The impact of different aetiologies on the cognitive performance of frontal patients.
Neuropsychological group study methodology is considered one of the primary methods to further understanding of the organisation of frontal 'executive' functions. Typically, patients with frontal lesions caused by stroke or tumours have been grouped together to obtain sufficient power. However, it has been debated whether it is methodologically appropriate to group together patients with neurological lesions of different aetiologies. Despite this debate, very few studies have directly compared the performance of patients with different neurological aetiologies on neuropsychological measures. The few that did included patients with both anterior and posterior lesions. We present the first comprehensive retrospective comparison of the impact of lesions of different aetiologies on neuropsychological performance in a large number of patients whose lesion solely affects the frontal cortex. We investigated patients who had a cerebrovascular accident (CVA), high (HGT) or low grade (LGT) tumour, or meningioma, all at the post-operative stage. The same frontal 'executive' (Raven's Advanced Progressive Matrices, Stroop Colour-Word Test, Letter Fluency-S; Trail Making Test Part B) and nominal (Graded Naming Test) tasks were compared. Patients' performance was compared across aetiologies controlling for age and NART IQ scores. Assessments of focal frontal lesion location, lesion volume, global brain atrophy and non-specific white matter (WM) changes were undertaken and compared across the four aetiology. We found no significant difference in performance between the four aetiology subgroups on the 'frontal' executive and nominal tasks. However, we found strong effects of premorbid IQ on all cognitive tasks and robust effects of age only on the frontal tasks. We also compared specific aetiology subgroups directly, as previously reported in the literature. Overall we found no significant differences in the performance of CVA and tumour patients, or LGT and HGT patients or LGT, HGT and meningioma's on our four frontal tests. No difference was found with respect to the location of frontal lesions, lesion volume, global brain atrophy and non-specific WM changes between the subgroups. Our results suggest that the grouping of frontal patients caused by different aetiologies is a pragmatic, justified methodological approach that can help to further understanding of the organisation of frontal executive functions.


Rabbit Calvarial Defect Model for Customized 3D-Printed Bone Grafts.
Bone graft materials are commonly used to regenerate various bone defects, but their application is often limited because of the complex defect shape in various clinical conditions. Hence, customized bone grafts using three-dimensional (3D) printing techniques have been developed. However, conventional simple bone defect models are limited for evaluating the benefits and manufacturing accuracy of 3D-printed customized bone grafts. Thus, the aim of the present study was to develop a complex-shaped bone defect model. We designed an 8-shaped bony defect that consists of two simple circles attached to the rabbit calvarium. To determine the critical-sized defect (CSD) of the 8-shaped defects, 5.6- and 7-mm-diameter trephine burs were tested, and the 7-mm-diameter bur could successfully create a CSD, which was easily reproducible on the rabbit calvarium. The rate of new bone formation was 28.65% ± 8.63% at 16 weeks following creation of the defect. To confirm its efficacy for clinical use, the 8-shaped defect was created on a rabbit calvarium and 3D computed tomography (CT) was performed. A stereolithography file was produced using the CT data, and a 3D-printed polycaprolactone graft was fabricated. Using our 8-shaped defect model, we were able to modify the tolerances of the bone graft and calvarial defect to fabricate a more precise bone graft. Customized characteristics of the bone graft were then used to improve the accuracy of the bone graft. In addition, we confirmed the fitting ability of the 3D-printed graft during implantation of the graft. Our 8-shaped defect model on the rabbit calvarium using a 7.0-mm trephine bur may be a useful CSD model for evaluating 3D-printed graft materials.


Process mapping evaluation of medication reconciliation in academic teaching hospitals: a critical step in quality improvement.
Medication reconciliation (MedRec) has been a mandated or recommended activity in Canada, the USA and the UK for nearly 10 years. Accreditation bodies in North America will soon require MedRec for every admission, transfer and discharge of every patient. Studies of MedRec have revealed unintentional discrepancies in prescriptions but no clear evidence that clinically important outcomes are improved, leading to widely variable practices. Our objective was to apply process mapping methodology to MedRec to clarify current processes and resource usage, identify potential efficiencies and gaps in care, and make recommendations for improvement in the light of current literature evidence of effectiveness. Process engineers observed and recorded all MedRec activities at 3 academic teaching hospitals, from initial emergency department triage to patient discharge, for general internal medicine patients. Process maps were validated with frontline staff, then with the study team, managers and patient safety leads to summarise current problems and discuss solutions. Across all of the 3 hospitals, 5 general problem themes were identified: lack of use of all available medication sources, duplication of effort creating inefficiency, lack of timeliness of completion of the Best Possible Medication History, lack of standardisation of the MedRec process, and suboptimal communication of MedRec issues between physicians, pharmacists and nurses. MedRec as practised in this environment requires improvements in quality, timeliness, consistency and dissemination. Further research exploring efficient use of resources, in terms of personnel and costs, is required.


Epidemiology of human infections with avian influenza A(H7N9) virus in China.
The first identified cases of avian influenza A(H7N9) virus infection in humans occurred in China during February and March 2013. We analyzed data obtained from field investigations to describe the epidemiologic characteristics of H7N9 cases in China identified as of December 1, 2013. Field investigations were conducted for each confirmed case of H7N9 virus infection. A patient was considered to have a confirmed case if the presence of the H7N9 virus was verified by means of real-time reverse-transcriptase-polymerase-chain-reaction assay (RT-PCR), viral isolation, or serologic testing. Information on demographic characteristics, exposure history, and illness timelines was obtained from patients with confirmed cases. Close contacts were monitored for 7 days for symptoms of illness. Throat swabs were obtained from contacts in whom symptoms developed and were tested for the presence of the H7N9 virus by means of real-time RT-PCR. Among 139 persons with confirmed H7N9 virus infection, the median age was 61 years (range, 2 to 91), 71% were male, and 73% were urban residents. Confirmed cases occurred in 12 areas of China. Nine persons were poultry workers, and of 131 persons with available data, 82% had a history of exposure to live animals, including chickens (82%). A total of 137 persons (99%) were hospitalized, 125 (90%) had pneumonia or respiratory failure, and 65 of 103 with available data (63%) were admitted to an intensive care unit. A total of 47 persons (34%) died in the hospital after a median duration of illness of 21 days, 88 were discharged from the hospital, and 2 remain hospitalized in critical condition; 2 patients were not admitted to a hospital. In four family clusters, human-to-human transmission of H7N9 virus could not be ruled out. Excluding secondary cases in clusters, 2675 close contacts of case patients completed the monitoring period; respiratory symptoms developed in 28 of them (1%); all tested negative for H7N9 virus. Most persons with confirmed H7N9 virus infection had severe lower respiratory tract illness, were epidemiologically unrelated, and had a history of recent exposure to poultry. However, limited, nonsustained human-to-human H7N9 virus transmission could not be ruled out in four families.


Mössbauer Spectral Study of the Low-Temperature Electronic and Magnetic Properties of α-FePO4 and the Mixed Valence Iron(II/III) Phosphate SrFe3(PO4)3.
The Mössbauer spectra of trigonal α-FePO4, measured between 4.2 and 300 K, exhibit hyperfine parameters characteristic of high-spin iron(III) in a pseudotetrahedral oxygen environment. Between 24.5 and 300 K, the spectra show a paramagnetic quadrupole doublet and at 24.0 K the spectrum reveals the onset of antiferromagnetic exchange. At 4.2 and 16 K, a single magnetic sextet is observed with hyperfine fields of 51.36(1) and 42.74(1) T, respectively, with an angle, θ, of 90° between the principal axis of the electric field gradient tensor in the basal plane of the trigonal unit cell and the hyperfine field along the c axis. The spectra obtained between 21 and 18 K have been fitted with two equal-area magnetic sextets with θ angles of 25 and 85°, angles which indicate that the iron(III) magnetic moments are canted away from the c axis. The reduced hyperfine field versus reduced temperature plot indicates a departure from a Brillouin S = 5/2 behavior, as a result of some magnetostriction at the Néel temperature. The Mössbauer spectra of class 1 mixed-valence SrFe3(PO4)3, measured between 4.2 and 300 K, exhibit hyperfine parameters characteristic of two high-spin iron(II) ions and one high-spin iron(III) ion in a pseudooctahedral oxygen environment. At and above 40 K, the spectra show two paramagnetic quadrupole doublets, whereas at 39.0 K the spectrum reveals the onset of ferrimagnetic exchange. Between 4.2 and 30 K, the spectra have been fitted with two magnetic sextets with θ angles of 85 and 10° for the iron(II) and iron(III) sites, respectively. The reduced hyperfine field versus reduced temperature plots for the iron(II) and iron(III) sites show a distinct departure from Brillouin S = 2 and S = 5/2 behavior, respectively, a departure that suggests a first-order magnetic transition at 39.5(5) K with differing magnetostrictions at the iron(II) and iron(III) sites.


Structure, Stiffness and Substates of the Dickerson-Drew Dodecamer.
The Dickerson-Drew dodecamer (DD) d-[CGCGAATTCGCG]2 is a prototypic B-DNA molecule whose sequence-specific structure and dynamics have been investigated by many experimental and computational studies. Here, we present an analysis of DD properties based on extensive atomistic molecular dynamics (MD) simulations using different ionic conditions and water models. The 0.6-2.4-µs-long MD trajectories are compared to modern crystallographic and NMR data. In the simulations, the duplex ends can adopt an alternative base-pairing, which influences the oligomer structure. A clear relationship between the BI/BII backbone substates and the basepair step conformation has been identified, extending previous findings and exposing an interesting structural polymorphism in the helix. For a given end pairing, distributions of the basepair step coordinates can be decomposed into Gaussian-like components associated with the BI/BII backbone states. The nonlocal stiffness matrices for a rigid-base mechanical model of DD are reported for the first time, suggesting salient stiffness features of the central A-tract. The Riemann distance and Kullback-Leibler divergence are used for stiffness matrix comparison. The basic structural parameters converge very well within 300 ns, convergence of the BI/BII populations and stiffness matrices is less sharp. Our work presents new findings about the DD structural dynamics, mechanical properties, and the coupling between basepair and backbone configurations, including their statistical reliability. The results may also be useful for optimizing future force fields for DNA.


Subdural hematoma and lupus anticoagulants.
Patients with lupus anticoagulants do not typically have a bleeding tendency. However, a few reports of hemorrhage in patients with lupus anticoagulants in the absence of known risk factors for bleeding have been published, raising the question of an etiologic connection between lupus anticoagulants and certain types of hemorrhage. The presentation of three patients with subdural hematoma and lupus anticoagulants within only 1 year at our institutions and the report of two such patients in the literature led us to conduct a retrospective study to determine whether patients with lupus anticoagulants may have an increased risk for the development of subdural hematoma. All patients with a discharge diagnosis of nontraumatic subdural hematoma and lupus anticoagulant at three medical institutions between 1985 and 1996 were identified, and their medical histories and laboratory evaluations were reviewed. Of 733 patients with a discharge diagnosis of nontraumatic subdural hematoma, 5 were diagnosed as having a lupus anticoagulant (0.7%). All had known risk factors for the development of subdural hematoma: thrombocytopenia, hypoprothrombinemia, intracerebral venous hemorrhage, warfarin therapy, and advanced age with a history of a fall. This study suggests that presence of a lupus anticoagulant by itself is not associated with an increased incidence of nontraumatic subdural hematoma.


Cognitive and behavioural strategies for weight management in overweight adults: Results from the Oxford Food and Activity Behaviours (OxFAB) cohort study.
Though many overweight and obese adults attempt to lose weight without formal support, little is known about the strategies used in self-directed weight loss attempts. We set out to assess cognitive and behavioural strategies for weight loss and their associations with weight change. Prospective, web-based cohort study of overweight UK adults (BMI≥25kg/m2) trying to lose weight through behaviour change. Strategy use was assessed using the OxFAB questionnaire and evaluated (1) at the domain level, (2) through exploratory factor analysis, and (3) in a model of strategies deemed a priori to be "essential" to weight management. Associations with weight change at 3 months were tested using linear regression. 486 participants answered all questions; 194 reported weight at baseline and at 3 months (mean weight change -3.3kg (SD 4.1)). Greater weight loss was significantly associated with the motivational support domain (-2.4kg, 95% CI -4.4 to -0.4), dietary impulse control (from factor analysis) (-0.6kg, 95% CI -1.1 to -0.03), and weight loss planning and monitoring (from factor analysis) (-1.3kg, 95% CI -2.0 to -0.5). Higher scores in the model of essential behavioural strategies were significantly associated with greater weight loss (compared to participants using 6 or fewer of the 9 strategies, using 7 or more of the 9 strategies was associated with a 2.13kg greater weight loss (SE 0.58, p<0.001)). Despite heterogeneity in the strategies employed for weight loss, coherent patterns of behaviours emerged for individual participants, some of which were associated with greater weight loss, including strategies relating to dietary impulse control, weight loss planning and monitoring, motivational support, information seeking and self-monitoring. Trials could test the effect of promoting use of these patterns on weight loss.


Convalescent plasma use in the USA was inversely correlated with COVID-19 mortality.
The US Food and Drug Administration authorized COVID-19 convalescent plasma (CCP) therapy for hospitalized COVID-19 patients via the Expanded Access Program (EAP) and the Emergency Use Authorization (EUA), leading to use in about 500,000 patients during the first year of the pandemic for the USA. We tracked the number of CCP units dispensed to hospitals by blood banking organizations and correlated that usage with hospital admission and mortality data. CCP usage per admission peaked in Fall 2020, with more than 40% of inpatients estimated to have received CCP between late September and early November 2020. However, after randomized controlled trials failed to show a reduction in mortality, CCP usage per admission declined steadily to a nadir of less than 10% in March 2021. We found a strong inverse correlation (r = -0.52, p=0.002) between CCP usage per hospital admission and deaths occurring 2 weeks after admission, and this finding was robust to examination of deaths taking place 1, 2, or 3 weeks after admission. Changes in the number of hospital admissions, SARS-CoV-2 variants, and age of patients could not explain these findings. The retreat from CCP usage might have resulted in as many as 29,000 excess deaths from mid-November 2020 to February 2021. A strong inverse correlation between CCP use and mortality per admission in the USA provides population-level evidence consistent with the notion that CCP reduces mortality in COVID-19 and suggests that the recent decline in usage could have resulted in excess deaths. There was no specific funding for this study. AC was supported in part by RO1 HL059842 and R01 AI1520789; MJJ was supported in part by 5R35HL139854. This project has been funded in whole or in part with Federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority under Contract No. 75A50120C00096.


The Effect of the Loading Rate on the Full-Field Strain Distribution on the Surface on the Intervertebral Discs.
Contrasting results are reported when the spine is tested at different strain rates. Tissue specimens from the ligaments or the intervertebral discs (IVD, including annulus fibrosus and nucleus pulposus) exhibit higher stiffness and lower dissipation at high strain rates. Counterintuitively, when spine segments are tested at high rates, the hysteresis area and loop width increase. It is unclear how the load is shared between the different structures at different loading rates. The hypotheses of this study were: (i) As the IVD stiffens at higher loading rates, the strain distribution around the disc would be different depending on the loading rate; (ii) Preconditioning attenuates the strain-rate dependency of the IVD, thus making differences in strain distribution smaller at the different rates. Six segments of three vertebrae (L4-L6) were extracted from porcine spines and tested in presso-flexion at different loading rates (reaching full load in 0.67, 6.7, and 67 s). The full-field strain maps were measured using digital image correlation on the surface of the IVDs from lateral. The posterior-to-anterior trends of the strain were computed in detail for each IVD, and compared between loading rates. The values and the direction of principal strain on the surface of the IVDs, vertebrae, and endplates remained unchanged at different rates. In the transition zone between IVD and vertebra, only slight differences due to the loading rate appeared but with no statistical significance. These findings will allow better understanding of the rate-dependent behavior and failure of the IVD.


Five-year risks of CIN 3+ and cervical cancer among women with HPV-positive and HPV-negative high-grade Pap results.
High-grade Pap results (e.g., atypical glandular cells [AGC], atypical squamous cells cannot rule out HSIL [ASC-H], and high-grade squamous intraepithelial lesion [HSIL]) predict high cancer risks, resulting in referral for colposcopy without HPV triage. However, new guidelines recommending cotesting for women 30 years and older imply that clinicians will often receive the HPV test result concurrently for high-grade Pap results. We examined whether HPV testing provides useful risk stratification in this context. From a cohort of 965,360 women aged 30 to 64 years undergoing cotesting at Kaiser Permanente Northern California, we estimated 5-year risks for cervical cancer and CIN 3+ after AGC (2,074 women), ASC-H (1,647 women), and HSIL (2,019 women) according to HPV test results. HPV positivity of AGC Pap results was 25% and decreased with age (30 to 34 vs 60 to 64 years, 44% vs 17%, p < .0001), whereas HPV positivity of ASC-H and HSIL was much higher (71% and 94%) and decreased less with age. Even for these high-grade Pap results, 5-year CIN 3+ risks differed substantially between HPV-positive and HPV-negative women (AGC, 33% vs 0.93%, p < .0001; ASC-H, 25% vs 3.5%, p < .0001; HSIL, 49% vs 30%, p = .006). However, except for AGC, cervical cancer risks differed less between HPV-positive and HPV-negative women (AGC, 9.0% vs 0.37%, p < .0001; ASC-H, 2.5% vs 2.1%, p = .8; HSIL, 6.6% vs 6.8%, p = .7). The risks of CIN 3+ among women with HPV-negative high-grade Pap results were lower than those among women with HPV-positive high-grade Pap results, especially after AGC. However, by the principle of "equal management of equal risks," all HPV-negative high-grade Pap results had cancer risks high enough to warrant colposcopy, confirming that there is no current role for HPV triage of high-grade Pap results.


Increased inositol phosphoglycan P-type in the second trimester in pregnant women with type 2 and gestational diabetes mellitus.
A progressive insulin resistant state develops throughout human pregnancy. Inositol phosphoglycan P-type (P-IPG), a second messenger of insulin, was reported to negatively correlate with the degree of insulin resistance in non-pregnant diabetic subjects. Urinary levels of P-IPG were assessed in insulin resistant states during pregnancy such as gestational diabetes mellitus (GDM, n=44) and type 2 diabetes mellitus (type 2 DM, n=25) and in 69 normal pregnant women. Urinary levels of P-IPG were higher in GDM than controls with a positive trend of release throughout normal pregnancy (P<0.01). P-IPG excretion was higher in diabetic (GDM and type 2 DM) than in healthy women in the second trimester (P<0.05). A higher P-IPG urinary excretion occurs during the second trimester in pregnant women with clinically evident insulin resistance with a positive association with poor glycemic control.


Advanced interactive preintegrated volume rendering with a power series.
Preintegrated volume rendering produces high-quality renderings without increased sampling rates. However, a look-up table of a conventional preintegrated volume rendering requires a dimensionality of two, which disturbs interactive renderings when the transfer function is changed. Furthermore, as the resolution of the volume data set increases, the memory space required is impractical or inefficient, especially on GPUs. In the past, several approximation methods have been proposed to reduce the complexity of both the time and memory requirement, but most of them do not correctly present thin opaque structures within slabs and ignore the self-attenuation. We propose an advanced interactive preintegrated volume rendering algorithm that achieves not only high-quality renderings comparable to the conventional ones, but also $(O(n))$ time and memory space requirements even with the self-attenuation within the slabs applied. The algorithm proposed in this paper decomposes the exponential term of the ray integration equation into a power series of a finite order in the form of a linear combination to build a one-dimensional look-up table. Moreover, the proposed algorithm effectively applies the self-attenuation that is caused by fully opaque isosurfaces, by introducing an opaque prediction table. Experimental results demonstrate that the proposed algorithm offers renderings visibly identical to existing preintegrated volume renderings without degrading rendering speed.


Adherence to Asthma Guidelines in Children, Tweens, and Adults in Primary Care Settings: A Practice-Based Network Assessment.
To assess primary care adherence to 2007 US asthma guidelines. Patients with persistent asthma aged 5 to 65 years from 22 primary care participating practices provided the data for this analysis of baseline information from the pragmatic randomized clinical trial the Asthma Tools Study. Using a combination of abstracted medical record data and patient-reported demographic information, we assessed the medical record documentation for elements of the 2007 US asthma guidelines. Elements assessed included documentation of (1) assessment of control, (2) factors that affect control (medication adherence evaluation, inhaler technique education, and evaluation for triggers), (3) self-management support (action plan), and (4) asthma medications prescribed (short-acting β-agonists and daily maintenance therapy). The baseline data was collected from March 16, 2009, to May 1, 2014. In 1176 patients (285 children, 211 tweens, and 680 adults) from 16 family medicine and 6 pediatric practices across the United States, documented guideline adherence was highest for prescription of medications (88.0% for short-acting β-agonists and 70.4% for maintenance medications) and lowest for an asthma action plan (3.1%). Documentation of control (15.0%) and factors that affect control (inhaler technique education, 7.6%; medication adherence assessment, 32.5%; and allergy evaluation, 32.5%) was not common and even less common for adults compared with children. A total of 22.2% of the enrolled patients had no asthma-related visit in the year before enrollment. Adherence to the nonmedication elements were higher in practices located in cities of more than 250,000 people and cities that used electronic medical records. Older patient age was negatively associated with guideline adherence. Adherence to asthma guidelines is poor in primary care practices, leaving many opportunities for improvement.


Mice heterozygous for both A1 and A(2A) adenosine receptor genes show similarities to mice given long-term caffeine.
Caffeine is believed to exert its stimulant effects by blocking A(2A) and A(1) adenosine receptors (A(2A)R and A(1)R). Although a genetic knockout of A(2A)R eliminates effects of caffeine, the phenotype of the knockout animal does not resemble that of caffeine treatment. In this study we explored the possibility that a mere reduction of the number of A(1)Rs and A(2A)Rs, achieved by deleting one of the two copies of the A(1)R and A(2A)R genes, would mimic some aspects of long-term caffeine ingestion. The A(1)R and A(2A)R double heterozygous (A(1)R-A(2A)R dHz) mice indeed had approximately one-half the number of A(1)R and A(2A)R, and there were little compensatory changes in A(2B) or A(3) adenosine receptor (A(2B)R or A(3)R) expression. The ability of a stable adenosine analog to activate receptors was shifted to the right by caffeine and in A(1)R-A(2A)R dHz tissue. Caffeine (0.3 g/l in drinking water for 7-10 days) and A(1)R-A(2A)R dHz genotype increased locomotor activity (LA) and decreased heart rate without significantly influencing body temperature. The acute stimulatory effect of a single injection of caffeine was reduced in A(1)R-A(2A)R dHz mice and in mice treated long term with oral caffeine. Thus at least some aspects of long-term caffeine use can be mimicked by genetic manipulation of the A(1)R and A(2A)R.


The balance of clinician and patient input into treatment decision-making in older women with operable breast cancer.
Primary endocrine therapy (PET) is an alternative to surgery for oestrogen receptor positive operable breast cancer in some older women. However the decision to offer PET involves complex trade-offs and is influenced by both patient choice and healthcare professional (HCP) preference. This study aimed to compare the views of patients and HCPs about this decision and explore decision-making (DM) preferences and whether these are taken into account during consultations. This multicentre, UK, mixed methods study had three components: (a) questionnaires to older women undergoing counseling about breast cancer treatment options which assessed their DM preferences and realities; (b) qualitative interviews with older women with operable breast cancer offered a choice of either surgery or PET and (c) qualitative interviews with HCPs (both of which focused on DM preferences in this setting). Thirty-three patients and 34 HCPs were interviewed. A range of opinions about patient involvement in DM were identified. Patients indicated varying preferences for DM involvement which were variably taken into account by HCPs. These qualitative findings were broadly supported by the questionnaire results. Most patients (536/729; 73.5%) achieved their preferred DM style; however, the remainder felt that their DM preferences had not been taken into consideration. These results suggest that whilst many older women achieve their desired level of DM engagement, some do not, raising the possibility that they may be making choices which are not concordant with their treatment preferences.


Harnessing the potential of multimodal radiotherapy in prostate cancer.
Radiotherapy in combination with androgen deprivation therapy (ADT) is a standard treatment option for men with localized and locally advanced prostate cancer. However, emerging clinical evidence suggests that radiotherapy can be incorporated into multimodality therapy regimens beyond ADT, in combinations that include chemotherapy, radiosensitizing agents, immunotherapy and surgery for the treatment of men with localized and locally advanced prostate cancer, and those with oligometastatic disease, in whom the low metastatic burden in particular might be treatable with these combinations. This multimodal approach is increasingly recognized as offering considerable clinical benefit, such as increased antitumour effects and improved survival. Thus, radiotherapy is becoming a key component of multimodal therapy for many stages of prostate cancer, particularly oligometastatic disease.


Point-by-Point Pulsed Field Ablation Using a Multimodality Generator and a Contact Force-Sensing Ablation Catheter: Comparison With Radiofrequency Ablation in a Remapped Chronic Swine Heart.
Pulsed field ablation (PFA) has emerged as an alternative to radiofrequency ablation. However, data on focal point-by-point PFA are scarce. The aim of this study was to compare lesion durability and collateral damage between focally delivered unipolar/biphasic PFA versus radiofrequency in swine. Eighteen swine were randomized to low-dose PFA, high-dose PFA, and radiofrequency using a multimodality generator. Radiofrequency delivered by market-available generator served as control group. A contact force-sensing catheter was used to focally deliver PFA/radiofrequency at the pulmonary veins and other predefined sites in the atria. Animals were remapped postprocedurally and 28 days postablation to test lesion durability followed by gross necroscopy and histology. All targeted sites were successfully ablated (contact force value, 13.9±4.1 g). Follow-up remapping showed persistent pulmonary vein isolation in all animals (100%) with lesion durability at nonpulmonary vein sites proven in most (98%). Regardless of the energy source used, the lesion size was similar across the study groups. Transmurality was achieved in 95% of targeted sites and 100% at pulmonary veins. On histology, PFA animals showed more mature scar formation than their radiofrequency counterpart without myocardial necrosis or inflammation. Finally, no sign of collateral damage was observed in any of the groups. In a randomized preclinical study, focally delivered unipolar/biphasic PFA guided by contact force values was associated with durable lesions on chronic remapping and with mature scar formation on histology without signs of collateral injury on necroscopy. Further studies are needed to investigate the long-term feasibility of this new approach to atrial fibrillation treatment.


A novel mutation in the interleukin-1 receptor antagonist associated with intrauterine disease onset.
Deficiency of the IL-1 receptor antagonist (DIRA) is a recently described rare autoinflammatory disease, caused by loss of function mutations in IL1RN leading to the unopposed activation of the IL-1 pathway. We describe a novel nonsense mutation in the IL1RN gene, associated with early intrauterine onset, death and multiorgan involvement in a prematurely born baby. The protein prediction model indicated that the novel Q119X mutation would result in a nonfunctional protein by impairing the ability of the IL-1Ra to bind and antagonize signaling through the IL-1R. Since the disorder may mimic severe bacterial infections and the treatment with anakinra is life saving, we intend to raise awareness of the syndrome and the possibility of a founder mutation that may lead to the diagnosis of additional cases in Turkey. The clinical suspicion of DIRA is critical to avoid improper management of the patients with antibiotics alone and death from multiorgan failure.


Association of Social Support and Medication Adherence in Chinese Patients with Type 2 Diabetes Mellitus.
The prevalence of diabetes is steadily increasing in China. When diabetes is uncontrolled, it generates dire consequences for health and well-being. Numerous studies have shown that health outcomes were associated with social support and medication adherence. Previous study confirmed that social support was associated with medication adherence in patients with heart failure, HIV diseases, and first-episode psychosis. However, the relationship between social support and medication adherence in patients with type 2 diabetes mellitus (T2DM) is remains unclear. This study aims to examine whether social support is associated with medication adherence in patients with T2DM. This study was conducted in the First Affiliated Hospital of the General Hospital of the People's Liberation Army (PLA). In Beijing, a systematic random sample of 412 patients with T2DM over 18 years was recruited at baseline, and demographic characteristics, clinical data and their assessment of social support were collected from medical records and self-reported questionnaires. 330 of these patients completed a self-report measure of medication adherence at the sixth month after baseline data collection. Regression analysis showed that social support presented a positive effect on medication adherence, additionally, support utilization and the subscale of social support exhibited a significantly strong influence on medication adherence in patients with T2DM. Although medication adherence was influenced by multiple factors, this finding confirmed that social support must be recognized as a core element in interventions aimed at improving in the management of patients with T2DM.


Reducing long-term remedial costs by transport modeling optimization.
The Department of Defense (DoD) Environmental Security Technology Certification Program and the Environmental Protection Agency sponsored a project to evaluate the benefits and utility of contaminant transport simulation-optimization algorithms against traditional (trial and error) modeling approaches. Three pump-and-treat facilities operated by the DoD were selected for inclusion in the project. Three optimization formulations were developed for each facility and solved independently by three modeling teams (two using simulation-optimization algorithms and one applying trial-and-error methods). The results clearly indicate that simulation-optimization methods are able to search a wider range of well locations and flow rates and identify better solutions than current trial-and-error approaches. The solutions found were 5% to 50% better than those obtained using trial-and-error (measured using optimal objective function values), with an average improvement of approximately 20%. This translated into potential savings ranging from 600,000 dollars to 10,000,000 dollars for the three sites. In nearly all cases, the cost savings easily outweighed the costs of the optimization. To reduce computational requirements, in some cases the simulation-optimization groups applied multiple mathematical algorithms, solved a series of modified subproblems, and/or fit "meta-models" such as neural networks or regression models to replace time-consuming simulation models in the optimization algorithm. The optimal solutions did not account for the uncertainties inherent in the modeling process. This project illustrates that transport simulation-optimization techniques are practical for real problems. However, applying the techniques in an efficient manner requires expertise and should involve iterative modification to the formulations based on interim results.


The influence of perceptual speed regulation on speed perception, choice, and control: tunnel wall characteristics and influences.
The present work sought to determine if the type of visual pattern and presence of texture applied to transportation tunnel walls differentially affected driving performance. Choice of speed and speed control were measured with 32 participants who drove through a simulated transportation tunnel environment. Participants experienced three visual patterns consisting of vertical segments that decreased, increased, and remained a constant width throughout the length of the tunnel. Participants also drove a baseline control condition in which no visual pattern was present. Each of these conditions was presented either with or without a homogenous texture. When compared to the baseline condition, results indicated drivers gradually decreased speed when exposed to the decreasing width visual pattern and increased speed with the increasing width visual pattern. The presence of texture served to attenuate overall driving speed. Results suggest drivers' perception of speed and their subsequent response to such perceptions were modified by the visual pattern and texture expressed on the tunnel wall. The evident speed control opportunities afforded to the traffic engineer are discussed.


Systematic review of hypofractionated radiation therapy for prostate cancer.
Prostate cancer is the second most prevalent solid tumor diagnosed in men in the United States and Western Europe. Conventionally fractionated external beam radiation therapy (1.8-2.0 Gy/fraction) is an established treatment modality for men in all disease risk groups. Emerging evidence from experimental and clinical studies suggests that the α/β ratio for prostate cancer may be as low as 1.5 Gy, which has prompted investigators around the world to explore moderately hypofractionated radiation therapy (2.1-3.5 Gy/fraction). We review the impetus behind moderate hypofractionation and the current clinical evidence supporting moderate hypofractionated radiation therapy for prostate cancer. Although hypofractionated radiation therapy has many theoretical advantages, there is no clear evidence from prospective, randomized, controlled trials showing that hypofractionated schedules have improved outcomes or lower toxicity than conventionally fractionated regimens. Currently, hypofractionated schedules should only be used in the context of clinical trials. High dose rate brachytherapy and stereotactic body radiation therapy (fraction size 3.5 Gy and greater) are alternative approaches to hypofractionation, but are beyond the scope of this report.


P2X7 receptor activation mediates organic cation uptake into human myeloid leukaemic KG-1 cells.
The P2X7 purinergic receptor is an ATP-gated cation channel with an emerging role in neoplasia. In this study we demonstrate that the human KG-1 cell line, a model of acute myelogenous leukaemia, expresses functional P2X7. RT-PCR and immunochemical techniques demonstrated the presence of P2X7 mRNA and protein respectively in KG-l cells, as well as in positive control multiple myeloma RPMI 8226 cells. Flow cytometric measurements demonstrated that ATP induced ethidium(+) uptake into KG-l cells suspended in sucrose medium (EC(50) of ≈ 3 μM), but not into cells in NaCl medium. In contrast, ATP induced ethidium(+) uptake into RPMI 8226 cells suspended in either sucrose or NaCl medium (EC(50) of ≈ 3 or ≈ 99 μM, respectively), as well as into RPMI 8226 cells in KCl medium (EC(50) of ≈ 18 μM). BzATP and to a lesser extent ATPγS and αβ-methylene ATP, but not ADP or UTP, also induced ethidium(+) uptake into KG-1 cells. ATP-induced ethidium(+) uptake was completely impaired by the P2X7 antagonists, AZ10606120 and A-438079. ATP-induced ethidium(+) uptake was also impaired by probenecid but not by carbenoxolone, both pannexin-1 antagonists. ATP induced YO-PRO-1(2+) and propidium(2+) uptake into KG-1 cells. Finally, sequencing of full-length P2X7 cDNA identified several single nucleotide polymorphisms (SNPs) in KG-1 cells including H155Y, A348T, T357S and Q460R. RPMI 8226 cells contained A348T, A433V and H521Q SNPs. In conclusion, the KG-1 cell line expresses functional P2X7. This cell line may help elucidate the signalling pathways involved in P2X7-induced survival and invasiveness of myeloid leukaemic cells.


Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice.
In the CNS, the hypothalamic arcuate nucleus (ARN) energy-balance circuit plays a key role in regulating body weight. Recent studies have shown that neurogenesis occurs in the adult hypothalamus, revealing that the ARN energy-balance circuit is more plastic than originally believed. Changes in diet result in altered gene expression and neuronal activity in the ARN, some of which may reflect hypothalamic plasticity. To explore this possibility, we examined the turnover of hypothalamic neurons in mice with obesity secondary to either high-fat diet (HFD) consumption or leptin deficiency. We found substantial turnover of neurons in the ARN that resulted in ongoing cellular remodeling. Feeding mice HFD suppressed neurogenesis, as demonstrated by the observation that these mice both generated fewer new neurons and retained more old neurons. This suppression of neuronal turnover was associated with increased apoptosis of newborn neurons. Leptin-deficient mice also generated fewer new neurons, an observation that was explained in part by a loss of hypothalamic neural stem cells. These data demonstrate that there is substantial postnatal turnover of the arcuate neuronal circuitry in the mouse and reveal the unexpected capacity of diet and leptin deficiency to inhibit this neuronal remodeling. This insight has important implications for our understanding of nutritional regulation of energy balance and brain function.


Colorful brains: 14 years of display practice in functional neuroimaging.
Neuroimaging results are typically graphically rendered and color-coded, which influences the process of knowledge generation within neuroscience as well as the public perception of brain research. Analyzing these issues requires empirical information on the display practice in neuroimaging. In our study we evaluated more than 9000 functional images (fMRI and PET) published between 1996 and 2009 with respect to the use of color, image structure, image production software and other factors that may determine the display practice. We demonstrate a variety of display styles despite a remarkable dominance of few image production sites and software systems, outline some tendencies of standardization, and identify shortcomings with respect to color scale explication in neuroimages. We discuss the importance of the finding for knowledge production in neuroimaging, and we make suggestions to improve the display practice in neuroimaging, especially on regimes of color coding.


A new trial design to accelerate tuberculosis drug development: the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP).
The standard 6-month four-drug regimen for the treatment of drug-sensitive tuberculosis has remained unchanged for decades and is inadequate to control the epidemic. Shorter, simpler regimens are urgently needed to defeat what is now the world's greatest infectious disease killer. We describe the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP) as a novel hybrid phase II/III trial design to accelerate regimen development. In the Phase IIC STEP trial, the experimental regimen is given for the duration for which it will be studied in phase III (presently 3 or 4 months) and patients are followed for clinical outcomes of treatment failure and relapse for a total of 12 months from randomisation. Operating characteristics of the trial design are explored assuming a classical frequentist framework as well as a Bayesian framework with flat and sceptical priors. A simulation study is conducted using data from the RIFAQUIN phase III trial to illustrate how such a design could be used in practice. With 80 patients per arm, and two (2.5 %) unfavourable outcomes in the STEP trial, there is a probability of 0.99 that the proportion of unfavourable outcomes in a potential phase III trial would be less than 12 % and a probability of 0.91 that the proportion of unfavourable outcomes would be less than 8 %. With six (7.5 %) unfavourable outcomes, there is a probability of 0.82 that the proportion of unfavourable outcomes in a potential phase III trial would be less than 12 % and a probability of 0.41 that it would be less than 8 %. Simulations using data from the RIFAQUIN trial show that a STEP trial with 80 patients per arm would have correctly shown that the Inferior Regimen should not proceed to phase III and would have had a high chance (0.88) of either showing that the Successful Regimen could proceed to phase III or that it might require further optimisation. Collection of definitive clinical outcome data in a relatively small number of participants over only 12 months provides valuable information about the likelihood of success in a future phase III trial. We strongly believe that the STEP trial design described herein is an important tool that would allow for more informed decision-making and accelerate regimen development.


Ancient convergent losses of Paraoxonase 1 yield potential risks for modern marine mammals.
Mammals diversified by colonizing drastically different environments, with each transition yielding numerous molecular changes, including losses of protein function. Though not initially deleterious, these losses could subsequently carry deleterious pleiotropic consequences. We have used phylogenetic methods to identify convergent functional losses across independent marine mammal lineages. In one extreme case, Paraoxonase 1 (PON1) accrued lesions in all marine lineages, while remaining intact in all terrestrial mammals. These lesions coincide with PON1 enzymatic activity loss in marine species' blood plasma. This convergent loss is likely explained by parallel shifts in marine ancestors' lipid metabolism and/or bloodstream oxidative environment affecting PON1's role in fatty acid oxidation. PON1 loss also eliminates marine mammals' main defense against neurotoxicity from specific man-made organophosphorus compounds, implying potential risks in modern environments.


The use of skill tests to predict status in junior Australian football.
This study examined whether skill tests were predictive of status in junior Australian football. Players were recruited from the 2013 under 18 (U18) West Australian Football League competition and classified into two groups: elite (state U18 squad representative; n = 25; 17.9 ± 0.5 years) and subelite (nonstate U18 squad representative; n = 25; 17.3 ± 0.6 years). Both groups completed the Australian football kicking (AFK) and Australian football handballing (AFHB) tests, assessing kicking accuracy/ball speed and handballing accuracy on dominant and nondominant sides. A multivariate analysis of variance (MANOVA) modelled the main effect of "status", whilst logistic regression models were built for the predictive analysis using the same test parameters. Between-group differences were noted across all parameters, with the combination of kicking accuracy and ball speed on the dominant and nondominant sides being the best predictor of status for the AFK test (wi = 0.25, AUC = 89.4%) and the combination of accuracy on the dominant and nondominant sides being the best predictor of status for the AFHB test (wi = 0.80, AUC = 88.4%). The AFK and AFHB tests are predictive of status, suggesting that their use is warranted as a means of talent identification in junior Australian football.


Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus.
Lymph nodes (LNs) capture microorganisms that breach the body's external barriers and enter draining lymphatics, limiting the systemic spread of pathogens. Recent work has shown that CD11b(+)CD169(+) macrophages, which populate the subcapsular sinus (SCS) of LNs, are critical for the clearance of viruses from the lymph and for initiating antiviral humoral immune responses. Here we show, using vesicular stomatitis virus (VSV), a relative of rabies virus transmitted by insect bites, that SCS macrophages perform a third vital function: they prevent lymph-borne neurotropic viruses from infecting the central nervous system (CNS). On local depletion of LN macrophages, about 60% of mice developed ascending paralysis and died 7-10 days after subcutaneous infection with a small dose of VSV, whereas macrophage-sufficient animals remained asymptomatic and cleared the virus. VSV gained access to the nervous system through peripheral nerves in macrophage-depleted LNs. In contrast, within macrophage-sufficient LNs VSV replicated preferentially in SCS macrophages but not in adjacent nerves. Removal of SCS macrophages did not compromise adaptive immune responses against VSV, but decreased type I interferon (IFN-I) production within infected LNs. VSV-infected macrophages recruited IFN-I-producing plasmacytoid dendritic cells to the SCS and in addition were a major source of IFN-I themselves. Experiments in bone marrow chimaeric mice revealed that IFN-I must act on both haematopoietic and stromal compartments, including the intranodal nerves, to prevent lethal infection with VSV. These results identify SCS macrophages as crucial gatekeepers to the CNS that prevent fatal viral invasion of the nervous system on peripheral infection.


Fabrication of biomolecules self-assembled on Au nanodot array for bioelectronic device.
In the present study, an nano-platform composed of Au nanodot arrays on which biomolecules could be self-assembled was developed and investigated for a stable bioelectronic device platform. Au nanodot pattern was fabricated using a nanoporous alumina template. Two different biomolecules, a cytochrome c and a single strand DNA (ssDNA), were immobilized on the Au nanodot arrays. Cytochorme c and single stranded DNA could be immobilized on the Au nanodot using the chemical linker 11-MUA and thiol-modification by covalent bonding, respectively. The atomic structure of the fabricated nano-platform device was characterized by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The electrical conductivity of biomolecules immobilized on the Au nanodot arrays was confirmed by scanning tunneling spectroscopy (STS). To investigate the activity of biomolecule-immobilized Au-nano dot array, the cyclic voltammetry was carried out. This proposed nano-platform device, which is composed of biomolecules, can be used for the construction of a novel bioelectronic device.


Production of autoantibodies against citrullinated antigens/peptides by human B cells.
Autoantibodies against citrullinated protein Ags (ACPA) are associated with the development of rheumatoid arthritis (RA). This immune response against citrullinated protein Ags, which is thought to be facilitated by certain MHC HLA-DR alleles, is highly specific for this disease and has been speculated to be involved in the pathogenesis. We have previously studied cultures of B cells for the production of Abs against HLA Ags. The aim of the current study was to examine the role of B cells in the production of ACPA in patients with RA. Peripheral blood B cells from RA patients and healthy people were cultured with EL4-B5, a murine cell line expressing human CD40L, and with T cell factors to stimulate the in vitro production of Abs by B cells isolated from peripheral blood. ACPA were produced by cultured B cells from RA patients, as determined by reactivity to cyclic citrullinated peptide (CCP). The results showed that 22% of the healthy persons tested also had B cells that could produce ACPA. Patients with HLA-DR alleles carrying the RA-associated shared epitope appeared to have more B cells with autoimmune potential for CCP than those without such HLA alleles (odds ratio 8.1, p = 0.001). In healthy individuals, anti-CCP-producing B cells were also observed more frequently if the RA-associated MHC genes were present (odds ratio 8.0, p = 0.01). Analysis of B cells in cultures may shed light on the interaction of genetic and environmental factors in the development of RA.


Monitoring C5aR2 Expression Using a Floxed tdTomato-C5aR2 Knock-In Mouse.
The biological significance of C5a receptor [(C5aR)2/C5L2], a seven-transmembrane receptor binding C5a and C5adesArg, remains ill-defined. Specific ligation of C5aR2 inhibits C5a-induced ERK1/2 activation, strengthening the view that C5aR2 regulates C5aR1-mediated effector functions. Although C5aR2 and C5aR1 are often coexpressed, a detailed picture of C5aR2 expression in murine cells and tissues is still lacking. To close this gap, we generated a floxed tandem dye (td)Tomato-C5aR2 knock-in mouse that we used to track C5aR2 expression in tissue-residing and circulating immune cells. We found the strongest C5aR2 expression in the brain, bone marrow, and airways. All myeloid-derived cells expressed C5aR2, although with different intensities. C5aR2 expression in blood and tissue neutrophils was strong and homogeneous. Specific ligation of C5aR2 in neutrophils from tdTomato-C5aR2 mice blocked C5a-driven ERK1/2 phosphorylation, demonstrating functionality of C5aR2 in the reporter mice. In contrast to neutrophils, we found tissue-specific differences in C5aR2 expression in eosinophils, macrophages, and dendritic cell subsets. Naive and activated T cells stained negative for C5aR2, whereas B cells from different tissues homogeneously expressed C5aR2. Also, NK cell subsets in blood and spleen strongly expressed C5aR2. Activation of C5aR2 in NK cells suppressed IL-12/IL-18-induced IFN-γ production. Intratracheal IL-33 challenge resulted in decreased C5aR2 expression in pulmonary eosinophils and monocyte-derived dendritic cells. In summary, we provide a detailed map of murine C5aR2 immune cell expression in different tissues under steady-state conditions and upon pulmonary inflammation. The C5aR2 knock-in mouse will help to reliably track and conditionally delete C5aR2 expression in experimental models of inflammation.


Monocyte Subsets Are Differentially Lost from the Circulation during Acute Inflammation Induced by Human Experimental Endotoxemia.
Three human monocyte subsets are recognized with different functions in the immune system: CD14++/CD16- classical monocytes (CM), CD14++/CD16+ intermediate monocytes (IM) and CD14+/CD16++ non-classical monocytes (NCM). Increased IM and NCM percentages have been reported under inflammatory conditions, yet little is known about monocyte subsets at the onset of inflammation. The human endotoxemia model is uniquely capable of studying the first phases of acute inflammation induced by intravenous injection of 2 ng/kg bodyweight lipopolysaccharide (LPS) into healthy volunteers. After that, monocyte subset counts, activation/differentiation status and chemokine levels were studied over 24 h. The numbers of all subsets were decreased by >95% after LPS injection. CM numbers recovered first (3- 6 h), followed by IM (6-8 h) and NCM numbers (8-24 h). Similarly, increased monocyte counts were observed first in CM (8 h), followed by IM and NCM (24 h). Monocytes did not display a clear activated phenotype (minor increase in CD11b and CD38 expression). Plasma levels of CCL2, CCL4 and CX3CL1 closely resembled the cell numbers of CM, IM and NCM, respectively. Our study provides critical insights into the earliest stages of acute inflammation and emphasizes the necessity to stain for different monocyte subsets when studying the role of monocytes in disease, as neither function nor kinetics of the subsets overlap.


Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele. The IMDIAB Group.
The IDDM2 type 1 diabetes susceptibility locus was mapped to and identified as allelic variation at the insulin gene (INS) VNTR regulatory polymorphism. In Caucasians, INS VNTR alleles divide into two discrete size classes. Class I alleles (26 to 63 repeats) predispose in a recessive way to type 1 diabetes, while class III alleles (140 to more than 200 repeats) are dominantly protective. The protective effect may be explained by higher levels of class III VNTR-associated INS mRNA in thymus such that elevated levels of preproinsulin protein enhance immune tolerance to preproinsulin, a key autoantigen in type 1 diabetes pathogenesis. The mode of action of IDDM2 is complicated, however, by parent-of-origin effects and possible allelic heterogeneity within the two defined allele classes. We have now analysed transmission of specific VNTR alleles in 1,316 families and demonstrate that a particular class I allele does not predispose to disease when paternally inherited, suggestive of polymorphic imprinting. But this paternal effect is observed only when the father's untransmitted allele is a class III. This allelic interaction is reminiscent of epigenetic phenomena observed in plants (for example, paramutation; ref. 17) and in yeast (for example, trans-inactivation; ref. 18). If untransmitted chromosomes can have functional effects on the biological properties of transmitted chromosomes, the implications for human genetics and disease are potentially considerable.


An abnormal cervicovaginal cytology smear in uterine carcinosarcoma is an adverse prognostic sign: analysis of 25 cases.
Carcinosarcoma of the uterus has been poorly characterized on cervicovaginal (Pap) smears, and we examine whether they effectively screen for carcinosarcoma and whether an abnormal Pap smear result has any clinical importance. Twenty-five patients with histologically confirmed carcinosarcoma had a conventional Pap smear shortly before diagnosis. Eleven smears (44%) originally were read as abnormal (malignant or atypical), and 4 additional cases were read as abnormal on retrospective review (15/25 [60%]). All malignant elements were epithelial, and 2 cases (8%) had atypical spindle cells, but no diagnostic sarcoma. Cervical involvement was the only histologic parameter correlating with an abnormal Pap smear result (P = .04). Univariate analysis found stage III or IV disease was an adverse prognostic sign compared with stage I or II disease (mean survival, 8 vs 36 months, respectively; P = .001), and multivariate analysis indicated that an abnormal Pap smear result correlated with worse survival (P = .023). The conventional Pap smear is insensitive (60%) for detecting carcinosarcoma, but when the result is abnormal, the Pap is an important stage-independent adverse prognosticator.


Mitochondrial and Chloroplast Stress Responses Are Modulated in Distinct Touch and Chemical Inhibition Phases.
Previous studies have identified a range of transcription factors that modulate retrograde regulation of mitochondrial and chloroplast functions in Arabidopsis (Arabidopsis thaliana). However, the relative importance of these regulators and whether they act downstream of separate or overlapping signaling cascades is still unclear. Here, we demonstrate that multiple stress-related signaling pathways, with distinct kinetic signatures, converge on overlapping gene sets involved in energy organelle function. The transcription factor ANAC017 is almost solely responsible for transcript induction of marker genes around 3 to 6 h after chemical inhibition of organelle function and is a key regulator of mitochondrial and specific types of chloroplast retrograde signaling. However, an independent and highly transient gene expression phase, initiated within 10 to 30 min after treatment, also targets energy organelle functions, and is related to touch and wounding responses. Metabolite analysis demonstrates that this early response is concurrent with rapid changes in tricarboxylic acid cycle intermediates and large changes in transcript abundance of genes encoding mitochondrial dicarboxylate carrier proteins. It was further demonstrated that transcription factors AtWRKY15 and AtWRKY40 have repressive regulatory roles in this touch-responsive gene expression. Together, our results show that several regulatory systems can independently affect energy organelle function in response to stress, providing different means to exert operational control.


Autologous stem-cell transplantation for Hodgkin's disease: results and prognostic factors in 494 patients from the Grupo Español de Linfomas/Transplante Autólogo de Médula Osea Spanish Cooperative Group.
To analyze clinical outcome and significant prognostic factors for overall (OS) and time to treatment failure (TTF) in a group of 494 patients with Hodgkin's disease (HD) undergoing autologous stem-cell transplantation (ASCT). Detailed records from the Grupo Español de Linfomas/Transplante Autólogo de Médula Osea Spanish Cooperative Group Database on 494 HD patients who received an ASCT between January 1984 and May 1998 were reviewed. Two hundred ninety-eight males and 196 females with a median age of 27 years (range, 1 to 63 years) received autografts while in complete remission (n = 203) or when they had sensitive disease (n = 206) or resistant disease (n = 75) at a median time of 26 months (range, 4 to 259 months) after diagnosis. Most patients received high-dose chemotherapy without radiation for conditioning (n = 443). The graft consisted of bone marrow (n = 244) or peripheral blood (n = 250). The 100-day mortality rate was 9%. The 5-year actuarial TTF and OS rates were 45.0% (95% confidence interval [CI], 39.5% to 50.5%) and 54.5% (95% CI, 48.4% to 60.6%), respectively. In multivariate analysis, the presence of active disease at transplantation, transplantation before 1992, and two or more lines of therapy before transplantation were adverse prognostic factors for outcome. Sixteen patients developed a secondary malignancy (5-year cumulative incidence of 4.3%) after transplantation. Adjuvant radiotherapy before transplantation, the use of total-body irradiation (TBI) in the conditioning regimen, and age > or = 40 years were found to be predictive factors for the development of second cancers after ASCT. ASCT achieves long-term disease-free survival in HD patients. Disease status before ASCT is the most important prognostic factor for final outcome; thus, transplantation should be considered in early stages of the disease. TBI must be avoided in the conditioning regimen because of a significantly higher rate of late complications, including secondary malignancies.


Biomechanics of the peafowl's crest reveals frequencies tuned to social displays.
Feathers act as vibrotactile sensors that can detect mechanical stimuli during avian flight and tactile navigation, suggesting that they may also detect stimuli during social displays. In this study, we present the first measurements of the biomechanical properties of the feather crests found on the heads of birds, with an emphasis on those from the Indian peafowl (Pavo cristatus). We show that in peafowl these crest feathers are coupled to filoplumes, small feathers known to function as mechanosensors. We also determined that airborne stimuli with the frequencies used during peafowl courtship and social displays couple efficiently via resonance to the vibrational response of their feather crests. Specifically, vibrational measurements showed that although different types of feathers have a wide range of fundamental resonant frequencies, peafowl crests are driven near-optimally by the shaking frequencies used by peacocks performing train-rattling displays. Peafowl crests were also driven to vibrate near resonance in a playback experiment that mimicked the effect of these mechanical sounds in the acoustic very near-field, reproducing the way peafowl displays are experienced at distances ≤ 1.5m in vivo. When peacock wing-shaking courtship behaviour was simulated in the laboratory, the resulting airflow excited measurable vibrations of crest feathers. These results demonstrate that peafowl crests have mechanical properties that allow them to respond to airborne stimuli at the frequencies typical of this species' social displays. This suggests a new hypothesis that mechanosensory stimuli could complement acoustic and visual perception and/or proprioception of social displays in peafowl and other bird species. We suggest behavioral studies to explore these ideas and their functional implications.


Clinical Features and Treatment of Fibrous Histiocytomas of the Tongue: A Systematic Review.
Introduction Benign fibrous histiocytomas are common lesions of the skin that rarely affect the tongue. Such cases are available in the literature exclusively as case reports. Similarly, malignant fibrous histiocytoma, now classified as undifferentiated pleomorphic sarcoma, is exceedingly rare in the tongue and not fully understood. Objectives This study systematically reviews the available literature discussing the clinical and pathological features of malignant and benign fibrous histiocytomas. Data Synthesis A total of 20 cases were included in this review. Patient-level data were extracted from cases to include clinical presentation, workup, treatment, and outcome. Conclusion Benign fibrous histiocytomas are consistent in clinical and histopathologic presentation. Surgical treatment provides excellent outcome, with no recurrence in all excised cases. Malignant tumors have a more aggressive clinical and pathological presentation. Surgical treatment with possible adjuvant radiotherapy resulted in recurrence in 40% of cases (follow-up of 24 months), and death due to disease in 47% of patients (follow-up of 19 months).


Corneal shape change during accommodation.
To investigate whether accommodation induces any changes in central corneal curvature. Shape changes were measured on 14 subjects using a keratometer modified to enable a change in focus to occur without a change in vergence. All subjects were emmetropic and their ages ranged from approximately 20 to 28 years. In 11 of the 14 subjects a difference in central corneal curvature, of around 0.4 D in at least one principal meridian, was found when focus was changed between distant and near targets. In 9 subjects the curvature was greater for near focus in at least one meridian. In 5 subjects the change in one meridian was opposite in effect to what would be expected, i.e. the curvature was greater at distance than at near. The study suggests that accommodation may have some effect on corneal shape.


Mapping Quantitative Trait Loci of Resistance to Tomato Spotted Wilt Virus and Leaf Spots in a Recombinant Inbred Line Population of Peanut (Arachis hypogaea L.) from SunOleic 97R and NC94022.
Peanut is vulnerable to a range of diseases, such as Tomato spotted wilt virus (TSWV) and leaf spots which will cause significant yield loss. The most sustainable, economical and eco-friendly solution for managing peanut diseases is development of improved cultivars with high level of resistance. We developed a recombinant inbred line population from the cross between SunOleic 97R and NC94022, named as the S-population. An improved genetic linkage map was developed for the S-population with 248 marker loci and a marker density of 5.7 cM/loci. This genetic map was also compared with the physical map of diploid progenitors of tetraploid peanut, resulting in an overall co-linearity of about 60% with the average co-linearity of 68% for the A sub-genome and 47% for the B sub-genome. The analysis using the improved genetic map and multi-season (2010-2013) phenotypic data resulted in the identification of 48 quantitative trait loci (QTLs) with phenotypic variance explained (PVE) from 3.88 to 29.14%. Of the 48 QTLs, six QTLs were identified for resistance to TSWV, 22 QTLs for early leaf spot (ELS) and 20 QTLs for late leaf spot (LLS), which included four, six, and six major QTLs (PVE larger than 10%) for each disease, respectively. A total of six major genomic regions (MGR) were found to have QTLs controlling more than one disease resistance. The identified QTLs and resistance gene-rich MGRs will facilitate further discovery of resistance genes and development of molecular markers for these important diseases.


[Association between LMP2/LMP7 gene polymorphism and the infection of hepatitis B virus].
To elucidate whether the antigen-processing gene (LMP2/LMP7) polymorphisms could influence the infection of hepatitis B virus. Genomic DNA of 176 patients infected with HBV and 208 healthy volunteers were extracted from the peripheral blood leukocytes. Polymorphisms of LMP genes in HBV patients were determined by polymerase chain reaction-restriction fragment length polymorphism (RFLP), the controls by DNA sequencing. We used the software PHASE1.0 to construct the haplotypes of every individual. At last the unconditional Logistic regression model was used to analyze the statistical association of genotypes or haplotypes in two groups adjusted by gender and age. The distributions of LMP2 genes between cases and controls did not differ. However, LMP7 gene frequency in patients was higher than that in controls [odds ratio 2.11(95% confidence interval 1.36-3.26); 2.66 (95% confidence interval 1.17-6.02), heterogenous or homologous respectively]. Similarly, we found the haplotype combinated by R-K had a significant difference in two groups [odds ratio 1.81 (95% confidence interval 1.19-2.76)]. These findings suggest that polymorphisms of LMP2/LMP7 gene is one of the important host factors which independently affect on the infection of hepatitis B virus.


Tonic activity level in the right prefrontal cortex predicts individuals' risk taking.
Human risk taking is characterized by a large amount of individual heterogeneity. In this study, we applied resting-state electroencephalography, which captures stable individual differences in neural activity, before subjects performed a risk-taking task. Using a source-localization technique, we found that the baseline cortical activity in the right prefrontal cortex predicts individual risk-taking behavior. Individuals with higher baseline cortical activity in this brain area display more risk aversion than do other individuals. This finding demonstrates that neural characteristics that are stable over time can predict a highly complex behavior such as risk-taking behavior and furthermore suggests that hypoactivity in the right prefrontal cortex might serve as a dispositional indicator of lower regulatory abilities, which is expressed in greater risk-taking behavior.


Isolation of plasmid DNA sequences that complement Rhodobacter sphaeroides mutants deficient in the capacity for CO2-dependent growth.
Mutants deficient in the proper regulation and derepression of ribulose-1.5-bisphosphate carboxylase oxygenase (RuBPC/O) in Rhodobacter sphaeroides were isolated by ethyl methanesulphonate (EMS) and Tn5 mutagenesis of a recA parental strain. Mutants were identified by their ability to grow under conditions where the organism requires basal levels of RuBPC C/O for growth yet fail to grow under conditions which require derepression of the enzyme (Aut-). The newly isolated Aut- mutants exhibited phenotypes distinguishable from the previously isolated Aut- mutant, strain KW25/11. Rocket immunoelectrophoretic examination of RuBPC/O levels revealed marked variance in the ability of mutants to derepress form I and form II RuBPC/O in the absence of exogenous carbon. Evidence that some of the mutants possessed different mutations was substantiated by complementation of the EMS-generated mutants by entirely different genes isolated from a genomic library of R. sphaeroides constructed in the broad-host-range cosmid vector pVK102. Southern hybridization analysis of the complementing library isolates showed the complementing genes to be normally carried on the endogenous plasmids of R. sphaeroides. The gene complementing mutant strain KW25/11 was mapped by Tn5 insertional inactivation and the complementing region found to reside on a 1.5 kb PstJ. BamHI fragment. Complemented strains were unable to match wild-type levels of RuBPC/O under conditions requiring derepression of the enzyme, except for mutant strain EMS45. The Aut- phenotype, represented by the mutants isolated in this study, stems from a deficiency in some aspect of photoautotrophic growth.


Neuroinflammation and status epilepticus: a narrative review unraveling a complex interplay.
Status epilepticus (SE) is a medical emergency resulting from the failure of the mechanisms involved in seizure termination or from the initiation of pathways involved in abnormally prolonged seizures, potentially leading to long-term consequences, including neuronal death and impaired neuronal networks. It can eventually evolve to refractory status epilepticus (RSE), in which the administration of a benzodiazepine and another anti-seizure medications (ASMs) had been ineffective, and super-refractory status epilepticus (SRSE), which persists for more than 24 h after the administration of general anesthesia. Objective of the present review is to highlight the link between inflammation and SE. Several preclinical and clinical studies have shown that neuroinflammation can contribute to seizure onset and recurrence by increasing neuronal excitability. Notably, microglia and astrocytes can promote neuroinflammation and seizure susceptibility. In fact, inflammatory mediators released by glial cells might enhance neuronal excitation and cause drug resistance and seizure recurrence. Understanding the molecular mechanisms of neuroinflammation could be crucial for improving SE treatment, wich is currently mainly addressed with benzodiazepines and eventually phenytoin, valproic acid, or levetiracetam. IL-1β signal blockade with Anakinra has shown promising results in avoiding seizure recurrence and generalization in inflammatory refractory epilepsy. Inhibiting the IL-1β converting enzyme (ICE)/caspase-1 is also being investigated as a possible target for managing drug-resistant epilepsies. Targeting the ATP-P2X7R signal, which activates the NLRP3 inflammasome and triggers inflammatory molecule release, is another avenue of research. Interestingly, astaxanthin has shown promise in attenuating neuroinflammation in SE by inhibiting the ATP-P2X7R signal. Furthermore, IL-6 blockade using tocilizumab has been effective in RSE and in reducing seizures in patients with febrile infection-related epilepsy syndrome (FIRES). Other potential approaches include the ketogenic diet, which may modulate pro-inflammatory cytokine production, and the use of cannabidiol (CBD), which has demonstrated antiepileptic, neuroprotective, and anti-inflammatory properties, and targeting HMGB1-TLR4 axis. Clinical experience with anti-cytokine agents such as Anakinra and Tocilizumab in SE is currently limited, although promising. Nonetheless, Etanercept and Rituximab have shown efficacy only in specific etiologies of SE, such as autoimmune encephalitis. Overall, targeting inflammatory pathways and cytokines shows potential as an innovative therapeutic option for drug-resistant epilepsies and SE, providing the chance of directly addressing its underlying mechanisms, rather than solely focusing on symptom control.


Therapeutic effect of a poly(ADP-ribose) polymerase-1 inhibitor on experimental arthritis by downregulating inflammation and Th1 response.
Poly(ADP-ribose) polymerase-1 (PARP-1) synthesizes and transfers ADP ribose polymers to target proteins, and regulates DNA repair and genomic integrity maintenance. PARP-1 also plays a crucial role in the progression of the inflammatory response, and its inhibition confers protection in several models of inflammatory disorders. Here, we investigate the impact of a selective PARP-1 inhibitor in experimental arthritis. PARP-1 inhibition with 5-aminoisoquinolinone (AIQ) significantly reduces incidence and severity of established collagen-induced arthritis, completely abrogating joint swelling and destruction of cartilage and bone. The therapeutic effect of AIQ is associated with a striking reduction of the two deleterious components of the disease, i.e. the Th1-driven autoimmune and inflammatory responses. AIQ downregulates the production of various inflammatory cytokines and chemokines, decreases the antigen-specific Th1-cell expansion, and induces the production of the anti-inflammatory cytokine IL-10. Our results provide evidence of the contribution of PARP-1 to the progression of arthritis and identify this protein as a potential therapeutic target for the treatment of rheumatoid arthritis.


Altered periodic rectal motor activity: a mechanism for slow transit constipation.
The pathophysiology of slow transit constipation is poorly understood. Both decreased and increased distal colonic motility have been reported. In healthy humans, a 3 cycles per minute (cpm), periodic rectal motor activity (PRMA) has been described. Our aim was to investigate the characteristics of PRMA and to assess its role in the pathogenesis of constipation. A six-sensor solid-state probe was placed with the tip sensor in the mid-transverse colon, without sedation, and prolonged colonic motility was recorded in nine patients with slow transit constipation (1M, 8F) and in 11 healthy subjects (3M, 8F). Subjects were free to ambulate. We examined the frequency, nocturnal vs. diurnal variation, and characteristics of PRMA, and its relationship to proximal colonic motility. All subjects showed PRMA. The rhythm was similar (2.5-4 cpm) in both groups. However, constipated patients exhibited a greater (P < 0.001) number of PRMA cycles than controls. The duration of each cycle and amplitude of pressure waves during PRMA were also greater (P < 0.05) at night in patients compared with controls. In patients, 40% of PRMA cycles were associated with a proximal colonic motor event compared with 81% in controls (P < 0.02). The area under the curve of all colonic pressure waves and incidence of specialized propagating pressure waves was lower (P < 0.05) in patients during daytime. When compared with controls, constipated patients exhibited reduced daytime colonic pressure waves and a higher frequency of PRMA. Most of the PRMA was unrelated to proximal colonic activity in constipated patients in contrast with findings in control patients. In addition to decreased colonic motility, this excessive and unco-ordinated phasic rectal activity may further impede stool transport and contribute to the pathogenesis of slow transit constipation.


Incomplete reporting of recruitment information in breast cancer trials published between 2003 and 2008.
To review the reporting of key items of recruitment information in trial reports and estimate the number needed to screen to recruit one additional participant. Review of breast cancer trials published in the years 2003-2005, 2007, and 2008. The search identified 1,570 potentially eligible studies. After a random selection of 20% from each year and checking against inclusion criteria, a total of 207 studies were included in the review. Some items of information were well reported, such as the number included in the analysis. Sample size calculations were often not presented, but reporting is slowly improving. Who recruits participants and how many individuals were screened are often not reported. The median number needed to screen to recruit one additional participant was two (range, 1-593). Without reporting the when, where, by whom, and how many of recruitment, trialists deny readers part of the contextual description they need to judge whether a trial's results are applicable to their own situation. Trialists and journal editors need to be more diligent in following the reporting recommendations of the Consolidated Standards of Reporting Trials statement.


Magneto-optical Faraday rotation of semiconductor nanoparticles embedded in dielectric matrices.
Faraday rotation has been studied for CdS, CdTe, and CdS:Mn semiconductor nanoparticles synthesized by colloidal chemistry methods. Additionally these materials were prepared in a form of semiconductor nanoparticles embedded in polyvinyl alcohol films. Transmission electron microscopy and atomic force microscopy analyses served as confirmation of nanocrystallinity and estimation of the average size of the nanoparticles. Spectral dependence of the Faraday rotation for the studied nanocrystals and nanocomposites is correlated with a blueshift of the absorption edge due to the confinement effect in zero-dimensional structures. Faraday rotation spectra and their temperature behavior in Mn-doped nanocrystals demonstrates peculiarities, which are associated with s, p-d exchange interaction between Mn²⁺ ions and band carriers in diluted magnetic semiconductor nanostructures.


Stability and change in callous-unemotional traits: Longitudinal associations with potential individual and contextual risk and protective factors.
This longitudinal study examines developmental heterogeneity in callous-unemotional (CU) traits in a large sample of school-age children in Cyprus. Latent Class Growth Analysis revealed 4 trajectory groups of CU traits across 3 time points: stable high, increasing, decreasing, and low. Findings suggested that children in the stable high CU trajectory were more likely to (a) exhibit high and stable levels of conduct problems, attention-deficit/hyperactivity disorder symptoms, impulsivity and narcissism, (b) experience low parental involvement and high parental distress, (c) report low peer support and school connectedness, and (d) score lower on academic performance, executive functioning, social competence, and self-regulation compared to children with low, decreasing, and increasing CU traits. These findings were verified by both parent and child reports. Repeated analysis of variance suggested that increases and decreases in CU traits were associated with similar changes in conduct problems, narcissism, impulsivity, and maternal involvement. Further, children in the decreasing trajectory group were not differentiated from children in the low risk group on measures of executive functioning, academic performance, school connectedness, and peer social support at the last wave of measurement. These findings provide evidence for the importance of taking longitudinal change into account for understanding developmental heterogeneity in CU traits and the association of these traits with possible protective (e.g., stable high maternal involvement) and risk (e.g., decreases in maternal involvement and increases in conduct problems, impulsivity and narcissism) variables. (PsycINFO Database Record


Challenges to the implementation of health sector decentralization in Tanzania: experiences from Kongwa district council.
During the 1990s, the government of Tanzania introduced the decentralization by devolution (D by D) approach involving the transfer of functions, power and authority from the centre to the local government authorities (LGAs) to improve the delivery of public goods and services, including health services. This article examines and documents the experiences facing the implementation of decentralization of health services from the perspective of national and district officials. The study adopted a qualitative approach, and data were collected using semi-structured interviews and were analysed for themes and patterns. The results showed several benefits of decentralization, including increased autonomy in local resource mobilization and utilization, an enhanced bottom-up planning approach, increased health workers' accountability and reduction of bureaucratic procedures in decision making. The findings also revealed several challenges which hinder the effective functioning of decentralization. These include inadequate funding, untimely disbursement of funds from the central government, insufficient and unqualified personnel, lack of community participation in planning and political interference. The article concludes that the central government needs to adhere to the principles that established the local authorities and grant more autonomy to them, offer special incentives to staff working in the rural areas and create the capacity for local key actors to participate effectively in the planning process.


Serum levels of vitamin D, sunlight exposure, and knee cartilage loss in older adults: the Tasmanian older adult cohort study.
To determine the associations between serum levels of vitamin D, sunlight exposure, and knee cartilage loss cross-sectionally and longitudinally in older adults. A total of 880 randomly selected subjects (mean age 61 years [range 51-79 years], 50% women) were studied at baseline, and 353 of these subjects were studied 2.9 years later. Serum levels of 25-hydroxyvitamin D (25[OH]D) were assessed by radioimmunoassay, and sunlight exposure was assessed by questionnaire. T1-weighted fat-suppressed magnetic resonance imaging (MRI) of the right knee was performed to determine knee cartilage volume and defects. Knee radiographic osteoarthritis (OA) and knee pain were also assessed. The mean 25(OH)D serum level was 52.8 nmoles/liter at baseline (range 13-119 nmoles/liter). Winter sunlight exposure and serum 25(OH)D level were both positively associated with medial and lateral tibial cartilage volume, and a serum 25(OH)D level<50 nmoles/liter was associated with increased medial tibiofemoral joint space narrowing (all P<0.05). Longitudinally, baseline serum 25(OH)D level predicted change in both medial and lateral tibial cartilage volume (beta=+0.04% per annum per nmole/liter for both; P<0.05), and change in serum 25(OH)D level was positively associated with change in medial tibial cartilage volume. These associations were consistent in subjects with radiographic OA and knee pain and/or in women, but not in men or in subjects without radiographic OA or knee pain. Sunlight exposure and serum 25(OH)D levels are both associated with decreased knee cartilage loss (assessed by radiograph or MRI). This is best observed using the whole range of 25(OH)D levels rather than predefined cut points and implies that achieving vitamin D sufficiency may prevent and/or retard cartilage loss in knee OA.


Prevalence of Campylobacter, Arcobacter, Helicobacter, and Sutterella spp. in human fecal samples as estimated by a reevaluation of isolation methods for Campylobacters.
The aims of this study were to investigate the prevalence of campylobacteria including Campylobacter jejuni subsp. jejuni (C. jejuni) and Campylobacter coli in human clinical samples and in samples from healthy individuals and to reevaluate the efficacies of conventional selective methods for isolation of Campylobacter spp. Two charcoal-based selective media, modified charcoal cefoperazone deoxycholate agar (mCCDA) and cefoperazone-amphotericin-teicoplanin (CAT) agar, were compared with Skirrow's blood-based medium and with a filter method (filter) applied to a yeast-enriched blood agar. A total of 1,376 specimens were tested on all four media, and the percentages of thermophilic Campylobacter-positive specimens isolated on Skirrow's medium, filters, CAT agar, and mCCDA were 82, 83, 85, and 95%, respectively. When additional samples were processed with the three selective media, mCCDA recovered significantly more thermophilic Campylobacter spp. than Skirrow's medium (P = 0.0034). No significant difference between Skirrow's medium and CAT agar was observed in this study. Another six taxa were identified, namely, Campylobacter concisus, Campylobacter curvus-like bacteria, Arcobacter butzleri, Arcobacter cryaerophilus, Helicobacter cinaedi, and Sutterella wadsworthensis. Most of these strains were isolated after 5 to 6 days of incubation by use of the filter technique. This paper provides evidence for the existence of S. wadsworthensis in human feces from clinical cases of gastrointestinal disorders and in feces from a healthy individual. Furthermore, C. concisus was isolated from a large number of diarrheal cases, particularly those at the extremes of age, but was additionally isolated from the feces of healthy people. Further investigations to establish the role of C. concisus and S. wadsworthensis in enteric disease is needed. We conclude that a range of campylobacteria may cause infections in Denmark.


Rehabilitation of stroke patients with apraxia: the role of additional cognitive and motor impairments.
The present study investigated which additional cognitive and motor impairments were present in stroke patients with apraxia and which of these factors influenced the effects of treatment. A group of 33 patients with apraxia were treated according to the guidelines of a therapy programme based on teaching patients strategies to compensate for the presence of apraxia. Patients were treated at occupational therapy departments in general hospitals, rehabilitation centres and nursing homes. The outcome of the strategy training was studied in a pre-post test design; measurements were conducted at baseline and after 12 weeks of therapy. The pretreatment scores of the patients with apraxia were compared to normscores and scores of a control group of patients without apraxia (n = 36) to investigate which impairments are present. The following variables were analysed in order to determine which factors influence outcome: additional neuropsychological deficits (comprehension of language, cognitive impairments due to dementia, neglect and short term memory), level of motor functioning, severity of apraxia and performance on activities of daily living (ADL), and some relevant patient characteristics (gender, age, type of stroke, time since stroke, and location of treatment). The results showed that the presence of apraxia is associated with the presence of additional cognitive and motor impairments. The successful outcome of strategy training was not negatively influenced by cognitive comorbidity. The outcome seemed to be more prominent in patients who were more severely impaired at the start of rehabilitation in terms of the degree of motor impairments, the severity of apraxia and the initial ADL dependence. The ADL observations, however, displayed a ceiling effect, which was taken into account in discussing the results. Demographic variables, especially age, did not predict the outcome of treatment. We suggest that the effect of this training is stronger in more severely disabled patients. However, neither the presence of additional cognitive impairments nor the severity of motor problems nor old age should be an indication for refraining from treating apraxia.


Amelotin: an enamel matrix protein that experienced distinct evolutionary histories in amphibians, sauropsids and mammals.
Amelotin (AMTN) is an ameloblast-secreted protein that belongs to the secretory calcium-binding phosphoprotein (SCPP) family, which originated in early vertebrates. In rodents, AMTN is expressed during the maturation stage of amelogenesis only. This expression pattern strongly differs from the spatiotemporal expression of other ameloblast-secreted SCPPs, such as the enamel matrix proteins (EMPs). Furthermore, AMTN was characterized in rodents only. In this study, we applied various approaches, including in silico screening of databases, PCRs and transcriptome sequencing to characterize AMTN sequences in sauropsids and amphibians, and compared them to available mammalian and coelacanth sequences. We showed that (i) AMTN is tooth (enamel) specific and underwent pseudogenization in toothless turtles and birds, and (ii) the AMTN structure changed during tetrapod evolution. To infer AMTN function, we studied spatiotemporal expression of AMTN during amelogenesis in a salamander and a lizard, and compared the results with available expression data from mouse. We found that AMTN is expressed throughout amelogenesis in non-mammalian tetrapods, in contrast to its expression limited to enamel maturation in rodents. Taken together our findings suggest that AMTN was primarily an EMP. Its functions were conserved in amphibians and sauropsids while a change occurred early in the mammalian lineage, modifying its expression pattern during amelogenesis and its gene structure. These changes likely led to a partial loss of AMTN function and could have a link with the emergence of prismatic enamel in mammals.


Discovery of 4,5-Dihydro-1H-thieno[2',3':2,3]thiepino [4,5-c]pyrazole-3-carboxamide Derivatives as the Potential Epidermal Growth Factor Receptors for Tyrosine Kinase Inhibitors.
The epidermal growth factor receptors (EGFRs), in which overexpression (known as upregulation) or overactivity have been associated with a number of cancers, has become an attractive molecular target for the treatment of selective cancers. We report here the design and synthesis of a novel series of 4,5-dihydro-1H-thieno [2',3':2,3]thiepino[4,5-c]pyrazole-3-carboxamide derivatives and the screening for their inhibitory activity on the EGFR high-expressing human A549 cell line using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). A Docking simulation was performed to fit compound 6g and gifitinib into the EGFR to determine the probable binding models, and the binding sites and modes conformation of 6g and gifitinib were exactly similar, the two compounds were stabilized by hydrogen bond interactions with MET769. Combining with the biological activity evaluation, compound 6g demonstrated the most potent inhibitory activity (IC50 = 9.68 ± 1.95 μmol·L⁻1 for A549). Conclusively, 4,5-dihydro-1H-thieno[2',3':2,3]thiepino[4,5-c]pyrazole-3-carboxamide derivatives as the EGFR tyrosine kinase inhibitors were discovered, and could be used as potential lead compounds against cancer cells.


Transpiration efficiency: new insights into an old story.
Producing more food per unit of water has never been as important as it is at present, and the demand for water by economic sectors other than agriculture will necessarily put a great deal of pressure on a dwindling resource, leading to a call for increases in the productivity of water in agriculture. This topic has been given high priority in the research agenda for the last 30 years, but with the exception of a few specific cases, such as water-use-efficient wheat in Australia, breeding crops for water-use efficiency has yet to be accomplished. Here, we review the efforts to harness transpiration efficiency (TE); that is, the genetic component of water-use efficiency. As TE is difficult to measure, especially in the field, evaluations of TE have relied mostly on surrogate traits, although this has most likely resulted in over-dependence on the surrogates. A new lysimetric method for assessing TE gravimetrically throughout the entire cropping cycle has revealed high genetic variation in different cereals and legumes. Across species, water regimes, and a wide range of genotypes, this method has clearly established an absence of relationships between TE and total water use, which dismisses previous claims that high TE may lead to a lower production potential. More excitingly, a tight link has been found between these large differences in TE in several crops and attributes of plants that make them restrict water losses under high vapour-pressure deficits. This trait provides new insight into the genetics of TE, especially from the perspective of plant hydraulics, probably with close involvement of aquaporins, and opens new possibilities for achieving genetic gains via breeding focused on this trait. Last but not least, small amounts of water used in specific periods of the crop cycle, such as during grain filling, may be critical. We assessed the efficiency of water use at these critical stages.


Influence of eye size and beam entry angle on dose to non-targeted tissues of the eye during stereotactic x-ray radiosurgery of AMD.
Age-related macular degeneration is a leading cause of vision loss for the elderly population of industrialized nations. The IRay® Radiotherapy System, developed by Oraya® Therapeutics, Inc., is a stereotactic low-voltage irradiation system designed to treat the wet form of the disease. The IRay System uses three robotically positioned 100 kVp collimated photon beams to deliver an absorbed dose of up to 24 Gy to the macula. The present study uses the Monte Carlo radiation transport code MCNPX to assess absorbed dose to six non-targeted tissues within the eye-total lens, radiosensitive tissues of the lens, optic nerve, distal tip of the central retinal artery, non-targeted portion of the retina, and the ciliary body--all as a function of eye size and beam entry angle. The ocular axial length was ranged from 20 to 28 mm in 2 mm increments, with the polar entry angle of the delivery system varied from 18° to 34° in 2° increments. The resulting data showed insignificant variations in dose for all eye sizes. Slight variations in the dose to the optic nerve and the distal tip of the central retinal artery were noted as the polar beam angle changed. An increase in non-targeted retinal dose was noted as the entry angle increased, while the dose to the lens, sensitive volume of the lens, and ciliary body decreased as the treatment polar angle increased. Polar angles of 26° or greater resulted in no portion of the sensitive volume of the lens receiving an absorbed dose of 0.5 Gy or greater. All doses to non-targeted structures reported in this study were less than accepted thresholds for post-procedure complications.