The face is the thing: Faces, not emotions, are responsible for chimeric perceptual asymmetry.
We used factor analysis to examine relationships among tasks that have previously shown right hemispheric processing asymmetries. We were interested in whether processing emotion displayed by a face constitutes a distinct perceptual process from processing other facial characteristics. Interest in this topic arose after Boles [ 1991 . Factor analysis and the cerebral hemispheres: Pilot study and parietal functions. Neuropsychologia, 29 ( 1 ), 59 - 91 ] found evidence of a common process underlying face processing and then Boles [ 1992 . Factor analysis and the cerebral hemispheres: Temporal, occipital and frontal functions. Neuropsychologia, 30 ( 11 ), 963 - 988 ] found evidence of a distinct process for the processing of the facial emotion. We used seven tasks that measured both face and non-face perception. Analysis of the asymmetries revealed measures from the five face tasks resulted in a single factor, thus failing to support the hypothesis that emotional face perception would involve a separate process from non-emotional face perception. A second factor revealed a separate process underlying enumeration, and a third factor revealed yet another process underlying line bisection. The results indicate that perceiving facial emotion results in right hemisphere processing, and faces as a whole are responsible for such processing.


Ossicle and vossicle implant model systems.
Bone regeneration and repair is a goal of many skeletal therapies and numerous agents positively or negatively impact these processes. New therapeutic agents and effective model systems are continually sought to identify agents and characterize their mechanisms of action are in constant demand. In addition, investigations of tumor cell-bone interaction in the skeletal metastatic microenvironment require well-defined and readily orchestrated models. This chapter describes a novel ectopic ossicle model and a vossicle modification that can be used to provide focused and rapid feedback of bone growth and bone-cellular interactions. The ossicle model is a bone marrow stromal cell (BMSC)-based model and the vossicle model is a neonatal vertebral bone transplant model. These models offer opportunities to mix and compare mesenchymal (donor derived) and hematopoietic elements (host derived). Multiple implants can be placed in one mouse to facilitate various outcome analyses, such as histomorphometry, micro-CT, gene expression studies, and cell tracking using markers such as luciferase, in response to pharma cological or genetic manipulation. Implants can also be combined with other cell types, such as cancer cells to evaluate the bone-tumor microenvironment.


Biophysical characterization of the insertion of two potent antimicrobial peptides-Pin2 and its variant Pin2[GVG] in biological model membranes.
The aim of this study was to investigate the factors that govern the activity and selectivity of two potent antimicrobial peptides (AMPs) using lipid membrane models of bacterial, erythrocyte and fungal cells. These models were used in calcein liposome leakage experiments to explore peptide efficiency. The AMPs (Pin2 and its variant Pin2[GVG]) showed highest affinity towards the bacterial models in the nanomolar range, followed by the erythrocyte and fungal systems. The presence of sterols modulated the variant's selectivity, while the wild type was unaffected. Liposome leakage experiments with Fluorescein Isothiocyanate-dextran (FITC)-dextran conjugates indicated that pore size depended on peptide concentration. Dynamic Light Scattering revealed peptide aggregation in aqueous solution, and that aggregate size was related to activity. The interacting peptides did not alter liposome size, suggesting pore forming activity rather than detergent activity. Atomic Force Microscopy showed differential membrane absorption, being greater in the bacterial model compared to the mammalian model, and pore-like defects were observed. Electrophysiological assays with the Tip-Dip Patch Clamp method provided evidence of changes in the electrical resistance of the membrane. Membrane potential experiments showed that liposomes were also depolarized in the presence of the peptides. Both peptides increased the Laurdan Generalized Polarization of the bacterial model indicating increased viscosity, on the contrary, no effect was observed with the erythrocyte and the fungal models. Peptide membrane insertion and pore formation was corroborated with Langmuir Pressure-Area isotherms and Brewster Angle Microscopy. Finally, molecular dynamics simulations were used to get an insight into the molecular mechanism of action.


Stability of Ni in nitinol oxide surfaces.
The stability of Ni in titanium oxide surface layers on nitinol wires known to release certain amounts of Ni was investigated by first principles density functional theory and transmission electron microscopy. The oxides were identified as a combination of TiO and TiO(2) depending on the thickness of the layer. The calculations indicate that free Ni atoms can exist in TiO at ambient temperature while Ni particles form in TiO(2), which was confirmed by the transmission electron microscopy observations. The results are discussed with respect to surface stability and Ni release due to free Ni atoms and Ni particles.


Staging of depressive disorders: Relevance of resistance to treatment and residual symptoms.
Clinical staging model for depression helps to better define the clinical situation of patients. The objectives of this study are: to correlate the Hetrick's staging model of depression with the severity of depression, associated disability, and resistance to treatment in the established disease stages and to test the modification introduced by our group consisting in the introduction of a substage for recurrence from a previous episode that was stabilized with a complete remission. A Cross-sectional study with 133 adult subjects having a current and primary diagnosis of Depressive disorder was developed. Patients were classified according to the model and assessed with: 17-item Hamilton Depression Scale (HAM-D), Clinical Global Impression (CGI); Global Assessment of Function (GAF); Maudsley Staging Method for treatment resistance (MSM) and Sheeham Disability Schedule (SDS). The variable that best contributes to the differentiation between clinical stages, in established Depression, is resistance to treatment evaluated by the MSM. Correlations between MSM and the clinical stages were statistically significant between most pairs of stages. Finally, we showed preliminary data in order to prove that a differential sub-stage for recurrent depression with and without inter-episodic remission in the current heuristic models could be a possible stage for better define depression staging model. Resistance to treatment should be included in the definition of clinical stages in established depression. Despite the difficulty of establishing a valid model for the staging of depression, it can certainly add great value to diagnosis, therapeutic interventions and clinical research.


The cancer growth suppressing gene mda-7 induces apoptosis selectively in human melanoma cells.
Human melanoma cells growth arrest irreversibly, lose tumorigenic potential and terminally differentiate after treatment with a combination of fibroblast interferon (IFN-beta) and the protein kinase C activator mezerein (MEZ). Applying subtraction hybridization to this model differentiation system permitted cloning of melanoma differentiation associated gene-7, mda-7. Expression of mda-7 inversely correlates with melanoma development and progression, with elevated expression in normal melanocytes and nevi and increasingly reduced expression in radial growth phase, vertical growth phase and metastatic melanoma. When expressed by means of a replication incompetent adenovirus (Ad.mda-7) growth of melanoma, but not normal early passage or immortal human melanocytes, is dramatically suppressed and cells undergo programmed cell death (apoptosis). Infection of metastatic melanoma cells with Ad.mda-7 results in an increase in cells in the G(2)/M phase of the cell cycle and changes in the ratio of pro-apoptotic (BAX, BAK) to anti-apoptotic (BCL-2, BCL-XL) proteins. Ad.mda-7 infection results in a temporal increase in mda-7 mRNA and intracellular MDA-7 protein in most of the melanocyte/melanoma cell lines and secretion of MDA-7 protein is readily detected following Ad.mda-7 infection of both melanocytes and melanoma cells. The present studies document a differential response of melanocytes versus melanoma cells to ectopic expression of mda-7 and support future applications of mda-7 for the gene-based therapy of metastatic melanoma.


Nek2A contributes to tumorigenic growth and possibly functions as potential therapeutic target for human breast cancer.
Nek2A (NIMA-related kinases 2A) has been known as an important centrosome regulatory factor. The aim of this study was to investigate the expression of Nek2A and the role it played in different stages of breast cancer. We detected the expression of Nek2A in both mRNA and protein levels in MCF10 cell lines including MCF-10A, MCF-10DCIS.com, MCF-10CA1a and in human breast samples which contained normal breast tissue (NBT), breast ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC). Our study revealed that the mRNA and protein expression of Nek2A were significantly up-regulated in MCF-10DCIS.com and MCF-10CA1a cell lines as well as in human primary breast cancer tissue (DCIS and IDC). Our study also presented a correlation between Nek2A mRNA expression and some clinic pathological factors. We found that Nek2A mRNA expression was associated with molecular subtypes, ER, PR and Ki-67 immunoreactivity (P<0.05) in DCIS and associated with histological grade, lymph node metastasis, molecular subtypes, c-erbB-2, and Ki-67 expression (P<0.05) in IDC. In addition, we observed that ectopic expression of Nek2A in "normal" immortalized MCF-10A breast epithelial cell resulted in increased Nek2A which lead to abnormal centrosomes. Furthermore, knockdown of Nek2A in MCF-10DCIS.com could remarkably inhibit cell proliferation and induce cell cycle arrest in MCF-10DCIS.com cell line. These data suggested that Nek2A might bear a close relationship with development and progression of breast carcinoma, and highlighted its role as a novel potential biomarker for diagnosis and a possible therapeutic target for human breast cancer especially for DCIS.


Predictors of Prolonged Euthyroidism After Radioactive Iodine Treatment for Graves' Disease: A Pilot Study.
Patients with Graves' disease who remain hyperthyroid under the treatment of antithyroid drugs (ATD) or cannot tolerate ATD usually receive radioactive iodine (RAI) to control disease activity. This pilot study aimed to identify predictors of prolonged euthyroidism > 12 months after receiving RAI. Demographic, clinical, and laboratory data from 117 patients receiving RAI were retrospectively collected, including age, gender, body surface area, smoking status, free thyroxine, thyrotropin, thyrotropin binding inhibiting immunoglobulin, microsomal antibody, thyroglobulin antibody, medication history, and thyroid volume. Only 85 patients without missing values were included in statistical analysis. The calculated RAI dose was the estimated thyroid volume × 0.4. The difference and ratio between the actual and calculated RAI doses were examined. A stepwise logistic regression analysis was conducted to identify important predictors of prolonged euthyroidism > 12 months. The cut-off values for discretizing continuous covariates were estimated by fitting generalized additive models. Among the 85 patients on RAI, 18 (21.2%) achieved prolonged euthyroidism > 12 months, 38 (44.7%) remained hyperthyroid with decreased ATD doses, but 29 (34.1%) suffered permanent hypothyroidism and needed long-term levothyroxine. Logistic regression analysis revealed that patients with age > 66 years, 33 < age ≤ 66 years, quitting smoking vs nonsmoking or current smoking, 600 < micorsomal antibody ≤ 1729 IU/mL, 47% < thyrotropin binding inhibiting immunoglobulin ≤ 81%, 7 < thyroglobulin antibody ≤ 162 IU/mL, 0.63 < ratio between actual and calculated RAI doses ≤ 1.96, or taking hydroxychloroquine would have a higher chance of reaching prolonged euthyroidism > 12 months after receiving RAI. Its area under the Receiver Operating Characteristic (ROC) curve was 0.932. Patients with Graves' disease who received an actual RAI dose close to the calculated RAI dose achieved prolonged euthyroidism > 12 months if they also took hydroxychloroquine during RAI treatment.


Nephropathy-gonadal dysgenesis, type 2: renal failure in three siblings with XY dysgenesis in one.
The nephropathy-XY gonadal dysgenesis syndrome in a 17-year-old phenotypical female with focal glomerulosclerosis was associated with renal failure in two sisters, one with crescentic glomerulonephritis at 27 months, and one with membranoproliferative glomerulonephritis at 10 years. Neither the propositus or the siblings had the distinctive mesangial sclerosis of nephropathy-XY dysgenesis, type 1 (Drash syndrome). The association of nephropathy-XY dysgenesis with familial nephritis of heterogeneous pathology suggests that nephropathy-XY dysgenesis, type 2, may relate to separate genetic loci for XY dysgenesis and glomerulopathy or reflect a loss of protection against familial renal disease when the Y chromosome is absent or defective.


Sema3A inhibits axonal regeneration of retinal ganglion cells via ROCK2.
Successful regeneration of injured axons in the adult mammalian central nervous system (CNS) is mainly limited by lesion-induced neuronal apoptosis and the inhibitory environment consisting of numerous extrinsic and intrinsic factors. Semaphorin 3A (Sema3A), a classic axonal guidance cue, contributes to the failure of axonal regeneration and can be neutralized to enhance axonal regeneration. Previous studies have suggested that blockage of rho-associated protein kinase 2 (ROCK2) also exerts a protective effect on the survival and axonal regeneration of retinal ganglion cells (RGC, RGCs) after injury. Yet unresolved question is the interaction between the two factors. We thus evaluated the role of Sema3A and ROCK2 in RGC axonal regeneration. In this study, we first examined the expression of Sema3A and ROCK2 against optic nerve crush in vivo and oxygen-glucose deprivation insult to RGCs in vitro at different time points. Then Sema3A, ROCK2 inhibitor Y-27632, combination of both and phosphate-buffered saline (PBS) only were injected into the vitreous cavity after optic nerve crush at various times in different experiments. In order to assess axonal regeneration, we detected the mRNA levels of small proline-rich protein 1A (Sprr1A) and growth-associated protein 43 (GAP43) by quantitative real time-polymerase chain reaction (RT-qPCR), evaluated visual function by Flash Visual Evoked Potentials (F-VEPs), and checked the protein level of GAP43 by immunofluorescent staining. Our results demonstrated that Sema3A significantly suppressed optic nerve regeneration and this effect can be attenuated via blocking ROCK2. Moreover, Sema3A promoted the phosphorylation of myosin light chain 2 (MLC2) (specific downstream effector of ROCK2 concerning neurite growth). Collectively, Sema3A may negatively regulate axonal regeneration through ROCK2 in RGCs.


A Challenge-Response Assisted Authorisation Scheme for Data Access in Permissioned Blockchains.
Permissioned blockchains can be applied for sharing data among permitted users to authorise the data access requests in a permissioned blockchain. A consensus network constructed using pre-selected nodes should verify a data requester's credentials to determine if he or she have the correct permissions to access the queried data. However, current studies do not consider how to protect users' privacy for data authorisation if the pre-selected nodes become untrusted, e.g., the pre-selected nodes are manipulated by attackers. When a user's credentials are exposed to pre-selected nodes in the consensus network during authorisation, the untrusted (or even malicious) pre-selected nodes may collect a user's credentials and other private information without the user's right to know. Therefore, the private data exposed to the consensus network should be tightly restricted. In this paper, we propose a challenge-response based authorisation scheme for permissioned blockchain networks named Challenge-Response Assisted Access Authorisation (CRA3) to protect users' credentials during authorisation. In CRA3, the pre-selected nodes in the consensus network do not require users' credentials to authorise data access requests to prevent privacy leakage when these nodes are compromised or manipulated by attackers. Furthermore, the computational burden on the consensus network for authorisation is reduced because the major computing work of the authorisation is executed by the data requester and provider in CRA3.


Histochemistry of MAO-A and MAO-B in the locus coeruleus of the Mongolian gerbil.
A coupled peroxidation technique for localization of monoamine oxidase (MAO-A and MAO-B), applied to post-mortem fixed tissue of the locus coeruleus of the Mongolian gerbil is demonstrated. Tyramine hydrochloride, beta-phenylethylamine and 5-hydroxytryptamine creatinine sulphate were used as substrates, 1-deprenyl and clorgyline served as specific inhibitors. All three substrates stained the neurons of locus coeruleus in the absence of inhibitor. In the presence of 1-deprenyl, tyramine hydrochloride and 5-hydroxytryptamine creatinine sulphate were metabolized, whereas in the presence of clorgyline no reaction with either substrate could be observed. Immunocytochemical staining of tyrosine hydroxylase (TH) was employed as comparison.


Interdisciplinary bacteria and phages.
A report of the meeting 'Molecular Genetics of Bacteria and Phages', Cold Spring Harbor, USA, 20-24 August 2008.


Burnout Assessment Among Surgeons and Surgical Trainees During the COVID-19 Pandemic: A Systematic Review.
The objective of the current study was to summarize current research on burnout among surgical trainees and surgeons during the COVID-19 pandemic. PubMed, SCOPUS, Embase, and Psych INFO were systematically searched for studies that evaluated burnout during the COVID-19 pandemic among surgical trainees and surgeons. A total of 29 articles met inclusion criteria, most of which originated from the United States (n = 18, 62.1%). Rates of burnout ranged from 6.0% to 86.0%. Personal factors responsible for burnout were fear of contracting/transmitting COVID-19 (8 studies, 27.6%), female gender (8, 27.6%), and younger age (5, 17.2%). Professional factors contributing to burnout included increased COVID-19 patient clinical load (6, 20.7%), limited work experience (6, 20.7%), reduction in operative cases (5, 17.2%) and redeployment to COVID-19 wards (4, 13.8%). The COVID-19 pandemic negatively impacted surgical education due to reduced number of operative cases (11, 37.9%), decreased hands-on experience (4, 13.8%), and not being able to complete case requirements (3, 10.34%). The shift of didactics to virtual formats (3, 10.3%), increased use of telemedicine (2, 6.9%), and improved camaraderie among residents (1, 3.4%) were viewed as positive consequences. COVID-19 related burnout was reported in as many as 1 in 2 surgical trainees and attending surgeons. Intrinsic- (i.e., gender, age), family- (i.e., family/being married/having children or being single/not having children), as well as work-related extrinsic- (i.e., work-force deployment, risk of infection/spread, changes in educational format) factors were strongly associated with risk of burnout. These factors should be considered when designing interventions to ameliorate burnout among surgical trainees and surgeons.


Evidence against a period of relative photorefractoriness during the recovery of photosensitivity in common starlings.
In many species of birds, the end of the breeding season is caused by the development of absolute photorefractoriness, characterised by spontaneous gonadal regression under a long photoperiod followed by a period during which gonadal maturation cannot be stimulated by further photostimulation. It has been suggested that during the dissipation of photorefractoriness under short photoperiods, birds become relatively photorefractory-that there is a gradual decrease in critical photoperiod. If true, birds should begin to respond to a very long photoperiod before they respond to a moderately long photoperiod. To test this, I transferred photorefractory castrated starlings (Sturnus vulgaris) from a long photoperiod of 18 h of light per day (18L:6D) to 8L:16D for 10, 20, or 30 days, before transferring them to either 20L:4D or to 13L:11D. There was a gradual increase in response (increase in plasma LH concentration) the longer birds had been on 8L:16D before transfer to the longer photoperiods, but there was no difference in the timing of these responses between birds moved to 20L:4D or to 13L:11D. Therefore, starlings do not pass through a period of relative photorefractoriness during the dissipation of absolute photorefractoriness.


Radiopharmaceutical chemistry for positron emission tomography.
Molecular imaging is an emerging technology that allows the visualization of interactions between molecular probes and biological targets. Molecules that either direct or are subject to homeostatic controls in biological systems could be labeled with the appropriate radioisotopes for the quantitative measurement of selected molecular interactions during normal tissue homeostasis and again after perturbations of the normal state. In particular, positron emission tomography (PET) offers picomolar sensitivity and is a fully translational technique that requires specific probes radiolabeled with a usually short-lived positron-emitting radionuclide. PET has provided the capability of measuring biological processes at the molecular and metabolic levels in vivo by the detection of the gamma rays formed as a result of the annihilation of the positrons emitted. Despite the great wealth of information that such probes can provide, the potential of PET strongly depends on the availability of suitable PET radiotracers. However, the development of new imaging probes for PET is far from trivial and radiochemistry is a major limiting factor for the field of PET. In this review, we provided an overview of the most common chemical approaches for the synthesis of PET-labeled molecules and highlighted the most recent developments and trends. The discussed PET radionuclides include ¹¹C (t₁(/)₂=20.4min), ¹³N (t₁(/)₂=9.9min), ¹⁵O (t₁(/)₂=2min), ⁶⁸Ga (t₁(/)₂=68min), ¹⁸F (t₁(/)₂=109.8min), ⁶⁴Cu (t₁(/)₂=12.7h), and ¹²⁴I (t₁(/)₂=4.12d).


Glucuronidation of labetalol at the two hydroxy positions by bovine liver microsomes. Isolation, purification, and structure elucidation of the glucuronides of labetalol.
Glucuronidation is known to be a major metabolic pathway for labetalol. As the drug contains a phenolic and an alcoholic hydroxy group, in principle two regio isomeric glucuronides can be formed. By incubating the substrate labetalol with bovine liver microsomes, in the presence of the co-substrate UDP-glucuronic acid, both hydroxy positions were glucuronidated. The different glucuronides were isolated from the incubation mixture using Bond-Elut extraction cartridges and separated by means of high performance liquid chromatography. The formation of glucuronides was confirmed by performing reference incubations using radiolabeled UDP-glucuronic acid. Structure elucidation of the various glucuronides was done by nuclear magnetic resonance, ultraviolet spectroscopy, and mass spectrometry.


What perceptions do patients have of decision making (DM)? Toward an integrative patient-centered care model. A qualitative study using focus-group interviews.
To understand patients' perceptions of decision making and identify relationships among decision-making models. This qualitative study was made up of four focus group interviews (elderly persons, users of health support groups, students, and rural inhabitants). Participants were asked to report their perceptions of decision making in three written clinical scenarios (hypertension, breast cancer, prostate cancer). The analysis was based on the principles of grounded theory. Most patients perceived decision making as shared decision making, a deliberative question-response interaction with the physician that allowed patients to be experts in obtaining clearer information, participating in the care process, and negotiating compromises with physician preferences. Requesting second opinions allowed patients to maintain control, even within the paternalistic model preferred by elderly persons. Facilitating factors (trust, qualitative non-verbal communication, time to think) and obstacles (serious/emergency situations, perceived inadequate scientific competence, problems making requests, fear of knowing) were also part of shared decision making. In the global concept of patient-centered care, shared decision making can be flexible and can integrate paternalistic and informative models. Physicians' expertise should be associated with biomedical and relational skills through listening to, informing, and advising patients, and by supporting patients' choices.


129I in the environment of the La Hague nuclear fuel reprocessing plant--from sea to land.
In recent years, particular attention was paid to the long-lived radionuclides discharged with authorized low-level radioactive liquid and gaseous effluents by the nuclear spent fuel reprocessing plants of La Hague and Sellafield. The knowledge of (129)I (half-life=15.7 x 10(6) a) distribution in the environment is required to assess the radiological impact to the environment and population living in the area under the direct influence of La Hague NRP discharges. Measurement difficulties of (129)I in environmental matrices, where it is usually present at trace level, limited data published on (129)I activity levels in the European and more particularly in the French territory. Studies conducted to qualify a new alternative measurement method, direct gamma-X spectrometry with experimental self-absorption correction, led to test samples collected in the La Hague marine and terrestrial environment : seaweeds, lichens, grass, bovine thyroids, etc. All these results, often already published separately for analytical purposes and treated for intercomparison exercises, are presented here together in a radioecological manner. The levels of (129)I activity and (129)I/(127)I ratios in these samples show the spatial and temporal influence of the La Hague NRP in its local near-field environment as well as at the regional scale along the French Channel coast.


Analytical method for the determination of sphinganine and sphingosine in serum as a potential biomarker for fumonisin exposure.
The toxins produced by Fusarium moniliforme, which include fumonisins, are possible human carcinogens. Fumonisins are inhibitors of de novo sphingolipid biosynthesis. Alterations of the ratio of sphinganine (Sa) to sphingosine (So) in urine and serum has been proposed as a possible biomarker of exposure to this toxin. A new method was developed for their analysis in tissues and urine. This work describes the further adaptation of the method to the analysis of Sa and So in serum and its validation in sera of untreated and fumonisin B1 (FB1 ) treated rats and mice. No significant differences in the Sa/So ratios were observed in the FB1 treated rats. In mice, the increase was only of marginal statistical significance. Determination of Sa/So ratios in human sera could readily be made in small volumes (from 0.3 to 0.5 ml) of serum.


Purity determination of gynalgin bactericidal tablets with HPLC method.
The study was aimed at developing a simple HPLC method for the determination of the content of impurities in Gynalgin, a two-component preparation. A satisfactory separation was performed on 250 x 4.6 mm Symmetry C8 column in a gradient elution system: mobile phase A--acetonitrile/buffer, pH 5.5 in 10:90, v/v proportion, and mobile phase B--acetonitrile/buffer, pH 5.5 in 75:25 v/v proportion. Two wavelengths: 250 nm and 315 nm were used for detection. Validation confirmed that the method was linear in a required concentration range. The values of correlation coefficients for specific drug substances and the related impurities were as high as 0.999. The results of the purity tests proved that the method was sufficiently selective and precise.


Comparing genomic prediction accuracy from purebred, crossbred and combined purebred and crossbred reference populations in sheep.
The accuracy of genomic prediction depends largely on the number of animals with phenotypes and genotypes. In some industries, such as sheep and beef cattle, data are often available from a mixture of breeds, multiple strains within a breed or from crossbred animals. The objective of this study was to compare the accuracy of genomic prediction for several economically important traits in sheep when using data from purebreds, crossbreds or a combination of those in a reference population. The reference populations were purebred Merinos, crossbreds of Border Leicester (BL), Poll Dorset (PD) or White Suffolk (WS) with Merinos and combinations of purebred and crossbred animals. Genomic breeding values (GBV) were calculated based on genomic best linear unbiased prediction (GBLUP), using a genomic relationship matrix calculated based on 48 599 Ovine SNP (single nucleotide polymorphisms) genotypes. The accuracy of GBV was assessed in a group of purebred industry sires based on the correlation coefficient between GBV and accurate estimated breeding values based on progeny records. The accuracy of GBV for Merino sires increased with a larger purebred Merino reference population, but decreased when a large purebred Merino reference population was augmented with records from crossbred animals. The GBV accuracy for BL, PD and WS breeds based on crossbred data was the same or tended to decrease when more purebred Merinos were added to the crossbred reference population. The prediction accuracy for a particular breed was close to zero when the reference population did not contain any haplotypes of the target breed, except for some low accuracies that were obtained when predicting PD from WS and vice versa. This study demonstrates that crossbred animals can be used for genomic prediction of purebred animals using 50 k SNP marker density and GBLUP, but crossbred data provided lower accuracy than purebred data. Including data from distant breeds in a reference population had a neutral to slightly negative effect on the accuracy of genomic prediction. Accounting for differences in marker allele frequencies between breeds had only a small effect on the accuracy of genomic prediction from crossbred or combined crossbred and purebred reference populations.


Phages as friends and enemies in food processing.
Phages can infect all bacterial genera on the planet leading to their abundance in ecosystems. While these bacterial viruses may represent a risk to industrial fermentations, they may also be valuable tools to control foodborne pathogens. Here we review these two sides of phage replication. As bacterial fermentations are constantly under threat of phage attacks, we will discuss phage diversity and industrial strategies employed to reduce their impact on food processing. Furthermore, we will explore the use of pathogen-infecting phages to reduce the risks associated with foodborne diseases.


An epidemiological survey of obstructive sleep apnea-hypopnea syndrome among edentulous population based on modified Berlin questionnaire.
This study aims to investigate the percentage of people in high risk of obstructive sleep apnea-hypopnea syndrome (OSAHS) in edentulous population using the modified Berlin questionnaire (MBQ), to identify sex difference in percentage of edentulous people at high risk of OSAHS, and to analyze the occurrence rate of OSAHS-related symptoms that were not included in the MBQ in this group of people. Five hundred and forty patients (edentulous in mandible or maxilla or both) were recruited to participate in this study. Demographic information, nocturnal denture wearing habit, and sleeping posture were recorded. Meanwhile, subjects completed the MBQ in which participants' snoring behavior, wake-time sleepiness or fatigue, and the presence of obesity or hypertension were investigated. Four hundred qualified questionnaires were obtained. According to the MBQ, about 31 % of the subjects were classified at high risk of OSAHS. No significant difference in the percentage of people at high risk of OSAHS was found between male and female groups. Dry or sore mouth and throat, polyuria during sleep, and difficult to fall asleep/easy to wake up showed high occurrence rate equal to or higher than 60 % in the high-risk group. According to the MBQ, about 31 % of the edentulous population was identified as high risk of OSAHS. Equal attention should be given to elderly edentulous female and male since they are at the same level of risk of developing OSAHS.


miR-3133 inhibits gastrointestinal cancer progression through activation of Hippo and p53 signalling pathways via multi-targets.
Malignant cell growth and chemoresistance, the main obstacles in treating gastrointestinal cancer (GIC), rely on the Hippo and p53 signalling pathways. However, the upstream regulatory mechanisms of these pathways remain complex and poorly understood. Immunohistochemistry (IHC), western blot and RT-qPCR were used to analyse the expression of RNF146, miR-3133 and key components of Hippo and p53 pathway. CCK-8, colony formation, drug sensitivity assays and murine xenograft models were used to investigate the effect of RNF146 and miR-3133 in GIC. Further exploration of the upstream regulatory mechanism was performed using bioinformatics analysis, dual-luciferase reporter gene, immunoprecipitation assays and bisulfite sequencing PCR (BSP). Clinical samples, in vitro and in vivo experiments demonstrated that RNF146 exerts oncogenic effects in GIC by regulating the Hippo pathway. Bioinformatics analysis identified a novel miRNA, miR-3133, as an upstream regulatory factor of RNF146. fluorescence in situ hybridization and RT-qPCR assays revealed that miR-3133 was less expressed in gastrointestinal tumour tissues and was associated with adverse pathological features. Functional assays and animal models showed that miR-3133 promoted the proliferation and chemotherapy sensitivity of GIC cells. miR-3133 affected YAP1 protein expression by targeting RNF146, AGK and CUL4A, thus activating the Hippo pathway. miR-3133 inhibited p53 protein degradation and extended p53's half-life by targeting USP15, SPIN1. BSP experiments confirmed that miR-3133 promoter methylation is an important reason for its low expression. miR-3133 inhibits GIC progression by activating the Hippo and p53 signalling pathways via multi-targets, including RNF146, thereby providing prognostic factors and valuable potential therapeutic targets for GIC.


Molecular cloning, tissue distribution, and pharmacologic function of melanocortin-3 receptor in common carp (Cyprinus carpio).
Melanocortin-3 receptor (MC3R) not only regulates energy homeostasis in animals, but also is an important regulator of inflammation. As one of the most widely farmed freshwater fish, common carp has attracted great interest for its feeding and inflammation regulation. In this study, we cloned the coding sequence (CDS) of common carp Mc3r (ccMc3r), examined its tissue expression profile, and investigated the function of this receptor in mediating downstream signaling pathways. The results showed that the CDS of ccMc3r was 975 bp, encoding a putative protein of 324 amino acids. Homology, phylogeny, and chromosomal synteny analyses revealed that ccMc3r is evolutionarily close to the orthologs of cyprinids. Quantitative real-time PCR (qPCR) indicated that ccMc3r was highly expressed in the brain and intestine. The luciferase reporter systems showed that four ligands, ACTH (1-24), α-MSH, β-MSH, and NDP-MSH, were able to activate the cAMP and MAPK/ERK signaling pathways downstream of ccMc3r with different potencies. For the cAMP signaling pathway, ACTH (1-24) had the highest activation potency; while for the MAPK/ERK signaling pathway, β-MSH had the greatest activation effect. In addition, we found that the four agonists were able to inhibit TNF-α-induced NF-κB signaling in approximately the same order of potency as cAMP signaling activation. This study may facilitate future studies on the role of Mc3r in common carp feed efficiency and immune regulation.


Calcium alginate gel as encapsulation matrix for coimmobilized enzyme systems.
Encapsulation within calcium alginate gel capsules was used to produce a coimmobilized enzyme system. Glucose oxidase (GOD) and catalase (CAT) were chosen as model enzymes. The same values of Vmax and Km app for the GOD encapsulated system and for the GOD-CAT coencapsulated system were calculated. When gel beads and capsules were compared, the same catalyst deactivation sequence for the two enzymes was observed. However, when capsules were employed as immobilization support, GOD efficiencies were higher than for the gel beads. These results were explained in terms of the structure of the capsules.


Functional detection of epithelial cell adhesion molecule specific cytotoxic T lymphocytes in patients with lung cancer, colorectal cancer and in healthy donors.
Epithelial cell adhesion molecule (Ep-CAM) derived antigenic peptides have been identified that can be recognized by cytotoxic T lymphocytes (CTL) in a major histocompatibility complex (MHC) class I restricted fashion. Thus, altered expression of Ep-CAM in a variety of human tumors might render a potential target for T cell mediated therapy. We have examined, whether the novel HLA-A*0201 restricted peptide ILYENNVIT (184-192) corresponding to Ep-CAM and one heteroclitic modified variant peptide previously demonstrated to be immunogenic in the human system can elicit antigen specific CTL responses in HLA-A2 positive patients with history of Ep-CAM expressing cancer of lung and colon. Specific CTL recognition of T2 target cells pulsed with the native peptide as well as of the lung cancer cell line A549 indicates that an appropriate T cell repertoire can be expanded from peripheral blood from patients in clinical remission and with advanced cancer. Despite an overall low frequency, peptide specific precursor CTLs could be readily expanded from peripheral blood from 6/8 patients that were diagnosed previously with Ep-CAM expressing lung cancer and 4/8 control individuals (2/5 healthy donors and 2/3 colon cancer patients). CTLs from three of five lung cancer patients tested also lyzed the HLA-A2(+) and Ep-CAM expressing lung cancer cell line A549. We did not detect an increased frequency of pCTLs after peripheral blood monocytes (PBMCs) were stimulated with the heteroclitic compound peptide. The results of our study indicate that Ep-CAM specific precursor CTL can be expanded in vitro and a specific T cell response against this epitope can be elicited in patients at various stages of lung cancer.


γδ T Cell‒Mediated Wound Healing Is Diminished by Allergic Skin Inflammation.
Atopic dermatitis results in profound changes in the function of the skin that include diminished barrier function and altered production of antimicrobial peptides. Our previous work in a model of allergic skin inflammation identified a defect in the wound healing process that was dependent on IL-4. In this report, we show that allergic skin inflammation results in a dramatic decrease in the presence of the Vγ3+ dendritic epidermal T-cell (DETC) population of γδ T cells in the skin. In mice that express an active signal transducer and activator of transcription 6 in T cells, DETCs are lost early in life. The loss of DETCs is entirely dependent on IL-4 and is recovered with a genetic deficiency of IL-4. Moreover, injection of IL-4 into wild-type mice results in acute loss of the DETC population. A similar loss of DETCs was observed in mice treated topically with MC903. Wounding of skin from Stat6VT-transgenic or MC903-treated mice resulted in decreased production of DETC-dependent cytokines in the skin, coincident with diminished wound closure. Importantly, intradermal injection of the DETC-produced cytokine fibroblast GF 7 rescued the rate of wound closure in mice with allergic skin inflammation. Together, these results suggest that the atopic environment diminishes prohealing T-cell populations in the skin, resulting in attenuated wound healing responses.


Moderate overweight is beneficial and severe obesity detrimental for patients with documented atherosclerotic heart disease.
Obesity is paradoxically associated with enhanced survival in patients with established cardiovascular disease. We explored this paradox further by examining the influence of obesity on survival in patients with verified atherosclerotic heart disease. This retrospective registry based cohort study included all patients from the Western Denmark Heart Registry with coronary atherosclerosis confirmed by coronary angiography from January 2000 to December 2010. Patients were divided into eight groups according to body mass index (BMI) based on WHO BMI classification. Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark. The study included 37 573 patients (70.7% men) with a mean age of (66.3 ± 11.1) years. During the 11 years of follow-up, 5866 (15.6%) patients died. Multivariable analysis confirmed that the risk of death was the lowest among the preobese patients (27.5 ≤ BMI<30 kg/m(2)) with adjusted HR of 0.82 (95% CI 0.71 to 0.95; p=0.008) and increased with both low (BMI<18.50 kg/m(2)) and very high (BMI ≥ 40 kg/m(2)) BMI, HR 2.04 (95% CI 1.63 to 2.57; p<0.001) and HR 1.35 (95% CI 1.05 to 1.72; p<0.01), respectively. Also the normal weight class I (18.5 ≤ BMI<23 kg/m(2)) had a significant risk of mortality HR 1.28 (95% CI 1.13 to 1.45; p<0.001). Obese classes I and II did not differ from the reference group (23 ≤ BMI<25 kg/m(2)). Overweight atherosclerotic heart disease patients have improved survival compared with normal weight patients. Underweight and severely obese patients have increased mortality. Our results lean more towards an overweight paradox than an obesity paradox.


Do patient intervention ratings predict alcohol-related consequences?
Little is known about treatment process for behavior change for brief interventions. Patient ratings of treatment process during a patient-centered brief intervention for alcohol were used to predict post-treatment alcohol use and consequences. We use data from a randomized clinical trial that compared the effects of BI (1 session) to BI and booster (BIB, 2 sessions) to reduce harmful drinking and alcohol consequences. Subjects were n=167 (BI) and n=82 (BIB). Five of the 12 ratings were rated significantly higher by those in the BIB condition compared to BI. The only predictor of reduced alcohol consequences at 12-months was higher ratings of, "I have obtained some new understanding," for BIB participants (t=-2.50, p<.05). Patient perspectives on treatment may have a role in patient outcomes and should be explored as a dimension of treatment process.


Ferroportin inhibitor vamifeport ameliorates ineffective erythropoiesis in a mouse model of β-thalassemia with blood transfusions.
β-thalassemia is an inherited anemia characterized by ineffective erythropoiesis. Blood transfusions are required for survival in transfusion-dependent β-thalassemia and are also occasionally needed in patients with non-transfusion-dependent β-thalassemia. Patients with transfusion-dependent b-thalassemia often have elevated transferrin saturation (TSAT) and non-transferrin-bound iron (NTBI) levels, which can lead to organ iron overload, oxidative stress, and vascular damage. Vamifeport is an oral ferroportin inhibitor that was previously shown to ameliorate anemia, ineffective erythropoiesis, and dysregulated iron homeostasis in the Hbbth3/+ mouse model of β-thalassemia, under non-transfused conditions. Our study aimed to assess the effects of oral vamifeport on iron-related parameters (including plasma NTBI levels) and ineffective erythropoiesis following blood transfusions in Hbbth3/+ mice. A single dose of vamifeport prevented the transient transfusion-mediated NTBI increase in Hbbth3/+ mice. Compared with vehicle treatment, vamifeport significantly increased hemoglobin levels and red blood cell counts in transfused mice. Vamifeport treatment also significantly improved ineffective erythropoiesis in the spleens of Hbbth3/+ mice, with additive effects observed when treatment was combined with repeated transfusions. Vamifeport corrected leukocyte counts and significantly improved iron-related parameters (serum transferrin, TSAT and erythropoietin levels) versus vehicle treatment in Hbbth3/+ mice, irrespective of transfusion status. In summary, vamifeport prevented transfusion-mediated NTBI formation in Hbbth3/+ mice. When given alone or combined with blood transfusions, vamifeport also ameliorated anemia, ineffective erythropoiesis, and dysregulated iron homeostasis. Administering vamifeport together with repeated blood transfusions additively ameliorated anemia and ineffective erythropoiesis in this mouse model, providing preclinical proof-of-concept for the efficacy of combining vamifeport with blood transfusions in β-thalassemia.


Crystal structure of TbEsa1 presumed Tudor domain from Trypanosoma brucei.
The essential SAS2-related acetyltransferase 1 (Esa1), as a acetyltransferase of MYST family, is indispensable for the cell cycle and transcriptional regulation. The Tudor domain consists of 60 amino acids and belongs to the Royal family, which serves as a module interacting with methylated histone and/or DNA. Although Tudor domain has been widely studied in higher eukaryotes, its structure and function remain unclear in Trypanosoma brucei (T. brucei), a protozoan unicellular parasite causing sleeping sickness in human and nagana in cattle in sub-Saharan Africa. Here, we determined a high-resolution structure of TbEsa1 presumed Tudor domain from T. brucei by X-ray crystallography. TbEsa1 Tudor domain adopts a conserved Tudor-like fold, which is comprised of a five-stranded β-barrel surrounded by two short α-helices. Furthermore, we revealed a non-specific DNA binding pattern of TbEsa1 Tudor domain. However, TbEsa1 Tudor domain showed no methyl-histone binding ability, due to the absence of key aromatic residues forming a conserved aromatic cage.


PGD2 stimulates osteoprotegerin synthesis via AMP-activated protein kinase in osteoblasts: Regulation of ERK and SAPK/JNK.
AMP-activated protein kinase (AMPK), a key enzyme sensing cellular energy metabolism, is currently known to regulate multiple metabolic pathways. Osteoprotegerin plays a pivotal role in the regulation of bone metabolism by inhibiting osteoclast activation. We have previously reported that prostaglandin D2 (PGD2) stimulates the synthesis of osteoprotegerin through the activation of p38 mitogen-activated protein (MAP) kinase, p44/p42 MAP kinase and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in osteoblast-like MC3T3-E1 cells. On the basis of these findings, we herein investigated the implication of AMPK in PGD2-stimulated osteoprotegerin synthesis in these cells. PGD2 induced the phosphorylation of AMPKα (Thr-172) and AMPKβ (Ser-108), and the phosphorylation of acetyl-coenzyme A carboxylase, a direct AMPK substrate. Compound C, an AMPK inhibitor, which suppressed the phosphorylation of acetyl-coenzyme A carboxylase, significantly attenuated both the release and the mRNA levels of osteoprotegerin stimulated by PGD2. The PGD2-induced phosphorylation of p44/p42 MAP kinase and SAPK/JNK but not p38 MAP kinase were markedly inhibited by compound C. These results strongly suggest that AMPK regulates the PGD2-stimulated osteoprotegerin synthesis at a point upstream of p44/p42 MAP kinase and SAPK/JNK in osteoblasts.


Inducible gene expression of activin A/erythroid differentiation factor in HL-60 cells.
Treatment of HL-60 cells with 12-O-tetradecanoyl-phorbol 13-acetate (TPA) for 48 h induced expression of mRNA of beta A chain of activin A/erythroid differentiation factor. Under the same condition, interferon-gamma caused a slight increase in beta A chain mRNA, whereas 1 alpha, 25-dihydroxyvitamin D3, dimethylsulfoxide and all-trans-retinoic acid failed to induce this mRNA in HL-60 cells. Furthermore, 4 h-treatment with TPA or lipopolysaccharide (LPS) induced a marked increase in beta A chain mRNA levels in interferon-gamma-pretreated HL-60 cells. In the cells pretreated with 1 alpha, 25-dihydroxyvitamin D3, TPA and LPS induced as little increase in beta A chain mRNA as in the control cells. Neither alpha nor beta B chain mRNA was detected in any sample. These results indicate that interferon-gamma has a priming effect on the activation of activin A/erythroid differentiation factor gene by TPA or LPS in HL-60 cells.


Epidemiology of carbapenem-resistant Klebsiella pneumoniae ST15 of producing KPC-2, SHV-106 and CTX-M-15 in Anhui, China.
It is well known that carbapenem-resistant Klebsiella pneumoniae (CRKP) has become a more problematic public health issue due to its widespread spread worldwide. In China, ST11-type CRKP is the most prevalent CRKP, but ST15-type CRKP, a recently prevalent high-risk clone, has emerged widely throughout China, posing a serious public health risk. Therefore, we conducted an epidemiological of an outbreak of ST15 CRKP of producing CTX-M-15, KPC-2 and SHV-106 in a tertiary hospital in Anhui, China, to Understanding the potential risks of the current STT15 CRKP outbreak. From July 2021 to December 2021, 13 ST15 CRKP isolates were identified by collecting non-repeated clinical multidrug-resistant isolates, with all capsular typing of serotype KL19. All ST15 CRKP isolates were resistant to cephalosporins, carbapenems and quinolones, but were sensitive to amikacin, tigecycline and polymyxin B. In addition, isolates carried blaSHV-106 (100%), blaKPC-2 (69%), blaCTX-M-15 (69%), blaTEM-1B (69%), blaOXA-1 (62%) and blaLAP-2 (8%), as well as iron chelators (iutA, ybt, fyuA, ent, fepA, irp1, irp2, 100%) were detected. In phenotyping experiments, all ST15 CRKP exhibited lower growth rates than NTUH-K2044, and all ST15 CRKP did not exhibit mucoviscositty characteristics. However, in the Galleria mellonella infection model, isolates 21081212, 21081241 and 21091216 were more lethal than the hypervirulent isolates NTUH-K2044. Sequencing results showed that the genetic environment surrounding the genes blaSHV-106, blaKPC-2, blaCTX-M-15, blaOXA-1 and blaTEM-1B were all identical in the ST15 CRKP isolates. Phylogenetic analysis showed that 13 ST15 CRKP isolates were divided into three subgroups, and when placed in global analysis, 10 of them were highly homologous to isolates from Jiangsu, two were highly homologous to isolates from Zhejiang, and one was homologous to an isolate from an unlabelled region. Our research shows that ST15 CRKP, which carries multiple β-lactamases genes and siderophores-encoding genes, may be evolving to hypervirulence and may have spread widely in localised areas. Therefore, environmental surveillance and clinical infection control in hospitals should be strengthened to prevent further spread of ST15 CRKP.


Phyllodes tumor of the prostate.
In this report, we describe a case of phyllodes tumor of the prostate with a high value of prostate-specific antigen (PSA). A 47-year-old man with symptoms of hematospermia presented with a steadily elevated serum PSA value of 60.76 ng/mL (normal range, < 4 ng/mL). A needle biopsy revealed atypical stromal cells without any evidence of malignancy. After radical prostatectomy, the tumor measured 2.9 cm in diameter and consisted of a single nodule composed of irregular, elongated epithelial ducts and atypical stromal cells with enlarged, occasionally multinucleated, pleomorphic, or hyperchromatic nuclei. Immunohistochemistry showed that the atypical stromal cells were positive for vimentin, androgen receptor, estrogen receptor, progesterone, and 5α-reductase, but negative for MIB-1, PSA, SMA, p53, desmin, CD34, c-kit, CD10, S-100, and EGFR. Excess PSA might be secreted by hyperplastic luminal cells driven by 5α-reductase-positive stromal and epithelial cells. Array-comparative genomic hybridization (array CGH) for genomic alterations revealed a gain of 11p13, which includes the WT1 gene, and a loss of 1p36.23 and 12p12.1. After surgery, the serum PSA value rapidly decreased to within the normal range; no recurrence or distant metastasis was noted after 2 years of follow up.


Structure-Based Affinity Maturation of Antibody Based on Double-Point Mutations.
Structure-based site-directed affinity maturation of antibodies can be expanded by multiple-point mutations to obtain various mutants. However, selecting the appropriate number of promising mutants for experimental evaluation from the vast number of combinations of multiple-point mutations is challenging. In this report, we describe how to narrow candidate mutants using the so-called weak interaction analysis such as CH-π and CH-O in addition to widely recognized interactions such as hydrogen bonds.


[Alopecia areata is an idiopathic disorder in which there is a rapidly developing loss of hair that usually begins on the scalp].
In this article a case of alopecia areata which developed due to combined headgear is presented. It is aimed to warn the orthodontists about this rarely seen adverse effect of the extraoral orthodontic appliances.


Interrelationships of factors of social development are more complex than Life History Theory predicts.
Life History Theory (LHT) predicts a monotonous relationship between affluence and the rate of innovations and strong correlations within a cluster of behavioral features. Although both predictions can be true in specific cases, they are incorrect in general. Therefore, the author's explanations may be right, but they do not prove LHT and cannot be generalized to other apparently similar processes.


Long-term results of definitive radiotherapy for stage I esophageal cancer.
To analyze retrospectively the long-term results of external beam radiotherapy (RT) with or without intraluminal brachytherapy (ILBT) for patients with Stage I esophageal cancer. A total of 34 patients with esophageal squamous cell carcinoma, clinically diagnosed as having Stage I disease, were treated with definitive RT, with or without ILBT. The median age was 69 years. Seven patients were treated with external beam RT alone (median, 64 Gy), and 27 were treated with external beam RT (median, 52 Gy) plus ILBT (8-12 Gy in two to three fractions). The 5-year overall survival, local relapse-free survival, and cause-specific survival rate was 58.9%, 68.4%, and 80.0%, respectively, with a median follow-up of 61 months. Of 9 patients with local recurrence after initial therapy, 7 were successfully treated, and the 5-year cumulative rate of esophagectomy was 19.6%. The 2-year local relapse-free rate for patients with and without ILBT was 79.1% and 53.6%, respectively. Although local recurrence was frequent within 2 years, the disease-specific survival rate was high owing to effective salvage therapy. Definitive RT is a reasonable treatment option for highly comorbid and elderly patients with Stage I esophageal cancer. The role of ILBT needs to be clarified.


Generation of a mouse model for studying the role of upregulated RTEL1 activity in tumorigenesis.
Regulator of telomere length 1 (RTEL1) is a DNA helicase protein that has been demonstrated to be required for the maintenance of telomere length and genomic stability. It has also been found to be essential for DNA homologous recombination during DNA repairing. Human RTEL1 genomic locus (20q13.3) is frequently amplified in multiple types of human cancers, including hepatocellular carcinoma and gastrointestinal tract tumors, indicating that upregulated RTEL1 activity could be important for tumorigenesis. In this study, we have developed a conditional transgenic mouse model that overexpress mouse Rtel1 in a Cre-excision manner. By crossing with a ubiquitous Cre mouse line, we further demonstrated that these established Rtel1 conditional transgenic mice allow to efficiently and highly express a functional Rtel1 that is able to rescue the embryonic defects of Rtel1 null mouse allele. Furthermore, we demonstrated that more than 70% transgenic mice that widely overexpress Rtel1 developed liver tumors that recapitulate many malignant features of human hepatocellular carcinoma (HCC). Our work not only generated a valuable mouse model for determining the role of RTEL1 in the development of cancers, but also provided the first genetic evidence to support that amplification of RTEL1, as observed in several types of human cancers, is tumorigenic.


Intravenous immunoglobulin utilization in the Canadian Atlantic provinces: a report of the Atlantic Collaborative Intravenous Immune Globulin Utilization Working Group.
Intravenous immunoglobulin (IVIG) use for labeled and unlabeled indications is growing steadily. By use of a collaborative regional strategy, baseline IVIG usage and appropriateness of utilization were determined for Atlantic Canada. The effectiveness of strategies designed to optimize utilization was also studied. A regional working group was created to monitor IVIG utilization for a 2-year period in the four Canadian Atlantic Provinces. A registry of IVIG was created. Assessment of indication appropriateness was determined with national and provincial guidelines along with expert clinical opinion. To optimize IVIG use, IVIG guidelines and feedback reports were distributed to stakeholders. Appropriateness of IVIG use was compared over the course of the study. The leading indications for IVIG use were idiopathic thrombocytopenic purpura (17.3%), primary immune deficiency conditions (14.9%), and chronic idiopathic demyelinating polyneuropathy (11.8%). The leading prescribing specialists were neurologists (32.2%) and hematologists (26.1%). A total of 37.1 percent of IVIG usage was in accordance with labeled indications. After optimization strategies were implemented, there was little change in labeled use. There was a 4.2 percent decrease in unlabeled use not supported by evidence (p<0.001). A regional collaborative strategy for monitoring IVIG use was established. Most of the IVIG use was for labeled or appropriate indications. The majority of unlabeled use was supported by the medical literature. Strategies to optimize IVIG utilization were associated with a decrease in inappropriate IVIG use and a plateau in IVIG utilization compared to the rest of the country.


Development of glomerular filtration rate and excretion of beta 2-microglobulin in neonates during gentamicin treatment.
Ten infants of different gestational ages (GA) and postnatal ages (PNA), treated with gentamicin, were compared with 10 control patients of similar GA and PNA to evaluate the possible nephrotoxic effects of this drug. Changes in the glomerular filtration rate (GFR) and the fractional excretion of beta 2-microglobulin in urine (FE beta) were used as indicators of renal dysfunction. In the control infants there was a postnatal increase in the GFR that was higher in full-term than in preterm infants. The FE beta decreased logarithmically as a function of both the GA and the PNA. The GFR was statistically lower in 5/10 and 6/10 of the patients on the first and the last days of gentamicin treatment (GT) respectively. Three weeks after GT, 8/10 had a normal GFR. The FE beta was statistically higher in 4/10 of the patients on their first day of GT and 7/10 on their last day of GT. Three weeks after GT, 9/10 of the patients had a normal FE beta for their postnatal and gestational ages. It is concluded that GT influences filtration and proximal reabsorption in GT infants by decreasing the GFR and increasing the FE beta. However, the observed renal dysfunction seemed to be reversible.


Topographical rearrangement of a plasma membrane antigen during capacitation of rat spermatozoa in vitro.
We have previously described an antigen (termed 2B1) on rat spermatozoa that is present on the plasma membrane overlying the tail domain. The antigen is mobile within the plane of the plasma membrane and a mAb to it blocks fertilization in vitro. In the present study we describe some dynamic properties of this antigen in relation to its topographical distribution. When spermatozoa were incubated in vitro in a capacitation medium and stained with 2B1 mAb/FITC-rabbit anti-mouse F(ab')2, strong fluorescence appeared over the acrosomal domain. Acute exposure of fresh spermatozoa to dissociating reagents (1 M NaCl or 5 mM 2-mercaptoethanol) or inducers of the acrosome reaction (lysolecithin + Ca2+ or A23187 + Ca2+) failed to mimic these effects. Spermatozoa prelabeled with FITC-2B1 IgG and then capacitated in the presence of excess "cold" 2B1 IgG also showed accumulation of fluorescence on the acrosomal domain, suggesting that the antigen had migrated from the tail. Migration was selective and Ca2(+)- and temperature-dependent but was not inhibited by metabolic poisons (NaF or NaN3). Motility was not obligatory for migration. Immunogold-labeling studies at the ultrastructural level showed that 2B1 antigen was restricted to the surface membrane over both the tail and the acrosomal domains and that during migration it did not change the type of membrane into which it was inserted. From a quantitative analysis of fluorescence on spermatozoa prelabeled with FITC-2B1 IgG and then capacitated, the amount of antigen that appeared on the acrosomal domain was approximately equivalent to that lost from the midpiece domain. The Mr of 2B1 antigen extracted from capacitated spermatozoa was 300-500 Da less than that extracted from noncapacitated cells, suggesting that the molecule had undergone processing concomitant with migration. These results are discussed in relation to mechanisms for targeting antigens to sites where they become physiologically active and are correctly positioned to participate in gamete recognition processes.


MRI physics and technical issues: Where do Italian radiographers search for information?
Our aim was to investigate the means radiographers and radiographers in training (RTrs) use to seek information on magnetic resonance imaging (MRI) physics and technical issues. An estimated 3000 radiographers and RTrs were reached by e-mail. We proposed an online survey with eight English-language multiple choice questions investigating how often radiographers have doubts about MRI physics or technical issues, where and what kind of information they search for, and on which websites. The statistical χ2 test was used. We obtained 300 answers from European professionals (228 radiographers, 72 RTrs) from 9 European countries, with 288 of 300 (96%) responses coming from Italy. Within the Italian respondents, 41% of RTrs have doubts about MRI physics versus 56% of radiographers (p = 0.028). Basic MRI sequences details are more searched by RTrs (36%) than radiographers (22%) (p = 0.088), as well as clinical protocols (64% versus 44%, p = 0.054). Radiographers and RTrs mostly search on the Internet (74% versus 81%, p = 0.404); "older colleagues" are more frequently asked for information by RTrs (27% versus 61%, p = 0.001), they consult the "MRI manufacturer" less frequently (11% versus 34%, p = 0.001); and 66% of radiographers and 72% of RTrs search "in mother-language and English" (p = 0.590). For clinical protocols RTrs prefer the website mriquestions.com (17% versus 44%, p = 0.001). Websites most used were: mriquestions.com (41%), radiopaedia.org (31%), and mrimaster.com (13%). In addition, 30 respondents mentioned using the Italian site fermononrespiri.com. Italian radiographers and RTrs frequently search for information about MRI physics and technical issues, with slight differences between groups regarding sources and clinical protocols. Protocol setting, and MRI physics and sequences seem to be the main limitations of RTr knowledge. To remedy this gap, more time on training/university lectures and a rethinking of the practical training activities is required.


The E318G substitution in PSEN1 gene is not connected with Alzheimer's disease in a large Polish cohort.
Mutations in the presenilin 1 (PSEN1) gene are known to cause nearly 50% of early-onset, familial Alzheimer's disease (AD) cases. To determine whether E318G mutation is related causally to AD in the Polish population E318G mutation frequency was assessed using PCR-RFLP method in a total of 659 subjects: 256 AD patients, 210 healthy, age-matched control subjects, 100 Parkinson's disease patients and 93 centenarians. When the mutation frequencies were compared to healthy controls, no significant differences between the groups were found. It could be concluded that E318G mutation is not related causally to AD in the Polish population, either as a risk factor or a disease causing mutation.


The neurofibromatosis type 1 gene encodes a protein related to GAP.
cDNA walking and sequencing have extended the open reading frame for the neurofibromatosis type 1 gene (NF1). The new sequence now predicts 2485 amino acids of the NF1 peptide. A 360 residue region of the new peptide shows significant similarity to the known catalytic domains of both human and bovine GAP (GTPase activating protein). A much broader region, centered around this same 360 amino acid sequence, is strikingly similar to the yeast IRA1 product, which has a similar amino acid sequence and functional homology to mammalian GAP. This evidence suggests that NF1 encodes a cytoplasmic GAP-like protein that may be involved in the control of cell growth by interacting with proteins such as the RAS gene product. Mapping of the cDNA clones has confirmed that NF1 spans a t(1;17) translocation mutation and that three active genes lie within an intron of NF1, but in opposite orientation.


Development of collagen/demineralized bone powder scaffolds and periosteum-derived cells for bone tissue engineering application.
The aim of this study was to investigate physical and biological properties of collagen (COL) and demineralized bone powder (DBP) scaffolds for bone tissue engineering. DBP was prepared and divided into three groups, based on various particle sizes: 75-125 µm, 125-250 µm, and 250-500 µm. DBP was homogeneously mixed with type I collagen and three-dimensional scaffolds were constructed, applying chemical crosslinking and lyophilization. Upon culture with human periosteum-derived cells (PD cells), osteogenic differentiation of PD cells was investigated using alkaline phosphatase (ALP) activity and calcium assay kits. The physical properties of the COL/DBP scaffolds were obviously different from COL scaffolds, irrespective of the size of DBP. In addition, PD cells cultured with COL scaffolds showed significantly higher cell adhesion and proliferation than those with COL/DBP scaffolds. In contrast, COL/DBP scaffolds exhibited greater osteoinductive potential than COL scaffolds. The PD cells with COL/DBP scaffolds possessed higher ALP activity than those with COL scaffolds. PD cells cultured with COL/DBP scaffolds with 250-500 mm particle size yielded the maximum calcium deposition. In conclusion, PD cells cultured on the scaffolds could exhibit osteoinductive potential. The composite scaffold of COL/DBP with 250-500 mm particle size could be considered a potential bone tissue engineering implant.


Outflow tract obstruction after mitral valve repair without an annuloplasty ring.
We report that systolic anterior motion of the mitral valve with significant left ventricular outflow tract obstruction can occur after mitral valve reconstruction without using an annuloplasty ring. A 69-year-old male patient with mitral regurgitation and ischemic heart disease underwent combined mitral valve reconstruction without an annuloplasty ring, and coronary artery bypass grafting. Intraoperative transesophageal echocardiography performed at the end of the operation revealed systolic anterior motion of the mitral valve with significant outflow tract obstruction requiring a second pump run with return to cardiopulmonary bypass and additional mitral valve replacement during the same thoracotomy.


Promoting smoking cessation among the elderly: what are the predictors of intention to quit and successful quitting?
To assess the predictors of smoking cessation and intention to quit among the Chinese elderly smokers. A cross-sectional survey of elderly smokers. Shamsuipo district, Hong Kong. A total of 1,318 elderly were interviewed (response rate = 83%). A structured questionnaire was used for data collection. The questionnaire sought information on the subject's sociodemographic background and smoking habits. The predictors for successful quitting and intention to quit were assessed by chi-square tests and multiple logistic regression. Of the respondents, 20.2% were current smokers, 25.4% were ex-smokers, and 54.4% were never smokers. Of the smoker (current and ex-smokers) respondents, 55.7% (335/601) had successfully quit at the time of enumeration. The predictors of quitting were living with others, receiving assistance for mobility, being nondrinkers, smoking for shorter duration, and smoking more cigarettes per day. Having health problems in the past, smoking for shorter duration, and smoking fewer cigarettes per day were predictors of intention to quit smoking. The study identified several predictors of successful quitting that could help improve the provision of current smoking cessation services. Population-based smoking cessation programs, especially those targeted to elderly, should take these predictors into consideration in the design of interventions.


Critical review on recent developments in solventless techniques for extraction of analytes.
The most recent contributions on solventless extraction techniques have been reviewed. This paper deals with those techniques that use solid phases, such as solid-phase microextraction, liquid phases, such as single-drop microextraction and hollow-fibre liquid-phase microextraction, and subcritical fluids, such as subcritical water extraction. In all cases, the most recent publications have been critically studied. Direct extraction and derivatization processes to facilitate the extraction of analytes in different areas have been included. Hyphenated approaches, if available, are also included in this review. Comparison of techniques organized by analytes and matrices also enhances this critical overview of solventless techniques.


[Neurotoxic syndrome of sheep due to the ingestion of plants of the Mediterranean scrub: clinical, histopathological, histochemical and ultrastructural observations].
A severe neurological disorder was observed during a very dry season, in sheep pasturing on land with mediterranean vegetation. During the crisis, lasting 5-20", ataxia and convulsions were the main clinical signs. Brain congestion, spongy appearance of the liver, interstitial nephritis and hyperpigmentation of visceral lymph nodes were the most important macroscopic lesions. Histopathological, histochemical and ultrastructural findings confirmed liver and kidney lesions and showed considerable neurovisceral storage of lipofuscin. Although further toxicological and experimental studies are needed to elucidate the origin of the disease, the Authors attribute the outbreak of the neurological syndrome to the ingestion of a neurotoxin containing plant.


Editorial: Farewell Message from the Outgoing Editor.
Xi-Cheng Zhang reflects on the growth and success of Optics Letters as his tenure as Editor-in-Chief draws to a close.


Antibacterial and mechanical properties of arginine-containing glass ionomer cements.
The study investigated the effect of incorporating l-arginine (Arg) in a glass ionomer cement (GIC) on its mechanical properties and antibacterial potential. Pre-determined proportions (1%, 2%, and 4% by wt.) of Arg were incorporated in GIC powder; while GIC without Arg served as control. The flexural strength, nanohardness, surface roughness, elemental analysis using SEM-EDX (n = 6) and F/Arg/Ca/Al/Si release in deionized water for 21 days were assessed. The antibacterial potential was evaluated in a multi-species biofilm model with Streptococcus mutans, Streptococcus sanguinis, Streptococcus gordonii, and Lactobacillus acidophilus for 72 h. Real-time qPCR was used to analyse biofilm bacterial concentrations. Propidium monoazide modification of real-time qPCR was performed to quantify viable/dead bacteria. The pH, lactic acid, ADS activity, and H2O2 metabolism were measured. Confocal microscopy was used to investigate the biofilm bacterial live/dead cells, density, and thickness. There was no difference in flexural strength among the different groups (p > 0.05). No significant difference in nanohardness and surface roughness was observed between 4% Arg + GIC and control (p > 0.05). The 4% Arg + GIC showed significantly higher F/Arg/Al/Si release than the other groups (p < 0.05), reduced total bacterial concentration and growth inhibition of viable S. mutans and S. sanguinis (p < 0.05). Lactic acid formation for 4% Arg + GIC was significantly higher than 1% Arg + GIC (p < 0.05). The spent media pH of 4% Arg + GIC was higher than the other groups (p < 0.05), with proportionately lower ammonia and higher H2O2 released (p < 0.05). Addition of 4% l-arginine in GIC enhanced its antibacterial activity via a biofilm modulatory effect for microbial homeostasis, with no detrimental effect on its mechanical properties.


The effects of zinc on the morphology of sickle red blood cell ghosts as observed by scanning electron microscopy.
The objective of these studies is to define the role of zinc in RBC ghost morphology specifically in comparison to the echinocytogenic effects of calcium. Erythrocyte ghosts were prepared from patients with sickle cell anemia, treated with zinc and/or calcium and the resulting cell morphology studied by scanning electron microscopy. Our results showed that zinc consistently and significantly antagonized the echinocytogenic effect of calcium. A simple log linear statistical model was used to evaluate the data and supported this conclusion. We discuss the potential significance of these findings to the effect of zinc treatment on patients with sickle cell anemia.


The reproductive strategy of the gregarious parasitoid, Pteromalus puparum (Hymenoptera: Pteromalidae) : 2. Host size discrimination and regulation of the number and sex ratio of progeny in a single host.
Host size of Pteromalus puparum, a gregarious pupal parasitoid, shows a wide inter- and intraspecific variation. Experiments were made to study the regulation of the number and sex ratio of progeny per host by the parasitoid. The parasitoid could discriminate inter- and intraspecific size differences of the host and regulate the number of eggs according to the host size when a single female attacked the host. The sex ratio of progeny (proportion males) was about 0.1. The number of progeny laid by the female agreed with the energetically most efficient number og eggs in order to maximize total weight of progeny per host but not with the reproductively most efficient number of eggs to maximize the total fecundity of the progeny. The parasitoid laid smaller number of eggs in a half buried host, but the number was much larger than a half of those in a fully exposed host. When more than one female attacked a single host, the number and sex ratio of progeny per host increased with the number of females attacking the host, but the number of progeny per female decreased. The change of the sex ratio agreed with the prediction of the local mate competition model.


pH-shifting encapsulation of curcumin in egg white protein isolate for improved dispersity, antioxidant capacity and thermal stability.
Curcumin (Cur) has many functions, such as antioxidant and anti-inflammatory. However, its poor solubility and thermal stability at aqueous solutions limit its application in the food industry. In this study, egg white protein isolate (EPI) was complexed with Cur via a pH-shifting method. The effects of ultimate pH (from 5.0 to 7.0) on the physicochemical properties of the complex were studied. Cur could reach 84.4% encapsulation efficiency at pH 6.0. Meanwhile, the EPI complex could remain stable at pH 7.0 after 30 days and protect Cur from thermal degradation, thereby improving the Cur retention rate with the increasing ultimate pH. Compared with those of EPI and free Cur, the antioxidant capacity of the complex was enhanced effectively. The EPI-Cur complex was certified using UV-vis and fluorescence spectra. The fluorescence results indicated that Cur and EPI are combined through a static quenching and with a strong affinity of 1.8 × 105 M-1 at pH 6.0. In summary, this work provides a biocompatible and straightforward method for the development of nanoparticles based on egg white protein isolates, which can be used as a promising carrier for insoluble nutritional compounds.


Editorial: The Developmental Science of Borderline Personality Disorder.
In a seminal review article on borderline personality disorder (BPD) for the American Journal of Psychiatry, John Gunderson once made the allusion that "borderline personality disorder is to psychiatry what psychiatry is to medicine," suggesting that the condition is frequently neglected, even among mental health professionals and researchers.1 For instance, BPD-related research received less than one-tenth of the US National Institutes of Health funding compared to bipolar disorder research, despite sharing similar rates of prevalence, impairment, and mortality.2 Along those lines, one could argue that borderline personality features in adolescence share the same hierarchical relationship with their counterparts in adults, being even more stigmatized and overlooked, even in the child and adolescent psychiatry community. Accordingly, only 1 of 4 randomized trials with psychosocial interventions for BPD were conducted in youth.3,4.


Immunocytochemical localization of cell adhesion molecule L1 in developing rat pyramidal tract.
L1 is a representative of a family of carbohydrate neural cell adhesion molecules. The expression of L1 was studied during postnatal development of the rat pyramidal tract by immunohistology using polyclonal antibodies to L1 in spinal cord cervical intumescences. On postnatal day 1 (P1), L1 immunoreactivity was present in the entire dorsal funiculus, consisting of the ascending fasciculus gracilis and fasciculus cuneatus and the descending pyramidal tract. At that time the cervical pyramidal tract contains the first outgrowing corticospinal axons. At P4 both the fasciculus gracilis and the pyramidal tract are immunoreactive whereas the fasciculus cuneatus is negative. At P10 the pyramidal tract is intensely labelled whereas both ascending bundles are negatively stained. In the period between P4 and P10 the pyramidal tract is characterized by a massive outgrowth of corticospinal axons. During pyramidal tract myelination, between P10 and the end of the third postnatal week (P21), L1 immunoreactivity is progressively reduced. These observations suggest that L1 may play a prominent role in outgrowth, fasciculation and the onset of myelination of rat pyramidal tract axons. The differential L1 immunoreactivity of the pyramidal tract and the earlier developing ascending systems in rat dorsal funiculus indicate that this polyclonal antiserum is a useful differentiating marker for outgrowing fibre tracts.


Non-traumatic spinal cord lesions: epidemiology, complications, neurological and functional outcome of rehabilitation.
Prospective cross-sectional study. To study epidemiology, complication, neurological and functional outcome in non-traumatic spinal cord lesions (NTSCL) after inpatient rehabilitation. Neurological rehabilitation unit of a tertiary research hospital. Sixty-four patients (M/F=28:36) with NTSCL admitted from June 2005 to January 2008 for multidisciplinary rehabilitation. Epidemiology, medical complications during stay in rehabilitation, admission and discharge--Barthel Index (BI) and American Spinal Injury Association (ASIA) impairment scale for functional and neurological recovery, respectively, were recorded and analyzed. NTSCL constituted 60% (64 of 106) of the total SCL patients admitted for rehabilitation during the same period. Female patients outnumbered males (56.25%) in the study. Mean age, duration of illness and duration of stay in rehabilitation were 30.64+/-13.67 years (6-57), 7.09+/-9.15 months (1-48) and 55.75+/-40.91 days (14-193), respectively. The ratio of paraplegia and quadriplegia was 2:1. Forty-four patients (68.75%) had incomplete cord lesion according to the ASIA impairment scale. Spinal tumors (26.6%) were found to be the most common etiology, followed by Pott's spine (25%) and transverse myelitis (22%). Urinary tract infection was found to be the most common complication (50%), followed by spasticity (35.93%) and urinary incontinence (31.25%). The mean BI scores showed significant (P=0.000) functional recovery during rehabilitation using paired Student's t-test. The ASIA impairment scale showed significant neurological recovery (P=0.001) using the Wilcoxon non-parametric test. NTSCL constitute a significant proportion of overall SCL. Female population, paraplegia and incomplete cord lesions are more common among NTSCL in this study. Patients with NTSCL recover significantly both neurologically and functionally with rehabilitation intervention.


An hierarchical location-allocation model for primary health care delivery in a developing area.
Location-allocation models can play an important role in making primary health care facilities more accessible to rural populations in the developing world. Traditional models, however, have failed to deal realistically with the fact that health care systems are hierarchical in nature, and that benefits and utilization decline with distance. In this paper, an hierarchical location-allocation model in which benefits accrue to facility level and decline exponentially with distance is presented as a possible approach to ameliorating problems of rural accessibility to health care in Third World settings. The model is subjected to sensitivity analysis with reference to data for Salcette Taluka, Goa, India. The analysis suggests that the traditional P-median model may be a much less appropriate solution to the problem than a simple strategy of locating facilities from the highest to the lowest level in centers of strictly decreasing population.


Basis of selectivity of cyhalofop-butyl in Oryza sativa L.
Cyhalofop-butyl (CB), 2-[4-(4-cyano-2-fluorophenoxy)phenoxy]propanoic acid, butyl ester (R), is an aryloxyphenoxypropionate (AOPP) herbicide for postemergence use in rice to control grasses, mainly Echinochloa spp. Similar to other AOPP and cyclohexanedione herbicides, the site of action of CB is acetyl-coenzyme A carboxylase (ACCase), an enzyme in fatty acid biosynthesis. The mechanisms involved in the selectivity of CB in rice (Oryza sativa L.)-absorption, translocation, metabolism, and ACCase susceptibility-were studied. Studies of in vitro inhibition of ACCase in E. oryzoides and O. sativa L. species discounted any differential active site sensitivity as the basis of tolerance to CB. The O. sativa L. cuticle was uniformly covered by waxes, with predominantly unshaped large waxes randomly distributed, obtaining absorption values of under 30%, 24 h after application (HAA). The E. oryzoides cuticle formed a non-uniform covered reticule, with less wax density and areas lacking in waxes reaching maximum values of absorption rising to 73%, 24 HAA. Translocation studies revealed no significant differences, either between species, or between times, remaining in the treated leaf. There was a good correlation between the rate of metabolism and plant tolerance. Plant metabolism studies demonstrated that tolerant rice inactivated the esterases producing a lack of functionality thus reducing the conversion of CB to cyhalofop acid, which is the active form of the herbicide. Moreover, it increased the metabolism of the herbicide forming non toxic metabolites much faster than E. oryzoides. It was concluded that the basis of rice tolerance to CB was a lack of esterase functionality, a reduced absorption through the cuticle and an increase in cyhalofop acid metabolism.


Examining the effects of adjuvant chemotherapy on cognition and the impact of any cognitive impairment on quality of life in colorectal cancer patients: study protocol.
Research suggests that chemotherapy can cause deficits in both patients' objectively measured and self-reported cognitive abilities which can in turn affect their quality of life (QoL). The majority of research studies have used post-treatment retrospective designs or have not included a control group in prospective cohorts. This has limited the conclusions that can be drawn from the results. There have also been a disproportionate number of studies focussed on women with breast cancer, which has limited the generalisability of the results to other cancer populations. This study aims to identify the extent and impact of chemotherapy-induced cognitive decline in colorectal cancer patients. Possible associations with poorer QoL will also be explored. This will be a longitudinal controlled cohort study. Questionnaires measuring subjective cognitive functioning, QoL, fatigue and mood, and neuropsychological assessments of objective cognitive function will be collected pre-, mid- and post- chemotherapy treatment from a consecutive sample of 78 colorectal cancer patients from five London NHS Trusts. A further 78 colorectal cancer surgery only patients will be assessed at equivalent time points; this will allow the researchers to compare the results of patients undergoing surgery, but not chemotherapy against those receiving both treatments. Pre- and post-chemotherapy difference scores will be calculated to detect subtle changes in cognitive function as measured by the objective neuropsychological assessments and the self-reported questionnaires. A standardised z-score will be computed for every patient on each neuropsychological test, and for each test at each time point. The post-chemotherapy score will then be subtracted from the pre-chemotherapy score to produce a relative difference score for each patient. ANCOVA will be used to compare mean difference z-scores between the chemotherapy and surgery-only groups while controlling for the effects of gender, age, depression, anxiety, fatigue and education. The result from this study will indicate whether a decline in cognitive functioning can be attributed to chemotherapy or to disease, surgical or some other confounding factor. Identification of risk factors for cognitive deficits may be used to inform targeted interventions, in order to improve QoL and help patients' cope.


Positive selection targeting the cathelin-like domain of the antimicrobial cathelicidin family.
The cathelin-like domain (CLD) of cathelicidins is grouped in the same superfamily with cystatins, natural cysteine protease inhibitors, due to their structural similarity. Intriguingly, human hCAP-18/LL37 and pig protegrin-3 (PG3) CLDs exhibit opposite effects against cathepsin L. Here, I evaluated the functional importance of the CLD through identifying whether positive selection has driven adaptive evolution of this domain. As a result, four positively selected sites were detected and three of them are located on a loop region previously recognized as a key determinant of the activating effect of the PG3 CLD. Analysis of amino acid variability of the CLD led to the discovery of a conserved region and three highly variable regions, in which two are subjected to positive selection. Positive selection targeting the variable regions provides a starting point for experimentally establishing a direct link between the observed amino acid changes and functional divergence of the CLD family.


Regulation of enzyme localization by polymerization: polymer formation by the SAM domain of diacylglycerol kinase delta1.
The diacylglycerol kinase (DGK) enzymes function as regulators of intracellular signaling by altering the levels of the second messengers, diacylglycerol and phosphatidic acid. The DGK delta and eta isozymes possess a common protein-protein interaction module known as a sterile alpha-motif (SAM) domain. In DGK delta, SAM domain self-association inhibits the translocation of DGK delta to the plasma membrane. Here we show that DGK delta SAM forms a polymer and map the polymeric interface by a genetic selection for soluble mutants. A crystal structure reveals that DGKSAM forms helical polymers through a head-to-tail interaction similar to other SAM domain polymers. Disrupting polymerization by polymer interface mutations constitutively localizes DGK delta to the plasma membrane. Thus, polymerization of DGK delta regulates the activity of the enzyme by sequestering DGK delta in an inactive cellular location. Regulation by dynamic polymerization is an emerging theme in signal transduction.


Population-Level Implications of Sodium-Glucose Cotransporter-2 Inhibitors for Heart Failure With Preserved Ejection Fraction in the US.
The expansion of sodium-glucose cotransporter-2 (SGLT-2) inhibitor use in patients with heart failure (HF) and left ventricular ejection fraction (LVEF) more than 40% following the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction) and the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trials have major implications in the US. To quantify the estimated US population-level impact of reducing worsening HF events with SGLT-2 inhibitors in individuals with LVEF more than 40%. This decision analytical model study used self-reported HF data from the National Health and Nutritional Examination Survey from 2015 to 2018, which was weighted across the entire US population and subsequently mapped onto newly eligible LVEF distributions from the Get With The Guidelines-Heart Failure registry. All patients older than 18 years with HF from the National Health and Nutritional Examination Survey were grouped into the following categories: all LVEF and LVEF more than 40%. Numbers needed to treat estimations over 3 years were obtained for outcome measures from the EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction), EMPEROR-Preserved, DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), and DELIVER trials. Worsening HF events (unplanned HF hospitalizations, urgent HF visits requiring intravenous therapy, or cardiovascular death). A projected 4 794 524 (95% CI, 3 997 363-5 591 684) adults (57% male; 67% White; mean age, 66 years) with HF would be eligible for SGLT-2 inhibitors. Of this total population, 2 619 248 (95% CI, 2 183 759-3 054 737) would be estimated as newly eligible with LVEF more than 40%. Based on estimates from the EMPEROR-Reduced/EMPEROR-Preserved and DAPA-HF/DELIVER trials, a projected 624 247 (95% CI, 520 457-728 037) to 627 124 (95% CI, 522 855-731 392) worsening HF events could be prevented across the LVEF spectrum with SGLT-2 inhibitors over 3 years, of which 232 589 (95% CI, 193 918-271 260) to 282 879 (95% CI, 235 846-329 912) events could be prevented in individuals with LVEF more than 40%. Moreover, an estimated 468 904 (95% CI, 390 942-546 867) to 499 110 (95% CI, 416 125-582 094) total HF hospitalizations could be prevented across the LVEF spectrum, of which 172 870 (95% CI, 144 128-201 613) to 231 018 (95% CI, 192 608-269 428) could be prevented in individuals with LVEF more than 40%. In addition to the proven benefit in HF with LVEF of 40% and less, optimal implementation of SGLT-2 inhibitor therapy for HF with LVEF more than 40% can potentially prevent/postpone an additional approximately 250 000 worsening HF events over 3 years in the US.


An outbreak of gastroenteritis due to Escherichia coli 0142 H6 in a neonatal department.
An outbreak of gastroenteritis due to Escherichia coli 0142 H6 in a neonatal ward is described. The epidemic affected 16 of 24 infants (infection-rate 66 per cent), of whom one died due to necrotizing enterocolitis. Administration of antibiotics was of limited value in treatment or in eradicating E. coli 0142 H6 from the stools. Termination of the epidemic was only accomplished by isolating the patients, accompanied by strict hygienic measures, including the use of disposable gloves. Gastroenteritis due to this organism occurred only in prematurely born infants during the first 2 weeks of life.


SBRT in non-spine bone metastases: a literature review.
Stereotactic Body Radiotherapy (SBRT) is a technique for delivering high doses of radiation to tumors while preserving the normal tissues located around this area. Bone metastases are frequent in cancer patients. They can be distressingly painful or may cause pathological fractures. Radiation therapy is a fundamental aspect of treatment for bone metastases. The objective of this study is to analyze the literature on non-spine bone metastasis treated with SBRT, including immobilization, volume delineation, dose and fractionation, local control, side effects, and assessment of response after treatment. Full-text articles written in English language and published in the last 10 years were included in this review and were accessible on PubMed and MEDLINE. We examined 78 articles. A total of 40 studies were included in this review. Most were retrospective studies. The articles included were evaluated for content and validation. The immobilization systems and imaging tests used for tumor delimitation were variable between studies. The use of CTV (Clinical Target Volume) has not been defined. Doses and fractions were variable from 15 to 24 Gy/1 fraction to 24-50 Gy in 3-5 fractions, with local control being around 90% with a low rate of side effects. We review state of the art in SBRT non-spine metastases. SBRT can result in better local control and pain management in non-spine bone metastases patients. We need more research in volume delineation determining whether or not to use CTV and the role of MRI in volume contouring, optimal doses, and fractionation according to histology and a reliable response assessment tool. Studies that compare SBRT to conventional radiotherapy in local control and pain control are needed.


The future of drug development: the paradigm shift towards systems therapeutics.
Progress in cell biology, genetics, molecular, and systems pharmacology is the driving force behind a current paradigm shift in drug research. This paradigm shift shapes new avenues for advanced treatments that are commonly referred to as 'systems therapeutics'. Systems therapeutics differ in many ways from current drugs because they target biological networks rather than single transduction pathways, and affect disease processes rather than physiological processes. Here, we examine how the paradigm shift towards systems therapeutics will change current scientific concepts of the interactions between drugs and diseases, the organization of research and development, as well as the clinical use and therapeutic evaluations of therapeutic interventions.


Regulation of cellular iron metabolism: Iron-dependent degradation of IRP by SCFFBXL5 ubiquitin ligase.
Because of essentiality and toxicity of iron in our body, iron metabolism is tightly regulated in cells. In mammalian cells, iron regulatory protein 1 and 2 (IRP1 and IRP2) are the central regulators of cellular iron metabolism. IRPs regulate iron metabolism by interacting with the RNA stem-loop structures, iron-responsive elements (IREs), found on the transcripts encoding proteins involved in iron metabolism only in iron depleted condition. It is also well-known that the ubiquitin system plays central roles in cellular iron regulation because both IRPs having the IRE binding activity are recognized and ubiquitinated by the SCFFBXL5 ubiquitin ligase in condition of iron-replete. FBXL5, which is a substrate recognition subunit of SCFFBXL5, senses iron availability via its hemerythrin-like domain. In this small article, current understanding of the roles of SCFFBXL5-mediated degradation of IRPs played in cellular iron metabolism is discussed.


Conversion from tacrolimus to cyclosporine in liver transplanted patients with diabetes mellitus.
Adverse effects associated with calcineurin inhibitors may impact their clinical utility in some patients. This study characterizes the clinical outcomes of liver transplanted (LT) patients who experienced diabetes mellitus (DM) on tacrolimus-based regimen and were converted to cyclosporine-based therapy. Since January 2002, all patients with DM on a tacrolimus-based regimen were recruited and converted to cyclosporine-based therapy, after a 6-month minimal follow-up after LT. Clinical and laboratory data related to the clinical course of the patients were recorded. Twenty-five patients were included after a median delay of 54 months after LT [seven women and 18 men, 51 years (range 30-69)]. There were 11 patients with insulin-treated DM (ITDM), 14 patients with noninsulin-treated DM (NITDM), and the glycemic control was poor (HbA1c > 6.5%) in 13/25 patients (52%). After a median follow-up of 20 months after conversion, there were four patients with ITDM, 17 patients with NITDM, and four patients without DM, and the glycemic control was poor in 3/25 patients (12%). Four patients returned to tacrolimus because of arterial hypertension or digestive side-effects. In conclusion, our results suggest that conversion from tacrolimus to cyclosporine in stable LT patients with DM is well tolerated and beneficial on glycemic control.