Epistaxis as the only initial symptom in pediatric naso-orbital-ethmoid fracture complicated with meningitis.
Epistaxis is a frequent finding in patients with facial trauma. Herein, we report an unusual presentation of pediatric naso-orbital-ethmoid (NOE) fracture with epistaxis as the only initial symptom. The course of the patient's condition was later complicated by meningitis, related in part to the delay in diagnosis. A 3-year-old girl with preexisting upper respiratory symptoms was involved in a traffic accident, sustaining blunt trauma to the right side of her face. During the initial examination, only right-sided epistaxis was noted. Five days later, she developed febrile convulsion and was admitted to the intensive care unit with other signs of meningitis such as mental status change and neck stiffness. Her craniofacial computed tomographic scan showed a right-sided NOE fracture with minimal displacement and without dura tear. The cerebrospinal fluid culture grew Streptococcus pneumoniae, which may be due to ascending infection as a result of cribriform plate fracture. Intravenous antibiotic therapy was initiated with good response, and she was discharged from the hospital after 2 weeks. The presence of epistaxis and periorbital bruise, together with other symptoms and signs, helps in the identification of NOE and cribriform plate fracture. A high index of suspicion with repetitive computed tomographic scans is necessary to achieve correct early diagnosis. Parental antibiotic therapy is indicated if ascending cerebrospinal fluid infection develops.


Mediation between the shamanistic model and the psychiatric model in a shamanistic climate: a viewpoint of medical anthropology.
It is suggested that any clinician working on the Miyako islands, Okinawa, Japan, be a mediator or a negotiator between two worlds, namely the shamanistic and the modern psychiatric ones. On these islands, to subscribe to either is possible only by ignoring conflicting clinical realities. The main point is to summarize the complementary practices of these two medical systems on these islands. Psychiatric illness attributed to kamidaari is introduced. The initiatory illness for seeing a shaman is called kamidaari or kamburi. From the viewpoint of medical anthropology, aspects of the treatment of such patients in a shamanistic 'climate' (which is called fudo in Japanese), will be reported. In the shamanistic fudo, it must be recognized that, at a critical moment, shamanistic epistemology and psychiatric epistemology penetrate each other, and they exist together in a clinical 'mesh'. Two epistemologies must join in a coalition to access, and build continuity into, psychiatric and shamanistic medical care. It is demonstrated that these two worlds almost merge in dialogue but do not fuse, and that clinical relations occur on the boundary between these two epistemologies. 'Climatic' specific therapeutic stances are introduced and are clinically illustrated.


A comparative study of heel-stick devices for infant blood collection.
To evaluate two heel-stick devices by comparing the volume of blood collected, blood sampling time, amount of hemolysis, pain inflicted during the procedure, and extent of bruising. Randomized trial. Primary care center in a tertiary-level perinatal hospital. Forty healthy, full-term newborns with a postnatal age of greater than 24 hours. Newborns were fed no more than 1 1/2 hours before blood sample collection and fulfilled the requirement for routine phenylketonuria and thyroid screening. Newborns were allocated to a single stab with either an automated incision or a lancet puncture device. The total volume of blood and blood sampling time were significantly better with the automated incision device (P < .001). Hemolysis was also reduced with the automated incision device (P < .03). Plasma hemoglobin levels were below 1.0 g/L in all samples obtained with the automated incision device and in 71% of samples obtained with the lancet device. There were no differences in the extent of bruising or in pain symptoms manifested by mean increases in heart rate and percentage of time crying during the procedure. The larger volume of blood obtained within a shorter period for blood collection and reduced hemolysis with the automated incision device make it a preferred instrument for neonatal blood collection.


The role of violent media preference in cumulative developmental risk for violence and general aggression.
The impact of exposure to violence in the media on the long-term development and short-term expression of aggressive behavior has been well documented. However, gaps in this literature remain, and in particular the role of violent media exposure in shaping violent and other serious antisocial behavior has not been investigated. Further, studies of violent media effects typically have not sampled from populations with confirmed histories of violent and/or nonviolent antisocial behavior. In this study, we analyzed data on 820 youth, including 390 juvenile delinquents and 430 high school students, to examine the relation of violent media use to involvement in violence and general aggression. Using criterion scores developed through cross-informant modeling of data from self, parent/guardian, and teacher/staff reports, we observed that childhood and adolescent violent media preferences contributed significantly to the prediction of violence and general aggression from cumulative risk totals. Findings represent a new and important direction for research on the role of violent media use in the broader matrix of risk factors for youth violence.


Systemic inflammatory response elicited by superantigen destabilizes T regulatory cells, rendering them ineffective during toxic shock syndrome.
Life-threatening infections caused by Staphylococcus aureus, particularly the community-acquired methicillin-resistant strains of S. aureus, continue to pose serious problems. Greater virulence and increased pathogenicity of certain S. aureus strains are attributed to higher prevalence of exotoxins. Of these exotoxins, the superantigens (SAg) are likely most pathogenic because of their ability to rapidly and robustly activate the T cells even in extremely small quantities. Therefore, countering SAg-mediated T cell activation using T regulatory cells (Tregs) might be beneficial in diseases such as toxic shock syndrome (TSS). As the normal numbers of endogenous Tregs in a typical host are insufficient, we hypothesized that increasing the Treg numbers by administration of IL-2/anti-IL-2 Ab immune complexes (IL2C) or by adoptive transfer of ex vivo expanded Tregs might be more effective in countering SAg-mediated immune activation. HLA-DR3 transgenic mice that closely recapitulate human TSS were treated with IL2C to increase endogenous Tregs or received ex vivo expanded Tregs. Subsequently, they were challenged with SAg to induce TSS. Analyses of various parameters reflective of TSS (serum cytokine/chemokine levels, multiple organ pathology, and SAg-induced peripheral T cell expansion) indicated that increasing the Tregs failed to mitigate TSS. On the contrary, serum IFN-γ levels were increased in IL2C-treated mice. Exploration into the reasons behind the lack of protective effect of Tregs revealed IL-17 and IFN-γ-dependent loss of Tregs during TSS. In addition, significant upregulation of glucocorticoid-induced TNFR family-related receptor on conventional T cells during TSS could render them resistant to Treg-mediated suppression, contributing to failure of Treg-mediated immune regulation.


The mechanism of cytotoxicity and DNA adduct formation by the anticancer drug ellipticine in human neuroblastoma cells.
Ellipticine is an antineoplastic agent, whose mode of action is based mainly on DNA intercalation, inhibition of topoisomerase II and formation of covalent DNA adducts mediated by cytochromes P450 and peroxidases. Here, the molecular mechanism of DNA-mediated ellipticine action in human neuroblastoma IMR-32, UKF-NB-3 and UKF-NB-4 cancer cell lines was investigated. Treatment of neuroblastoma cells with ellipticine resulted in apoptosis induction, which was verified by the appearance of DNA fragmentation, and in inhibition of cell growth. These effects were associated with formation of two covalent ellipticine-derived DNA adducts, identical to those formed by the cytochrome P450- and peroxidase-mediated ellipticine metabolites, 13-hydroxy- and 12-hydroxyellipticine. The expression of these enzymes at mRNA and protein levels and their ability to generate ellipticine-DNA adducts in neuroblastoma cells were proven, using the real-time polymerase chain reaction, Western blotting analyses and by analyzing ellipticine-DNA adducts in incubations of this drug with neuroblastoma S9 fractions, enzyme cofactors and DNA. The levels of DNA adducts correlated with toxicity of ellipticine to IMR-32 and UKF-NB-4 cells, but not with that to UKF-NB-3 cells. In addition, hypoxic cell culture conditions resulted in a decrease in ellipticine toxicity to IMR-32 and UKF-NB-4 cells and this correlated with lower levels of DNA adducts. Both these cell lines accumulated in S phase, suggesting that ellipticine-DNA adducts interfere with DNA replication. The results demonstrate that among the multiple modes of ellipticine antitumor action, formation of covalent DNA adducts by ellipticine is the predominant mechanism of cytotoxicity to IMR-32 and UKF-NB-4 neuroblastoma cells.


[Guillain Barré syndrome in association with Brucellosis].
We describe a case of a 47 years old male, with a history of 2 days of progressive, ascendant, symmetrical weakness in the lower extremities; a lumbar puncture was performed after the brain CT scan, as well as an electromyography, evidencing pure motor polyradiculopathy with axonal pattern, compatible with Guillain Barre syndrome. Afterwards, he received four plasmapheresis sessions, with clinical improvement from the second session. Due to his epidemiological background, Brucella set testing was done. Rose Bengal was positive, antibiotic treatment with rifampin and doxicicline was initiated, as well as rehabilitation. Three months later the patient recovered completely. The relevance of early treatment with plasmapheresis and the definition of the etiologic diagnosis determine that the prognosis of the Guillain Barre syndrome is favorable.


Comparative Research for the Healthcare Budget and Burden of Disease in Perspective Resource Allocation.
Burden of disease can be used to prioritize the healthcare budget allocation. We analyzed the research and development (R&D) budget of the Ministry of Health and Welfare (MOHW) in 2018 and compared the results with those of the 2015 Korean National Burden of Disease (KNBD) study. The 2018 MOHW R&D Project integrated implementation plan was used to analyze the R&D budget of the MOHW. The budget was allocated according to the KNBD disease group and according to the budget lines. The allocated budget was compared with the economic burden and the disability adjusted life years (DALYs) in 2015. Also, for budget targets for risk factors, DALYs of attributable risk factors were compared with corresponding budgets. In 2018, the MOHW major R&D budget of USD 435.1 million accounted for 3% of the total government budget. Within the disease specific R&D budget, 35.9% was allocated to communicable disease groups, 64.1% to non-communicable diseases, and 0% to injury and violence. Among level 2 disease groups, neoplasm was ranked first. Among risk factors, climate change and behavioral risk were targeted for R&D. It would be difficult to say that current R&D allocations focus to minimize the burden of disease. A mismatch was observed between the R&D budget and the burden of disease in terms of economic burden and DALYs. There was a similar finding for risk factors R&D. A novel approach for allocating government R&D funding that is based on the goal of minimizing the disease burden in the Korean population should be considered.


Recently evolved genes identified from Drosophila yakuba and D. erecta accessory gland expressed sequence tags.
The fraction of the genome associated with male reproduction in Drosophila may be unusually dynamic. For example, male reproduction-related genes show higher-than-average rates of protein divergence and gene expression evolution compared to most Drosophila genes. Drosophila male reproduction may also be enriched for novel genetic functions. Our earlier work, based on accessory gland protein genes (Acp's) in D. simulans and D. melanogaster, suggested that the melanogaster subgroup Acp's may be lost and/or gained on a relatively rapid timescale. Here we investigate this possibility more thoroughly through description of the accessory gland transcriptome in two melanogaster subgroup species, D. yakuba and D. erecta. A genomic analysis of previously unknown genes isolated from cDNA libraries of these species revealed several cases of genes present in one or both species, yet absent from ingroup and outgroup species. We found no evidence that these novel genes are attributable primarily to duplication and divergence, which suggests the possibility that Acp's or other genes coding for small proteins may originate from ancestrally noncoding DNA.


Reproductive endocrine disorders in women with partial seizures of temporal lobe origin.
Of 50 consecutive women with partial seizures of temporal lobe origin (temporal lobe epilepsy [TLE]) evaluated for reproductive dysfunction, 28 had menstrual problems. Of those, 19 had reproductive endocrine disorders. Polycystic ovarian syndrome and hypogonadotropic hypogonadism occurred significantly more often in women with TLE than in the general female population. Polycystic ovarian syndrome was associated with predominantly left-sided lateralization of interictal epileptic discharges; hypogonadotropic hypogonadism was more commonly found with right-sided discharges. Hyposexuality occurred more often in women with predominantly right-sided interictal epileptic discharges and was associated with low serum luteinizing hormone levels. There are several possible interpretations: epileptic discharges in medial temporal limbic structures may disrupt hypothalamic regulation of pituitary gonadotropin secretion; anovulatory cycles of reproductive endocrine disorders may promote the development of epileptic discharges; and TLE and some associated reproductive endocrine disorders may represent the parallel effects of prenatal factors common to the development of the brain and the reproductive system.


Catches in abandoned snow crab (Chionoecetes opilio) pots in the Barents Sea.
During a 2018 retrieval cruise for abandoned snow crab (Chionoecetes opilio) pots in the Barents Sea, approximately 8600 pots abandoned 1.5 years earlier were recovered. Forty-three percent of a subsample of 1000 pots contained snow crabs, with an average of three crabs per pot. Most of the crabs were alive (~98%) and dominated by large males. Pinch injuries and limb loss were common and tended to decline with increasing crab size. Reflex testing showed that the crabs were vital (i.e. the crabs moved their legs, chelipeds and maxillipeds when stimulated), which was supported by a relatively high meat content. However, energy reserves in the digestive glands (hepatopancreas reserves) were low, indicating overall energy deficiencies. Our results indicate considerable unaccounted mortality due to self-baiting, continued catch and cannibalism. The findings demonstrate that snow crab pots which are lost or abandoned in the Barents Sea fishery maintain huge potential for ghost-fishing impacts.


Non-parathyroid hypercalcemia associated with paraffin oil injection in 12 younger male bodybuilders: a case series.
Injection of paraffin oil to augment muscles size is a troubling phenomenon known to cause a foreign body reaction with formation of granulomas. In a few case reports, long-term side effects have been reported in terms of hypercalcemia and renal failure. We identified a case series of 12 male bodybuilders presenting with non-parathyroid hypercalcemia who previously had injected paraffin oil to increase muscles size. At admission, all patients had moderate-to-severe hypercalcemia with suppressed PTH levels and impaired renal function. Calcitriol levels were within the normal range or slightly elevated. Follow-up measurements showed marked hypercalciuria with nearly normal levels of bone turnover markers. A correlation was found between levels of peptidyl dipeptidase and calcitriol (R = 0.812, P = 0.050). Treatment with antiresorptive agents seemed less effective than glucocorticoids, which resulted in a significantly lowering of ionized calcium levels and improved renal function, although no patients were cured by this treatment. Immunosuppression with azathioprine or mycophenolate may have a glucocorticoid-saving effect. One patient had surgery with removal of affected muscle tissue, without any apparent effect on plasma calcium levels. The hypercalcemia and associated hypercalciuria seems to be due to an intestinal hyperabsorption of calcium. It remains to be elucidated, whether an increased calcitriol synthesis within granulomas is the only (main) mechanism by which intestinal calcium absorption is increased. Glucocorticoids seem most appropriate as the first choice for treatment. Bodybuilders should be warned against use of intramuscular oil injections (and other substances), as this may have severe adverse health consequences.


Relationship among antioxidant activity, vasodilation capacity, and phenolic content of red wines.
The relationship among antioxidant activity, based on the electron-spin resonance determination of the reduction of Fremy's radical, vasodilation activity, and phenolic content was investigated in 16 red wines. The wines were selected to provide a range of origins, grape varieties, and vinification methods. Sensitive and selective HPLC methods were used for the analysis of the major phenolics in red wine: free and conjugated myricetin, quercetin, kaempferol, and isorhamnetin; (+)-catechin, (-)-epicatechin, gallic acid, p-coumaric acid, caffeic acid, caftaric acid, trans-resveratrol, cis-resveratrol, and trans-resveratrol glucoside. Total anthocyanins were measured using a colorimetric assay. The total phenolic content of the wines was determined according to the Folin-Ciocalteu colorimetric assay and also by the cumulative measurements obtained by HPLC. The 16 wines exhibited a wide range in the values of all parameters investigated. However, the total phenol contents, measured both by HPLC and colorimetrically, correlated very strongly with the antioxidant activity and vasodilation activity. In addition, the antioxidant activity was associated with gallic acid, total resveratrol, and total catechin. In contrast, only the total anthocyanins were correlated with vasodilation activity. The results demonstrate that the different phenolic profiles of wines can produce varying antioxidant and vasodilatant activities, which opens up the possibility that some red wines may provide enhanced health benefits for the consumer.


Graphene-based nanoplatforms for surface-enhanced Raman scattering sensing.
Surface-enhanced Raman scattering (SERS) is one of the important techniques for sensing applications in biological analysis, disease diagnosis, environmental science, and food safety. Graphene provides an excellent nanoplatform for SERS sensing due to its two-dimensional flat structure, uniform electronic and photonic properties, excellent mechanical stability, atomic uniformity, and high biocompatibility. In this review, we summarize recent advances in the fabrication of various graphene-based nanoplatforms for SERS sensing. We present the strategies, such as self-assembly, in situ synthesis, one-pot synthesis, liquid phase reduction, and biomimetic synthesis, for the fabrication of graphene-based hybrid metallic and alloy nanoplatforms, and then demonstrate the potential applications of graphene-based nanoplatforms for the SERS sensing of ions, organic dyes, pesticides, bacteria, DNA, proteins, cells, and other chemicals in great detail. In addition, we also discuss the future development of this interesting research field and provide several perspectives. This work will be helpful for readers to understand the fabrication and sensing mechanisms of graphene-based SERS sensing nanoplatforms; meanwhile, it will promote the development of new materials and novel methods for high performance sensing and biosensing applications.


Metabolism of fensulfothion by a soil bacterium, Pseudomonas alcaligenes C1.
Fensulfothion (O,O-diethyl O-[4-(methylsulfinyl)phenyl]phosphorothioate), an organophosphorus pesticide used to control the golden nematode Heterodera rostochiensis, is used as a source of carbon by microorganisms isolated from soils treated with the pesticide. Two of the microbial isolates, Pseudomonas alcaligenes C1 and Alcaligenes sp. strain NC3, used more than 80% of the pesticide in 120 h in culture when supplemented as a source of carbon. P. alcaligenes C1, which showed maximal growth on fensulfothion, degraded the compound to p-methylsulfinyl phenol and diethyl phosphorothioic acid. The phenolic metabolite could be identified by conventional spectral analysis, whereas the spectral patterns of the phosphorus-containing metabolite suggested that the compound was complexed with some cellular molecules. However, utilization of the phosphoric acid ester and ethanol by P. alcaligenes C1 suggested that the microbe attacks fensulfothion by an initial hydrolysis of the compound and subsequent utilization of the phosphoric acid ester. The pathway of degradation of fensulfothion by P. alcaligenes is of great value in the detoxification of the pesticide residues and also in the environmentally stable phosphoric acid esters.


Gliding flight: speed and acceleration of ideal falcons during diving and pull out.
Some falcons, such as peregrines (Falco peregrinus), attack their prey in the air at the end of high-speed dives and are thought to be the fastest of animals. Estimates of their top speed in a dive range up to 157 m s-1, although speeds this high have never been accurately measured. This study investigates the aerodynamic and gravitational forces on 'ideal falcons' and uses a mathematical model to calculate speed and acceleration during diving. Ideal falcons have body masses of 0.5-2.0 kg and morphological and aerodynamic properties based on those measured for real falcons. The top speeds reached during a dive depend on the mass of the bird and the angle and duration of the dive. Given enough time, ideal falcons can reach top speeds of 89-112 m s-1 in a vertical dive, the higher speed for the heaviest bird, when the parasite drag coefficient has a value of 0.18. This value was measured for low-speed flight, and it could plausibly decline to 0.07 at high speeds. Top speeds then would be 138-174 m s-1. An ideal falcon diving at angles between 15 and 90 degrees with a mass of 1 kg reaches 95 % of top speed after travelling approximately 1200 m. The time and altitude loss to reach 95 % of top speed range from 38 s and 322 m at 15 degrees to 16 s and 1140 m at 90 degrees, respectively. During pull out at top speed from a vertical dive, the 1 kg ideal falcon can generate a lift force 18 times its own weight by reducing its wing span, compared with a lift force of 1.7 times its weight at full wing span. The falcon loses 60 m of altitude while pulling out of the dive, and lift and loss of altitude both decrease as the angle of the dive decreases. The 1 kg falcon can slow down in a dive by increasing its parasite drag and the angle of attack of its wings. Both lift and drag increase with angle of attack, but the falcon can cancel the increased lift by holding its wings in a cupped position so that part of the lift is directed laterally. The increased drag of wings producing maximum lift is great enough to decelerate the falcon at -1.5 times the acceleration of gravity at a dive angle of 45 degrees and a speed of 41 m s-1 (0.5 times top speed). Real falcons can control their speeds in a dive by changing their drag and by choosing the length of the dive. They would encounter both advantages and disadvantages by diving at the top speeds of ideal falcons, and whether they achieve those speeds remains to be investigated.


Borders of multiple visual areas in humans revealed by functional magnetic resonance imaging.
The borders of human visual areas V1, V2, VP, V3, and V4 were precisely and noninvasively determined. Functional magnetic resonance images were recorded during phase-encoded retinal stimulation. This volume data set was then sampled with a cortical surface reconstruction, making it possible to calculate the local visual field sign (mirror image versus non-mirror image representation). This method automatically and objectively outlines area borders because adjacent areas often have the opposite field sign. Cortical magnification factor curves for striate and extrastriate cortical areas were determined, which showed that human visual areas have a greater emphasis on the center-of-gaze than their counterparts in monkeys. Retinotopically organized visual areas in humans extend anteriorly to overlap several areas previously shown to be activated by written words.


Use of ionic liquids in the synthesis of nanocrystals and nanorods of semiconducting metal chalcogenides.
We have synthesized nanoparticles of hexagonal CdS in the diameter range 3-13 nm by the reaction of cadmium acetate dihydrate with thioacetamide in imidazolium [BMIM]-based ionic liquids. We have obtained three different particle sizes of CdS by changing the anion of the ionic liquid. Addition of trioctylphosphine oxide (TOPO) to the reaction mixture causes greater monodispersity as well as smaller particle size, while addition of ethylenediamine produces nanorods of 7 nm average diameter. Hexagonal ZnS and cubic PbS nanoparticles with average diameters of 3 and 10 nm, respectively, have been prepared by the reaction of the metal acetates with thioacetamide in [BMIM][BF4]. Hexagonal CdSe nanoparticles with an average diameter 12 nm were obtained by the reaction of cadmium acetate dihydrate with dimethylselenourea in [BMIM][BF4]. In this case also we observe the same effect of the addition of TOPO as in the case of CdS. Addition of ethylenediamine to the reaction mixture gives rise to nanorods. ZnSe nanowires with a cubic structures, possible diameters in the range 70-100 nm by the reaction of zinc acetate dihydrate with dimethylselenourea in [BMIM][MeSO4]. The nanostructures obtained are single crystalline in all the cases. Most of the nanostructures show characteristic UV/Vis absorption and photoluminescence emission spectra. The thermodynamically most stable structures are generally produced in the synthesis carried out in ionic liquids.


Postcranial robusticity in Homo. I: Temporal trends and mechanical interpretation.
Temporal trends in postcranial robusticity within the genus Homo are explored by comparing cross-sectional diaphyseal and articular properties of the femur, and to a more limited extent, the humerus, in samples of Recent and earlier Homo. Using both theoretical mechanical models and empirical observations within Recent humans, scaling relationships between structural properties and bone length are developed. The influence of body shape on these relationships is considered. These scaling factors are then used to standardize structural properties for comparisons with pre-Recent Homo (Homo sp. and H. erectus, archaic H. sapiens, and early modern H. sapiens). Results of the comparisons lead to the following conclusions: 1) There has been a consistent, exponentially increasing decline in diaphyseal robusticity within Homo that has continued from the early Pleistocene through living humans. Early modern H. sapiens are closer in shaft robusticity to archaic H. sapiens than they are to Recent humans. The increase in diaphyseal robusticity in earlier Homo is a result of both medullary contraction and periosteal expansion relative to Recent humans. 2) There has been no similar temporal decline in articular robusticity within Homo--relative femoral head size is similar in all groups and time periods. Thus, articular to shaft proportions are different in pre-Recent and Recent Homo. 3) These findings are most consistent with a mechanical explanation (declining mechanical loading of the postcranium), that acted primarily through developmental rather than genetic means. The environmental (behavioral) factors that brought about the decline in postcranial robusticity in Homo are ultimately linked to increases in brain size and cultural-technological advances, although changes in robusticity lag behind changes in cognitive capabilities.


Solifenacin for overactive bladder: a systematic review and meta-analysis.
This study aims to evaluate the efficacy and safety of solifenacin for treating overactive bladder. Randomized controlled trials (RCTs) were identified and extracted from MEDLINE, Embase, and CENTRAL. The quality of the included RCTs was assessed using the Jadad score, and heterogeneity was analyzed using the chi-squared test. The data of the included RCTs were collected, extracted, and assessed by our protocol. A total of nine RCTs were identified from the search strategy. Compared with the placebo and tolterodine treatments, both short-term (mostly 12-week) trials indicated that solifenacin significantly reduced urgency episodes, micturitions, and incontinence episodes per 24 h. Compared with the solifenacin (5 mg) group, the solifenacin (10 mg) group was significantly better in terms of the number of micturitions per 24 h. With regard to adverse effects, the patients treated with solifenacin had significantly higher rates of constipation and blurred vision than patients treated with tolterodine. The solifenacin therapy was not inferior to tolterodine in terms of efficacy profiles and had a similar incidence of overall adverse events compared with tolterodine treatment. Solifenacin (5 mg) is thus a recommended dose because of its reported balance between efficacy and acceptable tolerability.


Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images.
Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.


Severe maternal outcomes in eastern Ethiopia: Application of the adapted maternal near miss tool.
With the reduction of maternal mortality, maternal near miss (MNM) has been used as a complementary indicator of maternal health. The objective of this study was to assess the frequency of MNM in eastern Ethiopia using an adapted sub-Saharan Africa MNM tool and compare its applicability with the original WHO MNM tool. We applied the sub-Saharan Africa and WHO MNM criteria to 1054 women admitted with potentially life-threatening conditions (including 28 deaths) in Hiwot Fana Specialized University Hospital and Jugel Hospital between January 2016 and April 2017. Discharge records were examined to identify deaths or women who developed MNM according to the sub-Saharan or WHO criteria. We calculated and compared MNM and severe maternal outcome ratios. Mortality index (ratio of maternal deaths to SMO) was calculated as indicator of quality of care. The sub-Saharan Africa criteria identified 594 cases of MNM and all the 28 deaths while the WHO criteria identified 128 cases of MNM and 26 deaths. There were 7404 livebirths during the same period. This gives MNM ratios of 80 versus 17 per 1000 live births for the adapted and original WHO criteria. Mortality index was 4.5% and 16.9% in the adapted and WHO criteria respectively. The major difference between the two criteria can be attributed to eclampsia, sepsis and differences in the threshold for transfusion of blood. The sub-Saharan Africa criteria identified all the MNM cases identified by the WHO criteria and all the maternal deaths. Applying the WHO criteria alone will cause under reporting of MNM cases (including maternal deaths) in this low-resource setting. The mortality index of 4.5% among women who fulfilled the adapted MNM criteria justifies labeling these women as having 'life-threatening conditions'.


Extensive porto-splenic venous thrombosis postsplenectomy in a sickle cell disease: a rare complication.
Hereditary haemoglobinopathies are common disorders in Oman. The most common haematological disorder among Omani population is sickle cell disease (SCD). The spleen is one of the organs that is affected early in the first decade of life in SCD patients. Splenectomy has shown a high success rate in improving the quality of life in SCD patients, through eliminating acute splenic sequestration crises, thus reducing the need for hospital admission and transfusion requirements. One of the rare complications of splenectomy is porto-splenic vein thrombosis. Multiple factors are responsible for this complication including: thermal and mechanical injury during ligation of splenic hilum, sudden increase in the platelet count and large spleen size. We report a rare case of extensive porto-splenic vein thrombosis that responded to early initiation of anticoagulation with resolution of the thrombosis and recanalisation.


Spinal cord injury-induced immunodeficiency is mediated by a sympathetic-neuroendocrine adrenal reflex.
Acute spinal cord injury (SCI) causes systemic immunosuppression and life-threatening infections, thought to result from noradrenergic overactivation and excess glucocorticoid release via hypothalamus-pituitary-adrenal axis stimulation. Instead of consecutive hypothalamus-pituitary-adrenal axis activation, we report that acute SCI in mice induced suppression of serum norepinephrine and concomitant increase in cortisol, despite suppressed adrenocorticotropic hormone, indicating primary (adrenal) hypercortisolism. This neurogenic effect was more pronounced after high-thoracic level (Th1) SCI disconnecting adrenal gland innervation, compared with low-thoracic level (Th9) SCI. Prophylactic adrenalectomy completely prevented SCI-induced glucocorticoid excess and lymphocyte depletion but did not prevent pneumonia. When adrenalectomized mice were transplanted with denervated adrenal glands to restore physiologic glucocorticoid levels, the animals were completely protected from pneumonia. These findings identify a maladaptive sympathetic-neuroendocrine adrenal reflex mediating immunosuppression after SCI, implying that therapeutic normalization of the glucocorticoid and catecholamine imbalance in SCI patients could be a strategy to prevent detrimental infections.


The importance of comparative phylogeography in diagnosing introduced species: a lesson from the seal salamander, Desmognathus monticola.
In most regions of the world human influences on the distribution of flora and fauna predate complete biotic surveys. In some cases this challenges our ability to discriminate native from introduced species. This distinction is particularly critical for isolated populations, because relicts of native species may need to be conserved, whereas introduced species may require immediate eradication. Recently an isolated population of seal salamanders, Desmognathus monticola, was discovered on the Ozark Plateau, approximately 700 km west of its broad continuous distribution in the Appalachian Mountains of eastern North America. Using Nested Clade Analysis (NCA) we test whether the Ozark isolate results from population fragmentation (a natural relict) or long distance dispersal (a human-mediated introduction). Despite its broad distribution in the Appalachian Mountains, the primary haplotype diversity of D. monticola is restricted to less than 2.5% of the distribution in the extreme southern Appalachians, where genetic diversity is high for other co-distributed species. By intensively sampling this genetically diverse region we located haplotypes identical to the Ozark isolate. Nested Clade Analysis supports the hypothesis that the Ozark population was introduced, but it was necessary to include haplotypes that are less than or equal to 0.733% divergent from the Ozark population in order to arrive at this conclusion. These critical haplotypes only occur in < 1.2% of the native distribution and NCA excluding them suggest that the Ozark population is a natural relict. Our analyses suggest that the isolated population of D. monticola from the Ozarks is not native to the region and may need to be extirpated rather than conserved, particularly because of its potential negative impacts on endemic Ozark stream salamander communities. Diagnosing a species as introduced may require locating nearly identical haplotypes in the known native distribution, which may be a major undertaking. Our study demonstrates the importance of considering comparative phylogeographic information for locating critical haplotypes when distinguishing native from introduced species.


Mechanisms regulating the degradation of dentin matrices by endogenous dentin proteases and their role in dental adhesion. A review.
This systematic review provides an overview of the different mechanisms proposed to regulate the degradation of dentin matrices by host-derived dentin proteases, particularly as it relates to their role in dental adhesion. Significant developments have taken place over the last few years that have contributed to a better understanding of all the factors affecting the durability of adhesive resin restorations. The complexity of dentin-resin interfaces mandates a thorough understanding of all the mechanical, physical and biochemical aspects that play a role in the formation of hybrid layers. The ionic and hydrophilic nature of current dental adhesives yields permeable, unstable hybrid layers susceptible to water sorption, hydrolytic degradation and resin leaching. The hydrolytic activity of host-derived proteases also contributes to the degradation of the resin-dentin bonds. Preservation of the collagen matrix is critical to the improvement of resin-dentin bond durability. Approaches to regulate collagenolytic activity of dentin proteases have been the subject of extensive research in the last few years. A shift has occurred from the use of proteases inhibitors to the use of collagen cross-linking agents. Data provided by 51 studies published in peer-reviewed journals between January 1999 and December 2013 were compiled in this systematic review. Appraisal of the data provided by the studies included in the present review yielded a summary of the mechanisms which have already proven to be clinically successful and those which need further investigation before new clinical protocols can be adopted.


Lymphocyte blastogenic response to ovalbumin in a model for canine allergy.
Lymphocyte stimulation tests (LST) were performed in five dogs sensitised with ovalbumin (OVA) and seven healthy dogs. In addition, all five OVA-sensitised and two control dogs were tested after two in vivo provocations with OVA-containing eye drops. The isolated cells were suspended in culture media containing OVA and were cultured for up to 12 days. Proliferation was measured as reduction in 5,6-carboxylfluorescein diacetate succinimidyl ester (CFSE) intensity by flow cytometry on days 0, 3, 6, 9 and 12. A cell proliferation index (CPI) for each day and the area under the curve (AUC) of the CPI was calculated for each dog. All OVA-sensitised dogs demonstrated increased erythema after conjunctival OVA application. The presence of OVA-specific lymphocytes was demonstrated in 2/5 OVA-sensitised dogs before and 4/5 after in vivo provocation. Using the AUC, the difference between OVA-sensitised and control dogs was significant in all three LST before in vivo provocation (P<0.05) and borderline significant (P=0.053) in 2/3 LST after provocation. The most significant difference in CPI was observed after 9 days of culture (P=0.001). This pilot study indicates that the LST allows detection of rare antigen specific memory T-cells in dogs previously sensitised to, but not concurrently undergoing challenge by a specific antigen.


Thalamo-frontal psychosis.
A 43-year-old man presented with an 18-month history of acute-onset cyclical behavioural change affecting mood, appetite, sleep, and energy levels. This had followed an initial episode of transient drowsiness which lasted 24 hours. On examination, there was some evidence of visual memory and frontal lobe deficits. A brain CT scan showed bilateral thalamic infarcts and a brain SPECT scan showed bilateral hypoperfusion of the frontal lobes. To our knowledge, this is the first reported case of thalamic infarction associated with acute-onset cyclical affective psychosis with clinical and neurophysiological features of frontal lobe syndrome. The case also highlights the possible role of thalamo-frontal circuits in the pathogenesis of the Kleine-Levin syndrome.


Static and Dynamic Analysis of Electrostatically Actuated MEMS Shallow Arches for Various Air-Gap Configurations.
In this research, we investigate the structural behavior, including the snap-through and pull-in instabilities, of in-plane microelectromechanical COSINE-shaped and electrically actuated clamped-clamped micro-beams resonators. The work examines various electrostatic actuation patterns including uniform and non-uniform parallel-plates airgap arrangements, which offer options to actuate the arches in the opposite and same direction of their curvature. The nonlinear equation of motion of a shallow arch is discretized into a reduced-order model based on the Galerkin's expansion method, which is then numerically solved. Static responses are examined for various DC electrostatic loads starting from small values to large values near pull-in and snap-through instability ranges, if any. The eigenvalue problem of the micro-beam is solved revealing the variations of the first four natural frequencies as varying the DC load. Various simulations are carried out for several case studies of shallow arches of various geometrical parameters and airgap arrangements, which demonstrate rich and diverse static and dynamic behaviors. Results show few cases with multi-states and hysteresis behaviors where some with only the pull-in instability and others with both snap-through buckling and pull-in instabilities. It is found that the micro-arches behaviors are very sensitive to the electrode's configuration. The studied configurations reveal different possibilities to control the pull-in and snap-through instabilities, which can be used for improving arches static stroke range as actuators and for realizing wide-range tunable micro-resonators.


Hearing voices in the resting brain: A review of intrinsic functional connectivity research on auditory verbal hallucinations.
Resting state networks (RSNs) are thought to reflect the intrinsic functional connectivity of brain regions. Alterations to RSNs have been proposed to underpin various kinds of psychopathology, including the occurrence of auditory verbal hallucinations (AVH). This review outlines the main hypotheses linking AVH and the resting state, and assesses the evidence for alterations to intrinsic connectivity provided by studies of resting fMRI in AVH. The influence of hallucinations during data acquisition, medication confounds, and movement are also considered. Despite a large variety of analytic methods and designs being deployed, it is possible to conclude that resting connectivity in the left temporal lobe in general and left superior temporal gyrus in particular are disrupted in AVH. There is also preliminary evidence of atypical connectivity in the default mode network and its interaction with other RSNs. Recommendations for future research include the adoption of a common analysis protocol to allow for more overlapping datasets and replication of intrinsic functional connectivity alterations.


CSEO - the Cigarette Smoke Exposure Ontology.
In the past years, significant progress has been made to develop and use experimental settings for extensive data collection on tobacco smoke exposure and tobacco smoke exposure-associated diseases. Due to the growing number of such data, there is a need for domain-specific standard ontologies to facilitate the integration of tobacco exposure data. The CSEO (version 1.0) is composed of 20091 concepts. The ontology in its current form is able to capture a wide range of cigarette smoke exposure concepts within the knowledge domain of exposure science with a reasonable sensitivity and specificity. Moreover, it showed a promising performance when used to answer domain expert questions. The CSEO complies with standard upper-level ontologies and is freely accessible to the scientific community through a dedicated wiki at https://publicwiki-01.fraunhofer.de/CSEO-Wiki/index.php/Main_Page. The CSEO has potential to become a widely used standard within the academic and industrial community. Mainly because of the emerging need of systems toxicology to controlled vocabularies and also the lack of suitable ontologies for this domain, the CSEO prepares the ground for integrative systems-based research in the exposure science.


Gibberellic acid signaling is required for ambient temperature-mediated induction of flowering in Arabidopsis thaliana.
Distinct molecular mechanisms integrate changes in ambient temperature into the genetic pathways that govern flowering time in Arabidopsis thaliana. Temperature-dependent eviction of the histone variant H2A.Z from nucleosomes has been suggested to facilitate the expression of FT by PIF4 at elevated ambient temperatures. Here we show that, in addition to PIF4, PIF3 and PIF5, but not PIF1 and PIF6, can promote flowering when expressed specifically in phloem companion cells (PCC), where they can induce FT and its close paralog, TSF. However, despite their strong potential to promote flowering, genetic analyses suggest that the PIF genes seem to have only a minor role in adjusting flowering in response to photoperiod or high ambient temperature. In addition, loss of PIF function only partially suppressed the early flowering phenotype and FT expression of the arp6 mutant, which is defective in H2A.Z deposition. In contrast, the chemical inhibition of gibberellic acid (GA) biosynthesis resulted in a strong attenuation of early flowering and FT expression in arp6. Furthermore, GA was able to induce flowering at low temperature (15°C) independently of FT, TSF, and the PIF genes, probably directly at the shoot apical meristem. Together, our results suggest that the timing of the floral transition in response to ambient temperature is more complex than previously thought and that GA signaling might play a crucial role in this process.


Rosavirus: the prototype of a proposed new genus of the Picornaviridae family.
We describe a 8,724-nucleotide-long picornavirus genome encoding a single 2,470-aa polyprotein obtained from the feces of a wild mouse. Rosavirus is genetically closest to the double ORF Dicipivirus found in canine feces that is currently the only picornavirus with a second internal ribosome entry site (IRES). Of note, a section of rosavirus' 5'UTR showed strong sequence and structural conservation with the type II IRES from the Parechovirus and Hungarovirus genera possibly reflecting exchange of genetic modules between genera. Based on genetic distance criteria rosavirus qualifies as prototype of a new genus of the Picornaviridae family.


Sensitivity of coherent dual-comb spectroscopy.
Coherent dual comb spectroscopy can provide high-resolution, high-accuracy measurements of a sample response in both magnitude and phase. We discuss the achievable signal-to-noise ratio (SNR) due to both additive white noise and multiplicative noise, and the corresponding sensitivity limit for trace gas detection. We show that sequential acquisition of the overall spectrum through a tunable filter, or parallel acquisition of the overall spectrum through a detector array, can significantly improve the SNR under some circumstances. We identify a useful figure of merit as the quality factor, equal to the product of the SNR, normalized by the square root of the acquisition time, and the number of resolved frequency elements. For a single detector and fiber-laser based system, this quality factor is 10(6) - 10(7) Hz(1/2).


Signaling Complexity Measured by Shannon Entropy and Its Application in Personalized Medicine.
Traditional approaches to cancer therapy seek common molecular targets in tumors from different patients. However, molecular profiles differ between patients, and most tumors exhibit inherent heterogeneity. Hence, imprecise targeting commonly results in side effects, reduced efficacy, and drug resistance. By contrast, personalized medicine aims to establish a molecular diagnosis specific to each patient, which is currently feasible due to the progress achieved with high-throughput technologies. In this report, we explored data from human RNA-seq and protein-protein interaction (PPI) networks using bioinformatics to investigate the relationship between tumor entropy and aggressiveness. To compare PPI subnetworks of different sizes, we calculated the Shannon entropy associated with vertex connections of differentially expressed genes comparing tumor samples with their paired control tissues. We found that the inhibition of up-regulated connectivity hubs led to a higher reduction of subnetwork entropy compared to that obtained with the inhibition of targets selected at random. Furthermore, these hubs were described to be participating in tumor processes. We also found a significant negative correlation between subnetwork entropies of tumors and the respective 5-year survival rates of the corresponding cancer types. This correlation was also observed considering patients with lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) based on the clinical data from The Cancer Genome Atlas database (TCGA). Thus, network entropy increases in parallel with tumor aggressiveness but does not correlate with PPI subnetwork size. This correlation is consistent with previous reports and allowed us to assess the number of hubs to be inhibited for therapy to be effective, in the context of precision medicine, by reference to the 100% patient survival rate 5 years after diagnosis. Large standard deviations of subnetwork entropies and variations in target numbers per patient among tumor types characterize tumor heterogeneity.


'Causes of causes': ethnicity and social position as determinants of health inequality in Irish Traveller men.
This study sought to engage Traveller men in a discussion about their lives, their health and key determinants of their health, with a view to engaging Traveller men in health promotion initiatives. Irish Travellers are an indigenous ethnic minority, constituting 0.8% of the population. As a marginalized group, they experience significantly poorer health status than their counterparts in the settled community. Traveller men have 3.7 times the mortality of the males in the general population. Travellers are identified as a hard-to-reach group and Traveller men particularly so. Traveller men have rarely participated in the research studies on health and health service utilization, and the results of this study, in which Traveller men participated in three focus groups, are therefore of particular interest. The Traveller men, in discussing health, related it to the absence of specific illnesses and conditions, expressing a negative and a physical concept of health. The results of the study provide evidence for the role of social constructions of masculinity in determining the health and help-seeking behaviour of Traveller men, but also the influence of wider social determinants such as ethnicity and social status. The futility of approaches to health promotion that comprise simplistic health information/education interventions is outlined in this context. The study presents a challenge to both address hegemonic versions of masculinity and discrimination based on ethnic status, and rather than challenge the behaviour of men or of health services that they come into contact with, to changing the conditions of Traveller men's lives.


Effectiveness of population-based service screening with mammography for women ages 40 to 49 years: evaluation of the Swedish Mammography Screening in Young Women (SCRY) cohort.
The effectiveness of mammography screening for women ages 40 to 49 years still is questioned, and few studies of the effectiveness of service screening for this age group have been conducted. Breast cancer mortality was compared between women who were invited to service screening at ages 40 to 49 years (study group) and women in the same age group who were not invited during 1986 to 2005 (control group). Together, these women comprise the Mammography Screening of Young Women (SCRY) cohort, which includes all Swedish counties. A prescreening period was defined to facilitate a comparison of mortality in the absence of screening. The outcome measure was refined mortality, ie, breast cancer death for women who were diagnosed during follow-up at ages 40 to 49 years. Relative risks (RRs) with 95% confidence intervals (CIs) were estimated. There was no significant difference in breast cancer mortality during the prescreening period. During the study period, there were 803 breast cancer deaths in the study group (7.3 million person-years) and 1238 breast cancer deaths in the control group (8.8 million person-years). The average follow-up was 16 years. The estimated RR for women who were invited to screening was 0.74 (95% CI, 0.66-0.83), and the RR for women who attended screening was 0.71 (95% CI, 0.62-0.80). In this comprehensive study, mammography screening for women ages 40 to 49 years was efficient for reducing breast cancer mortality.


Survival rates of hybrid rough surface implants and their alveolar bone level alterations.
The design of hybrid surface implants takes advantage of characteristics of two different textures to improve clinical outcomes. To date, there are limited numbers of studies reporting the clinical results of hybrid surface implants. This study aimed to assess hybrid surface implants with two different rough textures in regard to survival, marginal bone level change, and biological complications. Retrospective review of dental records was conducted for 161 patients who had 460 hybrid surface implants to analyze survival rate. These implants had the dual sandblasted and anode oxidized surface. Sixty patients with 192 implants who had consecutive radiographs taken at specific time points and complete clinical examinations were included in the comprehensive analysis. The associations between patient- and implant-related characteristics, and clinical results were analyzed by log-rank test, Cox regression, and linear regression analysis. Cumulative survival at 12, 36, and 60 months after placement was 97.4%, 96.4%, and 95.8%, respectively. The average marginal bone level change from baseline to the last visit was 0.31 ± 0.68 mm and 0.34 ± 0.77 mm at the mesial and distal sites, respectively. Prevalence of peri-implantitis was 0.5% at the implant level and 1.7% at the patient level. Implant site was associated with implant failure (P = 0.03). Smoking habit, history of periodontitis, and implant site were significantly associated with marginal bone level change (P = 0.001, < 0.001, 0.01, respectively). Hybrid rough surface implants had high survival rate, stable bone level, and low prevalence of biological complications. This surface design demonstrated promising clinical outcomes. More studies are needed to further support the clinical advantages of hybrid surface implants.


Measurement of three-dimensional deformations using digital holography with radial sensitivity.
A measurement system based on digital holography for the simultaneous measurement of out-of-plane and radial in-plane displacement fields for the assessment of residual stress is presented. Two holograms are recorded at the same time with a single image taken by a digital camera, allowing the separate evaluation of in-plane and out-of-plane movement. An axis-symmetrical diffractive optical element is used for the illumination of the object, which causes radial sensitivity vectors. By the addition and, respectively, the subtraction, of the four phase maps calculated from two camera frames, the in-plane and out-of-plane deformation of an object can be calculated separately. The device presented is suitable for high-speed, high-resolution measurement of residual stress. In addition to the setup, first measurement results and a short comparison to a mature digital speckle pattern interferometry setup are shown.


Respiratory viruses in mechanically ventilated patients: a pilot study.
Respiratory virome is an integral part of the human microbiome and its characterization may contribute to a better understanding of the changes that arise in the disease and, consequently, influence the approach and treatment of patients with acute lower respiratory infections. The aim of this study was to evaluate the presence of respiratory viruses in the lower airways of individuals undergoing invasive mechanical ventilation, with and without acute lower respiratory infection (respectively WRI and WORI groups). We studied 44 mini-bronchoalveolar lavage samples (collected with a double catheter, Combicath® kit) from patients with mean age in the seventh decade, 20 from WORI group and 24 from WRI group, who were hospitalized for acute respiratory failure in Intensive Care Units of two hospitals in the Lisbon area. Real-time PCR was applied to verify analyse the presence of 15 common respiratory viruses (adenovirus, human bocavirus, influenza virus A and B, repiratory syncytial virus, human parainfluenza virus types 1, 2, 3 and 4, human enterovirus, human rhinovirus, human metapneumovirus, human coronavirus group 1 (229E, NL63) and 2 (OC43, HKU1). Respiratory viruses were detected in six of the 20 patients in the WORI group: influenza AH3 (n = 2), parainfluenza virus 1/3 (n = 2), human rhinovirus (n = 2), respiratory syncytial virus (n = 1) and human metapneumovirus (n = 1). In the WRI group, respiratory viruses were detected in 12 of the 24 patients: influenza AH3 (n = 3), human rhinovirus (n = 3), respiratory syncytial virus (n = 3), human metapneumovirus (n = 3), human bocavirus (n = 2) and human enterovirus (n = 1). Simultaneous detection of two viruses was recorded in two samples in both groups. The results of this study suggest the presence of common respiratory viruses in the lower respiratory tract without causing symptomatic infection, even in carefully collected lower samples. This may have important implications on the interpretation of the results on the diagnostic setting.


Characterization of gap junctions between cultured leptomeningeal cells.
Leptomeningeal cells in intact meninges or dissociated and cultured for 2 h to several weeks were dye-coupled (Lucifer yellow), and voltage-clamped pairs of freshly dissociated leptomeningeal cells were well coupled electrically. Unitary conductances of junctional channels were predominantly 40-90 pS. Junctional conductance was reversibly reduced by 2 mM halothane, 1 mM heptanol and 100% CO2 and was increased by 1 mM 8 Br-cAMP. Two gap junction proteins, connexin 26 and connexin 43, were identified between leptomeningeal cells using immunocytochemical methods; Northern blot analyses of RNA isolated from cultured leptomeningeal cells showed specific hybridization to cDNAs encoding connexins 26 and 43, but not to a cDNA encoding connexin 32. These studies demonstrate co-expression of two connexins in a single cell type in the nervous system; biophysical properties do not differ significantly from those of astrocytes and cardiac myocytes, which express only connexin 43.


APRIL promotes breast tumor growth and metastasis and is associated with aggressive basal breast cancer.
APRIL (a proliferation-inducing ligand) is a cytokine of the tumor necrosis factor family associated mainly with hematologic malignancies. APRIL is also overexpressed in breast carcinoma tissue lesions, although neither its role in breast tumorigenesis nor the underlying molecular mechanism is known. Here, we show that several breast cancer cell lines express APRIL and both its receptors, B cell maturation antigen (BCMA) and transmembrane activator and CAML-interactor (TACI), independently of luminal or basal tumor cell phenotype, and that the mitogen-activated protein kinases p38, ERK1/2, and JNK1/2 are activated in response to APRIL. The inflammatory stimulus poly I:C, a toll-like receptor (TLR) 3 ligand, enhanced APRIL secretion. Silencing experiments decreased cell proliferation, demonstrating that APRIL is a critical autocrine factor for breast tumor growth. Studies of 4T1 orthotopic breast tumors in APRIL transgenic mice showed that an APRIL-enriched environment increased tumor growth and promoted lung metastasis associated with enhanced tumor cell proliferation; BCMA and TACI expression suggests that both participate in these processes. We detected APRIL, BCMA and TACI in human luminal, triple-negative breast carcinomas and HER2 breast carcinomas, with increased levels in more aggressive basal tumors. APRIL was observed near Ki67(+) nuclei and was distributed heterogeneously in the cancer cells, in the leukocyte infiltrate, and in the myoepithelial layer adjacent to the tumor area; these results imply that APRIL provides proliferation signals to tumor cells through paracrine and autocrine signaling. Our study identifies participation of APRIL signaling in breast cancer promotion; we propose impairment of this pathway as a potential therapeutic strategy.


Comment on papers by Evans et al. and Mekel-Bobrov et al. on Evidence for Positive Selection of MCPH1 and ASPM.
Evans et al. and Mekel-Bobrov et al. (Reports, 9 September 2005, p. 1717 and 1720, respectively) reported that human genetic variants of Microcephalin (MCPH1) and abnormal spindle-like microcephaly associated (ASPM) are under strong positive selection. We genotyped these variants in 9000 children and find no meaningful associations with brain size and various cognitive measures, which indicates that contrary to previous speculations, ASPM and MCPH1 have not been selected for brain-related effects.


Effects of depolarizing or non-depolarizing preservation solutions on human endothelial cells during cold hypoxia.
1. Hypothermic storage of whole organs flushed with a preservation solution is common practice in clinical transplantation. This procedure leaves vascular endothelial cells in direct contact with the preservation solution during the length of the cold ischaemic period. 2. Aiming to study the effects of organ preservation on vascular endothelium, we subjected cultures of human umbilical vein endothelial cells to hypoxic and hypothermic storage conditions in vitro for 3 or 16 h. Four preservation solutions with different levels of sodium and potassium were tested. Morphometric analysis and 51Cr leakage index were used to assess monolayer continuity, cell viability and membrane integrity. 3. Hypothermic storage resulted in severe changes in endothelial cell morphology with formation of intercellular gaps that destroyed monolayer continuity after only 3h. Cellular blebbing was a common feature in seriously damaged cells. 4. Morphometric analysis and 51Cr leakage results correlated well. No significant differences between the solutions tested were found after 3h of hypothermic hypoxic storage. After 16h, viability and monolayer continuity were significantly better preserved (Mann-Whitney, P < 0.01) in cells stored in lactobionate-based solutions than in hypertonic citrate solutions. No significant differences were found between endothelial cells stored in extracellular versus intracellular types of solutions for the lactobionate-based solutions. 5. The results of the present experiment showed that after a period of hypothermic hypoxic storage, vascular endothelial cells appeared morphologically deformed and poorly attached in vitro. Lactobionate-based preservation solutions were more effective in preserving viability and continuity. Protection of vascular endothelium under cold hypoxic conditions could be a critical factor in successfully preserving organs for transplantation.


Chronic Subdural Hematoma ICU Management.
Patients with cSDH presenting with new or worsening neurological deficits, especially if they are debilitating and adversely affecting quality of life require urgent medical and surgical attention. Neurological and neurosurgical critical care team need to stabilize the patient by reversing any underlying coagulopathy states in order to prevent further hematoma expansion.In the event of brain herniation and presumed ICP elevation and CPP compromise, step-wise ICP management should be instituted promptly.Seizure prophylaxis treatment is reasonable. Timing of surgical evacuation is not always easy to determine but the presence of significant neurological deficits with impending herniation require immediate surgical Intervention. Consideration of the clot density along with patient's current neurological status would determine the timing and type of surgical interventions. Postoperative critical care management is not trivial. In addition to detecting any changes in neurological conditions, timely initiation (typically within the first 48 hours if clinical and radiographic conditions are stable with no co-existing coagulopathy) of venous thromboembolism prophylaxis is essential. Resuming antiplatelets and anticoagulants are warranted for those with clear indications including atrial fibrillation, atrial thrombus, known deep vein thrombosis, mechanical heart valves and other preexisting hypercoagulable conditions, but it is generally advised to hold antiplatelets and anticoagulants for about 10-14 post injury and/or surgical intervention.


Generation of optical vortices by using spiral phase plates made of polarization dependent devices.
A method to construct spiral phase plates (SPPs) from quarter-wave plates and spatially variable half-wave plates (SVHWPs) is proposed. Optical vortices were experimentally generated by using SPPs made of polarization-dependent devices. The topological charge of the optical vortex can be also determined by the structure of the SVHWP and the polarization of the incident beam.


Fumarate Hydratase-deficient Cell Line NCCFH1 as a New In Vitro Model of Hereditary Papillary Renal Cell Carcinoma Type 2.
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare autosomal dominant disorder characterized by fumarate hydratase (FH) gene mutation. It is associated with the development of very aggressive kidney tumors, characterized by early onset and high metastatic potential, and has no effective therapy. The aim of the study was to establish a new preclinical platform for investigating morphogenetic and metabolic features, and alternative therapy of metastatic hereditary papillary renal cell carcinoma type 2 (PRCC2). Fresh cells were collected from pleural fluid of a patient with metastatic hereditary PRCC2. Morphogenetic and functional characteristics were evaluated via microscopy, FH gene sequencing analysis, real-time polymerase chaine reaction and enzymatic activity measurement. We performed bioenergetic analysis, gene-expression profiling, and cell viability assay with 19 anti-neoplastic drugs. We established a new in vitro model of hereditary PRCC2 - the NCCFH1 cell line. The cell line possesses a c.1162 delA - p.Thr375fs frameshift mutation in the FH gene. Our findings indicate severe attenuation of oxidative phosphorylation and glucose-dependent growth of NCCFH1 cells that is consistent with the Warburg effect. Furthermore, gene-expression profiling identified that the most prominent molecular features reflected a high level of apoptosis, cell adhesion, and cell signaling. Drug screening revealed a marked sensitivity of FH(-/-) cells to mitoxantrone, epirubicin, topotecan and a high sensitivity to bortezomib. We demonstrated that the NCCFH1 cell line is a very interesting preclinical model for studying the metabolic features and testing new therapies for hereditary PRCC2, while bortezomib may be a potential efficient therapeutic option.


Impact of a century of climate change on small-mammal communities in Yosemite National Park, USA.
We provide a century-scale view of small-mammal responses to global warming, without confounding effects of land-use change, by repeating Grinnell's early-20th century survey across a 3000-meter-elevation gradient that spans Yosemite National Park, California, USA. Using occupancy modeling to control for variation in detectability, we show substantial ( approximately 500 meters on average) upward changes in elevational limits for half of 28 species monitored, consistent with the observed approximately 3 degrees C increase in minimum temperatures. Formerly low-elevation species expanded their ranges and high-elevation species contracted theirs, leading to changed community composition at mid- and high elevations. Elevational replacement among congeners changed because species' responses were idiosyncratic. Though some high-elevation species are threatened, protection of elevation gradients allows other species to respond via migration.


Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein.
Multiple sclerosis is a chronic disease of the central nervous system (CNS) characterized by inflammation, demyelination, and axonal loss. The immunopathogenesis of demyelination in multiple sclerosis involves an autoantibody response to myelin oligodendrocyte glycoprotein (MOG), a type I transmembrane protein located at the surface of CNS myelin. Here we present the crystal structures of the extracellular domain of MOG (MOGIgd) at 1.45-A resolution and the complex of MOGIgd with the antigen-binding fragment (Fab) of the MOG-specific demyelinating monoclonal antibody 8-18C5 at 3.0-A resolution. MOGIgd adopts an IgV like fold with the A'GFCC'C" sheet harboring a cavity similar to the one used by the costimulatory molecule B7-2 to bind its ligand CTLA4. The antibody 8-18C5 binds to three loops located at the membrane-distal side of MOG with a surprisingly dominant contribution made by MOG residues 101-108 containing a strained loop that forms the upper edge of the putative ligand binding site. The sequence R101DHSYQEE108 is unique for MOG, whereas large parts of the remaining sequence are conserved in potentially tolerogenic MOG homologues expressed outside the immuno-privileged environment of the CNS. Strikingly, the only sequence identical to DHSYQEE was found in a Chlamydia trachomatis protein of unknown function, raising the possibility that Chlamydia infections may play a role in the MOG-specific autoimmune response in man. Our data provide the structural basis for the development of diagnostic and therapeutic strategies targeting the pathogenic autoantibody response to MOG.


The H3K9 Methylation Writer SETDB1 and its Reader MPP8 Cooperate to Silence Satellite DNA Repeats in Mouse Embryonic Stem Cells.
SETDB1 (SET Domain Bifurcated histone lysine methyltransferase 1) is a key lysine methyltransferase (KMT) required in embryonic stem cells (ESCs), where it silences transposable elements and DNA repeats via histone H3 lysine 9 tri-methylation (H3K9me3), independently of DNA methylation. The H3K9 methylation reader M-Phase Phosphoprotein 8 (MPP8) is highly expressed in ESCs and germline cells. Although evidence of a cooperation between H3K9 KMTs and MPP8 in committed cells has emerged, the interplay between H3K9 methylation writers and MPP8 in ESCs remains elusive. Here, we show that MPP8 interacts physically and functionally with SETDB1 in ESCs. Indeed, combining biochemical, transcriptomic and genomic analyses, we found that MPP8 and SETDB1 co-regulate a significant number of common genomic targets, especially the DNA satellite repeats. Together, our data point to a model in which the silencing of a class of repeated sequences in ESCs involves the cooperation between the H3K9 methylation writer SETDB1 and its reader MPP8.


Structural characterization of glycerophospholipids by combinations of ozone- and collision-induced dissociation mass spectrometry: the next step towards "top-down" lipidomics.
The complete structural elucidation of complex lipids, including glycerophospholipids, using only mass spectrometry represents a major challenge to contemporary analytical technologies. Here, we demonstrate that product ions arising from the collision-induced dissociation (CID) of the [M + Na](+) adduct ions of phospholipids can be isolated and subjected to subsequent gas-phase ozonolysis - known as ozone-induced dissociation (OzID) - in a linear ion-trap mass spectrometer. The resulting CID/OzID experiment yields abundant product ions that are characteristic of the acyl substitution on the glycerol backbone (i.e., sn-position). This approach is shown to differentiate sn-positional isomers, such as the regioisomeric phosphatidylcholine pair of PC 16:0/18:1 and PC 18:1/16:0. Importantly, CID/OzID provides a sensitive diagnostic for the existence of an isomeric mixture in a given sample. This is of very high value for the analysis of tissue extracts since CID/OzID analyses can reveal changes in the relative abundance of isomeric constituents even within different tissues from the same animal. Finally, we demonstrate the ability to assign carbon-carbon double bond positions to individual acyl chains at specific backbone positions by adding subsequent CID and/or OzID steps to the workflow and that this can be achieved in a single step using a hybrid triple quadrupole-linear ion trap mass spectrometer. This unique approach represents the most complete and specific structural analysis of lipids by mass spectrometry demonstrated to date and is a significant step towards comprehensive top-down lipidomics.


Engineering Ru@Pt Core-Shell Catalysts for Enhanced Electrochemical Oxygen Reduction Mass Activity and Stability.
Improving the performance of oxygen reduction reaction (ORR) electrocatalysts is essential for the commercial efficacy of many renewable energy technologies, including low temperature polymer electrolyte fuel cells (PEFCs). Herein, we report highly active and stable carbon-supported Ru@Pt core-shell nanoparticles (Ru@Pt/C) prepared by a wet chemical synthesis technique. Through rotating disc electrode testing, the Ru@Pt/C achieves an ORR Pt mass-based activity of 0.50 A mgPt-1 at 0.9 V versus the reversible hydrogen electrode (RHE), which exceeds the activity of the state-of-the-art commercial Pt/C catalyst as well as the Department of Energy 2020 PEFC electrocatalyst activity targets for transportation applications. The impact of various synthetic parameters, including Pt to Ru ratios and catalyst pretreatments (i.e., annealing) are thoroughly explored. Pt-based mass activity of all prepared Ru@Pt/C catalysts was found to exceed 0.4 mgPt-1 across the range of compositions investigated, with the maximum activity catalyst having a Ru:Pt ratio of 1:1. This optimized composition of Ru@Pt/C catalyst demonstrated remarkable stability after 30,000 accelerated durability cycles (0.6 to 1.0 V vs. RHE at 125 mV s-1), maintaining 85% of its initial mass activity. Scanning transmission electron microscopy energy dispersive spectroscopy (STEM-EDS) analysis at various stages of electrochemical testing demonstrated that the Pt shell can provide sufficient protection against the dissolution of the otherwise unstable Ru core.


T cell targeting and phagocytosis of apoptotic biliary epithelial cells in primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) is characterized by loss of tolerance against ubiquitously expressed mitochondrial autoantigens followed by biliary and salivary gland epithelial cell (BEC and SGEC) destruction by autoreactive T cells. It is unclear why BECs and SGECs are targeted. Previous work demonstrated that the reduced form of the major PBC autoantigen predominated in apoptotic BECs and SGECs as opposed to an oxidized form in other apoptotic cells. This led to the hypothesis that presentation of novel self-peptides from phagocytosed apoptotic BECs might contribute to BEC targeting by autoreactive T cells. The effect of autoantigen redox status on self-peptide formation was examined along with the phagocytic ability of BECs. Oxidation of PBC autoantigens first was shown to be due to protein S-glutathionylation of lipoyllysine residues. Absence of protein S-glutathionylation generated novel self-peptides and affected T cell recognition of a lipoyllysine containing peptide. Liver biopsy staining revealed BEC phagocytosis of apoptotic BECs (3.74+/-2.90% of BEC) was present in PBC (7 of 7 cases) but not in normal livers (0 of 3). BECs have the ability to present novel mitochondrial self-peptides derived from phagocytosed apoptotic BECs. Apoptotic cell phagocytosis by non-professional phagocytes may influence the tissue specificity of autoimmune diseases.


Prevalence of Hypertension in Boloor Diabetes Study (BDS-II) and its Risk Factors.
Hypertension is a major public health problem in India and worldwide. Since hypertension is often asymptomatic, it commonly remains undetected, leading to serious complications if untreated. Hypertension is one of the leading causes of end stage renal disease. It doubles the risk of developing coronary artery disease, increases the risk of congestive heart failure by four folds and that of cerebrovascular disease and stroke by seven folds. Hypertension is directly responsible for 57% of all stroke deaths and 42% of coronary heart disease deaths in India. To identify prevalence and risk factors for hypertension in a semi urban population of Mangalore, who participated in Boloor Diabetes Study (BDS-II). This cross-sectional study was conducted on 551 subjects aged ≥ 20 years who were randomly selected. Hypertension was diagnosed and classified according to Joint National Committee 7 (JNC) criteria. Blood pressure was measured by a doctor using calibrated sphygmomanometer. Anthropometric measurements, lipid and glucose estimations were done for all subjects. Statistical analysis was done using Chi-square test and student's t-test (unpaired). Multivariate logistic regression analysis was done using hypertension as dependent variable and the various risk factors as independent variables. Overall prevalence of hypertension in the community was 41% (227/551) (40.9% in men, 41.3% in women). Prehypertension was found in 40% (223/551) (45.4% in men, 38.1% in women), and only 18.3% (101/551) had normal blood pressure. Stage I hypertension was seen in 29.7% (164/551) (28.9% in men, 30.1% in women). Stage II hypertension was seen in 11.4% (63/551) (12% in men, 11% in women). Age, obesity, diabetes, serum cholesterol and serum triglycerides were strongly associated with hypertension. Only 46% (254/551) of the hypertensive subjects were aware that they were hypertensive. Prevalence of hypertension was high in this population. Nearly 54% were unaware of their hypertensive status. Prevalence increased with age, obesity, diabetic status and dyslipidemia. Nearly half of subjects were prehypertensives. This study highlights the need for regular screening coupled with educational programmes to detect, improve awareness and optimally treat hypertension in the community to reduce cardiovascular and renal complications.


Male 11β-HSD1 Knockout Mice Fed Trans-Fats and Fructose Are Not Protected From Metabolic Syndrome or Nonalcoholic Fatty Liver Disease.
Nonalcoholic fatty liver disease (NAFLD) defines a spectrum of conditions from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis and is regarded as the hepatic manifestation of the metabolic syndrome. Glucocorticoids can promote steatosis by stimulating lipolysis within adipose tissue, free fatty acid delivery to liver and hepatic de novo lipogenesis. Glucocorticoids can be reactivated in liver through 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme activity. Inhibition of 11β-HSD1 has been suggested as a potential treatment for NAFLD. To test this, male mice with global (11β-HSD1 knockout [KO]) and liver-specific (LKO) 11β-HSD1 loss of function were fed the American Lifestyle Induced Obesity Syndrome (ALIOS) diet, known to recapitulate the spectrum of NAFLD, and metabolic and liver phenotypes assessed. Body weight, muscle and adipose tissue masses, and parameters of glucose homeostasis showed that 11β-HSD1KO and LKO mice were not protected from systemic metabolic disease. Evaluation of hepatic histology, triglyceride content, and blinded NAFLD activity score assessment indicated that levels of steatosis were similar between 11β-HSD1KO, LKO, and control mice. Unexpectedly, histological analysis revealed significantly increased levels of immune foci present in livers of 11β-HSD1KO but not LKO or control mice, suggestive of a transition to NASH. This was endorsed by elevated hepatic expression of key immune cell and inflammatory markers. These data indicate that 11β-HSD1-deficient mice are not protected from metabolic disease or hepatosteatosis in the face of a NAFLD-inducing diet. However, global deficiency of 11β-HSD1 did increase markers of hepatic inflammation and suggests a critical role for 11β-HSD1 in restraining the transition to NASH.


Exercise to prevent falls in older adults: an updated systematic review and meta-analysis.
Previous meta-analyses have found that exercise prevents falls in older people. This study aimed to test whether this effect is still present when new trials are added, and it explores whether characteristics of the trial design, sample or intervention are associated with greater fall prevention effects. Update of a systematic review with random effects meta-analysis and meta-regression. Cochrane Library, CINAHL, MEDLINE, EMBASE, PubMed, PEDro and SafetyLit were searched from January 2010 to January 2016. We included randomised controlled trials that compared fall rates in older people randomised to receive exercise as a single intervention with fall rates in those randomised to a control group. 99 comparisons from 88 trials with 19 478 participants were available for meta-analysis. Overall, exercise reduced the rate of falls in community-dwelling older people by 21% (pooled rate ratio 0.79, 95% CI 0.73 to 0.85, p<0.001, I2 47%, 69 comparisons) with greater effects seen from exercise programmes that challenged balance and involved more than 3 hours/week of exercise. These variables explained 76% of the between-trial heterogeneity and in combination led to a 39% reduction in falls (incident rate ratio 0.61, 95% CI 0.53 to 0.72, p<0.001). Exercise also had a fall prevention effect in community-dwelling people with Parkinson's disease (pooled rate ratio 0.47, 95% CI 0.30 to 0.73, p=0.001, I2 65%, 6 comparisons) or cognitive impairment (pooled rate ratio 0.55, 95% CI 0.37 to 0.83, p=0.004, I2 21%, 3 comparisons). There was no evidence of a fall prevention effect of exercise in residential care settings or among stroke survivors or people recently discharged from hospital. Exercise as a single intervention can prevent falls in community-dwelling older people. Exercise programmes that challenge balance and are of a higher dose have larger effects. The impact of exercise as a single intervention in clinical groups and aged care facility residents requires further investigation, but promising results are evident for people with Parkinson's disease and cognitive impairment.


Preparation of mussel-inspired injectable hydrogels based on dual-functionalized alginate with improved adhesive, self-healing, and mechanical properties.
Injectable hydrogels have aroused much attention for the advantages such as minimally invasive surgery, avoidance of surgical trauma, and filling and repairing irregularly shaped tissue defects. Mussel-inspired injectable hydrogels can be immobilized on the surface of tissues, resulting in stable biomaterial-tissue integration. However, the commonly used biomimetic mussel-inspired hydrogels are prepared by the oxidation of catechol groups, which involves the introduction or production of cytotoxic substances. Moreover, mussel-inspired hydrogels generally display weak mechanical strength and poor adhesiveness because of the consumption of catechol groups during oxidation. Herein, we described a strategy to prepare mussel-inspired injectable hydrogels via the Schiff base reaction. We grafted dopamine, an adhesive motif discovered in the holdfast pads of mussels, to aldehyde-modified alginate backbones. A series of injectable mussel-inspired adhesive, self-healing hydrogels were fabricated by in situ crosslinking of hydrazide-modified poly(l-glutamic acid) (PLGA-ADH) and dual-functionalized alginate (catechol- and aldehyde-modified alginate, ALG-CHO-Catechol). Also, oxidized ALG-CHO-Catechol hydrogels and PLGA/ALG-CHO hydrogels were prepared for comparison. The effects of the crosslinking method, catechol grafting ratio and solid content on the mechanical properties, self-healing behavior, adhesive properties, and hemostatic ability were investigated. Compared with the observations for oxidized ALG-CHO-Catechol hydrogels, more reasonable gelation time and notably enhanced mechanical properties and adhesive behavior were detected in the PLGA/ALG-CHO-Catechol hydrogel system. The PLGA/ALG-CHO-Catechol hydrogels also displayed clear self-healing ability and good cytocompatibility. The strong bioadhesion endowed the PLGA/ALG-CHO-Catechol hydrogels with superior hemostatic performance. These results suggested that PLGA/ALG-CHO-Catechol hydrogel might have great potential as an antibleeding and tissue repair material.


Novel axon projection after stress and degeneration in the Dscam mutant retina.
The Down syndrome cell adhesion molecule gene (Dscam) is required for normal dendrite patterning and promotes developmental cell death in the mouse retina. Loss-of-function studies indicate that Dscam is required for refinement of retinal ganglion cell (RGC) axons in the lateral geniculate nucleus, and in this study we report and describe a requirement for Dscam in the maintenance of RGC axon projections within the retina. Mouse Dscam loss of function phenotypes related to retinal ganglion cell axon outgrowth and targeting have not been previously reported, despite the abundance of axon phenotypes reported in Drosophila Dscam1 loss and gain of function models. Analysis of the Dscam deficient retina was performed by immunohistochemistry and Western blot analysis during postnatal development of the retina. Conditional targeting of Dscam and Jun was performed to identify factors underlying axon-remodeling phenotypes. A subset of RGC axons were observed to project and branch extensively within the Dscam mutant retina after eye opening. Axon remodeling was preceded by histological signs of RGC stress. These included neurofilament accumulation, axon swelling, axon blebbing and activation of JUN, JNK and AKT. Novel and extensive projection of RGC axons within the retina was observed after upregulation of these markers, and novel axon projections were maintained to at least one year of age. Further analysis of retinas in which Dscam was conditionally targeted with Brn3b or Pax6α Cre indicated that axon stress and remodeling could occur in the absence of hydrocephalus, which frequently occurs in Dscam mutant mice. Analysis of mice mutant for the cell death gene Bax, which executes much of Dscam dependent cell death, identified a similar axon misprojection phenotype. Deleting Jun and Dscam resulted in increased axon remodeling compared to Dscam or Bax mutants. Retinal ganglion cells have a very limited capacity to regenerate after damage in the adult retina, compared to the extensive projections made in the embryo. In this study we find that DSCAM and JUN limit ectopic growth of RGC axons, thereby identifying these proteins as targets for promoting axon regeneration and reconnection.


Forecasting cycles of seizure likelihood.
Seizure unpredictability is rated as one of the most challenging aspects of living with epilepsy. Seizure likelihood can be influenced by a range of environmental and physiological factors that are difficult to measure and quantify. However, some generalizable patterns have been demonstrated in seizure onset. A majority of people with epilepsy exhibit circadian rhythms in their seizure times, and many also show slower, multiday patterns. Seizure cycles can be measured using a range of recording modalities, including self-reported electronic seizure diaries. This study aimed to develop personalized forecasts from a mobile seizure diary app. Forecasts based on circadian and multiday seizure cycles were tested pseudoprospectively using data from 50 app users (mean of 109 seizures per subject). Individuals' strongest cycles were estimated from their reported seizure times and used to derive the likelihood of future seizures. The forecasting approach was validated using self-reported events and electrographic seizures from the Neurovista dataset, an existing database of long-term electroencephalography that has been widely used to develop forecasting algorithms. The validation dataset showed that forecasts of seizure likelihood based on self-reported cycles were predictive of electrographic seizures for approximately half the cohort. Forecasts using only mobile app diaries allowed users to spend an average of 67.1% of their time in a low-risk state, with 14.8% of their time in a high-risk warning state. On average, 69.1% of seizures occurred during high-risk states and 10.5% of seizures occurred in low-risk states. Seizure diary apps can provide personalized forecasts of seizure likelihood that are accurate and clinically relevant for electrographic seizures. These results have immediate potential for translation to a prospective seizure forecasting trial using a mobile diary app. It is our hope that seizure forecasting apps will one day give people with epilepsy greater confidence in managing their daily activities.


Enteric methane production in lactating dairy cows with continuous feeding of essential oils or rotational feeding of essential oils and lauric acid.
Rumen microbes can adapt to feed additives, which may make the decrease in enteric CH4 production upon feeding an additive a transient response only. This study investigated alternate feeding of 2 CH4 mitigating feed additives with a different mode of action on persistency of lowering CH4 production compared with feeding a single additive over a period of 10 wk. Four pairs of cows were selected, and within pairs, cows were randomly assigned to either the control (AR-AR) or the alternating (AR-LA) concentrate treatment. The AR concentrate contained a blend of essential oils (Agolin Ruminant, Agolin SA, Bière, Switzerland; 0.17 g/kg of dry matter) and the LA concentrate contained lauric acid (C12:0; 65 g/kg of dry matter). A basal concentrate without Agolin Ruminant and lauric acid was fed during the pretreatment period (2 wk). Thereafter, the cows assigned to the AR-AR treatment received the AR concentrate during all 10 treatment weeks (5 periods of 2 wk each), whereas cows assigned to the AR-LA treatment received AR and LA concentrates rotated on a weekly basis. Methane emission was measured in climate respiration chambers during periods 1, 3, and 5. From period 3 onward, dry matter intake and milk protein concentration were reduced with the AR-LA treatment. Milk fat concentration was not affected, but the proportion of C12:0 in milk fat increased upon feeding C12:0. Molar proportions of acetate and propionate in rumen fluid were lower and higher, respectively, with the AR-LA than with the AR-AR treatment. Methane yield (g/kg of dry matter intake) and intensity (g/kg of fat- and protein-corrected milk yield) were not affected by treatment. Methane yield and intensity were significantly lower (12 and 11%, respectively) in period 1 compared with the pretreatment period, but no significant difference relative to pretreatment period was observed in period 3 (numerically 9 and 7% lower, respectively) and in period 5 (numerically 8 and 4% lower, respectively). Results indicate a transient decrease in CH4 yield and intensity in time, but no improvement in extent or persistency of the decline in CH4 due to rotational feeding of essential oils and C12:0 in lactating dairy cows.


NMR-DMF: a modular nuclear magnetic resonance-digital microfluidics system for biological assays.
We present a modular nuclear magnetic resonance-digital microfluidics (NMR-DMF) system as a portable diagnostic platform for miniaturized biological assays. With increasing number of combinations between designed probes and a specific target, NMR has become an accurate and rapid assay tool, which is capable of detecting particular kinds of proteins, DNAs, bacteria and cells with a customized probe quantitatively. Traditional sample operation (e.g., manipulation and mixing) relied heavily on human efforts. We herein propose a modular NMR-DMF system to allow the electronic automation of multi-step reaction-screening protocols. A figure-8 shaped coil is proposed to enlarge the usable inner space of a portable magnet by 4.16 times, generating a radio frequency (RF) excitation field in the planar direction. By electronically managing the electro-wetting-on-dielectric (EWOD) effects over an electrode array, preloaded droplets with the inclusion of biological constituents and targets can be programmed to mix and be guided to the detection site (3.5 × 3.5 mm(2)) for high-sensitivity NMR screening (static B field: 0.46 T, RF field: 1.43 mT per ampere), with the result (voltage signal) displayed in real-time. To show the system's utility, automated real-time identification of 100 pM of avidin in a 14 μL droplet was achieved. The system shows promise as a robust and portable diagnostic device for a wide variety of biological analyses and screening applications.


Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy.
Mouth sores and/or difficulty swallowing are common and painful consequences of cytotoxic chemotherapy for cancer. In previous studies oral glutamine was found to protect animals from the effects of whole abdominal radiation and methotrexate-induced enteritis. Glutamine also was found to reduce oral mucositis in a nonrandomized pilot study in humans. Therefore, the authors attempted to determine the efficacy of oral glutamine in a randomized, double blind, crossover trial in cancer patients receiving chemotherapy. Twenty-four patients (16 children and 8 adults) received glutamine or placebo (glycine) suspension (2 g amino acid/M2/dose twice daily) to swish and swallow on days of chemotherapy administration and for at least 14 additional days. Patients completed a calendar indicating days of mouth pain associated with each chemotherapy course and the effect of mouth pain on oral intake. Paired data indicated significant amelioration of stomatitis associated with glutamine administration after chemotherapy. The duration of mouth pain was 4.5 days less in chemotherapy courses in which glutamine supplementation was compared with placebo (Wilcoxon's signed rank test, P=0.0005). The severity of oral pain also was reduced significantly when glutamine was provided with chemotherapy (the amount of days mucositis restricted oral intake to soft foods [> or =Grade 2; Modified Eastern Cooperative Oncology Group grading system] was 4 days less with glutamine compared with placebo; Wilcoxon's signed rank test, P=0.002). Low dose oral glutamine supplementation during and after chemotherapy significantly reduced both the duration and severity of chemotherapy-associated stomatitis. Oral glutamine appears to be a simple and useful measure to increase the comfort of many patients at high risk of developing mouth sores as a consequence of intensive cancer chemotherapy.