Acute renal failure in intensive care units--causes, outcome, and prognostic factors of hospital mortality; a prospective, multicenter study. French Study Group on Acute Renal Failure.
To assess the causes, the prognostic factors, and the outcome of patients with severe acute renal failure. Prospective, multicenter study. Twenty French multidisciplinary intensive care units (ICUs). All patients with severe acute renal failure were prospectively enrolled in the study for a 6-month period. Severe acute renal failure was defined by the following criteria: a) a serum creatinine concentration of > or = 3.5 mg/dL ( > or = 310 mumol/L) and/or a blood urea nitrogen concentration of > or = 100 mg/dL ( > or = 36 mmol/L); or b) an increase in blood urea nitrogen or serum creatinine concentration, such that the concentration is 100% above the baseline value in patients with previous chronic renal insufficiency (serum creatinine concentration of > 1.8 mg/dL [ > 150 mumol/L]), excluding those patients with a basal serum creatinine concentration of > 3.4 mg/dL ( > 300 mumol/L). None. Age, sex, previous health status and preexisting organ dysfunction, and type and origin of acute renal failure were recorded. The Simplified Acute Physiology Score, the Acute Physiology and Chronic Health Evaluation (APACHE II) score, and the number of Organ System Failures were calculated on ICU day 1 and at the time of inclusion in the study. Prognostic factors were determined by univariate methods and stepwise logistic regression analysis. There were 360 patients in the study; 217 patients were admitted to the study at the time of ICU admission and 143 patients were admitted to the study after ICU admission. Only 41% of these patients were in good health 3 months before ICU entry. The reason for admission was medical in 78% of cases. The type of acute renal failure was prerenal (n = 16), renal (n = 282), or postrenal (n = 17). Renal replacement therapy was used in 174 patients. Two hundred ten (58%) patients died during the hospital stay. Using stepwide logistic regression, seven variables were predictive of death. These variables were advanced age, altered previous health status, hospitalization before ICU admission, delayed occurrence of acute renal failure, sepsis, oliguria, and severity of illness as assessed at the time of study inclusion by Simplified Acute Physiology Score, APACHE II, or Organ System Failure. The hospital mortality rate of patients with severe acute renal failure in patients requiring intensive care remains high. In order to compare patient groups in further trials concerning acute renal failure, recorded characteristics of the population should include age, previous health status, disease characteristics (initial or delayed acute renal failure, oliguria, sepsis), and the severity of the illness as assessed by physiologic scoring systems recorded at the time of study inclusion.


Confusing terminology used in the abbreviation of pharmacy journal names.
The lack of commonly agreed terminology in pharmacy field is highly prevalent and may have influence on the relevance and robustness of the area, especially how others see pharmacy literature. Potential consequences of this poor perception of pharmacy field by the National Library of Medicine (NLM) could be the omission of several pharmacy-related Medical Subject Headings (MeSH) or the low indexing rate of pharmacy practice journals in MEDLINE. Journal name abbreviation, under the responsibility of the NLM, is the unambiguous way to identify a journal in bibliographic references and catalogs. The present study investigated the consistency of pharmacy journal abbreviations in the NLM Catalog. For the 290 journals containing any word with the root pharm in their names, a consistent procedure for NLM title abbreviations was found for 27 of the words in journal names but not for the abbreviation "Pharm", which represented several words with very different meanings: pharmaceutical, pharmaceutics, pharmacists, and pharmacy. The use by the NLM of different abbreviation for pharmaceutical and pharmaceutics would increase journal identification clarity.


Comparison of neurogenic contraction and relaxation in canine corpus cavernosum and penile artery and vein.
Functional roles of autonomic efferent nerves were compared in the isolated canine corpus cavernosum, penile artery and penile vein that participate in the penile erection by changing blood distribution. Nicotine produced moderate contraction in the arterial strips, but only a slight or no contraction in the corpus and venous strips. The contraction was suppressed or reversed to a relaxation by prazosin. Under alpha 1-adrenoceptor blockade, relaxations induced by nicotine were in the order of the corpus > artery > > vein. The response was abolished by NG-nitro-L-arginine (L-NA) and restored by L-arginine. The responses to nicotine and exogenous nitric oxide (NO) were abolished by oxyhemoglobin. The relaxant response to transmural electrical stimulation at 5 Hz was greater in the corpus than venous strips treated with prazosin, and it was abolished by L-NA. Contractions caused by nicotine under treatment with L-NA were greater in the artery than in the vein and corpus. Histochemical studies demonstrated nerve fibers containing NO synthase and tyrosine hydroxylase immunoreactivity in the corpus cavernosum, artery and vein. It is concluded that the canine corpus cavernosum, penile artery and penile vein are innervated by adrenergic, vasoconstrictor and nitroxidergic, vasodilator nerves; neurogenic vasodilatation is predominant in the corpus muscle, whereas neurogenic vasoconstriction predominates in the artery. Such a different functioning of the nerves may be responsible for the penile erection.


[Dependence on anticholinergics among schizophrenics. Iatrogenic disease or self-medication?].
This report concerns two schizophrenic patients who had ingested a biperiden overdose between 8 and 14 mg per day. This drug had been prescribed to treat extrapyramidal side effects of neuroleptics. Once the ingestion was suppressed, both patients complained about anxiety, discomfort and depression. These symptoms disappeared when reintroducing the biperiden. Both patients had a previous record of alcohol and cannabis abuse. One of them had also a recorder of sporadic consumption of other drugs such as heroin, amphetamines and hallucinogens. The predominant psychopathology was of the negative type. Through these cases we intend to support the likelihood of a cholinergic hyperactivity in the negative schizophrenic symptoms.


Nanodiscs and electrospray ionization mass spectrometry: a tool for screening glycolipids against proteins.
Electrospray ionization-mass spectrometry (ESI-MS) is extensively employed to detect and quantify protein-carbohydrate interactions in vitro and is increasingly used to screen carbohydrate libraries against target proteins. However, current ESI-MS methods are limited to carbohydrate ligands that are relatively soluble in water and are, therefore, not generally suitable for studying protein interactions with glycolipids, an important class of cellular receptors. Here, we describe a catch-and-release (CaR)-ESI-MS assay, which exploits nanodiscs (NDs) to solubilize glycolipids and mimic their natural cellular environment, suitable for screening libraries of glycosphingolipids (GSL) against proteins to identify specific interactions and to rank their relative affinities. Using the B subunit homopentamers of cholera toxin and heat labile toxin as model GSL-binding proteins, the CaR-ESI-MS was applied to NDs containing mixtures of gangliosides. The results demonstrate that the CaR-ESI-MS assay can simultaneously detect both high and low affinity GSL ligands using either a library of NDs that each contains one GSL or incorporating a mixture of GSLs into a single ND. Moreover, the relative abundances of the released ligands appear to reflect their relative affinities in solution. Application of the CaR-ESI-MS assay using NDs containing gangliosides extracted from porcine brain led to the discovery of a neolacto GSL as a cholera toxin ligand, highlighting the power of the assay for identifying specific protein-glycolipid interactions from biologically relevant mixtures.


Levels and patterns of objectively assessed physical activity--a comparison between Sweden and the United States.
This study compares levels and patterns of objectively assessed physical activity in Sweden and the United States by using identical accelerometer metrics. Data of adult respondents with > or =4 days with > or =10 hours per day of accelerometer wear from Sweden (2001-2002, n = 1,172) and the United States (2003-2004, n = 2,925) were compared. Outcomes reported by age and body mass index within sex include accelerometer counts per minute and amounts and bouts of activity at different intensities, that is, sedentary, low, lifestyle, and moderate or higher intensity physical activity. The mean counts per minute were 375 (95% confidence interval (CI): 360, 390) and 377 (95% CI: 363, 391) for Swedish and US males, respectively, and 363 (95% CI: 347, 379) and 298 (95% CI: 289, 307) for Swedish and US females. Older respondents and those with higher body mass index had lower activity levels. Swedish and US males spent 36 (95% CI: 34, 38) and 33 (95% CI: 31, 36) minutes per day, and Swedish and US females spent 32 (95% CI: 29, 34) and 19 (95% CI: 17, 21) minutes per day in moderate or higher intensity physical activity. Older Swedes were more active in moderate or higher intensity activities than were older US respondents. However, younger Swedish males had more sedentary behavior time than did younger US males. These results provide a framework for international comparisons of physical activity levels and patterns, and they represent strong evidence for the importance of investment in objective measurement of physical activity.


MabA (FabG1), a Mycobacterium tuberculosis protein involved in the long-chain fatty acid elongation system FAS-II.
The fatty acid elongation system FAS-II is involved in the biosynthesis of mycolic acids, which are very long-chain fatty acids of the cell envelope specific to Mycobacterium tuberculosis and other mycobacteria. A potential component of FAS-II, the protein MabA (FabG1), was overexpressed and purified. Sedimentation equilibrium analyses revealed that MabA undergoes a dimer to tetramer self-association with a dissociation constant of 22 microM. The protein was detected by Western blotting in a mycobacterial cell-wall extract that produces mycolic acids and in the FPLC FAS-II fraction. MabA was shown to catalyse the NADPH-specific reduction of beta-ketoacyl derivatives, equivalent to the second step of a FAS-II elongation round. Unlike the known homologous proteins, MabA preferentially metabolizes long-chain substrates (C(8)-C(20)) and has a poor affinity for the C(4) substrate, in agreement with FAS-II specificities. Molecular modelling of MabA structure suggested the presence of an unusually hydrophobic substrate-binding pocket holding a unique Trp residue, suitable for fluorescence spectroscopic analyses. In agreement with the enzyme kinetic data, the spectral properties of MabA were different in the presence of the C(8)-C(16) ligands as compared to the C(4) ligand. Altogether, these data bring out distinctive enzymic and structural properties of MabA, which correlate with its predilection for long-chain substrates, in contrast to most of the other known ketoacyl reductases.


A Multi-Fluorescent DNA/Graphene Oxide Conjugate Sensor for Signature-Based Protein Discrimination.
Signature-based protein sensing has recently emerged as a promising prospective alternative to conventional lock-and-key methods. However, most of the current examples require the measurement of optical signals from spatially-separated materials for the generation of signatures. Herein, we present a new approach for the construction of multi-fluorescent sensing systems with high accessibility and tunability, which allows generating protein fluorescent signatures from a single microplate well. This approach is based on conjugates between nano-graphene oxide (nGO) and three single-stranded DNAs (ssDNAs) that exhibit different sequences and fluorophores. Initially, the three fluorophore-modified ssDNAs were quenched simultaneously by binding to nGO. Subsequent addition of analyte proteins caused a partial recovery in fluorescent intensity of the individual ssDNAs. Based on this scheme, we have succeeded in acquiring fluorescence signatures unique to (i) ten proteins that differ with respect to pI and molecular weight and (ii) biochemical marker proteins in the presence of interferent human serum. Pattern-recognition methods demonstrated high levels of discrimination for this system. The high discriminatory power and simple format of this sensor system should enable an easy and fast evaluation of proteins and protein mixtures.


Regulation of differentiation and keratin protein expression by vitamin A in primary cultures of hamster tracheal epithelial cells.
Hamster tracheal epithelial (HTE) cells maintained in primary culture show the induction of specific keratin species under vitamin A-deficient conditions. A comparison was made between the morphology and the expression of keratins in HTE cells in vivo and in primary culture with and without vitamin A. HTE cells cultured in serum-free, vitamin A-supplemented medium formed a simple cuboidal, ciliated monolayer and produced four simple epithelial keratins (7, 8, 18, and 19). In contrast, vitamin A-deficient HTE cells, which were squamous-like and stratified in culture, produced a more complex keratin pattern, with the induction of four additional keratin species (5, 6, 14, and 17). A keratin pair whose expression serves as a marker of stratified epithelia was induced, as well as a single keratin species unique to lesions of squamous metaplasia in vitamin A-deficient hamster tracheal organ cultures. Thus it appears that HTe cells retain the ability to respond to a deficiency in vitamin A through squamous differentiation and increased keratin production when removed from the intact organ and maintained in primary culture in a chemically defined medium. This system may be useful for the study of mechanisms underlying the squamous differentiation of respiratory epithelial cells in the development of bronchogenic tumors.


Effect of a Novel Transition Program on Disability After Stroke: A Trial Protocol.
A gap in care for stroke survivors exists at the point of transition from inpatient rehabilitation to home, when survivors encounter new environmental barriers because of the cognitive and sensorimotor sequelae of stroke. Resolving these barriers and improving independence in the community have the potential to significantly improve stroke survivors' long-term morbidity. To investigate the efficacy and safety of a novel enhanced rehabilitation transition program to reduce environmental barriers and improve daily activity performance and community participation among stroke survivors. This is a phase 2b, single-blind, parallel-group, randomized clinical trial. Participants will be randomized using a 1:1 allocation ratio, stratified by Functional Independence Measure and age, to either attentional control or the intervention. Community Participation Transition After Stroke (COMPASS) is a complex intervention that uses 2 complementary evidence-based interventions: home modifications and strategy training delivered in the home. Community participation after stroke, measured by the Reintegration to Normal Living Index, is the primary outcome. Secondary outcomes include quality of life after stroke, measured by the Stroke Impact Scale, and daily activity performance and magnitude of environmental barriers in the home, both measured by the In-Home Occupational Performance Evaluation. An intention-to-treat analysis will be used. A total of 180 participants, who are 50 years or older, were independent in activities of daily living prior to stroke, and are undergoing inpatient rehabilitation following stroke with a plan to be discharged home, will be included in the study. Stroke is a leading cause of serious long-term disability in the United States. The COMPASS study is ongoing. To date, 99 participants have been recruited and 77 randomized, with 37 in the treatment group and 40 in the control group. Resumption of previous activities immediately after discharge can improve immediate and long-term community participation. Results from this study will fill a critical gap in stroke rehabilitation evidence by providing important information about the long-term community participation and daily activity performance among stroke survivors as well as environmental barriers in their homes. ClinicalTrials.gov identifier: NCT03485820.


Complicated infantile meningitis: evaluation by real-time sonography.
Real-time sonographic findings in 20 infants with bacterial meningitis are reported. The spectrum of features included normal scans, ventricular enlargement, focal areas of increased cortical echogenicity, ventricular bands, and cerebral abscess. Areas of increased cortical echogenicity on sonography representing meningoencephalitis corresponded to areas of contrast enhancement seen on computed tomography (CT). Excellent correlation was found between CT and sonography. Because of the advantage of obtaining sonographic scans at the bedside, it appears that sonography offers an attractive alternative to CT in the evaluation of infantile meningitis and meningoencephalitis.


Effects of amyloid precursor protein peptide APP96-110, alone or with human mesenchymal stromal cells, on recovery after spinal cord injury.
Delivery of a peptide (APP96-110), derived from amyloid precursor protein (APP), has been shown to elicit neuroprotective effects following cerebral stroke and traumatic brain injury. In this study, the effect of APP96-110 or a mutant version of this peptide (mAPP96-110) was assessed following moderate (200 kdyn, (2 N)) thoracic contusive spinal cord injury (SCI) in adult Nude rats. Animals received a single tail vein injection of APP96-110 or mAPP96-110 at 30 minutes post-SCI and were then assessed for functional improvements over the next 8 weeks. A cohort of animals also received transplants of either viable or non-viable human mesenchymal stromal cells (hMSCs) into the SC lesion site at one week post-injury to assess the effect of combining intravenous APP96-110 delivery with hMSC treatment. Rats were perfused 8 weeks post-SCI and longitudinal sections of spinal cord analyzed for a number of factors including hMSC viability, cyst size, axonal regrowth, glial reactivity and macrophage activation. Analysis of sensorimotor function revealed occasional significant differences between groups using Ladderwalk or Ratwalk tests, however there were no consistent improvements in functional outcome after any of the treatments. mAPP96-110 alone, and APP96-110 in combination with both viable and non-viable hMSCs significantly reduced cyst size compared to SCI alone. Combined treatments with donor hMSCs also significantly increased βIII tubulin+, glial fibrillary acidic protein (GFAP+) and laminin+ expression, and decreased ED1+ expression in tissues. This preliminary study demonstrates that intravenous delivery of APP96-110 peptide has selective, modest neuroprotective effects following SCI, which may be enhanced when combined with hMSC transplantation. However, the effects are less pronounced and less consistent compared to the protective morphological and cognitive impact that this same peptide has on neuronal survival and behaviour after stroke and traumatic brain injury. Thus while the efficacy of a particular therapeutic approach in one CNS injury model may provide justification for its use in other neurotrauma models, similar outcomes may not necessarily occur and more targeted approaches suited to location and severity are required. All animal experiments were approved by The University of Western Australia Animal Ethics Committee (RA3/100/1460) on April 12, 2016.


Influence of volumes of prostate, rectum, and bladder on treatment planning CT on interfraction prostate shifts during ultrasound image-guided IMRT.
The purpose of this study was to analyze the relationship between prostate, bladder, and rectum volumes on treatment planning CT day and prostate shifts in the XYZ directions on treatment days. Prostate, seminal vesicles, bladder, and rectum were contoured on CT images obtained in supine position. Intensity modulated radiation therapy plans was prepared. Contours were exported to BAT-ultrasound imaging system. Patients were positioned on the couch using skin marks. An ultrasound probe was used to obtain ultrasound images of prostate, bladder, and rectum, which were aligned with CT images. Couch shifts in the XYZ directions as recommended by BAT system were made and recorded. 4698 couch shifts for 42 patients were analyzed to study the correlations between interfraction prostate shifts vs bladder, rectum, and prostate volumes on planning CT. Mean and range of volumes (cc): Bladder: 179 (42-582), rectum: 108 (28-223), and prostate: 55 (21-154). Mean systematic prostate shifts were (cm, +/-SD) right and left lateral: -0.047 +/- 0.16 (-0.361-0.251), anterior and posterior: 0.14 0.3 (-0.466-0.669), and superior and inferior: 0.19 +/- 0.26 (-0.342-0.633). Bladder volume was not correlated with lateral, anterior/posterior, and superior/inferior prostate shifts (P > 0.2). Rectal volume was correlated with anterior/posterior (P < 0.001) but not with lateral and superior/inferior prostate shifts (P > 0.2). The smaller the rectal volume or cross sectional area, the larger was the prostate shift anteriorly and vice versa (P < 0.001). Prostate volume was correlated with superior/inferior (P < 0.05) but not with lateral and anterior/posterior prostate shifts (P > 0.2). The smaller the prostate volume, the larger was prostate shift superiorly and vice versa (P < 0.05). Prostate and rectal volumes, but not bladder volumes, on treatment planning CT influenced prostate position on treatment fractions. Daily image-guided adoptive radiotherapy would be required for patients with distended or empty rectum on planning CT to reduce rectal toxicity in the case of empty rectum and to minimize geometric miss of prostate.


Evolution of transient RNA structure-RNA polymerase interactions in respiratory RNA virus genomes.
RNA viruses are important human pathogens that cause seasonal epidemics and occasional pandemics. Examples are influenza A viruses (IAV) and coronaviruses (CoV). When emerging IAV and CoV spill over to humans, they adapt to evade immune responses and optimize their replication and spread in human cells. In IAV, adaptation occurs in all viral proteins, including the viral ribonucleoprotein (RNP) complex. RNPs consists of a copy of the viral RNA polymerase, a double-helical coil of nucleoprotein, and one of the eight segments of the IAV RNA genome. The RNA segments and their transcripts are partially structured to coordinate the packaging of the viral genome and modulate viral mRNA translation. In addition, RNA structures can affect the efficiency of viral RNA synthesis and the activation of host innate immune response. Here, we investigated if RNA structures that modulate IAV replication processivity, so called template loops (t-loops), vary during the adaptation of pandemic and emerging IAV to humans. Using cell culture-based replication assays and in silico sequence analyses, we find that the sensitivity of the IAV H3N2 RNA polymerase to t-loops increased between isolates from 1968 and 2017, whereas the total free energy of t-loops in the IAV H3N2 genome was reduced. This reduction is particularly prominent in the PB1 gene. In H1N1 IAV, we find two separate reductions in t-loop free energy, one following the 1918 pandemic and one following the 2009 pandemic. No destabilization of t-loops is observed in the IBV genome, whereas analysis of SARS-CoV-2 isolates reveals destabilization of viral RNA structures. Overall, we propose that a loss of free energy in the RNA genome of emerging respiratory RNA viruses may contribute to the adaption of these viruses to the human population.


The Effect of Lung Volume on the Size and Volume of Pulmonary Subsolid Nodules on CT: Intraindividual Comparison between Total Lung Capacity and Tidal Volume.
To examine the effect of lung volume on the size and volume of pulmonary subsolid nodules (SSNs) measured on CT. A total of 42 SSNs from 31 patients were included. CT examination was first performed at total lung capacity (TLC), and a section containing the nodule was additionally scanned at tidal volume (TV). The diameter and volume of each SSN, as well as the cross-sectional lung area containing the nodule, were measured. The significance of the changes in measurements between TLC and TV within the same individuals was evaluated. The lung area and the diameter and volume of SSNs decreased significantly at TV by 12.7 cm2, 0.5 mm, and 46.4 mm3 on average, respectively (p < 0.001), compared to those at TLC. Changes in lung area between TV and TLC were positively correlated with the change in SSN diameter (p = 0.027) and volume (p = 0.014). However, after correction (by considering the change in lung area), the changes in SSN diameter (p = 0.124) and volume (p = 0.062) were not significantly different. SSN size and volume can be significantly affected by lung volume during CT scans of the same individuals.


Light spectra as triggers for sorting improved strains of Tisochrysis lutea.
It is known that microalgae respond to different light colors, but not at single-cell level. This work aimed to assess if different light colors could be used as triggers to sort over-producing cells. Six light spectra were used: red + green + blue (RGBL), blue (BL), red (RL), green (GL), blue + red (BRL) and blue + green (BGL). Fluorescence-activated cell sorting method was used to analyse single-cell fluorescence and sort cells. BGL and RGBL lead to the highest fucoxanthin production, while RL showed the lowest. Therefore, it was hypothesized that hyper-producing cells can be isolated efficiently under the adverse condition (RL). After exposure to all light colors for 14 days, the top 1% fucoxanthin producing cells were sorted. A sorted strain from RL showed higher (16-19%) growth rate and fucoxanthin productivity. This study showed how light spectra affected single-cell fucoxanthin and lipid contents and productivities. Also, it supplied an approach to sort for high-fucoxanthin or high-lipid cells.


Glutathione transferase mu 2 protects glioblastoma cells against aminochrome toxicity by preventing autophagy and lysosome dysfunction.
U373MG cells constitutively express glutathione S-transferase mu 2 (GSTM2) and exhibit (3)H-dopamine uptake, which is inhibited by 2 µM of nomifensine and 15 µM of estradiol. We generated a stable cell line (U373MGsiGST6) expressing an siRNA against GSTM2 that resulted in low GSTM2 expression (26% of wild-type U373MG cells). A significant increase in cell death was observed when U373MGsiGST6 cells were incubated with 50 µM purified aminochrome (18-fold increase) compared with wild-type cells. The incubation of U373MGsiGST6 cells with 75 µM aminochrome resulted in the formation of autophagic vacuoles containing undigested cellular components, as determined using transmission electron microscopy. A significant increase in autophagosomes was determined by measuring endogenous LC3-II, a significant decrease in cell death was observed in the presence of bafilomycin A 1, and a significant increase in cell death was observed in the presence of trehalose. A significant increase in LAMP2 immunostaining was observed, a significant decrease in bright red fluorescence of lysosomes with acridine orange was observed, and bafilomycin A 1 pretreatment reduced the loss of lysosome acidity. A significant increase in cell death was observed in the presence of lysosomal protease inhibitors. Aggregation of TUBA/α-tubulin (tubulin, α) and SQSTM1 protein accumulation were also observed. Moreover, a significant increase in the number of lipids droplets was observed compared with U373MG cells with normal expression of GSTM2. These results support the notion that GSTM2 is a protective enzyme against aminochrome toxicity in astrocytes and that aminochrome cell death in U373MGsiGST6 cells involves autophagic-lysosomal dysfunction.


Mitogen activated protein kinase-1 and cell division control protein-42 are putative targets for the binding of novel natural lead molecules: a therapeutic intervention against Candida albicans.
Candida albicans, fungal yeast causes several lethal infections in immune-suppressed patients and recently emerged as drug-resistant pathogens worldwide. The present study aimed to screen putative drug targets of Candia albicans and to study the binding potential of novel natural lead compounds towards these targets by computational virtual screening and molecular dynamic (MD) simulation. Through extensive analysis of mitogen-activated protein kinase (MAPK) signalling pathways, mitogen-activated protein kinase-1 (HOG1) and cell division control protein-42 (CDC42) genes were prioritized as putative targets based on their virulent functions. The three-dimensional structures of these genes, not available in their native forms, were computationally modeled and validated. 76 lead molecules from various natural sources were screened and their drug likeliness and pharmacokinetic features were predicted. Among these ligands, two lead molecules that demonstrated ideal drug-likeliness and pharmacokinetic features were docked against HOG1 and CDC42 and their binding potential was compared with the binding of conventional drug Fluconazole with their usual target. The prediction was computationally validated by MD simulation. The current study revealed that Cudraxanthone-S present in Cudrania cochinchinensis and Scutifoliamide-B present in Piper scutifolium exhibited ideal drug likeliness, pharmacokinetics and binding potential to the prioritized targets in comparison with the binding of Fluconazole and their usual target. MD simulation showed that CDC42-Cudraxanthone-S and HOG1-Scutifoliamide-B complexes were exhibited stability throughout MD simulation. Thus, the study provides significant insight into employing HOG1 and CDC42 of MAPK as putative drug targets of C. albicans and Cudraxanthone-S and Scutifoliamide-B as potential inhibitors for drug discovery.Communicated by Ramaswamy H. Sarma.


Understanding cell homing-based tissue regeneration from the perspective of materials.
Homing of cells to their target organs for tissue defect repair poses a significant challenge to biomaterials scientists and tissue engineers, due to the low efficiency of homing of effective cells to defect sites as well as the difficulties in coordinating cell migration, adhesion, spreading and differentiations. Recent advances in biomaterials have successfully improved the efficiency of homing of mesenchymal stem cells (MSCs) and cell homing-based tissue regeneration. In this review, the process of cell-homing based tissue regeneration was discussed from three different perspectives, including cell surface engineering, scaffold optimization and signaling molecule interactions. Cell surface modification by using polymeric materials offers a simple way to administrate cell migration. Besides, the ordered or anisotropic structures are proved to be more efficient for cell adhesion, spreading and infiltration than relatively random or isotropy structures. Moreover, the coordinated release of different growth factors (GFs), e.g. achieved via core-shell microspheres, can orchestrate the biological processes, including cell growth and differentiations, and significantly enhance the osteogenic differentiation of low population density of MSCs. These developments in biomaterials are not only important for the fundamental understanding of material-cell interactions, but also help understand cell homing-based tissue regeneration from the perspective of materials, which is crucial for the design and fabrication of a new generation of highly functional biomaterials for tissue regeneration.


Doing the dance of culture change: complexity, evidence and leadership.
The challenge of culture change in hospitals must address three distinct but interwoven tensions: the need to shift paradigm and understand healthcare as a complex adaptive system; the challenge of knitting together the contributions of both evidence-based medicine and practice-based evidence; and the critical role of distributed, problem-focused leadership.The authors of the lead paper highlight five key issues in addressing this challenge: (1) the implementation of strategies like front-line ownership (FLO) in the context of macro-level social forces; (2) the central role of distributed leadership and its strengthening within the organization; (3) the need to attend to developing systems thinking skills at all levels; (4) the very significant challenge of how to scale up the labour-intensive change strategies within FLO, the role of "simple rules" and the potential for systems thinking tools such as concept mapping and dynamic modelling; and (5) the concurrent orchestration of not one culture change but three tensions in the challenge FLO represents to simpler versus complex adaptive systems, leadership and management and the balance between evidence-based medicine and practice-based evidence, at the clinical, organizational and macro-system levels.


Treatment of Cervicogenic Headache Concurrent With Cervical Stenosis by Anterior Cervical Decompression and Fusion.
Retrospective study. To report the efficacy of anterior cervical decompression and fusion surgery as treatment method for cervicogenic headache (CeH). The exact diagnostic criteria and optimal treatment of CeH is still under investigation. A total of 34 consecutive patients (mean age 55.8 y) with CeH (in addition to cervical stenosis symptomatology) resistant to nonoperative treatment were treated by anterior cervical decompression and fusion from 1 up to 3 levels and were followed for at least 1 year. Clinical visual analog pain scale for headache, patient satisfaction index as well as radiographic examinations (flexion-extension radiographs and, when diagnosis of fusion status was uncertain, computed tomography) were documented for all patients at regular intervals. Statistical comparisons of outcome measures between different time points of examinations were performed. All patients reported relief of their CeH with mean (range) visual analog pain scale scores as 8.1 (3-9), 2.4 (0-4), and 3.1 (0-5) preoperatively, at 2 months postoperatively, and at the final follow-up, respectively. There was a significant improvement (P<0.001) of visual analog pain scale score between before surgery and at 2 months postoperatively or at the last follow-up. Thirty patients (88%) reported satisfied with their treatment, whereas 4 patients (12%) were not satisfied with surgery. No major surgical complication was seen and only 1 patient had symptomless pseudoarthrosis. CeH when associated with cervical spinal stenosis of the subaxial spine can improve when stenosis is treated with anterior cervical discectomy and fusion.


[Cell membrane mechanism of action of prostaglandins E1 and F2 alpha on thrombocyte function].
PGE1 and PGF2 alpha were shown to exert an opposite action on Na, K-ATPase activity and protein fluorescence of the platelet membranes. The effect of the prostaglandins appeared to be unidirectional as regards the erythrocytic membranes. The prostaglandins were demonstrated to increase viscosity of the lipid bilayer and its permeability by uni- and bivalent cations.


Anterior Commissure Regulates Neuronal Activity of Amygdalae and Influences Locomotor Activity, Social Interaction and Fear Memory in Mice.
The two hemispheres of the vertebrate brain are connected through several commissures. Although the anterior commissure (AC) is the most conserved white matter structure in the brains of different vertebrates, its complete physiological functionality remains elusive. Since the AC is involved in the connection between two amygdalae and because amygdalae are critical for emotional behaviors and social interaction, we assessed amygdalar activity and function to investigate the physiological role of the AC. We first performed ex vivo electrophysiological recording on mouse brains to demonstrate that the AC delivers a positive signal to facilitate synaptic responses and to recruit basolateral amygdalar neurons via glutamatergic synapses. Transection was then undertaken to investigate the role of the AC in vivo. Results from in vivo optogenetic stimulation suggest that AC transection impairs mutual activation between two basolateral amygdalae. Behavioral analyses were then used to assess if AC surgical lesioning results in hyperactivity, anxiety, social reduction or learning/memory impairment, which are behavioral features associated with neuropsychiatric disorders, such as autism spectrum disorders. We found that AC transection results in higher locomotor activity, aberrant social interaction and reduced associative memory, but not anxiety. Moreover, systemic administration of D-cycloserine, a coagonist of N-methyl-D-aspartate receptor, ameliorated auditory fear memory in AC-transected mice, reinforcing our evidence that the AC potentiates the activity of basolateral amygdalae. Our study suggests that the AC regulates basolateral amygdalar activity and influences neuropsychiatry-related behaviors in mice.


In vivo fluorescence sensing of the salicylate-induced change of zinc ion concentration in the auditory cortex of rat brain.
This study demonstrates a fluorescence method for in vivo sensing of the dynamic change of Zn(2+) concentration in auditory cortex microdialysates induced by salicylate with N'-(7-nitro-2,1,3-benzoxadiazole-4-yl)-N,N,N'-tris(pyridine-2-ylmethyl) ethane-1,2-diamine (NBD-TPEA) as a probe. The excellent properties of the NBD-TPEA probe make it possible to achieve a high selectivity for Zn(2+) sensing with the co-existence of amino acids and other metal ions as well as the species commonly existing in the cerebral system. To validate the method for in vivo fluorescence sensing of Zn(2+) in the rat brain, we pre-mix the microdialysates in vivo sampled from the auditory cortex with the NBD-TPEA probe and then perfuse the mixtures into a fluorescent cuvette for continuous-flow fluorescence detection. The method demonstrated here shows a linear relationship between the signal output and Zn(2+) concentration within the concentration range from 0.5 μM to 4 μM, with a detection limit of 156 nM (S/N = 3). The basal level of extracellular Zn(2+) in auditory cortex microdialysates is determined to be 0.52 ± 0.082 μM (n = 4). This value is increased by the injection of 100 mg mL(-1) of salicylate (1 μL min(-1), 5 min, i.p.), reaches a peak at the time point of 90 min, and levels off with time. Such an increase is attenuated by the injection of MK-801, a potent and specific NMDA receptor antagonist, after the pre-injection of 100 mg mL(-1) salicylate for 5 min. This study offers a fluorescence method for in vivo sensing of Zn(2+) in the rat brain that could be useful for the investigations of chemical processes involved in brain functions.


Aquibacillus halophilus gen. nov., sp. nov., a moderately halophilic bacterium from a hypersaline lake, and reclassification of Virgibacillus koreensis as Aquibacillus koreensis comb. nov. and Virgibacillus albus as Aquibacillus albus comb. nov.
A novel Gram-stain-positive, moderately halophilic bacterium, designated strain B6B(T), was isolated from the water of an Iranian hypersaline lake, Aran-Bidgol, and characterized taxonomically using a polyphasic approach. Cells of strain B6B(T) were rod-shaped, motile and produced ellipsoidal endospores in terminal positions in non-swollen sporangia. Strain B6B(T) was a strictly aerobic bacterium and catalase- and oxidase-positive. The strain was able to grow at NaCl concentrations of 0.5-20.0% (w/v), with optimum growth occurring at 10.0% (w/v) NaCl. The optimum temperature and pH for growth were 35 °C and pH 7.0. On the basis of 16S rRNA gene sequence analysis, strain B6B(T) was shown to belong to the phylum Firmicutes and its closest phylogenetic similarities were with the species Virgibacillus koreensis BH30097(T) (97.5%), Virgibacillus albus YIM 93624(T) (97.4%), Sediminibacillus halophilus EN8d(T) (96.8%), Sediminibacillus albus NHBX5(T) (96.6%), Virgibacillus carmonensis LMG 20964(T) (96.3%) and Paraliobacillus quinghaiensis YIM-C158(T) (96.0%), respectively. Phylogenetic analysis revealed that strain B6B(T), along with V. koreensis BH30097(T) and V. albus YIM 93624(T), clustered in a separate clade in the family Bacillaceae. The DNA G+C content of the novel isolate was 35.8 mol%. DNA-DNA hybridization experiments revealed low levels of relatedness between strain B6B(T)and V. koreensis BH30097(T) (13%) and V. albus YIM 93624(T) (33%). The major cellular fatty acid of strain B6B(T) was anteiso-C15 : 0 (75.1%) and its polar lipid pattern consisted of phosphatidylglycerol, diphosphatidylglycerol, an unknown phospholipid and an unknown glycolipid. The isoprenoid quinones were MK-7 (90%) and MK-6 (3%). The peptidoglycan contained meso-diaminopimelic acid as the diagnostic diamino acid. All of these features support the placement of isolate B6B(T) within the phylum Firmicutes. It is closely related to V. koreensis and V. albus, but with features that clearly distinguish it from species of the genus Virgibacillus or of other related genera. On the basis of the polyphasic evidence derived in this study, we propose that strain B6B(T) be placed within a new genus, as Aquibacillus halophilus gen. nov., sp. nov., with B6B(T) as the type strain ( =IBRC-M 10775(T) =KCTC 13828(T)). We also propose that V. koreensis and V. albus should be transferred to this new genus and be named Aquibacillus koreensis comb. nov. and Aquibacillus albus comb. nov., respectively. The type strain of Aquibacillus koreensis comb. nov. is BH30097(T) ( =KCTC 3823(T) =IBRC-M 10657(T) =JCM 12387(T)) and the type strain of Aquibacillus albus comb. nov. is YIM 93624(T) ( =DSM 23711(T) =IBRC-M 10798(T) =JCM 17364(T)).


The role of Bcl-2 family proteins in therapy responses of malignant astrocytic gliomas: Bcl2L12 and beyond.
Glioblastoma (GBM) is a highly aggressive and lethal brain cancer with a median survival of less than two years after diagnosis. Hallmarks of GBM tumors include soaring proliferative indices, high levels of angiogenesis, diffuse invasion into normal brain parenchyma, resistance toward therapy-induced apoptosis, and pseudopallisading necrosis. Despite the recent advances in neurosurgery, radiation therapy, and the development of targeted chemotherapeutic regimes, GBM remains one of the deadliest types of cancer. Particularly, the alkylating agent temozolomide (TMZ) in combination with radiation therapy prolonged patient survival only marginally, and clinical studies assessing efficacies of targeted therapies, foremost ATP mimetics inhibiting the activity of receptor tyrosine kinases (RTKs), revealed only few initial responders; tumor recurrence is nearly universal, and salvage therapies to combat such progression remain ineffective. Consequently, myriad preclinical and clinical studies began to define the molecular mechanisms underlying therapy resistance of GBM tumors, and pointed to the Bcl-2 protein family, in particular the atypical member Bcl2-Like 12 (Bcl2L12), as important regulators of therapy-induced cell death. This review will discuss the multi-faceted modi operandi of Bcl-2 family proteins, describe their roles in therapy resistance of malignant glioma, and outline current and future drug development efforts to therapeutically target Bcl-2 proteins.


Structure-Based Prediction of G-Protein-Coupled Receptor Ligand Function: A β-Adrenoceptor Case Study.
The spectacular advances in G-protein-coupled receptor (GPCR) structure determination have opened up new possibilities for structure-based GPCR ligand discovery. The structure-based prediction of whether a ligand stimulates (full/partial agonist), blocks (antagonist), or reduces (inverse agonist) GPCR signaling activity is, however, still challenging. A total of 31 β1 (β1R) and β2 (β2R) adrenoceptor crystal structures, including antagonist, inverse agonist, and partial/full agonist-bound structures, allowed us to explore the possibilities and limitations of structure-based prediction of GPCR ligand function. We used all unique protein-ligand interaction fingerprints (IFPs) derived from all ligand-bound β-adrenergic crystal structure monomers to post-process the docking poses of known β1R/β2R partial/full agonists, antagonists/inverse agonists, and physicochemically similar decoys in each of the β1R/β2R structures. The systematic analysis of these 1920 unique IFP-structure combinations offered new insights into the relative impact of protein conformation and IFP scoring on selective virtual screening (VS) for ligands with a specific functional effect. Our studies show that ligands with the same function can be efficiently classified on the basis of their protein-ligand interaction profile. Small differences between the receptor conformation (used for docking) and reference IFP (used for scoring of the docking poses) determine, however, the enrichment of specific ligand types in VS hit lists. Interestingly, the selective enrichment of partial/full agonists can be achieved by using agonist IFPs to post-process docking poses in agonist-bound as well as antagonist-bound structures. We have identified optimal structure-IFP combinations for the identification and discrimination of antagonists/inverse agonist and partial/full agonists, and defined a predicted IFP for the small full agonist norepinephrine that gave the highest retrieval rate of agonists over antagonists for all structures (with an enrichment factor of 46 for agonists and 8 for antagonists on average at a 1% false-positive rate). This β-adrenoceptor case study provides new insights into the opportunities for selective structure-based discovery of GPCR ligands with a desired function and emphasizes the importance of IFPs in scoring docking poses.


Joint study of genetic regulators for expression traits related to breast cancer.
The mRNA expression levels of genes have been shown to have discriminating power for the classification of breast cancer. Studying the heritability of gene expression levels on breast cancer related transcripts can lead to the identification of shared common regulators and inter-regulation patterns, which would be important for dissecting the etiology of breast cancer. We applied multilocus association genome-wide scans to 18 breast cancer related transcripts and combined the results with traditional linkage scans. Regulatory hotspots for these transcripts were identified and some inter-regulation patterns were observed. We also derived evidence on interacting genetic regulatory loci shared by a number of these transcripts. In this paper, by restricting to a set of related genes, we were able to employ a more detailed multilocus approach that evaluates both marginal and interaction association signals at each single-nucleotide polymorphism. Interesting inter-regulation patterns and significant overlaps of genetic regulators between transcripts were observed. Interaction association results returned more expression quantitative trait locus hotspots that are significant.


Ultrasensitive Detection of Circulating Tumor DNA of Lung Cancer via an Enzymatically Amplified SERS-Based Frequency Shift Assay.
Circulating tumor DNA (ctDNA) is a promising noninvasive biomarker for the early diagnosis of cancers. However, it is challenging for accurate and sensitive detection of pico-to-femtomolar serum concentration of ctDNA, especially in the presence of its analogues that produce strong background noise. Herein, a DNA-rN1-DNA-mediated surface-enhanced Raman scattering frequency shift assay is developed, which enables sensitive detection of ctDNA with one single base pair mutation (KARS G12D mutation) from the normal ones (KARS G12D normal) of lung cancer. This sensing platform features in both the designed hairpin DNA-rN1-DNA probe for specific ctDNA recognition and the employed RNase HII enzyme that specifically hydrolyzes the DNA-rN1-DNA/ctDNA hybrid and thus allows ctDNA recycling in the system to realize signal amplification. The detection system shows sub-femtomolar-level sensitivity in the phosphate-buffered saline solution and is demonstrated to function well in both fetal bovine serum and human physiological media. In particular, the sensitive assay of ctDNA in serum samples from lung cancer patients is achieved, suggesting its high potential applications in clinical settings for early diagnosis and prognosis of lung cancer.


eGFR is a reliable preoperative renal function parameter in patients with gastric cancer.
To evaluate the validity of the estimated glomerular filtration rate (eGFR) as a preoperative renal function parameter in patients with gastric cancer. A retrospective study was conducted in 147 patients with gastric cancer. Preoperative creatinine clearance (Ccr), eGFR, and pre- and postoperative serum creatinine (sCr) data were examined. Preoperative Ccr and eGFR were then compared for their reliability in predicting postoperative renal dysfunction. Among 110 patients with normal preoperative Ccr values, 7 (6.3%) had abnormal postoperative sCr values, and among 112 patients with normal preoperative eGFR values, postoperative sCr was abnormal in 5 (4.5%) (P = 0.53). Among 37 patients with abnormal preoperative Ccr values, 30 (81.1%) had normal postoperative sCr values, and of 35 patients with abnormal preoperative eGFR values, postoperative sCr was normal in 25 (71.4%) (P = 0.34). Preoperative Ccr was significantly correlated with eGFR (r = 0.514), and postoperative sCr was significantly correlated with preoperative Ccr (r = -0.334) and eGFR (r = -0.02). Preoperative eGFR is as effective as Ccr for predicting postoperative renal dysfunction. eGFR should therefore be used as an indicator of preoperative renal function in place of Ccr since it is a cheaper and easier to perform test.


Two new tardigrade species from Sicily.
Two new species of tardigrades are described from Sicilian moss samples: Macrobiotus insuetus sp. nov. and Diphascon (Diphascon) procerum sp. nov. Macrobiotus insuetus sp. nov. is a species of the harmsworthi-group characterized by both posterior and anterior claws of the hind legs, which are different in shape from those of the first three leg pairs. The IV claws have extended basal tract where the branches are joined and the secondary branch breaks at near right angle to the primary branch and is clearly shorter than the main branch and the secondary branch of claws I-III. The eggs are not areolated and have conical processes with a reticular ornamentation. Diphascon (D.) procerum sp. nov. has a delicate cuticular ornamentation of very small tubercles, almost dots; two macroplacoids and septulum are present; thin accessory points are present on the main branches of the slender claws; lunules are absent but the base of the external claws of the hind legs are enlarged and slightly indented; a cuticular bar is present near the internal claw of the first three leg pairs and two cuticular bars are present on the hind legs between the base of the claws and near the base of the anterior claw.


Massive thrombosis of bilateral superior and inferior ophthalmic veins secondary to ethmoidal rhinosunisitis: imaging findings.
Ophthalmic vein thrombosis (OVT) is a rare condition occurring secondary to varied etiologies that commonly presents with proptosis, globe dystopia, ophthalmoplegia, periorbital edema, and occasionally diminished visual acuity. It may be related to inflammation of the orbit or paranasal sinuses. We herein report imaging findings of thrombosed superior and inferior ophthalmic veins in bilateral involvement in a 20-year-old male patient without cavernous sinus thrombosis. He presented with pain, swelling, and blurred vision in both eyes. Magnetic resonance (MR) imaging, cerebral MR angiography, and susceptibility weighted imaging were performed. Bilateral superior and inferior OVT due to a complication of ethmoidal sinusitis was diagnosed in the patient. Anticoagulant and systemic broad-spectrum antibiotic therapy was started. His symptoms were recorded at the end of 14 days of the treatment.


Short-term studies of MDL 19,660-induced canine thrombocytopenia.
After 2 days of dosing, platelet counts progressively declined in dogs treated orally with 30 mg/kg/day of the antidepressant compound MDL 19,660 for 8 days. Accompanying the decrease in platelet counts was an increase in both large and vacuolated degenerating platelets. Upon cessation of dosing, the platelet counts returned to levels equal to or exceeding predosing levels within 4-7 days. Co-administration with aspirin, a known antiaggregating agent, had no protective effect on the drug-induced thrombocytopenia. In vitro testing of normal canine platelets in the presence of MDL 19,660 further revealed that spontaneous aggregation did not occur and that ADP-induced aggregation was inhibited. Drug-related platelet loss was also not prevented by the co-administration of prednisone, a steroid with immunosuppressive effects and inhibitory properties against reticuloendothelial cell phagocytosis of platelets. The results of the present investigation indicate that MDL 19,660 may produce in the dog a reversible thrombocytopenia in the form of vacuolar degeneration and subsequent destruction of the platelet by means other than aggregation or steroid-responsive mechanisms.


Effect of an Acute Bout of Endurance Exercise on Serum 25(OH)D Concentrations in Young Adults.
Regular exercise or high physical activity levels are associated with higher serum 25-hydroxyvitamin D [25(OH)D] concentrations; however, the effect of acute exercise on serum 25(OH)D concentrations remains unclear. We aimed to clarify whether acute endurance exercise has a direct effect on the circulating 25(OH)D concentrations in young adults. Exercise intervention trial in an institutional practice. Twenty young, active adults (males, n = 10; females, n = 10). Participants were asked to perform a cycling exercise for 30 minutes at 70% maximal oxygen uptake. The serum concentrations of 25(OH)D and other blood parameters were assessed before exercise and at 0, 0.5, 1, 3, and 24 hours after exercise. The serum 25(OH)D concentrations were significantly increased not only at 0 (P < 0.01), 1 (P < 0.05), and 3 hours (P < 0.01) after exercise, but they were also increased at 24 hours (P < 0.05) after acute endurance exercise in young adults. A significant sex × time interaction effect was observed (P < 0.05), and the incremental areas under the curve for the 25(OH)D concentrations were significantly higher in men than in the women (P < 0.01). There is a direct effect of endurance exercise on serum 25(OH)D concentrations. In addition, sex disparity was observed in the serum 25(OH)D response to acute endurance exercise, and the increase in 25(OH)D concentrations was greater in men than in women.


Antibody concentrations against the infecting serotype in vaccinated and unvaccinated children with invasive pneumococcal disease in the United Kingdom, 2006-2013.
This study aimed to estimate, following invasive pneumococcal disease (IPD), the proportion of children with protective immunoglobulin G (IgG) concentrations against the infecting serotype compared with other vaccine serotypes, and to assess risk of recurrent IPD. Pneumococcal antibody concentrations were available for 413 children with vaccine-type IPD diagnosed during 2006-2013. We compared serotype-specific IgG concentrations against the infecting vs other vaccine serotypes, after adjusting for confounders such as age using multilevel analyses. After IPD, a higher proportion of vaccine-naive children had IgG concentrations ≥0.35 µg/mL against their infecting serotype than other vaccine serotypes (51% vs 36%; P < .001). In contrast, among children immunized with pneumococcal conjugate vaccine (PCV) both before and after IPD, the proportion with IgG concentrations ≥0.35 µg/mL against the infecting serotype was lower compared with other vaccine serotypes (71% vs 98%; P < .001). These children also had lower IgG geometric mean concentrations (GMCs) against the infecting serotype (2.22 µg/mL) vs other vaccine serotypes (15.64 µg/mL) in multilevel models (IgG GMC ratio, 0.24; 95% confidence interval, .18-.32), although their IgG GMC was higher compared with vaccine-naive children. Vaccinated children with IgG concentrations <0.35 µg/mL against their infecting serotype generally remained unresponsive despite further vaccine doses. However, recurrent IPD with the same infecting serotype was rare (7/3030 children [0.2%]) and not associated with unresponsiveness. Vaccination with PCV before and/or after IPD was associated with lower IgG concentrations against the infecting serotype compared with other vaccine serotypes, but recurrent IPD was rare. Further studies are needed to understand this phenomenon in immunized children.


Monitoring electron and proton diffusion flux through three-dimensional, paper-based, variable biofilm and liquid media layers.
The goal of this work is to pursue analytical approaches that elucidate electron and proton diffusion inside the Shewanella oneidensis biofilm and bulk liquid, which will inevitably promote the translation of Microbial Fuel Cell (MFC) technology for renewable, "green energy" solutions that are in demand to sustain the world's ever-increasing energy demands and to mitigate the depletion of current resources. This study provides a novel strategy for monitoring electron/proton fluxes in 3-D multi-laminate structures of paper as a scaffold to support S. oneidensis biofilms and bulk media liquid. Multiple layers of paper containing bacterial cells and/or media are stacked to form a layered 3-D model of the overall biofilm/bulk liquid construct. Mass transport of electrons and protons into this 3-D system can be quantified along with the exploration of microbial energy production. Assembly of a 3D paper stack can be modular and allows us to control the thickness of the overall biofilm/bulk liquid construct with the different diffusion distances of the electrons/protons through the stack. By measuring the current generated from the 3-D stack, the electron and proton diffusivity through biofilms were quantitatively investigated. We found that (i) the diffusion length of the electrons/protons in the S. oneidensis biofilm/bulk liquid is a determinant factor for the MFC performance, (ii) the electron transfer through the endogenous mediators of S. oneidensis can be a more critical factor to limit the current/power generation of the MFCs than the proton transfer in the MFC system and (iii) the thicker biofilm allows higher and longer current generation but requires more time to reach a peak current value and increases the total energy loss of the MFC system.


An update on glass-ionomer cements.
It has been claimed that glass-ionomer cements possess properties that could make them the "ideal' restorative material. In the light of current disquiet about the safety of dental amalgam, are glass-ionomer cements likely to become the replacement materials of choice?


Estimating the twist of beta-strands embedded within a regular parallel beta-barrel structure.
The parallel beta-barrel is a recurrent structural motif found in a large variety of different enzymes belonging to the family of alpha/beta-proteins. It has been shown previously that the hyperboloid can be considered as a scaffold describing the parallel beta-barrel structure. To assess restraints on beta-strand twist imposed by a given scaffold geometry, the notion of scaffold twist, Ts, is introduced. From Ts, the beta-strand twist (Tw beta) expected for a given scaffold geometry can be derived and it is verified that this computed twist can be used to identify beta-barrels characterized by good hydrogen bonding. It is noted that Tw beta is only slightly affected for beta-barrels differing in the number (N) of beta-strands, suggesting that restraints on main-chain conformation of beta-strands are not likely to account for the N = 8 invariability observed in natural parallel beta-barrels thereby strengthening previous work rationalizing this constancy.


Nitroxide-Mediated Polymerization of Methacrylic Esters: Insights and Solutions to a Long-Standing Problem.
Nitroxide-mediated polymerization (NMP) is one of the most powerful reversible deactivation radical polymerization techniques and has incredibly gained in maturity and robustness over the last decades. However, control of methacrylic esters is one of the different aspects of NMP that still requires improvement. This family of monomers always represented an important challenge for NMP, despite the many different nitroxide structures that have been designed over the course of time. This Review aims to present the most successful strategies directed toward the control of the NMP technique of methacrylic esters and especially methyl methacrylate. NMP-derived materials comprising uncontrolled methacrylate segments will also be discussed.


Cyclam-Based Chelators Bearing Phosphonated Pyridine Pendants for 64Cu-PET Imaging: Synthesis, Physicochemical Studies, Radiolabeling, and Bioimaging.
Herein we present the preparation of two novel cyclam-based macrocycles (te1pyp and cb-te1pyp), bearing phosphonate-appended pyridine side arms for the coordination of copper(II) ions in the context of 64Cu PET imaging. The two ligands have been prepared through conventional protection-alkylation sequences on cyclam, and their coordination properties have been thoroughly investigated. The corresponding copper complexes have been fully characterized in the solid state (X-ray diffraction analysis) and in solution (EPR and UV-vis spectroscopies). Potentiometric studies combined with spectrometry have also allowed us to determine their thermodynamic stability constants, confirming their high affinity for copper(II) cations. The kinetic inertness of the complexes has been verified by acid-assisted dissociation experiments, enabling their use in 64Cu-PET imaging in mice for the first time. Indeed, the two ligands could be quantitatively radiolabeled under mild conditions, and the resulting 64Cu complexes have demonstrated excellent stability in serum. PET imaging demonstrated a set of features emerging from the combination of picolinates and phosphonate units: high stability in vivo, fast clearance from the body via renal elimination, and most interestingly, very low fixation in the liver. This is in contrast with what was observed for monopicolinate cyclam (te1pa), which had a non-negligible accumulation in the liver, owing probably to its different charge and lipophilicity. These results thus pave the way for the use of such phosphonated pyridine chelators for in vivo 64Cu-PET imaging.


In vivo human tendinous tissue stretch upon maximum muscle force generation.
In the present study, we examined the hypothesis that stretch of tendinous tissue in the human tibialis anterior (TA) muscle-tendon unit upon isometric dorsiflexion maximum voluntary contraction (MVC) varies along the entire tendinous component length. Ultrasound-based measurements of the excursions of the TA tendon origin and proximal end of the TA central aponeurosis were taken in the transition from rest to MVC in six men. Subtracting the TA tendon origin excursion from the excursion of the aponeurosis proximal end, the aponeurosis excursion was estimated. Estimation of the aponeurosis proximal region excursion was obtained subtracting the excursion of the insertion point of a central region fascicle on the aponeurosis from the whole aponeurosis excursion. Subtracting tendon excursion from the excursion of the central fascicle insertion point, the aponeurosis distal region excursion was estimated. Strain values were calculated dividing the excursions obtained by the original resting lengths. All excursions and lengths were measured in the mid-longitudinal axis of the TA muscle-tendon unit at the neutral anatomical ankle position. Tendon excursion and strain were 0.5+/-0. 08 cm (mean+/-SE) and 3.1+/-0.2%, respectively. Aponeurosis excursion and strain were 1.1+/-0.15 cm and 6.5+/-0.6%, respectively. Aponeurosis distal region excursion and strain were 0.3+/-0.05 cm and 3.5+/-0.3%, respectively. Aponeurosis proximal region excursion and strain were 0.8+/-0.12 cm and 9.2+/-1%, respectively. Aponeurosis excursion and strain were larger by 110-120% (P<0.05) compared with tendon. Aponeurosis proximal region excursion and strain were larger by 165-170% (P<0.05) compared with aponeurosis distal region. These findings are in line with results from in vitro animal material testing and have important implications for theoretical models of muscle function.


Ca2+ regulation in the absence of the iplA gene product in Dictyostelium discoideum.
Stimulation of Dictyostelium discoideum with cAMP evokes an elevation of the cytosolic free Ca2+ concentration ([Ca2+]i). The [Ca2+]i-change is composed of liberation of stored Ca2+ and extracellular Ca2+-entry. The significance of the [Ca2+]i-transient for chemotaxis is under debate. Abolition of chemotactic orientation and migration by Ca2+-buffers in the cytosol indicates that a [Ca2+]i-increase is required for chemotaxis. Yet, the iplA- mutant disrupted in a gene bearing similarity to IP3-receptors of higher eukaryotes aggregates despite the absence of a cAMP-induced [Ca2+]i-transient which favours the view that [Ca2+]i-changes are insignificant for chemotaxis. We investigated Ca2+-fluxes and the effect of their disturbance on chemotaxis and development of iplA- cells. Differentiation was altered as compared to wild type amoebae and sensitive towards manipulation of the level of stored Ca2+. Chemotaxis was impaired when [Ca2+]i-transients were suppressed by the presence of a Ca2+-chelator in the cytosol of the cells. Analysis of ion fluxes revealed that capacitative Ca2+-entry was fully operative in the mutant. In suspensions of intact and permeabilized cells cAMP elicited extracellular Ca2+-influx and liberation of stored Ca2+, respectively, yet to a lesser extent than in wild type. In suspensions of partially purified storage vesicles ATP-induced Ca2+-uptake and Ca2+-release activated by fatty acids or Ca2+-ATPase inhibitors were similar to wild type. Mn2+-quenching of fura2 fluorescence allows to study Ca2+-influx indirectly and revealed that the responsiveness of mutant cells was shifted to higher concentrations: roughly 100 times more Mn2+ was necessary to observe agonist-induced Mn2+-influx. cAMP evoked a [Ca2+]i-elevation when stores were strongly loaded with Ca2+, again with a similar shift in sensitivity in the mutant. In addition, basal [Ca2+]i was significantly lower in iplA- than in wild type amoebae. These results support the view that [Ca2+]i-transients are essential for chemotaxis and differentiation. Moreover, capacitative and agonist-activated ion fluxes are regulated by separate pathways that are mediated either by two types of channels in the plasma membrane or by distinct mechanisms coupling Ca2+-release from stores to Ca2+-entry in Dictyostelium. The iplA- strain retains the capacitative Ca2+-entry pathway and an impaired agonist-activated pathway that operates with reduced efficiency or at higher ionic pressure.


Psychosocial working conditions and self-reported long-term illness: a population-based study of Swedish-born and foreign-born employed persons.
Knowledge pertaining to the relationship between migration status and psychosocial job characteristics and long-term illness is not readily available in the international literature. The aim of this study is to analyse the cross-sectional associations between high psychological job demands and low decision latitude (high job strain), work-related social support and long-term illness among foreign-born and Swedish-born people. The present study combines four annual simple random samples covering 1994-97 from the Swedish Annual Level of Living Survey (SALLS). A sub-sample, including only employed persons and consisting of 10,072 Swedish-born persons, 710 labour migrants and 333 refugees aged 25-64 years, was analysed using logistic regression. Refugees had a higher risk (OR=1.33; 95% CI: 1.05-1.69) of long-term illness than Swedes. Moreover, those experiencing both high job demands and a low decision latitude ran an increased risk (OR=1.74; 95% CI: 1.42-2.13) of long-term illness. About 63% of the refugees among the unskilled/skilled manual workers had low decision latitudes in comparison with 17% of the intermediate and senior salaried employees. There were only small differences in job demands between labour immigrants, refugees and Swedes. There was no interaction between migration status and high job strain. However, refugees with low social support had nearly twice as high a risk of long-term illness as Swedes with high-level work-related social support. Refugees ran a higher risk of long-term illness than Swedes. Although there were no differences in risk between labour immigrants, refugees and Swedes under job strain, refugees with low work-related social support had a high risk of long-term illness. Unskilled/skilled refugee workers had lower decision latitudes than Swedes.


Characteristics of the spread of apple proliferation by its vector Cacopsylla picta.
The distribution and natural phytoplasma infection of Cacopsylla picta were investigated during a long-term field survey between 2002 and 2009 in commercial and abandoned apple proliferation-infected orchards throughout Germany, northern Switzerland, and eastern France. Comparable population dynamics were described for the different sites whereas considerable variations in the absolute population densities were observed among the years. Individual polymerase chain reaction (PCR) testing revealed, for each year, a rather stable natural infection rate with ?Candidatus Phytoplasma mali? of ?10% for overwintered adults of C. picta. Both genders were equally highly infected although more females were caught. The overall male/female ratio was 1:1.5. No direct correlation was found between the infection status of the orchard and the infection rate of overwintered C. picta. No influence of agricultural practices was seen. However, a relationship between the incidence of the disease and the vector population density became evident on a regional scale. Successful transmission of ?Ca. P. mali? occurred each year with overwintered individuals as well as with new adults. The transmission efficiency varied among the years within 8 to 45% for overwintered adults and 2 to 20% for individuals of the new generation. The load of single C. picta with ?Ca. P. mali? was determined by quantitative real-time PCR. High phytoplasma titers were measured in overwintered adults already at their first appearance in the orchards after remigration from their overwintering hosts. Thus, the data indicate the transmission of the disease on a regional scale by remigrant adults of C. picta and at a local scale within the same season by emigrant adults which developed on infected plants.


Long-term stability of diagnosis and symptom dimensions in a systematic sample of patients with onset of schizophrenia in childhood and early adolescence. I: nosology, sex and age of onset.
Little is known about the long-term outcome of schizophrenia that has its onset during childhood and early adolescence (early-onset schizophrenia, or EO-SZ). Whether or not EO-SZ is an aetiologically separate form of schizophrenia (SZ) is unresolved. The study was a 14.8-year follow-up, using methods such as systematic sampling, evaluation of possible non-respondent bias, consensus best-estimate diagnoses (DSM-III-R) made independently in childhood and adulthood, measures of positive and negative dimensions, of non-psychotic behaviour disturbances (NPBD) and of developmental problems before the appearance of SZ. There was high stability of EO-SZ (n = 40) diagnoses (mean onset at 14.0 years) until adulthood (mean age at follow-up 28.8 years) but a lower stability of positive and negative schizophrenic dimensions. There was a poor outcome of EO-SZ, a strong over-representation of males but few gender differences, and no effect of age of onset on clinical features and outcome. EO-SZ taken as a whole shows no qualitative differences to adult-onset SZ. However, a distinction through the onset of preschizophrenic developmental problems or NPBD might be a way to investigate heterogeneity within EO-SZ.


The association between grandmaternal investment and early years overweight in the UK.
Previous studies show that in many pre-modern and traditional populations the presence of a grandmother correlates with increased child survival rates, maybe as a result of improved child nutrition. Grandmaternal investment aimed at improving grandchildren's nutritional status in subsistence societies may have different outcomes in contemporary affluent societies. Using the British Millennium Cohort Study I investigate the association between maternal and paternal grandmothers' childcare and early years overweight in the UK. Results show that children who were cared for mainly by their grandmothers between the ages of 9 months and 3 years were more likely overweight at age 3 than children who were cared for by their parents. My results are in line with Pearce, Abbas, Ferguson, Graham, and Law (2010), although they did not distinguish grandmothers by lineage. Grandmothers may influence children's nutritional status in contemporary societies, but as with many evolved behavioral strategies the outcome may be no longer beneficial.


Nerve growth factor and gangliosides stimulate the release of glycoproteins from PC12 pheochromocytoma cells.
PC12 pheochromocytoma cells in monolayer cultures secrete increased amounts of glycoproteins into the medium following the addition of nerve growth factor (NGF) or of brain gangliosides. After a 48-h incubation with 50 ng/ml NGF there is approximately a twofold increase in the total [14C]glucosamine-labeled, ethanol-precipitable cellular material released into the medium. Between 30 and 50% of the radioactivity is associated with a glycoprotein (Gpl) of molecular weight of 52,000; the remaining radioactivity is distributed between five and six major bands. Only a small amount (10%) is associated with a glycoprotein of Mr greater than 200,000 which might correspond to the NGF-induced large external glycoprotein. A substantial increase in the release of the glycoproteins is also seen on the addition of a variety of gangliosides including asialo GMl. This increase is independent of the presence of NGF. GMl and GDlb/GTlb but not GDla stimulate release above the levels seen in the presence of NGF. Addition of GDla (2 micrograms/ml) enhances selectively the release of various glycoproteins between 2.6- and 8-fold. The pattern of glycoprotein secretion is similar to that seen with NGF, although Gp2 (Mr 78,000) is more abundant. Stimulation of release by GDla is not accompanied by neurite outgrowth, suggesting that the glycoproteins are not directly associated with neuritogenesis. The release of these glycoproteins following the addition of NGF or gangliosides may relate to the neurotrophic properties that these two entirely different ligands exert on PC12 cells.


Candidate placental biomarkers for intrauterine alcohol exposure.
Fetal alcohol spectrum disorder (FASD) is a leading cause of nongenetic mental retardation and other neurodevelopmental deficits. Earlier diagnosis of FASD would greatly improve prognosis for individuals and families affected by this disorder. Here, we identify candidate placental biomarkers in an animal model of FASD that recapitulates many aspects of human FASD. Pregnant Sprague-Dawley (SD) females were assigned to 1 of 3 diet groups on gestation day 8 (G8): Ethanol (E), Pair-fed (PF) or Control (C). E dams received ethanol-containing liquid diet and PF dams received isocaloric liquid diet in an amount that matched the paired E dam's diet consumption the previous day. Control dams received laboratory chow and water ad libitum. Whole placentae from individual fetuses were collected on gestational day 21 (G21) for analyses. Western blotting and quantitative real-time RT-PCR were used to measure protein and mRNA levels of placental iodothyronine deiodinase III (Dio3), thyroid hormone receptor α1 (TRα1), and glucocorticoid receptor (GR). Placental mRNA levels of insulin-like growth factor 2 (Igf-2), pleckstrin homology-like domain family A member 2 (Phlda2), and cyclin-dependent kinase inhibitor 1C (Cdkn1c) were also measured. Placental protein and mRNA levels from ethanol (E)-consuming dams showed the following changes: increased Dio3, decreased TRα1, and decreased GR compared to both C and PF dams. Placental mRNA levels of intrauterine growth restriction (IUGR) markers Igf-2, Phlda2, and Cdkn1c were altered similarly in PF and E dams. We propose the specific pattern of increased Dio3 and decreased TRα1 and GR protein levels in the placenta as selective biomarker for intrauterine alcohol exposure.


Development of the PROMIS Pediatric Physical Activity Item Banks.
The purpose of this study was to develop self-report and parent-proxy measures of children's physical activity for clinical research and practice and to demonstrate a valid and reliable instrument of children's lived experience of physical activity as reported by the children themselves or their parent proxies. This study involved qualitative development of item pools followed by 2 cross-sectional validity and reliability studies. The National Institutes of Health Patient Reported Outcome Measurement Information System (PROMIS) instrument development standards were applied to create child self-report and parent-proxy physical activity instruments from previously developed, content-valid pools of physical activity items. Each item used a 7-day recall period and had 5 response options. Item bank calibration was based on national samples totaling 3033 children aged 8 to 17 years and 2336 parents of children aged 5 to 17 years. Quantitative analyses included reliability assessments, factor analyses, item response theory calibration, differential item functioning, and construct validation. The final item banks comprised 10 items each. The items were selected based on content and psychometric properties. The item banks appeared to be unidimensional and free from differential item functioning. They showed excellent reliability and a high degree of precision across the range of the latent variable. Child-report and parent-proxy 4- and 8-item fixed-length instruments were specified. The instruments showed moderate correlation with existing self-report measures of physical activity. The PROMIS Pediatric Physical Activity instruments provide precise and valid measurement of children's lived experiences of physical activity. The availability of the PROMIS Pediatric Physical Activity instruments will support advances in clinical practice and research that require measurement of pediatric physical activity by self- and parent-proxy report.


Additional operations after surgery for lumbar disc prolapse : indications, type of surgery, and long-term follow-up of primary operations performed from 2007 to 2008.
Lumbar disc prolapse is a frequent indication for surgery. The few available long-term follow-up studies focus mainly on repeated surgery for recurrent disease. The aim of this study was to analyze all reasons for additional surgery for patients operated on for a primary lumbar disc prolapse. We retrieved data from the Swedish spine register about 3,291 patients who underwent primary surgery for a lumbar disc prolapse between January 2007 and December 2008. These patients were followed until December 2020 to record all additional lumbar spine operations and the reason for them. In total, 681 of the 3,291 patients (21%) needed one or more additional operations. More than three additional operations was uncommon (2%; 15/906). Overall, 906 additional operations were identified during the time period, with a mean time to the first of these of 3.7 years (SD 3.6). The most common reason for an additional operation was recurrent disc prolapse (47%; 426/906), followed by spinal stenosis or degenerative spondylolisthesis (19%; 176/906), and segmental pain (16%; 145/906). The most common surgical procedures were revision discectomy (43%; 385/906) and instrumented fusion (22%; 200/906). Degenerative spinal conditions other than disc prolapse became a more common reason for additional surgery with increasing length of follow-up. Most patients achieved the minimally important change (MIC) for the patient-reported outcomes after the index surgery. After the third additional spinal operation, only 20% (5/25) achieved the MIC in terms of leg pain, and 29% (7/24) in terms of the EuroQol five-dimension index questionnaire visual analogue scale. More than one in five patients operated on for a lumbar disc prolapse underwent further surgery during the 13-year follow-up period. Recurrent disc prolapse was the most common reason for additional surgery, followed by spinal stenosis and segmental pain. This study shows that additional operations after primary disc surgery are needed more frequently than previously reported, and that the outcome profoundly deteriorates after the second additional operation. The findings from this study can be used in the shared decision-making process. Cite this article: Bone Joint J 2022;104-B(5):627-632.


Patterns in the skin microbiota differ in children and teenagers between rural and urban environments.
The composition of human microbiota is affected by a multitude of factors. Understanding the dynamics of our microbial communities is important for promoting human health because microbiota has a crucial role in the development of inflammatory diseases, such as allergies. We have studied the skin microbiota of both arms in 275 Finnish children of few months old to teenagers living in contrasting environments. We show that while age is a major factor affecting skin microbial composition, the living environment also discriminates the skin microbiota of rural and urban children. The effect of environment is age-specific; it is most prominent in toddlers but weaker for newborns and non-existent for teenagers. Within-individual variation is also related to age and environment. Surprisingly, variation between arms is smaller in rural subjects in all age groups, except in teenagers. We also collected serum samples from children for characterization of allergic sensitization and found a weak, but significant association between allergic sensitization and microbial composition. We suggest that physiological and behavioral changes, related to age and the amount of contact with environmental microbiota, jointly influence the dynamics of the skin microbiota, and explain why the association between the living environment skin microbiota is lost in teenager.


Prevalence of chronic kidney disease defined by using CKD-EPI equation and albumin-to-creatinine ratio in the Korean adult population.
An updated chronic kidney disease (CKD) definition and classification were proposed by Kidney Disease: Improving Global Outcomes (KDIGO), with adoption of a new equation to estimate glomerular filtration rate (GFR) and albuminuria to evaluate kidney structural damage. This study was performed to estimate the prevalence of CKD in the Korean adult population as defined and classified by the KDIGO guidelines. Cross-sectional samples of the fifth Korean National Health and Nutrition Examination Survey for 2011 to 2012 were examined for adults aged ≥ 19 years. CKD prevalence was determined based on decreased GFR and albuminuria. The GFR was estimated using the CKD Epidemiology Collaboration creatinine equation, and albuminuria was evaluated using the albumin-to-creatinine ratio (ACR) in spot urine. Of the 16,576 subjects participating in the survey, 10,636 (4,758 men, 5,878 women) were included in the present study. The prevalence of CKD was estimated as 7.9% (7.8% in 2011 and 8.0% in 2012, p = 0.770). The prevalence of low, moderately increased, high, and very high CKD risk prognosis was 92.0%, 6.3%, 1.1%, and 0.6%, respectively. The prevalence of albuminuria (ACR ≥ 30 mg/g) in individuals with GFR ≥ 60 mL/min/1.73 m2 has reached 5.7%. The odds ratios of hypertension and diabetes to CKD were 3.4 and 3.1 in men, and 2.9 and 2.0 in women (all p < 0.001), respectively. A large percentage of CKD patients had albuminuria prior to a decrease in GFR. Regular laboratory tests for albuminuria for the high-risk group, and especially for hypertensive or diabetic patients, might improve detection of CKD at an early stage.


On the Role of Mining Exposure in Epigenetic Effects in Parkinson's Disease.
To explore the possible influence of heavy metal mining on incidence of Parkinson's disease (PD), global DNA methylation was assessed in blood samples from a population of PD patients (n = 45) and control subjects (n = 52) in Antofagasta neighborhood, a Chilean city built for exclusive use of mining companies. Comparisons were made with PD subjects (n = 52) and control subjects (n = 59) from Santiago Chile, a city having little association with mining. All subjects were assessed by two neurologists and PD diagnosis was based on UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria. From blood samples obtained from each individual, a decrease in global DNA methylation was observed in PD patients either exposed (49% of control, P < 0.001) or not exposed (47% of control, P < 0.001) to mining activity. Although there was no difference in levels of DNA methylation between PD patients from the two cities, there was a lower level of DNA methylation in control subjects from Santiago versus Antofagasta.


Response-driven imaging biomarkers for predicting radiation necrosis of the brain.
Radiation necrosis is an uncommon but severe adverse effect of brain radiation therapy (RT). Current predictive models based on radiation dose have limited accuracy. We aimed to identify early individual response biomarkers based upon diffusion tensor (DT) imaging and incorporated them into a response model for prediction of radiation necrosis. Twenty-nine patients with glioblastoma received six weeks of intensity modulated RT and concurrent temozolomide. Patients underwent DT-MRI scans before treatment, at three weeks during RT, and one, three, and six months after RT. Cases with radiation necrosis were classified based on generalized equivalent uniform dose (gEUD) of whole brain and DT index early changes in the corpus callosum and its substructures. Significant covariates were used to develop normal tissue complication probability models using binary logistic regression. Seven patients developed radiation necrosis. Percentage changes of radial diffusivity (RD) in the splenium at three weeks during RT and at six months after RT differed significantly between the patients with and without necrosis (p = 0.05 and p = 0.01). Percentage change of RD at three weeks during RT in the 30 Gy dose-volume of the splenium and brain gEUD combined yielded the best-fit logistic regression model. Our findings indicate that early individual response during the course of RT, assessed by radial diffusivity, has the potential to aid the prediction of delayed radiation necrosis, which could provide guidance in dose-escalation trials.


[From drawing and photograph to printed illustration; engravers, lithographers and printers in action for the Nederlandsch Tijdschrift voor Geneeskunde to 1920].
From 1857 to 1920 a number of engravers and lithographers supplied the Nederlandsch Tijdschrift voor Geneeskunde with illustrations. Two lithographers may be regarded as regular contributors to the Journal. They were A.J. Wendel of Leiden, who from 1859 to 1875 was active as house lithographer, and the Amsterdam lithographer C. Mooy from 1883 to 1910. The new techniques of mechanical reproduction of photographs in printing slowly but surely replaced the lithos and wood engravings.


Electrochemical properties and relaxation times of the hematite/water interface.
Electric double layer properties and protonation rates at the surface of a mechanically and chemically polished (001) surface of hematite (α-Fe2O3) contacted with aqueous solutions of NaCl were extracted by electrochemical impedance spectroscopy (EIS). Effects of pH (4-12) and ionic strength (10-1000 mM) on the EIS response of the electrode were predicted using an electrical equivalent circuit model accounting for hematite bulk and interfacial processes. These efforts generated diffuse layer as well as compact layer capacitances and resistance values pertaining to interfacial processes. Diffuse layer capacitance values lie in the 0.5-0.6 μF cm(-2) region and are about 1.5 times smaller than those obtained on a roughened hematite surface. Compact layer capacitances are strongly pH dependent as they pertain to the transfer of ions (charge carriers) from the diffuse layer onto surface (hydr)oxo groups. These values, alongside those of resistance adsorption, pointed a 50% decrease in proton adsorption/desorption resistance under acidic and alkaline conditions relative to that of the point of zero charge (pH 8-9). Increasing ionic strength generally induces larger diffuse layer capacitances, larger adsorption capacitances, and lower resistance values. Such a response is in line with the concept for thinner electric double layers and facilitated proton adsorption reactions by solutions of high ionic strengths. Relaxation times pertaining to the transfer of charge carriers across the compact plane induced by the EIS experiments lie in the 0.7-4.2 s range and become larger under acidic conditions. Decreases in site availability and increases in electrostatic repulsion are two possible contributing factors impeding reaction rates below the point of zero charge. Collectively, these finding are underpinning important relationships between classical views on mineral surface complexation reactions and electrochemical views of semiconductor/water interfaces.


Influence of polysulfone and hemophan hemodialysis membranes on phagocytes.
The aim of the study was to compare the effect of hemophane and polysulfone membranes on the phagocyte-derived production of reactive oxygen species (ROS) as well as on neutrophil CD11b and CD62L expression in patients undergoing regular hemodialysis. The effects of hemodialysis membranes were also studied in in vitro conditions after coincubating them with differentiated HL-60 cells. ROS production was measured using chemiluminometric and flow cytometric methods. Expression of CD11b, CD62L and mitochondrial membrane potential were detected by monoclonal antibodies and by the JC-1 fluorescent probe, respectively. Depressed ROS production was observed in patients already before dialysis. Further decrease in ROS production and an increase in CD11b expression were observed especially in patients after hemophan hemodialysis. Decreased ROS production and increased CD11b expression were observed also after incubation of HL-60 cells with hemophan membranes. Mitochondrial membrane potential dropped only after incubating cells with hemophan membranes proving its more serious adverse effects in comparison with the polysulfone membrane. In conclusion, deleterious effects of hemodialysis on the metabolic activity of phagocytes were proved. Combining chemiluminescent and flow cytometric methods for the detection of ROS production and determining mitochondrial membrane potential can be useful tools for the analysis of material biocompatibility.


Aurora B and Cdk1 mediate Wapl activation and release of acetylated cohesin from chromosomes by phosphorylating Sororin.
Sister chromatid cohesion depends on Sororin, a protein that stabilizes acetylated cohesin complexes on DNA by antagonizing the cohesin release factor Wings-apart like protein (Wapl). Cohesion is essential for chromosome biorientation but has to be dissolved to enable sister chromatid separation. To achieve this, the majority of cohesin is removed from chromosome arms in prophase and prometaphase in a manner that depends on Wapl and phosphorylation of cohesin's subunit stromal antigen 2 (SA2), whereas centromeric cohesin is cleaved in metaphase by the protease separase. Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion. At centromeres, the cohesin protector shugoshin (Sgo1)-protein phosphatase 2A (PP2A) antagonizes Aurora B and Cdk1 partly by dephosphorylating Sororin and thus maintains cohesion until metaphase. We propose that the stepwise loss of cohesion between chromosome arms and centromeres is caused by local regulation of Wapl activity, which is controlled by the phosphorylation state of Sororin.


News Media Coverage of Stakeholder Views on Suicide and Its Reporting in New Zealand.
Background: Periodically, a debate around suicide reporting becomes prominent in the media. At one point, the Chief Coroner of New Zealand made a public call to the media to open up discussions around suicide and its reporting. Following this action, a high-profile debate emerged in the media. Aims: Our aim was to identify the key players in this debate and examine their perspectives. Method: From a Factiva search of news items from high-circulation newspapers, we identified key stakeholders and documented their perspectives using a framing matrix. Results: Seven stakeholder groups were identified with coroners and health service providers dominant in the news. Framing around the issues varied. There was consensus among the majority of stakeholders supporting continued public health type coverage of the issue of suicide, but a number of differences in levels of support for the reporting individual suicides. Limitations: Although specific to New Zealand, the findings will be of interest to countries considering reporting restrictions. Conclusion: The debate around suicide and its reporting appears to have been obfuscated by the conflating of two different types of media reporting on suicide: news media coverage of suicide as a public health issue and the reporting of individual suicide cases.


Expression of human herpesvirus 8 in primary pulmonary hypertension.
Severe pulmonary hypertension constitutes a group of diseases characterized by complex, lumen-occluding vascular lesions that develop in genetically susceptible persons. The only viral infection associated with severe pulmonary hypertension has been that due to human immunodeficiency virus type 1, but neither the viral genome nor viral antigens have been demonstrated in pathologic lesions. We examined lung-tissue samples from 16 patients with sporadic primary pulmonary hypertension and 14 patients with secondary pulmonary hypertension for evidence of infection with human herpesvirus 8 (HHV-8). HHV-8 infection was ascertained immunohistochemically with use of an antibody directed against latency-associated nuclear antigen 1 (LANA-1), and a polymerase-chain-reaction (PCR) assay was performed on lung DNA to detect the viral cyclin gene of HHV-8. Sequence analysis was also performed. In lung tissue from 10 of 16 patients with primary pulmonary hypertension (62 percent), cells within the plexiform lesions as well as cells outside the lesions were positive for LANA-1 on immunohistochemical analysis. Tissue from the same 10 patients contained viral cyclin on PCR analysis. No LANA-1 was detected in lung tissue from patients with secondary pulmonary hypertension, although one such patient had PCR evidence of viral cyclin. Plexiform lesions from patients with primary pulmonary hypertension had a histologic and immunohistochemical resemblance to cutaneous Kaposi's sarcoma lesions. The spectrum of trigger factors and molecular mechanisms leading to severe pulmonary hypertension and the formation of plexiform lesions is apparently wide, including both genetic and epigenetic factors. Our data suggest that infection with the vasculotropic virus HHV-8 may have a pathogenetic role in primary pulmonary hypertension.


Levels of empathy in undergraduate occupational therapy students.
Empathy is an important attribute for occupational therapists in establishing rapport and in better understanding their clients. However, empathy can be compromised by high workloads, personal stressors and pressures to demonstrate efficacy. Occupational therapists also work with patients from a variety of diagnostic groups. The objective of this study was to determine the extent of empathy and attitudes towards clients amongst undergraduate occupational therapy students at one Australian University. A cross-sectional study was undertaken using a written survey of the Jefferson Scale of Physician Empathy (JSPE) and the Medical Condition Regard Scale. Overall, a strong level of empathy was reported amongst students. Four medical conditions that occupational therapists work with (stroke, cerebral palsy, traumatic brain injury and depression) were held in high regard. Substance abuse, however, was held in comparatively low regard. Overall, the year of study appeared to have no significant impact on the students' empathy. Despite having a lower reported empathy level than found in health professions from other studies using the JSPE, occupational therapy students were found to have a good level of empathy. Of concern, however, was the bias reported against the medical condition of substance abuse, highlighting that the there may be a need to reinforce that patients from this diagnostic group are equally deserving of quality care irrespective of their clinical condition. Recommendations for future research include completing a longitudinal study of occupational therapy students' empathy levels and investigating the empathy levels of occupational therapists working with different client groups. Limitations of the study include the convenience sampling of occupational therapy students enrolled at one university which limits the generalizability of the results to groups of participants with similar characteristics.