Adherence to General Diabetes and Foot Care Processes, with Prompt Referral, Are Associated with Amputation-Free Survival in People with Type 2 Diabetes and Foot Ulcers: A Scottish National Registry Analysis.
To compare different packages of care across care providers in Scotland on foot-related outcomes. A retrospective cohort study with primary and secondary care electronic health records from the Scottish Diabetes Registry, including 6,845 people with type 2 diabetes and a first foot ulcer occurring between 2013 and 2017. We assessed the association between exposure to care processes and major lower extremity amputation and death. Proportional hazards were used for time-to-event univariate and multivariate analyses, adjusting for case-mix characteristics and care processes. Results were expressed in terms of hazard ratios with 95% confidence intervals. 2,243 (32.7%) subjects had a major amputation or death. Exposure to all nine care processes at all ages (HR = 0.63; 95% CI: 0.58-0.69; p < .001) and higher foot care attendance in people aged >70 years (HR = 0.88; 0.78-0.99; p = .03) were associated with longer major amputation-free survival. Waiting time ≥ 12 weeks between ulceration and clinic attendance was associated with worse outcomes (HR = 1.59; 1.37-1.84; p < .001). In people > 70 years, minor amputations were associated with improved major amputation-free survival (HR = 0.69; 0.52-0.92; p = .01). Strict adherence to a standardised package of general diabetes care before foot ulceration, timely foot care after ulceration, and specific treatment pathways were associated with longer major amputation-free survival among a large cohort of people with type 2 diabetes in Scotland, with a larger impact on older age groups.


Preadmission schooling context helps to predict examination performance throughout medical school.
This study investigates the effects of socioeconomic status and schooling on the academic attainment of a cohort of students at a single medical school (N = 240). Partial least squares structural equation modelling was used to explore how students' summative assessment scores over 4 years of medical school were affected by: attainment in secondary school examinations (GCSEs and A-levels); the Income Deprivation Affecting Children Index (IDACI) rank associated with students' home postcodes; the performance of students' A-level institutions, measured as the percentage of A-level students achieving 3 A-levels at AAB or higher in two or more facilitating subjects. The effects were consistent across time; the final linear regression model used students' cumulative scores (the basis of the medical school's UK Foundation Programme submission) as the dependent variable. The final model fit was quite poor (R2 = .184, n = 178). IDACI Rank was non-significant and excluded from the final model. Both GCSE (.340, p < .001) and A-level (.204, p < .005) scores were associated with increasing Cumulative Score; School Performance was associated with decreasing Cumulative Score (-.159, p < .05). This study confirmed the predictive validity of prior academic attainment and found the same inverse relationship between schooling and medical course performance as previous studies. The study found no evidence that socioeconomic background affects course performance; however, students admitted to medicine from poorly performing schools achieve higher academic attainment throughout the course than students admitted from better-performing schools with the same grades. Schooling could be taken into account for admissions purposes.


In situ tissue engineering: endothelial growth patterns as a function of flow diverter design.
Vascular remodeling in response to implantation of a tissue engineering scaffold such as a flow diverter (FD) leads to the cure of intracranial aneurysms. We hypothesize that the vascular response is dependent on FD design, and CD34+ progenitor cells play an important role in the endothelialization of the implant. Sixteen rabbit aneurysms were randomly treated with two different single-layer braided FDs made of cobalt-chrome alloys. The FD-48 and FD-72 devices had 48 and 72 wires, respectively. Aneurysm occlusion rate was assessed during the final digital subtraction angiogram at 10, 20, 30, and 60 days (n=2 per device per time point). Implanted vessels were analyzed with scanning electron microscopy for tissue coverage, endothelialization, and immuno-gold labeling for CD34+ cells. Complete aneurysm occlusion rates were similar between the devices; however, complete or near complete occlusion was more frequently observed in aneurysms with neck ≤4.2 mm (p=0.008). Total tissue coverage at 10 days over the surface of the FD-48 and FD-72 devices was 56.4±11.6% and 76.6±3.6%, respectively. Endothelial cell growth over the surface was time-dependent for the FD-72 device (Spearman's r=0.86, p=0.013) but not for the FD-48 device (Spearman's r=-0.59, p=0.094). The endothelialization score was marginally correlated with the distance from the aneurysm neck for the FD-48 device (Spearman's r=1, p=0.083) but not for the FD-72 device (Spearman's r=0.8, p=0.33). CD34+ cells were present along the entirety of both devices at all time points. This study gives preliminary evidence that temporal and spatial endothelialization is dependent on FD design. Circulating CD34+ progenitor cells contribute to endothelialization throughout the healing process.


Anticoagulants for acute ischaemic stroke.
Most ischaemic strokes are caused by a blood clot blocking an artery in the brain. Clot prevention with anticoagulants might improve outcomes if bleeding risks are low. This is an update of a Cochrane review first published in 1995, with recent updates in 2004 and 2008. To assess the effectiveness and safety of early anticoagulation (within the first 14 days of onset) in people with acute presumed or confirmed ischaemic stroke. We searched the Cochrane Stroke Group Trials Register (June 2014), the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Database of Systematic Reviews (CDSR), the Database of Reviews of Effects (DARE) and the Health Technology Assessment Database (HTA) (The Cochrane Library 2014 Issue 6), MEDLINE (2008 to June 2014) and EMBASE (2008 to June 2014). In addition, we searched ongoing trials registries and reference lists of relevant papers. For previous versions of this review, we searched the register of the Antithrombotic Trialists' (ATT) Collaboration, consulted MedStrategy (1995), and contacted relevant drug companies. Randomised trials comparing early anticoagulant therapy (started within two weeks of stroke onset) with control in people with acute presumed or confirmed ischaemic stroke. Two review authors independently selected trials for inclusion, assessed trial quality, and extracted the data. We included 24 trials involving 23,748 participants. The quality of the trials varied considerably. The anticoagulants tested were standard unfractionated heparin, low-molecular-weight heparins, heparinoids, oral anticoagulants, and thrombin inhibitors. Over 90% of the evidence relates to the effects of anticoagulant therapy initiated within the first 48 hours of onset. Based on 11 trials (22,776 participants) there was no evidence that anticoagulant therapy started within the first 14 days of stroke onset reduced the odds of death from all causes (odds ratio (OR) 1.05; 95% confidence interval (CI) 0.98 to 1.12) at the end of follow-up. Similarly, based on eight trials (22,125 participants), there was no evidence that early anticoagulation reduced the odds of being dead or dependent at the end of follow-up (OR 0.99; 95% CI 0.93 to 1.04). Although early anticoagulant therapy was associated with fewer recurrent ischaemic strokes (OR 0.76; 95% CI 0.65 to 0.88), it was also associated with an increase in symptomatic intracranial haemorrhages (OR 2.55; 95% CI 1.95 to 3.33). Similarly, early anticoagulation reduced the frequency of symptomatic pulmonary emboli (OR 0.60; 95% CI 0.44 to 0.81), but this benefit was offset by an increase in extracranial haemorrhages (OR 2.99; 95% CI 2.24 to 3.99). Since the last version of the review, no new relevant studies have been published and so there is no additional information to change the conclusions. Early anticoagulant therapy is not associated with net short- or long-term benefit in people with acute ischaemic stroke. Treatment with anticoagulants reduced recurrent stroke, deep vein thrombosis and pulmonary embolism, but increased bleeding risk. The data do not support the routine use of any of the currently available anticoagulants in acute ischaemic stroke.


Optimization of a genetically encoded biosensor for cyclin B1-cyclin dependent kinase 1.
Fluorescent protein (FP)-based biosensors have revolutionized the ability of researchers to monitor enzyme activities in live cells. While the basic design principles for FP-based biosensors are well established, first-generation biosensor constructs typically suffer from relatively low fluorescence responses that limit their general applicability. The protein engineering efforts required to substantially improve the biosensor responses are often both labour and time intensive. Here we report the application of a high throughput bacterial colony screen for improving the response of kinase biosensors. This effort led to the development of a second-generation cyclin B1-CDK1 biosensor with a 4.5-fold greater response than the first-generation biosensor.


MO-D-BRB-01: Accuracy Requirements and Uncertainties in Radiation Therapy: A Preview of an Upcoming IAEA Report.
The International Atomic Energy Agency (IAEA) has a mandate 'to accelerate and enlarge the contribution of atomic energy to peace, health and prosperity throughout the world'. Through its Human Health Division, this is done by developing guidance documents on standards of practice in radiation medicine. In recent years, there have been major advances in the technology of radiation oncology which have allowed for a transition from conventional 2-D radiation therapy to the implementation of 3-D conformal radiation therapy (CRT), intensity modulated radiation therapy (IMRT), image-guided radiation therapy (IGRT), adaptive radiation therapy (ART), and 4-D imaging and motion management in radiation therapy. Brachytherapy procedures have also evolved both for high dose rate (HDR) techniques as well as permanent implants, especially for prostate cancer treatments. Multiple imaging modalities are now available for target volume and normal tissue delineation for radiation treatment planning both for external beam radiation therapy and brachytherapy. With these new advanced technologies and improved outcome considerations for both external beam and brachytherapy, there is also a recognized need for greater accuracy in the radiation treatment process. While a number of reports and publications have defined accuracy needs in radiation oncology, most of these reports were developed in an era with different radiation technologies and date back to the 1980s and 90s. In view of the new technologies and techniques, improvements in dosimetry methodologies and new clinical dose- volume data, the IAEA is developing a new international guidance document on 'Accuracy Requirements and Uncertainties in Radiation Therapy' in order to reduce these uncertainties to provide more effective and safer patient treatments. This review will summarize the new IAEA report which is expected to be published later in 2012. This work is supported by the International Atomic Energy Agency.


Predictors of metabolic response in propensity-matched lymphoma patients on interim 18F-fluorodeoxyglucose positron-emission tomography/computed tomography using standardized imaging and reporting protocol: Do we really have one?
The purpose of this prospective study was to determine metabolic response predictor(s) in propensity-matched patients having lymphomas who had baseline and interim 18fluorodeoxyglucose (FDG) positron-emission tomography/computed tomography (PET/CT) using strict standardized imaging and reporting protocols. This prospective study was conducted at PET/CT section of a JCI-accredited healthcare facility from April 2017 to February 2018. Patients with baseline and interim 18FDG PET/CT scans using standardized protocol were selected. Interim scans were performed not earlier than 2nd or later than 4th chemotherapy. During the study period, 97 of 112 consecutive patients with lymphomas (Hodgkin-HL: 32/97 and Non-Hodgkin-NHL: 65/97) were included in the study. Mean age of cohort was 45 ± 19 years (71% male and 29% female) having a mean body mass index (BMI) of 25.57 ± 5.54 Kg/m2 having Stage I (21%), Stage II (18%), Stage III (16%), and Stage IV (45%) disease. Bulky disease was found in 14% and 18FDG-avid marrow deposits in 33%. Standardized PET/CT imaging protocol as per EANM guidelines was strictly adopted for baseline and interim studies. %Δ changes in fasting blood sugar, 18FDG dose, uptake time, and liver SUV mean were 3.96%, 2.83%, 2.49%, and 12.15%, respectively. Based on Deauville's scoring, cohort was divided into responders having Score 1-3 (49/97) and nonresponders having Score 4-5 (48/97). The demographic analysis found no significant difference between responders and nonresponders for age, gender, BMI, staging, bulky disease or marrow involvement, and study protocol. No significant coefficient or odd ratios were found on multivariate analysis for age, gender, maximum standardized uptake value (SUVmax), size, BMI, NHL, and advance disease (Stage III and IV) in both groups (χ2: 5.12; receiver operating characteristic [95% confidence interval]: 0.616 [0.51-0.713]; P =0.528). Among responders, baseline SUVmax and tumor size had a direct correlation with a metabolic response on iPET, more pronounced in NHL than HL groups (SUVmax: 13.4 vs. 19.5 and size: 52 vs. 87 mm; P < 0.0001). We conclude that no significant predictor was found for response in propensity-matched patients with lymphomas (both HL and NHL) who had baseline and interim PET/CTs acquired with a standardized protocol. However, NHL responders were found to have higher baseline median SUVmax and larger lesion size as compared to HL responders. Although, these data are not in concordance with published findings but need to be validated with larger studies using standardized imaging and reporting protocols in propensity-matched patients with lymphomas.


Tragic choices in intensive care during the COVID-19 pandemic: on fairness, consistency and community.
Tragic choices arise during the COVID-19 pandemic when the limited resources made available in acute medical settings cannot be accessed by all patients who need them. In these circumstances, healthcare rationing is unavoidable. It is important in any healthcare rationing process that the interests of the community are recognised, and that decision-making upholds these interests through a fair and consistent process of decision-making. Responding to recent calls (1) to safeguard individuals' legal rights in decision-making in intensive care, and (2) for new authoritative national guidance for decision-making, this paper seeks to clarify what consistency and fairness demand in healthcare rationing during the COVID-19 pandemic, from both a legal and ethical standpoint. The paper begins with a brief review of UK law concerning healthcare resource allocation, considering how community interests and individual rights have been marshalled in judicial deliberation about the use of limited health resources within the National Health Service (NHS). It is then argued that an important distinction needs to be drawn between procedural and outcome consistency, and that a procedurally consistent decision-making process ought to be favoured. Congruent with the position that UK courts have adopted for resource allocation decision-making in the NHS more generally, specific requirements for a procedural framework and substantive triage criteria to be applied within that framework during the COVID-19 pandemic are considered in detail.


Lactoferrin ameliorates aging-suppressed osteogenesis via IGF1 signaling.
Lactoferrin (LF) is an iron-binding glycoprotein that plays an important role in promoting bone formation and inhibiting bone resorption; however, its effects on senile osteoporosis remain unknown. This study aimed to investigate the effects and mechanism of LF intervention using a senile osteoporosis model (SAMP6 mice) and senescent osteoblasts. Micro-CT and hematoxylin and eosin staining demonstrated that the intragastric administration (2 g/kg/day) of LF could improve the bone mass and microstructure of SAMP6 mice. Furthermore, LF treatment improved bone metabolism and increased insulin-like growth factor 1 (Igf1) mRNA expression and activated phosphorylation status of AKT. Using osteoblasts passaged for ten generations as an in vitro senescence model, various markers associated with osteoblast formation and differentiation, as well as related indices of oxidative stress were analyzed. Our results revealed that after multiple generations, osteoblasts entered senescence, in conjunction with increased oxidative stress damage, reduced bone metabolism and enhanced expression of aging-related markers. While inhibiting oxidative stress, LF improved osteoblast proliferation by promoting the expression of osteogenesis markers, including alkaline phosphatase (ALP) activity, Igf1, bone gla protein (Bglap) and osteoprotegerin/receptor activator of nuclear factor-kB ligand (Opg/Rankl) mRNA and delayed senescence by decreasing the level of p16 and p21 expression. RNAI-mediated downregulation of IGF1 attenuated the effect of LF on osteogenesis. Therefore, the findings of the present study indicate that LF may promote osteogenesis via IGF1 signaling, thereby preventing senile osteoporosis.


Internal and external influences on the rate of sensory evidence accumulation in the human brain.
We frequently need to make timely decisions based on sensory evidence that is weak, ambiguous, or noisy resulting from conditions in the external environment (e.g., a cluttered visual scene) or within the brain itself (e.g., inattention, neural noise). Here we examine how externally and internally driven variations in the quality of sensory evidence affect the build-to-threshold dynamics of a supramodal "decision variable" signal and, hence, the timing and accuracy of decision reports in humans. Observers performed a continuous-monitoring version of the prototypical two-alternative dot-motion discrimination task, which is known to strongly benefit from sequential sampling and temporal accumulation of evidence. A centroparietal positive potential (CPP), which we previously established as a supramodal decision signal based on its invariance to motor or sensory parameters, exhibited two key identifying properties associated with the "decision variable" long described in sequential sampling models: (1) its buildup rate systematically scaled with sensory evidence strength across four levels of motion coherence, consistent with temporal integration; and (2) its amplitude reached a stereotyped level at the moment of perceptual report executions, consistent with a boundary-crossing stopping criterion. The buildup rate of the CPP also strongly predicted reaction time within coherence levels (i.e., independent of physical evidence strength), and this endogenous variation was linked with attentional fluctuations indexed by the level of parieto-occipital α-band activity preceding target onset. In tandem with the CPP, build-to-threshold dynamics were also observed in an effector-selective motor preparation signal; however, the buildup of this motor-specific process significantly lagged that of the supramodal process.


Empowering a Community from the Inside Out: Evaluation of a Yoga Teacher Training Program for Adults in Custody.
The current study evaluated a yoga teacher training program to understand the effect of bringing yoga psychology (as an integrated eight-limbed system) to adults in custody (AIC), who were trained to become yoga teachers who will in turn teach other AICs. The study used quantitative and qualitative measures to assess the yoga teacher training program's impact on individuals, their relationships, and the overall prison environment. The study included assessments and interviews with 12 AICs and nine yoga teacher volunteers, as well as key informant interviews with two correctional officers and five administrators who work within or directly with the Department of Corrections on the implementation of the program. Quantitative results revealed significant enhancements and sustainability in all key outcome variables (self-compassion, mindfulness, perceived stress, understanding of yoga philosophy, and teaching skills) from pretest to program completion and from completion to 3-month follow-up. Additionally, AIC yoga teachers became more similar on all outcome measures to the volunteer teachers from pretest to program completion and from completion to follow-up. Qualitative methods (used for 31 key informant and focus group interviews) revealed themes that illuminated positive effects on the prison community regarding participants' personal experiences, attitudes and values, behaviors, relationships, yoga philosophy in prison, culture, and future directions. Implications and recommendations are provided to support sustaining the current program and to help with the creation of new programs to infuse yoga philosophy into corrections departments.


Fear, Defensive Strategies and Caring for Cognitively Impaired Family Members.
One topic rarely addressed in the literature on older adults and interpersonal violence is the violence that can be experienced by family carers in relationship with a person living with cognitive impairment. This violence tends to remain hidden and is rarely framed as intimate partner violence. We examine how situations of intimidation and violence invoked fear in family carers and how they interpreted and reacted to these circum- stances. Interview and diary data were collected from family members who had previously or were currently experiencing some form of aggression in caring for someone with cognitive impairment or dementia. Drawing on discussions of fear and applying the analytic lens of defensive strategies, we explore how these carers responded to situations of intimidation and violence.


Structural, dynamic and photophysical properties of a fluorescent dye incorporated in an amorphous hydrophobic polymer bundle.
The properties of a low molecular weight organic dye, namely 4-naphthyloxy-1-methoxy-2,2,6,6-tetramethylpiperidine, covalently bound to an apolar polyolefin were investigated by means of a multi-level approach, combining classical molecular dynamics simulations, based on purposely parameterized force fields, and quantum mechanical calculations based on density functional theory (DFT) and its time-dependent extension (TD-DFT). The structure and dynamics of the dye in its embedding medium were analyzed and discussed taking the entangling effect of the surrounding polymer into account, and also by comparing the results to those obtained for a different environment, i.e. toluene solution. Finally, the influence was investigated of long lived cages found in the polymeric embedding on photophysical properties, in terms of the slow and fast dye's internal dynamics, by comparing computed IR and UV spectra with their experimental counterparts.


Physical map of tupaia adenovirus DNA by cleavage with restriction endonucleases and partial denaturation.
The double-stranded DNA of an adenovirus of tupaia (TAV) which has a mol. wt. of 21.5 X 10(6) was analysed as follows: the cleavage sites of restriction endonucleases BamHI, EcoRI, KpnI, SmaI, BstEII, ClaI and HpaI were determined by complete, partial and double digestion followed by gel electrophoretic separation of the resulting fragments. Terminal HpaI fragments were determined by hydrolysing the intact DNA with exonuclease III before restriction enzyme cleavage. Partial denaturation mapping of uncleaved DNA and EcoRI fragments revealed the cleavage sites of EcoRI as well as A + T-rich regions at both termini of the genome.


The Programmed Cell Death Ligand-1/Programmed Cell Death-1 Pathway Mediates Pregnancy-Induced Analgesia via Regulating Spinal Inflammatory Cytokines.
The maternal pain threshold gradually increases during pregnancy, especially in late pregnancy. A series of mechanisms underlying pregnancy-induced analgesia have been reported. However, these mechanisms are still not completely clear, and the underlying molecular mechanisms need further investigation. We examined the relationship between the antinociceptive effect and the expression level of programmed cell death ligand-1 (PD-L1) during pregnancy and further observed the changes in pain thresholds and expression levels of cytokines in late-pregnant mice before and after blockade of PD-L1 or programmed cell death-1 (PD-1). Part 1: Female mice were assigned to 3 groups (nonpregnant, late-pregnant, and postpartum). Part 2: Late-pregnant mice were assigned to 3 treatment groups (control [phosphate buffer solution], RMP1-14 [mouse anti-PD-1 antibody], and soluble PD-1 [sPD-1]). Behavioral testing (mechanical and thermal) and tissue (serum and spinal cord) analysis were performed on all groups. PD-L1, interleukin (IL)-10, tumor necrosis factor-α (TNF-α), and IL-6 expression levels in tissue were examined via reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and Western blot analysis. The mechanical and thermal pain thresholds were significantly increased in late pregnancy and decreased after delivery. PD-L1 expression was also elevated in late pregnancy and decreased after delivery. In addition, in the late stage of gestation, the maternal inflammatory microenvironment was dominated by anti-inflammatory factors. After administration of RMP1-14 or sPD-1, the pain thresholds of late-pregnant mice were significantly reduced. In late-pregnant mice, the high level of IL-10 was obviously reduced, and the low levels of TNF-α and IL-6 were elevated. The PD-L1/PD-1 pathway mediates pregnancy-induced analgesia, partially via the regulation of cytokines.


Aerobic Exercise Training Increases Muscle Water Content in Obese Middle-Age Men.
The objective of this study is to determine whether muscle water content (H2Omuscle) expands with training in deconditioned middle-age men and the effects of this expansion in other muscle metabolites. Eighteen obese (BMI = 33 ± 3 kg⁻¹·m⁻²) untrained (V˙O2peak = 29 ± 7 mL⁻¹·kg⁻¹·min⁻¹) metabolic syndrome men completed a 4-month aerobic cycling training program. Vastus lateralis muscle biopsies were collected before and 72 h after the completion of the last training bout. Water content, total protein, glycogen concentration, and citrate synthase activity were measured in biopsy tissue. Body composition was assessed using dual-energy X-ray absorptiometry, and cardiometabolic fitness was measured during an incremental cycling test. Body weight and fat mass were reduced -1.9% and -5.4%, respectively (P < 0.05), whereas leg fat free mass increased with training (1.8%, P = 0.023). Cardiorespiratory fitness (i.e., V˙O2peak), exercise maximal fat oxidation (i.e., FOmax), and maximal cycling power (i.e., Wmax) improved with training (11%, 33%, and 10%, respectively; P < 0.05). After 4 months of training, H2Omuscle increased from 783 ± 18 to 799 ± 24 g·kg⁻¹ wet weight (ww) (2%, P = 0.011), whereas muscle protein concentration decreased 11% (145 ± 15 to 129 ± 13 g·kg⁻¹ ww, P = 0.007). Citrate synthase activity (proxy for mitochondrial density) increased by 31% (17 ± 5 to 22 ± 5 mmol·min⁻¹·kg⁻¹ ww, P = 0.024). Muscle glycogen concentration increased by 14% (22 ± 7 to 25 ± 7 g·kg⁻¹ ww) although without reaching statistical significance when expressed as per kilogram of wet weight (P = 0.15). Our findings suggest that aerobic cycling training increases quadriceps muscle water although reduces muscle protein concentration in obese metabolic syndrome men. Reduced protein concentration coexists with increased leg lean mass suggestive of a water dilution effect that however does not impair increased cycling leg power with training.


Large conservation gains possible for global biodiversity facets.
Different facets of biodiversity other than species numbers are increasingly appreciated as critical for maintaining the function of ecosystems and their services to humans. While new international policy and assessment processes such as the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES) recognize the importance of an increasingly global, quantitative and comprehensive approach to biodiversity protection, most insights are still focused on a single facet of biodiversity-species. Here we broaden the focus and provide an evaluation of how much of the world's species, functional and phylogenetic diversity of birds and mammals is currently protected and the scope for improvement. We show that the large existing gaps in the coverage for each facet of diversity could be remedied by a slight expansion of protected areas: an additional 5% of the land has the potential to more than triple the protected range of species or phylogenetic or functional units. Further, the same areas are often priorities for multiple diversity facets and for both taxa. However, we find that the choice of conservation strategy has a fundamental effect on outcomes. It is more difficult (that is, requires more land) to maximize basic representation of the global biodiversity pool than to maximize local diversity. Overall, species and phylogenetic priorities are more similar to each other than they are to functional priorities, and priorities for the different bird biodiversity facets are more similar than those of mammals. Our work shows that large gains in biodiversity protection are possible, while also highlighting the need to explicitly link desired conservation objectives and biodiversity metrics. We provide a framework and quantitative tools to advance these goals for multi-faceted biodiversity conservation.


Health-related quality of life in patients with different stages of liver disease induced by hepatitis C.
Patients with hepatitis C have been shown to have impaired health-related quality of life (HRQoL). The aim of this study was to determine HRQoL in patients in different stages of hepatitis C virus (HCV) and to compare HRQoL in HCV cirrhosis with non-HCV-induced cirrhosis. Out of 489 consecutive patients who fulfilled the inclusion criteria, 472 (96%) agreed to participate in the study: 158 patients with mild/moderate fibrosis with chronic hepatitis C (CHC group), 76 patients with HCV compensated cirrhosis (CC), 53 patients with HCV decompensated (DC) cirrhosis, 52 non-cirrhotic patients with sustained viral response (SVR), and a control group consisting of 32 patients with non-HCV CC and 101 with non-HCV DC who completed the Short Form-36 (SF-36) and EQ-5D questionnaire. The CHC group had significantly lower SF-36 scores than healthy controls, with the exception of scores for the dimensions physical function and bodily pain. HCV patients with DC had lower scores in all SF-36 dimensions in comparison with those of the CHC group, as well as in physical and mental component summaries (p<0.001). In comparison with the CHC group, the HCV CC group had lower scores on the SF-36 general health dimension (p<0.05) and lower SF-36 physical component summary (PCS) scores (p<0.05). No major differences were seen in patients with HCV- and non-HCV-induced cirrhosis. Impairment in HRQoL in patients with HCV was associated with the severity of liver disease, patients with decompensated cirrhosis exhibiting the highest impairment in HRQoL. The etiology of liver disease does not seem to be important in determining HRQoL in cirrhosis.


Evaluation of the efficacy of laparoscopic resection for the management of exogenous cesarean scar pregnancy.
To retrospectively analyze the clinical data of 71 patients with exogenous cesarean scar pregnancy (CSP) treated in our hospital in the past 2 years, to compare the outcomes of exogenous CSP treated with different methods, and to evaluate the safety and feasibility of laparoscopic resection of exogenous CSP. Comparative observational study. Tertiary medical centers. 71 women with exogenous cesarean scar pregnancy. Hysteroscopic resection of CSP, and laparoscopic resection of CSP. Operation time, intraoperative blood loss, postoperative drainage of the uterine cavity, postoperative days in hospital, time for β-human chorionic gonadotropin (β-hCG) to return to normal levels, absorption time of the mass. For the laparoscopic group, the time for serum β-hCG to return normal levels and the postoperative drainage of the uterine cavity were significantly lower than in the patients who had undergone hysteroscopic resection. We found no statistically significant difference in the intraoperative blood loss and postoperative days in hospital between the two groups, but the operation time was longer in laparoscopic group. Laparoscopic surgery for a cesarean scar pregnancy has the advantages of a high success rate, fewer complications, and a shorter time for β-hCG levels to normalize. This procedure is especially suitable for the treatment of exogenous CSP.


Development of a quality indicator set to measure and improve quality of ICU care for patients with traumatic brain injury.
We aimed to develop a set of quality indicators for patients with traumatic brain injury (TBI) in intensive care units (ICUs) across Europe and to explore barriers and facilitators for implementation of these quality indicators. A preliminary list of 66 quality indicators was developed, based on current guidelines, existing practice variation, and clinical expertise in TBI management at the ICU. Eight TBI experts of the Advisory Committee preselected the quality indicators during a first Delphi round. A larger Europe-wide expert panel was recruited for the next two Delphi rounds. Quality indicator definitions were evaluated on four criteria: validity (better performance on the indicator reflects better processes of care and leads to better patient outcome), feasibility (data are available or easy to obtain), discriminability (variability in clinical practice), and actionability (professionals can act based on the indicator). Experts scored indicators on a 5-point Likert scale delivered by an electronic survey tool. The expert panel consisted of 50 experts from 18 countries across Europe, mostly intensivists (N = 24, 48%) and neurosurgeons (N = 7, 14%). Experts agreed on a final set of 42 indicators to assess quality of ICU care: 17 structure indicators, 16 process indicators, and 9 outcome indicators. Experts are motivated to implement this finally proposed set (N = 49, 98%) and indicated routine measurement in registries (N = 41, 82%), benchmarking (N = 42, 84%), and quality improvement programs (N = 41, 82%) as future steps. Administrative burden was indicated as the most important barrier for implementation of the indicator set (N = 48, 98%). This Delphi consensus study gives insight in which quality indicators have the potential to improve quality of TBI care at European ICUs. The proposed quality indicator set is recommended to be used across Europe for registry purposes to gain insight in current ICU practices and outcomes of patients with TBI. This indicator set may become an important tool to support benchmarking and quality improvement programs for patients with TBI in the future.


FROM Qutn TO Bt COTTON: DEVELOPMENT, ADOPTION AND PROSPECTS. A REVIEW.
Cotton has unique history of domestication, diversification, and utilization. Globally it is an important cash crop that provides raw material for textile industry. The story of cotton started from human civilization and the climax arrived with the efforts of developing transgenic cotton for various traits. Though conventional breeding brought steady improvement in developing resistance against biotic stresses but recent success story of gene transferfrom Bacillus thuringiensis into cotton showed game changing effects on cotton cultivation. Amongst various families of insecticidal proteins Bt Cry-toxins received more attention because of specificity against receptors on the cell membranes of insect midgut epithelial cells. Rapid Bt cotton adoption by farmers due to its economic and environmental benefits has changed the landscape of cotton cultivation in many countries. But the variable expression of Bt transgene in the newly developed Bt cotton genotypes in tropical environment is questionable. Variability of toxin level in different plant parts at various life stage of plant is an outcome of genotypic interaction with environmental factors. Temporal gene expression of Cry1Ac is also blamed for the epigenetic background in which transgene has been inserted. The presence of genotypes with sub-lethal level of Bt toxin might create resistance in Lepidopteron insects, limiting the use of Bt cotton in future, with the opportunityfor other resistance development strategies to get more attention like gene stacking. Until the farmers get access to more recent technology, best option is to delay the development of resistance by applying Insect Resistance Management (IRM) strategies.


Genetic analysis of disease subtypes and sexual dimorphisms in mouse experimental allergic encephalomyelitis (EAE): relapsing/remitting and monophasic remitting/nonrelapsing EAE are immunogenetically distinct.
Experimental allergic encephalomyelitis (EAE) is the principal animal model of multiple sclerosis (MS), the major inflammatory disease of the central nervous system. Murine EAE is generally either an acute monophasic or relapsing disease. Because the clinical spectrum of MS is more diverse, the limited range of disease subtypes observed in EAE has raised concern regarding its relevance as a model for MS. During the generation of a large F2 mapping population between the EAE-susceptible SJL/J and EAE-resistant B10.S/DvTe inbred lines, we identified four distinct subtypes of murine EAE resembling clinical subtypes seen in MS. We observed acute progressive, chronic/nonremitting, remitting/relapsing, and monophasic remitting/nonrelapsing EAE. An additional subtype, benign EAE, was identified after histologic examination revealed that some mice had inflammatory infiltrates of the central nervous system, but did not show clinical signs of EAE. Genome exclusion mapping was performed to identify the loci controlling susceptibility to each disease subtype. We report three novel EAE-modifying loci on chromosomes 16, 7, and 13 (eae11-13, respectively). Additionally, unique loci with gender-specific effects govern susceptibility to remitting/relapsing (eae12) and monophasic remitting/nonrelapsing (eae7 and 13) EAE.


Cystinosin, the small GTPase Rab11, and the Rab7 effector RILP regulate intracellular trafficking of the chaperone-mediated autophagy receptor LAMP2A.
The lysosomal storage disease cystinosis, caused by cystinosin deficiency, is characterized by cell malfunction, tissue failure, and progressive renal injury despite cystine-depletion therapies. Cystinosis is associated with defects in chaperone-mediated autophagy (CMA), but the molecular mechanisms are incompletely understood. Here, we show CMA substrate accumulation in cystinotic kidney proximal tubule cells. We also found mislocalization of the CMA lysosomal receptor LAMP2A and impaired substrate translocation into the lysosome caused by defective CMA in cystinosis. The impaired LAMP2A trafficking and localization were rescued either by the expression of wild-type cystinosin or by the disease-associated point mutant CTNS-K280R, which has no cystine transporter activity. Defective LAMP2A trafficking in cystinosis was found to associate with decreased expression of the small GTPase Rab11 and the Rab7 effector RILP. Defective Rab11 trafficking in cystinosis was rescued by treatment with small-molecule CMA activators. RILP expression was restored by up-regulation of the transcription factor EB (TFEB), which was down-regulated in cystinosis. Although LAMP2A expression is independent of TFEB, TFEB up-regulation corrected lysosome distribution and lysosomal LAMP2A localization in Ctns-/- cells but not Rab11 defects. The up-regulation of Rab11, Rab7, or RILP, but not its truncated form RILP-C33, rescued LAMP2A-defective trafficking in cystinosis, whereas dominant-negative Rab11 or Rab7 impaired LAMP2A trafficking. Treatment of cystinotic cells with a CMA activator increased LAMP2A localization at the lysosome and increased cell survival. Altogether, we show that LAMP2A trafficking is regulated by cystinosin, Rab11, and RILP and that CMA up-regulation is a potential clinically relevant mechanism to increase cell survival in cystinosis.


Force and stiffness in glycerinated rabbit psoas fibers. Effects of calcium and elevated phosphate.
Force (F) and stiffness (K) were measured in glycerinated psoas fibers at various calcium levels with 0, 10, 20, and 30 mM orthophosphate (Pi) added to the bathing solutions. The concentrations of bathing solution constituents were as follows: 110 mM potassium, 40 mM sodium, 4 mM MgATP, 10 mM total EGTA, and variable amounts of MOPS (pH buffer). The pH was 7.0, the ionic strength was 200 mM, and the temperature was 10 degrees C. Calcium levels were established by adding various amounts of CaCl2. All solutions contained 4% Dextran T-500. Fiber K was measured by imposing sinusoidal length changes (0.03-0.1%) at 1 kHz and by applying rapid steps in length and measuring the resulting F changes. At all [Pi] tested, K was more sensitive to calcium than F. Elevating bathing solution [Pi] caused a decrease in the calcium sensitivity of both F and K, while the slopes of F-calcium and K-calcium relations increased. In maximally activating calcium, raising [Pi] caused a continuous decrease in F over the range tested, while from very low to 10 mM Pi K remained constant. Above 10 mM Pi K declined, but to a lesser extent than did F. The results suggest that under our experimental conditions strongly attached crossbridges can exist in both force-producing and non-force-producing states, and that the relative population of these states may be calcium dependent.


Epimedium polysaccharide and propolis flavone can synergistically inhibit the cellular infectivity of NDV and improve the curative effect of ND in chicken.
Four prescriptions, epimedium flavone plus propolis flavone (EF-PF), epimedium flavone plus propolis extracts (EF-PE), epimedium polysaccharide plus propolis flavone (EP-PF) and epimedium polysaccharide plus propolis extracts (EP-PE), were prepared and their antiviral effects were compared. In test in vitro, the four prescriptions within safety concentration scope and Newcastle disease virus (NDV) were added into cultured chick embryo fibroblast (CEF) in three modes, pre-, post-adding drug and simultaneous-adding drug and virus after being mixed, the cellular A(570) values were determined by MTT method and the highest virus inhibitory rates were calculated to compare the antiviral activity of four prescriptions. In test in vivo, three hundred 21-day-old chickens were randomly divided into 6 groups and challenged with NDV except for blank control group. After 24h the chickens in four prescription groups were injected with corresponding drugs respectively, in virus control and blank control groups, with physiological saline, once a day for three successive days. On days 3, 7 and 14 after challenge, the serum antibody titer was determined. On day 15 after challenge, the mortality, morbidity and cure rate in every group were counted. The results showed that the most of A(570) values in EP-PF group were numberly or significantly larger than those of the corresponding virus control group and the highest virus inhibitory rates of EP-PF at optimal concentration group were the highest among four prescription groups in three drug-adding modes, which confirmed that EP-PF could significantly inhibit the infectivity of NDV to CEF, its action was stronger than those of other three prescriptions; in EP-PF group, the antibody titers and cure rate were the highest and the mortality and morbidity were lowest presenting numberly or significantly differences in comparison with other three prescription groups. These results indicated that epimedium polysaccharide and propolis flavone possessed synergistical action, EP-PF prescription could significantly inhibit the cellular infectivity of NDV, improve the curative effect of ND in chicken and would be expected to exploit into a new-type antiviral drug.


Optimization of protocols for derivation of mouse embryonic stem cell lines from refractory strains, including the non obese diabetic mouse.
The derivation of pluripotent embryonic stem cells (ESCs) from a variety of genetic backgrounds remains a desirable objective in the generation of mice functionally deficient in genes of interest and the modeling of human disease. Nevertheless, disparity in the ease with which different strains of mice yield ESC lines has long been acknowledged. Indeed, the generation of bona fide ESCs from the non obese diabetic (NOD) mouse, a well-characterized model of human type I diabetes, has historically proved especially difficult to achieve. Here, we report the development of protocols for the derivation of novel ESC lines from C57Bl/6 mice based on the combined use of high concentrations of leukemia inhibitory factor and serum-replacement, which is equally applicable to fresh and cryo-preserved embryos. Further, we demonstrate the success of this approach using Balb/K and CBA/Ca mice, widely considered to be refractory strains. CBA/Ca ESCs contributed to the somatic germ layers of chimeras and displayed a very high competence at germline transmission. Importantly, we were able to use the same protocol for the derivation of ESC lines from nonpermissive NOD mice. These ESCs displayed a normal karyotype that was robustly stable during long-term culture, were capable of forming teratomas in vivo and germline competent chimeras after injection into recipient blastocysts. Further, these novel ESC lines efficiently formed embryoid bodies in vitro and could be directed in their differentiation along the dendritic cell lineage, thus illustrating their potential application to the generation of cell types of relevance to the pathogenesis of type I diabetes.


Is There Any Association between Glutathione S-transferases M1 and Glutathione S-transferases T1 Gene Polymorphisms and Endometrial Cancer Risk? A Meta-analysis.
Epidemiological evidence on the association between genetic polymorphisms in glutathione S-transferases M1 (GSTM1) and T1 (GSTT1) genes and risk of endometrial cancer (EC) has been inconsistent. In this meta-analysis, we seek to investigate the relationship between GSTM1 and GSTT1 polymorphisms and the risk of EC. We searched Medline, PubMed, Web of Science, Embase, Chinese National Knowledge Infrastructure database, and Chinese Biomedical Literature database to identify eligible studies. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) for the association were determined using a fixed- or random-effect model. Tests for heterogeneity of the results and sensitivity analyses were performed. A total of six case-control studies were included in the final meta-analysis of GSTM1 (1293 cases and 2211 controls) and GSTT1 (1286 cases and 2200 controls) genotypes. Overall, GSTM1 null genotype was not significantly associated with an increased risk of EC (OR = 1.00, 95% CI = 0.76-1.30, P = 0.982). Similarly, for GSTT1 deletion genotype, we observed no association under the investigated model in the overall analysis (OR = 0.91, 95% CI = 0.64-1.30, P = 0.619). Subgroup analysis also showed no significant association between the GSTM1 null genotype and EC risk in hospital-based design (OR = 1.26, 95% CI = 0.93-1.71, P = 0.131) and no relationship between GSTT1 null genotype with EC risk in population-based design (OR = 1.18, 95% CI = 0.79-1.76, P = 0.407). However, GSTM1 null genotype contributed to an increased EC risk in population-based design (OR = 0.76, 95% CI = 0.60-0.97, P = 0.027), while null GSTT1 in hospital-based studies (OR = 0.70, 95% CI = 0.52-0.93, P = 0.015). The present meta-analysis suggested that GSTs genetic polymorphisms may not be involved in the etiology of EC. Large epidemiological studies with the combination of GSTM1 null, GSTT1 null, and design-specific with the development of EC are needed to prove our findings.


Breast cancer in Latinas: gene expression, differential response to treatments, and differential toxicities in Latinas compared with other population groups.
Disparities in clinical outcomes of breast cancer have been described among different racial and ethnic groups in the U.S. Convincing data exist showing that Latina women have a lower incidence of breast cancer but a higher breast cancer-related mortality rate compared with white women. Noticeable differences in breast cancer incidence are present even within different Latina subsets with a higher incidence in second- and third-generation women compared with foreign born. An increasing amount of data exists pointing to significant differences in the genetics and biology of breast cancer in Latinas as a significant contributor to the higher mortality, including a higher incidence of triple-negative breast cancers (which do not overexpress HER-2 protein and are negative for estrogen receptors and progesterone receptors). Other social and environmental factors are likely to play a significant role as well, including a lower rate of screening mammography, variable access to medical care, among others. Recent data are inconclusive regarding differences among racial/ethnic groups in the response to chemotherapy. Data on racial/ethnic variations in the pharmacogenomics of chemotherapy, endocrine treatments, and toxicity are more limited, with some data suggesting differences in frequencies of polymorphisms of genes involved in the metabolism of some of these agents. Further studies are needed on this subject.


Erratum to 'The management of chronic hepatitis B in the immunocompromised patient: recommendations from a single topic meeting' [J. Clin. Virol. 41 (4) 2008 243-254].
Patients with chronic hepatitis B virus (HBV) infection have a substantial risk of reactivation and jaundice following the use of immunosuppressant therapy. A single topic conference was convened to discuss the management of HBV patients undergoing chemotherapy for haematological malignancy, liver and renal transplantation and with HIV co-infection. In advance of the meeting a draft guideline was prepared and circulated to a participating expert panel. Presentations and consensus views were obtained on the day of conference to allow pragmatic algorithms to be established on each of these topics. Use of lamivudine prophylaxis for HBV patients undergoing chemotherapy and renal transplantation is strongly supported with good evidence. Patients with HBV cirrhosis who are candidates for transplantation should be started on nucleos(t)ide therapy prior to surgery and, in addition, hepatitis B immune globulin given from the time of transplantation onward. Co-infection with HBV and HIV offers unique challenges. If the patient is a candidate for highly active retroviral therapy then dual nucleos(t)ide analogues which are also active against HBV must be used to prevent immune reconstitution hepatitis. In all these conditions, awareness of possible HBV resistance to therapy must be kept in mind and HBV DNA levels monitored.


Simultaneous multifocal, multiphoton, photon counting microscopy.
We demonstrate a novel multifocal, multiphoton microscope that is capable of simultaneous dynamic imaging of multiple focal planes. We show for the first time that multimodal, multiphoton images excited with orthogonal polarizations can be acquired simultaneously in both the transmission and epi directions.


A luminescent and colorimetric probe based on the functionalization of gold nanoparticles by ruthenium(ii) complexes for heparin detection.
A sensitive assay was demonstrated for the colorimetric and luminescent detection of heparin. Positively charged [Ru(phen)2np]2+ (np: naphtho[2,3-f][1,10]phenanthroline) can interact with negatively charged AuNPs through electrostatic interaction, leading to the luminescence quenching of [Ru(phen)2np]2+via energy transfer as well as the aggregation of AuNPs together with a color change in solution from red to blue. Upon the addition of negatively charged heparin to gold nanoparticles functionalized by ruthenium(ii) complexes, the emission of [Ru(phen)2np]2+ recovered due to the competitive adsorption of [Ru(phen)2np]2+ to heparin and AuNPs. A linear calibration curve was obtained in the 0.4 μM to 100 μM range and 0.1 μM to 6 μM with a low detection limit of 0.22 μM and 0.024 μM based on 3σ/s for heparin quantification in buffer solution and in 1% fetal bovine serum (FBS), respectively. Interestingly, the naked eye alone can judge the presence of 0.02 μM heparin without the aid of any advanced instruments by color change. Thus a convenient and visual method to detect heparin was established.


Modeling and Experimental Evaluation of Bending Behavior of Soft Pneumatic Actuators Made of Discrete Actuation Chambers.
In this article, we have established an analytical model to estimate the quasi-static bending displacement (i.e., angle) of the pneumatic actuators made of two different elastomeric silicones (Elastosil M4601 with a bulk modulus of elasticity of 262 kPa and Translucent Soft silicone with a bulk modulus of elasticity of 48 kPa-both experimentally determined) and of discrete chambers, partially separated from each other with a gap in between the chambers to increase the magnitude of their bending angle. The numerical bending angle results from the proposed gray-box model, and the corresponding experimental results match well that the model is accurate enough to predict the bending behavior of this class of pneumatic soft actuators. Further, by using the experimental bending angle results and blocking force results, the effective modulus of elasticity of the actuators is estimated from a blocking force model. The numerical and experimental results presented show that the bending angle and blocking force models are valid for this class of pneumatic actuators. Another contribution of this study is to incorporate a bistable flexible thin metal typified by a tape measure into the topology of the actuators to prevent the deflection of the actuators under their own weight when operating in the vertical plane.


Management of thyroid nodules detected at US: Society of Radiologists in Ultrasound consensus conference statement.
The Society of Radiologists in Ultrasound convened a panel of specialists from a variety of medical disciplines to come to a consensus on the management of thyroid nodules identified with thyroid ultrasonography (US), with particular focus on which nodules should be subjected to US-guided fine needle aspiration and which thyroid nodules need not be subjected to fine-needle aspiration. The panel met in Washington, DC, October 26-27, 2004, and created this consensus statement. The recommendations in this consensus statement, which are based on analysis of the current literature and common practice strategies, are thought to represent a reasonable approach to thyroid nodular disease.


An Adenine Code for DNA: A Second Life for N6-Methyladenine.
DNA N6-methyladenine (6mA) protects against restriction enzymes in bacteria. However, isolated reports have suggested additional activities and its presence in other organisms, such as unicellular eukaryotes. New data now find that 6mA may have a gene regulatory function in green alga, worm, and fly, suggesting m6A as a potential "epigenetic" mark.


Biosensors coated with sulfated polysaccharides for the detection of hepatocyte growth factor/scatter factor in cell culture medium.
Process control methods for cell culture bioreactors include on-line monitoring of protein concentrations. Bioreactor samples typically contain high amounts of different proteins. The direct detection of a single protein in this complex medium is a challenging task within the development of biosensors with label-free detection. We introduce the development of a mass-sensitive biosensor based on surface acoustic waves (SAW) for the detection of hepatocyte growth factor/scatter factor (HGF/SF) in the serum containing medium of a miniaturized bioreactor for culturing hepatocytes. The specificity of the biosensor was obtained following two approaches. In the first approach, antibodies against HGF (anti-HGF) were immobilized covalently via an intermediate layer of dicarboxy polyethylene glycol on the biosensor surface. In the second approach, dextran sulfate and fucoidan were used as sensor coatings exploiting the fact that HGF binds specifically to those sulfated polysaccharides. Performing HGF assays, similar results were obtained using biosensors coated with dextran sulfate and biosensors coated with anti-HGF. Even higher sensor signals were obtained using biosensors coated with fucoidan, particularly at 37°C. Therefore, biosensor coatings based on biospecific sulfated polysaccharides offer a simple and cost-saving alternative compared to the commonly used coating with antibodies.


Differences in substance use, psychosocial characteristics and HIV-related sexual risk behavior between Black men who have sex with men only (BMSMO) and Black men who have sex with men and women (BMSMW) in six US cities.
We assessed associations in substance use, psychosocial characteristics, and HIV-related sexual risk behaviors, comparing characteristics of Black men who only have sex with other men only (BMSMO; n = 839) to Black men who have sex with men and women (BMSMW; n = 590). The study analyzed baseline data from the HIV Prevention Trials Network Brothers Study (HPTN 061), a feasibility study of a multi-component intervention for Black MSM in six US cities. Bivariate analyses compared BMSMO to BMSMW along demographics, substance use, psychosocial characteristics, and HIV-related sexual risk behaviors. Logistic regression models then assessed multivariable associations between being BMSMW and the odds of engaging in HIV-related sexual risk behaviors. Adjusted analyses revealed that BMSMW remained more likely to have unprotected anal intercourse while under the influence of alcohol (AOR: 1.45; 95 % CI:1.11-1.90) and were more likely to receive money/drugs for sex (AOR: 2.11; 95 % CI:1.48-3.03), compared to BMSMO. Substance use is an important factor to be considered when developing risk-reduction interventions for BMSMW. Structural interventions that address factors that may contribute to exchange sex among these men are also warranted.


A systematic literature mapping and meta-analysis of animal-based traits as indicators of production diseases in pigs.
The choice of animal-based traits to identify and deal with production diseases is often a challenge for pig farmers, researchers and other related professionals. This systematic review focused on production diseases, that is, the diseases that arise from management practices, affecting the digestive, locomotory and respiratory system of pigs. The aim was to classify all traits that have been measured and conduct a meta-analysis to quantify the impact of diseases on these traits so that these can be used as indicators for intervention. Data were extracted from 67 peer-reviewed publications selected from 2339 records. Traits were classified as productive (performance and carcass composition), behavioural, biochemical and molecular traits. A meta-analysis based on mixed models was performed on traits assessed more than five times across studies, using the package metafor of the R software. A total of 524 unique traits were recorded 1 to 31 times in a variety of sample material including blood, muscle, articular cartilage, bone or at the level of whole animal. No behavioural traits were recorded from the included experiments. Only 14 traits were measured on more than five occasions across studies. Traits within the biochemical, molecular and productive trait groups were reported most frequently in the published literature and were most affected by production diseases; among these were some cytokines (interleukin (IL) 1-β, IL6, IL8 and tumour necrosis factor-α), acute phase proteins (haptoglobin) and daily weight gain. Quantification of the influence of factors relating to animal characteristics or husbandry practices was not possible, due to the low frequency of reporting throughout the literature. To conclude, this study has permitted a holistic assessment of traits measured in the published literature to study production diseases occurring in various stages of the production cycle of pigs. It shows the lack of consensus and common measurements of traits to characterise production diseases within the scientific literature. Specific traits, most of them relating to performance characteristics or immunological response of pigs, are proposed for further study as potential tools for the prognosis and study of production diseases.


Targeted knockdown of Tim3 by short hairpin RNAs improves the function of anti-mesothelin CAR T cells.
T-cell immunoglobulin mucin 3 (Tim3) is an immune checkpoint receptor that plays a central role in chimeric antigen receptor (CAR) T cell exhaustion within the tumor microenvironment. This study was aimed to evaluate the effects of targeted-knockdown of Tim3 on the antitumor function of anti-mesothelin (MSLN)-CAR T cells. To knockdown Tim3 expression, three different shRNA sequences specific to different segments of the human Tim3 gene were designed and co-inserted with an anti-MSLN-CAR transgene into lentiviral vectors. To investigate the efficacy of Tim3 targeting in T cells, expression of Tim3 was assessed before and after antigen stimulation. Afterwards, cytotoxic effects, proliferative response and cytokine production of MSLN-CAR T cells and Tim3-targeted MSLN-CAR T cells were analyzed. Our results showed that activation of T cells and MSLN-CAR T cells led to up-regulation of Tim3. Tim3 knockdown significantly decreased its expression in different groups of MSLN-CAR T cells. Tim3 knockdown significantly improved cytotoxic function, cytokine production and proliferation capacity of MSLN-CAR T cells. Our findings indicate that targeted knockdown of Tim3 allows tumor-infiltrating CAR T cells that would otherwise be inactivated to continue to expand and carry out effector functions, thereby altering the tumor microenvironment from immunosuppressive to immunosupportive via mitigated Tim3 signaling.


Receptor editing in self-reactive bone marrow B cells.
A central paradigm of immunology is clonal selection: lymphocytes displaying clonally distributed antigen receptors are generated and subsequently selected by antigen for growth or elimination. Here we show that in mice transgenic for anti-H-2Kk,b antibody genes, in which a homogeneous clone of developing B cells can be analyzed for the outcome of autoantigen encounter, surface immunoglobulin M+/idiotype+ immature B cells binding to self-antigens in the bone marrow are induced to alter the specificity of their antigen receptors. Transgenic bone marrow B cells encountering membrane-bound Kb or Kk proteins modify their receptors by expressing the V(D)J recombinase activator genes and assembling endogenously encoded immunoglobulin light chain variable genes. This (auto)antigen-directed change in the specificity of newly generated lymphocytes is termed receptor editing.


Delivery outcome after maternal use of antidepressant drugs in pregnancy: an update using Swedish data.
Concerns have been expressed about possible adverse effects of the use of antidepressant medication during pregnancy, including risk for neonatal pathology and the presence of congenital malformations. Data from the Swedish Medical Birth Register (MBR) from 1 July 1995 up to 2007 were used to identify women who reported the use of antidepressants in early pregnancy or were prescribed antidepressants during pregnancy by antenatal care: a total of 14 821 women with 15 017 infants. Maternal characteristics, maternal delivery diagnoses, infant neonatal diagnoses and the presence of congenital malformations were compared with all other women who gave birth, using the Mantel-Haenszel technique and with adjustments for certain characteristics. There was an association between antidepressant treatment and pre-existing diabetes and chronic hypertension but also with many pregnancy complications. Rates of induced delivery and caesarean section were increased. The preterm birth rate was increased but not that of intrauterine growth retardation. Neonatal complications were common, notably after tricyclic antidepressant (TCA) use. An increased risk of persistent pulmonary hypertension of the newborn (PPHN) was verified. The congenital malformation rate was increased after TCAs. An association between use of paroxetine and congenital heart defects was verified and a similar effect on hypospadias was seen. Women using antidepressants during pregnancy and their newborns have increased pathology. It is not clear how much of this is due to drug use or underlying pathology. Use of TCAs was found to carry a higher risk than other antidepressants and paroxetine seems to be associated with a specific teratogenic property.


Temporal prey distribution affects the competitive ability of parasitized sticklebacks.
Parasitized animals are often reported to have a reduced competitive ability in experimental studies designed to examine foraging success under a specific type of competitive interaction; however, since animals compete under a range of competition regimes in natural situations, and because success is likely to require different foraging skills under each, it is unclear whether infected animals should be equally poor competitors under all competitive scenarios. We studied the foraging success of three-spined sticklebacks, Gasterosteus aculeatus, infected with plerocercoids of a cestode, Schistocephalus solidus, in competition with uninfected conspecifics. When pairs of differentially infected sticklebacks were presented with sequentially introduced items, the numbers of available prey taken by infected and uninfected competitors did not differ significantly, although nonparasitized fish were more successful at taking items over which there was direct competition. In contrast, when prey items were presented simultaneously in a locally dense patch, nonparasitized fish ingested significantly more of the available food than their infected counterparts: an apparent consequence of their greater ability to take items in rapid succession. Our results show that the type of competition conditions generated as a result of specific prey distribution patterns plays a role in determining the relative foraging success of parasitized sticklebacks, and suggest that this may have consequences for the distribution of different infection classes in natural, heterogeneous environments. (c) 1998 The Association for the Study of Animal Behaviour.


A cognitive-perceptual approach to conceptualizing speech intelligibility deficits and remediation practice in hypokinetic dysarthria.
Hypokinetic dysarthria is a common manifestation of Parkinson's disease, which negatively influences quality of life. Behavioral techniques that aim to improve speech intelligibility constitute the bulk of intervention strategies for this population, as the dysarthria does not often respond vigorously to medical interventions. Although several case and group studies generally support the efficacy of behavioral treatment, much work remains to establish a rigorous evidence base. This absence of definitive research leaves both the speech-language pathologist and referring physician with the task of determining the feasibility and nature of therapy for intelligibility remediation in PD. The purpose of this paper is to introduce a novel framework for medical practitioners in which to conceptualize and justify potential targets for speech remediation. The most commonly targeted deficits (e.g., speaking rate and vocal loudness) can be supported by this approach, as well as underutilized and novel treatment targets that aim at the listener's perceptual skills.


Rapid fabrication of miniature lens arrays by four-axis single point diamond machining.
A novel method for fabricating lens arrays and other non-rotationally symmetric free-form optics is presented. This is a diamond machining technique using 4 controlled axes of motion - X, Y, Z, and C. As in 3-axis diamond micro-milling, a diamond ball endmill is mounted to the work spindle of a 4-axis ultra-precision computer numerical control (CNC) machine. Unlike 3-axis micro-milling, the C-axis is used to hold the cutting edge of the tool in contact with the lens surface for the entire cut. This allows the feed rates to be doubled compared to the current state of the art of micro-milling while producing an optically smooth surface with very low surface form error and exceptionally low radius error.


[Does garlic influence rheologic properties and blood flow in progressive systemic sclerosis?].
According to traditional European naturopathy garlic is an agent that increases perfusion. In studies with healthy subjects and in-vitro research garlic has shown influences on erythrocyte and thrombocyte aggregation as well as on vasoregulation. However, data on its effects in clinical populations are still lacking. Garlic may be useful for systemic sclerosis which is characterised by impaired perfusion that often cannot sufficiently be influenced by standard treatment. We investigated if dried garlic powder can influence rheologic properties and vasomotor function in systemic sclerosis. During a randomised, double blind pilot study, 20 female inpatients with systemic sclerosis received a 7 day add-on therapy with either 900 mg dried garlic powder or placebo. Rheologic properties (erythrocyte aggregation, ADP-induced thromboycyte aggregation, plasma viscosity, fibrinogenous plasma level, blood sedimentation rate) were assessed initially as well as after 1 and 7 days of treatment. Vasomotor function was evaluated using near-infrared red photoplethysmography, a new diagnostic tool to assess microcirculation. Furthermore, acral skin temperature was measured. After 7 days, only the verum treatment had induced a significant reduction of ADP-induced thrombocyte aggregation and a decrease in erythrocyte aggregation. Results showed no significant effects on vasomotor function, but an immediate effect of garlic on acral skin temperature. According to the 'Qualitatenlehre' of traditional European naturopathy, garlic is classified as a 'heating agent'. Our results suggest that the improvement of rheologic properties could be a possible biological correlate for this. Although further research is required, we conclude garlic could be a rational add-on therapy in the 'Kaltekrankheit' ('cold disease') of systemic sclerosis.


Testosterone and prostate cancer: an evidence-based review of pathogenesis and oncologic risk.
Testosterone plays a central role in male development and health. Likewise, androgen deficiency, or hypogonadism, is associated with a variety of symptoms including decreased energy, diminished libido and erectile dysfunction, among others. Male androgen levels steadily decline with age, and, in a subset of symptomatic older men, can result in late-onset hypogonadism (LOH). Over the last decade, increased awareness of hypogonadism among patients and providers has led to a significant rise in the use of testosterone replacement therapy (TRT) for hypogonadism, and especially in LOH. Accompanying the rise in TRT are concerns of potential adverse effects, including cardiovascular risks and the promotion of prostate cancer. The 'androgen hypothesis' asserts that prostate cancer development and progression is driven by androgens, and thus TRT has the theoretical potential to drive prostate cancer development and progression. In this review, we examine existing data surrounding testosterone and prostate cancer. There is significant evidence that androgens promote prostate cancer in experimental systems. However, there is no clear evidence that elevations in endogenous testosterone levels promote the development of prostate cancer in humans. As a result of experimental and historical data on the progression of prostate cancer following TRT, there has been widespread belief that TRT will promote disease progression in prostate cancer patients. Despite these fears, there are a growing number of studies demonstrating no increase in prostate cancer incidence among men on TRT. Furthermore, in studies involving a small number of patients, there has been no discernable increase in disease progression in prostate cancer patients on TRT. While data from large, prospective, randomized, controlled trials are absent, TRT in select prostate cancer patients is likely safe. In the end, the use of TRT in prostate cancer patients is still considered experimental and should only be offered after well-informed shared decision making and with close monitoring.


Metabolism of anabolic androgenic steroids.
Anabolic androgenic steroids (AAS) are misused to a high extent in sports by athletes to improve their physical performance. Sports federations consider the use of these drugs in sports as doping. The misuse of AAS is controlled by detection of the parent AAS (when excreted into urine) and (or) their metabolites in urine of athletes. I present a review of the metabolism of AAS. Testosterone is the principal androgenic steroid and its metabolism is compared with that of AAS. The review is divided into two parts: the general metabolism of AAS, which is separated into phase I and phase II metabolism and includes a systematic discussion of metabolic changes in the steroid molecule according to the regions (A-D rings), and the specific metabolism of AAS, which presents the metabolism of 26 AAS in humans.


The salt-stress signal transduction pathway that activates the gpx1 promoter is mediated by intracellular H2O2, different from the pathway induced by extracellular H2O2.
Several genes encoding putative glutathione peroxidase have been isolated from a variety of plants, all of which show the highest homology to the phospholipid hydroperoxide isoform. Several observations suggest that the proteins are involved in biotic and abiotic stress responses. Previous studies on the regulation of gpx1, the Citrus sinensis gene encoding phospholipid hydroperoxide isoform, led to the conclusion that salt-induced expression of gpx1 transcript and its encoded protein is mediated by oxidative stress. In this paper, we describe the induction of gpx1 promoter:uidA fusions in stable transformants of tobacco (Nicotiana tabacum) cultured cells and plants. We show that the induction of gpx1 by salt and oxidative stress occurs at the transcriptional level. gpx1 promoter analysis confirmed our previous assumption that the salt signal is transduced via oxidative stress. We used induction of the fusion construct to achieve better insight into, and to monitor salt-induced oxidative stress. The gpx1 promoter responded preferentially to oxidative stress in the form of hydrogen peroxide, rather than to superoxide-generating agents. Antioxidants abolished the salt-induced expression of gpx1 promoter, but were unable to eliminate the induction by H2O2. The commonly employed NADPH-oxidase inhibitor diphenyleneiodonium chloride and catalase inhibited the H2O2-induced expression of gpx1 promoter, but did not affect its induction by salt. Our results led us to conclude that salt induces oxidative stress in the form of H2O2, its production occurs in the intracellular space, and its signal transduction pathway activating the gpx1 promoter is different from the pathway induced by extracellular H2O2.


High prevalence of pfcrt-CVIET haplotype in isolates from asymptomatic and symptomatic patients in south-central Oromia, Ethiopia.
As a result of extensive chloroquine resistance (CQR) in Plasmodium falciparum in late 1990s, Ethiopia replaced CQ with sulphadoxine-pyrimethamine (SP) as first-line drug, which in turn was replaced by artemisinin combination therapy in 2004. Plasmodium falciparum resistance to CQ is determined by the mutation at K76T of the P. falciparum chloroquine resistance transporter (pfcrt) gene. Understanding diversity in the P. falciparum genome is crucial since it has the potential to influence important phenotypes of the parasite such as drug resistance. Limited data is available regarding the type of pfcrt mutant allelic type, the effect of CQ withdrawal and diversity of the parasite population in south-central Oromia, Ethiopia. Finger-pricked blood spotted on Whatman 3MM filter papers were collected from falciparum malaria patients. Parasite DNA was extracted from individual blood spots on the filter papers. The presence of K76T mutations was determined using nested PCR for all isolates. Complete sequencing of mutations in pfcrt 72-76 was done for a set of randomly selected resistant isolates. Four microsatellite (MS) markers were analysed to determine the heterozygosity. Although CQ was withdrawn for more than a decade, 100% of the parasites still carried the pfcrt K76T mutation. All isolates were mutant at the K76T polymorphism. Based on combinations of MS markers, seven different Ethiopian CQR variants (E1-E7) were identified. Heterozygosity (H(e)) for MS flanking the pfcrt chloroquine resistance allele ranged from 0.00 (mscrt -29, -29.268 kb) to 0.21 (mscrt -2, -2.814 kb). H(e) ranged from 0.00 (msint 3, 0 kb) to 0.19 (msint 2, 0 kb) for MS within the pfcrt gene. Both intronic and MS flanking the pfcrt gene showed low levels of diversity. pfcrt CQR allele seems to be fixed in the study area. Of the different haplotypes associated with CQR, only the CVIET genotype was identified. No reversal to the wild-type has occurred in Ethiopia unlike in many Africa countries where CQR parasites declined after cessation of CQ use. Decreased diversity in CQR isolates surrounding pfcrt suggests CQ selection and homogenization among CQR parasite population. While mutation in msint 3 and mscrt -29 of the mutant pfcrt allele is being fixed, it seems that mutations in msint 2 and mscrt -2 are still evolving and may indicate the start of re-diversification of the population from a fixed 76 T population.


Inhibition of indoleamine 2,3-dioxygenase (IDO) enhances elimination of virus-infected macrophages in an animal model of HIV-1 encephalitis.
Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme in the kynurenine pathway of tryptophan metabolism. IDO activity is linked with immunosuppression by its ability to inhibit lymphocyte proliferation, and with neurotoxicity through the generation of quinolinic acid and other toxins. IDO is induced in macrophages by HIV-1 infection, and it is up regulated in macrophages in human brain tissue with HIV-1 encephalitis (HIVE). Using a model of HIVE, we investigated whether IDO inhibitor 1-methyl-d-tryptophan (1-MT) could affect the generation of cytotoxic T lymphocytes (CTLs) and clearance of virus-infected macrophages from the brain. Severe combined immunodeficient mice were reconstituted with human peripheral blood lymphocytes, and encephalitis was induced by intracranial injection of autologous HIV-1-infected monocyte-derived macrophages (MDMs). Animals treated with 1-MT demonstrated increased numbers of human CD3+, CD8+, CD8+/interferon-gamma+ T cells, and HIV-1(gag/pol)-specific CTLs in peripheral blood compared with controls. At week 2 after MDM injection in the basal ganglia, mice treated with 1-MT showed a 2-fold increase in CD8+ T lymphocytes in the areas of the brain containing HIV-1-infected MDMs compared with untreated controls. By week 3, 1-MT-treated mice showed 89% reduction in HIV-infected MDMs in brain as compared with controls. Thus, manipulation of immunosuppressive IDO activity in HIVE may enhance the generation of HIV-1-specific CTLs, leading to elimination of HIV-1-infected macrophages in brain.


Intramyocardial arterial cushions of coronary vessels in animals and humans: morphology, occurrence and relation to heart disease.
The existence of coronary endoarterial cushions (CEC) in the human heart as nonpathological, functional entities has been debated, and CEC have been sparsely reported in animals. Arterial cushions are localized thickenings that protrude into the lumen of specific arteries. We have identified CEC in the rhesus monkey, dog, sheep, goat, pig, rabbit and rat, and in the human heart. Two distinct types are described: the ovoid CEC arranged singly, in pairs, or in groups of three to four, and the less common polypoid CEC seen primarily in humans. The highest incidence of CEC in rabbits and humans was in the left ventricle in arteries 150-488 microns in diameter. Light and electron microscopy demonstrated intimal location with smooth muscle cells surrounded by ground substance, collagen and elastin fibers in a highly organized pattern. Nerve fibers identified by their immunoreactivity with antiserum to the vasodilatory calcitonin-gene-related peptide contacted the CEC along the tunica media and were occasionally seen within CEC. Arrangement and histological composition of CEC suggest a role in the regulation of local blood flow and myocardial perfusion. In human hearts, the CEC density index correlated highly with the degree of heart disease. In subjects with high heart disease rating, increased connective tissue, lipid-like infiltration and calcification was seen within CEC, and foam cells were present in CEC of obese rabbits. This suggests that CEC in coronary arteries could be predisposed sites of atherosclerosis, and that injured CEC can cause coronary artery spasm and ischemia. We conclude that CEC occur in animals and humans as innervated intimal smooth muscle cushions that might have a role in myocardial perfusion and heart disease.


The relationship between phonological and morphological deficits in Broca's aphasia: further evidence from errors in verb inflection.
A previous study of 10 patients with Broca's aphasia demonstrated that the advantage for producing the past tense of irregular over regular verbs exhibited by these patients was eliminated when the two sets of past-tense forms were matched for phonological complexity (Bird, Lambon Ralph, Seidenberg, McClelland, & Patterson, 2003). The interpretation given was that a generalised phonological impairment was central to the patients' language deficits, including their poor performance on regular past tense verbs. The current paper provides further evidence in favour of this hypothesis, on the basis of a detailed analysis of the errors produced by these same 10 patients in reading, repetition, and sentence completion for a large number of regular, irregular, and nonce verbs. The patients' predominant error types in all tasks and for all verb types were close and distant phonologically related responses. The balance between close and distant errors varied along three continua: the severity of the patient (more distant errors produced by the more severely impaired patients); the difficulty of the task (more distant errors in sentence completion>reading>repetition); the difficulty of the item (more distant errors for novel word forms than real verbs). A position analysis for these phonologically related errors revealed that vowels were most likely to be preserved and that consonant onsets and offsets were equally likely to be incorrect. Critically, the patients' errors exhibited a strong tendency to simplify the phonological form of the target. These results are consistent with the notion that the patients' relatively greater difficulty with regular past tenses reflects a phonological impairment that is sensitive to the complexity of spoken forms.


Prostaglandins E2 and F2 alpha are not involved in the monocytic-product (interleukin-1)-induced stimulation of hepatic fibrinogen synthesis in rats.
1. Monocytic products, especially interleukin-1 (IL-1), play an important role in the acute-phase response. Prostaglandins have been shown to act as second messengers in several physiological alterations of the acute-phase response, such as fever, muscle wasting and immunoregulation. The present study was undertaken to determine the role of prostaglandins in the monocytic-product-induced stimulation of the hepatic synthesis of fibrinogen, a well-known acute-phase protein. 2. Prostaglandin (PG) E2, PGF2 alpha and 16,16-dimethyl-PGE2 did not stimulate fibrinogen synthesis and fibrinogen polypeptide mRNA content when administered intraperitoneally to rats or when added to monolayer cultures of rat hepatocytes. 3. Cyclo-oxygenase inhibitors did not abolish the stimulation of fibrinogen synthesis and its mRNA content induced by monocytic products in vivo or in vitro. 4. These findings indicate that the enhanced synthesis of fibrinogen induced by monocytic products (including IL-1) during the acute-phase response is not mediated by prostaglandins or other products of the cyclo-oxygenase pathway of arachidonic acid.


Ocean warming slows coral growth in the central Red Sea.
Sea surface temperature (SST) across much of the tropics has increased by 0.4 degrees to 1 degrees C since the mid-1970s. A parallel increase in the frequency and extent of coral bleaching and mortality has fueled concern that climate change poses a major threat to the survival of coral reef ecosystems worldwide. Here we show that steadily rising SSTs, not ocean acidification, are already driving dramatic changes in the growth of an important reef-building coral in the central Red Sea. Three-dimensional computed tomography analyses of the massive coral Diploastrea heliopora reveal that skeletal growth of apparently healthy colonies has declined by 30% since 1998. The same corals responded to a short-lived warm event in 1941/1942, but recovered within 3 years as the ocean cooled. Combining our data with climate model simulations by the Intergovernmental Panel on Climate Change, we predict that should the current warming trend continue, this coral could cease growing altogether by 2070.


Effects of Deep Brain Stimulation on the Lived Experience of Obsessive-Compulsive Disorder Patients: In-Depth Interviews with 18 Patients.
Deep Brain Stimulation (DBS) is a relatively new, experimental treatment for patients suffering from treatment-refractory Obsessive Compulsive Disorder (OCD). The effects of treatment are typically assessed with psychopathological scales that measure the amount of symptoms. However, clinical experience indicates that the effects of DBS are not limited to symptoms only: patients for instance report changes in perception, feeling stronger and more confident, and doing things unreflectively. Our aim is to get a better overview of the whole variety of changes that OCD patients experience during DBS treatment. For that purpose we conducted in-depth, semi-structured interviews with 18 OCD patients. In this paper, we present the results from this qualitative study. We list the changes grouped in four domains: with regard to (a) person, (b) (social) world, (c) characteristics of person-world interactions, and (d) existential stance. We subsequently provide an interpretation of these results. In particular, we suggest that many of these changes can be seen as different expressions of the same process; namely that the experience of anxiety and tension gives way to an increased basic trust and increased reliance on one's abilities. We then discuss the clinical implications of our findings, especially with regard to properly informing patients of what they can expect from treatment, the usefulness of including CBT in treatment, and the limitations of current measures of treatment success. We end by making several concrete suggestions for further research.


Targeted Proteomics Approach Toward Understanding the Role of the Mitochondrial Protease FTSH4 in the Biogenesis of OXPHOS During Arabidopsis Seed Germination.
Seed germination provides an excellent model to study the process of mitochondrial biogenesis. It is a complex and strictly regulated process which requires a proper biogenesis of fully active organelles from existing promitochondrial structures. We have previously reported that the lack of the inner mitochondrial membrane protease FTSH4 delayed Arabidopsis seed germination. Here, we implemented a targeted mass spectrometry-based approach, Multiple Reaction Monitoring (MRM), with stable-isotope-labeled standard peptides for increased sensitivity, to quantify mitochondrial proteins in dry and germinating wild-type and ftsh4 mutant seeds, lacking the FTSH4 protease. Using total seed protein extracts we measured the abundance of the peptide targets belonging to the OXPHOS complexes, AOX1A, transport, and inner membrane scaffold as well as mitochondrial proteins that are highly specific to dry and germinating seeds. The MRM assay showed that the abundance of these proteins in ftsh4 did not differ substantially from that observed in wild-type at the level of dry seed and after stratification, but we observed a reduction in protein abundance in most of the examined OXPHOS subunits in the later stages of germination. These changes in OXPHOS protein levels in ftsh4 mutants were accompanied by a lower cytochrome pathway activity as well as an increased AOX1A amount at the transcript and protein level and alternative pathway activity. The analyses of the steady-state transcript levels of mitochondrial and nuclear genes encoding OXPHOS subunits did not show significant difference in their amount, indicating that the observed changes in the OXPHOS occurred at the post-transcriptional level. At the time when ftsh4 seeds were fully germinated, the abundance of the OXPHOS proteins in the mutant was either slightly lowered or comparable to these amounts in wild-type seeds at the similar developmental stage. By the implementation of an integrative approach combining targeted proteomics, quantitative transcriptomics, and physiological studies we have shown that the FTSH4 protease has an important role in the biogenesis of OXPHOS and thus biogenesis of mitochondria during germination of Arabidopsis seeds.


Limited Sampling Strategy for the Estimation of Mycophenolic Acid and its Acyl Glucuronide Metabolite Area under the Concentration-Time Curve in Japanese Lung Transplant Recipients.
The dose of mycophenolate mofetil (MMF) used to prevent rejection after lung transplantation is often adjusted based on the 12-hour area under the concentration-time curve (AUC0-12) of mycophenolic acid (MPA). A limited sampling strategy (LSS) is useful to define the pharmacokinetic (PK) profiles of MPA and mycophenolic acid acyl glucuronide (AcMPAG). Therefore, this study aimed to design a LSS based on multiple linear regression for estimating the AUC0-12 of MPA and AcMPAG at the minimum blood sampling points in Japanese lung transplant patients with concomitant tacrolimus. Forty-five lung transplantation recipients were enrolled in a PK study of MPA, mycophenolic acid glucuronide (MPAG), and AcMPAG. The plasma MPA, MPAG, and AcMPAG concentrations were determined just before and at 0.5, 1, 2, 4, 8, and 12 hours after dosing. The AUC0-12 of MPA and AcMPAG was calculated using a linear trapezoidal rule from the plasma concentration of each blood sampling time. LSS was used to develop models for estimated AUC in the model group (n = 23) and was evaluated in the validation group (n = 22). The best three time-point equation was 4.04 + 1.64·C1 + 3.08·C4 + 5.17·C8 for MPA, and -0.13 + 3.01·C1 + 3.51·C4 + 5.74·C8 for AcMPAG. The prediction errors (PE) and the absolute prediction errors (APE) were within the clinically acceptable ± 5% and 15% range, respectively (MPA: PE = 2.00%, APE = 11.66%, AcMPAG: PE = 0.98%, APE = 14.69%). The percentage of estimated AUC0-12 within ± 15% of the observed AUC0-12 was 77.27% for MPA and 81.82% for AcMPAG. LSS using three time-point (C1, C4, and C8) provides the most reliable and accurate simultaneous estimation of the AUC0-12 of MPA and AcMPAG in Japanese lung transplant patients.


Improving the Use of Mortality Data in Public Health: A Comparison of Garbage Code Redistribution Models.
Objectives. To describe and compare 3 garbage code (GC) redistribution models: naïve Bayes classifier (NB), coarsened exact matching (CEM), and multinomial logistic regression (MLR).Methods. We analyzed Taiwan Vital Registration data (2008-2016) using a 2-step approach. First, we used non-GC death records to evaluate 3 different prediction models (NB, CEM, and MLR), incorporating individual-level information on multiple causes of death (MCDs) and demographic characteristics. Second, we applied the best-performing model to GC death records to predict the underlying causes of death. We conducted additional simulation analyses for evaluating the predictive performance of models.Results. When we did not account for MCDs, all 3 models presented high average misclassification rates in GC assignment (NB, 81%; CEM, 86%; MLR, 81%). In the presence of MCD information, NB and MLR exhibited significant improvement in assignment accuracy (19% and 17% misclassification rate, respectively). Furthermore, CEM without a variable selection procedure resulted in a substantially higher misclassification rate (40%).Conclusions. Comparing potential GC redistribution approaches provides guidance for obtaining better estimates of cause-of-death distribution and highlights the significance of MCD information for vital registration system reform.


Peripheral and central venous blood glucose concentrations in dogs and cats with acute arterial thromboembolism.
Acute limb paralysis because of arterial thromboembolism (ATE) occurs in cats and less commonly in dogs. ATE is diagnosed based on physical examination findings and, occasionally, advanced imaging. Peripheral, affected limb venous glucose concentration is decreased in ATE, whereas its systemic concentration is within or above reference interval. Client-owned cats and dogs were divided into 3 respective groups: acute limb paralysis because of ATE (22 cats and 9 dogs); acute limb paralysis secondary to orthopedic or neurologic conditions (nonambulatory controls; 10 cats and 11 dogs); ambulatory animals presented because of various diseases (ambulatory controls; 10 cats and 9 dogs). Prospective observational, clinical study. Systemic and local (affected limb) blood glucose concentrations were measured. Their absolute and relative differences (ΔGlu and %ΔGlu, respectively) were compared among groups. ΔGlu and %ΔGlu were significantly higher in the ATE cats and dogs groups, compared to both of their respective controls (P < .0001 and P < .001, respectively). No significant differences were observed between the control groups. Receiver operator characteristics analysis of ΔGlu and %ΔGlu as predictors of ATE had area under the curve of 0.96 and 0.99 in cats, respectively, and 1.00 and 1.00, in dogs, respectively. ΔGlu cutoffs of 30 mg/dL and 16 mg/dL, in cats and dogs, respectively, corresponded to sensitivity and specificity of 100% and 90% in cats, respectively, and 100% in dogs. ΔGlu and %ΔGlu are accurate, readily available, diagnostic markers of acute ATE in paralyzed cats and dogs.


Genomic prediction models for grain yield of spring bread wheat in diverse agro-ecological zones.
Genomic and pedigree predictions for grain yield and agronomic traits were carried out using high density molecular data on a set of 803 spring wheat lines that were evaluated in 5 sites characterized by several environmental co-variables. Seven statistical models were tested using two random cross-validations schemes. Two other prediction problems were studied, namely predicting the lines' performance at one site with another (pairwise-site) and at untested sites (leave-one-site-out). Grain yield ranged from 3.7 to 9.0 t ha(-1) across sites. The best predictability was observed when genotypic and pedigree data were included in the models and their interaction with sites and the environmental co-variables. The leave-one-site-out increased average prediction accuracy over pairwise-site for all the traits, specifically from 0.27 to 0.36 for grain yield. Days to anthesis, maturity, and plant height predictions had high heritability and gave the highest accuracy for prediction models. Genomic and pedigree models coupled with environmental co-variables gave high prediction accuracy due to high genetic correlation between sites. This study provides an example of model prediction considering climate data along-with genomic and pedigree information. Such comprehensive models can be used to achieve rapid enhancement of wheat yield enhancement in current and future climate change scenario.


Self-harm in Oxford, England: epidemiological and clinical trends, 1996-2010.
Self-harm is a major healthcare problem and changes in its prevalence and characteristics can have important implications for clinical services, treatment and prevention. We analysed data on all self-harm presentations to the general hospital in Oxford between 1996 and 2010 using the Oxford Monitoring System for Self-harm. We investigated trends in prevalence, methods and repetition of self-harm, and receipt of psychosocial assessment. For patients receiving a psychosocial assessment, we investigated trends in alcohol use and misuse, prior psychiatric treatment and self-harm, problems, and suicidal intent. Rates of self-harm rose in both genders between 1996 and 2002/2003, after which they declined. There was evidence of a possible cohort effect, whereby higher rates in younger males in earlier years transferred over time to older age groups. Self-cutting, hanging and jumping became more common. Paracetamol was involved in 44.9 % of all self-poisoning episodes. Overdoses of antidepressants (particularly selective serotonin reuptake inhibitors) increased, as did those of mood stabilisers, non-opiate analgesics excluding paracetamol (e.g. non-steroidal anti-inflammatory drugs), and non-ingestible poisons. Alcohol use in relation to self-harm and alcohol-related problems became more common, as did history of prior psychiatric treatment and, especially, of self-harm, and employment problems from 2008. Despite national guidance, the proportion of patients undergoing psychosocial assessment declined. Major changes in the extent and nature of self-harm occurred over the study period, some suggestive of increased psychopathology and others reflecting prescribing practices and changes in drinking patterns. The findings emphasise the need for psychosocial assessment following self-harm, to identify treatment needs and reduce repetition.