These alterations are more severe in diabetes and accompany reduced relaxant efficacy of PDE5 inhibition. Thus, an exacerbated reduction of nitric oxide/cGMP signaling could be responsible for ED in diabetic men and would explain their reduced response to treatment.


The geographic distribution of the ACE II genotype: a novel finding.
Angiotensin converting enzyme (ACE) gene polymorphism insertion (I) or deletion (D) has been widely studied in different populations, and linked to various functional effects and associated with common diseases. The purpose of the present study was to investigate the relationship between the ACE I/D frequency in different populations and geographic location; ACE I/D allele frequency in the Lebanese population and ACE II genotype contribution to the geographic trend were also identified. Five hundred and seventy healthy volunteers were recruited from the Lebanese population. Genomic DNA was extracted from buccal cells, and amplified by polymerase chain reaction; products were then identified by gel electrophoresis. The frequencies of the different ACE I/D genotypes were determined and tested for Hardy-Weinberg equilibrium (HWE). To assess the relationship between ACE I/D frequency and geographic location, and to identify how the Lebanese population contributes to the geographic trend in ACE I/D frequencies, Eurasian population samples and Asians were incorporated in the analyses from the literature. The frequency of the I allele in the Lebanese population was 27% and the corresponding II genotype was at a frequency of 7.37% (in HWE; P=0.979). The ACE I allele and genotype frequencies show an association with longitude, with frequencies increasing eastwards and westwards from the Middle East.


Chromium-doped forsterite laser with 1.1 W of continuous-wave output power at room temperature.
We demonstrate stable continuous-wave operation of a Cr:forsterite laser pumped by a cw Nd:YAG laser at 288 K. We use no choppers to limit the duty cycle of the cw system. The proper adjustment of the pump- and cavity-mode overlap based on the ABCD concept simulation eliminates the output power decrease at the high-level pump power. An output power of 1.1 W and slope efficiency of 26% are derived.


Cancer and COVID-19 Experiences at African Cancer Centers: The Silver Lining.
The COVID-19 pandemic significantly disrupted cancer care in Africa, further exposing major health disparities. This paper compares and contrasts the experiences of 15 clinicians in six different African cancer centers to highlight the positive aspects (silver linings) in an otherwise negative situation. Data are from personal experience of the clinicians working at the six cancer centers blended with what is available in the literature. The impact of COVID-19 on cancer care appeared to vary not only across the continent but also over cancer centers. Different factors such as clinic location, services offered, available resources, and level of restrictions imposed because of COVID-19 were associated with these variations. Collectively, delays in treatment and limited access to cancer care were commonly reported in the different regions. There is a lack of data on cancer patients with COVID-19 and online COVID-19 and cancer registries for Africa. Analysis of the available data, however, suggests a higher mortality rate for cancer patients with COVID-19 compared with those without cancer. Positive or silver linings coming out of the pandemic include the adoption of hypofractionated radiation therapy and teleoncology to enhance access to care while protecting patients and staff members. Increasing collaborations using online technology with oncology health professionals across the world are also being seen as a silver lining, with valuable sharing of experiences and expertise to improve care, enhance learning, and reduce disparities. Advanced information and communication technologies are seen as vital for such collaborations and could avail efforts in dealing with the ongoing pandemic and potential future crises.


A novel antigen-processing-defective phenotype in major histocompatibility complex class II-positive CIITA transfectants is corrected by interferon-gamma.
Presentation of exogenous protein antigens to T lymphocytes is based on the intersection of two complex pathways: (a) synthesis, assembly, and transport of major histocompatibility complex (MHC) class II-invariant chain complexes from the endoplasmic reticulum to a specialized endosomal compartment, and (b) endocytosis, denaturation, and proteolysis of antigens followed by loading of antigenic peptides onto newly synthesized MHC class II molecules. It is believed that expression of MHC class II heterodimers, invariant chain and human leukocyte antigen-DM is both necessary and sufficient to reconstitute a functional MHC class II loading compartment in antigen-presenting cells. Expression of each of these essential molecules is under the control of the MHC class II transactivator CIITA. Unexpectedly, however, whereas interferon gamma stimulation does confer effective antigen-processing function to nonprofessional antigen presenting cells, such as melanoma cells, expression of the CIITA transactivator alone is not sufficient. Activation of antigen-specific T cells thus requires additional CIITA-independent factor(s), and such factor(s) can be induced by interferon gamma.


Data on characterization of metalloporphyrin-mediated HO-1 and DAF induction in rat glomeruli and podocytes.
The data presented pertain to a research article titled "Heme Oxygenase 1 Up-Regulates Glomerular Decay Accelerating Factor Expression and Minimizes Complement Deposition and Injury" (Detsika et al., 2016). The present work provides additional data on induction and immunolocalization of heme oxygenase (HO)-1 (an antioxidant enzyme) and decay-accelerating factor (DAF) (a complement activation inhibitor) in isolated rat glomeruli and in glomerular epithelial cells (podocytes) in response to Iron Protoporphyrin IX (FePP, heme), and to non-iron protoporphyrins (PPs) with varying metal functionalities (ZnPP, SnPP), including a metal-devoid PP. Induction and immuno-localization of HO-1 and DAF in response to these metalloporphyrins (MP) were assessed using western blot analyses and confocal microscopy in isolated glomeruli and in cultured podocytes. These analyses identified podocytes as a major localization site of HO-1 and DAF induction in response to the aforementioned MPs. Effects of these MPs on a key glomerular structural protein, Nephrin, are also reported. The data identify MPs most and least capable of inducing DAF and reducing Nephrin expression and provide clues into expected outcomes of animal studies assessing MP efficacy in upregulating the cytoprotective proteins HO-1 and DAF.


Frequency distribution of lymphatic filariasis microfilariae in human populations: population processes and statistical estimation.
This paper uses simple mathematical models and statistical estimation techniques to analyse the frequency distribution of microfilariae (mf) in blood samples from human populations which are endemic for lymphatic filariasis. The theoretical analysis examines the relationship between microfilarial burdens and the prevalence of adult (macrofilarial) worms in the human host population. The main finding is that a large proportion of observed mf-negatives may be 'true' zeros, arising from the absence of macrofilarial infections or unmated adult worms, rather than being attributable to the blood sampling process. The corresponding mf distribution should then follow a Poisson mixture, arising from the sampling of mf positives, with an additional proportion of 'true' mf-zeros. This hypothesis is supported by analysis of observed Wuchereria bancrofti mf distributions from Southern India, Japan and Fiji, in which zero-truncated Poisson mixtures fit mf-positive counts more effectively than distributions including the observed zeros. The fits of two Poisson mixtures, the negative binomial and the Sichel distribution, are compared. The Sichel provides a slightly better empirical description of the mf density distribution; reasons for this improvement, and a discussion of the relative merits of the two distributions, are presented. The impact on observed mf distributions of increasing blood sampling volume and extraction efficiency are illustrated via a simple model, and directions for future work are identified.


TuPPL: Tub-tag mediated C-terminal protein-protein-ligation using complementary click-chemistry handles.
We introduce a chemoenzymatic strategy for straightforward in vitro generation of C-terminally linked fusion proteins. Tubulin tyrosine ligase is used for the incorporation of complementary click chemistry handles facilitating subsequent formation of functional bispecific antibody-fragments. This simple strategy may serve as central conjugation hub for a modular protein ligation platform.


Retrospective analysis of changes in the anterior corneal surface after Q value guided LASIK and LASEK in high myopic astigmatism for 3 years.
To compare the corneal high-order aberrations (HOAs), asphericity and regularity after Q-value guided laser in situ keratomileusis (LASIK) and laser epithelial keratomileusis (LASEK) in high myopic astigmatism. In this retrospectively comparative study, we measured the corneal HOAs, asphericity indices (Q values) and corneal regularity indices preoperatively and 36 months postoperatively in 70 eyes (35 patients) with Q-value guided surgeries. All the patients with high myopic astigmatism were divided into two groups which included 34 eyes underwent LASIK and 36 eyes underwent LASEK procedures. The main impact factors of the high-order aberrations were also analyzed. In the two groups, the efficacy index was more than 1.00 and safety index approached 1.00 at year 3 postoperatively. Statistically significant (P < 0.05) increased in Q values and main corneal HOAs (spherical aberrations and coma) following Q-value guided LASIK and LASEK procedures. Spherical aberrations increased more in the LASEK group and there was statistically difference compared to the LASIK group (P < 0.05). LASEK had better effects in correcting corneal astigmatism (P < 0.05). All the corneal regularity indices after surgeries increased and there was no significant difference (P = 0.707, P = 0.8 and P = 0.224, respectively) between the two groups. The main impact factors of spherical aberration included the optic zone size, changes of Q value, surgical procedure and the corrected refraction. In high myopic astigmatism, Q-value guided ablation showed good safety, efficacy and predictability. Q value, regularity indices, spherical aberration and coma increased in both LASIK and LASEK procedures. Astigmatism could be corrected more effectively by LASEK but greater spherical aberration could be created. The difference might be related to the different healing mechanisms. Optic zone size and the corrected refraction might be the main influence factors on the anterior corneal high order aberrations.


Identification of possible adverse drug reactions in clinical notes: The case of glucose-lowering medicines.
Through manual review of clinical notes for patients with type 2 diabetes mellitus attending a Danish diabetes center, the aim of the study was to identify adverse drug reactions (ADRs) associated with three classes of glucose-lowering medicines: "Combinations of oral blood-glucose lowering medicines" (A10BD), "dipeptidyl peptidase-4 (DDP-4) inhibitors" (A10BH), and "other blood glucose lowering medicines" (A10BX). Specifically, we aimed to describe the potential of clinical notes to identify new ADRs and to evaluate if sufficient information can be obtained for causality assessment. For observed adverse events (AEs) we extracted time to onset, outcome, and suspected medicine(s). AEs were assessed according to World Health Organization-Uppsala Monitoring Centre causality criteria and analyzed with respect to suspected medicines, type of ADR (system organ class), seriousness and labeling status. A total of 207 patients were included in the study leading to the identification of 163 AEs. 14% were categorized as certain, 60% as probable/likely, and 26% as possible. 15 (9%) ADRs were unlabeled of which two were serious: peripheral edema associated with sitagliptin and stomach ulcer associated with liraglutide. Of the unlabeled ADRs, 13 (87%) were associated with "other blood glucose lowering medications," the remaining 2 (13%) with "DDP-4 inhibitors." Clinical notes could potentially reveal unlabeled ADRs associated with prescribed medicines and sufficient information is generally available for causality assessment. However, manual review of clinical notes is too time-consuming for routine use and hence there is a need for developing information technology (IT) tools for automatic screening of patient records with the purpose to detect information about potentially serious and unlabeled ADRs.


Prevalence of and Risk Factors Associated With Nonfatal Overdose Among Veterans Who Have Experienced Homelessness.
Individuals with a history of homelessness are at increased risk for drug or alcohol overdose, although the proportion who have had recent nonfatal overdose is unknown. Understanding risk factors associated with nonfatal overdose could guide efforts to prevent fatal overdose. To determine the prevalence of recent overdose and the individual contributions of drugs and alcohol to overdose and to identify characteristics associated with overdose among veterans who have experienced homelessness. This survey study was conducted from November 15, 2017, to October 1, 2018, via mailed surveys with telephone follow-up for nonrespondents. Eligible participants were selected from the records of 26 US Department of Veterans Affairs medical centers and included veterans who had received primary care at 1 of these Veterans Affairs medical centers and had a history of experiencing homelessness according to administrative data. Preliminary analyses were conducted in October 2018, and final analyses were conducted in January 2020. Self-report of overdose (such that emergent medical care was obtained) in the previous 3 years and substances used during the most recent overdose. All percentages are weighted according to propensity to respond to the survey, modeled from clinical characteristics obtained in electronic health records. A total of 5766 veterans completed the survey (completion rate, 40.2%), and data on overdose were available for 5694 veterans. After adjusting for the propensity to respond to the survey, the mean (SD) age was 56.4 (18.3) years; 5100 veterans (91.6%) were men, 2225 veterans (38.1%) were black, and 2345 veterans (40.7%) were white. A total of 379 veterans (7.4%) reported any overdose during the past 3 years; 228 veterans (4.6%) reported overdose involving drugs, including 83 veterans (1.7%) who reported overdose involving opioids. Overdose involving alcohol was reported by 192 veterans (3.7%). In multivariable analyses, white race (odds ratio, 2.44 [95% CI, 2.00-2.98]), self-reporting a drug problem (odds ratio, 1.66 [95% CI, 1.39-1.98]) or alcohol problem (odds ratio, 2.54 [95% CI, 2.16-2.99]), and having witnessed someone else overdose (odds ratio, 2.34 [95% CI, 1.98-2.76]) were associated with increased risk of overdose. These findings suggest that nonfatal overdose is relatively common among veterans who have experienced homelessness. While overdose involving alcohol was more common than any specific drug, 1.7% of veterans reported overdose involving opioids. Improving access to addiction treatment for veterans who are experiencing homelessness or who are recently housed, especially for those who have experienced or witnessed overdose, could help to protect this population.


Risk factors for pressure ulcers in the spinal cord injured in the community.
A retrospective review was performed on the medical records of 29 patients with traumatic spinal cord injury who were admitted for pressure ulcer research protocols within the Division of Plastic Surgery at a university medical center in Southeast Texas. The purpose of the study was to identify common factors in the community that may contribute to the development of pressure ulcers in the spinal cord injured person at home, as a prelude to development of a risk assessment scale for use by the home care nurse. Oot-Giromini's Web of Causation was used as the theoretical framework for this study. Findings support current pressure ulcer research literature, implicating a diverse array of physical and psychosocial elements such as nutrition, past history of pressure ulcers, and social support issues as risk factors. Further research is needed before a risk assessment scale is formulated.


A thermostable messenger RNA based vaccine against rabies.
Although effective rabies virus vaccines have been existing for decades, each year, rabies virus infections still cause around 50.000 fatalities worldwide. Most of these cases occur in developing countries, where these vaccines are not available. The reasons for this are the prohibitive high costs of cell culture or egg grown rabies virus vaccines and the lack of a functional cold chain in many regions in which rabies virus is endemic. Here, we describe the excellent temperature resistance of a non-replicating mRNA based rabies virus vaccine encoding the rabies virus glycoprotein (RABV-G). Prolonged storage of the vaccine from -80°C to up to +70°C for several months did not impact the protective capacity of the mRNA vaccine. Efficacy after storage was demonstrated by the induction of rabies specific virus neutralizing antibodies and protection in mice against lethal rabies infection. Moreover, storing the vaccine at oscillating temperatures between +4° and +56°C for 20 cycles in order to simulate interruptions of the cold chain during vaccine transport, did not affect the vaccine's immunogenicity and protective characteristics, indicating that maintenance of a cold chain is not essential for this vaccine.


Effect of A New Housing System on Skin Lesions, Performance and Soiling of Fattening Rabbits: A German Case Study.
The aim of the present study was to develop and evaluate a new housing system for fattening rabbits. Data were collected on a farm with rabbits housed either under new conditions (NC) or established (conventional) conditions (CC). NC housing was characterized by large groups (Ø 58 rabbits, max. 12 rabbits/m2), slatted plastic floor (11 mm slats and 11 mm gaps), elevated platforms with partly solid floor, boxes and different enrichment materials. CC rabbits were kept in small groups (eight rabbits, 23 rabbits/m2) in cages with wire-mesh floor, an elevated platform, a box and one gnawing stick. Skin lesions and weight gain of 524 rabbits, cleanliness of their hind feet as well as their mortality and morbidity were investigated from weaning to slaughter in five batches. The evaluations showed higher daily weight gain (46.3 ± 6.0 g vs. 43.1 ± 5.5 g) and final weight (2878 ± 328 g vs. 2707 ± 299 g), as well as a lower cumulative lesion score at the middle of the fattening period in NC than in CC rabbits. Nevertheless, cleanliness of hind feet was assessed to be worse and mortality was higher in the NC housing. The NC system provided some benefits in terms of animal welfare compared to the conventional system, but hygienic challenges posed by this system make further adjustment necessary.


Buried Alive: The Behavioural Response of the Mussels, Modiolus modiolus and Mytilus edulis to Sudden Burial by Sediment.
Sedimentation in the sea occurs through natural processes, such as wave and tidal action, which can be exacerbated during storms and floods. Changes in terrestrial land use, marine aggregate extraction, dredging, drilling and mining are known to result in substantial sediment deposition. Research suggests that deposition will also occur due to the modern development of marine renewable energy. The response to individual burial under three depths of sediment, three sediment fractions and five burial durations was investigated in two mussel species, Modiolus modiolus and Mytilus edulis in specialist mesocosms. Both mussel species showed substantial mortality, which increased with duration of burial and burial by finer sediment fractions. M. modiolus was better able to survive short periods of burial than M. edulis, but at longer durations mortality was more pronounced. No mortality was observed in M. modiolus in burial durations of eight days or less but by 16 days of burial, over 50% cumulative mortality occurred. Under variable temperature regimes, M. edulis mortality increased from 20% at 8°C to over 60% at 14.5 and 20°C. Only M. edulis was able to emerge from burial, facilitated by increased byssus production, laid mostly on vertical surfaces but also on sediment particles. Emergence was higher from coarse sediment and shallow burials. Byssus production in M. edulis was not related to the condition index of the mussels. Results suggest that even marginal burial would result in mortality and be more pronounced in warm summer periods. Our results suggest that in the event of burial, adult M. modiolus would not be able to emerge from burial unless local hydrodynamics assist, whereas a small proportion of M. edulis may regain contact with the sediment water interface. The physiological stress resulting in mortality, contribution of local hydrodynamics to survival and other ecological pressures such as mussels existing in aggregations, are discussed.


A population genetics model for multiple quantitative traits exhibiting pleiotropy and epistasis.
We study a population genetics model of an organism with a genome of L(tot)loci that determine the values of T quantitative traits. Each trait is controlled by a subset of L loci assigned randomly from the genome. There is an optimum value for each trait, and stabilizing selection acts on the phenotype as a whole to maintain actual trait values close to their optima. The model contains pleiotropic effects (loci can affect more than one trait) and epistasis in fitness. We use adaptive walk simulations to find high-fitness genotypes and to study the way these genotypes are distributed in sequence space. We then simulate the evolution of haploid and diploid populations on these fitness landscapes and show that the genotypes of populations are able to drift through sequence space despite stabilizing selection on the phenotype. We study the way the rate of drift and the extent of the accessible region of sequence space is affected by mutation rate, selection strength, population size, recombination rate, and the parameters L and T that control the landscape shape. There are three regimes of the model. If LT<<L(tot), there are many high fitness genotypes and the population may evolve neutrally on high-fitness plateaux. If LT approximately L(tot), there are a few high-fitness genotypes which tend to be close together. The population is confined to a small region of sequence space if selection is strong, but can explore more widely if selection is weaker. If LT>>L(tot), there are many small peaks that can be spread over a wide region of sequence space. Compensatory neutral mutations are important in the population dynamics in this case.


Radiomics and Machine Learning for Radiotherapy in Head and Neck Cancers.
Introduction: An increasing number of parameters can be considered when making decisions in oncology. Tumor characteristics can also be extracted from imaging through the use of radiomics and add to this wealth of clinical data. Machine learning can encompass these parameters and thus enhance clinical decision as well as radiotherapy workflow. Methods: We performed a description of machine learning applications at each step of treatment by radiotherapy in head and neck cancers. We then performed a systematic review on radiomics and machine learning outcome prediction models in head and neck cancers. Results: Machine Learning has several promising applications in treatment planning with automatic organ at risk delineation improvements and adaptative radiotherapy workflow automation. It may also provide new approaches for Normal Tissue Complication Probability models. Radiomics may provide additional data on tumors for improved machine learning powered predictive models, not only on survival, but also on risk of distant metastasis, in field recurrence, HPV status and extra nodal spread. However, most studies provide preliminary data requiring further validation. Conclusion: Promising perspectives arise from machine learning applications and radiomics based models, yet further data are necessary for their implementation in daily care.


Intracellular sorting of neuromodulin (GAP-43) mutants modified in the membrane targeting domain.
Neuromodulin (GAP-43) is a neurospecific calmodulin binding protein that is targeted to neuronal growth cones via fast axonal transport by an undefined mechanism. The protein is associated with membranes by palmitoylation of cys-3 and cys-4. The objective of this study was to examine the intracellular localization of neuromodulin and neuromodulin mutants modified in the membrane targeting domain of the protein in neurons and non-neuronal cells. The N-terminal palmitoylation domain of neuromodulin was found to be sufficient for membrane and Golgi targeting as well as neurite transport. A fusion protein consisting of the N-terminal 20 amino acids of neuromodulin and beta-galactosidase accumulated in neurite endings demonstrating that this sequence is sufficient for targeting to growth cone membranes. Mutations in the palmitoylation domain of neuromodulin that abolished its acylation and membrane association diminished its Golgi localization. Mutations that prevented Golgi accumulation of neuromodulin-beta-galactosidase fusion proteins also interfered with neurite transport of the fusion proteins. These data demonstrate a correlation between membrane targeting, Golgi localization, and neurite transport of neuromodulin.


Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3.
During the process of autophagy, autophagosomes undergo a maturation process consisting of multiple fusions with endosomes and lysosomes, which provide an acidic environment and digestive function to the interior of the autophagosome. Here we found that a fusion protein of monomeric red-fluorescence protein and LC3, the most widely used marker for autophagosomes, exhibits a quite different localization pattern from that of GFP-LC3. GFP-LC3 loses fluorescence due to lysosomal acidic and degradative conditions but mRFP-LC3 does not, indicating that the latter can label the autophagic compartments both before and after fusion with lysosomes. Taking advantage of this property, we devised a novel method for dissecting the maturation process of autophagosomes. mRFP-GFP tandem fluorescent-tagged LC3 (tfLC3) showed a GFP and mRFP signal before the fusion with lysosomes, and exhibited only the mRFP signal subsequently. Using this method, we provided evidence that overexpression of a dominant negative form of Rab7 prevented the fusion of autophagosomes with lysosomes, suggesting that Rab7 is involved in this step. This method will be of general utility for analysis of the autophagosome maturation process.


MBL2 Genetic Variants in HCV Infection Susceptibility, Spontaneous Viral Clearance and Pegylated Interferon Plus Ribavirin Treatment Response.
Hepatitis C is disease that damages the liver, and it is caused by the hepatitis C virus (HCV). The pathology became chronic in about 80% of the cases due to virus persistence in the host organism. The standard of care consists of pegylated interferon plus ribavirin; however, the treatment response is very variable and different host/viral factors may concur in the disease outcome. The mannose-binding protein C (MBL) is a component of the innate immune system, able to recognize HCV and consecutively activating the immune response. MBL is encoded by MBL2 gene, and polymorphisms, two in the promoter region (H/L and X/Y) and three in exon 1 (at codon 52, 54 and 57), have been described as functionally influencing protein expression. In this work, 203 Italian HCV patients and 61 healthy controls were enrolled and genotyped for the five MBL2 polymorphisms mentioned above to investigate their role in HCV infection susceptibility, spontaneous viral clearance and treatment response. MBL2 polymorphisms were not associated with HCV infection susceptibility and with spontaneous viral clearance, while MBL2 O allele, O/O genotype, HYO haplotype and DP combined genotype (all correlated with low or deficient MBL expression) were associated with sustained virological response. Moreover, a meta-analysis to assess the role of MBL2 polymorphisms in HCV infection susceptibility was also performed: YA haplotype could be associated with protection towards HCV infection.


A hybrid fiber-optic photoluminescence measurement system and its application in InGaN/GaN light emitting diode epi-wafer morphology studies.
We report a fiber optic photoluminescence (PL) measurement system using a novel hybrid probe composed of a series of single mode fiber (SMF) and double-clad fiber (DCF) terminated with a coreless silica fiber (CSF) segment and glass micro-lens formed on its cleaved-facet. The fiber probe provided a good guidance and focusing capability for the excitation photon with a focal length of 125 μm and a beam diameter of 13.6 μm. Utilizing a special DCF-to-DCF coupling scheme, the photoluminescence signals were efficiently collected and delivered to a photodetector with a low loss. Utilizing the proposed system, PL morphology was investigated over a 200 × 200 μm(2) area for two types of InGaN/GaN blue light emitting diode (LED) epi-wafers grown on 1) an un-patterned sapphire substrate (UPSS), and 2) a patterned sapphire substrate (PSS). The uniformity in the relative PL intensity and the spectral uniformity in terms of the peak PL wavelength were experimentally compared and analyzed.


Changes in early maladaptive schemas after residential treatment for substance use.
Early maladaptive schemas are cognitive and behavioral patterns that cause considerable distress and are theorized to underlie mental health problems. Research suggests that early maladaptive schemas may underlie substance abuse and that the intensity of early maladaptive schemas may decrease after brief periods of abstinence. The current study examined changes in early maladaptive schemas after a 4-week residential substance use treatment program. Preexisting records of a sample of male alcohol- and opioid-dependent treatment seeking adults (N = 97; mean age = 42.55) were reviewed for the current study. Pre-post analyses demonstrated that 8 of the early maladaptive schemas significantly decreased by the end of the 4-week treatment. Findings indicate that early maladaptive schemas can be modified during brief substance use treatment and may be an important component of substance use intervention programs. Implications of these findings for substance use treatment are discussed.


Fiber mediated receptor masking in non-infected bystander cells restricts adenovirus cell killing effect but promotes adenovirus host co-existence.
The basic concept of conditionally replicating adenoviruses (CRAD) as oncolytic agents is that progenies generated from each round of infection will disperse, infect and kill new cancer cells. However, CRAD has only inhibited, but not eradicated tumor growth in xenograft tumor therapy, and CRAD therapy has had only marginal clinical benefit to cancer patients. Here, we found that CRAD propagation and cancer cell survival co-existed for long periods of time when infection was initiated at low multiplicity of infection (MOI), and cancer cell killing was inefficient and slow compared to the assumed cell killing effect upon infection at high MOI. Excessive production of fiber molecules from initial CRAD infection of only 1 to 2% cancer cells and their release prior to the viral particle itself caused a tropism-specific receptor masking in both infected and non-infected bystander cells. Consequently, the non-infected bystander cells were inefficiently bound and infected by CRAD progenies. Further, fiber overproduction with concomitant restriction of adenovirus spread was observed in xenograft cancer therapy models. Besides the CAR-binding Ad4, Ad5, and Ad37, infection with CD46-binding Ad35 and Ad11 also caused receptor masking. Fiber overproduction and its resulting receptor masking thus play a key role in limiting CRAD functionality, but potentially promote adenovirus and host cell co-existence. These findings also give important clues for understanding mechanisms underlying the natural infection course of various adenoviruses.


Enoxacin compared with vancomycin for the treatment of experimental methicillin-resistant Staphylococcus aureus endocarditis.
Enoxacin administered orally was compared with vancomycin administered intravenously for the treatment of experimental methicillin-resistant Staphylococcus aureus endocarditis. The MICs and MBCs of both enoxacin and vancomycin for an inoculum of 5.0 X 10(5) CFU of the methicillin-resistant S. aureus strain per ml were 1.56 microgram/ml. With an inoculum of 10(8) CFU/ml, enoxacin at 6 micrograms/ml and vancomycin at 180 micrograms/ml resulted in similar decreases in numbers of methicillin-resistant S. aureus in broth. Methicillin-resistant S. aureus endocarditis in rabbits was treated with enoxacin at 100 mg/kg orally every 12 h or vancomycin at 30 mg/kg intravenously every 12 h for 3 or 5 days. Enoxacin treatment for 3 or 5 days and vancomycin treatment for 5 days significantly reduced bacterial counts of vegetations compared with those in untreated control rabbits after 1 day of infection. Bacterial counts of vegetations after vancomycin treatment for 3 days did not differ significantly from those of untreated controls. Bacterial counts of vegetations in the four therapeutic groups did not differ significantly from one another. In uninfected rabbits single doses of vancomycin at 30 mg/kg administered intravenously achieved much higher concentrations in serum than did single doses of enoxacin at 100 mg/kg administered orally. Enoxacin had an elimination half-life in serum that was approximately 1.5 times longer than that of vancomycin. This study demonstrated that enoxacin administered orally is as effective as vancomycin administered intravenously for the treatment of experimental methicillin-resistant S. aureus endocarditis.


Molecular basis of attenuation of neurovirulence of wild-type Japanese encephalitis virus strain SA14.
To identify the molecular determinants for attenuation of wild-type Japanese encephalitis (JE) virus strain SA14, the RNA genome of wild-type strain SA14 and its attenuated vaccine virus SA14-2-8 were reverse transcribed, amplified by PCR and sequenced. Comparison of the nucleotide sequence of SA14-2-8 vaccine virus with virulent parent SA14 virus and with two other attenuated vaccine viruses derived from SA14 virus (SA14-14-2/PHK and SA14-14-2/PDK) revealed only seven amino acids in the virulent parent SA14 had been substituted in all three attenuated vaccines. Four were in the envelope (E) protein (E-138, E-176, E-315 and E-439), one in non-structural protein 2B (NS2B-63), one in NS3 (NS3-105), and one in NS4B (NS4B-106). The substitutions at E-315 and E-439 arose due to correction of the SA14/CDC sequence published previously by Nitayaphan et al. (Virology 177, 541-552, 1990). The mutations in NS2B and NS3 are in functional domains of the trypsin-like serine protease. Attenuation of SA14 virus may therefore, in part, be due to alterations in viral protease activity, which could affect replication of the virus.


Enhanced skin carcinogenesis and lack of thymus hyperplasia in transgenic mice expressing human cyclin D1b (CCND1b).
Cyclin D1b is an alternative transcript of the cyclin D1 gene (CCND1) expressed in human tumors. Its abundance is regulated by a single base pair polymorphism at the exon 4/intron 4 boundary (nucleotide 870). Epidemiological studies have shown a correlation between the presence of the G870A allele (that favors the splicing for cyclin D1b) with increased risk and less favorable outcome in several forms of cancer. More recently, it has been shown that, unlike cyclin D1a, the alternative transcript D1b by itself has the capacity to transform fibroblasts in vitro. In order to study the oncogenic potential of cyclin D1b, we developed transgenic mice expressing human cyclin D1b under the control of the bovine K5 promoter (K5D1b mice). Seven founders were obtained and none of them presented any significant phenotype or developed spontaneous tumors. Interestingly, K5D1b mice do not develop the fatal thymic hyperplasia, which is characteristic of the cyclin D1a transgenic mice (K5D1a). Susceptibility to skin carcinogenesis was tested in K5D1b mice using two-stage carcinogenesis protocols. In two independent experiments, K5D1b mice developed higher papilloma multiplicity as compared with wild-type littermates. However, when K5D1b mice were crossed with cyclin D1KO mice, the expression of cyclin D1b was unable to rescue the carcinogenesis-resistant phenotype of the cyclin D1 KO mice. To further explore the role of cyclin D1b in mouse models of carcinogenesis we carried out in silico analysis and in vitro experiments to evaluate the existence of a mouse homologous of the human cyclin D1b transcript. We were unable to find any evidence of an alternatively spliced transcript in mouse Ccnd1. These results show that human cyclin D1b has different biological functions than cyclin D1a and confirm its oncogenic properties.


Two degrees-of-freedom Lloyd-mirror interferometer for superior pattern coverage area.
In this study, we have developed a tunable Lloyd-mirror interferometer with two degrees of freedom, in contrast to a traditional system with one degree of freedom. This new Lloyd-mirror interferometer allows an angular rotation of the mirror independently from that of a sample stage, resulting in an increased pattern coverage area with tunable pattern periodicity. Both theoretical and experimental results verify that the tunable characteristic of the modified configuration enhances the nanopatterning capabilities of the Lloyd-mirror interference lithography system especially in achieving greater pattern coverage area for larger pattern periodicities.


Patterns of psychological responses in parents of children that underwent stem cell transplantation.
Hematopoietic stem cell transplantation (HSCT) is curative in several life-threatening pediatric diseases but may affect children and their families inducing depression, anxiety, burnout symptoms, and post-traumatic stress symptoms, as well as post-traumatic growth (PTG). The aim of this study was to investigate the co-occurrence of different aspects of such responses in parents of children that had undergone HSCT. Questionnaires were completed by 260 parents (146 mothers and 114 fathers) 11-198 months after HSCT: the Hospital Anxiety and Depression Scale, the Shirom-Melamed Burnout Questionnaire, the post-traumatic stress disorders checklist, civilian version, and the PTG inventory. Additional variables were also investigated: perceived support, time elapsed since HSCT, job stress, partner-relationship satisfaction, trauma appraisal, and the child's health problems. A hierarchical cluster analysis and a k-means cluster analysis were used to identify patterns of psychological responses. Four clusters of parents with different psychological responses were identified. One cluster (n = 40) significantly differed from the other groups and reported levels of depression, anxiety, burnout symptoms, and post-traumatic stress symptoms above the cut-off. In contrast, another cluster (n = 66) reported higher levels of PTG than the other groups did. This study shows a subgroup of parents maintaining high levels of several aspects of distress years after HSCT. Differences between clusters might be explained by differences in perceived support, the child's health problems, job stress, and partner-relationship satisfaction.


Burden of dental caries and periodontal disease in South Korea: An analysis using the national health insurance claims database.
It is essential to measure and monitor the burden of dental caries and periodontal disease (PD) in Korea's ageing population due to their potential impact on morbidity, quality of life and economic condition. This study aimed to quantify the size of burden of dental caries and PD using the disability-adjusted life years (DALYs), and their trends. DALYs were estimated using incidence-based approaches to calculate the burden of dental caries and PD from 2013 to 2015 in Korea. Incidence and prevalence were estimated using medical claim data by specific algorithms. Additionally, sensitivity analysis was conducted to investigate possible weakness in the study methodology. To conduct the sensitivity analysis, we modified the algorithms to estimate prevalence and incidence. The burden of dental caries and PD increased by 39.2% and 57.0%, respectively, between 2013 and 2015. In 2015, dental caries and PD ranked 11th and 25th, respectively, in terms of the leading causes of DALYs. The burden of dental caries was the most substantial in children aged 0-9 years, while that of PD was the most substantial among those in their ages of 40 and 50 (per 100 000 population). After sensitivity analysis with a modified disease algorithm, the magnitude of disease burden changed considerably. Dental caries and PD constitute substantial burdens in South Korea. Despite the known limitations, medical claims data can be a powerful resource for conducting timely and cost-effective measurements of oral health. In countries, where universal dental schemes are available, there is need to estimate the burden of oral disease using claims data, for methodical advances in the research field.


Psychological autopsy study of suicides by people aged under 35.
In the past two decades the suicide rate in young people has risen in the UK and other countries. To identify the characteristics of people aged under 35 who commit suicide. Psychological autopsy study with case-control design. Cases were 84 suicides and probable suicides (open verdicts). Controls were 64 age- and gender-matched non-suicides obtained through the general practices of the matched cases. social, including employment status, marital status and living circumstances; life events and interpersonal difficulties; clinical, including current psychiatric disorder, alcohol and drug misuse, previous self-harm and personality disorder. A large number of highly significant social, interpersonal and clinical differences between suicides and controls was found. Factor analysis identified two groups of variables within each of the social, interpersonal and clinical domains which were independently linked to suicide, corresponding to: acute, severe mental disorder and chronic disorder of behaviour; rootlessness and social withdrawal; chronic and recent interpersonal problems. A broad prevention strategy is needed to reverse the recent rise in the suicide rate in young people.


The effect of racial residential segregation on black infant mortality.
Economic differences and proximal risk factors do not fully explain the persistent high infant mortality rates of African Americans (blacks). The authors hypothesized that racial residential segregation plays an independent role in high black infant mortality rates. Segregation restricts social and economic advantage and imposes negative environmental exposures that black women and infants experience. The study sample was obtained from the 2000-2002 US Linked Birth/Infant Death records and included 677,777 black infants residing in 64 cities with 250,000 or more residents. Outcomes were rates of all-cause infant mortality, postneonatal mortality, and external causes of death. Segregation was measured by using the isolation index (dichotomized at 0.60) from the 2000 US Census Housing Patterns. Propensity score matching methods were used. After matching on propensity scores, no independent effect of segregation on black infant mortality rates was found. Results show little statistical evidence that segregation plays an independent role in black infant mortality. However, a key finding is that it is difficult to disentangle contextual effects from the characteristics of individuals.


'Kids are just cruel anyway': lesbian and gay parents' talk about homophobic bullying.
Psychologists recognize homophobic bullying as a serious problem for young lesbians and gay men; however, when it comes to children in lesbian and gay households the issue is not so clear cut. Some psychologists sympathetic to lesbian and gay parenting regard it as a problem, but most do not. Despite this, the inevitability and severe psychological consequences of homophobic bullying is a prevalent theme in discussions of lesbian and gay parenting in contexts ranging from custody cases to television talk shows, and is used to implicate lesbians and gay men as unfit to parent. This is the broader context in which lesbian and gay parents discuss their children's experiences of bullying. In this study, we provide a discursive psychological analysis of six lesbian and gay parents' accounts of bullying. We argue that these accounts are discursively and rhetorically designed to deal with a heterosexist social/political context. Lesbian and gay parents face a dilemma of stake and accountability: reports of no bullying risk being heard as implausible given the prevalence of the bullying theme; at the same time, reports of bullying are equally if not more risky, raising the possibility of charges of bad parenting. We explore the detail of the parents' accounts of bullying to illustrate how they are designed to negotiate this web of accountability, and we argue for the importance for critical social psychology of analysing the talk of socially/politically marginalized groups.


Effectiveness of mentoring programs for youth: a meta-analytic review.
We used meta-analysis to review 55 evaluations of the effects of mentoring programs on youth. Overall, findings provide evidence of only a modest or small benefit of program participation for the average youth. Program effects are enhanced significantly, however, when greater numbers of both theory-based and empirically based "best practices" are utilized and when strong relationships are formed between mentors and youth. Youth from backgrounds of environmental risk and disadvantage appear most likely to benefit from participation in mentoring programs. Outcomes for youth at-risk due to personal vulnerabilities have varied substantially in relation to program characteristics, with a noteworthy potential evident for poorly implemented programs to actually have an adverse effect on such youth. Recommendations include greater adherence to guidelines for the design and implementation of effective mentoring programs as well as more in-depth assessment of relationship and contextual factors in the evaluation of programs.


Association of insurance status and ethnicity with cancer stage at diagnosis for 12 cancer sites: a retrospective analysis.
Individuals in the USA without private medical insurance are less likely to have access to medical care or participate in cancer screening programmes than those with private medical insurance. Smaller regional studies in the USA suggest that uninsured and Medicaid-insured individuals are more likely to present with advanced-stage cancer than privately insured patients; however, this finding has not been assessed using contemporary, national-level data. Furthermore, patients with cancer from ethnic minorities are more likely to be uninsured or Medicaid-insured than non-Hispanic white people. Separating the effects on stage of cancer at diagnosis associated with these two types of patient characteristics can be difficult. Patients with cancer in the USA, diagnosed between 1998 and 2004, were identified using the US National Cancer Database-a hospital-based registry that contains patient information from about 1430 facilities. Odds ratios and 95% CIs for the effect of insurance status (Medicaid, Medicare (65-99 years), Medicare (18-64 years), private, or uninsured) and ethnicity (white, Hispanic, black, or other) on disease stage at diagnosis for 12 cancer sites (breast [female], colorectal, kidney, lung, melanoma, non-Hodgkin lymphoma, ovary, pancreas, prostate, urinary bladder, uterus, and thyroid) were estimated, while controlling for patient characteristics. 3,742,407 patients were included in the analysis; patient characteristics were similar to those of the corresponding US population not included in the analysis. Uninsured and Medicaid-insured patients were significantly more likely to present with advanced-stage cancer compared with privately insured patients. This finding was most prominent for patients who had cancers that can potentially be detected early by screening or symptom assessment (eg, breast, colorectal, and lung cancer, as well as melanoma). For example, the odds ratios for advanced-stage disease (stage III or IV) at diagnosis for uninsured or Medicaid-insured patients with colorectal cancer were 2.0 (95% CI 1.9-2.1) and 1.6 (95% CI 1.5-1.7), respectively, compared with privately-insured patients. For advanced-stage melanoma, the odds ratios were 2.3 (2.1-2.5) for uninsured patients and 3.3 (3.0-3.6) for Medicaid-insured patients compared with privately insured patients. Black and Hispanic patients were noted to have an increased risk of advanced-stage disease (stage III or IV) at diagnosis, irrespective of insurance status, compared with White patients. In this US-based analysis, uninsured and Medicaid-insured patients, and those from ethnic minorities, had substantially increased risks of presenting with advanced-stage cancers at diagnosis. Although many factors other than insurance status also affect the quality of care received, adequate insurance is a crucial factor for receiving appropriate cancer screening and timely access to medical care.


Neuroprotective Effects of neuroEPO Using an In Vitro Model of Stroke.
Erythropoietin (EPO) is a glycoprotein initially identified as a hormone synthesized and secreted by the kidney that regulates erythropoiesis. EPO, and a group of its derivatives, are being evaluated as possible neuroprotective agents in cerebral ischemia. The objective of this study, using an in vitro model, was to determine how neuroEPO-which is a variant of EPO with a low sialic acid content-protects neurons from the toxic action of glutamate. Primary neuronal cultures were obtained from the forebrains of Wistar rat embryos after 17 days of gestation. Excitotoxicity was induced after nine days of in vitro culture by treatment with a medium containing 100 µM glutamate for 15 min. After this time, a new medium containing 100 ng of neuroEPO/mL was added. Morphological cell change was assessed by phase-contrast microscopy. Oxidative stress was analysed by measuring antioxidant and oxidant activity. After 24 h, the treatment with 100 ng of neuroEPO/mL showed a significant (p < 0.01) decrease in mortality, compared to cells treated with glutamate alone. neuroEPO treatment decreased mortality and tended to reproduce the morphological characteristics of the control. The oxidative stress induced by glutamate is reduced after neuroEPO treatment. These results confirm that neuroEPO has a protective effect against neuronal damage induced by excitotoxicity, improving antioxidant activity in the neuron, and protecting it from oxidative stress.


CD4+ T lymphocytes enumeration by an easy-to-use single platform image cytometer for HIV monitoring in resource-constrained settings.
HIV monitoring in resource-constrained settings demands affordable and reliable CD4(+) T lymphocytes enumeration methods. We developed a simple single platform image cytometer (SP ICM), which is a dedicated volumetric CD4(+) T lymphocytes enumeration system that uses immunomagnetic and immunofluorescent technologies. The instrument was designed to be a low-cost, yet reliable and robust one. In this article we test the instrument and the immunochemical procedures used on blood from HIV negative and HIV positive patients. After CD4 immunomagnetic labeling in whole blood, CD4(+) T lymphocytes, CD4(+dim) monocytes and some nonspecifically labeled cells are magnetically attracted to an analysis surface. Combining with CD3-Phycoerythrin (PE) labeling, only CD3(+)CD4(+) T lymphocytes are fluorescently labeled and visible in a fluorescent image of the analysis surface. The number of CD4(+) T lymphocytes is obtained by image analysis. Alternatively, CD3 immunomagnetic selection in combination with CD4 immunofluorescent labeling can also be applied for CD4(+) T lymphocytes enumeration. The SP ICM system was compared with two single platform flow cytometer (SP FCM) methods: tetraCXP and TruCount methods. The SP ICM system has excellent precision, accuracy and linearity for CD4(+) T lymphocytes enumeration. Good correlations were obtained between the SP ICM and the SP FCM methods for blood specimens of 44 HIV(-) patients, and of 63 HIV(+) patients. Bland-Altman plots showed interchangeability between the SP ICM and the SP FCM methods. The immunolabeling methods and the instrumentation are simple and easy-to-handle for less-trained operators. The SP ICM system is a good candidate for CD4(+) T lymphocytes enumeration in point-of-care settings of resource-constrained countries.


A locus control region adjacent to the human red and green visual pigment genes.
Deletion of sequences 5' of the human red and green pigment gene array results in blue cone monochromacy, a disorder in which both red and green cone function are absent. To test whether these sequences are required for transcription of the adjacent visual pigment genes in cone photoreceptors, we produced transgenic mice carrying sequences upstream of the red and green pigment genes fused to a beta-galactosidase reporter. The patterns of transgene expression indicate that the human sequences direct expression to both long and short wave-sensitive cones in the mouse retina and that a region between 3.1 kb and 3.7 kb 5' of the red pigment gene transcription initiation site is essential for expression. Sequences within this region are highly conserved among humans, mice, and cattle, even though the latter two species have only a single visual pigment gene at this locus. These experiments suggest a model in which an interaction between the conserved 5' region and either the red or the green pigment gene promoter determines which of the two genes a given cone expresses.


Patient coping strategies in COPD across disease severity and quality of life: a qualitative study.
Quality of life (QoL) has a weak relationship with lung function (LF) impairment in COPD; some cope well despite poor LF, whereas others suffer disproportionate QoL impairment despite well-preserved LF. Adjuvant non-pharmacological interventions such as rehabilitation and psychological/behavioural support may help if acceptable and targeted appropriately, but they are under-used and sometimes declined by patients. This study aimed to explore and understand variations in experiences and coping strategies in patients with different severities of disease and disease-specific QoL. Thirty-four participants were purposively sampled across a spectrum of LF and QoL impairment, to cover a grid of sub-groups ('very severe LF, good QoL', moderate LF, poor QoL' and so on). Semi-structured interviews, digitally recorded, were analysed by thematic analysis. Data saturation was achieved. Four themes emerged: symptom impact, coping strategies, coping challenges and support needs. Most of them described using multiple coping strategies, yet over half reported significant challenges coping with COPD, including psychological impact, non-acceptance of diagnosis and/or disease progression, effects of co-morbidities and inadequate self-management skills. Approximately half of the participants wanted further help, ideally non-pharmacological, across all LF impairment groups but mainly with lower QoL. Those with lower QoL additionally reported greater psychological distress and greater use of non-pharmacological support strategies where accessible. Patients who develop effective coping strategies have a better QoL independent of objective LF, whereas others cope poorly, are aware of this and report more use of non-pharmacological approaches. This study suggests that severely impaired QoL, irrelevant of lung function, is a powerful patient-centred indication to explore the positive benefits of psychological and behavioural support for distressed COPD patients.


Perturbation of lipids and glucose metabolism associated with previous 2,4-D exposure: a cross-sectional study of NHANES III data, 1988-1994.
Results from previous population studies showed that mortality rates from acute myocardial infarction and type-2 diabetes during the 1980s and 1990s in rural, agricultural counties of Minnesota, Montana, North and South Dakota, were higher in counties with a higher level of spring wheat farming than in counties with lower levels of this crop. Spring wheat, one of the major field crops in these four states, was treated for 85% or more of its acreage with chlorophenoxy herbicides. In the current study NHANES III data were reviewed for associations of 2,4-dichlorophenoxy acetic acid (2,4-D) exposure, one of the most frequently used chlorophenoxy herbicides, with risk factors that are linked to the pathogenesis of acute myocardial infarction and type-2 diabetes, such as dyslipidemia and impaired glucose metabolism. To investigate the toxicity pattern of chlorophenoxy herbicides, effects of a previous 2,4-D exposure were assessed by comparing levels of lipids, glucose metabolism, and thyroid stimulating hormone in healthy adult NHANES III subjects with urinary 2,4-D above and below the level of detection, using linear regression analysis. The analyses were conducted for all available subjects and for two susceptible subpopulations characterized by high glycosylated hemoglobin (upper 50th percentile) and low thyroxine (lower 50th percentile). Presence of urinary 2,4-D was associated with a decrease of HDL levels: 8.6% in the unadjusted data (p-value = 0.006), 4.8% in the adjusted data (p-value = 0.08), and 9% in the adjusted data for the susceptible subpopulation with low thyroxine (p-value = 0.02). An effect modification of the inverse triglycerides-HDL relation was observed in association with 2,4-D. Among subjects with low HDL, urinary 2,4-D was associated with increased levels of triglycerides, insulin, C-peptide, and thyroid stimulating hormone, especially in the susceptible subpopulations. In contrast, subjects with high HDL did not experience adverse 2,4-D associated effects. The results indicate that exposure to 2,4-D was associated with changes in biomarkers that, based on the published literature, have been linked to risk factors for acute myocardial infarction and type-2 diabetes.


Revealing dynamically-organized receptor ion channel clusters in live cells by a correlated electric recording and super-resolution single-molecule imaging approach.
The N-methyl-d-aspartate (NMDA) receptor ion-channel is activated by the binding of ligands, along with the application of action potential, important for synaptic transmission and memory functions. Despite substantial knowledge of the structure and function, the gating mechanism of the NMDA receptor ion channel for electric on-off signals is still a topic of debate. We investigate the NMDA receptor partition distribution and the associated channel's open-close electric signal trajectories using a combined approach of correlating single-molecule fluorescence photo-bleaching, single-molecule super-resolution imaging, and single-channel electric patch-clamp recording. Identifying the compositions of NMDA receptors, their spatial organization and distributions over live cell membranes, we observe that NMDA receptors are organized inhomogeneously: nearly half of the receptor proteins are individually dispersed; whereas others exist in heterogeneous clusters of around 50 nm in size as well as co-localized within the diffraction limited imaging area. We demonstrate that inhomogeneous interactions and partitions of the NMDA receptors can be a cause of the heterogeneous gating mechanism of NMDA receptors in living cells. Furthermore, comparing the imaging results with the ion-channel electric current recording, we propose that the clustered NMDA receptors may be responsible for the variation in the current amplitude observed in the on-off two-state ion-channel electric signal trajectories. Our findings shed new light on the fundamental structure-function mechanism of NMDA receptors and present a conceptual advancement of the ion-channel mechanism in living cells.


SPNS2 enables T cell egress from lymph nodes during an immune response.
T cell expression of sphingosine 1-phosphate (S1P) receptor 1 (S1PR1) enables T cell exit from lymph nodes (LNs) into lymph, while endothelial S1PR1 expression regulates vascular permeability. Drugs targeting S1PR1 treat autoimmune disease by trapping pathogenic T cells within LNs, but they have adverse cardiovascular side effects. In homeostasis, the transporter SPNS2 supplies lymph S1P and enables T cell exit, while the transporter MFSD2B supplies most blood S1P and supports vascular function. It is unknown whether SPNS2 remains necessary to supply lymph S1P during an immune response, or whether in inflammation other compensatory transporters are upregulated. Here, using a model of dermal inflammation, we demonstrate that SPNS2 supplies the S1P that guides T cells out of LNs with an ongoing immune response. Furthermore, deletion of Spns2 is protective in a mouse model of multiple sclerosis. These results support the therapeutic potential of SPNS2 inhibitors to achieve spatially specific modulation of S1P signaling.


The lncRNA MIR2052HG regulates ERα levels and aromatase inhibitor resistance through LMTK3 by recruiting EGR1.
Our previous genome-wide association study using the MA.27 aromatase inhibitors adjuvant trial identified SNPs in the long noncoding RNA MIR2052HG associated with breast cancer-free interval. MIR2052HG maintained ERα both by promoting AKT/FOXO3-mediated ESR1 transcription and by limiting ubiquitin-mediated ERα degradation. Our goal was to further elucidate MIR2052HG's mechanism of action. RNA-binding protein immunoprecipitation assays were performed to demonstrate that the transcription factor, early growth response protein 1 (EGR1), worked together with MIR2052HG to regulate that lemur tyrosine kinase-3 (LMTK3) transcription in MCF7/AC1 and CAMA-1 cells. The location of EGR1 on the LMTK3 gene locus was mapped using chromatin immunoprecipitation assays. The co-localization of MIR2052HG RNA and the LMTK3 gene locus was determined using RNA-DNA dual fluorescent in situ hybridization. Single-nucleotide polymorphisms (SNP) effects were evaluated using a panel of human lymphoblastoid cell lines. MIR2052HG depletion in breast cancer cells results in a decrease in LMTK3 expression and cell growth. Mechanistically, MIR2052HG interacts with EGR1 and facilitates its recruitment to the LMTK3 promoter. LMTK3 sustains ERα levels by reducing protein kinase C (PKC) activity, resulting in increased ESR1 transcription mediated through AKT/FOXO3 and reduced ERα degradation mediated by the PKC/MEK/ERK/RSK1 pathway. MIR2052HG regulated LMTK3 in a SNP- and aromatase inhibitor-dependent fashion: the variant SNP increased EGR1 binding to LMTK3 promoter in response to androstenedione, relative to wild-type genotype, a pattern that can be reversed by aromatase inhibitor treatment. Finally, LMTK3 overexpression abolished the effect of MIR2052HG on PKC activity and ERα levels. Our findings support a model in which the MIR2052HG regulates LMTK3 via EGR1, and LMTK3 regulates ERα stability via the PKC/MEK/ERK/RSK1 axis. These results reveal a direct role of MIR2052HG in LMTK3 regulation and raise the possibilities of targeting MIR2052HG or LMTK3 in ERα-positive breast cancer.


Long-term structural changes after mTBI and their relation to post-concussion symptoms.
To investigate sustained structural changes in the long-term (>1 year) after mild traumatic brain injury (mTBI) and their relationship to ongoing post-concussion syndrome (PCS). Morphological and structural connectivity magnetic resonance imaging (MRI) data were acquired from 16 participants with mTBI and nine participants without previous head injury. Participants with mTBI had less prefrontal grey matter and lower fractional anisotropy (FA) in the anterior corona radiata and internal capsule. Furthermore, PCS severity was associated with less parietal lobe grey matter and lower FA in the corpus callosum. There is evidence for both white and grey matter damage in participants with mTBI over 1 year after injury. Furthermore, these structural changes are greater in those that report more PCS symptoms, suggesting a neurophysiological basis for these persistent symptoms.


Therapeutic exercise for people with amyotrophic lateral sclerosis or motor neuron disease.
Despite the high incidence of muscle weakness in individuals with amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND), the effects of exercise in this population are not well understood. This is an update of a review first published in 2008. To systematically review randomised and quasi-randomised studies of exercise for people with ALS or MND. We searched The Cochrane Neuromuscular Disease Group Specialized Register (2 July 2012), CENTRAL (2012, Issue 6 in The Cochrane Library), MEDLINE (January 1966 to June 2012), EMBASE (January 1980 to June 2012), AMED (January 1985 to June 2012), CINAHL Plus (January 1938 to June 2012), LILACS (January 1982 to June 2012), Ovid HealthSTAR (January 1975 to December 2012). We also searched ProQuest Dissertations & Theses A&I (2007 to 2012), inspected the reference lists of all papers selected for review and contacted authors with expertise in the field. We included randomised or quasi-randomised controlled trials of people with a diagnosis of definite, probable, probable with laboratory support, or possible ALS, as defined by the El Escorial criteria. We included progressive resistance or strengthening exercise, and endurance or aerobic exercise. The control condition was no exercise or standard rehabilitation management. Our primary outcome measure was improvement in functional ability, decrease in disability or reduction in rate of decline as measured by a validated outcome tool at three months. Our secondary outcome measures were improvement in psychological status or quality of life, decrease in fatigue, increase in, or reduction in rate of decline of muscle strength (strengthening or resistance studies), increase in, or reduction in rate of decline of aerobic endurance (aerobic or endurance studies) at three months and frequency of adverse effects. We did not exclude studies on the basis of measurement of outcomes. Two review authors independently assessed trial quality and extracted the data. We collected adverse event data from included trials. The review authors contacted the authors of the included studies to obtain information not available in the published articles. We identified two randomised controlled trials that met our inclusion criteria, and we found no new trials when we updated the searches in 2012. The first, a study with overall unclear risk of bias, examined the effects of a twice-daily exercise program of moderate load endurance exercise versus "usual activities" in 25 people with ALS. The second, a study with overall low risk of bias, examined the effects of thrice weekly moderate load and moderate intensity resistance exercises compared to usual care (stretching exercises) in 27 people with ALS. After three months, when the results of the two trials were combined (43 participants), there was a significant mean improvement in the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) measure of function in favour of the exercise groups (mean difference 3.21, 95% confidence interval 0.46 to 5.96). No statistically significant differences in quality of life, fatigue or muscle strength were found. In both trials adverse effects, investigators reported no adverse effects such as increased muscle cramping, muscle soreness or fatigue The included studies were too small to determine to what extent strengthening exercises for people with ALS are beneficial, or whether exercise is harmful. There is a complete lack of randomised or quasi-randomised clinical trials examining aerobic exercise in this population. More research is needed.


Notchless is required for axial skeleton formation in mice.
Maintenance of cell survival is essential for proper embryonic development. In the mouse, Notchless homolog 1 (Drosophila) (Nle1) is instrumental for survival of cells of the inner cell mass upon implantation. Here, we analyze the function of Nle1 after implantation using the Meox2(tm1(cre)Sor) mouse that expresses the Cre recombinase specifically in the epiblast at E5.5. First, we find that NLE1 function is required in epiblast cells, as Nle1-deficient cells are rapidly eliminated. In this report, we also show that the Meox2(Cre) transgene is active in specific tissues during organogenesis. In particular, we detect high Cre expression in the vertebral column, ribs, limbs and tailbud. We took advantage of this dynamic expression profile to analyze the effects of inducing mosaic deletion of Nle1 in the embryo. We show that Nle1 deletion in this context, results in severe developmental anomalies leading to lethality at birth. Mutant embryos display multiple developmental defects in particular during axial skeletal formation. We also provide evidence that axial defects are due to an increase in apoptotic cell death in the somite at E9.5. These data demonstrate an essential role for Nle1 during organogenesis and in particular during axial development.


Perturbed human sub-networks by Fusobacterium nucleatum candidate virulence proteins.
Fusobacterium nucleatum is a gram-negative anaerobic species residing in the oral cavity and implicated in several inflammatory processes in the human body. Although F. nucleatum abundance is increased in inflammatory bowel disease subjects and is prevalent in colorectal cancer patients, the causal role of the bacterium in gastrointestinal disorders and the mechanistic details of host cell functions subversion are not fully understood. We devised a computational strategy to identify putative secreted F. nucleatum proteins (FusoSecretome) and to infer their interactions with human proteins based on the presence of host molecular mimicry elements. FusoSecretome proteins share similar features with known bacterial virulence factors thereby highlighting their pathogenic potential. We show that they interact with human proteins that participate in infection-related cellular processes and localize in established cellular districts of the host-pathogen interface. Our network-based analysis identified 31 functional modules in the human interactome preferentially targeted by 138 FusoSecretome proteins, among which we selected 26 as main candidate virulence proteins, representing both putative and known virulence proteins. Finally, six of the preferentially targeted functional modules are implicated in the onset and progression of inflammatory bowel diseases and colorectal cancer. Overall, our computational analysis identified candidate virulence proteins potentially involved in the F. nucleatum-human cross-talk in the context of gastrointestinal diseases.


Accommodation-based liquid crystal adaptive optics system for large ocular aberration correction.
According to ocular aberration property and liquid crystal (LC) corrector characteristics, we calculated the minimum pixel demand of the LC corrector used for compensating large ocular aberrations. Then, an accommodation based optical configuration was introduced to reduce the demand. Based on this an adaptive optics (AO) retinal imaging system was built. Subjects with different defocus and astigmatism were tested to prove this. For myopia lower than 5D it performs well. When myopia is as large as 8D the accommodation error increased to nearly 3D, which requires the LC corrector to have 667 x 667 pixels to get a well-corrected image.


Effects of parenteral infusion with fish-oil or safflower-oil emulsion on hepatic lipids, plasma amino acids, and inflammatory mediators in septic rats.
This study was designed to investigate the effects of preinfusion with total parenteral nutrition (TPN) using fish-oil (FO) versus safflower-oil (SO) emulsion as fat sources on hepatic lipids, plasma amino-acid profiles, and inflammatory-related mediators in septic rats. Normal rats, with internal jugular catheters, were assigned to two different groups and received TPN. TPN provided 300 kcal. kg(-1). d(-1), with 40% of the non-protein energy as fat. All TPN solutions were isonitrogenous and identical in nutrient composition except for the fat emulsion, which was made of SO or FO. After receiving TPN for 6 d, each group of rats was further divided into control and sepsis subgroups. Sepsis was induced by cecal ligation and puncture; control rats received sham operation. All rats were classified into four groups as follows: FO control group (FOC; n = 7), FO sepsis group (FOS; n = 8), SO control group (SOC; n = 8), and SO sepsis group (SOS; n = 9). The results of the study demonstrated that plasma concentrations of triacylglycerol and non-esterified fatty acids did not differ between the FO and SO groups, regardless of whether the animals were septic. SOS had significantly higher total lipids and cholesterol content in the liver than did the SOC group. The FOS group, however, showed no difference from the FOC group. Plasma leucine and isoleucine levels were significantly lower in the SOS group than in the SOC group, whereas no difference in these two amino acids was observed between the FOC and FOS groups. Plasma arginine levels were significantly lower in both septic groups than in the groups without sepsis when either FO or SO was infused. Plasma glutamine levels, however, did not differ across groups. No differences in interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, or leukotriene B(4) concentrations in peritoneal lavage fluid were observed between the two septic groups. These results suggest that catabolic reaction in septic rats preinfused with FO is not as obvious as those preinfused with SO. Compared with SO emulsion, TPN with FO emulsion prevents liver fat accumulation associated with sepsis. However, parenterally administered FO had no beneficial effect in lowering cytokines and LTB(4) levels in peritoneal lavage fluid in septic rats induced by cecal ligation and puncture.


Baseline topographic optic disc measurements are associated with the development of primary open-angle glaucoma: the Confocal Scanning Laser Ophthalmoscopy Ancillary Study to the Ocular Hypertension Treatment Study.
To determine whether baseline confocal scanning laser ophthalmoscopy (CSLO) optic disc topographic measurements are associated with the development of primary open-angle glaucoma (POAG) in individuals with ocular hypertension. Eight hundred sixty-five eyes from 438 participants in the CSLO Ancillary Study to the Ocular Hypertension Treatment Study with good-quality baseline CSLO images were included in this study. Each baseline CSLO parameter was assessed in univariate and multivariate proportional hazards models to determine its association with the development of POAG. Forty-one eyes from 36 CSLO Ancillary Study participants developed POAG. Several baseline topographic optic disc measurements were significantly associated with the development of POAG in both univariate and multivariate analyses, including larger cup-disc area ratio, mean cup depth, mean height contour, cup volume, reference plane height, and smaller rim area, rim area to disc area, and rim volume. In addition, classification as "outside normal limits" by the Heidelberg Retina Tomograph classification and the Moorfields Regression Analysis classifications (overall, global, temporal inferior, nasal inferior, and superior temporal regions) was significantly associated with the development of POAG. Within the follow-up period of this analysis, the positive predictive value of CSLO indexes ranged from 14% (Heidelberg Retina Tomograph classification and Moorfields Regression Analysis overall classification) to 40% for Moorfields Regression Analysis temporal superior classification. Several baseline topographic optic disc measurements alone or when combined with baseline clinical and demographic factors were significantly associated with the development of POAG among Ocular Hypertension Treatment Study participants. Longer follow-up is required to evaluate the true predictive accuracy of CSLO measures.