Expression of cocaine- and amphetamine-regulated transcript in the rat forebrain during postnatal development.
Cocaine- and amphetamine-regulated transcript (CART) is widespread in the rodent brain. CART has been implicated in many different functions including reward, feeding, stress responses, sensory processing, learning and memory formation. Recent studies have suggested that CART may also play a role in neural development. Therefore, in the present study we compared the distribution pattern and levels of CART mRNA expression in the forebrain of male and female rats at different stages of postnatal development: P06, P26 and P66. At 6 days of age (P06), male and female rats showed increased CART expression in the somatosensory and piriform cortices, indusium griseum, dentate gyrus, nucleus accumbens, and ventral premammillary nucleus. Interestingly, we found a striking expression of CART mRNA in the ventral posteromedial and ventral posterolateral thalamic nuclei. This thalamic expression was absent at P26 and P66. Contrastingly, at P06 CART mRNA expression was decreased in the arcuate nucleus. Comparing sexes, we found increased CART mRNA expression in the anteroventral periventricular nucleus of adult females. In other regions including the CA1, the lateral hypothalamic area and the dorsomedial nucleus of the hypothalamus, CART expression was not different comparing postnatal ages and sexes. Our findings indicate that CART gene expression is induced in a distinct temporal and spatial manner in forebrain sites of male and female rats. They also suggest that CART peptide participate in the development of neural pathways related to selective functions including sensory processing, reward and memory formation.


Non-dominant right coronary artery (RCA) is associated with suspected inferior ischemia on SPECT in patients without significant coronary artery disease (CAD).
There is a huge uncertainty in the medical community regarding the significance of non-dominant right coronary artery (RCA) in patients with inferior wall ischemia on myocardial perfusion single-photon emission computed tomography (SPECT). The purpose of this study is to determine the effect of non-dominant RCA on myocardial perfusion SPECT (MPS) with respect to the misleading detection of ischemia in the inferior wall of the myocardium. This is a retrospective study of 155 patients, who had undergone elective coronary angiography owing to an indication of inferior wall ischemia by MPS between 2012 and 2017. Patients were divided into two groups based on the coronary dominance: group 1 (n = 107), if RCA is the dominant artery, and group 2 (n = 48), if there are dominance of left artery and codominance of both arteries. Obstructive CAD was diagnosed in the case of stenosis that had severity greater than 50%. The positive predictive value (PPV), which was calculated as per the correlation between the inferior wall ischemia in MPS and obstruction level in RCA, was compared in both groups. Majority of patients were male (109, 70%) and the mean age was 59.5 ± 10.2. There were 45 patients with obstructive RCA disease (PPV: 42%) among 107 patients in group 1, whereas there were only 8 patients with obstructive coronary artery disease (CAD) in RCA among 48 patients in group 2, (PPV: 16% and p = 0.004). The results demonstrated that non-dominant RCA is associated with false-positive detection of inferior wall ischemia via MPS.


Bistability in feedback circuits as a byproduct of evolution of evolvability.
Noisy bistable dynamics in gene regulation can underlie stochastic switching and is demonstrated to be beneficial under fluctuating environments. It is not known, however, if fluctuating selection alone can result in bistable dynamics. Using a stochastic model of simple feedback networks, we apply fluctuating selection on gene expression and run in silico evolutionary simulations. We find that independent of the specific nature of the environment-fitness relationship, the main outcome of fluctuating selection is the evolution of increased evolvability in the network; system parameters evolve toward a nonlinear regime where phenotypic diversity is increased and small changes in genotype cause large changes in expression level. In the presence of noise, the evolution of increased nonlinearity results in the emergence and maintenance of bistability. Our results provide the first direct evidence that bistability and stochastic switching in a gene regulatory network can emerge as a mechanism to cope with fluctuating environments. They strongly suggest that such emergence occurs as a byproduct of evolution of evolvability and exploitation of noise by evolution.


Accumbal dopamine D2 receptor function is associated with individual variability in ethanol behavioral sensitization.
Striatal dopamine D2 receptors have been implicated in the development of behavioral sensitization after repeated exposure to drugs of abuse. There are clear individual differences in the level of sensitization to ethanol among species and even among individuals from the same strain. Albino Swiss mice treated with ethanol (2.2 g/kg) have been shown to present clear variations in the development of sensitization. While some mice developed ethanol (EtOH) induced sensitization, others did not. This variability was associated with differences in D2 dopaminergic receptor binding. In the present study, we evaluated the functional relevance of dopamine D2 receptor by measuring, in sensitized and non-sensitized mice, the locomotor response to a D2 receptor agonist (quinpirole, 0.5 and 2.0 mg/kg i.p. or 0.01 and 0.2 μg/side intra-accumbens) or antagonist (sulpiride, 10 or 50 mg/kg i.p. or 0.02 μg/side intra-accumbens + ethanol i.p.). Whereas the systemic administration of quinpirole decreased locomotor activity in a similar way in all the groups, intra-nucleus accumbens (NAc) administration induced significantly higher locomotor stimulation in the sensitized group alone. Our data show that functionally hyperresponsive D2 receptors are present in the NAcs of sensitized but not non-sensitized mice, suggesting that this could be a biomarker of behavioral sensitization. Furthermore, i.p. administration of sulpiride blocked the expression of sensitization in the sensitized group, and intra-NAc administration attenuated it, indicating that the activation of accumbal D2 receptors is essential for the expression of EtOH behavioral sensitization. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.


Adherence to vaccination guidelines of patients with complete splenectomy in Norway, 2008-2020.
The spleen is responsible for blood filtration and mounting an immune response against pathogens. In some people the spleen must be surgically removed because of traumatic events or oncological and hematological conditions. These patients are at higher risk of developing diseases caused by encapsulated bacteria throughout their lives. Thus, immunisations are advised for splenectomised persons to prevent infection caused by Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae type b (Hib). This study assessed vaccination coverage (VC) among Norwegian patients with surgical asplenia. Using the Nomesco Classification of Surgical Procedures codes, patient information (age, sex, date of initial diagnosis and date of surgery) was acquired from the Norwegian Patient Registry. The National Immunization Register provided information on vaccination status and data of any subsequent invasive bacterial infections were obtained from the Norwegian Surveillance System for Communicable Diseases. From the total population of Norway, 3155 patients who had undergone complete splenectomy were identified. Of these, 914 (29.0%) had received at least one dose of pneumococcal conjugate vaccine (PCV), 1324 (42.0%) at least one dose of pneumococcal polysaccharide vaccine and 589 (18.7%) had received both. Only 4.2% of the patients had received two doses of a meningococcal ACWY conjugate vaccine, while 8.0% of 1467 patients splenectomised after 2014 had received at least two doses of a serogroup B meningococcal vaccine. The VC for Hib was 18.7%. Nearly all splenectomised children under the age of 10 were vaccinated with Hib and PCV as these vaccines are included in the childhood immunisation program. For all vaccines, VC decreased with age. Twenty-nine invasive bacterial infections were registered post-splenectomy in 25 patients. Vaccination according to national recommendations could have prevented at least 8 (28%) of these infections. Our study showed that efforts are required to increase VC of splenectomised individuals in Norway.


A Comparison of Maternal and Paternal Experiences of Becoming Parents of a Very Preterm Infant.
To compare maternal and paternal experiences of very preterm (VPT) birth (gestational age < 32 weeks) and the NICU stay. Qualitative study. Data collection took place at parents' homes 3 to 6 months after NICU discharge. Ten parental couples participated in the study (20 parents). All VPT infants were healthy, without any neonatal or postnatal complications or injuries. Computer-assisted content analysis was used to highlight thematic clusters from parents' narratives, which were labeled through qualitative interpretation. Two main dimensions (Adjustment Process to Preterm Birth and Parental Role Assumption) and three main thematic clusters (Facing the Unexpected, Learning to Parent, and Finally Back Home) described the parental experience. Mothers focused mostly on the Finally Back Home cluster, which was characterized by moderate levels of adjustment to preterm birth and by awareness of their own maternal roles. Fathers focused mostly on the Learning to Parent cluster, which was characterized by low to moderate levels of adjustment to preterm birth and by a limited assumption of paternal role. To our knowledge, this study is unique in that we compared mothers and fathers who experienced the VPT births of their infants and described their experiences of the NICU stay. We found that the VPT birth experience for parents involves a dynamic adjustment. Differences in maternal and paternal experiences may indicate the need for tailored supportive interventions in the NICU.


Modeling of complex signals in nerve fibers.
Experiments have demonstrated that signals in nerve fibers are composed by electrical and mechanical components. In this paper a coupled mathematical model is described which unites the governing equations for the action potential, the pressure wave in the axoplasm and the longitudinal and the transverse waves in the surrounding biomembrane into one system of equations. As a solution of this system, an ensemble of waves is generated. The main hypotheses of such a model are related to the nature of coupling forces between the single waves in the ensemble. These coupling forces are assumed to have bi-polar shapes leading to energetically stable solutions. The in silico modeling demonstrates the qualitative resemblance of computed wave profiles to experimental ones. The ideas of possible experimental validation of the model are briefly described.


Validation of the Glasgow Facial Palsy Scale for the assessment of smile reanimation surgery in facial paralysis.
To evaluate the Glasgow Facial Palsy Scale as a tool to assess facial reanimation surgery in facial palsy. Software analysis of digital video data is used to measure facial movements, comparing the affected to the normal side. We present the first use of the Glasgow Facial Palsy Scale following facial re-animation surgery. A comparison of the Glasgow Facial Palsy Scale against the Nottingham scoring system. Subjects undergoing unilateral surgical smile reanimation procedures were selected. Comparison was made with the Nottingham facial palsy scale and the House-Brackmann Scale pre- and postoperatively. Patients were recruited in the facial palsy clinic of Canniesburn Plastic Surgery Unit, Glasgow. Seven consecutive patients were selected who were due to undergo unilateral facial reanimation. The difference in pre- and post-surgical facial movement as measured using the Glasgow Facial Palsy Scale with this value being compared to that obtained using the Nottingham scoring system. Note was also taken of the correlation with House-Brackmann system and clinical correlation. Statistical analysis indicated a linear relationship between the Glasgow Facial Palsy Scale and the Nottingham System. The Pearson correlation test was used to confirm the relationship between the two methods giving a result of -0.587, which indicates significant correlation between the two methods. We conclude that the Glasgow Facial Palsy Scale is a standardised objective method of assessing the change in facial movement following smile reanimation surgery. We commend it as a useful tool to objectively assess surgical results in this challenging field.


Beryllium-7 and (210)Pb atmospheric deposition measured in moss and dependence on cumulative precipitation.
This paper focuses on analysis of the time series of (7)Be and (210)Pb activity measured in moss, and the amount, as well as duration of precipitation, to gain a better understanding of the possible relationships between airborne radionuclide deposition and precipitation. Here we consider whether the amount of these airborne radionuclides in moss samples is a cumulative measure of radionuclide deposition and decay, and a new approach for analyses of the relationships between precipitation and moss activity concentrations is suggested. Through these analyses it was shown that comparison of cumulative activity measured at one location using moss, normalized by values of cumulative amount or duration of precipitation, showed different regimes of airborne radionuclide deposition.


Epidemiological characteristics and clinical findings in patients with serologically proven toxocariasis.
The enzyme-linked immunosorbent assay (ELISA) using Toxocara canis larva-specific antigens was used to confirm a presumptive clinical diagnosis of visceral larva migrans in patients whose serum specimens were submitted to the Center for Disease Control. The clinical and epidemiological characteristics of patients with diagnostic ELISA titres (greater than or equal to log2 5) were compared with patients who had less or no detectable antibody. The typical patient with serologically confirmed toxocaral visceral larva migrans was about five years of age and resided in the southern half of the USA. Clinical findings were likely to include leucocytosis, eosinophilia, an increased anti-A or anti-B isohaemagglutinin titre, and an elevated serum IgG level. Pica, as ascertained by a physician questionnaire, was not a consistent finding and both sexes were nearly equally represented.


Ergogenic effects of caffeine on peak aerobic cycling power during the menstrual cycle.
Recent investigations have established that the ingestion of a moderate dose of caffeine (3-6 mg kg-1) can increase exercise and sports performance in women. However, it is unknown whether the ergogenicity of caffeine is similar during all phases of the menstrual cycle. The aim of this investigation was to determine the ergogenic effects of caffeine in three phases of the menstrual cycle. Thirteen well-trained eumenorrheic triathletes (age = 31 ± 6 years; body mass = 58.6 ± 7.8 kg) participated in a double-blind, cross-over, randomised experimental trial. In the (1) early follicular (EF); (2) preovulation (PO); (3) and mid luteal (ML) phases, participants either ingested a placebo (cellulose) or 3 mg kg-1 of caffeine in an opaque and unidentifiable capsule. After a 60-min wait for substance absorption, participants performed an incremental maximal cycle ergometer test until volitional fatigue (25 W/min) to assess peak aerobic cycling power (Wmax). In comparison to the placebo, caffeine increased Wmax in the EF (4.13 ± 0.69 vs. 4.24 ± 0.71 W kg-1, Δ = 2.7 ± 3.3%, P = 0.01), in the PO (4.14 ± 0.70 vs. 4.27 ± 0.73 W kg-1, Δ = 3.3 ± 5.0%; P = 0.03) and in the ML (4.15 ± 0.69 vs. 4.29 ± 0.67 W kg-1, Δ = 3.6 ± 5.1%; P = 0.01) phases. The magnitude of the caffeine ergogenic effect was similar during all of the menstrual cycle phases (P = 0.85). Caffeine increased peak aerobic cycling power in the early follicular, preovulatory, and mid luteal phases. Thus, the ingestion of 3 mg of caffeine per kg of body mass might be considered an ergogenic aid for eumenorrheic women during all three phases of the menstrual cycle.


The faithful copy neuron.
Theoretical and experimental evidence is presented for the presence in nervous tissue of neurons whose firing rate faithfully follow their input stimulus. Such neurons are shown to deliver their spikes with minimum dissipation per spike. This optimal performance is likely accomplished by use of local circuitry that adjusts conductances to match input currents so that the neuron operates near the threshold for firing. This results in an unusual mechanism for neuronal firing that uses background noise to achieve the desired firing rate. This framework takes place dynamically, and the present deliberations apply under time varying conditions. It is shown that an analytically explicit probability distribution function, which depends on one dimensionless parameter, can account for the interspike interval statistics under general time varying conditions. An innovative analysis based on the unsteady firing rate fits data to the appropriate probability distribution function.


Gas-phase reactions of charged phenyl radicals with neutral biomolecules evaporated by laser-induced acoustic desorption.
A generally applicable method for the study of phenyl radicals' reactions with neutral biomolecules in the gas phase is demonstrated. Neutral biomolecules were evaporated into a Fourier-transform ion cyclotron resonance mass spectrometer (FT-ICR) by means of laser-induced acoustic desorption (LIAD) and subsequently reacted with trapped charged phenyl radicals. The structural integrity of the evaporated alanylalanine molecules was verified by reaction with dichlorophosphenium ions. Examination of the reactions of charged phenyl radicals with alanylalanine and thymidine evaporated via LIAD revealed hydrogen atom abstraction for both alanylalanine and thymidine as well as an addition/elimination product for the reaction with thymidine. These reactions are consistent with the results obtained by others in solution. Further, a previously unstudied reaction of the nucleotide of thymine (T1) with charged phenyl radical was found to yield analogous products as the reaction with thymidine.


Priming effect of exogenous oestradiol on luteinizing hormone secretion in prepubertal lambs.
The effect of repeated administration of oestradiol-17beta on luteinizing hormone (LH) secretion was studied in 3-month old female lambs (n = 20). Animals were randomly divided in five groups and treated or not treated (group I) with 1, 2 or 3 i.m. injections of oestradiol in corn oil vehicle (1 microg/kg). Animals were slaughtered 12 (group II) and 24 h (group III) after the first injection, 24 h after the second injection (group IV) and 24 h after the third injection (group V). Animals in groups IV and V were catheterized and blood samples were collected every 4 h starting before treatment until time of sacrifice. In the rest of the groups blood samples were taken at the time of slaughter. The number of follicles > 1 mm in diameter on the ovarian surface were recorded and classified according to size. Maximum levels of oestradiol ranged from 103 to 250 pmol/l and returned to baseline within 12 to 16 h after each injection. LH secretion showed a consistent pattern in all lambs, with increases between 8 and 16 h after each oestradiol injection. The highest amplitude and longest duration (8-12 h) of LH secretion was recorded after the second oestradiol injection. Preliminary data indicated that FSH secretion resembled that of LH. There was an increase in the number of follicles with a diameter of more than 2 mm. Plasma concentrations of progesterone and cortisol were low and did not differ within groups or between treatments. The findings confirm that the pituitary LH release system in ewe lambs is sensitive to the stimulatory effects of oestradiol long before puberty. Results indicate that priming with oestradiol increases pituitary LH release to subsequent challenges of oestradiol, but long time exposure to oestradiol may have a negative effect on LH secretion. Although none of the oestradiol-treated lambs ovulated, the increase in the number of large follicles with repeated injections of oestradiol suggests that small follicles were gonadotrophin-responsive and stimulated by the gonadotrophin release.


Critical roles of irradiance in the regulation of UVB-induced inflammasome activation and skin inflammation in human skin keratinocytes.
UVB dosage is generally regarded as the most critical factor that determines the severity of UVB-induced skin erythema. However, recent studies have demonstrated that different UV irradiances induce varying biological responses in mouse skin even at constant UV doses. UVB-induced inflammasome activation is particularly observed in human skin keratinocytes, which are classified as immunocompetent cells, but not in mouse skin keratinocytes, which do not express sufficient inflammasome complex components. In human skin UVB-induced sunburn reactions, NLRP1 inflammasome activation critically mediates the inflammatory responses. Here, we employed primary human skin keratinocytes to explore the impact of different irradiances of a constant UVB dosage on inflammasome activation and related inflammatory responses. Our findings indicated that low-irradiance UVB induced relatively stronger NLRP1 inflammasome activation, which manifested as more active IL-1β, IL-18 release, and enhanced procaspase-1 cleavage compared to high-irradiance UVB at the same dose. Irradiance did not influence cell lysis or the expression of inflammasome complex proteins including NLRP1, proIL-1β, proIL-18, procaspase-1, and ASC. The UVB-induced TNF-α and cyclooxygenase-2 expression was also relatively higher in keratinocytes exposed to low-irradiance UVB. Low-irradiance UVB also increased reactive oxygen species production. UVB-triggered signaling analysis revealed that low-irradiance UVB resulted in more prominent p38 and JNK activation. Therefore, our findings indicated that, in addition to the role of total dosage, irradiance crucially modulates UVB-elicited inflammation in human skin keratinocytes, thus providing novel insights into human skin photobiology.


High Valence State Sites as Favorable Reductive Centers for High-Current-Density Water Splitting.
Electrochemical water splitting is a promising approach for producing sustainable and clean hydrogen. Typically, high valence state sites are favorable for oxidation evolution reaction (OER), while low valence states can facilitate hydrogen evolution reaction (HER). However, here we proposed a high valence state of Co3+ in Ni9.5 Co0.5 -S-FeOx hybrid as the favorable center for efficient and stable HER, while structural analogues with low chemical states showed much worse performance. As a result, the Ni9.5 Co0.5 -S-FeOx catalyst could drive alkaline HER with an ultra-low overpotential of 22 mV for 10 mA cm-2 , and 175 mV for 1000 mA cm-2 at the industrial temperature of 60 °C, with an excellent stability over 300 h. Moreover, this material could work for both OER and HER, with a low cell voltage being 1.730 V to achieve 1000 mA cm-2 for overall water splitting at 60 °C. X-ray absorption spectroscopy (XAS) clearly identified the high valence Co3+ sites, while in situ XAS during HER and theoretical calculations revealed the favorable electron capture at Co3+ and suitable H adsorption/desorption energy around Co3+ , which could accelerate the HER. The understanding of high valence states to drive reductive reactions may pave the way for the rational design of energy-related catalysts.


Interventions in primary care to promote breastfeeding: an evidence review for the U.S. Preventive Services Task Force.
Evidence suggests that breastfeeding decreases the risk for many diseases in mothers and infants. It is therefore important to evaluate the effectiveness of breastfeeding interventions. To systematically review evidence for the effectiveness of primary care-initiated interventions to promote breastfeeding with respect to breastfeeding and child and maternal health outcomes. Electronic searches of MEDLINE, the Cochrane Central Register of Controlled Trials, and CINAHL from September 2001 to February 2008 and references of selected articles, restricted to English-language publications. Randomized, controlled trials of primary care-initiated interventions to promote breastfeeding, mainly in developed countries. Characteristics of interventions and comparators, study setting, study design, population characteristics, the proportion of infants continuing breastfeeding by different durations, and infant or maternal health outcomes were recorded. Thirty-eight randomized, controlled trials (36 in developed countries) met eligibility criteria. In random-effects meta-analyses, breastfeeding promotion interventions in developed countries resulted in significantly increased rates of short- (1 to 3 months) and long-term (6 to 8 months) exclusive breastfeeding (rate ratios, 1.28 [95% CI, 1.11 to 1.48] and 1.44 [CI, 1.13 to 1.84], respectively). In subgroup analyses, combining pre- and postnatal breastfeeding interventions had a larger effect on increasing breastfeeding durations than either pre- or postnatal interventions alone. Furthermore, breastfeeding interventions with a component of lay support (such as peer support or peer counseling) were more effective than usual care in increasing the short-term breastfeeding rate. Meta-analyses were limited by clinical and methodological heterogeneity. Reliable estimates for the isolated effects of each component of multicomponent interventions could not be obtained. Evidence suggests that breastfeeding interventions are more effective than usual care in increasing short- and long-term breastfeeding rates. Combined pre- and postnatal interventions and inclusion of lay support in a multicomponent intervention may be beneficial.


Efficient primary isolation of human immunodeficiency virus.
A highly-sensitive and efficient culture technique for human immunodeficiency virus type-1 (HIV-1) is described; HIV-1 was recovered from the lymphocytes of 44 (94%) antibody-seropositive healthy or symptomatic individuals. The reductions in the requirements for both the reagent volume and the number of patients' lymphocytes, together with an increased efficiency, has made this HIV-1 culture system more practical for diagnostic virology laboratories.


Marburg Virus VP24 Protein Relieves Suppression of the NF-κB Pathway Through Interaction With Kelch-like ECH-Associated Protein 1.
Marburg virus (MARV) is an emerging zoonotic pathogen that causes hemorrhagic fever. MARV VP24 (mVP24) protein interacts with the host cell protein Kelch-like-ECH-associated protein 1 (Keap1). Keap1 interacts with and promotes the degradation of IκB kinase β (IKKβ), a component of the IκB kinase (IKK) complex that regulates nuclear factor-κB (NF-κB) activity. We studied whether mVP24 could relieve Keap1 repression of the NF-κB pathway. Coimmunoprecipitation assays were used to examine the interaction between Keap1 and IKKβ in the presence of wild-type mVP24 and mutants of mVP24 defective for binding to Keap1. Western blotting was used to determine levels of IKKβ expression in the presence of Keap1 and mVP24. NF-κB promoter-luciferase assays were used to determine the effect of mVP24 on Keap1-induced repression of activity. Expression of wild-type mVP24 disrupted the interaction of IKKβ and Keap1, whereas weakly interacting and noninteracting mVP24 mutants did not disrupt the interaction between Keap1 and IKKβ. The interaction of mVP24 with Keap1 enhanced IKKβ levels in the presence of Keap1. The interaction of mVP24 with Keap1 also relieved Keap1 repression of NF-κB reporter activity. mVP24 can relieve Keap1 repression of the NF-κB pathway through its interaction with Keap1.


Lymphoabdominal paracoccidioidomycosis simulating primary neoplasia of the biliary tract.
The lymphoabdominal involvement in the sub-acute form of paracoccidioidomycosis shows a wide variety of clinical manifestations, ranging from fever and lymph node enlargement to infiltration of all abdominal organs, which can lead to a situation of abdominal surgical emergency. This case report presents paracoccidioidomycosis mimicking carcinoma of the biliary tract, The purpose of this paper is to call the general physician's attention for this important differential diagnosis of abdominal masses. Although paracoccidioidomycosis is rarely encountered in the United States and Europe, it should be considered in patients who are suspected of having a fungal infection and have had previous exposure in an endemic area for this disease.


Descending pathways to the spinal cord: II. Quantitative study of the tectospinal tract in 23 mammals.
To study the early evolution of the mammalian motor systems, we have collected quantitative data on the nuclear origins of tracts descending into the spinal cord in 99 individuals representing 23 species of mammals and one species of reptile. In each individual, the spinal cord was hemisected at the C1-C2 junction and raw HRP immediately applied to the cut fibers. After a 3-day survival period, brain and spinal cord sections were treated with conventional tetramethylbenzidine procedures. In every case, this procedure resulted in heavy retrograde labeling of neural somata throughout the neuraxis from coccygeal cord to cerebral neocortex. Many thousands of supraspinal neurons were vividly labeled within at least 27 discrete cell groups in every mammal (Nudo and Masterton, '88). Despite the vast number and wide diversity of heavily labeled neurons, however, relatively few labeled somata were found in the superior colliculus. The total number of labeled cells in the tectum contralateral to the hemisection was highest in the cat (909) and second highest in the raccoon (628). In the remaining animals, the number was considerably less--averaging only 243 in the 23 mammalian species, 193 in the 21 noncarnivores, and 95 in the iguana. In 7 species of primates the average was 220, and in 3 species of Old World monkeys the average was 142. This wide variation in the number of tectospinal neurons is not related to body size, brain size, or absolute and relative tectum size. Arranging the animals in order of their kinship or recency-of-last-common-ancestor with Man, the average number of labeled tectal cells tends to decrease slightly, whereas arranging the same animals in order of their kinship with the cat or raccoon shows a marked and statistically reliable increase. Neither the evolutionary increase in the tectospinal tract along the Carnivora lineage nor the slight decrease along Man's lineage is altered by mathematical corrections for allometric or scaling factors. Of an array of morphological, visual, motor, and ecological traits tested statistically as a possible source of the variation in size of the tectospinal tract, only a primarily carnivorous feeding preference was found to be reliably related. The relatively small number of tectospinal fibers in most mammals in our sample, including the primates, suggests that the tectospinal tract in Man may be quite small, perhaps far too small to warrant continuing description as a "major descending tract."


Peripubertal development of noradrenergic stimulation of luteinizing hormone-releasing hormone neurosecretion in vitro.
The effect of age on norepinephrine (NE) stimulation of luteinizing hormone-releasing hormone (LH-RH) secretion from preoptic area-mediobasal hypothalamic (POA-MBH) explants was examined in the present study. Explants were obtained from juvenile (9-day-old), prepubertal (29-day-old) and adult female rats. Following decapitation and surgical isolation, POA-MBH explants were individually perifused with culture medium which was collected for radioimmunoassay of LH-RH. Explants were exposed to two pulses of medium containing NE (5 x 10(-4) M, peak concentration) and a terminal pulse of medium containing KCl (45 mM, peak concentration) for assessment of viability. POA-MBH explants obtained from prepubertal female rats exhibited increased LH-RH release in response to the two pulses of NE and subsequent KCl pulse (P less than 0.05). NE was without effect in stimulating LH-RH neurosecretion from POA-MBH explants obtained from 9-day-old female rats although these explants were responsive to KCl (P less than 0.01). Two-day pretreatment of 9-day-old, and prepubertal rats with estradiol benzoate (EB) did not alter the LH-RH response to this dose of NE or KCl (no group or interaction effects) in prepubertal female rat explants and did not render the explants from 9-day-old rats responsive to NE. Furthermore, NE was equally effective in stimulating LH-RH release from explants obtained from estradiol-treated or control ovariectomized adult rats. These observations demonstrate a peripubertal activation of the stimulatory effect of NE on LH-RH release from POA-MBH explants in vitro. Although these data also suggest that estrogen is not obligatory for NE stimulation of LH-RH release from POA-MBH explants, further investigation is required to determine the developmental time course and estrogen dependency of the noradrenergic stimulation of LH-RH neurosecretion and to evaluate whether estrogen alters the sensitivity of POA-MBH explants to lower concentrations of NE as has been previously reported for median eminence fragments.


Isotopic modelling of the significance of bacterial sulphate reduction for phenol attenuation in a contaminated aquifer.
A Triassic sandstone aquifer polluted with a mixture of phenolic hydrocarbons has been investigated by means of high-resolution groundwater sampling. Samples taken at depth intervals of 1 m have revealed the presence of a diving pollutant plume with a sharply defined upper margin. Concentrations of pollutant phenols exceed 4 g/l in the plume core, rendering it sterile but towards the diluted upper margin evidence for bacterial sulphate reduction (BSR) has been obtained. Groundwaters have been analysed for both delta34S-SO4 and delta18O-SO4. Two reservoirs have been identified with distinct sulphate oxygen isotope ratios. Groundwater sulphate (delta18O-SO4 = 3-5/1000) outside the plume shows a simple linear mixing trend with an isotopically uniform pollutant sulphate reservoir (delta18O-SO4 = 10-12/1000) across the plume margin. The sulphur isotope ratios do not always obey a simple mixing relation, however, at one multilevel borehole, enrichment in 34SO4 at the plume margin is inversely correlated with sulphate concentration. This and the presence of 34S-depleted dissolved sulphide indicate that enrichment in 34SO4 is the result of bacterial sulphate reduction. Delta34S analysis of trace hydrogen sulphide within the plume yielded an isotope enrichment factor (epsilon) of -9.4/1000 for present-day bacterial sulphate reduction. This value agrees with a long-term estimate (-9.9/1000) obtained from a Rayleigh model of the sulphate reduction process. The model was also used to obtain an estimate of the pre-reduction sulphate concentration profile with depth. The difference between this and the present-day profiles then gave a mass balance for sulphate consumption. The organic carbon mineralisation that would account for this sulphate loss is shown to represent only 0.1/1000 of the phenol concentration in this region of the plume. Hence, the contribution of bacterial sulphate reduction to biodegradation has thus far been small. The highest total phenolic concentration (TPC) at which there is sulphur isotope evidence of bacterial sulphate reduction is 2000 mg/l. We suggest that above this concentration, the bactericidal properties of phenol render sulphate-reducing bacteria inactive. Dissolved sulphate trapped in the concentrated plume core will only be utilised by sulphate reducers when toxic phenols in the plume are diluted by dispersion during migration.


In vitro selection of anti-gliadin single-domain antibodies from a naïve library for cDNA-display mediated immuno-PCR.
Gluten intolerance, or adverse intestinal reactions to gluten, is a fairly common problem among certain groups of people. Celiac disease is the most severe form of gluten intolerance, which can lead to permanent damage in the digestive system. Since lifelong avoidance of gluten is the only available treatment, development of reliable techniques to identify gluten contamination in food is important. Gliadin, a component of gluten, is known to play a major role in gluten toxicity. In this study, cDNA display method was used to select specific single-domain antibodies against toxic gliadin from an alpaca-derived naïve VHH library. The cDNA display method is a promising in vitro display technique, which uniquely converts an unstable mRNA-protein fusion molecule to a stable mRNA/cDNA-protein fusion molecule using a well-designed puromycin linker. Three candidate VHHs were selected and the affinities of the VHHs were observed by pulldown assay and indirect ELISA method. In addition, a novel cDNA display mediated immuno-PCR method (cD-IPCR) was successfully applied to detect gliadin in food. We believe this work demonstrates the potential application of the cDNA display method in selecting binders against toxic and heterogeneous targets such as gliadin with an immunization-free preparation manner.


Clinicodemographic profile and predictors of poor outcome in hospitalised COVID-19 patients: a single-centre, retrospective cohort study from India.
Primary objective was to study the clinicodemographic profile of hospitalised COVID-19 patients at a tertiary-care centre in India. Secondary objective was to identify predictors of poor outcome. Single centre tertiary-care level. Retrospective cohort study. Consecutively hospitalised adults patients with COVID-19. Primary outcome variable was in-hospital mortality. Covariables were known comorbidities, clinical features, vital signs at the time of admission and on days 3-5 of admission, and initial laboratory investigations. Intergroup differences were tested using χ2 or Fischer's exact tests, Student's t-test or Mann-Whitney U test. Predictors of mortality were evaluated using multivariate logistic regression model. Out of 4102 SARS-CoV-2 positive patients admitted during 1-year period, 3268 (79.66%) survived to discharge and 834 (20.33%) died in the hospital. Mortality rates increased with age. Death was more common among males (OR 1.51, 95% CI 1.25 to 1.81). Out of 261 cases analysed in detail, 55.1% were in mild, 32.5% in moderate and 12.2% in severe triage category. Most common clinical presentations in the subgroup were fever (73.2%), cough/coryza (65.5%) and breathlessness (54%). Hypertension (45.2%), diabetes mellitus (41.8%) and chronic kidney disease (CKD; 6.1%) were common comorbidities. Disease severity on admission (adjusted OR 12.53, 95% CI 4.92 to 31.91, p<0.01), coagulation defect (33.21, 3.85-302.1, p<0.01), CKD (5.67, 1.08-29.64, p=0.04), high urea (11.05, 3.9-31.02, p<0.01), high prothrombin time (3.91, 1.59-9.65, p<0.01) and elevated ferritin (1.02, 1.00-1.03, p=0.02) were associated with poor outcome on multivariate regression. A strong predictor of mortality was disease progression on days 3-5 of admission (adjusted OR 13.66 95% CI 3.47 to 53.68). COVID-19 related mortality in hospitalised adult patients at our center was similar to the developed countries. Progression in disease severity on days 3-5 of admission or days 6-13 of illness onset acts as 'turning point' for timely referral or treatment intensification for optimum use of resources.


Teratogenic activity and metabolism of primidone in the mouse.
Primidone, 25, 50, 100, and 150 mg/kg, was administered orally to mice of the I.C.I. strain from days 6-16 of pregnancy. The fetuses were removed by caesarian section on day 19 and examined by dissection and alizarin staining for gross structural and skeletal defects. The most common abnormalities found were palatal defects with full-length or submucosal clefts. In the controls--25, 50, 100, and 150 mg/kg groups--the incidence of palatal defects was 0/85, 16/84, 18/117, 19/102, and 17/92 fetuses, respectively. Essentially no other major or minor drug-related abnormalities were found. The metabolism of primidone in the pregnant and nonpregnant mouse was also studied and shown to be similar to that previously reported in the rat. Peak blood levels of primidone were obtained after 1 hr; they fell to very low levels by 6 hr. and were completely cleared by 24 hr. The metabolites produced, PEMA and phenobarbital, are similar to those produced in other species including man. Blood levels following single oral doses of 5 to 150 mg/kg were dose-related so that no explanation for the lack of dose-related teratogenic effect was found.


Retracted: Upregulated microRNA-132 rescues cardiac fibrosis and restores cardiocyte proliferation in dilated cardiomyopathy through the phosphatase and tensin homolog-mediated PI3K/Akt signal transduction pathway.
Cardiac fibrosis is known to be present in dilated cardiomyopathy (DCM) and it predicts the occurrence of sudden death and congestive heart failure. The aim of our study is to investigate the expression of microRNA-132 (miR-132) and its effect on cardiocyte proliferation, apoptosis, and cardiac fibrosis by binding to phosphatase and tensin homolog (PTEN) through the phosphateidylinositol 3-kinase (PI3K)/protein kinase (Akt) signal transduction pathway in DCM rats. DCM rat models induced by doxorubicin were established and confirmed by an ultrasonic cardiogram. Epithelial cells were treated with inhibitors, activators, and small interfering RNAs to identify the mechanisms by which miR-132 controls cardiocyte activity and cardiac fibrosis. Angiotensin II (Ang II) and aldosterone (ALD) expressions were detected by an enzyme-linked immunosorbent assay. The relationship between PTEN and miR-132 was verified by a dual-luciferase reporter assay. Cell proliferation and apoptosis were tested by the MTT assay and flow cytometry. PTEN was determined to be the target gene of miR-132. Rat models of DCM exhibited a lower level of miR-132, PI3K, Akt, B-cell lymphoma 2, collagen I, and collagen III, but a higher level of PTEN, Bcl-2-associated X protein, and proliferating cell nuclear antigen as well as inflammatory response (Ang II and ALD), accompanied by declined cardiocyte proliferation and elevated apoptosis and cardiac fibrosis. Upregulated miR-132 or silenced PTEN activated the PI3K/Akt pathway, thus facilitating cardiocyte proliferation and repressing cardiocyte apoptosis and cardiac fibrosis, as well as inflammatory responses. Downregulated miR-132 reversed this tendency. These findings indicate that miR-132 activates the PI3K/Akt pathway by inhibiting PTEN expression, thus facilitating cardiocyte proliferation and inhibiting apoptosis and cardiac fibrosis in DCM rats.


The effects on epidermal DNA synthesis of topically applied cycloheximide.
An animal model for investigating topically applied epidermal cytotoxic drugs to determine optimum therapeutic doses and schedules is described. It is used here to examine the effects of cycloheximide on epidermal DNA synthesis, as measured by 3H-thymidine incorporation in vivo, in terms of dose/response and activity/time profiles and potential systemic toxicity.


The failure of cyclosporin to inhibit granulomatous inflammation in acute Arthus-like panophthalmitis.
Acute Arthus-like panophthalmitis (AP) was induced in Lewis rat eyes by lens injury after immunization with whole rabbit lens extract. AP consists of an acute anterior ocular inflammation, followed by a posterior choroidal granulomatous reaction. Neither inflammatory response was inhibited by daily treatment with cyclosporin, 10 mg/kg, beginning on the day of lens injury. Cyclosporin would not be expected to interfere with the lens-induced anterior Arthus-like inflammation. The lack of inhibition of the choroidal inflammation was unexpected. The results are interpreted to indicate that the posterior granulomatous choroidal inflammation is a non-immune reaction initiated by the severe lens-induced Arthus-like reaction.


Infant heart rate response to trigeminal airstream stimulation: determination of normal and deviant values.
In this study, trigeminal airstream stimulation is used on a group of normal, sleeping infants to screen for reflex bradycardia. Infants were tested at 1--3 days and at 4, 8, 12, and 16 weeks of age. The usual heart rate response was acceleration above the prestimulus level. The amount of heart rate change was seen to depend on prestimulus rate and, to a lesser extent, postconceptional age. Multiple regression analysis of the data provided estimates of expected responses, given postconceptional age and prestimulus heart rate. From these, ranges were established for classification of normal or abnormal responses. Six deviant data points over 2 SDs from expected values were identified. Two of these represented heart rate increases and four were heart rate decreases. One deviant heart rate decrease was over 3 SDs from the mean. Although the deviant increases were thought to represent exaggerated startles, the more severe heart rate decreases were believed to be a reflex resembling the diving reflex.


Determining the vapour pressures of plant volatiles from gas chromatographic retention data.
The frequently used vapour pressure versus Kováts retention index relationship has been evaluated in terms of its universal applicability, highlighting the problems associated with predicting the vapour pressures of structurally divergent organic compounds from experimentally measured isothermal Kováts retention indices. Two models differing in approximations adopted to express the activity coefficient ratio have been evaluated using 32 plant volatiles of different structural types as a test set. The validity of these models was established by checking their ability to reproduce 22 vapour pressures known from independent measurements. Results of the comparison demonstrated that (i) the original model, based on the assumption of equal activity coefficients for the test and reference substances, led, as expected, to a poor correlation (r2 = 89.1% only), with significantly deviating polar compounds and (ii) the model showed significant improvement after incorporating a new empirical term related to vaporization entropy and boiling point. The addition of this term allowed more than 99% of the vapour pressure variance to be accounted for. The proposed model compares favourably with existing correlations, while having an added advantage of providing a convenient tool for vapour pressure determination of chemically divergent chemicals.


ITS2 database IV: interactive taxon sampling for internal transcribed spacer 2 based phylogenies.
The first step of any molecular phylogenetic analysis is the selection of the species and sequences to be included, the taxon sampling. Already here different pitfalls exist. Sequences can contain errors, annotations in databases can be inaccurate and even the taxonomic classification of a species can be wrong. Usually, these artefacts become evident only after calculation of the phylogenetic tree. Following, the taxon sampling has to be corrected iteratively. This can become tedious and time consuming, as in most cases the taxon sampling is de-coupled from the further steps of the phylogenetic analysis. Here, we present the ITS2 Workbench (http://its2.bioapps.biozentrum.uni-wuerzburg.de/), which eliminates this problem by a tight integration of taxon sampling, secondary structure prediction, multiple alignment and phylogenetic tree calculation. The ITS2 Workbench has access to more than 280,000 ITS2 sequences and their structures provided by the ITS2 database enabling sequence-structure based alignment and tree reconstruction. This allows the interactive improvement of the taxon sampling throughout the whole phylogenetic tree reconstruction process. Thus, the ITS2 Workbench enables a fast, interactive and iterative taxon sampling leading to more accurate ITS2 based phylogenies.


Onset time of tumor repopulation for cervical cancer: first evidence from clinical data.
Accelerated tumor repopulation has significant implications in low-dose rate (LDR) brachytherapy. Repopulation onset time remains undetermined for cervical cancer. The purpose of this study was to determine the onset time of accelerated repopulation in cervical cancer, using clinical data. The linear quadratic (LQ) model extended for tumor repopulation was used to analyze clinical data and magnetic resonance imaging-based three-dimensional tumor volumetric regression data from 80 cervical cancer patients who received external beam radiotherapy (EBRT) and LDR brachytherapy. The LDR dose was converted to EBRT dose in 1.8-Gy fractions by using the LQ formula, and the total dose ranged from 61.4 to 99.7 Gy. Patients were divided into 11 groups according to total dose and treatment time. The tumor control probability (TCP) was calculated for each group. The least χ(2) method was used to fit the TCP data with two free parameters: onset time (T(k)) of accelerated repopulation and number of clonogens (K), while other LQ model parameters were adopted from the literature, due to the limited patient data. Among the 11 patient groups, TCP varied from 33% to 100% as a function of radiation dose and overall treatment time. Higher dose and shorter treatment duration were associated with higher TCP. Using the LQ model, we achieved the best fit with onset time T(k) of 19 days and K of 139, with uncertainty ranges of (11, 22) days for T(k) and (48, 1822) for K, respectively. This is the first report of accelerated repopulation onset time in cervical cancer, derived directly from clinical data by using the LQ model. Our study verifies the fact that accelerated repopulation does exist in cervical cancer and has a relatively short onset time. Dose escalation may be required to compensate for the effects of tumor repopulation if the radiation therapy course is protracted.


M-Ras/Shoc2 signaling modulates E-cadherin turnover and cell-cell adhesion during collective cell migration.
Collective cell migration is required for normal embryonic development and contributes to various biological processes, including wound healing and cancer cell invasion. The M-Ras GTPase and its effector, the Shoc2 scaffold, are proteins mutated in the developmental RASopathy Noonan syndrome, and, here, we report that activated M-Ras recruits Shoc2 to cell surface junctions where M-Ras/Shoc2 signaling contributes to the dynamic regulation of cell-cell junction turnover required for collective cell migration. MCF10A cells expressing the dominant-inhibitory M-RasS27N variant or those lacking Shoc2 exhibited reduced junction turnover and were unable to migrate effectively as a group. Through further depletion/reconstitution studies, we found that M-Ras/Shoc2 signaling contributes to junction turnover by modulating the E-cadherin/p120-catenin interaction and, in turn, the junctional expression of E-cadherin. The regulatory effect of the M-Ras/Shoc2 complex was mediated at least in part through the phosphoregulation of p120-catenin and required downstream ERK cascade activation. Strikingly, cells rescued with the Noonan-associated, myristoylated-Shoc2 mutant (Myr-Shoc2) displayed a gain-of-function (GOF) phenotype, with the cells exhibiting increased junction turnover and reduced E-cadherin/p120-catenin binding and migrating as a faster but less cohesive group. Consistent with these results, Noonan-associated C-Raf mutants that bypass the need for M-Ras/Shoc2 signaling exhibited a similar GOF phenotype when expressed in Shoc2-depleted MCF10A cells. Finally, expression of the Noonan-associated Myr-Shoc2 or C-Raf mutants, but not their WT counterparts, induced gastrulation defects indicative of aberrant cell migration in zebrafish embryos, further demonstrating the function of the M-Ras/Shoc2/ERK cascade signaling axis in the dynamic control of coordinated cell movement.


Supramolecular polymerization in microfluidic channels: spatial control over multiple intermolecular interactions.
A novel supramolecular assembly has been developed in conjugation with microfluidics. Self-assembly of the programmed molecules was controlled precisely, in space and time, in a microflow channel as a result of a homogeneous solvent mixing process. Furthermore, through continuous organization of component molecules followed by orientation along microflow, the self-assembling event containing different molecules was spatially controlled from nano to micrometer scale in a single stream (GMP=guanosine 5'-monophosphate).


The role of chitosan as nanofiller of graphite oxide for the removal of toxic mercury ions.
The present study focuses on the role of chitosan (CS) as nanofiller of graphite oxide (GO) in order to prepare composite materials with improved Hg(II) adsorption properties. The removal of Hg(II) from aqueous solutions was studied using adsorbents as graphite oxide (GO), graphite oxide nanofilled with chitosan (GO/CS) and magnetic chitosan (GO/mCS). Many possible interactions between materials and Hg(II) were observed after adsorption and explained via characterization with various techniques (SEM/EDAX, FTIR, XRD, DTG). The adsorption evaluation was done studying various parameters as the effect of pH (both in adsorption and desorption), contact time (pseudo-second order fitting), temperature (isotherms at 25, 45, 65 °C), in line with a brief thermodynamic analysis (ΔG(0), ΔH(0), ΔS(0)). The maximum adsorption capacity (fitting with Langmuir model) of GO at 25 °C was Qmax=187 mg/g, while after the CS nanofilling (formation of the composite GO/CS), Qmax was increased to 381 mg/g with a further enhancement for GO/mCS (Qmax=397 mg/g).


An early intervention for psychosis and its effect on criminal accusations and suicidal behaviour using a matched-cohort design.
Early interventions for psychosis have been shown to reduce psychotic symptoms and hospital use for first-episode patients, but the effect on suicidal and criminal behaviour has not been reliably determined. This study aimed to examine whether an early intervention for psychosis program (EPPIS) reduced criminal behaviour, suicide attempts, and hospital-based service use. The study utilized administrative data to match clients of EPPIS to historical controls. Regression was used to determine the effect of treatment by EPPIS on inpatient use, emergency department use, suicide attempts/deaths, and criminal accusations. A sample of 244 patients was matched to 449 controls. EPPIS patients had lower odds of being accused of a crime both during and after treatment. Suicidal behavior was less frequent among patients, both during treatment (p<0.0001) and after (HR=0.39; 95% CI: 0.17 to 0.94). During treatment there were more emergency department visits for the patients (RR=2.54; 95% CI: 1.56 to 4.58), but no difference in inpatient usage compared to controls. Post-treatment, both emergency department and inpatient usage were higher among patients. EPPIS patients had reduced suicide attempts and criminal accusations. Increased emergency department use could indicate that encouraging treatment during a crisis may increase service use, while reducing suicidal and criminal behaviour.


Origins of selective differential oxidation of β-lactam antibiotics with different structure in an efficient visible-light driving mesoporous g-C3N4 activated persulfate synergistic mechanism.
In the study, an efficient '1 + 1 > 2' synergistic coupling system driven by visible light consisting of mesoporous g-C3N4 (MCN) and persulfate (PS)was constructed. The free radical transformation, electron transfer and non-covalent interaction between the MCN layer and PS in the system were explored via experiments and DFT calculations. The similarity for the fate of the seven β-lactam antibiotics with typical structures in the oxidation system was studied systematically in depth. First, the consistencies and differences of the seven antibiotics were summarized from three aspects: three-dimensional structures, electron cloud distributions, and the vulnerable sites. Notably, the selective differential degradation of β-lactam antibiotics in the MCN/PS system was speculated to be related with the molecular ionization potential (MIP), as a key index to describe the difficulty of oxidation. The distribution relationship between MIP and the oxidation kinetic constant (K) was explored and showed the following trend: a higher MIP indicates a weaker ability to provide electrons, and this leads to a greater resistance to oxidative degradation. In total, four main oxidation pathways of β-lactam antibiotics were systematically summarized combining HPLC-QTOF-MS and the simplified Fukui function calculation. The toxicity assessment of intermediate products provided by the T.E.S.T software of USEPA also shows a decreasing trend in the oxidation process. In the end, the superior practicability and stability of the MCN/PS system was verified by complex environment simulation and cyclic test. This research clarified the selective differential degradation mechanism of β-lactam antibiotics and provided a possible idea for the effective removal of refractory organic pollutants in water.


Identification of inhibitors of dengue viral replication using replicon cells expressing secretory luciferase.
Dengue virus (DENV) is the causative agent of dengue fever (DF), dengue haemorrhagic fever (DHF), and dengue shock syndrome (DSS) and continues to be a public health problem in the tropical and subtropical areas. However, there is currently no antiviral treatment for DENV infection. In this study, our aim was to develop a stable reporter replicon cell system that supports constant viral RNA replication in cultured cells. The isolated replicon cells exhibited high levels of luciferase activity in the culture supernatant concomitant with expression of virus-encoded NS1, NS3 and NS5 proteins in the cells. The NS1, NS3 proteins and dsRNA were detected in the replicon cells by immunofluorescence analysis. Furthermore, the anti-DENV inhibitors ribavirin and bromocriptine significantly reduced the luciferase activity in a dose-dependent manner. High-throughput screening with a compound library using the stably-transfected replicon cells showed a Z' factor value of 0.57. Our screening yielded several candidates including one compound that has already shown anti-DENV activity. Taken together, our results demonstrate that this DENV subgenomic replicon cell system expressing a secretory luciferase gene can be useful for the high-throughput screening of anti-DENV compounds and the analysis of the replication mechanism of the DENV RNA.


Comparative evaluation of successive extracts of leaf and stem bark of Albizzia lebbeck for mast cell stabilization activity.
Successive chloroform, methanol and water extracts of bark and leaves of Albizzia lebbeck were tested for its in vitro mast cell stabilizing effect against compound 48/80. Methanolic extract of leaf and methanolic and water extracts of bark have shown maximum activity comparable to that of disodium chromoglycate.


The contribution of different parts of the visual field to the perception of upright.
We determined the relative effectiveness of different areas of the visual field in determining the perceptual upright. The perceptual upright was measured using the character 'p', the identity of which depended on its perceived orientation (the Oriented Character Recognition Test). The visual field was divided into left and right, upper and lower, and central and peripheral halves, with different backgrounds presented in each area. The left and right visual fields contributed equally to the perceptual upright while the lower visual field demonstrated a larger effect on the perceptual upright as compared to the upper visual field. The central and peripheral visual fields interacted with one another in a complex manner, although a separate experiment suggested that the peripheral visual field did not alter the perceived orientation of the central field.


TIGAR promotes neural stem cell differentiation through acetyl-CoA-mediated histone acetylation.
Cellular metabolism plays a crucial role in controlling the proliferation, differentiation, and quiescence of neural stem cells (NSCs). The metabolic transition from aerobic glycolysis to oxidative phosphorylation has been regarded as a hallmark of neuronal differentiation. Understanding what triggers metabolism reprogramming and how glucose metabolism directs NSC differentiation may provide new insight into the regenerative potential of the brain. TP53 inducible glycolysis and apoptosis regulator (TIGAR) is an endogenous inhibitor of glycolysis and is highly expressed in mature neurons. However, its function in embryonic NSCs has not yet been explored. In this study, we aimed to investigate the precise roles of TIGAR in NSCs and the possible involvement of metabolic reprogramming in the TIGAR regulatory network. We observed that TIGAR is significantly increased during brain development as neural differentiation proceeds, especially at the peak of NSC differentiation (E14.5-E16.5). In cultured NSCs, knockdown of TIGAR reduced the expression of microtubule-associated protein 2 (MAP2), neuron-specific class III beta-tubulin (Tuj1), glial fibrillary acidic protein (GFAP), Ngn1, and NeuroD1, and enhanced the expression of REST, suggesting that TIGAR is an important regulator of NSC differentiation. Furthermore, TIGAR enhanced the expression of lactate dehydrogenase B (LDHB) and the mitochondrial biogenesis and oxidative phosphorylation (OXPHOS) markers, peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1α), nuclear respiratory factor (NRF1), and MitoNEET during NSC differentiation. TIGAR can decrease lactate production and accelerate oxygen consumption and ATP generation to maintain a high rate of OXPHOS in differentiated NSCs. Interestingly, knockdown of TIGAR decreased the level of acetyl-CoA and H3K9 acetylation at the promoters of Ngn1, Neurod1, and Gfap. Acetate, a precursor of acetyl-CoA, increased the level of H3K9 acetylation and rescued the effect of TIGAR deficiency on NSC differentiation. Together, our data demonstrated that TIGAR promotes metabolic reprogramming and regulates NSC differentiation through an epigenetic mechanism.


The physician's role with the terminally ill patient.
The physician encounters many issues and problems when working with the terminally ill. It is important to remember that the most important aspect of care for the dying is to maintain open and honest communication among the doctor, the patient, and the family. In brief, the physician should play a major role in helping the dying patient. Open communication and support must be continually provided by the physician, both to the dying patient and to the family. All it takes, basically, is common sense and human compassion. No matter how often the physician treats dying patients, he or she should never be casual or matter-of-fact about death. Death should always command respect and awe, but it need never terrorize us or cause us to turn away from providing help to the dying patient. Those who care for the terminally ill may find, to their surprise, that great satisfaction can be derived from this work. One becomes enriched by observing the courage of many dying patients. Therein lies the challenge and the reward.


Core-shell nanosystems designed for effective oral delivery of polypeptide drugs.
The stomach acid degradation, mucus clearance and intestinal epithelial impermeability severely limit the oral delivery of polypeptide drugs. To simultaneously address the three major barriers, novel self-assembled core-shell nanosystems (CA-NPs) were designed. The fabricated shell of citric acid cross-linked carboxymethyl cellulose (CA-CMC) wrapped on core nanoparticles (HA-NPs) maintained the integrity of CA-NPs in the stomach. When CA-NPs passed through the stomach, the CA-CMC shell was gradually degraded to release the core HA-NPs in the intestine. HA-NPs with numerous hydrophilic groups and mannose side chains rapidly penetrated through the mucus layer and efficiently transcellular transported via the glucose transporter (GLUT)-mediated and paracellular transport through reversible opening of tight junctions (TJs) by CA-CMC. The oral bioavailability and therapeutic effects of CA-NPs-loaded polypeptide colistin against Escherichia coli (E. coli) bacteremia in mice were significantly increased compared with the native colistin, respectively. Good safety was observed following oral daily delivery for 14 consecutive days. Thus, CA-NPs may offer a promising strategy for the oral delivery of polypeptide drugs.


Experimental pneumococcus infection in mice: comparative in vitro and in vivo effect of cefuroxime, cefotaxime and ceftriaxone.
In a mouse model using intraperitoneal inoculation of Streptococcus pneumoniae type 3, the 50% effective dose, ED50, after single doses one hour post-inoculation was considerably lower for ceftriaxone (CRO) than for cefuroxime (CXM) and cefotaxime (CTX), in spite of the same minimal inhibitory concentration, MIC, of 0.02 mcg/ml against the pneumococcus for all 3 drugs. The bactericidal activity as measured by time-kill curves was similar for the 3 drugs, as was the post-antibiotic effect in vitro. Protein binding in mouse serum was considerably higher for CRO (87%) than for both CTX (35%) and CXM (15%), respectively. Of pharmacokinetic parameters investigated on doses equal to the ED50s, the time the serum antibiotic concentration remained above the MIC (delta T(MIC)) was the factor that varied the least among 3 drugs. Therefore, the superior in vivo effect for CRO is not due to higher intrinsic activity against the pathogen but to the long serum-elimination half-life resulting in an extended delta T(MIC), probably related to the high serum protein binding.


Operating costs and capacity in the airline industry.
This study illustrates how to calculate accurate costs, including the operating costs for individual airplanes and flights, as well as the costs per available seat kilometers, and per available ton kilometers using activity based costing. It also identifies the main activity items and drivers of each airplane and flight. Additionally, it uses a case study to illustrate the calculation of production variance, marketing variance and expected idle passenger capacity in the airline industry. This is useful information when the purchase or lease an airplane under the conditions of idle capacity.


Sequential versus concurrent anthracyclines and taxanes as adjuvant chemotherapy of early breast cancer: a meta-analysis of phase III randomized control trials.
We performed a meta-analysis of Phase III randomized trials to compare treatment outcomes for early-stage breast cancer patients receiving adjuvant chemotherapy with sequential or concurrent anthracyclines and taxanes. All Phase III randomized trials comparing adjuvant chemotherapy of sequential or concurrent anthracyclines and taxanes in early-stage breast cancer patients were considered eligible. A total of three trials that enrolled 8728 women were analyzed. A pooled analysis was accomplished and event-based risk ratios (RR) with 95% confidence intervals (95%CI) were derived. The significant differences in disease-free survival (DFS) and overall survival (OS) were explored. A heterogeneity test was applied as well. Among three eligible trials, significant differences in favor of sequential regimen were seen in DFS (RR: 0.90; 95%CI: 0.84 to 0.98; P=0.01) and in OS (RR: 0.88; 95%CI: 0.79 to 0.98; P=0.02). Considering all the available Phase III trials, sequential adjuvant chemotherapy for early breast cancer seems to add a significant benefit in both DFS and OS over concurrent regimens.


The effects of simulated microgravity on cultured chicken embryonic chondrocytes.
Using the cultured chicken embryonic chondrocytes as a model, the effects of simulated microgravity on the microtubular system of the cellular skeleton, extracellular matrix, alkaline phosphatase activity, intracellular free calcium concentration and mitochondrial ATP synthase activity with its oligomycin inhibition rate were studied with a clinostat. The microtubular content was measured by a flow cytometer. The decrease of microtubular content showed the impairment of the cellular skeleton system. Observation on the extracellular matrix by the scanning electron microscopy showed that it decreased significantly after rotating, and the fibers in the extracellular matrix were more tiny and disorderly than that of the control group. It can be concluded that the simulated microgravity can affect the secreting and assembly of the extracellular matrix. In contrast to the control, there was a time course decrease in alkaline phosphatase activity of chondrocytes, a marker of matrix mineralization. Meanwhile a significant drop in the intracellular calcium concentration happened at the beginning of rotation. These results indicate that simulated microgravity can suppress matrix calcification of cultured chondrocytes, and intracellular free calcium may be involved in the regulation of matrix calcification as the second signal transmitter. No significant changes happened in the mitochondrial ATP synthase activity and its oligomycin inhibition rate. Perhaps the energy metabolism wasn't affected by the simulated microgravity. The possible mechanisms about them were discussed.


The oculomotor system of Daphnia magna. The eye muscles and their motor neurons.
The highly mobile cyclopic compound eye of Daphnia magna is rotated by six muscles arranged as three bilateral pairs. The three muscles on each side of the head share a common origin on the carapace and insert dorsally, laterally and ventrally on the eye. The dorsal and ventral muscles are each composed of two muscle fibers and the lateral muscle is composed of from two to five fibers, with three the most common number. Individual muscle fibers are spindle-shaped mononucleated cells with organized bundles of myofilaments. Lateral eye-muscle fibers are thinner than those of the other muscles but are otherwise similar in ultrastructure. Two motor neurons innervate each dorsal and each ventral muscle and one motor neuron innervates each lateral muscle. The cell bodies of the motor neurons are situated dorsally in the supraesophageal ganglion (SEG) and are ipsilateral to the muscles they innervate. The dendritic fields of the dorsal-muscle motor neurons are ipsilateral to their cell bodies; those of the ventral-muscle motor neurons are bilateral though predominantly contralateral. The central projections of the lateral-muscle motor neurons are unknown. In the dorsal and ventral muscles one motor axon synapses principally with one muscle fiber; in each lateral muscle the single motor axon branches to, and forms synapses with, all the fibers. The neuromuscular junctions, characterized by pre- and postsynaptic densities and clear vesicles, are similar in all the eye muscles.


Safety and Preliminary Efficacy of the Acetylcholinesterase Inhibitor Huperzine A as a Treatment for Cocaine Use Disorder.
Cholinergic transmission is altered by drugs of abuse and contributes to psychostimulant reinforcement. In particular, acetylcholinesterase inhibitors, like huperzine A, may be effective as treatments for cocaine use disorder. The current report describes results from a double-blind, placebo-controlled study in which participants (n=14-17/group) were randomized to huperzine A (0.4 or 0.8 mg) or placebo. Participants received randomized infusions of cocaine (0 and 40 mg, IV) on days 1 and 9. On day 10, participants received noncontingent, randomized infusions of cocaine (0 and 20mg, IV) before making 5 choices to receive additional infusions. Huperzine A was safe and well-tolerated and compared with placebo, treatment with huperzine A did not cause significant changes in any cocaine pharmacokinetic parameters (all P>.05). Time-course and peak effects analyses show that treatment with 0.4 mg of huperzine A significantly attenuated cocaine-induced increases of "Any Drug Effect," "High," "Stimulated," "Willing to Pay," and "Bad Effects" (all P>.05). The current study represents a significant contribution to the addiction field since it serves as the first published report on the safety and potential efficacy of huperzine A as a treatment for cocaine use disorder.


The motivations and practices of vegetarian and vegan Saudis.
In the Middle East, particularly in Saudi Arabia, the offering of a meat dish to guests is a deeply embedded cultural tradition, and a meat-based diet is the standard in Saudi Arabia. Thus, the rise of veganism and vegetarianism within Saudi Arabia is surprising and worthy of attention, as is understanding the perceptions and motivations behind this phenomenon, particularly as they relate to food and sustainability. This research was designed to investigate this emerging phenomenon and to identify key differences in dietarian identity between Saudi vegetarians and vegans using Rosenfeld and Burrow's Dietarian Identity Questionnaire. Among other results, the vegan group scored significantly higher on the prosocial motivation construct, suggesting the desire to help society as a whole is a stronger motivating factor for vegans. As well, the vegan cohort scored higher in the personal motivation category. From an environmental and public health perspective, understanding the key factors motivating individuals to adopt a vegetarian or vegan diet in a meat-based culture like Saudi Arabia can be used to encourage others to pursue more healthy and sustainable food behaviors.


A transition-state analogue inhibitor of human renin (H.261): test in vitro and a comparison with captopril in the anaesthetized baboon.
H.261, a new transition state inhibitor of human renin with an IC50 of 6.9 X 10(-10) M, was given by intravenous infusion to six anaesthetized baboons. The inhibitor was infused first at 0.1 mumol/kg/h for 15 min, then at 1.0 mumol/kg/h for a further 15 min. After a recovery period of 2 h in which the animals received 5% dextrose, they were infused with captopril, 25 mumol/kg/h for 15 min. At both rates of infusion H.261 markedly and significantly reduced the enzymatic action of renin in plasma, the blood concentration of angiotensin I, the plasma concentration of angiotensin II and mean arterial pressure. All changes reverted towards or to control values in the subsequent control period. Captopril also lowered plasma angiotensin II concentration and mean arterial pressure markedly and significantly but, as expected for an inhibitor of the angiotensin I-converting enzyme, plasma active renin concentration and blood angiotensin I concentration increased. The changes of angiotensin II and arterial pressure were similar with captopril and H.261.


The prognostic significance of BMP-6 signaling in prostate cancer.
The importance of bone-morphogenetic proteins in prostate cancer is well recognized. Bone-morphogenetic protein-6 overexpression has been shown to increase the aggressiveness and invasiveness of prostate cancer cells. Recent studies on noggin and sclerostin, potent inhibitors of bone-morphogenetic protein signaling, have found that noggin also modifies the ability of prostate cancer cells to metastasize to bone. Taken together, these results suggest that bone-morphogenetic protein-6 signaling is important in prostate cancer progression. Our study investigated the expression of bone-morphogenetic protein-6, noggin and sclerostin in human prostate specimens (n=136) by immunohistochemical staining. We found that bone-morphogenetic protein-6 was increased (P<0.001), whereas sclerostin was decreased (P=0.004) in prostate cancer compared with nodular hyperplasia. In addition, significantly higher level of bone-morphogenetic protein-6 expression was observed in high-grade prostate cancer with Gleason score >or=7 (P=0.027). Bone-morphogenetic protein-6, noggin and sclerostin alone could not predict the development of distant metastasis in our patient cohort. However, high level of bone-morphogenetic protein-6 and low level of noggin, or high level of bone-morphogenetic protein-6 and low level of both noggin and sclerostin expression in primary prostate cancer significantly predicted development of distant metastasis. The predictive value was still valid when only high-grade prostate cancers were included or when patients with secondary lesion other than bone were excluded. Taken together, these results suggest that a high level of bone-morphogenetic protein-6 signaling, resulting from increased expression of bone-morphogenetic protein-6 and decreased expression of its inhibitors, might promote the development of prostate cancer metastases. Our results also imply the potential use of bone-morphogenetic protein-6, noggin and sclerostin expression together as a prognostic predictor for metastatic progression of prostate cancer.


Modulation of the humoral and cellular immune response in Abeta immunotherapy by the adjuvants monophosphoryl lipid A (MPL), cholera toxin B subunit (CTB) and E. coli enterotoxin LT(R192G).
Abeta vaccination or passive transfer of human-specific anti-Abeta antibodies are approaches under investigation to prevent and/or treat Alzheimer's disease (AD). Successful active Abeta vaccination requires a strong and safe adjuvant to induce anti-Abeta antibody formation. We compared the adjuvants monophosphoryl lipid A (MPL)/trehalose dicorynomycolate (TDM), cholera toxin B subunit (CTB) and Escherichia coli heat-labile enterotoxin LT(R192G) for their ability to induce a humoral and cellular immune reaction, using fibrillar Abeta1-40/42 as a common immunogen in wildtype B6D2F1 mice. Subcutaneous (s.c.) administration with MPL/TDM resulted in anti-Abeta antibodies levels up to four times higher compared to s.c. LT(R192G). Using MPL/TDM, the anti-Abeta antibodies induced were mainly IgG2b, IgG1 and lower levels of IgG2a and IgM, with a moderate splenocyte proliferation and IFN-gamma production in vitro upon stimulation with Abeta1-40/42. LT(R192G), previously shown by us to induce robust titers of anti-Abeta antibodies, generated predominantly IgG2b and IgG1 anti-Abeta antibodies with very low splenocyte proliferation and IFN-gamma production. Weekly intranasal (i.n.) administration over 11 weeks of Abeta40/42 with CTB induced only moderate levels of antibodies. All immunogens generated antibodies that recognized mainly the Abeta1-7 epitope and specifically detected amyloid plaques on AD brain sections. In conclusion, MPL/TDM, in addition to LT(R192G), is an effective adjuvant when combined with Abeta40/42 and may aid in the design of Abeta immunotherapy.


Psychometric testing of the nurse professional competence scale Arabic version: An exploratory and confirmatory factor analyses.
To translate the Nurse Professional Competence Scale-Short Form English version into Arabic and psychometrically validate its properties among Saudi citizen nurses. Evaluating nurses' professional competence is vital in delivering safe, cost-effective care and developing healthcare systems. However, psychometrically reliable and validated nurse competence scales in Arabic-speaking countries remain scant. A descriptive cross-sectional design adhering to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. Participant nurses (n = 598) were conveniently recruited from four government-owned hospitals and completed the Arabic-translated 35-item Nurse Professional Competence Scale-Short Form. We used Spearman's rank-order correlation, exploratory factor analysis, Kaiser-Meyer-Olkin test, and confirmatory factor analysis to analyze the data. After exploratory factor analysis and reliability analyses, several items of the Arabic-translated 35-item Nurse Professional Competence Scale-Short Form were omitted due to high inter-item correlations and low factor loading difference. The Arabic version of the Nurse Professional Competence Scale-Short Form was reduced to 21 items, consisting of a three-factor structure: Professional Care Pedagogics, Holistic Value-Based Care, and Direct Nursing Care. Results also demonstrated that the revised three-factor structure had good overall scale reliability, good subscale internal consistencies, and acceptable construct validity using the confirmatory factor analysis. The 21-item Nurse Professional Competence Scale-Short Form Arabic version is a useful scale, having demonstrated construct validity and reliability. Therefore, nurse managers in Arabic-speaking nations could assess their nurses' professional competence using the 21-item Nurse Professional Competence Scale-Short Form Arabic version to develop proactive programs that enhance professional competence.


Intravenous iron dextran therapy in patients with iron deficiency and normal renal function who failed to respond to or did not tolerate oral iron supplementation.
To evaluate the safety and effectiveness of using 500-mg doses of iron as intravenous iron dextran after premedication with diphenhydramine, cimetidine, and dexamethasone. We treated 135 iron-deficient adults (26 men, 109 women) with normal renal function (serum creatinine level </=1.5 mg/dL or blood urea nitrogen level </=26 mg/dL) who could not be treated adequately with oral iron supplements due to gastrointestinal symptoms (59%), inadequate hematologic response (39%), severe anemia (19%), or noncompliance (4%). Some patients had more than one reason for treatment. Resolution of iron deficiency was defined as the restoration of transferrin saturation, serum ferritin level, anemia, and abnormal erythrocyte indexes to normal or baseline values. Before treatment with iron dextran, patients had a mean (+/- SD) transferrin saturation of 8% +/- 5%, a median serum ferritin level of 11 ng/mL, and a mean hemoglobin level of 10 +/- 2 g/dL. Ninety-two percent were anemic; 60% had unrecognized or untreated causes of anemia other than iron deficiency. We administered 285 iron dextran infusions (median 2, mean 2 infusions per patient; range 1 to 7). Eighty-seven percent of patients had no adverse reaction; 13% had mild reactions, especially arthralgias and myalgias. No patient had an anaphylaxis-like reaction. Fifty-four (40%) patients had resolution of iron deficiency, 34 (25%) continue to receive therapy, 36 (27%) returned to the care of their primary physician, and 11 (8%) died before iron repletion could be achieved. Iron-deficient adults with normal renal function who cannot be treated adequately with oral iron supplements can be treated effectively and safely with this intravenous iron dextran regimen.


Fast Neuroimaging-Based Retrieval for Alzheimer's Disease Analysis.
This paper proposes a framework of fast neuroimaging-based retrieval and AD analysis, by three key steps: (1) landmark detection, which efficiently extracts landmark-based neuroimaging features without the need of nonlinear registration in testing stage; (2) landmark selection, which removes redundant/noisy landmarks via proposing a feature selection method that considers structural information among landmarks; and (3) hashing, which converts high-dimensional features of subjects into binary codes, for efficiently conducting approximate nearest neighbor search and diagnosis of AD. We have conducted experiments on Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, and demonstrated that our framework could achieve higher performance than the comparison methods, in terms of accuracy and speed (at least 100 times faster).


Survival implication of lymphadenectomy in patients surgically treated for apparent early-stage uterine serous carcinoma.
Uterine serous carcinoma (USC) is a rare highly aggressive disease. In the present study, we aimed to investigate the survival implication of the systematic lymphadenectomy in patients who underwent surgery for apparent early-stage USC. Consecutive patients with apparent early-stage USC surgically treated at six Italian referral cancer centers were analyzed. A comparison was made between patients who underwent retroperitoneal staging including at least pelvic lymphadenectomy "LND" vs. those who underwent hysterectomy alone "NO-LND". Baseline, surgical and oncological outcomes were analyzed. Kaplan- Meier curves were calculated for disease-free survival (DFS) and disease-specific survival (DSS). Associations were evaluated with Cox proportional hazard regression and summarized using hazard ratio (HR). One hundred forty patients were analyzed, 106 LND and 34 NO-LND. NO-LND group (compared to LND group) included older patients (median age, 73 vs.67 years) and with higher comorbidities (median Charlson Comorbidity Index, 6 vs. 5) (p<0.001). No differences in terms of recurrence rate (LND vs. NO-LND, 33.1% vs. 41.4%; p=0.240) were observed. At Cox regression analysis lymphadenectomy did not significantly influence DFS (HR=0.59; 95% confidence interval [CI]=0.32-1.08; p=0.09), and DSS (HR=0.14; 95% CI=0.02-1.21; multivariable analysis p=0.07). Positive node was independently associated with worse DFS (HR=6.22; 95% CI=3.08-12.60; p<0.001) and DSS (HR=5.51; 95% CI=2.31-13.10; p<0.001), while adjuvant chemotherapy was associated with improved DFS (HR=0.38; 95% CI=0.17-0.86; p=0.02) and age was independently associated with worse DSS (HR=1.07; 95% CI=1.02-1.13; p<0.001). Although lymphadenectomy did not show survival benefits in patients who underwent surgery for apparent early-stage USC, the presence of lymph node metastasis was the main adverse prognostic factors, supporting the prognostic role of the retroperitoneal staging also in this histological subtype.


2,4,6-Triphenylpyridinium: A Bulky, Highly Electron-Withdrawing Substituent That Enhances Properties of Nickel(II) Ethylene Polymerization Catalysts.
The reactivity of NiII and PdII olefin polymerization catalysts can be enhanced by introduction of electron-withdrawing substituents on the supporting ligands rendering the metal centers more electrophilic. Reported here is a comparison of ethylene polymerization activity of a classical salicyliminato nickel catalyst substituted with the powerful electron-withdrawing 2,4,6-triphenylpyridinium (trippy) group to the -CF3 analogue. The trippy substituent is substantially more electron-withdrawing (σmeta =0.63) than the trifluoromethyl group (σmeta =0.43) which results in a ca. 8-fold increase in catalytic turnover frequency. An additional advantage of trippy is the high steric bulk relative to the trifluoromethyl group. This feature results in a four-fold increase in polymer molecular weight owing to enhanced retardation of chain transfer. A significant increase in catalyst lifetime is observed as well.


DDAVP-induced release of von Willebrand factor from endothelial cells in vitro: the effect of plasma and blood cells.
The vasopressin analogue 1-deamino-8-D-arginine vasopressin (DDAVP) causes an immediate, transient rise in plasma levels of von Willebrand factor (vWF) after its administration. Although it is recognized that vascular endothelial cells play an essential role in this process, the molecular basis of the response is not understood. We have investigated the phenomenon using human umbilical vein endothelial cells as an in vitro model. When normal individuals were stimulated with DDAVP, plasma from blood samples collected subsequently caused the release of vWF from cultured endothelial cells over a 24 h period (22-46% increase over baseline), compared to control plasma (5-17%). DDAVP added directly to the endothelial cells produced no increase in vWF release. When whole blood was treated in vitro with DDAVP, and the plasma subsequently added to endothelial cells, a significant increase in vWF secretion was found. Peripheral blood mononuclear cells were then tested. In the presence of DDAVP, an increased response occurred. Further fractionation of these cells showed that monocytes were largely responsible, causing an increased vWF release of 162% at 2 h. These observations were reinforced by finding that the supernatants of monocytes incubated with DDAVP were also effective in causing increased vWF release (118% compared to 58% for the control sample). Our studies suggest that DDAVP plays an indirect role in causing the release of vWF from endothelial cells, and that peripheral blood monocytes may act as intermediary target cells, which then produce factor(s) acting directly on endothelial cells.


Local anti-P32 humoral response in tuberculous meningitis.
We report five cases of severe pulmonary tuberculosis admitted to hospital with a suspicion of meningeal involvement. The diagnosis of tuberculous meningitis was confirmed by standard bacteriological techniques in two of the five patients. Specific IgG class antibodies directed against the recently purified BCG antigen P32 were detected by a dot immunoblotting technique in the serum and in the cerebrospinal fluid of each patient; however, a higher anti-P32 immunoglobulins/total immunoglobulins ratio was observed in the cerebrospinal fluid of patients with tuberculous meningitis than in their serum while the reverse situation was observed in the other patients.


Effects of constant illumination on vision in the albino rat.
The characteristics of photically-induced blinding in the albino rat were investigated with physiological (the electroretinogram--ERG) and behavioral (luminance discrimination) techniques. These indices were obtained both before and during exposure to constant illumination (2600 lux). In trast to previous results, the findings of this study indicate that both the amplitude of the ERG and the ability to discriminate test lights decline rapidly and at approximately the same rate following the onset of constant illumination. These results, in conjunction with others already in the literature, lead to the suggestion that the degree of correspondence between behavioral and other measures of photically-induced blinding is dependent on the rate of retinal degeneration.


Identification of the diamond-like B-C phase by confocal Raman spectroscopy.
The new diamond-like B-C phase was obtained from the graphite-like BC phase in a laser-heated diamond anvil cell at high temperature 2230+/-140 K and high pressure 45 GPa. Raman spectra of the new phase measured at ambient conditions revealed a peak at 1315 cm(-1), which was attributed to longitudinal-optical (LO) mode. The X-Y Raman mapping was used to investigate spatial distribution of the diamond-like phases and was shown to be a powerful tool in studying the sp(2)-to-sp(3) phase transformations occurring in the diamond cell under high temperature and high pressure.


Acute, severe cardiomyopathy as main symptom of late-onset very long-chain acyl-coenzyme A dehydrogenase deficiency.
A 5-year-old boy with late-onset very long-chain acyl-CoA-dehydrogenase (VLCAD) deficiency presented with acute cardiomyopathy, myopathy, gross myoglobinuria and normoglycaemia. The clinical course after diagnosis was favourable. late-onset VLCAD deficiency may present as acute cardiomyopathy.


Spatiotemporally resolved metabolomics and isotope tracing reveal CNS drug targets.
Deconvolution of potential drug targets of the central nervous system (CNS) is particularly challenging because of the complicated structure and function of the brain. Here, a spatiotemporally resolved metabolomics and isotope tracing strategy was proposed and demonstrated to be powerful for deconvoluting and localizing potential targets of CNS drugs by using ambient mass spectrometry imaging. This strategy can map various substances including exogenous drugs, isotopically labeled metabolites, and various types of endogenous metabolites in the brain tissue sections to illustrate their microregional distribution pattern in the brain and locate drug action-related metabolic nodes and pathways. The strategy revealed that the sedative-hypnotic drug candidate YZG-331 was prominently distributed in the pineal gland and entered the thalamus and hypothalamus in relatively small amounts, and can increase glutamate decarboxylase activity to elevate γ-aminobutyric acid (GABA) levels in the hypothalamus, agonize organic cation transporter 3 to release extracellular histamine into peripheral circulation. These findings emphasize the promising capability of spatiotemporally resolved metabolomics and isotope tracing to help elucidate the multiple targets and the mechanisms of action of CNS drugs.


Sexual IPV and non-partner rape of female sex workers: Findings of a cross-sectional community-centric national study in South Africa.
Globally female sex workers (FSWs) are vulnerable to violence from intimate partners, police and clients due to stigma and criminalisation. In this paper we describe South African FSWs' exposure to violence and factors associated with having been raped in the past year. We conducted a multi-stage, community-centric, cross-sectional survey of 3005 FSWs linked to sex worker programmes in 12 sites across all nine provinces that had a SW programme. Adult women who sold sex in the preceding six months were recruited for interviews via sex worker networks. Survey tools were developed in consultation with peer educators and FSWs. In the past year, 70.4% of FSWs experienced physical violence and 57.9% were raped: by policemen (14.0%), clients (48.3%), other men (30.2%) and/or and intimate partner (31.9%). Sexual IPV was associated with food insecurity, entering sex work as a child, childhood trauma exposure, post-traumatic stress disorder (PTSD), drinking alcohol to cope with sex work, working more days, partner controlling behaviour, having an ex-client partner, and having no current partner to protect from ex-partners. Rape by a client, other men or policemen was associated with food insecurity, childhood trauma, PTSD, depression, using alcohol and drugs, being homeless or staying in a sex work venue, selling sex on the streets, working more days and having entered sex work as a child and been in sex work for longer. South African FSWs are very vulnerable to rape. Within the social climate of gender inequality, sex work stigma, criminalisation, and repeated victimisation, the key drivers are structural factors, childhood and other trauma exposure, mental ill-health, circumstances of sex work and, for SIPV, partner characteristics. Mostly these are amenable to intervention, with legislative change being foundational for ending abuse by policemen, enhancing safety of indoor venues and providing greater economic options for women.


A comparative clinical and functional assessment of cortical button versus suture anchor in distal biceps brachii tendon repair.
The studies comparing the fixation methods being used for the ruptured distal biceps brachii tendon reinsertion show similar outcomes of cortical button and suture anchors usage, however, longer follow-up studies remain necessary. The goal of this study was to compare the clinical and functional three-year outcomes of the cortical button in contrast to the suture anchor fixation. A retrospective cohort study comprised of 28 males on average 3 years after surgical reinsertion of the distal biceps brachii tendon with the use of a cortical button (Group I, n = 11) or a suture anchor (Group II, n = 17). The outcomes assessed were range of elbow joint and forearm motion (ROM), arm circumferences, visual analogue scale (VAS), Mayo Elbow Performance Index (MEPI), Quick Disability of the Arm, Shoulder, and Hand (Quick DASH) and forearm flexor and supinator muscle torques measured under isometric and isokinetic conditions. The comparison between the two studied groups revealed no statistically significant differences in ROM (p = 0.24-1.00), circumferences (p = 0.15-0.50), VAS (p = 0.71), MEPI (p = 0.23), Quick DASH (p = 0.61) or in the obtained muscle torque values (p = 0.07-1.00). However, differences in supination ROM between the surgical and non-surgical side were found in both groups (p = 0.01-0.02), and differences in pronation (p = 0.02) were found in Group II. The muscle torque values obtained in the surgical, dominant limb were lower than those in the nonsurgical, nondominant limb. The comprehensive comparison of three-year outcomes of cortical button versus suture anchor fixations did not favour one fixation method over the other, and the results justify the clinical usage of both methods.


Properties of a newly isolated, serologically distinct avian paramyxovirus.
The morphological, bio-physical and growth properties of the isolate duck/Hong Kong/D3/75 (D3/75) were consistent with this virus being a member of the paramyxovirus group. Using haemagglutination inhibition and neuraminidase inhibition tests no serological relationships between D3/75 and other paramyxoviruses could be demonstrated. The structural polypeptides of D3/75 were also typical of paramyxoviruses, consisting of 6--7 polypeptides ranging in molecular weight from 46,000--200,000 under reduced conditions. Two polypeptides were glycosylated.


Altered tissue tropism of human-avian reassortant influenza viruses.
Avian influenza viruses replicate to high titers in the cells lining the intestinal tract of birds; however, human strains do not. A series of reassortant viruses with all six internal genes from an avian strain and one or both genes for the surface antigens from a human strain failed to transit and infect the intestinal tracts of ducks. However, these reassortants did replicate in the bursa of ducks after rectal inoculation. These studies provide the first evidence that the hemagglutinin and neuraminidase are critical for the enterotropism of avian viruses but are not essential for replication in other avian tissues.


The mode of inheritance in idiopathic cardiomyopathy, preliminary report.
Genetic analyses of 565 first-degree relatives of 99 patients with ICM suggests that ICM has both simple dominant and recessive modes of inheritance. There was no clinical form of ICM specific to the mode of inheritance, both hypertrophic and congestive types almost equally observed both modes of inheritance. Two pairs of identical twins who suggested the simple recessive mode were reported.