Potential benefits and limits of psychopharmacological therapies in pervasive developmental disorders.
The core symptoms of Autistic Spectrum Disorder (ASD) are impairment in reciprocal social interaction, communication, narrow interests, and stereotyped behaviour. These are frequently severe and persistent, although their severity may change over the course of life. Furthermore, the frequently associated symptoms of self-injury, aggressive behaviour, impulsivity, poor attention, anxiety, depression, and sleep disruption, can become a major source of additional distress and interference in functioning. The causes of autism are not yet known, but there is a general consensus that ASDs are highly heritable. Comprehension of the neurobiological basis for autism-spectrum disorders is still in its initial stages: a large body of research, however, has established ASD signs and symptoms are of neurological origin, and suggest that autism is a distributed neural system disorder, which disproportionately impairs many higher order abilities. Currently available medical treatments, primarily address co-morbid symptoms, rather than core symptoms. Thus, in spite of recent advances in psychopharmacology, the treatment approach still has important limits and shows poor efficacy on global outcomes. A potential pathway for improving clinical outcomes is that of the personalised treatment for autism, by using therapeutic drug monitoring (TDM) - a valuable tool for drugs with narrow therapeutic index - as well as systematic genetic background assessment, foreseen in future applications. However, it is already possible to implement an active surveillance programme to address safety concerns and to optimise therapeutic drug interventions in ASD.


Community-based perceptions of emergency care in Zambian communities lacking formalised emergency medicine systems.
In Zambia, an increasing burden of acute illness and injury emphasised the necessity of strengthening the national emergency care system. The objective of this study was to identify critical interventions necessary to improve the Zambian emergency care system by determining the current pattern of emergency care delivery as experienced by members of the community, identifying the barriers faced when trying to access emergency care and gathering community-generated solutions to improve emergency care in their setting. We used a qualitative research methodology to conduct focus groups with community members and healthcare providers in three Zambian provinces. Twenty-one community focus groups with 183 total participants were conducted overall, split equally between the provinces. An additional six focus groups were conducted with Zambian healthcare providers. Data were coded, aggregated and analysed using the content analysis approach. Community members in Zambia experience a wide range of medical emergencies. There is substantial reliance on family members and neighbours for assistance, commonly with transportation. Community-identified and provider-identified barriers to emergency care included transportation, healthcare provider deficiencies, lack of community knowledge, the national referral system and police protocols. Creating community education initiatives, strengthening the formal prehospital emergency care system, implementing triage in healthcare facilities and training healthcare providers in emergency care were community-identified and provider-identified solutions for improving access to emergency care.


The correlation grid: analysis of synchronous spiking in multi-dimensional spike train data and identification of feasible connection architectures.
This paper presents a visualization technique specifically designed to support the analysis of synchronous firings in multiple, simultaneously recorded, spike trains. This technique, called the correlation grid, enables investigators to identify groups of spike trains, where each pair of spike trains has a high probability of generating spikes approximately simultaneously or within a constant time shift. Moreover, the correlation grid was developed to help solve the following reverse problem: identification of the connection architecture between spike train generating units, which may produce a spike train dataset similar to the one under analysis. To demonstrate the efficacy of this approach, results are presented from a study of three simulated, noisy, spike train datasets. The parameters of the simulated neurons were chosen to reflect the typical characteristics of cortical pyramidal neurons. The schemes of neuronal connections were not known to the analysts. Nevertheless, the correlation grid enabled the analysts to find the correct connection architecture for each of these three data sets.


Serum Neurofilament Levels in Children With Febrile Seizures and in Controls.
Neuroaxonal damage is reflected by serum neurofilament light chain (sNfL) values in a variety of acute and degenerative diseases of the brain. The aim of this study was to investigate the impact of febrile and epileptic seizures on sNfL, serum copeptin, and prolactin levels in children compared with children with febrile infections without convulsions. A prospective cross-sectional study was performed in children aging 6 months to 5 years presenting with fever (controls, n = 61), febrile seizures (FS, n = 78), or epileptic seizures (ES, n = 16) at our emergency department. sNfL, copeptin, and prolactin were measured within a few hours after the event in addition to standard clinical, neurophysiological, and laboratory assessment. All children were followed up for at least 1 year after presentation concerning recurrent seizures. Serum copeptin values were on average 4.1-fold higher in FS and 3.2-fold higher in ES compared with controls (both p < 0.01). Serum prolactin values were on average 1.3-fold higher in FS compared with controls ( p < 0.01) and without difference between ES and controls. There was no significant difference of mean sNfL values (95% CI) between all three groups, FS 21.7 pg/ml (19.6-23.9), ES 17.7 pg/ml (13.8-21.6), and controls 23.4 pg/ml (19.2-27.4). In multivariable analysis, age was the most important predictor of sNfL, followed by sex and C reactive protein. Neither the duration of seizures nor the time elapsed from seizure onset to blood sampling had an impact on sNfL. None of the three biomarkers were related to recurrent seizures. Serum neurofilament light is not elevated during short recovery time after FS when compared with children presenting febrile infections without seizures. We demonstrate an age-dependent decrease of sNfL from early childhood until school age. In contrast to sNfL levels, copeptin and prolactin serum levels are elevated after FS.


The two Caenorhabditis elegans metallothioneins (CeMT-1 and CeMT-2) discriminate between essential zinc and toxic cadmium.
The nematode Caenorhabditis elegans expresses two metallothioneins (MTs), CeMT-1 and CeMT-2, that are believed to be key players in the protection against metal toxicity. In this study, both isoforms were expressed in vitro in the presence of either Zn(II) or Cd(II). Metal binding stoichiometries and affinities were determined by ESI-MS and NMR, respectively. Both isoforms had equal zinc binding ability, but differed in their cadmium binding behaviour, with higher affinity found for CeMT-2. In addition, wild-type C. elegans, single MT knockouts and a double MT knockout allele were exposed to zinc (340 microm) or cadmium (25 microm) to investigate effects in vivo. Zinc levels were significantly increased in all knockout strains, but were most pronounced in the CeMT-1 knockout, mtl-1 (tm1770), while cadmium accumulation was highest in the CeMT-2 knockout, mtl-2 (gk125) and the double knockout mtl-1;mtl-2 (zs1). In addition, metal speciation was assessed by X-ray absorption fine-structure spectroscopy. This showed that O-donating, probably phosphate-rich, ligands play a dominant role in maintaining the physiological concentration of zinc, independently of metallothionein status. In contrast, cadmium was shown to coordinate with thiol groups, and the cadmium speciation of the wild-type and the CeMT-2 knockout strain was distinctly different to the CeMT-1 and double knockouts. Taken together, and supported by a simple model calculation, these findings show for the first time that the two MT isoforms have differential affinities towards Cd(II) and Zn(II) at a cellular level, and this is reflected at the protein level. This suggests that the two MT isoforms have distinct in vivo roles.


Bronchoscopic lung-volume reduction with Exhale airway stents for emphysema (EASE trial): randomised, sham-controlled, multicentre trial.
Airway bypass is a bronchoscopic lung-volume reduction procedure for emphysema whereby transbronchial passages into the lung are created to release trapped air, supported with paclitaxel-coated stents to ease the mechanics of breathing. The aim of the EASE (Exhale airway stents for emphysema) trial was to evaluate safety and efficacy of airway bypass in people with severe homogeneous emphysema. We undertook a randomised, double-blind, sham-controlled study in 38 specialist respiratory centres worldwide. We recruited 315 patients who had severe hyperinflation (ratio of residual volume [RV] to total lung capacity of ≥0·65). By computer using a random number generator, we randomly allocated participants (in a 2:1 ratio) to either airway bypass (n=208) or sham control (107). We divided investigators into team A (masked), who completed pre-procedure and post-procedure assessments, and team B (unmasked), who only did bronchoscopies without further interaction with patients. Participants were followed up for 12 months. The 6-month co-primary efficacy endpoint required 12% or greater improvement in forced vital capacity (FVC) and 1 point or greater decrease in the modified Medical Research Council dyspnoea score from baseline. The composite primary safety endpoint incorporated five severe adverse events. We did Bayesian analysis to show the posterior probability that airway bypass was superior to sham control (success threshold, 0·965). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00391612. All recruited patients were included in the analysis. At 6 months, no difference between treatment arms was noted with respect to the co-primary efficacy endpoint (30 of 208 for airway bypass vs 12 of 107 for sham control; posterior probability 0·749, below the Bayesian success threshold of 0·965). The 6-month composite primary safety endpoint was 14·4% (30 of 208) for airway bypass versus 11·2% (12 of 107) for sham control (judged non-inferior, with a posterior probability of 1·00 [Bayesian success threshold >0·95]). Although our findings showed safety and transient improvements, no sustainable benefit was recorded with airway bypass in patients with severe homogeneous emphysema. Broncus Technologies.


Improved temperature precision in rotational coherent anti-stokes raman spectroscopy with a modeless dye laser.
Single-shot thermometry with dual-broadband rotational coherent anti-Stokes Raman spectroscopy that employs amplified spontaneous emission from a broadband modeless dye laser has been examined. Evaluation of single-shot spectra of air, N2, and O2 showed an improved temperature precision at room temperature compared with the precision obtained with a conventional dye laser. A comparison was also made between the use of single-mode and multimode Nd:YAG lasers as sources for narrowband radiation, and in all cases the single-mode Nd:YAG laser resulted in higher precision. The experimental results are compared with theoretical predictions.


Timing of vaccination does not affect antibody response or survival after pneumococcal challenge in splenectomized rats.
Pneumococcal vaccination after splenectomy for trauma decreases the incidence of overwhelming postsplenectomy infection. The optimal timing of vaccination has not been established. This study was conducted to determine whether timing of vaccination after splenectomy affects antibody response or survival after pneumococcal challenge. Sprague-Dawley rats were used for all experiments. Control rats (n=30) were divided into three equal groups and underwent splenectomy followed by sham vaccination 1, 7, or 42 days after splenectomy. Treated rats (n=66) were divided into three equal groups and underwent splenectomy followed by vaccination with polyvalent pneumococcal vaccine 1, 7, or 42 days after splenectomy. All rats then underwent intraperitoneal Streptococcus pneumoniae inoculation with the predetermined lethal dose for 50% of the population 10 days after vaccination. Rats were observed for a 72-hour period after inoculation, and mortality was recorded. Immunoglobulin G and immunoglobulin M antibody titers were determined before vaccination and before inoculation to determine antibody response. Mortality was greater in the control group than in the treatment group (21 of 30 [70%] vs. 2 of 64 [3%]; p < 0.01). There were no differences in mortality within either the control group (1 day, 6 of 10; 7 days, 7 of 10; 42 days, 8 of 10; p=0.62) or the treatment group (1 day, 0 of 21; 7 days, 0 of 21; 42 days, 2 of 22; p=0.14). Immunoglobulin G and immunoglobulin M antibody responses were greater in vaccinated than in nonvaccinated rats. There was no effect of timing of vaccination on antibody response. Pneumococcal vaccine reduces mortality from postsplenectomy infection. Timing of vaccination after splenectomy does not affect survival from a pneumococcal challenge or antibody response in rats. This study supports the practice of administering vaccine within 24 hours of splenectomy when vaccine cannot be administered before surgery.


Putative tissue markers in prostate cancer*.
A variety of putative prostate cancer markers have been described in human serum, urine, seminal fluid, and histological specimens. These markers exhibit varying capacities to detect prostate cancer and to predict disease course. In order to be considered markers for diagnosis or prognosis of disease course, and to be brought forward for large-scale clinical evaluation, they should fulfill several criteria. Firstly, there should be a biological or therapeutic rationale for choosing the marker, or at least a consistent association with disease presence, disease characteristics such as stage, or disease aggressiveness. Secondly, there should be an assessment of the strength of marker association with disease outcome. Thirdly, the marker should be assessed as an independent predictor in a multivariate analysis.


Genomic and physiological characterization of the chromate-reducing, aquifer-derived Firmicute Pelosinus sp. strain HCF1.
Pelosinus spp. are fermentative firmicutes that were recently reported to be prominent members of microbial communities at contaminated subsurface sites in multiple locations. Here we report metabolic characteristics and their putative genetic basis in Pelosinus sp. strain HCF1, an isolate that predominated anaerobic, Cr(VI)-reducing columns constructed with aquifer sediment. Strain HCF1 ferments lactate to propionate and acetate (the methylmalonyl-coenzyme A [CoA] pathway was identified in the genome), and its genome encodes two [NiFe]- and four [FeFe]-hydrogenases for H(2) cycling. The reduction of Cr(VI) and Fe(III) may be catalyzed by a flavoprotein with 42 to 51% sequence identity to both ChrR and FerB. This bacterium has unexpected capabilities and gene content associated with reduction of nitrogen oxides, including dissimilatory reduction of nitrate to ammonium (two copies of NrfH and NrfA were identified along with NarGHI) and a nitric oxide reductase (NorCB). In this strain, either H(2) or lactate can act as a sole electron donor for nitrate, Cr(VI), and Fe(III) reduction. Transcriptional studies demonstrated differential expression of hydrogenases and nitrate and nitrite reductases. Overall, the unexpected metabolic capabilities and gene content reported here broaden our perspective on what biogeochemical and ecological roles this species might play as a prominent member of microbial communities in subsurface environments.


BCOR-CCNB3 fusions are frequent in undifferentiated sarcomas of male children.
The BCOR-CCNB3 fusion gene, resulting from a chromosome X paracentric inversion, was recently described in translocation-negative 'Ewing-like' sarcomas arising in bone and soft tissue. Genetic subclassification of undifferentiated unclassified sarcomas may potentially offer markers for reproducible diagnosis and substrates for therapy. Using whole transcriptome paired-end RNA sequencing (RNA-seq) we unexpectedly identified BCOR-CCNB3 fusion transcripts in an undifferentiated spindle-cell sarcoma. RNA-seq results were confirmed through direct RT-PCR of tumor RNA and cloning of the genomic breakpoints from tumor DNA. Five additional undifferentiated sarcomas with BCOR-CCNB3 fusions were identified in a series of 42 pediatric and adult unclassified sarcomas. Genomic breakpoint analysis demonstrated unique breakpoint locations in each case at the DNA level even though the resulting fusion mRNA was identical in all cases. All patients with BCOR-CCNB3 sarcoma were males diagnosed in mid childhood (7-13 years of age). Tumors were equally distributed between axial and extra-axial locations. Five of the six tumors were soft-tissue lesions with either predominant spindle-cell morphology or spindle-cell areas interspersed with ovoid to round cells. CCNB3 immunohistochemistry showed strong nuclear positivity in five tumors before oncologic therapy, but was patchy to negative in post-treatment tumor samples. An RT-PCR assay developed to detect the fusion transcript in archival formalin-fixed tissue was positive in all six cases, with high sensitivity and specificity in both pre- and post-treated samples. This study adds to recent reports on the clinicopathologic spectrum of BCOR-CCNB3 fusion-positive sarcomas, a newly emerging entity within the undifferentiated unclassified sarcoma category and describes a simple RT-PCR assay that in conjunction with CCNB3 immunohistochemistry can be useful in diagnosing these tumors.


An overview of homologous pairing and DNA strand exchange proteins.
Processes fundamental to all models of genetic recombination include the homologous pairing and subsequent exchange of DNA strands. Biochemical analysis of these events has been conducted primarily on the recA protein of Escherichia coli, although proteins which can promote such reactions have been purified from many sources, both prokaryotic and eukaryotic. The activities of these homologous pairing and DNA strand exchange proteins are either ATP-dependent, as predicted based on the recA protein paradigm, or, more unexpectedly, ATP-independent. This review examines the reactions promoted by both classes of proteins and highlights their similarities and differences. The mechanistic implications of the apparent existence of 2 classes of strand exchange protein are discussed.


Shear bond strength of repaired adhesive filling materials using different repair procedures.
Matrices of adhesive restorative materials and repair procedures may both influence bond strength of repaired adhesive materials. This study examined the bond strength of adhesive filling materials to mature adhesive materials after pretreatment with Co-Jet, Monobond S, and Silibond. A hybrid composite (Tetric Ceram), a polyacid-modified composite resin (Dyract), and an ormocer (Definite) and their corresponding bonding agents were tested in combination with the repair systems. Restorative materials were placed in molds and polymerized. In group A (control), homologous materials were applied on the polymerized surface directly. In group B, homologous filling materials were placed onto the respective material with the corresponding bonding agent. In group C, adhesive repair filling material was applied after solely pretreating with the repair systems. In group D, the restorative material was applied after pretreatment with the repair systems and application of the corresponding bonding agent. Each subgroup consisted of 20 specimens. The shear bond strength of the samples was measured in a universal testing machine according to the test procedure ISO 10477. The significantly best bond strength of repair filling material on Tetric was achieved by pretreating with Co-Jet followed by application of the corresponding bonding agent (25.5 +/- 5.4 MPa, p < 0.05). A single application of the bonding agent or use of Monobond with bonding agent also yielded bond strengths of 20 MPa or more on Tetric. For Dyract or Definite, bond strengths of 15.5 +/- 5.3 MPa or less were achieved with the different repair procedures. Successful pretreatment of hybrid composites for repair can be achieved by application of Co-Jet followed by the corresponding bonding material, whereas sufficient repair of ormocers and polyacid-modified resin composites is limited.


Pressure-volume regulation in hypertension.
In all forms of hypertension, including human essential hypertension, pressure natriuresis is abnormal because sodium excretion is the same as in normotension despite increased arterial pressure. Considerable evidence indicates that this resetting of pressure natriuresis plays a key role in causing hypertension, rather than merely occurring as an adaptation to increased blood pressure. Because human essential hypertension is a heterogeneous disease, it is likely that multiple neurohumoral and intrarenal defects contribute to abnormal pressure natriuresis and increased blood pressure. Physiological studies have shown that renal abnormalities that cause increased distal and collecting tubule reabsorption, decreased glomerular filtration coefficient or loss of nephrons also cause decreased slope of pressure natriuresis (salt-sensitive hypertension), whereas increased preglomerular resistance causes a parallel shift of pressure natriuresis (salt-insensitive hypertension). Comparison of the characteristics of pressure natriuresis (such as salt-sensitivity of blood pressure) in hypertensive subjects with those forms of experimental hypertension of known origin can provide insight into the etiology of human hypertension. With long-standing hypertension, pathological changes in the glomeruli and renal arterioles may further shift pressure natriuresis and exacerbate hypertension.


Long-Term Outcomes of Postpartum Psychosis: A Systematic Review and Meta-Analysis.
There is limited information on the longitudinal disease course after first-onset postpartum psychosis (PP). Some women will experience severe affective episodes outside the postpartum period, while for other women their vulnerability to mania and psychosis may be restricted to the postpartum period. This meta-analysis estimates the risk of recurrence after first-onset PP. A computerized literature search was conducted using Embase, MEDLINE, Web of Science, PsycINFO, Cochrane Central, PubMed, and Google Scholar (first 100 hits) combining key terms regarding longitudinal studies of first-onset PP from inception through May 9, 2019. Two levels of screening were used on 2,807 citations. A total of 6 English-language articles including patients with a first-onset PP within 1 year after childbirth and a minimum follow-up period of 18 months or more after the index episode were included in the quantitative analysis. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines were used for data extraction, and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were used to independently assess the quality of the included studies. The primary outcome was recurrence, defined as any subsequent psychiatric episode after first-onset PP. Six studies and 645 patients could be included in the quantitative analyses; follow-up periods were 11-26 years. Of these patients, 279 did not experience subsequent severe episodes outside the postpartum period. Meta-analysis using random-effect estimation resulted in a weighted estimate of 43.5% (95% CI, 37.7% to 49.4%). In this meta-analysis, more than 40% of women were classified as having "isolated postpartum psychosis," which could be considered a distinct diagnostic category with a more favorable prognosis. The remaining women had severe non-puerperal psychiatric episodes during longitudinal follow-up.


Distance Management of Spinal Disorders During the COVID-19 Pandemic and Beyond: Evidence-Based Patient and Clinician Guides From the Global Spine Care Initiative.
The COVID-19 pandemic has greatly limited patients' access to care for spine-related symptoms and disorders. However, physical distancing between clinicians and patients with spine-related symptoms is not solely limited to restrictions imposed by pandemic-related lockdowns. In most low- and middle-income countries, as well as many underserved marginalized communities in high-income countries, there is little to no access to clinicians trained in evidence-based care for people experiencing spinal pain. The aim of this study is to describe the development and present the components of evidence-based patient and clinician guides for the management of spinal disorders where in-person care is not available. Ultimately, two sets of guides were developed (one for patients and one for clinicians) by extracting information from the published Global Spine Care Initiative (GSCI) papers. An international, interprofessional team of 29 participants from 10 countries on 4 continents participated. The team included practitioners in family medicine, neurology, physiatry, rheumatology, psychology, chiropractic, physical therapy, and yoga, as well as epidemiologists, research methodologists, and laypeople. The participants were invited to review, edit, and comment on the guides in an open iterative consensus process. The Patient Guide is a simple 2-step process. The first step describes the nature of the symptoms or concerns. The second step provides information that a patient can use when considering self-care, determining whether to contact a clinician, or considering seeking emergency care. The Clinician Guide is a 5-step process: (1) Obtain and document patient demographics, location of primary clinical symptoms, and psychosocial information. (2) Review the symptoms noted in the patient guide. (3) Determine the GSCI classification of the patient's spine-related complaints. (4) Ask additional questions to determine the GSCI subclassification of the symptom pattern. (5) Consider appropriate treatment interventions. The Patient and Clinician Guides are designed to be sufficiently clear to be useful to all patients and clinicians, irrespective of their location, education, professional qualifications, and experience. However, they are comprehensive enough to provide guidance on the management of all spine-related symptoms or disorders, including triage for serious and specific diseases. They are consistent with widely accepted evidence-based clinical practice guidelines. They also allow for adequate documentation and medical record keeping. These guides should be of value during periods of government-mandated physical or social distancing due to infectious diseases, such as during the COVID-19 pandemic. They should also be of value in underserved communities in high-, middle-, and low-income countries where there is a dearth of accessible trained spine care clinicians. These guides have the potential to reduce the overutilization of unnecessary and expensive interventions while empowering patients to self-manage uncomplicated spinal pain with the assistance of their clinician, either through direct in-person consultation or via telehealth communication.


Solar Water Splitting Using Semiconductor Photocatalyst Powders.
Solar energy conversion is essential to address the gap between energy production and increasing demand. Large scale energy generation from solar energy can only be achieved through equally large scale collection of the solar spectrum. Overall water splitting using heterogeneous photocatalysts with a single semiconductor enables the direct generation of H2 from photoreactors and is one of the most economical technologies for large-scale production of solar fuels. Efficient photocatalyst materials are essential to make this process feasible for future technologies. To achieve efficient photocatalysis for overall water splitting, all of the parameters involved at different time scales should be improved because the overall efficiency is obtained by the multiplication of all these fundamental efficiencies. Accumulation of knowledge ranging from solid-state physics to electrochemistry and a multidisciplinary approach to conduct various measurements are inevitable to be able to understand photocatalysis fully and to improve its efficiency.


Influence of leptomeningeal collateral pattern on the prognostic value of mismatch in acute anterior circulation stroke.
This study aimed to investigate whether and to what degree leptomeningeal collateral flow as detected on angiography influences the prognostic value of computed tomography perfusion-estimated mismatch in interventional treatment of acute anterior circulation stroke. Thirty-eight consecutive patients with acute anterior circulation stroke who received interventional neuroradiologic treatment were assigned one of 2 groups depending on the patient's degree of collateral flow (18 patients with poor collaterals, 20 patients with high degree collaterals) according to the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology grading system. In a multiregression model, we investigated a possible interaction between 2 independent variables mismatch ratio and degree of collateral flow using a "centered" variable approach. The mismatch ratio per se showed a significant correlation with final clinical outcome (β coefficient, -0.79; P = 0.02); whereas, there was no interaction shown between mismatch degree of collateral flow (β coefficient, 0.54; P = 0.1). This study suggests that the predictive value of computed tomography perfusion-estimated mismatch is not influenced by the degree of leptomeningeal collateral flow.


Use of indocyanine green to minimise uretero-enteric strictures after robotic radical cystectomy.
To evaluate the impact of indocyanine green (ICG) for assessing ureteric vascularity on the rate of uretero-enteric stricture formation after robot-assisted radical cystectomy (RARC) with intracorporeal urinary diversion (ICUD). We identified 179 patients undergoing RARC and ICUD between January 2014 and May 2017, and divided the patients into two groups based on the utilisation of ICG for the assessment of ureteric vascularity (non-ICG group and ICG group). We retrospectively reviewed the medical records to identify the length of ureter excised. Demographic, perioperative outcomes (including 90-day complications and readmissions), and the rate of uretero-enteric stricture were compared between the two groups. The two groups were compared using the t-test for continuous variables and the chi-squared test for categorical variables. A P < 0.05 was considered statistically significant. A total of 132 and 47 patients were in the non-ICG group and the ICG group, respectively. There were no differences in baseline characteristics and perioperative outcomes including operating time, estimated blood loss, and length of stay. The ICG group was associated with a greater length of ureter being excised during the uretero-enteric anastomosis and a greater proportion of patients having long segment (>5 cm) ureteric resection. The median follow-up was 14 and 12 months in the non-ICG and ICG groups, respectively. The ICG group was associated with no uretero-enteric strictures compared to a per-patient stricture rate of 10.6% and a per-ureter stricture rate of 6.6% in the non-ICG group (P = 0.020 and P = 0.013, respectively). The use of ICG fluorescence to assess distal ureteric vascularity during RARC and ICUD may reduce the risk of ischaemic uretero-enteric strictures. The technique is simple, safe, and reproducible. Larger studies with longer follow-up are needed to confirm our findings.


Correlation between interferon- gamma secretion and cytotoxicity, in virus-specific memory T cells.
ELISpot and intracellular cytokine staining are replacing the traditional cytolytic ((51)Cr release) assay method in vaccine trials using human immunodeficiency virus (HIV)-1, and it is widely assumed that the number of interferon (IFN)- gamma -secreting T cells is a surrogate for the level of cytolytic activity. Thus, we sought to determine whether the detection of IFN- gamma in CD8(+) T cells correlates with cytolytic ability in vitro. In 29 (69.0%) of 42 HIV-1-seronegative immunocompetent individuals (22 unvaccinated and 20 vaccinated), virus-specific T cell responses recognizing cytomegalovirus, Epstein-Barr virus, and influenza and HIV-1 Gag epitopes were detected by at least 1 assay method (ELISpot, intracellular cytokine staining, and/or (51)Cr release), and 18 (62.1%) of these 29 demonstrated both IFN- gamma secretion and cytolysis. There was strong correlation between the results of IFN- gamma ELISpot and those of IFN- gamma intracellular cytokine staining ( rho =0.88) and between the results of (51)Cr release and those of intracellular cytokine staining ( rho =0.81); although the correlation is not absolute, intracellular cytokine staining can be used--and is superior to ELISpot--as a surrogate for cytolytic assays.


Mutation analysis by direct and whole exome sequencing in familial and sporadic tooth agenesis.
Dental agenesis is one of the most common congenital craniofacial abnormalities. Dental agenesis can be classified, relative to the number of missing teeth (excluding third molars), as hypodontia (1 to 5 missing teeth), oligodontia (6 or more missing teeth), or anodontia (lack of all teeth). Tooth agenesis may occur either in association with genetic syndromes, based on the presence of other inherited abnormalities, or as a non-syndromic trait, with both familiar and sporadic cases reported. In this study, we enrolled 16 individuals affected by tooth agenesis, prevalently hypodontia, and we carried out direct Sanger sequencing of paired box 9 (PAX9) and Msh homeobox 1 (MSX1) genes in 9 subjects. Since no mutations were identified, we performed whole exome sequencing (WES) in the members of 5 families to identify causative gene mutations either novel or previously described. Three individuals carried a known homozygous disease mutation in the Wnt family member 10A (WNT10A) gene (rs121908120). Interestingly, two of these individuals were siblings and also carried a heterozygous functional variant in EDAR-associated death domain (EDARADD) (rs114632254), another disease causing gene, generating a combination of genetic variants never described until now. The analysis of exome sequencing data in the members of other 3 families highlighted new candidate genes potentially involved in tooth agenesis and considered suitable for future studies. Overall, our study confirmed the major role played by WNT10A in tooth agenesis and the genetic heterogeneity of this disease. Moreover, as more genes are shown to be involved in tooth agenesis, WES analysis may be an effective approach to search for genetic variants in familiar or sporadic tooth agenesis, at least in more severe clinical manifestations.


The Effects of Forced Exhalation and Inhalation, Grunting, and Valsalva Maneuver on Forehand Force in Collegiate Tennis Players.
To examine the effects of forced expiration (FE), forced inspiration (FI), grunting (GR), and valsalva maneuver (VM), on air volume, maximum force production, and muscle recruitment during a simulated forehand stroke in collegiate tennis players. Superficial electrodes were placed over the anterior deltoid, pectoralis major, rectus abdominis, lumbar and thoracic erector spinae, and external and internal obliques. Subjects stood in a simulated forehand stroke stance with their dominant hand positioned on a force plate. Subjects performed 3 repetitions of maximal 2- to 3-second isometric forehands with randomly assigned breathing conditions (FE, FI, VM, and GR) and 30-seconds rest between contractions. Air volumes were also collected during each trial. A repeated-measures multivariate analysis of variance compared normalized peak electromyographic activity across the 7 muscle groups. Separate repeated measures ANOVAs compared the effect of breathing conditions on peak force production and air volume. Statistical significance was set at p ≤ 0.05 for all analyses. Overall muscle activity differed significantly by breathing condition (p = 0.031) with greater anterior deltoid activity was seen in FE and GR vs. VM. Internal oblique activity was significantly greater in GR than FI or VM, and thoracic erector spinae activity was significantly greater during FE and VM than FI. Force production did not differ significantly among breathing conditions (p = 0.74); however, GR forces were greater than FI and VM forces (p ≤ 0.05). Forced expiration air volume was significantly greater (p < 0.001) than FI, GR, or VM. These findings suggest that either GR or a more quiescent FE can be used to enhance force production. Forced expiration is a potentially safer alternative to VM and more aurally pleasing than GR.


Differential effects of ferritin, calcium, zinc, and gallic acid on in vitro proliferation of human glioblastoma cells and normal astrocytes.
In vitro, when using low concentrations of ferritin (ng/ml) or CaCl2 (micrograms/ml), multiplication of a human, 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU)-resistant glioblastoma cell line (U251) is enhanced 1.5 to 2 times more actively than multiplication of a normal astrocyte line (CRL 1656). Ferritin and Ca2+ ions exhibit a marked effect on DNA isolated from these cells: glioblastoma DNA relaxation is strongly increased (as evidenced by increased 260 nm ultraviolet absorbance), being from 5 to 6 times that of astrocyte DNA, which remains only slightly affected. Under identical experimental conditions, Zn2+ and gallium ions selectively inhibit glioblastoma cell multiplication but at the same concentrations do not inhibit astrocyte multiplication. Ultraviolet absorbance measurements demonstrate that both of these agents condense relaxed glioblastoma DNA in vitro. Zn2+ or gallium ions added to culture medium containing stimulatory concentrations of ferritin or Ca2+ ions selectively and strongly inhibit enhancement of glioblastoma cell multiplication by these mitogens while not affecting normal multiplication of astrocytes.


Fully automated synthesis of [(18) F]fluoro-dihydrotestosterone ([(18) F]FDHT) using the FlexLab module.
Imaging of androgen receptor expression in prostate cancer using F-18 FDHT is becoming increasingly popular. With the radiolabelling precursor now commercially available, developing a fully automated synthesis of [(18) F] FDHT is important. We have fully automated the synthesis of F-18 FDHT using the iPhase FlexLab module using only commercially available components. Total synthesis time was 90 min, radiochemical yields were 25-33% (n = 11). Radiochemical purity of the final formulation was > 99% and specific activity was > 18.5 GBq/µmol for all batches. This method can be up-scaled as desired, thus making it possible to study multiple patients in a day. Furthermore, our procedure uses 4 mg of precursor only and is therefore cost-effective. The synthesis has now been validated at Austin Health and is currently used for [(18) F]FDHT studies in patients. We believe that this method can easily adapted by other modules to further widen the availability of [(18) F]FDHT.


Distress screening using distress thermometer in head and neck cancer patients undergoing radiotherapy and evaluation of causal factors predicting occurrence of distress.
Distress is commonly seen in head and neck cancer patients undergoing radiotherapy. Causal factors of distress are multifactorial; which encompasses physical, psychological, spiritual, and existential factors with complex interrelationship among the factors. Thirty patients undergoing head and neck radiotherapy were included in the study. Patients were screened for pain scores, distress scores, physical and psychological symptoms, and spiritual and emotional distress. Significant increasing trend seen for pain score, distress score, and total number of symptoms during 2(nd) week, 4(th) week, and on completion of radiotherapy treatment (all P's < 0.001) compared to pretreatment. Those who had chemotherapy (CT) along with radiation had significantly greater pain score (t = 5.54, P = 0.03) and distress score (t = 3.9, P = 0.05) at 2 weeks into radiotherapy compared to those who did not receive CT. There was significantly higher grade of skin toxicity in those with spiritual distress (Somers' d = 0.36, P = 0.02) and higher grade of mucositis in those with existential distress (d = 0.34, P = 0.02) at 4 weeks into radiotherapy. Positive correlation between distress score and pain score and occurrence of physical symptoms. Increasing trend seen for pain score, distress score, and total number of symptoms during 2(nd) week, 4(th) week, and completion of radiotherapy treatment compared to pretreatment. Increase in distress score in those with existential and spiritual distress.


Role of Erythronium americanum Ker. in Energy Flow and Nutrient Dynamics of a Northern Hardwood Forest Ecosystem.
The aboveground activity of the spring herb, Erythronium americanum, is restricted to the period between snowmelt and forest canopy development. Its phenology and production capacity closely adapt the species to this temporal niche in northern deciduous forests. While E. americanum has a minor effect on energy flow, it may reduce losses of potassium and nitrogen from the ecosystem during the period of maximum removal by incorporating these elements in accumulating biomass. Later, during the summer, these nutrients are made available when the above-ground, nonperennating tissues decay.


Retrievability of implant-supported zirconia restorations cemented on zirconia abutments.
Retrievability of implant-supported restorations is important. Data are lacking for cemented zirconia crowns on zirconia abutments. The purpose of this in vitro study was to investigate the influence of different cements and marginal discrepancy on the retrievability of implant-supported zirconia crowns. Furthermore, the influence of thermocycling on retrievability was evaluated. Thirty tapered Camlog zirconia abutments (6-degree taper, 6×4.3 mm) were used. Thirty zirconia crowns with 3 different marginal cementation discrepancies (70, 130, 190 μm) were fabricated by using computer-aided design and computer-aided manufacturing (CAD-CAM) technology. Five cements for interim or semidefinitive cementation were used: eugenol-free zinc oxide (Freegenol) and acrylurethane (ImProv) and 3 different composite resin cements (X-Pand Implant, Dyna Implant, Telio CS Cem Implant). Specimens underwent either 3-day storage in sodium chloride or thermocycling (10 000 cycles). Crowns were removed by using a universal testing machine (UTM) and a clinical removal device. Data were analyzed using 1-way ANOVA and the Scheffé test (α=.05). Thermocycling decreased the retention force significantly (P<.001). Marginal discrepancy (70 to 190 μm) was not significantly influential on retrievability (P>.05). Therefore, groups were pooled according to the factor of marginal discrepancy. The mean retention force using the UTM after 3-day storage and thermocycling was as follows: Freegenol, 235 ±42 N (thermocycling, 29 ±9 N); Improv, 110 ±50 N (thermocycling, 35 ±38 N); Telio CS, 104 ±17 N (thermocycling, 6 ±10 N); Dyna implant, 61 ±17 N (thermocycling, 1 ±1 N); and X-Pand, 50 ±16 N (thermocycling, 2 ±2 N). Retention forces of the tested cements were significantly different and decreased considerably after thermocycling. Marginal cementation discrepancy between 70 and 190 μm did not influence retrievability.


LIM kinase inhibition reduces breast cancer growth and invasiveness but systemic inhibition does not reduce metastasis in mice.
Metastasis is the major cause of morbidity and mortality in cancer patients. An understanding of the genes that regulate metastasis and development of therapies to target these genes is needed urgently. Since members of the LIM kinase (LIMK) family are key regulators of the actin cytoskeleton and are involved in cell motility and invasion, LIMK is considered to be a good therapeutic target for metastatic disease. Here we investigated the consequences of LIMK inhibition on growth and metastasis of human and mouse mammary tumors. LIMK activity was reduced in tumor cells by expression of dominant-negative LIMK1, by RNA interference or with a selective LIMK inhibitor. The extent of phosphorylation of the LIMK substrate, cofilin, of proliferation and invasion in 2D and 3D culture and of tumor growth and metastasis in mice were assessed. Inhibition of LIMK activity efficiently reduced the pro-invasive properties of tumor cells in vitro. Tumors expressing dominant-negative LIMK1 grew more slowly and were less metastatic in mice. However, systemic administration of a LIMK inhibitor did not reduce either primary tumor growth or spontaneous metastasis. Surprisingly, metastasis to the liver was increased after administration of the inhibitor. These data raise a concern about the use of systemic LIMK inhibitors for the treatment of metastatic breast cancer.


Overexpression of eCLCA1 in small airways of horses with recurrent airway obstruction.
The human hCLCA1 and murine mCLCA3 (chloride channels, calcium-activated) have recently been identified as promising therapeutic targets in asthma. Recurrent airway obstruction in horses is an important animal model of human asthma. Here, we have cloned and characterized the first equine CLCA family member, eCLCA1. The 913 amino acids eCLCA1 polypeptide forms a 120-kDa transmembrane glycoprotein that is processed to an 80-kDa protein in vivo. Three single nucleotide polymorphisms were detected in the eCLCA1 coding region in 14 horses, resulting in two amino acid changes (485H/R and 490V/L). However, no functional differences were recorded between the channel properties of the two variants in transfected HEK293 cells. The eCLCA1 protein was detected immunohistochemically in mucin-producing cells in the respiratory and intestinal tracts, cutaneous sweat glands, and renal mucous glands. Strong overexpression of eCLCA1 was observed in the airways of horses with recurrent airway obstruction using Northern blot hybridization, Western blotting, immunohistochemistry, and real-time quantitative RT-PCR. The results suggest that spontaneous or experimental recurrent airway obstruction in horses may serve as a model to study the role of CLCA homologs in chronic airway disease with overproduction of mucins.


Helios, a novel dimerization partner of Ikaros expressed in the earliest hematopoietic progenitors.
Normal hematopoietic development depends on the activity of the Ikaros transcription factor, which contains distinct zinc-finger domains that mediate DNA binding and protein dimerization. Mice homozygous for a transgene encoding a dominant-negative version of Ikaros that lacks the DNA-binding domain but not the dimerization domain have a more severe phenotype than Ikaros null mice. This observation suggests the presence of factor(s) that can dimerize with Ikaros and partially complement its function. One previously identified factor, Aiolos, probably serves this role in the lymphoid system; a related factor involved in hematopoietic progenitors remains unknown, however. Here, we describe the cloning of an Ikaros-related gene, Helios. Analysis of the primary sequences of Helios, Ikaros and Aiolos revealed that the DNA-binding, transcriptional activation and dimerization domains are functionally conserved. Helios activated transcription from Ikaros DNA-binding sites and could dimerize with itself, Ikaros or Aiolos. Expression of Helios was detected in the earliest hematopoietic sites of the embryo, in hematopoietic stem cells in the adult and was subsequently restricted to a subset of cells in the T cell lineage. Helios co-localized with Ikaros and Aiolos proteins in macromolecular nuclear structures and formed stable complexes in vivo with the dominant-negative version of Ikaros. Distinct but overlapping expression patterns of members of the Ikaros gene family during hematopoiesis might result in the formation of different multimeric complexes that have specific roles in lineage progression. The preferential expression of Helios in the earliest stages of hematopoiesis suggests that this gene functions predominantly in early progenitors.


Differential expression of voltage-gated K+ channel subunits in adult rat heart. Relation to functional K+ channels?
Polyclonal antibodies against each of the K+ channel subunits (Kv1.2, Kv1.4, Kv1.5, Kv2.1, and Kv4.2) shown previously to be expressed in adult rat heart at the mRNA level were used to examine the distributions of these K+ channel subunits in adult rat atrial and ventricular membranes. Immunohistochemistry on isolated adult rat ventricular myocytes revealed strong labeling with the anti-Kv4.2 and anti-Kv1.2 antibodies. Although somewhat weaker (than with anti-Kv1.2 or anti-Kv4.2), positive staining was also observed with the anti-Kv1.5 and anti-Kv2.1 antibodies. Ventricular myocytes exposed to the anti-Kv1.4 antibody, in contrast, did not appear significantly different from background. Qualitatively similar results were obtained on isolated adult rat atrial myocytes. Western blots of atrial and ventricular membrane proteins confirmed the presence of Kv1.2, Kv1.5, Kv2.1, and Kv4.2 and revealed differences in the relative abundances of these subunits in the two membrane preparations. Kv4.2, for example, is more abundant in ventricular than in atrial membranes, whereas Kv1.2 and Kv2.1 are higher in atrial membranes; Kv1.5 levels are comparable in the two preparations. In contrast to these results, nothing was detected in Western blots of atrial or ventricular membrane proteins with the anti-Kv1.4 antibody at concentrations that revealed intense labeling of a 97-kD protein in adult rat brain membranes. A very faint band was detected at 97 kD in the atrial and ventricular preparations when the anti-Kv1.4 antibody was used at a 5- to 10-fold higher concentration. The simplest interpretation of these results is that Kv1.4 is not an abundant protein in adult rat atrial or ventricular myocytes. Therefore, it seems unlikely that Kv1.4 plays an important role in the formation of functional depolarization-activated K+ channels in these cells. The relation(s) between the (other four) K+ channel subunits and the depolarization-activated K+ channels identified electrophysiologically in adult rat atrial and ventricular myocytes is discussed in the present study.


Factors that drive the increasing use of FFPE tissue in basic and translational cancer research.
The decision to use 10% neutral buffered formalin fixed, paraffin embedded (FFPE) archival pathology material may be dictated by the cancer research question or analytical technique, or may be governed by national ethical, legal and social implications (ELSI), biobank, and sample availability and access policy. Biobanked samples of common tumors are likely to be available, but not all samples will be annotated with treatment and outcomes data and this may limit their application. Tumors that are rare or very small exist mostly in FFPE pathology archives. Pathology departments worldwide contain millions of FFPE archival samples, but there are challenges to availability. Pathology departments lack resources for retrieving materials for research or for having pathologists select precise areas in paraffin blocks, a critical quality control step. When samples must be sourced from several pathology departments, different fixation and tissue processing approaches create variability in quality. Researchers must decide what sample quality and quality tolerance fit their specific purpose and whether sample enrichment is required. Recent publications report variable success with techniques modified to examine all common species of molecular targets in FFPE samples. Rigorous quality management may be particularly important in sample preparation for next generation sequencing and for optimizing the quality of extracted proteins for proteomics studies. Unpredictable failures, including unpublished ones, likely are related to pre-analytical factors, unstable molecular targets, biological and clinical sampling factors associated with specific tissue types or suboptimal quality management of pathology archives. Reproducible results depend on adherence to pre-analytical phase standards for molecular in vitro diagnostic analyses for DNA, RNA and in particular, extracted proteins. With continuing adaptations of techniques for application to FFPE, the potential to acquire much larger numbers of FFPE samples and the greater convenience of using FFPE in assays for precision medicine, the choice of material in the future will become increasingly biased toward FFPE samples from pathology archives. Recognition that FFPE samples may harbor greater variation in quality than frozen samples for several reasons, including variations in fixation and tissue processing, requires that FFPE results be validated provided a cohort of frozen tissue samples is available.


Evaluation of Hemolysis as a Severe Feature of Preeclampsia.
Hemolysis predisposes to adverse pregnancy outcomes. Yet, there are limited data on hemolysis in hypertensive disorders of pregnancy other than hemolysis, elevated liver enzymes, and low platelet count syndrome. To evaluate the prevalence and impact of hemolysis in hypertensive disorders of pregnancy, we performed a retrospective cohort study at a single center (October 2013-May 2017), among women screened for hemolysis using lactate dehydrogenase (LDH) levels. We compared LDH levels by hypertensive disorder (chronic hypertension, gestational hypertension, preeclampsia, and preeclampsia with severe features) and evaluated impact on adverse pregnancy outcomes. Data were analyzed by χ2 or t test, ANOVA, test of medians, and logistic regression. Among 8645 deliveries, 1188 (13.7%) had a hypertensive disorder. Of these, 812 (68.4%) had LDH measurement before delivery: chronic hypertension (n=152); gestational hypertension (n=209); preeclampsia (n=216); and preeclampsia with severe features (n=235). LDH ≥400 U/L (≥1.6× normal) was more common in preeclampsia with severe features compared with other hypertensive disorders of pregnancy (9.8% versus 2.3%; P<0.001); adjusted odds ratio 4.52 (95% confidence interval, 2.2-9.2; P<0.001). LDH ≥400 U/L was associated with adverse maternal outcomes (41.7% versus 15.3%; P<0.001), adjusted odds ratio 3.05 (95% confidence interval, 1.4-6.7; P=0.006), and adverse neonatal outcomes (eg, preterm birth 59.4% versus 22.5%; P<0.001). We find that elevated LDH levels are associated with adverse maternal and neonatal outcomes in hypertension and preeclampsia, independent of hemolysis, elevated liver enzymes, and low platelet count syndrome. Therefore, elevated LDH levels (≥1.6× normal or ≥400 U/L) may be considered a severe feature of preeclampsia.


Early effects of climate change: do they include changes in vector-borne disease?
The world's climate appears now to be changing at an unprecedented rate. Shifts in the distribution and behaviour of insect and bird species indicate that biological systems are already responding to this change. It is well established that climate is an important determinant of the spatial and temporal distribution of vectors and pathogens. In theory, a change in climate would be expected to cause changes in the geographical range, seasonality (intra-annual variability), and in the incidence rate (with or without changes in geographical or seasonal patterns). The detection and then attribution of such changes to climate change is an emerging task for scientists. We discuss the evidence required to attribute changes in disease and vectors to the early effects of anthropogenic climate change. The literature to date indicates that there is a lack of strong evidence of the impact of climate change on vector-borne diseases (i.e. malaria, dengue, leishmaniasis, tick-borne diseases). New approaches to monitoring, such as frequent and long-term sampling along transects to monitor the full latitudinal and altitudinal range of specific vector species, are necessary in order to provide convincing direct evidence of climate change effects. There is a need to reassess the appropriate levels of evidence, including dealing with the uncertainties attached to detecting the health impacts of global change.


Climate adaptation and policy-induced inflation of coastal property value.
Human population density in the coastal zone and potential impacts of climate change underscore a growing conflict between coastal development and an encroaching shoreline. Rising sea-levels and increased storminess threaten to accelerate coastal erosion, while growing demand for coastal real estate encourages more spending to hold back the sea in spite of the shrinking federal budget for beach nourishment. As climatic drivers and federal policies for beach nourishment change, the evolution of coastline mitigation and property values is uncertain. We develop an empirically grounded, stochastic dynamic model coupling coastal property markets and shoreline evolution, including beach nourishment, and show that a large share of coastal property value reflects capitalized erosion control. The model is parameterized for coastal properties and physical forcing in North Carolina, U.S.A. and we conduct sensitivity analyses using property values spanning a wide range of sandy coastlines along the U.S. East Coast. The model shows that a sudden removal of federal nourishment subsidies, as has been proposed, could trigger a dramatic downward adjustment in coastal real estate, analogous to the bursting of a bubble. We find that the policy-induced inflation of property value grows with increased erosion from sea level rise or increased storminess, but the effect of background erosion is larger due to human behavioral feedbacks. Our results suggest that if nourishment is not a long-run strategy to manage eroding coastlines, a gradual removal is more likely to smooth the transition to more climate-resilient coastal communities.


Engineering poly(ethylene glycol) particles for improved biodistribution.
We report the engineering of poly(ethylene glycol) (PEG) hydrogel particles using a mesoporous silica (MS) templating method via tuning the PEG molecular weight, particle size, and the presence or absence of the template and investigate the cell association and biodistribution of these particles. An ex vivo assay based on human whole blood that is more sensitive and relevant than traditional cell-line based assays for predicting in vivo circulation behavior is introduced. The association of MS@PEG particles (template present) with granulocytes and monocytes is higher compared with PEG particles (template absent). Increasing the PEG molecular weight (from 10 to 40 kDa) or decreasing the PEG particle size (from 1400 to 150 nm) reduces phagocytic blood cell association of the PEG particles. Mice biodistribution studies show that the PEG particles exhibit extended circulation times (>12 h) compared with the MS@PEG particles and that the retention of smaller PEG particles (150 nm) in blood, when compared with larger PEG particles (>400 nm), is increased at least 4-fold at 12 h after injection. Our findings highlight the influence of unique aspects of polymer hydrogel particles on biological interactions. The reported PEG hydrogel particles represent a new class of polymer carriers with potential biomedical applications.


Insulin increases resistance to burn wound infection-associated sepsis.
This study was designed to determine the ability of insulin to improve outcome following a Pseudomonas aeruginosa wound infection in a rodent model of severe burn injury. Severe burn injury predisposes patients to burn wound infections that can disseminate, lead to uncontrolled inflammation, and induce septic shock. Whereas insulin administration has been extensively discussed to improve morbidity and mortality in critically ill patients, the ability of insulin to improve outcomes of severely burned patients with infected burn wounds is not known. Sprague-Dawley rats. University setting. Burn-injured Sprague Dawley rats were randomized into treatment groups that received either saline or insulin. Burn wounds were topically inoculated with a lethal dose of Pseudomonas aeruginosa 6 days after injury. Survival, systemic dissemination of bacteria, systemic inflammation, and immune activation were examined. Insulin decreased the early inflammatory response to a severe burn injury. Treatment with low doses of insulin following burn injury improved the outcome of rats in response to a lethal burn wound infection. Specifically, survival was improved and systemic dissemination of bacteria from the wound was decreased. Systemic inflammation, indicated by serum interleukin-6 levels, was significantly decreased by insulin treatments after injury. Additionally, insulin treatments were associated with alterations in B and T lymphocyte responses to wound infection. Although the mechanisms by which insulin improves outcome following a lethal burn wound infection are not known, the data suggest that immunologic responses to infection may be altered by postburn insulin treatments.


The vasovagal response.
The vasovagal response is the development of inappropriate cardiac slowing and arteriolar dilatation. Vasovagal responses reflect autonomic neural changes: bradycardia results from sudden augmentation of efferent vagal activity, and hypotension results from sudden reduction or cessation of sympathetic activity and relaxation of arterial resistance vessels. Two different neural pathways are thought to be involved, one originating in the hypothalamus, the other in the heart. Direct hypothalamic activation of the medullary cardiovascular centres triggered by emotional stress or pain causes a vasovagal response (central type). The combination of a reduced central blood volume secondary to venous pooling or blood loss, and an increased inotropic state of the heart, may stimulate ventricular mechanoreceptors and provoke vasodilatation and bradycardia (peripheral type). Cardiovascular afferents originating from stretch receptors in various parts of the vascular tree sometimes induce opposite reflexes when compared with those from ventricular afferents. The depressor reflex involved in the peripheral type of vasovagal response originates in the heart itself and overrides normal baroreflex circulatory control; an antagonism between the control of volume and pressure on the filling side of the heart and the control system of arterial pressure becomes apparent. Vasovagal responses are not necessarily abnormal; the neural pathways involved in the vasovagal response are probably present in all healthy subjects who individually mainly differ in susceptibility.


Peripherin-IgG association with neurologic and endocrine autoimmunity.
Peripherin-IgG has been reported a pertinent autoantibody in non-obese type 1 diabetic (NOD) mice. However, it has not previously been recognized in any human disease. In blinded evaluation of serum for markers of neurological autoimmunity in a high-volume diagnostic laboratory, we incidentally identified 26 patients (61% female) with an IgG that bound selectively to neural elements in enteric ganglia, sympathetic nerve trunks and discrete nerve tracts in mid-brain and hind-brain. The target antigen was identified as peripherin, a 55kDa - type III intermediate filament protein. Review of clinical histories revealed that 54% of seropositive patients had dysautonomia (predominantly gastrointestinal dysmotility), 30% had neuropathies with varied sensory symptoms and 35% had clinical or serological evidence of endocrinopathy (type 1 diabetes, thyroiditis or premature ovarian failure). Collectively, 73% had autonomic dysfunction or endocrinopathy. None of 173 healthy subjects was seropositive. Subsequent western blot evaluation of archival sera from patients with small fiber/autonomic neuropathies (with or without endocrinopathy) revealed a 33% seropositivity rate for peripherin-IgG. Our further demonstration that peripherin-immunoreactive autonomic fibers in pancreas, thyroid and ovary are juxtaposed to endocrine epithelium, complement our clinical observations in suggesting that neuronal elements may be a pertinent initial target for immune attack in multiple forms of endocrine autoimmunity (intermolecular epitope spreading). It remains to be determined whether or not peripherin-IgG is predictive for development of small fiber neuropathy (autonomic or somatic).


Generalized matrix method for calculation of internal light energy flux in mixed coherent and incoherent multilayers.
A generalized matrix method to treat multilayer systems with mixed coherent and incoherent optical behavior is presented. The method is based on the calculation of the light energy flux inside the multilayer, whose internal light absorption is straightforwardly derived. The Poynting vector is used to derive the light energy flux in the case of a layer with coherent behavior. Multilayer structures with any distribution of layers with coherent or incoherent behavior can be treated, including the case of oblique incidence. Use of the light energy flux instead of the more commonly used light intensity permits the calculation of light absorption with a better accuracy and a much shorter computation time.


Overexpression of PGC-1α increases peroxisomal activity and mitochondrial fatty acid oxidation in human primary myotubes.
Peroxisomes are indispensable organelles for lipid metabolism in humans, and their biogenesis has been assumed to be under regulation by peroxisome proliferator-activated receptors (PPARs). However, recent studies in hepatocytes suggest that the mitochondrial proliferator PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1α) also acts as an upstream transcriptional regulator for enhancing peroxisomal abundance and associated activity. It is unknown whether the regulatory mechanism(s) for enhancing peroxisomal function is through the same node as mitochondrial biogenesis in human skeletal muscle (HSkM) and whether fatty acid oxidation (FAO) is affected. Primary myotubes from vastus lateralis biopsies from lean donors (BMI = 24.0 ± 0.6 kg/m2; n = 6) were exposed to adenovirus encoding human PGC-1α or GFP control. Peroxisomal biogenesis proteins (peroxins) and genes (PEXs) responsible for proliferation and functions were assessed by Western blotting and real-time qRT-PCR, respectively. [1-14C]palmitic acid and [1-14C]lignoceric acid (exclusive peroxisomal-specific substrate) were used to assess mitochondrial oxidation of peroxisomal-derived metabolites. After overexpression of PGC-1α, 1) peroxisomal membrane protein 70 kDa (PMP70), PEX19, and mitochondrial citrate synthetase protein content were significantly elevated (P < 0.05), 2) PGC-1α, PMP70, key PEXs, and peroxisomal β-oxidation mRNA expression levels were significantly upregulated (P < 0.05), and 3) a concomitant increase in lignoceric acid oxidation by both peroxisomal and mitochondrial activity was observed (P < 0.05). These novel findings demonstrate that, in addition to the proliferative effect on mitochondria, PGC-1α can induce peroxisomal activity and accompanying elevations in long-chain and very-long-chain fatty acid oxidation by a peroxisomal-mitochondrial functional cooperation, as observed in HSkM cells.


Mechanical versus manual chest compressions for cardiac arrest.
Mechanical chest compression devices have been proposed to improve the effectiveness of cardiopulmonary resuscitation (CPR). To assess the effectiveness of resuscitation strategies using mechanical chest compressions versus resuscitation strategies using standard manual chest compressions with respect to neurologically intact survival in patients who suffer cardiac arrest. On 19 August 2017 we searched the Cochrane Central Register of Controlled Studies (CENTRAL), MEDLINE, Embase, Science Citation Index-Expanded (SCI-EXPANDED) and Conference Proceedings Citation Index-Science databases. Biotechnology and Bioengineering Abstracts and Science Citation abstracts had been searched up to November 2009 for prior versions of this review. We also searched two clinical trials registries for any ongoing trials not captured by our search of databases containing published works: Clinicaltrials.gov (August 2017) and the World Health Organization International Clinical Trials Registry Platform portal (January 2018). We applied no language restrictions. We contacted experts in the field of mechanical chest compression devices and manufacturers. We included randomised controlled trials (RCTs), cluster-RCTs and quasi-randomised studies comparing mechanical chest compressions versus manual chest compressions during CPR for patients with cardiac arrest. We used standard methodological procedures expected by Cochrane. We included five new studies in this update. In total, we included 11 trials in the review, including data from 12,944 adult participants, who suffered either out-of-hospital cardiac arrest (OHCA) or in-hospital cardiac arrest (IHCA). We excluded studies explicitly including patients with cardiac arrest caused by trauma, drowning, hypothermia and toxic substances. These conditions are routinely excluded from cardiac arrest intervention studies because they have a different underlying pathophysiology, require a variety of interventions specific to the underlying condition and are known to have a prognosis different from that of cardiac arrest with no obvious cause. The exclusions were meant to reduce heterogeneity in the population while maintaining generalisability to most patients with sudden cardiac death.The overall quality of evidence for the outcomes of included studies was moderate to low due to considerable risk of bias. Three studies (N = 7587) reported on the designated primary outcome of survival to hospital discharge with good neurologic function (defined as a Cerebral Performance Category (CPC) score of one or two), which had moderate quality evidence. One study showed no difference with mechanical chest compressions (risk ratio (RR) 1.07, 95% confidence interval (CI) 0.82 to 1.39), one study demonstrated equivalence (RR 0.79, 95% CI 0.60 to 1.04), and one study demonstrated reduced survival (RR 0.41, CI 0.21 to 0.79). Two other secondary outcomes, survival to hospital admission (N = 7224) and survival to hospital discharge (N = 8067), also had moderate quality level of evidence. No studies reported a difference in survival to hospital admission. For survival to hospital discharge, two studies showed benefit, four studies showed no difference, and one study showed harm associated with mechanical compressions. No studies demonstrated a difference in adverse events or injury patterns between comparison groups but the quality of data was low. Marked clinical and statistical heterogeneity between studies precluded any pooled estimates of effect. The evidence does not suggest that CPR protocols involving mechanical chest compression devices are superior to conventional therapy involving manual chest compressions only. We conclude on the balance of evidence that mechanical chest compression devices used by trained individuals are a reasonable alternative to manual chest compressions in settings where consistent, high-quality manual chest compressions are not possible or dangerous for the provider (eg, limited rescuers available, prolonged CPR, during hypothermic cardiac arrest, in a moving ambulance, in the angiography suite, during preparation for extracorporeal CPR [ECPR], etc.). Systems choosing to incorporate mechanical chest compression devices should be closely monitored because some data identified in this review suggested harm. Special attention should be paid to minimising time without compressions and delays to defibrillation during device deployment.


Ketorolac and patient controlled analgesia in the treatment of postoperative pain.
Ketorolac tromethamine (Toradol [Syntex, Palo Alto]), a new commercially available nonsteroidal antiinflammatory drug (NSAID), has appropriate solubility and minimal tissue irritation, making it suitable for intramuscular injection. Previously, NSAID have only been available for oral use in the United States for the treatment of pain. Ketorolac, the most potent NSAID known, relieves pain through inhibition of arachidonic acid synthesis at the cyclooxygenase level and has no central opioid effects. The results of previous studies using parenteral ketorolac in combination with patient administered narcotics have shown a 40 percent reduction in narcotic requirements. However, ketorolac is presently only approved for intramuscular injection and oral use in the United States. In a prospective, randomized study, we compared intramuscular ketorolac in combination with patient controlled intravenous narcotic analgesia (morphine) (PCA-M) to PCA-M alone for the control of pain after extensive colonic resections. The combination of intramuscular ketorolac and PCA-M provided equal pain relief with no increased side effects when compared with narcotics alone. However, narcotic requirements of the patients were decreased by an average of 45 percent. Ketorolac and narcotics in combination provide effective postoperative pain relief and significantly decrease narcotic requirements. This combination may be particularly beneficial in the subpopulation of patients especially prone to narcotic related complications.


Low muscarinic receptor binding in prefrontal cortex from subjects with schizophrenia: a study of Brodmann's areas 8, 9, 10, and 46 and the effects of neuroleptic drug treatment.
Aberrant cholinergic inputs and synaptic neurotransmission in the prefrontal cortex induce cognitive impairment, which is a central feature of schizophrenia. Postsynaptic excitatory muscarinic cholinergic M(1) and M(4) receptors are the major cholinoceptive targets in the prefrontal cortex and hence may be involved in the pathology and/or pharmacotherapeutics of schizophrenia. Using quantitative autoradiography, the authors analyzed the binding of the M(1)/M(4) receptor selective antagonist [(3)H]pirenzepine in prefrontal cortex (Brodmann's areas 8, 9, 10, and 46) from schizophrenia patients who had (N=6) or had not (N=11) been treated with the anticholinergic agent benztropine mesylate and from normal comparison subjects (N=20). Moreover, preliminary studies of [(3)H]pirenzepine binding in rat frontal cortex following administration of antipsychotic drugs or benztropine mesylate were performed. Relative to those of comparison subjects, the mean levels of [(3)H]pirenzepine binding were significantly lower in Brodmann's areas 9 and 46 of the schizophrenia patients not treated with benztropine mesylate (18% lower in Brodmann's area 9 and 21% lower in Brodmann's area 46) and in all four examined regions of the patients who had received benztropine (51%-64% lower). Antipsychotic or anticholinergic drugs tended to increase or have no effect on the density of [(3)H]pirenzepine-labeled receptors in rat frontal cortex. Because M(1) and M(4) receptors are critical to the functions of prefrontal cortical acetylcholine, the present findings suggest a functional impairment in cholinergic neurotransmission in schizophrenia and the possibility that muscarinic receptors are involved in the pharmacotherapeutics of the disorder.


Are joint structure and function related to medial knee OA pain? A pilot study.
Although the severity of knee osteoarthritis (OA) usually is assessed using different measures of joint structure, function, and pain, the relationships between these measures are unclear. Therefore, we: (1) examined the relationships between the measures of knee structure (flexion-extension range of motion, radiographic tibiofemoral angle, and medial joint space), function (Knee Osteoarthritis Outcome Scores [KOOS], peak adduction angle, and moment), and pain (visual analog scale [VAS]); and (2) identified variables that best predicted knee pain. We assessed 15 patients with medial knee OA using VAS pain, KOOS questionnaire, 3-D gait analysis, and radiographic examination. Parameter relationships were assessed using Pearson correlation, and variables most predictive of knee pain were determined using a stepwise multiple regression. Subjective measurements correlated (|r| ≥ 0.54) with one another, as did most of the objective measurements (|r| ≥ 0.56) except for adduction moment which did not correlate with any variable. All variables correlated (|r| > 0.54) with VAS knee pain except peak adduction moment. Medial joint space and peak adduction angle best predicted knee pain, accounting for approximately three-quarters of the model variance (r(2) = 0.73). Medial joint space and peak adduction angle may be useful for predicting knee pain in patients with medial knee OA. Therapies that target these structural and functional variables may reduce knee pain in this population. Increasing the medial joint space and limiting the peak knee adduction angle may be critical in achieving effective pain relief in patients with varus knee OA.


7 Tesla MRI of the ex vivo human brain at 100 micron resolution.
We present an ultra-high resolution MRI dataset of an ex vivo human brain specimen. The brain specimen was donated by a 58-year-old woman who had no history of neurological disease and died of non-neurological causes. After fixation in 10% formalin, the specimen was imaged on a 7 Tesla MRI scanner at 100 µm isotropic resolution using a custom-built 31-channel receive array coil. Single-echo multi-flip Fast Low-Angle SHot (FLASH) data were acquired over 100 hours of scan time (25 hours per flip angle), allowing derivation of synthesized FLASH volumes. This dataset provides an unprecedented view of the three-dimensional neuroanatomy of the human brain. To optimize the utility of this resource, we warped the dataset into standard stereotactic space. We now distribute the dataset in both native space and stereotactic space to the academic community via multiple platforms. We envision that this dataset will have a broad range of investigational, educational, and clinical applications that will advance understanding of human brain anatomy in health and disease.


MYBA2 gene involved in anthocyanin and flavonol biosynthesis pathways in grapevine.
MYBA2 transcription factor (Myb-related gene) affects the coloring in grapevine berry and plays an important role in the biosynthesis of anthocyanin. The MYBA2 gene was cloned from Vitis vinifera L. cv. Cabernet Sauvignon and polyclonal antibodies for VvmybA2 were prepared. The VvmybA2 gene expression patterns were observed in seven tissues (the leaf, stem, flower, bud, root, berry, and tendril) and during the berry development stage at transcriptional and translational levels, respectively. The results indicated that the expression of VvmybA2 was approximately 11-fold higher in the berry than that in the other six tissues, and increased rapidly from 60 days after full bloom reaching a maximum on day 80. Furthermore, both the anthocyanin content and UDP-glucose:flavonoid-3-O-glucosyltransferase (UFGT) gene expression levels increased rapidly 60 days after full bloom. Moreover, correlation analysis indicated that the transcriptional and translational expression levels of the VvmybA2 gene were significantly positively correlated with not only UFGT and DFR genes but also with the anthocyanin content during berry development. These results suggested that VvmybA2 could not only regulate the transcription of both UFGT and DFR but also is involved in the expression of the UFGT gene associated with color determination in grape berries.


Epidemiology and Outcome of Microbial Keratitis: Private University Versus Urban Public Hospital Care.
To review the epidemiology, risk factors, microbiologic spectrum, and treatment of microbial keratitis during a 5-year period at an urban public hospital in comparison with an adjacent private university practice. Retrospective chart review in the 5-year interval, 2009 through 2014. Primary outcome measures included patient age at presentation, best-corrected visual acuity (BCVA), risk factors, culture and sensitivities, treatment, and complication occurrence. A total of 528 eyes with microbial keratitis were identified, 318 in the public cohort and 210 in the private cohort. Contact lens wear was the most common risk factor in the public cohort, whereas ocular surface disease was the most common risk factor in the private cohort. Gram-positive organisms represented 47.3%, gram-negative organisms 32.1%, fungal organisms 13.6%, and Acanthamoeba 6.4% of corneal isolates. Gentamicin resistance was 4.4% and tobramycin resistance was 2.9%. The inpatient treatment rate of the public cohort was 40% compared with 4% in the private cohort. In the public cohort, average BCVA at resolution was 20/82 (log of minimal angle of resolution [logMAR] 0.61). For the private cohort, average BCVA at resolution was 20/73 [logMAR, 0.56]. The perforation rate was 8% in the public cohort compared with 4% in the private cohort. Six percent of cases underwent urgent penetrating keratoplasty in the public cohort versus 2% in the private cohort. Microbial keratitis remains a clinical challenge in the urban public hospital setting. The risk profile of patients presenting in the public hospital setting may be different from patients presenting in a private care setting. Public hospital patients may present later in the course of their infection and thus have a higher rate of complications regardless of effective antimicrobial therapy.


A Task-Based Taxonomy of Cognitive Biases for Information Visualization.
Information visualization designers strive to design data displays that allow for efficient exploration, analysis, and communication of patterns in data, leading to informed decisions. Unfortunately, human judgment and decision making are imperfect and often plagued by cognitive biases. There is limited empirical research documenting how these biases affect visual data analysis activities. Existing taxonomies are organized by cognitive theories that are hard to associate with visualization tasks. Based on a survey of the literature we propose a task-based taxonomy of 154 cognitive biases organized in 7 main categories. We hope the taxonomy will help visualization researchers relate their design to the corresponding possible biases, and lead to new research that detects and addresses biased judgment and decision making in data visualization.


Modulating the Oxytocin System During the Perinatal Period: A New Strategy for Neuroprotection of the Immature Brain?
Oxytocin is a neurohypophysal hormone known for its activity during labor and its role in lactation. However, the function of oxytocin (OTX) goes far beyond the peripheral regulation of reproduction, and the central effects of OTX have been extensively investigated, since it has been recognized to influence the learning and memory processes. OTX has also prominent effects on social behavior, anxiety, and autism. Interaction between glucocorticoids, OTX, and maternal behavior may have long-term effects on the developmental program of the developing brain subjected to adverse events during pre and perinatal periods. OTX treatment in humans improves many aspects of social cognition and behavior. Its effects on the hypothalamic-pituitary-adrenal axis and inflammation appear to be of interest in neonates because these properties may confer benefits when the perinatal brain has been subjected to injury. Indeed, early life inflammation and abnormal adrenal response to stress have been associated with an abnormal white matter development. Recent investigations demonstrated that OTX is involved in the modulation of microglial reactivity in the developing brain. This review recapitulates state-of-the art data supporting the hypothesis that the OTX system could be considered as an innovative candidate for neuroprotection, especially in the immature brain.


Diagnosis of alcohol dependence in epidemiological surveys: an epidemic of youthful alcohol dependence or a case of measurement error?
To review the literature on the prevalence of alcohol dependence according to age, presenting data suggesting that the increased prevalence of alcohol dependence among young adults may be inflated because of measurement error. Household surveys with random selection of respondents. General population. Survey respondents 12 years of age and older. Alcohol dependence. Data for male current drinkers show that 4.6% of adolescents (aged 12-17 years) meet criteria for past year dependence, and the rate increases to 8.5% in the 18-23 age group, decreasing thereafter. Symptom level prevalence estimates indicate that younger age groups report higher rates of tolerance and withdrawal symptoms than older age groups. Young adults may be reporting tolerance and withdrawal symptoms partly because the wording of structured interview schedules leads to confusion of binge drinking and its sequelae with physical symptoms of alcohol dependence. There is a need to examine whether young adults are confusing the sequelae of acute intoxication with alcohol withdrawal, and rapid initial tolerance with the classical tolerance reported by alcoholics. Epidemiologists and clinicians need to be cautious of the tendency of structured psychiatric interviews to classify young adults as being alcohol-dependent. It may be useful to characterize individuals who meet alcohol dependence criteria at a young age (e.g. prior to age 25 years) as manifesting a form of 'adolescent alcohol dependence', which may represent a less severe form of alcohol use disorder than that observed in adults.


Dynamic perfusion CT in brain tumors.
Dynamic perfusion CT (PCT) is an imaging technique for assessing the vascular supply and hemodynamics of brain tumors by measuring blood flow, blood volume, and permeability-surface area product. These PCT parameters provide information complementary to histopathologic assessments and have been used for grading brain tumors, distinguishing high-grade gliomas from other brain lesions, differentiating true progression from post-treatment effects, and predicting prognosis after treatments. In this review, the basic principles of PCT are described, and applications of PCT of brain tumors are discussed. The advantages and current challenges, along with possible solutions, of PCT are presented.


Optimization of extraction of circulating RNAs from plasma--enabling small RNA sequencing.
There are several protocols and kits for the extraction of circulating RNAs from plasma with a following quantification of specific genes via RT-qPCR. Due to the marginal amount of cell-free RNA in plasma samples, the total RNA yield is insufficient to perform Next-Generation Sequencing (NGS), the state-of-the-art technology in massive parallel sequencing that enables a comprehensive characterization of the whole transcriptome. Screening the transcriptome for biomarker signatures accelerates progress in biomarker profiling for molecular diagnostics, early disease detection or food safety. Therefore, the aim was to optimize a method that enables the extraction of sufficient amounts of total RNA from bovine plasma to generate good-quality small RNA Sequencing (small RNA-Seq) data. An increased volume of plasma (9 ml) was processed using the Qiagen miRNeasy Serum/Plasma Kit in combination with the QIAvac24 Plus system, a vacuum manifold that enables handling of high volumes during RNA isolation. 35 ng of total RNA were passed on to cDNA library preparation followed by small RNA high-throughput sequencing analysis on the Illumina HiSeq2000 platform. Raw sequencing reads were processed by a data analysis pipeline using different free software solutions. Seq-data was trimmed, quality checked, gradually selected for miRNAs/piRNAs and aligned to small RNA reference annotation indexes. Mapping to human reference indexes resulted in 4.8±2.8% of mature miRNAs and 1.4±0.8% of piRNAs and of 5.0±2.9% of mature miRNAs for bos taurus.


Surviving cancer or other serious illness: a review of individual and community resources.
In order to provide appropriate individual and community support for cancer survivors, there is a great need to better understand how people who have survived cancer or other serious illness adapt positively to health challenges and to identify effective approaches for helping people cope with health challenges over their lifetime. Studies have identified a number of personal factors that are associated with resilience, increased quality of life, and positive adaptation to illness. Of particular interest is the ability of individuals to survive or even thrive despite an adverse event, as influenced by both individual factors such as resiliency and external factors like social support. The experience of having a potentially life-threatening illness can lead to positive adaptation and increased ability to thrive despite difficult circumstances. The cancer survivorship movement and the cancer community in general provide important resources for improving quality of life and alleviating human suffering and distress among patients and survivors and for adding personal meaning and hope to people's lives.


Freedom to act enhances the sense of agency, while movement and goal-related prediction errors reduce it.
The Sense of Agency (SoA) is the experience of controlling one's movements and their external consequences. Accumulating evidence suggests that freedom to act enhances SoA, while prediction errors are known to reduce it. Here, we investigated if prediction errors related to movement or to the achievement of the goal of the action exert the same influence on SoA during free and cued actions. Participants pressed a freely chosen or cued-colored button, while observing a virtual hand moving in the same or in the opposite direction-i.e., movement-related prediction error-and pressing the selected or a different color-i.e., goal-related prediction error. To investigate implicit and explicit components of SoA, we collected indirect (i.e., Synchrony Judgments) and direct (i.e., Judgments of Causation) measures. We found that participants judged virtual actions as more synchronous when they were free to act. Additionally, movement-related prediction errors reduced both perceived synchrony and judgments of causation, while goal-related prediction errors impaired exclusively the latter. Our results suggest that freedom to act enhances SoA and that movement and goal-related prediction errors lead to an equivalent reduction of SoA in free and cued actions. Our results also show that the influence of freedom to act and goal achievement may be limited, respectively, to implicit and explicit SoA, while movement information may affect both components. These findings provide support to recent theories that view SoA as a multifaceted construct, by showing that different action cues may uniquely influence the feeling of control.


Gene expression profiling of periodontitis-affected gingival tissue by spatial transcriptomics.
Periodontitis is a highly prevalent chronic inflammatory disease of the periodontium, leading ultimately to tooth loss. In order to characterize the gene expression of periodontitis-affected gingival tissue, we have here simultaneously quantified and localized gene expression in periodontal tissue using spatial transcriptomics, combining RNA sequencing with histological analysis. Our analyses revealed distinct clusters of gene expression, which were identified to correspond to epithelium, inflamed areas of connective tissue, and non-inflamed areas of connective tissue. Moreover, 92 genes were identified as significantly up-regulated in inflamed areas of the gingival connective tissue compared to non-inflamed tissue. Among these, immunoglobulin lambda-like polypeptide 5 (IGLL5), signal sequence receptor subunit 4 (SSR4), marginal zone B and B1 cell specific protein (MZB1), and X-box binding protein 1 (XBP1) were the four most highly up-regulated genes. These genes were also verified as significantly higher expressed in gingival tissue of patients with periodontitis compared to healthy controls, using reverse transcription quantitative polymerase chain reaction. Moreover, the protein expressions of up-regulated genes were verified in gingival biopsies by immunohistochemistry. In summary, in this study, we report distinct gene expression signatures within periodontitis-affected gingival tissue, as well as specific genes that are up-regulated in inflamed areas compared to non-inflamed areas of gingival tissue. The results obtained from this study may add novel information on the genes and cell types contributing to pathogenesis of the chronic inflammatory disease periodontitis.


Viability of using a computer tablet to monitor an upper limb home exercise program in stroke.
Aims: To evaluate the feasibility of using a tablet computer to monitor the amount of upper limb practice completed by stroke patients prescribed with a home program and to explore factors that influence adherence. Method: Ten consecutive participants randomized to the intervention arm of a randomized controlled trial investigating therapy after spasticity management for stroke patients (ACTRN 12615000616572) were recruited for this sub-study. Participants were asked to perform and record a prescribed 60-min upper limb program, based on the Graded Arm Supplementary Program, on a tablet computer daily. Four randomly selected recorded sessions for each participant were analyzed by the physiotherapist to assess adherence to the amount of exercise and content. Results: Mean score for the System Usability Scale was 85.5 (range 47.5-100) indicating that participants were accepting of the technology. Participants performed exercises on average for 50.32 min (range 26.42-68.37). Self-reported practice time was 59.44 min (range 48-67.5). Conclusion: Monitoring of patient practice using a tablet computer is feasible and may prove more reliable than self-report. There is variability in the amount of upper limb exercise stroke patients do at home.


Diet and Crohn's disease: characteristics of the pre-illness diet.
Thirty newly diagnosed patients with Crohn's disease were interviewed about their habitual, pre-illness diet and compared with 30 healthy controls, matched for age, sex, social class, and marital status. The patients ate substantially more refined sugar, slightly less dietary fibre, and considerably less raw fruit and vegetables than the controls. A diet high in refined sugar and low in raw fruit and vegetables precedes and may favour the development of Crohn's disease.


Smoking-related glomerulopathy: expanding the morphologic spectrum.
Chronic smoking and hypertension may lead to smoking-related nodular glomerulopathy (SRNG), a well-recognized entity that clinically and pathologically mimics nodular diabetic nephropathy (DN). However, like DN, diffuse mesangial sclerosis may occur in this setting without nodules. The clinicopathologic features of 10 non-diabetic patients with a long smoking history diagnosed from 2003-2012 showing diffuse mesangial glomerulosclerosis (6) or SRNG (4) were analyzed. Nine of 10 patients were men, aged 58-80 with a 20-58 pack-year smoking history. None of the patients manifested diabetes, but all of them had hypertension. Numerous other cardiovascular comorbidities were present. At biopsy, the mean creatinine was 1.9 mg/dl (range 1.4-3) and the mean proteinuria was 3.9 g/24 h. The renal pathologic findings were similar in all patients except mesangial nodules in SRNG. Global glomerulosclerosis was seen in 6-72% of glomeruli (mean 31%), glomerulomegaly in all cases, and a range of interstitial fibrosis in 10-70% (mean 43%). Moderate (40%) and severe (50%) arteriosclerosis and arteriolar hyalinosis (80%) were also observed. Glomerular hilar or mesangial neovascularization was prominent. Endothelial swelling, subendothelial widening, and new basement membrane formation suggesting chronic healing thrombotic microangiopathy (TMA) was noted in 80%. No immune complexes were localized. Kidney biopsies from patients with proteinuria and chronic renal insufficiency in the setting of prolonged smoking and hypertension show either diffuse or nodular mesangial glomerulosclerosis. Chronic glomerular mesangial and endothelial injury associated with smoking leads to a chronic TMA appearance in the appropriate setting, even in the absence of mesangial nodule formation.


Understanding nurses' communication with patients in accident & emergency departments using a symbolic interactionist perspective.
Much research has examined the nature and duration of nurse-patient communication. However, few studies sufficiently acknowledge the extent to which communication is influenced by the meanings and perceptions of those involved or the social context in which it occurs. This paper reports on a study which used in-depth interviews with 21 nurses in two accident and emergency departments to explore how their perceptions of their work and patients influenced communication and the way in which patients' anxieties were addressed. A grounded theory approach was used to guide the process of data collection and analysis, and interpretation of findings discussed with reference to a symbolic interactionist perspective. The core category was identified as 'Defining the role of the accident and emergency department nurse'. This category illuminates the nurses' perception of their role and purpose as being primarily concerned with dealing with emergencies and providing urgent physical care. Two other categories, 'Nurses' priorities and patients' anxieties' and 'Keeping the department running smoothly', delineate the impact this view had on the organization and delivery of nursing care in accident and emergency departments and its effect on nurse-patient communication.