First Do No Harm: Legal Principles Regulating the Future of Artificial Intelligence in Health Care in South Africa.
What sets AI systems and AI-powered medical robots apart from all other forms of advanced medical technology is their ability to operate at least to some degree autonomously from the human health care practitioner and to use machine-learning to generate new, often unforeseen, analysis and predictions. This poses challenges under the current framework of laws, regulations, and ethical guidelines applicable to health care in South Africa. The article outlines these challenges and sets out guiding principles for a normative framework to regulate the use of AI in health care. The article examines three key areas for legal reform in relation to AI in health care. First, it proposes that the regulatory framework for the oversight of software as a medical device needs to be updated to develop frameworks for adequately regulating the use of such new technologies. Secondly, it argues that the present HPCSA guidelines for health care practitioners in South Africa adopt an unduly restrictive approach centred in the outmoded semantics of telemedicine. This may discourage technological innovation that could improve access to health care for all, and as such the guidelines are inconsistent with the national digital health strategy. Thirdly, it examines the common law principles of fault-based liability for medical negligence, which could prove inadequate to provide patients and users of new technologies with redress for harm where fault cannot clearly be attributed to the healthcare practitioner. It argues that consideration should be given to developing a statutory scheme for strict liability, together with mandatory insurance, and appropriate reform of product liability pertaining to technology developers and manufacturers. These legal reforms should not be undertaken without also developing a coherent, human-rights centred policy framework for the ethical use of AI, robotics, and related technologies in health care in South Africa.


[Changes in the central and intracardiac hemodynamics of patients with rheumatoid arthritis (an echocardiographic study)].
It was found that rheumatoid arthritis patients with clinical signs of cardiac involvement showed significant changes of the central and intracardiac hemodynamics that were characterized by suppression of the contractile and pumping function of the left ventricle as compared with patients showing no heart involvement. The authors describe in detail special treatment of RA patients with cardiac involvement.


Laser versus loop electrosurgical excision in vulvar condyloma for eradication of subclinical reservoir demonstrated by assay for 2'5' oligosynthetase human papillomavirus.
We studied, in an open clinical trial, 28 women with giant solitary human papillomavirus (HPV) lesions of the vulva that were treated by both laser and the loop electrosurgical excision procedure (LEEP), and analyzed the biopsy specimens of normal skin adjacent to the lesions for papillomavirus sequences by Southern blot hybridization and 2'-5' oligo-A synthetase (interferon) activity. The patients were reexamined after 3 weeks when a second treatment to the still infected areas was reapplied. They were reexamined for recurrence after 3 months: 4 patients harbored HPV-DNA genomes on the laser-treated side, adjacent to the original lesion, compared to 1 patient who developed recurrence on the LEEP side in a more distant, previously untreated, area. The optimal extent of laser or LEEP treatment necessary to reduce recurrence of vulvar condyloma remains to be established. Good in situ hybridization tests combined with the polymerase chain reaction and measurements of oligosynthetase activity to determine the types of cells involved at different sites of infection and to assess harboring of latent HPV genomes in histologically normal tissue are necessary in order to plan proper HPV treatment modality strategies.


Immediate placement of implant into impacted maxillary canine extraction socket.
Impaction of a maxillary canine is common. Orthodontic realignment is not always the therapy of choice. Instead, the impacted tooth can be extracted and replaced by an implant. The replacement of a single tooth with an implant in the anterior maxilla is a topic of interest for clinicians because of its esthetic implications, mostly when immediate loading has been planned. This article describes a clinical case in which an impacted maxillary canine was replaced by an immediately restored osseointegrated implant. A 21-year-old woman with a palatally impacted maxillary canine and the corresponding primary tooth still remaining in the arch was treated. Both the primary and permanent teeth were surgically extracted. A conical-shaped blasted implant was immediately placed into the socket of the primary canine. A self-contained osseous defect remained on the palatal aspect and was filled with bovine bone mineral. The implant achieved excellent primary stability, so it was immediately restored with a provisional acrylic resin crown in light centric occlusion. After 6 months, the definitive metal-ceramic crown was placed. The therapy provided an excellent esthetic result, maintaining ideal soft tissue contours and papillary height. No signs of radiolucency were visible at the 1-year evaluation. The case presented supports the use of single implants for the replacement of extracted primary teeth, especially in areas where esthetics is a high priority. Furthermore, because the prosthetic restoration was done immediately, the overall time needed to restore the patient was considerably reduced in comparison with the time required for the conventional approach.


High-frequency ventilation augments the effect of inhaled nitric oxide in persistent pulmonary hypertension of the newborn.
Does inhaled nitric oxide (iNO) during high-frequency ventilation (HFV) lead to a more pronounced improvement in oxygenation than iNO during conventional ventilation? We report two cases of newborn infants with profound hypoxaemia, who did not respond with an increase in arterial oxygenation following iNO therapy during conventional mechanical ventilation. The first infant was a term neonate with persistent pulmonary hypertension of the newborn (PPHN) following postnatal hypoxia, the second patient a premature infant of 29 weeks of gestation with PPHN secondary to lung hypoplasia and perinatal asphyxia. After the initial failure of iNO we switched both neonates to HFV without NO, which did not lead to a significant improvement of oxygenation in either case. Shortly after the initiation of HFV a second trial of iNO was started. Both infants responded favourably to iNO with a marked and sustained increase in arterial oxygenation and absent right-to-left shunting via the ductus arteriosus and the foramen ovale. We conclude that the favourable response to inhaled nitric oxide is dependent on the degree of lung expansion and is more readily achieved by the use of high-frequency ventilation than conventional ventilation.


A novel system with positive selection for the chromosomal integration of replicative plasmid DNA in Corynebacterium glutamicum.
A simple system has been developed for generating Corynebacterium glutamicum strains containing stable replicative plasmids integrated into the chromosome via homologous recombination. The system is based upon extremely strong incompatibility between two plasmids, which cannot be co-maintained even under antibiotic selective pressure. Integration of the resident plasmid that contained the trpD gene of C. glutamicum was achieved by introduction of a second plasmid and subsequent selection for the maintenance of both plasmids. Plasmid integrates positive for both plasmid markers were obtained at a frequency about 10(-3) of the normal transformation frequency with selection for the maintenance of only the second plasmid. Southern analysis revealed that the integration had occurred through a single-crossover homologous recombination between the trpD regions of the host genome and the plasmid. On the basis of the Campbell-type integration, chromosome walking was attempted by using Escherichia coli replication origins that were also present in the integrated plasmid. The chromosomal DNA was digested, ligated, and used to transform E. coli, which enabled recovery of the expected adjacent genomic DNA regions. The plasmid integrate was stably maintained for 30 generations under non-selective culture conditions, suggesting that the integrated sequences carrying a replicon active in the host were maintained as a stable chromosomal insert in C. glutamicum.


Assessment of local carotid stiffness in seronegative and seropositive rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic, inflammatory disease associated with increased risk of cardiovascular (CV) disease. Arterial stiffness (AS) is an independent predictor of CV events. This study aimed to analyse local carotid AS parameters in seronegative and seropositive RA patients. Of 347 consecutive RA patients, we selected specifically those who were free of established CV diseases and risk factors. As a result, 140 patients (126 women, 52.2 ± 10 years) and 140 healthy controls (122 women, 52.7 ± 8.0 years) were enrolled into this study. The common carotid AS was evaluated using radio frequency echo-tracking system to determine the local carotid pulse wave velocity (cPWV) and carotid intima-media thickness (cIMT). Based on rheumatoid factor (RF) and/or anti-citrullinated protein antibody (ACPA) positivity, RA patients were categorized into seronegative and seropositive subgroups. Carotid PWV was determined to be significantly higher in all patients and subgroups than controls (p < .001 for all). Although cIMT was similar between the patients, controls and seropositive subgroup, seronegative patients had significantly higher cIMT compared to controls (p = .035) and seropositive group (p = .010). Moreover, a significant positive correlation was found between cPWV and age (r: 0.603, p < .001), ESR (r: 0.297, p = .004), ACPA (r: 0.346, p = .001) and cIMT (r: 0.290, p = .005) in seropositive patients. RA per se is sufficient to cause arteriosclerosis in the absence of classical CV risk factors. However, arterial hypertrophy is only increased in seronegative patients but not in seropositive group.


Peters' anomaly and associated congenital malformations.
We reviewed the clinical findings in 29 patients with Peters' anomaly. There was developmental delay in 15 patients, congenital heart disease in eight patients, external ear abnormalities in five patients, structural defects of the central nervous system in four patients, genitourinary malformations in four patients, cleft lip/palate in three patients, hearing loss in three patients, spinal defects in two patients, and single cases of other less common defects. One patient had fetal alcohol syndrome; one, Pfeiffer's syndrome; and one, short stature, ulnar hypoplasia, and joint laxity. Colobomatous microphthalmia was present in seven patients, and persistent hyperplastic primary vitreous in three patients. Ten patients developed glaucoma, and three had retinal detachment unrelated to ocular surgery. Peters' anomaly may be due to a developmental field defect, or the complex ocular and systemic malformations may be the result of a contiguous gene syndrome or of a defective homeotic gene controlling the development of the eye and other body structures.


Lithium and neuropsychiatric therapeutics: neuroplasticity via glycogen synthase kinase-3beta, beta-catenin, and neurotrophin cascades.
Mood disorders are not merely attributed to the functional defect of neurotransmission, but also are due to the structural impairment of neuroplasticity. Chronic stress decreases neurotrophin levels, precipitating or exacerbating depression; conversely, antidepressants increase expression of various neurotrophins (e.g., brain-derived neurotrophic factor and vascular endothelial growth factor), thereby blocking or reversing structural and functional pathologies via promoting neurogenesis. Since the worldwide approval of lithium therapy in 1970, lithium has been used for its anti-manic, antidepressant, and anti-suicidal effects, yet the therapeutic mechanisms at the cellular level remain not-fully defined. During the last five years, multiple lines of evidence have shown that the mood stabilization and neurogenesis by lithium are due to the lithium-induced inhibition of glycogen synthase kinase-3beta (GSK-3beta), allowing accumulation of beta-catenin and beta-catenin-dependent gene transcriptional events. Altered levels of GSK-3beta and beta-catenin are associated with various neuropsychiatric and neurodegenerative diseases, while various classical neuropsychiatric drugs inhibit GSK-3beta and up-regulate beta-catenin expression. In addition, evidence has emerged that insulin-like growth factor-I enhances antidepression, anti-anxiety, memory, neurogenesis, and angiogenesis; antidepressants up-regulate expression of insulin-like growth factor-I, while insulin-like growth factor-I up-regulates brain-derived neurotrophic factor expression and its receptor TrkB level, as well as brain-derived neurotrophic factor-induced synaptic protein levels. More importantly, physical exercise and healthy diet raise transport of peripheral circulating insulin-like growth factor I into the brain, reinforcing the expression of neurotrophins (e.g., brain-derived neurotrophic factor) and the strength of cell survival signalings (e.g., phosphoinositide 3-kinase / Akt / GSK-3beta pathway). This review will focus on the rapidly advancing new trends in the last five years about lithium, GSK-3beta/beta-catenin, and neurotrophin cascades.


Scyphoproctus Gravier, 1904 (Annelida, Capitellidae): description of three new species and relocation of Heteromastides Augener, 1914 in Scyphoproctus.
Capitellids of the genus Scyphoproctus are most readily identified by the distinctive pygidial region, generally consisting of a number of segments fused with the pygidium, forming a weakly or well-developed anal plaque. To date, there are 17 valid species, however, only one species has been previously recorded in Brazil. The aim of this study was to investigate the diversity of the genus occurring along the Northeast and Southeast coasts and sublittoral areas of Brazil. Three new species have been found in samples collected in a variety of habitats and depths, Scyphoproctus paivai sp. nov., S. profundus sp. nov., and S. robustus sp. nov. The new species are herein described and compared to other species of the genus and type material of two additional species are re-described, Scyphoproctus oculatus Reish, 1959 and S. pseudoarmatus (Silva 1965). The genus Heteromastides Augener, 1914 is herein relocated in Scyphoproctus Gravier, 1904 and the previous species Heteromastides platyproctus Pillai, 1961 (junior homonym) renamed as Scyphoproctus telesphorei n. nov. after the species author Telesphore Gottfried Pillai, because there is already a species named Scyphoproctus platyproctus Jones, 1961 (senior homonym). A taxonomic key of the valid and new species is also given.


Design, synthesis, characterization, and biological evaluation of triazine dendrimers bearing paclitaxel using ester and ester/disulfide linkages.
The design, synthesis, characterization, and preliminary biological assessment of three dendrimers are reported. All three dendrimers, 1-3, present twelve paclitaxel groups linked by acylation of the 2'-hydroxyl group. The linker for dendrimers 2 and 3 also includes a disulfide. Installation of the paclitaxel group relies on reacting twelve primary amines of a second generation triazine dendrimer, a scaffold available on kilogram scale, with a dichlorotriazine bearing the drug. This dichlorotriazine is available in four steps by (i) reacting paclitaxel with glutaric anhydride, (ii) activating with N-hydroxysuccinimide (NHS), (iii) treating the resulting ester with either 1,3-diaminopropane (for 1) or cystamine (for 2 and 3), and (iv), finally, reacting with cyanuric chloride. After reaction with the dendrimer, the resulting monochlorotriazine groups are reacted with 4-aminomethylpiperidine (AMP) and then a poly(ethylene glycol) (PEG) group of molecular weight 2 kDa. Two different PEG-NHS esters are employed that differ in lability. For 1 and 2, the PEG incorporates an ester-linked succinic acid group. For 3, the PEG incorporates an ether-linked acetic acid group. Both mass spectrometry and 1H NMR spectroscopy prove valuable for determining the final ratios of dendrimer:paclitaxel:AMP:PEG. These values are typically 1:12:12:9. Cytotoxicity of these constructs using an MTT-based assay and PC-3 cells reveals IC(50) values in the low nanomolar range with dithiothreitol and glutathione enhancing the toxicity of the disulfide-containing constructs 2 and 3. Preliminary toxicology assessment of 1 suggests that it is well tolerated in vivo with preferential renal clearance. The elimination half-lives of all of the dendrimers appear shorter than predicted from the previous results. Tumor localization is observed for all the three dendrimers.


Acromion and glenoid shape: Why are they important predictive factors for the future of our shoulders?
The shape of the acromion differs between patients with degenerative rotator cuff tears and individuals without rotator cuff pathology.It can be assessed in the sagittal plane (acromion type, acromion slope) and in the coronal plane (lateral acromion angle, acromion index, critical shoulder angle).The inter-observer reliability is better for the measurements in the coronal plane.A large lateral extension (high acromion index or high critical shoulder angle) and a lateral down-sloping of the acromion (low lateral acromion angle) are associated with full-thickness supraspinatus tears.The significance of glenoid inclination for rotator cuff disease is less clear.The postulated patho-mechanism is the compression of the supraspinatus tendon between the humeral head and the acromion. Bursal side tears might be caused by friction and abrasion of the tendon. Articular side tears could be due to impairment of the gliding mechanism between tendon fibrils leading to local stress concentration. Further research is needed to understand the exact pathomechanism of tendon degeneration and tear. Cite this article: EFORT Open Rev 2017;2. DOI: 10.1302/2058-5241.2.160076. Originally published online at www.efortopenreviews.org.


Efavirenz plasma concentrations and cytochrome 2B6 polymorphisms.
Interpatient variability in efavirenz concentrations may be due to CYP2B6 genetic polymorphisms. Efavirenz concentration and pharmacogenomic data are scarce in Latino patients. To evaluate the difference in trough and midpoint efavirenz plasma concentrations between HIV-positive Latino and white patients. In addition, this study evaluated the association between efavirenz concentrations and CYP2B6 polymorphisms in Latino and white HIV-positive subjects. This pilot study included 10 Latinos and 10 whites. Two efavirenz blood concentrations were determined: a trough and a midpoint. CYP2B6 genetic polymorphisms were analyzed at the 516 (G to T) and 785 (A to G) codons. The Mann-Whitney test was used to determine whether efavirenz concentrations varied with ethnicity. The Kruskal-Wallis test was used to determine whether efavirenz concentrations varied with CYP2B6 genetic polymorphisms. Efavirenz concentrations were expressed as medians (minimum, maximum). Midpoint concentrations were 1.58 μg/mL (1.36, 6.02) and 3.14 μg/mL (1.74, 7.72) for whites and Latinos, respectively (p < 0.05). Trough concentrations did not vary as a function of ethnicity. Ten percent of Latinos and whites tested positive for homozygous variants of CYP2B6-516 and CYP2B6-785. One white subject tested positive for the homozygous variant of CYP2B6-1459. Trough concentrations for 516TT, 516GT, and 516GG (wild type) were 5.13 μg/mL (4.13, 6.12), 2.13 μg/mL (1.33, 3.37), and 1.44 μg/mL (0.59, 2.92), respectively (p < 0.05). Trough concentrations for 785GG, 785AG, and 785AA (wild type) were 5.12 μg/mL (4.13, 6.12), 1.98 μg/mL (1.33, 3.37), and 1.27 μg/mL (0.59, 2.92), respectively (p < 0.05). None of the patients took concomitant medications that impacted CYP2B6 metabolism. Trough efavirenz concentrations were significantly higher in patients with the 785 (A to G) and 516 (G to T) variants. Midpoint efavirenz concentrations in Latinos were significantly higher than those of whites.


Arbutus menziesii (Ericaceae) facilitates regeneration dynamics in mixed evergreen forests by promoting mycorrhizal fungal diversity and host connectivity.
In the mixed evergreen forests in the western United States, Arbutus menziesii is able to quickly resprout following disturbance and, as such, act as a nurse tree during forest regeneration. The mechanism for this nurse tree effect has frequently been ascribed to mycorrhizal fungi, but no detailed molecular-based studies of the mycorrhizal fungal communities associated with A. menziesii roots have yet been conducted. • We examined the structure of the mycorrhizal fungal communities associated with A. menziesii in varying forest types and seasons and assessed the potential for common mycelial networks between A. menziesii and Pinaceae hosts, particularly Pseudotsuga menziesii. Study sites were located in the Klamath-Siskyou region in southern Oregon, United States. Molecular approaches were used to identify the mycorrhizal fungi (ITS rDNA) and plant hosts (trnL cDNA). • Arbutus menziesii hosts a highly diverse mycorrhizal fungal community with similar composition to communities found on other angiosperm and Pinaceae hosts. Phylogenetic analyses of the mycorrhizal genus Piloderma revealed that host species and geographic location had little effect on fungal taxon relatedness. Multihost fungal taxa were significantly more frequent and abundant than single-host fungal taxa, and there was high potential for the formation of common mycelial networks with P. menziesii. • Our results suggest A. menziesii is a major hub of mycorrhizal fungal diversity and connectivity in mixed evergreen forests and plays an important role in forest regeneration by enhancing belowground resilience to disturbance.


Prognostic relevance of elevated pulmonary arterial pressure assessed non-invasively: Analysis in a large patient cohort with invasive measurements in near temporal proximity.
The clinical relevance of non-invasively derived pulmonary arterial pressure (PAP) by Doppler echocardiography (DE) has been questioned in the past. However, transthoracic echocardiography is used as a cornerstone examination for patients with dyspnea and suspected pulmonary hypertension (PH). This study aimed to evaluate the prognostic value of non-invasive assessed PAP in a large population of patients with known or suspected cardiopulmonary disease. The analyses are based on data of patients of a tertiary cardiology center that received right heart catheterization (RHC) as well as non-invasively assessed PAP by DE within five days, and includes serological and clinical parameters in a retrospective follow-up for up to eight years. Of 1,237 patients, clinical follow-up was possible in 1,038 patients who were included in the statistical analysis. The mean-follow up time was 1,002 days. The composite endpoint of heart transplantation (HTx) or death occurred in n = 308 patients. Elevated PAP measured non-invasively as well as invasively had significant prognostic impact (hazard ratio (HR) 2.32; 95% confidence interval (CI) 1.78-3.04; χ2 = 37.9; p<0.001 versus HR 2.84; 95%CI 2.11-3.82; χ2 = 51.9; p<0.001, respectively). By multivariate analysis, NYHA functional class, N-terminal pro-brain natriuretic peptide, cardiac troponin T, left ventricular ejection fraction, and right ventricular dysfunction remained independently predictive. Incremental prognostic information in a multimodal approach was highly relevant. In this comprehensive study, elevated pulmonary arterial pressure measured by DE offers similar prognostic information on survival or need for HTx as right heart catheterization. Furthermore, the addition of functional capacity and serological biomarkers delivered incremental prognostic information.


The P.E.A.N.U.T. Method: Update on an Integrative System Approach for the Treatment of Chronic Otitis Media with Effusion and Adenoid Hypertrophy in Children.
Based on our previous single-center study on optimization of treatment of chronic otitis media with effusion (COME) and adenoid hypertrophy (AH) in children using a noninvasive system approach to lower the necessity of antibiotics, analgesic use, and surgical interventions, we proceeded to perform a multicenter investigation in an outpatient setting. The purpose of the previous prospective study in 2013-2015 was to compare outcomes in the treatment of COME and AH using the noninvasive multimodal integrative method (IM) versus conventional treatment practice (COM). In this paper, we retrospectively analyze the data of patients treated with the integrative method between 2017 and 2020 in a multicenter setting and compared the outcomes with data from 2013-2015 in order to evaluate generalizability. In both periods, all eligible and willing participants were included and treated with the IM protocol under real-life conditions. The treatment involved pneumatization exercises, education, an antiallergic diet, nasal hygiene, useful constitutional therapy, and thermal interventions (P.E.A.N.U.T.). A total of 48 versus 28 patients, aged 1-8, were assessed, presenting with COME and AH, with moderate to severe hearing impairment at entry. The significant improvement found in both audiometric measures (intact hearing) and tympanometric measures (normal A-type curve) was similar in both datasets with respect to conventional treatment. The new data confirms that the P.E.A.N.U.T. method results in a significant reduction of antibiotics, analgesic use, and surgical interventions. In this multicenter trial, we confirm the effectiveness of the noninvasive system approach for the treatment of COME in lowering the need for antibiotics and analgesic use and elective surgery. This could be especially important with respect to a generally observed increase in antibiotic resistance. The method is easy to perform in different clinical settings and is effective, safe, and well-tolerated.


Metagenomic Next-Generation Sequencing of Cerebrospinal Fluid for the Diagnosis of Cerebral Aspergillosis.
Purpose: Cerebral aspergillosis (CA) is a rare but often fatal, difficult-to-diagnose, opportunistic infection. The utility of metagenomic next-generation sequencing (mNGS) for diagnosis of CA is unclear. We evaluated the usefulness of mNGS of the cerebrospinal fluid (CSF) for the diagnosis of CA. Methods: This prospective study involved seven consecutive patients with confirmed CA in whom CSF mNGS was performed. Serum (1→3)-β-D-glucan and galactomannan levels were determined, and histopathological examination and mNGS of the CSF were conducted. CSF specimens from three non-infected patients were used as positive controls. Results: mNGS of the CSF was positive in six of the seven confirmed CA cases (85.71% sensitivity). In the cryptococcal meningitis group (control), mNGS of the CSF was positive for Aspergillus in two patients (84.62% specificity). The positive likelihood ratio, negative likelihood ratio, and Youden's index of mNGS for CA in the CSF were 5.565, 0.169, and 0.7, respectively. Among the six mNGS-positive cases, more than two Aspergillus species were found in four (4/6, 66.67%). In the positive controls, the addition of one A. fumigatus spore yielded a standardised species-specific read number (SDSSRN) of 25.45 by mNGS; the detection rate would be 0.98 if SDSSRN was 2. Conclusion: mNGS facilitates the diagnosis of CA and may reduce the need for cerebral biopsy in patients with suspected CA. Trial Registration Number: Chinese Clinical Trial Registry, ChiCTR1800020442.


Unveiling a bimetallic FeCo-coupled MoS2 composite for enhanced energy storage.
Sodium and potassium-ion batteries are promising for energy storage owing to their source abundance and low cost; however, most active materials still suffer from sluggish kinetics, huge volume variations, and poor conductivity and cycle stability. It remains a great challenge to explore appropriate electrode materials for scaled practical applications. Herein, mesoporous FeCo-incorporated MoS2 nanosheets encapsulated into a porous carbon framework (FeCo@C@MoS2) are smartly designed, artistically fabricated and evaluated for sodium and potassium storage. The FeCo@C@MoS2 electrode displays high reversible capacities of 380 mA h g-1 and 147 mA h g-1 at 500 mA g-1 for sodium and potassium storage, respectively. FeCo derived from a Prussian blue analogue promotes fast reaction kinetics of Na+/K+ transport, introduces the formation of a stable solid electrolyte interphase layer (SEI) in both the interior and exterior of the cube-like porous nanostructure and controls the Na+/K+ fluxes, suppressing the growth of metal dendrites. The porous carbon framework with large interstitial voids can effectively buffer volume variations and mitigate mechanical stress, contributing significantly to alleviate strain intensification on the surface layer between MoS2 and FeCo during repeated plating/stripping processes. Density functional theoretical calculations (DFT) further confirm that the synthesized nanostructure shows an intensified electron state, elevated anti-stress ability, high-quality SEI film and preferable Na+/K+ adsorption energies. This in-depth investigation of the electrochemical performance and the extended energy storage mechanism based on metal alloy/sulfide nanostructures for sodium and potassium storage provides guidance for the smart design of heterojunctions for remarkable energy storage.


Interaction of T4 UvsW helicase and single-stranded DNA binding protein gp32 through its carboxy-terminal acidic tail.
Bacteriophage T4 UvsW helicase contains both unwinding and annealing activities and displays some functional similarities to bacterial RecG and RecQ helicases. UvsW is involved in several DNA repair pathways, playing important roles in recombination-dependent DNA repair and the reorganization of stalled replication forks. The T4 single-stranded DNA (ssDNA) binding protein gp32 is a central player in nearly all DNA replication and repair processes and is thought to facilitate their coordination by recruiting and regulating the various proteins involved. Here, we show that the activities of the UvsW protein are modulated by gp32. UvsW-catalyzed unwinding of recombination intermediates such as D-loops and static X-DNA (Holliday junction mimic) to ssDNA products is enhanced by the gp32 protein. The enhancement requires the presence of the protein interaction domain of gp32 (the acidic carboxy-terminus), suggesting that a specific interaction between UvsW and gp32 is required. In the absence of this interaction, the ssDNA annealing and ATP-dependent translocation activities of UvsW are severely inhibited when gp32 coats the ssDNA lattice. However, when UvsW and gp32 do interact, UvsW is able to efficiently displace the gp32 protein from the ssDNA. This ability of UvsW to remove gp32 from ssDNA may explain its ability to enhance the strand invasion activity of the T4 recombinase (UvsX) and suggests a possible new role for UvsW in gp32-mediated DNA transactions.


Local vs systemic effects of acoustic trauma on cochlear structure and transport.
Whether certain effects of acoustic trauma on cochlear structure and function were due to local or systemic agents was investigated in the chinchilla. After unilateral ossicular disarticulation, the animals were given a noise exposure known to cause cochlear damage and vessel transport changes in the stria vascularis. The cochleas with disarticulated ossicular chains received an effective exposure well below one that causes pathologic damage. Only the cochleas with intact ossicular chains showed an increase in the permeability of the strial vessels to horseradish peroxidase tracer and manifested strial edema and organ of Corti damage. These results indicate that the effects of acoustic trauma on cochlear structure and strial vessel transport are induced locally, not systemically. In addition, the minimum time of exposure to 120-dB, 700- to 2800-Hz noise that causes massive cochlear damage in the chinchilla was shown to be between five and ten minutes.


Comparison of survival rates after bland arterial embolization and ablation versus surgical resection for treating solitary hepatocellular carcinoma up to 7 cm.
The vast majority of hepatocellular carcinomas (HCC) occur in patients with underlying liver dysfunction, making surgical resection available to only a subset of patients with adequate hepatic reserve. This study analyzes the authors' results with bland arterial embolization combined with radiofrequency ablation (RFA) or percutaneous ethanol injection (PEIT) compared with surgical resection for the treatment of solitary HCC up to 7 cm in size. A retrospective review of all patients undergoing either surgical resection or bland embolization combined with local ablation for solitary HCC between January 1996 and August 2002 was performed. Progression-free survival rate and overall survival rate were calculated by the Kaplan-Meier method. There were 40 patients who underwent surgical resection and 33 patients who underwent embolization and ablation. Age, gender, and size of the treated lesion were not significantly different between the groups. The embolization/ablation group had more patients classified as Okuda stage II (P<.001). The surgical group had a longer median recurrence-free survival rate (53.1 vs 25.1 months). With a median follow-up of 23 months, the 1-, 3- and 5-year actuarial overall survival rates were 97%, 77%, and 56% for the embolization/ablation group and 81%, 70%, and 58% for the surgical group, respectively. There was no statistical difference in overall survival rates (P=.20). Bland arterial embolization in combination with ablation is effective in treating solitary HCC lesions up to 7 cm and achieves similar overall survival rates to surgical resection in selected patients.


Multidimensionality and scale in a landscape ethnoecological partitioning of a mountainous landscape (Gyimes, Eastern Carpathians, Romania).
Traditional habitat knowledge is an understudied part of traditional knowledge. Though the number of studies increased world-wide in the last decade, this knowledge is still rarely studied in Europe. We document the habitat vocabulary used by Csángó people, and determine features they used to name and describe these categories. Csángó people live in Gyimes (Carpathians, Romania). The area is dominated by coniferous forests, hay meadows and pastures. Animal husbandry is the main source of living. Data on the knowledge of habitat preference of 135 salient wild plant species were collected (2908 records, 44 interviewees). Data collected indoors were counterchecked during outdoor interviews and participatory field work. Csángós used a rich and sophisticated vocabulary to name and describe habitat categories. They distinguished altogether at least 142-148 habitat types, and named them by 242 habitat terms. We argue that the method applied and the questions asked ('what kind of place does species X like?') helped the often implicit knowledge of habitats to be verbalized more efficiently than usual in an interview. Habitat names were highly lexicalized and most of them were widely shared. The main features were biotic or abiotic, like land-use, dominant plant species, vegetation structure, successional stage, disturbance, soil characteristics, hydrological, and geomorphological features. Csángós often used indicator species (28, mainly herbaceous taxa) in describing habitats of species. To prevent reduction in the quantity and/or quality of hay, unnecessary disturbance of grasslands was avoided by the Csángós. This could explain the high number of habitats (35) distinguished dominantly by the type and severity of disturbance. Based on the spatial scale and topological inclusiveness of habitat categories we distinguished macro-, meso-, and microhabitats. Csángó habitat categories were not organized into a single hierarchy, and the partitioning was multidimensional. Multidimensional description of habitats, made the nuanced characterization of plant species' habitats possible by providing innumerable possibilities to combine the most salient habitat features. We conclude that multidimensionality of landscape partitioning and the number of dimensions applied in a landscape seem to depend on the number of key habitat gradients in the given landscape.


Differential cargo mobilisation within Weibel-Palade bodies after transient fusion with the plasma membrane.
Inflammatory chemokines can be selectively released from Weibel-Palade bodies (WPBs) during kiss-and-run exocytosis. Such selectivity may arise from molecular size filtering by the fusion pore, however differential intra-WPB cargo re-mobilisation following fusion-induced structural changes within the WPB may also contribute to this process. To determine whether WPB cargo molecules are differentially re-mobilised, we applied FRAP to residual post-fusion WPB structures formed after transient exocytosis in which some or all of the fluorescent cargo was retained. Transient fusion resulted in WPB collapse from a rod to a spheroid shape accompanied by substantial swelling (>2 times by surface area) and membrane mixing between the WPB and plasma membranes. Post-fusion WPBs supported cumulative WPB exocytosis. To quantify diffusion inside rounded organelles we developed a method of FRAP analysis based on image moments. FRAP analysis showed that von Willebrand factor-EGFP (VWF-EGFP) and the VWF-propolypeptide-EGFP (Pro-EGFP) were immobile in post-fusion WPBs. Because Eotaxin-3-EGFP and ssEGFP (small soluble cargo proteins) were largely depleted from post-fusion WPBs, we studied these molecules in cells preincubated in the weak base NH4Cl which caused WPB alkalinisation and rounding similar to that produced by plasma membrane fusion. In these cells we found a dramatic increase in mobilities of Eotaxin-3-EGFP and ssEGFP that exceeded the resolution of our method (∼ 2.4 µm2/s mean). In contrast, the membrane mobilities of EGFP-CD63 and EGFP-Rab27A in post-fusion WPBs were unchanged, while P-selectin-EGFP acquired mobility. Our data suggest that selective re-mobilisation of chemokines during transient fusion contributes to selective chemokine secretion during transient WPB exocytosis. Selective secretion provides a mechanism to regulate intravascular inflammatory processes with reduced risk of thrombosis.


HTLV-1 bZIP factor HBZ promotes cell proliferation and genetic instability by activating OncomiRs.
Viruses disrupt the host cell microRNA (miRNA) network to facilitate their replication. Human T-cell leukemia virus type I (HTLV-1) replication relies on the clonal expansion of its host CD4(+) and CD8(+) T cells, yet this virus causes adult T-cell leukemia/lymphoma (ATLL) that typically has a CD4(+) phenotype. The viral oncoprotein Tax, which is rarely expressed in ATLL cells, has long been recognized for its involvement in tumor initiation by promoting cell proliferation, genetic instability, and miRNA dysregulation. Meanwhile, HBZ is expressed in both untransformed infected cells and ATLL cells and is involved in sustaining cell proliferation and silencing virus expression. Here, we show that an HBZ-miRNA axis promotes cell proliferation and genetic instability, as indicated by comet assays that showed increased numbers of DNA-strand breaks. Expression profiling of miRNA revealed that infected CD4(+) cells, but not CD8(+) T cells, overexpressed oncogenic miRNAs, including miR17 and miR21. HBZ activated these miRNAs via a posttranscriptional mechanism. These effects were alleviated by knocking down miR21 or miR17 and by ectopic expression of OBFC2A, a DNA-damage factor that is downregulated by miR17 and miR21 in HTLV-1-infected CD4(+) T cells. These findings extend the oncogenic potential of HBZ and suggest that viral expression might be involved in the remarkable genetic instability of ATLL cells.


Topotecan/carboplatin regimen for refractory/recurrent rhabdomyosarcoma in children: Report from the AIEOP Soft Tissue Sarcoma Committee.
From 2002 to 2011, the Italian Soft Tissue Sarcoma Committee explored a combination of topotecan and carboplatin as a second-line strategy for children with resistant or relapsing rhabdomyosarcoma. Patients received two blocks of topotecan 2 mg/m2 on days 1, 2, and 3, and carboplatin 250 mg/m2 on days 4 and 5, followed by alternating blocks of topotecan-cyclophosphamide and carboplatin-etoposide for a total of six courses with 3-week intervals. Tumor response was assessed after two cycles, and local control was implemented when feasible. A total of 38 patients were included in this study: 18/38 had alveolar rhabdomyosarcoma (RMS), 10/38 had metastatic disease at diagnosis, 8/38 had tumor progression during first-line chemotherapy, 21/38 had locoregional relapses, and 9/38 had distant relapses. Thirty-two patients could be assessed for tumor response to topotecan-carboplatin, and 9 (28%) showed a complete or partial response. Twenty-four patients experienced grade IV hematologic toxicity, while transient grade 1 tubulopathy, grade 3 mucositis, transient grade 2 nephrotoxicity, and a grade 2 decline in cardiac function occurred in one patient each. The 5-year overall and progression-free survival rates were 17% and 14%, respectively. the prognosis for children with resistant or relapsing RMS remains unsatisfactory. The topotecan-carboplatin regimen was well-tolerated. Though in case of late relapse the response rate was similar to those reported for other regimes, the result achieved remains unsatisfactory. New approaches, possibly including target agents, seem more attractive for future studies.


Validity of Amino Terminal pro-Brain Natiuretic Peptide in a Medically Complex Elderly Population.
The routine use of natiuretic peptides in severely dyspneic patients has recently been called into question. We hypothesized that the diagnostic utility of Amino Terminal pro Brain Natiuretic Peptide (NT-proBNP) is diminished in a complex elderly population. We studied 502 consecutive patients in whom NT-proBNP values were obtained to evaluate severe dyspnea in the emergency department. The diagnostic utility of NT-proBNP for the diagnosis of congestive heart failure (CHF) was assessed utilizing several published guidelines, as well as the manufacturers suggested age dependent cut-off points. The area under the receiver operator curve (AUC) for NT-proBNP was 0.70. Using age-related cut points, the diagnostic accuracy of NT-proBNP for the diagnosis of CHF was below prior reports (70% vs. 83%). Age and estimated creatinine clearance correlated directly with NT-proBNP levels, while hematocrit correlated inversely. Both age > 50 years and to a lesser extent hematocrit < 30% affected the diagnostic accuracy of NT-proBNP, while renal function had no effect. In multivariate analysis, a prior history of CHF was the best predictor of current CHF, odds ratio (OR) = 45; CI: 23-88. The diagnostic accuracy of NT-proBNP for the evaluation of CHF appears less robust in an elderly population with a high prevalence of prior CHF. Age and hematocrit levels, may adversely affect the diagnostic accuracy off NT-proBNP. Congestive Heart Failure; Natriuretic peptides; Diagnosis; Elderly Patients.


Is arterial proximity a valid indication for arteriography in penetrating extremity trauma? A prospective analysis.
Three hundred seventy-three patients with a penetrating extremity injury were studied to assess the yield of arteriography. Patients underwent arteriography if any of the following was present: bruit, history of hemorrhage or hypotension, fracture, hematoma, decreased capillary refill, major soft-tissue injury, or nerve or pulse deficit. In the absence of these findings, arteriography was performed if the injury was in "proximity" to a major neurovascular bundle. In 216 patients, arteriography was performed when an abnormal finding was noted. Sixty-five injuries were identified, 19 requiring intervention. Proximity was the indication for arteriography in 157 patients. Seventeen injuries were identified, of which one required repair. In penetrating extremity trauma, the need for arteriography is based on clinical findings. The use of arteriography to screen for an arterial injury when proximity alone is the indication rarely identifies a significant injury and should be abandoned.


The glycoinositol phospholipids of Leishmania mexicana promastigotes. Evidence for the presence of three distinct pathways of glycolipid biosynthesis.
Most macromolecules at the cell surface of parasitic protozoa of the genus Leishmania, including the major surface glycoproteins and a complex lipophosphoglycan (LPG), are attached to the plasma membrane via glycosyl-phosphatidylinositol (GPI) anchors. Free glycoinositol phospholipids (GIPLs) which are not linked to protein or phosphoglycan have also been found. In this study, we show that L. mexicana promastigotes synthesize two distinct GIPL lineages, comprising at least 10 glycolipid species. These structures were characterized using a combination of gas-liquid chromatography-mass spectrometry, methylation linkage analysis, and chemical and exoglycosidase sequencing. The major lineage contains GIPLs with the glycan structures Man alpha 1-3Man alpha 1-4GlcN (iM2), Man alpha 1-6(Man alpha 1-3)Man alpha 1-4GlcN (iM3), and Man alpha 1-2Man alpha 1-6(Man alpha 1-3)Man alpha 1-4GlcN (iM4), which are linked to alkylacyl-PI containing predominantly C16:0 and C18:0 fatty acids and C18:0 alkyl chains (referred to as the hybrid type GIPLs). A proportion of the iM3 and iM4 species (32 and 4%, respectively) are substituted with an ethanolamine-phosphate residue. The location of this residue on the core glucosamine residue was inferred from the results of methylation analyses and alpha-mannosidase digestion. The minor GIPL lineage contains GIPLs with the same glycan sequences as the glycolipid anchor of LPG (referred to as the type-2 GIPLs). The alkylacyl-PI or lyso-alkyl-PI lipid moieties of these GIPLs differ from those of the hybrid type GIPLs and from the main pool of alkylacyl-PI in containing significant levels of C24:0 and C26:0 alkyl chains. The most polar of these GIPLs, LPGp, has the properties expected of a biosynthetic precursor to the LPG, having the structure, [formula: see text] Finally, the GPI anchors of the major promastigote proteins were found to contain the glycan sequence Man alpha 1-2Man alpha 1-6Man alpha 1-4GlcN, and an alkylacyl-PI lipid moiety which was highly enriched for C24:0 or C26:0 alkyl chains. These data suggest that L. mexicana promastigotes contain three distinct pathways of GPI biosynthesis. The possibility that the distinct alkyl chain compositions of the different GPI glycolipids reflects the subcellular compartmentalization of different GPI biosynthetic pathways is discussed.


Peculiarities of the free radical processes in rat liver mitochondria under toxic hepatitis on the background of alimentary protein deficiency.
The rate of superoxide anion radical, hydroxyl radical and hydrogen peroxide generation, the level of oxidative modification of mitochondrial proteins in the liver of rats with toxic hepatitis was investigated on the background of alimentary protein deficiency. We did not find significant increases of the intensity of free radical processes in liver mitochondria of rats maintained on the protein-deficient ration. The most significant intensification of free radical processes in liver mitochondria is observed under the conditions of toxic hepatitis, induced on the background of alimentary protein deprivation. Under these conditions the aggravation of all studied forms of reactive oxygen species generation was observed in liver mitochondria. The generation rates were increased as follows: O2 – by 1.7 times, Н2О2 – by 1.5 times, •ОН – practically double on the background of accumulation of oxidized mitochondria-derived proteins. The established changes in thiol groups' redox status of respiratory chain proteins insoluble in 0.05 M sodium-phosphate buffer (pH 11.5), and changes of their carbonyl derivatives content may be considered as one of the regulatory factors of mitochondrial energy-generating function.


Suppression of central noradrenergic neuronal activity inhibits hyperglycemia.
Hypothalamic noradrenergic neuronal activity (NNA) and hepatic glucose output are stimulated by stress. The aim of the present investigation was to examine whether the blockade of noradrenergic responses to stress might suppress the associated hyperglycemia. Mass spectrometry was used for analysis of norepinephrine (NE) and its neuronal metabolite 3,4-dihydroxyphenylglycol (DHPG) in rat hypothalamus, and the ratio DHPG/NE was used as an index of NNA. Treatment of rats with 2-deoxy-D-glucose (500 mg/kg ip, -30 min), yohimbine (10 mg/kg ip, -20 min), or neostigmine (2 micrograms icv, -60 min) increased both NNA and serum glucose (P < 0.05). When rats were additionally pretreated with pentobarbital (60 mg/kg ip; -60 min), the NNA responses were blocked (P < 0.01). At the same time the hyperglycemic responses were also inhibited (P < 0.01). In rats that had reduced NNA due to 7 days "gentling," serum glucose levels were also significantly reduced (P < 0.001) compared with naive controls. The data demonstrate that inhibition of central noradrenergic activity is also associated with an inhibition of hyperglycemia, raising the concept that therapies aimed at reducing central NNA may have a role in the management of diseases with excessive hepatic glucose output such as non-insulin-dependent diabetes mellitus.


Effect of Hibiscus sabdariffa and Zingiber officinale on pharmacokinetics and pharmacodynamics of amlodipine.
To study the effect of Zingiber officinale and Hibiscus sabdariffa on pharmacokinetics and pharmacodynamics of amlodipine. Hypertension was induced in rats (SBP 173.2 ± 1.7 mmHg, mean, 1-24 h). Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP) and heart rate (HR) of group-I (amlodipine treated), group-II (Z. officinale, and Z. officinale + amlodipine) and group-III (H. sabdariffa, and H. sabdariffa + amlodipine) animals were measured by "tail-cuff system". Pharmacokinetics of amlodipine with and without herbs (Z. officinale or H. sabdariffa) was also investigated. Z. officinale as well as H. sabdariffa decreased the SBP, DBP and MBP. Concurrent treatment with Z. officinale + amlodipine (SBP 129.4 ± 4.5) or H. sabdariffa + amlodipine (SBP 130.4 ± 3.9) showed higher decrease in BP (mean, 1-24h), than individually administered amlodipine (SBP 149.5 ± 2.4) or Z. officinale (SBP 150.2 ± 3.1) or H. sabdariffa (SBP 139.1 ± 1.2). These herbs also influenced the Cmax, AUC0-t, and Tmax of amlodipine. H. sabdariffa increased AUC0-t of amlodipine from 81.8 ± 14.7 to 125.0 ± 10.6 (ng h/mL). Simultaneous administration of Z. officinale or H. sabdariffa with amlodipine, improves its pharmacodynamic response.


Reproductive behavior of Atlantic halibut (Hippoglossus hippoglossus) interpreted from electronic tags.
Reproductive timing, location, and behavior are important characteristics that determine marine population dynamics, structure, and resilience to threats, including fishing and climate change. It is challenging to evaluate factors driving variability in these reproductive traits in wild fishes because of the difficulty observing individuals in their natural environments. In the present study, we used high-resolution depth, temperature, and acceleration time series recorded by pop-up satellite archival tags to (1) identify and characterize patterns in depth and acceleration that may be indicative of spawning events in large Atlantic halibut (Hippoglossus hippoglossus), and (2) estimate the effects of individual traits (body size and sex) and environmental factors (location and temperature) on spawning time and frequency. Unique rapid rises observed in the winter depth profiles were interpreted as spawning events. The initiation of the first presumed spawning rise was negatively correlated to water temperature experienced during the prespawning season, suggesting that currently increasing water temperature in the Gulf of St. Lawrence may induce phenological change in halibut spawning time. The number of rises of batch-spawning females was unrelated to female body size. The present study demonstrates how electronic tagging can be used for in-depth characterization of timing, location, and behaviors associated with spawning in a large flatfish species. Such information can inform spatiotemporal management and conservation measures aiming to protect species from directed fishing and by-catch during spawning.


Von Hippel-Lindau syndrome with microscopic hemangioblastomas of the spinal nerve roots. Case report.
The authors describe a case of von Hippel-Lindau syndrome diagnosed at autopsy in a 49-year-old woman. She died suddenly following hemorrhage from a cerebellar hemangioblastoma. Other autopsy findings included a retinal hemangioblastoma, an adrenal pheochromocytoma, and a clear-cell renal tumor. The case was distinguished by the unexpected finding of multiple microscopic hemangioblastomas of the spinal nerve roots. The case is discussed with emphasis on the incidence of spinal hemangioblastomas in von Hippel-Lindau syndrome.


Bedside Sonography Performed by Emergency Physicians to Detect Appendicitis in Children.
The aim of this study was to evaluate the ability of emergency physicians with various levels of point-of-care ultrasound (POCUS) experience to detect appendicitis with POCUS among children visiting a pediatric emergency department (ED). A prospective cohort study was conducted in an urban, tertiary care pediatric ED. Children aged 2 to 18 years old who presented with acute abdominal pain suggesting appendicitis were included. Patients were excluded if they had a history of appendectomy or hemodynamic instability requiring resuscitation or were transferred with proven diagnosis of appendicitis. Participating physicians had various levels of POCUS experience. Four of the 22 physicians were experienced in bowel sonography while the others had basic experience in abdominal POCUS. All the participating physicians received a 1-hour didactic and practical training session on appendix ultrasound. The treating physician performed POCUS following initial physical examination, before further radiologic evaluation. POCUS examinations were recorded as positive for appendicitis, normal, or inconclusive, with normal or inconclusive studies considered negative. Final outcomes were determined by pathology and/or operative reports for surgical cases and telephone follow-up at 3 weeks for those who did not have surgery. The primary analysis was a simple proportion for sensitivity and specificity for POCUS. Expecting a sensitivity of 80% based on previous studies, we calculated that a sample size of 50 cases would provide a 95% confidence interval (CI) ranging from 66% to 90%. Of the 140 approached patients, 121 accepted to participate and were recruited. After four patients were excluded for missing POCUS data, 117 patients were included in the primary analysis, of whom 51 (44%) had appendicitis. Twenty-two physicians performed between one and 20 POCUS procedures. The POCUS was positive in 39, negative in nine, and inconclusive in 69 patients. POCUS was interpreted as positive in 27 of 51 appendicitis for a sensitivity of 0.53 (95% CI = 0.40-0.66). A negative or inconclusive POCUS was reported for 54 of 66 patients without appendicitis (specificity = 0.82; 95% CI = 0.71-0.89). This study shows limited sensitivity and specificity of POCUS for appendicitis in children, with a high proportion of inconclusive examinations, when performed by emergency physicians with various level of experience in POCUS.


Mechanistic insights into landscape genetic structure of two tropical amphibians using field-derived resistance surfaces.
Conversion of forests to agriculture often fragments distributions of forest species and can disrupt gene flow. We examined effects of prevalent land uses on genetic connectivity of two amphibian species in northeastern Costa Rica. We incorporated data from field surveys and experiments to develop resistance surfaces that represent local mechanisms hypothesized to modify dispersal success of amphibians, such as habitat-specific predation and desiccation risk. Because time lags can exist between forest conversion and genetic responses, we evaluated landscape effects using land-cover data from different time periods. Populations of both species were structured at similar spatial scales but exhibited differing responses to landscape features. Litter frog population differentiation was significantly related to landscape resistances estimated from abundance and experiment data. Model support was highest for experiment-derived surfaces that represented responses to microclimate variation. Litter frog genetic variation was best explained by contemporary landscape configuration, indicating rapid population response to land-use change. Poison frog genetic structure was strongly associated with geographic isolation, which explained up to 45% of genetic variation, and long-standing barriers, such as rivers and mountains. However, there was also partial support for abundance- and microclimate response-derived resistances. Differences in species responses to landscape features may be explained by overriding effects of population size on patterns of differentiation for poison frogs, but not litter frogs. In addition, pastures are likely semi-permeable to poison frog gene flow because the species is known to use pastures when remnant vegetation is present, but litter frogs do not. Ongoing reforestation efforts will probably increase connectivity in the region by increasing tree cover and reducing area of pastures.


Copper inhibits P2Y(2)-dependent Ca(2+) signaling through the effects on thapsigargin-sensitive Ca(2+) stores in HTC hepatoma cells.
Purinergic P2Y(2) G-protein coupled receptors play a key role in the regulation of hepatic Ca(2+) signaling by extracellular ATP. The concentration of copper in serum is about 20muM. Since copper accumulates in the liver in certain disease states, the purpose of these studies was to assess the effects of copper on P2Y(2) receptors in a model liver cell line. Exposure to a P2Y(2) agonist UTP increased [Ca(2+)](i) by stimulating Ca(2+) release from thapsigargin-sensitive Ca(2+) stores. Pretreatment of HTC cells for several minutes with copper did not affect cell viability, but potently inhibited increases in [Ca(2+)](i) evoked by UTP and thapsigargin. During this pretreatment, copper was not transported into the cytosol, and inhibited P2Y(2) receptors in a concentration-dependent manner with the IC(50) of about 15muM. These results suggest that copper inhibits P2Y(2) receptors through the effects on thapsigargin-sensitive Ca(2+) stores by acting from an extracellular side. Further experiments indicated that these effect of copper may lead to inhibition of regulatory volume decrease (RVD) evoked by hypotonic solution. Thus, copper may contribute to defective regulation of purinergic signaling and liver cell volume in diseases associated with the increased serum copper concentration.


Intravitreal cortisone injection for refractory diffuse diabetic macular edema.
The purpose of this study was to evaluate the safety and efficacy of intravitreal triamcinolone acetonide injection in patients with diffuse diabetic macular edema. We also compared the effect of intravitreal triamcinolone with macular grid laser photocoagulation in macular edema. Thirty patients with diabetic diffuse macular edema unresponsive to grid laser photocoagulation for at least 4 months received 0.1 ml (4 mg/ml) intravitreal triamcinolone acetonide (Kenakort-A) injection as treatment. This study group was compared with a control group of 30 patients (30 eyes) who had undergone grid laser macular coagulation. Mean follow-up time was 17 months (range 14-24 months) in the study group and 19 months (range 16-24 months) in the control group. In the study group, mean improvement in visual acuity measured 3.8, 3.4, 0.9 and 0.2 Snellen lines at the follow-up intervals of 1, 3, 6 and 12 months, respectively. Improvement in visual acuity was statistically significant only at 1 month (p = 0.002) and 3 months (p = 0.003) after injection. Visual acuity was significantly (p < 0.05) better in the study group than the control group at 1 and 3 months. Overall, 6 of 30 eyes (20%) required a second injection and 3 eyes (10%) a third due to regression in visual acuity. Towards the end of the follow-up period, the visual acuity decreased to almost baseline levels. Elevation of intraocular pressure was found in 4 patients and controlled with topical antiglaucomatosis treatment. Sterile endophthalmitis was detected in only one eye. No eye exhibited cataract progression during the follow-up period. Intravitreal injection of triamcinolone may be beneficial for temporarily increasing visual acuity in patients with diabetic diffuse macular edema who are unresponsive even to grid laser photocoagulation. But the regression of visual acuity looks inevitable in the long term after injection. Therefore, repeated injections with/without increasing doses might be required for the stabilization of visual acuity.


Maladaptive Shifts in Life History in a Changing Environment.
Many species facing climate change have complex life cycles, with individuals in different stages differing in their sensitivity to a changing climate and their contribution to population growth. We use a quantitative genetics model to predict the dynamics of adaptation in a stage-structured population confronted with a steadily changing environment. Our model assumes that different optimal phenotypic values maximize different fitness components, consistent with many empirical observations. In a constant environment, the population evolves toward an equilibrium phenotype, which represents the best compromise given the trade-off between vital rates. In a changing environment, however, the mean phenotype in the population will lag behind this optimal compromise. We show that this lag may result in a shift along the trade-off between vital rates, with negative consequences for some fitness components but, less intuitively, improvements in some others. Complex eco-evolutionary dynamics can emerge in our model due to feedbacks between population demography and adaptation. Because of such feedback loops, selection may favor further shifts in life history in the same direction as those caused by maladaptive lags. These shifts in life history could be wrongly interpreted as adaptations to the new environment, while in reality they only reflect the inability of the population to adapt fast enough.


A Genetic Screen to Identify Gain- and Loss-of-Function Modifications that Enhance T-cell Infiltration into Tumors.
T-cell-mediated cancer immunotherapies, including anti-PD-1 and T cells expressing chimeric antigen receptors (CAR-T cells), are becoming standard treatments for many cancer types. CAR-T therapy, in particular, has been successful in treating circulating, but not solid, tumors. One challenge limiting immunotherapy success is that tumors lacking T-cell infiltration do not respond to treatment. Therefore, one potential strategy to overcome resistance is to enhance the ability of T cells to traffic into tumors. Here, we describe an unbiased in vivo genetic screen approach utilizing the Sleeping Beauty mutagenesis system to identify candidate genes in T cells that might be modified to drive intratumoral T-cell accumulation. This screen identified over 400 candidate genes in three tumor models. These results indicated substantial variation in gene candidate selection, depending on the tumor model and whether or not mice were treated with anti-PD-1, yet some candidate genes were identified in all tumor models and with anti-PD-1 therapy. Inhibition of the most frequently mutated gene, Aak1, affected chemokine receptor expression and enhanced T-cell trafficking in vitro and in vivo Screen candidates should be further validated as therapeutic targets, with particular relevance to enhancing infiltration of adoptively transferred T cells into solid tumors.


Interleukin-6 role in the severity of COVID-19 and intensive care unit stay length.
Evaluation of cytokine production in COVIID-19 disease, in which the cytokine storm is one of the most important pathological features in complicated cases, especially interleukin 6 as a pre-inflammatory cytokine that exacerbates the immune response, could help determine the pathophysiology of the disease. Examining the level of this cytokine along with other related factors can help to better understand the pathogenesis of this disease. In this cross-sectional study, 48 patients with COVID-19 whose disease was confirmed by swap testing were evaluated. The demographic information of the individuals, the symptoms of the disease, and the ward in which they were admitted were recorded. Blood samples were taken from patients to test for interleukin-6 levels by electrochemiluminescence immunoassay (ECLIA, Roche Diagnostics). Due to the lack of specific treatment protocols for patients and the use of supportive treatments based on meeting the nutritional needs for all patients, blood albumin levels and nutritional status of patients were also evaluated using Subjective Global Assessment (SGA) Form. Their calorie intake was assessed by calculating the number of calories received based on the type of nutrition and compared to the required amount calculated through the Harris-Benedict equation. 48 laboratory-confirmed 2019-nCoV infected patients were included in the study with the mean age of 46.4 ± 8.3 years. 21 patients were admitted to the intensive care unit (ICU). There was no significant difference between the ICU admitted and patients admitted inward in terms of demographic characteristics, and history of previous diseases (p > 0.05). The average interleukin 6 (IL-6) in patients was 72.3±34.4 pg/ml. ICU admitted patients had higher IL6 levels (p=0.001). The mean interleukin 6 level was 89.04±34.1 pg/ml in patients admitted for less than 7 days and it was significantly higher (119.2±28.3) in patients hospitalized for more than 7 days (p=0.001). there was no significant difference in terms of nutritional status and albumin level between ICU admitted and ward admitted patients (p >0.05). Our study shows that there may be possible associations of IL6 and disease severity and ICU stay length.


OCT4 Expression Enhances Features of Cancer Stem Cells in a Mouse Model of Breast Cancer.
The cancer stem cell (CSC) hypothesis proposes that CSCs are responsible for metastasis and disease recurrence. Therefore, targeting CSCs has the potential to significantly improve outcomes for cancer patients. The OCT4 transcription factor gene is a master gene that plays a key role in the self-renewal and pluripotency of stem cells. In this study, we introduced an OCT4 reporting vector into 4T1 mouse breast cancer cells and sorted OCT4 high and OCT4 low cell populations. We then determined whether OCT4 expression is associated with maintenance and expansion of CSCs. We found that OCT4(high) 4T1 cells have an increased ability to form tumorsphere and a high expression of stem cell markers such as Sca-1, CD133, CD34, and ALDH1, when compared with OCT4(low) 4T1 cells. In addition, OCT4(high) 4T1 cells have greater tumorigenic potential in vivo. These findings suggest that OCT4 expression may be a useful target for stem cell-specific cancer therapy.


Drug resistant tuberculosis: a diagnostic challenge.
Tuberculosis (TB) is responsible for 1.4 million deaths annually. Wide-spread misuse of anti-tubercular drugs over three decades has resulted in emergence of drug resistant TB including multidrug-resistant TB and extensively drug-resistant TB globally. Accurate and rapid diagnosis of drug-resistant TB is one of the paramount importance for instituting appropriate clinical management and infection control measures. The present article provides an overview of the various diagnostic options available for drug resistant TB, by searching PubMed for recent articles. Rapid phenotypic tests still requires days to weeks to obtain final results, requiring biosafety and quality control measures. For newly developed molecular methods, infrastructure, training and quality assurance should be followed. Successful control of drug resistant TB globally will depend upon strengthening TB control programs, wider access to rapid diagnosis and provision of effective treatment. Therefore, political and fund provider commitment is essential to curb the spread of drug resistant TB.


Quantum Plasmonics: Energy Transport Through Plasmonic Gap.
At the interfaces of metal and dielectric materials, strong light-matter interactions excite surface plasmons; this allows electromagnetic field confinement and enhancement on the sub-wavelength scale. Such phenomena have attracted considerable interest in the field of exotic material-based nanophotonic research, with potential applications including nonlinear spectroscopies, information processing, single-molecule sensing, organic-molecule devices, and plasmon chemistry. These innovative plasmonics-based technologies can meet the ever-increasing demands for speed and capacity in nanoscale devices, offering ultrasensitive detection capabilities and low-power operations. Size scaling from the nanometer to sub-nanometer ranges is consistently researched; as a result, the quantum behavior of localized surface plasmons, as well as those of matter, nonlocality, and quantum electron tunneling is investigated using an innovative nanofabrication and chemical functionalization approach, thereby opening a new era of quantum plasmonics. This new field enables the ultimate miniaturization of photonic components and provides extreme limits on light-matter interactions, permitting energy transport across the extremely small plasmonic gap. In this review, a comprehensive overview of the recent developments of quantum plasmonic resonators with particular focus on novel materials is presented. By exploring the novel gap materials in quantum regime, the potential quantum technology applications are also searched for and mapped out.


Subcellular Distribution of p53 by the p53-Responsive lncRNA NBAT1 Determines Chemotherapeutic Response in Neuroblastoma.
Neuroblastoma has a low mutation rate for the p53 gene. Alternative ways of p53 inactivation have been proposed in neuroblastoma, such as abnormal cytoplasmic accumulation of wild-type p53. However, mechanisms leading to p53 inactivation via cytoplasmic accumulation are not well investigated. Here we show that the neuroblastoma risk-associated locus 6p22.3-derived tumor suppressor NBAT1 is a p53-responsive lncRNA that regulates p53 subcellular levels. Low expression of NBAT1 provided resistance to genotoxic drugs by promoting p53 accumulation in cytoplasm and loss from mitochondrial and nuclear compartments. Depletion of NBAT1 altered CRM1 function and contributed to the loss of p53-dependent nuclear gene expression during genotoxic drug treatment. CRM1 inhibition rescued p53-dependent nuclear functions and sensitized NBAT1-depleted cells to genotoxic drugs. Combined inhibition of CRM1 and MDM2 was even more effective in sensitizing aggressive neuroblastoma cells with p53 cytoplasmic accumulation. Thus, our mechanistic studies uncover an NBAT1-dependent CRM1/MDM2-based potential combination therapy for patients with high-risk neuroblastoma. SIGNIFICANCE: This study shows how a p53-responsive lncRNA mediates chemotherapeutic response by modulating nuclear p53 pathways and identifies a potential treatment strategy for patients with high-risk neuroblastoma.


Application of the 2013 ACR/EULAR classification criteria for systemic sclerosis to patients with Raynaud's phenomenon.
We investigated how many patients, who presented with Raynaud's phenomenon (RP) and who had not been classified as systemic sclerosis (SSc), would be reclassified as SSc, if the 2013 American College of Rheumatology (ACR)/the European League Against Rheumatism (EULAR) classification criteria were used. We also analyzed the predictive values of the reclassification as SSc in those patients. We consecutively enrolled 64 patients with RP and 60 patients with SSc. We applied the new classification criteria to them, reclassified them, and compared variables between those who were newly classified as SSc and those who were not or previously classified as SSc. Seventeen of 64 patients (26.5%), who presented with RP, but did not fulfill the 1980 ACR classification criteria, were newly classified as SSc by the 2013 ACR/EULAR classification criteria. The newly classified patients as SSc showed increased frequencies of sclerodactyly, digital tip ulcer, telangiectasia, abnormal nailfold capillaries and the presence of anti-centromere antibody, compared to those not and telangiectasia and anti-centromere antibody, compared to the previously classified patients. For the reclassification as SSc, the variables with independent predictive value were sclerodactyly (odds ratio (OR) 60.025), telangiectasia (OR 13.353) and the presence of anti-centromere antibody (OR 11.168). Overall, 26.5% of the patients, who presented with RP, but who did not fulfill the 1980 ACR classification criteria, were newly classified as SSc according to the 2013 ACR/EULAR classification criteria. Sclerodactyly, telangiectasia, and the presence of anti-centromere antibody had independent predictive value for reclassifying patients with RP as SSc.


Heterogeneity of human neutrophil phagolysosomes: functional consequences for candidacidal activity.
Opsonized yeast phase Candida albicans, incubated with human neutrophils, are internalized into two classes of phagosomes. One class, termed "unsealed vacuoles," comprises approximately 40% of the total and maintains functional communication to the cell's exterior that is sufficient to permit ingress of dyes, such as trypan or methylene blue. The remaining cell-associated yeasts are contained in "sealed vacuoles," completely sequestered from the external milieu. Approximately 71.8% of C albicans within sealed vacuoles are rendered nonviable within 60 minutes, whereas only 14.5% of organisms within unsealed vacuoles are killed during this time. We conclude that vacuolar sealing mechanisms are imperfectly developed in normal human neutrophils and that incompletely sealed vacuoles support antimicrobial processes substantially less well than do completely sealed ones.


Disparities in rates of inpatient mortality and adverse events: race/ethnicity and language as independent contributors.
Patients with limited English proficiency have known limitations accessing health care, but differences in hospital outcomes once access is obtained are unknown. We investigate inpatient mortality rates and obstetric trauma for self-reported speakers of English, Spanish, and languages of Asia and the Pacific Islands (API) and compare quality of care by language with patterns by race/ethnicity. Data were from the United States Agency for Healthcare Research and Quality, Healthcare Cost and Utilization Project, 2009 State Inpatient Databases for California. There were 3,757,218 records. Speaking a non-English principal language and having a non-White race/ethnicity did not place patients at higher risk for inpatient mortality; the exception was significantly higher stroke mortality for Japanese-speaking patients. Patients who spoke API languages or had API race/ethnicity had higher risk for obstetric trauma than English-speaking White patients. Spanish-speaking Hispanic patients had more obstetric trauma than English-speaking Hispanic patients. The influence of language on obstetric trauma and the potential effects of interpretation services on inpatient care are discussed. The broader context of policy implications for collection and reporting of language data is also presented. Results from other countries with and without English as a primary language are needed for the broadest interpretation and generalization of outcomes.


Impaired KIN10 function restores developmental defects in the Arabidopsis trehalose 6-phosphate synthase1 (tps1) mutant.
Sensing carbohydrate availability is essential for plants to coordinate their growth and development. In Arabidopsis thaliana, TREHALOSE 6-PHOSPHATE SYNTHASE 1 (TPS1) and its product, trehalose 6-phosphate (T6P), are important for the metabolic control of development. tps1 mutants are embryo-lethal and unable to flower when embryogenesis is rescued. T6P regulates development in part through inhibition of SUCROSE NON-FERMENTING1 RELATED KINASE1 (SnRK1). Here, we explored the role of SnRK1 in T6P-mediated plant growth and development using a combination of a mutant suppressor screen and genetic, cellular and transcriptomic approaches. We report nonsynonymous amino acid substitutions in the catalytic KIN10 and regulatory SNF4 subunits of SnRK1 that can restore both embryogenesis and flowering of tps1 mutant plants. The identified SNF4 point mutations disrupt the interaction with the catalytic subunit KIN10. Contrary to the common view that the two A. thaliana SnRK1 catalytic subunits act redundantly, we found that loss-of-function mutations in KIN11 are unable to restore embryogenesis and flowering, highlighting the important role of KIN10 in T6P signalling.


Report of a review of the induction and refresher scheme placement report tools.
GPs undertaking the Induction and Refresher (I&R) Scheme in England spend a period of between 4 weeks and 6 months in placements in a General Practice setting. During this time they have to complete a number of workplace-based assessments, and their Educational Supervisor is required to complete a report which confirms that they have demonstrated an adequate level of competence to enable them to be accepted by NHS England onto the National Medical Performers List without conditions. This report describes a process (using an online survey completed by Educational Supervisors) of reviewing and improving the end-of-placement report forms to make them clearer and easier to use. The word pictures used in the revised forms could be adapted to become a competency framework for members of the primary care workforce.


Genome-wide association study of suicidal behaviour severity in mood disorders.
Suicide is a major public health problem and it has a prominent genetic component. We performed a genome-wide association study (GWAS) of suicidal behaviour severity. Suicide behaviour severity was assessed within the Schedules for Clinical Assessment in Neuropsychiatry in our mood disorder sample (n = 3506) for the GWAS. We also performed polygenic risk score analyses to explore genetic sharing between suicidal behaviour severity and a number of phenotypes, including bipolar disorder, major depressive disorder, alcoholism, post-traumatic stress disorder, impulsivity, insomnia, educational attainment, loneliness, maltreatment, and amygdala volume. We did not detect genome-wide significant findings at the single-marker or gene level. We report a number of suggestive single-marker and gene-based findings. Our polygenic risk score analyses did not yield significant findings with these phenotypes. Larger sample sizes are required to detect moderate effects.


Requirement of novel competence genes pilT and pilU of Pseudomonas stutzeri for natural transformation and suppression of pilT deficiency by a hexahistidine tag on the type IV pilus protein PilAI.
The ubiquitous species Pseudomonas stutzeri has type IV pili, and these are essential for the natural transformation of the cells. An absolute transformation-deficient mutant obtained after transposon mutagenesis had an insertion in a gene which was termed pilT. The deduced amino acid sequence has identity with PilT of Pseudomonas aeruginosa (94%), Neisseria gonorrhoeae (67%), and other gram-negative species and it contains a nucleotide-binding motif. The mutant was hyperpiliated but defective for further pilus-associated properties, such as twitching motility and plating of pilus-specific phage PO4. [(3)H]thymidine-labeled DNA was bound by the mutant but not taken up. Downstream of pilT a gene, termed pilU, coding for a putative protein with 88% amino acid identity with PilU of P. aeruginosa was identified. Insertional inactivation did not affect piliation, twitching motility, or PO4 infection but reduced transformation to about 10%. The defect was fully complemented by PilU of nontransformable P. aeruginosa. When the pilAI gene (coding for the type IV pilus prepilin) was manipulated to code for a protein in which the six C-terminal amino acids were replaced by six histidine residues and then expressed from a plasmid, it gave a nonpiliated and twitching motility-defective phenotype in pilAI::Gm(r) cells but allowed transformability. Moreover, the mutant allele suppressed the absolute transformation deficiency caused by the pilT mutation. Considering the hypothesized role of pilT(+) in pilus retraction and the presumed requirement of retraction for DNA uptake, it is proposed that the pilT-independent transformation is promoted by PilA mutant protein either as single molecules or as minimal pilin assembly structures in the periplasm which may resemble depolymerized pili and that these cause the outer membrane pores to open for DNA entry.


Effects of anthropometric variables and electrode placement on the SEMG activity of the biceps brachii muscle during submaximal isometric contraction in arm wrestling.
Surface electromyography (SEMG) has been widely used to analyze the biceps brachii (BB) muscle during voluntary contraction, and the effect of the interelectrode distance has been studied. However, the effect of anthropometric variations and the placement of electrodes on the BB activity during arm wrestling (i.e., during isometric contraction at a submaximal intensity) has seldom been investigated. In this study, the BB strength throughout this type of static contraction was evaluated. The SEMG signals were recorded from three locations on the BB: the muscle belly (M), near proximal (P), and distal tendon (L) regions. Twenty subjects who participated in the experiment were divided into five groups (A, B, C, D, and E). The average SEMG, root mean square, and variability of the signal were calculated using the coefficient of variance. The results indicated that the M region was more active and exhibited increased signal consistency (10.91%) compared with the other two regions (P: 24.47% and L: 19.13%). Significant differences were observed between the L and P regions and between the M and P regions (p<0.05); however, there were no differences between the M and L regions (p>0.05). The increase in the SEMG value in groups B and C was significant (p<0.05), whereas groups A, D, and E did not exhibit a significant increase (p>0.05). In addition, muscle size was the strongest predictor of strength compared with body weight and height. The results suggest that the M region displays considerable SEMG effects and signal reliability. Furthermore, the SEMG measurements were found to correlate strongly with the strength of the contractions and the muscle size, and not with weight and height.


[Corynebacterium D2 as a ureolytic organism: report of 5 cases].
Corynebacterium D2, a saprophytic microorganism of skin, causes alkaline encrusted cystitis in patients with a previous bladder injury. In 5 patients that had presented this nosological entity, these gram-positive rods were isolated in urine cultures and calculi. Four patients had undergone urological instrumentation maneuvers and one patient (female) had a history of recurrent cystitis from gram-negative bacteria. Corynebacterium D2 grows slowly and under certain conditions, as those described above, must be considered pathological despite counts of less than 100,000/ufc-cc. It is ureolytic and highly resistant to antibiotics. The synergistic effects of antimicrobials, acetohydroxamic acid and transurethral resection of the lithiasic plaques achieve satisfactory treatment of alkaline encrusted cystitis from Corynebacterium D2.


Online research article discussion board to increase knowledge translation during emergency medicine residency.
Many clinicians have difficulties reading current best practice journal articles on a regular basis. Discussion boards are one method of online asynchronous learning that facilitates active learning and participation. We hypothesized that an online repository of best practice articles with a discussion board would increase journal article reading by emergency medicine residents. PARTICIPANTS ANSWERED THREE QUESTIONS WEEKLY ON A DISCUSSION BOARD: What question does this study address? What does this study add to our knowledge? How might this change clinical practice? A survey regarding perceived barriers to participating was then distributed. Most participants completed an article summary once or twice in total (23/32, 71.9%). Only three were involved most weeks (3/32, 9.4%) whereas 5/32 (15.6%) participated monthly. The most common barriers were lack of time (20/32, 62.5%), difficulty logging on (7/32, 21.9%), and forgetting (6/32, 18.8%). Although subjects were provided weekly with an article link, email, and feedback, journal article reading frequency did not increase.


Lineage commitment of dermal fibroblast progenitors is controlled by Kdm6b-mediated chromatin demethylation.
Dermal Fibroblast Progenitors (DFPs) differentiate into distinct fibroblast lineages during skin development. However, the epigenetic mechanisms that regulate DFP differentiation are not known. Our objective was to use multimodal single-cell approaches, epigenetic assays, and allografting techniques to define a DFP state and the mechanism that governs its differentiation potential. Our initial results indicated that the overall transcription profile of DFPs is repressed by H3K27me3 and has inaccessible chromatin at lineage-specific genes. Surprisingly, the repressive chromatin profile of DFPs renders them unable to reform the skin in allograft assays despite their multipotent potential. We hypothesized that chromatin derepression was modulated by the H3K27me3 demethylase, Kdm6b/Jmjd3. Dermal fibroblast-specific deletion of Kdm6b/Jmjd3 in mice resulted in adipocyte compartment ablation and inhibition of mature dermal papilla functions, confirmed by additional single-cell RNA-seq, ChIP-seq, and allografting assays. We conclude that DFPs are functionally derepressed during murine skin development by Kdm6b/Jmjd3. Our studies therefore reveal a multimodal understanding of how DFPs differentiate into distinct fibroblast lineages and provide a novel publicly available multiomics search tool.


Pelvic ring injury and associated urologic trauma: an orthopaedic perspective.
Pelvic ring trauma is frequently associated with damage to many organ systems, including the vascular, genitourinary, nervous, reproductive, and intestinal systems. The orthopaedic treatment of these patients must incorporate the presence of these injured soft tissue structures and the physicians who are knowledgeable in the care of these anatomic regions in treatment decision making. Improvement in the treatment of these patients has been based on progress in areas of interventional radiology, general surgery, urology, and orthopaedics. The purposes of this report are to define the natural history and the survival rate after a pelvic fracture or dislocation, as well as to present classification schemes used by the orthopaedic surgeon, define current controversies, and recommend treatment based on the pattern of injury to the pelvic ring.


Combining Multiple High-Resolution In Situ Techniques to Understand Phosphorous Availability Around Rice Roots.
Resolving chemical/biological drivers of P behavior around lowland/flooded rice roots remains a challenge because of the heterogeneity of the plant-soil interactions, compounded by sampling and analytical constraints. High-spatial-resolution (sub-mm) visualization enables these processes to be isolated, characterized, and deciphered. Here, three advanced soil imaging systems, diffusive gradients in thin-film technique coupled with laser ablation-ICPMS (DGT-LA-ICPMS), O2 planar optode, and soil zymography, were integrated. This trio of approaches was then applied to a rice life cycle study to quantify solute-P supply, through two dimensions, in situ, and low-disturbance high-resolution (HR) chemical imaging. This allowed mechanisms of P release to be delineated by O2, Fe, and phosphatase activity mapping at the same scale. HR-DGT revealed P depletion around both living and dead rice roots but with highly spatially variable Fe/P ratios (∼0.2-12.0) which aligned with changing redox conditions and root activities. Partnering of HR-DGT and soil zymography revealed concurrent P depletion and phosphatase hotspots in the rhizosphere and detritusphere zones (Mantel: 0.610-0.810, p < 0.01). This close affinity between these responses (Pearson correlation: -0.265 to -0.660, p < 0.01) cross-validates the measurements and reaffirms that P depletion stimulates phosphatase activity and Porg mineralization. The μ-scale biogeochemical landscape of rice rhizospheres and detritusphere, as documented here, needs greater consideration when implementing interventions to improve sustainable P nutrition.


The Literacy of Suicide Scale.
Background: Until recently, little was known about the public's knowledge of suicide or its association with help-seeking. Aims: In this article we describe the development, validation, and application of the Literacy of Suicide Scale (LOSS). Method: A total of 658 people participated in the development of the LOSS, while 191 participated in a validation study. Item response theory was used to identify LOSS items. A systematic review of the literature was conducted to ascertain the breadth of use and application of the LOSS. Results: Overall, 26 items were selected for the final version of the LOSS, with 12 items identified for a short form of the scale. The LOSS has been included in 25 studies across nine countries with general community, student, and clinical populations. The LOSS has demonstrated change in response to psychoeducation interventions and is associated with suicide stigma and help-seeking in select studies. Limitations: Further validation of the LOSS in clinical populations is needed. Conclusion: The LOSS is a comprehensive measure of suicide literacy that may be used to identify knowledge gaps, inform awareness-raising activities, and assess the effectiveness of interventions to improve suicide literacy. The LOSS has been used in a broad range of settings, demonstrating application to diverse populations and cultural contexts.


Spontaneous bone formation on the maxillary sinus floor in association with surgery to remove a migrated dental implant: a case report.
A variety of surgical techniques have been developed to reconstruct the posterior maxilla when bone volume is insufficient. For some decades, sinus augmentation, using various bone substitutes, has been used to reconstruct the posterior maxilla for dental implant placement. Even if new bone formation is achieved in the sinus after bone grafting, the possibility of new bone formation with only a membrane elevation in the maxillary sinus has been reported in human and animal studies. The aim of this case report was to document an unexpected healing pattern after the removal of a dental implant migrated in the maxillary sinus. In October 2009 a 49-year-old man with a partially edentulous maxilla underwent implant placement. Specifically, a total of 5 implants were inserted, 2 in the left and 3 in the right posterior maxilla. Four months later, at the time of abutment connection, the implant at the site of the maxillary left first molar was accidentally pushed in the sinus. A surgical removal of the implant from the maxillary sinus was proposed and the patient consented to the surgical intervention. Computed axial tomography (CAT) scan images revealed opacification of the left maxillary sinus with mucosal thickening, and the dental implant displaced within the sinus. The planned treatment sequence was: 1) removal of the implant; 2) sinus augmentation procedure after 5 months; 3) implant insertion 5 months after the bone graft. The implant was removed. Five months later, the patient was admitted for the bone-grafting augmentation procedure. A new CAT scan image revealed normal mucosal thickness and no opacification of the left maxillary sinus; bone formation was evident. The surgery was undertaken with local anesthesia and conscious sedation. At reentry, the sinus wall was found to be totally healed. Newly formed bone (21.2%) with wide osteocyte lacunae and large marrow spaces (73.8%) were present with newly formed vessels and no inflammatory cell infiltrate. The surgical trauma and the creation of a secluded space between the bone surfaces and the healed sinus mucosa resulted in a spontaneous bone formation in the maxillary sinus. The surgical approach described may be used to achieve bone formation to enable placement of dental implants without the addition of any grafting material.


Gliadin Sequestration as a Novel Therapy for Celiac Disease: A Prospective Application for Polyphenols.
Celiac disease is an autoimmune disorder characterized by a heightened immune response to gluten proteins in the diet, leading to gastrointestinal symptoms and mucosal damage localized to the small intestine. Despite its prevalence, the only treatment currently available for celiac disease is complete avoidance of gluten proteins in the diet. Ongoing clinical trials have focused on targeting the immune response or gluten proteins through methods such as immunosuppression, enhanced protein degradation and protein sequestration. Recent studies suggest that polyphenols may elicit protective effects within the celiac disease milieu by disrupting the enzymatic hydrolysis of gluten proteins, sequestering gluten proteins from recognition by critical receptors in pathogenesis and exerting anti-inflammatory effects on the system as a whole. This review highlights mechanisms by which polyphenols can protect against celiac disease, takes a critical look at recent works and outlines future applications for this potential treatment method.


An Alternative Strategy for Pan-acetyl-lysine Antibody Generation.
Lysine acetylation is an important post-translational modification in cell signaling. In acetylome studies, a high-quality pan-acetyl-lysine antibody is key to successful enrichment of acetylated peptides for subsequent mass spectrometry analysis. Here we show an alternative method to generate polyclonal pan-acetyl-lysine antibodies using a synthesized random library of acetylated peptides as the antigen. Our antibodies are tested to be specific for acetyl-lysine peptides/proteins via ELISA and dot blot. When pooled, five of our antibodies show broad reactivity to acetyl-lysine peptides, complementing a commercial antibody in terms of peptide coverage. The consensus sequence of peptides bound by our antibody cocktail differs slightly from that of the commercial antibody. Lastly, our antibodies are tested in a proof-of-concept to analyze the acetylome of HEK293 cells. In total we identified 1557 acetylated peptides from 416 proteins. We thus demonstrated that our antibodies are well-qualified for acetylome studies and can complement existing commercial antibodies.


Ethanol raises prostacyclin in vivo and in vitro.
Moderate doses of ethanol were shown to induce a significant rise in prostacyclin (PGI2) concentration in cultures of endothelial cells derived from umbilical veins. Administration of 32 g of ethanol to six volunteers elevated plasma levels of PGI2 in parallel with those of blood alcohol. Although not specific for ethanol, this alcohol induced the largest change in PGI2. Withdrawal of the stimulant alcohol caused prompt reduction of the elevated prostacyclin to baseline values. The activity of ethanol appears to be due to a direct stimulation of cyclooxygenase. The release of [14C]arachidonic acid from prelabeled endothelial cells was decreased by ethanol. PGE2 production was also enhanced by exposure of endothelial cells to ethanol. The physiologic significance of these alcohol-induced changes in PGI2 levels remains to be established.


[Estramustinphosphate in the treatment of prostatic cancer].
This study describes our experience in the treatment of disseminated prostatic cancer with stramustine phosphate. We reviewed our series of 41 patients with disseminated prostatic cancer; of these, 6 were treated with stramustine phosphate. Patient age, clinical features, tumor stage and diagnostic methods utilized were analyzed. All patients received 600 mg/day oral stramustine in two doses. All 6 patients treated with stramustine phosphate showed clinical improvement, the levels of tumor markers returned to normal and bone metastasis disappeared. Moreover, no side effects were observed. Further research is necessary on the effective use of stramustine phosphate and at the appropriate time in order to obtain the best results as there is no other alternative except radical surgery and at an early stage.


A catechin nanoformulation inhibits WM266 melanoma cell proliferation, migration and associated neo-angiogenesis.
We validated the anticancer potential of a nanoformulation made by (+)-catechin, gelatin and carbon nanotubes in terms of inhibition of cancer cell proliferation, migration and associated neo-angiogenesis. Gelatin was selected to stabilize the catechin without compromising its anti-oxidant potential and the carbon nanotubes were used to increase its intracellular bioavailability. The anticancer potential of the resulting nanohybrid was validated on an aggressive melanoma cell line, in vitro and in zebrafish xenotransplants. The nanohybrid strongly enhances the cytotoxic effect of (+)-catechin. At a concentration of (+)-catechin 50μg/ml, the nanohybrid inhibited the ability of melanoma cells to proliferate (100% increase of cell doubling time and severe impairment in zebrafish xenotransplants), to migrate (totally inhibition in vitro and 50% reduction of cell motility in zebrafish xenotransplants) and to induce neo-angiogenesis (100% inhibition in zebrafish xenotransplants). Conversely, the free (+)-catechin and carrier (CNT:gel) had no statistically significant effects over the control, at any concentration tested. Our results suggest that the use of the nanohybrid, able to improve the therapeutic efficacy of the catechins, could represent a successful strategy for a future clinical translation.