Musculoskeletal Injuries in Yoga.
While yoga has been widely studied for its benefits to many health conditions, little research has been performed on the nature of musculoskeletal injuries occurring during yoga practice. Yoga is considered to be generally safe, however, injury can occur in nearly any part of the body-especially the neck, shoulders, lumbar spine, hamstrings, and knees. As broad interest in yoga grows, so will the number of patients presenting with yoga-related injuries. In this literature review, the prevalence, types of injuries, forms of yoga related with injury, specific poses (asanas) associated with injury, and preventive measures are discussed in order to familiarize practitioners with yoga-related injuries.


The Type of Conservative Management Could Be Related to the Strength of the Inspiratory Muscles of Adolescents with Idiopathic Scoliosis-A Case Series.
Adolescent idiopathic scoliosis (AIS) is a lateral curvature of the spine with a Cobb angle of at least 10° with an unknown etiology. It is recognized that AIS may affect respiratory function. This study aims to describe and compare respiratory function in a case series of patients with scoliosis who underwent different types of therapeutic management: no intervention, orthotic brace, and global postural reeducation (GPR). Fifteen AIS patients were included in this study (seven no intervention, four orthotic brace and four GPR). Lung function and inspiratory muscle strength were measured and analyzed, as well as sociodemographic, clinical, and anthropometric variables. Significant correlations were observed between height (cm) and maximum inspiratory pressure (MIP) reference (cmH2O) and forced vital capacity (FVC) (liters) (r = 0.650 and r = 0.673, respectively; p < 0.01); weight (Kg) and MIP reference (cmH2O) (r = 0.727; p < 0.01); and Main curve degrees (Cobb angle) and FVC% (r = -0.648; p < 0.01). The AIS cases that underwent GPR treatment presented a greater MIP (% predictive) compared to the no intervention and brace cases (201.1% versus 126.1% and 78.4%, respectively; p < 0.05). The results of this case series show a possible relation whereby patients undergoing treatment with the GPR method have greater inspiratory muscle strength compared to the no intervention and brace cases. Studies with larger samples and prospective designs must be performed to corroborate these results.


Sex and the city in decline: Midnight Cowboy (1969) and Klute (1971).
This essay looks at two popular and influential films of the late 1960s and early 1970s, which were both shot in New York City: Midnight Cowboy (1969) and Klute (1971). It places them in film history, New York City history, and U.S. urban history more generally, finding that they offer an update on earlier century narratives of the connections between urban areas and deviant sexuality. In this modern version, it is not just a moral tale but also an economic one, where, because of the historical decline of the U.S. city and of New York in particular, sex work becomes a plausible, if unsettling means of support. These films find both narrative and spatial terms for advancing the contemporary antiurban narrative, envisioning New York as an impinging vertical space and seeing possible redemption only in the protagonists leaving the city.


Cytotoxic CD8+ T cell-neuron interactions: perforin-dependent electrical silencing precedes but is not causally linked to neuronal cell death.
Cytotoxic CD8(+) T cells are considered important effector cells contributing to neuronal damage in inflammatory and degenerative CNS disorders. Using time-lapse video microscopy and two-photon imaging in combination with whole-cell patch-clamp recordings, we here show that major histocompatibility class I (MHC I)-restricted neuronal antigen presentation and T cell receptor specificity determine CD8(+) T-cell locomotion and neuronal damage in culture and hippocampal brain slices. Two separate functional consequences result from a direct cell-cell contact between antigen-presenting neurons and antigen-specific CD8(+) T cells. (1) An immediate impairment of electrical signaling in single neurons and neuronal networks occurs as a result of massive shunting of the membrane capacitance after insertion of channel-forming perforin (and probably activation of other transmembrane conductances), which is paralleled by an increase of intracellular Ca(2+) levels (within <10 min). (2) Antigen-dependent neuronal apoptosis may occur independently of perforin and members of the granzyme B cluster (within approximately 1 h), suggesting that extracellular effects can substitute for intracellular delivery of granzymes by perforin. Thus, electrical silencing is an immediate consequence of MHC I-restricted interaction of CD8(+) T cells with neurons. This mechanism is clearly perforin-dependent and precedes, but is not causally linked, to neuronal cell death.


Historical perspective on mitochondrial medicine.
In this review, we trace the origins and follow the development of mitochondrial medicine from the premolecular era (1962-1988) based on clinical clues, muscle morphology, and biochemistry into the molecular era that started in 1988 and is still advancing at a brisk pace. We have tried to stress conceptual advances, such as endosymbiosis, uniparental inheritance, intergenomic signaling and its defects, and mitochondrial dynamics. We hope that this historical review also provides an update on mitochondrial medicine, although we fully realize that the speed of progress in this area makes any such endeavor akin to writing on water.


Identifying Circular RNA and Predicting Its Regulatory Interactions by Machine Learning.
Circular RNA (circRNA) is a closed long non-coding RNA (lncRNA) formed by covalently closed loops through back-splicing. Emerging evidence indicates that circRNA can influence cellular physiology through various molecular mechanisms. Thus, accurate circRNA identification and prediction of its regulatory information are critical for understanding its biogenesis. Although several computational tools based on machine learning have been proposed for circRNA identification, the prediction accuracy remains to be improved. Here, first we present circLGB, a machine learning-based framework to discriminate circRNA from other lncRNAs. circLGB integrates commonly used sequence-derived features and three new features containing adenosine to inosine (A-to-I) deamination, A-to-I density and the internal ribosome entry site. circLGB categorizes circRNAs by utilizing a LightGBM classifier with feature selection. Second, we introduce circMRT, an ensemble machine learning framework to systematically predict the regulatory information for circRNA, including their interactions with microRNA, the RNA binding protein, and transcriptional regulation. Feature sets including sequence-based features, graph features, genome context, and regulatory information features were modeled in circMRT. Experiments on public and our constructed datasets show that the proposed algorithms outperform the available state-of-the-art methods. circLGB is available at http://www.circlgb.com. Source codes are available at https://github.com/Peppags/circLGB-circMRT.


Metal-complexes as ligands to generate asymmetric homo- and heterodinuclear M(A)(III)M(B)(II) species: a magneto-structural and spectroscopic comparison of imidazole-N versus pyridine-N.
Ten hetero- and homodinuclear M(A)(III)M(B)(III) complexes, 1-10, containing the metal centers Fe(III)Zn(II) (1), Fe(III)Cu(II) (2), Fe(III)Ni(II) (3), Fe(III)Fe(II) (4), Fe(III)Mn(II) (5), Cr(III)Ni(II) (6), Cr(III)Zn(II) (7), Ga(III)Ni(II) (8), Co(III)Fe(II) (9), and Mn(III)Mn(II) (10) are described. The tridentate ligation property of the divalent metal complexes tris(1-methylimidazole-2-aldoximato)metal(II) with three facially disposed pendent oxime O-atoms has been utilized to generate the said complexes. Complexes were characterized by various physical methods including MS, IR, UV-vis, Mossbauer and EPR spectroscopy, cyclic voltammetry (CV), variable-temperature (2-290 K) magnetic susceptibility, and X-ray diffraction techniques. Binuclear complexes 1-10 contain three oximato anions as bridging ligands and are isostructural in the sense that they all contain a metal(III) ion, LM(A)(III) (L = 1,4,7-trimethyl-1,4,7-triazacyclononane), in a distorted octahedral environment M(A)(III)N(3)O(3) and a second six-coordinated divalent metal ion, M(B)(II), in a trigonally distorted M(B)(II)N(6) geometry. A comparison of the cyclic voltammograms of the complexes with those of similar systems reveal both ligand-centered and metal-centered redox processes. Complexes 2, 3, 5, and 6 display antiferromagnetic exchange coupling of the neighboring metal centers in the order Fe(III)Mn(II) (5) < Fe(III)Ni(II) (3) < Fe(III)Cu(II) (2) whereas Fe(III)Ni(II) (3) > Cr(III)Ni(II) (6). On the contrary, complex 10, containing high-spin Mn(III) and Mn(II) centers, exhibits ferromagnetic coupling yielding a "high-spin" molecule with an S(t) = (9)/(2) ground state. X-band electron paramagnetic resonance (EPR) spectroscopy for 6, Cr(III)Ni(II) and 3, Fe(III)Ni(II) has been used to establish the electronic ground state in great detail and to complement the magnetic susceptibility measurements. Moreover, computational results have been included to compare the sigma-bonding character of the nitrogen lone pair in imidazole-containing ligand and the analogous pyridine-containing oxime.


Spatial and developmental profiling of miraculin accumulation in transgenic tomato fruits expressing the miraculin gene constitutively.
We previously developed a transgenic tomato that expresses the miraculin gene using a constitutive promoter. In this study, we profiled the developmental and spatial accumulation of the miraculin protein and mRNA in transgenic tomato fruits. Miraculin mRNA expression was almost constant up to orange stage, and then the expression increased at red stage. The miraculin protein accumulated gradually during fruit development and reached its highest level at the overripe stage. At the red stage of fruit, miraculin protein was accumulated at the highest level in the exocarp, and similar in other fruit tissues: mesocarp, dissepiment, upper placenta, lower placenta and jelly. Moreover, the pattern of miraculin accumulation in fruit tissues was the same regardless of genetic background and position at which the miraculin gene was inserted in the genome. We also discuss suitable tomato types expressing miraculin for their commercial use.


12-lead electrocardiogram features of arrhythmic risk: A focus on early repolarization.
The 12-lead electrocardiogram (ECG) is still the most used tool in cardiology clinical practice. Considering its easy accessibility, low cost and the information that it provides, it remains the starting point for diagnosis and prognosis. More specifically, its ability to detect prognostic markers for sudden cardiac death due to arrhythmias by identifying specific patterns that express electrical disturbances of the heart muscle, which may predispose to malignant arrhythmias, is universally recognized. Alterations in the ventricular repolarization process, identifiable on a 12-lead ECG, play a role in the genesis of ventricular arrhythmias in different cardiac diseases. The aim of this paper is to focus the attention on a new marker of arrhythmic risk, the early repolarization pattern in order to highlight the prognostic role of the 12-lead ECG.


Extrasensory electroencephalographic induction between identical twins.
Alpha rhythms have been elicited in one of a pair of identical twins as a result of evoking these rhythms in a conventional manner solely in the other.


Participation in a public insurance program: subsidies, crowd-out, and adverse selection.
This paper examines how varying the level of subsidies affects participation in a public insurance program, crowd-out of private insurance, and adverse selection. We study the experience in Washington's Basic Health program in 1997. Findings show that adverse selection is not a problem in voluntary public programs. Increasing subsidies have only modest effects on participation in subsidized programs, though the gains are not at the expense of the private market. Overall participation in the subsidized plan is also modest, even though participants benefit from it. The challenge to policymakers is to find program design characteristics, beyond subsidies, that attract the uninsured.


Early student-patient interactions: the views of patients regarding their experiences.
This study was designed to investigate the experience and attitudes of patients to being interviewed by first-year medical students. A questionnaire was sent to 120 patients who have been interviewed during the last four years. Patients were asked what they felt about the process, what they understood was the purpose of the interview and if they felt they had benefited in any way from the interview. There was a 76% response rate. The majority of respondents (82%) felt they had benefited from the process, describing the experience as useful and interesting. Benefits included the opportunity to talk to someone about their problems, a feeling of use and improving the skills of future generations of doctors. It is concluded that patients enjoy being involved in the early education of medical students. As patients prefer students to be well prepared it is important that the students are adequately briefed before the exercise.


Protein-protein interaction: a genetic selection for compensating mutations at the barnase-barstar interface.
Barnase and barstar are trivial names of the extracellular RNase and its intracellular inhibitor produced by Bacillus amyloliquefaciens. Inhibition involves the formation of a very tight one-to-one complex of the two proteins. With the crystallographic solution of the structure of the barnase-barstar complex and the development of methods for measuring the free energy of binding, the pair can be used to study protein-protein recognition in detail. In this report, we describe the isolation of suppressor mutations in barstar that compensate for the loss in interaction energy caused by a mutation in barnase. Our suppressor search is based on in vivo selection for barstar variants that are able to protect host cells against the RNAse activity of those barnase mutants not properly inhibited by wild-type barstar. This approach utilizes a plasmid system in which barnase expression is tightly controlled to keep the mutant barnase gene silent. When expression of barnase is turned on, failure to form a complex between the mutant barnase and barstar has a lethal effect on host cells unless overcome by substitution of the wild-type barstar by a functional suppressor derivative. A set of barstar suppressors has been identified for barnase mutants with substitutions in two amino acid positions (residues 102 and 59), which are critically involved in both RNase activity and barstar binding. The mutations selected as suppressors could not have been predicted on the basis of the known protein structures. The single barstar mutation with the highest information content for inhibition of barnase (H102K) has the substitution Y30W. The reduction in binding caused by the R59E mutation in barnase can be partly reversed by changing Glu-76 of barstar, which forms a salt bridge with the Arg-59 in the wild-type complex, to arginine, thus completing an interchange of the two charges.


In defence of oxidation states.
In this Perspective, some of the criticisms which have been made concerning the use of oxidation states are addressed, particularly in the context of the teaching of inorganic chemistry. The Oxidation State method and the Covalent Bond Classification method are compared and contrasted, and it is concluded that while each method has its strengths and weaknesses, both are important in teaching and it should be recognized that no single model or method is appropriate in all circumstances.


Wolffish antifreeze protein genes are primarily organized as tandem repeats that each contain two genes in inverted orientation.
The antifreeze protein genes of the wolffish (Anarhichas lupus) constitute a large multigene family of 80 to 85 copies, which can be classified into two sets. One-third of the genes were linked but irregularly spaced. The other two-thirds were organized as 8-kilobase-pair (kbp) tandem direct repeats that each contained two genes in inverted orientation; DNA sequence analysis suggests that both genes are functional. Except for a single region specific to each gene, the genes and their immediate flanking sequences were 99.2% identical. This degree of identity ended soon after a putative transcription termination sequence; as the 3' ends of the genes were only 1.3 kbp apart, these sequences might confer mutual protection from interference by transcriptional runoff. A Southern blot of wolffish DNA restricted with enzymes that do not cut within the tandem repeats indicated that the repeats were clustered in groups of six or more. The organization of antifreeze protein genes in the wolffish was very similar to that in the unrelated winter flounder, which produces a completely different antifreeze. This similarity might reflect common dynamics by which their progenitors adapted to life in ice-laden sea water.


Gluten-Free Cereal Products and Beverages: A Review of Their Health Benefits in the Last Five Years.
In the past decades, food products and beverages made from gluten-free cereals were initially created for certain groups of people who experience gluten-related disorders such as wheat allergies, gluten ataxia, non-celiac gluten sensitivity, and the most well-known, celiac disease. Nowadays, the consumption of gluten-free products is not only restricted to targeted groups, but it has become a food trend for normal consumers, especially in countries such as the UK, the US, and some European countries, who believe that consuming a gluten-free product is a healthier choice compared to normal gluten-containing products. However, some research studies have disapproved of this claim because the currently available gluten-free products in the market are generally known to be lower in proteins, vitamins, and minerals and to contain higher lipids, sugar, and salt compared to their gluten-containing counterparts. The use of other gluten-free cereals such as sorghum, millet, and teff as well as pseudo cereals such as buckwheat and quinoa has gained significant interest in research in terms of their various potential health benefits. Hence, this review highlights the potential health benefits of some gluten-free cereals and pseudo cereals apart from corn and rice in the last decade. The potential health benefits of gluten-free products such as bread, pasta, crackers, and cookies and the health benefits of some other non-alcoholic beverages made from gluten-free cereals and pseudo cereals are reported.


Matchett Brown hemiarthroplasty for displaced subcapital fractures of the hip.
Matchett Brown hemiarthroplasty has been routinely performed at Middlemore Hospital in elderly patients following subcapital fracture of the hip. The outcome of patients undergoing Matchett Brown hemiarthroplasty was evaluated. Matchett Brown hemiarthroplasties performed at Middlemore Hospital during 1987 were retrospectively reviewed. Medical records were reviewed and where possible patients were interviewed, examined and radiographs of their hip taken. The overall survival at follow up was 34%, with the greatest predictor of survival being whether the patient had been living alone prior to the accident. The majority of patients who survived the 4 year follow up had excellent mobility at the time of fracture. At follow up most patients had little or no pain from their hip, but three complained of constant pain. Hemiarthroplasty proved to be a satisfactory form of replacement in this group. If one were to select a patient for total hip replacement, rather than hemiarthroplasty, then age alone is not as important as other factors such as degree of mobility and independence of living.


Utilizing theatrical tools in consultation training. A way to facilitate students' reflection on action?
The aim was to give the individual student a group-based opportunity to reflect on possible consultation strategies as the consultation was evolving. An actress acted as patient in the consultation training for a group of 30 students. The consultation was stopped at each critical incidence, and time-out given to allow the students to reflect on possible continuation strategies, and then to carry out one of them. The project was evaluated adopting a pragmatic version of the reflective practitioner research strategy as developed by Taylor. The evaluation was based on tutor and actress's field notes, students' written free text evaluation and students' evaluation through two focus groups. The qualitative analysis resulted in the three categories: the fiction created, temporality manipulated, and students' learning through reflection. Implications for students' learning process are discussed. We conclude that our way of creating fiction and manipulating temporality in the consultation training was paralleled by most students' report on substantial learning feed-forward abilities from reflection on action.


Prognostic significance of moderate primary mitral regurgitation and concomitant paroxysmal atrial fibrillation.
Severe primary mitral regurgitation [degenerative MR (DMR)] is associated with poor outcomes, including cardiac death and hospitalization due to worsening heart failure. However, little information is available regarding the characteristics of moderate DMR and their impacts on prognostic outcome. The aim of the present study was to investigate the prognosis and its determinants in patients with moderate DMR. We retroactively reviewed 13,700 consecutive patients who underwent transthoracic echocardiography and selected those with moderate DMR but without other underlying cardiac diseases. We assessed the characteristics and event-free rate of patients with moderate DMR compared with those of age- and gender-matched patients with mild or no MR. The cohort included 182 (1%) patients with moderate DMR, and these were compared with 182 age- and gender-matched patients with mild or no MR. During the follow-up period of 1376 ± 652 days, 30 patients (8%) met the composite endpoint defined as cardiac death or hospitalization due to worsening heart failure. Kaplan-Meier analysis showed that patients with moderate DMR were significantly associated with a poor outcome compared to patients with mild or no MR (log-rank test p < 0.0001). Cox proportional hazard ratio revealed that moderate DMR and paroxysmal atrial fibrillation (PAF) were the independent predictors of the composite endpoint. Patients with moderate DMR and concomitant PAF had a significantly worse outcome compared to those with mild or no MR. Active surveillance and some intervention for patients with PAF and moderate DMR may be required.


Overview of gene therapy clinical progress including cancer treatment with gene-modified T cells.
It is now twenty years since the first legal gene transfer studies were approved, and there has been considerable disappointment in the slow rate of progress that followed the initial studies. Gradually, however, as the limitations of available vectors are acknowledged and overcome, and with advances in our understanding of the molecular and cell biology of genetic diseases and of cancer, unequivocal successes are now being reported. In this paper we describe the remaining major roadblocks to successful gene therapy and outline approaches to overcome them. We also illustrate how genetically modified immune system cells are already being used for the effective treatment of hematological and other malignancies, and how these approaches are being modified so that they can be effective in treating a broader range of malignancies.


Attentional requirements for location and distance of movement: encoding and recognition.
The purpose of this experiment was to study the early processing stages of encoding and recognition of slow movement in a short-term motor-memory paradigm. These stages were examined by determining whether Laabs' (1973) differential decay rates for location of movement and distance of movement could be replicated when the interfering activity was performed during the criterion and replication movements. 20 subjects performed a linear-positioning task in a 2 X 2 X 2 (count X movement type X retention interval) experimental design. 10 subjects in one condition counted backwards by 3s during the criterion and replication movements. There were no detrimental effects for location and distance-cue reproduction when attention was shared with counting backwards. Like Laabs' results, location of movement was maintained over the 15-sec. interval while distance of movement spontaneously changed. These results supported the notion that the early stages of encoding and recognition of cues for movement can occur unaffected by a secondary task.


The rat intrinsic factor gene: its 5'-upstream region and chief cell-specific transcription.
A DNA segment containing the 5'-upstream region and amino terminal reading frame of the gastric intrinsic factor gene was cloned from rat and its nucleotide sequence was determined. S1 mapping demonstrated that the transcription initiation site is located downstream of the second TATA-box sequence. Similar sequence motifs to those in the pepsinogen genes transcribed in gastric chief cells were found in the deduced sequence, suggesting that the rat intrinsic factor gene is transcribed in these cells. The genes for the intrinsic factor and its homologous protein transcobalamin I were apparently derived from a common ancestoral gene, since the positions of their intron insertions as well as the amino acid residues are conserved. Northern blot hybridization showed that the gene for the intrinsic factor is transcribed in the stomach but not detectably in the intestine, kidney, testis, brain, heart, liver, lung, or spleen. In situ hybridization using radioactive complementary RNA clearly indicated that the major transcription site in gastric glands is chief cells. Different locations of expression of intrinsic factor proteins in various mammals were observed previously using antibodies: in rat parietal cells and chief cells, in mouse chief cells, and in human parietal cells. The present results clearly demonstrated the intrinsic factor mRNA mainly in chief cells of adult rats, as in mice, suggesting that transcriptional regulation of the intrinsic factor gene is essentially the same in rodents.


Induction of immunity by DNA vaccination: application to influenza and tuberculosis.
DNA vaccination is an effective means of inducing both humoral and cell-mediated immunity in animal models of infectious disease. Presented here are data generated in two distinct disease models; one viral (influenza) and one bacterial (tuberculosis). Specifically, plasmid DNA encoding an influenza virus antigen (nucleoprotein; NP) and a Mycobacterium tuberculosis antigen (antigen 85; Ag85) were prepared and tested as DNA vaccines in mice. In both cases, high titer antibody responses and robust cell-mediated immune responses were induced against the respective antigens. With respect to the latter, lymphocyte proliferation, Th1-type cytokine secretion, and cytotoxic T lymphocyte responses were observed upon restimulation with antigen in vitro. Furthermore, protective efficacy in animal challenge models was demonstrated in both systems. The data support the hypothesis that DNA vaccination will prove to be a broadly applicable technique for inducing immunity against various infectious diseases.


Effect of hydrogen peroxide on cytoskeletal proteins of Drosophila cells: comparison with heat shock and other stresses.
Hydrogen peroxide, which was shown to trigger the heat-shock response by activating the immediate binding of the heat-shock factor to DNA heat shock regulatory elements in the promoter of heat-shock genes of Drosophila cells, has also been reported to enhance the synthesis of actin. We show here that very short and transient H2O2 treatments, from 1 s to 2 min, are sufficient to induce an increase of actin synthesis. This increase becomes apparent 2 to 3 h after the short H2O2 treatment. It is inhibited if actinomycin D is present during the short H2O2 treatment. An increase of actin synthesis was also observed during the recovery period after two other stresses: reoxygenation after anoxia and ethanol treatment. The synthesis of two cytoskeletal proteins, tubulin and a 46-kDa insoluble protein of the intermediate filament fraction, was also slightly increased by H2O2 in Drosophila cells, but this increase was not actinomycin D-dependent. H2O2 does not provoke the translocation of the 46-kDa protein to the nuclear fraction as does heat shock. The very rapid stimulation of actin synthesis by H2O2 and the involvement of cytoskeletal elements in many stress situations suggest that actin may play a key role in the response to external stimuli.


[Chlamydia trachomatis].
Almost 11,000 cases of Chlamydia trachomatis (CT) are diagnosed every year in Denmark. The most important epidemiologic factor is age under 25 years. The prevalence of CT among women applying for legal abortion is five to eight percent and in a recent study the prevalence of CT among second trimester pregnant women was found to be 2.9 percent. The consequences of CT-caused infections are many, including risk of infertility, ectopic pregnancies, perinatal transmission etc. The perinatal transmission rate is high in untreated cases of CT during pregnancy, but it can be prevented by treatment of the expecting woman with erythromycin. The Danish National Board of Health do recommend screening for CT before transcervical interventions, but there are no such recommendations concerning pregnancy health care. A recent Danish study as well as many other studies have shown that it is cost-effective to screen high risk women i.e. women younger than 25 years. An introduction of such screening of Danish pregnant women younger than 25 years should therefore be considered.


A case of actinic prurigo and solar urticaria.
Actinic prurigo and solar urticaria are uncommon chronic idiopathic photodermatoses in the United Kingdom. To our knowledge, their occurrence in the same patient has not hitherto been described.


Criminal defectors lead to the emergence of cooperation in an experimental, adversarial game.
While the evolution of cooperation has been widely studied, little attention has been devoted to adversarial settings wherein one actor can directly harm another. Recent theoretical work addresses this issue, introducing an adversarial game in which the emergence of cooperation is heavily reliant on the presence of "Informants," actors who defect at first-order by harming others, but who cooperate at second-order by punishing other defectors. We experimentally study this adversarial environment in the laboratory with human subjects to test whether Informants are indeed critical for the emergence of cooperation. We find in these experiments that, even more so than predicted by theory, Informants are crucial for the emergence and sustenance of a high cooperation state. A key lesson is that successfully reaching and maintaining a low defection society may require the cultivation of criminals who will also aid in the punishment of others.


Association of intraventricular hemorrhage secondary to prematurity with cerebrospinal fluid shunt surgery in the first year following initial shunt placement.
The neurosurgical literature has conflicting findings regarding the association between indications for CSF shunt placement and subsequent shunt surgery. The object of this study was to identify baseline factors at the time of initial CSF shunt placement that are independently associated with subsequent surgery. This was a retrospective cohort study of children ages 0-18 years who underwent initial CSF shunt placement between January 1, 1997, and October 12, 2006, at a tertiary care children's hospital. The outcome of interest was CSF shunt surgery (either for revision or infection) within 12 months after initial placement. Associations between subsequent CSF shunt surgery and indication for the initial shunt, adjusting for patient age and surgeon factors at the time of initial placement, were estimated using multivariate logistic regression. Medical and surgical decisions, which varied according to surgeon, were examined separately in a univariate analysis. Of the 554 children in the study cohort, 233 (42%) underwent subsequent CSF shunt surgery, either for revision (167 patients [30%]) or infection (66 patients [12%]). In multivariate logistic regression modeling, significant risk factors for subsequent CSF shunt surgery included (compared with aqueductal stenosis) intraventricular hemorrhage (IVH) secondary to prematurity (adjusted odds ratio [AOR] 2.2, 95% CI 1.1-4.5) and other unusual indications (AOR 3.7, 95% CI 1.0-13.6). The patient's age at initial CSF shunt placement was not significantly associated with increased odds of subsequent surgery after adjusting for other associated factors. The occurrence of IVH is associated with increased odds of subsequent CSF shunt surgery within 12 months after shunt placement. Families of and care providers for children with IVH should be attuned to their increased risk of shunt failure.


Penetration of the human nail plate: the effects of vehicle pH on the permeation of miconazole.
In order to assess the relative permeability of the nail plate to ionized and unionized drugs the permeation of miconazole at varying pH has been followed as a function of time. The pH was adjusted from 3.1 to 8.2 to obtain between 5 and 100% dissociation of the drug. No significant difference in the rate of permeation was demonstrated. The data suggests that the ionic form of miconazole dissolves as easily in the nail plate as the free base and, therefore, topical bioavailability can be enhanced by decreasing the formulation pH thereby increasing drug solubility.


Effluent syntaxin3 from dying cells affords protection against apoptosis in epidermal keratinocytes.
Ultra-violet B (UVB)-induced oxidative stress crucially perturbs the epidermal homeostasis, and the skin is endowed with protective mechanisms to take action against such damage. Here, we show the possible involvement of t-SNARE protein syntaxin3, a membrane fusion mediator of cytoplasmic vesicles, and which is released from dying keratinocytes, to play a role in this response. UVB irradiation, which generates reactive oxidative stress in cells, was shown to lead to the keratinocyte cell death accompanied by a release of cytoplasmic syntaxin3. We found that such extracellularly sourced syntaxin3 completely blocked the processing of a crucial effector for apoptotic cell death, caspase-3, and thus facilitated the survival of keratinocytes damaged by oxidative stress. These results demonstrate the latent prosurvival function of syntaxin3 and underline the importance of intracellular molecular elements for the maintenance of homeostasis in epidermal keratinocytes.


Abortion in South Australia, 1971-86: an update.
Official statistics on abortion in South Australia for the period 1971-86 are analysed in terms of incidence, age of patients and nuptiality, reasons for abortion, method of termination, period of gestation, previous abortions and concurrent sterilisation. Demographic implications are discussed and recommendations are made for more education and counselling, especially for younger and unmarried women for whom the incidence of abortion seems to be rising.


Production of Hydroxycarboxylic Acid Receptor 3 (HCA3) Ligands by Bifidobacterium.
Hydroxycarboxylic acid receptor 3 (HCA3) was recently identified in the genomes of humans and other hominids but not in other mammals. We examined the production of HCA3 ligands by Bifidobacterium spp. In addition to 4-hydroxyphenyllactic acid, phenyllactic acid (PLA), and indole-3-lactic acid (ILA), we found that LeuA was produced by Bifidobacterium as an HCA3 ligand. The four ligands produced were the mixtures of enantiomers, and D-ILA, D-PLA, and D-LeuA showed stronger activity of the HCA3 ligand than their respective L-isomers. However, there was no difference in AhR activity between the two ILA enantiomers. These results provide new insights into the HCA3 ligands produced by Bifidobacterium and suggest the importance of investigating the absolute stereo structures of these metabolites.


The effect of smiling on the perceived age of male and female faces across the lifespan.
Previous research has shown an unintuitive effect of facial expression on perceived age: smiling faces are perceived as older compared to neutral faces of the same people. The aging effect of smiling (AES), which is thought to result from the presence of smile-related wrinkles around the eyes, contradicts the common belief that smiling faces should be perceived as younger, not older. Previous research, however, has focused on faces of young adults, where the absence of inherent, age-related wrinkles and other age signs is offset by the weight of the smile-related wrinkles. In a series of experiments, we tested whether the AES extends to male and female faces in older age groups. We replicated the AES in young adults (20-39) and showed that it disappeared in older adults (60-79) of both genders. For photos of middle-aged adults (40-59), however, AES was found only for male, but not for female faces, who showed fewer and less prominent smile-related wrinkles. The results suggest that a person's apparent age is perceived in a holistic manner in which age-related cues in the region of the eyes are weighted against age cues in other regions of the face.


A mixed-method process evaluation of an East Midlands county summer 2021 holiday activities and food programme highlighting the views of programme co-ordinators, providers, and parents.
The Holiday Activities and Food (HAF) Programme is a UK Government initiative created to alleviate food insecurity and promote health and well-being among children and their families, who are eligible for Free School Meals (FSM), during the school holidays. This process evaluation investigated factors that facilitated and acted as a barrier to the delivery of the HAF Programme from the perspectives of key stakeholders (Co-ordinators, Providers, and Parents) involved in the HAF Programme across an East Midlands county. This evaluation utilized a mixed-methods approach, incorporating focus groups and online surveys to gain rich, multifaceted data. The focus groups were analyzed using a hybrid inductive-deductive thematic analysis and the online surveys were analyzed using mixed-methods approach due to the variation in question type (i.e., quantitative, Likert scale and open response) to align themes to the Government Aims and Standards of the HAF Programme. The stakeholders highlighted several factors that facilitated and acted as a barrier to the delivery of the HAF Programme. Facilitating factors included existing and maintaining relationships between Co-ordinators, Providers, and facilities/schools/communities as this improved communication and attendance. Additionally, transport provision for those attending the Programme helped overcome barriers to attendance. The primary barrier of the Programme was the late awarding of the Programme contract as this limited the time available to prepare and organize the Programme. This in turn, had several "knock on" effects that created more barriers and resulted in some of the Government Aims and Standards not being met such as, nutrition education for children and parents. Despite the challenges faced, Co-ordinators and Providers were able to deliver the Programme and positively impact upon the children and their families that attended the Programme. Following the facilitators and barriers that were highlighted in this evaluation, several recommendations have been made to enhance the delivery of the HAF Programme and ensure Government Aims and Standards, to improve children and family's health and well-being, are attained.


MGED standards: work in progress.
The Microarray Gene Expression Data (MGED) society is an international organization established in 1999 for facilitating sharing of functional genomics and proteomics array data. To facilitate microarray data sharing, the MGED society has been working in establishing the relevant data standards. The three main components (which will be described in more detail later) of MGED standards are Minimum Information About a Microarray Experiment (MIAME), a document that outlines the minimum information that should be reported about a microarray experiment to enable its unambiguous interpretation and reproduction; MAGE, which consists of three parts, The Microarray Gene Expression Object Model (MAGE-OM), an XML-based document exchange format (MAGE-ML), which is derived directly from the object model, and the supporting tool kit MAGEstk; and MO, or MGED Ontology, which defines sets of common terms and annotation rules for microarray experiments, enabling unambiguous annotation and efficient queries, data analysis and data exchange without loss of meaning. We discuss here how these standards have been established, how they have evolved, and how they are used.


Orthogonal Screening of Anticancer Drugs Using an Open-Access Microfluidic Tissue Array System.
Screening for potential drug combinations presents significant challenges to the current microfluidic cell culture systems, due to the requirement of flexibility in liquid handling. To overcome this limitation, we present here an open-access microfluidic tissue array system specifically designed for drug combination screening. The microfluidic chip features a key structure in which a nanoporous membrane is sandwiched by a cell culture chamber array layer and a corresponding media reservoir array layer. The microfluidic approach takes advantage of the characteristics of the nanoporous membrane: on one side, this membrane permits the flow of air but not liquid, thus acting as a flow-stop valve to enable automatic cell distribution; on the other side, it allows diffusion-based media exchange and thus mimics the endothelial layer. In synergy with a liquid-transferring platform, the open-access microfluidic system enables complex multistep operations involving long-term cell culture, medium exchange, multistep drug treatment, and cell-viability testing. By using the microfluidic protocol, a 10 × 10 tissue array was constructed in 90 s, followed by schedule-dependent drug testing. Morphological and immunohistochemical assays indicated that the resultant tumor tissue was faithful to that in vivo. Drug-testing assays showed that the incorporation of the nanoporous membrane further decreased killing efficacy of the anticancer agents, indicating its function as an endothelial layer. Robustness of the microfluidic system was demonstrated by implementing a three-factor, three-level orthogonal screening of anticancer drug combinations, with which 67% of the testing (9 vs. 27) was saved. Experimental results demonstrated that the microfluidic tissue system presented herein is flexible and easy-to-use, thus providing an ideal tool for performing complex multistep cell assays with high efficiencies.


Highly Flexible, Multipixelated Thermosensitive Smart Windows Made of Tough Hydrogels.
In a cold night, a clear window that will become opaque while retaining the indoor heat is highly desirable for both privacy and energy efficiency. A thermally responsive material that controls both the transmittance of solar radiance (predominantly in the visible and near-infrared wavelengths) and blackbody radiation (mainly in the mid-infrared) can realize such windows with minimal energy consumption. Here, we report a smart coating made from polyampholyte hydrogel (PAH) that transforms from a transparency state to opacity to visible radiation and strengthens opacity to mid-infrared when lowering the temperature as a result of phase separation between the water-rich and polymer-rich phases. To match a typical temperature fluctuation during the day, we fine-tune the phase transition temperature between 25 and 55 °C by introducing a small amount of relatively hydrophobic monomers (0.1 to 0.5 wt % to PAH). To further demonstrate an actively controlled, highly flexible, and high-contrast smart window, we build in an array of electric heaters made of printed elastomeric composite. The multipixelated window offers rapid switching, ∼70 s per cycle, whereas the device can withstand high strain (up to 80%) during operations.


The correlation between the recovery rate of neurotoxic esterase activity and sensitivity to organophosphorus-induced delayed neurotoxicity.
Neurotoxic esterase (NTE) has been proposed to be the initiation site of organophosphorus compound-induced delayed neurotoxicity (OPIDN). There are two apparent problems associated with this hypothesis: NTE activity in the brain returns to nearly normal levels before the onset of the neuropathy, and NTE is present in and inhibited by organophosphorus compounds in young animals and other species which are relatively insensitive to the neurotoxic effects of these compounds. This paper presents data suggesting that differences in the recovery rates of NTE activity may account for some of these discrepancies. First, the onset of recovery of NTE activity following sc administration of 1.7 mg/kg of O,O-diisopropylphosphorofluoridate (DFP) in the hen sciatic nerve occurred several days later than in the brain. Furthermore, recovery was slower in distal than proximal parts of the nerve. This information indicates that NTE activity is depressed for a longer period at the site of the neuropathy than it would appear from the measurement of NTE activity in brain. Second, the rate of recovery of NTE activity was faster in the brains of chicks, of rats, and of hens treated with a daily po dose of 15 mg/kg cortisone acetate than it was in untreated hens. However, there was no significant increase in the NTE recovery rate in the peripheral nerves of the chicks or the cortisone-treated hens. Thus, it appears that although slower distal recovery could account for the greater sensitivity of longer axons to OPIDN, other factors are operating in chicks and cortisone-treated hens.


Importance of viscosity in the dissolution rate of cholesterol in monooctanoin solutions.
Several factors affecting the dissolution rate of cholesterol in monooctanoin were investigated. This solvent is used clinically for dissolution of residual cholesterol gallstones in the bile duct after cholecystectomy. The effect of added water on dissolution rate, measured using the static- or rotating-disk methods, was not consistent with the previously measured solubility. The discrepancy was found to be due to the decreasing viscosity of the solvent as water was added. Addition of cholesterol, however, increased the viscosity of monooctanoin. The viscosity effect on dissolution rate was investigated further by addition of polymers (povidone and poloxamer 237) which increased solvent viscosity. Dissolution rate was proportional to viscosity to the -0.4 power with these polymers. An equation was derived which predicts that dissolution rate should be proportional to viscosity to the -2/3 power. The predicted exponent was very close to reported experimental values for benzoic acid, but the dissolution rate/viscosity relationship for cholesterol in aqueous monooctanoin was nonlinear with apparent exponents of -0.65 to -2.3. Although the Arrhenius activation energies for viscosity (3.79 kcal/mol) and dissolution rate constant (3.66 kcal/mol) were almost equal for benzoic acid, a nonlinear relationship was again observed for cholesterol in aqueous monooctanoin with approximate Ea values of 5.6-10 kcal/mol. The strong influence of viscosity on dissolution rate in this system is attributed to the viscosity-increasing effect of cholesterol in the diffusion layer. The increased viscosity at higher cholesterol concentrations reduces the diffusion coefficient of cholesterol and causes the dissolution rate to be slower even though solubility may have been higher.(ABSTRACT TRUNCATED AT 250 WORDS)


Understanding the safety of the new ultra long acting basal insulin.
Hypoglycaemia is a key safety concern in diabetes management. It is potentially dangerous and the fear of hypoglycaemia may lead to sub-optimal dosing and inadequate glycaemic control. On the other hand, hypoglycaemia may generate adverse effects and disease complications, will compromise the quality of life and will substantially increase the economic burden of treatment budged. Today, treat to target clinical trial designs are mandate for clinical development of any newer anti-diabetic medication. While similar glycaemic targets are expected to be achieved by test and comparator, the newer molecules are definitely expected to show advantage over standard comparator in terms of reduction in frequency and severity of hypoglycaemia. An ultra-long acting basal analogue insulin degludec (IDeg), has been recently approved for the treatment of type 2 and type 1 diabetes mellitus (T2DM and T1DM). The pooled patient-level data for self-reported hypoglycaemia from seven phase 3a trials with IDeg has shown significantly lower episodes of nocturnal confirmed and numerical low overall confirmed hypoglycaemia with IDeg, compared to Insulin glargine (IGlar), which was more pronounced during maintenance phase of treatment in all populations. The most plausible explanation being that, the flat peakless profile of IDeg with least glycaemic variability leads to less hypoglycaemia and adds to the safety profile of this ultra-long acting insulin. The real life practice will further validate the findings of clinical trials.


Joint multiple imputation for longitudinal outcomes and clinical events that truncate longitudinal follow-up.
Longitudinal cohort studies often collect both repeated measurements of longitudinal outcomes and times to clinical events whose occurrence precludes further longitudinal measurements. Although joint modeling of the clinical events and the longitudinal data can be used to provide valid statistical inference for target estimands in certain contexts, the application of joint models in medical literature is currently rather restricted because of the complexity of the joint models and the intensive computation involved. We propose a multiple imputation approach to jointly impute missing data of both the longitudinal and clinical event outcomes. With complete imputed datasets, analysts are then able to use simple and transparent statistical methods and standard statistical software to perform various analyses without dealing with the complications of missing data and joint modeling. We show that the proposed multiple imputation approach is flexible and easy to implement in practice. Numerical results are also provided to demonstrate its performance. Copyright © 2015 John Wiley & Sons, Ltd.


A Retrospective and Anatomical Study Describing the Injection of Botulinum Neurotoxins in the Depressor Anguli Oris.
The depressor anguli oris acts to lower the lateral corners of the mouth and can cause an individual to appear sad or angry and contribute to the development of the labiomental folds. Many patients can benefit from the injection of small amounts of botulinum neurotoxin into the depressor anguli oris to enable the lip elevators to reposition the corners of the mouth. Although effective, the procedure is off-label, and the proximity of the depressor anguli oris to the depressor labii inferioris, particularly inferiorly, can lead to inadvertent treatment of the latter, resulting in lip asymmetry. The authors have taken a threefold approach to establish a depressor anguli oris injection technique that provides optimal aesthetic outcomes with a low incidence of adverse events. This involved, first, reviewing the limited existing literature for studies discussing depressor anguli oris anatomy and botulinum neurotoxin treatment technique; second, supplementing information from the published literature with information from cadaver dissections to demonstrate the relationship between the depressor anguli oris and surrounding anatomical structures; and third, performing a retrospective chart review of 275 patients treated with the authors' three-point injection technique. Combining data from published studies, cadaver dissections, and clinical experience, the authors demonstrate that a three-point technique performed in the upper half of the depressor anguli oris is associated with good clinical outcome and avoids common side effects related to injection or spread of neurotoxin to adjacent muscles. Therapeutic, IV.


Raman spectroscopy of single-wall boron nitride nanotubes.
Single-wall boron nitride nanotubes samples synthesized by laser vaporization of a hexagonal BN target under a nitrogen atmosphere are studied by UV and visible Raman spectroscopy. We show that resonant conditions are necessary for investigating phonon modes of BNNTs. Raman excitation in the UV (229 nm) provides preresonant conditions, allowing the identification of the A1 tangential mode at 1370 cm(-1). This is 5 cm(-1) higher than the E(2g) mode in bulk h-BN. Ab initio calculations show that the lower frequency of bulk h-BN with respect to large diameter nanotubes and the single sheet of h-BN is related to a softening of the sp2 bonds in the bulk due to interlayer interaction.


[Physicians and occupational health: a qualitative study in south-eastern France].
Occupational health is a major public health problem in France. However, the level of investment of general practitioners and specialist physicians in this field is not well documented. We aimed at studying elements moving closer or differentiating groups of professionals (notably physicians) in the field of occupational health in terms of conceptions of their roles (prevention and care) and of practices (in particular detection and notification of occupational diseases and perceived barriers). We conducted a qualitative study in south-eastern France which consisted of in-depth interviews of physicians and actors involved in the prevention of occupational hazards or in their indemnification. Then discourse analysis was carried out on the corpus collected. Content analysis grouped the data into themes. Several reasons could explain the low investment of physicians in the field of occupational health: insufficient detection of occupational causes of diseases, complexity of administrative procedures of declaration and bias of causal interpretation for the patients exposed to other risk factors such as smoking. The fear that notifying an occupational disease might have repercussions on patients' socio-professional situations places physicians in a situation of ethical dilemma: inducing a social risk on one side, ignoring his rights on the other. Physicians are not sufficiently prepared to deal with these situations, because they lack appropriate knowledge and support from specialists in the field, due to an important bulk-heading of actors and their practices. To sensitize and train physicians to occupational health and to support multi-field practices are essential.


Early postnatal benzo(a)pyrene exposure in Sprague-Dawley rats causes persistent neurobehavioral impairments that emerge postnatally and continue into adolescence and adulthood.
Previous studies have demonstrated that benzo(a)pyrene (BaP) may disrupt the development of key biological systems, thus leaving children more vulnerable to functional impairments in adulthood. The current study was conducted to determine whether neurotoxic effects of postnatal BaP exposure on behavioral performance persist in juvenile and young adult stages. Therefore, neonate Sprague-Dawley pups were given oral doses of BaP (0.02, 0.2, and 2 mg/kg/day) continuing through a period of rapid brain development (on postnatal days [PNDs] 5-11). Further, developmental milestones and behavioral endpoints assessing sensory and motor maturation were examined. Also, in this study, Morris water maze and elevated plus maze were used for evaluating the cognitive function and anxiety-like behavior. Our results showed that there was altered ontogeny in a few measures of neuromotor development; however, other developmental milestones and sensory responses were not altered significantly. Moreover, the locomotor activity deficit in BaP-treated pups was evident at PND 36 and was most pronounced in the PND 69. Also, exposure to BaP during early postnatal development had an adverse effect on adult rats (PND 70) in the elevated plus maze, and the swim maze suggests that low doses of BaP impair spatial learning functions at adult test period. In contrast, BaP exposure had no evident effect on behaviors in these two mazes for adolescent animals. These data clearly indicate that behavioral impairments resulting from postnatal BaP exposure are potentially long-lasting and may not be apparent in juveniles, but are present in young adulthood.


Influence of blood vessels on the measurement of hemoglobin oxygenation as determined by time-resolved reflectance spectroscopy.
We report the development of a heterogeneous resin-tube model to study the influence of blood vessels on the apparent absorption of the system, mu a(sys), using a time-resolved technique. The experimental results show that mu a(sys) depends on the absorption inside the tubes, mu a(tube), tube diameters, and tube-to-sample volume ratios. A mathematical expression relating mu a(sys) and mu a(tube) is derived based on the experimental results and is verified by time-resolved Monte Carlo simulations for heterogeneous models. This analytical formula predicts that the apparent absorption coefficient measured on a biological organ is a volume-weighted sum of the absorption coefficients of different absorbing components. We present some apparent absorption coefficients measured in vivo in animals and humans and discuss improved algorithms that calculate the hemoglobin saturation by including background-tissue absorption and blood vessel distribution.


Ultra-Efficient and Robust Auto-Nonvolatile Schmitt Trigger-Based Latch Design Using Ferroelectric CNTFET Technology.
In designing ultra-efficient noise immune nanoscale circuits and systems, Schmitt triggers (STs) are vital components influencing total functionality. This article proposes an ultracompact ST using ferroelectric carbon nanotube field-effect transistors (Fe-CNTFETs) and a robust ST latch. By using the unique electrical futures of the Fe-CNTFETs, the proposed ST has been designed in a particular way to only employ two transistors similar to a conventional binary inverter. Moreover, by utilizing the negative capacitance feature of the Fe-CNTFETs, the proposed ST can perform the backup and restore operation during a scheduled power gating or a sudden power outage without imposing any additional transistors, interconnects, and control signals. The proposed ST latch is hardened to soft errors occurring due to unwanted single-event upsets (SEUs). Our extensive simulations demonstrate that our proposed ST latch offers lower transistors counts (on average 34%) and more energy savings (on average 79%). On the other hand, our design has shown 5.6 times on average higher critical charge tolerance than the previous counterparts due to its soft error hardening circuity and the superior hysteresis behavior of the proposed Fe-CNTFET-based ST. Moreover, the auto-nonvolatility of the proposed ST makes the proposed latches immune to the sudden power outage, which was not devised in the previous ST latches. Our results show new pathways in designing ultracompact and efficient nonvolatile ST latches using the Fe-CNTFET technology.


Relationship between ultrasonically detected phasic antral contractions and antral pressure.
The relationships between gastric wall motion and intraluminal pressure are believed to be major determinants of flows within and from the stomach. Gastric antral wall motion and intraluminal pressures were monitored in five healthy subjects by concurrent antropyloroduodenal manometry and transabdominal ultrasound for 60 min after subjects drank 500 ml of clear soup. We found that 99% of antral contractions detected by ultrasound were propagated aborally, and 68% of contractions became lumen occlusive at the site of the ultrasound marker. Of the 203 contractions detected by ultrasound, 53% were associated with pressure events in the manometric reference channel; 86% of contractions had corresponding pressure events detectable somewhere in the antrum. Contractions that occluded the lumen were more likely to be associated with a pressure event in the manometric reference channel (P < 0.01) and to be of greater amplitude (P < 0.01) than non-lumen-occlusive contractions. We conclude that heterogeneous pressure event patterns in the antrum occur despite a stereotyped pattern of contraction propagation seen on ultrasound. Lumen occlusion is more likely to be associated with higher peak antral pressure events.


Method Validation of Human Chorionic Gonadotropin and α-Fetoprotein in Cerebrospinal Fluid: Aiding the Diagnosis of Intracranial Germ Cell Tumors.
Our study objective was to validate 2 individual methods to measure α-fetoprotein (AFP) and human chorionic gonadotropin (hCG) in cerebrospinal fluid (CSF) on the Roche cobas® 6000 analyzer. A 3-year retrospective chart review of CSF samples analyzed for AFP and hCG was also conducted. Serum samples with high concentrations of AFP or hCG were added to aliquots of pooled CSF. Precision, linearity, detection limit, recovery, carryover, stability, and interference studies of the AFP and hCG+β assays were performed. Within-day and day-to-day assay imprecision for AFP and hCG assays were <5% at all concentrations tested. The linear range of the AFP assay was established as 1.0-1100 μg/L, and limit of quantification (LOQ) was <1.0 μg/L. The linear range of the hCG assay was established as 1.0-9500 IU/L and LOQ 0.7 IU/L. There was no demonstrable matrix effect, and neither assay was affected by the presence of hemolysis or xanthochromia. AFP in CSF was stable at room and refrigerated temperatures for up to 48 h at concentrations of 19 and 306 μg/L but increased by 24 h at a concentration of 908 μg/L. AFP in CSF was stable frozen (-20 °C) for up to 7 days. hCG in CSF at all concentrations tested was stable at room, refrigerated, and frozen temperatures for up to 7 days. The Roche cobas 6000 AFP and hCG+β assays accurately quantify AFP and hCG in CSF, facilitating rapid and accurate diagnosis as well as monitoring of intracranial germ cell tumors.


Low rectal cancer: Sphincter preserving techniques-selection of patients, techniques and outcomes.
Low rectal cancer is traditionally treated by abdominoperineal resection. In recent years, several new techniques for the treatment of very low rectal cancer patients aiming to preserve the gastrointestinal continuity and to improve both the oncological as well as the functional outcomes, have been emerged. Literature suggest that when the intersphincteric resection is applied in T1-3 tumors located within 30-35 mm from the anal verge, is technically feasible, safe, with equal oncological outcomes compared to conventional surgery and acceptable quality of life. The Anterior Perineal PlanE for Ultra-low Anterior Resection technique, is not disrupting the sphincters, but carries a high complication rate, while the reports on the oncological and functional outcomes are limited. Transanal Endoscopic MicroSurgery (TEM) and TransAnal Minimally Invasive Surgery (TAMIS) should represent the treatment of choice for T1 rectal tumors, with specific criteria according to the NCCN guidelines and favorable pathologic features. Alternatively to the standard conventional surgery, neoadjuvant chemo-radiotherapy followed by TEM or TAMIS seems promising for tumors of a local stage T1sm2-3 or T2. Transanal Total Mesorectal Excision should be performed only when a board approved protocol is available by colorectal surgeons with extensive experience in minimally invasive and transanal endoscopic surgery.


Benzoylphloroglucinol derivatives from Hypericum scabrum.
Nine new polyprenylated benzoylphloroglucinol derivatives, hyperibones A-I (1-9), were isolated from the aerial parts of the Uzbekistan medicinal plant Hypericum scabrum. Their structures were determined mainly on the basis of spectroscopic evidence (2D NMR and HRMS). Compounds 1, 2, and 4 showed mild in vitro antibacterial activity against methicillin-resistance Staphylococus aureus (MRSA) and methicillin-sensitive Staphylococus aureus (MSSA).


Complementary Nucleobase Interactions Drive Co-Assembly of Drugs and Nanocarriers for Selective Cancer Chemotherapy.
A new concept in cooperative adenine-uracil (A-U) hydrogen bonding interactions between anticancer drugs and nanocarrier complexes was successfully demonstrated by invoking the co-assembly of water soluble, uracil end-capped polyethylene glycol polymer (BU-PEG) upon association with the hydrophobic drug adenine-modified rhodamine (A-R6G). This concept holds promise as a smart and versatile drug delivery system for the achievement of targeted, more efficient cancer chemotherapy. Due to A-U base pairing between BU-PEG and A-R6G, BU-PEG has high tendency to interact with A-R6G, which leads to the formation of self-assembled A-R6G/BU-PEG nanogels in aqueous solution. The resulting nanogels exhibit a number of unique physical properties, including extremely high A-R6G-loading capacity, well-controlled, pH-triggered A-R6G release behavior, and excellent structural stability in biological media. Importantly, a series of in vitro cellular experiments clearly demonstrated that A-R6G/BU-PEG nanogels improved the selective uptake of A-R6G by cancer cells via endocytosis and promoted the intracellular release of A-R6G to subsequently induce apoptotic cell death, while control rhodamine/BU-PEG nanogels did not exert selective toxicity in cancer or normal cell lines. Overall, these results indicate that cooperative A-U base pairing within nanogels is a critical factor that improves selective drug uptake and effectively promotes apoptotic programmed cell death in cancer cells.


Relevance of Electrical Light on Circadian, Neuroendocrine, and Neurobehavioral Regulation in Laboratory Animal Facilities.
Light is a key extrinsic factor to be considered in operations and design of animal room facilities. Over the past four decades, many studies on typical laboratory animal populations have demonstrated impacts on neuroendocrine, neurobehavioral, and circadian physiology. These effects are regulated independently from the defined physiology for the visual system. The range of physiological responses that oscillate with the 24 hour rhythm of the day include sleep and wakefulness, body temperature, hormonal secretion, and a wide range of other physiological parameters. Melatonin has been the chief neuroendocrine hormone studied, but acute light-induced effects on corticosterone as well as other hormones have also been observed. Within the last two decades, a new photosensory system in the mammalian eye has been discovered. A small set of retinal ganglion cells, previously thought to function as a visual output neuron, have been shown to be directly photosensitive and act differently from the classic photoreceptors of the visual system. Understanding the effects of light on mammalian physiology and behavior must take into account how the classical visual photoreceptors and the newly discovered ipRGC photoreceptor systems interact. Scientists and facility managers need to appreciate lighting impacts on circadian, neuroendocrine, and neurobehavioral regulation in order to improve lighting of laboratory facilities to foster optimum health and well-being of animals.


Ciprofloxacin or tamsulosin in men with chronic prostatitis/chronic pelvic pain syndrome: a randomized, double-blind trial.
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in men is principally defined by pain in the pelvic region lasting more than 3 months. No cause of the disease has been established, and therapies are empirical and mostly untested. Antimicrobial agents and alpha-adrenergic receptor blockers are frequently used. To determine whether 6-week therapy with ciprofloxacin or tamsulosin is more effective than placebo at improving symptoms in men with refractory, long-standing CP/CPPS. Randomized, double-blind trial with a 2 x 2 factorial design comparing 6 weeks of therapy with ciprofloxacin, tamsulosin, both drugs, or placebo. Urology outpatient clinics at 10 tertiary care medical centers in North America. Patients were identified from referral-based practices of urologists. One hundred ninety-six men with a National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score of at least 15 and a mean of 6.2 years of symptoms were enrolled. Patients had received substantial previous treatment. The authors evaluated NIH-CPSI total score and subscores, patient-reported global response assessment, a generic measure of quality of life, and adverse events. Ciprofloxacin, 500 mg twice daily; tamsulosin, 0.4 mg once daily; a combination of the 2 drugs; or placebo. The NIH-CPSI total score decreased modestly in all treatment groups. No statistically significant difference in the primary outcome was seen for ciprofloxacin versus no ciprofloxacin (P = 0.15) or tamsulosin versus no tamsulosin (P > 0.2). Treatments also did not differ significantly for any of the secondary outcomes. Treatment lasting longer than 6 weeks was not tested. Patients who had received less pretreatment may have responded differently. Ciprofloxacin and tamsulosin did not substantially reduce symptoms in men with long-standing CP/CPPS who had at least moderate symptoms.


Kinetic models in n-dimensional Euclidean spaces: From the Maxwellian to the Poisson kernel.
In this work, minimal kinetic theories based on unconventional entropy functions, H∼ln f (Burg entropy) for 2D and H∼f(1-2/n) (Tsallis entropy) for nD with n≥3, are studied. These entropy functions were originally derived by Boghosian et al. [Phys. Rev. E 68, 025103 (2003)] as a basis for discrete-velocity and lattice Boltzmann models for incompressible fluid dynamics. The present paper extends the entropic models of Boghosian et al. and shows that the explicit form of the equilibrium distribution function (EDF) of their models, in the continuous-velocity limit, can be identified with the Poisson kernel of the Poisson integral formula. The conservation and Navier-Stokes equations are recovered at low Mach numbers, and it is shown that rest particles can be used to rectify the speed of sound of the extended models. Fourier series expansion of the EDF is used to evaluate the discretization errors of the model. It is shown that the expansion coefficients of the Fourier series coincide with the velocity moments of the model. Employing two-, three-, and four-dimensional (2D, 3D, and 4D) complex systems, the real velocity space is mapped into the hypercomplex spaces and it is shown that the velocity moments can be evaluated, using the Poisson integral formula, in the hypercomplex space. For the practical applications, a 3D projection of the 4D model is presented, and the existence of an H theorem for the discrete model is investigated. The theoretical results have been verified by simulating the following benchmark problems: (1) the Kelvin-Helmholtz instability of thin shear layers in a doubly periodic domain and (2) the 3D flow of incompressible fluid in a lid-driven cubic cavity. The present results are in agreement with the previous works, while they show better stability of the proposed kinetic model, as compared with the BGK type (with single relaxation time) lattice Boltzmann models.


Identification of differentially expressed proteins of normal and cancerous human colorectal tissues by liquid chromatograph-mass spectrometer based on iTRAQ approach.
Liquid chromatograph-mass spectrometer (LC/MS) based labeled with isobaric mass tags for relative and absolute quantitation (iTRAQ) analyses were performed to identify differentially expressed proteins from normal and cancerous human colorectal tissues. Around 802 proteins were identified, 68 proteins of which were defined as differentially expressed proteins. Bioinformatics analysis indicated that these differentially expressed proteins correlated with several specific cellular processes and pathways which have relationships with pathological changes of colorectal cancer (CRC). EHD2 were selected to verify its expression patterns and localization using western blotting and immunohistochemistry respectively. LC/MS-based iTRAQ proteomic approach would provide new information about the character of CRC.


Time-Frequency Decomposition of Scalp Electroencephalograms Improves Deep Learning-Based Epilepsy Diagnosis.
Epilepsy diagnosis based on Interictal Epileptiform Discharges (IEDs) in scalp electroencephalograms (EEGs) is laborious and often subjective. Therefore, it is necessary to build an effective IED detector and an automatic method to classify IED-free versus IED EEGs. In this study, we evaluate features that may provide reliable IED detection and EEG classification. Specifically, we investigate the IED detector based on convolutional neural network (ConvNet) with different input features (temporal, spectral, and wavelet features). We explore different ConvNet architectures and types, including 1D (one-dimensional) ConvNet, 2D (two-dimensional) ConvNet, and noise injection at various layers. We evaluate the EEG classification performance on five independent datasets. The 1D ConvNet with preprocessed full-frequency EEG signal and frequency bands (delta, theta, alpha, beta) with Gaussian additive noise at the output layer achieved the best IED detection results with a false detection rate of 0.23/min at 90% sensitivity. The EEG classification system obtained a mean EEG classification Leave-One-Institution-Out (LOIO) cross-validation (CV) balanced accuracy (BAC) of 78.1% (area under the curve (AUC) of 0.839) and Leave-One-Subject-Out (LOSO) CV BAC of 79.5% (AUC of 0.856). Since the proposed classification system only takes a few seconds to analyze a 30-min routine EEG, it may help in reducing the human effort required for epilepsy diagnosis.


The effect of Ca++ and Mg++ on the action of Clostridium perfringens enterotoxin on Vero cells.
Clostridium perfringens enterotoxin binds to receptors on Vero cells. This process does not depend on the presence of divalent cations (Ca++, Mg++). Binding of enterotoxin causes inhibition of 14C-leucine incorporation into proteins, probably because of depression of amino acid transport. The presence of Mg++ speeds up this effect of the enterotoxin. The enterotoxin produces membrane leakage only in the presence of Ca++, but additional Mg++ increases the rate of this process. These results indicate that the dissociation constant of the enterotoxin receptor interaction is reduced in the presence of Mg++. A model for the mode of action of the enterotoxin is proposed.


Herbicide Resistance in Datura innoxia: Cross-Resistance of Sulfonylurea-Resistant Cell Lines to Imidazolinones.
Cells resistant to the sulfonylurea herbicides chlorsulfuron and sulfometuron methyl were isolated from a predominantly haploid cell suspension culture of Datura innoxia P. Mill. Exponentially growing cell colonies (aggregates of about 40 cells) were mutagenized with ethyl methane sulfonate, subcultured for 10 days to allow growth recovery and plated on a medium containing either chlorsulfuron or sulfometuron methyl at a concentration (10(-8) molar) which killed wild type cells. Surviving clones were picked up after 3 to 4 weeks, further proliferated as callus or cell suspension cultures, and tested for their resistance to both the sulfonylureas and imidazolinones, a chemically different class of herbicides. The variants were stable and showed high (100- to 1000-fold) resistance to the sulfonylureas. While some also exhibited cross resistance to imidazolinones, others showed no cross-resistance at all or, as in one case, greater sensitivity than wild type cells to the imidazolinones. Both classes of herbicides tested inhibited acetolactate synthase activity isolated from wild type cells. The acetolactate synthase of the resistant variants, however, was found to be resistant to the sulfonylureas and also to the imidazolinone(s) in those cells showing cross-resistance to the latter. The lack of cross-resistance observed in some cases provides evidence that the two groups of herbicides have slightly different sites on the acetolactate synthase molecule.


2D oriented covalent organic frameworks for alcohol-sensory synapses.
Resistive random access memories (RRAMs) based on the electrochemical metallization mechanism (ECM) have potential applications in high-density data storage and efficient neuromorphic computing. However, the high variability of ECM devices still hinders their application in artificial intelligence owing to the random formation of conductive filaments (CFs). Here, we demonstrate 2D covalent organic framework (COF) RRAM with electroforming-free resistive switching behavior, low spatial/temporal variations, and excellent retention capability up to 105 s. The one-dimensional channels of the oriented COF-5 film can not only confine the shape of filaments but also modulate the transition direction of Ag ions. Moreover, alcohol vapors could activate the device to achieve gas-mediated multilevel resistive switching since COF materials can absorb small molecules through host guest interactions to vary the conductivity. An alcohol gas recognition system constructed by integrating the COF RRAM as a sensor and filter part with the k-nearest neighbors (KNN) algorithm as a classifier was demonstrated with a recognition accuracy of 87.2%. Furthermore, the effect of alcohol inhibition stimulation in the human nervous system is successfully emulated by the COF RRAM.


Nonsuicidal self-injury: an emotion regulation perspective.
Nonsuicidal self-injury (NSSI) is widely thought to serve an emotion-regulatory function. The focus of the present paper is to provide a conceptual framework for understanding how NSSI might modify a person's emotions. Drawing upon the process model of emotion regulation, we argue that 5 families of emotion regulation strategies may be engaged by NSSI. Individuals may engage in NSSI as an alternative to more distressing situations. They also may use NSSI to modify their social environment. Individuals may shift their attention away from unpleasant emotions or thoughts via NSSI. NSSI may change cognitions about the self via self-punishment or transformation of the self from higher-order to lower-order awareness. NSSI may also bring about various physiological effects, such as changes in endogenous opioids or parasympathetic nervous system activation, as a way of modulating emotional responses. Simply labeling NSSI as 'emotion regulatory' does not tell us precisely what is going on. This is because at any given moment, NSSI can serve to regulate emotions in many different ways. One key challenge is to clarify the precise functions NSSI may be serving for a given individual in a particular context.


Subterminal polygalacturonase, a nonmacerating enzyme, attacks pectate from the reducing end.
Subterminal polygalacturonase from Aspergillus, which fails to macerate soft plant tissue in spite of a rapid action on pectate in vitro, was examined for its action at pH 3.5 on substrate (degree of polymerization 9-50) altered by the reduction of the reducing end to (3)H labeled l-galactonic acid, and the introduction of unsaturation in a portion of the nonreducing end groups. Endo-polygalacturonase from Saccharomyces fragilis was used as a control. The hydrolysis products were separated by gel filtration chromatography and the sugar residues, the tritium label, and the ultraviolet absorption (of the unsaturated groups) were measured. Endo-polygalacturonase gave equal production of the two end-labeled oligomers. Subterminal polygalacturonase rapidly produced a mixture of tritiated oligomers (mainly trimer, dimer, and tetramer), 2.5 times faster than it liberated unsaturated oligomers, and 3 times faster than it liberated unlabeled oligomers, showing that its action begins at the reducing end. The unsaturated pentamer and hexamer, which accumulated during the rapid phase of enzyme action, were subsequently hydrolyzed to the unsaturated tetramer, in accord with action from the reducing end.


Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice.
Ascorbic acid is an essential nutrient commonly regarded as an antioxidant. In this study, we showed that ascorbate at pharmacologic concentrations was a prooxidant, generating hydrogen-peroxide-dependent cytotoxicity toward a variety of cancer cells in vitro without adversely affecting normal cells. To test this action in vivo, normal oral tight control was bypassed by parenteral ascorbate administration. Real-time microdialysis sampling in mice bearing glioblastoma xenografts showed that a single pharmacologic dose of ascorbate produced sustained ascorbate radical and hydrogen peroxide formation selectively within interstitial fluids of tumors but not in blood. Moreover, a regimen of daily pharmacologic ascorbate treatment significantly decreased growth rates of ovarian (P < 0.005), pancreatic (P < 0.05), and glioblastoma (P < 0.001) tumors established in mice. Similar pharmacologic concentrations were readily achieved in humans given ascorbate intravenously. These data suggest that ascorbate as a prodrug may have benefits in cancers with poor prognosis and limited therapeutic options.


Cell cycle-dependent recruitment of telomerase RNA and Cajal bodies to human telomeres.
Telomerase is a ribonucleoprotein enzyme that counteracts replicative telomere erosion by adding telomeric sequence repeats onto chromosome ends. Despite its well-established role in telomere synthesis, telomerase has not yet been detected at telomeres. The RNA component of human telomerase (hTR) resides in the nucleoplasmic Cajal bodies (CBs) of interphase cancer cells. Here, in situ hybridization demonstrates that in human HeLa and Hep2 S phase cells, besides accumulating in CBs, hTR specifically concentrates at a few telomeres that also accumulate the TRF1 and TRF2 telomere marker proteins. Surprisingly, telomeres accumulating hTR exhibit a great accessibility for in situ oligonucleotide hybridization without chromatin denaturation, suggesting that they represent a structurally distinct, minor subset of HeLa telomeres. Moreover, we demonstrate that more than 25% of telomeres accumulating hTR colocalize with CBs. Time-lapse fluorescence microscopy demonstrates that CBs moving in the nucleoplasm of S phase cells transiently associate for 10-40 min with telomeres. Our data raise the intriguing possibility that CBs may deliver hTR to telomeres and/or may function in other aspects of telomere maintenance.


Tumors carrying BRAF-mutations over-express NAMPT that is genetically amplified and possesses oncogenic properties.
Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) biosynthesis, is up-regulated in several cancers, including metastatic melanoma (MM). The BRAF oncogene is mutated in different cancer types, among which MM and thyroid carcinoma (THCA) are prominent. Drugs targeting mutant BRAF are effective, especially in MM patients, even though resistance rapidly develops. Previous data have linked NAMPT over-expression to the acquisition of BRAF resistance, paving the way for therapeutic strategies targeting the two pathways. Exploiting the TCGA database and a collection of MM and THCA tissue microarrays we studied the association between BRAF mutations and NAMPT expression. BRAF wild-type (wt) cell lines were genetically engineered to over-express the BRAF V600E construct to demonstrate a direct relationship between over-activation of the BRAF pathway and NAMPT expression. Responses of different cell line models to NAMPT (i)nhibitors were studied using dose-response proliferation assays. Analysis of NAMPT copy number variation was performed in the TCGA dataset. Lastly, growth and colony forming assays were used to study the tumorigenic functions of NAMPT itself. The first finding of this work is that tumor samples carrying BRAF-mutations over-express NAMPT, as demonstrated by analyzing the TCGA dataset, and MM and THC tissue microarrays. Importantly, BRAF wt MM and THCA cell lines modified to over-express the BRAF V600E construct up-regulated NAMPT, confirming a transcriptional regulation of NAMPT following BRAF oncogenic signaling activation. Treatment of BRAF-mutated cell lines with two different NAMPTi was followed by significant reduction of tumor growth, indicating NAMPT addiction in these cells. Lastly, we found that several tumors over-expressing the enzyme, display NAMPT gene amplification. Over-expression of NAMPT in BRAF wt MM cell line and in fibroblasts resulted in increased growth capacity, arguing in favor of oncogenic properties of NAMPT. Overall, the association between BRAF mutations and NAMPT expression identifies a subset of tumors more sensitive to NAMPT inhibition opening the way for novel combination therapies including NAMPTi with BRAFi/MEKi, to postpone and/or overcome drug resistance. Lastly, the over-expression of NAMPT in several tumors could be a key and broad event in tumorigenesis, substantiated by the finding of NAMPT gene amplification.


Molecular docking studies of YKT tripeptide and drug delivery system with poly(ε-caprolactone) nanoparticles.
Tyrosyllysylthreonine (YKT) is a peptide structure that contains three different amino acids in its structure and has anticancer properties. The main purpose of this study is to reveal the structural interactions of the peptide and to increase the efficiency of the peptide with nanoformulation. For these purposes, YKT-loaded poly(ε-caprolactone) (PCL) nanoparticles (NPs) were synthesized using the double-emission precipitation method and the obtained NPs were characterized with a Zeta Sizer, UV-Vis, Fourier transform infrared-attenuated total reflection spectrometers, scanning electron microscopy, and transmission electron microscopy. The in vitro release profile of the peptide-loaded PCL NPs was determined. In molecular modeling studies, PCL, PCL-polyvinyl alcohol (PVA), and PCL-PVA-YKT systems were simulated in an aqueous medium by molecular dynamics simulations, separately. The information about the interactions between the YKT tripeptide and the epidermal growth factor and androgen, estrogen, and progesterone receptors were obtained with the molecular docking study. Additionally, the ADME profile of YKT was determined as a result of each docking study. In conclusion, tripeptide-based nanodrug development studies of the YKT tripeptide are presented in this study.


Critical fluctuations near the smectic-hexatic phase transition with anticlinic structure.
Layer compression modulus B measurements have been conducted near the transitions between smectic and hexatic phases with synclinic and anticlinic structures. In the synclinic structure, B shows no pretransitional softening near the phase transition. However, in the anticlinic structure, we observed evident critical softening of B near the smectic-hexatic phase transition. These results clearly reveal that the introduction of the in-plane hexatic order in the anticlinic structure is different from the usual smectic-hexatic phase transition.


Does pain neuroscience education improve pain knowledge, beliefs and attitudes in undergraduate physiotherapy students?
To evaluate the effect of a brief pain neuroscience education (PNE) session on physiotherapy students' knowledge of pain and their beliefs and attitudes about the treatment of patients with chronic low back pain. This study was a single-center, cross-sectional study including 205 physiotherapy undergraduate students. The participants completed the Neurophysiology of Pain Questionnaire (NPQ) and Pain Attitudes and Beliefs Scale for Physiotherapists (PABS-PT). They then received a 70-min neuroscience education session covering the mechanisms and biopsychosocial aspects of chronic low back pain. The questionnaires were readministered immediately after the educational session and at 6 months posteducation. Our analysis included data from 156 participants (mean age: 20.9 ± 2.51, 69.8% women) who completed the questionnaires pre-, post-, and 6 months after the educational session. To assess the effect of the education on the scores of the questionnaires, a repeated-measures ANOVA was conducted. There was a significant interaction observed for NPQ over time (p = 0.00; η 2 = 0.654), for PABS-PT factor 1(p < 0.001; η2 = 0.50) and for PABS-PT factor 2 over time (p = 0.02; η 2 = 0.04) CONCLUSION: This study showed that a 70-min session of PNE improves the level of pain knowledge in undergraduate physiotherapy students and influences their beliefs and attitudes concerning chronic low back pain. These findings suggest that adding PNE to the curricula of physiotherapy and rehabilitation programs may be beneficial.


[Evaluation of influenza A virus nucleoprotein based on baculovirus surface-display technology].
Nucleoprotein (NP) of influenza virus is highly conserved and type-specific. NP can trigger strong cell-mediated immune responses in host and is involved in the protection against the challenges with different subtype influenza viruses. Here, NP of an avian H5N1 (A/Hubei/1/2010, HB) was expressed by baculovirus surface-display technology and its immunogenicity as well as protective mechanism was investigated in mice infection model. Western blot and immunolabeled electron microscopy assay showed NP was displayed on baculovirus surface. ELISA results showed NP could induce high level of anti-NP IgG in the sera from NP-Bac-inoculated mice. Two cellular immune peptides (NP57-74 IQNSITIERMVLSAFDER and NP441-458 RTEIIKMMESARPEDLSF) were identified by IFN-gamma ELISPOT assay. NP57-66 and NP441-450 and NP protein could be able to trigger the activation of CD4+ and CD8+ T cells, and the response of CD8+ T was more predominant. The challenge study of mice-adapted virus A/PR/8/34 (H1N1) showed that NP-Bac could reduce viral load and attenuate the damage to lung tissue. 50% protection ratio against the virus could be detected.


[Infectious diseases, the veritable pandora's box].
The past few years, much attention has been given to the problems regarding new and emerging infectious diseases. Four groups may be considered: (1) new agents discovered among the causes of classical medical syndromes, these do not constitute new dangers but decrease the proportion of unknown causes within these syndromes; (2) increased importance of infectious agents resulting from modified ways of living or production procedures; (3) the really new agents, the spread of which is generally favoured by the same factors and (4) organisms with acquired resistance against antibiotics and pesticides. There is need for extended epidemiological surveillance, that can be improved in our country by better collaboration between different organisations. Most importantly epidemiological surveillance should be organized on an European level with the entire support of our regional and federal authorities.


Human calcitonin gene related peptide: a potent endogenous vasodilator in man.
In addition to calcitonin and katacalcin, it is now known that the human calcitonin gene encodes a novel peptide called calcitonin gene related peptide (CGRP). In experimental animals, CGRP produces vasodilatation and complex changes in plasma calcium. We have now assessed its biological activity in man by infusing human CGRP (hCGRP) into six normal volunteers. hCGRP (545 pmol/min) caused the diastolic pressure to fall from 64 +/- 5 to 55 +/- 7 mmHg (P less than 0.05), the heart rate to increase from 61 +/- 7 to 87 +/- 5 beats/min (P less than 0.05) and the skin temperature to increase from 33.7 +/- 0.9 to 34.9 +/- 0.5 degrees C. Plasma noradrenaline increased from 481 +/- 126 to 835 +/- 65 pg/ml (P less than 0.05) and plasma adrenaline from 57 +/- 17 to 82 +/- 12 pg/ml (P less than 0.05). There were no significant changes in the albumin-corrected plasma calcium. hCGRP is thus a potent endogenous vasodilator in man and is in fact more potent than any other known vasodilator. Together with the observations that CGRP circulates in normal subjects at relatively high concentration (approximately 25 pmol/l) and that CGRP is present in perivascular nerves, this study suggests a possible role for CGRP in controlling peripheral vascular tone in man.


Newly identified Gon4l/Udu-interacting proteins implicate novel functions.
Mutations of the Gon4l/udu gene in different organisms give rise to diverse phenotypes. Although the effects of Gon4l/Udu in transcriptional regulation have been demonstrated, they cannot solely explain the observed characteristics among species. To further understand the function of Gon4l/Udu, we used yeast two-hybrid (Y2H) screening to identify interacting proteins in zebrafish and mouse systems, confirmed the interactions by co-immunoprecipitation assay, and found four novel Gon4l-interacting proteins: BRCA1 associated protein-1 (Bap1), DNA methyltransferase 1 (Dnmt1), Tho complex 1 (Thoc1, also known as Tho1 or HPR1), and Cryptochrome circadian regulator 3a (Cry3a). Furthermore, all known Gon4l/Udu-interacting proteins-as found in this study, in previous reports, and in online resources-were investigated by Phenotype Enrichment Analysis. The most enriched phenotypes identified include increased embryonic tissue cell apoptosis, embryonic lethality, increased T cell derived lymphoma incidence, decreased cell proliferation, chromosome instability, and abnormal dopamine level, characteristics that largely resemble those observed in reported Gon4l/udu mutant animals. Similar to the expression pattern of udu, those of bap1, dnmt1, thoc1, and cry3a are also found in the brain region and other tissues. Thus, these findings indicate novel mechanisms of Gon4l/Udu in regulating CpG methylation, histone expression/modification, DNA repair/genomic stability, and RNA binding/processing/export.


Osteoporosis in children with severe congenital neutropenia: bone mineral density and treatment with bisphosphonates.
A high incidence of decreased bone mineral density (BMD) has been described in patients with severe congenital neutropenia (SCN). The objectives of the study are to describe changes in BMD in children with SCN treated with granulocyte colony-stimulating factor and evaluate the response to treatment with bisphosphonates in those who had osteoporosis. A prospective open-label study was performed evaluating BMD and metabolism in 9 Chilean patients with SCN, administrating bisphosphonates in those with osteoporosis. Follow-up ranged between 7 months and 3.5 years. Six out of 9 patients had reduced BMD on initial assessment: 3 had osteoporosis (z score <-2) and 3 had osteopenia (z score <-1). Four children presented vertebral fractures. Two presented osteopenia on follow-up without clinical symptoms. Five patients were treated with bisphosphonates, increasing their BMD z score (mean increase 1.2, range 0.27 to 2.62). z Score of hydroxyproline/creatinine ratios, which was elevated in 4 patients with osteoporosis, decreased during treatment (mean decrease 2.18, range 1.56 to 2.53). Four patients remodeled and reexpanded fractured vertebrae during treatment. No side effects of bisphosphonates were seen on follow-up. Osteoporosis is an important comorbidity in SCN patients probably due to increased bone resorption. Bisphosphonates seem to be an effective treatment for osteoporosis in these patients.


Ischemic ocular manifestations of giant cell arteritis: A Canadian case series.
Diagnosing giant cell arteritis (GCA) can be challenging due to the variable clinical presentation and lack of systemic symptoms in approximately 20% of cases, which are termed occult GCA. GCA affects the ocular circulation in more than half of cases and can cause irreversible bilateral blindness if not rapidly recognized and treated. We compared clinical and laboratory findings of patients with occult and systemic temporal artery biopsy (TAB)-positive GCA with ocular manifestations. Retrospective chart review of patients with TAB-positive GCA with ocular manifestations seen at a tertiary neuro-ophthalmology practice between 2015 and 2020. GCA was occult in 14.3% (6/42) and systemic in 85.7% (36/42) of patients. Occult GCA affected older patients (average age 84.6 ± 5.3 vs 75.9 ± 8.2). There was no significant difference in ESR or CRP levels between two cohorts. In patients with occult GCA, 83.3% (5/6) presented with AION, and 16.7% (1/6) with isolated cranial nerve six palsy (CN6P). In the systemic GCA cohort, 47.2% (17) presented with AION, 5.6% (2) with CRAO, 2.8% (1) with PION, 2.8% (1) with isolated CWS, 2.8% (1) had both CRAO and AION, 2.8% (1) isolated cranial nerve 4 palsy (CN4P), 2.8% (1) isolated CN6P, 22.2% (8) had history of amaurosis fugax but normal examination, and 11.1% (4) had visual symptoms but a normal exam. Three of the above patients with AION also had CN4P. Of patients diagnosed with AION, presenting visual acuity in the affected eye(s) was significantly worse in patients with occult GCA. Involvement of multiple ocular circulations was seen in six patients in the systemic group but none in the occult group. Occult GCA occurs more commonly in older patients who most of the time present with AION. Levels of inflammatory markers were similar in the occult and systemic groups. Though ocular ischemic manifestations were similar in both cohorts, in systemic GCA involvement of multiple ocular circulations is likely more common GCA should always be considered in older patients who present with signs of retinal and/or optic nerve head ischemia (AION and/or CWS) and new onset of CNPs, especially in patients where more than one ocular arterial circulation is involved.