Development of the HOOSglobal to Assess Patient-Reported Outcomes in Patients Undergoing Hip Preservation Procedures.
The creation of a single patient-reported outcome (PRO) platform validated across hip preservation, osteoarthritis (OA), and total hip arthroplasty (THA) populations may reduce barriers and streamline the routine collection of PROs in clinical practice. As such, the purpose of this study was to determine if augmenting the Hip disability and Osteoarthritis Outcome Score-Joint Replacement (HOOS, JR) with additional HOOS questions would result in a PRO platform that could be used across a wider spectrum of hip patient populations. The HOOS, JR would demonstrate a notable ceiling effect, but by augmenting the HOOS, JR with additional HOOS questions, a responsive PRO platform could be created. Cohort study (diagnosis); Level of evidence, 2. Using preoperative and postoperative HOOS responses from a sample of 304 patients undergoing periacetabular osteotomy (PAO), additional items were identified to augment the HOOS, JR. The psychometric properties of a newly created PRO tool (HOOSglobal) were then compared with the HOOS, JR and other PRO instruments developed for patients with hip OA and/or undergoing THA. By augmenting the HOOS, JR with 2 additional questions, the HOOSglobal was more responsive than all other included PRO tools and had significantly fewer maximum postoperative scores than the HOOS, JR ( P < .0001), HOOS-Physical Function Short form ( P < .0001), Western Ontario and McMaster Universities Osteoarthritis Index ( P = .02), University of California, Los Angeles activity scale ( P = .0002), and modified Harris Hip Score ( P = .04). The postoperative HOOSglobal score threshold associated with patients achieving the patient acceptable symptom state (PASS) was 62.5. The HOOSglobal is a valid and responsive PRO tool after PAO and may potentially provide the orthopaedic community with a PRO platform to be used across hip-related subspecialties. For patients undergoing PAO, a postoperative HOOSglobal score ≥62.5 was associated with patients achieving the PASS.


Tissue-resident macrophages can be generated de novo in adult human skin from resident progenitor cells during substance P-mediated neurogenic inflammation ex vivo.
Besides monocyte (MO)-derived macrophages (MACs), self-renewing tissue-resident macrophages (trMACs) maintain the intracutaneous MAC pool in murine skin. Here, we have asked whether the same phenomenon occurs in human skin using organ-cultured, full-thickness skin detached from blood circulation and bone marrow. Skin stimulation ex vivo with the neuropeptide substance P (SP), mimicking neurogenic skin inflammation, significantly increased the number of CD68+MACs in the papillary dermis without altering intracutaneous MAC proliferation or apoptosis. Since intraluminal CD14+MOs were undetectable in the non-perfused dermal vasculature, new MACs must have differentiated from resident intracutaneous progenitor cells in human skin. Interestingly, CD68+MACs were often seen in direct cell-cell-contact with cells expressing both, the hematopoietic stem cell marker CD34 and SP receptor (neurokinin-1 receptor [NK1R]). These cell-cell contacts and CD34+cell proliferation were up-regulated in SP-treated skin samples. Collectively, our study provides the first evidence that resident MAC progenitors, from which mature MACs can rapidly differentiate within the tissue, do exist in normal adult human skin. That these NK1R+trMAC-progenitor cells quickly respond to a key stress-associated neuroinflammatory stimulus suggests that this may satisfy increased local MAC demand under conditions of wounding/stress.


National survey of the ophthalmic use of anti-vascular endothelial growth factor drugs in Israel.
Intravitreal injections of the anti-vascular endothelial growth factor (VEGF) drugs bevacizumab (Avastin) and ranibizumab (Lucentis) became the mainstay of treatment for various retinal pathologies, but there is no consensus among ophthalmologists on the precise use of these drugs. To describe the routine practices of retinal specialists in Israel regarding anti-VEGF drug treatment. A questionnaire was sent via email to all 62 members of the Israeli Society of Retinal Specialists. The survey included 34 questions on various aspects of the use of anti-VEGF drugs: diagnosis, treatment, follow-up of different retinal pathologies, and the measures taken for ensuring sterile administration of the intravitreal injections. Fifty members (80%) completed the survey. Most of them (56%) offered both bevacizumab and ranibizumab to their patients for age-related macular degeneration, but 70% were influenced by the patient's socioeconomic status. Three consecutive monthly injections were usually recommended (58%) for the first 3 months, and treatment was extended as long as subretinal or intraretinal fluids persisted (57%). Over two-thirds (68%) switched the drugs after the 3-monthly series if the first one yielded no improvement in fluid status. The routine practice for intravitreal injection (> 80%) involved the wearing of sterile gloves, using an eyelid speculum, and administering povidone-iodine pretreatment and topical antibiotics after treatment. Intravitreal VEGF administration varies widely among Israeli retinal specialists. The current survey is intended to assist Israeli ophthalmologists in establishing their own treatment strategy for patients with retinal pathologies.


An exploration of factors influencing adherence to highly active anti-retroviral therapy (HAART) among people living with HIV/AIDS in Northern Thailand.
This paper presents the first of a three-phase study exploring the experiences of people living with HIV/AIDS (PLWHA) in Northern Thailand. The principal aim of the study was to gain an in-depth understanding of the factors contributing to adherence in patients taking highly active anti-retroviral therapy (HAART). These insights were used in phase two to inform a number of interventions aimed at improving medication adherence in patients commencing HAART for the first time. The study comprised a cohort of 32 PLWHA over the age of 18 years who had taken HAART for at least three months. Both qualitative and quantitative methods were used. The qualitative component used a multiple case study approach to explore and describe the experiences of patients receiving HAART. The quantitative component comprised the Morisky Medication Adherence Scale and a demographic survey of the respondents. This demographic data were used to provide descriptive statistics of the research population and assist with the interpretation of the qualitative data. The findings identified a number of social, clinical, and economic factors influencing adherence to HAART. These findings led to a number of recommendations that health care providers and policy-makers can implement to improve medication adherence rates in patients taking HAART. The findings demonstrated that improved adherence not only led to improved clinical outcomes, but also the overall quality of life of PLWHA.


Evolutionary design of explainable algorithms for biomedical image segmentation.
An unresolved issue in contemporary biomedicine is the overwhelming number and diversity of complex images that require annotation, analysis and interpretation. Recent advances in Deep Learning have revolutionized the field of computer vision, creating algorithms that compete with human experts in image segmentation tasks. However, these frameworks require large human-annotated datasets for training and the resulting "black box" models are difficult to interpret. In this study, we introduce Kartezio, a modular Cartesian Genetic Programming-based computational strategy that generates fully transparent and easily interpretable image processing pipelines by iteratively assembling and parameterizing computer vision functions. The pipelines thus generated exhibit comparable precision to state-of-the-art Deep Learning approaches on instance segmentation tasks, while requiring drastically smaller training datasets. This Few-Shot Learning method confers tremendous flexibility, speed, and functionality to this approach. We then deploy Kartezio to solve a series of semantic and instance segmentation problems, and demonstrate its utility across diverse images ranging from multiplexed tissue histopathology images to high resolution microscopy images. While the flexibility, robustness and practical utility of Kartezio make this fully explicable evolutionary designer a potential game-changer in the field of biomedical image processing, Kartezio remains complementary and potentially auxiliary to mainstream Deep Learning approaches.


An engineered pathway for glyoxylate metabolism in tobacco plants aimed to avoid the release of ammonia in photorespiration.
The photorespiratory nitrogen cycle in C₃ plants involves an extensive diversion of carbon and nitrogen away from the direct pathways of assimilation. The liberated ammonia is re-assimilated, but up to 25% of the carbon may be released into the atmosphere as CO₂. Because of the loss of CO₂ and high energy costs, there has been considerable interest in attempts to decrease the flux through the cycle in C₃ plants. Transgenic tobacco plants were generated that contained the genes gcl and hyi from E. coli encoding glyoxylate carboligase (EC 220.127.116.11) and hydroxypyruvate isomerase (EC 22.214.171.124) respectively, targeted to the peroxisomes. It was presumed that the two enzymes could work together and compete with the aminotransferases that convert glyoxylate to glycine, thus avoiding ammonia production in the photorespiratory nitrogen cycle. When grown in ambient air, but not in elevated CO₂, the transgenic tobacco lines had a distinctive phenotype of necrotic lesions on the leaves. Three of the six lines chosen for a detailed study contained single copies of the gcl gene, two contained single copies of both the gcl and hyi genes and one line contained multiple copies of both gcl and hyi genes. The gcl protein was detected in the five transgenic lines containing single copies of the gcl gene but hyi protein was not detected in any of the transgenic lines. The content of soluble amino acids including glycine and serine, was generally increased in the transgenic lines growing in air, when compared to the wild type. The content of soluble sugars, glucose, fructose and sucrose in the shoot was decreased in transgenic lines growing in air, consistent with decreased carbon assimilation. Tobacco plants have been generated that produce bacterial glyoxylate carboligase but not hydroxypyruvate isomerase. The transgenic plants exhibit a stress response when exposed to air, suggesting that some glyoxylate is diverted away from conversion to glycine in a deleterious short-circuit of the photorespiratory nitrogen cycle. This diversion in metabolism gave rise to increased concentrations of amino acids, in particular glutamine and asparagine in the leaves and a decrease of soluble sugars.


Synthesis of 28a-homoselenolupanes and 28a-homoselenolupane saponins.
A practical synthesis of 28a-homo-28a-selenolupane triterpenes and the corresponding selenosaponins containing d-mannose, l-arabinose, l-rhamnose, and d-idose moieties is described. Selenium containing triterpenes were obtained from the readily available 3-O-allyl-homobetulin mesylate by nucleophilic substitution with the selenocyanate ion which upon reduction of the -SeCN group afforded the free selenol. Glycosylation using classical Schmidt donors gave 1,2-trans selenosaponins as the main product as well as minute amounts of 1,2-cis isomers. This is one of the very few examples of the synthesis of selenoglycosides by direct glycosylation of free selenols. The studied selenol showed high resistance to air oxidation resulting in good stability during the synthesis of selenolupane derivatives. Cytotoxic activities of new homoselenolupane derivatives were also evaluated in vitro and revealed that some triterpenes exhibited an interesting profile against human cancer cell lines.


Intraoperative magnetic tracker calibration using a magneto-optic hybrid tracker for 3-D ultrasound-based navigation in laparoscopic surgery.
This paper describes a ultrasound (3-D US) system that aims to achieve augmented reality (AR) visualization during laparoscopic surgery, especially for the liver. To acquire 3-D US data of the liver, the tip of a laparoscopic ultrasound probe is tracked inside the abdominal cavity using a magnetic tracker. The accuracy of magnetic trackers, however, is greatly affected by magnetic field distortion that results from the close proximity of metal objects and electronic equipment, which is usually unavoidable in the operating room. In this paper, we describe a calibration method for intraoperative magnetic distortion that can be applied to laparoscopic 3-D US data acquisition; we evaluate the accuracy and feasibility of the method by in vitro and in vivo experiments. Although calibration data can be acquired freehand using a magneto-optic hybrid tracker, there are two problems associated with this method--error caused by the time delay between measurements of the optical and magnetic trackers, and instability of the calibration accuracy that results from the uniformity and density of calibration data. A temporal calibration procedure is developed to estimate the time delay, which is then integrated into the calibration, and a distortion model is formulated by zeroth-degree to fourth-degree polynomial fitting to the calibration data. In the in vivo experiment using a pig, the positional error caused by magnetic distortion was reduced from 44.1 to 2.9 mm. The standard deviation of corrected target positions was less than 1.0 mm. Freehand acquisition of calibration data was performed smoothly using a magneto-optic hybrid sampling tool through a trocar under guidance by realtime 3-D monitoring of the tool trajectory; data acquisition time was less than 2 min. The present study suggests that our proposed method could correct for magnetic field distortion inside the patient's abdomen during a laparoscopic procedure within a clinically permissible period of time, as well as enabling an accurate 3-D US reconstruction to be obtained that can be superimposed onto live endoscopic images.


Assessment of tissue-engineered islet graft viability by fluorine magnetic resonance spectroscopy.
Despite significant progress in the last decade, islet transplantation remains an experimental therapy for a limited number of patients with type 1 diabetes. Tissue-engineered approaches may provide promising alternatives to the current clinical protocol and would benefit greatly from concurrent development of graft quality assessment techniques. This study was designed to evaluate whether viability of tissue-engineered islet grafts can be assessed using fluorine magnetic resonance spectroscopy ((19)F-MRS), by the noninvasive measurement of oxygen partial pressure (pO(2)) and the subsequent calculation of islet oxygen consumption rate (OCR). Scaffolds composed of porcine plasma were seeded with human islets and perfluorodecalin. Each graft was covered with the same volume of culture media in a Petri dish. Four scaffolds were seeded with various numbers (0-8000) of islet equivalents (IE) aliquoted from the same preparation. After randomizing run order, grafts were examined by (19)F-MRS at 37°C using a 5T spectrometer and a single-loop surface coil placed underneath. A standard inversion recovery sequence was used to obtain characteristic (19)F spin-lattice relaxation times (T1), which were converted to steady-state average pO(2) estimates using a previously determined linear calibration (R(2) = 1.000). Each condition was assessed using replicate (19)F-MRS measurements (n = 6-8). Grafts exhibited IE dose-dependent increases in T1 and decreases in pO(2) estimates. From the difference between scaffold pO(2) estimates and ambient pO(2), the islet preparation OCR was calculated to be 95 ± 12 (mean ± standard error of the mean) nmol/(min·mg DNA) using theoretical modeling. This value compared well with OCR values measured using established methods for human islet preparations. (19)F-MRS can be used for noninvasive pre- and possibly posttransplant assessment of tissue-engineered islet graft viability by estimating the amount of viable, oxygen-consuming tissue in a scaffold.


Lessons Learned From Dissemination of Evidence-Based Interventions for HIV Prevention.
In 1999, IOM issued a report that recommended that the Centers for Disease Control and Prevention should disseminate evidence-based HIV prevention interventions (EBIs) to be implemented by health departments, community-based organizations, drug treatment centers, and clinics. Based on these recommendations, the Diffusion of Effective Behavioral Interventions Project was initiated in 2000 and began disseminating interventions into public health practice. For 15 years, the Centers for Disease Control and Prevention has disseminated 29 EBIs to more than 11,300 agencies. Lessons were identified during the 15 years of implementation regarding successful methods of dissemination of EBIs. Lessons around selecting interventions for dissemination, developing a dissemination infrastructure including a resource website (https://effectiveinterventions.cdc.gov), and engagement with stakeholders are discussed. A continuous development approach ensured that intervention implementation materials, instructions, and technical assistance were all tailored to the needs of end users, focus populations, and agency capacities. Six follow-up studies demonstrated that adopters of EBIs were able to obtain comparable outcomes to those of the original efficacy research. The Diffusion of Effective Behavioral Interventions Project may offer guidance for other large, national, evidence-based public health dissemination projects.


Synthesis of a pentasaccharide and neoglycoconjugates related to fungal α-(1→3)-glucan and their use in the generation of antibodies to trace Aspergillus fumigatus cell wall.
3-Aminopropyl α-(1→3)-pentaglucoside, a fragment of α-(1→3)-glucan of the cell wall of Aspergillus fumigatus, has been synthesized in a blockwise approach. The application of mono- and disaccharide N-phenyltrifluoroacetimidates bearing a stereodirecting 6-O-benzoyl group was essential for stereoselective α-glucosylations. In the products, p-methoxyphenyl and levulinoyl groups served as orthogonal protecting groups for the anomeric position and 3-OH group, respectively. Their removal from shared blocks led to donors and acceptors that were used for the synthesis of pentasaccharides. Coupling of free α-(1→3)-pentaglucoside with biotin and bovine serum albumin (BSA) gave glycoconjugate tools for mycological studies. Immunization of mice with the BSA conjugate induced the generation of antibodies that recognize α-(1→3)-glucan on A. fumigatus cell wall and distinguish its morphotypes. This discovery represents a first step to the development of a diagnostic test system and a vaccine to detect and fight this life-threatening pathogen.


Micromotion at the tibial plateau in primary and revision total knee arthroplasty: fixed versus rotating platform designs.
Initial stability of tibial trays is crucial for long-term success of total knee arthroplasty (TKA) in both primary and revision settings. Rotating platform (RP) designs reduce torque transfer at the tibiofemoral interface. We asked if this reduced torque transfer in RP designs resulted in subsequently reduced micromotion at the cemented fixation interface between the prosthesis component and the adjacent bone. Composite tibias were implanted with fixed and RP primary and revision tibial trays and biomechanically tested under up to 2.5 kN of axial compression and 10° of external femoral component rotation. Relative micromotion between the implanted tibial tray and the neighbouring bone was quantified using high-precision digital image correlation techniques. Rotational malalignment between femoral and tibial components generated 40% less overall tibial tray micromotion in RP designs than in standard fixed bearing tibial trays. RP trays reduced micromotion by up to 172 µm in axial compression and 84 µm in rotational malalignment models. Reduced torque transfer at the tibiofemoral interface in RP tibial trays reduces relative component micromotion and may aid long-term stability in cases of revision TKA or poor bone quality.Cite this article: Mr S. R. Small. Micromotion at the tibial plateau in primary and revision total knee arthroplasty: fixed versus rotating platform designs. Bone Joint Res 2016;5:122-129. DOI: 10.1302/2046-3758.54.2000481.


Memory or amnesia: the dilemma of stem cell therapy in muscular dystrophies.
Muscular dystrophies are monogenetic diseases that are often characterized by the degeneration of both cardiac and skeletal muscle. Gene therapy to correct the mutated gene has shown promise in both animal models and clinical trials; however, current gene delivery strategies are limited to the introduction of the corrected gene into only one tissue. Strategies to target multiple striated muscle types would provide a much-needed improvement for the treatment of muscular dystrophies. In this issue of the JCI, Quattrocelli and colleagues demonstrate that induced pluripotent stem cells (iPSCs) with a myogenic propensity are able to engraft into both cardiac and skeletal muscles. The authors also identified a novel pool of mesodermal iPSC-derived progenitors (MiPs). Moreover, the authors show that these MiPs are amenable to gene correction and can restore function in murine dystrophic models. Together, the results of this study provide an important advance in improving gene delivery to treat patients with muscular dystrophy.


Postmenopausal circulating levels of 2- and 16α-hydroxyestrone and risk of endometrial cancer.
It has been suggested that the relative importance of oestrogen-metabolising pathways may affect the risk of oestrogen-dependent tumours including endometrial cancer. One hypothesis is that the 2-hydroxy pathway is protective, whereas the 16α-hydroxy pathway is harmful. We conducted a case-control study nested within three prospective cohorts to assess whether the circulating 2-hydroxyestrone : 16α-hydroxyestrone (2-OHE1 : 16α-OHE1) ratio is inversely associated with endometrial cancer risk in postmenopausal women. A total of 179 cases and 336 controls, matching cases on cohort, age and date of blood donation, were included. Levels of 2-OHE1 and 16α-OHE1 were measured using a monoclonal antibody-based enzyme assay. Endometrial cancer risk increased with increasing levels of both metabolites, with odds ratios in the top tertiles of 2.4 (95% CI=1.3, 4.6; P(trend)=0.007) for 2-OHE1 and 1.9 (95% CI=1.1, 3.5; P(trend)=0.03) for 16α-OHE1 in analyses adjusting for endometrial cancer risk factors. These associations were attenuated and no longer statistically significant after further adjustment for oestrone or oestradiol levels. No significant association was observed for the 2-OHE1 : 16α-OHE1 ratio. Our results do not support the hypothesis that greater metabolism of oestrogen via the 2-OH pathway, relative to the 16α-OH pathway, protects against endometrial cancer.


Effects of tick infestation on Boran (Bos indicus) cattle immunised against theileriosis in an endemic area of Kenya.
Boran (Bos indicus) heifers were immunised by infection with local Theileria parva parva, T p lawrencei and T mutans stocks and treated with parvaquone and later exposed to natural tick and tick-borne disease challenge in the Trans-Mara Division of Kenya. The Theileria species parasites in the challenge were maintained in African buffalo and cattle and the tick vectors were supported by several species of wild Bovidae and domestic livestock present in the area. Thirty immune cattle were observed for 30 weeks while grazing on a ranch in the Trans-Mara Division. Of these, 15 were immersed in toxaphene at weekly or twice-weekly intervals while 15 cattle remained without acaricide application. Cattle which became pregnant were withdrawn from the experiment. There was no evidence of any clinical tick-borne disease in either group of cattle during the experiment. Five species of ixodid ticks infested the cattle during the experiment and cattle which were not treated with acaricide had far more ticks. Rhipicephalus appendiculatus was the most abundant tick species, with a mean infestation of 46 adults per animal in the undipped cattle. This tick also appeared to be the cause of the observed reduction in weight gains. Major haematological parameters did not differ significantly between the groups. Behavioural studies showed that the undipped cattle spent less time grazing and ruminating. This study has shown that, at the expense of some loss in productivity, zebu cattle, immunised against ticks and theileriosis, can be kept despite tick infestation.


Effects of current generation and electrolyte pH on reverse salt flux across thin film composite membrane in osmotic microbial fuel cells.
Osmotic microbial fuel cells (OsMFCs) take advantages of synergy between forward osmosis (FO) and microbial fuel cells (MFCs) to accomplish wastewater treatment, current generation, and high-quality water extraction. As an FO based technology, OsMFCs also encounter reverse salt flux (RSF) that is the backward transport of salt ions across the FO membrane into the treated wastewater. This RSF can reduce water flux, contaminate the treated wastewater, and increase the operational expense, and thus must be properly addressed before any possible applications. In this study, we aimed to understand the effects of current generation and electrolyte pH on RSF in an OsMFC. It was found that electricity generation could greatly inhibit RSF, which decreased from 16.3 ± 2.8 to 3.9 ± 0.7 gMH when the total Coulomb production increased from 0 to 311 C. The OsMFC exhibited 45.9 ± 28.4% lower RSF at the catholyte pH of 3 than that at pH 11 when 40 Ω external resistance was connected. The amount of sodium ions transported across the FO membrane was 18.3-40.7% more than that of chloride ions. Ion transport was accomplished via diffusion and electrically-driven migration, and the theoretical analysis showed that the inhibited electrically-driven migration should be responsible for the reduced RSF. These findings are potentially important to control and reduce RSF in OsMFCs or other osmotic-driven processes.


The dentin phosphoprotein repeat region and inherited defects of dentin.
Nonsyndromic dentin defects classified as type II dentin dysplasia and types II and III dentinogenesis imperfecta are caused by mutations in DSPP (dentin sialophosphoprotein). Most reported disease-causing DSPP mutations occur within the repetitive DPP (dentin phosphoprotein) coding sequence. We characterized the DPP sequences of five probands with inherited dentin defects using single molecule real-time (SMRT) DNA sequencing. Eight of the 10 sequences matched previously reported DPP length haplotypes and two were novel. Alignment with known DPP sequences showed 32 indels arranged in 36 different patterns. Sixteen of the 32 indels were not represented in more than one haplotype. The 25 haplotypes with confirmed indels were aligned to generate a tree that describes how the length variations might have evolved. Some indels were independently generated in multiple lines. A previously reported disease-causing DSPP mutation in Family 1 was confirmed and its position clarified (c.3135delC; p.Ser1045Argfs*269). A novel frameshift mutation (c.3504_3508dup; p.Asp1170Alafs*146) caused the dentin defects in Family 2. A COL1A2 (c.2027G>A or p.Gly676Asp) missense mutation, discovered by whole-exome sequencing, caused the dentin defects in Family 3. We conclude that SMRT sequencing characterizes the DPP repeat region without cloning and can improve our understanding of normal and pathological length variations in DSPP alleles.


Pretreatment of Sialic Acid Efficiently Prevents Lipopolysaccharide-Induced Acute Renal Failure and Suppresses TLR4/gp91-Mediated Apoptotic Signaling.
Lipopolysaccharides (LPS) binding to Toll-like receptor 4 (TLR4) activate NADPH oxidase gp91 subunit-mediated inflammation and oxidative damage. Recognizing the high binding affinity of sialic acid (SA) with LPS, we further explored the preventive potential of SA pretreatment on LPS-evoked acute renal failure (ARF). We determined the effect of intravenous SA 30 min before LPS-induced injury in urethane-anesthetized female Wistar rats by evaluating kidney reactive oxygen species (ROS) responses, renal and systemic hemodynamics, renal function, histopathology, and molecular mechanisms. LPS time-dependently reduced arterial blood pressure, renal microcirculation, and increased blood urea nitrogen and creatinine in the rats. LPS enhanced monocyte/macrophage infiltration and ROS production, and subsequently impaired kidneys with the enhancement of TLR4/NADPH oxidase gp91/Caspase 3/poly-(ADP-ribose)-polymerase (PARP)-mediated apoptosis in the kidneys. SA pretreatment effectively alleviated LPS-induced ARF. The levels of LPS-increased ED-1 infiltration and ROS production in the kidney were significantly depressed by SA pretreatment. Furthermore, SA pretreatment significantly depressed TLR4 activation, gp91 expression, and Caspase 3/PARP induced apoptosis in the kidneys. We suggest that pretreatment of SA significantly and preventively attenuated LPS-induced detrimental effects on systemic and renal hemodynamics, renal ROS production and renal function, as well as, LPS-activated TLR4/gp91/Caspase3 mediated apoptosis signaling.


Structural Basis for Xenon Inhibition in a Cationic Pentameric Ligand-Gated Ion Channel.
GLIC receptor is a bacterial pentameric ligand-gated ion channel whose action is inhibited by xenon. Xenon has been used in clinical practice as a potent gaseous anaesthetic for decades, but the molecular mechanism of interactions with its integral membrane receptor targets remains poorly understood. Here we characterize by X-ray crystallography the xenon-binding sites within both the open and "locally-closed" (inactive) conformations of GLIC. Major binding sites of xenon, which differ between the two conformations, were identified in three distinct regions that all belong to the trans-membrane domain of GLIC: 1) in an intra-subunit cavity, 2) at the interface between adjacent subunits, and 3) in the pore. The pore site is unique to the locally-closed form where the binding of xenon effectively seals the channel. A putative mechanism of the inhibition of GLIC by xenon is proposed, which might be extended to other pentameric cationic ligand-gated ion channels.


Endoleaks after endovascular aortic aneurysm repair: Improved detection with noise-optimized virtual monoenergetic dual-energy CT.
To assess image quality and diagnostic performance of a noise-optimized algorithm to reconstruct virtual monoenergetic images (VMI+) for the detection of endoleaks after endovascular abdominal aortic aneurysm repair (EVAR) using dual-energy CT angiography (DE-CTA). Seventy-five patients (42 men; 66.2±11.7years) underwent DE-CTA following EVAR. Arterial phase images were acquired in dual-energy mode for the reconstruction of standard linearly-blended M_0.5, VMI+ and traditional monoenergetic images (VMI) at 40-100keV in 10-keV intervals. Contrast-to-noise ratios (CNR) were calculated for the area of leakage in patients with endoleaks. Diagnostic accuracy for endoleak detection was evaluated by three blinded radiologists using the objectively best series for each reconstruction technique. Thirty-four out of 75 patients showed endoleaks. Quantitative image parameters were highest at 40-keV VMI+ (CNR, 21.3±11.1), compared to M_0.5 (CNR, 10.9±5.5) and all VMI series that showed highest values at 70keV (CNR, 13.5±6.6; all P<0.001). ROC analysis for endoleak detection revealed an area under the curve (AUC) of 0.992 for 40-keV VMI+ series, which was significantly higher (P≤0.039) compared to 70-keV VMI (0.914) and M_0.5 series (0.916). Noise-optimized VMI+ series at 40keV improve diagnostic accuracy for the detection and rule-out of endoleaks after EVAR.


Recording the free-living behaviour of small-bodied, shallow-diving animals with data loggers.
1. Time-depth data recorders (TDRs) have been widely used to explore the behaviour of relatively large, deep divers. However, little is known about the dive behaviour of small, shallow divers such as semi-aquatic mammals. 2. We used high-resolution TDRs to record the diving behaviour of American mink Mustela vison (weight of individuals 580-1275 g) in rivers in Oxfordshire (UK) between December 2005 and March 2006. 3. Dives to > 0.2 m were measured in all individuals (n = 6). Modal dive depth and duration were 0.3 m and 10 s, respectively, although dives up to 3 m and 60 s in duration were recorded. Dive duration increased with dive depth. 4. Temperature data recorded by TDRs covaried with diving behaviour: they were relatively cold (modal temperature 4-6 degrees C across individuals) when mink were diving and relatively warm (modal temperature 24-36 degrees C across individuals) when mink were not diving. 5. Individuals differed hugely in their use of rivers, reflecting foraging plasticity across both terrestrial and aquatic environments. For some individuals there was < 1 dive per day while for others there was > 100 dives per day. 6. We have shown it is now possible to record the diving behaviour of small free-living animals that only dive a few tens of centimetres, opening up the way for a new range of TDR studies on shallow diving species.


HIV/AIDS-Related Stigma and Discrimination: A Study of Health Care Providers in Bangladesh.
People living with HIV/AIDS (PLWHA) are stigmatized and looked at negatively by people at large. Stigma, discrimination, and prejudice extend its reach to people associated with HIV-positive people such as health providers, hospital staff, as well as family member and friends. Studies demonstrate that, in low-income countries, especially in South Asia and sub-Saharan Africa, health providers' views toward the HIV-positive individuals is not very much different from the general population. The study has been qualitative in nature and conducted among health providers such as physicians and nurses attached to different hospitals. The study was conducted from March 2005 to May 2007. The study shows that 80% of the nurses and 90% of the physicians' behavior with the HIV-positive individuals were discriminatory. They talk to their patients standing far from them. The interview revealed that the spouses of the physicians and nurses in charge of the HIV-positive individuals put pressure to stop serving the patient or even quit the job. The notion that HIV is only transmitted through sexual activities is prevalent among them. Interestingly, although the physicians know well about the routes of transmission, they do not believe it by heart. Therefore, their fear of being infected makes them discriminate against the HIV-positive individuals. HIV-related stigma remains a barrier to effectively fighting this pandemic. Fear of discrimination often prevents people from seeking treatment publicly. There are evidences that they were evicted from home by their families and rejected by their friends and colleagues. The stigma attached to HIV/AIDS can extend into the next generation, placing an emotional burden on them.


Genome-wide association study of familial lung cancer.
To identify genetic variation associated with lung cancer risk, we performed a genome-wide association analysis of 685 lung cancer cases that had a family history of two or more first or second degree relatives compared with 744 controls without lung cancer that were genotyped on an Illumina Human OmniExpressExome-8v1 array. To ensure robust results, we further evaluated these findings using data from six additional studies that were assembled through the Transdisciplinary Research on Cancer of the Lung Consortium comprising 1993 familial cases and 33 690 controls. We performed a meta-analysis after imputation of all variants using the 1000 Genomes Project Phase 1 (version 3 release date September 2013). Analyses were conducted for 9 327 222 SNPs integrating data from the two sources. A novel variant on chromosome 4p15.31 near the LCORL gene and an imputed rare variant intergenic between CDKN2A and IFNA8 on chromosome 9p21.3 were identified at a genome-wide level of significance for squamous cell carcinomas. Additionally, associations of CHRNA3 and CHRNA5 on chromosome 15q25.1 in sporadic lung cancer were confirmed at a genome-wide level of significance in familial lung cancer. Previously identified variants in or near CHRNA2, BRCA2, CYP2A6 for overall lung cancer, TERT, SECISPB2L and RTEL1 for adenocarcinoma and RAD52 and MHC for squamous carcinoma were significantly associated with lung cancer.


Genomes of Candidatus Wolbachia bourtzisii wDacA and Candidatus Wolbachia pipientis wDacB from the Cochineal Insect Dactylopius coccus (Hemiptera: Dactylopiidae).
Dactylopius species, known as cochineal insects, are the source of the carminic acid dye used worldwide. The presence of two Wolbachia strains in Dactylopius coccus from Mexico was revealed by PCR amplification of wsp and sequencing of 16S rRNA genes. A metagenome analysis recovered the genome sequences of Candidatus Wolbachia bourtzisii wDacA (supergroup A) and Candidatus Wolbachia pipientis wDacB (supergroup B). Genome read coverage, as well as 16S rRNA clone sequencing, revealed that wDacB was more abundant than wDacA. The strains shared similar predicted metabolic capabilities that are common to Wolbachia, including riboflavin, ubiquinone, and heme biosynthesis, but lacked other vitamin and cofactor biosynthesis as well as glycolysis, the oxidative pentose phosphate pathway, and sugar uptake systems. A complete tricarboxylic acid cycle and gluconeogenesis were predicted as well as limited amino acid biosynthesis. Uptake and catabolism of proline were evidenced in Dactylopius Wolbachia strains. Both strains possessed WO-like phage regions and type I and type IV secretion systems. Several efflux systems found suggested the existence of metal toxicity within their host. Besides already described putative virulence factors like ankyrin domain proteins, VlrC homologs, and patatin-like proteins, putative novel virulence factors related to those found in intracellular pathogens like Legionella and Mycobacterium are highlighted for the first time in Wolbachia Candidate genes identified in other Wolbachia that are likely involved in cytoplasmic incompatibility were found in wDacB but not in wDacA.


Hierarchical mechanics of connective tissues: integrating insights from nano to macroscopic studies.
As the key component of the musculoskeletal system, the extracellular matrix of soft connective tissues such as ligaments and tendons is a biological example of fibre-reinforced composite but with a complex hierarchical architecture. To establish a comprehensive structure-function relationship at the respective levels (i.e., from molecule to tissue) of the hierarchical architecture is challenging and requires a multidisciplinary approach, involving the integration of findings from the fields of molecular biology, biochemistry, structural biology, materials science and biophysics. Accordingly, in recent years, some of these fields, namely structural biology, materials science and biophysics, have made significant progress in the microscale and nanoscale studies of extracellular matrix using new tools, such as microelectromechanical systems, optical tweezers and atomic force microscopy, complemented by new techniques in simultaneous imaging and mechanical testing and computer modelling. The intent of this paper is to review the key findings on the mechanical response of extracellular matrix at the respective levels of the hierarchical architecture. The main focus is on the structure and function--the findings are compared across the different levels to provide insights that support the goal of establishing a comprehensive structure-function relationship of extracellular matrix. For this purpose, the review is divided into two parts. The first part explores the features of key structural units of extracellular matrix, namely tropocollagen molecule (the lowest level), microfibril, collagen fibril, collagen fibre and fascicle. The second part examines the mechanics of the structural units at the respective levels. Finally a framework for extracellular matrix mechanics is proposed to support the goal to establish a comprehensive structure-function relationship. The framework describes the integration of the mechanisms of reinforcement by the structural units at the respective levels of the hierarchical architecture in a consistent manner, both to allow comparison of these mechanisms, and to make prediction of the interconnection of these mechanisms that can also assist in the identification of effective mechanical pathways. From a design perspective, this is a step in the direction towards the development of effective strategies for engineering materials to replace or repair damaged tissues, and for exogenous cross-linking therapy to enhance the mechanical properties of injured tissues.


Keeping an eye on retinoblastoma control of human embryonic stem cells.
Human embryonic stem cells (hESCs) hold great promise in regenerative medicine. However, before the full potential of these cells is achieved, major basic biological questions need to be addressed. In particular, there are still gaps in our knowledge of the molecular mechanisms underlying the derivation of hESCs from blastocysts, the regulation of the undifferentiated, pluripotent state, and the control of differentiation into specific lineages. Furthermore, we still do not fully understand the tumorigenic potential of hESCs, limiting their use in regenerative medicine. The RB pathway is a key signaling module that controls cellular proliferation, cell survival, chromatin structure, and cellular differentiation in mammalian cells. Members of the RB pathway are important regulators of hESC biology and manipulation of the activity of this pathway may provide novel means to control the fate of hESCs. Here we review what is known about the expression and function of members of the RB pathway in hESCs and discuss areas of interest in this field.


The timing of conscious experience: a critical review and reinterpretation of Libet's research.
An extended examination of Libet's works led to a comprehensive reinterpretation of his results. According to this reinterpretation, the Minimum Train Duration of electrical brain stimulation should be considered as the time needed to create a brain stimulus efficient for producing conscious sensation and not as a basis for inferring the latency for conscious sensation of peripheral origin. Latency for conscious sensation with brain stimulation may occur after the Minimum Train Duration. Backward masking with cortical stimuli suggests a 125-300 ms minimum value for the latency for conscious sensation of threshold skin stimuli. Backward enhancement is not suitable for inferring this latency. For determining temporal relations between stimuli that correspond to subjects' reports, the end of cerebral Minimum Train Duration should be used as reference, rather than its onset. Results of coupling peripheral and cortical stimuli are explained by a latency after the cortical Minimum Train Duration, having roughly the same duration as the latency for supraliminal skin stimuli. Results of coupling peripheral stimuli and stimuli to medial lemniscus (LM) are explained by a shorter LM latency and/or a longer peripheral latency. This interpretation suggests a 230 ms minimum value for the latency for conscious sensation of somatosensory near-threshold stimuli. The backward referral hypothesis, as formulated by Libet, should not be retained. Long readiness potentials preceding spontaneous conscious or nonconscious movements suggest that both kinds of movement are nonconsciously initiated. The validity of Libet's measures of W and M moments (Libet et al., 1983a) is questionable due to problems involving latencies, training, and introspective distinction of W and M. Veto of intended actions may be initially nonconscious but dependent on conscious awareness.


Molecular variation of Potato yellow vein virus isolates.
To evaluate the variation of Potato yellow vein virus from potato fields, 12 isolates were collected from Colombia and one was collected from Peru. Double-stranded RNA was extracted from the plants and used as a template for RT-PCR amplification of the coat protein ( CP) gene and, in separate reactions the C-terminal region of the heat shock protein 70 homologue ( Hsp70h) gene and the N-terminal region of the p60 open reading frame. The CP amplicons were subjected to single-strand conformation polymorphism (SSCP) analysis and, together with the other amplicon, nucleotide sequence analysis. These analyses suggested that there is low genetic diversity in the PYVV isolates examined and that the Peruvian isolate of PYVV may have originated in Colombia.


Hypnosis Treatment of Gastrointestinal Disorders: A Comprehensive Review of the Empirical Evidence.
Hypnotherapy has been investigated for 30 years as a treatment for gastrointestinal (GI) disorders. There are presently 35 studies in the published empirical literature, including 17 randomized controlled trials (RCTs) that have assessed clinical outcomes of such treatment. This body of research is reviewed comprehensively in this article. Twenty-four of the studies have tested hypnotherapy for adult irritable bowel syndrome (IBS) and 5 have focused on IBS or abdominal pain in children. All IBS hypnotherapy studies have reported significant improvement in gastrointestinal symptoms, and 7 out of 10 RCTs in adults and all 3 RCTs in pediatric patient samples found superior outcomes for hypnosis compared to control groups. Collectively this body of research shows unequivocally that for both adults and children with IBS, hypnosis treatment is highly efficacious in reducing bowel symptoms and can offer lasting and substantial symptom relief for a large proportion of patients who do not respond adequately to usual medical treatment approaches. For other GI disorders the evidence is more limited, but preliminary indications of therapeutic potential can be seen in the single randomized controlled trials published to date on hypnotherapy for functional dyspepsia, functional chest pain, and ulcerative colitis. Further controlled hypnotherapy trials in those three disorders should be a high priority. The mechanisms underlying the impact of hypnosis on GI problems are still unclear, but findings from a number of studies suggest that they involve both modulation of gut functioning and changes in the brain's handling of sensory signals from the GI tract.


Assessing the impact of the green revolution, 1960 to 2000.
We summarize the findings of a recently completed study of the productivity impacts of international crop genetic improvement research in developing countries. Over the period 1960 to 2000, international agricultural research centers, in collaboration with national research programs, contributed to the development of "modern varieties" for many crops. These varieties have contributed to large increases in crop production. Productivity gains, however, have been uneven across crops and regions. Consumers generally benefited from declines in food prices. Farmers benefited only where cost reductions exceeded price reductions.


Anticancer drug-induced kidney disorders.
Nephrotoxicity is an inherent adverse effect of certain anticancer drugs. Renal dysfunction can be categorised as prerenal uraemia, intrinsic damage or postrenal uraemia according to the underlying pathophysiological process. Renal hypoperfusion promulgates prerenal uraemia. Intrinsic renal damage results from prolonged hypoperfusion, exposure to exogenous or endogenous nephrotoxins, renotubular precipitation of xenobiotics or endogenous compounds, renovascular obstruction, glomerular disease, renal microvascular damage or disease, and tubulointerstitial damage or disease. Postrenal uraemia is a consequence of clinically significant urinary tract obstruction. Clinical signs of nephrotoxicity and methods used to assess renal function are discussed. Mechanisms of chemotherapy-induced renal dysfunction generally include damage to vasculature or structures of the kidneys, haemolytic uraemic syndrome and prerenal perfusion deficits. Patients with cancer are frequently at risk of renal impairment secondary to disease-related and iatrogenic causes. This article reviews the incidence, presentation, prevention and management of anticancer drug-induced renal dysfunction. Dose-related nephrotoxicity subsequent to administration of certain chloroethylnitrosourea compounds (carmustine, semustine and streptozocin) is commonly heralded by increased serum creatinine levels, uraemia and proteinuria. Additional signs of streptozocin-induced nephrotoxicity include hypophosphataemia, hypokalaemia, hypouricaemia, renal tubular acidosis, glucosuria, aceturia and aminoaciduria. Cisplatin and carboplatin cause dose-related renal dysfunction. In addition to increased serum creatinine levels and uraemia, electrolyte abnormalities, such as hypomagnesaemia and hypokalaemia, are commonly reported adverse effects. Rarely, cisplatin has been implicated as the underlying cause of haemolytic uraemic syndrome. Pharmaceutical antidotes to cisplatin-induced nephrotoxicity include amifostine, sodium thiosulfate and diethyldithiocarbamate. Dose- and age-related proximal tubular damage is an adverse effect of ifosfamide. In addition to renal wasting of electrolytes, glucose and amino acids, Fanconi syndrome, rickets and osteomalacia have occurred with ifosfamide treatment. High dose azacitidine causes renal dysfunction manifested by tubular acidosis, polyuria and increased urinary excretion of electrolytes, glucose and amino acids. Haemolytic uraemia is a rare adverse effect of gemcitabine. Methotrexate can cause increased serum creatinine levels, uraemia and haematuria. Acute renal failure is reported following administration of high dose methotrexate. Urinary alkalisation and hydration confer protection against methotrexate-induced renal dysfunction. Dose-related nephrotoxicity, including acute renal failure, are reported subsequent to treatment with pentostatin and diaziquone. Acute renal failure is a rare adverse effect of treatment with interferon-alpha. Haemolytic uraemic syndrome occurs with mitomycin administration. A mortality rate of 50 to 100% is reported in patients developing mitomycin-induced haemolytic uraemic syndrome. Capillary leak syndrome occurring with aldesleukin therapy can cause renal dysfunction. Infusion-related hypotension during infusion of high dose carmustine can precipitate renal dysfunction.


Analysis of a risk-based model for the growth of AIDS infection.
Several models for the spread of AIDS within a homosexual community have been proposed that incorporate biased mixing of different risk groups. A simple model is presented that captures many of the features of these more complex models. Analytical expressions are derived for the time to the state of maximum infection (SMI) in a particular risk group, the proportion infected at SMI, and the number of infected individuals as the group approaches SMI. These results agree qualitatively with numerical simulations of the model.


Predicting response and survival in chemotherapy-treated triple-negative breast cancer.
In this study, we evaluated the ability of gene expression profiles to predict chemotherapy response and survival in triple-negative breast cancer (TNBC). Gene expression and clinical-pathological data were evaluated in five independent cohorts, including three randomised clinical trials for a total of 1055 patients with TNBC, basal-like disease (BLBC) or both. Previously defined intrinsic molecular subtype and a proliferation signature were determined and tested. Each signature was tested using multivariable logistic regression models (for pCR (pathological complete response)) and Cox models (for survival). Within TNBC, interactions between each signature and the basal-like subtype (vs other subtypes) for predicting either pCR or survival were investigated. Within TNBC, all intrinsic subtypes were identified but BLBC predominated (55-81%). Significant associations between genomic signatures and response and survival after chemotherapy were only identified within BLBC and not within TNBC as a whole. In particular, high expression of a previously identified proliferation signature, or low expression of the luminal A signature, was found independently associated with pCR and improved survival following chemotherapy across different cohorts. Significant interaction tests were only obtained between each signature and the BLBC subtype for prediction of chemotherapy response or survival. The proliferation signature predicts response and improved survival after chemotherapy, but only within BLBC. This highlights the clinical implications of TNBC heterogeneity, and suggests that future clinical trials focused on this phenotypic subtype should consider stratifying patients as having BLBC or not.


Intraocular scattering compensation in retinal imaging.
Intraocular scattering affects fundus imaging in a similar way that affects vision; it causes a decrease in contrast which depends on both the intrinsic scattering of the eye but also on the dynamic range of the image. Consequently, in cases where the absolute intensity in the fundus image is important, scattering can lead to a wrong estimation. In this paper, a setup capable of acquiring fundus images and estimating objectively intraocular scattering was built, and the acquired images were then used for scattering compensation in fundus imaging. The method consists of two parts: first, reconstruct the individual's wide-angle Point Spread Function (PSF) at a specific wavelength to be used within an enhancement algorithm on an acquired fundus image to compensate for scattering. As a proof of concept, a single pass measurement with a scatter filter was carried out first and the complete algorithm of the PSF reconstruction and the scattering compensation was applied. The advantage of the single pass test is that one can compare the reconstructed image with the original one and see the validity, thus testing the efficiency of the method. Following the test, the algorithm was applied in actual fundus images in human eyes and the effect on the contrast of the image before and after the compensation was compared. The comparison showed that depending on the wavelength, contrast can be reduced by 8.6% under certain conditions.


Domestication and early agriculture in the Mediterranean Basin: Origins, diffusion, and impact.
The past decade has witnessed a quantum leap in our understanding of the origins, diffusion, and impact of early agriculture in the Mediterranean Basin. In large measure these advances are attributable to new methods for documenting domestication in plants and animals. The initial steps toward plant and animal domestication in the Eastern Mediterranean can now be pushed back to the 12th millennium cal B.P. Evidence for herd management and crop cultivation appears at least 1,000 years earlier than the morphological changes traditionally used to document domestication. Different species seem to have been domesticated in different parts of the Fertile Crescent, with genetic analyses detecting multiple domestic lineages for each species. Recent evidence suggests that the expansion of domesticates and agricultural economies across the Mediterranean was accomplished by several waves of seafaring colonists who established coastal farming enclaves around the Mediterranean Basin. This process also involved the adoption of domesticates and domestic technologies by indigenous populations and the local domestication of some endemic species. Human environmental impacts are seen in the complete replacement of endemic island faunas by imported mainland fauna and in today's anthropogenic, but threatened, Mediterranean landscapes where sustainable agricultural practices have helped maintain high biodiversity since the Neolithic.


Levels and patterns of nucleotide variation in domestication QTL regions on rice chromosome 3 suggest lineage-specific selection.
Oryza sativa or Asian cultivated rice is one of the major cereal grass species domesticated for human food use during the Neolithic. Domestication of this species from the wild grass Oryza rufipogon was accompanied by changes in several traits, including seed shattering, percent seed set, tillering, grain weight, and flowering time. Quantitative trait locus (QTL) mapping has identified three genomic regions in chromosome 3 that appear to be associated with these traits. We would like to study whether these regions show signatures of selection and whether the same genetic basis underlies the domestication of different rice varieties. Fragments of 88 genes spanning these three genomic regions were sequenced from multiple accessions of two major varietal groups in O. sativa--indica and tropical japonica--as well as the ancestral wild rice species O. rufipogon. In tropical japonica, the levels of nucleotide variation in these three QTL regions are significantly lower compared to genome-wide levels, and coalescent simulations based on a complex demographic model of rice domestication indicate that these patterns are consistent with selection. In contrast, there is no significant reduction in nucleotide diversity in the homologous regions in indica rice. These results suggest that there are differences in the genetic and selective basis for domestication between these two Asian rice varietal groups.


The Superiorly Based Partial Rectus Abdominis and External Oblique Flap: A New Technique for Breast Asymmetry Reconstruction.
Breast asymmetry has a wide spectrum of presentations with several employable strategies for surgical correction. Historically, the external oblique muscle has proven to be a versatile flap option for the reconstruction of both local and distant defects. It has also been described for use in breast reconstruction for coverage of the lower pole of implant prostheses. The external oblique muscle flap can be harvested in several ways to capture overlying fat and skin. In this study, we describe the use of a superiorly based partial rectus and external oblique flap for surgical correction of lower pole breast hypoplasia. This flap provides vascularized autologous volume to the lower pole of the breast with minimal donor morbidity. Other advantages of this flap are that it can increase the nipple to inframammary fold distance and lower the inframammary fold. This technique represents an evolution of an under-utilized flap and is the first study describing the use of the external oblique flap in the management of breast asymmetry.


Plant roots release phospholipid surfactants that modify the physical and chemical properties of soil.
• Plant root mucilages contain powerful surfactants that will alter the interaction of soil solids with water and ions, and the rates of microbial processes. • The lipid composition of maize, lupin and wheat root mucilages was analysed by thin layer chromatography and gas chromatography-mass spectrometry. A commercially available phosphatidylcholine (lecithin), chemically similar to the phospholipid surfactants identified in the mucilages, was then used to evaluate its effects on selected soil properties. • The lipids found in the mucilages were principally phosphatidylcholines, composed mainly of saturated fatty acids, in contrast to the lipids extracted from root tissues. In soil at low tension, lecithin reduced the water content at any particular tension by as much as 10 and 50% in soil and acid-washed sand, respectively. Lecithin decreased the amount of phosphate adsorption in soil and increased the phosphate concentration in solution by 10%. The surfactant also reduced net rates of ammonium consumption and nitrate production in soil. • These experiments provide the first evidence we are aware of that plant-released surfactants will significantly modify the biophysical environment of the rhizosphere.


Risk factors for postsurgical trichiasis recurrence in a trachoma-endemic area.
The World Health Organization recommends trichiasis surgery to prevent blindness caused by trachoma; however, recurrence is common. Risk factors for recurrence have not been widely studied, particularly in trachoma hyperendemic areas. Three hundred ninety-four persons with trichiasis in Tanzania were examined. Participants had undergone surgery >18 months before the study. Trichiasis recurrence and active trachoma at study visit were assessed. Ocular swabs were collected and tested for Chlamydia trachomatis. Household members were examined for active trachoma. Of the surgical eyes, 28% had recurrence; 40% of patients had recurrence in one or both eyes. Rates did not vary by time since surgery. Eye-level recurrence rates varied significantly across districts, ranging from 16% to 38%. Current chlamydial infection among surgical cases was low (6%) and was not associated with recurrence. Recurrence was associated with tarsal conjunctival inflammation (OR: 2.4; 95% confidence interval [CI]: 1.6-3.8) and residence in the Kongwa district (OR: 2.3; 95% CI: 1.2-4.6). Recurrence after trichiasis surgery is high, suggesting that vigilant follow-up in surgical cases is needed to reduce blindness. Recurrence is associated with evidence of inflammation in the tarsal conjunctiva, although it is not clear whether the inflammation contributes to recurrence, or is a result of the recurrence. Longitudinal studies of trichiasis patients after surgery are needed.


Effect of birthplace on infants with low birth weight.
From December 1983 to June 1985, 162 infants of less than 32 weeks' gestation or weighing less than 1,500 g, or both, were cared for at the regional neonatal intensive care unit in Leeds. Of the 162, 64 (40%) were born in the unit because their mothers had received antenatal care there, 58 (36%) were born in another hospital and subsequently transferred, and 40 (25%) were transferred in utero because of potential complications. The overall mortalities for each group were 14%, 38%, and 18% respectively. These differences were significant, but when they were corrected for gestation, birth weight, and mode of delivery there was no difference in either the mortality or the incidence of intraventricular haemorrhage in the three study populations. Although there seem to be no distinct advantages of in utero transfer in terms of mortality and morbidity, there are other psychological and emotional advantages.


Noncanonical E2 recruitment by the autophagy E1 revealed by Atg7-Atg3 and Atg7-Atg10 structures.
Core functions of autophagy are mediated by ubiquitin-like protein (UBL) cascades, in which a homodimeric E1 enzyme, Atg7, directs the UBLs Atg8 and Atg12 to their respective E2 enzymes, Atg3 and Atg10. Crystallographic and mutational analyses of yeast (Atg7-Atg3)(2) and (Atg7-Atg10)(2) complexes reveal noncanonical, multisite E1-E2 recognition in autophagy. Atg7's unique N-terminal domain recruits distinctive elements from the Atg3 and Atg10 'backsides'. This, along with E1 and E2 conformational variability, allows presentation of 'frontside' Atg3 and Atg10 active sites to the catalytic cysteine in the C-terminal domain from the opposite Atg7 protomer in the homodimer. Despite different modes of binding, the data suggest that common principles underlie conjugation in both noncanonical and canonical UBL cascades, whereby flexibly tethered E1 domains recruit E2s through surfaces remote from their active sites to juxtapose the E1 and E2 catalytic cysteines.


Anti-CD28 monoclonal antibody-stimulated cytokines released from blood suppress CYP1A2, CYP2B6, and CYP3A4 in human hepatocytes in vitro.
Like most infections and certain inflammatory diseases, some therapeutic proteins cause a cytokine-mediated suppression of hepatic drug-metabolizing enzymes, which may lead to pharmacokinetic interactions with small-molecule drugs. We propose a new in vitro method to evaluate the whole blood-mediated effects of therapeutic proteins on drug-metabolizing enzymes in human hepatocytes cocultured with Kupffer cells. The traditional method involves treating hepatocyte cocultures with the therapeutic protein, which detects hepatocyte- and macrophage-mediated suppression of cytochrome P450 (P450). The new method involves treating whole human blood with a therapeutic protein to stimulate the release of cytokines from peripheral blood mononuclear cells (PBMCs), after which plasma is prepared and added to the hepatocyte coculture to evaluate P450 enzyme expression. In this study, human blood was treated for 24 hours at 37°C with bacterial lipopolysaccharide (LPS) or ANC28.1, an antibody against human T-cell receptor CD28. Cytokines were measured in plasma by sandwich immunoassay with electrochemiluminescense detection. Treatment of human hepatocyte cocultures with LPS or with plasma from LPS-treated blood markedly reduced the expression of CYP1A2, CYP2B6, and CYP3A4. However, treatment of hepatocyte cocultures with ANC28.1 did not suppress P450 expression, but treatment with plasma from ANC28.1-treated blood suppressed CYP1A2, CYP2B6, and CYP3A4 activity and mRNA levels. The results demonstrated that applying plasma from human blood treated with a therapeutic protein to hepatocytes cocultured with Kupffer cells is a suitable method to identify those therapeutic proteins that suppress P450 expression by an indirect mechanism-namely, the release of cytokines from PBMCs.


Autocrine growth of transitional cell carcinoma of the bladder induced by granulocyte-colony stimulating factor.
Granulocyte-colony stimulating factor (G-CSF) produced by nonhematopoietic malignant cells has been reported to be capable of inducing a leukemoid reaction in the host through intense stimulation of leukocyte production. Furthermore, this is frequently associated with aggressive tumor cell growth and a detrimental clinical outcome. In this study, we identified bladder cancer cells producing G-CSF with the expression of the functional receptor, which provides direct evidence of autocrine growth of bladder cancer cells induced by G-CSF. The cancer cells used in this study were obtained from a 76-year-old man who had a metastatic transitional cell carcinoma of the bladder and who demonstrated marked leukocytosis, his peripheral blood leukocyte count was 94,900 leukocytes/mm3, and his serum G-CSF level was 103 pg/ml. The culture medium in which the cancer cells were grown exclusively contained a significant amount of G-CSF (5560 pg/ml). Significant G-CSF mRNA expression and G-CSF receptor mRNA expression in the cultured cells were demonstrated by the reverse transcription-PCR method. In addition, binding studies with the use of radiolabeled recombinant G-CSF demonstrated the presence of high-affinity G-CSF binding receptors on the cultured cancer cells. Finally, the proliferation of the cultured cancer cells was stimulated by exogenous G-CSF administration, and this stimulation was inhibited by adding anti-G-CSF antibody, as demonstrated by both the flow cytometric bromodeoxyuridine incorporation technique and the [3H]thymidine incorporation assay. These results strongly suggest that G-CSF production by the bladder cancer cells studied augments autocrine growth. Therefore, we recommend exercising caution in the clinical use of G-CSF for bladder cancer patients.


Exploring infection of wheat and carbohydrate metabolism in Mycosphaerella graminicola transformants with differentially regulated green fluorescent protein expression.
A Mycosphaerella graminicola strain transformed with the green fluorescent protein (GFP) downstream of either a carbon source-repressed promoter or a constitutive promoter was used to investigate in situ carbohydrate uptake during penetration of the fungus in wheat leaves. The promoter region of the acu-3 gene from Neurospora crassa encoding isocitrate lyase was used as a carbon source-repressed promoter. The promoter region of the Aspergillus nidulans gpdA gene encoding glyceraldehyde-3-phosphate dehydrogenase was used as a constitutive promoter. Fluorometric measurement of GFP gene expression in liquid cultures of acu-3-regulated transformants indicated that the N. crassa acu-3 promoter functions in M. graminicola as it does in N. crassa, i.e., acetate induced and carbon source repressed. Glucose, fructose, and saccharose triggered the repression, whereas mannitol, xylose, and cell wall polysaccharides did not. Monitoring the GFP level during fungal infection of wheat leaves revealed that acu-3 promoter repression occurred after penetration until sporulation, when newly differentiated pycnidiospores fluoresced. The use of GFP transformants also allowed clear visualization of M. graminicola pathogenesis. No appressoria were formed, but penetration at cell junctions was observed. These results give new insight into the biotrophic status of M. graminicola.


An entanglement filter.
The ability to filter quantum states is a key capability in quantum information science and technology, in which one-qubit filters, or polarizers, have found wide application. Filtering on the basis of entanglement requires extension to multi-qubit filters with qubit-qubit interactions. We demonstrated an optical entanglement filter that passes a pair of photons if they have the desired correlations of their polarization. Such devices have many important applications to quantum technologies.


An Integrated Approach to Unravel Hidradenitis Suppurativa Etiopathogenesis.
Hidradenitis suppurativa/acne inversa (HS) is a chronic inflammatory disease involving hair follicles that presents with painful nodules, abscesses, fistulae, and hypertrophic scars, typically occurring in apocrine gland bearing skin. Establishing a diagnosis of HS may take up to 7 years after disease onset. HS severely impairs the quality of life of patients and its high frequency causes significant costs for health care system. HS patients have an increased risk of developing associated diseases, such as inflammatory bowel diseases and spondyloarthropathies, thereby suggesting a common pathophysiological mechanism. Familial cases, which are around 35% of HS patients, have allowed the identification of susceptibility genes. HS is perceived as a complex disease where environmental factors trigger chronic inflammation in the skin of genetically predisposed individuals. Despite the efforts made to understand HS etiopathogenesis, the exact mechanisms at the basis of the disease need to be still unraveled. In this review, we considered all OMICs studies performed on HS and observed that OMICs contribution in the context of HS appeared as not clear enough and/or rich of useful clinical information. Indeed, most studies focused only on one aspect-genome, transcriptome, or proteome-of the disease, enrolling small numbers of patients. This is quite limiting for the genetic studies, from different geographical areas and looking at a few aspects of HS pathogenesis without any integration of the findings obtained or a comparison among different studies. A strong need for an integrated approach using OMICs tools is required to discover novel actors involved in HS etiopathogenesis. Moreover, we suggest the constitution of consortia to enroll a higher number of patients to be analyzed following common and consensus OMICs strategies. Comparison and integration with the findings present in the OMICs repositories are mandatory. In a theoretic pipeline, the Skin-OMICs profile obtained from each HS patient should be compared and integrated with repositories and literature data by using appropriate InterOMICs approach. The final goal is not only to improve the knowledge of HS etiopathogenesis but also to provide novel tools to the clinicians with the eventual aim of offering a tailored treatment for HS patients.


Murine adenovirus infection of SCID mice induces hepatic lesions that resemble human Reye syndrome.
Murine adenovirus type 1 (MAV-1) infection of CB-17 SCID mice (which are homozygous for the severe combined immunodeficiency mutation) induces hepatic histopathologic and ultrastructural features that are strikingly similar to human Reye syndrome. Gross pathologic examination of MAV-1-infected mice revealed only pale yellow liver tissue. Histopathologic studies of tissue from MAV-1-infected mice revealed diffuse hepatic injury manifested by microvesicular fatty degenerative changes of hepatocytes and electron microscopic evidence of focal mitochondrial swelling with disruption of cristae and depletion of glycogen. Serum aminotransferase activities increased markedly in the infected animals; however, plasma ammonia levels were not elevated at the times assayed. Although all mice infected with MAV-1 died, neutralizing anti-MAV-1 monoclonal antibodies provided a dose-dependent delay in the appearance of clinical disease and hepatic histopathologic findings. Other findings included rare viral inclusions with only minimal inflammation in spleen, adrenal, and liver of infected mice. Our findings indicate that MAV-1 infection of SCID mice may provide important insights into the pathogenesis of the hepatic lesions of Reye syndrome.


Identification and characterization of a novel cytoskeleton-associated pp60src substrate.
Transformation of cells by the src oncogene results in elevated tyrosine phosphorylation of two related proteins, p80 and p85 (p80/85). Immunostaining with specific monoclonal antibodies revealed a striking change of subcellular localization of p80/85 in src-transformed cells. p80/85 colocalizes with F-actin in peripheral extensions of normal cells and rosettes (podosomes) of src-transformed cells. Sequence analysis of cDNA clones encoding p80/85 revealed an amino-terminal domain composed of six copies of a direct tandem repeat, each repeat containing 37 amino acids, a carboxyl-terminal SH3 domain, and an interdomain region composed of a highly charged acidic region and a region rich in proline, serine, and threonine. The multidomain structure of p80/85 and its colocalization with F-actin in normal and src-transformed cells suggest that these proteins may associate with components of the cytoskeleton and contribute to organization of cell structure.


MaxQuant Software for Ion Mobility Enhanced Shotgun Proteomics.
Ion mobility can add a dimension to LC-MS based shotgun proteomics which has the potential to boost proteome coverage, quantification accuracy and dynamic range. Required for this is suitable software that extracts the information contained in the four-dimensional (4D) data space spanned by m/z, retention time, ion mobility and signal intensity. Here we describe the ion mobility enhanced MaxQuant software, which utilizes the added data dimension. It offers an end to end computational workflow for the identification and quantification of peptides and proteins in LC-IMS-MS/MS shotgun proteomics data. We apply it to trapped ion mobility spectrometry (TIMS) coupled to a quadrupole time-of-flight (QTOF) analyzer. A highly parallelizable 4D feature detection algorithm extracts peaks which are assembled to isotope patterns. Masses are recalibrated with a non-linear m/z, retention time, ion mobility and signal intensity dependent model, based on peptides from the sample. A new matching between runs (MBR) algorithm that utilizes collisional cross section (CCS) values of MS1 features in the matching process significantly gains specificity from the extra dimension. Prerequisite for using CCS values in MBR is a relative alignment of the ion mobility values between the runs. The missing value problem in protein quantification over many samples is greatly reduced by CCS aware MBR.MS1 level label-free quantification is also implemented which proves to be highly precise and accurate on a benchmark dataset with known ground truth. MaxQuant for LC-IMS-MS/MS is part of the basic MaxQuant release and can be downloaded from http://maxquant.org.


Private health insurance and catastrophic health expenditures of households with cancer patients in South Korea.
This study examines the effects of private health insurance (PHI) on the incidence of catastrophic health expenditures (CHE) for households with a patient with cancer. This study uses 1-year data from 2013 and households with cancer patients as the unit of research rather than individual household members. The sample thus includes 468 households with members with cancer who also used emergency, outpatient and hospitalisation services. Households with PHI had a lower incidence of CHE for all thresholds than those without did. At the 10% threshold, the incidence became significantly lower, by 0.59 and 0.60 times, respectively, if householders had higher education and income levels. Moreover, the incidence of CHE was higher by 8.71 times if the householders are female, and lower by 0.84 times if the householders did not have a spouse at the 20% threshold. From the analysis of households with cancer patients that hold PHI as the key variable, these households showed a lower incidence of CHE than the others did. PHI provides healthcare payments not secured through national health insurance (NHI) and protects households from health expenditures, thereby complementing NHI to a certain degree.


Amisulpride and olanzapine followed by open-label treatment with clozapine in first-episode schizophrenia and schizophreniform disorder (OPTiMiSE): a three-phase switching study.
No established treatment algorithm exists for patients with schizophrenia. Whether switching antipsychotics or early use of clozapine improves outcome in (first-episode) schizophrenia is unknown. This three-phase study was done in 27 centres, consisting of general hospitals and psychiatric specialty clinics, in 14 European countries and Israel. Patients aged 18-40 years who met criteria of the DSM-IV for schizophrenia, schizophreniform disorder, or schizoaffective disorder were treated for 4 weeks with up to 800 mg/day amisulpride orally in an open-label design (phase 1). Patients who did not meet symptomatic remission criteria at 4 weeks were randomly assigned to continue amisulpride or switch to olanzapine (≤20 mg/day) during a 6-week double-blind phase, with patients and staff masked to treatment allocation (phase 2). Randomisation was done online by a randomisation website; the application implemented stratification by site and sex, and applied the minimisation method for randomisation. Patients who were not in remission at 10 weeks were given clozapine (≤900 mg/day) for an additional 12 weeks in an open-label design (phase 3). The primary outcome was the number of patients who achieved symptomatic remission at the final visits of phases 1, 2, and 3, measured by intention-to-treat analysis. Data were analysed with a generalised linear mixed model, with a logistic link and binomial error distribution. This trial is registered with ClinicalTrials.gov, number NCT01248195, and closed to accrual. Between May 26, 2011, and May 15, 2016, we recruited 481 participants who signed informed consent. Of the 446 patients in the intention-to-treat sample, 371 (83%) completed open-label amisulpride treatment, and 250 (56%) achieved remission after phase 1. 93 patients who were not in remission continued to the 6-week double-blind switching trial, with 72 (77%) patients completing the trial (39 on olanzapine and 33 on amisulpride); 15 (45%) patients on amisulpride versus 17 (44%) on olanzapine achieved remission (p=0·87). Of the 40 patients who were not in remission after 10 weeks of treatment, 28 (70%) started on clozapine; 18 (64%) patients completed the 12-week treatment, and five (28%) achieved remission. The number of serious adverse events did not differ between the treatment arms in phase 2: one patient on olanzapine was admitted to hospital because of an epileptic seizure, and one patient on amisulpride was admitted to hospital twice because of exacerbations of psychotic symptoms. Over the course of the trial, two serious suicide attempts were reported. For most patients in the early stages of schizophrenia, symptomatic remission can be achieved using a simple treatment algorithm comprising the sequential administration of amisulpride and clozapine. Since switching to olanzapine did not improve outcome, clozapine should be used after patients fail a single antipsychotic trial-not until two antipsychotics have been tried, as is the current recommendation. European Commission Seventh Framework Program.


Differential dendritic remodeling in prelimbic cortex of male and female rats during recovery from chronic stress.
Chronic stress produces differential dendritic remodeling of pyramidal neurons in medial prefrontal cortex of male and female rats. In males, this dendritic remodeling is reversible. However, the timeline of recovery, as well as the potential for reversibility in females, is unknown. Here, we examined dendritic recovery of pyramidal neurons in layer II-II of prelimbic cortex in male and female rats following chronic restraint stress (3h/day for 10days). Dendritic morphology and spine density were analyzed immediately following the cessation of stress, or following a 7- or 10-day recovery period. Chronic stress produced apical dendritic retraction in males, which was coupled with a decrease in the density of stubby spine on apical dendrites. Further, following a 10-day recovery period, the morphology of neurons from stressed rats resembled that of unstressed rats. Male rats given a 7-day recovery period had apical dendritic outgrowth compared to unstressed rats. Immediately after cessation of stress, females showed only minimal dendritic remodeling. The morphology of neurons in stressed females resembled those of unstressed rats following only 7days of recovery, at which time there was also a significant increase in stubby spine density. Males and females also showed different changes in baseline corticosterone concentrations during recovery. These findings not only indicate that dendritic remodeling in prelimbic cortex following chronic stress is different between males and females, but also suggest chronic stress induces differential hypothalamic-pituitary-adrenal axis dysregulation in males and females. These differences may have important implications for responses to subsequent stressors.


Architectural specialization of the intrinsic thoracic limb musculature of the American badger (Taxidea taxus).
Evaluation of the relationships between muscle structure and digging function in fossorial species is limited. Badgers and other fossorial specialists are expected to have massive forelimb muscles with long fascicles capable of substantial shortening for high power and applying high out-force to the substrate. To explore this hypothesis, we quantified muscle architecture in the thoracic limb of the American badger (Taxidea taxus) and estimated the force, power, and joint torque of its intrinsic musculature in relation to the use of scratch-digging behavior. Architectural properties measured were muscle mass, belly length, fascicle length, pennation angle, and physiological cross-sectional area. Badgers possess hypertrophied shoulder flexors/humeral retractors, elbow extensors, and digital flexors. The triceps brachii is particularly massive and has long fascicles with little pennation, muscle architecture consistent with substantial shortening capability, and high power. A unique feature of badgers is that, in addition to elbow joint extension, two biarticular heads (long and medial) of the triceps are capable of applying high torques to the shoulder joint to facilitate retraction of the forelimb throughout the power stroke. The massive and complex digital flexors show relatively greater pennation and shorter fascicle lengths than the triceps brachii, as well as compartmentalization of muscle heads to accentuate both force production and range of shortening during flexion of the carpus and digits. Muscles of most functional groups exhibit some degree of specialization for high force production and are important for stabilizing the shoulder, elbow, and carpal joints against high limb forces generated during powerful digging motions. Overall, our findings support the hypothesis and indicate that forelimb muscle architecture is consistent with specializations for scratch-digging. Quantified muscle properties in the American badger serve as a comparator to evaluate the range of diversity in muscle structure and contractile function that exists in mammals specialized for fossorial habits.


Myogenic specification of somites is mediated by diffusible factors.
Specification of myogenesis in early chicken somites and segmental plate was studied using transfilter explant cultures to determine if myogenic specification by axial structures is mediated by cell-cell contact. Formation of muscle fibers that express myosin heavy chain was assessed in somites transfilter from neural tube and notochord. Either the neural tube or the notochord from early chick embryos (ED 2) induces myogenesis in unspecified somites (Hamburger and Hamilton (HH) stages 11-14) when these tissues are separated by a 0.2- or a 0.05-micron pore filter. The ventral neural tube is found to be a strong inducer of myogenesis, while the dorsal neural tube is found to have low inducing activity. The reduced myogenic inducing activity of the dorsal neural tube is associated with an activity that inhibits myogenic differentiation in specified somites, somites containing cells already committed to myogenesis. Only 6-8 hr of transfilter exposure to neural tube is required to initiate somite myogenesis that is sustained in the absence of neural tube. Other tissues such as specified somites, heart, or ectoderm from the same aged embryo do not induce myogenesis in unspecified somites. Removal of the prospective floor plate of the caudal neural plate at HH stage 8 or 9 does not eliminate the inducing activity of the neurectoderm on unspecified somites (HH stage 11-14). Recombination of somites with neural tube or spinal cord from progressively older embryos (ED 4-20) showed myogenesis inducing activity at all ages, though the activity waned as development proceeded. Paraxial mesoderm need not segment into somites to respond to the inducing activity of the neural tube. We conclude that induction of myogenesis in somites does not require cell-cell contact between either the neural tube or the notochord and therefore induction is mediated by diffusible factor(s); that the inducing activity is localized principally to the notochord and ventral half of the neural tube, but not necessarily to the floor plate; that the myogenic response is specific to neural tube and notochord; and that the dorsal neural tube weakly induces myogenesis and contains an activity that inhibits myogenic cells from differentiating.


Health workforce response to Covid-19: What pandemic preparedness planning and action at the federal and state levels in Germany?: Germany's health workforce responses to Covid-19.
The Covid-19 pandemic has required countries to prepare their health workforce for a rapid increase of patients. This research aims to analyse the planning and health workforce policies in Germany, a country with a largely decentralised workforce governance mechanism. Systematic search between 18 and 31 May 2020 at federal and 16 states on health workforce action and planning (websites of ministries of health, public health authorities), including pandemic preparedness plans and policies. The search followed World Health Organisation (WHO) Europe's health workforce guidance on Covid-19. Content analysis was performed, informed by the themes of WHO. The pandemic preparedness plans consisted of no or limited information on how to expand and prepare the health workforce during pandemics. The 16 states varied considerably regarding implementing strategies to expand health workforce capacities. Only one state adopted a policy on task-shifting despite a federal law on task-shifting during pandemics. Planning on the health workforce, its capacity and skill-mix during pandemics was limited in the pandemic response plans. Actions during the peak of the pandemic varied considerably across states, were implemented ad hoc and with limited planning. Future action should focus on integrated planning and evaluation of workforce policies.


Immediate-type hypersensitivity drug reactions.
Hypersensitivity reactions including anaphylaxis have been reported for nearly all classes of therapeutic reagents and these reactions can occur within minutes to hours of exposure. These reactions are unpredictable, not directly related to dose or the pharmacological action of the drug and have a relatively high mortality risk. This review will focus on the clinical presentation, immune mechanisms, diagnosis and prevention of the most serious form of immediate onset drug hypersensitivity reaction, anaphylaxis. The incidence of drug-induced anaphylaxis deaths appears to be increasing and our understanding of the multiple and complex reasons for the unpredictable nature of anaphylaxis to drugs is also expanding. This review highlights the importance of enhancing our understanding of the biology of the patient (i.e. immune response, genetics) as well as the pharmacology and chemistry of the drug when investigating, diagnosing and treating drug hypersensitivity. Misdiagnosis of drug hypersensitivity leads to substantial patient risk and cost. Although oral provocation is often considered the gold standard of diagnosis, it can pose a potential risk to the patient. There is an urgent need to improve and standardize diagnostic testing and desensitization protocols as other diagnostic tests currently available for assessment of immediate drug allergy are not highly predictive.


Similar secondary stroke prevention and medication persistence rates among rural and urban patients.
Rural residents are less likely to obtain optimal care for many serious conditions and have poorer health outcomes than those residing in more urban areas. We determined whether rural vs urban residence affected postdischarge medication persistence and 1 year outcomes after stroke. The Adherence eValuation After Ischemic Stroke-Longitudinal (AVAIL) study is a multicenter registry of stroke patients enrolled in 101 hospitals nationwide. Medications were recorded at hospital discharge and again after 3 and 12 months. Persistence was defined as continuation of prescribed discharge medications. Participants were categorized as living in rural or urban settings by cross-referencing home ZIP code with metropolitan statistical area (MSA) designation. Rural patients were younger, more likely to be white, married, smokers, and less likely to be college graduates. There was no difference in stroke type or working status compared to urban patients, and there were minor differences in comorbid conditions. There were no differences based on rural vs urban residence in medication persistence at 3 or 12 months postdischarge and no differences in outcomes of recurrent stroke or rehospitalization at 12 months. Despite differences in patient characteristics, there was no difference in medication persistence or outcomes between rural and urban dwellers after hospitalization for ischemic stroke or transient ischemic attack (TIA).


Re-assessment of the Conservation Status of the Atlantic Humpback Dolphin, Sousa teuszii (), Using the IUCN Red List Criteria.
The Atlantic humpback dolphin (Sousa teuszii) is an obligate shallow water dolphin that is endemic to the western coasts of Africa, ranging from Western Sahara to Angola. The species occurs exclusively in a limited number of near-shore habitats, a tendency that routinely exposes it to a suite of lethal and deleterious anthropogenic threats. These include habitat degradation, accidental capture in artisanal fishing nets, and hunting for use as food and bait. The species also competes with rapidly expanding human populations for coastal resources in some of the poorest countries on Earth. Data for most aspects of the species' ecology are sparse, but S. teuszii is considered by most qualified observers to be rare and greatly threatened. A lack of appropriate survey data precludes a quantitative assessment of population trends and status. Most populations for which any data are available are considered to be extremely small, numbering in the tens or low hundreds of individuals. The available published estimates suggest that the total population likely falls below 3000 individuals. Declines in abundance have been observed or are suspected for each population and will continue, given projected expansions of identified threats that affect most of the species' known range, and a corresponding lack of appropriate management actions. The apparent scale of threats, the presumed isolation of most populations, and a lack of directed conservation efforts in most areas suggest that the species qualifies for a listing of Critically Endangered (under criteria A3cd) on the IUCN Red List.


Repellency to Stomoxys calcitrans (Diptera: Muscidae) of plant essential oils alone or in combination with Calophyllum inophyllum nut oil.
The repellency to female Stomoxys calcitrans (L.) (Diptera: Muscidae) of 21 essential oils (EOs) alone or in combination with Calophyllum inophyllum L. (Clusiaceae) nut oil (tamanu oil) was examined using an exposed human hand bioassay. Results were compared with those of commonly used repellent N,N-diethyl-3-methylbenzamide (DEET). In tests with six human male volunteers at a dose of 0.5 mg/cm2, patchouli (protection time [PT], 3.67 h) was the most effective EO but less active than DEET (4.47 h), as judged by the PT to first bite. Very strong repellency also was produced by clove bud, lovage root, and clove leaf EOs (PT, 3.50-3.25 h), whereas strong repellency was obtained from thyme white EO (2.12 h). Thyme red, oregano, and geranium EOs exhibited moderate repellency (PT, 1.24-1.11 h). At 0.25 mg/cm2, protection time of clove bud, clove leaf, and lovage root EOs (PT, approximately equal to 1 h) was shorter than that of DEET (2.17 h). An increase in the protection time was produced by binary mixtures (PT, 2.68-2.04 h) of five EOs (clove bud, clove leaf, thyme white, patchouli, and savory) and tamanu oil (0.25:2.0 mg/cm2) compared with that of either the constituted essential oil or tamanu oil alone (PT, 0.56 h). The protection time of these binary mixtures was comparable with that of DEET. With the exception of savory EO, the other EOs, tamanu oil, and binary mixtures did not induce any adverse effects on the human volunteers at 0.5 mg/cm2. Thus, binary mixtures of essential oils and tamanu oil described merit further study as potential repellents for protection from humans and domestic animals from biting and nuisance caused by S. calcitrans.


Molecular determination of selectivity of the site 3 modulator (BmK I) to sodium channels in the CNS: a clue to the importance of Nav1.6 in BmK I-induced neuronal hyperexcitability.
BmK I, a site-3-specific modulator of VGSCs (voltage-gated sodium channels) from the Chinese scorpion Buthus martensi Karsch, can induce spontaneous nociception and hyperalgesia and generate epileptiform responses in rats, which is attributed to the modulation of VGSCs in the neural system. However, which VGSC subtype is targeted by BmK I remains to be identified. Using two-electrode voltage-clamp recording, we studied the efficacy and selectivity of BmK I to three neuronal VGSCs co-expressed with the auxiliary β1 subunit in Xenopus oocytes. Results revealed that BmK I induced a large increase in both transient and persistent currents in mNav1.6α/β1 (where m indicates mouse), which correlated with a prominent reduction in the fast component of inactivating current. In comparison, BmK I-increased currents of rNav1.2α/β1 (where r indicates rat) and rNav1.3α/β1 were much smaller. The EC50 values of BmK I for rNav1.2α/β1 (252±60 nM) and mNav1.6α/β1 (214±30 nM) were similar and roughly half of that for rNav1.3α/β1 (565±16 nM). Moreover, BmK I only accelerated the slow inactivation development and delay recovery of mNav1.6α/β1 through binding to the channel in the open state. Residue-swap analysis verified that an acidic residue (e.g. Asp1602 in mNav1.6) within the domain IV S3-S4 extracellular loop of VGSCs was crucial for the selectivity and modulation pattern of BmK I. Our findings thus provide the molecular determinant explaining the divergent and intriguing behaviour of neuronal VGSCs in response to site-3-specific modulators, indicating that these subtypes play different roles in BmK I-induced hyperexcitablity in rat models.


Development and evaluation of 'briefing notes' as a novel knowledge translation tool to aid the implementation of sex/gender analysis in systematic reviews: a pilot study.
There is increasing recognition of sex/gender differences in health and the importance of identifying differential effects of interventions for men and women. Yet, to whom the research evidence does or does not apply, with regard to sex/gender, is often insufficiently answered. This is also true for systematic reviews which synthesize results of primary studies. A lack of analysis and reporting of evidence on sex/gender raises concerns about the applicability of systematic reviews. To bridge this gap, this pilot study aimed to translate knowledge about sex/gender analysis (SGA) into a user-friendly 'briefing note' format and evaluate its potential in aiding the implementation of SGA in systematic reviews. Our Sex/Gender Methods Group used an interactive process to translate knowledge about sex/gender into briefing notes, a concise communication tool used by policy and decision makers. The briefing notes were developed in collaboration with three Cochrane Collaboration review groups (HIV/AIDS, Hypertension, and Musculoskeletal) who were also the target knowledge users of the briefing notes. Briefing note development was informed by existing systematic review checklists, literature on sex/gender, in-person and virtual meetings, and consultation with topic experts. Finally, we held a workshop for potential users to evaluate the notes. Each briefing note provides tailored guidance on considering sex/gender to reviewers who are planning or conducting systematic reviews and includes the rationale for considering sex/gender, with examples specific to each review group's focus. Review authors found that the briefing notes provided welcome guidance on implementing SGA that was clear and concise, but also identified conceptual and implementation challenges. Sex/gender briefing notes are a promising knowledge translation tool. By encouraging sex/gender analysis and equity considerations in systematic reviews, the briefing notes can assist systematic reviewers in ensuring the applicability of research evidence, with the goal of improved health outcomes for diverse populations.