Host-Microbiota Interactions in Ileum and Caecum of Pigs Divergent in Feed Efficiency Contribute to Nutrient Utilization.
The composition of the intestinal microbiota plays an important role in the digestion and utilization of nutrients and for gut health. Low-fiber diets stimulate digestion and absorption processes, predominantly in the upper region of the gastrointestinal tract, thereby increasing the conversion of feed into body weight. As a consequence, the chemical composition of digesta after duodenal and jejunal absorption processes and passage has a limited complexity affecting colonization and molecular profiles of enterocytes in the hind gut. To decipher ileal and caecal microbial ecosystems and host transcriptional profiles that are beneficial for effective use of the remaining nutrients, pigs differing in feeding efficiency were studied. Biological functions that were consistently enriched at both the gene and microbiota levels comprise immunity-related processes, which ensure the integrity of the gastrointestinal tract. In addition, the differential abundance of certain genera, including Rothia, Subdoligranulu, Leeia and Cellulosilyticum, reflects the establishment of a microbial profile that supports the digestion of endogenously indigestible dietary components in highly feed-efficient pigs. Overall, the results indicate the potential to promote these beneficial functions and further improve feed efficiency through manipulation of dietary and probiotic strategies.


[Extra-intestinal Manifestations of chronic inflammatory Bowel diseases].
Approximately one third of all patients with Crohn's disease and ulcerative colitis suffer from extra-intestinal manifestations of their inflammatory bowel disease. Most commonly those symptoms occur simultaneously with the CED symptoms; they can, however, either precede them or appear later on in the course of the disease. The most frequent extra-intestinal symptoms are arthralgias of peripheral joints and spine, which are usually bland and self-limiting, while ankylosing spondylitis and erosive arthritides are rare. Skin lesion and eye affections can also parallel the bowel condition, but occasionally they precede intestinal manifestations and can be a first diagnostic clue. In addition, different extra-intestinal symptoms tend to simultaneously co-occur more frequently in some patients with CED, while others are not affected at all. Immunogenetic parameters play a role for the manifestations of the pathologic immune response both in the gut and in the musculo-skeletal systems, as indicated by associations with MHC class I alleles. Enteropathic microorganisms are also thought to be involved in the pathogenetic mechanisms.


The elusiveness of context effects in decision making.
Contextual features influence human and non-human decision making, giving rise to preference reversals. Decades of research have documented the species and situations in which these effects are observed. More recently, however, researchers have focused on boundary conditions, that is, settings in which established effects disappear or reverse. This work is scattered across academic disciplines and some results appear to contradict each other. We synthesize recent findings and resolve apparent contradictions by considering them in terms of three core categories of decision context: spatial arrangement, attribute concreteness, and deliberation time. We suggest that these categories could be understood using theories of choice representation, which specify how context shapes the information over which deliberation processes operate.


Hyperreactive malarial splenomegaly in Venezuela.
A cross-sectional seroepidemiological survey seeking hyperreactive malarial splenomegaly was carried out in isolated Yanomami hamlets in Amazonas Territory in Venezuela. All 110 inhabitants greater than 1 year of age were evaluated clinically and 98 were studied immunologically. The spleen index for individuals greater than 10 years of age was 44%. Only 3 patients had Plasmodium spp. on thick blood smears. All had serological evidence of infection with Plasmodium falciparum and P. vivax. Twenty-three patients were considered to show hyperreactive malarial splenomegaly. Clinical manifestations of the syndrome did not differ from those described in other parts of the world.


High-Efficiency Continuous-Luminescence-Controllable Performance and Antithermal Quenching in Bi3+-Activated Phosphors.
Recently, Bi3+-activated phosphors have been widely researched for phosphor-converted light-emitting diode (pc-LED) applications. Herein, novel full-spectrum A3BO7:Bi3+ (A = Gd, La; B = Sb, Nb) phosphors with a luminescence-tunable performance were achieved by a chemical substitution strategy. In the La3SbO7 host material, a new luminescent center was introduced, with Gd3+ replacing La3+. The photoluminescence (PL) spectra show a large blue shift from 520 to 445 nm, thus achieving regulation from green to blue lights. Moreover, a series of solid solution-phase phosphors La3Sb1-xNbxO7:Bi3+ were prepared by replacing Sb with Nb, and a PL spectral tunability from green (520 nm) to orange-red (592 nm) was realized. Temperature-dependent PL spectra show that La3-xGdxSbO7:Bi3+ phosphors have excellent thermal stability. Upon 350 nm excitation, the PL intensity of La3-xGdxSbO7:Bi3+ phosphors at 150 °C remained at more than 93% at room temperature. With Gd3+ doping, the thermal stability gradually improved, and LaGd2SbO7:0.03Bi3+ represents splendid antithermal quenching (135.2% at 150 °C). Finally, a full-visible spectrum for pc-LED with a high color-rendering index (Ra = 94.4) was obtained. These results indicated that chemical substitution is an effective strategy to adjust the PL of Bi3+, which is of great significance in white-light illumination and accurate plant lighting.


Crowding and Binding: Not All Feature Dimensions Behave in the Same Way.
Humans often fail to identify a target because of nearby flankers. The nature and stages at which this crowding occurs are unclear, and whether crowding operates via a common mechanism across visual dimensions is unknown. Using a dual-estimation report (N = 42), we quantitatively assessed the processing of features alone and in conjunction with another feature both within and between dimensions. Under crowding, observers misreported colors and orientations (i.e., reported a flanker value instead of the target's value) but averaged the target's and flankers' spatial frequencies (SFs). Interestingly, whereas orientation and color errors were independent, orientation and SF errors were interdependent. These qualitative differences of errors across dimensions revealed a tight link between crowding and feature binding, which is contingent on the type of feature dimension. These results and a computational model suggest that crowding and misbinding are due to pooling across a joint coding of orientations and SFs but not of colors.


6-Methoxy-2-benzoxazolinone: A semiochemical for host location by western corn rootworm larvae.
A bioassay-driven sequential fractionation scheme was used to isolate all portions of a crude dichloromethane corn seedling extract behaviorally active to larvae of the western corn rootworm,Diabrotica virgifera virgifera LeConte. 6-Methoxy-2-benzoxazolinone (MBOA) was identified as one of the most important components of an attractive crude corn extract. MBOA was found on or in the intact root tissues by injecting an extract of undamaged roots onto an HPLC immediately after extraction. MBOA was demonstrated to be volatile and functions as a semiochemical in conjunction with carbon dioxide in host location by western corn rootworm larvae, which are oligophagous on the roots of maize and several other species of grasses. Because MBOA occurs almost exclusively in maize and other grasses, it offers a simple way for the larvae to distinguish possible hosts from non-hosts. MBOA has previously been reported as a chemical defense against other insect species. This is the first report in grasses of a secondary compound that is toxic or a deterrent to nonadapted insect herbivores but that is used as a semiochemical in host location by a specialist insect species.


Using REDCap to track stakeholder engagement: A time-saving tool for PCORI-funded studies.
Research Electronic Data Capture (REDCap) is a secure, web-based electronic data capture application for building and managing surveys and databases. It can also be used for study management, data transfer, and data export into a variety of statistical programs. REDcap was developed and supported by the National Center for Advancing Translational Sciences Program and is used in over 3700 institutions worldwide. It can also be used to track and measure stakeholder engagement, an integral element of research funded by the Patient-Centered Outcomes Research Institute (PCORI). Continuously and accurately tracking and reporting on stakeholder engagement activities throughout the life of a PCORI-funded trial can be challenging, particularly in complex trials with multiple types of engagement. In this paper, we show our approach for collecting and capturing stakeholder engagement activities using a shareable REDCap tool in one of the PCORI's first large pragmatic clinical trials (the Comprehensive Post-Acute Stroke Services) to inform other investigators planning cluster-randomized pragmatic trials. Benefits and challenges are highlighted for researchers seeking to consistently monitor and measure stakeholder engagement. We describe how REDCap can provide a time-saving approach to capturing how stakeholders engage in a PCORI-funded study and reporting how stakeholders influenced the study in progress reports back to PCORI.


Proanthocyanidins in wild sea buckthorn (Hippophaë rhamnoides) berries analyzed by reversed-phase, normal-phase, and hydrophilic interaction liquid chromatography with UV and MS detection.
A rapid and sensitive method for profiling of proanthocyanidins (PAs) of sea buckthorn (Hippophaë rhamnoides) berries was established based on aqueous, acidified acetone extraction. The extract was purified by Sephadex column chromatography and analyzed using reversed-phase, normal-phase, and hydrophilic interaction liquid chromatography (HILIC). Negative ion electrospray ionization mass spectrometry (ESI-MS) in single ion recording (SIR) and full scan modes combined with UV detection were used to define the combinations and ratios of PA oligomer classes. PAs with degree of polymerization from 2 to 11 were detected by HILIC-ESI-MS. Quantification of dimeric, trimeric, and tetrameric PAs was carried out with ESI-MS-SIR, and their molar proportions were 40, 40, and 20%, respectively. Only B-type PAs were found, and (epi)gallocatechins were the main monomeric units. More than 60 combinations of (epi)catechins and (epi)gallocatechins of proanthocyanidin dimers and trimers were found. A majority of the PAs were shown to be higher polymers based on the HILIC-UV analysis.


Titanium Dioxide Nanoparticles: Prospects and Applications in Medicine.
Metallic and metal oxide nanoparticles (NPs), including titanium dioxide NPs, among polymeric NPs, liposomes, micelles, quantum dots, dendrimers, or fullerenes, are becoming more and more important due to their potential use in novel medical therapies. Titanium dioxide (titanium(IV) oxide, titania, TiO2) is an inorganic compound that owes its recent rise in scientific interest to photoactivity. After the illumination in aqueous media with UV light, TiO2 produces an array of reactive oxygen species (ROS). The capability to produce ROS and thus induce cell death has found application in the photodynamic therapy (PDT) for the treatment of a wide range of maladies, from psoriasis to cancer. Titanium dioxide NPs were studied as photosensitizing agents in the treatment of malignant tumors as well as in photodynamic inactivation of antibiotic-resistant bacteria. Both TiO2 NPs themselves, as well as their composites and combinations with other molecules or biomolecules, can be successfully used as photosensitizers in PDT. Moreover, various organic compounds can be grafted on TiO2 nanoparticles, leading to hybrid materials. These nanostructures can reveal increased light absorption, allowing their further use in targeted therapy in medicine. In order to improve efficient anticancer and antimicrobial therapies, many approaches utilizing titanium dioxide were tested. Results of selected studies presenting the scope of potential uses are discussed in this review.


Case study of a 15-year-old boy with McCune-Albright syndrome combined with pituitary gigantism: effect of octreotide-long acting release (LAR) and cabergoline therapy.
The use of octreotide-LAR and cabergoline therapy has shown great promise in adults with acromegaly; however, the experience in pediatric patients has rarely been reported. We described a clinical course of a 15-year-old boy of McCune-Albright syndrome (MAS) with pituitary gigantism. At the age of 8 years, a growth hormone (GH) and prolactin (PRL) producing pituitary adenoma was diagnosed at our hospital. He also had multiple fibrous dysplasia, so that he was diagnosed as having MAS. The tumor was partially resected, and GNAS1 gene mutation (R201C) was identified in affected tissues. We introduced octreotide to suppress GH secretion (100 mug 2/day s.c). During therapy with octreotide, IGF-1 and GH levels could not be suppressed and the patient frequently complained of nausea from octreotide treatment. Therefore, the therapy was changed to monthly injections of octreotide-LAR at the age of 12.3 years and was partially effective. However, as defect of left visual field worsened due to progressive left optic canal stenosis, he underwent second neurological decompression of the left optic nerve at 13.4 years of age. After surgery, in addition to octreotide-LAR, cabergoline (0.25 mg twice a month) was started. This regimen normalized serum levels of GH and IGF-1; however, he showed impaired glucose tolerance and gallstones at 15.7 years of age. Therefore, the dose of octreotide-LAR was reduced to 10 mg and the dose of cabergoline increased. This case demonstrated the difficulty of treating pituitary gigantism due to MAS. The use of octreotide-LAR and cabergoline should be considered even in pediatric patients; however, adverse events due to octreotide-LAR must be carefully examined.


Systemic zoledronate treatment both prevents resorption of allograft bone and increases the retention of new formed bone during revascularization and remodelling. A bone chamber study in rats.
In osteonecrosis the vascular supply of the bone is interrupted and the living cells die. The inorganic mineral network remains intact until ingrowing blood vessels invade the graft. Accompanying osteoclasts start to resorb the bone trabeculae and gradually replace the bone. If the osteonecrosis occurs in mechanically loaded parts, like in the subchondral bone of a loaded joint, the remodelling might lead to a weakening of the bone and, in consequence to a joint collapse. Systemic bisphosphonate treatment can reduce the resorption of necrotic bone. In the present study we investigate if zoledronate, the most potent of the commercially available bisphosphonates, can be used to reduce the amount or speed of bone graft remodeling. Bone grafts were harvested and placed in a bone chamber inserted into the tibia of a rat. Host tissue could grow into the graft through openings in the chamber. Weekly injections with 1.05 microg zoledronate or saline were given subcutaneously until the rats were harvested after 6 weeks. The specimens were fixed, cut and stained with haematoxylin/eosin and used for histologic and histomorphometric analyses. By histology, the control specimens were almost totally resorbed in the remodeled area and the graft replaced by bone marrow. In the zoledronate treated specimens, both the old graft and new-formed bone remained and the graft trabeculas were lined with new bone. By histomorphometry, the total amount of bone (graft+ new bone) within the remodelled area was 35 % (SD 13) in the zoledronate treated grafts and 19 % (SD 12) in the controls (p = 0.001). Also the amount of new bone was increased in the treated specimens (22 %, SD 7) compared to the controls (14 %, SD 9, p = 0.032). We show that zoledronate can be used to decrease the resorption of both old graft and new-formed bone during bone graft remodelling. This might be useful in bone grafting procedure but also in other orthopedic conditions, both where necrotic bone has to be remodelled i.e. after osteonecrosis of the knee and hip and in Perthes disease, or in high load, high turnover conditions like delayed union, periprosthetic osteolysis or bone lengthening operations. In our model an increased net formation of new bone was found which probably reflects that new bone formed was retained by the action of the bisphosphonates rather than a true anabolic effect.


Persimmon (Diospyros kaki L.) leaves: a review on traditional uses, phytochemistry and pharmacological properties.
Persimmon (Diospyros kaki L.) leaves, known as Shi Ye (in Chinese), have a long history as a Chinese traditional medicine for the treatment of ischemia stroke, angina, internal hemorrhage, hypertension, atherosclerosis and some infectious diseases, etc. Additionally, persimmon leaves could be used as healthy products, cosmetics and so on, which have become increasingly popular in Asia, such as Japan, Korea and China etc. The present paper reviewed the ethnopharmacology, phytochemistry, analytical methods, biological activities and toxicology of persimmon leaves in order to assess the ethnopharmacological use and to explore therapeutic potentials and future opportunities for research. Information on persimmon leaves were gathered via the Internet (using Google Scholar, Baidu Scholar, Elsevier, ACS, Pudmed, Web of Science, CNKI and EMBASE) and libraries. Additionally, information was also obtained from some local books. Persimmon leaves have played an important role in Chinese system of medicines. The main compositions of persimmon leaves were flavonoids, terpenoids, etc. Scientific studies on extracts and formulations revealed a wide range of pharmacological activities, such as, antioxidative, hypolipidemic, antidiabetic, antibacterial, hemostasis activities and effects on cardiovascular system. Based on the pharmacological activities, persimmon leaves were widely used in clinic including treatment of cardiovascular disease, hemostasis, antibacterial, anti-inflammatory and beauty treatment. Persimmon leaves probably have therapeutic potential in the prevention and treatment for cerebral arteriosclerosis, diabetes, hypertension. It showed significant neuroprotection against ischemia/reperfusion injury in vivo and in vitro. Moreover, it can regulate immune function and inhibite inflammation. Further investigations are needed to explore individual bioactive compounds responsible for these pharmacological effects in vitro and in vivo and the mode of actions. Further safety assessments and clinical trials should be performed before it can be integrated into medicinal practices.


Multifaceted roles of TAX1BP1 in autophagy.
TAX1BP1 is a selective macroautophagy/autophagy receptor that plays a central role in host defense to pathogens and in regulating the innate immune system. TAX1BP1 facilitates the xenophagic clearance of pathogenic bacteria such as Salmonella typhimurium and Mycobacterium tuberculosis and regulates TLR3 (toll-like receptor 3)-TLR4 and DDX58/RIG-I-like receptor (RLR) signaling by targeting TICAM1 and MAVS for autophagic degradation respectively. In addition to these canonical autophagy receptor functions, TAX1BP1 can also exert multiple accessory functions that influence the biogenesis and maturation of autophagosomes. In this review, we will discuss and integrate recent findings related to the autophagy function of TAX1BP1 and highlight outstanding questions regarding its functions in autophagy and regulation of innate immunity and host defense.Abbreviations: ATG: autophagy related; CALCOCO: calcium binding and coiled-coil domain; CC: coiled-coil; CHUK/IKKα: conserved helix-loop-helix ubiquitous kinase; CLIR: noncanonical LC3-interacting region; GABARAP: gamma-aminobutyric acid receptor associated protein; HTLV-1: human T-lymphotropic virus 1; IFN: interferon; IL1B/IL1β: interleukin 1 beta; LIR: LC3-interacting region; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK/JNK: mitogen-activated protein kinase; mATG8: mammalian Atg8 homolog; MAVS: mitochondrial antiviral signaling protein; MEF: mouse embryonic fibroblast; MTB: Mycobacterium tuberculosis; MYD88: myeloid differentiation primary response gene 88; NBR1: NBR1, autophagy cargo receptor; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; OPTN: optineurin; Poly(I:C): polyinosinic:polycytidylic acid; PTM: post-translational modification; RB1CC1: RB1-inducible coiled-coil 1; RIPK: receptor (TNFRSF)-interacting serine-threonine kinase; RLR: DDX58/RIG-I-like receptor; RSV: respiratory syncytia virus; SKICH: SKIP carboxyl homology; SLR: SQSTM1 like receptor; SQSTM1: sequestosome 1; TAX1BP1: Tax1 (human T cell leukemia virus type I) binding protein 1; TBK1: TANK-binding kinase 1; TICAM1: toll-like receptor adaptor molecule 1; TLR: toll-like receptor; TNF: tumor necrosis factor; TNFAIP3: TNF alpha induced protein 3; TNFR: tumor necrosis factor receptor; TOM1: target of myb1 trafficking protein; TRAF: TNF receptor-associated factor; TRIM32: tripartite motif-containing 32; UBD: ubiquitin binding domain; ZF: zinc finger.


Development information systems for clinical laboratories and their integration into HIS.
The basic laboratory program module was developed using a summarized information model of a clinical laboratory's functionality. Then, information systems for laboratories of different specialties were quickly implemented by adaptation, addition, and tuning of this basic module. Integrating this system into an HIS considerably improved the interaction between clinical departments and laboratories.


Multidimensional assessment of self-regulated learning with middle school math students.
This study examined the convergent and predictive validity of self-regulated learning (SRL) measures situated in mathematics. The sample included 100 eighth graders from a diverse, urban school district. Four measurement formats were examined including, 2 broad-based (i.e., self-report questionnaire and teacher ratings) and 2 task-specific measures (i.e., SRL microanalysis and behavioral traces). Convergent validity was examined across task-difficulty, and the predictive validity was examined across 3 mathematics outcomes: 2 measures of mathematical problem solving skill (i.e., practice session math problems, posttest math problems) and a global measure of mathematical skill (i.e., standardized math test). Correlation analyses were used to examine convergent validity and revealed medium correlations between measures within the same category (i.e., broad-based or task-specific). Relations between measurement classes were not statistically significant. Separate regressions examined the predictive validity of the SRL measures. While controlling all other predictors, a SRL microanalysis metacognitive-monitoring measure emerged as a significant predictor of all 3 outcomes and teacher ratings accounted for unique variance on 2 of the outcomes (i.e., posttest math problems and standardized math test). Results suggest that a multidimensional assessment approach should be considered by school psychologists interested in measuring SRL. (PsycINFO Database Record


Immunochemical studies of antitoxin produced in normal and allergic individuals hyperimmunized with diphtheria toxoid. VI. Further investigations on the identity and specificity of non-precipitating skin-sensitizing antitoxin.
Studies were carried out on sera from eight subjects hyperimmunized with toxoid who developed marked immediate skin reactivity to toxoid associated with circulating non-precipitating antitoxin. With the use of the rabbit skin test, the agar diffusion technique, and three different methods for passive transfer of skin sensitivity, it was possible to obtain detailed qualitative and quantitative data relating to the antitoxin in these sera. It was found that specimens from six individuals contained only skin-sensitizing antitoxin. Two sera showed a lack of parallelism between antitoxin titers as obtained by rabbit skin test and titers as demonstrated by tests in human skin. It was presumed that these sera contained two different varieties of non-precipitating antitoxins, and that only one of them was skin-sensitizing antitoxin. A new technique is described for measurement of skin-sensitizing antitoxin. Its specificity is based upon the ability of this antitoxin to remain at skin sites and later neutralize the delayed specific toxic effects of intradermal Schick test reagent.


Smoking, alcohol consumption, and susceptibility to the common cold.
This study was conducted to test the supposition that both smoking and consuming alcohol suppress host resistance to viral infections. The relations between smoking, alcohol consumption, and the incidence of documented clinical colds were prospectively studied among 391 subjects intentionally exposed to one of five respiratory viruses and 26 subjects given saline. Clinical colds were defined as clinical symptoms verified by the isolation of virus or by an increase in virus-specific antibody titer. Analyses included control variables for demographics; body weight; virus; and environmental, immunological and psychological factors. Smokers were at greater risk for developing colds than nonsmokers because smokers were more likely both to develop infections and to develop illness following infection. Greater numbers of alcoholic drinks (up to three or four per day) were associated with decreased risk for developing colds because drinking was associated with decreased illness following infection. However, the benefits of drinking occurred only among nonsmokers. Susceptibility to colds was increased by smoking. Although alcohol consumption did not influence risk of clinical illness for smokers, moderate alcohol consumption was associated with decreased risk for nonsmokers.


O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1.
Indoleamine 2,3-dioxygenase-1 (IDO1) is a promising therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. Recently important advances have been made in understanding IDO1's catalytic mechanism. Although much remains to be discovered, there is strong evidence that the mechanism proceeds through a heme-iron bound alkylperoxy transition or intermediate state. Accordingly, we explored stable structural mimics of the alkylperoxy species and provide evidence that such structures do mimic the alkylperoxy transition or intermediate state. We discovered that O-benzylhydroxylamine, a commercially available compound, is a potent sub-micromolar inhibitor of IDO1. Structure-activity studies of over forty derivatives of O-benzylhydroxylamine led to further improvement in inhibitor potency, particularly with the addition of halogen atoms to the meta position of the aromatic ring. The most potent derivatives and the lead, O-benzylhydroxylamine, have high ligand efficiency values, which are considered an important criterion for successful drug development. Notably, two of the most potent compounds demonstrated nanomolar-level cell-based potency and limited toxicity. The combination of the simplicity of the structures of these compounds and their excellent cellular activity makes them quite attractive for biological exploration of IDO1 function and antitumor therapeutic applications.


Effects of same- and different-modality cues in a Posner task: extinction-type, spatial, and non-spatial deficits after right-hemispheric stroke.
The response delay to left target stimuli preceded by right-side cues, first described by Posner et al. [J. Neurosci. 4 (1984) 1863-1874] appears to be a stable marker of right-parietal injury. However, only few studies compared patients' performance to age-matched controls. Furthermore, only few studies compared visual and auditory stimuli in this task. Therefore, two groups of right-hemisphere stroke patients, with and without left visual hemineglect, and a healthy control group were studied in three versions of Posner's paradigm. Visual or auditory target stimuli were presented to the subject's left or right, following a visual or auditory cue by 150 ms. The classical 'extinction-type' effect, an increase in missing responses for right visual cue/left visual target, was specifically observed in neglect patients. In the same condition, an 'extinction-type' response delay was present in patients with neglect and in those without neglect. No such delay occurred in any group when cues were auditory. Specifically in neglect patients, response times were generally longer for left than for right visual targets, regardless of cue side and of cue modality. Response times were generally prolonged in neglect patients regardless of target modality. This suggests that three components impair neglect patients' performance in this paradigm: a non-spatial, supramodal deficit, a global, neglect-type deficit of the contralesional hemi-field, and the extinction-type impairment. The latter two deficits appear to be most marked within the visual domain.


[Dorsal vertebral chordoma with intrathoracic invasion. Surgical treatment of a case].
A case of thoracic spinal chordoma extending into the postero-inferior mediastinal region is reported. This case was treated by sub-total surgical removal and subsequent radiotherapy. The radiologic features and the possible surgical treatment of this particular tumor with intrathoracic extension are discussed.


Tellurite microspheres for nanoparticle sensing and novel light sources.
High index Er-Yb codoped tellurite spheres with diameter of 9 μm and good sphericity were fabricated using a CO(2) laser. Upconversion modulated whispering gallery modes with a quality factor of 45,000 were observed in the sphere dipped in methanol. Refractometric sensing with detection sensitivity of 7.7 nm/RIU was demonstrated using a 9 μm diameter sphere. Such high index spheres have the potential to be used for nanoparticle sensing and mid-IR frequency conversion.


A Case of Cavernous Sinus Syndrome Due to Extranodal Diffuse Large B-Cell Lymphoma.
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma accounting for approximately one-third of all cases. DLBCL can present as a lymph node or extranodal tumor. Cavernous sinus (CS) is a small but complex structure in which various arteries, sympathetic plexuses, and cranial nerves are passing through. Cavernous sinus syndrome (CSS) results from any disease process that affects CS including tumor, vascular disease, infection, or inflammation. Herein, we report a case of extranodal DLBCL diagnosed by skin biopsy presenting as CSS. A 58-year-old male presented with a 3-week-old, gradually growing subcutaneous nodule on the left upper lip. He also suffered from ptosis, ophthalmoplegia, diplopia, and headache confined to the right side for 3 months. Histopathologic examination of the left upper lip showed dense dermal infiltration of atypical large tumor cells resembling centroblasts and immunoblasts. Immunohistochemistry studies revealed that the tumor cells were positive for CD20, BCL2, BCL6, MUM1, and MYC. After additional radiologic evaluation with positron emission tomography-computed tomography (PET-CT), brain magnetic resonance imaging, and orbital CT, he was finally diagnosed with extranodal DLBCL involving the right CS, oculomotor muscles, and left upper lip.


Predictors of upstage and treatment strategies for stage IA lung cancers after sublobar resection for adenocarcinoma in situ and minimally invasive adenocarcinoma.
Invasive adenocarcinoma intraoperatively underestimated as adenocarcinoma in situ (AIS) or minimally invasive adenocarcinoma (MIA) based on frozen section (FS) is more likely to undergo insufficient resection. We aimed to investigate the predictors of upstage and treatment strategies for stage IA invasive adenocarcinoma after sublobar resection for AIS and MIA. We identified 2,006 patients from January 2012 to December 2016 with early-stage lung adenocarcinoma who underwent sublobar resection based on FS diagnosis to guide surgical decision-making. All FS were categorized into three groups in real-time: (I) atypical adenomatous hyperplasia (AAH), (II) AIS, and (III) MIA. A total of 272 (13.5%, 272/2,006) cases were upstaged in the final pathology (FP) diagnosis (82 AAH to AIS, 127 AIS to MIA, and nine AIS and 54 MIA to invasive adenocarcinoma), and most upstage cases (64.3%, 175/272) were attributed to sampling error. Multivariate logistic regression showed that tumor size ≥1 cm was the only independent predictor of upstage. The upstage of 209 cases to AIS or MIA had no influence on the therapy because the extent of their resection was enough. Of the 63 cases upstaged to invasive adenocarcinoma, only 13 cases agreed to receive complementary treatment: five patients underwent complementary lobectomy, and seven patients received chemotherapy. Two invasive adenocarcinoma cases without complementary treatment experienced a local recurrence after surgery. No recurrence was observed in AAH, AIS and MIA. No patient died until December 01, 2019. Timely complementary treatment is encouraged in AIS/MIA upstaged to invasive adenocarcinoma based on the FP after sublobar resection to avoid local recurrence. Pathologists should be more cautious about AIS and MIA with tumor size ≥1 cm to avoid underestimation and potentially insufficient resection.


Surface-Modified Carbon Nanotubes with Ultrathin Co3O4 Layer for Enhanced Oxygen Evolution Reaction.
Alkaline water electrolysis is a vital technology for sustainable and efficient hydrogen production. However, the oxygen evolution reaction (OER) at the anode suffers from sluggish kinetics, requiring overpotential. Precious metal-based electrocatalysts are commonly used but face limitations in cost and availability. Carbon nanostructures, such as carbon nanotubes (CNTs), offer promising alternatives due to their abundant active sites and efficient charge-transfer properties. Surface modification of CNTs through techniques such as pulsed laser ablation in liquid media (PLAL) can enhance their catalytic performance. In this study, we investigate the role of surface-modified carbon (SMC) as a support to increase the active sites of transition metal-based electrocatalysts and its impact on electrocatalytic performance for the OER. We focus on Co3O4@SMC heterostructures, where an ultrathin layer of Co3O4 is deposited onto SMCs using a combination of PLAL and atomic layer deposition. A comparative analysis with aggregated Co3O4 and Co3O4@pristine CNTs reveals the superior OER performance of Co3O4@SMC. The optimized Co3O4@SMC exhibits a 25.6% reduction in overpotential, a lower Tafel slope, and a significantly higher turnover frequency (TOF) in alkaline water splitting. The experimental results, combined with density functional theory (DFT) calculations, indicate that these improvements can be attributed to the high electrocatalytic activity of Co3O4 as active sites achieved through the homogeneous distribution on SMCs. The experimental methodology, morphology, composition, and their correlation with activity and stability of Co3O4@SMC for the OER in alkaline media are discussed in detail. This study contributes to the understanding of SMC-based heterostructures and their potential for enhancing electrocatalytic performance in alkaline water electrolysis.


Determination of the mechanical properties of normal and calcified human mitral chordae tendineae.
The aim of the present research is to determine the influence of the calcification of human mitral valves on the mechanical properties of their marginal chordae tendineae. The study was performed on marginal chords obtained from thirteen human mitral valves, explanted at surgery, including six non-calcified, four moderately calcified and three strongly calcified valves. The mechanical response of the chords from the non-calcified and moderately calcified valves was determined by means of quasi-static tensile tests (the poor condition of the strongly calcified valves prevented them from being mechanically characterised). The material parameters that were obtained and analysed (the Young's modulus, the secant modulus, the proportional limit stress, the ultimate strength, the strain at fracture and the density of energy stored up to maximum load) revealed noticeable differences in mechanical behaviour between the two groups of mitral chordae tendineae. Large scatter was obtained in all cases, nevertheless, considering the mean values, it was observed that the normal chords are between three and seven times stiffer or more resistant than the moderately calcified ones. On the contrary, the results obtained for the strain at fracture showed a rather different picture as, in this case, no significant differences were observed between the two families of chords. A scanning electron microscopy study was conducted in order to find out the relevant features of the calcium deposits present in the calcified chordae tendineae. In addition, the general aspects appreciated in the stress vs. strain curves were correlated with the collagen morphological evidences determined microscopically. Finally, the calcium content present in the three groups of chords was quantitatively determined through atomic absorption spectroscopy; then, the relation between the mechanical properties of normal and moderately calcified chords as a function of its calcium content was obtained. This analysis confirmed the existence of a strong correlation between calcium content and stiffness or resistance whereas the influence on the ductility seems to be negligible.


Transpiration of Eucalyptus woodlands across a natural gradient of depth-to-groundwater.
Water resources and their management present social, economic and environmental challenges, with demand for human consumptive, industrial and environmental uses increasing globally. However, environmental water requirements, that is, the allocation of water to the maintenance of ecosystem health, are often neglected or poorly quantified. Further, transpiration by trees is commonly a major determinant of the hydrological balance of woodlands but recognition of the role of groundwater in hydrological balances of woodlands remains inadequate, particularly in mesic climates. In this study, we measured rates of tree water-use and sapwood 13C isotopic ratio in a mesic, temperate Eucalypt woodland along a naturally occurring gradient of depth-to-groundwater (DGW), to examine daily, seasonal and annual patterns of transpiration. We found that: (i) the maximum rate of stand transpiration was observed at the second shallowest site (4.3 m) rather than the shallowest (2.4 m); (ii) as DGW increased from 4.3 to 37.5 m, stand transpiration declined; (iii) the smallest rate of stand transpiration was observed at the deepest (37.5 m) site; (iv) intrinsic water-use efficiency was smallest at the two intermediate DGW sites as reflected in the Δ13C of the most recently formed sapwood and largest at the deepest and shallowest DGW sites, reflecting the imposition of flooding at the shallowest site and the inaccessibility of groundwater at the deepest site; and (v) there was no evidence of convergence in rates of water-use for co-occurring species at any site. We conclude that even in mesic environments groundwater can be utilized by trees. We further conclude that these forests are facultatively groundwater-dependent when groundwater depth is <9 m and suggest that during drier-than-average years the contribution of groundwater to stand transpiration is likely to increase significantly at the three shallowest DGW sites.


Efficacy Evaluation of Neurofeedback-Based Anxiety Relief.
Anxiety disorder is a mental illness that involves extreme fear or worry, which can alter the balance of chemicals in the brain. This change and evaluation of anxiety state are accompanied by a comprehensive treatment procedure. It is well-known that the treatment of anxiety is chiefly based on psychotherapy and drug therapy, and there is no objective standard evaluation. In this paper, the proposed method focuses on examining neural changes to explore the effect of mindfulness regulation in accordance with neurofeedback in patients with anxiety. We designed a closed neurofeedback experiment that includes three stages to adjust the psychological state of the subjects. A total of 34 subjects, 17 with anxiety disorder and 17 healthy, participated in this experiment. Through the three stages of the experiment, electroencephalography (EEG) resting state signal and mindfulness-based EEG signal were recorded. Power spectral density was selected as the evaluation index through the regulation of neurofeedback mindfulness, and repeated analysis of variance (ANOVA) method was used for statistical analysis. The findings of this study reveal that the proposed method has a positive effect on both types of subjects. After mindfulness adjustment, the power map exhibited an upward trend. The increase in the average power of gamma wave indicates the relief of anxiety. The enhancement of the wave power represents an improvement in the subjects' mindfulness ability. At the same time, the results of ANOVA showed that P < 0.05, i.e., the difference was significant. From the aspect of neurophysiological signals, we objectively evaluated the ability of our experiment to relieve anxiety. The neurofeedback mindfulness regulation can effect on the brain activity pattern of anxiety disorder patients.


Successful Cord Blood Stem Cell Transplantation for Primary Cutaneous CD8-positive Aggressive Epidermotropic Cytotoxic T-cell Lymphoma Complicated with Cerebral Infiltration.
A 16-year-old boy, who had been initially examined for bilateral blepharedema and slight eruption, presented with rapidly deteriorating symptoms in associating with headache and consciousness disturbance. He was diagnosed to have primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma (PCAE-CTL) by a biopsy of the skin and brain. After whole-brain radiation and some courses of chemotherapy, cord blood transplantation was performed with myeloablative conditioning. After transplantation, the cerebral dysfunction gradually improved. Disease remission was confirmed by the disappearance of any abnormal findings on electroencephalogram and magnetic resonance imaging. PCAE-CTL is reported to be an extremely aggressive disease with a poor prognosis, but the timely performance of cord blood transplantation is considered to be a promising treatment strategy.


Encapsulation of protonated diamines in a water-soluble, chiral, supramolecular assembly allows for measurement of hydrogen-bond breaking followed by nitrogen inversion/rotation.
Amine nitrogen inversion, difficult to observe in aqueous solution, is followed in a chiral, supramolecular host molecule with purely rotational T-symmetry that reduces the local symmetry of encapsulated monoprotonated diamines and enables the observation and quantification of Delta G (++) for the combined hydrogen-bond breaking and nitrogen inversion/rotation (NIR) process. Free energies of activation for the combined hydrogen-bond breaking and NIR process inside of the chiral assembly were determined by the NMR coalescence method. Activation parameters for ejection of the protonated amines from the assembly confirm that the NIR process responsible for the coalescence behavior occurs inside of the assembly rather than by a guest ejection/NIR/re-encapsulation mechanism. For one of the diamines, N, N, N', N'-tetramethylethylenediamine, the relative energy barriers for the hydrogen-bond breaking and NIR process were calculated at the G3(MP2)//B3LYP/6-31++G(d,p) level of theory, and these agreed well with the experimental data.


An allele-selective inter-chromosomal protein bridge supports monogenic antigen expression in the African trypanosome.
UPF1-like helicases play roles in telomeric heterochromatin formation and X-chromosome inactivation, and also in monogenic variant surface glycoprotein (VSG) expression via VSG exclusion-factor-2 (VEX2), a UPF1-related protein in the African trypanosome. We show that VEX2 associates with chromatin specifically at the single active VSG expression site on chromosome 6, forming an allele-selective connection, via VEX1, to the trans-splicing locus on chromosome 9, physically bridging two chromosomes and the VSG transcription and splicing compartments. We further show that the VEX-complex is multimeric and self-regulates turnover to tightly control its abundance. Using single cell transcriptomics following VEX2-depletion, we observed simultaneous derepression of many other telomeric VSGs and multi-allelic VSG expression in individual cells. Thus, an allele-selective, inter-chromosomal, and self-limiting VEX1-2 bridge supports monogenic VSG expression and multi-allelic VSG exclusion.


Protein adaptation to high hydrostatic pressure: Computational analysis of the structural proteome.
Hydrostatic pressure has a vital role in the biological adaptation of the piezophiles, organisms that live under high hydrostatic pressure. However, the mechanisms by which piezophiles are able to adapt their proteins to high hydrostatic pressure is not well understood. One proposed hypothesis is that the volume changes of unfolding (ΔVTot ) for proteins from piezophiles is distinct from those of nonpiezophilic organisms. Since ΔVTot defines pressure dependence of stability, we performed a comprehensive computational analysis of this property for proteins from piezophilic and nonpiezophilic organisms. In addition, we experimentally measured the ΔVTot of acylphosphatases and thioredoxins belonging to piezophilic and nonpiezophilic organisms. Based on this analysis we concluded that there is no difference in ΔVTot for proteins from piezophilic and nonpiezophilic organisms. Finally, we put forward the hypothesis that increased concentrations of osmolytes can provide a systemic increase in pressure stability of proteins from piezophilic organisms and provide experimental thermodynamic evidence in support of this hypothesis.


Synovial chondromatosis in raptors.
Fourteen raptors, consisting of 13 great horned owls (Bubo virginianus) and one red-tailed hawk (Buteo jamaicensis), from central and north central Minnesota, western Wisconsin, and eastern South Dakota (USA) were admitted to a raptor rehabilitation center between June 1992 and June 1995, with perisynovial and synovial chondromatosis affecting multiple joints. Birds were severely debilitated primarily due to loss of shoulder motion. The etiology of these lesions in raptors is unknown.


The Impact of Omitting 5-FU Bolus From mFOLFOX6 Chemotherapy Regimen on Hematological Adverse Events Among Patients With Metastatic Colorectal Cancer.
Metastatic colorectal cancer (mCRC) is often treated with a mFOLFOX6 regimen. The 5-fluorouracil (5-FU) bolus is often omitted from the regimen to reduce the risk of hematological adverse events (AEs) in patients with poor performance status. We aimed to investigate the incidence of hematological AEs in Asian patients with mCRC who were treated with the mFOLFOX6 with and without 5-FU bolus dosing. This retrospective chart review was conducted at King Chulalongkorn Memorial Hospital, Thailand from June 2021 to June 2022. The primary endpoints were hematological AEs. Secondary endpoints were any AEs. The comparison of continuous data was conducted with an independent t-test. The Chi-squared test was used to compare categorical data. From 110 patients, we found that hematological and non-hematological AEs of any grade in the two groups were not significantly different. However, patients in the bolus arm had a significantly lower absolute neutrophil count (ANC) than those in the non-bolus arm (mean difference = 43.13 (95% confidence interval (CI): 20.74, 65.51), P-value = 0.0002). A subgroup analysis in patients who received first-line treatment with mFOLFOX6 showed that the bolus arm had a significantly lower ANC (mean difference = 46.01 (95% CI: 19.99, 72.03), P-value = 0.0007). mCRC patients who were treated with bolus 5-FU had lower ANC. The 5-FU bolus omission from the mFOLFOX6 regimen may be required in patients with a high risk of neutropenia.


Measuring femoral neck loads in healthy young and older adults during stair ascent and descent.
Understanding the hip loading environment for daily activities is useful for hip fracture prevention, rehabilitation, and the design of osteogenic exercises. Seventeen older adults (50-70 yrs) and twenty young adults (18-30 yrs) were recruited. A rigid body model combined with a musculoskeletal model was used to estimate lower extremity loading. An elliptical cross-section model of the femoral neck was used to estimate femoral neck stress during stair ascent and descent. Two peaks were identified in the stress curves, corresponding to the peaks in the vertical ground reaction force. During stair ascent, significantly higher tension on the superior femoral neck was found for the young group at peak 1 (young: 13.5±6.1 MPa, older: 4.2±6.5 MPa, p<0.001). Also during stair ascent, significantly higher compression on the posterior femoral neck was found for the older group at peak 2 (young: -11.4±4.9 MPa, old: -18.1±8.6 MPa, p = 0.006). No significant difference was found for stair descent. Components of stress (muscle vs. reaction forces; axial forces vs. bending moments) were also examined for each trial of stair ascent and descent. The stresses and their components provided loading magnitude and locations of higher stress on the femoral neck during stair ascent and descent. Understanding femoral neck stresses may be used to help prevent hip fractures, reduce pain, improve rehabilitation, and design osteogenic exercises.


Assessing ototoxicity due to chronic lead and cadmium intake with and without noise exposure in the mature mouse.
Exposure to heavy metals may lead to hearing impairment. However, experimental studies have not explored this issue with and without noise exposure in mature animals with environmentally relevant doses. The aim of this study was to investigate ototoxicity produced by lead (Pb) and cadmium (Cd) and noise, singly and in combination, in the adult CBA/CaJ mouse. Metals were delivered via drinking water (0.03 mM, 1 mM, and 3 mM Pb; or 30, 100, and 300 μM Cd) for 12 weeks, resulting in environmentally- and occupationally relevant mean (± standard deviations) blood levels of Pb (2.89 ± 0.44, 38.5 ± 4.9, and 60.1 ± 6.6 μg/dl, respectively) and Cd (1.3 ± 0.23, 6.37 ± 0.87, 27.2 ± 4.1 μg/L, respectively). Metal treatment was also combined with a noise exposure consisting of a 105 dB broadband (2-20 kHz) stimulus for 2 hr or a sham exposure. Auditory performance was determined by comparing auditory brainstem responses (ABR) and distortion product otoacoustic emissions (DPOAE) at baseline and after 11 weeks of metal treatment. Metal-exposed animals did not develop significant auditory deficits and did not exhibit morphological damage to cochlear hair cells. In contrast, noise-exposed animals, including those exposed to combinations of metals and noise, demonstrated significant hair cell loss, reduced DPOAE amplitudes, and ABR threshold shifts of 42.2 ± 13 dB at 32 kHz (105 dB noise alone). No significant potentiation or synergistic effects were found in groups exposed to multiple agents. This study establishes a highly reproducible adult mouse model that may be used to evaluate a variety of environmental exposure mixtures.


Use of preoperative MRI to predict vestibular schwannoma intraoperative consistency and facial nerve outcome.
Objectives We sought to identify if preoperative schwannoma magnetic resonance imaging (MRI) intensities might predict intraoperative consistency. We then determined whether consistency correlated with facial nerve outcomes. Design Operative reports from 2000 to 2010 were searched for tumor description as either soft and/or suckable or firm and/or fibrous. Preoperative T1 and T2 sequences were then reviewed to identify intensities relative to gray matter. Facial nerve function was recorded at the time of most recent follow-up. Results Forty-six patients were included. No tumors were T1 hyperintense. Soft and firm schwannomas were equally likely to be T1 hypointense. On T2 sequences, however, soft schwannomas were more likely to be hyperintense (88% versus 14%, p < 0.005) whereas firm schwannomas were more likely to be hypointense (86% versus 6%, p < 0.005). There was a tendency for firm schwannomas to have worse facial nerve outcomes (43% versus 19%, p = 0.14). Conclusions Prediction of vestibular schwannoma intraoperative consistency based on T2 intensity seems promising. Furthermore, though not statistically significant, in this small pilot study firm schwannomas tended to have worse facial nerve outcomes. This potential ability to predict consistency and its correlation with facial nerve outcome may assist the surgeon in preoperative planning and patient counseling, though further data needs to be accumulated.


Influence of energy cost and physical fitness on the preferred walking speed and gait variability in elderly women.
Typically gait speed decreases and gait variability increases in elderly. The aim of this study was to define the influence of energy cost of walking on gait speed and of health-related physical fitness on gait variability. Thirty healthy young and older women were recruited in the study. Energy cost of walking (NetCW) was analyzed with indirect calorimetry while a kinematic analysis was performed with an optoelectronic system to calculate gait variability (GV) during treadmill walking at different speeds. Gait speed was defined as the preferred walking speed (PWS) of the subject and health related physical fitness (HRPF) comprised body fat, strength, flexibility, and cardiorespiratory fitness. In healthy elderly women, the coefficient of variation of step width was found to be a better indicator of GV than stride time, stride length and double support coefficients of variation. GV was not affected by age allowing a high PWS. Furthermore, significant associations, adjusted for age, body mass index and number of falls, were identified neither between NetCW and the PWS, nor between HRPF and GV; only a significant association was found between hand-grip strength and gait stability. Findings highlighted the importance to evaluate hand-grip strength as an indicator of gait efficiency.


Bleeding Risk of Warfarin and Direct Oral Anticoagulants in Younger Population: A Historical Cohort Study Using a Japanese Claims Database.
A historical cohort analysis of the Japan medical data center (JMDC) claims databases was performed to compare the incidence rates of bleeding events with warfarin (WF) versus direct oral anticoagulant (DOAC) treatment in patients with non-valvular atrial fibrillation. The aim of this study is to clarify the risk factors for bleeding events in younger patients newly treated with WF or DOAC in clinical practice setting. Patients who newly initiated WF or DOAC treatment from April 2012 to March 2015 were selected from the JMDC claims database. A 1:1 propensity score matching analysis was used for new users of WF or DOAC. Kaplan-Meier curves were generated to depict the time to bleeding event (total bleeding events, gastrointestinal hemorrhage, and intracranial hemorrhage) during the follow-up period. Cox proportional regression models were used to estimate the hazard ratios for total bleeding events caused by oral anticoagulants. Overall, 2,046 patients (503 WF and 1,543 DOAC) were included. After applying propensity score matching, Kaplan-Meier analysis of the WF and DOAC groups displayed comparable incidences of total bleeding events, gastrointestinal hemorrhage, and intracranial hemorrhage. Cox proportional hazards modeling showed that the use of WF was not associated with total bleeding events compared with DOAC (hazard ratio: 1.21, 95% confidence interval: 0.93-1.54, p = 0.15). This historical cohort study using a claims database indicates that the bleeding risk of DOAC was comparable to that of WF in Japanese younger population.


Analysis of expression and function of CD40 on normal and leukemic human B cell precursors.
CD40 was originally identified on circulating and tonsillar human B cells, and anti-CD40 monoclonal antibodies (MoAb) are known to deliver a progression signal to activated B cells. However, the expression and function of CD40 on human B cell precursors (BCP) have not been examined in detail. Two new anti-CD40 MoAb were produced and shown to recognize an epitope indistinguishable from the anti-CD40 antibody G28-5. CD40 was readily detected on normal and leukemic BCP by flow cytometry, and cell surface expression was upregulated by phorbol ester. Despite the ability of normal and leukemic BCP to respond to phorbol ester (PMA) and/or low molecular weight B cell growth factor (L-BCGF), anti-CD40 exerted no stimulatory action and could not enhance the response of these cells to PMA, L-BCGF, or both. Cross-linking anti-CD40 MoAb with rabbit anti-mouse Ig also failed to induce a proliferative response in normal BCP. We conclude that anti-CD40 does not exert demonstrable agonistic effects on normal and leukemic human BCP. Our results suggest that signal delivery through CD40 and/or subsequent intracellular signal processing may require accessory molecules not expressed in BCP, or CD40 may subserve a different function for BCP.


Pharmacokinetics of cannabidiol in children with refractory epileptic encephalopathy.
Growing interest in the clinical use of cannabidiol (CBD) as adjuvant therapy for pediatric refractory epileptic encephalopathy emphasizes the need for drug treatment optimization. The aim of this study was to characterize the pharmacokinetics of CBD in pediatric patients with refractory epileptic encephalopathy receiving an oil-based oral solution. To evaluate CBD concentrations, six serial blood samples per patient were collected after the morning dose of CBD, at least 21 days after the beginning of treatment. Twelve patients who received a median (range) dose of 12.2 (5.3-19.4) mg/kg/d (twice daily) were included in the analysis. Median (range) CBD time to maximum plasma concentration, maximum plasma concentration, and area under the concentration versus time curve up to 6 hours after dosing were 3.2 hours (1.9-6.2), 49.6 ng/mL (14.4-302.0), and 226.3 ng ⋅ h/mL (70.5-861.3), respectively. CBD systemic exposure parameters were in the lower range of previous reports in pediatric patients receiving doses in a similar range. Most of our patients (83%) showed little CBD plasma level fluctuation during a dosing interval, comparable to that encountered after oral administration of an extended release drug delivery system. CDB administration was generally safe and well tolerated, and a novel levothyroxine-CBD interaction was recorded. Similar to other studies, large interindividual variability in CBD exposure was observed, encouraging the use of CBD therapeutic drug monitoring.


Bone grafting with microvascular anastomosis in osteonecrosis of the femoral head.
Vascularized fibular grafting decompresses the femoral head, augments structural stability, and places healthy vascularized bone in the area of femoral head necrosis. Patients are selected for the procedure on the basis of symptomatology, age, mobility of the hip, and radiographic stage of the disease. Twenty-four patients were reviewed in the current report. Mean patient age was 33. Seven patients had stage II disease, 4 patients had stage III disease, 10 had early (less than 2 mm collapse) stage IV disease, and 1 had stage V disease. The mean follow-up was 32.8 months (range, 24-54 months). Five procedures failed. The remaining patients have had gratifying results in terms of pain relief, functional improvement, and cessation of disease progression. Longer follow-up will determine if vascularized fibular grafting alters the natural history of the condition and if vascularization of the fibular bone graft offers superior results to those obtained in the past with nonvascularized grafts.


Classifier models and architectures for EEG-based neonatal seizure detection.
Neonatal seizures are the most common neurological emergency in the neonatal period and are associated with a poor long-term outcome. Early detection and treatment may improve prognosis. This paper aims to develop an optimal set of parameters and a comprehensive scheme for patient-independent multi-channel EEG-based neonatal seizure detection. We employed a dataset containing 411 neonatal seizures. The dataset consists of multi-channel EEG recordings with a mean duration of 14.8 h from 17 neonatal patients. Early-integration and late-integration classifier architectures were considered for the combination of information across EEG channels. Three classifier models based on linear discriminants, quadratic discriminants and regularized discriminants were employed. Furthermore, the effect of electrode montage was considered. The best performing seizure detection system was found to be an early integration configuration employing a regularized discriminant classifier model. A referential EEG montage was found to outperform the more standard bipolar electrode montage for automated neonatal seizure detection. A cross-fold validation estimate of the classifier performance for the best performing system yielded 81.03% of seizures correctly detected with a false detection rate of 3.82%. With post-processing, the false detection rate was reduced to 1.30% with 59.49% of seizures correctly detected. These results represent a comprehensive illustration that robust reliable patient-independent neonatal seizure detection is possible using multi-channel EEG.


Comprehensive expression analysis suggests overlapping and specific roles of rice glutathione S-transferase genes during development and stress responses.
Glutathione S-transferases (GSTs) are the ubiquitous enzymes that play a key role in cellular detoxification. Although several GSTs have been identified and characterized in various plant species, the knowledge about their role in developmental processes and response to various stimuli is still very limited. In this study, we report genome-wide identification, characterization and comprehensive expression analysis of members of GST gene family in crop plant rice, to reveal their function(s). A systematic analysis revealed the presence of at least 79 GST genes in the rice genome. Phylogenetic analysis grouped GST proteins into seven classes. Sequence analysis together with the organization of putative motifs indicated the potential diverse functions of GST gene family members in rice. The tandem gene duplications have contributed a major role in expansion of this gene family. Microarray data analysis revealed tissue-/organ- and developmental stage-specific expression patterns of several rice GST genes. At least 31 GST genes showed response to plant hormones auxin and cytokinin. Furthermore, expression analysis showed the differential expression of quite a large number of GST genes during various abiotic stress (20), arsenate stress (32) and biotic stress (48) conditions. Many of the GST genes were commonly regulated by developmental processes, hormones, abiotic and biotic stresses. The transcript profiling suggests overlapping and specific role(s) of GSTs during various stages of development in rice. Further, the study provides evidence for the role of GSTs in mediating crosstalk between various stress and hormone response pathways and represents a very useful resource for functional analysis of selected members of this family in rice.


Hippocampal morphology and distinguishing late-onset from early-onset elderly depression.
Despite evidence for hippocampal abnormalities in elderly depression, it is unknown whether these changes are regionally specific. This study used three-dimensional mapping techniques to identify regional hippocampal abnormalities in early- and late-onset depression. Neuropsychological correlates of hippocampal morphology were also investigated. With high-resolution magnetic resonance imaging, hippocampal morphology was compared among elderly patients with early- (N=24) and late-onset (N=22) depression and comparison subjects (N=34). Regional structural abnormalities were identified by comparing distances, measured from homologous hippocampal surface points to the central core of each individual's hippocampal surface model, between groups. Hippocampal volumes differed between depressed patients and comparison subjects but not between patients with early- and late-onset depression. However, statistical mapping results showed that regional surface contractions were significantly pronounced in late- compared to early-onset depression in the anterior of the subiculum and lateral posterior of the CA1 subfield in the left hemisphere. Significant shape differences were observed bilaterally in anterior CA1-CA3 subfields and the subiculum in patients in relation to comparison subjects. These results were similar when each disease group was separately compared to comparison subjects. Hippocampal surface contractions significantly correlated with memory measures among late- but not early-onset depressed patients or comparison subjects. More pronounced regional volume deficits and their associations with memory in late-onset depression may suggest that these patients are more likely to develop cognitive impairment over time than individuals with early-onset depression. Mapping regional hippocampal abnormalities and their cognitive correlates may help guide research in defining risk profiles and treatment strategies.


Ajuga turkestanica increases Notch and Wnt signaling in aged skeletal muscle.
The declining myogenic potential of aged skeletal muscle is multifactorial. Insufficient satellite cell activity is one factor in this process. Notch and Wnt signaling are involved in various biological processes including orchestrating satellite cell activity within skeletal muscle. These pathways become dysfunctional during the aging process and may contribute to the poor skeletal muscle competency. Phytoecdysteroids are natural adaptogenic compounds with demonstrated benefit on skeletal muscle. To determine the extent to which a phytoecdysteroid enriched extract from Ajuga turkestanica (ATE) affects Notch and Wnt signaling in aged skeletal muscle. Male C57BL/6 mice (20 months) were randomly assigned to Control (CT) or ATE treatment groups. Chow was supplemented with either vehicle (CT) or ATE (50 mg/kg/day) for 28 days. Following supplementation, the triceps brachii muscles were harvested and immunohistochemical analyses performed. Components of Notch or Wnt signaling were co-labelled with Pax7, a quiescent satellite cell marker. ATE supplementation significantly increased the percent of active Notch/Pax7+ nuclei (p = 0.005), Hes1/Pax7+ nuclei (p = 0.038), active B-catenin/Pax7+ nuclei (p = 0.011), and Lef1/Pax7+ nuclei (p = 0.022), compared to CT. ATE supplementation did not change the resting satellite cell number. ATE supplementation in aged mice increases Notch and Wnt signaling in triceps brachii muscle. If Notch and Wnt benefit skeletal muscle, then phytoecdysteroids may provide a protective effect and maintain the integrity of aged skeletal muscle.


Rolling out Efavirenz for HIV Precision Medicine in Africa: Are We Ready for Pharmacovigilance and Tackling Neuropsychiatric Adverse Effects?
The introduction of antiretroviral therapy (ART) led to huge reductions in human immunodeficiency virus (HIV)-related deaths, turning HIV-infection into a chronic condition. Attention is now turning to quality of life for patients on lifelong ART treatment, reflecting on the safety of antiretroviral drugs. In sub-Saharan Africa, efavirenz (EFV) forms the preferred first-line ART but adverse drug events have also been reported. We express our concern on EFV-based regimens being part of mass rollout programs without full attention to toxicities. EFV is associated with various neuropsychiatric adverse events (AEs). If EFV use is not monitored, a huge burden of neuropsychiatric AEs and elevated risk of drug resistance due to nonadherence are likely to follow. A monumental EFV-based ART regimen rollout program, through the UNAIDS 90-90-90 and option B plus programs/approaches, is planned, which will more than double the number of patients on EFV-containing ART. According to this ambitious treatment target, by 2020, 90% of all people living with HIV will know their HIV status; 90% of all people with diagnosed HIV infection will receive sustained ART; and 90% of all people receiving ART will have viral suppression. On the other hand, HIV patients of African origin are predisposed to developing EFV-induced neuropsychiatric AEs due to specific CYP2B6 genetic variants causing impaired metabolism of EFV. It is our considered opinion that the potential quantitative and qualitative burden of EFV-induced neuropsychiatric AEs, which can vary from person-to-person and between populations, deserve special attention and action during the ART rollout program. We here make a case for Africa in particular where we project the burden of neuropsychiatric AEs to be greatest. We advocate for surveillance of neuropsychiatric AEs due to EFV therapy, incorporation of pharmacogenetics testing for CYP2B6 to assist in EFV dosing, and measurement of plasma EFV concentration, as a three-pronged rational therapeutic drug monitoring strategy to guide EFV treatment toward precision medicine.


Prediction of the mechanical behaviour of crystalline solids.
To explore the use of crystal inter-planar d-spacings and slip-plane interaction energies for predicting and characterising mechanical properties of crystalline solids. Potential relationships were evaluated between mechanical properties and inter-planar d-spacing, inter-planar interaction energy, and dispersive surface energy as determined using inverse gas chromatography (IGC) for a set of pharmaceutical materials. Inter-planar interaction energies were determined by molecular modelling. General trends were observed between mechanical properties and the largest inter-planar d-spacing, inter-planar interaction energies, and IGC dispersive surface energy. A number of materials showed significant deviations from general trends. Weak correlations and outliers were rationalised. Results suggest that the highest d-spacing of a material could serve as a first-order indicator for ranking mechanical behaviour of pharmaceutical powders, but with some reservation. Inter-planar interaction energy normalised for surface area shows only a weak link with mechanical properties and does not appear to capture essential physics of deformation. A novel framework linking mechanical properties of crystals to the distinct quantities, slip-plane energy barrier and inter-planar interaction (detachment) energy is proposed.


Comparisons of magnetic defects and coercive forces for Co/Si(100) and Co/rubrene/Si(100).
Spintronics can add new functionalities to electronic devices by utilizing the spin degree of freedom of electrons. Investigating magnetic defects is crucial for the performance of spintronics devices. However, the effects of magnetic defects that are introduced by the presence of organic materials on their magnetic properties remain unclear. Herein, we report on a novel method using rubrene combined with Kerr microscopy that enables quantitative and direct measurements of magnetic defect density. For Co/Si(100) at a magnetic field near the coercivity value, Kerr microscopy images show a dark image with some magnetic defects. Because of domain wall motion, small patches gradually change the contrast. These magnetic defects are immovable at different magnetic fields and serve as pinning sites for domain wall motion. Experimental evidence shows that coercive force can be reduced by controlling the magnetic defect density by introducing small amounts of rubrene into the films. Furthermore, direct quantitative measurements of magnetic defects show both a one-dimensional bowing of domain walls and strong defect-domain wall interactions in the films. Based on these findings, we propose a viable strategy for reducing the coercive force of Co/Si(100) by controlling the magnetic defect density and this new information promises to be valuable for future applications of spintronics devices.


Learning Representations from Medical Text for Effective Diagnoses and Knowledge Discovery.
Discovering knowledge and effectively predicting target events are two main goals of medical text mining. However, few models can achieve them simultaneously. In this study, we investigated the possibility of discovering knowledge and predicting diagnosis at once via raw medical text. We proposed the Enhanced Neural Topic Model (ENTM), a variant of the neural topic model, to learn interpretable representations. We introduced the auxiliary loss set to improve the effectiveness of learned representations. Then, we used learned representations to train a softmax regression model to predict target events. As each element in representations learned by the ENTM has an explicit semantic meaning, weights in softmax regression represent potential knowledge of whether an element is a significant factor in predicting diagnosis. We adopted two independent medical text datasets to evaluate our ENTM model. Results indicate that our model performed better than the latest pretrained neural language models. Meanwhile, analysis of model parameters indicates that our model has the potential discover knowledge from data.Clinical relevance- This work provides a model that can effectively predict patient diagnosis and has the potential to discover knowledge from medical text.


Retrospective Comparison of Pulmonary Arteriovenous Malformation Embolization with the Polytetrafluoroethylene-Covered Nitinol Microvascular Plug, AMPLATZER Plug, and Coils in Patients with Hereditary Hemorrhagic Telangiectasia.
To evaluate effectiveness of the polytetrafluoroethylene-covered nitinol mesh microvascular plug (MVP) and compare it with other devices in pulmonary arteriovenous malformation (PAVM) embolization in patients with hereditary hemorrhagic telangiectasia (HHT). Twenty-five patients (average age 35 y; range, 15-56 y) with hereditary hemorrhagic telangiectasia (HHT) and de novo PAVM embolization with at least 1 MVP between November 2015 and May 2017 were retrospectively evaluated. Retrospective data were also obtained from prior embolization procedures in the same patient population with other embolic devices dating back to 2008. Technical success, complications, PAVM persistence rates, and category of persistence were analyzed. In 25 patients, 157 PAVMs were treated: 92 with MVP, 35 with AMPLATZER vascular plug (AVP), 6 with AVP plus coils, and 24 with coils. The per-PAVM technical success rates were 100% with MVP; 97%, AVP; 100%, AVP plus coils; and 100%, coils. PAVM persistence rates and median follow-up were as follows: MVP, 2% (1/92) (510 d); AVP, 15% (3/20) (1,447 d); AVP plus coils, 20% (1/5) (1,141 d); coils, 46.7% (7/15) (1,141 d). Persistence owing to recanalization for MVP, AVP, AVP plus coils, and coils was 2%, 15%, 0%, and 33%. No difference was found between persistence rates of MVP vs AVP (P = .098). Embolization with a vascular plug (MVP or AVP) with or without coils had a statistically significant lower persistence rate (5.4%) than embolization with coils alone (46.7%) (P = .022). PAVM embolization with MVP had a high technical success rate and a low persistence rate comparable to AVP and lower than coil embolization alone.


Prediction of adult height and risk of overweight in females born small-for-gestational-age.
The risk of short adult stature in women born small-for-gestational age (SGA) was estimated in this prospective cohort study of 43 872 singleton females, born between 1973 and 1983, who gave birth to a child between 1989 and 1999. The risk of overweight in females born SGA, with and without short adult stature, was also studied. All data on birth characteristics and adult height and weight were obtained from the Swedish Birth Register. SGA-born females were divided into being born short only for gestational age [birth length < -2 standard deviation scores (SDS)], born light for gestational age (birthweight < -2 SDS) or being born both short and light for gestational age. Short adult stature was defined as adult height below -2 SDS. Among females, being born SGA (<-2 SDS in birth length or birthweight) was associated with increased risk of short adult stature, compared with being born appropriate for gestational age. The risk varied substantially within different subgroups of females born SGA: being born short for gestational age was associated with an almost fivefold increased risk [odds ratio (OR) 4.89; 95% confidence interval (CI) 3.70, 6.47] of short adult stature, whereas being born light for gestational age was associated with an almost twofold increased risk [OR 1.95, 95% CI 1.43, 2.65]. Overall, females born SGA did not have increased risk of overweight compared with females with appropriate size at birth. However, among females born short for gestational age, short adult stature was associated with an increased risk of overweight in adulthood [OR 1.77, 95% CI 1.01, 3.12]. In conclusion, among females born SGA, of the birth characteristics, short birth length is associated with the highest increased risk of short adult stature. Spontaneous growth in height to normal adult stature reduced the risk of overweight in females born short for gestational age.


Vitamin E supplementation and stress affect tissue alpha-tocopherol content of beef heifers.
The effect of stress on tissue alpha-tocopherol was investigated in 16 crossbred heifers fed a corn/corn silage-based diet. For 28 d, eight heifers (379 +/- 10 kg BW) received a dietary supplement of 1,000 IU of dl-alpha-tocopheryl acetate, whereas the controls (375 +/- 10 kg BW) received no supplemental vitamin E. Tissue samples of plasma, red blood cells, liver, trapezius, and longissimus muscles and subcutaneous fat immediately dorsal to each muscle were taken on d 1 for determination of alpha-tocopherol concentration. On d 2 through 4 each heifer was restricted to 2.61 kg of grass hay and allowed water. On d 5, 6, and 7 no feed or water was given, 100 IU of ACTH and .0024 mg of epinephrine/kg BW were given every 8 h, and biopsies for alpha-tocopherol content were again taken on d 7. The stress reduced (P < .01) mean BW, increased (P < .01) serum cortisol, creatine kinase, and urea. After stress, supplemental vitamin E reduced (P < .13) the increase in creatine kinase relative to that in heifers not supplemented with vitamin E. Stress also increased (P < .04) serum Se in heifers fortified with the vitamin E. Alpha-tocopherol content of plasma, red blood cells, liver, and subcutaneous fat dorsal to the trapezius muscle was increased (P < .01) by supplemental vitamin E. The stress treatment reduced (P < .01) alpha-tocopherol content of plasma in those fed the vitamin E and increased it (P < .05) in the nonsupplemented vitamin E-deficient heifers. Stress also decreased red blood cell (P < .01) and liver (P < .05) alpha-tocopherol content in cattle supplemented with vitamin E. Tissue alpha-tocopherol concentrations were reduced by stress only when a diet adequate in vitamin E was fed. In addition, in most sampled tissues, stress did not affect alpha-tocopherol concentrations.


Hormones and homocysteine.
Hyperhomocysteinemia is a well-established risk factor for cardiovascular disease. Various factors, both modifiable and non-modifiable, interact with the homocysteine metabolism and determine the plasma homocysteine concentrations. These include genetic abnormalities, age, sex and various nutritional and hormonal determinants, all of which play a role in atherosclerosis and accelerated peripheral and cardio-vascular disease (CVD). Several hormones modulate homocysteine metabolism and hence may play a role in the pathogenesis of CVD. The mechanisms involved are unclear. The association of hyperhomocysteinemia with diabetes mellitus is complex and may explain some of the risk of CVD in diabetics not explained by traditional risk factors. Much conflicting data exists in the literature on the role of insulin on homocysteine metabolism, although insulin affects the enzymes regulating the homocysteine metabolism. Treatment of hyperhomocysteinemia with vitamins lowers plasma homocysteine concentrations. Little data is available on the effect of this intervention on cardiovascular outcomes. This review briefly outlines the homocysteine metabolism, summarizes its hormonal determinants, and discusses the role of hyperhomocysteinemia in diabetes, hyperlipidemia and other endocrine disorders.


Evaluation of the Efficacy of Psychological Interventions in Promoting Preparedness to Armed Conflicts - A Randomized Controlled Study.
Despite efforts by civil defense authorities, levels of households' preparedness to emergencies remain insufficient in many countries. Engaging the public in preparedness behavior is a challenge worldwide. The purpose of this study was to explore the efficacy of psychological intervention in promoting preparedness behavior to armed conflicts in Israel. A randomized controlled trial (N = 381) with two control groups and three intervention groups was used. The psychological interventions studied were elevated threat perception, external reward, and manipulation of a cognitive cluster related to preparedness. The results of the analysis suggest a significant effect of intervention on the increase of reported preparedness (F4,375 = 4.511, P = 0.001). The effect is attributed to the intervention group in which external reward was offered. Participants in this group were about two times more likely to report greater levels of preparedness compared to the control group (RR = 1.855; 95% CI: 1.065, 3.233). The findings suggest that preparedness behavior can be promoted through external incentives. These are presumably effective motivators because they encourage preparedness while allowing subjects to retain their denial as an adaptive coping mechanism. Innovative thinking is required to overcome the psychological barriers associated with public reluctance to engage in preparedness. (Disaster Med Public Health Preparedness. 2018;13:713-723).


Harnessing Microbiota to Improve Immunotherapy for Gastrointestinal Cancers.
Immune checkpoint blockade has revolutionized opportunities for therapeutic intervention in cancer but demonstrates a low frequency of response in most patients and in some common types of tumors. An emerging paradigm supports the notion that trillions of normally beneficial microbes inhabiting the gastrointestinal tract, termed the microbiota, critically impact the success or failure of antitumor immunity induced by immune checkpoint blockade. Here, we briefly summarize the current knowledge on how interactions between the microbiota and immune system are contributing to the outcome of cancer immunotherapy. We propose that this immune-microbiota dialogue is particularly important in gastrointestinal cancers that exhibit striking resistance to immune checkpoint blockade and inherently develop in a unique environment that is rich in both immune-cell networks and direct exposure to the microbiota. Finally, we focus on how future studies should determine whether microbiota can be harnessed as a strategy to boost antitumor immunity in these contexts and beyond. See related article, p. 1291.


The Bcvic1 and Bcvic2 vegetative incompatibility genes in Botrytis cinerea encode proteins with domain architectures involved in allorecognition in other filamentous fungi.
Vegetative incompatibility is a fungal allorecognition system characterised by the inability of genetically distinct conspecific fungal strains to form a viable heterokaryon and is controlled by multiple polymorphic loci termed vic (vegetative incompatibility) or het (heterokaryon incompatibility). We have genetically identified and characterised the first vic locus in the economically important, plant-pathogenic, necrotrophic fungus Botrytis cinerea. A bulked segregant approach coupled with whole genome Illumina sequencing of near-isogenic lines of B. cinerea was used to map a vic locus to a 60-kb region of the genome. Within that locus, we identified two adjacent, highly polymorphic open reading frames, Bcvic1 and Bcvic2, which encode predicted proteins that contain domain architectures implicated in vegetative incompatibility in other filamentous fungi. Bcvic1 encodes a predicted protein containing a putative serine esterase domain, a NACHT family of NTPases domain, and several Ankyrin repeats. Bcvic2 encodes a putative syntaxin protein containing a SNARE domain; such proteins typically function in vesicular transport. Deletion of Bcvic1 and Bcvic2 individually had no effect on vegetative incompatibility. However, deletion of the region containing both Bcvic1 and Bcvic2 resulted in mutant lines that were severely restricted in growth and showed loss of vegetative incompatibility. Complementation of these mutants by ectopic expression restored the growth and vegetative incompatibility phenotype, indicating that Bcvic1 and Bcvic2 are controlling vegetative incompatibility at this vic locus.


PASTA-kinase-mediated signaling drives accumulation of the peptidoglycan synthesis protein MurAA to promote cephalosporin resistance in Enterococcus faecalis.
The bacterial PASTA kinase, IreK, is required for intrinsic cephalosporin resistance in the Gram-positive opportunistic pathogen, Enterococcus faecalis. IreK activity is enhanced in response to cell wall stress, such as cephalosporin exposure. The downstream consequences of IreK activation are not well understood in E. faecalis, but recent work in other low-GC Gram-positive bacteria demonstrated PASTA kinase-dependent regulation of MurAA, an enzyme that performs the first committed step in the peptidoglycan synthesis pathway. Here, we used genetic suppressor selections to identify MurAA as a downstream target of IreK signaling in E. faecalis. Using complementary genetic and biochemical approaches, we demonstrated that MurAA abundance is regulated by IreK signaling in response to physiologically relevant cell wall stress to modulate substrate flux through the peptidoglycan synthesis pathway. Specifically, the IreK substrate, IreB, promotes proteolysis of MurAA through a direct physical interaction in a manner responsive to phosphorylation by IreK. MurAB, a homolog of MurAA, also promotes MurAA proteolysis and interacts directly with IreB. Our results therefore establish a connection between the cell wall stress sensor IreK and one critical physiological output to modulate peptidoglycan synthesis and drive cephalosporin resistance.


[The hypothalamo-hypophyseal neurosecretory system in rats with hereditary arterial hypertension].
Histochemical and cytometrical analysis of the peptidergic Gomori-positive or hypothalamo-hypophyseal neurosecretory system (HHNS) was made in the 3 strains of rats: spontaneously hypertensive rats (SHR), rats with inherited stress-induced arterial hypertension (ISIAH), and normotensive Wistar rats. A significant increase in the production of the peptide neurohormones by the supraoptic nuclei was found in two hypertensive strains (SHR and ISIAH) compared to the normotensive Wistar rats. For ISIAH-rats, the excretion of neurohormones was more pronounced in the region of median eminence, and for SHR--in the posterior hypophyseal lobe. It was concluded that hyperfunction of HHNS can play an important role in the hypertension development in two strains or rats studied.


Nanocomposites: structure, phase behavior, and properties.
It is well recognized that nanocomposites formed by adding nanoparticles to polymers can have significantly enhanced properties relative to the native polymer. This review focuses on three aspects that are central to the outstanding problem of realizing these promised property improvements. First, we ask if there exist general strategies to control nanoparticle spatial distribution. This is an important question because it is commonly accepted that the nanoparticle dispersion state crucially affects property improvements. Because ideas on macroscale composites suggest that optimizing different properties requires different dispersion states, we next ask if we can predict a priori the particle dispersion and organization state that can optimize one (or more) properties of the resulting nanocomposite. Finally, we examine the role that particle shape plays in affecting dispersion and hence property control. This review focuses on recent advances concerning these underpinning points and how they affect measurable properties relevant to engineering applications.


Caring as emancipatory nursing praxis: the theory of relational caring complexity.
In the culture of health care, nurses are challenged to understand their values and beliefs as humanistic within complex technical and economically driven bureaucratic systems. This article outlines the language of social justice and human rights and the advance of a Theory of Relational Caring Complexity, which offers insights into caring as emancipatory nursing praxis. Recommendations provide knowledge of the struggle to balance economics, technology, and caring. As nurses practice from a value-driven, philosophical, and ethical social justice framework, they will find "their voice" and realize the full potential that the power of caring has on patient and organizational outcomes.


The conundrum of primary snoring in children: what are we missing in regards to cognitive and behavioural morbidity?
Sleep disordered breathing (SDB) is common in children and describes a continuum of nocturnal respiratory disturbance from primary snoring (PS) to obstructive sleep apnoea (OSA). Historically, PS has been considered benign, however there is growing evidence that children with PS exhibit cognitive and behavioural deficits equivalent to children with OSA. There are two popular mechanistic theories linking SDB with daytime morbidity: hypoxic insult to the developing brain; and sleep disruption due to repeated arousals. These theories apply well to OSA, but children with PS experience neither hypoxia nor increased arousals when compared to non snoring controls. So what are we missing? This review summarises the literature examining daytime morbidity in children with PS and discusses the current debates surrounding this relationship. Specifically, questions exist as to the sensitivity of our standard assessment techniques to measure subtle hypoxia and arousal. There is also a suggestion that the association between PS and daytime morbidity may not be mediated by nocturnal respiratory disturbance at all, but by a number of other comorbid, but perhaps unrelated factors. As approximately 70% of children with SDB are diagnosed with PS, but are rarely treated, a paradigm shift in the investigation of PS may be required.


Synthesis and characterization of bisoxazolines- and pybox-copper(II) complexes and their application in the coupling of α-carbonyls with functionalized amines.
Binuclear complexes [{(DMOX)CuCl}2(μ-Cl)2] (1), mononuclear complexes [(DMOX)CuBr2] (2) (DMOX = 4,5-dihydro-2-(4,5-dihydro-4,4-dimethyloxazol-2-yl)-4,4-dimethyloxazole) and the pybox Cu(II) complex [(Dm-Pybox)CuBr2] (3) (Dm-Pybox = 2,6-bis[4',4'-dimethyloxazolin-2'-yl]pyridine) were obtained by reactions of CuX2 (X = Cl, Br) with DMOX and Dm-Pybox ligands, respectively. The molecular structures of 1, 2 and 3 have been determined by single-crystal X-ray diffraction analyses. The complexes 2 and 3 are efficient in catalyzing α-amination of ketones and esters through α-bromo carbonyl intermediate. The procedures are environmentally benign methods using molecular oxygen as an oxidant with water as the only byproduct.


Debulking surgery and intraperitoneal chemotherapy are associated with decreased morbidity in women receiving neoadjuvant chemotherapy for ovarian cancer.
The aims of this study were to compare the rate of completion of optimal debulking and/or 6 cycles of intraperitoneal (IP) chemotherapy in women with International Federation of Gynecologists and Obstetricians stage III/IV ovarian cancer undergoing neoadjuvant chemotherapy (NACT) versus primary surgery (PS) and to compare morbidity between these 2 groups. Ninety-six subjects with stage III/IV ovarian cancer who underwent either NACT or PS were identified. Data comparisons include rate of optimal debulking and completion rate of 6 cycles of IP chemotherapy. Other data collected included surgical times, length of stay, intensive care unit admissions, blood transfusions, bowel resections, major complications, and dose reductions. SigmaStat version 2.0 was used for statistical analysis. Of the 96 subjects, 38 received NACT and 58 had PS. All 14 subjects with stage IV disease received NACT, and all experienced resolution of pleural effusion, based on computed tomographic imaging. Thirty-five (92%) of 38 NACT subjects versus 47 (81%) of 58 PS subjects were optimally debulked (P = 0.08). Thirty-six (95%) of 38 NACT subjects versus 37 (64%) of 58 PS subjects completed IP chemotherapy (P < 0.001). Length of stay was 3.26 (NACT) versus 5.08 (PS) days (P < 0.001). Intensive care unit admissions were 1 of 38 (NACT) versus 12 of 58 (PS) (P < 0.001). Bowel resections were done in 2 of 38 (NACT) versus 14 of 38 (PS) (P < 0.05). Duration of surgery was 96 minutes (NACT) versus 138 minutes (PS) (P < 0.001). A trend to fewer dose reductions occurred in NACT (1/38) versus PS (8/58) (P = 0.056). The NACT subjects were more likely to complete IP chemotherapy and had decreased length of stay, intensive care unit admissions, bowel resections, and duration of surgery. Both optimal debulking and dose reductions were numerically but not statistically associated with NACT versus PS. This likely reflects a relatively high overall rate of optimal debulking and low rate of dose reductions in these subjects and would require a larger group to determine significance.


Utility of tPA Administration in Acute Treatment of Internal Carotid Artery Occlusions.
Intravenous tissue plasminogen activator (IV-tPA) remains part of the guidelines for acute ischemic stroke treatment, yet internal carotid artery occlusions (ICAO) are known to be poorly responsive to IV-tPA. It is unknown whether bridging thrombolysis (BT) is beneficial in such cases. We sought to evaluate whether the use of IV-tPA improved overall clinical outcomes in patients undergoing endovascular thrombectomy (EVT) for ICA occlusions. Data from 1367 consecutive stroke cases treated with EVT from 2012-2019 were prospectively collected from a single center. Univariate and multivariate logistic regression were used to assess the relationship between IV-tPA administration and clinical outcome. 153 patients were found to have carotid terminus and tandem ICAO who received EVT and presented within 4.5h of last seen well. 50% (n = 82) received IV tPA. There were no differences between the groups with respect to age, NIHSS, time to EVT and ASPECTS score. 53% had tandem ICA-MCA occlusions. Rate of recanalization (≥ TICI 2B) and sICH did not significantly differ between the two groups. Regression analysis demonstrated no effect of IV-tPA on modified Rankin Score (mRS) at 90 days and overall mortality. Factors significantly associated with reduced mortality included lower age, lower NIHSS, and better rate of recanalization. There was no significant difference in clinical outcomes in those receiving BT vs. direct EVT for ICAO. For centers with optimal door-to-puncture times, bypassing IV-tPA may expedite recanalization times and potentially yield more favorable outcomes. Patients with higher NIHSS and tandem lesions may have better outcomes with BT.


Positively cooperative sites for drug transport by P-glycoprotein with distinct drug specificities.
In this paper, we show that P-glycoprotein contains two distinct sites for drug binding and transport, and that, unexpectedly, these sites interact in a positively cooperative manner. The kinetics of transport of rhodamine 123 and Hoechst 33342 in isolated P-glycoprotein-rich plasma membrane vesicles from Chinese hamster ovary CH(R)B30 cells were followed by continuous fluorescence monitoring. Each substrate stimulated P-glycoprotein-mediated transport of the other. Colchicine and quercetin stimulated rhodamine 123 transport and inhibited Hoechst 33342 transport. In contrast, anthracyclines such as daunorubicin and doxorubicin stimulated Hoechst 33342 transport and inhibited rhodamine 123 transport. Vinblastine, actinomycin D, and etoposide inhibited transport of both dyes. The results are consistent with a functional model of P-glycoprotein containing at least two positively cooperative sites (H site and R site) for drug binding and transport. This model is consistent with earlier observations of competitive and non-competitive effects of P-glycoprotein substrates and chemosensitizers. Such a two-site model may be fundamental to multidrug transport by P-glycoprotein, and it may be a feature common to other ATP-dependent transporters belonging to the ATP-binding cassette superfamily.


A diet survey in Zimbabwe.
The diets of various Zimbabweans: black and white, middle class and working class, rural and urban are compared. Urban volunteers were recruited from a number of business premises in Harare, the capital of Zimbabwe. Rural volunteers were recruited at several villages and cooperative farms averaging 200 km from the capital. The composition of the diets, expressed as per cent total energy obtained from fat, carbohydrate, and protein, and megajoules (MJ) energy respectively, were: white middle class, 40 per cent, 39 per cent, 16 per cent, 9.35 MJ (M), 6.65 MJ (F); black middle class, 30 per cent, 49 per cent, 17 per cent, 10.96 MJ (M), 6.60 MJ (F); black urban working class, 25 per cent, 53 per cent, 17 per cent, 10.96 MJ (M), 7.53 MJ (F); black urban middle class, 23 per cent, 54 per cent, 16 per cent, 10.88 MJ (M), 7.67 MJ (F); and black rural working class, 22 per cent, 58 per cent, 17 per cent, 9.43 MJ (M), 8.02 MJ (F). The results suggest that the sample of Zimbabweans studied here are well nourished, even by the standards of developed countries. Anthropometric data supports this, showing that Zimbabwean peasants are both taller and heavier than their counterparts in Malawi, Uganda, Tanzania, and Kenya, all members of the Bantu cultural group in East and Central Africa.