A rapid, whole-tissue determination of the functional fraction of PSII after photoinhibition of leaves based on flash-induced P700 redox kinetics.
Assaying the number of functional PSII complexes by the oxygen yield from leaf tissue per saturating, single-turnover flash, assuming that each functional PSII evolves one oxygen molecule after four flashes, is one of the most direct methods but time-consuming. The ratio of variable to maximum Chl fluorescence yield (F(v)/F(m)) in leaves can be correlated with the oxygen yield per flash during a progressive loss of PSII activity associated with high-light stress and is rapid and non-intrusive, but suffers from being representative of chloroplasts near the measured leaf surface; consequently, the exact correlation depends on the internal leaf structure and on which leaf surface is being measured. Our results show that the average F(v)/F(m) of the adaxial and abaxial surfaces has a reasonable linear correlation with the oxygen yield per flash after varied extents of photoinactivation of PSII. However, we obtained an even better linear correlation between (1) the integrated, transient electron flow (Sigma) to P700+, the dimeric Chl cation in PSI, after superimposing a single-turnover flash on steady background far-red light and (2) the relative oxygen yield per flash. Leaves of C3 and C4 plants, woody and herbaceous species, wild-type and a Chl-b-less mutant, and monocot and dicot plants gave a single straight line, which seems to be a universal relation for predicting the relative oxygen yield per flash from Sigma. Measurement of Sigma is non-intrusive, representative of the whole leaf tissue, rapid and applicable to attached leaves; it may even be applicable in the field.


Effect of leptin replacement on brain structure in genetically leptin-deficient adults.
The hormone leptin profoundly affects body weight and metabolism. Three human adults (two women, 35 and 40 yr old; one man, age 27) have been identified with a recessive mutation in the ob gene, which is homologous to the mutation in ob/ob mice, and produces leptin deficiency and morbid obesity. Because leptin replacement increases brain weight and changes brain protein and DNA content in ob/ob mice, we hypothesized that analogous treatment of leptin-deficient humans would alter brain tissue composition. Volumetric T1-weighted magnetic resonance images of the brain were acquired before and at 6 and 18 months after initiation of replacement therapy (daily sc injections of recombinant methionyl human leptin), which produced dramatic loss in body weight. We used voxel-based morphometry to test for increased gray matter tissue concentration after initiation of leptin replacement and detected increases at 6 months in the anterior cingulate gyrus, the inferior parietal lobule, and the cerebellum. These increases were maintained for over 18 months, with identical stereotaxic coordinates of the maxima for the effects. Our findings suggest that leptin can have sustained effects on tissue composition in the human brain and broaden the potential spectrum of leptin's influence beyond feeding behavior and endocrine function.


Primary leptomeningeal lymphoma: International Primary CNS Lymphoma Collaborative Group report.
To evaluate clinical presentation, optimal diagnostic evaluation and treatment, and outcome in primary leptomeningeal lymphoma, a rare form of primary CNS lymphoma without parenchymal or systemic involvement. The International Primary CNS Lymphoma Collaborative Group, a multidisciplinary group of physicians with a particular interest in primary CNS lymphoma, retrospectively identified cases of lymphoma isolated to the leptomeninges as diagnosed by CSF cytology, flow cytometry, or biopsy, without systemic or parenchymal brain/spinal cord lymphoma or immunodeficiency. Forty-eight patients were identified, with median age at diagnosis of 51 years and median Eastern Cooperative Oncology Group performance status of 2. Presenting symptoms were multifocal in 68%. Leptomeningeal enhancement was seen in 74% and CSF profile was abnormal in all cases. CSF cytology detected malignant lymphocytes in 67%. Flow cytometry identified monoclonal population in 80%, as did receptor gene rearrangement studies in 71%. Sixty-two percent had B-cell lymphoma, 19% T-cell, and 19% unclassified. Treatment varied and included fractionated radiotherapy (36%), systemic chemotherapy (78%), and intra-CSF chemotherapy (66%), with 66% receiving ≥ 2 modalities. Seventy-one percent had a favorable clinical response; ultimately, 44% received salvage treatment. Median overall survival was 24 months, with 11 patients still alive at 50 months follow-up. Primary leptomeningeal lymphoma is a rare form of primary CNS lymphoma. Patients usually present with multifocal symptoms, with evidence of leptomeningeal enhancement and diagnostic CSF analysis. Although treatment is highly variable, patients have a better prognosis than previously reported and a subset may be cured.


What's new in Obstetric Anesthesia? The 2013 Gerard W. Ostheimer lecture.
The "What's New in Obstetric Anesthesia?" keynote lecture was established by the Society for Obstetric Anesthesia and Perinatology in memory of the eminent obstetric anesthesiologist, Dr. Gerard W. Ostheimer. From a wide selection of journals encompassing the fields of obstetric anesthesia, obstetrics, and perinatology, the designated lecturer identifies articles of significant impact and interest published in the preceding year. The Ostheimer lecture, delivered this year at the annual meeting of the Society in April 2013 in San Juan, Puerto Rico, included highly relevant papers that have the potential to change obstetric anesthesia practice or impact public health. This review summarizes 5 categories of pertinent articles that were published in 2012 and discussed in the 2013 Ostheimer lecture: maternal diseases, labor and delivery, advances in obstetric anesthesia, obstetric complications, and anesthesia-related complications.


Characterization of chicken TNFR superfamily decoy receptors, DcR3 and osteoprotegerin.
Tumor necrosis factor (TNF) family ligands bind to death domain-containing TNF receptors (death receptors), which can subsequently activate intracellular signaling pathways to initiate caspase activity and apoptotic cell death. Decoy receptors, without intracellular death domains, have been reported to prevent cytotoxic effects by binding to and sequestering such ligands, or by interfering with death receptor trimerization. The chicken death receptors, Fas, TNFR1, DR6, and TVB, are constitutively expressed in a relatively wide variety of hen tissues. In this study, two chicken receptors with sequence homology to the mammalian decoys, DcR3 and osteoprotegerin, were identified and their pattern of expression was characterized. Unlike the previously identified chicken death receptors, the newly characterized decoy receptors show comparatively limited expression among tissues, suggesting a tissue-specific function. Finally, characterization of these chicken receptors further contributes to understanding the evolutionary divergence of TNFR superfamily members among vertebrate species.


Safety and efficacy of bilateral simultaneous XEN implant surgery: a pilot study.
To evaluate the efficacy and safety of the bilateral simultaneous XEN (BISIXEN) surgery in open-angle glaucoma patients. Retrospective analysis of a prospective data base conducted on uncontrolled glaucoma patients who underwent BISIXEN surgery. Primary endpoint measure was the incidence of sight-threatening complications. Secondary endpoints included intraocular pressure (IOP) reduction and in number of required antiglaucoma medications. Ten patients (20 eyes) were included in the analysis. Median (95% confidence interval) follow-up was 12.0 (7.0-12.0) months, with 14 eyes having a follow-up of 12 months. No sight-threatening complications, such as endophthalmitis, retinal detachment, corneal decompensation, or intraocular hemorrhages were observed in any eye of study sample. Mean IOP decreased significantly from 25.2 (21.5-28.9) mm Hg at baseline to 15.1 (13.4-16.8) mm Hg at the last follow-up visit (p = 0.0001). Mean number of antiglaucoma medications was significantly reduced from 2.9 (2.5 to 3.3) drugs at baseline to 0.40 (0.00-0.70) at the end of the study (p < 0.0001). At the last study visit, 14 (70.0%) eyes had an IOP ≥ 6 and ≤ 18 mm Hg without treatment. Two eyes needed surgical revision and three ones needed a new glaucoma surgery: two underwent Ahmed valves (one eye with aniridia and the other previously operated on) and one underwent non-penetrating deep sclerectomy. Bilateral simultaneous XEN implantation may be a feasible strategy in those patients with high anesthetic risk.


Angiotensin converting enzyme inhibitors and progression of chronic renal failure.
Renal failure, once established by loss of a critical amount of functional renal mass, tends to be progressive. A large body of experimental evidence supports the hypothesis that glomerular capillary hypertension is important in the pathogenesis of progressive chronic renal failure of diverse types, including subtotal renal ablation and diabetic nephropathy. Converting enzyme inhibitors are effective in slowing or arresting the progression of glomerular injury in these experimental models, in association with normalization of both systemic and intrarenal pressures. Clinical studies of diabetic nephropathy and chronic renal failure of other etiologies support the concept that these same renal hemodynamic factors are important in human renal disease and that treatment with converting enzyme inhibitors may prove to be a useful therapeutic intervention. Whether the converting enzyme inhibitors have specific advantages over other antihypertensive agents due to beneficial renal hemodynamic effects, as suggested by experimental studies, is a question that awaits further investigation. Furthermore, the pathogenesis of hypertensive glomerular injury is complex and involves the participation of diverse biologic systems. We predict that a wide variety of therapeutic maneuvers, with disparate mechanisms of action, may be effective in arresting or preventing glomerular injury.


Glucose Metabolism in Children With Growth Hormone Deficiency.
The growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis has a fundamental impact on glucose metabolism. Therefore, both untreated GH deficiency (GHD) and GH treatment (GHT) may be associated with some metabolic alterations, although the abnormalities of glucose metabolism have been investigated by relatively few studies as main outcomes. The present review summarizes the available data on glucose metabolism in children with GHD, providing an overview of the current state of the art in order to better clarify the real metabolic impact of GHD and GHT. Among all the existing studies, we evaluated all original studies that fulfilled our criteria for analysis reporting parameters of glucose metabolism as the primary or secondary objective. The reported impact of GHD per se on glucose metabolism is quite homogeneous, with the majority of studies reporting no significant difference in metabolic parameters between GHD children and controls. Conversely, GHT proves to be more frequently associated with a subtle form of insulin resistance, while both fasting glucose and HbA1c levels remain almost always within the normal range. The different methods to study glucose metabolism, the heterogeneity of the populations evaluated, the different doses of GH used together with the variable duration of follow-up may be responsible for discrepancy in the results. Long-term longitudinal studies having glucose homeostasis as their primary outcome are still needed in order better to clarify the real metabolic impact of GHD and GHT in children.


Promoting toddlers' vegetable consumption through interactive reading and puppetry.
Picture books with characters that promote healthy eating are increasingly being used to make this behavior more attractive. The first aim of this study was to investigate whether the effect of vegetable-promoting picture books on toddlers' vegetable consumption differed according to the reading style and the use of a hand puppet during reading. The second aim was to investigate whether these effects were mediated by toddlers' narrative involvement and character imitation. In a 2 (reading style: interactive vs. passive) x 2 (puppet use: with vs. without puppet) between-subjects design, 163 toddlers (2-3 years) were randomly assigned to one of the four reading conditions. The story was about a rabbit that loves to eat carrots. After the fourth reading day, the eating task was conducted in which children could eat freely from four different snacks, including carrots. The main finding was that interactive reading produced the greatest carrot consumption. The explanation for this effect was that interactive reading stimulated toddlers to imitate poses of the book characters, even more when interactive reading was supported by the use of a hand puppet. The findings underline that young children should be actively involved with health interventions in order for them to be effective.


Prophylactic cancer vaccines: development and challenges for HBV and HPV vaccines in Latin America.
Vaccines against hepatitis B virus (HBV) and human papillomaviruses (HPV) are two safe and highly effective vaccines that were developed at the end of the 20th century and can prevent human cancer. HBV vaccine prevents liver cancer, and HPV prevents cervical and other HPV-related cancers. Starting with the immunogen identification, 15 years were necessary to reach the industrial production of HBV vaccine, and 20 years, for the HPV vaccines. However, while HBV vaccines have been commercially available for over 40 years and are used in most countries, there are still significant challenges to achieve universal childhood immunization against hepatitis B. Similarly, HPV vaccines have been commercially available for 17 years, and yet, countries with higher cervical cancer still have the lowest HPV vaccination rates. We describe the development of HBV and HPV vaccines and discuss the challenges to reaching equitable access to these vaccines in Latin America.


DNA sequence of the major capsid protein gene of herpes simplex virus type 1.
The DNA sequence of the region of the herpes simplex virus type 1 genome encoding the major capsid protein was determined. The predicted protein contains 1374 amino acid residues and has a molecular weight of 149,075. Comparisons of the amino acid sequence of this protein with those predicted from the published DNA sequences of two other herpesviruses, varicella-zoster virus and Epstein-Barr virus, resulted in the identification of the major capsid protein gene in each genome.


Influence of Th2 Cytokines on the Cornified Envelope, Tight Junction Proteins, and ß-Defensins in Filaggrin-Deficient Skin Equivalents.
Atopic dermatitis is a chronic skin condition with complex etiology. It is characterized by skin barrier defects and T helper type 2 (Th2)-polarized inflammation. Although mutations in the filaggrin gene are known to be prominent genetic risk factors for the development of atopic dermatitis, the interdependency between these and an altered cytokine milieu is not fully understood. In this study, we evaluated the direct effects of filaggrin deficiency on the cornified envelope, tight junction proteins, and innate immune response, and report the effects of Th2 cytokines in normal and filaggrin-deficient skin equivalents. Supplementation with IL-4 and IL-13 led to distinct histologic changes and significantly increased skin surface pH, both of which were enhanced in filaggrin knockdown skin equivalents. We detected a compensatory up-regulation of involucrin and occludin in filaggrin-deficient skin that was dramatically disturbed when simultaneous inflammation occurred. Furthermore, we found that a lack of filaggrin triggered an up-regulation of human ?-defensin 2 via an unknown mechanism, which was abolished by Th2 cytokine supplementation. Taken together, these results indicate that defects in the epidermal barrier, skin permeability, and cutaneous innate immune response are not primarily linked to filaggrin deficiency but are rather secondarily induced by Th2 inflammation.


Exploring beyond the oral mucosa in patients affected with autoimmune blistering diseases: the importance of endoscopic procedures.
Autoimmune blistering diseases (AIBD) comprise several entities characterized by the presence of autoantibodies targeted against structural proteins either in desmosomes or in the dermoepidermal junction of polystratified squamous epithelium. Patients develop blisters, erosions in cutaneous surfaces or mucosas. Diagnosis is based on the characteristic mucocutaneous lesions, the typical findings on histological studies and direct immunofluorescence assays, and the presence of specific autoantibodies against the epidermal antigens. It may not be possible for dermatologists to appropriately explore the nose and throat (NT). Thus, a clinical exploration by endoscopic procedures of NT may be a useful tool during the conventional dermatological exam. The aims of this review are to draw attention to the most frequent NT manifestations in AIBD patients, and underline the utility of endoscopic procedures to achieve a more successful and rationale management of patients. Additionally, we will provide brief information related to the anatomical structures and type of epithelium in NT areas which may explain the extent and type of NT involvement in AIBD. Endoscopic exploration in AIBD patients is important for several reasons. Firstly, it will allow the real NT mucosal involvement in each patient to be determined, thus making a differential diagnosis during the endoscopic exam possible, based on the localization of mucosal lesions. Secondary mucosal morbidity can also be ruled out. Secondly, the clinical response to treatment may be established, especially in NT mucosa, as these are anatomical areas subjected to important local traumas, and physiological functions such as breathing, swallowing, speech production and phonation may be damaged. Therefore, a multidisciplinary management in AIBD is mandatory by both dermatologists and otorhinolaryngologists, adding the clinical exploration by endoscopic procedures of NT to the conventional dermatological exam in all AIBD patients, irrespective of whether they exhibit associated symptoms.


A Dynamic Risk Model for Multitype Recurrent Events.
Recurrent events can occur more than once in the same individual; such events may be of different types, known as multitype recurrent events. They are very common in longitudinal studies. Often there is a terminating event, after which no further events can occur. The risk of any event, including terminating events such as death or cure, is typically affected by prior events. We propose a flexible joint multitype recurrent-events model that explicitly provides estimates of the change in risk for each event due to subject characteristics, including number and type of prior events and the absolute risk for every event type (terminating and nonterminating), and predicts event-free survival probability over a desired time period. The model is fully parametric, and therefore a standard likelihood function and robust standard errors can be constructed. We illustrate the model with applications to the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (1994-2002) and provide discussion of the results and model features.


Light-dependent osmoregulation in pea stem protoplasts. photoreceptors, tissue specificity, ion relationships, and physiological implications.
Light-induced changes in the volume of protoplasts bathed in a medium of constant osmolarity are useful indications of light-dependent cellular osmoregulation. With this in mind, we investigated the effect of light on the volume of protoplasts isolated from the elongating stems of pea (Pisum sativum) seedlings raised under red light. The protoplasts were isolated separately from epidermal peels and the remaining peeled stems. Under continuous red light, the protoplasts of peeled stems swelled steadily, but those of epidermal peels maintained a constant volume. Experiments employing far-red light and phytochrome-deficient mutants revealed that the observed swelling is a light-induced response mediated mainly by phytochromes A and B with a little greater contribution by phytochrome A. Protoplasts of epidermal peels and peeled stems shrank transiently in response to a pulse of blue light. The blue light responsiveness in this shrinking response, which itself is probably mediated by cryptochrome, is under the strict control of phytochromes A and B with equal contributions by these phytochromes. We suggest that the swelling response participates in the maintenance of high tissue tension of elongating stems and that the shrinking response is involved in stem growth inhibition. Other findings include the following: The swelling is caused by uptake of K+ and Cl-. The presence of Ca2+ in the bathing medium is required for phytochrome signaling in the swelling response, but not in the response establishing blue light responsiveness. Phytochrome A mediates the two responses in a totally red/far-red light reversible manner, as does phytochrome B.


Temperature-Independent Kinetic Isotope Effects as Evidence for a Marcus-like Model of Hydride Tunneling in Phosphite Dehydrogenase.
Phosphite dehydrogenase catalyzes the transfer of a hydride from phosphite to NAD+, producing phosphate and NADH. We have evaluated the role of hydride tunneling in a thermostable variant of this enzyme (17X-PTDH) by measuring the temperature dependence of the primary 2H kinetic isotope effects (KIEs) between 5 and 45 °C. Pre-steady-state kinetic measurements were used to demonstrate that the hydride transfer is rate-determining across this temperature range and that the observed KIEs are equal to the intrinsic isotope effect on the chemical step. The KIEs on the pre-exponential factor (AH/AD) and the activation energy (ΔEa) were 1.6 ± 0.1 and 0.21 ± 0.05 kcal/mol, respectively, suggesting that 17X-PTDH facilitates extensive tunneling of both isotopes via a Marcus-like model. Site-directed mutagenesis was used to evaluate the role of an active site threonine (Thr104) found on the back face of the nicotinamide in promoting the close packing of the substrates. In mutants with reduced steric bulk at this position, values of AH/AD and ΔEa fall within the range describing semiclassical "over the barrier" reactivity, suggesting that Thr104 acts as a steric backstop to promote tunneling in 17X-PTDH. Whereas hydrogen tunneling is now a widely appreciated feature of C-H activating enzymes, these observations with a P-H activating system are consistent with the proposal that tunneling is likely to be a common feature on all enzymes that catalyze hydrogen transfers.


Physiological and conjugated linoleic acid-induced changes of adipocyte size in different fat depots of dairy cows during early lactation.
The aim of this study was to investigate the effects of lactation and conjugated linoleic acid (CLA) supplementation on adipocyte sizes of subcutaneous (s.c.) and visceral (VC) fat depots in primiparous dairy cows during the first 105 d in milk (DIM). German Holstein heifers (n=25) were divided into a control (CON) and a CLA group. From 1 DIM until sample collection, CLA cows were fed 100g of CLA supplement/d (about 6% of c9,t11 and t10,c12 isomers each), whereas the CON cows received 100g of fatty acid mixture/d instead of CLA. The CON cows (n=5 each) were slaughtered at 1, 42, and 105 DIM, and the CLA cows (n=5 each) were slaughtered at 42 and 105 DIM. Adipose tissues from 3s.c. depots (tailhead, withers, and sternum) and from 3 VC depots (omental, mesenteric, and retroperitoneal) were sampled. Hematoxylin-eosin staining was done to measure adipocyte area (μm(2)). Retroperitoneal adipocyte sizes were mostly larger than adipocytes from the other sites, independent of lactation time and treatment. Significant changes related to duration of lactation were limited to retroperitoneal fat: adipocyte sizes were significantly smaller at 105 DIM than at 1 DIM in CON cows. Adipocyte sizes were decreased in s.c. depots from the tailhead at 105 DIM and from the sternum at 42 DIM in CLA versus CON cows, whereas for VC depots, adipocyte sizes were decreased in mesenteric fat at 42 and 105 DIM, and in omental and retroperitoneal fat, at 105 DIM in CLA versus CON cows. Within the CLA group, adipocyte sizes were smaller in the s.c. depot from the tailhead at 105 DIM than at 42 DIM. Adipocyte sizes and depot weights were significantly correlated in s.c. depots (r=0.795) in the CLA group and in retroperitoneal fat both in the CON (r=0.698) and the CLA (r=0.723) group. In conclusion, CLA-induced decreases in adipocyte size indicate lipolytic or antilipogenic effects of CLA, or both effects, on adipose tissue in primiparous dairy cows.


Cigarette smoke-induced pulmonary inflammation is attenuated in CD69-deficient mice.
Cluster of differentiation 69 (CD69) has been identified as a lymphocyte early activation marker, and recent studies have indicated that CD69 mediates intracellular signals and plays an important role in various inflammatory diseases. Cigarette smoke (CS) is a strong proinflammatory stimulus that induces the release of proinflammatory mediators by recruiting macrophages and neutrophils into the lung tissue, and is one of the main risk factors for a number of chronic diseases. However, the potential role of CD69 in CS-induced pulmonary inflammation has not been determined. To address to this question, CD69-deficient (KO) and wild-type (WT) mice were subjected to CS-induced acute pulmonary inflammation. After the exposure with CS, the expression of CD69 in the lung of WT mice was significantly induced, it was predominantly observed in macrophages. In conjunction with this phenomenon, neutrophil and macrophage cell counts, and expression of several cytokines were significantly higher in the bronchoalveolar lavage fluid (BALF) of CS-exposed WT mice compared with air-exposed WT mice. Likewise, the CS-induced accumulation of inflammatory cells and cytokines expression were significantly lower in CD69-KO mice than in WT mice. These results suggest that CD69 on macrophages is involved in CS-induced acute pulmonary inflammation.


A systematic review of genetic syndromes with obesity.
Syndromic monogenic obesity typically follows Mendelian patterns of inheritance and involves the co-presentation of other characteristics, such as mental retardation, dysmorphic features and organ-specific abnormalities. Previous reviews on obesity have reported 20 to 30 syndromes but no systematic review has yet been conducted on syndromic obesity. We searched seven databases using terms such as 'obesity', 'syndrome' and 'gene' to conduct a systematic review of literature on syndromic obesity. Our literature search identified 13,719 references. After abstract and full-text review, 119 relevant papers were eligible, and 42 papers were identified through additional searches. Our analysis of these 161 papers found that 79 obesity syndromes have been reported in literature. Of the 79 syndromes, 19 have been fully genetically elucidated, 11 have been partially elucidated, 27 have been mapped to a chromosomal region and for the remaining 22, neither the gene(s) nor the chromosomal location(s) have yet been identified. Interestingly, 54.4% of the syndromes have not been assigned a name, whereas 13.9% have more than one name. We report on organizational inconsistencies (e.g. naming discrepancies and syndrome classification) and provide suggestions for improvements. Overall, this review illustrates the need for increased clinical and genetic research on syndromes with obesity.


Complex Functional Systems with Three Different Types of Dynamic Covalent Bonds.
Multicomponent surface architectures are introduced that operate with three different dynamic covalent bonds. Disulfide exchange under basic conditions accounts for the growth of π stacks on solid surfaces. Hydrazone exchange under acidic conditions is used to add a second coaxial string or stack, and boronic ester exchange under neutral conditions is used to co-align a third one. The newly introduced boronic ester exchange chemistry is compatible with stack and string exchange without interference from the orthogonal hydrazone and disulfide exchange. The functional relevance of surface architectures with three different dynamic covalent bonds is exemplified with the detection of polyphenol natural products, such as epigallocatechin gallate, in competition experiments with alizarin red. These results describe synthetic strategies to create functional systems of unprecedented sophistication with regard to dynamic covalent chemistry.


Toward full restoration of synaptic and terminal function of the dopaminergic system in Parkinson's disease by stem cells.
New therapeutic nonpharmacological methodology in Parkinson's disease (PD) involves cell and synaptic renewal or replacement to restore function of neuronal systems, including the dopaminergic (DA) system. Using fetal DA cell therapy in PD patients and laboratory models, it has been demonstrated that functional motor deficits associated with parkinsonism can be reduced. Similar results have been observed in animal models with stem cell-derived DA neurons. Evidence obtained from transplanted PD patients further shows that the underlying disease process does not destroy transplanted fetal DA cells, although degeneration of the host nigrostriatal system continues. The optimal DA cell regeneration system would reconstitute a normal neuronal network capable of restoring feedback-controlled release of DA in the nigrostriatal system. The success of cell therapy for PD is limited by access to preparation and development of highly specialized dopaminergic neurons found in the A9 and A10 region of the substantia nigra pars compacta as well as the technical and surgical steps associated with the transplantation procedure. Recent laboratory work has focused on using stem cells as a starting point for deriving the optimal DA cells to restore the nigrostriatal system. Ultimately, understanding the cell biological principles necessary for generating functional DA neurons can provide many new avenues for better treatment of patients with PD.


Evaluating treatments and corresponding costs of prostate cancer patients treated within an inpatient or hospital-based outpatient setting.
To describe treatments and cost of care for prostate cancer (PCa) in hospital-based outpatient and inpatient settings. Hospital encounters associated with PCa (ICD-9 codes 185, 233.4) and PCa-related treatment in a hospital claims database were included. There were 211,440 encounters for PCa between January 2006 and December 2010 (88,151 inpatient and 123,289 outpatient). Average cost per inpatient stay was US$12,286 versus US$4364 per outpatient visit. Most common treatment during an inpatient stay and outpatient visit was surgery (57%) and radiation (76%), respectively. A total of 80% of outpatient visits and 69.9% inpatient stays were associated with a single treatment; remaining encounters were associated with ≥2 treatments. Costs are consistent with previous estimates; however, multimodal therapy is an emerging trend that may be related to greater costs in the future which may also be a challenge for hospital decision makers.


Reactions of chlorinated ethenes with surface-sulfidated iron materials: reactivity enhancement and inhibition effects.
Recent studies on the use of controlled sulfur amendment to improve the reactivity and selectivity of zerovalent iron (ZVI) in reductive dechlorination reactions have generated renewed interest in ZVI-based remediation materials. However, existing studies have focused on the reactions between trichloroethene (TCE) and lab-synthesized ZVI, and the applicability of sulfidation to ZVIs with different material characteristics for reductive dechlorination of chloroethenes such as tetrachloroethene (PCE) and cis-dichloroethene (cis-DCE) has not been systematically examined. In this study, four ZVI materials from commercial sources having different sizes and morphological and compositional characteristics were subjected to various sulfidation treatments and were assessed in batch reactions with PCE, TCE, or cis-DCE. Sulfur amendment induces modest increases in PCE degradation rates and steers reactions towards a cleaner pathway that has minimum accumulation of partially dechlorinated intermediates. In the case of cis-DCE, bifurcating outcomes were observed that include enhancement effects for two high-purity ZVIs and inhibitory effects for two ZVIs possessing low levels of metal impurities. Further investigations based on controlled metal dosing reveal that the trace metals commonly present in cast iron or recycled metal scraps, such as Cu and Ni, can act as adventitious catalysts for cis-DCE reduction. Sulfidation results in poisoning of these catalytic ingredients and accounts for the adverse effect observed with a subset of ZVIs. Collectively, this study confirms enhanced degradation of highly chlorinated ethenes (PCE and TCE) by sulfidation of ZVIs from diverse origins; nonetheless, the effects of sulfidation can be highly variable for the less chlorinated ethenes due to differences in the material characteristics of ZVI and the predominant dechlorination pathways.


Hot water soluble sesquiterpenes [anhydroperoxy-costunolide and 3-oxoeudesma-1,4(15),11(13)triene-12,6alpha-olide] isolated from laurel (Laurus nobilis L.) induce cell death and morphological change indicative of apoptotic chromatin condensation in leukemia cells.
Hot water soluble (HWS)-sesquiterpenes [anhydroperoxycostunolide and 3-oxo-eudesma-1,4(15),11(13)triene-12,6alpha-olide] were purified from Laurel (Laurus nobilis L.) and identified by Mass, and 1H- and 13C-NMR. These HWS-sesquiterpenes displayed strong growth inhibitory effect against human promyelotic leukemia HL-60 cells. Apoptotic morphological changes of the nucleus, including chromatin condensation were induced in the HL-60 cells treated with the sesquiterpenes. Flow cytometric analysis showed that the hypodiploid nuclei of HL-60 cells were increased to 10.5, 46.5, and 91.3% after a 3 day-treatment with 2.5, 5 and 10 micromoles anhydroperoxycostunolide, respectively. And the same analysis showed that the hypodiploid nuclei of HL-60 cells were increased to 9.8, 39.2 and 89.6% after a 3 day-treatment with 5, 10 and 20 micromoles 3-oxo-eudesma-1,4(15),11(13)triene-12,6alpha-olide, respectively. These findings suggest that growth inhibition by anhydroperoxycostunolide and 3-oxo-eudesma-1,4(15),11(13)triene-12,6alpha-olide of HL-60 cells results from the induction of chromatin condensation in the HL-60 cells. On the other hand, fragmentations by these compounds of DNA to oligonucleosomal-sized fragments were not observed in the HL-60 cells.


Metabolic Profile of Flunitrazepam: Clinical and Forensic Toxicological Aspects.
Flunitrazepam (FNZ) is a potent hypnotic, sedative, and amnestic drug used to treat insomnia and as a pre-anesthetic agent. The illicit practice in drug-facilitated sexual assault led to important clinical and forensic concerns. In this work the metabolism of FNZ, and pharmacological- and toxicological-related effects, were fully reviewed. FNZ and related known metabolizing enzymes and metabolites were searched in books and in PubMed (U.S. National Library of Medicine) without a limiting period. Major metabolic pathways include N-demethylation, 3-hydroxylation, nitro-reduction, and further N-acetylation of the amino group, yielding N-desmethylflunitrazepam, 3-hydroxy-flunitrazepam, 7-aminoflunitrazepam, and 7-acetamidoflunitrazepam, respectively. A combination of these reactions may lead to the formation of 7-amino-N-desmethylflunitrazepam, 7-acetamido-N-desmethylflunitrazepam, 3- hydroxy-7-aminoflunitrazepam, 3-hydroxy-7-acetamidoflunitrazepam, 3-hydroxy-N-desmethylflunitrazepam and glucuronide conjugates. Genotypic variations in enzymes, interactions with other drugs or stability of FNZ during storage can result in large interindividual variability in the toxicological results. It is aimed that knowing the metabolism of FNZ may lead to the development of new analytical strategies for early detection, since this drug is typically present in very low concentrations in blood and urine when used to facilitate sexual assault.


[Gunshot wounds of the chest and abdomen in peacetime].
320 gunshot wounds of the trunk in peacetime are analyzed. Wounds from hunting rifle (71.2%) dominated, penetration into pleural or abdominal cavity was revealed in 89.4% cases. Thoracoabdominal and combined wounds of the chest and abdomen reached 23.8%. Significant destruction of the soft tissues and bones, multiple damages of organs were seen often. Causes of infectious complications and lethal outcomes were analyzed. Improving of care quality has reduced lethality from 21.8 to 15.6%.


Cyanotic episodes in a male child with fragile X syndrome.
A 9-year-old male with a diagnosis of fragile X syndrome (FXS) was evaluated for cyanotic episodes of unknown etiology. Clinical observation revealed frequent episodes of hyperventilation lasting several minutes, only while the patient was awake. This was followed by apnea associated with cyanosis and oxygen desaturation. Polysomnogram confirmed episodic central apnea temporally associated with hypocapnia, only during the awake state. Extensive evaluation failed to reveal other neurological, cardiac, gastrointestinal, or pulmonary etiologies for the events. The clinical observations and investigations allowed us to conclude that the patient's cyanotic episodes were caused by primary behavioral hyperventilation in the awake state. Similar behaviors have been reported in children with a variety of diagnoses but to our knowledge have not been previously reported in children with FXS. Treatment for this unusual behavior in FXS consists of reassurance and behavior modification to decrease the frequency and severity of the cyanotic episodes.


Possible Role of Amyloid Cross-Seeding in Evolvability and Neurodegenerative Disease.
Aging-related neurodegenerative disorders are frequently associated with the aggregation of multiple amyloidogenic proteins (APs), although the reason why such detrimental phenomena have emerged in the post-reproductive human brain across evolution is unclear. Speculatively, APs might provide physiological benefits for the human brain during developmental/reproductive stages. Of relevance, it is noteworthy that cross-seeding (CS) of APs has recently been characterized in cellular and animal models of neurodegenerative disease, and that normal physiological CS of multiple APs has also been observed in lower organisms, including yeast and bacteria. In this context, our main objective is to discuss a possible involvement of the CS of APs in promoting evolvability, a hypothetical view regarding the function of APs as an inheritance of acquired characteristics against human brain stressors, which are transgenerationally transmitted to offspring via germ cells. Mechanistically, the protofibrils formed by the CS of multiple APs might confer hormesis more potently than individual APs. By virtue of greater encoded stress information in parental brains being available, the brains of offspring can cope more efficiently with forth-coming stressors. On the other hand, subsequent neurodegeneration caused by APs in parental brain through the antagonistic pleiotropy mechanism in aging, may suggest that synergistically, multiple APs might be more detrimental compared to singular AP in neurodegeneration. Taken together, we suggest that the CS of multiple APs might be involved in both evolvability and neurodegenerative disease in human brain, which may be mechanistically and therapeutically important.


The use of telomere length as a predictive biomarker for injury prognosis in juvenile rats following a concussion/mild traumatic brain injury.
Telomeres were originally believed to be passive players in cellular replication, but recent research has highlighted their more active role in epigenetic patterning and promotion of cellular growth and survival. Furthermore, literature demonstrates that telomere length (TL) is responsive to environmental manipulations such as prenatal stress and dietary programming. As the search for a prognostic biomarker of concussion has had limited success, this study sought to examine whether or not telomere length (TL) could be an efficacious predictor of symptom severity in juvenile rats following concussion. Rats from four distinct experimental groups (caloric restriction (CR), high fat diet (HFD), exercise (EX), and standard controls (STD)) received a mild traumatic brain injury (mTBI)/concussion and were then subjected to a behavioural test battery. The test battery was scored and the animals were categorized as poor, average, or good, based on their performance on the 6 tests examined. Skin cells (from ear notch samples) were taken 17days post-injury and DNA was extracted for telomere length analysis. Ear notch skin cell TL was highly correlated with brain tissue TL for a given individual. Animals in the CR and EX cohorts had significantly longer telomeres, while animals in the HFD cohort had significantly shorter telomeres, when compared to controls. The mTBI/concussion reduced TL in all cohorts except the EX group. A significant linear relationship was found between TL and performance on the behavioural test battery, whereby shorter telomeres were associated with poorer performance and longer telomeres with better performance. As performance on the test battery is linked to symptom severity, this study found TL to be a reasonable tool for concussion prognosis. Future studies with human populations should examine the validity of TL in peripheral cells, as a predictor of concussion pathology.


Maternal smoking during pregnancy and cord blood DNA methylation: new insight on sex differences and effect modification by maternal folate levels.
Maternal smoking during pregnancy may affect newborn DNA methylation (DNAm). However, little is known about how these associations vary by a newborn's sex and/or maternal nutrition. To fill in this research gap, we investigated epigenome-wide DNAm associations with maternal smoking during pregnancy in African American mother-newborn pairs. DNAm profiling in cord (n = 379) and maternal blood (n = 300) were performed using the Illumina HumanMethylation450 BeadChip array. We identified 12 CpG sites whose DNAm levels in cord blood were associated with maternal smoking, at a false discovery rate <5%. The identified associations in the GFI1 gene were more pronounced in male newborns than in females (P = 0.002 for maternal smoking × sex interaction at cg18146737). We further observed that maternal smoking and folate level may interactively affect cord blood DNAm level at cg05575921 in the AHRR gene (P = 5.0 × 10-4 for interaction): compared to newborns unexposed to maternal smoking and with a high maternal folate level (>19.2 nmol/L), the DNAm level was about 0.03 lower (P = 3.6 × 10-4) in exposed newborns with a high maternal folate level, but was 0.08 lower (P = 1.2 × 10-8) in exposed newborns with a low maternal folate level. Our data suggest that adequate maternal folate levels may partly counteract the impact of maternal smoking on DNAm. These findings may open new avenues of inquiry regarding sex differences in response to environmental insults and novel strategies to mitigate their intergenerational health effects through optimization of maternal nutrition.


Radiation exposure during pediatric videourodynamics.
Videourodynamics is useful for evaluating and treating neurological disorders in children. Traditional urodynamic parameters can be obtained while simultaneous visualization of the urinary system can reveal anatomical anomalies. This additional information comes at the cost of radiation exposure to the child. We characterized radiation exposure from videourodynamics. We reviewed all recent videourodynamic studies and recorded patient demographics, urological diagnoses, physical attributes, total fluoroscopy time, total radiation exposure in mGy, bladder capacity and the number of filling cycles performed. Multivariate linear regression was used to identify patient factors that independently influenced total radiation exposure. A total of 64 videourodynamic studies were performed in 34 female and 28 male patients with a mean age of 8.6 years (95% CI 7.2-10.0). The most common diagnosis was neurogenic bladder in 40 patients, although 49 had multiple diagnoses. Mean total fluoroscopy time was 1.8 minutes (95% CI 1.4-2.1) and mean total radiation exposure was 10 mGy (95% CI 7.5-13.3). On multivariate linear regression patient weight and bladder capacity were the only independent predictors of total radiation exposure. Videourodynamics entail significant radiation exposure. Patient weight and bladder capacity were independent predictors of total radiation exposure. Physician awareness of radiation exposure may result in the judicious use of fluoroscopy and aid in counseling parents on the risk of videourodynamics. Further research is needed to quantify organ specific doses of radiation due to medical imaging in children and the associated cancer risks.


Few-mode frequency-modulated LiDAR receivers.
We present a few-mode frequency-modulated receiver for light detection and ranging (LiDAR). We show that using a few-mode local oscillator (LO) with spatial modes at different frequencies at the receiver can significantly improve the performance of the LiDAR detection range. A preferred receiver architecture features LO modes with unequal frequency separations based on optical orthogonal codes (OOC) to allow range detection via cross correlation. The required signal-to-noise ratio (SNR) for the frequency-modulated continuous wave (FMCW) LiDAR decreases with the number of LO modes. This receiver can have a potential impact in the area of automotive LiDARs.


SNAP-II for prediction of mortality and morbidity in extremely preterm infants.
To determine the specific Score of Neonatal Acute Physiology (SNAP-II) cut-off scores associated with outcomes in extremely preterm infants, and to examine its contribution to predictive models that include nonmodifiable birth predictors. Retrospective observational study of 9240 infants born at 22-28 weeks' gestation and admitted to the Canadian Neonatal Network from 2010 to 2015. Outcomes included early and hospital mortality, composite of mortality/morbidity and individual morbidities. The SNAP-II cut-off to predict each outcome was determined using the Youden index. Additional contributions were evaluated using a base model that adjusted for gestational age, birth weight z-score and sex and by comparing the area under the curve (AUC). The mortality/morbidity rate was 63% (5859/9240). Specific SNAP-II cut-offs ranged from 12 to 20 and were associated with each adverse outcome. Adding SNAP-II cut-offs to predictive models that included birth variables significantly improved (p < .05) the prediction of early mortality (AUC 0.84 versus 0.79), hospital mortality (AUC 0.80 versus 0.78), mortality/morbidity (AUC 0.76 versus 0.75), and severe neurological injury (AUC 0.69 versus 0.66) but had little or no effect on predictive models for retinopathy of prematurity, bronchopulmonary dysplasia, necrotizing enterocolitis, and nosocomial infection. SNAP-II cut-offs were independently associated with each adverse outcome and using the proposed SNAP-II cut-offs improved the performance of predictive models for certain short-term outcomes.


[Cardioprotective effect of the selective sigma-1 receptor agonist, SA4503].
We previously reported that the sigma-1 receptor is down-regulated in cardiomyocytes following heart failure in transverse aortic constriction (TAC) mice. In this review, we summarized the anti-hypertrophic action of selective sigma-1 receptor agonist, SA4503 in the hypertrophied cultured cardiomyocytes and discussed its possible mechanism of cardioprotection. Treatment with SA4503 (0.1-1 μM) dose-dependently inhibited hypertrophy in cultured cardiomyocytes induced by angiotensin II (Ang II). We also found that α1 receptor stimulation by phenylephrine (PE) promotes ATP production through IP3 receptor-mediated Ca(2+) mobilization into mitochondria in cultured cardiomyocytes. Interestingly, the PE-induced ATP production was impaired after Ang II-induced hypertrophy and SA4503 treatment largely restored PE-induced ATP production. The impaired PE-induced ATP production was associated with reduced mitochondrial size. The SA4503 treatment completely restored mitochondrial size concomitant with restored ATP production. These effects were blocked by sigma-1 receptor antagonist, NE-100 and sigma-1 receptor siRNA. We also confirmed that chronic SA4503 administration also significantly attenuates myocardial hypertrophy and restores ATP production in transverse aortic constriction mice. Taken together, sigma-1 receptor stimulation with selective agonist SA4503 ameliorates cardiac hypertrophy and dysfunction by restoring both mitochondrial Ca(2+) mobilization and ATP production via sigma-1 receptor stimulation. Sigma-1 receptor stimulation represents a new therapeutic strategy to rescue heart from hypertrophic dysfunction in heart failure.


Integration of hepadnavirus DNA in infected liver: evidence for a linear precursor.
DNA of the avian hepadnavirus, duck hepatitis B virus, was found to be integrated at low abundance into the cellular DNA extracted from the livers of infected ducklings. The frequency of integration was estimated to be at least one viral genome per 10(3) to 10(4) cells by 6 days postinfection. The structures of virus-cell junctions determined by sequencing were compared with those of virus-virus junctions formed by nonhomologous recombination between the ends of linear viral DNA forms. This comparison allowed us to conclude that linear viral DNA was the preferential form used as an integration substrate. Potential factors promoting viral DNA integration during chronic infection are discussed.


Structural role of the flanking DNA in mariner transposon excision.
During cut-and-paste mariner/Tc1 transposition, transposon DNA is cut precisely at its junction with flanking DNA, ensuring the transposon is neither shortened nor lengthened with each transposition event. Each transposon end is flanked by a TpA dinucleotide: the signature target site duplication of mariner/Tc1 transposition. To establish the role of this sequence in accurate DNA cleavage, we have determined the crystal structure of a pre-second strand cleavage mariner Mos1 transpososome. The structure reveals the route of an intact DNA strand through the transposase active site before second strand cleavage. The crossed architecture of this pre-second strand cleavage paired-end complex supports our proposal that second strand cleavage occurs in trans. The conserved mariner transposase WVPHEL and YSPDL motifs position the strand for accurate DNA cleavage. Base-specific recognition of the flanking DNA by conserved amino acids is revealed, defining a new role for the WVPHEL motif in mariner transposition and providing a molecular explanation for in vitro mutagenesis data. Comparison of the pre-TS cleavage and post-cleavage Mos1 transpososomes with structures of Prototype Foamy Virus intasomes suggests a binding mode for target DNA prior to Mos1 transposon integration.


Clinical pharmacology of polyethylene glycol-L-asparaginase.
Polyethylene glycol (PEG)-L-asparaginase, at doses ranging from 500 to 8000 units/m2, was infused iv over 60 min in 31 patients of whom 27 were evaluable pharmacokinetically. The plasma disappearance of PEG-L-asparaginase is described by a monophasic curve with a mean half-life of 357 +/- 243 hr which is much longer than that of the unconjugated enzyme (half-life of approximately 20 hr). The rate of total clearance (128 +/- 74 ml/m2 X day) is much slower than that of L-asparaginase (2196 +/- 1098 ml/m2 X day). The volume of distribution is 2093 +/- 643 ml/m2, which is similar to that of L-asparaginase, indicating that PEG-L-asparaginase is mainly localized in the plasma. No enzyme could be measured in urine samples taken from nine patients for a period of up to 4 days. Additionally, no enzyme was measurable in one patient's pleural fluid obtained at the end of infusion and 6 days after infusion of a 1000-unit/m2 dose; the corresponding concentrations in plasma were 0.64 and 0.62 units/ml, respectively. In general, the plasma enzyme concentrations at the end of the 1-hr infusion and at 14 days after drug administration were proportional to the dose given. However, in two patients, a sudden disappearance of enzyme levels occurred which preceded anaphylactic reactions during subsequent treatment. A third patient developed severe bronchospasm 30 min after the first dose, but his enzyme levels were within the normal range.


[The discovery of IgE and its importance for allergologists].
During the 30 years that IgE has been known the knowledge about allergy has improved immensely. We have now available reliable procedures for allergy diagnosis, standardised allergen preparations for diagnosis and treatment, an improved knowledge about mechanisms behind allergy and tests to monitor the efficiency of therapeutic procedures. New sophisticated procedures for modulation of IgE function and production are waiting around the corner. However, despite this increase in our knowledge the prevalence of allergic diseases is still increasing. More efforts must be dedicated to the understanding why an atopic individual is sensitised and how this sensitisation can be avoided by primary prevention.


Malignant peripheral nerve sheath tumors: the St. Jude Children's Research Hospital experience.
Malignant peripheral nerve sheath tumors (MPNSTs) are uncommon in young patients. To contribute to the understanding of these tumors, we reviewed the records of all patients treated for PNSTs at one institution over a 30-year period. We reviewed the records of eight patients treated for benign PNSTs and 28 patients treated for 29 MPNSTs. We focused on the latter group, statistically testing several clinical factors for their significance in affecting survival. Five-year survival in patients with MPNSTs was 39%. The most significant prognostic factor was gross tumor resectability (p = 0.0004). Five-year survival for patients with resectable tumors was 65%, whereas no patient with unresectable disease survived > 25 months. Tumor grade, site, and patient race were also significant factors by univariate analysis but were not significant when adjusted for resectability. Gross tumor resection is crucial in treating malignant PNSTs. Supplemental radiation therapy is recommended for positive microscopic margins. More effective treatment is still being sought for unresectable disease.


Defining Oracy: Second Language Listening and Speaking Motivation in Higher Education and the Role of Demographic Factors.
Since listening and speaking are two integral skills for effective second language (L2) communication, enhancing learners' motivation to listen to and speak in the target language will engage them in the learning process, eventually leading to improvements in these two skills. Yet despite its importance, L2 listening and speaking motivation is underexplored in the current literature. Drawing on self-determination theory, this study adapted, validated, and administered one L2 listening motivation scale and one L2 speaking motivation scale to 863 undergraduate students from different regions of China. Correlation analysis, confirmatory factor analysis, and inferential statistical analyses (e.g., ANOVA) were used to compute the data. The results revealed that the learners were both intrinsically and extrinsically motivated to listen to and speak in English. A strong association between L2 listening motivation and speaking motivation was observed. Furthermore, gender, geographical, and disciplinary differences were found in the two kinds of motivation, and overseas experience also affected the learners' motivation. The results provide insights into L2 learner motivation in specific linguistic domains and yield pedagogical implications for L2 teaching and learning.


The preferences of people with asthma or chronic obstructive pulmonary disease for self-management support: A qualitative descriptive study.
The aim of this study was to explore and describe the self-management support (SMS) preferences of adults with asthma and/or chronic obstructive pulmonary disease (COPD). Self-management support interventions have had beneficial outcomes for people with asthma and people with COPD, though challenges remain in their implementation. Increased understanding of the support preferences of people with asthma/COPD can help inform the development of future interventions to address patients' preferences. A qualitative descriptive design was used. Semi-structured focus group and individual interviews were conducted with 20 adult participants who had asthma and/or COPD in Ireland. Qualitative content analysis was used to analyse interviews. The SRQR reporting guideline was used. Three themes were identified. Support accessibility included having access to routine and unscheduled support from healthcare professionals with specialist knowledge. Consultation content described the need for comprehensive and person-centred support. The person-provider relationship described the value of healthcare professionals acknowledging patient concerns, noted as a challenge for people with asthma, and continuity in relationships over time. Routine support for people with asthma/COPD needs to be comprehensive in addressing the individual patient's challenges. Access to timely advice during exacerbations was a priority for people with asthma/COPD, suggesting that flexible access to services as well as routine review may be optimal for supporting self-management of asthma/COPD. Feeling listened to regarding symptoms experienced may be of intrinsic value to people with asthma/COPD. The study emphasises the importance of continued training in communications skills for healthcare professionals supporting people with asthma/COPD, particularly acknowledging the patient's concerns in the context of symptom changes/flare-up. A respiratory nurse specialist was valued as being a care coordinator who could support routine management as well as managing exacerbations, having specialist knowledge and knowing the patient over time.


Asian low-androstenone haplotype on pig chromosome 6 does not unfavorably affect production and reproduction traits.
European pigs that carry Asian haplotypes of a 1.94-Mbp region on pig chromosome 6 have lower levels of androstenone, one of the two main compounds causing boar taint. The objective of our study was to examine potential pleiotropic effects of the Asian low-androstenone haplotypes. A single nucleotide polymorphism marker, rs81308021, distinguishes the Asian from European haplotypes and was used to investigate possible associations of androstenone with production and reproduction traits. Eight traits were available from three European commercial breeds. For the two sow lines studied, a favorable effect on number of teats was detected for the low-androstenone haplotype. In one of these sow lines, a favorable effect on number of spermatozoa per ejaculation was detected for the low-androstenone haplotype. No unfavorable pleiotropic effects were found, which suggests that selection for low-androstenone haplotypes within the 1.94 Mbp would not unfavorably affect the other eight relevant traits.


Persistent proteomic alterations in the medial prefrontal cortex with abstinence from cocaine self-administration.
Neuroproteomic studies of drug abuse offer the potential for a systems-level understanding of addiction. Understanding cocaine-responsive alterations in brain protein expression that persist even with extended abstinence may provide insight into relapse liability. In the current study, protein changes in the medial prefrontal cortex of cocaine self-administering rats following 1 and 100 days of enforced abstinence were quantified by 2D-DIGE. We have previously reported increased drug-seeking and drug-taking, as well as mRNA and epigenetic changes in this model even after 100 days of enforced abstinence. A number of statistically-significant changes in proteins relating to synapse function and neuronal remodeling were evident, including neurofilament medium and heat shock protein 73 (Hsp73) which increased at 1 day of abstinence, but returned to normal levels following 100 days of abstinence. -1 and synaptosome-associated protein 25 kDa (SNAP-25) were unchanged at 1 day of abstinence, but were significantly decreased after 100 days. These data demonstrate that while some protein changes return to normal levels following enforced cocaine abstinence, a number remain or become altered after long periods, up to 100 days, of cocaine abstinence. Those protein expression changes that do not reset to pre-cocaine exposure levels may contribute to the persistent relapse potential that occurs in response to cocaine abstinence.


Substrate Recognition Properties from an Intermediate Structural State of the UreA Transporter.
Through a combination of comparative modeling, site-directed and classical random mutagenesis approaches, we previously identified critical residues for binding, recognition, and translocation of urea, and its inhibition by 2-thiourea and acetamide in the Aspergillus nidulans urea transporter, UreA. To deepen the structural characterization of UreA, we employed the artificial intelligence (AI) based AlphaFold2 (AF2) program. In this analysis, the resulting AF2 models lacked inward- and outward-facing cavities, suggesting a structural intermediate state of UreA. Moreover, the orientation of the W82, W84, N279, and T282 side chains showed a large variability, which in the case of W82 and W84, may operate as a gating mechanism in the ligand pathway. To test this hypothesis non-conservative and conservative substitutions of these amino acids were introduced, and binding and transport assessed for urea and its toxic analogue 2-thiourea, as well as binding of the structural analogue acetamide. As a result, residues W82, W84, N279, and T282 were implicated in substrate identification, selection, and translocation. Using molecular docking with Autodock Vina with flexible side chains, we corroborated the AF2 theoretical intermediate model, showing a remarkable correlation between docking scores and experimental affinities determined in wild-type and UreA mutants. The combination of AI-based modeling with classical docking, validated by comprehensive mutational analysis at the binding region, would suggest an unforeseen option to determine structural level details on a challenging family of proteins.


Designing a guideline for empowering married adolescent girls in reproductive health: a mixed-method study protocol.
Investing in adolescent's health, especially, the role of girls in community health and future generations is one of the most important strategies of the Millennium Development Goals. In this regard, supplying adolescents' special needs including access to educational, health and counseling services for promoting reproductive health have been emphasized. About 36% of registered marriages in Iran are under the age of 19 though, reproductive health services based on married adolescent girls` needs in social-cultural context were not predicted in national health system. Therefore, this study aim was designing a guideline for empowering married adolescents in reproductive health. This is a sequential exploratory Mixed-method study conducted in three consecutive phases. The first phase, with a qualitative approach, explores needs, barriers and strategies for empowering married adolescent girls in reproductive health. In the second phase, a systematic review will be conducted to identify the recommendation and strategies for empowering married adolescent girls in reproductive health in other countries. Finally, in third phase, data from qualitative study and systematic review are emerged and the most important solutions and recommendations related to the issue are extracted and the final guideline is adapted by the experts. This study is attempting to provide a guideline containing comprehensive recommendations for health system` policy makers and providers in order to empowering adolescent girls in reproductive health.


Quality of life in patients undergoing inguinal hernia repair.
Inguinal hernia repair is one of the most common surgical procedures undertaken in the NHS. Despite this, no previous work has examined quality of life in this patient group. This study examines quality of life preoperatively and at 3 and 6 months postoperatively in 140 patients undergoing inguinal hernia repair in the context of a randomised controlled trial of laparoscopic versus open hernia repair. Surgery was undertaken on a day case basis, and quality of life was assessed using the Short Form 36 (SF36). In the initial phase of the study, 57% of those screened for suitability met the study inclusion criteria and were randomised. No significant differences were found between laparoscopic and open hernia repair in terms of quality of life at 3 and 6 months postoperatively. No difference was found between 3 and 6 month scores, suggesting that patients had already made a good recovery by 3 months. A significant improvement was found between preoperative and postoperative scores, with the greatest change arising on dimensions assessing pain, physical function, and role limitation owing to physical restriction. After standardising for age, sex, and social class, a comparison of the hernia patients to population norms for the SF36 was consistent with improvement from preoperative to postoperative assessment. This study has demonstrated the improvement in quality of life in patients undergoing elective inguinal hernia repair by experienced surgeons on a day case basis. It has also demonstrated the feasibility of assessing quality of life using generic measures in this patient group. Further work in this area is required. Ultimately, the priority given to elective inguinal hernia repair will depend on how the demonstrated benefits compare with those derived from other elective surgical procedures.


Reduction of Fe(III), Cr(VI), U(VI), and Tc(VII) by Deinococcus radiodurans R1.
Deinococcus radiodurans is an exceptionally radiation-resistant microorganism capable of surviving acute exposures to ionizing radiation doses of 15,000 Gy and previously described as having a strictly aerobic respiratory metabolism. Under strict anaerobic conditions, D. radiodurans R1 reduced Fe(III)-nitrilotriacetic acid coupled to the oxidation of lactate to CO(2) and acetate but was unable to link this process to growth. D. radiodurans reduced the humic acid analog anthraquinone-2,6-disulfonate (AQDS) to its dihydroquinone form, AH(2)DS, which subsequently transferred electrons to the Fe(III) oxides hydrous ferric oxide and goethite via a previously described electron shuttle mechanism. D. radiodurans reduced the solid-phase Fe(III) oxides in the presence of either 0.1 mM AQDS or leonardite humic acids (2 mg ml(-1)) but not in their absence. D. radiodurans also reduced U(VI) and Tc(VII) in the presence of AQDS. In contrast, Cr(VI) was directly reduced in anaerobic cultures with lactate although the rate of reduction was higher in the presence of AQDS. The results are the first evidence that D. radiodurans can reduce Fe(III) coupled to the oxidation of lactate or other organic compounds. Also, D. radiodurans, in combination with humic acids or synthetic electron shuttle agents, can reduce U and Tc and thus has potential applications for remediation of metal- and radionuclide-contaminated sites where ionizing radiation or other DNA-damaging agents may restrict the activity of more sensitive organisms.


Vat Polymerization by Three-Dimensional Printing and Curing of Antibacterial Zinc Oxide Nanoparticles Embedded in Poly(ethylene glycol) Diacrylate for Biomedical Applications.
Digital light processing (DLP) is a vat photopolymerization 3D printing technique with increasingly broad application prospects, particularly in personalized medicine, such as the creation of medical devices. Different resins and printing parameters affect the functionality of these devices. One of the many problems that biomedical implants encounter is inflammation and bacteria growth. For this reason, many studies turn to the addition of antibacterial agents to either the bulk material or as a coating. Zinc oxide nanoparticles (ZnO NPs) have shown desirable properties, including antibacterial activity with negligible toxicity to the human body, allowing their use in a wide range of applications. In this project, we developed a resin of poly(ethylene glycol) diacrylate (PEGDA), a cross-linker known for its excellent mechanical properties and high biocompatibility in a 4:1 weight ratio of monomers to water. The material's mechanical properties (Young's modulus, maximum elongation, and ultimate tensile strength) were found similar to those of human cartilage. Furthermore, the ZnO NPs embedding matrix showed strong antibacterial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S.A.). As the ZnO NPs ratio was changed, only a minor effect on the mechanical properties of the material was observed, whereas strong antibacterial properties against both bacteria were achieved in the case of 1.5 wt.% NPs.


A novel device to simplify intraoperative radiographic visualization of the cervical spine by producing transient caudal shoulder displacement: a 2-center case series of 80 patients.
Intraoperative radiographic localization within the cervical spine can be a challenge because of the anatomical relation of the musculoskeletal structures of the pectoral girdle. On standard cross-table lateral radiographs, these structures can produce shadowing that obscure the anatomical features of the cervical vertebrae, particularly at the caudal levels. Surgical guidelines recommend accurate intraoperative localization as a means to reduce wrong-level spine surgery, and unobstructed visualization is needed for fluoroscopy-guided placement of spinal instrumentation. In this article, the authors describe and evaluate a novel device designed to provide transient intraoperative caudal displacement of the shoulders to improve and simplify radiographic visualization of the cervical spine. A 2-center prospective study was conducted to evaluate the device. The study included a total of 80 patients undergoing cervical spine surgery. The device was evaluated in a cohort of 50 patients undergoing elective single-level anterior discectomy and fusion and also in a second cohort of 30 patients at an independent institution. The patients in this second cohort were undergoing a variety of cervical spine procedures for multiple indications and were included in the study to allow the authors to assess the effectiveness of the device in a general neurosurgical practice. After the patients were anesthetized and positioned, consecutive standard cross-table lateral radiographs or intraoperative fluoroscopic were obtained before and after use of the device. The images were compared in order to determine the difference in lowest vertebral level visible. There was an average difference in cervical spine visualization of +2.8 ± 0.9 vertebral levels in the first cohort, while in the second the improvement was +1.2 ± 0.7 levels (p < 0.0001 between cohorts, unpaired t-test). There was one complication, a minor shoulder abrasion, which required no specific management. This device is safe and effective for increasing the radiographic visualization of the cervical spine for intraoperative localization.


Serodiagnosis of Lyme disease by kinetic enzyme-linked immunosorbent assay using recombinant VlsE1 or peptide antigens of Borrelia burgdorferi compared with 2-tiered testing using whole-cell lysates.
In a study of US patients with Lyme disease, immunoglobulin (Ig) G and IgM antibody responses to recombinant Borrelia burgdorferi antigen VlsE1 (rVlsE1), IgG responses to a synthetic peptide homologous to a conserved internal sequence of VlsE (C6), and IgM responses to a synthetic peptide comprising the C-terminal 10 amino acid residues of a B. burgdorferi outer-surface protein C (pepC10) were evaluated by kinetic enzyme-linked immunoassay. At 99% specificity, the overall sensitivities for detecting IgG antibody to rVlsE1 or C6 in samples from patients with diverse manifestations of Lyme disease were equivalent to that of 2-tiered testing. When data were considered in parallel, 2 combinations (IgG responses to either rVlsE1 or C6 in parallel with IgM responses to pepC10) maintained high specificity (98%) and were significantly more sensitive than 2-tiered analysis in detecting antibodies to B. burgdorferi in patients with acute erythema migrans. In later stages of Lyme disease, the sensitivities of the in parallel tests and 2-tiered testing were high and statistically equivalent.


Stress distribution analysis during an intermaxillary dysjunction: A 3-D FEM study of an adult human skull.
With the increased interest in adult orthodontics, maxillary width problems in the nongrowing patients have been encountered with greater frequency. In view of the negative outlook for successful nonsurgical palatal expansion in adult patients it seemed appropriate to evaluate the biomechanical effects of nonsurgical rapid maxillary expansion (RME) in adults using the finite element method (FEM). To evaluate the biomechanical effects of RME on the craniofacial complex as applied to three-dimensional (3D) model of an adult human skull using the finite element method. The Department of Orthodontics and Dentofacial Orthopedics at Government Dental College and Hospital, Nagpur. The study was done on an analytical model developed from a dry human skull of an adult female with an approximate age of 20 years. A 3D finite element analysis of the craniofacial complex was developed from sequential computed tomography scan images. Known transversal (X) displacement with magnitudes of 1, 3, and 5 mm were applied and the displacement and Von-Mises stresses in different planes were studied on different nodes located at various structures of the craniofacial complex. Transverse orthopedic forces not only produced an expansive force at the intermaxillary suture but also high forces on various structures of the craniofacial complex, particularly at the base of the sphenoid bone and frontal process of the zygomatic bone. Lateral bending of the free ends of the pterygoid plates were noted. RME must be used judiciously in adults because of its far-reaching effects involving heavy stresses being noted at the sphenoid bone, zygomatic bone, nasal bone, and their adjacent sutures.


Toward solar biodiesel production from CO2 using engineered cyanobacteria.
Metabolic engineering of cyanobacteria has received attention as a sustainable strategy to convert carbon dioxide to various biochemicals including fatty acid-derived biodiesel. Recently, Synechococcus elongatus PCC 7942, a model cyanobacterium, has been engineered to convert CO2 to fatty acid ethyl esters (FAEEs) as biodiesel. Modular pathway has been constructed for FAEE production. Several metabolic engineering strategies were discussed to improve the production levels of FAEEs, including host engineering by improving CO2 fixation rate and photosynthetic efficiency. In addition, protein engineering of key enzyme in S. elongatus PCC 7942 was implemented to address issues on FAEE secretions toward sustainable FAEE production from CO2. Finally, advanced metabolic engineering will promote developing biosolar cell factories to convert CO2 to feasible amount of FAEEs toward solar biodiesel.


Cold Sintered Ceramic Nanocomposites of 2D MXene and Zinc Oxide.
Nanocomposites containing 2D materials have attracted much attention due to their potential for enhancing electrical, magnetic, optical, mechanical, and thermal properties. However, it has been a challenge to integrate 2D materials into ceramic matrices due to interdiffusion and chemical reactions at high temperatures. A recently reported sintering technique, the cold sintering process (CSP), which densifies ceramics with the assistance of transient aqueous solutions, provides a means to circumvent the aforementioned problems. The efficacious co-sintering of Ti3 C2 Tx (MXene), a 2D transition carbide, with ZnO, an oxide matrix, is reported. Using CSP, the ZnO-Ti3 C2 Tx nanocomposites can be sintered to 92-98% of the theoretical density at 300 °C, while avoiding oxidation or interdiffusion and showing homogeneous distribution of the 2D materials along the ZnO grain boundaries. The electrical conductivity is improved by 1-2 orders of magnitude due to the addition of up to 5 wt% MXene. The hardness and elastic modulus show an increase of 40-50% with 0.5 wt% MXene, and over 150% with 5 wt% of MXene. The successful densification of ZnO-MXene nanocomposite demonstrates that the cold sintering of ceramics with 2D materials is a promising processing route for designing new nanocomposites with a diverse range of applications.


Tailoring Photoelectrochemical Performance and Stability of Cu(In,Ga)Se2 Photocathode via TiO2-Coupled Buffer Layers.
We report on the photoelectrochemical (PEC) performance and stability of Cu(In,Ga)Se2 (CIGS)-based photocathodes for photocatalytic hydrogen evolution from water. Various functional overlayers, such as CdS, TiO2, ZnxSnyOz, and a combination of the aforementioned, were applied on the CIGS to improve the performance and stability. We identified that the insertion of TiO2 overlayer on p-CIGS/n-buffer layers significantly improves the PEC performance. A multilayered photocathode consisting of CIGS/CdS/TiO2/Pt exhibited the best current-potential characteristics among the tested photocathodes, which demonstrates a power-saved efficiency of 2.63%. However, repeated linear sweep voltammetry resulted in degradation of performance. In this regard, we focused on the PEC durability issues through in-depth chemical characterization that revealed the degradation was attributed to atomic redistribution of elements constituting the photocathode, namely, in-diffusion of Pt catalysts, out-diffusion of elements from the CIGS, and removal of the metal-oxide layers; the best-performing CIGS/CdS/TiO2/Pt photocathode retained its initial performance until the TiO2 overlayer was removed. It was also found that the durability of CIGS photocathodes with a TiO2-coated metal-oxide buffer layer such as ZnxSnyOz was better than those with a TiO2-coated CdS, and the degradation mechanism was different, suggesting that the stability of a CIGS-based photocathode can be improved by careful design of the structure.


The use of botulinum toxin in Frey's Syndrome.
Frey's Syndrome, or gustatory sweating, occurs in over 50% of patients following superficial parotidectomy. In the vast majority of cases, these symptoms are not severe enough to require surgical treatment and can be effectively treated with topical anticholinergics and antihyperhydrotics. Patients with recalcitrant Frey's Syndrome can be treated by a variety of surgical procedures. However, the potential risks and side effects of these surgical procedures often outweigh the benefits. Botulinum toxin A has recently emerged as a popular treatment option for a number of head and neck conditions. The anticholinergic effects of Botox make it particularly suitable for the treatment of Frey's Syndrome. We report our experience.


Design principles for robust vesiculation in clathrin-mediated endocytosis.
A critical step in cellular-trafficking pathways is the budding of membranes by protein coats, which recent experiments have demonstrated can be inhibited by elevated membrane tension. The robustness of processes like clathrin-mediated endocytosis (CME) across a diverse range of organisms and mechanical environments suggests that the protein machinery in this process has evolved to take advantage of some set of physical design principles to ensure robust vesiculation against opposing forces like membrane tension. Using a theoretical model for membrane mechanics and membrane protein interaction, we have systematically investigated the influence of membrane rigidity, curvature induced by the protein coat, area covered by the protein coat, membrane tension, and force from actin polymerization on bud formation. Under low tension, the membrane smoothly evolves from a flat to budded morphology as the coat area or spontaneous curvature increases, whereas the membrane remains essentially flat at high tensions. At intermediate, physiologically relevant, tensions, the membrane undergoes a "snap-through instability" in which small changes in the coat area, spontaneous curvature or membrane tension cause the membrane to "snap" from an open, U-shape to a closed bud. This instability can be smoothed out by increasing the bending rigidity of the coat, allowing for successful budding at higher membrane tensions. Additionally, applied force from actin polymerization can bypass the instability by inducing a smooth transition from an open to a closed bud. Finally, a combination of increased coat rigidity and force from actin polymerization enables robust vesiculation even at high membrane tensions.


Effect of standardized fruit extract of Luffa cylindrica on oxidative stress markers in hydrogen peroxide induced cataract.
The ability of Luffa cylindrica Roem fruit extract (LCE) to modulate biochemical parameters was investigated by in vitro studies for its role in hydrogen peroxide induced cataract on isolated goat lenses which were incubated for 72 h at 37°C. Test groups contained 5, 10, 15, 20, 25, and 30 µg/ml of LCE along with 1 ml of H2O2 (0.5 mM) as cataract inducer. Lenses were examined for morphological variation and transparency periodically during the incubation. Biochemical parameters such as superoxide dismutase (SOD), reduced glutathione (GSH), total protein content (TPC), and malondialdehyde (MDA) were estimated. SOD, GSH, and TPC levels were found to increase proportionally with the concentration of LCE. However, MDA levels were found to be inversely proportional to the concentration of LCE. Opacity was graded as per "lens opacities classification system III." Morphological examination suggested that LCE (25 µg/ml) maintained a vision for 44 h. No lens in LCE dose groups developed dense nuclear opacity after 24 h as opposed to 80% in negative control. The results suggest that LCE can delay the onset and/or prevent the progression of cataract which can be attributed to the presence of adequate phenolics, flavonoids, and Vitamin A and its high nutritional value. This preliminary study can be further synergized by testing LCE against other in vivo and in vitro models of cataract.


Development of a Conceptual Map of Negative Consequences for Patients of Overuse of Medical Tests and Treatments.
Overuse of medical tests and treatments is an increasingly recognized problem across health systems; best practices for reducing overuse are not clear. Framing the problem in terms of the spectrum of potential patient harm is likely to be an effective strategy for clinician and patient engagement in efforts to reduce overuse, but the scope of negative consequences of overuse for patients has not been well described. We sought to generate a comprehensive conceptual map documenting the processes through which overused tests and treatments lead to multiple domains of negative consequences for patients. For map development, an iterative consensus process was informed by structured review of the literature on overuse using PubMed and input from a panel of 6 international experts. For map verification, a systematic review was performed of case reports involving overused services, identified through literature review and manual review of relevant article collections. The conceptual map documents that overused tests and treatments and resultant downstream services generate 6 domains of negative consequences for patients: physical, psychological, social, financial, treatment burden, and dissatisfaction with health care. Negative consequences can result from overused services and from downstream services; they can also trigger further downstream services that in turn can lead to more negative consequences, in an ongoing feedback loop. Case reports on overuse confirmed the processes and domains of the conceptual map. Cases also revealed strengths and weaknesses in published communication about overuse: they were dominated by physical harms, with other negative consequences receiving far less attention. This evidence-based conceptual map clarifies the processes by which overused tests and treatments result in negative consequences for patients; it also documents multiple domains of negative consequences experienced by patients. The map will be useful for facilitating comprehensive communication about overuse, estimating harms and costs associated with overused services, and informing health system efforts to reduce overuse.


Association between advanced glycation end-products and functional performance in Alzheimer's disease and mixed dementia.
People with Alzheimer's disease (AD) experience, in addition to the progressive loss of cognitive functions, a decline in functional performance such as mobility impairment and disability in activities of daily living (ADL). Functional decline in dementia is mainly linked to the progressive brain pathology. Peripheral biomechanical changes by advanced glycation end-products (AGEs) have been suggested but have yet to be thoroughly studied. A multi-center, longitudinal, one-year follow-up cohort study was conducted in 144 people with early stage AD or mixed Alzheimer's/Vascular dementia. Linear mixed model analyses was used to study associations between AGE-levels (AGE reader) and mobility (Timed Up and Go), and ADL (Groningen Activity Restriction Scale and Barthel index), respectively. A significant association between AGE levels and mobility (β = 3.57, 95%CI: 1.43-5.73) was revealed; however, no significant association between AGE levels and ADL was found. Over a one-year time span, mean AGE levels significantly increased, and mobility and ADL performance decreased. Change in AGE levels was not significantly correlated with change in mobility. This study indicates that high AGE levels could be a contributing factor to impaired mobility but lacks evidence for an association with ADL decline in people with early stage AD or mixed dementia. Future research is necessary on the reduction of functional decline in dementia regarding the effectiveness of interventions such as physical activity programs and dietary advice possibly in combination with pharmacologic strategies targeting AGE accumulation.


The time-course of psoralen ultraviolet A (PUVA) erythema.
The time-course for the development of ultraviolet A-induced erythema in psoralen-sensitized skin differs from that caused by ultraviolet B or ultraviolet A but objective data are not available. During psoralen ultraviolet A therapy, the minimal phototoxic dose is determined 72 h after exposure, when psoralen ultraviolet A erythema is assumed to be maximal. This measurement is of fundamental importance in optimizing the therapeutic regimen. We examined a detailed time-course for development of psoralen ultraviolet A erythema in 16 subjects. The erythemal responses to ultraviolet B, ultraviolet A and psoralen ultraviolet A were assessed visually and using a reflectance device. Ultraviolet B erythema was maximal 24 h after exposure compared with subsequent time-points. Psoralen ultraviolet A erythema was evident at 24 h, with reduction in the median ultraviolet A minimal erythema dose from 14 to 5 J per cm2 in the presence of psoralen (p < 0.01; n = 9). Peak psoralen ultraviolet A erythema, assessed by minimal phototoxic dose, did not occur until 96 h or later in 75% of subjects. Using individual dose- response curves, we determined that only 67% of mean maximum psoralen ultraviolet A erythemal intensity had developed by 72 h. Furthermore, at the time of maximal erythema, the slope of the psoralen ultraviolet A dose-response curve was approximately 2-fold shallower than that for ultraviolet B-induced erythema. If assessment of psoralen ultraviolet A erythemal sensitivity had been made at 96 h instead of the conventional 72 h time-point, peak erythemal responses would not have been missed in any of the subjects. Based on these findings, it seems appropriate to consider whether psoralen ultraviolet A minimal phototoxic dose measurements should be performed 96 h after exposure.


Tracing the Growth, Gaps, and Characteristics in Positive Education Science: A Long-Term, Large-Scale Review of the Field.
This large-scale quantitative review used publication data to track the presence of positive education terms over a 100+ year period across 35 psychology journals and education journals utilizing two analytical methods. First, computer-generated linguistic word count analysis identified that positive education terms have shown small but steady growth in psychology and education research for more than a century. From 1904 to 2016, positive education terms have risen consistently, with increases in 1952, 1982, 2010, and 2014 to over 4, 5, 6, and 7 percent, respectively. Four new terms were present in the top 20 most prevalent terms following the official launch of positive education in 2009: well-being, satisfaction, motivat*, and engag* (note: terms ending with an asterisk are word stems). Three terms also increased in rank order prevalence from 2009 onwards: emotion*; health; and goal*. The second analytical method involved in-depth human coding of a subset of positive education abstracts (n=2,805) by a team of five researchers to identify trends pertaining to how positive education research has been conducted in terms of paradigms, designs, methods, tools, samples, and settings from 1950 to 2016. College students and students in secondary school make up the most common samples, with little research in the early childhood years. Quantitative, cross-sectional studies using self-report surveys have been the most common design and method used over the past six decades, suggesting room for growth in qualitative methods and the need for greater longitudinal and intervention designs. The human coding was also used to classify positive education variables into broader categories of research. Nine categories were identified: positive functioning; well-being; ill-being; strengths; agency; connection and belonging; identity and personality; school climate and outcomes; and demographics. By tracking positive education science over time, the current paper allows researchers to take stock of the field, identify gaps, outline areas of growth, and pursue fruitful topics for future research.


Direct determination of ionic solvation from neutron diffraction.
Much information on ionic solvation in electrolyte solutions has been inferred from macroscopic thermodynamic and transport properties and from spectroscopy. These ion-water interactions can now be probed directly and unambiguously by neutron diffraction. Such measurements have been done with neodymium trichloride solutions in heavy water that are identical in every respect except the isotopic state of the neodymium ions; these experiments yield in a straightforward manner the distribution of oxygen and deuterium atoms from the water molecules in the first hydration sphere of the neodymium ion. Each ion is surrounded by 8.6 oxygen atoms at a distance of 2.48 angstroms and 16.7 deuterium atoms at 3.13 angstroms indicating a well-defined first hydration sphere of water molecules, the deuterium atoms pointing away from the cation.


Zebrafish Rpgr is required for normal retinal development and plays a role in dynein-based retrograde transport processes.
Mutations in the human RPGR gene cause one of the most common and severe forms of inherited retinal dystrophy, but the function of its protein product remains unclear. We have identified two genes resembling human RPGR (ZFRPGR1, ZFRPGR2) in zebrafish (Danio rerio), both of which are expressed within the nascent and adult eye as well as more widely during development. ZFRPGR2 appears to be functionally orthologous to human RPGR, because it encodes similar protein isoforms (ZFRPGR2(ORF15), ZFRPGR2(ex1-17)) and causes developmental defects similar to other ciliary proteins, affecting gastrulation, tail and head development after morpholino-induced knockdown (translation suppression). These defects are consistent with a ciliary function and were rescued by human RPGR but not by RPGR mutants causing retinal dystrophy. Unlike mammals, RPGR knockdown in zebrafish resulted in both abnormal development and increased cell death in the dysplastic retina. Developmental abnormalities in the eye included lamination defects, failure to develop photoreceptor outer segments and a small eye phenotype, associated with increased cell death throughout the retina. These defects could be rescued by expression of wild-type but not mutant forms of human RPGR. ZFRPGR2 knockdown also resulted in an intracellular transport defect affecting retrograde but not anterograde transport of organelles. ZFRPGR2 is therefore necessary both for the normal differentiation and lamination of the retina and to prevent apoptotic retinal cell death, which may relate to its proposed role in dynein-based retrograde transport processes.


Acute mesenteric venous thrombosis. Revisited in a time of diagnostic clarity.
Historically, mesenteric venous thrombosis (MVT) has been found during laparotomy or at autopsy. Improvements in computed tomography (CT) and ultrasound (U/S) may identify patients earlier in their clinical course. How has this altered the treatment strategy of the authors? This 10-year retrospective study of acute MVT consisted of 12 men and three women (average age 43). Presenting signs and symptoms were nonspecific in 10/15 patients resulting in multiple diagnostic tests. All CT scans (10) and angiograms (4) revealed mesenteric clot. U/S exams detected clot in 6/9 patients. The remaining five patients exhibited clinical signs requiring operations rather than diagnostic studies. The only consistent laboratory abnormality was an elevated white blood cell count in 12/15 patients. Management of MVT varied. Five patients, heparinized once the diagnosis was made, did not experience dysfunction from MVT. Ten patients were not initially treated with heparin and were divided into three groups. Three patients received neither heparin nor surgery and have had no sequelae. MVT contributed to the death of two patients. The remaining five patients were diagnosed in the operating room following bowel resection. Two of these patients received postoperative heparin and had a favorable outcome. Two of the three patients not heparinized after surgery suffered additional bowel infarction. MVT can present as nonspecific abdominal pain, but also as peritonitis requiring operation. CT and U/S can identify patients with early MVT. It appears that heparin has both a primary therapeutic role in early disease and a postoperative adjunctive role in advanced disease. With such care, these patients can expect an acceptable prognosis (86% survival).


Body Mass Index and Risk for COVID-19-Related Hospitalization, Intensive Care Unit Admission, Invasive Mechanical Ventilation, and Death - United States, March-December 2020.
Obesity* is a recognized risk factor for severe COVID-19 (1,2), possibly related to chronic inflammation that disrupts immune and thrombogenic responses to pathogens (3) as well as to impaired lung function from excess weight (4). Obesity is a common metabolic disease, affecting 42.4% of U.S. adults (5), and is a risk factor for other chronic diseases, including type 2 diabetes, heart disease, and some cancers.† The Advisory Committee on Immunization Practices considers obesity to be a high-risk medical condition for COVID-19 vaccine prioritization (6). Using data from the Premier Healthcare Database Special COVID-19 Release (PHD-SR),§ CDC assessed the association between body mass index (BMI) and risk for severe COVID-19 outcomes (i.e., hospitalization, intensive care unit [ICU] or stepdown unit admission, invasive mechanical ventilation, and death). Among 148,494 adults who received a COVID-19 diagnosis during an emergency department (ED) or inpatient visit at 238 U.S. hospitals during March-December 2020, 28.3% had overweight and 50.8% had obesity. Overweight and obesity were risk factors for invasive mechanical ventilation, and obesity was a risk factor for hospitalization and death, particularly among adults aged <65 years. Risks for hospitalization, ICU admission, and death were lowest among patients with BMIs of 24.2 kg/m2, 25.9 kg/m2, and 23.7 kg/m2, respectively, and then increased sharply with higher BMIs. Risk for invasive mechanical ventilation increased over the full range of BMIs, from 15 kg/m2 to 60 kg/m2. As clinicians develop care plans for COVID-19 patients, they should consider the risk for severe outcomes in patients with higher BMIs, especially for those with severe obesity. These findings highlight the clinical and public health implications of higher BMIs, including the need for intensive COVID-19 illness management as obesity severity increases, promotion of COVID-19 prevention strategies including continued vaccine prioritization (6) and masking, and policies to ensure community access to nutrition and physical activities that promote and support a healthy BMI.