Differences in uptake and translocation of selenate and selenite by the weeping willow and hybrid willow.
Due to its essentiality, deficiency, and toxicity to living organisms and the extensive use in industrial activities, selenium (Se) has become an element of global environmental and health concern. Se removal from contaminated sites using physical, chemical, and engineering techniques is quite complicated and expensive. The goal of this study was to investigate uptake and translocation of Se in willows and to provide quantitative information for field application whether Se phytoremediation is feasible and ecologically safe. Intact pre-rooted plants of hybrid willows (Salix matsudana Koidz x alba L.) and weeping willows (Salix babylonica L.) were grown hydroponically and treated with selenite or selenate at 24.0 +/- 1 degrees C for 144 h. Removal of leaves was also performed as a treatment to quantify the effect of transpiration on translocation and volatilization of Se. At the end of the study, total Se in the hydroponic solution and in different parts of plant tissues was analyzed quantitatively by hydride generation-atomic fluorescence spectrometry. The capacity of willows to assimilate both chemical forms of Se was also evaluated using detached leaves and roots in sealed glass vessels in vivo. Translocation efficiency of Se in both plants was estimated. Significant amounts of the applied selenite and selenate were eliminated from plant growth media by willows during the period of incubation. Both willows showed a significantly higher removal rate for selenate than for selenite (p < 0.05). Substantial differences existed in the distribution of both chemical forms of Se in plant materials: lower stems and roots were the major sites for accumulation of selenite and selenate, respectively. Translocation efficiency for selenite was significantly higher than that for selenate in both willow species (p < 0.01). Compared to the intact trees, remarkable decrease in the removal rate of both chemical forms of Se was found for willows without any leaves (p < 0.01). Volatilization of Se by plant leaves was estimated to be approximately 10% of the total applied selenite or selenate. Significant reduction (>20%) of selenate was observed in the sealed vessel with excised roots of willows, whereas trace amounts of selenite were eliminated from the hydroponic solution in the presence of roots. Detached leaves from neither of them reduced the concentration of selenite or selenate in the solution. Due to the significant difference in the removal rate and the distribution of the two chemical forms of Se in plant materials, the conversion of selenate to selenite in hydroponic solution prior to uptake and within plant tissues is unlikely. An independent uptake and translocation mechanisms are likely to exist for each Se chemical species. Uptake of selenate is mediated possibly through an active transport mechanism, whereas that of selenite may possibly depend on plant transpiration. Uptake velocities of selenite are linear (zero-order kinetics), while selenate removal processes obey first-order kinetics. In experiments with detached leaves in closed bottles, the cuticle of leaves was the major obstacle to extract both chemical forms of Se from the hydroponic solution. Phytovolatilization is a biological process playing an important role in Se removal. Although faster removal rates of selenate than selenite from plant growth media were observed by both willow species, selenite in plant materials was more mobile than selenate. Significant decrease in removal rates of both chemical forms of Se was detected for willows without any leaves. Significant differences in extraction, assimilation and transport pathways for selenite and selenate exist in willow trees. Phytoremediation of Se is an attractive approach of cleaning up Se contaminated environmental sites. More detailed investigation on the assimilation of Se in plant roots and transport in tissues will provide further biochemical evidence to explain the differences in uptake and translocation mechanisms between selenite and selenate in willows. A relevant phytoremediation scheme can then be designed to clean up Se contaminated sites. Willows show a great potential for uptake, assimilation and translocation of both selenite and selenate. Phytotreatment of Se is potentially an efficient and practical technology for cleaning up contaminated environmental sites.


Effect of different sources of dietary protein on muscle hypertrophy in functionally overloaded mice.
Dietary protein intake is important for skeletal muscle protein synthesis. In this study, we investigated the differential effect of protein sources on hypertrophy of plantaris muscle induced by surgical ablation of gastrocnemius and soleus muscles. Six-week old mice were fed diets containing caseinate, whey, or soy as protein sources for 2 weeks. Plantaris muscle hypertrophy was induced by a unilateral ablation of synergistic muscles after a week. Food intake of soy protein-fed mice was higher than that of caseinate and whey-fed mice, resulting in higher body and fat weights. Plantaris muscle weight in sham-operated mice was not different across the groups. Overload-operated plantaris muscle weight and increased ratio of overloaded muscle to sham-operated muscle weights were higher in caseinate-fed mice than in whey- and soy protein-fed mice, suggesting caseinate as a promising protein source for muscle hypertrophy.


Mdm2 associates with Ras effector NORE1 to induce the degradation of oncoprotein HIPK1.
The Ras effector NORE1 is frequently silenced in primary adenocarcinomas, although the significance of this silencing for tumorigenesis is unclear. Here we show that NORE1 induces polyubiquitination and proteasomal degradation of oncoprotein HIPK1 by facilitating its interaction with the Mdm2 E3 ubiquitin ligase. Endogenous HIPK1 is stabilized in Nore1-deficient mouse embryonic fibroblasts, and depletion of HIPK1 in NORE1-silenced lung adenocarcinoma cells inhibits anchorage-independent cell growth and tumour formation in nude mice. These findings indicate that the control of HIPK1 stability by Mdm2-NORE1 has a major effect on cell behaviour, and epigenetic inactivation of NORE1 enables adenocarcinoma formation in vivo through HIPK1 stabilization.


Clinical and Psychosocial Predictors of Community Reintegration of Stroke Survivors Three Months Post In-Hospital Discharge.
There appears to be a dearth of published literature on the biopsychosocial predictors of community reintegration (CR) among stroke survivors. This study aims to investigate the clinical and psychosocial predictors of CR among stroke survivors three months post in-hospital discharge. Fifty-two stroke survivors took part in this prospective exploratory study. The participants' clinical attributes of motor function (MF), balance (Bal) and psychosocial characteristics of Fall Self-Efficacy (FSE), Balance Self-Efficacy (BSE), Self-Esteem (SEst) and Social Support (SS) were assessed pre-discharge and at three months post-discharge. CR was also assessed at three months post-discharge. Data were analyzed using paired t-test, Pearson's Moment correlation and multiple regressions. Level of significance was set at p = 0.05. The mean age of the participants was 61.21±11.25 years with mean hospital length of stay of 5.31±3.71weeks. There were significant differences in the mean MF, Bal, FSE, BSE, SEst and SS scores of the participants pre- and post-discharge (p < 0.05). Also, there was a significant correlation between CR and each of MF, Bal, FSE, BSE, SEst and SS. Pre-discharge Age (β = -0.226, p = 0.001) and FSE (β = 1.387, p = 0.040) significantly predicted CR. Post-discharge age (β = -0.164, p = 0.005) and Bal (β = 0.142, p = 0.048). FSE (β = 1.243, p = 0.034) also significantly predicted CR. Age, Bal and FSE are important predictors of CR among stroke survivors. Therefore, rehabilitation programmes should focus on improving Bal and FSE in order to enhance community reintegration among stroke survivors.


Diel use of a saltwater creek by white-tip reef sharks Triaenodon obesus (Carcharhiniformes: Carcharhinidae) in Academy Bay, Galapagos Islands.
White-tip reef sharks are common inhabitants of the shallow waters surrounding the Galapagos Islands, where several known aggregation sites have become touristic attractions. With the aim to describe site fidelity and residency patterns of the white-tip reef sharks in a saltwater creek, we used the ultrasonic telemetry method. The study was undertaken in a saltwater channel South of Academy Bay, Santa Cruz Island, from May 2008-September 2009. A total of nine transmitters were attached to sharks and ultrasonic receivers were deployed at the inner and outside areas of the creek. From the total of fitted sharks, four lost their transmitters. The results obtained with the remaining sharks showed an elevated use of the inner area of the channel during the day, with more use of the external area during the night. However, none of the sharks were detected at the site every day, suggesting that they may have a number of preferred sites within their home range. More studies are needed to detail the home range and habitat use of this species, and to guide its protection level in the Academy Bay area.


Social work assessment at end of life: practice guidelines for suicide and the terminally ill.
As social workers, we are educated about the values of client self-determination as well as the affirmation of uniqueness in how the client experiences life and death. In terms of choices at the end of life, assisted suicide has begun to come out of the closet, so to speak, and as a result, the National Association of Social Worker's adopted a policy in 1993 which addresses this end of life option. Oregon passed Ballot Measure 16 in November of 1994 which allows for a terminally ill person to request drugs to end life. As the legalities of assisted suicide are decided by judges and courts, some terminally ill people will think about and decide to take their own lives rather than wait for the disease process to come to its own ending. There are very few practice guidelines available to social workers who work with the suicidal terminally ill. A traditional mental health model for evaluation of lethality cannot be imposed onto this population. A three-part model for assessment and evaluation of a suicidal request from a terminally ill person is proposed in this article.


A cross-sectional examination of conflict-of-interest disclosures of physician-authors publishing in high-impact US medical journals.
To assess the accuracy of self-reported financial conflict-of-interest (COI) disclosures in the New England Journal of Medicine (NEJM) and the Journal of the American Medical Association (JAMA) within the requisite disclosure period prior to article submission. Cross-sectional investigation. Original clinical-trial research articles published in NEJM (n=206) or JAMA (n=188) from 1 January 2017 to 31 December 2017; self-reported COI disclosure forms submitted to NEJM or JAMA with the authors' published articles; Open Payments website (from database inception; latest search: August 2019). Financial data reported to Open Payments from 2014 to 2016 (a time period that included all subjects' requisite disclosure windows) were compared with self-reported disclosure forms submitted to the journals. Payments selected for analysis were defined by Open Payments as 'general payments.' Payment types were categorised as 'disclosed,' 'undisclosed,' 'indeterminate' or 'unrelated'. Thirty-one articles from NEJM and 31 articles from JAMA met inclusion criteria. The physician-authors (n=118) received a combined total of US$7.48 million. Of the 106 authors (89.8%) who received payments, 86 (81.1%) received undisclosed payments. The top 23 most highly compensated received US$6.32 million, of which US$3.00 million (47.6%) was undisclosed. High payment amounts, as well as high proportions of undisclosed financial compensation, regardless of amount received, comprised potential COIs for two influential US medical journals. Further research is needed to explain why such high proportions of general payments were undisclosed and whether journals that rely on self-reported COI disclosure need to reconsider their policies.


Comparison of incidental parathyroid tissue detection rates on pathology after total thyroidectomy performed with or without near-infrared autofluorescence imaging.
Near-infrared autofluorescence imaging is an adjunct to parathyroid identification. As it does not show perfusion, it is important to study its impact during thyroidectomy by measuring quantifiable data on parathyroid detection rather than function. The aim of this study was to compare incidental parathyroidectomy rates in patients undergoing total thyroidectomy with or without near-infrared autofluorescence. Retrospective study of patients who underwent total thyroidectomy between 2014 and 2022 at one center. Clinical parameters, including rates of incidental parathyroid tissue on pathology reports, were compared between near-infrared autofluorescence and non-near-infrared autofluorescence groups. Near-infrared autofluorescence was used to guide dissection (identification) and/or to confirm tissue as parathyroid (confirmation). Statistical analysis was done with Wilcoxon rank sum test and χ2 analysis. There were 300 patients in the near-infrared autofluorescence and 750 patients in the non-near-infrared autofluorescence group. The rate of incidental parathyroid tissue detection on final pathology was 13.3% (n = 40) in the near-infrared autofluorescence and 23.2% (n = 174) in the non-near-infrared autofluorescence group (P < .001). The rate of incidental parathyroid tissue detected on pathology with near-infrared autofluorescence decreased when used for identification and confirmation of parathyroid tissue (30.0% to 13.4%, P < .001), but not when used for confirmation only (19.6% to 18.5%, P = .89). Impact of near-infra red autofluorescence in decreasing the rate of incidental parathyroid tissue was more profound for early (38.5% to 17.1%) versus mid-late career surgeons (20% to 13%). Our results suggest that the use of near-infrared autofluorescence may help decrease the rate of incidental parathyroid tissue detected on final pathology if used for both identification and confirmation of parathyroid glands during thyroidectomy.


Sclerosis of a rib associated with a healed fracture of a contiguous thoracic vertebra.
A patient who suffered a fracture of the body of the 10th dorsal vertebra as a result of an automobile accident was examined seven years later. He complained of local pain over the gibbus site. All movements in the back and the joints of the extremities were within normal limits. Radiographs disclosed a healed compressed fracture of the body of the 10th thoracic vertebra with bony bridges contiguous with the 9th and 11th thoracic vertebrae. An unusual finding was the presence of a uniform sclerosis of a single rib at the level of the fracture site. Other bones of the rib cage, as well as the lumbar and pelvic bones, were normal. The basis for the abnormal density of the affected rib may be due to abnormal stress factors (Wolff's law).


Dexamethasone infusion testing in the diagnosis of Cushing's syndrome.
Cushing's syndrome and its various aetiologies is a markedly difficult diagnosis to make given its subtle signs, sometime cyclical nature, and the lack of a single definitive diagnostic test. Although a great variety of diagnostic tests have been developed to assist in the diagnosis, even with the best clinical acumen, biochemistry and medical imaging the diagnosis can remain elusive. The long low and high dose oral dexamethasone suppression test is cumbersome, costly and often requiring an extended inpatient stay. The utility of the dexamethasone suppression test would be greatly enhanced if it could be performed as a short outpatient procedure. In this study we sought to confirm and refine the clinical utility of the high dose 4 mg intravenous dexamethasone suppression test as an alternative diagnostic test for Cushing's syndrome. There were a total of 31 subjects: 8 patients with proven pituitary Cushing's disease, 3 with primary adrenal tumors, 10 with pseudo-Cushing's syndrome and 10 healthy controls. All subjects with pseudo-Cushing's syndrome suppress serum cortisol at +5 and at +24 hours. In subjects with pituitary Cushing's disease, 7 out of 8 (88%) had serum cortisol suppressed at +5 hours but rebounded at +24 hours to at least 70% of the original serum level. Primary adrenal tumors showed a pattern of non-suppression throughout. The 4 mg intravenous dexamethasone suppression test is excellent in ruling out pseudo-Cushing's syndrome. This test is much simpler and more convenient than the oral dexamethasone suppression test in confirming clinical suspicion of pituitary Cushing's disease.


Fission yeast Rad17 associates with chromatin in response to aberrant genomic structures.
Fission yeast checkpoint protein Rad17 is required for the DNA integrity checkpoint responses. A fraction of Rad17 is chromatin bound independent of the other checkpoint proteins throughout the cell cycle. Here we show that in response to DNA damage induced by either methyl methanesulfonate treatment or ionizing radiation, increased levels of Rad17 bind to chromatin. Following S-phase stall induced by hydroxyurea or a cdc22 mutation, the chromatin-bound Rad17 progressively dissociates from the chromatin. After S-phase arrest by hydroxyurea in cds1Delta or rad3Delta cells or by replication mutants, Rad17 remains chromatin bound. Rad17 is able to complex in vivo with an Rfc small subunit, Rfc2, but not with Rfc1. Furthermore, cells with rfc1Delta are checkpoint proficient, suggesting that Rfc1 does not have a role in checkpoint function. A checkpoint-defective mutant protein, Rad17(K118E), which has similar nuclear localization to that of the wild type, is unable to bind ATP and has reduced ability in chromatin binding. Mutant Rad17(K118E) protein also has reduced ability to complex with Rfc2, suggesting that Lys(118) of Rad17 plays a role in Rad17-Rfc small-subunit complex formation and chromatin association. However, in the rad17.K118E mutant cells, Cds1 can be activated by hydroxyurea. Together, these results suggest that Rad17 binds to chromatin in response to an aberrant genomic structure generated from DNA damage, replication mutant arrest, or hydroxyurea arrest in the absence of Cds1. Rad17 is not required to bind chromatin when genomic structures are protected by hydroxyurea-activated Cds1. The possible checkpoint events induced by chromatin-bound Rad17 are discussed.


Foliar treatments with Gaultheria procumbens essential oil induce defense responses and resistance against a fungal pathogen in Arabidopsis.
Essential oil from Gaultheria procumbens is mainly composed of methylsalicylate (MeSA) (>96%), a compound which can be metabolized in plant tissues to salicylic acid, a phytohormone inducing plant immunity against microbial pathogens. The potential use of G. procumbens essential oil as a biocontrol agent was evaluated on the model plant Arabidopsis thaliana. Expression of a selection of defense genes was detected 1, 6, and 24 h after essential oil treatment (0.1 ml/L) using a high-throughput qPCR-based microfluidic technology. Control treatments included methyl jasmonate and a commercialized salicylic acid (SA) analog, benzo(1,2,3)-thiadiazole-7carbothiolic acid (BTH). Strong induction of defense markers known to be regulated by the SA pathway was observed after the treatment with G. procumbens essential oil. Treatment induced the accumulation of total SA in the wild-type Arabidopsis line Col-0 and analysis of the Arabidopsis line sid2, mutated in a SA biosynthetic gene, revealed that approximately 30% of MeSA sprayed on the leaves penetrated inside plant tissues and was demethylated by endogenous esterases. Induction of plant resistance by G. procumbens essential oil was tested following inoculation with a GFP-expressing strain of the Arabidopsis fungal pathogen Colletotrichum higginsianum. Fluorescence measurement of infected tissues revealed that treatments led to a strong reduction (60%) of pathogen development and that the efficacy of the G. procumbens essential oil was similar to the commercial product BION(®). Together, these results show that the G. procubens essential oil is a natural source of MeSA which can be formulated to develop new biocontrol products.


The role of radiotherapy and intrathecal CNS prophylaxis in extralymphatic craniofacial aggressive B-cell lymphomas.
To define the role of radiotherapy and intrathecal prophylaxis in extralymphatic craniofacial involvement (ECFI) of aggressive B-cell lymphoma, we analyzed 11 consecutive German High-Grade Non-Hodgkin Lymphoma Study Group trials. ECFI occurred in 290/4155 (7.0%) patients (orbita, 31; paranasal sinuses, 93; main nasal cavity, 38; tongue, 27; remaining oral cavity, 99; salivary glands, 54). In a multivariable analysis adjusted for International Prognostic Index rituximab improved event-free and overall survival both in patients with and without ECFI. Three-year event-free (79% vs 79%; P = .842) and overall survival (86% vs 88%; P = .351) rates were similar in 145 patients receiving and 57 not receiving radiotherapy. Without rituximab, the 2-year cumulative rate of central nervous system (CNS) disease was increased in 205 ECFI patients compared with 2586 non-ECFI patients (4.2% vs 2.8%; P = .038), whereas this was not observed with rituximab (1.6% in 83 ECFI vs 3.4% in 1252 non-ECFI patients; P = .682). In 88 ECFI patients who received intrathecal prophylaxis with methotrexate, the 2-year rate of CNS disease was 4.2% compared with 2.3% in 191 patients who did not (P = .981). In conclusion, rituximab eliminates the increased risk for CNS disease in patients with ECFI. This retrospective analysis does not support intrathecal prophylaxis or radiotherapy to ECFI patients in complete remission/unconfirmed complete remission. These findings should be confirmed in a prospective study.


Clinical characteristics of responders to interferon therapy for relapsing MS.
To determine the proportion of patients with multiple sclerosis (MS) who respond to interferon-beta (IFNB) therapy and assess whether clinical characteristics differ in IFNB responders vs nonresponders. Data on all patients who received IFNB who were entered in the prospective European Database for Multiple Sclerosis (EDMUS) database in Lyon as of March 31, 2001, were reviewed. Responders were defined as having a lower relapse rate on IFNB compared with the year or 2 years prior to IFNB therapy. Two hundred sixty-two patients with relapsing MS received at least 6 months of IFNB: 200 relapsing remitting (RR) and 62 relapsing secondary progressive (SP). One-third of patients experienced a higher or identical annual relapse rate while on IFNB treatment. Compared with nonresponders, responders were older and had longer disease duration at the time IFNB was initiated. RRMS responders also had a higher relapse rate during the year prior to IFNB therapy and SPMS responders had a higher Disability Status Scale score at initiation of IFNB. Clinical profiles of patients with relapsing MS who respond to IFNB may differ from those who do not with a more inflammatory and less neurodegenerative disease at the time IFNB is initiated.


Experimental selection of long-term intracellular mycobacteria.
Some intracellular bacteria are known to cause long-term infections that last decades without compromising the viability of the host. Although of critical importance, the adaptations that intracellular bacteria undergo during this long process of residence in a host cell environment remain obscure. Here, we report a novel experimental approach to study the adaptations of mycobacteria imposed by a long-term intracellular lifestyle. Selected Mycobacterium bovis BCG through continuous culture in macrophages underwent an adaptation process leading to impaired phenolic glycolipids (PGL) synthesis, improved usage of glucose as a carbon source and accumulation of neutral lipids. These changes correlated with increased survival of mycobacteria in macrophages and mice during re-infection and also with the specific expression of stress- and survival-related genes. Our findings identify bacterial traits implicated in the establishment of long-term cellular infections and represent a tool for understanding the physiological states and the environment that bacteria face living in fluctuating intracellular environments.


Biomarkers for Response of Melanoma Patients to Immune Checkpoint Inhibitors: A Systematic Review.
Immune checkpoint inhibitors (ICIs), targeting CTLA-4 or PD-1 molecules, have shown impressive therapeutic results. However, only 20-40% of advanced melanoma patients have durable responses to ICI, and these positive effects must be balanced against severe off-target immune toxicity and high costs. This urges the development of predictive biomarkers for ICI response to select patients with likely clinical benefit from treatment. Although many candidate biomarkers exist, a systematic overview of biomarkers and their usefulness is lacking. Here, we systematically review the current literature of clinical data of ICI treatment to provide an overview of candidate predictive biomarkers for ICI in melanoma patients. To identify studies on biomarkers for clinical response or survival to ICI therapy in melanoma patients, we performed a systematic search in OVID MEDLINE and retrieved 429 publications, of which 67 met the eligibility criteria. Blood and genomic biomarkers were mainly studied for CTLA-4 ICI, while tumor tissue markers were analyzed for both CTLA-4 and PD-1 ICI. Blood cytology and soluble factors correlated more frequently to overall survival (OS) than to response, indicating their prognostic rather than predictive nature. Systemic T-cell response and regulation markers correlated to response, but progression-free survival or OS were not analyzed. Tumor tissue analyses revealed response correlations with mutational load, neoantigen load, immune-related gene expression, and CD8+ T-cell infiltration at the invasive margin. The predictive value of PD-L1 varied, possibly due to the influence of T-cell infiltration on tumor PD-L1 expression. Genomic biomarker studies addressed CTLA-4 and other immune-related genes. This review outlines all published biomarkers for ICI therapy and highlights potential candidate markers for future research. To date, PD-L1 is the best studied biomarker for PD-1 ICI response. The most promising candidate predictive biomarkers for ICI response have not yet been identified. Variations in outcome parameters, statistical power, and analyses hampered summary of the results. Further investigation of biomarkers in larger patient cohorts using standardized objectives and outcome measures is recommended.


The effect of clozapine on glucose metabolism.
Although there have been several reports that clozapine precipitated hyperglycemia and diabetic ketoacidosis in some patients, the mechanism by which clozapine impairs glucose metabolism is not known. This study investigated the effect of clozapine on glucose metabolism in six schizophrenic patients while they were free of medication and receiving 200 mg/d and 450 mg/d of clozapine. Clozapine increased mean levels of blood glucose, insulin and C-peptide. It is possible, based on these findings, that the glucose intolerance was due to increased insulin resistance.


The effects of selection indices for sustainable hill sheep production on carcass composition and muscularity of lambs, measured using X-ray computed tomography.
A multi-trait selection index designed to improve the overall economic performance of hill sheep, including both maternal and lamb traits, has been developed and tested in a selection experiment over 7 years. Two versions of the index were tested, with different economic weights applied to the traits, on two different hill farms: one version including maternal and growth traits; the other version with additional breeding goals of carcass weight, fatness and conformation scores. Responses to selection, using both versions of the index, suggest that improvements are being made in overall index score and lamb growth. This study investigated the indirect effects of these selection indices on lamb carcass composition and muscularity traits, as measured using X-ray computed tomography (CT) scanning. A total of 499 lambs from the two hill farms were CT scanned at weaning (approximately 120 days of age). Approximately half of the lambs from each farm were from the selection line (S, animals with highest index scores selected for breeding), while the other half were from a control line (C, animals with average index scores selected). Composition and muscularity traits were estimated on each lamb from CT data and differences between genetic lines investigated, within farm, using restricted maximum likelihood analyses, adjusting for either live weight or age. Results showed that the selection index without carcass traits produced lambs with carcass composition that was not significantly different to control lambs at a given live weight or age. Including carcass traits in the index resulted in lambs with no compositional differences (except for a slight increase in bone) at a set age compared with controls. At a given live weight however, selection lambs had less fat and lower carcass weights and killing-out percentage. Muscularity (3-D muscle shape) and muscle area shape (2-D) were not improved as a result of selection on either version of the index (including carcass weight and grades in the breeding goals or not) and, at a fixed live weight, muscularity in hind leg and lumbar regions tended to be higher in the C line. To accelerate changes in carcass composition and muscularity within the context of a multi-trait selection index for hill sheep, consideration should therefore be given to including objective CT-derived carcass traits in the index in addition to the Meat and Livestock Commission (MLC) carcass grades or ultrasound measurements.


Resveratrol couples apoptosis with autophagy in UVB-irradiated HaCaT cells.
UVB radiation causes about 90% of non-melanoma skin cancers by damaging DNA either directly or indirectly by increasing levels of reactive oxygen species (ROS). Skin, chronically exposed to both endogenous and environmental pro-oxidant agents, contains a well-organised system of chemical and enzymatic antioxidants. However, increased or prolonged free radical action can overwhelm ROS defence mechanisms, contributing to the development of cutaneous diseases. Thus, new strategies for skin protection comprise the use of food antioxidants to counteract oxidative stress. Resveratrol, a phytoalexin from grape, has gained a great interest for its ability to influence several biological mechanisms like redox balance, cell proliferation, signal transduction pathways, immune and inflammatory response. Therefore, the potential of resveratrol to modify skin cell response to UVB exposure could turn out to be a useful option to protect skin from sunlight-induced degenerative diseases. To investigate into this matter, HaCaT cells, a largely used model for human skin keratinocytes, were treated with 25 or 100 µM resveratrol for 2 and 24 hours prior to UVB irradiation (10 to 100 mJ/cm(2)). Cell viability and molecular markers of proliferation, oxidative stress, apoptosis, and autophagy were analyzed. In HaCaT cells resveratrol pretreatment: reduces UVB-induced ROS formation, enhances the detrimental effect of UVB on HaCaT cell vitality, increases UVB-induced caspase 8, PARP cleavage, and induces autophagy. These findings suggest that resveratrol could exert photochemopreventive effects by enhancing UVB-induced apoptosis and by inducing autophagy, thus reducing the odds that damaged cells could escape programmed cell death and initiate malignant transformation.


American Clinical Neurophysiology Society Guideline 4: Recording Clinical EEG on Digital Media.
Digital EEG recording systems are now widely available and relatively inexpensive. They offer multiple advantages over previous analog/paper systems, such as higher fidelity recording, signal postprocessing, automated detection, and efficient data storage. This document provides guidance for the creation of digital EEG recordings including (1) documentation of patient information, (2) notation of information during the recording, (3) digital signal acquisition parameters during the recording, (4) storage of digital information, and (5) display of digital EEG signals.


Single-incision laparoscopic right colectomy in an unselected patient population.
Single-incision laparoscopic surgery has become increasingly utilized for colorectal surgery, with the most frequently reported single-incision laparoscopic operation being right hemicolectomy. While current data suggest that single-incision laparoscopic right colectomy is feasible, safe, and roughly equivalent to standard laparoscopic right colectomy, the technique has to date only been described in highly selected patients. Single-incision laparoscopic right colectomy has not yet been assessed in a standard patient population. A retrospective review was conducted to evaluate all single-incision right hemicolectomies performed by a single surgeon between May 2010 and April 2011. Demographic data, operative parameters, and postoperative outcomes were assessed. Single-incision laparoscopic colectomy was performed in a series of 30 consecutive patients with indications for right colectomy. One patient required conversion to an open procedure for extensive adhesions, while no patients required additional port placement. Mean operative time was 107 min. All patients had negative margins and had an average of 20 lymph nodes harvested. Mean length of stay was 6 days. There were no intraoperative complications and no mortality in the study. The perioperative complication rate was 37%, with 71% of complications being grade 1. Single-incision laparoscopic colectomy is feasible, safe, efficient, and oncologically sound for most patients who are seen in a typical colorectal practice. These data are useful as single-incision laparoscopic colectomy becomes more broadly implemented.


An efficient route for the preparation of a 21-fluoro progestin-16 alpha,17 alpha-dioxolane, a high-affinity ligand for PET imaging of the progesterone receptor.
Two different synthetic routes were explored for the synthesis of fluoro furanyl norprogesterone (FFNP) 1, a high-affinity ligand for the progesterone receptor (PgR) that is being developed as a PET imaging agent for PgR-positive breast cancer. Both approaches proceed through a key intermediate, triol 5. The first approach, starting from keto-ketal 2, employed a dioxenyl group as a synthon for installing a corticosteroid side chain in keto-alcohol 4. The second approach, starting from propargylic acetate 12b, involved the application of a two-step method, a Pd(II)-catalyzed oxidative rearrangement followed by a base-catalyzed acetate rearrangement of the intermediate unsaturated acetate 13b, to generate the requisite corticosteroid side chain in keto-acetate 14b. This intermediate was further elaborated to the final product 1 via efficient dihydroxylation with potassium permangnate, furan acetalization with scandium triflate, and mesylation and fluorination reactions. The palladium-catalyzed route is considerably more efficient than the dioxene approach for the synthesis of key intermediate triol 5, and the scandium triflate-catalyzed acetalization, in particular, led to a considerable improvement in the overall yield of the endo furan acetal alcohol 16a. This route provides a major improvement in the overall yield of the final progestin target, FFNP 1.


An algorithm to allow humerus translation in the indeterminate problem of shoulder abduction.
The shoulder is one of the most complex joints of the human body, mainly because of its large range of motion, but also because of its active muscular stabilisation. Actually, the numerous stabilizing muscles and degrees of freedom yield indeterminate biomechanical models. To solve this indeterminate, most models use reverse dynamics with a simplified ball-socket joint, preventing therefore the natural humerus translation. In this paper, an algorithm was specifically developed to solve the indeterminate problem by a feedback control of muscle activation, allowing the natural humerus translation. Abduction was considered in the scapular plane, accounting for the three deltoid parts and the rotator cuff muscles. The major aim of this study was to validate the numerical algorithm, which was here restricted to two-dimensions in order to compare the numerical solution to a known algebraic one. This comparison gave a relative error below 0.1%. The joint reaction force was comparable to other models and the humerus translation was in agreement with in vivo or in vitro studies.


Microencapsulation of bovine spermatozoa for use in artificial insemination: a review.
A technique for microencapsulation of bovine spermatozoa has been developed with minimal spermatozoal injury and thus of potential use in artificial insemination. The polymers poly-l-lysine, polyvinylamine and protamine sulfate have proven best for membranes. Encapsulation has been successful with capsules ranging in size from 0.75 to 1.5 mm, and with sperm concentrations from 45 to 180 x 10(6) cells mL-1. Successful extenders include CUE, CAPROGEN, and egg yolk-citrate-glycerol (maximum 10% v/v egg yolk for normal capsular shape). Capsule fragility (ability to rupture under ageing and physical stress) is negatively related to membrane thickness which ranges from 1.92 to 5.32 microns (depending on the concentration of polymer used) and positively related to concentration of sperm encapsulated. Heterospermic studies have shown that encapsulated sperm are capable of fertilization in vivo, but are at a disadvantage to unencapsulated sperm when cows are inseminated at conventional times. Uterine retention of inseminates is favoured by capsules having a 'sticky' membrane. Using current procedures, preliminary homospermic fertility studies indicate that sperm encapsulated with poly-l-lysine or protamine sulfate may achieve normal fertility.


Treatment of alveolar-pleural fistula with endobronchial application of synthetic hydrogel.
Alveolar-pleural fistula with persistent air leak is a common problem causing significant morbidity, prolonged hospital stay, and increased health-care costs. When conventional therapy fails, an alternative to prolonged chest-tube drainage or surgery is needed. New bronchoscopic techniques have been developed to close the air leak by reducing the flow of air through the leak. The objective of this study was to analyze our experience with bronchoscopic application of a synthetic hydrogel for the treatment of such fistulas. We conducted a retrospective study of patients with alveolar-pleural fistula with persistent air leaks treated with synthetic hydrogel application via flexible bronchoscopy. Patient characteristics, underlying disease, and outcome of endoscopic treatment were analyzed. Between January 2009 and December 2013, 22 patients (14 men, eight women; mean age ± SD, 62 ± 10 years) were treated with one to three applications of a synthetic hydrogel per patient. The primary etiology of persistent air leak was necrotizing pneumonia (n = 8), post-thoracic surgery (n = 6), bullous emphysema (n = 5), idiopathic interstitial pneumonia (n = 2), and sarcoidosis (n = 1). Nineteen patients (86%) had complete resolution of the air leak, leading to successful removal of chest tube a mean ( ± SD) of 4.3 ± 0.9 days after last bronchoscopic application. The procedure was very well tolerated, with two patients coughing up the hydrogel and one having hypoxemia requiring bronchoscopic suctioning. Bronchoscopic administration of a synthetic hydrogel is an effective, nonsurgical, minimally invasive intervention for patients with persistent pulmonary air leaks secondary to alveolar-pleural fistula.


Growth and release of several alphaviruses in chick and BHK cells.
The growth and release of several alphaviruses, including several strains of Sindbis virus (the wild-type strain, the large plaque and small plaque variants of the HR strain, and the HR mutant ts103), Semliki Forest virus(SFV) and Middelburg virus, and of the unrelated rhabdovirus, vesicular stomatitis virus (VSV), have been compared in chick cells and in BHK-21 cells as a function of the culture conditions for the host cell and the ionic strength of the medium. The small plaque strain of Sindbis HR, as well as SFV, grew better in BHK cells, whereas the large plaque strain of Sindbis HR showed a preference for chick cells. Wild-type Sindbis and VSV grew equally well in either cell. The optimum ionic strength for virus production as well as inhibition of virus release into the medium at low ionic strength depended upon both the virus and the host cell. Thus, VSV grown in medium of low ionic strength gave no additional release of virus on incubation with hypertonic medium (minimum effect), whereas ts103 released very little virus without exposure to hypertonic conditions (maximum effect). The viruses could be ordered as follows: minimum effect = vesicular stomatitis virus < Middelburg virus < Semliki Forest virus < Sindbis wt < Sindbis HR (large plaque) < Sindbis HR (small plaque) < Sindbis ts103 = maximum effect. After several passages in culture, chick cells required hypertonic conditions for optimum production and release of Sindbis virus. Furthermore, BHK cells cultured in different media responded differently to ionic strength for virus production and release. These results suggest that there is a charge-dependent stop in the maturation of alpha-viruses, possibly a configurational rearrangement of glycoprotein E2 upon its formation from the precursor PE2, which is sensitive to the ionic strength of the medium, to the composition of the host plasmalemma and to differences in the virus glycoproteins.


Tinnitus as a comorbidity to temporomandibular disorders-A systematic review.
The aim of this systematic review was to evaluate the prevalence of tinnitus in patients with temporomandibular disorders (TMD) and the possible effects of TMD treatment on tinnitus symptoms. A search of the PubMed, Web of Science and Cochrane databases from inception of each database up to January 2017 found 222 articles. After independent screening of abstracts by two of the authors, we assessed 46 articles in full text. The inclusion and exclusion criteria reduced these to 25 articles of which 22 studies reported prevalence based on 13 358 patients and 33 876 controls, and eight studies reported effect of TMD treatment on tinnitus based on 536 patients and 18 controls. The prevalence of tinnitus in patients with TMD varied from 3.7% to 70% (median 42.3%) whereas the prevalence in control groups without TMD varied between 1.7% and 26% (median 12%). The eight treatment studies indicated that treatment of TMD symptoms may have a beneficial effect on severity of tinnitus. However, only one treatment study included a control group, meaning that the overall level of evidence is low. The finding that tinnitus is more common in patients with TMD means that it can be regarded as a comorbidity to TMD. However, in view of the lack of evidence currently available, further well-designed and randomised studies with control groups are needed to investigate whether possible mechanisms common to tinnitus and TMD do exist and whether TMD treatment can be justified to try to alleviate tinnitus in patients with TMD and comorbidity of tinnitus.


Threshold extraction in metabolite concentration data.
Continued development of analytical techniques based on gas chromatography and mass spectrometry now facilitates the generation of larger sets of metabolite concentration data. An important step towards the understanding of metabolite dynamics is the recognition of stable states where metabolite concentrations exhibit a simple behaviour. Such states can be characterized through the identification of significant thresholds in the concentrations. But general techniques for finding discretization thresholds in continuous data prove to be practically insufficient for detecting states due to the weak conditional dependences in concentration data. We introduce a method of recognizing states in the framework of decision tree induction. It is based upon a global analysis of decision forests where stability and quality are evaluated. It leads to the detection of thresholds that are both comprehensible and robust. Applied to metabolite concentration data, this method has led to the discovery of hidden states in the corresponding variables. Some of these reflect known properties of the biological experiments, and others point to putative new states. An implementation of this approach can be obtained from the authors upon request.


Efficient resolution of replicated poxvirus telomeres to native hairpin structures requires two inverted symmetrical copies of a core target DNA sequence.
The terminal hairpin sequences of the linear double-stranded DNA genome of the leporipoxvirus Shope fibroma virus (SFV) has been cloned in Saccharomyces cerevisiae and in recombination-deficient Escherichia coli as a palindromic insert within circular plasmid vectors. This sequence configuration is equivalent to the inverted repeat structure detected as a telomeric replicative intermediate during poxvirus replication in vivo. Previously, it has been shown that when circular plasmids containing this palindromic insert were transfected into SFV-infected cells, efficient replication and resolution generated linear minichromosomes with bona fide viral hairpin termini (A. M. DeLange, M. Reddy, D. Scraba, C. Upton, and G. McFadden, J. Virol. 59:249-259, 1986). To localize the minimal target DNA sequence required for efficient resolution, a series of staggered unidirectional deletions were constructed at both ends of the inverted repeat. Analyses of the resolution efficiencies of the various clones indicate that up to 240 base pairs (bp) centered at the symmetry axis were required for maximal resolution to minichromosomes. To investigate the role of the AT-rich central axis sequences, which in SFV include 8 nonpalindromic bp, a unique AflII site at the symmetry axis was exploited. Bidirectional deletions extending from this AflII site and insertions of synthetic oligonucleotides into one of the deletion derivatives were constructed and tested in vivo. The efficiency with which these plasmids resolved to linear minichromosomes with hairpin termini has enabled us to define the minimal target DNA sequence as two inverted copies of an identical DNA sequence between 58 and 76 bp in length. The nonpalindromic nucleotides, which, after resolution, constitute the extrahelical residues characteristic of native poxviral telomeres, were not required for resolution. The close resemblance of the SFV core target sequence to the analogous region from the orthopoxvirus vaccinia virus is consistent with a conserved mechanism for poxviral telomere resolution.


Mice Lacking Endoglin in Macrophages Show an Impaired Immune Response.
Endoglin is an auxiliary receptor for members of the TGF-β superfamily and plays an important role in the homeostasis of the vessel wall. Mutations in endoglin gene (ENG) or in the closely related TGF-β receptor type I ACVRL1/ALK1 are responsible for a rare dominant vascular dysplasia, the Hereditary Hemorrhagic Telangiectasia (HHT), or Rendu-Osler-Weber syndrome. Endoglin is also expressed in human macrophages, but its role in macrophage function remains unknown. In this work, we show that endoglin expression is triggered during the monocyte-macrophage differentiation process, both in vitro and during the in vivo differentiation of blood monocytes recruited to foci of inflammation in wild-type C57BL/6 mice. To analyze the role of endoglin in macrophages in vivo, an endoglin myeloid lineage specific knock-out mouse line (Eng(fl/fl)LysMCre) was generated. These mice show a predisposition to develop spontaneous infections by opportunistic bacteria. Eng(fl/fl)LysMCre mice also display increased survival following LPS-induced peritonitis, suggesting a delayed immune response. Phagocytic activity is impaired in peritoneal macrophages, altering one of the main functions of macrophages which contributes to the initiation of the immune response. We also observed altered expression of TGF-β1 target genes in endoglin deficient peritoneal macrophages. Overall, the altered immune activity of endoglin deficient macrophages could help to explain the higher rate of infectious diseases seen in HHT1 patients.


Complications of endoscopic retrograde cholangiopancreatography. A study in a small ERCP unit.
endoscopic retrograde cholangiopancreatography (ERCP) is an established procedure to drain the biliary and pancreatic ducts. Nevertheless, there are complications which seem to be more common in centers performing less than 200 ERCPs per year. Sometimes, however, due to the distribution of health resources, it is necessary to perform this technique in centers with a smaller number of procedures. We present the experience of ERCP-related complications in a small unit. this is a retrospective study on prospective data recorded during six years (1997-2002). In this period, two endoscopists working together performed 507 ERCPs, which yields an approximately average of 84 procedures per year. in 507 ERCPs performed during this period of time, 55 complications arose (10.85%), and four patients died (0.79%) as a consequence of the procedure. There were 28 pancreatitis (5.5%), eight post-sphincterotomy bleeding events (1.6%), seven bilioduodenal perforations (1.4%), eight sepsis episodes of biliary origin (1.6%), and other 4 different complications. There were 418 (82.4%) successful ERCPs--either diagnostic or therapeutic--,which gave rise to 46 (11%) complications. There were 89 (17.6%) failed diagnostic or therapeutic ERCPs, which gave rise to 9 (10.11%) complications (p = 0.8 between both groups). Thirty five (7%) ERCPs were exclusively diagnostic and caused 6 (17%) complications. The 187 procedures performed for choledocholithiasis originated 14 (7.4%) complications, and represented the group with the lowest morbidity rate (p = 0.04). the complications rate in our center is within the range of reported figures. ERCPs performed for choledocholithiasis was associated with the lowest complications rate. The risk-benefit ratio in the anticipated, purely diagnostic ERCP must be carefully weighed due to its morbidity.


Positive and negative affect and risk of coronary heart disease: Whitehall II prospective cohort study.
To examine the associations between positive and negative affect and subsequent coronary heart disease events independently of established risk factors. Prospective cohort study with follow-up over 12 years. 20 civil service departments originally located in London. 10,308 civil servants aged 35-55 years at entry into Whitehall II study in 1985. Fatal coronary heart disease, clinically verified incident non-fatal myocardial infarction, and definite angina (n=619, mean follow-up 12.5 years). In Cox regression analysis adjusted for age, sex, ethnicity, and socioeconomic position, positive affect (hazard ratio=1.01, 95% confidence interval 0.82 to 1.24) and the balance between positive and negative affect, referred to as the affect balance score (hazard ratio=0.89, 0.73 to 1.09), were not associated with coronary heart disease. Further adjustment for behaviour related risk factors (smoking, alcohol consumption, daily fruit and vegetable intake, exercise, body mass index), biological risk factors (hypertension, blood cholesterol, diabetes), and psychological stress at work did not change these results. However, participants in the highest third of negative affect had an increased incidence of coronary events (hazard ratio=1.32, 1.09 to 1.60), and this association remained unchanged after adjustment for multiple confounders. Positive affect and affect balance did not seem to be predictive of future coronary heart disease in men and women who were free of diagnosed coronary heart disease at recruitment to the study. A weak positive association between negative affect and coronary heart disease was found and needs to be confirmed in further studies.


Cultural competence: assessment and education resources for home care and hospice clinicians.
Home healthcare and hospice clinicians face many challenges in the complex healthcare system caring for patients and their families in the home environment. One of those challenges is providing culturally competent care for an increasingly diverse population. This article will highlight free, easily accessible, online resources to assist clinicians and organizations to assess organizational and individual cultural competence and provide many resources for cultural competency education programs.


San Diego suicide study. I. Young vs old subjects.
The suicide rate among people under 30 years of age has nearly tripled in the past several decades. We compared 133 suicides under the age of 30 years with 150 aged 30 years and over. After gathering and reviewing extensive clinical information and postmortem toxicologic data, we assigned diagnoses using DSM-III criteria. A major diagnostic finding was the occurrence of more drug abuse than had been previously reported, significantly more often in the young people. Few other differences were found either between our total sample and previous studies or between our younger and older groups. We conclude that a closer look at the young group is necessary to see what other differences might occur between the drug abusers and other young suicides.


Neutralizing interleukin-1beta (IL-1beta) induces beta-cell survival by maintaining PDX1 protein nuclear localization.
The transcription factor PDX1 plays a critical role during β-cell development and in glucose-induced insulin gene transcription in adult β-cells. Acute glucose exposure leads to translocalization of PDX1 to the nucleoplasm, whereas under conditions of oxidative stress, PDX1 shuttles from the nucleus to the cytosol. Here we show that cytosolic PDX1 expression correlated with β-cell failure in diabetes. In isolated islets from patients with type 2 diabetes and from diabetic mice, we found opposite regulation of insulin and PDX1 mRNA; insulin was decreased in diabetes, but PDX1 was increased. This suggests that elevated PDX1 mRNA levels may be insufficient to regulate insulin. In diabetic islets, PDX1 protein was localized in the cytosol, whereas in non-diabetic controls, PDX1 was in the nucleus. In contrast, overexpression of either IL-1 receptor antagonist or shuttling-deficient PDX1 restored β-cell survival and function and PDX1 nuclear localization. Our results show that nuclear localization of PDX1 is essential for a functional β-cell and provides a novel mechanism of the protective effect of IL-1 receptor antagonist on β-cell survival and function.


[Value of salt loads in the evaluation of functional status of the kidneys in patients with hypertension].
A 5% NaCl solution (500.0) was administered during 40-50 min to 20 patients with essential hypertension (10 with labile and 10 with stable hypertension) and 10 normal subjects. Total sodiuresis and diuresis values over 5 post-load hours, the timing of their peaks, and the ratio of diuresis/sodiuresis rates (d/s coefficient) were examined. In hypertensive patients, particularly those with stable hypertension, the peak of sodium excretion was displaced towards the beginning of the salt load, yet salty diuresis stopped earlier, and the total five-hour sodium excretion was significantly reduced, as compared to normal subjects. The d/s coefficient showed a less steep decline, and was generally higher, as compared to that of normal subjects at all stages of the study. The findings obtained demonstrate that 5-hour monitoring of the diuresis, sodiuresis and the d/s coefficient following a salt load can detect disorders of renal function.


Eye care in Fiji: a population-based study of use and barriers.
To determine the use of medical services for eye problems in Fiji, and barriers to seeking that care. An interview-based questionnaire was administered as part of a population-based cross-sectional survey of adults selected by multistage random sampling from those aged ≥40 years living on Fiji's main island. Participation rate was 73.0% (n = 1381). A current vision or eye problem was reported by 931 participants, and a further 235 recalled a previous difficulty. Urban dwellers (P = 0.002) and those aged ≥50 years (P = 0.017) were more likely to report a problem. Gender was not predictive (P = 0.215). "Blurred/poor vision" was the most common complaint (78.5%). Over half (53.3%) had not sought care for the problem most important to them. For current problems, being younger (P < 0.001) and from a household without paid income (P = 0.007) were predictive of being less likely to seek treatment. Gender was not (P = 0.416). The most frequently cited principal reason for not seeking care was "able to manage/accept the problem" (66.5%; of whom 84.7% claimed vision problems). Direct and indirect costs were mentioned as deterrents. "Thought nothing could be done" (P = 0.032) and "lack of awareness of service availability" (P = 0.026) were more common among rural dwellers. Of participants who sought care, 75.6% used government services. Most participants requiring spectacles or medication incurred costs for these. Satisfaction with overall care was independent of provider (P = 0.062) and user gender (P = 0.851). With expanding service delivery, increased eye health promotion, and attention to the financing of treatments, improved service use ought to be possible in Fiji.


A novel application of the Intent to Attend assessment to reduce bias due to missing data in a randomized controlled clinical trial.
Missing data are unavoidable in most randomized controlled clinical trials, especially when measurements are taken repeatedly. If strong assumptions about the missing data are not accurate, crude statistical analyses are biased and can lead to false inferences. Furthermore, if we fail to measure all predictors of missing data, we may not be able to model the missing data process sufficiently. In longitudinal randomized trials, measuring a patient's intent to attend future study visits may help to address both of these problems. Leon et al. developed and included the Intent to Attend assessment in the Lithium Treatment - Moderate dose Use Study (LiTMUS), aiming to remove bias due to missing data from the primary study hypothesis. The purpose of this study is to assess the performance of the Intent to Attend assessment with regard to its use in a sensitivity analysis of missing data. We fit marginal models to assess whether a patient's self-rated intent predicted actual study adherence. We applied inverse probability of attrition weighting (IPAW) coupled with patient intent to assess whether there existed treatment group differences in response over time. We compared the IPAW results to those obtained using other methods. Patient-rated intent predicted missed study visits, even when adjusting for other predictors of missing data. On average, the hazard of retention increased by 19% for every one-point increase in intent. We also found that more severe mania, male gender, and a previously missed visit predicted subsequent absence. Although we found no difference in response between the randomized treatment groups, IPAW increased the estimated group difference over time. LiTMUS was designed to limit missed study visits, which may have attenuated the effects of adjusting for missing data. Additionally, IPAW can be less efficient and less powerful than maximum likelihood or Bayesian estimators, given that the parametric model is well specified. In LiTMUS, the Intent to Attend assessment predicted missed study visits. This item was incorporated into our IPAW models and helped reduce bias due to informative missing data. This analysis should both encourage and facilitate future use of the Intent to Attend assessment along with IPAW to address missing data in a randomized trial.


Polarization-insensitive colorful meta-holography employing anisotropic nanostructures.
Benefiting from advances in nanofabrication technology, emerging metasurfaces are promising for compact and wearable multicolor meta-holograms with large fields of view. However, due to the inherent electromagnetic properties of the structures that are used, current multicolor meta-holograms are often sensitive to the incident light polarization, which greatly restricts the application of meta-holography. Here, we took advantage of the amplitude properties of metasurfaces and the off-axis illumination method to carry out experiments involving polarization-insensitive colorful meta-holography with anisotropic nanostructures. With red, green and blue lasers illuminating the meta-hologram along different angles, a polarization-insensitive colorful holographic image was achieved and the disturbance from zero-order diffraction light was essentially eliminated. To the best of our knowledge, the current work was the first time that a polarization-insensitive colorful meta-hologram with anisotropic nanostructures was experimentally demonstrated. We expect our approach to provide promising prospects for the use of metasurfaces in applications such as flat meta-lenses, data storage and virtual/augmented reality.


HLA class II genes in soybean epidemic asthma patients.
From 1981 to 1987, 26 outbreaks of asthma caused by the inhalation of soybean dust, affecting a total of 688 individuals, were detected in Barcelona, Spain. Because only a small proportion of asthmatic individuals living in Barcelona expressed the epidemic phenotype, it is hypothesized that a genetically determined human leukocyte antigen (HLA) Class II factor could have played a role in the susceptible individuals. Accordingly, we studied the distribution of both HLA-DR and HLA-DQ in soybean epidemic asthmatic patients. An analysis of the HLA-DR and HLA-DQ genes for genetic polymorphisms of the beta 1 chain was done with the polymerase chain reaction (PCR) in 78 soybean epidemic asthma patients, and the findings were compared with those for 67 nonepidemic asthmatic individuals and 168 individuals from the general population. An allelic disequilibrium could be established; the risk of epidemic asthma was particularly associated with the DRB1*13 gene (p value corrected for multiple comparisons < 0.02). The association observed for the DRB1*13 gene was stronger in individuals in the lowest tertile for total IgE, with an estimated risk with a 95% confidence interval (CI), of 14.5 (1.6 to 130.8). The combination of two genes from among the DRB1*05-05, DRB1*05-06, and DRB1*06-06 genes was present in epidemic asthmatic subjects only. No association with an HLA-DQB1 allele could be observed. Genetic predisposition could contribute to the response of some asthmatic patients to exposure to soybean dust, having led to their being affected during the epidemics of asthma in Barcelona.


May I give my heart away? On the permissibility of living vital organ donation.
The dead donor rule (DDR) regulates current practice for vital organ donation, which means that organs may only be retrieved from people who are already dead (or brain dead). However, several authors criticize the DDR and argue that we should instead adopt a rule that allows us to retrieve vital organs before people are dead. They call this proposal organ donation euthanasia (ODE). While I am sympathetic to this proposal I do not think it goes far enough. In this paper, I show that the key reasons put forward in favor of permitting ODE actually justify a more far-reaching suggestion for regulation, permitting people to become living vital organ donors even when they are not about to die for other reasons. Further, I argue that only accepting imminently dying people as eligible donors for living vital organ donation would be objectionably paternalistic.


Analysis of gene targeting and intrachromosomal homologous recombination stimulated by genomic double-strand breaks in mouse embryonic stem cells.
To investigate the effects of in vivo genomic DNA double-strand breaks on the efficiency and mechanisms of gene targeting in mouse embryonic stem cells, we have used a series of insertion and replacement vectors carrying two, one, or no genomic sites for the rare-cutting endonuclease I-SceI. These vectors were introduced into the hypoxanthine phosphoribosyltransferase (hprt) gene to produce substrates for gene-targeting (plasmid-to-chromosome) or intrachromosomal (direct repeat) homologous recombination. Recombination at the hprt locus is markedly increased following transfection with an I-SceI expression plasmid and a homologous donor plasmid (if needed). The frequency of gene targeting in clones with an I-SceI site attains a value of 1%, 5,000-fold higher than that in clones with no I-SceI site. The use of silent restriction site polymorphisms indicates that the frequencies with which donor plasmid sequences replace the target chromosomal sequences decrease with distance from the genomic break site. The frequency of intrachromosomal recombination reaches a value of 3.1%, 120-fold higher than background spontaneous recombination. Because palindromic insertions were used as polymorphic markers, a significant number of recombinants exhibit distinct genotypic sectoring among daughter cells from a single clone, suggesting the existence of heteroduplex DNA in the original recombination product.


Draft genome sequences of five new strains of methylophilaceae isolated from lake washington sediment.
We sequenced the genomes of five new Methylophilaceae strains isolated from Lake Washington sediment. We used the new sequences to sort these new strains into specific Methylophilaceae ecotypes, including one novel ecotype. The new genomes expand the known diversity of Methylophilaceae and provide new models for studying the ecology of methylotrophy.


Dual role of physical workload and occupational noise in the association of the metabolic syndrome with risk of coronary heart disease: findings from the Helsinki Heart Study.
Previous evidence indicates that occupational exposure to physical workload or noise entails development of hypertension and risk of coronary heart disease (CHD). However, vigorous physical activity lessens the risks of the metabolic syndrome (MetS) and CHD. We explored this issue by studying the joint effect of physical workload or noise and MetS on risk of CHD. This 18-year follow-up study comprised 1502 middle-aged men employed in industry who participated in the second screening for the Helsinki Heart Study but were not treated with gemfibrozil, the trial drug. The CHD endpoints (ICD-9 codes 410-414 and ICD-10 codes 120-125) were obtained from official Finnish registers. The Finnish job-exposure matrix FINJEM provided information on occupational exposures. The joint effect of baseline MetS levels and both occupational exposures was estimated using Cox's regression models. Workload and noise increased CHD risk due to increased blood pressure, glucose or body mass index (BMI), separately or combined: the joint effect of workload and MetS defined using these three components yielded an RR of 5.21 (95% CI 2.70 to 10.05). However, when MetS was defined using elevated BMI, high triglycerides and low high-density lipoprotein cholesterol, an RR of 2.19 (95% CI 1.11 to 4.30) among those with MetS only reduced to 1.20 (95% CI 0.61 to 2.35) if concurrently exposed to workload. Occupational exposure to workload or noise modifies CHD risk differently depending on which definition of MetS is used. In the presence of physical workload or noise, hypertension and blood glucose were the best predictors.


Targeted Induction of Ceramide Degradation Leads to Improved Systemic Metabolism and Reduced Hepatic Steatosis.
Sphingolipids have garnered attention for their role in insulin resistance and lipotoxic cell death. We have developed transgenic mice inducibly expressing acid ceramidase that display a reduction in ceramides in adult mouse tissues. Hepatic overexpression of acid ceramidase prevents hepatic steatosis and prompts improvements in insulin action in liver and adipose tissue upon exposure to high-fat diet. Conversely, overexpression of acid ceramidase within adipose tissue also prevents hepatic steatosis and systemic insulin resistance. Induction of ceramidase activity in either tissue promotes a lowering of hepatic ceramides and reduced activation of the ceramide-activated protein kinase C isoform PKCζ, though the induction of ceramidase activity in the adipocyte prompts more rapid resolution of hepatic steatosis than overexpression of the enzyme directly in the liver. Collectively, our observations suggest the existence of a rapidly acting "cross-talk" between liver and adipose tissue sphingolipids, critically regulating glucose metabolism and hepatic lipid uptake.


Global and cultural perinatal nursing research: improving clinical practice.
High-quality perinatal nursing care should be based on the best evidence including research findings, clinical expertise, and the preferences of women and their families. Principles of perinatal research initiatives are defined, with suggested research priorities designed to close current gaps in the micro and macro environments of perinatal nursing throughout the world. Nearly a decade ago, the following question was asked, "Where is the 'E' (evidence) in maternal child health?" Improving the quality and safety of perinatal nursing care for culturally diverse women globally is the primary goal of nurse researchers leading the future of perinatal healthcare.


Canine prostatic disease--comparison of ultrasonographic appearance with morphologic and microbiologic findings: 30 cases (1981-1985).
A retrospective analysis was made of 30 cases of canine prostatic disease, with the objective of identifying (via a prepubic approach) the 2-dimensional, gray-scale ultrasonographic appearance most often associated with the various spontaneous prostatic diseases. Ultrasonography was of value in characterizing the parenchymal architecture as normal vs focally hyperechoic and diffusely hyperechoic (associated with chronic inflammation and neoplasia) or focally hypoechoic or anechoic (either accompanied by distant enhancement), which was associated with retention cyst or abscess. Further specificity based only on abnormal echotexture was not possible. Ultrasonography facilitated the differentiation of radiographically identifiable prostatomegaly attributable to abscess or neoplasia from apparent prostatomegaly attributable to paraprostatic cyst. An imaging protocol consisting of distention retrograde urethrocystography and prepubic ultrasonography was recommended, as a distended bladder aided ultrasonographic identification of the prostate gland. In addition, the combination of urethral morphologic features and urethroprostatic reflux appearance complemented the ultrasonographic appearance for differentiation of prostatic abscess from prostatic carcinoma. A classification scheme for spontaneous canine prostatic disease combining germane imaging morphologic features with microscopic and microbiologic findings was proposed.


The epigenetic regulation of SOX9 by miR-145 in human chondrosarcoma.
Chondrosarcoma is the most common primary bone malignancy in the adult population with a high rate of pulmonary metastasis. Chondrosarcoma is managed with surgical excision as the tumors do not respond well to conventional chemotherapy or radiation therapy. Thus, there exists a dire need to develop systemic treatment options to target chondrosarcoma cells for metastatic spread. We hypothesized that the expression of miR-145 is low in chondrosarcoma, leading to decreased transcriptional control of SOX9 (the master regulator of chondrogenesis), and downstream activation of the transcription factor ETV5. We have previously shown that ETV5 activates MMP-2 expression in chondrosarcoma, which in turn increases local bone matrix resorption. In this study, we confirm high expression of SOX9 in human chondrosarcoma using real-time PCR, Western blotting, and immunofluorescence. An ETV5 promoter-reporter plasmid was transfected into chondrosarcoma cells to determine if SOX9 directly regulates the expression of ETV5. Co-transfection of the ETV5 promoter-plasmid with SOX9 lentivirus significantly increased the luciferase activity derived from the ETV5 promoter, from which the regulatory relationship between SOX9 and ETV5 is established. MiR-145 was found to be down-regulated in chondrosarcoma cell lines, patient samples, and further confirmed with a public sarcoma database. After stable miR-145 lentiviral transfection, the subsequent mRNA expression levels of SOX9, ETV5, and MMP-2 were significantly decreased in chondrosarcoma cells. The results generated by this study may have important clinical significance in the treatment of patients with chondrosarcoma in that targeted miRNA may have the potential to downregulate the upstream activators of proteases such as MMP-2.


Understanding individual differences in color appearance of "#TheDress" based on the optimal color hypothesis.
We performed a theoretical analysis based on our optimal color hypothesis to explain why "#TheDress" image had a different color appearance for different observers (observer-dependent perception). We then carried out an experiment to test the hypothesis derived from the aforementioned theoretical analysis. In the optimal color hypothesis, the visual system picks the optimal color distribution that provides the best fit to the luminance distribution at a scene. The peak of the best-fit optimal color distribution corresponds with the illuminant's color temperature. In the theoretical analysis, we found that as the luminance level was increased the best-fit optimal color temperature changes abruptly from high to low at a specific luminance-level. Under the dark-blue (low luminance and high color temperature) illuminant the dress should appear white/gold whereas under the bright-white (high luminance and low color temperature) illuminant the dress should appear blue/black. The observer-dependent appearances of the dress may be explained by this luminance-dependent illuminant prediction. In the experiment, we used the original dress, a chromatically inverted dress, and an achromatic dress as stimuli. The observer adjusted chromaticity and luminance of a test field drawn onto the dress image so that it appeared as a full-white surface. We found that the white/gold group estimated the illuminant to be darker and bluish and the blue/black group estimated it to be brighter and yellowish. The observer's estimated illuminant was consistent with the predicted illuminant by the optimal color theory. It was newly discovered that even when the dress was achromatic, these two groups estimated the illuminant to be darker or brighter in the same way as for the original dress.


Surgical validation of functional magnetic resonance urography in the study of ureteropelvic junction obstruction in a pediatric cohort.
Ureteropelvic junction obstruction (UPJO) is one of the most common urological diseases in children. The etiology can be intrinsic, extrinsic (crossing vessel [CV] or adhesions), or mixed. To date, ultrasonography and scintigraphy are considered gold-standard imaging techniques for the study of UPJO. Functional magnetic resonance urography (fMRU) combines anatomical and functional information and has been recently evaluated for the detection of CVs in UPJO. The objective of the study was to evaluate the concordance between fMRU and surgery in determining the etiology of UPJO and the presence of obstructing/non-obstructing CVs. Patients with unilateral hydronephrosis who underwent surgery after an fMRU were included in the sample. Surgical data regarding the etiology of UPJO were compared with radiological results. The etiology was divided into intrinsic, extrinsic due to CV, extrinsic due to adhesions, and mixed or cicatricial (postoperative). The concordance was calculated by means of the Cohen's kappa coefficient. The observed agreement between fMRU and surgical findings regarding the etiology and the presence of CV were 83.2% and 89.4%, respectively (with substantial Cohen's kappa coefficient). The sensitivity and specificity of fMRU were 0.84 and 0.93, respectively; the positive predictive value (PPV) and negative predictive value (NPV) were 0.889 and 0.897, respectively. The observed agreement regarding the type of vessel was 88.3% with a Cohen's kappa coefficient of 0.787 (substantial). In children with hydronephrosis, it is very important for the surgeon to quantify the extent of dilation, define the etiology of the obstruction, and the presence or absence of CVs. fMRU is a 'one-stop-shop' technique which provides both anatomical and functional information showing a high concordance with surgical findings, avoiding radiation exposure. fMRU should be considered a valid imaging technique in the study of pediatric UPJO, as it provides the surgeon with important information regarding the etiology of the obstruction for the preoperative planning.


Foot and ankle manifestations of Charcot-Marie-Tooth disease.
The term Charcot-Marie-Tooth disease represents a spectrum of neurological dysfunction more recently described as hereditary motor-sensory neuropathies. An abnormality of myelination is thought to be responsible for the clinical manifestations. While histological findings have been well described, the exact biochemical basis for this disorder remains unknown. Over one half of patients with Charcot-Marie-Tooth disease manifest foot and ankle problems, including pain, weakness, deformity, and, rarely, paresthesias. Characteristic patterns of neuromuscular weakness have been identified. Bilateral pes cavovarus is the most common pathologic foot deformity seen. The specific components include hindfoot varus, anterior or forefoot cavus, and, often clawtoes. The etiology of this abnormal foot posture usually results from tibialis posterior overpowering peroneus brevis coupled with peroneus longus overpowering tibialis anterior. Multiple treatment options have been described. Rationale for specific tendon transfers, soft tissue release, osteotomies, and arthrodesis is discussed. Results of surgical intervention are difficult to interpret and compare because of the wide spectrum of both neurological dysfunction and described operative procedures. In the presence of flexible deformity, early soft tissue release and tendon transfers may help prevent or delay more extensive bony procedures. The clinical results of triple arthrodesis in the Charcot-Marie-Tooth disease patient appear to deteriorate with time. Genetic transmission, progression of the neurological dysfunction, flexibility of the deformity, distribution of muscular weakness, and anticipated foot demands vary a great deal within this patient population. Treatment decisions, therefore, must be individualized and based upon a clear history, careful examination, and well-defined patient goals.


Cost-effectiveness of introducing national seasonal influenza vaccination for adults aged 60 years and above in mainland China: a modelling analysis.
China has an aging population with an increasing number of adults aged ≥ 60 years. Influenza causes a heavy disease burden in older adults, but can be alleviated by vaccination. We assessed the cost-effectiveness of a potential government-funded seasonal influenza vaccination program in older adults in China. We characterized the health and economic impact of a fully funded influenza vaccination program for older adults using China-specific influenza disease burden, and related cost data, etc. Using a decision tree model, we calculated the incremental costs per quality-adjusted life year (QALY) gained of vaccination from the societal perspective, at a willingness-to-pay threshold equivalent to GDP per capita (US$8840). Moreover, we estimated the threshold vaccination costs, under which the fully funded vaccination program is cost-effective using GDP per capita as the willingness-to-pay threshold. Compared to current self-paid vaccination, a fully funded vaccination program is expected to prevent 19,812 (95% uncertainty interval, 7150-35,783) influenza-like-illness outpatient consultations per year, 9418 (3386-17,068) severe acute respiratory infection hospitalizations per year, and 8800 (5300-11,667) respiratory excess deaths due to influenza per year, and gain 70,212 (42,106-93,635) QALYs per year. Nationally, the incremental costs per QALY gained of the vaccination program is US$4832 (3460-8307), with a 98% probability of being cost-effective. The threshold vaccination cost is US$10.19 (6.08-13.65). However, variations exist between geographical regions, with Northeast and Central China having lower probabilities of cost-effectiveness. Our results support the implementation of a government fully funded older adult vaccination program in China. The regional analysis provides results across settings that may be relevant to other countries with similar disease burden and economic status, especially for low- and middle-income countries where such analysis is limited.


Genetics of congenital deafness in the Palestinian population: multiple connexin 26 alleles with shared origins in the Middle East.
In some Palestinian communities, the prevalence of inherited prelingual deafness is among the highest in the world. As an initial step towards understanding the genetic causes of hearing loss in the Palestinian population, 48 independently ascertained probands with non-syndromic hearing loss were evaluated for mutations in the connexin 26 gene. Of the 48 deaf probands, 11 (23%) were homozygous or compound heterozygous for mutations in GJB2. Five different mutations were identified: ivs1(+1) G-->A, 35delG, 167delT, T229C, 235delC. Nine deaf probands were homozygous and only two compound heterozygous. Among 400 hearing Palestinian controls, one carrier was observed (for 167delT). We show that GJB2 ivs1(+1) G-->A disrupts splicing, yielding no detectable message. Linkage disequilibrium analysis suggests, in the Palestinian and Israeli populations, a common origin of the 35delG mutation, which is worldwide, and of 167delT, which appears specific to Israeli Ashkenazi and Palestinian populations. A high prevalence of deafness, high frequency of homozygosity rather than compound heterozygosity among deaf, and low mutation carrier frequency together reflect the high levels of consanguinity of many extended Palestinian families. Some of the 25 families with multiple cases of inherited prelingual deafness and wildtype GJB2 sequences may represent as-yet-unknown genes for inherited hearing loss.


[Conflict of intentions associated with leukodystrophy: a case report].
A 50-year-old woman developed a slowly progressive inability to control her motor functions over the past 3 years. For example, she would close the refrigerator door immediately after opening it against her intension, or at intersections she would go in a direction that she did not intend. These symptoms were regarded as "conflict of intentions (COI)." Brain magnetic resonance imaging (MRI) revealed diffuse atrophy of the corpus callosum with hyperintense lesions in the rostral portion of its body and the splenium. Based on these findings, her COI could be attributable to leukodystrophy of an unknown origin.


Competitive binding of small ligands to nucleobases in AP site-containing DNA duplexes.
By using lumichrome (Lch) as a masking ligand, we successfully control the binding selectivity of 2-amino-5,6,7-trimethyl-1,8-naphthyridine (ATMND) when binding to nucleobases in AP site-containing DNA duplexes (5'-TCT GCG TCC AGX GCA ACG CAC AC-3'/3'-AGA CGC AGG TCN CGT TGC GTG TG-5', X = AP site; Spacer C3, N = C or T). In solutions buffered to pH 7.0 (I = 0.11 M, at 5 degrees C), ATMND binds to cytosine and thymine with a comparable binding affinity (K(d) / nM: C: 7.7, T: 15). By contrast, in the presence of Lch, ATMND shows a clear binding selectivity for cytosine over thymine (K(d)/nM: C: 17, T: 204). Such competitive binding events are discussed with a view towards development of ligand-based fluorescence assay for single-nucleotide polymorphisms (SNPs) typing.


Conformational adaptation of Asian macaque TRIMCyp directs lineage specific antiviral activity.
TRIMCyps are anti-retroviral proteins that have arisen independently in New World and Old World primates. All TRIMCyps comprise a CypA domain fused to the tripartite domains of TRIM5alpha but they have distinct lentiviral specificities, conferring HIV-1 restriction in New World owl monkeys and HIV-2 restriction in Old World rhesus macaques. Here we provide evidence that Asian macaque TRIMCyps have acquired changes that switch restriction specificity between different lentiviral lineages, resulting in species-specific alleles that target different viruses. Structural, thermodynamic and viral restriction analysis suggests that a single mutation in the Cyp domain, R69H, occurred early in macaque TRIMCyp evolution, expanding restriction specificity to the lentiviral lineages found in African green monkeys, sooty mangabeys and chimpanzees. Subsequent mutations have enhanced restriction to particular viruses but at the cost of broad specificity. We reveal how specificity is altered by a scaffold mutation, E143K, that modifies surface electrostatics and propagates conformational changes into the active site. Our results suggest that lentiviruses may have been important pathogens in Asian macaques despite the fact that there are no reported lentiviral infections in current macaque populations.


Animal Models to Understand the Etiology and Pathophysiology of Polycystic Ovary Syndrome.
More than 1 out of 10 women worldwide are diagnosed with polycystic ovary syndrome (PCOS), the leading cause of female reproductive and metabolic dysfunction. Despite its high prevalence, PCOS and its accompanying morbidities are likely underdiagnosed, averaging > 2 years and 3 physicians before women are diagnosed. Although it has been intensively researched, the underlying cause(s) of PCOS have yet to be defined. In order to understand PCOS pathophysiology, its developmental origins, and how to predict and prevent PCOS onset, there is an urgent need for safe and effective markers and treatments. In this review, we detail which animal models are more suitable for contributing to our understanding of the etiology and pathophysiology of PCOS. We summarize and highlight advantages and limitations of hormonal or genetic manipulation of animal models, as well as of naturally occurring PCOS-like females.


The SNF2, SNF5 and SNF6 genes are required for Ty transcription in Saccharomyces cerevisiae.
The Saccharomyces cerevisiae SNF2, SNF5 and SNF6 genes were initially identified as genes required for expression of SUC2 and other glucose repressible genes. The Suc- defect in all three of these classes of mutants is suppressed by mutations in the SPT6 gene. Since mutations in SPT6 had also been identified as suppressors of Ty and solo delta insertion mutations at the HIS4 and LYS2 loci, we have examined Ty transcription in snf2, snf5 and snf6 mutants and have found that Ty transcription is abolished or greatly reduced. The snf2, snf5 and snf6 defect for Ty transcription, like the defect for SUC2 transcription, is suppressed by spt6 mutations. In contrast to other mutations that abolish or greatly reduce Ty transcription (in the SPT3, SPT7 and SPT8 genes), mutations in these SNF genes do not cause suppression of insertion mutations. This result suggests that the SNF2, SNF5 and SNF6 gene products act by a distinct mechanism from the SPT3, SPT7 and SPT8 gene products to promote transcription of Ty elements. This result also suggests that a reduction of Ty transcription is not always sufficient for activation of adjacent gene expression.


Quantitation of DNA adducts by stable isotope dilution mass spectrometry.
Exposure to endogenous and exogenous chemicals can lead to the formation of structurally modified DNA bases (DNA adducts). If not repaired, these nucleobase lesions can cause polymerase errors during DNA replication, leading to heritable mutations and potentially contributing to the development of cancer. Because of their critical role in cancer initiation, DNA adducts represent mechanism-based biomarkers of carcinogen exposure, and their quantitation is particularly useful for cancer risk assessment. DNA adducts are also valuable in mechanistic studies linking tumorigenic effects of environmental and industrial carcinogens to specific electrophilic species generated from their metabolism. While multiple experimental methodologies have been developed for DNA adduct analysis in biological samples, including immunoassay, HPLC, and ³²P-postlabeling, isotope dilution high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) generally has superior selectivity, sensitivity, accuracy, and reproducibility. As typical DNA adduct concentrations in biological samples are between 0.01-10 adducts per 10⁸ normal nucleotides, ultrasensitive HPLC-ESI-MS/MS methodologies are required for their analysis. Recent developments in analytical separations and biological mass spectrometry, especially nanoflow HPLC, nanospray ionization MS, chip-MS, and high resolution MS, have pushed the limits of analytical HPLC-ESI-MS/MS methodologies for DNA adducts, allowing researchers to accurately measure their concentrations in biological samples from patients treated with DNA alkylating drugs and in populations exposed to carcinogens from urban air, drinking water, cooked food, alcohol, and cigarette smoke.


Modeling and Simulations of the Dynamic Behaviors of Actin-Based Cytoskeletal Networks.
The cytoskeleton, a dynamic network of biopolymers with their associated cross-linking and motor proteins, is responsible for stabilizing cell shape and driving cell movement. This paper aims to provide an overview of the theoretical and computational approaches that have been developed to understand the dynamic behaviors and underlying mechanisms of actin-based cytoskeletal networks, connecting their microscopic structure to macroscopic performance across various scales, with implications for the observed nonlinear stress-strain relation, viscoelastic properties, stiffening induced by active motors as well as their biological functions in important processes such as cell adhesion, motility, and mechanosensing. In the future, more sophisticated constitutive theories, continuum level, and molecular dynamics-based simulations of biopolymer networks are expected to provide critical insights for understanding the material-structure-function relation in the cytoskeleton of cells and guiding the development of active biomimetic materials.


Experimental Analysis and Mathematical Modeling on Mg-Li Alloy Sheets with Three Crystal Structures during Cold Rolling and Heat Treatment.
The microstructural evolution, mechanical properties, and mathematical relationship of an α, α + β, and β phase Mg-Li alloy during the cold rolling and annealing process were investigated. The results showed that the increased Li element gradually transformed the Mg matrix structure from hcp to bcc. Simultaneously, the alloy plasticity was improved remarkably during cold rolling. In the annealing process, a sort of abnormal grain growth was found in Mg-11Li-3Al-2Zn-0.2Y, but was not detected in Mg-5Li-3Al-2Zn-0.2Y and Mg-8Li-3Al-2Zn-0.2Y. Moreover, the mechanical properties of alloy were evidently improved through a kind of solid solution in the β matrix. To accurately quantify this strengthening effect, the method of mathematical modeling was used to determine the relationship between strength and multiple factors.


Evidence from Mendelian randomization: increased risk of miscarriage in patients with asthma.
Several observational studies have revealed a possible association between asthma and miscarriage. However, inferring causal relationships from observational studies may be fraught with problems like bias, reverse causation, and residual confounding. Therefore, to assess the possible causal effect of asthma on miscarriage, we performed a two-sample Mendelian randomization (MR) analysis. Asthma (56,167 cases and 352,255 controls) and miscarriage (9,113 cases and 89,340 controls) data from two GWAS of European ancestry were evaluated. Single nucleotide polymorphisms (SNPs) were used as instrumental variables (IVs). The random effect inverse-variance weighted (IVW) Mendelian randomization approach was used as the primary method, and MR-Egger, weighted-median, and MR-PRESSO approaches were replenished as sensitivity analysis to test the robustness of the results. In total, 70 SNPs were obtained using the SNP criteria. Additionally, the MR study found substantial evidence of the causality between asthma and miscarriage [IVW, OR=1.092; 95% CI=1.017-1.174; p<0.05]. The sensitivity analysis demonstrated the reliability of the MR findings [horizontal pleiotropy (MR-Egger, intercept=-0.0002; Standard error of mean, se=0.006; p=0.975)]. Asthma is a causal risk factor for miscarriage in European populations, according to MR evidence. Our results emphasize the significance of asthma management in reducing the risk of miscarriage in individuals with asthma.


Liver-specific deletion of the NADPH-cytochrome P450 reductase gene: impact on plasma cholesterol homeostasis and the function and regulation of microsomal cytochrome P450 and heme oxygenase.
A mouse model with liver-specific deletion of the NADPH-cytochrome P450 reductase (Cpr) gene (designated Alb-Cre/Cprlox mice) was generated and characterized in this study. Hepatic microsomal CPR expression was significantly reduced at 3 weeks and was barely detectable at 2 months of age in the Alb-Cre+/-/Cprlox+/+ (homozygous) mice, with corresponding decreases in liver microsomal cytochrome P450 (CYP) and heme oxygenase (HO) activities, in pentobarbital clearance, and in total plasma cholesterol level. Nevertheless, the homozygous mice are fertile and are normal in gross appearance and growth rate. However, at 2 months, although not at 3 weeks, the homozygotes had significant increases in liver weight, accompanied by hepatic lipidosis and other pathologic changes. Intriguingly, total microsomal CYP content was increased in the homozygotes about 2-fold at 3 weeks and about 3-fold at 2 months of age; at 2 months, there were varying degrees of induction in protein (1-5-fold) and mRNA expression (0-67-fold) for all CYPs examined. There was also an induction of HO-1 protein (nearly 9-fold) but no induction of HO-2. These data indicate the absence of significant alternative redox partners for liver microsomal CYP and HO, provide in vivo evidence for the significance of hepatic CPR-dependent enzymes in cholesterol homeostasis and systemic drug clearance, and reveal novel regulatory pathways of CYP expression associated with altered cellular homeostasis. The Alb-Cre/Cprlox mouse represents a unique model for studying the in vivo function of hepatic HO and microsomal CYP-dependent pathways in the biotransformation of endogenous and xenobiotic compounds.


Effectiveness of photoperiod stimulation on reproductive performance of sheep housed continuously indoors on an accelerated breeding schedule.
Over five breeding periods, the reproductive performance (fertility, prolificacy and fecundity) of three strains of sheep housed continuously indoors was measured. The sheep were maintained as two separate flocks, A and B, with similar genetic background on an eight month accelerated breeding schedule under one of three lighting regimes, abrupt, contracted or constant, to induce ovarian activity. Overall fertility to one estrus was 59%. For flock A, fertility was greatest under the contracted lighting regime and lowest under the constant lighting regime; the opposite was true for flock B. Among the three strains, fertility was lowest for the Dam 2 strain in flock A. Prolificacy averaged 1.8 lambs per ewe lambing and was similar under each of the three lighting regimes. Fecundity (averaging 106%), the number of lambs born per 100 ewes exposed to rams, generally followed the pattern of fertility.


Role of yeast glutaredoxins as glutathione S-transferases.
The yeast Saccharomyces cerevisiae contains two glutaredoxins, encoded by GRX1 and GRX2, that are required for resistance to reactive oxygen species. We recently reported that Grx1 is active as a glutathione peroxidase and can directly reduce hydroperoxides (Collinson, E. J., Wheeler, G. L., Garrido, E. O., Avery, A. M., Avery, S. V., and Grant, C. M. (2002) J. Biol. Chem. 277, 16712-16717). We now show that Grx2 is also a general hydroperoxidase, and kinetic data indicate that both enzymes have a similar pattern of activity, which is highest with hydrogen peroxide, followed by cumene hydroperoxide and tert-butyl hydroperoxide. Furthermore, both Grx1 and Grx2 are shown be active as glutathione S-transferases (GSTs), and their activity with model substrates such as 1-chloro-2,4-dinitrobenzene is similar to their activity with hydroperoxides. Analysis of the Grx1 active site residues shows that Cys-27, but not Cys-30, is required for both the peroxidase and transferase activities, indicating that these reactions proceed via a monothiol mechanism. Deletion analysis shows that Grx1 and Grx2 have an overlapping function with yeast GSTs, encoded by GTT1 and GTT2, and are responsible for the majority of cellular GST activity. In addition, multiple mutants lacking GRX1, GRX2, GTT1, and GTT2 show increased sensitivity to stress conditions, including exposure to xenobiotics, heat, and oxidants. In summary, glutaredoxins are multifunctional enzymes with oxidoreductase, peroxidase, and GST activity, and are therefore ideally suited to detoxify the wide range of xenobiotics and oxidants that can be generated during diverse stress conditions.