The gamification of healthcare: emergence of the digital practitioner?
The application of behavioral economics principles in healthcare has been transformed through the use of technology and recently the advent of video gaming concepts, or gamification, to modify patient behaviors. The role of practitioners in the era of gamification has not been well established, but it is possible that the need has arisen for development of clinical practice guidelines and the "digital practitioner": one who specializes in healthcare apps, accepts referrals from other practitioners, identifies the best programs to meet individual patient needs, and consults to assess whether game apps might improve clinical outcomes.


Pharmacogenomic dosing of warfarin: ready or not?
Warfarin is a medication with a narrow therapeutic index, nonlinear intrapatient pharmacokinetics, and high interpatient variability in its dose-response relationship. These characteristics create great difficulty in determining an appropriate dose; sub- or supratherapeutic doses can increase the risk of bleeding and venous thromboembolism complications. Algorithms based on nongenetic factors of patient age, gender, body weight, diseases, diet, smoking, and medication traditionally have been used to determine warfarin dose requirements. However, these formulas account for less than 20% of the variability in warfarin response. Following completion of the Human Genome Project, several genetic variants of CYP2C9 and VKORC1 have been identified that account for a greater proportion of the variability in patient response to warfarin than is explained by nongenetic factors. Moreover, algorithms that analyze both patient genetic and nongenetic factors, i.e., pharmacogenomics, in warfarin response account for 55% to 60% of the variability. This raises the prospect of enhancing the ability to predict warfarin dose requirements and, thereby, improving its safety, effectiveness, and therapy efficiency. This review evaluates the impact of combining genetic and nongenetic factors in accounting for the variability in warfarin response and the prospect that pharmacogenomic algorithms will improve warfarin dosing early in therapy, possibly achieving a more rapid attainment of the therapeutic dose, improving safety, and increasing effectiveness. The most comprehensive and widely available pharmacogenomic algorithms for estimating warfarin dose requirements when initiating therapy, www.WarfarinDosing.org, is reviewed.


Discovery of a mRNA mitochondrial localization element in Saccharomyces cerevisiae by nonhomologous random recombination and in vivo selection.
In budding yeast, over 100 nuclear-encoded mRNAs are localized to the mitochondria. The determinants of mRNA localization to the mitochondria are not well understood, and protein factors involved in this process have not yet been identified. To reveal the sequence determinants for mitochondrial localization in a comprehensive and unbiased manner, we generated highly diversified libraries of 3' UTR regions from a known mitochondrially localized mRNA by nonhomologous random recombination (NRR) and subjected the resulting sequences to an in vivo selection that links cell survival to mitochondrial mRNA localization. When applied to the yeast ATP2 mRNA, this approach rapidly identified a 50-nt consensus motif, designated Min2, as well as two Min2-homologous regions naturally present downstream of the ATP2 stop codon, which are sufficient when appended to the 3' end of various reporter mRNAs to induce mitochondrial localization. Site-directed mutagenesis of Min2 revealed primary and secondary structure elements that contribute to localization activity. In addition, the Min2 motif may facilitate the identification of proteins involved in this mode of establishing cellular asymmetry.


Diagnostic Approach to Recurrent Intracardiac Masses That Present With Systemic Symptoms.
Cardiac masses are difficult to diagnose in the pediatric population, especially in the setting of systemic symptoms. Although multiple imaging modalities are available to characterize cardiac masses, it is important to consider a different diagnostic approach in the setting of recurrent cardiac masses and nonspecific systemic symptoms. We present a case involving a previously healthy adolescent with multiple hospitalizations because of persistent fevers, cachexia, and recurrent cardiac masses. Echocardiography and cardiac computed tomography imaging suggested endocarditis, but the patient failed to respond to multiple intravenous antibiotic treatments. He developed recurrent cardiac masses in the right atrium and right ventricle that were debulked and biopsied. The biopsy did not yield a conclusive diagnosis. The patient returned to the hospital with hemoptysis and large pulmonary pseudoaneurysms that had to be occluded during cardiac catheterization. Given his constellation of symptoms and improvement with steroids during surgical procedures, he was ultimately diagnosed with a variant of Behcet's disease known as Hughes-Stovin syndrome. His symptoms resolved completely with steroids and immunosuppression therapy. Our report reveals the limitations of the standard diagnostic approach toward cardiac masses and the importance of considering response to treatment as a clue to the etiology of an unusual cardiac mass.


Auto-transition of vortex- to vector-Airy beams via liquid crystal q-Airy-plates.
We propose the auto-transition of vortex-Airy to vector-Airy beams realized via a liquid crystal q-Airy-plate, whose director distribution is the integration of a q-plate and a polarization Airy mask. The polarization, phase, intensity distributions of the vortex-vector-Airy beams (VVABs) during the transition process and individual trajectories of the vortex beam, vector beam and Airy beam components are both theoretically and experimentally investigated. Interesting findings show that the pair of vortex components firstly experience transverse deflection with a smaller acceleration than the Airy components and then automatically evolve into a vector component propagating in a straight path. The polarization mode of the VVABs can be easily switched by tuning the incident polarization direction. Meanwhile, the Airy component still maintains its intrinsic self-accelerating and self-healing properties. The asymmetric intensity distribution and variation of VVABs are revealed, and the energy flows are simulated to better illustrate the interaction of the Airy, vortex and vector components. This work provides an approach for the manipulation of the spatially structured light beams, which may inspire their potential applications in optics, photonics and multidisciplinary fields.


Incidence of vaginal breech delivery in singleton in Siriraj Hospital.
To determine the incidence of vaginal breech delivery at Siriraj Hospital and to evaluate factor affecting mode of delivery. Cross-sectional study. Department of Obstetrics and Gynecology, Faculty of Medicine Siriraj Hospital, Mahidol University. A total of 317 women with singleton breech presentation, > or =28 weeks of gestation, who had their deliveries at Siriraj Hospital during January 1st to December 31st 2003. The medical records of these women were reviewed to determine the incidence of vaginal breech delivery. Characteristics regarding current pregnancy and delivery and maternal and fetal outcomes were evaluated, including parity, gestational age, estimate fetal weight, cervical dilation, membranes status, maternal complications, types of breech presentation, and being a private case. The incidence of vaginal breech delivery among these women was 17.7%. Univariate analysis showed that multiparity, gestational age of <32 weeks, estimate fetal weight of < or =2500 grams, advanced cervical dilatation, ruptured membranes, and not being a private case increased the risk of vaginal breech delivery. Multiple logistic regression analysis demonstrated that only advanced cervical dilatation (4-7 cm, adjusted OR 10.7, 95% CI 3.5-33.0; >7 cm adjusted OR 40.4, 95% CI 12.6-129.2), ruptured membranes (adjusted OR 2.9, 95% CI 1.3-6.3), multiparity (adjusted OR 6.4, 95% CI 2.6-15.7), and gestational age <32 weeks (adjusted OR 9.7, 95% CI 2.7-35.7) were independently associated with vaginal breech delivery. However, lower apgar scores and neonatal complications, especially prematurity, were more frequent in vaginal than cesarean delivery. Vaginal breech delivery was found in 17.7% of singleton breech presentation in Siriraj Hospital. Certain characteristics during labor and delivery were associated with mode of delivery including advanced cervical dilatation, ruptured membranes, multiparity, and preterm gestational age.


HIV Incidence Estimates Using the Limiting Antigen Avidity EIA Assay at Testing Sites in Kiev City, Ukraine: 2013-2014.
To estimate HIV incidence and highlight the characteristics of persons at greatest risk of HIV in the Ukraine capital, Kiev. Residual samples from newly-diagnosed persons attending the Kiev City AIDS Centre were tested for evidence of recent HIV infection using an avidity assay. Questions on possible risk factors for HIV acquisition and testing history were introduced. All persons (≥16yrs) presenting for an HIV test April'13-March'14 were included. Rates per 100,000 population were calculated using region-specific denominators. During the study period 6370 individuals tested for HIV. Of the 467 individuals newly-diagnosed with HIV, 21 had insufficient samples for LAg testing. Of the remaining 446, 39 (8.7%) were classified as recent with an avidity index <1.5ODn, 10 were reclassified as long-standing as their viral load was <1000 copies/mL, resulting in 29 (6.5%) recent HIV infections. The only independent predictor for a recent infection was probable route of exposure, with MSM more likely to present with a recent infection compared with heterosexual contact [Odds Ratio 8.86; 95%CI 2.65-29.60]. We estimated HIV incidence at 21.5 per 100,000 population, corresponding to 466 new infections. Using population estimates for MSM and PWID, incidence was estimated to be between 2289.6 and 6868.7/100,000 MSM, and 350.4 for PWID. A high proportion of persons newly-infected remain undiagnosed, with MSM disproportionally affected with one in four newly-HIV-diagnosed and one in three recently-HIV-infected. Our findings should be used for targeted public health interventions and health promotion.


Barriers to childhood asthma care in sub-Saharan Africa: a multicountry qualitative study with children and their caregivers.
This study identifies barriers and provides recommendations to improve asthma care in children across sub-Saharan Africa, where qualitative data is lacking despite high rates. One of the aims of our National Institute for Health Research global health research group 'Achieving Control of Asthma in Children in Africa' was to use qualitative thematic analysis of transcribed audio recordings from focus group discussions (FGDs) to describe barriers to achieving good asthma control. Schools in Blantyre (Malawi), Lagos (Nigeria), Durban (South Africa), Kampala (Uganda) and Harare (Zimbabwe). Children (n=136), 12-14 years with either asthma symptoms or a diagnosis and their caregivers participated in 39 FGDs. All were recruited using asthma control questions from the Global Asthma Network survey. There were four key themes identified: (1) Poor understanding, (2) difficulties experienced with being diagnosed, (3) challenges with caring for children experiencing an acute asthma episode and (4) suboptimal uptake and use of prescribed medicines. An inadequate understanding of environmental triggers, a hesitancy in using metred dose inhalers and a preference for oral and alternate medications were identified as barriers. In addition, limited access to healthcare with delays in diagnosis and an inability to cope with expected lifestyle changes was reported. Based on these findings, we recommend tailored education to promote access to and acceptance of metred dose inhalers, including advocating for access to a single therapeutic, preventative and treatment option. Furthermore, healthcare systems should have simpler diagnostic pathways and easier emergency access for asthma. In a continent with rapidly increasing levels of poorly controlled asthma, we identified multiple barriers to achieving good asthma control along the trajectory of care. Exploration of these barriers reveals several generalisable recommendations that should modify asthma care plans and potentially transform asthma care in Africa. 269211.


Characteristics and trends in required home care by GPs in Austria: diseases and functional status of patients.
Almost all societies carry responsibility towards patients who require continuous medical care at home. In many health systems the general practitioner cooperates with community based services of home care and coordinates all medical and non medical activities. In Austria the general practitioner together and in cooperation with relatives of the patient and professional organisations usually takes on this task by visiting his patients. This study was carried out to identify diseases that need home care and to describe the functional profile of home care patients in eastern Austria. Cross sectional observational study with 17 GP practices participating during 2 study periods in 1997 and in 2004 in eastern Austria. Each GP identified patients requiring home care and assessed their underlying diseases and functional status by filling in a questionnaire personally after an encounter. Patients in nursing homes were excluded. Statistical tests used were t-tests, contingency tables, nonparametric Wilcoxon signed rank sum test and Fisher-combination test. Patients with degenerative diseases of the central nervous system (65%) caused by Alzheimer's disease and cerebrovascular occlusive disease and patients with degenerative diseases of the skeletal system (53%) were the largest groups among the 198 (1997) and 261 (2004) home care cases of the 11 (1997) and 13 (2004) practices. Malignant diseases in a terminal state constituted only 5% of the cases. More than two thirds of all cases were female with an average age of 80 years. Slightly more than 70% of the patients were at least partially mobile. Home care and home visits for patients with degenerative diseases of the central nervous and skeletal system are important elements of GP's work. Further research should therefore focus on effective methods of training and rehabilitation to better the mental and physical status of patients living in their private homes.


Dopaminergic efferent inhibition of carotid body chemoreceptors in chronically hypoxic cats.
The observations that the dopamine concentration of the carotid body and efferent inhibition of carotid chemoreceptors are increased during chronic hypoxia led to the hypothesis that the inhibition was due to the effect of an increased dopamine release by the activity of carotid sinus nerve (CSN) efferents. The hypothesis was tested by measuring the effect of dopamine receptor blockade on efferent inhibition of carotid chemosensory responses to graded levels of arterial O2 partial pressure in chronically hypoxic and normoxic cats. Chronically hypoxic cats were prepared by exposing the cats to 10% O2 at sea level for 30-34 days. Carotid chemosensory activity was first measured from a slip of an otherwise intact CSN. The measurements were then repeated after sectioning the remaining nerve trunk. The effect of sectioning the CSN provided the measure of efferent inhibition. In each group of cats the effects of sectioning the CSN with and without dopamine receptor blockade by haloperidol were also studied. CSN section augmented the chemosensory responses in the chronically hypoxic cats. Haloperidol, a dopamine antagonist, augmented the responses further, indicating that a part of the endogenous dopamine effect was independent of the CSN efferents. After haloperidol treatment CSN section did not influence the chemosensory responses. This study confirmed that the efferent inhibition significantly increased in the chronically hypoxic cats and demonstrated that haloperidol blocked the efferent inhibition, suggesting that the mechanism of the augmented inhibition is dopaminergic.


Neurochemical and behavioral aspects of lamotrigine.
Lamotrigine (LTG), a new anticonvulsant, chemically unrelated to current antiepileptic drugs (AEDs), resembles phenytoin (PHT) and carbamazepine (CBZ) in ability to block hindlimb extension in both the maximal electroshock test and leptazol-induced seizures. Results indicate that LTG may be of value in both partial and generalized seizures. In in vitro studies, LTG has been shown to inhibit veratrine-evoked release of glutamate when a threshold depolarizing concentration (4 micrograms/ml) is used, and also inhibits aspartate release when a larger stimulus is given (10 micrograms/ml). However, LTG does not block potassium-evoked transmitter release. LTG is a less potent inhibitor of the release of gamma-aminobutyric acid (GABA), acetylcholine, noradrenaline, and dopamine. LTG blocks the neurotoxicity of kainic acid in vivo, supporting the in vitro findings, and suggests that the anticonvulsant effect of LTG may be due to inhibition of glutamate release. In a test of working memory and phencyclidine (PCP) discrimination studies, LTG had no effect, indicating no sharing of the same PCP-like side effects associated with NMDA receptor blockade. In the gerbil model of global ischemia, high doses of LTG provided protection against damage to the CA1 region of the hippocampus. Analogues of LTG of higher potency to block the release of glutamate may be necessary to ensure protection against ischemic brain damage.


Research group as helpers due to the war in Ukraine: Focus group experiences of women researchers.
World Health Organization studies have shown that one in every five people who have experienced war or other conflicts suffers from a mental health disorder, the most vulnerable groups being children and women. According to international guidelines, mental health care should be made available immediately in the event of disaster. With the first influx of Ukrainian refugees to Hungary at the outbreak of the war, the Research Group of Childhood Mental Health at Eötvös Loránd University and Semmelweis University in Budapest immediately decided to help by transforming itself into a support group for refugee families. The members of the support group are all women. The aim of the present study is to explore the motivation behind the transformation of the research group and the help it provided. A further aim was to compare the group's experiences with descriptions in the literature of impacts on helpers who work with refugees. The current paper reflects on the transformation from researchers to helpers and the effects of that transformation at group and individual level using the focus group method and consensual text analysis. The transformation of the support group necessitated the involvement of students, whose experiences are also examined. We identified five main categories: context; the help recipients' perspective; the personal level; the professional level; and the level between the personal and professional. The analysis revealed the way in which the voluntary helping developed, the resulting difficulties, and coping options. Volunteering among Ukrainian refugees has both positive and negative psychological consequences. While stress and trauma threaten the psychological well-being of the helpers, positive aspects, such as flexibility and professional development, are also reported. Due to the strong motivation among group members and their experience in practical work, the all female research group was quickly able to transform itself into a support group.


Engineered Substrate for Cyclooxygenase-2: A Pentapeptide Isoconformational to Arachidonic Acid for Managing Inflammation.
Beyond the conventional mode of working of anti-inflammatory agents through enzyme inhibition, herein, COX-2 was provided with an alternate substrate. A proline-centered pentapeptide isoconformational to arachidonic acid, which exhibited appreciable selectivity for COX-2, overcoming acetic acid- and formalin-induced pain in rats to almost 80%, was treated as a substrate by the enzyme. Remarkably, COX-2 metabolized the pentapeptide into small fragments consisting mainly of di- and tripeptides that ensured the safe breakdown of the peptide under in vivo conditions. The kinetic parameter Kcat/Km for COX-2-mediated metabolism of the peptide (6.3 × 105 M-1 s-1) was quite similar to 9.5 × 105 M-1 s-1 for arachidonic acid. Evidenced by the molecular dynamic studies and the use of Y385F COX-2, it was observed that the breakage of the pentapeptide has probably been taken place through H-bond activation of the peptide bond by the side chains of Y385 and S530.


Eggs: conveniently packaged antibodies. Methods for purification of yolk IgG.
Eggs from immunized chickens may provide a convenient and inexpensive source of antibodies. We describe two simple and efficient methods for purification of IgG from yolk. The antibody is rendered useful for most currently employed immunological techniques. Amounts of antibody corresponding to almost half a litre of antiserum may be recovered from a chicken in one month.


Prophylactic Effect of Recombinant Human Soluble Thrombomodulin for Hepatic Sinusoidal Obstruction Syndrome Model Mice.
The present study aimed to examine the effects of prophylactic administration of recombinant human soluble thrombomodulin (rTM) for the prevention of sinusoidal obstruction syndrome (SOS). Crl:CD1 mice were allocated to the rTM, placebo, and control groups. The rTM group received an intraperitoneal administration of rTM, with intraperitoneal administration of monocrotaline (MCT) 1 h later. The placebo group received PBS instead of rTM, and the control group received PBS instead of rTM and MCT. Mice were sacrificed 48 h after MCT administration, and blood and liver tissues were evaluated. Immunostaining was performed using anti-CD42b and anti-SE-1 antibodies, and AZAN staining. Levels of plasminogen activator inhibitor (PAI-1) and endothelial nitric oxide synthase (eNOS) in whole liver tissues were estimated using RT-PCR. Hematoxylin-eosin staining showed that SOS-related findings were markedly attenuated in the rTM group compared to the placebo group. CD42b immunostaining showed the presence of extravasated platelet activation (EPA) in the Disse space in the placebo group, but this was less noticeable in the rTM group. PAI-1 levels were significantly lower in the rTM group than in the placebo group in RT-PCR. However, eNOS levels were significantly higher in the rTM group than in the placebo group. Administration of rTM may prevent SOS by protecting sinusoidal endothelial cells.


Numerical expression of paternity test results using predetermined indexes.
Relative chance of paternity (RCP) is a numerical expression used to indicate either paternity (near 100%) or nonpaternity (0% or close to 0%). RCP is derived by converting the paternity index (PI) to a percentage, RCP = PI/(PI+1). PI represents the chance that the alleged father is or is not the father, and is expressed as a number for a given phenotype combination of the mother-child-alleged-father trio. These PI values have been determined and are listed in several tables. Thus, one can find in these tables the individual PI value for each genetic marker system for a given trio, multiply the numbers, and convert the combined PI value into RCP. In this way, a qualitative and quantitative report of a paternity testing can be readily derived.


The metastasis suppressor, N-myc downregulated gene 1 (NDRG1), is a prognostic biomarker for human colorectal cancer.
Metastasis remains to be one of the most prevalent causes leading to poor long-term survival of colorectal cancer (CRC) patients. The clinical significances of tumor metastatic suppressor, N-myc downregulated gene 1 (NDRG1), have been inconsistently reported in a variety of cancerous diseases. In this study with 240 CRC clinical specimens, we showed that NDRG1 expression was significantly decreased in most of CRC tissues compared to the paired non-tumor counterparts. Statistical analysis revealed a significant inverse correlation of NDRG1 expression with tumor stage, differentiation status and metastasis. Compared with NDRG1-negative group, NDRG1-positve group had better disease-free/overall survival (p = 0.000) over 5 years' follow-up. Furthermore, NDRG1 was considered to be an independent prognostic factor for overall survival (p = 0.001) and recurrence (p = 0.003). Our study concludes that NDRG1 is a novel favorable predictor for the prognosis in CRC patients.


Oleuropein aglycone induces autophagy via the AMPK/mTOR signalling pathway: a mechanistic insight.
The healthy effects of plant polyphenols, some of which characterize the so-called Mediterranean diet, have been shown to arise from epigenetic and biological modifications resulting, among others, in autophagy stimulation. Our previous work highlighted the beneficial effects of oleuropein aglycone (OLE), the main polyphenol found in the extra virgin olive oil, against neurodegeneration both in cultured cells and in model organisms, focusing, in particular, autophagy activation. In this study we investigated more in depth the molecular and cellular mechanisms of autophagy induction by OLE using cultured neuroblastoma cells and an OLE-fed mouse model of amylod beta (Aβ) deposition. We found that OLE triggers autophagy in cultured cells through the Ca2+-CAMKKβ-AMPK axis. In particular, in these cells OLE induces a rapid release of Ca2+ from the SR stores which, in turn, activates CAMKKβ, with subsequent phosphorylation and activation of AMPK. The link between AMPK activation and mTOR inhibition was shown in the OLE-fed animal model in which we found that decreased phospho-mTOR immunoreactivity and phosphorylated mTOR substrate p70 S6K levels match enhanced phospho-AMPK levels, supporting the idea that autophagy activation by OLE proceeds through mTOR inhibition. Our results agree with those reported for other plant polyphenols, suggesting a shared molecular mechanism underlying the healthy effects of these substances against ageing, neurodegeneration, cancer, diabetes and other diseases implying autophagy dysfunction.


Single-Step Synthesis of Atmospheric CO2 Sorbents through Radiation-Induced Graft Polymerization on Commercial-Grade Fabrics.
Primary amines form a key component of a well-studied mechanism for capturing carbon dioxide (CO2) from the atmosphere. This study comprises a single-step synthesis of a novel sorbent for CO2 by grafting monomers rich in primary amines to three commercial-grade fabrics: polyethylene terephthalate, high-density polyethylene and nylon 6. An initial evaluation of the sorbency of the chosen monomers, allylamine and butenylamine, qualitatively confirmed their ability to extract CO2 from the atmosphere. Six novel copolymers, comprised of each of the three fabrics grafted with one of each monomer, were synthesized using radiation-induced graft copolymerization through electron beam irradiation. All fabrics achieved greater grafting with butenylamine compared to allylamine, likely given the closer proximity of the primary amine to the radical on the latter's structure. Primary amines can stabilize radicals, preventing copolymerization reactions. Characterization of sorbency revealed that the majority of the grafted amines likely reacted to adsorb CO2. Therefore, the amount of amine grafted comprises the primary limiting factor on the sorbents' CO2 capacity.


Evidence-based practice: to be or not to be, this is the question!
Evidence-based nursing is the current fashion. It is being touted as the mechanism to achieve best practice in the clinical setting. But while evidence-based practice (EBP) is being presented in the literature, discussed at nursing practice forums, and evidence-based centres of excellence have developed, there seems to be very little impact in the practice that nurses deliver on a daily basis. The case in point is the collection of vital signs. While not historically a nursing skill, over the last 60 years it has become an integral component of practice in the postoperative general surgical setting. The evidence to support these practices is scant. Policies and text purport traditional routine-regulated practice without substantive evidence to support their claims. These policies are being used to control rather than support EBP. In conjunction with the traditional practice of vital sign collection and the culture of the clinical settings, the policies are limiting opportunities for clinicians to make individual decisions about care delivery based on the unique needs of each patient. Rather than focusing on EBP as the solution to the development of best practice, is it not time to change the focus to real strategies that will assist in achieving best practice? These include the creation of rigorous relevant evidence, the valuing of clinical expertise and the changing of the cultures in which nurses develop and practice.


Spontaneous spinal subarachnoid haemorrhage and subdural haematoma upon customary bowing: a case report.
Spinal subarachnoid haemorrhage is a rare clinical condition, and a spinal subarachnoid haemorrhage associated with subdural haematoma is extremely infrequent. Iatrogenic causes such as trauma and lumbar puncture, coagulopathy, arteriovenous malformation, spinal artery aneurysm, vasculitis or neoplasm are known predisposing factors. Minor effort or trauma can be a cause of spontaneous spinal subarachnoid haemorrhage. Herein, we report a rare case of spontaneous spinal subarachnoid haemorrhage and subdural haematoma that occurred when the patient engaged in a kneeling bow on the floor.


Selected Copper-Based Reactions for C-N, C-O, C-S, and C-C Bond Formation.
Metal-catalyzed cross-coupling reactions belong to the most important transformations in organic synthesis. Copper catalysis has received great attention owing to the low toxicity and low cost of copper. However, traditional Ullmann-type couplings suffer from limited substrate scopes and harsh reaction conditions. The introduction of several bidentate ligands, such as amino acids, diamines, 1,3-diketones, and oxalic diamides, over the past two decades has totally changed this situation as these ligands enable the copper-catalyzed coupling of aryl halides and nucleophiles at both low reaction temperatures and catalyst loadings. The reaction scope has also been greatly expanded, rendering this copper-based cross-coupling attractive for both academia and industry. In this Review, we have summarized the latest progress in the development of useful reaction conditions for the coupling of (hetero)aryl halides with different nucleophiles. Additionally, recent advances in copper-catalyzed coupling reactions with aryl boronates and the copper-based trifluoromethylation of aromatic electrophiles will be discussed.


Organellar genome analysis of rye (Secale cereale) representing diverse geographic regions.
Rye (Secale cereale) is an important diploid (2n = 14, RR) crop species of the Triticeae and a better understanding of its organellar genome variation can aid in its improvement. Previous genetic analyses of rye focused on the nuclear genome. In the present study, the objective was to investigate the organellar genome diversity and relationships of 96 accessions representing diverse geographic regions using chloroplast (cp) and mitochondrial (mt) DNA PCR-RFLPs. Seven cpDNA and 4 mtDNA coding and noncoding regions were amplified using universal cpDNA and mtDNA primer pairs. Each amplified fragment was digested with 13 different restriction enzymes. mtDNA analysis indicated that the number of polymorphic loci (20) was low and genetic differentiation (GST) was 0.60, excluding the outgroups (hexaploid wheat, Triticum aestivum, 2n = 6x = 42, AABBDD; triticale, xTriticosecale Wittmack, 2n = 6x = 42, AABBRR). cpDNA analysis revealed a low level of polymorphism (40%) among the accessions, and GST was 0.39. Of the 96 genotypes studied, 70 could not be differentiated using cpDNA PCR-RFLPs even though they are from different geographic regions. This is most likely due to germplasm exchange, indicating that genotypes might have a common genetic background. Two cpDNA and 3 mtDNA fragments were significantly correlated to the site of germplasm collection. However, there was no clear trend. These results indicate that the level of organellar polymorphism is low among the cultivated rye genotypes. The cpDNA and mtDNA PCR-RFLP markers used in the present study could be used as molecular markers in rye genetics and breeding programs.


Long-Term Neonatal Estrogen Exposure Causes Irreversible Inhibition of LH Pulses by Suppressing Arcuate Kisspeptin Expression via Estrogen Receptors α and β in Female Rodents.
Exposure to estrogen during the developmental period causes reproductive dysfunction in mammals, because the developing brain is highly sensitive to estrogens. In the present study, we report that long-term exposure to supraphysiological doses of estrogen during the neonatal critical period causes irreversible suppression of Kiss1/kisspeptin expression in the arcuate nucleus (ARC) via estrogen receptor-alpha (ERα) and ERβ, resulting in reproductive dysfunction in female rats. Daily estradiol-benzoate (EB) administration from days 0 to 10 postpartum caused persistent vaginal diestrus in female rats. The female rats showed profound suppression of pulsatile luteinizing hormone (LH) release and ARC Kiss1/kisspeptin expression even after ovariectomy at adulthood. In contrast, female rats treated with a single EB injection at day 5 postpartum exhibited persistent vaginal estrus and showed comparable LH pulses and numbers of ARC Kiss1-expressing cells to vehicle-treated controls after ovariectomy at adulthood. Because the LH secretory response to exogenous kisspeptin was spared in female rats with neonatal long-term estrogen exposure, the LH pulse suppression was most probably due to ARC kisspeptin deficiency. Furthermore, neonatal estrogen might act through both ERα and ERβ, because EB exposure significantly reduced the number of ARC Kiss1-expressing cells in wild-type mice but not in ERα or ERβ knockout mice. Taken together, long-term exposure to supraphysiological doses of estrogen in the developing brain might cause defects in ARC kisspeptin neurons via ERα and ERβ, resulting in inhibition of pulsatile LH release and lack of estrous cyclicity.


An unusual knee injury: Isolated tibiofibular dislocation.
Isolated proximal tibiofibular dislocation is an extremely rare condition with potentially serious complications if missed. The mechanism of injury, clinical presentation and treatment options are discussed. This injury was more common in previous centuries, when horse riding was the preferred method of transport. The young man we present was involved in a pastime that is rising in popularity and it is therefore likely that this injury will be a more common presentation to EDs.


Characterization of purified pp60c-src protein tyrosine kinase from human platelets.
Intact pp60c-src, the cellular homologue of the transforming protein of Rous sarcoma virus, was purified from human platelets. The purified fractions also contained small amounts of a 54-kDa proteolytic degradation product of pp60c-src. We investigated some of the biochemical and kinetic properties of pp60c-src protein tyrosine kinase. Maximum kinase activity occurred at pH 6.5 and required a mixture of 2 mM Mn2+/Mg2+ as divalent cations. The enzyme most strongly phosphorylated casein, followed by enolase and alcohol dehydrogenase. The Km value for ATP was 4 microM for substrate phosphorylation and for autophosphorylation. Using casein, we determined a Vmax for substrate phosphorylation by pp60c-src in the range of 1.9-3.4 nmol.min-1.mg-1. Since the Vmax value for the purified 54-kDa fragment of pp60c-src was also included in this value, we conclude that proteolytic degradation of a 6-kDa fragment from the N-terminus of pp60c-src did not affect its kinase activity. Tryptic phosphopeptide analysis identified Tyr-416 as the major autophosphorylation site. Preincubation of purified pp60c-src with ATP increased the amount of autophosphorylation accompanied by an increase in Vmax, whereas the Km values were not altered. Our data directly demonstrate that autophosphorylation at Tyr-416 exerts, in contrast to phosphorylation at Tyr-527, a positive regulatory effect on the pp60c-src kinase activity.


Microchip laser operation of Tm,Ho:KLu(WO₄)₂ crystal.
A microchip laser is realized on the basis of a monoclinic Tm,Ho-codoped KLu(WO₄)₂crystal cut for light propagation along the Ng optical indicatrix axis. This crystal cut provides positive thermal lens with extremely weak astigmatism, S/M = 4%. High sensitivity factors, M = dD/dP(abs), of 24.9 and 24.1 m(-1)/W for the mg- and pg- tangential planes are calculated with respect to the absorbed pump power. Such thermo-optic behavior is responsible for mode stabilization in the plano-plano microchip laser cavity, as well as the demonstrated perfect circular beam profile (M(2) < 1.1). Maximum continuous-wave output power of 450 mW is obtained with a slope efficiency of 31%. A set of output couplers is employed to achieve lasing in the spectral range of 2060-2096 nm. The increase of output coupler transmission results in deterioration of the laser performance attributed to the increased up-conversion losses.


Assessing the willingness of the public to pay to conserve urban green space: the Hangzhou City, China, case.
The authors assessed the willingness of residents to pay for urban green-space conservation in Hangzhou, China, using the contingent-valuation method. The aim of the study was to provide policy makers with information that would be useful for making informed decisions in urban-development planning. The findings of the study are as follows: 1) The willingness of residents to pay for urban green-space conservation was positively correlated with their perceptions of the benefits of green spaces and negatively correlated with perceptions of the annoyances. 2) The willingness to pay a higher premium for green-space conservation is directly related to gender, income level, and residential-ownership status. Age and education level are not significantly correlated with willingness to pay. 3) A majority of respondents view the conservation of urban green spaces as a very important function of the city, and most of them are willing to pay additional taxes for this conservation. 4) The total value per year to the public of the conservation program in Hangzhou is about $15.4 million. These qualitative and quantitative findings can be used in the policy-making process for urban-development plans.


Home treatment of obstructive sleep apnoea with continuous positive airway pressure applied through a nose-mask.
Continuous positive airway pressure (CPAP) applied through the nose completely prevented obstructive apnoea during all night testing in 50 patients with severe obstructive apnoea. In early 1981, we began a home treatment trial of nasal CPAP. Patients were treated in hospital for 3 to 5 nights, a period in which they were trained to fit the custom made nose-mask used to provide nasal CPAP. Patients subsequently continued treatment at home. Daytime somnolence resolved within days of starting therapy, and did not recur while the nasal CPAP unit was used on a regular basis. At present, we have 35 patients who have been on therapy for periods ranging between 3 and 30 months. Although each patient has displayed a reduction of severity of the underlying sleep apnoea when tested without nasal CPAP, the majority continue to require regular nightly nasal CPAP. In a few patients, treatment with nasal CPAP appeared to help in weight control such that obstructive apnoea and snoring have resolved. Nasal CPAP is a safe, fully effective therapy for obstructive apnoea, and can be used indefinitely by the patient at home.


Quantitative assessment of the effect of CNQX on paired-pulse facilitation in the anterior cingulate cortex.
Paired-pulse facilitation (PPF) is a form of short-term plasticity which has been used qualitatively to characterize the action of neuroactive compounds. The aims of the present study were to develop a model that allows the quantitative assessment of PPF and to evaluate the influence of CNQX, an AMPA receptor antagonist, on synaptic plasticity based on parameters derived from this model. Experiments were performed on brain slices taken from the coronal anterior cingulate cortex (ACC) of Sprague-Dawley rats. Stimulation was applied to layer 5 of the ACC. In all experiments, the stimuli comprised a pair of biphasic pulses generated by an isolated pulse stimulator under software control. An inter-pulse interval of 40 ms was employed, and the evoked extracellular field potentials in layer 2/3 of the ACC were recorded. An equation was adopted to describe the PPF at different stimulation intensities. Nonlinear fitting was used to obtain the coefficients of the equation which would allow the description of the experimental data. CNQX exerted an influence on the area under the curve for the PPF versus stimulation plot by changing the values of the parameter K (the voltage causing a half-maximal response). The model was elaborated based on features of the ligand-receptor interaction which can be reliably specified empirically, and its applicability was illustrated by characterizing the influence of CNQX on PPF in the ACC. An algorithm for the assessment of PPF using different sets of parameters is also discussed.


A P element with a novel fusion of reporters identifies regular, a C2H2 zinc-finger gene downstream of the circadian clock.
Elucidating the mechanisms that link the circadian pacemaker to the timing of behaviors it controls is one of the greatest challenges in circadian biology. We report the generation of a P element, Pluc+, containing a novel reporter fusion. Our fusion reporter capitalizes on the use of luciferase bioluminescence to easily analyze temporal expression as well as the strength of myc epitopes and GFP to identify spatial expression. Using Pluc+ we have identified and characterized a novel C2H2 zinc-finger gene, regular (rgr), that cycles circadianly in phase with period (per) gene expression, but shifts to light-dark regulation in Clk(Jrk) mutant flies. By following myc expression of the Pluc+ reporter, we demonstrate that Rgr is expressed in a discrete number of neurons in the brain which overlap with axons expressing pigment-dispersing factor.


Phase transitions of capillary-held liquids in a slit-like pore.
Dynamics of capillary held liquids plays important roles in a wide range of systems including adhesion, printing of paints and inks, the behavior of wet granular materials, and the mass transfer through porous media. Recent study suggested the presence of two distinct modes for the disappearance of capillary-held liquids in a slit-like pore of adjustable slit width that depended on the slit-opening rates. In contrast to the first mode that is well-documented in terms of the Young-Laplace equation, a novel and unexpected mode was observed when the liquid bridge was held in the vicinity of the thermodynamic phase boundary (equilibrium Kelvin length). Here we extended the study to three new compounds that have a wide range of vapor pressures. An evaporating liquid bridge developed large refractive index gradients that extended over a few micrometers from the edge of the meniscus once the slit width was increased beyond the equilibrium Kelvin length. This interfacial region with depleted refractive index retreated inward as the meniscus shrank with time, and the refractive index of the entire bridge subsequently fell from that of the liquid once the interfacial regions from the opposite sides of the shrinking bridge met at the center. The refractive index recovered to that of the liquid when the slit width was closed to below the Kelvin length and the vapor was allowed to recondense. The time scale of the evaporation and condensation depended on the size of the surface gap, and, when the surfaces were placed at a separation very close to the Kelvin length, it was possible to detect a stage in which the system was in an apparent kinetic equilibrium between two physical states--with and without the liquid connecting the two surfaces.


A clinical and microbiological evaluation of systemic and local metronidazole delivery in early onset periodontitis patients.
The present study describes selected clinical and microbiological results obtained by treatment with local (Elyzol) and systemic (Flagyl) use of metronidazole alone and/or mechanical subgingival debridement in early onset periodontitis (EOP). Twelve patients, with lesions not distributed as in classical localized juvenile periodontitis, were included. They were randomly divided into local and systemic treatment groups each comprising 6 individuals, in each of whom 4 sites (one site/quadrant) with a probing depth of > or = 5 mm were selected and treated with separate treatment modalities. The overall treatment design provided 6 different test groups. Groups of quadrants received 1) scaling and root planing 2) local metronidazole treatment 3) systemic metronidazole treatment 4) local metronidazole combined with scaling and root planing 5) systemic metronidazole combined with scaling and root planing 6) No treatment. The microbiological and clinical effects of treatment modalities were monitored over 42 days. The results demonstrated reductions in mean counts of obligate anaerobic and capnophilic microorganisms coupled with significant improvements in mean clinical measurements (gingivitis, probing depth, attachment level) in all groups, except the untreated. Scaling and root planing provided an initial clinical improvement with a selective reduction of periodontopathogens (92.6% obligate anaerobes, 42.9% capnophilic microorganisms), whereas the combination of local or systemic metronidazole with scaling and root planing were found superior in reducing capnophilic bacteria (93.7% and 93.4%, respectively). It is of critical importance to have a treatment rationale for EOP, since bacterial differences exist in the etiological subforms of periodontitis. Microbial testing may be justified before prescribing the adjunctive antibiotic and selecting the mode of delivery for the successful clinical management of EOP.


Antidepressant treatment before hospitalization for major depression: often prescribed, often undertitrated.
Fifty-three patients hospitalised for major depression were given a semi-structured interview to collect data allowing to consider the question of treatment in the period preceding hospitalisation. Twenty-one patients were discarded because they did not consult any physician (n = 5) or because they did it too late ( n = 11) or for they reached the threshold of major depression too late to allow sufficient time for efficacy of the treatment (n = 5). There remained a subsample of 20 potentially treatable patients. The majority of them refused their treatment (17%), were given no antidepressant treatment (14%) or at an insufficient dose (41%). If they received a sufficient dose, it was too lately (3%) or it was a maintenance therapy, which had not been modified in spite of a recurrence (14%), and finally only 10% of the potentially treatable patients could be considered as adequately treated, from a psychopharmacological point of view.


A standardized differential stain for hematology.
A stain composed of purified Azure B and Eosin Y has been developed for use in conjunction with an automated stainer. This system provides the consistency in chromatic properties required for automated blood-cell analysis by pattern recognition systems. The stain represents a marked improvement in stability over those presently used with differential analyzers, but it is also an important advance toward a standardized stain for general hematological use. The purity of the component dyes, the stability of the final stain and the dependence of staining intensity on the stain/buffer ratio and dye concentration are discussed.


Trauma in pregnancy: an updated systematic review.
We reviewed recent data on the prevalence, risk factors, complications, and management of trauma during pregnancy. Using the terms "trauma" and "pregnancy" along with specified mechanisms of injury, we queried the PubMed database for studies reported from Jan. 1, 1990, through May 1, 2012. Studies with the largest number of patients for a given injury type and that were population-based and/or prospective were included. Case reports and case series were used only when more robust studies were lacking. A total of 1164 abstracts were reviewed and 225 met criteria for inclusion. Domestic violence/intimate partner violence and motor vehicle crashes are the predominant causes of reported trauma during pregnancy. Management of trauma during pregnancy is dictated by its severity and should be initially geared toward maternal stabilization. Minor trauma can often be safely evaluated with simple diagnostic modalities. Pregnancy should not lead to underdiagnosis or undertreatment of trauma due to unfounded fears of fetal effects. More studies are required to elucidate the safest and most cost-effective strategies for the management of trauma in pregnancy.


Multimodal and widespread somatosensory abnormalities in persistent shoulder pain in the first 6 months after stroke: an exploratory study.
To explore the role of multimodal and widespread somatosensory abnormalities in the development of persistent poststroke shoulder pain (pPSSP) in the first 6 months after stroke. Prospective inception cohort study. Stroke units of 2 teaching hospitals. The data of a strict selection of patients (N=31) with a clinical diagnosis of stroke were analyzed. Not applicable. The development of pPSSP within the first 6 months after stroke. Bilateral sensation and pain thresholds at 3 (t1) and 6 (t2) months, and conditioned pain modulation (CPM) at 3 months after stroke. Clinical examination within 2 weeks after stroke (t0), at t1, and at t2. pPSSP (n=9) was associated with increased sensation and pain threshold ratios at the affected side (t1, t2), and with reduced cold pain tolerance at the unaffected side (t1). CPM was not different from patients without pPSSP (n=22). Notably, in patients with pPSSP reporting increased sensation on clinical examination, multiple body sites across multiple stimulus modalities were involved, and increased sensation persisted from t1 to t2. pPSSP in the first 6 months after stroke was associated with somatosensory loss to both innocuous and noxious stimuli (affected side). In addition, pPSSP was associated with sensitization to cold pain (unaffected side) and with widespread sensitization to multimodal innocuous stimuli (affected side). The results support the notion that central somatosensory sensitization could play an important role in the development of pPSSP, the maintenance of pPSSP, or both.


Peripheral neuropathy in course of progressive systemic sclerosis. Light and ultrastructural study.
Progressive systemic sclerosis (PSS) is a chronic inflammatory disease of the connective tissue with involvement of the skin and other organs. The disease is characterized by an abnormal accumulation of collagen in all tissues and by microangiopathy. The involvement of the peripheral nervous system during PSS is very unusual and few cases are reported in the literature. A morphological study on the neuropathy associated with sclerodermia has been performed in rare cases. In this paper we demonstrate the role that the vascular lesions have in the pathogenesis of neuropathy during scleroderma. In particular, the primary role of the peripheral microangiopathy during PSS (observed in different clinical cases) is verified.


Cryptic diversity of stygobiotic shrimp genus Xiphocaridinella Sadowsky, 1930 (Crustacea: Decapoda: Atyidae): the first case of species co-occurrence in the same cave system in the Western Caucasus.
DNA barcoding of stygobiotic shrimps of the genus Xiphocaridinella Sadowsky, 1930 (Crustacea: Decapoda: Atyidae) collected in underground streams flowing inside two neighboring large karst caves (Otap and Abrskil сaves) revealed the presence of two distinct genetic lineages representing the first case of species co-occurrence in the Western Caucasus. The paper presents the complete morphological re-description of stygobiotic atyid shrimp Xiphocaridinella ablaskiri (Birštein, 1939) and the description of a new species using genetic and morphological analysis. Other known cases of co-occurrence of several stygobiotic shrimp species in the same cave system as well as new genetic data (COI mtDNA) on Western Caucasian species of the genus Xiphocaridinella are discussed in the paper.


Pure Amorphagnosia without Tactile Object Agnosia.
A 54-year-old female showed amorphagnosia without ahylognosia and tactile agnosia 40 days after the onset of right cerebral infarction. Her basic somatosensory functions were normal. The appreciation of substance qualities (hylognosia) was preserved, but the patient's inability to recognize the size and shape (morphagnosia) was confined to 2- and 3-dimensional shapes (amorphagnosia) in the left hand. However, the patient's ability to recognize real daily objects was well preserved. Brain MRI after admission showed ischemic lesions confined to the right pre- and postcentral gyri and the medial frontal cortex on DWI and FLAIR images. An analysis of SPECT images revealed that the most decreased areas were localized to the pre- and postcentral gyri, superior and inferior parietal lobules, supramarginal gyrus, and angular gyrus. Considering the previous reported cases, the responsible lesion for the impaired perception of hylognosia and morphagnosia may not necessarily be confined to the right hemisphere. To date, 5 reports (6 cases) of tactile agnosia have been published; 4 cases presented with both ahylognosia and amorphagnosia, while 1 presented with only amorphagnosia, and another showed amorphagnosia and mild ahylognosia. Our case is the first to present with only amorphagnosia without tactile agnosia. The mechanism for the well-preserved recognition of real objects may depend on the preserved hylognosia. Of note, there have been no reports showing only ahylognosia without amorphagnosia. Further studies are necessary to clarify whether or not patients with preserved hylognosia or morphagnosia retain the ability to perceive real objects.


An Investigation into the Relation between the Technique of Movement and Overload in Step Aerobics.
The aim of this research was to determine the features of a step workout technique which may be related to motor system overloading in step aerobics. Subjects participating in the research were instructors (n = 15) and students (n = 15) without any prior experience in step aerobics. Kinematic and kinetic data was collected with the use of the BTS SMART system comprised of 6 calibrated video cameras and two Kistler force plates. The subjects' task was to perform basic steps. The following variables were analyzed: vertical, anteroposterior, and mediolateral ground reaction forces; foot flexion and abduction and adduction angles; knee joint flexion angle; and trunk flexion angle in the sagittal plane. The angle of a foot adduction recorded for the instructors was significantly smaller than that of the students. The knee joint angle while stepping up was significantly higher for the instructors compared to that for the students. Our research confirmed that foot dorsal flexion and adduction performed while stepping up increased load on the ankle joint. Both small and large angles of knee flexion while stepping up and down resulted in knee joint injuries. A small trunk flexion angle in the entire cycle of step workout shut down dorsal muscles, which stopped suppressing the load put on the spine.


'Doing school food!': a practical toolkit for adopting a whole school food approach.
The dietary intake and reported eating behaviours of adolescents in the UK are a public health concern. Schools are identified as an ideal 'place' setting to promote health and improve young peoples' nutrition outcomes. A gap in the understanding of how healthy secondary school food policy can be implemented, sustainable and effective, may hamper progress to improving school food provision and nutrition education in the UK. Research was conducted to understand the factors which influence healthy school food provision and the adolescent's food choice to inform and develop a practical framework for schools. This research involves the development of a practical toolkit which synthesises evidence generated from a mixed methods study and a systematic review. This was informed by an exploration of the secondary school food environment as a potentially 'obesogenic' setting, the effectiveness of school food interventions and policy in Europe and UK, included young people's (11-18 years of age) eating behaviours and priorities in food choice. A pragmatic approach was taken in the integration of evidence, using ecological and behaviour change theory, and joint display principles. A six-phase practical toolkit is presented, guided by 'What Good Looks Like' and 'Whole Systems Approach to Obesity' principles which can be used to translate the evidence from this research into good school food practice. Improving secondary school food provision across the school day and having a coherent whole school food approach to healthy eating have the potential to significantly improve a young person's food choice, therefore impacting the nutrient intake of adolescents in the UK. This toolkit helps working towards operationalising this idea.


Transferrin is made and bound by photoreceptor cells.
Retinal pigment epithelial cells, which form one aspect of the blood-retinal barrier, control the access of blood-borne components such as diferric transferrin to the neural retina. It has recently been shown that RPE cells remove iron from diferric transferrin in a low pH compartment and subsequently release it in a low molecular weight form that can be chelated by apo-transferrin (Hunt and Davis: J. Cell Physiol. 152:102-110, 1992). It is now shown that photoreceptor cells can bind diferric transferrin to receptors on their inner segments. Moreover, polymerase chain reaction and in situ hybridization show that cells of the neural retina, particularly photoreceptors, make apo-transferrin.


GABA and glycine have different effects on monaural response properties in the dorsal nucleus of the lateral lemniscus of the mustache bat.
1. We studied the monaural response properties of 81 neurons in the dorsal nucleus of the lateral lemniscus (DNLL) of the mustache bat before and during the iontophoretic application of antagonists that blocked gamma-aminobutyric acid-A (GABAA) receptors (bicuculline) or glycine receptors (strychnine). The main finding is that GABAergic inhibition had substantial effects, whereas glycine had little or no effect on the activity evoked by contralateral stimulation. 2. Before the application of drugs, the monaural response properties of DNLL cells were characterized by two main features. The first was that the majority (86%) of neurons had monotonic rate-intensity functions, whereas only 14% had weakly nonmonotonic functions. The second was that most (66%) neurons displayed some form of chopping response pattern, in which there was a regular interval between discharges that was unrelated to the period of the tone burst frequency. 3. Bicuculline had two major effects on the majority of DNLL cells. It caused large increases in spike counts and changes in temporal discharge patterns. In 38 of 47 cells (81%) bicuculline changed the temporal discharge patterns into a sustained chopper pattern. In addition, the duration of the discharge train continued for a period of time longer than the duration of the tone burst in many but not all neurons. Prolonged firing of this sort was rarely seen in the predrug condition. Furthermore, in a few cells bicuculline caused a decrease in the interspike interval as well as a lengthening of the discharge train. 4. Blocking glycine, in contrast, caused either small increases in spike count or no increase at all and did not affect the temporal discharge patterns in the majority (87%) of neurons. 5. In most DNLL cells the shapes of the rate-intensity functions were virtually the same before and during the application of either antagonist. The rate-intensity functions of 91% of the cells were unaffected by bicuculline and 98% were unaffected by strychnine. 6. Blocking either GABAergic inhibition or glycinergic inhibition had no effect on discharge latency in the vast majority of DNLL cells. In a few neurons application of bicuculline or strychnine had a small influence and caused discharge latency to decrease by < or = 1 ms. 7. These results show that the excitation from stimulation of the contralateral ear evokes a sustained chopping discharge pattern in the vast majority of DNLL neurons. The sustained chopping response is changed into another discharge pattern by the GABAergic innervation that is also evoked by stimulation of the contralateral ear.(ABSTRACT TRUNCATED AT 400 WORDS)


Clinical Profile and 30-Day Mortality of Invasively Managed Patients with Suspected Acute Coronary Syndrome During the COVID-19 Outbreak.
The COVID-19 pandemic severely disrupted cardiovascular care during the spring of 2020 in Europe. Our study analyzed the clinical profile, COVID-19 impact, and 30-day prognosis of invasively managed patients with acute coronary syndrome (ACS) compared to a historical cohort.All invasively managed ACS patients from March 1st to April 30th, 2020 were compared to a cohort from the same timeframe of 2019 (n = 316). COVID-19 confirmed cases were defined by a positive SARS-CoV-2 polymerase chain reaction (PCR) test (CoV+). The primary outcome was all-cause 30-day mortality and multivariable predictors of this outcome.A 40.4% reduction in ACS patients was noted (198 cases in 2019 to 118 in 2020), and 11% of 2020 ACS patients were CoV+. Baseline characteristics were similar between groups. There were significantly more in-hospital patients with ACS (15.3% versus 6.1%, P = 0.007), and fewer patients were found to have a culprit lesion (58.5% versus 74.2%, P = 0.004) in 2020 compared to 2019. Thirty-day mortality in 2020 (7%) was not different from that in 2019 (4.2%), P = 0.294, but it was significantly higher in CoV+ patients (23.1%) compared to that in negative SARS-CoV-2 PCR test (CoV-) patients (5%), P = 0.047, in the 2020 group. In the multivariate analysis, CoV+ was an independent mortality predictor (OR = 9.8, 95% CI = 1.48-64.78), along with the left ventricular ejection fraction (LVEF) (OR = 0.91, 95% CI = 0.86-0.97), P = 0.0006.This study found increased 30-day mortality of invasively managed CoV+ ACS patients compared to that of CoV- patients during the 2020 COVID-19 spring outbreak. In the multivariable analysis, a SARS-CoV-2 positive test was independently associated with 30-day mortality. Further investigations of the underlying physiopathological relations between COVID-19 and ACS are warranted.


Straight from the heart.
Lipids called ceramides may be better predictors of cardiovascular problems than cholesterol. Doctors and pharma are waking up to their potential.


The M4 Helix Is Involved in α7 nACh Receptor Function.
Nicotinic acetylcholine receptors (nAChR) are the archetypal members of the pentameric ligand-gated ion channel (pLGIC) family, an important class of cell signaling proteins. In all members of this family, each of the five subunits has four transmembrane α-helices (M1-M4) with M2 lining the pore and then M1 and M3, with M4 outermost and adjacent to the membrane lipids. M4 has a variety of roles: its interaction with neighboring M1 and M3 helices is important for receptor assembly, it can a transmit information on the lipid content of the membrane to the gating mechanism, and it may form a vital link to the extracellular domain via the Cys-loop. This study examines the role of M4 receptor residues in the α7 nAChR using site-directed mutagenesis and subsequent expression in Xenopus oocytes. The data indicate that many of the residues in M4 play a role in receptor function, as substitution with Ala can modify functional parameters; 11 of 24 mutants showed a small gain of function (<10-fold decrease in EC50), and 1 (D446A) did not respond to the agonist; it was also not expressed at the cell surface. Removal or addition of aromatic residues had small or no effects. These results demonstrate the α7 nAChR M4 has a role in receptor function, and a structural model suggests possible interactions of some of these residues with their neighbors.


Cell-phone camera Raman spectrometer.
In this report, we describe the design, construction, and operation of a cell-phone-based Raman and emission spectral detector, which when coupled to a diffraction grating and cell-phone camera system provides means for the detection, recording, and identification of chemicals, drugs, and biological molecules, in situ by means of their Raman and fluorescence spectra. The newly constructed cell-phone spectrometer system was used to record Raman spectra from various chemicals and biological molecules including the resonance enhanced Raman spectra of carrots and bacteria. In addition, we present the quantitative analysis of alcohol-water Raman spectra, performed using our cell-phone spectrometer. The designed and constructed system was also used for constructing Raman images of the samples by utilizing a position scanning stage in conjunction with the system. This compact and portable system is well suited for in situ field applications of Raman and fluorescence spectroscopy and may also be an integrated feature of future cell-phones.


Augmented ventilatory response to exercise in pulmonary hypertension.
The ventilatory response to submaximal exercise, defined as the slope of minute ventilation over carbon dioxide production (VE/VCO2), was determined in 12 normal subjects, ten patients with pulmonary hypertension before and after heart-lung transplantation, and eight patients following heart transplantation. Patients with pulmonary hypertension show an augmented ventilatory response compared to normal subjects (pulmonary hypertension [mean, 57.7 +/- 6.8 (SE) ml/ml VCO2; normal subjects, 22.3 +/- 1.4 ml/ml VCO2; p less than 0.001]). Following heart-lung transplantation, VE/VCO2 slope fell to 24.7 +/- 1.6 ml/ml VCO2, a value which is not significantly different than the value in normal subjects. Patients after heart transplantation show a mean slope value of 25.3 +/- 1.3 ml/ml VCO2, which is not significantly different than the normal value or the value found after heart-lung transplantation. The augmented ventilatory response to exercise did not correlate with the usual chemical modulators of ventilation (arterial pH, arterial carbon dioxide tension, or arterial oxygen tension). These results suggest the following: the existence of a neural system in patients with pulmonary hypertension which results in an augmentation of ventilatory drive in response to exercise; the augmented ventilatory response reflects excessive neural activity of pulmonary afferents during exercise; narrow regulation of the ventilatory response to exercise in normal subjects which is preserved in the denervated lung, indicating that pulmonary afferents are not critical to ventilatory control during exercise in the normal subject; and the possible use of measurements of the ventilatory response to exercise as a noninvasive screening test for pulmonary hypertension.


Behavioral Changes in Patients With Diabetes During the COVID-19 Pandemic in Saudi Arabia: A Cross-Sectional Study.
On March 2, 2020, the first case of coronavirus disease 2019 (COVID-19) was dedicated in Saudi Arabia. The government established partial quarantine, and all precautions were mandatory on March 23, 2020. This in turn forced people to spend more time at home, leading to changes in the physical activity and dietary habits of individuals. In this study, we aimed to assess the behavioral changes of Saudi diabetic individuals during the COVID-19 pandemic and measure the effectiveness of the behavioral changes of Saudi diabetic individuals during the COVID-19 pandemic on the control of the glucose level. A cross-sectional study was conducted through an online questionnaire sent to diabetic patients in Riyadh, Saudi Arabia. Participants ranging from 18 years old and above of both genders were selected. Diabetic patients (type 1 and 2) were included. All collected data for this study were analyzed using Stata 17 (StataCorp LLC, College Station, Texas, USA). A total of 223 people responded. For 45% of individuals, doctor visits significantly decreased (p<0.05), and the percentage of doctor visits also decreased for individuals who previously visited their doctor more regularly. Furthermore, the number of hours spent on tablets increased significantly during COVID-19 (p<0.05). Our findings demonstrate that there are no significant changes in lifestyle factors or glycemic control during the pandemic compared with the pre-pandemic year in individuals with diabetes. However, the rate of patient visits to the doctor was lower than pre-pandemic, with an increase in the rate of physical activity.


Biochemical analysis of the complex between the tetrameric export adapter protein Rec of HERV-K/HML-2 and the responsive RNA element RcRE pck30.
The RNA export adaptor protein Rec, encoded for by the human endogenous retrovirus HERV-K/HML-2 elements, binds to the Rec responsive element (RcRE) located in the 3' untranslated region of HERV-K/HML-2 transcripts. Binding allows the nucleocytoplasmic export of unspliced viral RNA, thereby overcoming host restriction. Chemical probing of the secondary structure of the RcRE corroborated the theory that the RcRE forms a complex folded structure with seven stem-loop regions. Laser-induced liquid beam ion desorption mass spectrometry revealed that Rec forms stable tetramers, which are further stabilized upon RNA binding. The RNA protein complex consists of three Rec tetramers, which bind to multiple sites on the RcRE-preferentially to purine-rich motifs-which represent several low-affinity binding sites. Mutated RcREs, with one to three purine-rich motifs deleted, were still bound and exported by Rec, indicating that the complex folded structure of the RcRE is important for Rec binding. This suggests a binding model where up to three Rec tetramers bind to the complex folded structure of the RcRE and the binding seems to be tightened by recognition of the purine-rich motifs.


A comparison of methods for staining tubercle bacilli in histological sections.
The Ziehl-Neelsen stain is compared with three alternative methods of staining tubercle bacilli in paraffin sections: Fite's method (1938); a modification by Armstrong and Price (1947) of Fite's method; and a fluorescent method using the auramine-phenol stain. The fluorescent method was found to be the most effective of the four methods and its use is recommended as a routine tool in diagnostic histopathology.


Interleukin-1alpha inhibits insulin signaling with phosphorylating insulin receptor substrate-1 on serine residues in 3T3-L1 adipocytes.
Proinflammatory cytokines are recently reported to inhibit insulin signaling causing insulin resistance. IL-1alpha is also one of the proinflammatory cytokines; however, it has not been clarified whether IL-1alpha may also cause insulin resistance. Here, we investigated the effects of IL-1alpha treatment on insulin signaling in 3T3-L1 adipocytes. IL-1alpha treatment up to 4 h did not alter insulin-stimulated insulin receptor tyrosine phosphorylation, whereas tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and the association with phosphatidylinositol 3-kinase were partially inhibited with the maximal inhibition in around 15 min. IRS-1 was transiently phosphorylated on some serine residues around 15 min after IL-1alpha stimulation, when several serine kinases, IkappaB kinase, c-Jun-N-terminal kinase, ERK, and p70S6K were activated. Chemical inhibitors for these kinases inhibited IL-1alpha-induced serine phosphorylation of IRS-1. Tyrosine phosphorylation of IRS-1 was recovered only by the IKK inhibitor or JNK inhibitor, suggesting specific involvement of these two kinases. Insulin-stimulated Akt phosphorylation and 2-deoxyglucose uptake were not inhibited only by IL-1alpha. Interestingly, Akt phosphorylation was synergistically inhibited by IL-1alpha in the presence of IL-6. Taken together, short-term IL-1alpha treatment transiently causes insulin resistance at IRS-1 level with its serine phosphorylation. IL-1alpha may suppress insulin signaling downstream of IRS-1 in the presence of other cytokines, such as IL-6.


Multidrug-resistant Acinetobacter meningitis in children.
Acinetobacter species have emerged as one of the most troublesome pathogens for healthcare institutions globally. In more recent times, nosocomial infections involving the central nervous system, skin and soft tissue, and bone have emerged as highly problematic. Acinetobacter species infection is common in intensive care units; however, Acinetobacter baumannii meningitis is rarely reported. Here, we report two cases of Acinetobacter baumannii meningitis which was multidrug resistance and ultimately required the carbapenem group of drugs for the treatment.


[20 years of prostate surgery. Reduction in the number of complications through application of a new concept in TUR, cryosurgery and surgical procedures].
During the last 20 years a deep change took place in the technique as well as in the conception of the operations of the prostate gland in adenomas and carcinomas. The endoscopic methods were adapted to the physiology of the urinary tract and to the condition of the patient; thus the general complication and lethality rate was decisively lowered (reduction of the general postoperative lethality from 1.2% to 0.77%). -- The operation method is selected according to the degree of risk of the patient. The TURP with the new low pressure technique (72%) and the freezing (25%) also in the adenoma of supersize are preferred. On the other hand, the surgical interventions rich in loss (lethality 3.3-4.3%) are decisively reduced (below 3%). -- The new endoscopic technique of cryosurgery guarantees a high value operation also for patients with a high risk (lethality 1.8%), in which cases the failure rate of the other method is indirectly decisively reduced (TURP 0.3%, radical TUR 0.7%). The carcinoma is (sub-) radically resected, and resected with increased risk or relapse, respectively; lymphadenectomy and radiation therapy supplement these operations.


Enzyme activities of urinary alanine aminopeptidase (AAP) and N-acetyl-beta-D-glucosaminidase (NAG) in healthy dogs.
The activity of the urinary enzymes alanine aminopeptidase (AAP; EC 188.8.131.52) and N-acetyl-beta-D-glucosaminidase (NAG; EC 220.127.116.11) was measured after eliminating distorting factors in ten healthy dogs on three consecutive days in order to determine inter- and intra-individual variability. All the animals were being housed and fed in the same way. The urine (2nd morning urine) was collected between 8:30 and 10:00 a.m. by means of ultrasound-controlled cystocentesis. Our comparative measurements of native and gel-filtered urine showed an increase in enzyme activity in all of the samples in the case of AAP and in most of the samples in the case of NAG, thus proving the existence in the dog of AAP and NAG urinary enzyme inhibitors. The large inter- and intra-individual AAP and NAG fluctuation ranges were reduced considerably by relating enzyme activity to urine creatinine concentration. The provisional upper limit of the AAP reference range is 6.3 U/g creatinine (90% percentile), that of NAG 6.2 U/g creatinine (90% percentile). The AAP and NAG enzyme activities remained constant in gel-filtered samples kept at 4 degrees C for at least 5 days, in those kept at -18 degrees C for at least 4 weeks.


Dosimetric predictors of radiation-induced lung injury in stereotactic body radiation therapy.
The aim was to retrospectively investigate correlations between potential predictive parameters and the occurrence of radiation-induced lung injury in patients with primary or secondary lung tumours treated with stereotactic body radiation therapy (SBRT). Sixty patients (63 tumours) underwent SBRT, with a dose of 45 Gy in 3 fractions over 5 days or 26 Gy in single fraction. The following parameters were tested for correlation with Radiation Therapy Oncology Group (RTOG) lung toxicity score: planning target volume (PTV), tumour location, primary vs. metastatic tumour, and Mean Lung Dose (in 2 Gy fractions, MLD2). Normal Tissue Complication Probability (NTCP) values were then estimated. The median follow-up time was 30.9 months (range 6.7-56.7). RTOG grade 0-1 toxicity was observed in 54/63 (85.7%) and grade 2-3 in 9/63 (14.3%) cases. Mean values of MLD(2) for RTOG grade 0-1 and 2-3 were respectively 11.2 Gy (95% Confidence Interval (CI) 10.1-12.3 Gy) and 20.3 Gy (95% CI 16.6-23.9 Gy). NTCP mean values for RTOG grade 0-1 and 2-3 were respectively 4% (95% CI 2-5.9%) and 37% (95% CI 11.6-62.3%). Univariate analysis, performed with t-Student test, showed a statistically significant difference between MLD(2) values in the two groups (t=5.93 and p < or = 0.001). Logistic regression analysis showed a good correlation between MLD(2) and toxicity scores 2-3 (p=0.008, odds ratio 1.5). From logistic regression relationship between the observed rates of grade 2-3 and MLD(2), a D(50)=19.8 Gy and a gamma50= 2.2 were obtained. From the sigmoid-shaped dose-response relationship between NTCP and MLD(2), a D(50)=22.4 Gy and gamma(50)= 2.2 were derived. MLD(2) is strongly associated to the risk of lung injury. Higher NTCP values are associated with a higher risk, but when comparing the expected to the observed toxicity rate, NTCP seems to underestimate the risk.


Epstein-Barr virus in inflammatory diseases of the liver and liver allografts: an in situ hybridization study.
The Epstein-Barr virus is associated with a broad spectrum of lymphoproliferative diseases in liver allograft recipients. To investigate the effects of primary infection in children following liver transplantation and the possible role of Epstein-Barr virus in the pathogenesis of unexplained chronic hepatitis after transplantation, we used an in situ hybridization technique to detect small virus encoded nuclear RNAs in posttransplant specimens. For comparison, other posttransplant complications and diseases occurring in the nontransplanted liver were studied with the same method. We examined 114 specimens in the following categories: (a) children with primary Epstein-Barr virus infection after transplant (n = 25), (b) chronic hepatitis more than 12 mo after transplant (n = 14), (c) rejection (n = 15), (d) normal/near-normal histology more than 12 mo after transplant (n = 13) (e) end-stage acute liver disease (n = 9) and (f) end-stage cirrhosis (n = 38). Thirty-three of 114 specimens had labeling of occasional portal and parenchymal lymphoid cells. These were present in each of the six main diagnostic categories listed above: 2 of 25, pediatric; 6 of 14, chronic hepatitis; 4 of 15, rejection; 1 of 13, normal; 4 of 9, acute; and 16 of 38, cirrhosis. In none of the patients with Epstein-Barr virus-infected cells did lymphoproliferative disease subsequently develop. In conclusion, we have been unable to show an obvious association between Epstein-Barr virus infection and graft dysfunction after liver transplantation. Our results suggest that immunological response to primary infection in children after liver transplantation may be adequate.(ABSTRACT TRUNCATED AT 250 WORDS)


Mutational library analysis of selected amino acids in the receptor binding domain of envelope of Akv murine leukemia virus by conditionally replication competent bicistronic vectors.
The envelope protein of retroviruses is responsible for viral entry into host cells. Here, we describe a mutational library approach to dissect functional domains of the envelope protein involving a retroviral vector, which expresses both the envelope protein of Akv murine leukemia virus (MLV) and the neomycin phosphotransferase II (Neo) selection marker from the same transcript. Envelope expression was achieved by inserting an internal ribosome entry site (IRES) between the neo and the env genes. We found the structure of the linker between the IRES element and env to be critical for sufficient envelope expression. This vector functions as a replication competent mini-virus in a culture of NIH 3T3 derived semi-packaging cells that express the viral Gag and Pol proteins. Titers comparable to those of wild type virus were achieved by this system. To test this vector system, we created a random mutational library of Arg 85 and Asp 86 in the first variable region of Akv envelope protein. Homologous amino acids to Asp 86 in Moloney and Friend murine leukemia viruses are thought to be directly involved in receptor binding. Subsequent selection of mutants capable of infecting murine NIH 3T3 cells indicated that the wild type aspartic acid or another hydrophilic residue at position 86 is an important determinant for envelope function.


Serum fetuin A and chemerin levels correlate with hepatic steatosis and regional adiposity in maintenance hemodialysis patients.
A deficiency of fetuin A is linked to cardiovascular calcification and mortality in dialysis patients. But, high levels of fetuin A and chemerin correlate with hepatic steatosis and regional adiposity in general population. The association between hepatic steatosis and fetuin A/chemerin levels in hemodialysis (HD) remains unclear. We performed a cross-sectional, observational study; 216 prevalent HD patients from a single center were enrolled. Baseline serum fetuin A, chemerin levels, conicity index and anthropometric parameters were checked. Presence of hepatic steatosis was qualified by liver ultrasound and quantified by the hepato-renal index (HRI); central obesity defined by waist circumference (WC). ROC analyses and multivariate logistic regression analyses for prediction of hepatic steatosis and central obesity on the basis of fetuin A/chemerin levels, anthropometric parameters, and other relevant covariates were performed. Data from 103 women and 113 men (mean age 60±12 years) were analyzed. Eighty subjects had hepatic steatosis and their HRIs were significantly higher than those without hepatic steatosis (P<0.001). Serum fetuin A levels were positively associated with HRIs (P<0.001) and chemerin levels (P<0.001). Fetuin A, chemerin and WC were predictors for hepatic steatosis and central obesity by ROC curve. In multivariate logistic regression analysis, fetuin A and WC independently predicted hepatic steatosis defined by HRIs. And chemerin predicted central obesity and regional adiposity after covariate adjustments (all P<0.05). Serum fetuin A levels were higher in prevalent HD patients with hepatic steatosis, and positively correlated with chemerin levels. Chemerin levels predicted central obesity as well as regional adiposity in the HD patients.


Electron spin resonance studies of erythrocytes from spontaneously hypertensive rats and humans with essential hypertension.
The purpose of the present study was to investigate erythrocyte membrane abnormalities in hypertension by means of an electron spin resonance and spin-label technique. The erythrocytes from spontaneously hypertensive rats (SHR) and humans with untreated essential hypertension were examined and compared with their normotensive counterparts, and electron spin resonance spectra were obtained for a fatty spin-label agent (5-nitroxy stearate) incorporated into the erythrocyte membranes. The value of outer hyperfine splitting (2T' parallel) was significantly higher in erythrocytes of SHR and humans with essential hypertension than in erythrocytes of normotensive controls (at 37 degrees C: SHR, 56.14 +/- 0.51 gauss [G], n = 8; Wistar-Kyoto rats, 52.22 +/- 0.86 G, n = 4, p less than 0.01; humans with essential hypertension, 56.94 +/- 0.27 G, n = 11; normotensive subjects, 55.44 +/- 0.36 G, n = 8, p less than 0.01). The order parameter (S) was also increased in the hypertensive rats and humans compared to their respective normotensive controls. When calcium was loaded to erythrocytes with calcium ionophore A23187 (0.9 microM) and CaCl2 (1.0 mM), the parameters of the spectra were increased. These changes were more prominent in the hypertensive groups than in the normotensive controls. These results revealed that the erythrocyte membranes of the hypertensive subjects tolerated different spin motions than those of the normotensive controls in the electron spin resonance study and that membrane fluidity might be decreased in hypertension. Additionally, calcium loading to erythrocytes caused the reduction of membrane fluidity. Therefore, it is suggested that an abnormality of calcium handling at the cellular level might affect physical properties of the biomembranes in hypertension.


Lytic Polysaccharide Monooxygenases in Biomass Conversion.
The derivation of second-generation biofuels from non-edible biomass is viewed as crucial for establishing a sustainable bio-based economy for the future. The inertness of lignocellulosic biomass makes its breakdown for conversion into fuels and other compounds a challenge. Enzyme cocktails can be utilized in the bio-refinery for lignocellulose deconstruction but until recently their costs were regarded as high. Lytic polysaccharide monooxygenases (LPMOs) offer tremendous promise for further process improvements owing to their ability to boost the activity of biomass-degrading enzyme consortia. Combining data from multiple disciplines, progress has been made in understanding the biochemistry of LPMOs. We review the academic literature in this area and highlight some of the key questions that remain.


Detection of hepatitis E virus RNA in raw sausages and liver sausages from retail in Germany using an optimized method.
Hepatitis E virus (HEV) is a pathogen of increasing importance, which can be zoonotically transmitted from domestic pigs, wild boar, and deer to humans. Foodborne transmission by consumption of raw and undercooked liver, meat, or sausages prepared from infected animals has been documented. The aim of this study was to investigate the distribution of HEV in different types of sausages sold in Germany. As no standardized methods for HEV detection in food exist, several techniques of sample homogenization, virus concentration and nucleic acid extraction followed by real-time RT-PCR were compared using artificially contaminated sausages. A method using TRI Reagent® Solution showed the best efficacy of matrix disruption and a treatment with chloroform followed by a silica-based RNA extraction method resulted in the highest HEV detection rates. The detection limit of the method was 2.9 × 10(3) and 5.3 × 10(4) genome equivalents per 5 g raw sausage and 2 g liver sausage, respectively. Application of the method to raw and liver sausages from retail in Germany resulted in the HEV genome detection in 14 out of 70 (20%) raw sausages and in 11 out of 50 (22%) liver sausages. The detected HEV sequences showed a high diversity and belonged to different subtypes of HEV genotype 3. The results indicate a broad distribution of HEV-RNA in meat products sold in Germany; however, the infectivity of the detected virus remains to be assessed in future.


A novel quinazoline-based analog induces G2/M cell cycle arrest and apoptosis in human A549 lung cancer cells via a ROS-dependent mechanism.
6-amino-4-(4-phenoxyphenylethylamino)quinazoline (QNZ) is an excellent quinazoline-containing NF-κB inhibitor also acting as a novel anticancer agent. Considering both the medicinal significance of quinazoline scaffold and the tunable functionality of Michael acceptor-centric pharmacophores in the electrophilicity-based prooxidant strategy, we designed a novel QNZ-inspired electrophilic molecule QNZ-A by introducing a Michael acceptor unit at position-6 of quinazoline ring in QNZ. Our results identified QNZ-A as a promising selective cytotoxic agent against A549 cells. QNZ-A, by virtue of its Michael acceptor unit, induced reactive oxygen species (ROS) accumulation associated with collapse of the redox buffering system in A549 cells. This caused up-regulation of p53-inducible p21 and down-regulation of redox sensitive Cdc25C along with Cyclin B1/Cdk1, leading to a G2/M cell cycle arrest and final cell apoptosis. By contrast, QNZ-B, a reduction product of QNZ-A lacking the Michael acceptor unit failed to induce ROS generation and all these cell cycle-related events. In conclusion, this work provided a successful example of designing QNZ-directed anticancer agent by a ROS-promoting strategy and identified QNZ-A as a selective anticancer agent against A549 cells through G2/M cell cycle arrest and apoptosis via a ROS-dependent mechanism.


Motion compensation in radiotherapy.
Image-guided radiotherapy (IGRT) has helped to dramatically reduce safety margins compensating for positioning uncertainties in radiotherapy. A remaining issue posing problems for photon radiotherapy (RT), but even more so for particle RT, is target motion during treatment delivery. This review outlines the various strategies currently being developed or already in clinical use to compensate for organ motion, predominantly breathing-induced motion of liver and lung targets. Several motion compensation strategies have recently been introduced clinically. Among these are optimized margins encompassing the individual range of target motion, treatment under breath hold, gated treatments, and tumor tracking with a dedicated treatment device. A variety of surveillance strategies for gating and tracking, such as indirect tracking with external fiducial markers and surface scanning devices, direct tracking with implanted electromagnetic markers, fiducial markers, and fluoroscopy, and ultrasound-based tracking are already in clinical use or are under development. Tracked treatment with linear accelerators based on tumor-synchronous MLC- or treatment-table adaptation are moving toward clinical use. A multitude of strategies to reduce the impact of intrafractional target motion in RT have been developed and are increasingly being used clinically. The clinical introduction of advanced strategies currently under development is imminent. After IGRT minimized treatment margins for static tumors, the implementation of motion compensation strategies will achieve the same for targets being subject to intrafractional breathing-induced motion.


The Short-Term Efficacy of an Unguided Internet-Based Cognitive-Behavioral Therapy for Insomnia: A Randomized Controlled Trial With a Six-Month Nonrandomized Follow-Up.
Insomnia is a major health problem, and the need for effective and accessible treatment is urgent. The aim of the current study was to evaluate the short-term efficacy of an unguided Internet-based cognitive-behavioral treatment program for insomnia (CBTi), called SHUTi (Sleep Healthy Using the Internet). This study used a parallel arm randomized controlled trial in Norway. Participants were randomly allocated to the SHUTi condition or a Web-based patient education condition. Both groups were assessed before and after the nine-week intervention period (online sleep diaries and questionnaires). The SHUTi participants were reassessed in a six-month nonrandomized follow-up. Primary outcome measures were the Insomnia Severity Index (ISI) and the Bergen Insomnia Scale (BIS). A total of 181 participants were included in the study; SHUTi condition (n = 95), patient education condition (n = 86). Intention-to-treat mixed-model repeated-measures analysis revealed that the SHUTi group had better short-term outcomes compared with the patient education group on most sleep measures. The SHUTi group showed a significant decrease on the primary outcomes, the ISI (dbetween = -1.77, 95% CI = -2.23, -1.31) and the BIS (dbetween = -1.00, 95% CI = -1.32, -.68). Improvements were maintained among the completing SHUTi participants at the six-month nonrandomized follow-up. However, dropout attrition was high. Unguided Internet-based CBTi produced significant short-term improvements in sleep in patients with chronic insomnia. This highlights the benefits of making Internet-delivered CBTi programs available as a standard first-line treatment option in public health services. Nevertheless, the rate of dropout attrition (participants not completing post-assessment) in this trial limits the generalizability of the findings.


Developmental changes in the structure of the synapse on the myelinated cell bodies of the chicken ciliary ganglion.
Electron micrographs, stained Epon-embedded sections, and silver stains of the ciliary ganglion of chickens 19 days prehatched, 4 days, 5 weeks, 6 months, and 1 to 2 years of age were studied. The majority of ganglion cells are large neurons; smaller cells are restricted to a dorsal, distal part of the ganglion. The following description applies to the large neurons. Three to twenty lamellae of loose, semicompact, and compact myelin ensheathe virtually every neuron. All these types of myelin form the sheath of a single neuron. The lamellae greatly increase in number and in compactness during the period between the 19-day embryo and the 4-day-old chick. During the period between the 4-day chick and the adult chicken, the myelin becomes only slightly thicker and denser. The calyx is a large synaptic terminal encircling virtually every neuron in the ganglion up to 5 weeks of age. At 6 months of age, the calyx appears to break up; only about half the number of neurons in the ganglion have this large terminal, while the remaining neurons have numerous relatively small, boutonlike synapses. This rather remarkable transformation in the structure of the calyx is virtually complete in the 1- to 2-year-old chickens. In these older chickens all the cells have boutons, and calyces are no longer present. The entering preterminal fiber, the calyx, the neuron, and the axon hillock can all have myelin lamellae on them. It is possible that this entire complex is effectively insulated by the myelin sheath. No synaptic discs or fusion of the membranes of the preterminal fiber and the postganglionic neuron are seen. The chick ciliary ganglion cells are the only myelinated neurons so far described which receive synapses. The neurons in the small-cell part of the ganglion do not have calyces and are not ensheathed by myelin lamellae at any age.


Attention and memory-related responses of neurons in the lateral intraparietal area during spatial and shape-delayed match-to-sample tasks.
When a monkey attends to, remembers, and looks toward targets, the activity of some neurons in the lateral intraparietal area (LIP) changes. We recorded from isolated neurons during both a spatial and a shape match-to-sample task to examine and characterize voluntary active processes in LIP. Many LIP neurons show spatially selective activity during the delay period that depends on the location of the sample, but for most cells, this activity does not differ between the two tasks. Although much past work in posterior parietal cortex has explained responses in this region in terms of active processes such as decision-making and motor planning, our findings suggest that much of that activity represents more passive processing. Nevertheless, we do see a significant minority of units that demonstrate instruction-dependent activity during the delay period, suggesting that these units could represent the neural correlates of voluntary or active processes. Separately, we found that during the presentation of the sample stimulus and test array, some units show stronger responses to the stimulus in the shape-matching task when the animal must attend to the shape of a stimulus. This elevated response to the sample during the shape task provides evidence for feature-based attention in LIP. Attention to shape is a property that has not previously been described in primate cortex.


Chemically active substitutional nitrogen impurity in carbon nanotubes.
We investigate the nitrogen substitutional impurity in semiconducting zigzag and metallic armchair single-wall carbon nanotubes using ab initio density functional theory. At low concentrations (less than 1 at. %), the defect state in a semiconducting tube becomes spatially localized and develops a flat energy level in the band gap. Such a localized state makes the impurity site chemically and electronically active. We find that if two neighboring tubes have their impurities facing one another, an intertube covalent bond forms. This finding opens an intriguing possibility for tunnel junctions, as well as the functionalization of suitably doped carbon nanotubes by selectively forming chemical bonds with ligands at the impurity site. If the intertube bond density is high enough, a highly packed bundle of interlinked single-wall nanotubes can form.


Registry-Based Randomized Controlled Trials: A New Paradigm for Surgical Research.
Randomized controlled trials (RCTs) are the gold standard to establish evidence for surgical practice but can be hindered by high costs, complexity, and time requirements. Recently, observational registries have been leveraged as platforms for clinical trials to address these limitations, though few registry-based surgical RCTs have been conducted. Here, we present our group's approach to surgical registry-based RCTs and early results. To facilitate these trials, we focused on registry integration into surgeons' workflows, routine collection of patient-reported outcomes at clinic visits, and pragmatic trial design featuring broad inclusion criteria and standard of care follow-up. These features maximize generalizability and facilitate follow-up by minimizing visits and tests outside of normal practice. Since 2017, our group has completed enrollment in 4 registry-based RCTs with another 5 trials ongoing. Of these, 4 trials have been multicenter. Over 1000 patients have been enrolled in these studies, with follow-up rates of 90% or greater. Most of these trials are on track to complete enrollment in approximately 2 y from their start date. Beyond salary support, resource utilization is low. None of our trials has been terminated due to lack of resources or futility. Registry-based RCTs allow for efficient conduct of pragmatic surgical trials. Thoughtful study design, registry integration into surgeons' routines, and a team culture embracing research are paramount. We believe registry-based trials are the future of affordable, high-level, prospective surgical research.