The subunits and biological activity of polymorphic forms of tropomyosin.
1. Free thiol groups were shown to be essential for tropomyosin to effect maximum inhibition of the Ca(2+)-stimulated ATPase (adenosine triphosphatase) of desensitized actomyosin but not for its activity in the regulatory-protein system. 2. The activity of tropomyosin on the Mg(2+)-stimulated ATPase in the regulatory-protein system was more susceptible to enzymic digestion and thermal denaturation than its effect on the Ca(2+)-stimulated ATPase of actomyosin. 3. Rabbit skeletal tropomyosin migrated as two distinct electrophoretic components in the presence of sodium dodecyl sulphate and urea and as four components on isoelectric focusing in urea. 4. The two main subunits present in rabbit skeletal tropomyosin, which have been named the alpha- and beta-chains, were separated by chromatography on CM-cellulose in urea at pH4.0. They were shown to be virtually identical in amino acid composition, except for their cysteine contents. The alpha(2) and beta(2) forms of tropomyosin possessed all the biological activities characteristic of normal tropomyosin preparations. 5. In skeletal muscle the alpha and beta components of tropomyosin were present in the proportion of 4:1. Somewhat lower ratios were obtained in skeletal muscle of sheep, pig and cow. 6. Tropomyosin isolated from cardiac muscle and Pecten maximus adductor muscle migrated as one band only. These tropomyosins possessed similar biological activities to those isolated from skeletal muscle.


[Structural modifications of the surface of Escherichia coli bacteria and copper-induced permeability of plasma membrane].
The effect of Cu2+ on the structural organization of the cell surface of Escherichia coli bacteria during the induction of conductivity of a plasma membrane was studied. A fluorescent study did not reveal any substantial changes in the microviscosity of lipids by the action of copper ions. At the same time, a substantial reorganization of membrane proteins during plasmolysis was observed. A model of the copper-induced structural reorganization of membrane lipids was constructed, according to which the reorganization leads to the opening in the membrane of channels of nonspecific conductivity for cations. The opening of conductivity channels results from the break of disulfide bonds in critical membrane proteins during the interaction with Cu+, which form either due to the reduction of Cu2+ on specific sites of cell surface or by means of external reducing agents.


Effects of Myricitrin and Relevant Molecular Mechanisms.
In humans, oxidative stress is thought to be involved in the development of Parkinson's disease, Alzheimer's disease, atherosclerosis, heart failure, myocardial infarction and depression. Myricitrin, a botanical flavone, is abundantly distributed in the root bark of Myrica cerifera, Myrica esculenta, Ampelopsis grossedentata, Nymphaea lotus, Chrysobalanus icaco, and other plants. Considering the abundance of its natural sources, myricitrin is relatively easy to extract and purify. Myricitrin reportedly possesses effective anti-oxidative, anti-inflammatory, and anti-nociceptive activities, and can protect a variety of cells from in vitro and in vivo injuries. Therefore, our current review summarizes the research progress of myricitrin in cardiovascular diseases, nerve injury and anti-inflammatory, and provides new ideas for the development of myricitrin.


Ribosomal protein gene-based phylogeny for finer differentiation and classification of phytoplasmas.
Extensive phylogenetic analyses were performed based on sequences of the 16S rRNA gene and two ribosomal protein (rp) genes, rplV (rpl22) and rpsC (rps3), from 46 phytoplasma strains representing 12 phytoplasma 16Sr groups, 16 other mollicutes and 28 Gram-positive walled bacteria. The phylogenetic tree inferred from rp genes had a similar overall topology to that inferred from the 16S rRNA gene. However, the rp gene-based tree gave a more defined phylogenetic interrelationship among mollicutes and Gram-positive walled bacteria. Both phylogenies indicated that mollicutes formed a monophyletic group. Phytoplasmas clustered with Acholeplasma species and formed one clade paraphyletic with a clade consisting of the remaining mollicutes. The closest relatives of mollicutes were low-G+C-content Gram-positive bacteria. Comparative phylogenetic analyses using the 16S rRNA gene and rp genes were performed to evaluate their efficacy in resolving distinct phytoplasma strains. A phylogenetic tree was constructed based on analysis of rp gene sequences from 87 phytoplasma strains belonging to 12 16Sr phytoplasma groups. The phylogenetic relationships among phytoplasmas were generally in agreement with those obtained on the basis of the 16S rRNA gene in the present and previous works. However, the rp gene-based phylogeny allowed for finer resolution of distinct lineages within the phytoplasma 16Sr groups. RFLP analysis of rp gene sequences permitted finer differentiation of phytoplasma strains in a given 16Sr group. In this study, we also designed several semi-universal and 16Sr group-specific rp gene-based primers that allow for the amplification of 11 16Sr group phytoplasmas.


Recent developments and perspectives in palladium-catalyzed cyanation of aryl halides: synthesis of benzonitriles.
The palladium-catalyzed cyanation of Ar-X (X = I, Br, Cl, OTf, and H) allows for an efficient access towards benzonitriles. After its discovery in 1973 and following significant improvements in recent decades, this methodology has become nowadays the most popular for preparation of substituted aromatic nitriles. In this critical review, we summarize the important developments in this area from 2000 until 2010 (151 references).


Carbon isotopes and lipid biomarkers from organic-rich facies of the Shuram Formation, Sultanate of Oman.
The largest recorded carbon isotopic excursion in Earth history is observed globally in carbonate rocks of middle Ediacaran age. Known from the Sultanate of Oman as the 'Shuram excursion', this event records a dramatic, systematic shift in δ(13) Ccarbonate values to ca. -12‰. Attempts to explain the nature, magnitude and origin of this excursion include (i) a primary signal resulting from the protracted oxidation of a large dissolved organic carbon reservoir in seawater, release of methane from sediment-hosted clathrates, or water column stratification; and (ii) a secondary signal from diagenetic processes. The compositions and isotope ratios of organic carbon phases during the excursion are critical to evaluating these ideas; however, previous work has focused on localities that are low in organic carbon, hindering straightforward interpretation of the observed time-series trends. We report carbon isotope data from bulk organic carbon, extracted bitumen and kerogen, in addition to lipid biomarker data, from a subsurface well drilled on the eastern flank of the South Oman Salt Basin, Sultanate of Oman. This section captures Nafun Group strata through the Ediacaran-Cambrian boundary in the Ara Group and includes an organic-rich, deeper-water facies of the Shuram Formation. Despite the high organic matter contents, the carbon isotopic compositions of carbonates - which record a negative δ(13) C isotope excursion similar in shape and magnitude to sections elsewhere in Oman - do not covary with those of organic phases (bulk TOC, bitumen and kerogen). Paired inorganic and organic δ(13) C data only display coupled behaviour during the latter part of the excursion's recovery. Furthermore, lipid biomarker data reveal that organic matter composition and source inputs varied stratigraphically, reflecting biological community shifts in non-migrated, syngenetic organic matter deposited during this interval.


Neutron-induced signal on the single crystal chemical vapor deposition diamond-based neutral particle analyzer.
A diamond-based neutral particle analyzer (DNPA) array composed of single-crystal chemical vapor deposition (sCVD) diamond detectors was installed on the Large Helical Device (LHD) for measuring the helically trapped energetic particles. In high neutron flux experiments, the unwanted neutron-induced pulse counting rate should be estimated using the neutron diagnostics because a diamond detector is sensitive to neutrons as well as energetic neutral particles. In order to evaluate the quantitative neutron-induced pulse counting rate on the DNPA, the response functions of the sCVD diamond detector for mono-energetic neutrons were obtained using accelerator-based D-D and D-7Li neutron sources in Fast Neutron Laboratory (FNL). As a result of the neutron flux estimation by the Monte Carlo N-Particle code at the NPA position in the LHD and the response function obtained in the FNL experiment, the counting rate of the neutron-induced signal was predicted to be 1.1 kcps for the source neutron emission rate of Sn = 1 × 1015 n/s. In the LHD experiment, the neutron-induced signals were observed by closing the gate valve during the plasma discharges. It is found that the counting rates of the neutron-induced signals proportional to Sn reached 1.1 kcps at Sn = 1 × 1015 n/s. As a result of the quantitative estimation of the neutron-induced signals on the DNPA using other neutron measurements, it has become possible to accurately measure energetic neutral particles in the high neutron flux experiment.


Resection and reconstruction of pelvic bone tumors.
The objective of this study was to assess outcome and recurrence rate after limb-salvage surgery with reconstruction for pelvic bone tumors and analyze complications and their relationship with surgery. The authors analyzed 129 patients followed for a mean of 6 years (range, 2-19 years). Chondrosarcoma was the most frequent histotype. Thirty-one cases with no acetabular involvement were reconstructed with allograft only. Acetabular resections were reconstructed with allograft prosthetic composite (n=60), allograft only (n=11), trabecular metal components (n=2), prosthesis only (n=10), saddle prosthesis (n=11), and iliofemoral arthrodesis (n=1). Margins were wide (n=94), wide contaminated (n=22), marginal (n=7), and intralesional (n=6). Oncologic outcomes were as follows: 75 patients were continuously disease free, 6 were disease free after treatment of relapse, 13 were alive with disease, 28 were dead of disease, and 5 were dead of other causes. Survival was 66% at 10 years. Local recurrence rate of malignant tumors was 22.1% and was not statistically influenced by margins (P=.140) or site (P=.933). Metastasis rate was 32.8%. Deep infection was observed in 30 (23.6%) cases, with no statistical difference between reconstructions with and without allograft (P=.09). Final external hemipelvectomy was performed in 16 cases. Newer techniques of reconstruction using stemmed acetabular cups or porous metal components combined with allograft are now available. Local control and satisfactory survival is achievable long term in patients with pelvic tumors, but this surgery implies a high rate of complications. Infection is a major complication, not influenced by the use of allografts. Amputation is rarely needed.


Comparison of the adsorption capacities of an activated-charcoal--yogurt mixture versus activated-charcoal--water slurry in vivo and in vitro.
An activated charcoal--yogurt mixture was evaluated in vivo to determine the effect on the gastrointestinal absorption of paracetamol, as compared to activated-charcoal--water slurry. The potential advantage of the activated-charcoal--yogurt mixture is a better palatability and general acceptance by the patients without loss of efficacy. In addition, paracetamol adsorption studies were carried out in vitro to calculate the maximum adsorption capacity of paracetamol to activated-charcoal--yogurt mixture. In vivo: A randomized crossover study on 15 adult volunteers, using paracetamol 50 mg/kg as a simulated overdose. Each study day volunteers were given a standard meal 1 h before paracetamol, then 50 g activated charcoal 1 h later in either of two preparations: standard water slurry or mixed with 400 mL yogurt. Paracetamol serum concentrations were measured using HPLC. The areas under the concentration-time curve (AUC) of the two preparations were compared and used to estimate the efficacy of each preparation. The palatability of both preparations was evaluated using a visual-analogue scale where the volunteers were asked to evaluate the appearance, smell, flavor, texture, ability to swallow, and overall impression of the mixtures. The time spent to consume the activated charcoal was also registered. In vitro: Activated charcoal, simulated gastric (pH 1.2) or intestinal (pH 7.2) fluid, and paracetamol were mixed with yogurt followed by 1 h incubation. The maximum adsorption capacity of paracetamol to activated charcoal was calculated using Langmuir's adsorption isotherm. Paracetamol concentration was analyzed using HPLC. In vivo there was no significant difference (p > 0.05) in the AUC of paracetamol between the two activated-charcoal preparations. Geometric mean values and 95% CI for the AUCs were (in mg/l x min): 6307 (4932-8065) for the activated charcoal--water slurry and 6525 (5111-8330) for the activated charcoal--yogurt mixture. The palatability study showed significant difference (p < 0.05) only in duration of administration, in favor of the activated charcoal--water slurry. In vitro the maximum adsorption capacity of activated charcoal with added yogurt was 544 mg paracetamol/g activated charcoal (pH 1.2), and 569 mg paracetamol/g activated charcoal (pH 7.2). The two activated-charcoal preparations showed equal (NS) absorption reduction of paracetamol in vivo. Mixing activated charcoal with yogurt rather than water prolonged the ingestion time, but did not improve the palatability in adults. The presence of yogurt reduced the adsorption capacity in vitro by 9-13% (p < 0.05) compared to control without yogurt (previous study with the same setup).


Potential role of the combination of galantamine and memantine to improve cognition in schizophrenia.
The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and Schizophrenia projects were designed to facilitate the development of new drugs for the treatment of cognitive impairments in people with schizophrenia. The MATRICS project identified three drug mechanisms of particular interest: dopaminergic, cholinergic, and glutamatergic. As a group, while people with schizophrenia have moderate cognitive impairment, it is the best predictor of long-term outcome. Unfortunately, there are no approved medications for cognitive impairment in this population. Hence, the development of new pharmacological approaches is critical for reducing illness-related disability. The combination of an acetylcholinesterase inhibitor (AChEI) and memantine is more effective than either medication alone to improve cognition in Alzheimer's dementia. Galantamine is not only an AChEI, but also a positive allosteric modulator of the α4β2 and α7 nicotinic receptors. Hypofunction of N-methyl-d-aspartate (NMDA) receptors has been implicated in the pathophysiology of cognitive symptoms in schizophrenia and hence memantine may positively impact cognition. Memantine decreases the tonic NMDA current and galantamine enhances the action potential mediated by a postsynaptic NMDA current. This results in an increased signal transmission; therefore, a greater signal-to-noise ratio occurs with the combination than memantine alone. Galantamine improves the α-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA)-mediated signaling which could be neuroprotective and may improve memory coding. The combination of galantamine and memantine may be particularly effective in schizophrenia in order to increase the selective cognition enhancement produced by either medication alone. In the future, multitarget-directed ligands may play a role in the treatment of complex diseases like schizophrenia.


Noninvasive ventilation as a weaning strategy for mechanical ventilation in adults with respiratory failure: a Cochrane systematic review.
Noninvasive ventilation has been studied as a means of reducing complications among patients being weaned from invasive mechanical ventilation. We sought to summarize evidence comparing noninvasive and invasive weaning and their effects on mortality. We identified relevant randomized and quasirandomized trials through searches of databases, conference proceedings and grey literature. We included trials comparing extubation and immediate application of noninvasive ventilation with continued invasive weaning in adults on mechanical ventilation. Two reviewers each independently screened citations, assessed trial quality and abstracted data. Our primary outcome was mortality. We identified 16 trials involving 994 participants, most of whom had chronic obstructive pulmonary disease (COPD). Compared with invasive weaning, noninvasive weaning significantly reduced mortality (risk ratio [RR] 0.53, 95% confidence interval [CI] 0.36 to 0.80), weaning failures (RR 0.63, 95% CI 0.42 to 0.96), ventilator-associated pneumonia (RR 0.25, 95% CI 0.15 to 0.43), length of stay in the intensive care unit (mean difference [MD] -5.59 d, 95% CI -7.90 to -3.28) and in hospital (MD -6.04 d, 95% CI -9.22 to -2.87), and total duration of mechanical ventilation (MD -5.64 d, 95% CI -9.50 to -1.77). Noninvasive weaning had no significant effect on the duration of ventilation related to weaning, but significantly reduced rates of tracheostomy (RR 0.19, 95% CI 0.08 to 0.47) and reintubation (RR 0.65, 95% CI 0.44 to 0.97). Mortality benefits were significantly greater in trials enrolling patients with COPD than in trials enrolling mixed patient populations (RR 0.36 [95% CI 0.24 to 0.56] v. RR 0.81 [95% CI 0.47 to 1.40]). Noninvasive weaning reduces rates of death and pneumonia without increasing the risk of weaning failure or reintubation. In subgroup analyses, mortality benefits were significantly greater in patients with COPD.


Interleukin-4 promoter polymorphisms: a genetic prognostic factor for survival in metastatic renal cell carcinoma.
Renal cell carcinoma (RCC) is considered a cytokine-responsive tumor. The clinical course of a patient may thus be influenced by the patient's capacity to produce distinct cytokines. Therefore, cytokine gene polymorphisms in RCC patients were analyzed to determine haplotype combinations with prognostic significance. A selection of 21 single nucleotide polymorphisms within the promoter regions of 13 cytokine genes were analyzed in a cross-sectional single-center study of 80 metastatic RCC patients. Univariate and multivariate analyses and the Cox forward-stepwise regression model were chosen to assess genetic risk factors. Multivariate Cox regression analysis confirmed by a bootstrap technique identified the heterozygous IL4 genotype -589T-33T/-589C-33C as an independent prognostic risk factor (risk ratio, 3.1; P < .01; 95% CI, 1.4 to 6.9; adjusted for age, sex, and nuclear grading) in metastatic RCC patients. IL4 haplotype -589T-33T and -589C-33C were found with a frequency of 0.069 and 0.925, respectively, which represents a two-fold decrease of IL4 haplotype -589T-33T (P < .01) and an increase of IL4 haplotype -589C-33C frequency (P < .05) in metastatic RCC compared with other white reference study populations. The median overall survival was decreased 3.5-fold (P < .05) in heterozygote patients carrying IL4 haplotype -589T-33T and -589C-33C (3.78 months) compared with patients homozygote for IL4 haplotype -589C-33C (13.44 months). In addition, a linkage disequilibrium between the IL4 gene and the KIF3A gene was detected. Our findings indicate that IL4 promoter variants influence prognosis in patients with metastatic RCC and suggest that genetically determined interleukin-4 (IL-4) production affects the clinical course of the disease possibly through regulation of immune surveillance.


The Effects of Repetition on Children's True and False Reports.
As children are often called upon to provide testimony in court proceedings, determining the veracity of their statements is an important issue. In the course of investigation by police and social workers, children are often repeatedly interviewed about their experiences, though the impact of this repetition on children's true and false statements remains largely unexamined. The current study analysed semantic differences in children's truthful and fabricated statements about an event they had or had not participated in. Results revealed that children's truthful and fabricated reports differed in linguistic content, and that their language also varied with repetition. Discriminant analyses revealed that with repetition, children's true and false reports became increasingly difficult to differentiate using linguistic markers, though true reports were consistently classified correctly at higher rates than false reports. The implications of these findings for legal procedures concerning child witnesses are discussed.


Clinical pharmacology of vigabatrin.
1. Upon oral administration vigabatrin is rapidly absorbed. Plasma elimination half-life ranges between 5 and 7 h in normal volunteers. Vigabatrin is eliminated primarily via the kidneys with about 65% of the administered dose found unchanged in the urine within 24 h. Kinetics are dose-linear within the range of usual therapeutic doses. 2. At therapeutic doses in man vigabatrin produces dose-related increases in CSF concentrations of free and total GABA, homocarnosine (the GABA-histidine dipeptide) and beta-alanine. These biochemical changes are consistent with an inhibition of GABA-transaminase activity in brain. 3. Thus, with systemic availability upon oral administration and biochemical activity in the CNS, the prerequisites for potential uses of vigabatrin in neurological disorders have been demonstrated in clinical pharmacological studies.


Retained intracranial splinters : a follow up study in survivors of low intensity military conflicts.
With improvements in the ballistic physics, patient evacuation, imaging, neurosurgical management and intensive care facilities, there has been overall improvement in the survival of patients with missile injuries of the brain. Patients with retained intracranial fragments have been followed up and the sequelae of such fragments were analysed. We present our observations in 43 such patients who had survived low velocity missile injuries of the brain during military conflicts and had retained intracranial fragments. Over a follow up period of 2 to 7 years, suppurative sequelae (brain abscess, recurrent meningitis) were seen in 6 patients, two of these progressing to formation of brain abscess. Three patients developed hydrocephalus and one seizures. Patients with orbitocranial or faciocranial wound of entry had a higher incidence of suppurative complications (3 out of 4), while those with skull vault entry had a lower incidence of such sequelae (7 out of 30). Nine patients were lost to follow up. Other determinants of suppurative complications were postoperative CSF leak and intraventricular lodgement of the fragment.


Dendritic remodeling and growth of motoneurons during metamorphosis of Drosophila melanogaster.
Insect motoneurons display dramatic dendritic plasticity during metamorphosis. Many larval motoneurons survive to adulthood but undergo dendritic regression and outgrowth as they are incorporated into developing circuits. This study explores the dendritic remodeling and development of Drosophila motoneurons MN1-MN5, which innervate indirect flight muscles of the adult. MN1-MN5 are persistent larval neurons exhibiting two distinct metamorphic histories. MN1-MN4 are born in the embryo, innervate larval muscles, and undergo dendritic regression and regrowth during metamorphosis. MN5, which was identified through a combination of intracellular dye injection and retrograde staining at all stages, is also born embryonically but remains developmentally arrested until the onset of metamorphosis. In the larva, MN5 lacks dendrites, and its axon stops in the mesothoracic nerve without innervating a target muscle. It is dye coupled to the peripherally synapsing interneuron, which will become part of the giant fiber escape circuit of the adult fly. During pupal development, MN5 undergoes de novo dendritic growth and extension of its axon to innervate the developing target muscle. Its unique developmental history and identifiability make MN5 well suited for the study of dendritic growth using genetic and neurophysiological approaches.


Mitophagy in yeast: actors and physiological roles.
Mitochondria are essential for oxidative energy production in aerobic eukaryotic cells, where they are also required for multiple biosynthetic pathways to take place. Mitochondria also monitor and evaluate complex information from the environment and intracellular milieu, including the presence or absence of growth factors, oxygen, reactive oxygen species, and DNA damage. It follows that disturbances of the integrity of mitochondrial function lead to the disruption of cell function, expressed as disease, aging, or cell death. It has been assumed that the degradation of damaged mitochondria by an autophagy-related pathway specific to mitochondria (mitophagy), recently found to be strictly regulated, is a fundamental process essential for cell homeostasis. Until now, the main role of mitophagy has been tentatively defined as a 'house-cleaning' pathway that allows to eliminate altered mitochondria, but mitophagy may also play a role in the adaptation of the number and quality of mitochondria to new environmental conditions. In yeast, recent data defined two categories of mitophagy actors: ones constitutively required for mitophagy and those with mitophagy-regulatory functions. Situations were also uncovered in normal physiology in which cells utilize mitophagy to eliminate damaged, dysfunctional, and superfluous mitochondria to adjust to changing physiological demands.


Intra-rater reliability and criterion-related validity of using an accelerometer to measure the impact force and knee joint sway during single-leg drop landing.
[Purpose] This study aimed to clarify the reliability and validity of the impact force and knee joint sway measurement during single-leg drop landing by using a motion sensor with two built-in accelerometers. [Participants and Methods] Ten healthy college students (4 males and 6 females) who joined a basketball club participated in this study. Peak vertical acceleration, time between initial contact and peak vertical acceleration, and knee joint mediolateral sway were measured using the accelerometer during the landing motion. Reliability of the measurement with the accelerometer and the criterion-related validity between the accelerometer and force plate data were examined. [Results] The intraclass correlation coefficients indicated a peak vertical acceleration of 0.88, time between initial contact and peak vertical acceleration of 0.96, and knee joint mediolateral sway of 0.62. The magnitude and timing of the peak values between both measurement instruments showed high validity. [Conclusion] The measurement method using a motion sensor for the evaluation of the impact force and knee joint sway during landing has a moderate to high reliability and criterion-related validity. A motion sensor measurement might be a useful and easy method for evaluating landing impact force and knee joint stability.


cDNA cloning and characterization of tobacco ABC transporter: NtPDR1 is a novel elicitor-responsive gene.
We isolated an INF1 elicitin-inducible cDNA encoding a pleiotropic drug resistance (PDR)-type ATP-binding cassette (ABC) transporter homolog (NtPDR1) in suspension-cultured tobacco Bright Yellow-2 (BY-2) cells by application of differential display PCR. The NtPDR1 (Nicotiana tabacum PDR protein 1) gene also encodes a 162 kDa protein that includes two putative hydrophilic domains containing the ABC signature motif and two putative hydrophobic domains. Expression of the NtPDR1 gene was rapidly and strongly activated by treatment of BY-2 cells with INF1 elicitin. Further, treatment of BY-2 cells with flagellin, a bacterial proteinaceous hypersensitive reaction elicitor, or yeast extract, a general elicitor, also induced NtPDR1 gene expression. These results indicate that NtPDR1 may be involved in the general defense response in tobacco. This is the first report that microbial elicitors induce the expression of a plant ABC transporter gene.


Rare causes of dystonia parkinsonism.
The list of genetic causes of syndromes of dystonia parkinsonism grows constantly. As a consequence, the diagnosis becomes more and more challenging for the clinician. Here, we summarize the important causes of dystonia parkinsonism including autosomal-dominant, recessive, and x-linked forms. We cover dopa-responsive dystonia, Wilson's disease, Parkin-, PINK1-, and DJ-1-associated parkinsonism (PARK2, 6, and 7), x-linked dystonia-parkinsonism/Lubag (DYT3), rapid-onset dystonia-parkinsonism (DYT12) and DYT16 dystonia, the syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA) including pantothenate kinase (PANK2)- and PLA2G6 (PARK14)-associated neurodegeneration, neuroferritinopathy, Kufor-Rakeb disease (PARK9) and the recently described SENDA syndrome; FBXO7-associated neurodegeneration (PARK15), autosomal-recessive spastic paraplegia with a thin corpus callosum (SPG11), and dystonia parkinsonism due to mutations in the SLC6A3 gene encoding the dopamine transporter. They have in common that in all these syndromes there may be a combination of dystonic and parkinsonian features, which may be complicated by pyramidal tract involvement. The aim of this review is to familiarize the clinician with the phenotypes of these disorders.


Dietary patterns and mortality in Danish men and women: a prospective observational study.
The analysis of dietary patterns emerged recently as a possible approach to examining diet-disease relation. We analysed the risk of all-cause and cardiovascular mortality associated with dietary patterns in men and women, while taking a number of potential confounding variables into account. Data were from a prospective cohort study with follow-up of total and cause-specific mortality. A random sample of 3698 men and 3618 women aged 30-70 years and living in Copenhagen County, Denmark, were followed from 1982 to 1998 (median 15 years). Three dietary patterns were identified from a twenty-eight item food frequency questionnaire, collected at baseline: (1) a predefined healthy food index, which reflected daily intakes of fruits, vegetables and wholemeal bread, (2) a prudent and (3) a Western dietary pattern derived by principal component analysis. The prudent pattern was positively associated with frequent intake of wholemeal bread, fruits and vegetables, whereas the Western was characterized by frequent intakes of meat products, potatoes, white bread, butter and lard. Among participants with complete information on all variables, 398 men and 231 women died during follow-up. The healthy food index was associated with reduced all-cause mortality in both men and women, but the relations were attenuated after adjustment for smoking, physical activity, educational level, BMI, and alcohol intake. The prudent pattern was inversely associated with all-cause and cardiovascular mortality after controlling for confounding variables. The Western pattern was not significantly associated with mortality. This study partly supports the assumption that overall dietary patterns can predict mortality, and that the dietary pattern associated with the lowest risk is the one which is in accordance with the current recommendations for a prudent diet.


Modeling forces and moments at the base of a rat vibrissa during noncontact whisking and whisking against an object.
During exploratory behavior, rats brush and tap their whiskers against objects, and the mechanical signals so generated constitute the primary sensory variables upon which these animals base their vibrissotactile perception of the world. To date, however, we lack a general dynamic model of the vibrissa that includes the effects of inertia, damping, and collisions. We simulated vibrissal dynamics to compute the time-varying forces and bending moment at the vibrissa base during both noncontact (free-air) whisking and whisking against an object (collision). Results show the following: (1) during noncontact whisking, mechanical signals contain components at both the whisking frequency and also twice the whisking frequency (the latter could code whisking speed); (2) when rats whisk rhythmically against an object, the intrinsic dynamics of the vibrissa can be as large as many of the mechanical effects of the collision, however, the axial force could still generate responses that reliably indicate collision based on thresholding; and (3) whisking velocity will have only a small effect on the transient response generated during a whisker-object collision. Instead, the transient response will depend in large part on how the rat chooses to decelerate its vibrissae after the collision. The model allows experimentalists to estimate error bounds on quasi-static descriptions of vibrissal shape, and its predictions can be used to bound realistic expectations from neurons that code vibrissal sensing. We discuss the implications of these results under the assumption that primary sensory neurons of the trigeminal ganglion are sensitive to various combinations of mechanical signals.


Development of a fraction collection approach in capillary electrophoresis SELEX for aptamer selection.
Aptamers have attracted much attention due to their ability to bind to target molecules with high affinity and specificity. The development of an approach capable of efficiently generating aptamers through systematic evolution of ligands by exponential enrichment (SELEX) is particularly challenging. Herein, a fraction collection approach in capillary electrophoresis SELEX (FCE-SELEX) for the partition of a bound DNA-target complex is developed. By integrating fraction collection with a facile oil seal method for avoiding contamination while amplifying the bound DNA-target complex, in a single round of selection, a streptavidin-binding aptamer (SBA) has been generated. The affinity of aptamer SBA-36 for streptavidin (SA) is determined as 30.8 nM by surface plasmon resonance (SPR). Selectivity and biotin competition experiments demonstrate that the SBA-36 aptamer selected by FCE-SELEX is as efficient as those from other methods. Based on the ability of fraction collection in partition and collection of the aptamer-target complex from the original DNA library, FCE-SELEX can be a universal tool for the development of aptamers.


A comparison of physical activity, physical fitness levels, BMI and blood pressure of adults with intellectual disability, who do and do not take part in Special Olympics Ireland programmes: Results from the SOPHIE study.
People with an intellectual disability are less physically active, live more sedentary lives, have lower fitness levels and are more likely to be overweight or obese than the general population. No evidence exists on the impact of participation in Special Olympics Ireland (SOI) on physical activity and physical fitness levels. Adults with intellectual disabilities (16-64 years) were recruited from services and SOI clubs. Physical measures included waist circumference, height, weight, blood pressure, heart rate and 6-min walking test. Self-report questionnaires gathered data on physical activity levels. Actigraph (GT3X) accelerometers were used to gain an objective measure of physical activity. SOI participants accumulated more moderate to vigorous physical activity per day, had higher fitness levels and more positive health profile scores than those not taking part in SOI. SOI has the potential to make a positive difference to people's physical health and subsequently their overall health and well-being.


Estimating the prevalence and intensity of Schistosoma mansoni infection among rural communities in Western Tanzania: The influence of sampling strategy and statistical approach.
Schistosoma mansoni is a parasite of major public health importance in developing countries, where it causes a neglected tropical disease known as intestinal schistosomiasis. However, the distribution of the parasite within many endemic regions is currently unknown, which hinders effective control. The purpose of this study was to characterize the prevalence and intensity of infection of S. mansoni in a remote area of western Tanzania. Stool samples were collected from 192 children and 147 adults residing in Gombe National Park and four nearby villages. Children were actively sampled in local schools, and adults were sampled passively by voluntary presentation at the local health clinics. The two datasets were therefore analysed separately. Faecal worm egg count (FWEC) data were analysed using negative binomial and zero-inflated negative binomial (ZINB) models with explanatory variables of site, sex, and age. The ZINB models indicated that a substantial proportion of the observed zero FWEC reflected a failure to detect eggs in truly infected individuals, meaning that the estimated true prevalence was much higher than the apparent prevalence as calculated based on the simple proportion of non-zero FWEC. For the passively sampled data from adults, the data were consistent with close to 100% true prevalence of infection. Both the prevalence and intensity of infection differed significantly between sites, but there were no significant associations with sex or age. Overall, our data suggest a more widespread distribution of S. mansoni in this part of Tanzania than was previously thought. The apparent prevalence estimates substantially under-estimated the true prevalence as determined by the ZINB models, and the two types of sampling strategies also resulted in differing conclusions regarding prevalence of infection. We therefore recommend that future surveillance programmes designed to assess risk factors should use active sampling whenever possible, in order to avoid the self-selection bias associated with passive sampling.


Kinetochore-associated Stu2 promotes chromosome biorientation in vivo.
Accurate segregation of chromosomes to daughter cells is a critical aspect of cell division. It requires the kinetochores on duplicated chromosomes to biorient, attaching to microtubules from opposite poles of the cell. Bioriented attachments come under tension, while incorrect attachments lack tension and must be released to allow proper attachments to form. A well-studied error correction pathway is mediated by the Aurora B kinase, which destabilizes low tension-bearing attachments. We recently discovered that in vitro, kinetochores display an additional intrinsic tension-sensing pathway that utilizes Stu2. The contribution of kinetochore-associated Stu2 to error correction in cells, however, was unknown. Here, we identify a Stu2 mutant that abolishes its kinetochore function and show that it causes biorientation defects in vivo. We also show that this Stu2-mediated pathway functions together with the Aurora B-mediated pathway. Altogether, our work indicates that cells employ multiple pathways to ensure biorientation and the accuracy of chromosome segregation.


Risk factors for vitamin D deficiency among HIV-infected and uninfected injection drug users.
Vitamin D deficiency is highly prevalent and is associated with bone disease, cardiovascular disease, metabolic syndrome and malignancy. Injection drug users (IDUs), with or without HIV infection, are at risk for these conditions; however, limited data on vitamin D deficiency exist in this population. We determined the prevalence and correlates of vitamin D deficiency among urban IDUs in the AIDS Linked to the IntraVenous Experience (ALIVE) Study cohort. For this cross-sectional sub-study, vitamin D deficiency was defined as a serum 25(OH)-vitamin D level <20 ng/mL. Multivariable logistic regression was used to identify factors independently associated with vitamin D deficiency. Of 950 individuals analyzed, 29% were HIV-infected. The median age was 49 years; 65% were male, and 91% were black. The median vitamin D level was 13.5 ng/mL (IQR, 9.0-20.3); 74% were deficient (68% in HIV-infected vs. 76% in HIV-uninfected, p = 0.01). Non-black race, fall/winter season, multivitamin intake, higher serum albumin, HCV seropositivity and HIV-infection were associated with significantly lower odds of vitamin D deficiency. Vitamin D deficiency is prevalent among IDUs. Notably, HIV-infected IDUs were less likely to be vitamin D deficient. Higher vitamin D levels were associated with multivitamin intake and with higher albumin levels, suggesting that nutritional status contributes substantially to deficiency. The association between HCV serostatus and vitamin D level remains unclear. Further investigation is needed to define the clinical implications of the heavy burden of vitamin D deficiency in this high-risk, aging population with significant co-morbidities.


Combining behavioral harm-reduction treatment and extended-release naltrexone for people experiencing homelessness and alcohol use disorder in the USA: a randomised clinical trial.
The rate of alcohol-related mortality in people experiencing homelessness and alcohol use disorder is high and necessitates accessible and effective treatment for alcohol use disorder. However, typical abstinence-based treatments do not optimally engage this population. Recent studies have shown that harm-reduction treatment, which does not require abstinence, but instead aims to incrementally reduce alcohol-related harm and improve health-related quality of life, is acceptable to and effective for this population. The aim of this study was to test the efficacy of combined pharmacological and behavioural harm-reduction treatment for alcohol use disorder (HaRT-A) in people experiencing homelessness and alcohol use disorder. This randomised clinical trial was done at three community-based service sites (low-barrier shelters and housing programmes) in Seattle (WA, USA). Eligible participants were adults (aged 21-65 years) who met the DSM-IV-TR criteria for alcohol use disorder and who experienced homelessness in the past year. Participants were randomly assigned (1:1:1:1) by permuted block randomisation, stratified by site, to receive either HaRT-A plus intramuscular injections of 380 mg extended-release naltrexone (XR-NTX; HaRT-A plus XR-NTX group); HaRT-A plus placebo injection (HaRT-A plus placebo group); HaRT-A alone (HaRT-A alone group); or community-based supportive services as usual (services-as-usual control group). Patients assigned to receive HaRT-A attended sessions at baseline (week 0) and in weeks 1, 4, 8, and 12. XR-NTX and placebo injections were administered in weeks 0, 4, and 8. During the study, participants, interventionists, and investigators were masked to group assignment in the two injection arms. All participants were invited to follow-up assessments at weeks 4, 8, 12, 24, and 36. The primary outcomes were self-reported alcohol use quantity (ie, alcohol quantity consumed on peak drinking occasion, as measured with the Alcohol Quantity Use Assessment questionnaire) and frequency (measured with the Addiction Severity Index), alcohol-related harm (measured with the Short Inventory of Problems-2R questionnaire), and physical and mental health-related quality of life (measured with the Short Form-12 survey). Using piecewise growth modelling and an intention-to-treat model, we compared the effects of the three active treatment groups with the services-as-usual control group, and the HaRT-A plus XR-NTX group with the HaRT-A plus placebo group, over the 12-week treatment course and during the 24 weeks following treatment withdrawal. Safety analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT01932801. Between Oct 14, 2013, and Nov 30, 2017, 417 individuals experiencing homelessness and alcohol use disorder were screened, of whom 308 were eligible and randomly assigned to the HaRT-A plus XR-NTX group (n=74), the HaRT-A plus placebo group (n=78), the HaRT-A alone group (n=79), or the services-as-usual control group (n=77). Compared with the services-as-usual control group, the HaRT-A plus XR-NTX group showed significant improvements from baseline to 12 weeks post-treatment across four of the five primary outcomes: peak alcohol quantity (linear B -0·48 [95% CI -0·79 to -0·18] p=0·010; full model Cohen's d=-0·68), alcohol frequency (linear B -4·42 [-8·09 to -0·76], p=0·047; full model Cohen's d=-0·16), alcohol-related harm (linear B -2·22 [-3·39 to -1·06], p=0·002; full model Cohen's d=-0·56), and physical health-related quality of life (linear B 0·66 [0·23 to 1·10], p=0·012; full model Cohen's d=0·43). Compared with the services-as-usual control group, the HaRT-A plus placebo group showed significant improvements in three of the five primary outcomes: peak alcohol quantity (linear B -0·41 [95% CI -0·67 to -0·15] p=0·010; full model Cohen's d=-0·23), alcohol frequency (linear B -5·95 [-9·72 to -2·19], p=0·009; full model Cohen's d=-0·13), and physical health-related quality of life (linear B 0·53 [0·09 to 0·98], p=0·050; full model Cohen's d=0·35). Compared with the services-as-usual control group, the HaRT-A alone group showed significant improvements in two of the five primary outcomes: alcohol-related harm (linear B -1·58 [95% CI -2·73 to -0·42] p=0·025; full model Cohen's d=-0·40) and physical health-related quality of life (linear B 0·63 [0·18 to 1·07], p=0·020; full model Cohen's d=0·41). After treatment discontinuation at 12 weeks, the active treatment groups plateaued, whereas the services-as-usual group showed improvements. Thus, during the post-treatment period (weeks 12 to 36), the services-as-usual control group showed greater reductions in alcohol-related harm compared with both the HaRT-A plus XR-NTX group (linear B 0·96 [0·24 to 1·67], p=0·028; full model Cohen's d=0·24) and the HaRT-A alone group (linear B 1·02 [0·35 to 1·70], p=0·013; full model Cohen's d=0·26). During the post-treatment period, the services-as-usual control group significantly improved on mental health-related quality of life compared with the HaRT-A alone group (linear B -0·46 [-0·79 to -0·12], p=0·024; full model Cohen's d=-0·28), and on physical health-related quality of life compared with the HaRT-A plus XR-NTX group (linear B -0·42 [-0·67 to -0·17], p=0·006; full model Cohen's d=-0·27), the HaRT-A plus placebo group (linear B -0·42 [-0·69 to -0·15], p=0·009; full model Cohen's d=-0·27), and the HaRT-A alone group (linear B -0·47 [-0·72 to -0·22], p=0·002; full model Cohen's d=-0·31). For all other primary outcomes, there were no significant linear differences between the services-as-usual and active treatment groups. When comparing the HaRT-A plus placebo group with the HaRT-A plus XR-NTX group, there were no significant differences for any of the primary outcomes. Missing data analysis indicated that participants were more likely to drop out in the services-as-usual control group than in the active treatment groups; however, primary outcome findings were found to be robust to attrition. Participants in the HaRT-A plus XR-NTX, HaRT-A plus placebo, and HaRT-A alone groups were not more likely to experience adverse events than those in the services-as-usual control group. Compared with existing services, combined pharmacological and behavioural harm-reduction treatment resulted in decreased alcohol use and alcohol-related harm and improved physical health-related quality of life during the 12-week treatment period for people experiencing homelessness and alcohol use disorder. Although not as consistent, there were also positive findings for behavioural harm-reduction treatment alone. Considering the non-significant differences between participants receiving HaRT-A plus placebo and HaRT-A plus XR-NTX, the combined pharmacological and behavioural treatment effect cannot be attributed to XR-NTX alone. Future studies are needed to further investigate the relative contributions of the pharmacological and behavioural components of harm-reduction treatment for alcohol use disorder, and to ascertain whether a maintenance treatment approach could extend these positive outcome trajectories. National Institute on Alcohol Abuse and Alcoholism.


Genetic Potential and Inheritance Patterns of Physiological, Agronomic and Quality Traits in Bread Wheat under Normal and Water Deficit Conditions.
Water scarcity is a major environmental stress that adversatively impacts wheat growth, production, and quality. Furthermore, drought is predicted to be more frequent and severe as a result of climate change, particularly in arid regions. Hence, breeding for drought-tolerant and high-yielding wheat genotypes has become more decisive to sustain its production and ensure global food security with continuing population growth. The present study aimed at evaluating different parental bread wheat genotypes (exotic and local) and their hybrids under normal and drought stress conditions. Gene action controlling physiological, agronomic, and quality traits through half-diallel analysis was applied. The results showed that water-deficit stress substantially decreased chlorophyll content, photosynthetic efficiency (FV/Fm), relative water content, grain yield, and yield attributes. On the other hand, proline content, antioxidant enzyme activities (CAT, POD, and SOD), grain protein content, wet gluten content, and dry gluten content were significantly increased compared to well-watered conditions. The 36 evaluated genotypes were classified based on drought tolerance indices into 5 groups varying from highly drought-tolerant (group A) to highly drought-sensitive genotypes (group E). The parental genotypes P3 and P8 were identified as good combiners to increase chlorophyll b, total chlorophyll content, relative water content, grain yield, and yield components under water deficit conditions. Additionally, the cross combinations P2 × P4, P3 × P5, P3 × P8, and P6 × P7 were the most promising combinations to increase yield traits and multiple physiological parameters under water deficit conditions. Furthermore, P1, P2, and P5 were recognized as promising parents to improve grain protein content and wet and dry gluten contents under drought stress. In addition, the crosses P1 × P4, P2 × P3, P2 × P5, P2 × P6, P4 × P7, P5 × P7, P5 × P8, P6 × P8, and P7 × P8 were the best combinations to improve grain protein content under water-stressed and non-stressed conditions. Certain physiological traits displayed highly positive associations with grain yield and its contributing traits under drought stress such as chlorophyll a, chlorophyll b, total chlorophyll content, photosynthetic efficiency (Fv/Fm), proline content, and relative water content, which suggest their importance for indirect selection under water deficit conditions. Otherwise, grain protein content was negatively correlated with grain yield, indicating that selection for higher grain yield could reduce grain protein content under drought stress conditions.


Efficacy and safety of fixed low-dose dalteparin in preventing venous thromboembolism among obese or elderly hospitalized patients: a subgroup analysis of the PREVENT trial.
We were concerned that a fixed rather than a weight-based dosing regimen of dalteparin sodium to prevent venous thromboembolism (VTE) might result in decreased efficacy in obese patients and decreased safety in elderly patients. We retrospectively performed subgroup analyses using the database from the Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients (PREVENT) Trial, a study of 3706 hospitalized, medically ill patients randomized to receive either dalteparin sodium, 5000 U/d, or placebo. The primary end point was a composite of symptomatic VTE, fatal pulmonary embolism, sudden death, or asymptomatic proximal deep venous thrombosis by day 21. Obesity was defined as a body mass index (calculated as weight in kilograms divided by the square of height in meters) of 30 or greater for men and 28.6 or greater for women. Overall, 1118 patients (30.4%) were obese and 1226 (33.3%) were 75 years or older. In obese patients, the primary end point occurred in 2.8% of the dalteparin and in 4.3% of the placebo groups (relative risk, 0.64; 95% confidence interval [CI], 0.32-1.28). In patients 75 years or older, the primary end point was reported in 4.2% of the dalteparin and in 8.0% of the placebo groups (relative risk, 0.52; 95% CI, 0.31-0.87). The dalteparin effect for the primary end point (odds ratio, 0.51; 95% CI, 0.32-0.82) was not attenuated when adjusted for age, sex, obesity, history of VTE, and varicose veins. Dalteparin was not associated with an increase in major hemorrhage by day 21 in obese (0% vs 0.7% placebo; P>.99) and in elderly (1.1% vs 0.7%; P=.12) patients. Our findings suggest that a fixed low dose of dalteparin sodium of 5000 U/d is effective and safe in preventing VTE in obese and elderly hospitalized medical patients.


Visual pattern recognition in Drosophila is invariant for retinal position.
Vision relies on constancy mechanisms. Yet, these are little understood, because they are difficult to investigate in freely moving organisms. One such mechanism, translation invariance, enables organisms to recognize visual patterns independent of the region of their visual field where they had originally seen them. Tethered flies (Drosophila melanogaster) in a flight simulator can recognize visual patterns. Because their eyes are fixed in space and patterns can be displayed in defined parts of their visual field, they can be tested for translation invariance. Here, we show that flies recognize patterns at retinal positions where the patterns had not been presented before.


Stress and Coping Style of High-risk Pregnant Women's Spouses.
This study determined the level of stress and type of coping style of spouses with high-risk pregnant women. Subjects were 102 spouses with high-risk pregnant women at 6 hospitals in Seoul and Gyeonggi province from January to August, 2009. The tools for this study were stress scale and coping scale. The data were analyzed by t-test, ANOVA, Scheffe's test and Pearson's correlation coefficient. The average score of subjects stress was 2.18 and coping score was 2.46 point out of 4.00. The highest score of stress categories was 2.44 point in emotional problems and the lowest score was 1.72 in communication and support resources. The stress level was significant differences according to length of marriage, number of hospital visits, satisfaction with marriage relationship, hospitalization days and gestational age respectively. Spouses tended to use an active coping style (2.60) rather than a passive coping style (2.31). There were significant differences according to mother's age and gestational age in active coping and educational level in passive coping. Considering the level of stress coping style and characteristics of high-risk pregnant women's spouses, a nursing intervention should be provided to help them alleviate stress and to encourage active coping.


Ionization of carboxylic acid clusters in the gas phase and on free ArN and (H2O)N nanoparticles: valeric acid as a model for small carboxylic acids.
We investigate ionization of valeric (n-pentanoic) acid clusters both in the gas phase and on argon and water nanoparticles using mass spectrometry. Compared to the ionization of a single valeric acid molecule, new reaction channels are observed in clusters, mostly attributed to proton transfer between two valeric acid molecules and formation of valeric anhydride. These reactions are also observed when valeric acid molecules are deposited and generate clusters on ArN, and are independent of the ionization method, whether electron ionization or photoionization is used. Valeric acid clusters exhibit a high water affinity, both in neutral clusters and after ionization. When valeric acid is adsorbed on (H2O)M ice nanoparticles, no new specific reactions with water are observed. However, in this case, electron ionization yields mostly protonated water clusters while the photoionization spectrum does not differ significantly from free and ArN-deposited valeric acid clusters. Based on quantum chemical calculations, we extrapolate our results to carboxylic acids with 1-8 carbon atoms. The calculations show that the high affinity to water can be expected in the whole investigated size range while the highest probability of anhydride formation is predicted for n = 3-6. The observed reaction patterns in the ionization of valeric acid are thus prototypical for ionization of clusters of short-chain fatty acids.


Local intravascular pressure habituation in relation to G-induced arm pain.
During high +Gz loads, pilots may experience arm pain. It is commonly assumed that such pain is caused by distension of blood vessels and that vascular distensibility adapts to the prevailing transmural pressure. The aim was to investigate whether vascular pressure habituation (PH) is as efficient in alleviating G-induced arm pain as using counterpressure/support garments. In Series I, 7 subjects underwent a 5-wk PH regimen, consisting of 15 40-min sessions, during which intravascular pressures in one arm were elevated by 65-105 mmHg. Before and after PH, arm pain was determined during incremental +Gz-exposures in a centrifuge. In Series II, the effect on G-induced arm pain of wearing protective garments around the lower part of the upper arm was investigated in 10 subjects in 4 conditions: 1) counterpressure; 2) rigid support; 3) sham support; and 4) no support (control). Pain was rated using a 10-point graded scale. PH reduced arm pain at 7.5 G from [median (range)] 4 (2-9) to 2 (0-5) in the pressure-habituated arm. The sham support did not affect pain compared to in the control condition (5.2; 3.0-10.0), whereas pain was reduced by both the rigid support (3.7; 1.0-8.0) and the counterpressure (2.5; 0.0-5.5). PH was as efficient in alleviating pain as the counterpressure and more efficient than the rigid support. The results support the notion that G-induced arm pain is caused by vascular overdistension. Repeated moderate elevations of local intravascular pressure reduce G-induced arm pain, presumably because such PH reduces vascular distensibility.


Application of response functions to make efficient Monte Carlo simulations of germanium detectors.
A new Monte Carlo procedure to compute the efficiency and the coincidence summing corrections for closed end HPGe detectors was developed. In this procedure detector specific response functions that give the probability of getting a signal in the peak or in the total spectrum for photons incident on the end cap of the detector are used. The procedure is time efficient in the case of large scale computations because part of the simulation is circumvented by the use of pre-computed response functions.


Pediatric Sepsis Diagnosis, Management, and Sub-phenotypes.
Sepsis and septic shock are major causes of morbidity, mortality, and health care costs for children worldwide, including >3 million deaths annually and, among survivors, risk for new or worsening functional impairments, including reduced quality of life, new respiratory, nutritional, or technological assistance, and recurrent severe infections. Advances in understanding sepsis pathophysiology highlight a need to update the definition and diagnostic criteria for pediatric sepsis and septic shock, whereas new data support an increasing role for automated screening algorithms and biomarker combinations to assist earlier recognition. Once sepsis or septic shock is suspected, attention to prompt initiation of broad-spectrum empiric antimicrobial therapy, fluid resuscitation, and vasoactive medications remain key components to initial management with several new and ongoing studies offering new insights into how to optimize this approach. Ultimately, a key goal is for screening to encompass as many children as possible at risk for sepsis and trigger early treatment without increasing unnecessary broad-spectrum antibiotics and preventable hospitalizations. Although the role for adjunctive treatment with corticosteroids and other metabolic therapies remains incompletely defined, ongoing studies will soon offer updated guidance for optimal use. Finally, we are increasingly moving toward an era in which precision therapeutics will bring novel strategies to improve outcomes, especially for the subset of children with sepsis-induced multiple organ dysfunction syndrome and sepsis subphenotypes for whom antibiotics, fluid, vasoactive medications, and supportive care remain insufficient.


Accuracy of three pre- and intra-operative measurement techniques for osteotomy positioning in the tibial plateau levelling procedure.
To prospectively compare the accuracy of three preoperative measurement techniques in tibial plateau levelling osteotomy (TPLO) planning. Fifty-nine dogs were randomly assigned to one of three measurement techniques; A, B or C. Surgeons measured the intended osteotomy location on preoperative radiographs according to the assigned technique. Measurements were used intra-operatively during osteotomy placement. Postoperative measurements were made by a single blinded observer and compared to preoperative measurements. Fifty-one dogs were included for final statistical analysis. The mean absolute differences between pre- and postoperative measurements was 1.72 mm ± 0.958, 1.79 mm ± 1.010, and 3.56 mm ± 1.839, for techniques A, B and C, respectively. No significant differences were identified for patient age, gender, limb or surgeon. Techniques A and B were not significantly different (p = 0.8799). Techniques A and B were significantly more accurate than C (p = 0.0001 and p = 0.0003, respectively). Weight was significantly different among the groups (p = 0.047) but the statistical results did not change when an adjustment was made for bodyweight (p = 0.4971, p <0.001 and p = 0.0007, respectively). Preoperative measuring for planning a TPLO osteotomy is recommended. Techniques A and B in the current study were clinically practical and significantly more accurate compared to technique C.


Fibronectin degradation in chronic wounds depends on the relative levels of elastase, alpha1-proteinase inhibitor, and alpha2-macroglobulin.
The goal of our studies was to learn about the mechanism of fibronectin degradation in chronic ulcers. We found that the appearance of fibronectin fragments in chronic ulcer wound fluid correlated with elevated levels of elastase and cleavage of the proteinase inhibitors alpha2-macroglobulin (alpha2-M) and alpha 1-proteinase inhibitor (alpha1-P1). Some wound fluid samples retained the capacity to degrade fibronectin in vitro. Degradation of fibronectin by these samples was blocked by specific inhibitors of neutrophil elastase but not by inhibitors of metalloproteinases. Addition of human neutrophil elastase to mastectomy fluid, an acute wound fluid, resulted in formation of alpha1-PI and alpha2-M complexes and cleavage products resembling those observed in chronic wound fluid. Moreover, degradation of fibronectin and processing of matrix metalloproteinase MMP-9 occurred under these conditions. Taken together, our findings suggest that elevated levels of neutrophil elastase are responsible for fibronectin degradation in the chronic wound environment.


Microarray gene expression analysis of murine tumor heterogeneity defined by dynamic contrast-enhanced MRI.
Current methods of studying angiogenesis are limited in their ability to serially evaluate in vivo function throughout a target tissue. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and pharmacokinetic modeling provide a useful method for evaluating tissue vasculature based on contrast accumulation and washout. While it is often assumed that areas of high contrast enhancement and washout comprise areas of increased angiogenesis and tumor activity, the actual molecular pathways that are active in such areas are poorly understood. Using DCE-MRI in a murine subcutaneous tumor model, we were able to perform pharmacokinetic functional analysis of a tumor, coregistration of MRI images with histological cross-sections, immunohistochemistry, laser capture microdissection, and genetic profiling of tumor heterogeneity based on pharmacokinetic parameters. Using imaging as a template for biologic investigation, we have not found evidence of increased expression of proangiogenic modulators at the transcriptional level in either distinct pharmacokinetic region. Furthermore, these regions show no difference on histology and CD31 immunohistochemistry. However, the expression of ribosomal proteins was greatly increased in high enhancement and washout regions, implying increased protein translation and consequent increased cellular activity. Together, these findings point to the potential importance of posttranscriptional regulation in angiogenesis and the need for the development of angiogenesis-specific contrast agents to evaluate in vivo angiogenesis at a molecular level.


Neuroprotective effect of YM90K, an AMPA-receptor antagonist, against delayed neuronal death induced by transient global cerebral ischemia in gerbils and rats.
We investigated the neuroprotective effect of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-receptor antagonist YM90K in transient global ischemia models. In a gerbil model, transient ischemia was induced by bilateral common carotid artery (CCA) occlusion for 5 min. On administration at 1 hr after ischemia, the AMPA antagonists NBQX (30 mg/kg, i.p. x 3) and YM90K (15 mg/kg, i.p. x 3 or 30 mg/kg, i.p. x 3) significantly reduced the delayed neuronal death in the hippocampal CA1 region from 4 days after bilateral CCA occlusion. Furthermore, YM90K (30 mg/kg, i.p. x 3) showed a neuroprotective effect even when given at 6 hr after ischemia. In contrast, the N-methyl-D-aspartate receptor antagonists CGS19755, MNQX (30 mg/kg, i.p. x 3, each) and (+/-)MK-801 (10 mg/kg, i.p.) were not effective on injection at 1 hr after ischemia in this model. In a rat model, ischemia was induced by 4-vessel occlusion (4-VO) for 10 min. YM90K was administered 60 min after reperfusion. Rectal and temporal muscle temperatures were maintained at the same level as in the control group for 6 hr. YM90K markedly prevented the development of delayed neuronal death from 7 days after 4-VO at doses of 15 or 30 mg/kg, i.p. x 3, with neuroprotective efficacy similar to that in the gerbil model. These results suggest that the AMPA receptor plays a critical role in the development of the delayed neuronal death induced by transient global cerebral ischemia. They also suggest that the neuroprotective effect of YM90K is not related to its hypothermic effect.


The Gossypium longicalyx Genome as a Resource for Cotton Breeding and Evolution.
Cotton is an important crop that has made significant gains in production over the last century. Emerging pests such as the reniform nematode have threatened cotton production. The rare African diploid species Gossypium longicalyx is a wild species that has been used as an important source of reniform nematode immunity. While mapping and breeding efforts have made some strides in transferring this immunity to the cultivated polyploid species, the complexities of interploidal transfer combined with substantial linkage drag have inhibited progress in this area. Moreover, this species shares its most recent common ancestor with the cultivated A-genome diploid cottons, thereby providing insight into the evolution of long, spinnable fiber. Here we report a newly generated de novo genome assembly of G. longicalyx This high-quality genome leveraged a combination of PacBio long-read technology, Hi-C chromatin conformation capture, and BioNano optical mapping to achieve a chromosome level assembly. The utility of the G. longicalyx genome for understanding reniform immunity and fiber evolution is discussed.


Colorectal cancer mortality and factors related to the insulin resistance syndrome.
It has been proposed that hyperinsulinemia is involved in colon carcinogenesis. An association between post-load plasma glucose (PLG) levels and risk of colorectal cancer mortality would be consistent with this hypothesis. We used data from the Chicago Heart Association Detection Project in Industry to examine the associations of nonfasting PLG and other variables related to the insulin resistance syndrome (i.e., systolic blood pressure, body mass index, uric acid, and resting heart rate) with colorectal cancer mortality. After excluding participants reporting a history of diabetes, 191 and 126 colorectal cancer deaths occurred among 20,433 men and 15,149 women, respectively. In multivariate Cox regression analysis, there was a positive relationship between PLG levels and colorectal cancer mortality for women (P for trend = 0.08) but not for men. When men and women were combined, a trend (P = 0.05) for PLG remained. Examination of clustering of insulin resistance syndrome-related risk factors revealed that men with at least 3 of 4 risk factors (i.e., in the highest quartile of the sex-specific distribution for PLG, systolic blood pressure, body mass index, or resting heart rate) had a relative risk (RR) of 1.67 [95% confidence interval (CI), 1.04-2.70] as compared with men who were not in the upper quartile for any of these factors. For women, the RR was 1.29 (95% CI, 0.70-2.37). For men and women combined, the RR was 1.50 (95% CI, 1.03-2.19). These findings provide evidence for a modest association of PLG and insulin resistance syndrome with colorectal cancer mortality and support the insulin hypothesis.


Tri-state myoelectric control of bilateral upper extremity neuroprostheses for tetraplegic individuals.
For the purpose of bimanual control of tetraplegic hands that have useful movement restored by a neuroprosthetic device, the use of myoelectric signals from bilateral sternoclei-domastoid muscles is proposed. Three state control has been proposed where each sternocleidomastoid controls its ipsilateral hand. Demonstration was made with spinal-cord-injured and nonspinal-cord-injured subjects providing three levels of activation that can be repeatably made with each of these muscles. The agonist and antagonist sternocleidomastoids during this command control were differentiated so that the desired hand will respond to a command. Neither normal head movements nor head position within its comfortable range of motion were shown to interfere with the proposed command. The provision of feedback was shown as important to provide robustness in the operation for the users selection of the right or left hand. The performance of spinal cord injured and noninjured persons using this controller was quantitatively measured through the completion of precision tracking tasks by the manipulation of on-screen virtual hands. All subjects were able to operate the controller with a degree of skill acceptable for completion of functional tasks with bilateral stimulated hand grasps. The sensitivity of the subjects performance to variation in controller parameters was also measured.


A natural immunological adjuvant enhances T cell clonal expansion through a CD28-dependent, interleukin (IL)-2-independent mechanism.
The adoptive transfer of naive CD4(+) T cell receptor (TCR) transgenic T cells was used to investigate the mechanisms by which the adjuvant lipopolysaccharide (LPS) enhance T cell clonal expansion in vivo. Subcutaneous administration of soluble antigen (Ag) resulted in rapid and transient accumulation of the Ag-specific T cells in the draining lymph nodes (LNs), which was preceded by the production of interleukin (IL)-2. CD28-deficient, Ag-specific T cells produced only small amounts of IL-2 in response to soluble Ag and did not accumulate in the LN to the same extent as wild-type T cells. Injection of Ag and LPS, a natural immunological adjuvant, enhanced IL-2 production and LN accumulation of wild-type, Ag-specific T cells but had no significant effect on CD28-deficient, Ag-specific T cells. Therefore, CD28 is critical for Ag-driven IL-2 production and T cell proliferation in vivo, and is essential for the LPS-mediated enhancement of these events. However, enhancement of IL-2 production could not explain the LPS-dependent increase of T cell accumulation because IL-2-deficient, Ag-specific T cells accumulated to a greater extent in the LN than wild-type T cells in response to Ag plus LPS. These results indicate that adjuvants improve T cell proliferation in vivo via a CD28-dependent signal that can operate in the absence of IL-2.


Fractures: pathophysiology, treatment and nursing care.
Many nurses working in the primary and secondary sectors will care for patients who have sustained fractures. The ability to assess these patients systemically in addition to the injury is important in detecting complications and enhancing bone healing at the various stages of injury or treatment. This article describes different types of fracture and principles for their management. The nursing care of patients who has sustained a fracture is discussed from admission to discharge.


The expression of a catalytically active cholesterol 7 alpha-hydroxylase cytochrome P450 in Escherichia coli.
We have recently cloned a full-length cDNA encoding the rat hepatic cholesterol 7 alpha-hydroxylase cytochrome P450 (P450c7) (Li, Y. C., Wang, D. P., and Chiang, J. Y. L. (1990) J. Biol. Chem. 265, 12012-12019), which catalyzes the rate-limiting reaction of bile acid synthesis in the liver. By using the polymerase chain reaction, we have designed two P450c7 cDNAs. One has the second Met codon deleted and the third Thr codon replaced with an Ala. The other lacks codons for the NH2-terminal hydrophobic sequence of amino acids 2-24 (P450c7 delta 2-24). The cDNAs were separately cloned into the expression vector pKK233-2 and transformed into Escherichia coli. After induction with isopropyl-beta-D-thiogalactopyranoside, bacteria harboring recombinant plasmids expressed a polypeptide which reacted with the antibody against cholesterol 7 alpha-hydroxylase in immunoblots. The slightly modified full-length enzyme was expressed to 0.2% of the total bacterial lysate and was located in the membrane fraction, whereas P450c7 delta 2-24 was expressed at a 10-fold higher level (2%), of which 85% was in the cytosol and the remaining associated with the membranes. We have purified P450c7 delta 2-24 which showed a typical reduced-CO difference spectrum of cytochrome P450 and reconstituted cholesterol 7 alpha-hydroxylase activity in the presence of NADPH-cytochrome P450 reductase. P450c7 delta 2-24 has a similar Km for cholesterol (24.6 microM) but a lower Vmax (0.10 nmol/min) and a lower turnover number (1.93 min-1) as compared with the enzyme isolated from rat liver microsomes. The purified P450c7 delta 2-24 has an unique hydrophilic NH2 terminus and contains monomers and dimers in equal amounts. This is the first report demonstrating that a genetically engineered cytochrome P450 enzyme lacking a typical NH2-terminal hydrophobic sequence is mainly cytosolic and catalytically active.


Review of research studies that evaluated the impact of treatment for childhood cancers on neurocognition and behavioral and social competence: nursing implications.
Given the increasing incidence of childhood cancer, increasing survivor rates, and documented incidence of sequelae, nurses need evidence on which to base interventions for families at risk. The authors review and critique research studies that evaluated the impact of treatment for childhood cancers. Implications for nursing practice are discussed. Research to evaluate the effects of treatment on neurocognition and behavioral and social competency of children with cancer has produced conflicting results. Most studies found deleterious effects on all three areas associated with childhood cancer treatment. Some studies, however, found no differences between childhood cancer survivors and children on therapy compared to normative data or healthy controls. Knowledge of the short- and long-term impact of treatment for childhood cancer on neurocognition and behavioral and social competence allows nurses to design interventions that mitigate neurocognitive effects, decrease behavioral problems, and improve social competence.


Models to interpret kinetic data in stable isotope tracer studies.
In contrast to "weightless" radioactive tracers, stable isotope tracers have nonnegligible mass and are naturally present in the system, and the measured variable is a ratio of two isotopic species. These features do not allow stable isotopic tracer data analysis using straightforward analogy with radioactive tracer approaches, even though this practice is common. In this study, we present kinetic variables, models, and measurements for the analysis and interpretation of stable isotope tracer data. Assumptions and mathematical techniques for modeling the data when perturbation is both nonnegligible and negligible are discussed. Emphasis is placed on the rich information content of the dynamic portion of a stable isotope tracer curve and on the role of compartmental and noncompartmental modeling approaches for its interpretation. A presumed and commonly used analogy between the radioactive specific activity and stable isotopic enrichment is shown to be incorrect. We show that the proper analogue of specific activity is the tracer-to-tracee molar ratio. This variable is not a directly measurable one, but a formula is derived that allows its computation from the data. A method for reconstructing the time course in blood of the concentration component due to endogenous synthesis is presented. This allows measurement of the extent of the perturbation in the case where a nonweightless tracer is used. Special attention is given to data analysis originating from a multiple tracer experiment, a configuration necessary for studying more complex systems, e.g., the kinetics of interacting substrates.


Synthesis of UDP-apiose in Bacteria: The marine phototroph Geminicoccus roseus and the plant pathogen Xanthomonas pisi.
The branched-chain sugar apiose was widely assumed to be synthesized only by plant species. In plants, apiose-containing polysaccharides are found in vascularized plant cell walls as the pectic polymers rhamnogalacturonan II and apiogalacturonan. Apiosylated secondary metabolites are also common in many plant species including ancestral avascular bryophytes and green algae. Apiosyl-residues have not been documented in bacteria. In a screen for new bacterial glycan structures, we detected small amounts of apiose in methanolic extracts of the aerobic phototroph Geminicoccus roseus and the pathogenic soil-dwelling bacteria Xanthomonas pisi. Apiose was also present in the cell pellet of X. pisi. Examination of these bacterial genomes uncovered genes with relatively low protein homology to plant UDP-apiose/UDP-xylose synthase (UAS). Phylogenetic analysis revealed that these bacterial UAS-like homologs belong in a clade distinct to UAS and separated from other nucleotide sugar biosynthetic enzymes. Recombinant expression of three bacterial UAS-like proteins demonstrates that they actively convert UDP-glucuronic acid to UDP-apiose and UDP-xylose. Both UDP-apiose and UDP-xylose were detectable in cell cultures of G. roseus and X. pisi. We could not, however, definitively identify the apiosides made by these bacteria, but the detection of apiosides coupled with the in vivo transcription of bUAS and production of UDP-apiose clearly demonstrate that these microbes have evolved the ability to incorporate apiose into glycans during their lifecycles. While this is the first report to describe enzymes for the formation of activated apiose in bacteria, the advantage of synthesizing apiose-containing glycans in bacteria remains unknown. The characteristics of bUAS and its products are discussed.


Crafting a Compelling Abstract That Gets Accepted.
Presenting an abstract at the Society of Nuclear Medicine and Molecular Imaging annual meeting is an opportunity to gain peer recognition and share knowledge. This article explains how to craft a winning conference abstract. The goal of an abstract is to summarize the main points of a research project or topic. There are 2 types of abstracts: scientific and educational. Scientific abstracts generally involve data collection or a survey and follow a specific formula. The introduction provides a brief background and states the research question. The methods describe the study design and variables. The results present key findings, and the conclusion summarizes the findings' implications and significance. Educational abstracts are unstructured and usually describe a single topic, such as a case study, literature review, or new technique. Crafting an abstract requires clear communication, attention to detail, and an emphasis on practical applications. Effectively structuring a compelling abstract increases your abstract's acceptance chances.


The Anatomy of the Dorsal Capsulo-Scapholunate Septum: A Cadaveric Study.
Background Tears of the dorsal radiocarpal capsule at the level of the scapholunate interosseous ligament (SLIL) have recently been described in association with predynamic scapholunate instability. Purpose The aim of this anatomical study of the dorsal capsulo-scapholunate septum (DCSS) was to examine the connection of the dorsal capsule on the SLIL and dorsal intercarpal ligament (DICL). Methods Fourteen fresh frozen wrists from seven adult cadavers were dissected through a dorsal approach. Any dorsal attachment of the DICL on the dorsal surface of the SLIL, that is, the DCSS, was identified and measured (height and width). Results The DCSS was consistently found connecting the DICL, the dorsal radiocarpal capsule, and the dorsal aspect of the SLIL. It was formed by the confluence of three arches like intersecting ribs in gothic architecture. The mean dimensions of the DCSS were 5.8 mm in height and 4.0 mm in maximum width. Conclusion The DCSS that connects the SLIL with the dorsal capsule and DICL could be a constant structure of dorsal wrist. Further investigation is required to study the histology of the DCSS and its biomechanical properties in isolation to know whether the DCSS can be considered a secondary stabilizer of the scapholunate ligament complex. Clinical Relevance A better anatomical knowledge of scapholunate ligament complex could help understand and manage instability of the wrist.


The clinical characteristics of Werner syndrome: molecular and biochemical diagnosis.
Werner syndrome (WS) is an adult onset segmental progeroid syndrome caused by mutations in the WRN gene. The WRN gene encodes a 180 kDa nuclear protein that possesses helicase and exonuclease activities. The absence of WRN protein leads to abnormalities in various DNA metabolic pathways such as DNA repair, replication and telomere maintenance. Individuals with WS generally develop normally until the third decade of life, when premature aging phenotypes and a series of age-related disorders begin to manifest. In Japan, where a founder effect has been described, the frequency of Werner heterozygotes appears to be as high as 1/180 in the general population. Due to the relatively non-specific nature of the symptoms and the lack of awareness of the condition, this disease may be under-diagnosed in other parts of the world. Genetic counseling of WS patients follows the path of other autosomal recessive disorders, with special attention needed for cancer surveillance in relatives. Molecular diagnosis of WS is made by nucleotide sequencing and, in some cases, protein analysis. It is also of potential interest to measure WRN activities in WS patients. More than 50 different disease-causing mutations in the WRN gene have been identified in WS patients from all over the world. All but one of these cases has mutations that result in the premature termination of the protein. Here we describe the clinical, molecular and biochemical characteristics of WS for use by medical professionals in a health care setting. Additional information is available through the International Registry of WS (http://www.wernersyndrome.org).


Bis(isoquinoline-1-carboxylato-kappa2O,N)(1,10-phenanthroline-kappa2N,N')zinc(II) dimethylformamide sesquisolvate.
The asymmetric unit of the title compound, [Zn(C(10)H(6)NO(2))(2)(C(12)H(8)N(2))] x 1.5C(3)H(7)NO, contains one monomeric zinc complex and 1.5 disordered dimethylformamide solvate molecules. The Zn atom is coordinated to one 1,10-phenanthroline ligand and to two isoquinolinecarboxylate anions (IQC-) via their N and O atoms. The complex exhibits a distorted octahedral geometry around the Zn(II) atom, with the apical positions occupied by the O atoms of the IQC- ligands. The Zn atom lies 0.049 (1) A out of the basal plane. The crystal packing is characterized by several hydrogen bonds.


Optical properties of apple skin and flesh in the wavelength range from 350 to 2200 nm.
Optical measurement of fruit quality is challenging due to the presence of a skin around the fruit flesh and the multiple scattering by the structured tissues. To gain insight in the light-tissue interaction, the optical properties of apple skin and flesh tissue are estimated in the 350-2200 nm range for three cultivars. For this purpose, single integrating sphere measurements are combined with inverse adding-doubling. The observed absorption coefficient spectra are dominated by water in the near infrared and by pigments and chlorophyll in the visible region, whose concentrations are much higher in skin tissue. The scattering coefficient spectra show the monotonic decrease with increasing wavelength typical for biological tissues with skin tissue being approximately three times more scattering than flesh tissue. Comparison to the values from time-resolved spectroscopy reported in literature showed comparable profiles for the optical properties, but overestimation of the absorption coefficient values, due to light losses.


Bcl-2 does not protect Burkitt's lymphoma cells from oxidant-induced cell death.
Bcl-2 is an oncogene that confers deregulated growth potential to B lymphocytes through its ability to inhibit apoptotic cell death. A specific molecular activity for the Bcl-2 protein has not been identified, but several lines of evidence have supported a role in protection of cells from oxidative stress. We investigated whether there is a correlation between expression of high levels of Bcl-2 and susceptibility of human Burkitt's lymphoma cell lines to H2O2-induced killing. The amount of H2O2 required to kill 50% of cells in 24 hours varied widely in the seven different lymphoma cell lines that were tested, ranging from 35 to 500 micromol/L H2O2. However, expression of high levels of endogenous Bcl-2 did not protect the cells from H2O2-induced killing, even though it was effective in protecting the cells from apoptosis induced by agents such as A23187. Thus, Bcl-2 was functional in preventing apoptosis but did not act in an antioxidant capacity. The results were confirmed using a Burkitt's lymphoma cell line overexpressing transfected bcl-2. The results may be explained by the observation that H2O2 was inefficient at inducing apoptosis in these mature B-cell lines. Nonapoptotic death induced by H2O2 was not prevented by Bcl-2.


Human intrahepatic biliary epithelial cells engulf blebs from their apoptotic peers.
The phagocytic clearance of apoptotic cells is critical for tissue homeostasis; a number of non-professional phagocytic cells, including epithelial cells, can both take up and process apoptotic bodies, including the release of anti-inflammatory mediators. These observations are particularly important in the case of human intrahepatic biliary cells (HiBEC), because such cells are themselves a target of destruction in primary biliary cirrhosis, the human autoimmune disease. To address the apoptotic ability of HiBECs, we have focused on their ability to phagocytize apoptotic blebs from autologous HiBECs. In this study we report that HiBEC cells demonstrate phagocytic function from autologous HiBEC peers accompanied by up-regulation of the chemokines CCL2 [monocyte chemotactic protein-1 (MCP-1)] and CXCL8 [interleukin (IL)-8]. In particular, HiBEC cells express the phagocytosis-related receptor phosphatidylserine receptors (PSR), implying that HiBECs function through the 'eat-me' signal phosphatidylserine expressed by apoptotic cells. Indeed, although HiBEC cells acquire antigen-presenting cell (APC) function, they do not change the expression of classic APC function surface markers after engulfment of blebs, both with and without the presence of Toll-like receptor (TLR) stimulation. These results are important not only for understanding of the normal physiological function of HiBECs, but also explain the inflammatory potential and reduced clearance of HiBEC cells following the inflammatory cascade in primary biliary cirrhosis.


Impact of Body Mass Index on the Development of Inflammatory Bowel Disease: A Systematic Review and Dose-Response Analysis of 15.6 Million Participants.
A growing trove of literature describes the effect of malnutrition and underweight on the incidence of inflammatory bowel disease (IBD). However, evidence regarding the association between underweight or obesity and IBD is limited. The study aimed to assess the association of body mass index (BMI) with a risk of IBD (Crohn's disease (CD) and ulcerative colitis (U.C.)) incidence. We systematically searched PubMed/Medline, Cochrane, Web of Science, and Scopus for observational studies assessing the association between BMI and IBD that were published up to 30 June 2020. We estimated pooled hazard ratios (HR) with corresponding 95% confidence intervals (CI). Random effect dose-response meta-analysis was performed using the variance weighted least-squares regression (VWLS) models to identify non-linear associations. A total of ten studies involving 15.6 million individuals and 23,371 cases of IBD were included. Overall, obesity was associated with an increased IBD risk (HR: 1.20, 95% CI: 1.08-1.34, I 2 = 0%). Compared to normal weight, underweight (BMI < 18.5 kg/m2) and obesity (BMI ≥ 30 kg/m2) were associated with a higher risk of CD, and there was no difference in the risk of U.C. among those with BMI < 18.5 kg/m2 and BMI ≥ 30 kg/m2. There was a significant non-linear association between being underweight and obesity and the risk of development of CD (Coef1 = -0.0902, p 1 < 0.001 Coef2 = 0.0713, p 2 < 0.001). Obesity increases the risk of IBD development. Underweight and obesity are independently associated with an increased risk of CD, yet there is no evident association between BMI and the risk of U.C. Further studies are needed to clarify the underlying mechanism for these findings, particularly in CD.


Thrombin-mediated permeability of human microvascular pulmonary endothelial cells is calcium dependent.
In response to inflammation, endothelial cytoskeleton rearrangement, cell contraction, and intercellular gap formation contribute to a loss of capillary barrier integrity and resultant interstitial edema formation. The intracellular signals controlling these events are thought to be dependent on intracellular calcium concentration ([Ca2+]i). We hypothesized that, in human pulmonary microvascular endothelial cells, a thrombin-induced increase in permeability to albumin would be dependent on Ca2+i and subsequent actin cytoskeleton rearrangements. Human lung microvascular endothelial cells, grown on 0.4 micromol/L pore membranes, were activated with 10 nmol/L human thrombin in Hank's balanced salt solution/0.5% fetal bovine serum. Select cultures were pretreated (45 minutes) with 4 micromol Fura-2/AM to chelate Ca2+i. Permeability was assessed as diffusion of bovine serum albumin/biotin across the monolayer. Similarly treated cells were stained with rhodamine-phalloidin to demonstrate actin cytoskeletal morphology. Separately, cells loaded 2 micromol Fura-2/AM were assessed at OD340/380nm after thrombin exposure to detect free Ca2+i. Intracellular Ca2+ levels increased 15-fold (2 seconds) and fell to baseline (10 minutes) after thrombin. Permeability increased 10-fold (30 minutes), and a shift from cortical to actin stress fiber morphology was observed. Chelation of Ca2+i diminished permeability to baseline and reduced the percentage of cells exhibiting stress fiber formation. Thrombin stimulates pulmonary capillary leak by affecting the barrier function of activated pulmonary endothelial cells. These data demonstrate a thrombin-stimulated increase in monolayer permeability, and cytoskeletal F-actin stress fibers were, in part, regulated by endothelial Ca2+i. This early, transient rise in Ca2+i likely activates downstream pathways that more directly affect the intracellular endothelial structural changes that control vascular integrity.


Targets for therapy in sarcomeric cardiomyopathies.
To date, no compounds or interventions exist that treat or prevent sarcomeric cardiomyopathies. Established therapies currently improve the outcome, but novel therapies may be able to more fundamentally affect the disease process and course. Investigations of the pathomechanisms are generating molecular insights that can be useful for the design of novel specific drugs suitable for clinical use. As perturbations in the heart are stage-specific, proper timing of drug treatment is essential to prevent initiation and progression of cardiac disease in mutation carrier individuals. In this review, we emphasize potential novel therapies which may prevent, delay, or even reverse hypertrophic cardiomyopathy caused by sarcomeric gene mutations. These include corrections of genetic defects, altered sarcomere function, perturbations in intracellular ion homeostasis, and impaired myocardial energetics.


Degradation of Chlorpyrifos by an alkaline phosphatase from the cyanobacterium Spirulina platensis.
Spirulina is a photosynthetic, filamentous, spiral-shaped, multicellular, blue-green microalga. The two most important species are Spirulina maxima and Spirulina platensis. Spirulina is considered an excellent food, lacking toxicity and having corrective properties against viral attacks, anemia, tumor growth and malnutrition. We have observed that cultures of Spirulina platensis grow in media containing up to 80 ppm of the organophosphorous pesticide, Chlorpyrifos. It was found to be due to an alkaline phosphatase (ALP) activity that was detected in cell free extracts of Spirulina platensis. This activity was purified from the cell free extracts using ammonium sulphate precipitation and gel filtration and shown to belong to the class of EC 126.96.36.199 ALP. The purified enzyme degrades 100 ppm Chlorpyrifos to 20 ppm in 1 h transforming it into its primary metabolite 3, 5, 6-trichloro-2-pyridinol. This is the first report of degradation of Chlorpyrifos by Spirulina platensis whose enzymic mechanism has been clearly identified. These findings have immense potential for harnessing Spirulina platensis in bioremediation of polluted ecosystems.


Sexual behavior at work: Fun or folly?
Sexual behavior at work (e.g., sexual jokes and propositions) has been largely portrayed as offensive and harmful. The current research represents the first studies to test whether this is typically the case. Study 1 surveyed manufacturing and social service workers (N = 238) about their psychological well-being, work withdrawal, and exposure to sexual behavior at work. Respondents indicated how often they were exposed to different sexual behaviors and how much they enjoyed or were bothered by them. Study 2 surveyed university staff (N = 1,004) about their psychological well-being, drug use, feelings of being valued at work, and exposure to sexual behavior at work. Fifty-eight percent of employees in Study 1 were exposed to sexual behavior in the past 2 years; 40% of employees in Study 2 were exposed to sexual behavior in the past year. Some women and many men reported enjoying sexual behavior at work. Despite this, exposure to sexual behavior at work predicted negative employee work and psychological well-being, even for employees who said they enjoyed the experience. (PsycINFO Database Record (c) 2009 APA, all rights reserved).


Autocorrelation functions of noisy electron micrographs of stained polynucleotide chains.
Polyuridylic acid was deposited on carbon films in the presence of the thallous salt of mercury-p-dihydroquinone-O,O-diacetic acid under conditions leading to attachment of one of these molecules to each nucleotide. In electron micrographs of the stained polynucleotide chain, detail was obscured by the noise resulting from the substrate. Optically obtained autocorrelation functions of the distribution of density along the strands revealed peaks suggesting a structural regularity of 8 angstroms; this was interpreted as the internucleotide spacing.


Exploring Patient Preferences for Adjunct-to-Insulin Therapy in Type 1 Diabetes.
While sodium-glucose cotransporter inhibitor (SGLTi) therapy has been evaluated in type 1 diabetes (T1D) trials, patient reactions to benefits and risks are unknown. Using established methodology, we evaluated patient preferences for different adjunct-to-insulin therapy options in T1D. An online survey, completed by 701 respondents with T1D (231 U.S., 242 Canada, and 228 Germany), used conjoint analysis to present six hypothetical, masked, pairwise drug profile choices composed of different benefit-risk attributes and effect ranges. Data used in analyses were derived from actual phase 3 trials of a low-dose SGLTi (comparable to oral empagliflozin 2.5 mg q.d.), a high-dose SGLTi (comparable to oral sotagliflozin 400 mg q.d.), and an available adjunct-to-insulin therapy (comparable to subcutaneous pramlintide 60 μg t.i.d.). Conjoint analysis identified diabetic ketoacidosis risk as most important to patients (23% relative score; z test, P < 0.05); ranked second were HbA1c reduction (14%), risk of severe hypoglycemia (13%), oral versus injectable treatment (12%), and risk of genital infection (12%). Next was risk of nausea (11%), followed by weight reduction (8%) and the risk of diarrhea (7%). A low-dose SGLTi drug profile was identified by conjoint analysis as the top patient preference (83% of participants; z test, P < 0.05) versus high-dose SGLTi (8%) or pramlintide (9%). Separate from conjoint analysis, when respondents were asked to choose their preferred adjunct-to-insulin therapy (masked to drug name/dose), 69%, 17%, 6%, and 9% of respondents chose low-dose SGLTi, high-dose SGLTi, pramlintide, and insulin therapy alone, respectively. Low-dose SGLTi profile was the favored adjunct-to-insulin therapy by persons with T1D.